BEHAVIORAL NEUROLOGY AND NEUROPSYCHIATRY

more information - www.cambridge.org/9780521875011
Behavioral Neurology
& Neuropsychiatry
Behavioral Neurology
& Neuropsychiatry
Edited by
David B. Arciniegas, MD
The Michael K. Cooper
Professor of Neurocognitive Disease,
Director of the Neurobehavioral Disorders Program, and
Associate Professor of Psychiatry and Neurology at the
University of Colorado School of Medicine
C. Alan Anderson, MD
Professor of Neurology, Emergency Medicine, and Psychiatry at the
University of Colorado School of Medicine, and
Staff Neurologist at the Denver Veterans Affairs Medical Center
and
Christopher M. Filley, MD
Professor of Neurology and Psychiatry, and
Director of the Behavioral Neurology Section at the
University of Colorado School of Medicine, and
Neurology Service Chief at the Denver Veterans Affairs Medical Center
Managing Editor
T. Angelita Garcia
CAMBRID GE UNIVERSIT Y PRESS
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9780521875011
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First published 2013
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Library
Library of Congress Cataloging in Publication data
Behavioral neurology & neuropsychiatry / edited by David B.
Arciniegas, C. Alan Anderson, Christopher M. Filley.
p. ; cm.
Behavioral neurology and neuropsychiatry
Includes bibliographical references and index.
ISBN 978-0-521-87501-1 (hbk.) – ISBN 0-521-87501-3 (hbk.)
I. Arciniegas, David B. (David Brian), 1967– II. Anderson, C.
Alan. III. Filley, Christopher M., 1951– IV. Title: Behavioral
neurology and neuropsychiatry.
[DNLM: 1. Brain Diseases – psychology. 2. Behavior –
physiology. WL 348]
616.8 – dc23
2012030788
ISBN 978-0-521-87501-1 Hardback
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Contents
List of contributors vii
Foreword xi
M. Marsel-Mesulam
Preface xiii
1
Introduction 1
Christopher M. Filley, C. Alan Anderson,
and David B. Arciniegas
Section I – Structural and
Functional Neuroanatomy
184
14 Praxis 199
Kenneth M. Heilman
15 Visuospatial function 214
Doron Merims and Morris Freedman
2
Behavioral neuroanatomy 12
C. Alan Anderson, David B. Arciniegas,
Deborah A. Hall, and Christopher M. Filley
3
Cerebellum 32
Jeremy D. Schmahmann
4
White matter 47
Christopher M. Filley
5
Frontal-subcortical circuits
David G. Lichter
6
Arousal 88
C. Alan Anderson, Christopher M. Filley,
David B. Arciniegas, and James P. Kelly
16 Executive function
David B. Arciniegas
225
17 Comportment 250
Michael Henry Rosenbloom, Oliver
Freudenreich, and Bruce H. Price
18 Emotion 266
David B. Arciniegas
59
7
Sleep 98
Martin L. Reite
8
Attention 115
Joshua Cosman and Matthew Rizzo
9
Motivation 134
Brian D. Power and Sergio E. Starkstein
10 Perception and recognition 144
Benzi M. Kluger and Gila Z. Reckess
11 Memory 161
Felipe DeBrigard, Kelly S. Giovanello, and
Daniel I. Kaufer
12 Language 174
Mario F. Mendez
13 Affective prosody
Elliott D. Ross
19 Personality 299
Sita Kedia and C. Robert Cloninger
Section II – Neurobehavioral and
Neuropsychiatric Assessment
20 Neuropsychiatric evaluation
Fred Ovsiew
21 Neurological examination
Stuart A. Schneck
310
319
22 Assessment for subtle neurological
signs 333
Igor Bombin, Celso Arango, and Robert
W. Buchanan
23 Mental status examination
David B. Arciniegas
344
24 Neuropsychological assessment
C. Munro Cullum
394
v
Contents
25 Forensic assessment 406
Hal S. Wortzel and Robert L. Trestman
26 Structural neuroimaging 415
Robin A. Hurley, Deborah M. Lucas, and
Katherine H. Taber
27 Advanced neuroimaging 430
Deborah M. Little, David B. Arciniegas,
and John Hart, Jr.
28 Electroencephalography 442
Lauren C. Frey and Mark C. Spitz
29 Advanced electrophysiology
Donald C. Rojas
459
30 Neurotoxicology 474
Christopher M. Filley
31 Neuropathological assessment 485
B. K. Kleinschmidt-DeMasters, Katherine
L. Howard, Steven G. Ojemann, and
Christopher M. Filley
Section III – Treatments in
Behavioral Neurology
& Neuropsychiatry
32 Principles of pharmacotherapy
Jonathan M. Silver
vi
33 Rehabilitation and pharmacotherapy
of cognitive impairments 511
David B. Arciniegas, Hal S. Wortzel, and
Kimberly L. Frey
34 Pharmacotherapy of emotional
disturbances 543
Steven L. Dubovsky
35 Pharmacotherapy of behavioral
disturbances 566
Thomas W. McAllister and David B.
Arciniegas
36 Psychotherapy 587
Lynne Fenton and Robert Feinstein
37 Environmental and behavioral
interventions 604
Laura A. Flashman and Thomas W.
McAllister
38 Procedural interventions 627
C. Alan Anderson and David B. Arciniegas
Index 649
498
The color plates are to be found between
pp. 224 and 225.
Contributors
C. Alan Anderson, MD
Professor of Neurology, Emergency Medicine and
Psychiatry, University of Colorado School of
Medicine, Aurora, CO, USA; Staff Neurologist,
Denver Veterans Affairs Medical Center, Denver,
CO, USA
Celso Arango, MD, PhD
Head, Adolescent Unit, Department of Psychiatry,
Hospital General Universitario Gregorio Marañón,
Madrid, Spain; Adjunct Associate Professor of
Psychiatry, Maryland Psychiatric Research Center,
University of Maryland, Baltimore, MD, USA
David B. Arciniegas, MD
The Michael K. Cooper Professor of Neurocognitive
Disease; Director, Neurobehavioral Disorders
Program; Associate Professor of Psychiatry and
Neurology, University of Colorado School of
Medicine, Aurora, CO, USA
Joshua Cosman, PhD
Postdoctoral Fellow, Department of Neuroscience,
University of Iowa, Iowa City, IA, USA
C. Munro Cullum, PhD
Professor of Psychiatry and Neurology &
Neurotherapeutics; Director of Neuropsychology;
Pam Blumenthal Distinguished Professor of Clinical
Psychology, The University of Texas Southwestern
Medical Center, Dallas, TX, USA
Felipe DeBrigard
Graduate Student, Department of Philosophy and
Coginitive Neuroscience of Memory Laboratory, The
University of North Carolina at Chapel Hill, NC, USA
Steven L. Dubovsky, MD
Professor and Chair, Department of Psychiatry, The
State University of New York at Buffalo, Buffalo, NY;
Adjoint Professor of Psychiatry and Medicine,
University of Colorado School of Medicine, Aurora,
CO, USA
Igor Bombin
Department of Psychology, Centro de Investigación
Biomédica en Red de Salud Mental, CIBERSAM,
University of Oviedo, Oviedo, Spain; Reintegra
Foundation, Centro de Rehabilitación Neurológica,
Spain
Robert Feinstein, MD
Professor of Psychiatry and Vice Chairman for
Clinical Education and Evidence Based Medicine,
Integration, Department of Psychiatry, University of
Colorado School of Medicine, Aurora, CO, USA
Robert W. Buchanan, MD
Professor of Psychiatry, University of Maryland
School of Medicine, Baltimore, MD, USA
Lynne Fenton, MD
Assistant Professor, Department of Psychiatry,
University of Colorado School of Medicine, Aurora,
CO, USA
C. Robert Cloninger, MD
Wallace Renard Professor of Psychiatry; Professor of
Genetics and Psychology; Director, Center for
Psychobiology of Personality, Department of
Psychiatry, Washington University School of
Medicine, St Louis, MO, USA
Christopher M. Filley, MD
Professor of Neurology and Psychiatry; Director,
Behavioral Neurology Section, University of
Colorado School of Medicine, Aurora, CO, USA;
Neurology Service Chief, Denver Veterans Affairs
Medical Center, Denver, CO, USA
vii
List of contributors
Laura A. Flashman, PhD
Professor, Department of Psychiatry, Dartmouth
Medical School, Hanover, NH, USA
Katherine L. Howard
Coordinator, Department of Neurology, University of
Colorado School of Medicine, Aurora, CO, USA
Morris Freedman, MD, FRCP
Head, Division of Neurology and Director,
Behavioural Neurology Program, Baycrest Hospital;
Professor, Faculty of Medicine (Neurology) and
Director, Behavioural Neurology Section, Division of
Neurology, University of Toronto, Toronto, ON,
Canada
Robin A. Hurley, MD
Professor of Psychiatry & Behavioral Medicine and
Radiology, Wake Forest School of Medicine,
Winston-Salem, NC, USA
Oliver Freudenreich, MD
Associate Professor of Psychiatry, Harvard Medical
School; Director, First Episode and Early Psychosis
Program, Massachusetts General Hospital, Boston,
MA, USA
Kimberly L. Frey, MS, CCC-SLP, CBIS
Instructor, Neurobehavioral Disorders Program,
Department of Psychiatry, University of Colorado
School of Medicine, Aurora, CO, USA
Lauren C. Frey, MD
Assistant Professor, Department of Neurology,
University of Colorado School of Medicine, Aurora,
CO, USA
Kelly S. Giovanello, PhD
Assistant Professor, Department of Psychology
Biomedical Research, Imaging Center, The University
of North Carolina at Chapel Hill, NC, USA
Deborah A. Hall, MD, PhD
Assistant Professor, Department of Neurology, Rush
University Medical Center, Chicago, IL, USA
John Hart, Jr., MD
Medical Science Director, Center for Brain Health,
Jane and Bud Smith Distinguished Chair, Cecil Green
Distinguished Chair, Professor, Behavioral and Brain
Sciences, UT Dallas; Professor, Neurology &
Psychiatry, UT Southwestern Medical Center, Dallas,
TX, USA
Kenneth M. Heilman, MD
The James E. Brooks Jr. Distinguished Professor of
Neurology and Health Psychology, Center for
Movement Disorders and Neurorestoration,
University of Florida, Gainesville, FL, USA
viii
Daniel I. Kaufer, MD
Assistant Professor, Department of Neurology, and
Director, UNC Memory Disorders Program,
University of North Carolina at Chapel Hill School of
Medicine, NC, USA
Sita Kedia, MD
Assistant Professor, Department of Pediatrics,
Children’s Hospital Colorado and University of
Colorado School of Medicine, Aurora, CO, USA
James P. Kelly, MD
Director, National Intrepid Center of Excellence,
Bethesda, MD, USA
B. K. Kleinschmidt-DeMasters, MD
Professor and Head of Neuropathology, Department
of Pathology, University of Colorado School of
Medicine, Aurora, CO, USA
Benzi M. Kluger, MD, MS
Assistant Professor, Department of Neurology,
University of Colorado School of Medicine, Aurora,
CO, USA
David G. Lichter, MB, ChB, FRACP
Clinical Professor of Neurology and Psychiatry, The
State University of New York University at Buffalo,
Buffalo, NY, USA
Deborah M. Little, PhD
Assistant Professor of Neurology and Rehabilitation
Anatomy and Cell Biology, University of Illinois
College of Medicine at Chicago, Chicago, IL,
USA
Deborah M. Lucas, MD
Radiology Preceptor, W.G. “Bill” Hefner VA Medical
Center, 1601 Benner Avenue, Salisbury, NC 28144,
USA
List of contributors
Thomas W. McAllister, MD
Millennium Professor of Psychiatry and Neurology;
Vice Chair for Neuroscience Research, Department of
Neurology, Dartmouth Medical School, Hanover,
NH, USA
Mario F. Mendez, MD, PhD
Professor of Neurology and Psychiatry &
Biobehavioral Sciences, UCLA School of Medicine;
Director, Neurobehavior Unit, Greater Los Angeles
VA Medical Center, Los Angeles, CA, USA
Doron Merims, MD
Neurologist, Movement Disorders Unit, Department
of Neurology, Tel-Aviv Sourasky Medical Center,
Sackler School of Medicine, Tel-Aviv University,
Tel-Aviv, Israel
Steven G. Ojemann, MD
Associate Professor and Director, Stereotactic and
Functional Neurosurgery, University of Colorado
School of Medicine, Aurora, CO, USA
Fred Ovsiew, MD
Professor of Clinical Psychiatry and Behavioral
Sciences, Northwestern University Feinberg School of
Medicine, Chicago IL, USA
Brian D. Power
Clinical Lecturer, School of Psychiatry, University of
Western Australia, Australia
Bruce H. Price, MD
Assistant Professor of Neurology, Harvard Medical
School; Chief, Department of Neurology, McLean
Hospital, Belmont, MA, USA
Gila Z. Reckess
Graduate Student, Department of Clinical
and Health Psychology, University of Florida,
FL, USA
Martin L. Reite, MD
Clinical Professor, Department of Psychiatry,
University of Colorado School of Medicine, Aurora,
CO, USA
Matthew Rizzo, MD
Professor of Neurology, Engineering and Public
Policy; Director, Division of Neuroergonomics;
Director, University of Iowa Aging Mind and Brain
Initiative, Department of Neurology, University of
Iowa, Iowa City, IA, USA
Donald C. Rojas, PhD
Associate Professor, Department of Psychiatry,
University of Colorado School of Medicine, Aurora,
CO, USA
Michael Henry Rosenbloom, MD
Health Partner Specialty Center, Center for Dementia
and Alzheimer’s Care, St. Paul, MN, USA
Elliott D. Ross, MD
Professor, Department of Neurology, The University
of Oklahoma College of Medicine; Director, OKC
VAMC Center for Alzheimer’s and
Neurodegenerative Disorders, University of
Oklahoma Health Sciences Center, Oklahoma City,
OK, USA
Jeremy D. Schmahmann, MD
Professor of Neurology, Harvard Medical School;
Director, Ataxia Unit; Cognitive and Behavioral
Neurology Unit; Laboratory for Neuroanatomy and
Cerebellar Neurobiology, Massachusetts General
Hospital and Harvard Medical School, Boston, MA,
USA
Stuart A. Schneck, MD
Professor Emeritus, Department of Neurology,
University of Colorado School of Medicine, Aurora,
CO, USA
Jonathan M. Silver, MD
Clinical Professor, Department of Psychiatry, NYU
School of Medicine, New York, NY, USA
Mark C. Spitz, MD
Professor of Neurology, Director, Comprehensive
Epilepsy Center, Medical Director, Clinical
Neurophysiology Laboratory, University of Colorado
School of Medicine, Aurora, CO, USA; Staff
Neurologist, Denver Veterans Affairs Medical Center,
Denver, CO, USA
ix
List of contributors
Sergio E. Starkstein, MD, PhD, FRANZCP
Winthrop Professor, Fremantle Hospital, The
University of Western Australia, Crawley, WA,
Australia
Katherine H. Taber, PhD
Research Health Scientist, Salisbury VAMC; Assistant
Co-Director, MIRECC Education Component
x
Robert L. Trestman, PhD, MD
Professor, Department of Psychiatry, University of
Connecticut Health Center, Farmington, CT, USA
Hal S. Wortzel, MD
Assistant Professor of Psychiatry, University of
Colorado School of Medicine, Aurora, CO, USA;
Director, Neuropsychiatric Consultation Services,
Denver Veterans Affairs Medical Center, Denver,
CO, USA
Foreword
Practitioners of Behavioral Neurology & Neuropsychiatry should consider themselves privileged to have
been assigned the uniquely challenging task of treating
the most complex disorders of the most complex organ
in the body. The facts and figures are quite daunting.
The cerebral cortex alone contains 40 billion neurons
crowded into 30 square feet of surface area. Each neuron makes thousands of contacts with other neurons.
At these contact points, known as synapses, information flows from one neuron to another at a rate of
approximately 100 times per second. The total number of neural contacts on the surface of the brain alone
is 40 followed by 12 zeros, a number that is as large as
the number of all the stars in our galaxy.
This complexity is not devoid of order. A distinctive
principle of brain function is the regional variation of
specializations – different parts of the brain have different responsibilities. Some of these job descriptions
defy common sense. What kind of engineering logic
would have made memory for recent events, a faculty
essential for all aspects of behavior, critically dependent on a tiny part of the temporal lobe known as the
hippocampus? Why is language, a faculty that permeates all aspects of thought, critically dependent on only
one hemisphere?
The past 150 years have allowed us to accumulate
mountains of facts at a continuously accelerating rate.
The classic case reports of the late nineteenth and early
twentieth centuries, the advent of new methods for
tracing structural and chemical neuroanatomy, single
cell recordings in behaving primates, and the modern
revolution in neuroimaging are some of the engines
that powered this growth. The next revolution will
arise when these facts are linked to explanatory the-
ories of brain function, theories that can explain, in
some principled way, how patterned synaptic activity
can transform muscle contractions and sensory input
into memories, words, and actions.
While we wait for new insights to emerge, we have
patients that need our help. In many instances, the diseases we see are irreversible. Few of our patients can
be restored to former states of normalcy and many
turn out to have relentlessly progressive neurodegenerative disorders. However, the practitioner in this field
needs to understand (and believe) that “incurable” diseases are nonetheless “treatable.” Characterizing the
neurobehavioral parameters of the disease, specifying
the chief deficit that undermines daily activities, educating the patient and family, identifying appropriate
resources for rehabilitation, and the judicious use of
pharmacotherapy are some of the modalities that allow
the informed practitioner to make a real difference in
patient care.
This volume covers key theoretical and practical
topics in Behavioral Neurology & Neuropsychiatry. A
special strength is the section on treatment. Edited by
three leaders in this field, this volume will allow seasoned practitioners as well as novices to have a better
understanding of this complex area of medicine and to
take better care of their patients.
M. Marsel-Mesulam, MD
Director, Cognitive Neurology and Alzheimer’s
Disease Center; Ruth Dunbar Davee Professor of
Neuroscience, Department of Neurology, Northwestern
University Feinberg School of Medicine, Chicago, IL,
USA
xi
Preface
The recent merger of behavioral neurology and neuropsychiatry into a single medical subspecialty, Behavioral Neurology & Neuropsychiatry (BN&NP), represents a substantive rapprochement between the parent
disciplines from whence its trainees and practitioners
hail. This event occasions an approach to brain–
behavior relationships that transcends the traditional
perspectives of neurology and psychiatry, and creates
an enduring context for the combined study of the psychiatry of neurology and the neurology of psychiatry.
Most importantly, it identifies a cadre of clinicians dedicated to caring for persons and families affected by all
manner of brain disorders producing cognitive, emotional, behavioral, and sensorimotor disturbances.
The clinical approach of subspecialists in BN&NP
reflects a materialist philosophy of mind that regards
mental events as brain events and, by extension, mental disorders as brain disorders. Critical evaluation of
the relationships between psychological and neurobiological phenomena is encouraged, as are revisions or
elimination of concepts or theories that do not comport with modern neuroscience. Reciprocal interactions between neurobiological, psychological, social,
and environmental factors and their influences on
neuropsychiatric health are appreciated, and they are
considered relevant to understanding brain–behavior
disorders and their treatments to the extent that they
affect brain structure and/or function. This philosophy
precludes guild-based division of brain disorders into
neurological and psychiatric types, and requires subspecialists in BN&NP to employ a comprehensive clinical approach that blends and adds to the historically
distinct methods of neurology and psychiatry.
For more than a decade, our BN&NP faculty group
at the University of Colorado School of Medicine has
applied this philosophy and approach to our daily
practice. As BN&NP clinicians, teachers, and educators, we are an integrated transdisciplinary faculty
group who bring a uniform body of subspecialty
knowledge and skills to the clinic and bedside despite
differences in our primary training backgrounds. Our
model informed the work of the Joint Advisory Committee on Subspecialty Certification of the American Neuropsychiatric Association and the Society for
Behavioral and Cognitive Neurology, their creation
of the BN&NP training curriculum adopted by the
United Council for Neurologic Subspecialties [1], and
that organization’s development of BN&NP fellowship
program accreditation standards and practitioner certification processes [2] – all endeavors to which the
editors of this volume and many of its chapter authors
contributed substantively.
This book complements and extends those efforts
by translating the philosophy and clinical approach
used in our clinical and teaching efforts into a compendium of the concepts and principles of BN&NP.
It draws naturally from information presented in the
many volumes in this field that we have studied,
and it extends and complements the writings of the
many great teachers from whom we have learned. It is
unique, however, in its specific focus on BN&NP and
its organization around a peer-reviewed and nationally
accepted curriculum for training in this subspecialty
as well as its development by editors and authors committed to the growth of this area of clinical practice and
study. Where material offered in this book imitates or
critiques prior works, our aim – both as editors and as
contributors – has been to ensure that its presentation
honors the sources from which it derives, reflects the
best traditions of scholarship, and serves to advance
our field.
Designed as a primer of concepts and principles in BN&NP, rather than an exhaustive survey
of neurobehavioral disorders, the text divides into
three parts: Structural and Functional Neuroanatomy
(Section I), Clinical Assessment (Section II), and
Treatment (Section III). Part I begins with an
introduction to the history and current practice of
BN&NP. Chapter 2 offers an overview of essential
behavioral neuroanatomy, including brain–behavior
xiii
Preface
relationships associated with the brainstem, cerebellum, diencephalon, subcortical structures, limbic
and paralimbic areas, white matter, and neocortex.
The next several chapters provide detailed reviews
of the neuroanatomy of frontal-subcortical and
limbic-subcortical circuits, white matter, and the
cerebellum and the neurobehavioral functions these
systems support. Subsequent chapters in Section I
discuss brain–behavior relationships from the vantage
point of neurobehavioral functions (i.e., cognition,
emotion, and behavior) and the neuroanatomy on
which they are predicated. Given the importance of
executive function and emotion in BN&NP, extended
discussions of the history of ideas on these subjects
and current views of their phenomenology and
neuroanatomy are offered in Chapters 16 and 18.
The principles of clinical assessment presented
in Section II draw on the brain–behavior relationships described in Section I, and their application
to everyday practice facilitates construction of
subspecialty-relevant clinical histories and examinations. Chapter 20 outlines an approach to obtaining
a neuropsychiatric history that is complemented by
the bedside examination techniques and standardized
assessments presented in Chapters 21–25. Recognizing that neuropsychiatric problems sometimes result
in civil and criminal legal entanglements, special
consideration is given to forensic neuropsychiatric
assessment in Chapter 25. Current and emerging
uses of neuroimaging, electrophysiologic, and other
laboratory measures that may inform clinical evaluation and/or treatment planning are considered in
Chapters 26–31. Throughout Section II, emphasis
is placed on interpreting clinical symptoms, signs,
and syndromes in terms of the neural processes
underlying them, considering but not relying upon
conventional (i.e., Diagnostic and Statistical Manual
of Mental Disorders-based) psychiatric diagnoses, and
avoiding dichotomization of clinical conditions into
strict “psychiatric” or “neurological” types.
The chapters comprising Section III of this volume describe treatments in BN&NP and the principles
of their application to the care of patients and families affected by neurobehavioral disorders. The breadth
of the clinical problems encompassed by BN&NP
requires expertise in environmental, behavioral, rehabilitative, psychological, social, pharmacologic, and
procedural interventions. The evidence base for the
treatment of many neurobehavioral disorders is evolving rapidly, and their popularity often waxes and wanes
xiv
in short order. Nonetheless, the principles of treatment remain relatively stable and consistently applicable across the many conditions for which subspecialists in BN&NP are consulted and the various settings in
which they practice. We therefore have limited consideration of condition-specific treatment issues throughout this volume and offer such only when their discussion illustrates the application of, or an exception to, a
principle of treatment in BN&NP.
We developed this volume over several years, constantly weighing the need to publish timely information against the necessity of producing a principlesfocused, stylistically coherent, and enduringly useful
volume. The carefully selected group of international
experts contributing to this work made these tasks easier. Their diverse training and practice backgrounds
provide readers with a broad set of perspectives on the
subjects addressed and their collective effort on this
volume exemplifies the type of transdisciplinary collaboration that defines BN&NP. For chapters focused
on subjects within the externally acknowledged expertise of our faculty groups, as well as for those topics on
which we wanted to contribute a novel perspective, we
functioned as both editors and authors. Thoughtfully
approached and deliberately completed, we anticipate
that this book will contribute usefully to the continued
growth and development of BN&NP and will equip its
readers to apply its principles to the study of neurobehavioral disorders and to the care of the individuals
and families they affect.
We appreciate deeply the time and effort offered by
the authors who contributed the chapters comprising
this volume as well as their patience and support
during the editorial phase of its development. We also
are grateful for the invaluable advice and consistent
support for this project offered by the editorial group
at Cambridge University Press, including Pauline
Graham, Alison C. Evans, Katie James, Joanna Chamberlin, and Richard Marley, whose generosity and flexibility ensured that we were provided the time needed
to develop this work according to its own requirements. We are thankful for the insights, feedback,
and encouragement offered by colleagues, students,
friends, family, and advisors who provided guidance
on the development of this volume, including: Laura B.
Arciniegas, JD, Marsha S. Anderson, MD, Richard L.
Gallimore, PhD, Kimberly L. Frey, MS, Hal S. Wortzel,
MD, Peter Wagner, MD, Donald C. Rojas, PhD, Jody
Newman, MA, Jonathan M. Silver, MD, Thomas W.
McAllister, MD, Stuart C. Yudofsky, MD, and Steven L.
Preface
Dubovsky, MD. We also acknowledge the support and
contributions of the many other colleagues who provided the inspiration and support for the approach to
BN&NP we established at the University of Colorado
School of Medicine, including: Norman Geschwind,
MD, Michael P. Alexander, MD, Jeffrey L. Cummings,
MD, C. Edward Coffey, MD, Daniel I. Kaufer, MD,
Tiffany Chow, MD, Robin A. Hurley, MD, Randolph B.
Schiffer, MD, John Hart, Jr., MD, John J. Campbell, III,
MD, Robert A. Bornstein, PhD, Sandra Bornstein, OT,
C. Munro Cullum, PhD, Louis R. Caplan, MD, Harold
P. Adams, MD, James P. Kelly, MD, Bruce H. Price,
MD, Neill R. Graff-Radford, MD, Bruce L. Miller, MD,
Jeremy D. Schmahmann, MD, Kenneth M. Heilman,
MD, Kirk R. Daffner, MD, Antonio R. Damasio,
MD, Hanna Damasio, MD, Thomas P. Beresford,
MD, Lawrence E. Adler, MD, Martin L. Reite, MD,
Robert Freedman, MD, James H. Austin, MD, Stuart
A. Schneck, MD, Donald H. Gilden, MD, Kenneth L.
Tyler, MD, Steven P. Ringel, MD, Hans E. Neville, MD,
Roy R. Wright, MD, Edward Lewin, MD, Victoria
S. Pelak, MD, Mark C. Spitz, MD, John R. Corboy,
MD, Maureen A. Leehey, MD, Richard L. Hughes,
MD, Patrick J. Bosque, MD, Jonathan H. Woodcock,
MD, Ann H. Craig, MD, Elizabeth Kozora, PhD,
Josette G. Harris, PhD, Bruce F. Pennington, PhD,
Lisa A. Brenner, PhD, Catharine H. Johnston-Brooks,
Brian D. Hoyt, PhD, Michael R. Greher, PhD, Yechiel
Kleen, MD, William A. Locy, EdD, Cindy Kreutz,
MBA, Estela Bogaert-Martinez, PhD, Jason Nupp,
PsyD, Gail Ramsberger, PhD, Lise Menn, PhD, G.
Vernon Wood, PhD, Robert B. Goos, MD, Lawrence
Rodriguez, RN, James D. Hooker, MD, Al O. Singleton, III, MD, John DeQuardo, MD, Keith LaGrenade,
MD, Bruce D. Leonard, MD, Jack H. Simon, MD,
David Rubinstein, MD, Jody Tanabe, MD, Bette K.
Kleinschmidt-DeMasters, MD, Philip J. Boyer, MD,
and Jonathan Filley, PhD. We are honored by the contributions of M.-Marsel Mesulam, MD, who reviewed
the structure and content of this volume early in its
development and generously offered its Foreword.
Most importantly, we are thankful to our families for
their support, encouragement, and tolerance of our
efforts on this project and forbearance of its familial
costs.
We are especially indebted to T. Angelita Garcia,
who served as the Managing Editor of this project
at the University of Colorado School of Medicine.
Ms. Garcia contributed to the review of every chapter included in this volume, constructed a master
database containing its several thousand citations and
ensured their uniform presentation, secured permissions for the use of materials reproduced from other
works, assembled the final manuscript for submission
to Cambridge University Press, and coordinated communication between the editors and publisher. Her
efforts were essential to the successful completion of
this work, and for her contributions we offer our most
grateful acknowledgment and thanks.
1.
Arciniegas DB, Kaufer DI, , Joint Advisory Committee
on Subspecialty Certification of the American
Neuropsychiatric Association, Society for Behavioral
and Cognitive Neurology. Core curriculum for
training in Behavioral Neurology & Neuropsychiatry.
J Neuropsychiatry Clin Neurosci. 2006;18(1):6–13.
2.
Silver JM. Behavioral Neurology & Neuropsychiatry is
a subspecialty. J Neuropsychiatry Clin Neurosci.
2006;18(2):146–8.
xv
Chapter
1
Introduction
Christopher M. Filley, C. Alan Anderson, and David B. Arciniegas
The writing of a new textbook in medicine presents
both an exciting opportunity and a daunting challenge. Whereas any contemporary medical field
witnesses timely new developments that call for rapid
dissemination, it is uncertain how much time busy
clinicians and investigators can devote to reading
an entire textbook, especially when ready access to
a range of online resources is increasingly available.
We have ventured forth nonetheless, with the goal of
creating a novel synthesis of the strong intellectual
and academic traditions of Behavioral Neurology &
Neuropsychiatry (BN&NP).
The unification of the historically separate but parallel subspecialties of behavioral neurology and neuropsychiatry is a relatively recent event [1, 2]. These
subspecialties were joined through the work of the
American Neuropsychiatric Association and the Society for Behavioral and Cognitive Neurology to create the BN&NP subspecialty under the auspices of the
United Council for Neurologic Subspecialties (UCNS).
The goals of this effort included advancing and enriching this area of clinical practice and scientific research,
in which the brain is recognized as the organ of the
mind, as well as facilitating the continued growth of
this subspecialty through standardization and accreditation of fellowship training programs and certification of its practitioners.
This development reflects a broader re-engagement
between neurology and psychiatry more generally
[3–5]. Traditional academic boundaries are being
reassessed from all sides as medical progress continues. As we have observed and contributed to this process of gradual rapprochement [2], and because we
apply an integrated model of BN&NP in our daily work
as clinicians, educators, and scientists, the idea of producing this volume arose naturally. This book thus
embodies a summary of our thoughts and practice in
these fields – as well as those of our colleagues – as
developed over more than two decades of clinical care,
education, research, and reflection. As an overture to
what follows, some preliminary information will help
set the stage.
Historical background
Neurology and psychiatry
Neurology and psychiatry are securely established
medical specialties with well-demarcated areas of
clinical and research expertise. Although it seems
natural that their common interest in focusing on
the brain would foster interdisciplinary ties, close
collaboration between these fields and their practitioners are the exception rather than the rule. Many
physicians – past and present – have promulgated various degrees of separation between the two fields and
rigidly maintained that neurologists study the brain
and psychiatrists study the mind. This split fosters
a strict dichotomy that keeps apart the professions
and professionals most concerned with the myriad
and often disabling problems of human behavior.
Some argue that neurology will remain separated
from psychiatry because each does something unique
[6, 7] – the former being “objective” and the latter
“humanistic” – while critics respond by chiding the
simplistic gap between “mindless neurology” and
“brainless psychiatry” [3, 8].
These fields share common origins in Western
philosophical and medical traditions [9]. Many
Renaissance-era physicians were committed to the
thesis that mental states are brain states, and that
aberrations of mental functioning are the products of
Behavioral Neurology & Neuropsychiatry, eds. David B. Arciniegas, C. Alan Anderson, and Christopher M. Filley.
C Cambridge University Press 2013.
Published by Cambridge University Press. 1
Behavioral Neurology & Neuropsychiatry
a disordered brain. Cullen (1710–1790) was the first
among such physicians to include the mental disorders
in his taxonomy of brain illnesses, and was the progenitor of the term “neuroses.” In his classification of
disease, the neuroses included the comata, adynamiae,
spasmi, and vesaniae, with this latter group consisting of many of the classic “psychiatric” illnesses (e.g.,
mania, depression, psychosis, and dementia). His work
influenced Coombe (1797–1847) in his classification
of brain diseases into two major categories, “organic”
and “functional.” Coombe intended these terms to
sort diseases of the brain into two categories based on
the presence or absence of localizable abnormalities. It
does not appear to have been his intention to establish
a system in which some brain diseases are considered
“real” brain problems and others are not considered
brain problems at all. Griesinger (1817–1868) subsequently advanced the thesis that even normal mental
processes are the direct result of brain activity alone,
echoing Hippocrates’ view that mental illness has its
origin in the brain [10]. Griesinger viewed psychiatry
and neuropathology as a single field with one language
and one set of operative laws, and advised physicians
to “primarily and in every case of mental disease, recognize a morbid action of that organ [the brain]” [11].
In the following 50 years, a host of European
physicians began in earnest to examine the brain
with respect to mental processes. A common body
of work by pioneering physician-scientists of the
nineteenth and early twentieth centuries – among
them Theodor Meynert, Jean-Martin Charcot, Sergei
Korsakoff, John Hughlings Jackson, Henry Harlow,
Eugen Bleuler, Emil Kraepelin, Arnold Pick, and
Alois Alzheimer – whose efforts were neither guildspecific nor dominated by concerns regarding the
primacy of one or another medical specialty. Their
efforts steadily advanced knowledge of neuroanatomy,
neurophysiology, and neuropathology as applied to
behavioral phenomena in the quest to understand the
mind as a function of the brain. This unity of purpose
was so pervasive that these physicians were typically
referred to as neuropsychiatrists, heralding more
formal developments in this direction a century later.
During this same period, however, neurology
began to develop as an independent field of study, most
notably after the formation of the National Hospital for
the “Relief of Paralysis, Epilepsy, and Allied Diseases”
in Britain in 1860. Concurrently, Charcot (1825–1893)
and his students began concentrating on the “neuroses,” and pursuing a line of inquiry that turned the
2
interest of psychiatry at the beginning of the twentieth
century toward introspection, reflection, and consideration of the person as a whole. Notably, as psychoanalysis became a more dominant force within psychiatry, this “person as a whole” became increasingly less
whole with respect to a complete understanding of the
neurology underlying neurotic conditions.
As the twentieth century progressed, neurology
and psychiatry became polarized with respect to the
focus and content of their studies. Neurology was
interested in localizable pathology, the “organic” problems, and psychiatry focused on the functioning of
an individual’s psyche, internally and interpersonally. These “functional” problems, whose consideration was divorced of their neurological bases, became
the province of psychiatry. Interestingly, this was not
the initial objective of Sigmund Freud (1856–1939),
the progenitor of psychoanalysis. A neurologist by
training, Freud was committed to a form of substance
materialism: “Research has afforded irrefutable proof
that mental activity is bound up with the function of
the brain as with no other organ. The discovery of the
unequal importance of the different parts of the brain
and their individual relations to particular parts of the
body and to intellectual activities takes us a step further . . . ” [10].
Freud maintained that the science of his time
could not establish clearly the relationship between
the complex operations of mental processes and brain
function. His theories therefore assumed a form of
logical positivism in which he identified the concepts and mechanisms of mental operations from
a purely psycho-philosophical perspective. Early in
this endeavor, he offered cautionary notes on this
approach: “Our mental topography has for the present
nothing to do with anatomy . . . In this respect, then,
our work is untrammeled and may proceed according to its own requirements. It will, moreover, be useful to remind ourselves that our hypotheses can in the
first instance lay claim only to the value of illustrations”
[10].
Freud (1895) [12] envisioned a future in which a
scientific account of mental processes would be possible. However, de facto dualist perspectives on mind–
body issues supplanted his early materialist positions on such matters and pervaded early and midtwentieth century psychiatric practice and popular
culture. Indeed, when previously “functional” disorders like general paresis of the insane (a form of neurosyphilis) were discovered to have an “organic” basis,
Chapter 1: Introduction
they were quickly eschewed as proper subjects of psychiatric study and treatment and taken up by neurology. As a result, the early part of the twentieth century witnessed the progressive movement of a significant part of psychiatry away from its neuropsychiatric
foundations, and facilitated the continued division of
neurology and psychiatry into separate disciplines.
As described by Hollender (1991) in American
Board of Psychiatry and Neurology: The First Fifty
Years [13], the unification of neurology and psychiatry under the American Board of Psychiatry and Neurology (ABPN) in 1934 had the potential to unify the
fields. However, the manner in which the ABPN was
created contributed substantially to the formal separation of psychiatry and neurology. In the early 1930s,
a group of neuropsychiatrists within the Section on
Nervous and Mental Disease of the American Medical Association (AMA) suggested that psychiatry and
neurology be united under a common board of examiners for the purpose of establishing criteria and examinations for certification to practice in these medical
specialties. Their explicit purposes were to recognize
the common interests of these specialties in brain–
behavior relationships, and to protect both the public
and also the reputations of these fields by distinguishing qualified from unqualified practitioners.
In order to develop a board that would be widely
accepted by the practicing clinicians of that time, the
AMA solicited the participation of representatives
from the American Psychiatric Association (APA)
and the American Neurological Association (ANA)
in discussions regarding the development of a unified
examining board. In recommending a unified board,
the AMA made clear its position that the content
and practice of psychiatry and neurology overlapped
substantially, and that both fields would be best served
by an examining board that acknowledged their
similarity.
Ongoing tensions between the fields with respect
to public legitimacy and scientific dominance limited
the ability of the participating psychiatrists and neurologists to work cooperatively on this task. Although
the AMA representatives initiating these discussions
were self-described neuropsychiatrists, the representatives from the APA and the ANA elected not to recognize neuropsychiatry as a field of practice. Instead,
Hollender (1991) [13] notes that the APA and ANA
representatives elected first to demarcate sharply the
differences in training and certification between psychiatry and neurology and then argued over the order
in which the two fields should be represented in the
Board’s official title.
Despite their posturing, the ABPN administered
the same examination to candidates in both areas for
the first decade of its operations. Over time, and as
a consequence of training differences driven by the
ABPN guidelines, the examination became increasingly focused on the candidate’s field of training.
Nonetheless, 25% or more of the board examination
content for each remains based on the other specialty’s
material. This continues to acknowledge, albeit implicitly, that much of what constitutes neurology and psychiatry is scientifically inseparable and the practice
of both specialties requires a transdisciplinary knowledge base and skill set.
Nonetheless, the creation of ABPN left a legacy of
an uneasy, if not occasionally hostile, alliance between
psychiatrists and neurologists. Its creation also effected
an apparent amnesia within these specialties for the
historical and philosophical background that resulted
in their regulation under a combined board. As noted
earlier in this chapter, thought leaders in both fields
occasionally call for reunification of psychiatry and
neurology [3–5]. However, attempts to unite these
fields are met with skepticism, at best, outside of a
small number of academic and private institutions.
Similarly, requests to the ABPN for the establishment
of Added Qualifications in Neuropsychiatry have not
thus far been successful.
Behavioral Neurology & Neuropsychiatry
The contemporary subspecialties of behavioral neurology and neuropsychiatry have taken separate
but converging paths to their current positions.
Behavioral neurology is widely held to have begun
with the work of Norman Geschwind in the midtwentieth century [14], who established a fellowship
program at the Boston Veterans Administration
Hospital while rising to the position of James Jackson
Putnam Professor of Neurology at Harvard Medical
School. Geschwind reintroduced and expanded
on observations of brain lesions and behavioral
disturbances made by neurologists such as Paul
Broca, Karl Wernicke, Hugo Liepmann, Hienrich
Lissauer, and Jules Dejerine in the previous century,
and wrote a seminal paper on disconnection syndromes in 1965 that inspired a generation of research
on brain–behavior relationships [15, 16]. With
this foundation, behavioral neurology firmly took
3
Behavioral Neurology & Neuropsychiatry
hold; the lesion method of studying brain–behavior
relationships proved highly productive [17] and
the idea of distributed neural networks subserving
cognition appeared as a major organizing principle in
the field [18].
Neuropsychiatry, on the other hand, flourished
first as a discipline in the late nineteenth century as
discussed above, but then fell into relative obscurity
during the mid-twentieth century. Psychoanalytic theory and practice dominated psychiatry for the first
half of the twentieth century, especially in the USA
where psychoanalysts fleeing Hitler’s Germany exerted
much influence [19], and neurobiological correlates
of behavior were relatively neglected. This situation
began to change with the introduction of modern psychopharmacology in the 1950s that ushered in the
field of biological psychiatry – a powerful stimulus for
adopting a neurobiological model of mental function.
In this setting, a neuropsychiatric approach to patient
care began to reemerge and steadily gain momentum
as physicians increasingly appreciated the neurologic
bases of psychiatric disease and the psychiatric aspects
of neurologic disease [19–22]. The organization of a
professional association for neuropsychiatrists and the
development of neuropsychiatry as a medical subspecialty derive from the efforts of many physicians, most
notably Jeffrey L. Cummings, Randall B. Schiffer, and
Stuart C. Yudofsky.
Two other factors also fueled the development
of both behavioral neurology and neuropsychiatry; the rapid growth of neuropsychology, arising
in large part from the influence of Alexander R.
Luria in mid-century Russia [23], and the spectacular
advances of neuroimaging from the 1970s onward that
increasingly enabled precise structural [24] and later
functional imaging of the brain [25]. These fields contributed cognitive measures and neuroradiologic techniques for detailed study of brain–behavior relationships that substantially augmented existing methods
of clinical–pathologic correlation. With the advent of
the twenty-first century, clinical neuroscience is flourishing, leading to thoughtful commentary advocating
the closing, or at least narrowing, of the “great divide”
that has existed between neurology and psychiatry [3].
Philosophical antecedents to Behavioral
Neurology & Neuropsychiatry
The fluctuating relationship between the previously
separate subspecialties of behavioral neurology
4
and neuropsychiatry derives principally from the
challenges of investigating the human mind and its
disorders in a medical context. At the root of this
conundrum is the ancient philosophical question of
the relation of mind and body, recast in the modern
formulation of the mind–brain debate. What is
the source of human consciousness – an ineffable,
immaterial mind that exists apart from any physical structure, or the collection of nerve cells and
chemicals known as the brain that accounts for all
behavior? To many, it is inconceivable that the “gray
and white gook” inside the skull could actually be conscious [26], and thus responsible for such cherished
capacities as intelligence, creativity, and altruism. The
towering influence of the seventeenth-century dualist
philosopher Rene Descartes [27] continues today in
our society – and even to some extent in medicine.
The era in which psychoanalysis dominated psychiatric practice created an intellectual environment
in medicine that was sympathetic to dualistic thinking
despite Freud’s early career as a neurologist. While
not avowedly dualistic in the philosophical sense,
mainstream psychiatry for much of the twentieth
century contrasted “functional” with “organic” disorders as a way of establishing a group of mental
disorders in which brain structure and function
were essentially irrelevant [3]. Psychiatry focused
primarily on symptoms rather than signs, and as the
metaphors of psychoanalytic theory captured public
and professional imagination, the use of neurological
examination and laboratory data in studying behavior
diminished [3]. Simultaneously, neurology chose
to care for those patients in whom structural brain
disease could be detected, eschewing the unavoidable
subjectivity of behavioral analysis in favor of the
“hard” scientific data of the neurological examination,
cerebrospinal fluid analysis, electroencephalography,
and neuropathology [3].
As the influence of psychoanalysis began to recede
in the mid-twentieth century, strong proponents
of mind–brain unity questioned the authority of
Descartes [28–30], and the dichotomy of mind versus
brain began to lose ground in medical thinking.
Neurology and psychiatry gradually became more
inclined to share the view that the brain is central to
human behavior, and by 1987 the organic–functional
distinction was explicitly discouraged by the influential Diagnostic and Statistical Manual of Mental
Disorders [31]. Nonetheless, vestiges of philosophical
dualism persist in medicine, in part because the
Chapter 1: Introduction
study of behavior and the vexing emotional disorders
commonly considered “psychiatric” are so complex.
To cite a clinical example, the floridly abnormal
behavior of many psychotic patients with normal
conventional clinical neuroimaging and laboratory
studies seems to some critics to undermine arguments
asserting that this illness is neurobiologically based –
how can such abnormal behavior derive from a person
whose brain is structurally normal? Perhaps it is
not a surprise that lingering dualism sometimes still
impacts clinical thinking [32]. Modern neuroscience
notwithstanding, the fact remains that disorders of
behavior are the most challenging and among the
most difficult to describe objectively.
The unifying foundation of BN&NP, however,
is the shared philosophical position that brain and
behavior are inseparable [2]. The organic–functional
dichotomy cannot be maintained because all thought,
emotion, and behavior are brain-based. Although
traditionally trained behavioral neurologists tend to
focus on brain disorders in which structural pathology
is in some way demonstrable, and neuropsychiatrists
hailing from general psychiatry are comfortable
conceptualizing mental disorders as stemming from
neurochemical deficits, all agree that higher functions – normal or abnormal – originate as neural
events that involve the macro- or microstructure of
the brain in the process of subserving mental operations. Thus, whereas the assessment and treatment
of a person with Broca’s aphasia from an observable
left inferior frontal lobe infarct differs markedly
from that of an acutely psychotic schizophrenic
individual with normal conventional neuroimaging,
the underlying principle in dealing with both patients
is the same: both syndromes involve an alteration of
brain–behavior relationships that requires a thorough
understanding of how the brain operates at all levels of
analysis. The triage of patients into neurologic versus
psychiatric settings should depend only on the evaluation and services required – such as a neurologic
intensive care unit for emergent stroke treatment, or a
locked psychiatric unit for acute agitated psychosis –
and not on archaic notions of whether a patient has
“organic” or “functional” disease.
Individual temperament and interest will naturally
influence the kind of clinical setting in which a physician may prefer to work, but the common principle
that all patients in these settings have disorders of the
brain must be honored if patient care is to be optimal and intellectual progress facilitated. Indeed, we
have described an integrated practice of BN&NP that
fosters excellence in patient care, education, and
research within a setting that explicitly avoids the arbitrary divisions that have often hampered collaboration
between neurology and psychiatry [33].
The state of the field
The prospect of behavioral neurology and neuropsychiatry drawing together finds considerable support
in academia. Textbooks of behavioral neurology [34–
36] and neuropsychiatry [8, 37, 38] have proliferated
in recent years. Annual scholarly meetings are held
conjointly by the Society for Behavioral and Cognitive
Neurology and the American Neuropsychiatric Association in order to disseminate new research findings
and educate practitioners. Structural and functional
neuroimaging, neuroanatomy, neuropsychology, neuropharmacology, neuropathology, clinical neurophysiology, and genetics are all receiving much-needed
attention. Moreover, in a remarkable development,
topics previously regarded as unapproachable for neuroscientists are being vigorously considered; accounts
of the neural correlates of consciousness [39], ethics
[40], and creativity [41], for example, are now regular
reading for devotees of brain–behavior relationships.
However, postgraduate training in neurology or
psychiatry exerts a powerful socializing force, and
fellowship experiences in the higher functions of the
brain modify but do not undo these fundamental affiliations. The development of an integrated core curriculum for fellowship training [2] and the development of
the UCNS fellowship accreditation processes may create a structure within which a professional identity and
practice as a subspecialist in BN&NP becomes possible. This comprehensive curriculum is derived from
the traditions of neurology, psychiatry, behavioral
neurology, and neuropsychiatry, while drawing heavily
from neuroanatomy, neurophysiology, neuroimaging,
neuropsychology, neuropharmacology, and internal
medicine. A range of supplementary topics is also
included, including neurosurgery, neuropathology,
neurorehabilitation, neurogenetics, sleep medicine,
forensic psychiatry, epidemiology, and public policy.
Fellowship training in this subspecialty requires the
participation of faculty from both the psychiatry and
the neurology departments at each institution, and
requires that these faculties possess expertise in this
area and the ability to provide clinical training in a
transdisciplinary manner. A minimum of one year is
5
Behavioral Neurology & Neuropsychiatry
required for fellowship training in BN&NP, and more
time can be arranged as indicated by the individual
fellow’s interests and the availability of program
resources.
Although many fellowship trainees may work
in academic settings upon completing their training, community practice opportunities are emerging
rapidly. Among these are: (1) the need for physicians
prepared to care for patients with complex, multifactorial disorders of behavior that call upon the expertise of both neurology and psychiatry; (2) the aging
of the population in industrialized countries that will
render more people at risk for common late-life neurodegenerative disorders such as Alzheimer’s disease
(AD); (3) the continuing epidemic of traumatic brain
injury (TBI) in times of peace as well as in war; and
(4) astonishing advances in diagnosis and treatment
of many neuropsychiatric disorders that formerly had
mysterious etiologies, limited therapeutic options, and
relatively poor prognoses. Certification in BN&NP will
enhance opportunities by signifying special competence in these disciplines.
Future prospects
While gazing ahead is always fraught with uncertainty,
some speculations about where the future will lead are
warranted as this combined subspecialty moves ahead.
One prediction likely to be met is that the intellectual
vigor of these fields will stimulate much continued discussion and steady development of concepts.
A major goal of these two disciplines is the integration of structural and molecular paradigms in
constructing a modern synthesis of brain–behavior
relationships. As discussed above, those who think
about structural brain lesions can learn from those
whose emphasis is on abnormal neurotransmission,
and surely the converse is true as well. How does
the intricate neurochemistry of the brain map onto
the familiar gyri, tracts, and nuclei to enrich our
knowledge of distributed neural networks? Such a portrait will enable increasing sophistication of medical
and surgical therapy based on manipulation of neuroanatomically localized neurotransmitter systems. A
complete understanding of the brain as the organ of
the mind requires the unification of knowledge from
both traditions.
This approach may plausibly lead to the reintegration of Freudian thinking into the mainstream
of medicine. Freud himself harbored the belief
6
that the phenomena of psychoanalytic theory – the
unconscious, the id, ego, and superego, repression,
transference, dream analysis, and the like – would
someday find correlates in the brain, and that a
neurobiological model of the mind would develop
[10]. Such a synthesis may become more feasible with
modern investigative techniques [42]. Subspecialists
in BN&NP do not see a need to vindicate Freudianism – indeed, difficulty establishing the neural basis
of psychoanalytic theory and its clinical efficacy has
been a major source of criticism – but the notion that
complex psychological processes have a basis in brain
function is fundamental. Freudian concepts may not
readily be seen to correlate with brain structures as
our understanding increases; however, the behaviors
Freud observed in his patients – like any other –
should result from the operations of neural systems.
As Geschwind aptly wrote: “It must be realized that
every behavior has an anatomy” [43]. The ultimate
goal is to understand how the brain mediates behavior, whether investigators use a model of structural
cortical damage affecting language, or examine altered
neurotransmitter systems that influence personality.
A topic sure to garner much attention is the continued application of functional imaging technology
to understanding brain–behavior relationships. The
lesion method has a time-honored tradition in behavioral neurology, and will continue to flourish, but what
of functional magnetic resonance imaging (fMRI),
positron emission tomography (PET), single-photon
emission computed tomography (SPECT), and the
like? Will these tools add significantly to the understanding of brain and behavior, or will they turn out
to be no more than neo-phrenological instruments
producing appealing but easily misinterpreted images?
The impressive technique of fMRI has become the
most promising of these modalities, about which thousands of research papers are now published every
year, but fMRI remains limited by the extraordinary
complexity of the brain’s functional organization [44].
SPECT scanning has the advantage of being readily
available, but has proven disappointing when applied
to clinical disorders [45].
At the same time, much excitement attends the
advances of structural neuroimaging, which is now
disclosing details of neuroanatomy and neuropathology as never before. Exploiting the remarkable success
of MRI, investigators are pursuing more detailed volumetric quantitation of cerebral structures with voxelbased morphometry [46], and measurement of the
Chapter 1: Introduction
chemical composition of brain regions has become
possible with magnetic resonance spectroscopy [47].
The study of white matter, long relegated to the background of cognitive neuroscience as the cerebral cortex has dominated thinking and research, will now be
feasible with diffusion tensor imaging [48], which is
generating elegant depictions of white matter tracts in
health and disease. White matter disorders in general
will stimulate wide-ranging investigation as the importance of white matter for human behavior is increasingly appreciated [49, 50]. All of these techniques create a context in which the study of the structure of
distributed neural networks can be integrated with
an understanding of their functional connectivity and
role in neurobehavioral health and disease.
Advances in genetics that are occurring at a rapid
pace will also enhance understanding and clinical
diagnosis of neurobehavioral disorders. Testing for
autosomal dominant transmission in Huntington’s disease is a straightforward and well-known example of
how genetic analysis can be applied clinically [51], and
the list of genetic diseases in which such testing can be
considered is quickly growing. Genetic testing for AD,
while only exceptionally providing definitive results
for patients and families, is gradually improving [52],
and may be able to identify presymptomatic individuals in whom dementia can someday be prevented.
While these developments are encouraging, the reality that genetic diseases are, presently, for the most part
irreversible provides a strong impetus for further study
of the pathogenesis of neurogenetic disorders.
Nevertheless, treatment of patients with disorders
of all types affecting behavior will surely come to
be a major topic in the coming years. Many of the
treatment options for patients with these disorders
are based on scanty evidence, and convincing clinical
trials are sorely needed. Randomized controlled trials
for treatment of AD have been familiar to clinicians
for decades, and serve as a model for large-scale investigation of treatments for a host of cognitive disorders.
Traumatic brain injury occupies a major portion of
the practice of many subspecialists in BN&NP and
additional studies are needed to better define the
best methods of neurorehabilitation. More study of
neurosurgical interventions, such as for the treatment
of neoplasms and hydrocephalus, will be helpful. More
controversially, the oft-reviled area of psychosurgery
may merit reconsideration as a treatment option
for those with intractable and devastating disorders,
particularly as modern surgical techniques permit
more precise procedures and research advances
allow accurate evaluation of safety and efficacy [53].
The assessment of the efficacy of psychotherapy –
recognized three decades ago to be a neurobiological
phenomenon in which the brain undergoes synaptic
change as in any other kind of learning [54] – is now
feasible by functional neuroimaging [55], and is being
further pursued. Evolving new modalities such as
embryonic stem cell transplantation [56], gene therapy [57], deep brain stimulation [58], and transcranial
magnetic stimulation [59] hold forth much promise.
In the foreseeable future, basic science advances may
disclose strategies for enhancing synaptic plasticity
[60], stimulating remyelination [61], and promoting
neurogenesis [62] – even in the brains of older adults.
Lastly, a host of issues with public policy implications spring directly from the advances of BN&NP.
Some examples will prove illustrative. What are the
sociopolitical implications of the study of aggression,
violence, and war as neurally based behaviors [63]?
Which individuals with brain disorders should be held
accountable for criminal behavior and punished, and
which should be exonerated and treated as patients?
How is the question of free will to be addressed in
light of modern technology? What are the implications
for individuals who will be found to have genetic diseases for which no cure is available? Will new treatments for cognitive disorders involving the activation
of endogenous or surgically implanted stem cells produce cures for dreaded diseases, or might they possibly result in grossly aberrant behavior from novel
and unpredictable neuronal connections? What are the
implications of detecting residual cerebral activity with
fMRI in patients diagnosed with vegetative or minimally conscious state? While not presuming to answer
such imposing questions, subspecialists in BN&NP are
ideally suited to illuminate the issues and inform public discourse so that society can more rationally adopt
meaningful solutions.
Whither Behavioral Neurology
& Neuropsychiatry?
As this book goes to press, several clinical neuroscientific principles enjoy wide support: the constructs
of mindless brain and brainless mind are outdated,
the descriptors organic and functional are no longer
meaningful, and human behavior is usefully conceptualized as no more, or less, than the product
of brain activity. From these statements, hard won
7
Behavioral Neurology & Neuropsychiatry
through much effort over many years, all physicians
dealing with neurobehavioral or neuropsychiatric
disorders can legitimately aspire to be both objective
and humanistic. Behavior is a measurable neural
phenomenon, but its understanding also requires an
exceptional degree of interpersonal sensitivity and
interpretive skill. Nowhere is the art of medicine more
critical – objective data such as mental status test
scores and neuroimaging findings must be adroitly
combined with subjective assessment of the person
suffering with the disorder. The notion that only those
in neurology can lay claim to neuroscience, while only
those in psychiatry can appreciate the whole person,
is confining, inaccurate, and unproductive. But there
remains the issue of what exactly is the subject matter
of BN&NP.
A reasonable listing of the major disorders currently regarded as falling within the scope of this
subspecialty includes the focal neurobehavioral syndromes (e.g., aphasia, apathy, orbitofrontal syndrome);
delirium, dementia (e.g., AD), and major primary
psychiatric disorders; neurological conditions with
prominent cognitive, emotional, and behavioral features such as movement disorders, stroke, epilepsy,
multiple sclerosis, and TBI [2]. Others can be added to
or subtracted from this list, and physicians will naturally gravitate toward those disorders for which their
training and inclination render them most suitable.
Many subspecialists in BN&NP with primary training
in neurology assume the care of dementia or stroke
with focal syndromes, for example, while those with
primary training in psychiatry take on schizophrenia, depression, obsessive-compulsive disorder, and
the psychiatric sequelae of neurological conditions.
Traumatic brain injury appears to be a special case,
as subspecialists in BN&NP are increasingly committed to this common problem [64, 65]. As knowledge of
brain–behavior relationships grows, these areas can be
expected to evolve concomitantly, and with them practice patterns as well.
Despite the enthusiasm generated by the development of BN&NP as a subspecialty [1], uncertainty persists about the future organization and direction of
the combined field. Will a single name for this discipline come to replace the combined moniker? If so,
what should it be? Perhaps “cognitive neuroscience”
would suffice, but does this adequately capture the disorders traditionally considered to be “emotional?” An
alternative is “medical neuroscience,” which serves to
distinguish it from the surgical neurosciences but its
8
referents may be too broad. Will neurology and psychiatry residences modify their curricula to reflect a
converging interest in brain–behavior relationships?
Will there be combined clinical services where “neurologic” and “psychiatric” patients with cognitive disorders are evaluated and treated as a single group with
altered brain function? Many influential opinions will
doubtlessly line up on all sides of such questions.
Whether some overarching category comes to
encompass all the work in these fields remains to be
disclosed, and we do not presume to make a prediction. For now, we believe this evolving alliance stands
as a productive approach to bridge the gaps between
neurology and psychiatry, body and mind, physical
and mental. Whatever one’s perspective on the status of the subspecialty, continuing advances in understanding neuroscience as applied to patient care, education, and research demand attention. Given the powerful recent findings of neuroscience, adopting this
attitude in clinical medicine seems eminently appropriate. Our attitude has always been that getting the
work done is far more important than debating what
to call ourselves.
About this book
We have noted, as have many before us, that neurology
and psychiatry suffer needlessly from arbitrary interdisciplinary barriers, maintained by the power of tradition, that often impede intellectual progress. While
differences between these fields clearly exist and will
not soon disappear, their commonalities promise to
further understanding of brain–behavior relationships
as never before. BN&NP represents the flagship subspecialty that aims to find and develop the intellectual
common ground that beckons so strongly to students
of human behavior. The mind and the brain are but two
constructs describing the same entity, and medicine
and society are best served by acknowledging this fundamental principle.
This book reflects our view of the clinical neuroscience of behavior in the context of patients coping with a host of brain disorders, be they neurologic
or psychiatric. Intended primarily for physicians and
investigators entering the field or early in their careers,
we hope the book can both inform and inspire its readers. Those farther along in their careers may also find
information of value in these pages. We hope this book
builds upon and extends the work of many previous
volumes from which we have learned [8, 34–38] in a
Chapter 1: Introduction
comprehensive attempt to draw behavioral neurology
and neuropsychiatry closer. We present this book in
the spirit of promoting this effort for the good of our
patients, our profession, and our world.
The structure of the book follows the core curriculum for fellowship training discussed above [2].
Included are major sections on structural and functional neuroanatomy, assessment, and treatments,
reflecting the primary topic areas for fellowship training [2]. The book is intended to convey principles of
BN&NP rather than to present an exhaustive account
of disease states. Accordingly, condition-specific chapters are not presented. Instead, disorders will be introduced when they serve to illustrate the principles
under consideration. Readers may recognize points
made in our previous work that have served to build
a foundation for this text [66, 67], but this book
offers something new: our combined approach to
this intriguing area, including the expert contributions of many colleagues who have graciously devoted
their time and effort to this project, that we hope
will serve as a model for productive transdisciplinary
collaboration.
12. Freud S, Strachey J, Freud A et al. The Standard Edition
of the Complete Psychological Works of Sigmund Freud.
London: Hogarth Press; 1953.
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Chapter 1: Introduction
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Introductory Approach. Cambridge: Cambridge
University Press; 2001.
11
Section I
Structural and Functional Neuroanatomy
Chapter
Behavioral neuroanatomy
2
C. Alan Anderson, David B. Arciniegas, Deborah A. Hall,
and Christopher M. Filley
Understanding human behavior in health and disease
begins with structural and functional neuroanatomy.
The two major divisions of the human nervous system
are the central nervous system (CNS) and the peripheral nervous system (PNS). The CNS consists of the
brain and the spinal cord. The PNS includes the cranial
and spinal nerves, the distal branches of which form
efferent and afferent connections carrying information
between the CNS and the entire body. The autonomic
nervous system includes components of both the CNS
and the PNS, and serves to regulate many aspects of
visceral function that provide homeostatic balance and
the capacity to adjust to the ever-changing demands of
both internal and environmental needs.
There are approximately 100 billion neurons in the
human brain, and these are supported by, and interact with, as many as ten times that number of glial
cells [1]. Each neuron makes contact with thousands
of other neurons as well as with a large number of glial
cells. The vast majority of brain neurons are classified
as interneurons, which are thought to participate in
the processing of information rather than with sensory input or motor output. This enormous degree of
connectivity is the basis of the computational power
that produces human arousal, awareness, consciousness, and behavior.
While our knowledge of the full complement of
mechanisms by which the brain produces consciousness and other neuropsychiatric functions remains
incomplete, it is clear that all aspects of human behavior are firmly grounded in brain function. From the
meticulous dissections performed by generations of
neuroanatomists through the information obtained
through advanced functional imaging techniques, our
knowledge and understanding of the structure of the
brain as well as the functional relationship between its
components has advanced substantially.
In this chapter, we focus on those aspects of structural and functional neuroanatomy that are most relevant to Behavioral Neurology & Neuropsychiatry
(BN&NP). We consider the general structure of the
brain from the brainstem through the cerebral cortex (Figure 2.1), including a review of white matter
anatomy, the cerebral vasculature, and the ventricular system. With this background, we then discuss the
interactions of cortical, subcortical, and white matter regions, and cerebral lateralization. This approach
leads us to the general concept of distributed neural
networks, which will serve as a comprehensive organizing principle for understanding the neurobiology
of cognition, emotion, and behavior. In the chapters
that follow, in-depth consideration is given to several
aspects of specific brain structures and functional systems. For those interested in a more detailed review
of general and behavioral neuroanatomy, several excellent resources are available [2–5].
As a general principle, normal function at any level
depends in part on normal function at lower levels.
The CNS includes (in ascending order) the spinal cord,
brainstem, cerebellum, hypothalamus, thalamus, and
the paired cerebral hemispheres. The neuroanatomy
relevant to BN&NP therefore begins with the brainstem.
Brainstem and cerebellum
The brainstem comprises the medulla oblongata (myelencephalon), pons and cerebellum (metencephalon),
and midbrain (mesencephalon). Each of these areas
and the neurobehaviorally salient structures they
Behavioral Neurology & Neuropsychiatry, eds. David B. Arciniegas, C. Alan Anderson, and Christopher M. Filley.
C Cambridge University Press 2013.
Published by Cambridge University Press. 12
Chapter 2: Behavioral neuroanatomy
(A)
(B)
(C)
(D)
(E)
Figure 2.1. General structure of the brain (A). Major areas considered in this chapter include the brainstem and cerebellum (B),
diencephalon (C), limbic and paralimbic structures (D), basal ganglia (see Figure 2.5), and cerebral cortex (E). This figure is presented in color in
the color plate section.
contain are reviewed briefly in this section. The reticular formation (which is contributed to by several brainstem substructures) and the cranial nerves (some, but
not all, of which are located within the brainstem) also
are discussed in this section.
Myelencephalon
The medulla oblongata is the most caudal part of
the brain, forming the junction of the brain with
the spinal cord [6]. Anteriorly the medulla lies
against the basilar portion of the occipital bone
and posteriorly it abuts the ventral surface of the
cerebellum. Descending pyramidal (motor) tracts
and ascending spinothalamic tracts (pain and temperature sensation) decussate as they pass through
the medulla. Cranial nerve (CN) nuclei located in
the medulla include the inferior portions of CN
V (trigeminal), and VIII (vestibulocochlear), IX
(glossopharyngeal), X (vagus), XI (accessory), and
XII (hypoglossal). The medulla also contains the
nuclei for a variety of modulatory ascending and
descending pathways including serotonergic, adrenocorticotropic, ␤-endorphin, melanocyte stimulating
hormone, and adrenergic fibers. These systems are
involved in modulating ascending and descending
tracts, and also provide input into the reticular
activating system more rostrally.
Metencephalon
Pons
The word pons means “bridge” in Latin, which is
appropriate given the extensive motor, sensory, and
other pathways between the cerebrum, the cerebellum,
and the spinal cord that pass through it. The pons has
extensive connections with the cerebellum, forming
bundles of transversely oriented fibers that link pontine nuclei and the cerebellum via the middle cerebellar peduncles. The ventral surface of the pons abuts
the occipital bone and its dorsal surface lies along the
ventral surface of the cerebellum. The pons contains
the nuclei for CN VI (abducens), VII (facial), and the
superior portions of the nuclei for CN V (trigeminal),
and VIII (vestibulocochlear). The pons also contains
the locus ceruleus, a noradrenergic nucleus with diffuse projections throughout the cerebral hemispheres
[7], and serotonergic nuclei (the pontine raphe nuclei)
providing modulatory input into the reticular formation [6, 8].
13
Section I: Structural and Functional Neuroanatomy
14
Cerebellum
Mesencephalon
The cerebellum also is a portion of the metencephalon.
Together with the brainstem, the cerebellum occupies
the posterior cranial fossa and is separated from the
cerebrum rostrally by the tentorium cerebelli. For
practical purposes, the cerebellum has three major
functional subdivisions [3]. The first is the archicerebellum (flocculonodular lobe). It is the oldest part
of the cerebellum phylogenetically, which includes
the nodules and flocculi of the vermis, and connects
extensively to the vestibular system. The second
subdivision is the paleocerebellum, which includes
portions of the anterior lobe, the lingula, the central
lobule and portions of the lower vermis, the paraflocculus, and the cerebellar tonsils. This subdivision
of the cerebellum receives its principal input from
spinocerebellar pathways. The third subdivision is
the neocerebellum, which includes the remainder of
the vermis and the cerebellar hemispheres. It is the
youngest subdivision phylogenetically and the largest.
The neocerebellum receives its major input from the
pons, and is involved in the maintenance of posture,
motor coordination, and the cerebellar contributions
to higher cognitive and emotional processing.
Dense bidirectional cerebellar connections to the
brainstem are carried by the paired peduncles to the
medulla (inferior cerebellar peduncles or corpora
restiformia), the pons (middle cerebellar peduncles or
brachia pontis), and the midbrain (superior cerebellar
peduncles or brachia conjunctiva). The surface of the
cerebellum forms small parallel convolutions called
folia, separated by fissures into various subdivisions.
At a microscopic level, the cerebellar cortex is
divided into three layers: the molecular layer, the
Purkinje cell layer, and the granular layer. The Purkinje cells provide the output of the cortical layers to
deeper cerebellar nuclei. Input into the cerebellum
includes afferent fibers originating in the cerebral cortex, the brainstem (including the reticular formation,
vestibular nuclei, and inferior olive), and the spinal
cord [3].
The cerebellum possesses tremendous processing
power and plays a role in the integration of motor and
sensory information coordinating movement, posture,
motor learning, memory, and other higher-order cognitive functions [9, 10]. The role of the cerebellum in
cognitive and emotional function, as well as the neurobehavioral consequences of cerebellar injury or disease, is discussed in detail in Chapter 3.
The mesencephalon is the midbrain, and comprises
the tectum (corpora quadrigemina), tegmentum, the
cerebral peduncles, multiple nuclei and fasciculi, and
the ventricular mesocoelia (or iter, which refers to the
passage between the third and fourth ventricles, or
the aqueduct of Sylvius). Ventral to the midbrain lies
the basilar portion of the occipital bone, and the dorsal surface of the midbrain forms an isthmus between
the cerebrum and the cerebellum. Rostrally, the midbrain adjoins the pons and caudally it adjoins the diencephalon. CN nuclei located in the midbrain include
cranial nerves III (oculomotor), IV (trochlear), and
the most superior portions of cranial nerves V and
VIII.
The midbrain connections with the cerebrum are
carried by the cerebral peduncles, which contain the
afferent and efferent connections between the spinal
cord, brainstem, and the neocortex. The most dorsal portion of the midbrain is the tectum, with its
quadrigeminal plate formed by the paired inferior and
superior colliculi. The colliculi are relay stations for
auditory information (the inferior colliculi) and visual
information (the superior colliculi). The superior colliculi receive inputs from fibers of the optic tract, the
occipital cortex, the inferior colliculi, and the spinal
cord; these nuclei play a role in sensory processing and
integration, reflex responses to visual threat including
eye closure, aversive movements, and defensive posturing [3].
The upper brainstem, including the mesencephalon and upper pons, also contain several of the
major ascending modulatory neurotransmitter nuclei
(see Figures 2.2 and 2.3). Within the midbrain are the
substantia nigra and the ventral tegmental area. The
substantia nigra provides much of the dopaminergic
innervation of the basal ganglia and plays a critical
role in the modulation of “extrapyramidal” motor
function. In addition, afferent fibers from dopaminergic nuclei in the ventral tegmental area project to
the limbic system through the mesolimbic pathway,
and to the neocortex via the mesocortical pathway.
The midbrain also provides serotonergic innervation
to the cerebrum from the dorsal raphe nucleus. Like
other brainstem nuclei, these collections of serotonergic neurons extend caudally into the pons and
medulla. Serotonergic afferent fibers from these nuclei
project diffusely to the cerebral cortex and modulate
arousal through the reticular activating system.
Chapter 2: Behavioral neuroanatomy
Figure 2.2. Modulatory neurotransmitter nuclei. A major input to
the relay and reticular nuclei of the thalamus originates from
cholinergic (ACh) cell groups in the upper pons, the
pedunculopontine (PPT) and laterodorsal tegmental nuclei (LDT).
These inputs facilitate thalamocortical transmission. A second
pathway activates the cerebral cortex to facilitate the processing of
inputs from the thalamus; this arises from neurons in the
monoaminergic cell groups, including the tuberomammillary
nucleus (TMN) containing histamine (His), ventral periaqueductal
gray (vPAG) dopamine-containing cell groups (DA), the dorsal and
median raphe nuclei containing serotonin (5-HT), and the
noradrenergic locus coeruleus (LC) containing noradrenaline (NA,
also known as norepinephrine). This pathway also receives
contributions from peptidergic neurons in the lateral hypothalamus
(LH) containing orexin (ORX) or melanin-concentrating hormone
(MCH), and from basal forebrain (BF) neurons that contain
gamma-aminobutyric acid (GABA) or ACh. Reproduced from Saper
CB, Scammell TE, Lu J. Hypothalamic regulation of sleep and
circadian rhythms. Nature 2005;437(7063):1257–63, with permission
from Nature Publishing Group.
The serotonergic system provides largely inhibitory
modulation to the activity of frontal–subcortical and
limbic circuits [8]. The pedunculopontine tegmental
cholinergic nuclei (Ch5 and Ch6, commonly abbreviated as Ch5–6) also are located predominantly in the
mesencephalon [11, 12]. This group of cells provides
cholinergic innervation to the thalamus, cerebellum,
globus pallidus, subthalamic nucleus, substantia
nigra (pars compacta); medullary reticular formation
and spinal cord; and, to a lesser extent, the striatum
(caudate nucleus and putamen).
The periaqueductal gray (PAG) is the gray matter
surrounding the cerebral aqueduct in the midbrain
tegmentum and is a behaviorally relevant structure.
Figure 2.3. Modulatory neurotransmitter nuclei. A schematic
drawing to show the key projections of the ventrolateral preoptic
nucleus (VLPO) to the main components of the ascending arousal
system. It includes the monoaminergic cell groups such as the
tuberomammillary nucleus (TMN), the A10 cell group, the raphe cell
groups and the locus coeruleus (LC). It also innervates neurons in
the lateral hypothalamus, including the perifornical (PeF) orexin
(ORX) neurons, and interneurons in the cholinergic (ACh) cell
groups, the pedunculopontine (PPT) and laterodorsal tegmental
nuclei (LDT). Additional abbreviations: 5-HT – serotonin;
GABA – gamma-aminobutyric acid; Gal – galanin; NA –
noradrenaline; His – histamine. Reproduced from Saper CB,
Scammell TE, Lu J. Hypothalamic regulation of sleep and circadian
rhythms. Nature 2005;437(7063):1257–63, with permission from
Nature Publishing Group.
This collection of nuclei is connected to multiple
cortical, limbic, diencephalic, and brainstem areas
and also is connected extensively with the reticular
formation. Functionally, the periaqueductal gray area
is part of the limbic system, participating in the modulation of pain, arousal in the face of threat, emotional
expression, sexual and feeding behaviors, and the
regulation of metabolism. It may also have a role in
modulating attention for salient internal and external
stimuli related to survival, emotion, and memory [8].
Reticular formation
The reticular formation is the collective term for a
group of brainstem nuclei along with their projections
that are spread throughout the brainstem from the
medulla through the midbrain. Its name derives from
its net-like organization (from the Latin reticulum for
15
Section I: Structural and Functional Neuroanatomy
“little net”). The reticular formation extends rostrally
from the brainstem into the intralaminar nuclei of
the thalamus and certain aggregations of subthalamic cells (the zona incerta). These are discrete nuclei
with specific interconnections involved in the modulation of arousal and associated autonomic functions
[13, 14].
The nuclei of the reticular formation can be divided
into three zones with distinct anatomy and function.
First is the median and paramedian zone formed by
the serotonergic raphe nuclei. Second is a medial zone
that appears to integrate signals from ascending sensory and descending motor pathways. The third group
is the lateral zone that includes cholinergic, noradrenergic, and adrenergic nuclei. Nuclei in the more rostral portion of all three zones contribute to the maintenance and modulation of arousal, wakefulness, and
thus consciousness. Nuclei in the more caudal portion
of all three zones support respiratory drive, and modulate reflex mechanisms involving the gastrointestinal, genitourinary, cardiopulmonary, and vestibular
systems.
The reticular formation’s role in arousal can be
divided into an ascending reticular activating system (ARAS) and (providing homeostatic balance)
an ascending reticular inhibiting system (ARIS). The
ARAS is a collection of nuclei including the noradrenergic nuclei in the locus coeruleus in the pons,
dopaminergic nuclei in the ventral tegmental area
in the midbrain and Ch5–6 cholinergic nuclei, with
widely distributed projections including the thalamus,
subthalamic nuclei, limbic system, and widespread
regions of the cerebral cortex. The ARAS integrates
both bottom-up and top-down input to modulate levels of general and specific arousal and attention based
on internal and external stimuli and circumstances
[13].
We find it useful to use the construct of a corresponding ARIS as the opposing system to the
ARAS, reducing arousal and modulating attention
when appropriate [8]. This system is composed of the
ascending serotonergic projections of the raphe nuclei
providing an inhibitory balance to the activating
influence of the cholinergic, noradrenergic, and
dopaminergic systems. The system modulates wakefulness, promoting sleep. Thus, sleep is not simply the
loss of activation from the ARAS, but rather an active
process with input from these inhibitory fibers originating largely in the medullary portions of the reticular formation. Ascending serotonergic projections
16
III
IV
V.
V
V
(Motor root)
VI
VII
XII
Nucleus
ambiguus
IX and X
XI
Cervical nerves
Figure 2.4. Lateral view of the brainstem showing the relative
positions of the nuclei of cranial nerves III to XII. Adapted from Gray’s
Anatomy of the Human Body originally published in 1918.
from the dorsal raphe and central superior nuclei in
the midbrain influence behavior through their modulation of frontal-subcortical circuits. The complex
interaction of these fundamental systems regulating
arousal and awareness will be described further in later
chapters.
Cranial nerves
The 12 cranial nerves (CNs) provide motor and sensory innervation to the head and neck. All but CN
I and II connect to the brain via the brainstem
(Figure 2.4). The CNs each exist in pairs, and their
crossed and uncrossed connections with other structures in the CNS are important in understanding the
anatomy of the brain [3].
The olfactory nerve (CN I) mediates the sense of
smell. The collected axons of olfactory receptor cells in
the roof of the nasal cavity form the olfactory nerve.
These fibers pass through the cribriform plate of the
ethmoid bone, and terminate in the olfactory bulb at
the base of the frontal lobe. From there, the olfactory
tract projects to the olfactory cortex in the medial temporal lobe.
Chapter 2: Behavioral neuroanatomy
The optic nerve (CN II) carries visual information
from the eye to the rest of the brain. The optic nerve
is actually a tract of the brain. More than any other
sensory modality, the sense of vision is of central
importance in human life. Light signals are initially
processed in the eye, where photoreceptor cells in
the retina transduce the patterns of light into electrochemical signals carried by the optic nerves. The optic
nerve splits in the optic chiasm with the result that
each hemisphere receives input from the contralateral
visual field. Thus the right hemisphere receives input
from the left visual field and vice versa. The bulk
of the visual information generated by the retina
goes to the lateral geniculate nucleus (LGN) of the
thalamus. Efferent connections from the LGN form
the optic radiations coursing through the temporal
and parietal lobes carrying visual information to the
primary visual cortex in the occipital lobes. Other
areas of the brain receiving retinal input include
the superior colliculus, suprachiasmatic nucleus,
medial, lateral and dorsal terminal accessory optic
nuclei, olivary nucleus, and the inferior pulvinar [15].
These projections play a role in visual targeting and
visual processing, and may serve as alternate routes
for visual information when the LGN pathway is
injured.
The oculomotor (CN III), trochlear (CN IV), and
abducens (CN VI) nerves are considered together
because of their role in conjugate eye movements. CN
III also provides the afferent limb of the pupillary light
reflex, and mediates eyelid opening.
The trigeminal nerve (CN V) has both motor
and sensory functions. The trigeminal nerve mediates somatic sensation from the face via its three divisions: ophthalmic (V1), maxillary (V2), and mandibular (V3). Afferent fibers from the three divisions form
the trigeminal ganglion outside the brainstem, and
then coalesce to enter the pons as a single nerve. Facial
somatosensory information then projects to the ventral posterior medial nucleus of the thalamus and on
to primary sensory cortex. The motor nuclei of CN V
supply the muscles of mastication.
The facial nerve (CN VII) originates from the facial
nucleus in the pons and is primarily motor in its function, innervating the ipsilateral muscles of the face.
Facial weakness related to CN VII dysfunction is frequently seen in clinical neurology. In addition to its
motor component, CN VII also has one notable sensory function, carrying taste sensation from the anterior two-thirds of the tongue, via a branch named the
chorda tympani, to the solitary tract extending from
the pons into medulla.
The vestibulocochlear nerve (CN VIII) has two
sensory components, the vestibular and cochlear
divisions. These mediate the vestibular (balance) system and the sense of audition (hearing), respectively.
Mechanoreceptors located in the inner ear respond
to physical stimulation with the cells that form the
vestibular division responding to positional head
movements, and those of the cochlear division
responding to sound stimuli. CN VIII carries auditory
and positional sensory input to the vestibular and
cochlear nuclei in the pons. This information is
extensively processed in the brainstem and cerebellum, with auditory input relayed on to the medial
geniculate nucleus of the thalamus and then on to the
primary auditory cortex in the temporal lobe (Heschl’s
gyrus).
The glossopharyngeal nerve (CN IX) mediates
motor, sensory, and autonomic functions of the face.
Its motor fibers innervate the muscles of the pharynx,
and its sensory fibers mediate somatic sensation of the
tongue, nasopharynx, and middle and external ear as
well as taste from the posterior one-third of the tongue.
Autonomic fibers carried by CN IX supply parasympathetic input to the parotid gland.
The vagus nerve (CN X) is the most widely distributed of the CNs, carrying parasympathetic signals to thoracic and abdominal organs, as well as
motor and sensory innervation to the larynx, pharynx,
and external ear. The accessory nerve (CN XI) arises
from the lower medulla and upper spinal cord supplying motor innervation to the ipsilateral sternocleidomastoid and trapezius muscles. The hypoglossal
nerve (CN XII) originates in the medulla and provides
ipsilateral motor innervation to the muscles of the
tongue.
Diencephalon
The diencephalon includes the thalamus, metathalamus (medial and lateral geniculate nuclei), epithalamus (habenula, stria medullaris, and pineal body),
and subthalamus (often referred to as the prethalamus
by developmental neurobiologists, of which the major
part is the subthalamic nucleus). Of these, we will consider briefly the thalamus, hypothalamus (and pituitary), and the epithalamus; the subthalamic nucleus is
discussed in the context of frontal-subcortical circuits
(see Chapter 5).
17
Section I: Structural and Functional Neuroanatomy
Table 2.1. Thalamic nuclei, their afferent and efferent connections, and their major functions.
Region
Nucleus
Afferent(s)
Efferent(s)
Function(s)
Motor
Ventroanterior
Globus pallidus
Frontal cortex
Modulation of motor
function
Ventrolateral
Cerebellum
Frontal cortex
Modulation, coordination,
and learning of
movements
Ventral posterolateral
Sensory tracts from body
Parietal cortex
Somatosensation
Ventral posteromedial
Sensory tracts from body
Parietal cortex
Facial sensation
Solitary tract
Cortical gustatory area,
anterior insula
Taste
Lateral geniculate
Optic tracts
Occipital cortex
Vision
Medial geniculate
Inferior colliculi
Temporal cortex
Hearing
Medial dorsal
Globus pallidus, amygdala,
temporal cortex, frontal
cortex
Prefrontal cortices
Executive function,
memory, social cognition,
emotion
Lateral nuclear group
(pulvinar)
Frontal, parietal, temporal,
and occipital cortices
Frontal, parietal, temporal,
and occipital cortices
Coordination of intra- and
cross-modal cortical
information processing
Limbic
Anterior and laterodorsal
Mammillary bodies
Posterior cingulate,
retrosplenial area,
entorhinal-hippocampal
complex
Learning and memory
Non-specific
Midline
Hypothalamus
Amygdala, cingulate,
hypothalamus
Visceral function
Intralaminar
Reticular formation,
precentral and premotor
cortex
Striatum, cortex
Activation
Reticular
Thalamic nuclei, cortex
Dorsal thalamic nuclei
Sampling, gating, and
focusing thalamocortical
outputs
Sensory
Association
Thalamus
The thalamus relays and integrates ascending information from arousal networks in the brainstem and
sensory pathways from the visual system, olfactory
system, brainstem, and spinal cord with connections
traversing between cortical and subcortical structures
[8]. The thalamus is not a unitary structure but rather
a collection of smaller nuclei that are topographically
related to the parts of the brain to which they are
connected (Table 2.1). The anterior thalamus has bidirectional connections to frontal cortical regions, the
superior and posterior thalamus are interconnected
with parietal and occipital cortex, the inferior tier
of thalamic nuclei is connected to the orbitofrontal,
insular, and temporal regions, and the ventral thalamus is connected with limbic structures. The various
subgroups of nuclei of the thalamus are interconnected as well. As such, the thalamus plays an integral
18
role in arousal systems, sensory and motor processing, attention, language, visuospatial function, and
memory [16, 17].
Hypothalamus
The hypothalamus rests inferior to the thalamus and
superior to the pituitary gland. It is composed of
nuclei involved in the integration and the expression
of higher cerebral functions (in particular the limbic system) through autonomic, endocrine, and emotional systems (Table 2.2). The hypothalamus monitors
and modulates fluid electrolyte balance, body temperature, sexual function, circadian rhythms, satiety and
appetitive behaviors, and arousal in the setting of environmental threat. Anterior regions of the hypothalamus innervate the parasympathetic autonomic nervous system with posterior regions affiliated with the
sympathetic branch.
Chapter 2: Behavioral neuroanatomy
Table 2.2. Selected nuclei of the hypothalamus and their key
functions.
Region
Zone
Preoptic
Anterior
Medial
Nucleus
Function(s)
Periventricular
Thirst and hunger
Thyroid releasing
hormone
production
Somatostatin, leptin,
and gastrin
production
Paraventricular
Corticotropinreleasing
hormone
Oxytocin release
Vasopressin release
Thermoregulation
Thyrotropin
inhibition
Vasopressin release
Circadian rhythms
Oxytocin release
Vasopressin release
Thirst and hunger
Anterior
Suprachiasmatic
Lateral
Supraoptic
Lateral
Tuberal
Medial
Lateral
Mammillary
Medial
Lateral
Ventromedial
Satiety
Neuroendocrine
control
Dorsomedial
Blood pressure
Heart rate
Gastrointestinal
stimulation
Lateral
Thirst and hunger
Tuberomammillary Histamine release
Mammillary
Dorsal
premammillary
Posterior
Memory
Thirst and hunger
Blood pressure
control
Pupillary dilation
Temperature control
Ventral
Reproductive
premammillary
control
Tuberomammillary Histamine release
Lateral
Thirst and hunger
The hypothalamus governs endocrine functions
through its innervation and vascular connections
with the pituitary gland. The hypothalamus is closely
linked to the limbic system, contributing to emotional
function and matching the autonomic response to
internal drive states and the response to environmental needs. A dramatic example of this is the change in
autonomic function seen as part of the flight or fight
response.
Epithalamus
This portion of the diencephalon comprises the pineal
body, habenula, and stria medullaris. The pineal body
is a midline structure located in the posterior portion
of the diencephalon, rostral and dorsal to the superior
colliculus and beneath the stria medullaris. It produces
a variety of neurotransmitters (serotonin, melatonin,
norepinephrine, luteinizing hormone, thyrotropinreleasing hormone, and somatostatin), is connected
to the visual system and the suprachiasmatic nucleus
of the hypothalamus, and plays a role in sleep–wake
cycles and the maintenance and regulation of circadian
rhythms [18].
The habenula (also referred to as the habenular
nuclei or habenular complex) refers to a cell mass
embedded in the posterior end of the stria medullaris,
through which they receive their principal afferents
from limbic structures (e.g., hypothalamus, septum
[11]). The medial habenula includes, among other
components, the Ch7 cholinergic nucleus [19]. It,
along with the other medial and lateral habenular
subnuclei, projects to the interpeduncular nucleus
(located at the base of the midbrain between the cerebral peduncles) via the retroflex fasciculus (i.e., habenulointerpeduncular tract) [11]. The interpeduncular
nucleus, in turn, projects to the serotonergic mesencephalic raphe nuclei, as well as the PAG. The habenula
is involved in multiple neurobehaviorally important
functions, including pain processing, stress responses,
sleep regulation, appetitive and reproductive behaviors, and learning (including encoding of negative
reward signals) [20, 21].
Basal ganglia
Basal ganglia include several subcortical gray matter
nuclei deep in the cerebral hemisphere (Figure 2.5).
The structures included under the umbrella term basal
ganglia vary, but typically include the caudate nucleus,
the putamen, and globus pallidus. The caudate nucleus
is contiguous with the putamen in its ventral portions,
and is divided into three parts: head, body, and tail.
The caudate head bulges into the anterior horn of the
lateral ventricle, the body extends along the thalamus,
and the tail ends in the temporal lobe. The putamen is
the largest nucleus of the basal ganglia; its dorsal and
lateral portions surround the medial elements of the
basal ganglia (hence the name putamen, meaning shell
in Latin). The globus pallidus, also called the pallidum,
lies medial to the putamen and is divided into external
(lateral) and internal (medial) components.
The caudate and putamen comprise the striatum.
The striatum also may be divided into dorsal and ventral components; the dorsal striatum (neostriatum)
19
Section I: Structural and Functional Neuroanatomy
decision-making. These networks have the same general anatomy as the motor circuit with reciprocal connections between specific regions of cortex, specific
thalamic nuclei, and the basal ganglia. These networks
are discussed in more detail in Chapter 5. The close
relationship between these networks serving motivation, attention, cognition, visuospatial function, and
voluntary movement help us understand the frequent
existence of cognitive problems, visuospatial disturbances, motivational disturbances, and movement disorders across a variety of illnesses including Parkinson’s disease, Huntington’s disease, Wilson’s disease,
and schizophrenia.
Figure 2.5. Subcortical structures (coronal view). Labeled areas
are: A – caudate nucleus; B – thalamus; C – putamen; D – globus
pallidus; E – hypothalamus; F – mammillary body.
refers to the combination of the caudate and putamen,
and the ventral striatum (limbic striatum) consists of
the nucleus accumbens and olfactory tubercle. The
putamen and the globus pallidus (which is anatomically a component of the prethalamus) comprise the
lenticular nucleus. The basal ganglia are functionally
connected to several other brain structures, including
the substantia nigra (pars compacta and reticulata),
subthalamic nucleus, thalamus, raphe nuclei, and cerebral cortex (motor and premotor).
The basal ganglia “bias” the automatic manner in
which sensory inputs are interpreted and movements
selected. These nuclei serve to integrate and modulate
cerebral cortical control with sensory feedback for the
generation of voluntary movement. The basal ganglia
serve as a component of parallel loops, in combination with the cortex and the thalamus via connections
mediated through internal and external capsules forming the extrapyramidal motor system [22]. The system is distinguished from the pyramidal motor system that includes the corticobulbar and corticospinal
tracts. The extrapyramidal system links the globus pallidus to the ventroanterior and ventrolateral thalamic
nuclei with connections to motor cortex which then
connects back to the globus pallidus completing the
loop. The basal ganglia are thought to modulate the initiation, cessation, and timing of voluntary movement.
More recently recognized is the basal ganglia’s role
in frontal-subcortical circuits involved in attention
and visuospatial function, executive function, motivation, and the modulation of social behavior and
20
Limbic system
The French neurologist Paul Broca initially described
the limbic system in 1878 as a collection of structures
at the junction of the cerebral hemispheres and the
diencephalon (Figure 2.6). The term limbic, derived
from the Latin term limbus (“edge,” “border,” ‘band,”
or “girdle”), reflects both the location and orientation
of the structures as well as the extensive connections
between the limbic system and the thalamus, hypothalamus, and cortex.
In 1937, James Papez wrote a paper hypothesizing
that a network of cerebral structures that included
the parahippocampal gyrus, hippocampus, fornix,
mammillary bodies, mammillothalamic tract, anterior nucleus of the thalamus and the cingulate gyrus
formed the neuroanatomic substrate for emotion
[23] (described subsequently as the Papez circuit).
Although the neuroanatomy of emotion is considerably more extensive than suggested by this early
formulation (see Chapter 18), the structures in this
circuit are intimately involved in the processing of
episodic memory (memory with spatial and temporal
context such as specific events), survival functions
(eating, fighting, fear, sexual desire/mating, grooming,
nurturing), and the complex interplay between these
cerebral functions.
As currently conceived, the fundamental components of the limbic system include the cingulate
and orbitofrontal gyri, hippocampus, parahippocampal gyrus, hypothalamus, anterior and dorsomedial
nuclei of the thalamus, amygdala, medial temporal
cortex, and the periaqueductal gray area (the limbic
midbrain) [1, 24]. Several major pathways (including
the fornix, medial forebrain bundle, and the stria terminalis) form reciprocal connections to other areas
Chapter 2: Behavioral neuroanatomy
Corpus callosum
Cingulate
gyrus
Orbital and medial
prefrontal cortex
Cut edge
of midbrain
Parahippocampal
gyrus
Temporal
lobe
Mammillothalamic
tract
Figure 2.6. Limbic and paralimbic areas
(green shading) viewed parasagittally. The
top panel depicts these areas as if viewed
through the left hemisphere. The bottom
panel illustrates these areas in greater
detail. Reprinted from Purves D,
Augustine GJ, Fitzpatrick D et al. (editors),
Neuroscience, 2nd edition; 2001, with
permission from Sinauer Associates. This
figure is presented in color in the color
plate section.
Anterior nucleus
of the thalamus
Fornix
Medial dorsal
nucleus of the thalamus
Anterior
commissure
Ventral basal
ganglia
Hypothalamus
Optic chiasm
Amygdala
Mammillary
body
Hippocampus
of the brain including the frontal-subcortical circuits,
tightly linking these areas as well as the reticular activating system described above. The limbic system plays
a central role in assessing the importance of incoming
sensory information with high emotional and survival
value, evaluating the current situation with reference
to past experience, decision-making, and directing the
behavioral response.
The limbic system thus monitors and regulates
internal emotional states, and integrates that information with the response to the external environment
[24]. The connections to the ARAS modulate the
overall level of arousal to meet the needs of the
behavioral response [13]. The cingulate gyrus, septal
nuclei, and other frontotemporal areas contribute to
the experience of positive emotions while the amygdala, in connection with other frontotemporal areas,
plays a prominent role in the experience of negative
emotions. The external manifestations of emotion
involve both hypothalamic modulation of autonomic
(e.g., visceral) function through sympathetic and
parasympathetic pathways (via the hypothalamus)
and the corresponding automatic motor responses
(via the basal ganglia). The amygdala, a collection of
21
Section I: Structural and Functional Neuroanatomy
nuclei located in the anterior temporal lobe adjacent
to the hippocampus, is centrally involved in emotional
learning, and in processing sensory input so as to link
emotional valence with new information.
As an adaptive phenomenon, it makes teleological
sense that the limbic system evolved to integrate emotion and new learning (episodic memory) where emotional associations with high survival value are best
remembered so they may be repeated (or avoided). It
also makes sense that the type of memory mediated
by limbic structures should include episodic memory,
with spatial and temporal components evoking memories of prior similar situations in response to current
sensory input [25].
Just as our understanding of the role of the amygdala in emotion has advanced, so has our appreciation
of the role of the hippocampus in memory. The hippocampus is a curved structure in the medial temporal
lobe, comprised of three-layered archicortex divided
into the dentate gyrus, hippocampus proper, and the
subiculum. The hippocampus has an integral role in
the learning of facts and events (declarative memory).
The acquisition of new memories also includes other
structures, tightly connected to the hippocampus,
including the basal forebrain and the dorsal medial
nucleus of the thalamus [26, 27]. A long history of
clinical experience demonstrates that bilateral injury
to any of these structures produces severe impairment
of recent declarative memory.
In summary, the limbic system is integrally
involved with episodic memory and emotion. Key
structures including the amygdala and hippocampus
process sensory input, assign an emotional valance,
and initiate the process encoding new events into
memory. This is an active process with the “emotional”
elements of the circuit (e.g., extended amygdala and
cingulate areas) modulating the focus of attention
and the priority with which memories are created. A
potent emotional valence (either positive or negative)
attached to a candidate input for memory serves as
strong internal reinforcement (i.e., has high survival
value) for learning and the eventual formation of
permanent memories; conversely, input with limited
emotional impact (i.e., low survival value) is less likely
to be encoded and retained for later recall.
Cerebral cortex (telencephalon)
The cerebral cortex varies from 1.5 to 4.5 mm in depth
and consists of a thin sheet of neurons and supporting
22
Figure 2.7. Drawings of cortical lamination by Santiago Ramon y
Cajal. Each shows a vertical cross-section of the cortex, the surface
of which is at the top. Left: Nissl-stained visual cortex of a human
adult. Middle: Nissl-stained motor cortex of a human adult. Right:
Golgi-stained cortex of a 1.5-month-old infant. The Nissl stain shows
the cell bodies of neurons; the Golgi stain shows the dendrites and
axons of a random subset of neurons.
glial cells that form the outermost layer of the brain.
It has been estimated that there are 14 billion neurons in the cerebral cortex with as many as 300 trillion
synapses [18]. An appreciation of the structure and
function of the cerebral cortex is key to understanding
brain–behavior relationships. More than 90% of the
cerebral cortex is classified as neocortex, recognized
for its recent arrival in the course of brain evolution.
Microscopically, the neocortex is formed as a horizontally laminated structure with six layers: the outermost molecular layer, the external granular cell layer,
the external pyramidal cell layer, the internal granular cell layer, the internal pyramidal cell layer, and
deepest, the multiform layer (Figure 2.7). Functionally,
columns of cells arranged perpendicular to the surface
of the cortex respond as a unit, both receiving and processing incoming stimuli and then generating efferent
signals.
Traditionally, the neocortex has been divided into
the frontal, temporal, parietal, and occipital lobes
based on the gross anatomy of the cortical surface
Chapter 2: Behavioral neuroanatomy
Table 2.3. Traditional brain–behavior relationships.
Frontal
Temporal
Parietal
Occipital
Motor planning
Audition
Somatosensation
Vision
Voluntary movement
Auditory association
Somatosensory association
Visual perception
Language (fluency)
Language (comprehension)
Cross-modal sensory association
Motor prosody
Sensory prosody
Visuospatial function
Motivation
Visual recognition
Praxicon
Working memory
Declarative memory
Derivative language functions (reading, writing, calculation)
Executive function
Emotional generation
Comportment
Olfaction
Figure 2.8. Lobar divisions of the cerebral hemispheres (left lateral
view). This figure is presented in color in the color plate section.
(Figure 2.8); these areas are associated traditionally
with specific neurobehavioral functions (Table 2.3).
The frontal lobe is the most rostral portion of the brain,
with its boundaries defined posteriorly by the Rolandic
fissure and inferiorly by the Sylvian fissure. The temporal lobe is demarcated superiorly by the Sylvian fissure
with its posterior boundary defined by the junction of
two lines: the first a line from the parieto-occipital sulcus to the pre-occipital notch and the second a continuation extending posteriorly from the Sylvian fissure.
The parietal lobe has the Rolandic fissure as its anterior boundary, and its inferior and posterior extent are
determined by the lines that demarcate the temporal
and occipital lobes. The occipital lobe is located posterior to the temporal and parietal lobes. The insula, a
small neocortical region of neurobehavioral relevance,
lies deep in the Sylvian fissure beneath the overlying
cortex of the frontal, temporal, and parietal lobes [18].
While the surface of the brain is commonly
divided into the frontal, parietal, temporal, and
occipital lobes, a more detailed and functionally
relevant mapping of the cerebral cortex comes from
Korbinian Brodmann, a German neurologist and
neuroanatomist who based his cortical maps on the
cytoarchitectonic arrangement of neurons established
with meticulous dissections using the Nissl stain
[28]. These histologically based areas described by
Brodmann remain useful (and in use) today for
neurobehavioral localization (Figure 2.9).
Another way of classifying the functional areas of
the neocortex is to divide it into primary and association (secondary, tertiary, or quaternary) cortices based
on the level of information processing (Figure 2.10).
The primary motor cortex is located in the precentral
gyrus of the frontal lobe. Secondary motor association
cortex (supplementary motor cortex) generates the
impulses that are then developed into motor output
by the primary motor cortex. Primary motor cortex
generates afferent signals that directly control voluntary movement. The majority of ascending sensory
tracts project to primary sensory cortex. The assorted
primary cortical areas project to adjacent secondary
association cortices where sensory input (e.g., visual,
auditory, tactile, olfactory, gustatory) is compared with
previously experienced (encoded) sensory inputs. This
processed information from the sensory association
cortex is then further communicated to tertiary and
quaternary association areas for further elaboration,
identification, comparison, and integration into
cognitive, emotional, and behavioral networks.
Primary sensory processing is subserved by
the postcentral gyrus (tactile and proprioceptive),
the medial and superior temporal lobe (olfactory/gustatory and auditory, respectively), and the
occipital lobe (visual). These sensory areas are unimodal (serving only one sensory type), and project to
unimodal secondary association areas associated with
and adjacent to them. These unimodal association
23
Section I: Structural and Functional Neuroanatomy
Figure 2.9. Brodmann’s areas in the human brain. Reprinted with permission from Mark Dubin, PhD, Department of Molecular, Cellular &
Developmental Biology, University of Colorado at Boulder (http://spot.colorado.edu/∼dubin/talks/brodmann/brodmann.html). This figure is
presented in color in the color plate section.
areas project to higher-order areas for cross-modal
processing and integration of sensory information
into memory, cognitive, and emotional networks.
Two of the higher-order association areas are integral to the function of the human brain, and therefore
warrant additional description. First, the inferior parietal lobule (including the supramarginal and angular
gyri) receives input from all of the secondary association areas, and is classified as a cross-modal (heteromodal) or tertiary association cortex. This area of
cortex serves to integrate sensory information across
modalities, giving humans the ability to associate
sights with sounds, sight with touch, smell with sight,
and so on. This tertiary association cortex has reciprocal connections with the reticular formation, the limbic system, and the frontal lobes, which both modulate
and integrate arousal, attention, and emotion with sen-
24
sory experiences, based in large part on their relative
emotional valence and/or survival value.
Second, the frontal lobes serve as quaternary
association areas integrating extensively processed
information from four areas, the tertiary sensory
association cortices (heteromodal cortex), the secondary association cortices, and limbic-subcortical
and reticular areas, for the highest level of synthesis,
elaboration, and regulation of emotional, cognitive,
and behavioral/motor processes. The frontal lobes
are the most phylogenetically recent addition to
the brain, and the slowest to mature during human
development. Their connections with the rest of the
brain are dense and richly reciprocal. Input to the
frontal lobes is segregated, with sensory information
largely projecting to the lateral convexities of the
prefrontal cortices, and limbic information projecting
Chapter 2: Behavioral neuroanatomy
2º M 1º M
1º S
2º S
2º V
3º
4º
1º V
1º A
2º A
2º V
heteromodal cortices with efferents back to tertiary
and secondary association cortices [24]. This system
modulates directed attention to sensory and emotional
information with high survival value. These reciprocal
cortico-cortical circuits control and determine where
internal and external attentional systems are directed,
and determine which mental processes will be continued, and when and how any changes in mental direction will occur.
White matter
Motor Output Ascending Input
Figure 2.10. Schematic diagram of the information flow between
the primary, secondary, tertiary, and quaternary cortical areas. The
ascending input and motor outputs are simplified in order to
highlight the cortical elements through which representational
information processing networks are developed. Abbreviations:
M – motor; S – somatosensory; A – auditory; V – visual; 1◦ – primary
cortical area; 2◦ – secondary association cortex; 3◦ – heteromodal
cortex; and 4◦ – prefrontal cortex.
to the basilar (orbitomedial) surface of the frontal
lobes.
Subcortical structures (striatum, globus pallidus,
subthalamic nucleus, and thalamus) form five major
circuits with various frontal gyri, including primary
motor cortex, frontal eye fields, dorsolateral prefrontal
cortex (made up of the middle and superior frontal
gyri), orbitofrontal cortices (gyrus rectus and medial
orbital gyrus medially and lateral orbital gyrus and
medial inferior frontal gyrus laterally), and the anterior cingulate gyrus [29]. The five major frontalsubcortical circuits subserve key functions including motor (voluntary motor function), frontal eye
fields (eye movements), dorsolateral prefrontal (executive function), lateral orbitofrontal (“social cognition”), and anterior cingulate (motivation and emotional experience) and are discussed in detail in
Chapter 5.
Reticular formation afferents project diffusely
throughout the frontal lobes, modulating arousal and
attention in response to sensory and limbic inputs.
Output from the frontal lobes is essentially reciprocal
to these same structures, as well as to frontal motor
areas for the final step of generating a motor response.
The dorsolateral, orbitofrontal, and anterior cingulate areas integrate cognitive, emotional, and motivational information with somatosensory information
received from the secondary sensory association and
While much of the focus of neuroanatomy is on
gray matter and the relationships between and within
the cerebral cortex and subcortical structures, we
should emphasize that cerebral white matter occupies nearly one half the total volume of the brain,
serving to link cortical and other gray matter regions
[30]. The white matter is formed by collections of
CNS axons ensheathed with myelin that are most
commonly called tracts, but that may also be termed
fasciculi, bundles, lemnisci, funiculi, and peduncles
based on their location and the structures they connect. A detailed discussion of the structural and
functional anatomy of white matter is presented in
Chapter 4.
The myelin sheath surrounding axons dramatically
increases conduction velocity allowing for the rapid
transfer of information along white matter tracts that
is necessary for efficient communication in sensory
and motor systems, as well as the integration of higher
functions mediated by other cortical and subcortical
networks subserving cognition, emotion, and attention. These tracts connect widely dispersed gray matter
regions, linking cortical and subcortical areas to form
unified neural networks. These networks in turn subserve the many unique functions of the brain, from
basic sensation and motor function to cognition and
emotion.
In particular, the commissural and association
fibers play a major role in the mediation of higher cerebral functions. Commissural fibers are white matter
tracts that link the left and right cerebral hemispheres
via the cerebral commissures. The corpus callosum, the
largest of these commissures, is a massive tract that
connects all four lobes of the brain with the homologous regions in the contralateral hemisphere. The anterior and hippocampal commissures are much smaller
commissural fiber systems serving a similar function
on a much smaller scale.
25
Section I: Structural and Functional Neuroanatomy
Association tracts link gray matter regions within
each hemisphere. Neuroanatomists have distinguished
two types of association fibers: short (arcuate or U
fibers) and long association fibers. The short association fibers connect adjacent cortical gyri throughout the cerebrum in contrast to the long association
fiber systems that are longer and link cerebral lobes
within the ipsilateral cerebral hemisphere. Examples of
the long association fibers include the superior occipitofrontal fasciculus, the inferior occipitofrontal fasciculus, the arcuate fasciculus, the uncinate fasciculus,
and the cingulum. An interesting neuroanatomic feature of these tracts, and a measure of the central role of
the frontal lobes, is that they all have one terminus in
a frontal lobe, while the other terminus is variably in
more posterior regions.
Given their relevance to BN&NP, two other white
matter tracts are particularly relevant to neuropsychiatry and merit special mention: the fornix and the
medial forebrain bundle. The fornix is a prominent
arched tract that connects the hippocampus with the
mammillary bodies as part of the Papez circuit, playing a key role in attention and memory formation. The
medial forebrain bundle joins the hypothalamus with
both caudal and rostral brain regions and participates
in the hypothalamic control of the autonomic nervous
system. These examples emphasize the essential role of
white matter in the operations of all distributed neural
networks [30].
Vascular supply
Normal brain function requires a steady delivery
of well-oxygenated blood. Brain ischemia or anoxia
causes neurologic symptoms within seconds, and irreversible neuronal and glial damage and ultimately cell
death occurs if the interruption lasts more than a
few minutes. The clinical effects of hypoxic-ischemic
injury comprise an important area of BN&NP [31]
and the effects of focal ischemic injury inform much
of what we know about brain–behavior relationships
[3]. A working knowledge of the complex system of
arteries and veins supplying the brain is necessary for
understanding the neurobehavioral effects of many
neurologic disorders, including one of the most common, ischemic stroke.
At the microscopic level, numerous cerebral
capillaries serve as the bridging vessels between the
arterial and venous systems. These capillaries consist
of tightly packed endothelial cells mediating the
26
exchange of oxygen, glucose and other critical nutrients and removing the byproducts of metabolism.
These capillaries regulate the interchange between
the CNS and the blood supply, forming a major part
of the blood–brain barrier and protecting the brain
from the entry of pathogens and toxins from the
bloodstream.
Four large arteries, sometimes called great vessels
of the neck, provide the blood supply to the brain
(Figures 2.11 and 2.12). The right and left common
carotid arteries usually arise from the right subclavian artery and the ascending aorta, respectively, and
midway through their course through the neck they
bifurcate into the external carotid artery supplying the
face and other extracranial structures, and the internal
carotid artery (ICA) irrigating a substantial portion of
the brain. The paired vertebral arteries, typically somewhat smaller than the common carotids, usually arise
from the subclavian arteries and ascend in parallel to
a level just below the pons, where they merge to form
the single basilar artery. The basilar artery links with
the paired internal carotid arteries to form the Circle of Willis, a vascular loop at the base of the brain
from which arise all the arteries supplying the cerebrum. The Circle of Willis is formed by the paired
posterior cerebral arteries (PCAs) that bifurcate from
the top of the basilar artery and proceed on to supply
posterior and basal cerebral regions, the paired posterior communicating arteries (PCoAs) that connect the
PCAs with the ICAs, the paired anterior cerebral arteries (ACAs) that arise from the ICAs and go on to irrigate anterior and dorsal regions of the cerebrum, and
a single anterior communicating artery (ACoA) that
joins the two ACAs.
The largest vessels arising from the Circle of Willis
are the two middle cerebral arteries (MCAs), each
ascending to supply a substantial portion of the ipsilateral cerebral hemisphere. Whereas vascular disease of
many kinds can affect any of the cerebral vasculature
and dramatically disrupt neurologic function, occlusions of the MCA, ACA, and the PCA are most important in terms of neurobehavioral function because of
the key cortical and subcortical structures they supply. It is important to note the variability of the vascular anatomy and region of distribution of these vessels
in normal individuals. There are a variety of normal
anatomical variants of the origin of the great vessels
from the aorta, the anatomy of the Circle of Willis, and
the specific territory and volume of brain irrigated by
any given vessel [32].
Chapter 2: Behavioral neuroanatomy
A richly anastomosed system of cerebral veins provides the venous drainage of the cranium [32]. These
venous systems are conventionally divided into superficial and deep groups, both of which drain into a
network of dural sinuses. Superficial veins near the
brain surface typically drain into the superior sagittal sinus, a long, tubular structure that runs along the
inner table of the skull in the interhemispheric fissure
at the top of the brain. Deep veins draining subcortical structures including the basal ganglia and thalamus
empty into the straight sinus that courses superior to
the cerebellum. The major deep and superficial dural
venous sinuses coalesce at the confluence of sinuses,
and then empty into the bilateral transverse sinuses
and on to the internal jugular veins returning blood to
the heart via the superior vena cava. Vascular disorders
involving the cerebral venous system are less common
than those of the arterial system, but the neurological
and neuropsychiatric outcomes can be equally catastrophic.
Ventricular system
Figure 2.11. Orthogonal frontal projection of the cerebral and
cerebellar arteries in situ, together with some bony landmarks and
the lateral ventricles. Labeled structures include: 1 – Calvaria (inner
border). 2 – Medial occipital artery, parieto-occipital branch.
3 – Trunk of the corpus callosum. 4 – Lateral ventricle. 5 – Insula.
6 – Medial occipital artery. 7 – Superior cerebellar artery, medial
branch. 8 – Lateral occipital artery. 9 – Free margin of the lesser
wing of the sphenoid bone. 10 – Middle meningeal artery,
intraosseous part (in-constant). 11 – Middle meningeal artery,
frontal branch. 12 – Middle meningeal artery, parietal branch.
13 – Superior margin of petrous part of the temporal bone.
14 – Superior cerebellar artery, lateral branch. 15 – Posterior cerebral
artery. 16 – Superior cerebellar artery. 17 – Basilar artery.
18 – Anterior inferior cerebellar artery. 19 – Posterior inferior
cerebellar artery, medial branch. 20 – Posterior inferior cerebellar
artery, lateral branch. 21 – Posterior inferior cerebellar artery.
22 – Vertebral artery, intracranial part. 23 – Maxillary artery, pterygoid
part. 24 – Middle meningeal artery. 25 – Superficial temporal artery.
26 – Maxillary artery, manidibular part. 27 – Vertebral artery, atlantal
part. 28 – External carotid artery. 29 – Facial artery. 30 – Vertebral
artery, cervical part. 31 – Paracentral artery. 32 – Pericallosal artery.
33 – Callosomarginal artery. 34 – Middle cerebral artery, terminal
part. 35 – Middle cerebral artery, insular part. 36 – Anterior cerebral
artery, post-communicating part. 37 – Anterior communicating
artery. 38 – Anterior cerebral artery, pre-communicating part.
39 – Middle cerebral artery, sphenoid part. 40 – Internal carotid
artery, cavernous part. 41 – Internal carotid artery, petrous part.
42 – Internal carotid artery, cervical part. 43 – Common carotid
artery. Reprinted from Nieuwenhuys R, Voogd J, Huijzen CV. The
Human Central Nervous System. 4th edition. New York, NY:
Springer; 2008, with permission from Springer Science+Business
Media. This figure is presented in color in the color plate section.
Four internal cavities called ventricles sit in the center
of the brain. These cavities are filled with cerebrospinal
fluid (CSF), a colorless liquid produced by the choroid
plexuses within the ventricles and that surrounds and
bathes the entire CNS (Figure 2.13). The ventricular
system together with the production and reabsorption
of the CSF are important in governing the intracranial pressure and fluid dynamics of the brain. The CSF
plays a supportive role in normal CNS function, and
abnormalities of the CSF may reflect the presence of
infection, malignancies, inflammatory processes, and
many other neurologic disorders. The two largest ventricles are the lateral ventricles, one in each cerebral
hemisphere, and deep within the frontal, temporal,
parietal, and occipital lobes. Both lateral ventricles
communicate with a single third ventricle, a narrow
cavity located on the midline between the right and
left thalami, via an opening in each lateral ventricle
called the foramen of Monro. The tent-shaped fourth
ventricle lies on the dorsum of the brainstem and is
connected to the third ventricle by a small conduit
through the midbrain known as the cerebral aqueduct.
Finally, the fourth ventricle empties into the cisterna
magna through three apertures, the midline foramen
of Magendie and the two lateral foramina of Luschka.
From there the CSF then circulates through the spinal
canal, irrigating and supporting the spinal cord to its
27
Section I: Structural and Functional Neuroanatomy
Figure 2.12. Orthogonal lateral projection of the cerebral and cerebellar arteries, together with external and bony landmarks. Some neural
structures are illustrated in outline; in the center, two lines tangential to the anterior and posterior commisures (AC and PC, respectively) are
seen: the one passing above the AC and beneath the PC is part of the bicommissural line of Talairach (BC); the other tangent is part of the
upper horizontal line of Krönlein (CH). Additional abbreviations include: CM – canthus-meatus line; FH – horizontal line of Frankfurt;
GI – glabella-inion line; VCA – vertical tangent to anterior commissure; and VCP – vertical tangent to posterior commissure. Labeled structures
include: 1 – Central sulcus. 2 – Pericallosal artery. 3 – Callosomarginal artery. 4 – Corpus callosum. 5 – Outline of ventricles. 6 – Outline of
insula. 7 – Anterior cerebral artery. 8 – Middle cerebral artery, frontal trunk. 9 – Anterior commissure. 10 – Middle cerebral artery, parietal trunk.
11 – Middle cerebral artery, temporal trunk. 12 – Posterior commissure. 13 – Medial occipital artery. 14 – Lateral occipital artery. 15 – Superior
cerebellar artery, medial branch. 16 – Superior cerebellar artery, lateral branch. 17 – Superior cerebellar artery. 18 – Posterior cerebral artery.
19 – Posterior communicating artery. 20 – Internal carotid artery, cerebral part. 21 – Internal carotid artery, cavernous part. 22 – Siphon point.
23 – Middle cerebral artery, sphenoid part. 24– Ektocanthion (Canthus externus). 25 – Glabella. 26 – Orbital (on infraorbital margin).
27 – Internal carotid artery, petrous part. 28 – Basilar artery. 29 – Superior margin of petrous part of the temporal bone. 30 – Anterior inferior
cerebellar artery. 31 – Porion (on supramental margin). 32 – Fourth ventricle. 33– Posterior inferior cerebellar artery, medial branch.
34 – Posterior inferior cerebellar artery, lateral branch. 35 – Posterior inferior cerebellar artery. 36 – Vertebral artery, intracranial part.
37 – Vertebral artery, atlantal part. 38 – Internal carotid artery, cervical part. 39 – Maxillary artery. 40 – Middle meningeal artery. 41 – External
carotid artery. 42 – Vertebral artery, cervical part. 43 – Common carotid artery. 44 – Spinal cord. 45 – Inion (external occipital protuberance).
Reprinted from Nieuwenhuys R, Voogd J, Huijzen CV. The Human Central Nervous System. 4th edition. New York, NY: Springer; 2008, with
permission from Springer Science+Business Media. This figure is presented in color in the color plate section.
lower end and then recirculating rostrally to the convexities of the brain, where it is eventually absorbed
into the cerebral venous sinuses through structures
called the arachnoid villi.
The choroid plexus in all four ventricles steadily
produces CSF at a rate of about 450 ml per day. Thus
the total CSF volume turns over about three times
daily. The total volume of CSF in and around the CNS
28
is approximately 140 ml, whereas the volume of CSF
contained within the ventricles at any given time is a
small fraction of this, about 25 ml. The neuroanatomic
importance of the CSF is twofold: physically, it serves
a supportive role in providing buoyancy that cushions the brain from the rigid bony protuberances of
the inner aspect of the skull, and functionally, the CSF
takes part in regulating the chemical environment of
Chapter 2: Behavioral neuroanatomy
Figure 2.13. The ventricular system, including the lateral
ventricles (dark blue, rostral), third ventricle (purple), cerebral
aqueduct (green), fourth ventricle (light blue, caudal), and choroid
plexus (red). Adapted from 3D Brain from G2C Online
(www.g2conline.org), produced by the Dolan DNA Learning Center,
Cold Spring Harbor Laboratory. This figure is presented in color in
the color plate section.
brain neurons. Directly related to these roles, the ventricular system and the CSF have many important clinical implications. Enlargement of the ventricular system, known as hydrocephalus, results from an excess
of CSF production, disturbed circulation, or impaired
absorption, and can have major neurologic consequences. Analysis of the constituents of the CSF after
lumbar puncture is crucial for diagnosis of many neurologic disorders, such as meningitis and encephalitis.
Conclusion
Our understanding of the neuroanatomy of cognition, emotion, behavior, and sensorimotor function
is an amalgam of traditional neuroanatomic dissection, the information gleaned from the clinical study
of neurologic patients, and the methods of modern
neuroscience, all of which are expanding our insights
into brain–behavior relationships as never before. The
localization of higher function in the brain is a central
goal of neuroscience, and with our expanding knowledge of the relationships between brain structure and
function, the neurobiological basis of human behavior
becomes ever more clear.
How the brain generates cognitive and especially
emotional function has long been the subject of vigorous debate. Accepting the premise that all behavioral
function originates in brain activity was the first step,
but the understanding of the specific localization
and nature of higher functions within the brain
requires more work. Much of our knowledge of the
relation between specific regions and structures in the
brain and specific cognitive functions was obtained
through careful clinical description combined with
detailed post-mortem study. The advent of modern
neuroimaging techniques has expanded and refined
our understanding.
However, even with this large body of knowledge,
uncertainty remains about how any given brain region
generates a specific cognitive function. Reduced to
its simplest formulations, theories about the cerebral
representation of higher mental function fall into
two camps: localization and equipotentiality. The
foundation of the localizationist’s conception of brain
function originated in the time-honored practice of
neurologists and neuropsychiatrists that emphasizes
a detailed understanding of neuroanatomy and
the localization of functions within it. The lesion
method, the study of focal brain injury and the resultant disturbance of function, produced a relatively
secure, and clinically useful map of brain–behavior
relationships. While the lesion method has proved
highly effective in demonstrating the anatomy of
elemental neurologic deficits such as CN deficits and
hemiparesis, it has been less helpful in identifying
the sites, or explaining the underlying mechanism of
higher functions. While the description of the effects
of frontal, temporal, and parietal lesions has advanced
our general understanding of the anatomic underpinnings of language, visual processing, and memory, it
is increasingly clear that there is no simple correspondence between a given gyrus and a discrete cognitive
domain.
At the other end of the spectrum were the equipotential theorists, who contended that any specific
localization of higher functions in the brain is impossible, and that all cerebral cortical areas are capable of
supporting the operations of higher functions [1]. The
cortex was considered to be essentially undifferentiated with respect to cognitive function and the effect
of any lesion, anywhere in the cerebral hemispheres,
would impair neurobehavioral function in proportion
to the amount of tissue damaged. This notion, originally supported by experimental studies in higher
primates, was then countered by evidence from a
century of clinical and decades of neuroimaging
studies that confirmed the specialization of cerebral
areas with regard to higher functions. Thus, like strict
29
Section I: Structural and Functional Neuroanatomy
localization, pure equipotentiality is insupportable in
light of current knowledge.
Rather than either of these extremes, the current
formulation of brain function is based on the idea
of distributed neural networks [24]. The central concept of neural networks is that integrated ensembles
of interconnected cerebral structures subserve specific
neurobehavioral domains. Thus there is no exclusive
relationship between any single brain structure and
a corresponding mental function, but rather, a neuroanatomically linked network operating as a functional unit subserves a given function. Examples of
these distributed networks include the left perisylvian
language zone and medial temporal, frontal, and thalamic contributions to memory formation, storage, and
retrieval.
Higher-order brain function is predicated on
the structures and function of lower and more fundamental regions of the brain. Thus, the reticular
activating system in the brainstem supports and
modulates higher functions through its modulation of
the diencephalon, basal ganglia, and cerebral cortex.
The interaction of these structures as components
of distributed neural networks provides the fundamental organization of cognition and emotion.
Throughout the following chapters, the concept of
distributed neural networks will serve as a foundation for brain–behavior relations and their clinical
relevance.
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31
Section I
Structural and Functional Neuroanatomy
Chapter
Cerebellum
3
Jeremy D. Schmahmann
The inclusion of a chapter on the cerebellum in a textbook devoted to Behavioral Neurology & Neuropsychiatry (BN&NP) reflects a paradigm shift in understanding the role of the cerebellum and the neural
substrates of cognition. The cerebellum has long been
recognized as important for motor control. Clinical
evidence reveals, however, that some cerebellar lesions
do not produce motor incapacity, and that cerebellar
lesions can impair a number of higher-order functions.
The focus of this chapter is to present an overview and
practical approach to conceptualizing these manifestations of cerebellar lesions, and to outline the principles
that govern the cerebellar contribution to cognition
and emotion as well as to sensorimotor function.
The cerebellum and cognition – the
underlying neurobiology
Distributed neural circuits
Understanding how the cerebellum contributes to cognition is key to developing a clinical approach to
evaluation and management. Central to this concept
is the notion of distributed neural circuits, the idea
that all behaviors are subserved by neural systems
comprising anatomic regions, or nodes, each displaying unique architectural properties, distributed geographically throughout the nervous system, and linked
anatomically and functionally in a precise and unique
manner [1]. These nodes are not exclusive to the cerebral cortex, but include subcortical regions – striatum,
thalamus, and cerebellum. The clinical manifestations
of cerebellar lesions may thus be viewed as disconnection syndromes – focal disruptions of distributed cortical and subcortical neural circuits that are the basis
of all neurological function [2–4].
Essential cerebellar anatomy
Situated in the posterior fossa, the cerebellum is comprised of two hemispheres joined across the midline,
or vermis. It contains cerebellar cortex, white matter,
and deep nuclei (Figure 3.1).
Cerebellar fissures (equivalent to cerebral sulci)
separate the cerebellar folia (equivalent to cerebral
gyri) to form ten lobules identified by the roman
numerals I through X, grouped into three lobes. Lobules I through V constitute the anterior lobe, lobules
VI through IX the posterior lobe, and lobule X is the
flocculonodular lobe [5–7].
The histology of the deeply folded cerebellar
cortex is essentially uniform throughout [8]. It has
three layers: the Purkinje cell monolayer situated
between the granule cell layer beneath and the
molecular layer above. Purkinje cells (PCs) provide
the sole axonal efferent from the cortex to the deep
nuclei. The flattened arbor of the PC dendritic tree
extends up into the molecular layer. Granule cells
receive mossy fiber afferents from the spinal cord
and brainstem including basis pontis, and send their
axons into the molecular layer where they divide to
form parallel fibers running along the long axis of the
folium, synapsing with the distal dendrites of hundreds of PCs. Climbing fiber (CF) axons from
the neurons of the inferior olivary nucleus in the
medulla entwine themselves around the proximal
dendrites of PCs in a one-CF-to-one-PC relationship, terminating in the cerebellar cortex in
discretely organized parasagittal zones. Cortical
interneurones include stellate and basket cells in
the molecular layer that inhibit the PCs, and Golgi
cells in the granule cell layer that inhibit the granule
cells.
Behavioral Neurology & Neuropsychiatry, eds. David B. Arciniegas, C. Alan Anderson, and Christopher M. Filley.
C Cambridge University Press 2013.
Published by Cambridge University Press. 32
Chapter 3: Cerebellum
(A)
(B)
(C)
(F)
(D)
(G)
(E)
(H)
Figure 3.1. A, Posterior, and B, right lateral surface reconstructions of the human cerebellum derived from MRI images. The named fissures
are demarcated in color, and the fissures and lobules are identified. C, Surface reconstruction of the cerebellum seen from the oblique
posterior view, with lobules demarcated. Parasagittal images of human cerebellum on MRI 2 mm lateral to midline in D, and 18 mm lateral to
midline in E. Fissures are color coded according to the convention used in A and B, and the lobules are designated. F, Superior (SCP), middle
(MCP), and inferior (ICP) cerebellar peduncles in human identified with diffusion spectrum imaging, overlaid on diffusion-weighted image of
cerebellum and brainstem. G, Cryosection image of post-mortem human cerebellum in the coronal plane 52 mm behind the anterior
commissure – posterior commissure (AC-PC), with deep cerebellar nuclei identified: D – dentate nucleus, E – emboliform nucleus, F – fastigial
nucleus, G – globose nucleus. H, Diagram of a single cerebellar folium is shown sectioned in its longitudinal axis (diagram right) and
transversely (left) to depict the histology of the cerebellar cortex. Purkinje cells are red; superficial and deep stellate, basket, and Golgi cells are
black; granule cells and ascending axons and parallel fibers are yellow; mossy and climbing fibers are blue. Also shown are the glomeruli with
mossy fiber rosettes, claw-like dendrites of granule cells, and Golgi axons. (A, B, D, E, G reproduced from Schmahmann JD, Doyon J, Toga A,
Evans A, Petrides M. MRI Atlas of the Human Cerebellum. San Diego, CA: Academic Press; Copyright Elsevier, 2000, with permission from
Elsevier; C from Makris N, Schlerf JE, Hodge SM et al. MRI-based surface-assisted parcellation of human cerebellar cortex: an anatomically
specified method with estimate of reliability. Neuroimage 2005;25(4):1146–60, with permission from Academic Press; F reproduced from
Granziera C, Schmahmann JD, Hadjikhani N et al. Diffusion spectrum imaging shows the structural basis of functional cerebellar circuits in the
human cerebellum in vivo. PLoS One 2009;4(4):e5101, with permission; H reproduced from Williams PL, Bannister LH, Berry MM et al. (editors).
Gray’s Anatomy. 38th edition. New York, NY: Churchill Livingstone; 1995; Copyright Elsevier, 1995, with permission from Elsevier. Redrawn
from Eccles JC, Ito M, Szentágothai J. The Cerebellum as a Neuronal Machine. Berlin: Springer-Verlag; Copyright Elsevier, 1967. This figure is
presented in color in the color plate section.
33
Section I: Structural and Functional Neuroanatomy
The cerebellar nuclei are, from medial to lateral, the fastigial, globose, emboliform, and dentate
nuclei; these are supplemented by the lateral vestibular nucleus in the medulla that has direct connections
with cerebellar lobule X cortex.
Three peduncles link the cerebellum to the neuraxis. The inferior cerebellar peduncle conveys afferents from the spinal cord (spinocerebellar tracts) and
the climbing fiber inputs from the inferior olivary
nucleus, as well as cerebellar efferents to the inferior
olive and to vestibular nuclei. The middle cerebellar
peduncle is the conduit of mossy fiber afferents from
the pontine nuclei in the massively expanded ventral
part of the pons. The superior cerebellar peduncle carries efferents from the cerebellar nuclei to the cerebral
hemispheres, as well as some spinocerebellar afferents
to cerebellum.
Three pairs of blood vessels derived from the posterior circulation (vertebrobasilar system) irrigate the
cerebellum. These are relevant in understanding the
consequences of stroke. The posterior inferior cerebellar arteries (PICAs) irrigate the medial and lateral
aspects of the posterior lobe, the ventral aspect of the
cerebellar nuclei, and the medulla. The anterior inferior cerebellar arteries irrigate the anterior aspects of
the posterior lobe, part of the anterior lobe, the middle cerebellar peduncle and the inferior aspect of the
lateral pons. The superior cerebellar arteries supply the
anterior lobe and rostral part of the posterior lobe, the
superior aspect of the deep nuclei, the superior cerebellar peduncle, and the rostral part of the lateral pons.
Cerebrocerebellar connections
The anatomical connections of the cerebellum with
spinal cord, brainstem and cerebral hemispheres are
discretely organized in parallel anatomic subsystems
(or loops) that provide the structural basis for the role
of the cerebellum in movement, cognition, and emotion. Its connections with the cerebral hemispheres are
via a two-stage feedforward projection from cerebral
cortex through the nuclei of the basis pontis and a
two-stage feedback system from the cerebellar nuclei
through thalamus to cerebral cortex.
Sensorimotor information reaches the cerebellum
from the spinal cord via the spinocerebellar tracts,
the spinal-recipient parts of the inferior olivary complex, and the motor recipient nuclei in the basis pontis
[9–13]. Sensorimotor projections to cerebellar cortex
terminate in the anterior lobe (lobules I–V), adjacent
34
parts of lobule VI, and lobule VIII. The sensorimotorrelated corticonuclear complexes engage the interpositus nucleus (globose and emboliform in the human)
and the dorsal part of the dentate nucleus [14, 15] and
project back to motor-related areas of the cerebral cortex [16]. The cerebrocerebellar link is predominantly
contralateral, so that the right cerebellum communicates mostly with the left cerebral hemisphere, and vice
versa. Cerebellar control of movement is overwhelmingly ipsilateral; i.e., the right cerebellum coordinates
movements of the right side of the body.
Higher-order information gains access to the cerebellum via the corticopontine pathway, transmitted
from the pons through the middle cerebellar peduncle to the cerebellum. These inputs are derived from
association areas in the prefrontal, posterior parietal,
superior temporal, and dorsal parastriate cortices; and
from paralimbic areas in the posterior parahippocampus, limbic regions of the cingulate gyrus and the anterior insular cortex [12, 17, 18]. The cerebellar cortical destinations of these afferents are predominantly in
lobules VI and VII (Crus I and II being hemispheric
extensions of lobule VIIA; and lobule VIIB). The more
recently evolved ventral parts of the dentate nucleus
[19] convey information from these cerebellar regions
via thalamus back to the cerebral cortical association
areas, thus closing the loop [17, 20]. Limbic and paralimbic cortices are interconnected with the cerebellar
vermis and fastigial nucleus [21].
Cerebellar functional topography
Physiological studies in cat [22] and human [23, 24]
reveal cerebellar somatotopy confined to the anterior
lobe, parts of lobule VI, and lobule VIII. Resting-state
functional connectivity magnetic resonance imaging
(fcMRI) in humans shows that activity in the anterior
lobe, lobules VI and VIII, correlates with sensorimotor regions of the cerebral cortex, whereas activity in
the posterior lobe (mostly Crus I and II of lobule VII)
correlates with prefrontal, parietal, and temporal association areas and the cingulate gyrus [25]. Functional
MRI (fMRI) studies indicate that whereas the cerebellar anterior lobe, adjacent parts of lobule VI, and lobule VIII are activated in sensorimotor tasks, lobules
VI and VII in the posterior lobe are active during language, spatial, and executive function tasks, and affective processing engages the posterior lobes including
the vermis [26, 27] (Figures 3.2 and 3.3).
Chapter 3: Cerebellum
(A)
(D)
(B)
(C)
Figure 3.2. Activation Likelihood Estimation (ALE) activation maps for the domains of A, spatial cognition, B, motor tapping with the right
hand, and C, language tasks drawn from a meta-analysis of functional imaging studies [26]. The right cerebellum is depicted on the right. The
results are overlaid upon an image of the cerebellum in the coronal plane at y = −70 from the MRI Atlas of the Human Cerebellum [7], and
the cerebellar fissures and lobules at this level are identified in D. Reproduced from Schmahmann JD, Doyon J, Toga A, Evans A, Petrides M.
MRI Atlas of the Human Cerebellum. San Diego, CA: Academic Press; Copyright Elsevier, 2000, with permission of Elsevier; and with permission
of Academic Press from Stoodley CJ, Schmahmann JD. Functional topography in the human cerebellum: a meta-analysis of neuroimaging
studies. Neuroimage 2009;44(2):489–501. This figure is presented in color in the color plate section.
The recognition that sensorimotor control is topographically separate and distinct from cognitive and
emotional regulation in the cerebellum represents a
major departure from earlier conventional wisdom
[28]. It now appears that the anterior lobe and parts of
medial lobule VI, together with lobule VIII of the posterior lobe and the globose and emboliform nuclei (or,
more accurately the interpositus nucleus in the experimental animal) constitute the sensorimotor cerebellum.
Lobule VII (that includes crus I and crus II of lobule
VIIA, and lobule VIIB), parts of lobule VI, and the ventral part of the dentate nucleus, constitute the anatomical substrate of the cognitive cerebellum. The limbic
cerebellum appears to have an anatomical signature in
the fastigial nucleus and the cerebellar vermis, particularly the posterior vermis. Little is known of the possible cognitive role of lobule IX, although early fcMRI
data provide some insights into its potential incorporation into the default mode network [29]. [As discussed in Chapter 5, Frontal-subcortical circuits] Lobule X is an essential node in the vestibular system.
Clinical manifestations of
cerebellar lesions
The cerebellar motor syndrome
Lesions of the cerebellum have traditionally been
regarded as producing motor impairments only. The
cerebellar motor syndrome is characterized by widebased and unsteady, or ataxic, gait; incoordination, or
dysmetria, of the arms and legs; articulation impairment, or dysarthria; and eye movement abnormalities
that disturb vision, among other problems [30, 31].
These deficits are present in patients with neurodegenerative ataxias involving the entire cerebellum, but in
stroke patients they arise following lesions principally
in the anterior lobe [32, 33]. Oculomotor abnormalities and vestibular symptoms (vertigo, nausea, emesis) result from lesions of lobules IX and X, but lesions
in the hemispheres that avoid the anterior lobe do not
result in the cerebellar motor syndrome. Indeed, when
these patients are examined a few days after stroke
35
Section I: Structural and Functional Neuroanatomy
Figure 3.3. Representative rostral (y = −44) to caudal (y = −76) coronal sections through a human cerebellum showing activation patterns
in a functional magnetic resonance imaging experiment in a single subject [28]. Tasks investigated sensorimotor function (finger tapping,
red), language (verb generation, blue), spatial cognition (mental rotation, green), working memory (n-back task, purple), and emotional
processing (viewing images from the International Affective Picture System, yellow). Lobules V, VI, Crus I (Cr I), Crus II (Cr II), VIIB and VIII are
labeled. The right and left cerebellar hemispheres are as indicated. Reproduced with permission of Masson Spa from Stoodley CJ,
Schmahmann JD. Evidence for topographic organization in the cerebellum of motor control versus cognitive and affective processing. Cortex
2010;48(7):831–844. This figure is presented in color in the color plate section.
when the vestibular symptoms have subsided, it can be
difficult to detect any sign of a motor disorder [33].
The cerebellar cognitive affective syndrome
The importance of the cerebellum for non-motor function was highlighted by the description of the cerebellar cognitive affective syndrome (CCAS) [34]. The
CCAS results from lesions of the posterior lobe, characterized by clinically relevant deficits in executive
function, visual spatial performance, linguistic processing, and dysregulation of affect (Table 3.1).
In the original report of 20 patients, 18 demonstrated problems with executive functions, including
poor working memory (in 11 of 16 tested), motor or
ideational set shifting (in 16 of 19), and perseveration
of actions or drawings (in 16 of 20). Verbal fluency
was impaired in 18 patients, presenting as telegraphic
speech, occasionally so limited as to resemble mutism.
Decreased verbal fluency was unrelated to dysarthria.
Visuospatial disintegration was found in 19 patients,
36
who were disorganized in their sequential approach to
drawing, and the conceptualization of the figures was
disorganized. Four patients demonstrated simultanagnosia. Naming was impaired in 13 patients, generally
being spared in those with smaller lesions. Six with
bilateral acute disease had agrammatic speech, and elements of abnormal syntactic structure were noted in
others. Prosody was abnormal in eight patients, with
tone of voice characterized by a high-pitched, whining, childish, and hypophonic quality. Mental arithmetic was deficient in 14 patients. Verbal learning and
recall were mildly abnormal in 11, and visual learning
and recall were impaired in four (of 13 patients tested).
Ideational apraxia was evident in two individuals.
Difficulty modulating behavior and personality
style was a prominent feature of the bedside mental state examination in 15 patients, particularly those
with large or bilateral PICA territory infarcts, and in
one with surgical excision of the vermis and paravermian structures. Flattening of affect or disinhibition
were manifested as overfamiliarity, flamboyant and
Chapter 3: Cerebellum
Table 3.1. Deficits that characterize the cerebellar cognitive
affective syndrome (CCAS). The net effect of these disturbances
in cognitive functioning is a general lowering of overall
intellectual function.
Neurobehavioral
domain
Deficits characterizing CCAS
Executive function
Spatial cognition
Deficient planning, motor or ideational
set-shifting, abstract reasoning, working
memory and multi-tasking; decreased
verbal fluency, sometimes to the point
of telegraphic speech or mutism;
perseverative ideation in thought and/or
action
Visuospatial disintegration with impaired
attempts to draw or copy a diagram;
disorganized conceptualization of
figures; impaired visual-spatial memory;
in some cases, simultanagnosia may be
present
Language
Anomia, agrammatic speech, abnormal
syntactic structure, abnormal prosody
Personality
Aberrant modulation of behavior and
personality with posterior lobe lesions
that involve midline structures;
flattening or blunting of affect alternates
or coexists with disinhibited behaviors
such as overfamiliarity, flamboyant and
impulsive actions, and humorous but
inappropriate and flippant comments;
regressive, childlike behaviors and
obsessive-compulsive traits can be
observed
impulsive actions, and humorous but inappropriate
and flippant comments. Behavior was regressive and
childlike, and obsessive-compulsive traits were occasionally observed.
Autonomic changes were a central feature in a
patient with stroke involving the fastigial nucleus and
paravermian cortex. This manifested as spells of hiccupping and coughing, which precipitated bradycardia
and syncope.
Neuropsychological testing confirmed the observations from the bedside evaluation (Table 3.2).
Deficits were more pronounced and generalized in
patients with large, bilateral, or pancerebellar disorders, and particularly in those with acute onset cerebellar disease. Lesions of the posterior lobe were particularly important in the generation of the CCAS;
the vermis was consistently involved in patients with
pronounced affective presentations; and the anterior
lobe seemed to be less involved in the generation of
these cognitive and behavioral deficits. Patients with
stroke improved over time, although executive function remained abnormal.
Table 3.2. Neuropsychological findings in the cerebellar
cognitive affective syndrome reported by Schmahmann and
Sherman, 1998 [34]. These findings are grouped according to
major functional category. Abbreviations: WAIS: Wechsler Adult
Intelligence Scale; WAIS–R: Wechsler Adult Intelligence
Scale–Revised; WMS–R: Wechsler Memory Scale–Revised; n =
number of patients who received each test. ∗∗∗ P ⬍ 0.001; ∗∗ P ⬍
0.01; and ∗ P ⬍ 0.05. Reprinted from Schmahmann JD, Sherman
JC. The cerebellar cognitive affective syndrome. Brain
1998;121(Pt 4):561–79, by permission of Oxford University Press.
Test
Z-score
Mean
SD
Intellectual functioning
WAIS – Full-scale IQ
WAIS–R Verbal IQ
WAIS–R Performance IQ
−1.0
−0.93
−1.3
0.123 0.0002∗∗∗
13
0.145 ⬍0.0001∗∗∗ 15
∗∗∗
0.127 0.0006
13
Executive functioning
Word Association
Animal Naming
Trails A
Trails B
Wisconsin Card Sorting Test
−2.7
−1.5
−1.2
−0.89
−0.83
1.8
0.77
1.3
0.76
1.7
⬍0.0001∗∗∗
0.0002∗∗∗
0.0067∗∗
0.0030∗∗
0.2205
16
10
12
11
8
Reasoning and abstraction
Similarities
Comprehension
Picture Completion
Arithmetic
Picture Arrangement
−0.42
−0.79
−0.77
−0.86
−1.4
0.99
0.67
0.98
1.1
0.74
0.1141
0.0120∗
0.0150∗
0.0112∗
⬍0.0001∗∗∗
16
8
13
13
14
Visuospatial/visual
construction
Rev Complex Figure: Copy
WAIS–R Block Design
WAIS–R Object Assembly
Hooper Visual Orientation
−5.9
−1.2
−0.81
−0.42
3.2
0.90
0.84
0.89
0.0002∗∗∗
0.0006∗∗∗
0.0431∗
0.3038
13
12
7
6
−1.4
−0.40
1.4
1.4
0.0047∗∗
0.6097
13
4
−0.13
−0.51
1.3
0.93
0.7448
0.0501
10
15
Attention and orientation
Digit Span – forward
Digit Span – backward
Tapping Span – forward
Tapping Span – backward
Digit Symbol
Stroop
−0.51
−0.61
−0.78
−0.85
−1.3
0.07
1.3
1.2
1.0
0.84
0.67
0.95
0.1501
0.0644
0.0844
0.0571
0.0004∗∗∗
0.8769
15
15
7
7
9
4
Memory WMS–R
Logical Memory I
Logical Memory II
Visual Reproduction I
Visual Reproduction II
Rey Complex Figure:
Memory
−0.40
−0.42
−1.1
−1.4
−1.7
1.1
0.89
1.1
0.84
0.76
0.1756
0.1046
0.0038∗∗
0.0001∗∗∗
0.0012∗∗
14
14
12
12
7
Language
Boston Naming Test
Peabody Picture Vocab.
PPVT-R
WAIS–R Vocabulary
WAIS–R Information
P-value
n
The principal features and clinical relevance of the
CCAS have been emphasized and elaborated upon in
subsequent clinical reports (cerebellar stroke [35–39];
mass lesions [40]; and superficial siderosis [41, 42]).
37
Section I: Structural and Functional Neuroanatomy
Cerebellar stroke patients have been reported to show
deficits in executive function as revealed by poor performance on phonemic and alternate categorical fluency, naming with and without interference, and a
paced auditory serial addition task; and visual spatial
deficits with low scores on the Wechsler Adult Intelligence Scale–Revised (WAIS–R) Block Design subtest [43]. These deficits are clinically relevant; young
adults (ages 18–44) with cerebellar strokes producing impaired working memory, visuospatial skills, and
cognitive flexibility have delayed return to the work
force because of cognitive limitations, not motor incapacity [44].
Our understanding of the manifestations of the
CCAS continues to evolve, as exemplified by cerebellar patients who report problems with multi-tasking,
organizing their thoughts, sustaining their level of concentration and energy, and being somewhat forgetful. One with post-infectious cerebellitis developed
impaired judgment, diminished insight, and inability to predict consequences of his actions. An artist
with a PICA territory infarct reported loss of creativity that persisted for almost a year, no longer
able to experience the flow of visual images that premorbidly characterized his artistic process. Another
suffered bilateral cerebellar strokes – one in the left
anterior lobe that resulted in left-sided dysmetria,
and the other in the right posterior lobe and vermis. His chief complaints were post-stroke executive
impairments, irritability, poor impulse control, and
depression.
The CCAS occurs in children as well. Children
who had undergone resection of cerebellar tumors but
who did not receive radiation therapy or methotrexate
achieved poor scores on tests of expressive language,
word finding, and digit span, visual-spatial functions
and verbal memory, and they showed perseveration
and difficulties establishing set [45]. More than half of
these children with vermis involvement experienced
the posterior fossa syndrome (PFS) [46, 47], which
was described initially as mutism without behavioral
impairment [48, 49]; pseudobulbar palsy [50]; cerebellar speech syndrome [51]; and mutism and subsequent
dysarthria [52]. In our series [45], this phenomenon
developed after a 1–2-day latent period of normal
behavior following surgery, and was characterized
by the development of mutism followed by recovery
over months with dysarthria, and buccal and lingual
apraxia. Children also exhibited behavioral changes
including regressive personality, apathy, and poverty
38
of spontaneous movement. Emotional lability was
marked, with rapid fluctuation of emotional expression gravitating between irritability with inconsolable
crying and agitation, to giggling and easy distractibility. The PFS generally follows a surgical approach to
tumor resection through the cerebellar vermis, occurring in about 15–50% of patients according to different studies. The relationship between PFS and CCAS
in the post-operative population has been specifically
considered [53], although it should be noted that
PFS, the hallmark feature of which is post-operative
mutism following a delay, is not a prerequisite for the
development of the intellectual and emotional deficits
that comprise the CCAS, either acutely (as in stroke
or tumor patients) or more chronically as occurs in
destructive or degenerative lesions of the cerebellum.
Subsequent analyses of children following cerebellar tumor resection reveal auditory sequential memory and language deficits following right-sided tumors,
and deficient spatial and visual sequential memory
with left hemisphere tumors [54]. Impaired executive functions have been reported, including impaired
planning, sequencing, mental flexibility and hypothesis generation and testing, visual-spatial function,
expressive language, and verbal memory [55–60].
Behavioral changes have been noted, with apparent increased thoughtfulness, anxiety and aggression
[61], hyperspontaneous, disinhibited behavior, and
hypospontaneous, flattened affect [62]. Vermal lesions
in particular lead to post-surgical mutism and agrammatism, and behavioral disturbances include irritability, decreased ability to tolerate the company of others,
and autistic features such as avoidance of physical and
eye contact, complex repetitive and rhythmic rocking movements, stereotyped linguistic utterances, and
lack of empathy [63]. Attention deficit disorder, addiction, anorexia, uncontrolled temper tantrums and
phobias have also been described in the post-tumor
resection pediatric population [64], and the posttumor CCAS deficits in children may be persistent
[65, 66].
The cerebellar cognitive affective
syndrome – the emotional deficits
Emotional dysregulation can be a striking aspect of
the CCAS [34, 45]. Behavioral aberrations in children
following cerebellar tumor resection include disinhibition, impulsivity and irritability [67], dysphoria,
Chapter 3: Cerebellum
inattention and irritability [57], anxiety and aggression [61], and stereotypies and aberrant interpersonal
relations that meet criteria for the diagnosis of autism
[63]. The immune-mediated syndrome of opsoclonus–
myoclonus–ataxia that occurs in children [68] and
adults [69] produces a psychiatric constellation of
mood changes and inconsolable irritability with lability, aggression, and night terrors. Dysphoric mood,
disinhibition and poor affect regulation, disruptive
behaviors and temper tantrums occur together with
the cognitive and language impairments typically seen
in the CCAS. Further, these behavioral changes have
a predilection for lesions involving the vermis and
paravermian regions, findings that are consistent with
earlier clinical [70] and electrophysiological studies in
experimental animals [71] and patients [72] that led to
the first indication of the cerebellum as an “emotional
pacemaker” [73].
Pathological laughing and crying (PLC), a manifestation of disordered voluntary control of emotional
expression, occurs following lesions of the pontocerebellar circuit [74, 75] including post-infectious cerebellitis [76] and stroke in the basis pontis [13, 77],
and it is described in patients with the cerebellar form
of multiple system atrophy (MSA) [78]. These findings provide support for the notion that the cerebellum is engaged in the voluntary control of emotional expression. PLC may occur in the absence of
a mood disorder, but some MSA patients also report
true depression, suggesting that the cerebellum may
influence the feeling state as well as the affective
display.
In our continuing observations of adults and
children with cerebellar lesions we have noted altered
regulation of mood and personality, psychotic thinking, and behaviors that meet criteria for diagnoses
of attention-deficit hyperactivity disorder, obsessivecompulsive disorder, depression, bipolar disorder,
disorders on the autism spectrum, anxiety, panic, and
often, “atypical psychosis.” Other features include
a lack of initiation, apathy, and irritability. We have
conceptualized these behaviors as either excessive
or reduced responses to the external or internal
environment. The exaggerated, positive, released, or
hypermetric responses may be regarded as analogous
to the overshoot in the motor domain resulting from
cerebellar lesions (akin to “cognitive overshoot” [79]).
The diminished, negative, restricted or hypometric
responses may be likened to hypotonia [80], or to
hypometric movements (undershoot) in the motor
Table 3.3. Neuropsychiatric manifestations in patients with
cerebellar disorders, arranged according to major
neurobehavioral domains, each with positive and negative
symptoms. Adapted from Schmahmann JD, Weilburg JB,
Sherman JC. The neuropsychiatry of the cerebellum – insights
from the clinic. Cerebellum 2007;6(3):254–67 and reproduced
with permission from Taylor & Francis Ltd.
Positive
(exaggerated)
symptoms
Negative
(diminished)
symptoms
Attentional
control
Inattentiveness
Distractibility
Hyperactivity
Compulsive and
ritualistic behaviors
Ruminativeness
Perseveration
Difficulty shifting focus
of attention
Obsessional thoughts
Emotional
control
Impulsiveness
Disinhibition
Lability
Unpredictability
Incongruous feelings
Pathological laughing
and crying
Anxiety
Panic
Agitation
Anergy
Anhedonia
Dysphoria
Sadness
Depression
Hopelessness
Autism
Stereotypical behaviors Avoidant behaviors
spectrum Self-stimulation
Tactile defensiveness
behaviors
Easy sensory overload
Psychosis
Illogical thought
spectrum Paranoia
Hallucinations
Lack of empathy
Muted affect
Emotional blunting
Apathy
Social skill
set
Passivity
Immaturity
Childishness
Difficulty with social
cues and interactions
Unawareness of social
boundaries
Overly gullible and
trusting
Anger
Aggression
Irritability
Overly territorial
Oppositional behavior
system following cerebellar lesions. Further, we
conceptualize these manifestations as falling into
five neuropsychiatric domains – attentional control,
emotional control, social skill set, autism spectrum
disorders, and psychosis spectrum disorders [66]
(Table 3.3). Certain manifestations, such as the social
skill set negative symptoms, are reminiscent of observations regarding the cerebellar role in theory of mind
studies [81, 82], providing a clinical underpinning to
this observation from experimental psychology. Some
patients with acquired cerebellar lesions develop panic
disorder, perhaps reflecting overshoot of anticipatory
fear [83] resulting from cerebellar-induced emotional
dyscontrol.
39
Section I: Structural and Functional Neuroanatomy
Effect of cerebellar lesions on
development
The developing nervous system appears to require
an intact cerebellum for normal intellectual and
social/emotional function as well as for motor skill.
The cerebellum has a protracted developmental trajectory: it reaches its peak volume later than the cerebrum
and more phylogenetically recent cerebellar regions
(engaged in cognitive processing) mature particularly
late [84]. This renders the cerebellum vulnerable to
environmental influences, and is clinically relevant in
infants born prematurely, as the rapid rate of growth
of the cerebellum during late gestation is impeded by
the premature birth [85]. Thus, adolescents who had
been born very pre-term (⬍33 weeks’ gestation) have
reduced cerebellar volumes and testing reveals deficits
in executive, visual-spatial, and language skills including impaired reading [86]. Malformations, agenesis,
and hypoplasia of the cerebellum are associated with a
range of motor, linguistic, intellectual, and emotional
manifestations [61, 87–89]. Children with cerebellar
hypoplasia and nonprogressive cerebellar ataxia struggle with cognitive and emotional deficits conforming
to the description of the CCAS [90]. Indeed, autistic
features and speech delay, together with ataxia, hypotonia, and ocular signs correctly predict 86% of children with cerebellar hypoplasia [91].
Early damage to the cerebellar vermis is particularly relevant for the later emergence of neuropsychiatric phenomena. Vermal regions are among the
brain areas showing structural differences in autism
spectrum disorders [92–94]; pre-term infants with
cerebellar hemorrhage in the vermis have pervasive developmental disorder and diagnostic scores on
autism screening questionnaires [95]; the vermis has
been implicated in psychoneurotic symptoms following early childhood trauma, and in addictive behaviors that underlie substance abuse [96, 97]; and morphometric studies reveal reduced size of the posterior
vermis (lobules VIII through X) in attention-deficit
hyperactivity disorder [98–100].
The recognition that cerebellum appears to have
a trophic influence on the development of interconnected brain systems subserving higher-order function is of great interest and also has practical implications for diagnosis and management. Even at the
level of gross morphology, early damage to cerebellar
hemispheres results in volume loss in the contralateral cerebral hemisphere [101, 102], a phenomenon
40
that harks back to the early descriptions by Gudden
and von Monakow of sustaining projections [103], and
which appears to be clinically significant.
The cerebellar component of primary
psychiatric disease
Reports in the 1800s noted deviant and aberrant
behaviors in individuals with cerebellar anomalies.
Later clinical observers [70, 104] noted a relationship
between the cerebellum and personality, aggression,
and emotion, suggesting a casual link between cerebellar structural abnormalities and psychosis. The connections of the cerebellum with brain circuits implicated in psychiatric illness, and notably in schizophrenia, are particularly important in this regard [21,
105–109]. There is now a sizeable literature examining structural and functional imaging observations
in cerebellum in early infantile autism, schizophrenia, depression, bipolar disorder, panic and obsessivecompulsive disorder (for more recent reviews, see
[110–113]). These observations build upon early
reports suggesting that the vermis and fastigial nucleus
in humans and monkeys play a role in emotion, aggression, and psychosis [73, 104, 114–116]. The definition
of the five domains of neuropsychiatric impairments
arising from lesions of the cerebellum – attentional
control, emotional control, social skill set, autism spectrum disorders, and psychosis spectrum disorders,
provides a clinical framework within which to consider the role of the cerebellum in psychiatric illness.
The implications of a cerebellar role in the pathophysiology of mental illness are far-reaching, and include
new approaches to treatment.
Cognition in ataxic disorders
To develop an understanding of the cerebellar role in
non-motor function, it has been necessary to study
patients with lesions confined to the cerebellum. Disorders such as the hereditary spinocerebellar ataxias
(SCAs) are noteworthy for at least two opposing reasons. Whereas the neuropathology in some like SCA
5, SCA 6, and SCA 8 involves cerebellum exclusively
or overwhelmingly, in many others like SCA 1, SCA 2,
SCA 3, and SCA 17 the brainstem, basal ganglia, and
cerebral cortex are also affected. In these cases it is prudent to be cautious about ascribing to cerebellum functional impairments, including dementia, which may
arise in these patients from lesions of cerebral cortex,
Chapter 3: Cerebellum
cerebral white matter tracts, or other subcortical areas
including striatum and thalamus. Patients with SCA
17, for example, may present with cognitive decline
and psychiatric manifestations resembling the phenotype of Huntington’s disease [117]. From the perspective of clinical diagnosis and management, however, it
is important to recognize that patients with the inherited ataxias may have cognitive and/or neuropsychiatric impairments, and to treat these clinical symptoms
no matter the precise location of the pathology.
Mechanisms of the cerebellar
contribution to cognition and emotion
Earlier investigators regarded the cerebellum as the
“great modulator of neurologic function” [73, 114].
The fundamental mechanism by which the cerebellum
modulates movement, intellect, and emotion remains
a matter of debate [118–121]. Our dysmetria of
thought theory [4, 17, 34, 108, 109] is based upon two
complementary facts of anatomical organization. First,
cerebellar histology is essentially uniform throughout.
This enables a computation we have termed the
Universal Cerebellar Transform (UCT), allowing the
cerebellum to modulate behavior, acting as an oscillation dampener maintaining function in equilibrium
around a homeostatic baseline and smoothing out performance, modifying it according to context. It does
so automatically, and without conscious awareness.
Second, the specificity of the anatomical connections
between cerebellum and the spinal cord and brainstem, and the feedforward (cortico-ponto-cerebellar)
and feedback (cerebellar-thalamic-cortical) connections with sensorimotor as well as association areas of
the cerebral hemispheres facilitates functional topography within the cerebellum. Thus, in the same way
that the cerebellum regulates the rate, force, rhythm,
and accuracy in the motor domain, so does it regulate
the speed, capacity, consistency, and appropriateness
of cognitive and emotional processes. If the UCT is
the essential functional contribution that the cerebellum makes to the distributed neural system, then
by corollary, there should be a Universal Cerebellar
Impairment – namely, dysmetria (the Greek term
originally used to designate motor incoordination).
When the motor cerebellum is damaged the dysmetria
manifests as ataxia of extremity movements, eye
movements, speech and equilibrium. When the lesion
is in the cognitive cerebellum, the result is dysmetria
of thought (or, more recently, cognitive dysmetria
[122]), which manifests as the various components of
the CCAS. When the limbic (midline) cerebellum is
damaged, the dysmetria of emotional control manifests predominantly as neuropsychiatric impairments.
Studies employing the contemporary methods of
cognitive neuroscience are under way in a number of
centers to attempt to define whether the UCT indeed
exists, and the precise nature of the computation that
defines the transform.
Implications for therapy
Appreciation of the cerebellar contribution to higher
function has relevance for understanding the neural
bases of intellect and emotion and the role of cerebellum in neuropsychiatric diseases. Knowledge of the
characteristic features of the CCAS provides an opportunity for counseling and education, thus fulfilling
the patient’s “need-to-know-imperative.” It facilitates
therapeutic intervention by cognitive and behavioral
therapy for previously unrecognized emotional disturbances in the cerebellar patient population. It opens
the way to the use of available pharmacologic agents
that treat the presenting neurobehavioral and neuropsychiatric symptoms. There is already considerable
anecdotal experience from our Ataxia Unit and elsewhere that treatment of the neuropsychiatric symptoms resulting from cerebellar lesions can be effective,
regardless of which node in the distributed circuit is
disturbed. Prospective studies of the pharmacologic
treatment of the CCAS have not yet been performed.
The role of cerebellar–vestibular interactions in
dyslexia has been proposed previously [123–125], and
we have postulated that cross-model therapies may be
useful in disorders of higher function [126]. Some have
claimed success in the management of attention deficit
disorder and dyslexia by maneuvers that emphasize
cerebellar motor control [127] but this approach is
controversial and requires further empirical study.
Earlier investigators [73, 128] reported that
electrical stimulation of the cerebellum resulted in
successful treatment of behavioral disorders including
aggression and psychosis. We have suggested that
applying repetitive transcranial magnetic stimulation
(TMS) to the limbic cerebellum in the vermis may
improve psychiatric disorders such as schizophrenia
by upregulating cerebellar modulation of cerebrocerebellar circuits engaged in cognition and emotion [66,
112]. Our preliminary results using intermittent theta
burst stimulation in eight patients with refractory
41
Section I: Structural and Functional Neuroanatomy
schizophrenia provide support for this contention,
resulting in improvements in mood as well as working
memory, attention, and visual-spatial ability [129].
Conclusion
The recognition that the cerebellum is a key element in
the neural substrates of cognition is a relatively recent
development, and there are many outstanding questions still to be answered. Among the most interesting
is why some patients with cerebellar disorders appear
cognitively intact despite a prominent cerebellar motor
syndrome. A ready explanation may be that in these
patients with focal lesions the non-motor cerebellum is
spared. In patients with cerebellar neurodegenerative
disease, however, widespread degeneration throughout the cerebellum and a prominent cerebellar motor
syndrome may be accompanied by only subtle cognitive impairments. It remains to be shown whether this
is a result of such factors as time course and age of onset
of the illness, and variations in the neuronal elements
of the cerebrocerebellar circuit involved, or whether
this is simply a reflection of insufficiently sensitive testing in these cases. We have shown, for example, that
language deficits do occur in nondemented patients
with degeneration confined to the cerebellum [130].
These and other aspects of the relationship between
cerebellum and higher function need further investigation.
Acknowledgments
Supported in part by R01 MH67980, the Birmingham
Foundation, and the MINDLink Foundation. Valuable
assistance was provided by Jason MacMore.
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and Cognition. San Diego, CA: Academic Press; 1997,
pp. 637–47.
127. Reynolds D, Nicolson RI, Hambly H. Evaluation of an
exercise-based treatment for children with reading
difficulties. Dyslexia 2003;9(1):48–71; discussion 46–7.
128. Riklan M, Marisak I, Cooper IS. Psychological studies
of chronic cerebellar stimulation in man. In Cooper IS,
Riklan M, Snider RS, editors. The Cerebellum, Epilepsy
and Behavior. New York, NY: Plenum Press; 1974,
pp. 285–342.
129. Demirtas-Tatlidede A, Freitas C, Cromer J et al. Safety
and proof of principle study of cerebellar vermal theta
burst stimulation in refractory schizophrenia.
Schizophr Res. 2010;124:91–100.
130. Stoodley CJ, Schmahmann JD. The cerebellum and
language: evidence from patients with cerebellar
degeneration. Brain Lang. 2009;110(3):149–53.
Section I
Structural and Functional Neuroanatomy
Chapter
White matter
4
Christopher M. Filley
The white matter of the brain has recently assumed a
prominent role in the study of brain–behavior relationships. Although recognized by neuroanatomists
for centuries, and long understood by clinicians as crucial for elemental neurologic function, white matter
has come to be appreciated as a major contributor to
higher function by virtue of its key position within the
distributed neural networks that subserve all aspects of
cognition, emotion, and behavior [1–3]. Clinical and
basic neuroscience advances have offered new insights
into the structure and function of myelinated systems
that promise to enhance our understanding of the normal brain and the many disorders that may disturb its
operations and produce neurobehavioral dysfunction.
This chapter presents a summary of current knowledge
in this field and its implications for the future of Behavioral Neurology & Neuropsychiatry (BN&NP).
Historical background
White matter was first depicted as a neuroanatomic
structure by the great anatomist Andreas Vesalius
(1514–1564) in 1543 [1]. In his monumental work De
Humani Corporis Fabrica, a treatise that still stands as
a landmark in the history of science, Vesalius clearly
demarcated the white matter from the gray in drawings of the brain made from cadavers. In the spirit
of the Renaissance – the first era in which dissection
of the human body was fully explored – the drawings of this book display impressive artistic as well as
scientific merit, reflecting the influence of the great
painter Titian on Vesalius and his co-workers [1].
Progress on the function of white matter was slower
to come, but in the seventeenth century Thomas Willis
(1621–1675) proposed that white matter areas including the corpus callosum elaborated sensory signals
into perceptions destined to be stored in the cerebral cortex [1]. Anticipating modern systems neuroscience, Franz Joseph Gall (1758–1828), who was a
highly competent neuroanatomist despite his unfortunate forays into phrenology, established in the early
1800s that white matter was comprised of fascicles that
connected cortical gray matter areas devoted to mental activity [1]. Later in the nineteenth century, the
neurologist Jean-Martin Charcot (1825–1893) gained
well-deserved fame for advancing the understanding
of white matter and its functions through the study
of multiple sclerosis (MS) and similar diseases [1].
In the mid-twentieth century, Norman Geschwind
(1926–1984) emphasized the importance of white matter tracts in behavioral neurology in a classic treatise
on disconnection syndromes that inspired a generation of clinicians and investigators [4, 5]. Geschwind’s
Harvard Medical School associate M-Marsel Mesulam then advanced the influential notion of distributed
neural networks by which cognitive operations are
organized, leading to the concept that higher functions are subserved by gray and white matter structures
integrated within widespread regions of the brain [6].
Today, as the twenty-first century begins, the understanding of white matter structure and function is
rapidly advancing as increasingly sophisticated methods of study build on the steady accomplishments of
the past [3, 7].
Neuroanatomy
The anatomy of white matter is fundamental to understanding its role in brain–behavior relationships, and
the bridging of structure and function is the principal goal of current investigations. Despite the bewildering array of fiber tracts coursing throughout the
Behavioral Neurology & Neuropsychiatry, eds. David B. Arciniegas, C. Alan Anderson, and Christopher M. Filley.
C Cambridge University Press 2013.
Published by Cambridge University Press. 47
Section I: Structural and Functional Neuroanatomy
brain, progress is being made in sorting out the location and connectivity of these myelinated systems, as
well as their functional affiliations.
White matter makes up nearly one-half the brain
volume [1], and it has been estimated that 135,000 km
of myelinated fibers can be found interconnecting the
roughly 100 billion neurons of the brain whose cell
bodies reside in cortical and subcortical gray matter
[8]. Organized in tracts, fasciculi, funiculi, lemnisci,
peduncles, and bundles, white matter travels within
and between the cerebral hemispheres and links these
regions with the brainstem, cerebellum, and spinal
cord [9]. Convenient distinctions between the projection, commissural, and association tracts are familiar
from neuroanatomy textbooks, and it is recognized
that the latter two categories are most important for
the mediation of higher functions [9]. However, with
few exceptions, the role of individual tracts is not well
characterized in BN&NP, and even the identification
of most tracts is impossible in routine clinical practice. Radiologists as well as clinicians tend to consider
the cerebral white matter as an undifferentiated whole
because the homogeneity of white matter on clinical
imaging prohibits visualization of all but the largest
tracts. Descriptive terms such the centrum semiovale
and the corona radiata are used for clinical purposes,
but reflect limited understanding of the tracts lying
within the amorphous areas implied by these terms.
The microstructure of brain white matter plays a
complementary, and equally important, role in the
organization of cognition and emotion. The defining
neuroanatomical feature is myelin, the fatty insulation
that invests most axons in the brain and dramatically
increases neuronal conduction velocity [10]. Myelin,
a complex mixture of about 70% lipid and 30% protein, encircles axons in a circumferential manner after
being laid down by oligodendrocytes, glial cells in the
brain responsible for myelination [11]. The white hue
of the brain sectioned at autopsy in fact derives from
myelin. At the neuronal level, myelin forms a concentric sheath along the length of the axon, leaving bare
small unmyelinated segments called nodes of Ranvier [10]. These nodes permit saltatory conduction, by
which the action potential “jumps” from one node to
the next as it rapidly traverses the length of the axon to
the terminal dendrites and synapses [10].
Traditional teaching on the anatomy of white matter systems relevant to brain–behavior relationships
is founded on the knowledge of tracts established
with gross brain dissection, myelin-staining, and
48
degeneration techniques developed in the centuries
after the seminal observations of Vesalius [12]. A
standard current formulation is that of Nolte [9], in
which tracts within the association, commissural, and
projection systems are distinguished (Table 4.1). Best
understood is the corpus callosum, by far the largest
single tract in the brain and easily recognized as the
primary interhemispheric connection. The association tracts are divided into the short association
fibers, also known as uncinate or U fibers, linking
adjacent cortical gyri, and the long association tracts
that connect intrahemispheric regions: the superior
occipitofrontal fasciculus, the inferior occipitofrontal
fasciculus, the arcuate fasciculus (superior longitudinal fasciculus), the cingulum bundle, and the uncinate
fasciculus [9].
While this classification can still be productively
used, advances in neuroimaging and experimental
neuroanatomy are revising our understanding of the
complexity of white matter systems. The burgeoning
field of tractography with the use of diffusion tensor imaging (DTI) [13] is moving swiftly to clarify
and expand knowledge of white matter tracts, and
recent investigations of the rhesus monkey brain using
autoradiography [12, 14] have introduced markedly
different conceptualizations of previously accepted
classifications. Table 4.1 lists three classifications of
cerebral white matter systems based on the knowledge that is rapidly accumulating from these advances.
Much uncertainty remains, as different tracts are
apparent from the various methods employed, and the
correspondence between monkey and human white
matter systems is not fully established. Based on
detailed studies of the rhesus monkey brain, for example, Schmahmann and colleagues have raised the possibility that the arcuate fasciculus may not in fact be
related to language, potentially overturning neurologic
teaching of the past century [12, 14]. As the field progresses, it can be anticipated that controversies such as
this will be addressed and increasing consensus gained
on the anatomy of white matter tracts by the combined
application of complementary techniques. In parallel
with this process, the functional affiliations of these
tracts are likely to become more evident as well.
Neurophysiology
The major function of white matter can be conceived
as the transfer of information within the nervous system, in contrast to the processing of information that
Chapter 4: White matter
Table 4.1. Evolving formulations of cerebral white matter pathways. The white matter pathways identified by anatomical examination of
the human brain (gross dissection, myelin staining of human brain, lesion degeneration) as described in [9] are listed in the column on the
left; those identified with diffusion tensor imaging of human brain, as described by [13], are listed in the center column; and those
identified with autoradiography and diffusion spectrum imaging of rhesus monkey brain [12, 14] are listed in the column on the right.
These pathways are organized in the table as association, commissural, and projection types.
Anatomical examination of
human brain
Diffusion tensor imaging of human
brain
Autoradiography and diffusion spectrum
imaging of rhesus monkey brain
Short association (U) fibers
Short association (U) fibers
Local (U) fiber system
Neighborhood fiber system
Arcuate fasciculus
Superior longitudinal (arcuate) fasciculus
Arcuate fasciculus
Superior longitudinal fasciculus 1
Superior longitudinal fasciculus 2
Superior longitudinal fasciculus 3
Middle longitudinal fasciculus
Extreme capsule
Association pathways
Superior occipitofrontal fasciculus Superior fronto-occipital (subcallosal) fasciculus
Fronto-occipital fasciculus
Inferior occipitofrontal fasciculus
Inferior fronto-occipital fasciculus
Inferior longitudinal fasciculus
Inferior longitudinal fasciculus
Uncinate fasciculus
Cingulum
Uncinate fasciculus
Cingulum
Uncinate fasciculus
Cingulum bundle
Striatal pathways
External capsule
Subcallosal fasciculus of Muratoff (Muratoff
bundle)
Corpus callosum
Corpus callosum
Corpus callosum
Anterior commissure
Anterior commissure
Anterior commissure
Hippocampal commissure
Hippocampal commissure
Habenular commissure
Posterior commissure
Tectal commissure
Hippocampal commissure
Internal capsule
Internal capsule
Internal capsule
Optic radiation
Optic radiation
Optic radiation (within the sagittal stratum)
Thalamocortical radiation
Acoustic radiation
Fornix
Thalamic peduncles
Commissural pathways
Projection pathways
is the responsibility of gray matter [15]. The myelination of white matter enables the rapid transfer of information within distributed neuronal networks that subserve all higher functions of the brain [1–3, 15]. By
virtue of the myelin sheath and critically placed nodes
of Ranvier permitting saltatory conduction, myelinated fibers conduct impulses up to 100 times faster
that unmyelinated fibers, vastly increasing the speed
of information transfer. It is not surprising, therefore,
that one of the most salient, albeit non-specific, neurobehavioral features of white matter disorders is cognitive slowing [1, 2, 15]. Myelination also enhances
the timing and synchronization of neuronal arrays
that are thus enabled to engage in highly integrative
operations such as executive function, sustained attention, and working memory. Myelinated systems confer efficiency to the operations of neural networks so
that the cognitive processing within cortical and subcortical gray matter structures can be optimized. In
clinical practice, neurophysiological assessment using
short latency evoked potentials has long been used for
quantitating the integrity of primary sensory tracts,
but the more challenging study of higher function
has been limited to the research arena, where longer
latency potentials such as the P50 and P300 have been
employed to investigate cognitive systems [1].
49
Section I: Structural and Functional Neuroanatomy
White matter makes another unique contribution
to function of large-scale distributed neural networks.
The faster electrical conduction enabled by myelinated
systems appears to have evolutionary importance.
Myelin, a recent development in phylogeny, is almost
exclusively confined to the nervous systems of vertebrate species [10]. Recent findings indicate a selective
increase in prefrontal white matter volume in humans
compared with non-human primates, whereas gray
matter volume is not significantly different [16]. These
observations suggest that the myelin within white matter has a special role not only in enhancing neuronal conduction velocity within the brain as a whole,
but specifically within frontal networks subserving the
most highly evolved human behaviors.
Development and aging
While the expansion and then reduction of cortical
gray matter has long been assumed as crucial in normal cognitive development and aging, there is increasing recent evidence for a role of white matter in these
processes. Since the early twentieth century, white
matter systems in the forebrain have been known to
continue developing into adolescence, with myelination generally regarded as an index of cerebral maturation [1]. More recent data suggest that, whereas
gray matter development peaks at age four, myelination continues well into midlife [17] and even the sixth
decade [18]. The implications of this protracted developmental course are notable, as it may be that cerebral
myelination plays an essential role in normal cognitive
and behavioral maturation, and conversely, white matter disorders during the multi-decade process of development may exert a profound effect on the transition
to adulthood [1].
In the later decades of life, conversely, considerable
support exists for a decline of white matter integrity
[1]. The contribution of cortical gray matter loss to
cognitive aging may have been overestimated in the
past, as estimates of cortical neuronal loss were likely
excessive, and in fact loss of white matter volume may
actually be more significant [1, 17, 19]. Thus, whereas
the dementia of Alzheimer’s disease (AD) features cortical volume loss in medial temporal and other areas,
normal aging is characterized by prominent loss of
white matter volume, especially in anterior cerebral
regions [20, 21]. These structural differences have clinical correlates that implicate the oft-noted differences
between the “cortical” cognitive features of AD and the
50
contrasting cognitive changes of normal aging: in AD,
the familiar syndromes of amnesia, aphasia, apraxia,
and agnosia result from widespread cortical involvement, whereas in the latter, slowed cognition, impaired
vigilance, and executive dysfunction may represent the
effects of progressive white matter decline most evident in the frontal lobes [1, 20–22].
Neuroimaging
The development of magnetic resonance imaging
(MRI) in the early 1980s has proven to be a pivotal
event in the understanding of white matter and its
impact on higher brain function [1]. As a clinical tool,
MRI offered a major advance over computed tomography; not only did MRI improve the visualization of
white matter in known myelin diseases such as MS,
it enabled the identification of previously unrecognized white matter disorders such as the syndrome of
dementia, ataxia, and other neurologic deficits in longterm solvent abusers who develop toluene leukoencephalopathy (TL) [1, 2]. Perhaps the most familiar
discovery made possible by MRI was the unexpectedly high prevalence of cerebral white matter hyperintensities (Figure 4.1), seen to some degree in approximately 95% of community-dwelling older people [23].
The origin and consequences of these abnormalities
remain incompletely understood, but many believe
they represent ischemic white matter damage, and that
Binswanger’s disease (BD) or subcortical ischemic vascular dementia (SIVD) can result if the lesion burden
becomes sufficiently severe [1]. White matter hyperintensities have thus stimulated much interest in the possibility that millions of people have subtle brain lesions
that may potentially be addressed by medical intervention before any clinical manifestations appear.
As MRI grew more sophisticated, additional techniques were introduced to improve still further the
neuroimaging of white matter tracts. One such technique is magnetic resonance spectroscopy (MRS),
which enables measurement of the chemical composition of white matter to assess the integrity of axons
and myelin [1]. MRS has the potential to be “noninvasive biopsy” of white matter that may significantly improve diagnosis since it can detect changes
in the so-called “normal-appearing white matter” [1].
Another method attracting much attention is DTI,
which allows the characterization of individual tracts –
tractography – with unprecedented detail (Figure 4.2).
Advances in understanding the connectivity of white
Chapter 4: White matter
Figure 4.2. Diffusion tensor image showing the arcuate fasciculus.
Note the additional fascicle extending to Geschwind’s territory in
the inferior parietal cortex, not recognized by traditional
neuroanatomic investigation. Reproduced from Catani M, Jones DK,
Ffytche DH. Perisylvian language networks of the human brain. Ann
Neurol. 2005;57(1):8–16, with permission from John Wiley & Sons,
Inc. This figure is presented in color in the color plate section.
Figure 4.1. Brain MRI scan (FLAIR sequence) showing
periventricular white matter hyperintensities in an older man with
hypertension and cognitive impairment.
matter appear most promising with DTI, which brings
a new level of precision to the study of disconnection
syndromes in a host of clinical disorders [24]. Combined with functional neuroimaging techniques such
as positron emission tomography (PET) and functional MRI (fMRI), DTI promises to help define the
distributed neural networks subserving higher function by identifying the white matter components of
these networks that interact with cortical and subcortical gray matter structures [15].
Disorders of white matter
Well over 100 white matter disorders of the brain have
been described by neurologists, neuropathologists,
and most recently, neuroradiologists [1]. Many of
these disorders are classic neurologic diseases such as
MS, but some, such as TL, have only become apparent
with the routine application of MRI to clinical populations. Remarkably, despite the traditional emphasis on
non-cognitive aspects of white matter disorders such
as impaired vision, weakness, spasticity, ataxia, gait
disorder, and sensory loss, close reading of clinical
reports describing patients with cerebral white matter
disorders reveals evidence of cognitive or emotional
dysfunction in every one of these afflictions [1]. Ten
categories of white matter disorder can be considered:
genetic, demyelinative, infectious, inflammatory,
toxic, metabolic, vascular, traumatic, neoplastic, and
hydrocephalic [1]. Table 4.2 provides a listing of
entities within these categories; additional entries
are likely as knowledge accumulates. A brief consideration of representative disorders will serve to
highlight the diversity of white matter pathology, and
standard neurology textbooks can be consulted for
more information.
Metachromatic leukodystrophy (MLD), an autosomal recessive leukodystrophy that typically causes a
devastating and rapidly fatal illness in infants or, in
older children and adults, psychosis or dementia in
association with extensive cerebral dysmyelination, is
the prototype genetic white matter disorder [25]. MS
is the most familiar demyelinative disorder, the neurobehavioral effects of which have been known since
the time of Charcot but are now better appreciated as
correlating with cerebral plaque burden and associated
cerebral atrophy [26]. Among the infectious diseases,
the acquired immumodeficiency syndrome dementia complex involves prominent leukoencephalopathy
as well as subcortical gray matter involvement [27].
Systemic lupus erythematosus illustrates the growing
recognition of the impact of inflammatory white matter disease on cognition [28]. TL is the best example of white matter neurotoxicity producing impaired
51
Section I: Structural and Functional Neuroanatomy
Table 4.2. Cerebral white matter disorders.
52
Genetic
Leukodystrophies (e.g., metachromatic
leukodystrophy)
Aminoacidurias (e.g., phenylketonuria)
Phakomatoses (e.g., neurofibromatosis)
Mucopolysaccharidoses
Muscular dystrophy
Callosal agenesis
Demyelinative
Multiple sclerosis
Acute disseminated encephalomyelitis
Acute hemorrhagic encephalomyelitis
Schilder’s disease
Marburg’s disease
Balo’s concentric sclerosis
Infectious
HIV-associated dementia
Progressive multifocal leukoencephalopathy
Subacute sclerosing panencephalitis
Progressive rubella panencephalitis
Varicella zoster encephalitis
Cytomegalovirus encephalitis
Lyme encephalopathy
Inflammatory
Systemic lupus erythematosus
Behcet’s disease
Sjögren’s syndrome
Wegener’s granulomatosis
Temporal arteritis
Polyarteritis nodosa
Scleroderma
Isolated angiitis of the central nervous system
Sarcoidosis
Toxic
Cranial irradiation
Therapeutic drugs
Drugs of abuse (e.g., toluene)
Environmental toxins (e.g., carbon monoxide)
Metabolic
Vitamin B12 (cobalamin) deficiency
Folate deficiency
Central and/or extra-pontine myelinolysis
Hypoxia
Hypertensive encephalopathy
Eclampsia
High altitude cerebral edema
Vascular
Binswanger’s disease
CADASIL (cerebral autosomal dominant
arteriopathy with subcortical infarcts and
leukoencephalopathy)
Leukoaraiosis
Cerebral amyloid angiopathy
White matter disease of prematurity
Migraine
Traumatic
Traumatic brain injury
Shaken baby syndrome
Corpus callosotomy
Neoplastic
Gliomatosis cerebri
Diffusely infiltrative gliomas
Lymphomatosis cerebri
Focal white matter tumors
Hydrocephalic
Early hydrocephalus
Normal pressure hydrocephalus
cognition [29], and one of the most convincing examples of white matter dementia (see below). Among
the metabolic disorders, vitamin B12 (cobalamin) deficiency has been documented to produce reversible
dementia related to white matter involvement [30].
White matter ischemia and infarcts lead to BD, the
form of SIVD in which cerebral white matter damage gradually erodes cognitive function [31]; the vascular disease cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy
(CADASIL) is similar neuropathologically and clinically [32]. Among the many neuropathological insults
of traumatic brain injury (TBI), diffuse axonal injury
(DAI) within the white matter is arguably the most
common and devastating [33]. Neoplastic white matter results from the propensity of gliomas to originate
and spread in myelinated regions of the brain, and
gliomatosis cerebri vividly illustrates these features
[34]. Finally, hydrocephalus, either in children or in
adults, exerts its most prominent effects on white matter; in older adults, dementia as a result of normal pressure hydrocephalus (NPH) is a common sequel [35].
Many other examples can be found, including diseases,
injuries, and intoxications occurring at all ages and
presenting in any medical or surgical setting [1].
Neurobehavioral syndromes
While the diversity of white matter disorders is surely
impressive, common clinical patterns of cognitive and
emotional dysfunction can nevertheless be discerned
that cut across all etiological and neuropathological categories. From a comprehensive consideration
of these unifying phenomena, it is possible to establish a coherent classification of neurobehavioral syndromes – a behavioral neurology of white matter [1–3].
Three major groups of syndromes emerge that capture
the variety of cognitive and emotional impairments
related to cerebral white matter disorders: focal neurobehavioral syndromes, white matter dementia, and
neuropsychiatric syndromes [1–3].
Focal syndromes
Focal neurobehavioral syndromes are well known to
subspecialists in BN&NP from the classic literature
beginning in late nineteenth century Europe that
produced the first modern descriptions of aphasia,
apraxia, agnosia, and related syndromes [1]. In 1965,
Geschwind reintroduced these syndromes in the
context of cerebral disconnection and revitalized
Chapter 4: White matter
Table 4.3. Focal neurobehavioral syndromes.
Table 4.4. The profile of white matter dementia.
Amnesia
Cognitive slowing
Aphasia
Broca’s
Wernicke’s
Conduction
Global
Transcortical motor
Transcortical sensory
Anomic
Mixed transcortical
Executive dysfunction
Apraxia
Ideomotor
Callosal
Normal extrapyramidal function
Alexia
Pure alexia
Alexia with agraphia
Developmental dyslexia
Gerstmann’s syndrome
Agnosia
Visual
Auditory
Neglect
Visuospatial dysfunction
Akinetic mutism
Executive dysfunction
Callosal disconnection
behavioral neurology after decades of relative neglect
[4, 5]. In some cases, these disconnections involve
lesions in gray matter regions, but most imply white
matter pathology, and examples of stroke, neoplasia, and demyelinative plaques interrupting neural
networks to produce focal syndromes constitute a
growing literature (Table 4.3). Today these syndromes
remain foundational to behavioral neurology and
continue to attract interest with the evolving neuroimaging that is further clarifying the underlying
neuroanatomy of cognition [13].
White matter dementia
White matter dementia is a term introduced in 1988
to call attention to the cognitive loss that can occur in
patients with white matter disorders [36]. Examples
such as MS [37] and TL [38] leave no doubt that
cognitive impairment, often reaching the level of
dementia, can occur with widespread white matter
involvement. In individuals with early white matter
pathology, symptoms are relatively mild and nonspecific – forgetfulness, lassitude, personality changes,
Sustained attention (vigilance) deficit
Memory retrieval impairment
Visuospatial dysfunction
Psychiatric disturbance
Normal language
Normal procedural memory
and the like – and at the most severe end of the
spectrum, the profound disturbances of the persistent
vegetative and minimally conscious states can result
from white matter destruction. Most patients fall
between these extremes, where a need for defining
the neurobehavioral profile of white matter dementia
has been apparent. Whereas caution is advisable when
attempting to compile a cognitive profile of white
matter dementia, there are striking cognitive similarities among the disorders that may cause white matter
dementia [1], and evidence suggests that white matter
dementia can be differentiated phenomenologically
from both cortical and subcortical dementia.
Table 4.4 summarizes neurobehavioral features
that emerge from preliminary compilation of the
deficits encountered in white matter dementia, irrespective of the specific neuropathology involved [1, 15,
39, 40]. This profile, which should be regarded as a
common but not invariant description, is most useful in the early stages of white matter dementia; clinical differentiation of various dementias becomes more
difficult as neuropathology of any type advances and
erases subtle distinctions based on relative involvement or sparing of critical cerebral areas. Table 4.4 is
based on an initial consideration of subcortical (more
recently frontal-subcortical) dementia, and like subcortical dementia, white matter dementia involves cognitive slowing, executive dysfunction, sustained attention (vigilance) deficits, memory retrieval impairment,
visuospatial dysfunction, and psychiatric disturbance
while memory encoding and language are spared [1,
15, 39]. Unlike subcortical dementia, however, white
matter dementia features normal extrapyramidal function and, importantly, procedural memory [1, 15,
40]. Both these dementia syndromes are to be distinguished from cortical dementia, in which amnesia (memory encoding deficit), aphasia, apraxia, and
53
Section I: Structural and Functional Neuroanatomy
agnosia are typical [1, 15, 39, 40]. More work is
needed on refining these distinctions, but they point
the way toward better recognition of the neurobehavioral deficits of patients whose white matter disorders
might be identified and treated before dementia worsens. Milder forms of this syndrome may even serve
to call attention to unrecognized cerebral white matter disease that has not yet caused dementia, as can
be seen in SLE patients with cognitive impairment but
normal conventional MRI who have MRS abnormalities consistent with early myelinopathy [28]. Indeed,
one of the most useful aspects of pursuing such diagnostic distinctions is the opportunity to identify cognitive loss from white matter disorders when the potential for reversibility is at its highest.
Further support for the concept of white matter
dementia comes from both clinical and experimental
laboratory studies. Mendez and colleagues reviewed 28
patients with white matter disorders causing dementia and found a neuropsychological profile similar
to that depicted in Table 4.4 [41]. Studies of braininjured monkeys demonstrated DAI identical to that
seen in humans after TBI, and the duration of coma
and neurologic outcome were directly proportional to
the degree of DAI [42]. Using a vascular disease model,
Shibata and colleagues found that mice with bilateral
carotid stenosis for 30 days had white matter ischemia
sparing the hippocampus and cortices, and developed
selective impairment in working memory [43].
The concept of white matter dysfunction producing a unique dementia syndrome has merit as a clinical
model and a framework for brain–behavior research.
However, overlap of white and gray matter pathology
is often observed neuropathologically and complicates
analysis. A particularly illustrative example of this
complexity can be seen with AD, in which white matter is implicated in several ways. While indisputably a
cortical neurodegenerative disorder, the neuropathology of AD often includes white matter changes related
to three phenomena – cerebral ischemia [31], cerebral amyloid angiopathy [44], and Wallerian degeneration [45]. An intriguing hypothesis has also been
advanced proposing that oligodendrocyte injury and
myelin breakdown are core pathogenetic events in AD
[46]. While certain disorders can be usefully conceptualized as white matter disorders – TL is an excellent
example – in many others a commingling of gray and
white matter pathology cannot be avoided and poses a
major challenge for the study of higher function and
its dissolution. Such complexity is in fact typical of
54
Table 4.5. Neuropsychiatric syndromes associated with white
matter abnormalities.
Psychiatric
syndromes in white Psychiatric disorders with
matter disorders
white matter abnormalities
Depression
Schizophrenia
Mania
Depression
Psychosis
Bipolar disorder
Pathologic affect
Attention-deficit hyperactivity disorder
Euphoria
Autism
Fatigue
Aggression
brain function, and while humbling, should encourage rather than deter a comprehensive effort to further
explicate brain–behavior relationships.
Neuropsychiatric syndromes
Neuropsychiatric syndromes associated with white
matter disorders prove to be the most difficult
to describe because many uncertainties linger with
regard to correlating psychiatric symptoms with any
neuropathology, whether in white or gray matter.
However, the frequent complaints of personality
change, depression, inattention, fatigue, and similar
non-specific symptoms heard in clinical settings often
herald the onset of white matter disorders that will
later produce more disabling deficits [1, 47]. From
a nosologic perspective, it is useful to consider (1)
the psychiatric syndromes that arise in patients with
known white matter disorders, and (2) the evidence for
white matter involvement in known psychiatric disorders [47]. To summarize a large and diverse literature,
the white matter disorders have been noted to produce
a variety of syndromes with prominent psychiatric features, whereas many established psychiatric disorders
have been theorized to have a basis in white matter
pathology [1, 25, 47].
Table 4.5 presents a sampling of entities within
each of these categories, and many others are likely
to be added to these lists. A recurring theme is that
neuropsychiatric dysfunction in white matter disorders may be produced by microstructural injury that is
more subtle than the neurologic lesions leading to focal
neurobehavioral syndromes and dementia [1, 25, 47,
48]. By implication, neuropsychiatric dysfunction may
reflect primary circuitry disturbances and “higherorder” disconnection syndromes [4, 5, 47, 48]. However, it must be acknowledged that these notions are
Chapter 4: White matter
largely speculative, and much work will be necessary
to establish the precise contribution of white matter
dysfunction or damage in the pathogenesis of many
neuropsychiatric syndromes. At the same time, recognition of the possibility that study of the white matter
may offer clues to understanding baffling diseases such
as schizophrenia may be central to major advances that
lie ahead.
Treatment and prognosis
The treatment of cerebral white matter disorders
depends on the specific problem disclosed by the diagnostic search. Therapeutic options are well covered in
standard textbooks of neurology, and may be (1) preventive, as in the case of reduction of cerebrovascular
risk, prevention of TBI, or avoidance of leukotoxins;
(2) pharmacologic, as with MS, various infectious and
inflammatory diseases, metabolic disorders, or stroke;
or (3) neurosurgical, as in neoplasia, NPH, and some
cases of cerebrovascular and genetic disease. The range
of medical and surgical interventions varies greatly,
reflecting the diverse neuropathology of these disorders, but the goal from the perspective of BN&NP is
the alleviation of suffering related to the often disabling
cognitive and emotional effects of these disorders.
In most cases, complete recovery cannot be
expected, although with such a range of neuropathology, this generalization has exceptions. Symptomatic
treatment, however, can often be provided with
salutary effect. Non-pharmacologic approaches may
be invaluable, offering patients much-needed explanation of their illness, counseling about future prospects,
and specific psychotherapy as indicated. Antidepressant, antipsychotic, mood-stabilizing, anxiolytic,
cholinesterase-inhibiting, stimulant, corticosteroid,
immunomodulatory, antiepileptic, and anti-fatigue
medications may all have a role in these patients.
Caution is in order, however, since many patients are
particularly vulnerable to adverse effects of treatment
because of advanced age and concurrent medical
problems. It is also well to keep in mind that few
adequately controlled studies of the efficacy or safety
of these drugs are available to guide treatment in this
context.
The prognosis of white matter disorders is as
varied as the etiologies of these conditions. In some
patients, a cure is possible, as in B12 deficiency that
is recognized early and treated promptly. In many
others, such as those with MS, lingering symptoms
will typically be expected. In still others, including
many with TBI, lifelong disability is inevitable. As a
general rule, however, the prognosis for white matter
disorders is more favorable than that of gray matter
disorders such as AD, the best-recognized dementia
that serves as a useful contrast to the white matter
disorders. As the inexorable neuronal loss of AD does
not necessarily occur in many white matter disorders,
they are often preventable, partially reversible, or even
curable. In addition, many white matter disorders
only involve myelin loss or injury while sparing the
axon – this phenomenon leaves intact the cellular
apparatus supporting remyelination and preserves
some potential for spontaneous recovery [1]. When
the axons are damaged, the prognosis clearly worsens
[49], but it has long been known in MS, for example,
that remyelination can occur [1]. Even the renewal
of axons has been proposed as a possible mechanism
of recovery. Intriguing recent DTI data in post-TBI
minimally conscious patients have suggested axonal
regrowth in white matter that correlates with clinical
improvement [50]. Another exciting possibility is
the application of evolving stem cell techniques that
propose the use of oligodendrocyte progenitor cells as
precursors to remyelination [51].
Finally, the concept of plasticity has recently come
to be applied to the white matter. The concept of
activity-dependent myelination has been shown in
several animal models, and it is likely that electrical activity within axons enhances the number of
both oligodendrocytes and myelinated axons [52]. In
humans, data consistent with this idea have been presented in piano players who developed increased white
matter organization in the pyramidal tract that was
proportional to the number of hours spent practicing [53]. The notion that “experience changes white
matter” has far-reaching implications both for the
development and maintenance of normal white matter structures and for the rehabilitation of patients with
white matter disorders [52].
Conclusion
White matter has become a crucial component of the
study of higher brain function. The disorders of white
matter that present to the subspecialist in BN&NP
are common, often diagnostically difficult, and still
more therapeutically challenging. These conditions are
often unrecognized or underappreciated, leaving many
patients undiagnosed and untreated. White matter
55
Section I: Structural and Functional Neuroanatomy
dementia merits particular attention as a frequent and
problematic syndrome for large numbers of patients
at all ages. Treatment of white matter disorders and
their neurobehavioral syndromes is not well understood, but prognosis may be favorable in many cases,
especially when axons are spared and myelin can
be restored. Despite these intriguing possibilities, the
understanding of the behavioral neurology of white
matter is in its infancy, reflecting a long-standing tradition of studying cortical and subcortical gray matter
as the most prominent neurobehavioral substrate.
From a theoretical perspective, white matter and
its disorders offer an extraordinary opportunity to
expand our appreciation of brain–behavior relationships by combining the lesion method of behavioral neurology with increasingly impressive neuroanatomical techniques, neuroimaging methods, and
neuropathological examination to establish the neuroanatomical basis of white matter syndromes. The
study of white matter is a natural outgrowth of prior
investigations highlighting the importance of brain
connectivity, and promises to fill an enormous gap in
our understanding of the brain and its many complex
operations. Allied with the study of microconnectivity in the cerebral cortex and subcortical gray matter,
a focus on the macroconnectivity provided by white
matter tracts promises to expand our understanding
of the distributed neural networks that subserve all
aspects of cognition, emotion, and behavior.
The modern appreciation of white matter as fundamental to BN&NP began with Geschwind’s ideas
on disconnection in 1965 [4, 5], but uncertainty persisted then about the role of myelinated tracts in higher
function, and lingers to some extent today [54]. However, white matter is steadily receiving increased neuroscientific attention. In 2009, for example, the Human
Connectome Project was launched by the US National
Institutes of Health to compile functional (i.e., fMRI)
and structural (i.e., DTI) imaging from hundreds of
participants into a circuitry map of the human brain
[55, 56]. The intent is to develop a large, publically
accessible database derived from normal and abnormal brains, with the goals of improving knowledge of
brain–behavior relationships and exploring network
causes of brain disorders such as AD, schizophrenia,
and autism. This project offers more evidence that the
time has come to modify the familiar but overly narrow “corticocentric” approach to higher function [57]
by focusing on the connectome as much as the synaptome [58, 59].
56
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Section I
Structural and Functional Neuroanatomy
Chapter
Frontal-subcortical circuits
5
David G. Lichter
A series of parallel segregated frontal-subcortical circuits (FSCs) connect specific regions of the frontal cortex (including paralimbic frontal areas) to the striatum, the globus pallidus (GP) and substantia nigra
(SN), and the thalamus [1–3]. Together, these constitute an important effector mechanism that allows
the individual to interact adaptively with the environment. This chapter reviews the neuroanatomy and
neurochemistry of FSCs, and outlines the signature
syndromes of FSC circuit dysfunction. The similarity of cognitive and behavioral changes that accompany cortical and subcortical lesions is discussed
within this framework. Select neuropsychiatric disorders that appear linked to FSC dysfunction are then
presented. Finally, we explore the manner in which
these insights may better inform clinical management
of patients with relevant neuropsychological, behavioral, and neuropsychiatric disorders.
Frontostriatal systems
The frontal lobe may be viewed as comprising two
distinct anatomical/functional systems, which reflect
its dual developmental origin [4]. The sequential
processing of sensory, spatially related, and motivational information is mediated by a dorsal system,
which comprises dorsolateral and medial portions of
the frontal lobes, interconnected with the posterior
parietal lobe and cingulate gyrus. Emotional tone is
mediated by a second, ventral system, which involves
the orbital surface of the frontal lobes. The architectonic organization of the prefrontal cortex [5, 6] is
reflected in the pattern of prefrontostriatal projections
[7]. Thus, the dorsal architectonic trend, which originates in the rostral cingulate gyrus and culminates in
the dorsal portion of the frontal eye field, maps onto
the dorsal caudate nucleus. In contrast, the ventral
architectonic trend, which originates in the ventral
orbital region and extends to the ventral portion of
the frontal eye field, maps onto the ventro-medial
portion of the caudate and adjacent portion of nucleus
accumbens (NAc). Closely connected cortical areas
send converging projections into the striatum [8, 9].
Early experimental observations supported a
role for discrete dorsal and ventral frontostriatal
systems in cognition and behavior. Thus, lesions or
electrical stimulation of the dorsolateral prefrontal
(DLPF) cortex or of the anterodorsal head of the
caudate nucleus, to which this region projects,
produce deficits in delayed response and delayed
alternation tasks [10, 11]. In contrast, lesions or
electrical stimulation of either the orbitofrontal (OF)
cortex or of the ventrolateral head of the caudate
result in deficits in object alternation or response
inhibition paradigms [12]. Disruption to discrete
cognitive processes following striatal injury can be
interpreted as the “downstream” interruption of
anatomically congruent outflow from the frontal
cortex [12–14].
Frontal-subcortical circuits:
shared anatomy
Basic circuit structure
The following principal circuits may now be recognized: a motor circuit that originates in the supplementary motor area (SMA), an oculomotor circuit
originating in the frontal eye fields, and three primary
circuits/circuit networks mediating cognitive, behavioral, and affective functions [1–3]. Of these, the DLPF
Behavioral Neurology & Neuropsychiatry, eds. David B. Arciniegas, C. Alan Anderson, and Christopher M. Filley.
C Cambridge University Press 2013.
Published by Cambridge University Press. 59
Section I: Structural and Functional Neuroanatomy
Frontal cortex
Figure 5.1. The general structure shared by
all frontal-subcortical circuits (direct
connections).
Striatum
Globus pallidus/
substantia nigra
Thalamus
circuit mediates “executive functions,” i.e., the organization of information to facilitate a response. The lateral OF (LOF) circuit is involved with integration of
limbic and emotional information into goal-directed
and contextually appropriate behavioral responses.
Finally, the rostromedial limbic network consists of the
medial OF (MOF) circuit, which facilitates integration
of information pertaining to emotions, and the linked
anterior cingulate (AC) circuitry. The AC network is
involved primarily in motivational mechanisms but
also, through the activity of its subgenual portion, in
mood regulation.
All circuits share a basic anatomy, with an origin in the frontal lobes and sequential projections
to the striatum (caudate, putamen, or ventral striatum), GP/SN, and then to specific thalamic nuclei,
with a final link back to the frontal lobe (Figure 5.1).
The circuits have two pathways: (1) a direct pathway,
featuring a monosynaptic link between the striatum
and GP interna (GPi)/SN pars reticulata (SNr) complex, and (2) an indirect pathway that projects from
striatum to GP externa (GPe), linking to GPi/SNr
via the subthalamic nucleus [3] (Figure 5.2). Both
direct and indirect circuits project to the thalamus;
the direct pathway disinhibits the thalamus, whereas
the indirect pathway inhibits it. The relative influence of the two pathways therefore determines the
final output of the circuit. All circuits thus share common structures and are parallel and contiguous, but
remain largely segregated anatomically, despite the
progressive focusing of succeeding projections onto
smaller numbers of neurons. Thus, the DLPF cortex projects to the dorsolateral region of the caudate nucleus, the LOF cortex projects to the ventral
60
Figure 5.2. The general anatomy of the direct and indirect
frontal-subcortical pathways. 1 – Excitatory cortico-striatal fibers. 2 –
Direct loop’s inhibitory striato-pallidal (GPi) fibers. 3 – Indirect loop’s
inhibitory striato-pallidal (GPe) fibers. 4 – Indirect loop’s inhibitory
GPe-subthalamic nucleus fibers. 5 – Indirect loop’s excitatory
subthalamic-GPi/SNr fibers. 6 – Inhibitory outflow from GPi/SNr to
specific thalamic regions. 7 – Excitatory fibers returning from
thalamus to cortex (shown for convenience in contralateral
hemisphere). Excitatory fibers are glutaminergic, inhibitory fibers
mediated via GABA. Note: these circuits are unilateral: each set of
projections from cortex to subcortical structures to cortex remains
within a single hemisphere. In this figure, projection from cortex to
subcortical structures as well as projections between subcortical
structures are illustrated on the left half of the figure whereas
projections from thalamus to cortex are illustrated on the right side
of the figure. This does not suggest that these circuits cross from
one hemisphere to the other; instead, they are diagrammed in this
manner here in order to preserve readability of the figure.
caudate area, and the MOF and AC circuitry connects
to the medial striatal/NAc region. Similar anatomic
arrangements are maintained in the GP and thalamus
(Figure 5.3).
Open-loop elements
While each circuit comprises a closed loop of anatomically segregated dedicated neurons, open-loop elements support the functional connectivity of FSCs.
Circuit structures receive projections from non-circuit
cortical areas, thalamic and amygdaloid nuclei, and
also project to regions outside the circuits. Brain
regions linked by these afferent or efferent projections are functionally related [15, 16]. Circuits mediating limbic functions, for example, have connections
to other limbic areas whereas those involved with
executive functions (EFs) interact with brain structures involved with cognition. In this manner, circuits
integrate information from anatomically disparate but
Chapter 5: Frontal-subcortical circuits
cortex [1, 3]. These areas project principally to the
putamen and thence to ventrolateral GPi, GPe, and
caudolateral SNr. The GP connects to ventral lateral,
ventral anterior, and centromedian nuclei of the thalamus whose major efferents are to the SMA, premotor cortex, and motor cortex, completing the circuit.
Throughout the circuit, the discrete somatotopic organization of movement-related neurons is maintained,
although information processing in the circuits is not
strictly sequential [3].
The oculomotor circuit
The oculomotor circuit originates in the frontal eye
field, Brodmann’s area (BA) 8, as well as prefrontal and
posterior parietal cortex and connects sequentially to
the central body of the caudate nucleus, dorsomedial
GPi and ventrolateral SNr, ventral anterior and medial
dorsal thalamic nuclei, and back to the frontal eye field
[1–3].
The dorsolateral prefrontal circuit
Figure 5.3. The segregated anatomy of the frontal-subcortical
circuits: dorsolateral prefrontal (horizontal stripes), lateral
orbitofrontal (stippling), and anterior cingulate/medial orbitofrontal
(cross-hatched) circuits in the striatum (top), pallidum (center), and
mediodorsal thalamus (bottom).
functionally related brain regions, the cascade of the
closed circuit constituting the eventual effector mechanism [17].
Organization of individual
frontal-subcortical circuits
The motor circuit
The motor circuit originates from neurons in the SMA,
premotor cortex, motor cortex, and somatosensory
Figure 5.4 illustrates the anatomy of the direct pathways of two of the behaviorally relevant FSCs. The
DLPF circuit originates in BA 9 and 10 (areas reciprocally connected with adjacent BA 46) on the lateral surface of the anterior frontal lobe. Neurons in
these regions project to the dorsolateral head of the
caudate nucleus [18], thence to the lateral aspect of
the mediodorsal GPi and rostrolateral SNr via the
direct pathway [19]. The indirect pathway projects
sequentially to the dorsal GPe, lateral subthalamic
nucleus [20] and GPi/SNr. Output from the basal ganglia projects to the ventral anterior and mediodorsal
(parvocellular portion) thalamic nuclei [21–23]. The
circuit is closed by projections from these thalamic
regions back to the dorsolateral frontal lobe [24, 25].
The lateral orbitofrontal circuit
The LOF circuit originates in the lateral orbital gyrus
of BA 11 and the medial inferior frontal gyrus of
areas 10 and 47 [26]. Multiple sensory inputs, including olfactory, gustatory, visceral, somatic, and visual
afferents converge on this region. Projections are to
the ventrolateral caudate and dorsal edge of the NAc
[27] with subsequent links to the most medial portion
of the mediodorsal GPi and to the dorsomedial SNr
[28]. The ventrolateral caudate also sends an indirect
loop through the dorsal GPe to the lateral subthalamic
61
Section I: Structural and Functional Neuroanatomy
The anterior cingulate and subgenual
cingulate circuits
Figure 5.4. The anatomy of the direct pathways of the
dorsolateral prefrontal and lateral orbitofrontal circuits. NAc, nucleus
accumbens; GPi, globus pallidus, internal segment; SNr, substantia
nigra, pars reticulata; VAmc, ventral anterior nucleus, magnocellular
portion; VApc, ventral anterior nucleus, parvocellular portion; MDpc,
mediodorsal nucleus, parvocellular portion; MDmc, mediodorsal
nucleus, magnocellular portion; MDpl, mediodorsal nucleus,
paralaminar portion.
nucleus, thence to GPi and SNr [20]. Neurons are sent
from the GPi and SNr to the medial section of the magnocellular division of the ventral anterior thalamus as
well as the paralaminar portion and inferomedial sector of the magnocellular division of the mediodorsal
thalamus [18, 21, 29]. The circuit then closes with projections from these thalamic regions to the LOF cortex
(Figure 5.4).
The rostromedial limbic circuitry
Emotional, motivational, and affective information
processed by the basal ganglia is represented in the rostromedial limbic circuitry arising from the orbital and
medial prefrontal cortex. Closely integrated anatomically and functionally, this comprises AC circuitry
(including that related to the subgenual cingulate) and
the MOF circuit (Figure 5.5).
62
There are two major subdivisions of the AC cortex,
which subserve distinct functions (Figure 5.6). The
dorsal cognitive division (BA 24, 24a’–b’ and 32’),
also referred to as the cognitive effector region [26],
is more developed in its cytoarchitecture than the
rostral-ventral division, and is part of a distributed
attentional network which has reciprocal interconnections with DLPF cortex (BA 46/9), parietal cortex (BA
7), and premotor and supplementary motor areas [30–
32]. This region is connected via the Muratoff bundle
to dorsal and medial portions of the head and body of
the caudate nucleus [7, 18, 33], with succeeding projections to the GPi/SNr and thence to the parvocellular mediodorsal thalamus as well as the ventral anterior and midline/intralaminar thalamic nuclei [25, 34].
These thalamic regions then reconnect with the cognitive division of AC via the inferior thalamic peduncle
and anterior internal capsule (Figure 5.5). Functions
of the cognitive effector region include modulation of
attention or executive functions by influencing sensory
or response selection; monitoring competition, complex motor control, motivation, novelty, error detection and working memory; and anticipation of cognitively demanding tasks [35].
The rostral-ventral affective division of the AC
cortex comprises the subgenual cingulate (BA 25),
adjacent (caudal) portions of BA 32 (pregenual cingulate), area 33, and the rostral portions of AC cortex,
subcallosal areas 24a and 24b (Figure 5.6). These
regions project to the medial part of the ventral striatum [18, 36], which includes the ventromedial caudate,
ventral putamen [37], and core and shell of the NAc
(the shell region receiving projections especially from
the subgenual cingulate [38]). Projections from the
ventral striatum and NAc core innervate the rostromedial GPi and ventral pallidum (VP, the portion of the
globus pallidus inferior to the anterior commissure)
as well as the rostromedial SNr and ventral tegmental
area (VTA) [39–41]. The NAc shell projects to the
VP, VTA and SNpc, allowing this region to influence
dopaminergic inputs to other parts of the striatum
[41]. The VP and GPi then project to the dorsal portion
of the magnocellular mediodorsal thalamus, midline
and intralaminar (parafascicular) thalamic nuclei
[23, 40, 42–44], with closed-loop projections back
to the anterior and subgenual cingulate (Figure 5.5)
[25, 34].
Chapter 5: Frontal-subcortical circuits
Figure 5.5. The anatomy of the direct
pathways of the rostromedial limbic
circuits. VP, ventral pallidum; Pf,
parafascicular nucleus. Other
abbreviations follow Figure 5.4. The pale
arrows indicate open-loop connections
between engaged thalamic nuclei and the
lateral orbitofrontal and dorsolateral
prefrontal cortices.
While the OF cortex mediates information concerning the internal environment, the AC circuitry
facilitates the intentional selection of environmental
stimuli based on their internal relevance [45], thereby
mediating motivated behavior. Through both its dorsal and rostral-ventral divisions and their connections with motor pathways, lateral PFC, and afferents
from the midline thalamus and brainstem (including arousal systems), the AC cortex is ideally positioned to participate in the willed control of behavior
[46].
The subgenual cingulate component of AC
circuitry (Figures 5.5 and 5.6) includes substantial predominantly ipsilateral connections with
the amygdala [44], MOF cortex (see below), other
portions of both anterior and posterior cingulate,
anterior insula, medial temporal lobe, hypothalamus,
periaqueductal gray and dorsal brainstem [47]. The
strong projections to the dorsal raphe suggest a role
in regulating the overall function of the serotonergic
system [44]. With its major outflow to autonomic,
visceromotor, and endocrine systems [30, 35, 48], this
circuit has been implicated in salience monitoring of
emotional and motivational information, mediation
of emotional and autonomic response to socially
significant or provocative stimuli, affective processing,
and inhibitory control [35, 49, 50].
The medial orbitofrontal circuit
Arising from the gyrus rectus (areas 14r, 14c) and
related areas on the medial orbital surface, including BA 11m, 13a and 13b, the MOF cortex is
integrated anatomically and functionally with the
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Section I: Structural and Functional Neuroanatomy
Figure 5.7. The direct and indirect frontal-subcortical pathways.
Filled arrows represent inhibitory (GABAergic) pathways; open
arrows, excitatory (glutamatergic) pathways. Note that
dopaminergic input from the substantia nigra pars compacta and
ventral tegmental area is inhibitory, via D2 receptors, to
GABA/enkephalin neurons projecting to the indirect pathway, and
excitatory, via D1 receptors, to GABA/substance P neurons
projecting to the direct pathway.
Figure 5.6. The medial surface of the right hemisphere (anterior
towards the left), showing a schematic representation of
cytoarchitectural areas of the anterior cingulate cortex. The areas
forming the dorsal cognitive division and the skeletomotor effector
region (striped) are outlined by solid lines, the rostro-ventral
affective division areas being outlined by dotted lines.
specialized connections with the amygdala, the MOF
circuit may serve both as an integrator of visceral
drives as well as a sensor of information pertaining to
emotions [51, 58].
Neurochemical organization
Shared neurochemical organization
infracallosal AC and subgenual cingulate (“visceral
effector region”) [27, 51], with which it shares subcortical projections (Figure 5.5). Sequentially, these
links are to the ventromedial caudate and NAc (core);
ventromedial pallidum and dorsomedial SNr; magnocellular portions of the ventral anterior and medial
mediodorsal thalamic nuclei, with a closed-loop projection back to the MOF cortex [18, 23, 38–40, 52,
53]. In addition to its connections with the infracallosal cingulate, the MOF cortex has strong reciprocal connections with the medial portion of the
basal and magnocellular division of the accessory
basal amygdala, as well as with the ventromedial temporal pole and rostral (agranular) insula [51, 54–
57]. The subgenual cingulate provides motivational
input to gustatory, olfactory and alimentary information from anterior insular processing converging
on the MOF cortex. Considering its robust connections with high-order sensory association cortices and
64
Common to all circuits is an origin in the frontal lobes
with excitatory glutamatergic fibers that terminate in
the striatum (caudate, putamen, and ventral striatum).
These striatal cells then project inhibitory gammaaminobutyric acid (GABA) fibers both to neurons in
the GPi/SNr (direct loop connection) and to the GPe
(indirect loop connection). Via the indirect loop, the
GPe projects inhibitory GABA fibers to the subthalamic nucleus which then connects with the GPi/SNr
through excitatory glutamatergic fibers [2, 59]. The
direct pathway expresses dopamine (DA) D1 receptors and utilizes substance P with its GABA projection to the pallidum while the indirect loop receives
its dopaminergic influence via D2 receptors and combines GABA with enkephalin [60]. The GPi/SNr then
project inhibitory GABA fibers to specific thalamic
targets, which complete the circuit by sending a final
excitatory connection to the cortical site of the circuit’s
origin in the frontal lobe (Figure 5.7).
Chapter 5: Frontal-subcortical circuits
Circuit-discrete neurochemical organization
The striatum is organized as two separate systems, the
striosomes and the matrix. These elements are differentiated by their distinct ontological, connectional,
and chemical characteristics [61]. Relative to matrix
neurons, striosomal cells mature earlier, have lower
concentrations of DA, serotonin and acetylcholine,
and have high concentrations of limbic-associated
membrane protein [62, 63]. Striosomes receive dense
orbitofrontal and insular input and have high levels
of D1 receptors, with dopaminergic projections from
the ventral tier of the substantia nigra pars compacta
(SNpc). In contradistinction, matrix cells receive afferents predominantly from the sensorimotor cortex and
express primarily D2 receptors, with dopaminergic
input from the dorsal tier of the SNpc [64]. The matrix
stains selectively for adenylate cyclase whereas the
phosphoinositide system is selectively concentrated
in the striosomes of the medial and ventral striatum
[65]. GABAergic output from the striosomes is to the
medial portion of the SNpc, dedicated to the OF circuit, whereas the GABAergic output of the matrix is to
the GPe, GPi, and SNr.
Mirroring the circuit-discrete neurochemical organization of the striatum, the NAc region of the ventromedial striatum is also divided into two functionally
distinct components with discrete histochemistries.
Thus, the core or dorsolateral portion of the NAc,
which receives projections from the MOF and AC
cortex, is distinguished by a lower concentration of
mu opiate receptors and a higher concentration of
calcium-binding proteins. This region is virtually identical histologically to the ventromedial caudate. In distinction, the shell or ventromedial portion of NAc,
which receives a segregated pool of projections from
the subgenual cingulate (BA 25) and pregenual cingulate (BA 32), is inversely devoid of calcium-binding
proteins and replete with mu opiate receptors [38].
Neurotransmitter systems influencing
frontal-subcortical circuits
Processing of the detailed information contained in
the FSCs is modulated by input from dopaminergic,
cholinergic, noradrenergic, and serotonergic systems.
The dopamine system
Dopaminergic projections from the SNpc (primarily
cell group A9), the caudal extension of SNpc into the
retrorubral region (cell group A8) and the VTA (A10
cell group) innervate the entire striatum, thereby influencing each of the FSCs. This provides an anatomic
basis for the multifaceted effects of dopaminergic
agents on motor activity, motivation, thought, and
behavior. Reflecting DA’s modulatory function, DAcontaining axon terminals synapse directly on striatal output neurons, many on the necks of dendritic
spines. The VTA is the primary source of DA for the
ventral striatum, prefrontal cortex, and limbic targets.
The nigra has inhibitory connections, via D1 receptors,
with the indirect portions of the FSCs and excitatory
connections, via D2 receptors, with the direct circuits
(see Figure 5.2). Representing an important convergence within the otherwise segregated FSCs, the SNpc
receives diffuse input from the limbic circuits, providing a means for limbic emotional input to influence
both motor activity and cognition.
The cholinergic system
Cholinergic input to the basal ganglia and most of
the thalamus is derived from the pedunculopontine
nucleus and laterodorsal tegmentum of the brainstem.
Second, portions of the mediodorsal, ventroanterior,
and reticular nuclei of the thalamus, as well as limbic structures and neocortex, receive cholinergic input
from the basal forebrain, which includes the septum,
diagonal band of Broca, and the nucleus basalis of
Meynert [66]. Acetylcholine facilitates thalamic activation of the cortex and also assists in the septal hippocampal pathway supporting mnemonic function.
Within the striatum, there are important interactions between the cholinergic and dopaminergic
systems. Activation of D2 DA receptors, located
on cholinergic interneurons, inhibits acetylcholine
release, whereas D1 receptor agonists enhance acetylcholine release. Conversely, acetylcholine enhances
DA release via nicotinic and muscarinic receptors
located on presynaptic DA terminals [67].
The norepinephrine system
Noradrenergic neurons from the locus coeruleus
project to the entire cortex and hippocampus as well
as cerebellum and spinal cord. A ventral pathway originating below the locus coeruleus innervates the brainstem and hypothalamus. Beta 1 receptors are present in
the cerebral cortex while beta 2 receptors predominate
in the cerebellum. Electrophysiologic studies suggest
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Section I: Structural and Functional Neuroanatomy
that a balance between norepinephrine and DA levels may set the signal-to-noise ratio of the attentional
system [68, 69], which incorporates a distributed network involving the cingulate, DLPF, and inferior parietal cortices [70].
The serotonergic system
The serotonin 5-HT1 receptor is the most abundant
serotonin receptor in the basal ganglia. 5-HT1C receptors are very dense in the globus pallidus and moderately dense in the caudate, putamen, and accumbens regions, which also contain intermediate levels of
the 5-HT2 receptor. The highest densities of 5-HT1D
receptors are found in the basal ganglia and SN. 5-HT3
is enriched in the striatal matrix and is the most abundant receptor in the ventral striatum [62, 71] and other
areas functionally related to the AC circuit, including
hippocampus, septum, and amygdala. This receptor is
linked to a ligand-gated cation channel that also modulates the release of acetylcholine and DA.
Mechanisms for interactions between
motor and behavioral circuits
Although the FSCs remain largely segregated throughout their course, several mechanisms may allow for
complex interactions between motor and behavioral
systems [52]. At higher levels, thalamic relay nuclei
form not only reciprocal but also non-reciprocal cortical connections, linking multiple frontal cortical areas,
allowing for information flow between cortical circuits [23] (see Figure 5.5 as an example). At the level
of the striatum, striosomes interdigitate with the surrounding matrix, so that matrix-striosome borders
may serve as interfaces where the sensorimotor systems of the matrix interact with the striosomal processing of prefrontal and limbic inputs [72]. Linkage
between the sensorimotor and limbic related regions
of the striatum can also occur through corticonigral
influences on the striatum and through the overlapping efferent striatal projections to the SN. Whereas
the main output from the striatal matrix is to the GPi
and SNr, striosomes project primarily to the dopaminergic SNpc. In this manner, the ventral striatum is able
to exert a global regulatory influence on the dopaminergic input to the entire striatum. This provides an
important mechanism for limbic “motivational” input
to modulate motor behavior and provides for the
“anchoring” or reinforcement of successful experience.
66
A recent re-evaluation [41] supports the original
concept of the NAc part of the ventral striatum as
a functional interface between the limbic and motor
systems [73]. Thus, its afferent connections position
this region as a site for integration of signals with
emotional content (amygdala); contextual information
(hippocampus); motivational significance (dopaminergic inputs); information about the state of arousal
(midline thalamus); and executive/cognitive information (prefrontal cortex) [41]. Outputs of the ventral
striatum include projections to the brainstem dorsal
raphe, the midbrain parabrachial region and to the
habenula, which may also play an important role in
integration of the motor and behavioral circuits [74].
The habenula, which receives input from the anterior
thalamic nuclei and GP, projects to the rostral midbrain with connections to the dopaminergic VTA and
to the serotonergic dorsal raphe. Both of these cell
groups project diffusely to multiple tiers of the FSCs.
In particular, the limbic ventral striatal and habenular
input to the dorsal raphe suggests another important
mechanism for cross-talk between circuits and for limbic modulation of motor function [75].
Also providing for circuit linkage between
limbic and motor systems are the cholinergic
interneurons of the caudate and putamen and somatostatin/neuropeptide Y-containing interneurons that
ramify between compartments [76]. Differences
in peptide cotransmitters and in monoaminergic,
GABAergic and glutamatergic synaptic receptor
expression at subcortical sites (see above) provide
other mechanisms for differential response within
FSCs and for a complex interplay between these
circuits [75].
From a neurophysiologic perspective, integration
of the temporal coincidence of processing in FSCs,
occurring particularly at the level of the thalamus [74],
may also contribute importantly to linkage and synthesis of information between FSCs.
Prototypical frontal-subcortical
circuit syndromes
Three principal frontal lobe symptom complexes are
recognizable: a medial frontal-AC syndrome with apathy and diminished initiative; an OF syndrome with
prominent disinhibition and irritability; and a DLPF
syndrome, with neuropsychological deficits involving
Chapter 5: Frontal-subcortical circuits
EFs. Supporting the concept of circuit-specific behavioral syndromes, similar disorders have been observed
with lesions of subcortical structures of these circuits.
The anterior cingulate syndrome: akinetic
mutism and abulia
Akinetic mutism (AM) [77] represents a wakeful state
of profound apathy, with indifference to pain, thirst,
or hunger, and absence of motor or psychic initiative,
manifested by lack of spontaneous movement, absent
verbalization, and failure to respond to questions or
commands. The term abulia, derived from the Greek
boul, or will [78] refers to a similar but less severe psychomotor syndrome, encompassing lack of spontaneity, apathy, and paucity of speech and movement.
Akinetic mutism has been described with AC
lesions, craniopharyngiomas, obstructive hydrocephalus, tumors in the region of the third ventricle,
and other conditions involving the ventral striatum
(NAc and ventromedial caudate), ventral GP, and
medial thalamus [79]. Although reports of the clinical
consequences of lesions restricted to limbic structures
of the basal ganglia are scarce [57], larger lesions that
include both ventral striatum and more dorsal areas of
the basal ganglia are associated with severe apathetic
states. In a review of patients with focal lesions of
the basal ganglia [80], abulia occurred in 18 of 64
(28%) small and large caudate lesions sparing the
lentiform nucleus, 15 of which were unilateral. Abulia
was also seen in six of 22 (27%) restricted GP lesions,
all bilateral, but did not accompany isolated lesions of
the putamen (a link in the motor circuit). Lesions of
the mediodorsal and anterior nuclei of the thalamus
may also result in apathy [81–83].
Unilateral lesions of the AC cortex produce
transient AM [84] while the most dramatic examples
of AM follow bilateral AC lesions [85], particularly
lesions that extend from the cognitive effector region
posteriorly into the skeletomotor effector division of
the cingulate [51], a region connected with primary
motor and SMA [29, 86]. There are non-overlapping
representations for hand movements and speech
within the AC cortex, reflecting separate AC motor
channels [29]. While there are no published reports
of isolated speech deficits with restricted cingulate
lesions, bilateral lesions in monkeys to the rostral
AC cortex, located around the genu of the corpus
callosum, significantly impair spontaneous vocalization whereas deficits involving limb movements in
humans have been associated with lesions affecting
both rostral and caudal cingulate motor areas [46].
Reflecting reciprocal connections between the AC
cortex and the MOF cortex [51], orbito-medial prefrontal cortical lesions may also result in severe forms
of apathy [46, 57]. Data suggest a functional continuum along the rostral-caudal axis of medial frontal
lobe regions from cognitive and emotional functions
to motor functions devoted to self-initiation of action
and thought [57]. Reflecting this continuum, a similar disorder affecting the “drive” for willed movement and speech (“motor neglect”) has been seen in
patients with lesions of the SMA [87–89]. Such patients
exhibit initial global akinesia and neglect, which then
lateralizes in unilateral cases. Primarily part of the
motor circuit, the SMA also receives reciprocal projections from the AC (area 24c’). Positron emission
tomography (PET) studies in humans have shown that
regional cerebral blood flow in the rostral SMA and
adjacent mesial frontal cortex is associated with the
self-generation of motor actions but not with externally cued ones [90].
Conceptually distinct, DLPC circuit lesions
may produce a “cognitive” rather than “emotionalaffective” form of apathy, cognitive inertia resulting
from difficulties in elaborating the plan of actions
necessary for ongoing or forthcoming behavior [57].
This reflects links between layer V of the dorsal
cingulate cortex and superficial layers of the DLPF
cortex (see Figure 5.5), a powerful avenue of communication between cognitive and motor systems [31].
Thus, while the AC can be considered broadly as the
cortical gateway for limbic motivation to influence
goal-directed behavior [26], subtypes of apathy may
be defined based on the connections of the cingulate
with other regions [30, 91].
The orbitofrontal syndrome: personality and
emotional changes
The OF cortex is the neocortical representation of the
limbic system [92] and is involved in the determination
of the appropriate time, place, and strategy for environmentally elicited behavioral responses. Lesions in
this area disconnect frontal monitoring systems from
limbic input [93]. In particular, visceral sensory input
to OF cortex is normally used to provide information about the internal milieu and guide bodily reactions to that status (“somatic marker hypothesis”) [94].
Lesions of the LOF may then result in an “interoceptic
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Section I: Structural and Functional Neuroanatomy
agnosia,” which may provide the basis for the variety of
emotional and social deficits commonly observed with
such lesions.
Impulsivity and behavioral disinhibition are
the hallmark symptoms of OF lesions. Common
manifestations include lack of judgment and social
tact, improper sexual remarks or gestures and other
antisocial acts [95, 96]. Patients may exhibit inappropriate jocularity (witzelsucht) or emotional lability
and irritability, trivial stimuli often resulting in abrupt
outbursts of anger [97]. Inattention, distractibility,
and increased motor activity may be seen, as well
as hypomania or mania. MOF lesions are associated
with abnormal autonomic responses to socially
meaningful behavior and difficulty extinguishing
unreinforced behavior, which correlate with antisocial acts [98]. Large bilateral OF lobe lesions may
result in enslavement to environmental cues, with
automatic imitation of the gestures of others, or
enforced utilization of environmental objects [99].
Typically, however, patients with OF dysfunction
exhibit a dissociation between impairment of behavior necessary for activities of daily living and normal
performance on psychological tests sensitive to frontal
lobe dysfunction, such as the Wisconsin Card-Sorting
Test (WCST) [93, 100, 101].
Although the OF syndrome usually follows bilateral OF cortex injury [93, 101], unilateral lesions
may produce a similar disorder [102]. Patients with
ventral caudate lesions may also appear disinhibited,
euphoric, impulsive and inappropriate, reproducing
the corresponding OF lobe syndrome [103]. It is likely
that the early appearance of comparable personality alterations in Huntington’s disease (HD) reflects
the involvement of medial caudate regions receiving
OF and AC circuit projections [104]. Similarly, mania
(see below) may result not only from injury to MOF
cortex and caudate nuclei but also from lesions to
the right thalamus [105–108]. Mixed behavioral syndromes commonly accompany focal lesions of the GP
and thalamus, reflecting the progressive spatial restriction of the parallel circuits at these levels [109].
The dorsolateral prefrontal syndrome:
executive function deficits
Both experimental and clinical data link the DLPF cortex and its subcortical connections with EFs. Executive functions incorporate anticipation, goal selection, planning, monitoring, and use of feedback to
68
adjust task performance. Patients with restricted DLPF
cortex lesions have difficulty focusing and sustaining
attention, generating hypotheses, and maintaining or
shifting sets in response to changing task demands,
as required by the WCST [110]. Associated features
include reduced verbal and design fluency, impairment of memory search strategies and of organizational and constructional strategies on learning and
copying tasks, and motor programming disturbances.
Similar syndromes have been reported in patients
with lesions of subcortical structures of the DLPF
circuit [109]. Thus, impairment on tests of memory
and EF, including the WCST, have been noted in
patients with dorsal caudate lesions [103], bilateral GP hemorrhages [111] and bilateral or left
paramedian/medio-dorsal thalamic infarction [112,
113]. Executive functions deficits and other features of
“subcortical” dementia [114] in such conditions as HD,
Parkinson’s disease (PD), progressive supranuclear
palsy (PSP), Wilson’s disease, neuroacanthocytosis
and other subcortical disorders are believed to reflect
involvement of the DLPF circuit as it projects through
the basal ganglia [109, 115–117].
Movement disorders and
frontal-subcortical circuits
Basal ganglia dysfunction frequently results not only
in disorders of movement, but also in alterations in
intellectual function, mood, personality, and behavior. The nature and severity of such changes reflect
the extent of involvement of the behaviorally relevant
FSC structures, which project through the caudate and
ventral striatum, rather than the motor circuit, which
projects to the putamen. Diseases affecting primarily the putamen, such as PD, thus exhibit less striking intellectual and emotional alterations than diseases that affect primarily the caudate, such as HD. In
PD, executive dysfunction and dementia is associated
with involvement of the medial substantia nigra and
VTA, which project to the caudate nucleus and medial
frontal cortex, and is not present when changes are
confined to the lateral nigral neurons, which project to
the putamen [118]. While patients with PSP, a hypokinetic disease, exhibit hypoactive behaviors such as
apathy, patients with HD, a hyperkinetic syndrome,
exhibit predominantly hyperactive behaviors, such as
agitation, irritation, euphoria, or anxiety. Such behaviors may result from an excitatory subcortical output
through the medial and OF cortical circuits [119].
Chapter 5: Frontal-subcortical circuits
Subcortical dementia and
amnestic syndromes
Subcortical dementia is generally characterized by
neuropsychological deficits typical of DLPF circuit
lesions [114, 120]. Such deficits may be combined with
amnesia, however, when subcortical lesions involve the
thalamus [109]. The thalamus is poised at the interface
of the FSCs and the medial temporal-limbic circuit
(incorporating the hippocampus, fornix, hypothalamus, and thalamus). While the FSCs mediate memory
activation and search functions, the medial temporalthalamic circuit mediates memory storage (both recall
and recognition) [113].
A related syndrome involving amnesia, fluctuating inattention, apathy and psychomotor retardation,
may occur with capsular genu infarction. It has been
inferred that such lesions interrupt the inferior and
anterior thalamic peduncles, functionally deactivating
the ipsilateral frontal cortex [121]. The anterior thalamic peduncle conveys reciprocal connections between
the thalamic dorsomedial nucleus and the cingulate
gyrus, as well as the prefrontal and OF cortex; the inferior thalamic peduncle carries fibers which connect
with the OF, insular and temporal cortices, and amygdala. Injury to these tracts thus produces a thalamocortical disconnection syndrome combining amnesia
with FSC circuit deficits.
Frontal-subcortical circuit dysfunction
associated with neuropsychiatric
disorders
Obsessive-compulsive disorder and
Tourette syndrome
Convergent data, including ethological and experimental observations [122, 123], clinicopathologic
findings [124, 125], behavioral observations [126],
magnetic resonance imaging (MRI) [127–129] and
PET studies [130–133] have implicated the basal ganglia and related cortical and thalamic structures in
the pathobiology of both obsessive-compulsive disorder (OCD) and Gilles de la Tourette syndrome
(TS). The neurobiologic substrates for these disorders include both corticostriatothalamocortical circuits and monoaminergic pathways that modulate the
activity of these circuits [134–139].
In OCD, functional imaging studies have shown
increased glucose metabolism or blood flow in the
medial and OF cortex and AC gyrus, in the caudate nucleus, and, to a lesser extent, in the thalamus.
This has suggested aberrant OF and limbic circuits as
pathophysiologic mechanisms in OCD [130, 140, 141].
The prevailing theory is that the observed cortical, striatal, and thalamic overactivity in OCD results from a
relative imbalance favoring the direct versus indirect
pathways within this circuitry, leading to failed striatothalamic inhibition [140, 142, 143].
In TS, studies have suggested both anatomical and functional disturbances in basal gangliathalamocortical circuits. Diffusion-tensor (DT)-MRI
has shown smaller left caudate and bilateral thalamic volumes in TS children compared with controls, tic severity being positively correlated with
group differences in radial water perfusion in the
right thalamus [144]. Resting state fluorodeoxyglucose
(FDG)–PET has suggested reduced activity in a limbic
basal ganglia-thalamocortical network, with covariate
decreases in caudate and thalamic metabolism associated with smaller reductions in lentiform and hippocampal activity. The expression of this metabolic
pattern correlated closely with ratings on the Tourette
Syndrome Global Scale [133]. Tic severity in TS has
also been correlated with hypoperfusion of the left
caudate and cingulate gyrus [145] and differences in
D2 DA receptor binding in the head of the caudate
nucleus has predicted differences in tic severity within
monozygotic twin pairs [146].
The preceding observations link tics to the “associative” (non-motor) neural circuits in which the caudate nucleus (not the putamen) is a key node, and
has suggested that dopaminergic dysfunction in the
caudate may underlie the integrated ideational-motor
symptomatology of TS and the “compulsive” quality
of tics [146]. Other studies have supported the importance of sensory elements in tic pathophysiology. Thus,
functional MRI (fMRI) has identified a brain network
of paralimbic and sensory association areas which are
activated before tic onset, analogous to movements
triggered internally by unpleasant sensations, such as
itch and pain [147].
It has been hypothesized that discrete sets of striatal neurons may become overactive in TS, and that
the production of simple tics (via motor circuit activation), complex tics (via activation of premotor areas,
SMAs, and cingulate motor areas), and compulsions
(with OF circuit involvement) might be determined
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Section I: Structural and Functional Neuroanatomy
by the specific FSC that is impacted [148]. Consistent
with this hypothesis, increasing complexity of cognitive and behavioral symptoms in TS has been associated with increasing, apparently dysfunctional synaptic activity within the medial, lateral, and caudal OF
cortices on FDG-PET scans [149].
PET data have also suggested an alteration of
cortical–subcortical interactions in TS, with increased
metabolic rates in frontal motor regions and decreases
in glucose utilization in paralimbic prefrontal cortices and in the ventral striatum [131]. Ventral striatal dysfunction has also been shown with PET using
[11C] dihydrotetrabenazine (DTBZ) to label the type
2 vesicular monoamine transporter, TS patients showing increased DTBZ binding in the ventral striatum
relative to controls [150]. Pertinent to such findings,
and by analogy with animal models of stereotypy, it has
been postulated that the pathophysiology of TS may
be related to an imbalance between dorsal and ventral
striato-pallidal systems, perhaps arising from striosomal dysfunction [148, 151, 152].
Attention-deficit hyperactivity disorder
Characterized by inattention, impulsivity and hyperactivity, attention-deficit hyperactivity disorder
(ADHD) shares clinical features with other neuropsychiatric conditions, including the OF and
DLPF syndromes. It has been hypothesized that the
neural substrates of ADHD involve disturbances in
frontal-subcortical interactions involving arousal and
reward systems [153] which are driven primarily by
dopaminergic activity and modulated by adrenergic and serotonergic mechanisms. Dysfunction of
fronto-striatal type in ADHD has been inferred from
neuropsychological studies [154–156], the pattern of
cognitive deficits resembling those found in “striatal”
disorders such as TS [157] and HD [158].
Both MRI and quantitative morphologic studies have shown smaller caudate volumes in ADHD
patients compared with controls [159, 160]. Xenon
inhalation and emission tomography have revealed
striatal hypoperfusion in childhood ADHD, partially
reversible by methylphenidate [161], and fMRI has
also shown differences between ADHD children and
controls in frontal-striatal function and its modulation by methylphenidate [162]. Performance on
response inhibition tasks have correlated significantly
with fMRI measures of the prefrontal cortex and caudate nuclei, predominantly in the right hemisphere
70
[163]. Comparable PET studies have shown caudate
hypofunction in response-inhibition paradigms [164].
The relevance of these findings may relate to the integration of the caudate nuclei not only in the DLPF
(executive function) circuit but also in the OF circuit,
which subserves delayed responding in primates.
Impaired signaling of delayed rewards is also integral to ADHD and has been linked to disturbances
in motivation processes. This implicates the AC circuit [165], which links the ventral striatum, especially NAc [166] to both AC and OF cortex [167].
Dysfunction in NAc in ADHD is consistent with the
observed variability in response to psychostimulant
therapy in affected children [168]. A dual pathway
hypothesis [169, 170] proposes that alterations within
the DLPF circuit, modulated by mesocortical DA,
and the AC/reward circuit, modulated by mesolimbic DA, constitute discrete neuropsychologic bases for
dissociable psychological processes in ADHD, leading to executive/inhibitory deficits and delay aversion,
respectively.
It is likely that both DA and norepinephrine
actions contribute to the therapeutic effects of stimulants in patients with ADHD. Electrophysiologic
studies in animals suggest that DA decreases “noise”
through modest levels of stimulation of D1 receptors,
abundantly present in prefrontal cortex, while norepinephrine enhances “signals” through post-synaptic
alpha2A-adrenoceptors in prefrontal cortex [70, 171].
Alpha2-receptor stimulation increases delay-related
neuronal firing [172], the cellular measure of working
memory and behavioral inhibition.
Depression
Both structural and functional brain-imaging studies have supported an association between lesions
disrupting frontostriatal or paralimbic pathways
and depressed mood. OF-inferior prefrontal cortex
metabolism is lower in depressed when compared
with non-depressed HD patients [173], and PD
patients with depression show significantly lower
metabolic activity both in the orbital-inferior frontal
cortex and head of the caudate nucleus compared
with those without depression [174]. This is consistent
with pathological evidence in depressed, cognitively
impaired parkinsonian patients of disproportionate
degeneration of DA neurons in the VTA, a system that
is linked to motivation and reward (see below) [152]
and which projects to OF and prefrontal cortex.
Chapter 5: Frontal-subcortical circuits
Frontolimbic DA deficiency may underlie clinical
similarities between the anhedonia and “psychomotor retardation” (PsR) of major depression and the
lethargy of thought, affect, and movement that constitutes “bradyphrenia” in PD [175]. Anhedonia has been
linked with novelty reward, mediated by dopaminergic
projections to the ventral striatum, and reward scores
in response to a dopaminergic challenge correlate with
activity changes in ventrolateral prefrontal cortex and
caudate/putamen on fMRI in major depression [176].
Depressed patients with PsR show decreased presynaptic DA function in the left caudate [177] and elevated putaminal D2 receptor binding [178]. The DA
metabolite homovanillic acid (HVA) is diminished
in depressed patients with PsR [179] and levodopa
improves the PsR of major depression [180]. Furthermore, clinical improvement in depressed patients with
PsR parallels the dopamimetic specificity of the antidepressants administered [181]. However, DA agonists
alone have limited effect on depressive symptoms in
PD [182] and cerebrospinal fluid (CSF) HVA levels do
not correlate with mood in PD [183].
Based on convergent findings from patients with
primary and secondary depression, a model of depression has been proposed which implicates failure of the
coordinated interactions of a distributed network of
cortical-limbic pathways [184]. In this model, a dorsal
(“attention-cognition”) compartment which includes
both neocortical (DLPF) and superior limbic (AC) elements is postulated to regulate attentional and cognitive aspects of depression, such as apathy, psychomotor slowing, and impaired attention and EF. A ventral
(“vegetative-circadian”) compartment, which is composed of limbic, paralimbic, and subcortical regions
(anterior insula, hippocampus, subgenual cingulate,
and hypothalamus) is recognized as mediating circadian and vegetative aspects of the illness, including
sleep, appetite, libidinal, and endocrine disturbances.
Both PET and fMRI studies have revealed decreased
function of dorsal regions, such as the ventral AC cortex, and increased limbic metabolism and activation
in depression [185], while fMRI has shown reciprocal
effects of antidepressant treatment on activity and connectivity in these regions [186]. The rostral anterior
(pregenual) cingulate is isolated from both the ventral
and dorsal compartments based on its cytoarchitectural characteristics and its reciprocal connections to
both compartments and may serve an important regulatory role in mediating interactions between them
[187].
An important role for the subgenual cingulate (BA
25) in depression was first provided by the observation of metabolic change (overactivity) in this region
in treatment-resistant depression, which uniquely predicted antidepressant response [184, 185]. Deep brain
stimulation (DBS) of white matter tracts adjacent to
the subgenual cingulate was subsequently shown to
effectively reverse symptoms in otherwise treatmentresistant depression [188, 189] (see below). Disturbances in the subgenual cingulate circuit have been
linked also with the rapid mood shifts in bipolar disorder, and may have a role in the pathophysiology of
OCD [190, 191].
Mania and the lateralization
of emotional behavior
Affective response to brain injury may reflect the
hemisphere involved. Thus, crying is more common
in patients with left hemispheric lesions, while laughter occurs with right-sided lesions [192]. Left frontal
and left basal ganglia infarctions are most likely to
be associated with depression [103, 193] and in PD
depression is more common with right hemiparkinsonism (left striato-frontal dysfunction) [194]. Conversely, mania frequently results from right-sided thalamic or right medial diencephalic lesions that may
disrupt hypothalamic circuits or disturb modulating
transmitters traversing the medial forebrain bundle
[106, 107]. Mania has also been observed in patients
with MOF cortex lesions and caudate dysfunction in
basal ganglia disorders such as HD [193, 195]. The
increase in appetite drives that often accompanies
mania has suggested underlying hyperfunctioning of
the paleocortical paralimbic belt [51].
Whereas depressed patients show bilateral temporal hypometabolism on FDG-PET scans, patients
with mania exhibit unilateral, right-sided temporal hypometabolism [194]. A differential biochemical response to injury in the two hemispheres may
contribute to the polarity of the expressed mood
disorder. Thus, right but not left frontolateral cortical lesions in rat models produce hyperactivity,
widespread depletion of brain norepinephrine, and an
increased turnover of DA in the NAc. Correspondingly, right but not left hemispheric stroke in humans
leads to an increase in 5-HT-2 serotonin receptor binding in both temporal and parietal cortex [194].
71
Section I: Structural and Functional Neuroanatomy
Bipolar disorder
Vulnerability to bipolar disorder (BD) is linked with
the gene coding for diacylglycerol (DAG) kinase
eta, an enzyme that metabolizes DAG, inhibiting
phosphatidylinositol-protein kinase C intracellular
signaling [196–198]. The phospho-inositol second
messenger system is concentrated in striosomes in
limbic brain regions. This chemoarchitectural disorganization in BD is consistent with a disease model
that involves dysfunction within both striato-thalamoprefrontal networks and limbic modulating regions
[199–202]. Support for this model includes MRI
abnormalities in prefrontal cortical areas, striatum and
amygdala, and activation differences in anterior limbic
regions shown by functional imaging studies. Specifically, reduced ventral and orbital prefrontal activity and increased amygdala activity has been noted,
both during episodes and in remission. This suggests
that dysregulation of mood in BD may result from
diminished prefrontal modulation of subcortical limbic structures [199, 203].
Schizophrenia
Failures of stimulus filtering and gating in
schizophrenic patients have been linked with
abnormalities of cortico-striato-pallido-thalamic
circuitry [204–206]. Evidence implicating the DLPF
circuit in schizophrenia includes the similarity of
observed neuropsychological deficits to symptoms
associated with DLPF lesions, decreased regional
metabolism and blood flow activation, disruption of
cortical subplate activity (required for connectivity
of thalamocortical neurons), and decreases in major
components of the GABA cortical inhibitory system
[207–209].
The DLPF cortex is part of a task-related frontoparietal neuronal network, the activity of which
is anticorrelated with a “default” network that is
normally active at rest. The latter network, which
includes medial prefrontal and posterior cortices,
has been linked with internally generated “stimulusindependent” thought as well as self-monitoring and
salience monitoring [210]. Using a brain-imaging
technique based on low-frequency fluctuations of
the blood oxygen level-dependent (BOLD) signal,
schizophrenic patients exhibited striking deficits in
regions associated with the default network, including
the posterior cingulate and medial prefrontal regions
[211]. This supports earlier data showing deficits in
72
small interneurons in cingulate and prefrontal cortices in schizophrenic patients [212]. It has been suggested that if the default network in schizophrenia
is associated with decreased communication between
the medial prefrontal and posterior cingulate regions,
self-monitoring systems may become split, leading to
the perception that auditory thoughts are externally
produced [213].
Substance abuse disorders and impulse
control disorders
The principal components of the drug reward circuit
are the A10 dopaminergic cell group of the VTA, limbic structures of the basal forebrain (OF cortex, AC
cortex and ventral striatum, particularly NAc) and
the dopaminergic connection between the VTA and
basal forebrain limbic system (mesocorticolimbic DA
system). This network links substance addiction to
brain motivational and reward systems. Linked brain
regions include the amygdala, which provides affective
salience, and the hippocampus, relaying contextual
memories. While early phases of drug-seeking behavior and addiction are probably characterized by interactions between these systems, the dorsal striatum
appears to become involved in later phases when drugtaking has become a habit [214–218]. Other components of the drug reward circuit are the opioid peptide,
GABA, glutamate, and serotonin systems, and other
neural inputs that interact with the VTA and basal
forebrain [219–221].
Impulse control disorders (ICDs), including pathological gambling, compulsive sexual behavior, and
compulsive buying, are characterized by a failure to
resist an impulse, drive, or temptation to perform a
typically pleasurable activity. A range of ICDs occur at
a greater frequency in PD than in the general population and are linked particularly with the use of direct
DA agonist drugs [222]. Compared with levodopa,
DA agonists have significantly greater occupation of
D3 DA receptors which are concentrated in limbic
brain regions, including ventral striatum, with highest concentrations in the shell of the NAc [223]. Even
within the dorsal striatum, the D3 receptor is primarily localized to the patch/striosome compartment that
is anatomically connected to limbic structures [224,
225]. This and other evidence suggests that pathological gambling and other ICDs in PD may result from
dopaminergic overstimulation of a relatively preserved
Chapter 5: Frontal-subcortical circuits
mesocorticolimbic DA pathway in predisposed individuals [226].
Although considered by some as OCD-spectrum
disorders, there is broader support for categorizing
ICDs as behavioral addictions [227–230]. Supporting
such a model, a single photon emission computed
tomography (SPECT) study of PD patients with pathological gambling showed resting state overactivity in a
right hemisphere network that included the OF cortex,
hippocampus, amygdala, insula, and ventral pallidum
[226]. The ventral pallidum is part of the limbic circuitry (see above) and is implicated in the modulation
of hedonic responses to natural and drug rewards,
and subsequent reward seeking-motivated drive
[231].
Therapeutic interventions for
frontal-subcortical circuit disorders
Pharmacologic interventions
The dorsolateral prefrontal syndrome:
executive dysfunction
In PD, specific executive functions, including working
memory, cognitive sequencing, and attention shifting,
may respond at least partially to dopaminergic therapies [232, 233]. This reflects the combined impact in
PD of caudate nuclear DA deficiency, which creates a
partial “disconnection syndrome” of subcortical origin
[234] and a lesser reduction of DA in the DLPF cortex [235]. However, incomplete reversal of cognitive
deficits with DA agonists is typically noted in PD [233,
236], reflecting the importance of non-dopaminergic
neuronal dysfunction, especially cholinergic dysfunction, in PD dementia.
Executive dysfunction in PD may also be ameliorated by the selective norepinephrine reuptake
inhibitor atomoxetine [237]. This is consistent with
psychopharmacologic and anatomical studies, which
implicate the noradrenergic as well as the dopaminergic system as an important modulator of frontal
lobe function [172, 238, 239]. Noradrenergic agents
may also ameliorate executive dysfunction in a variety of other clinical states. The alpha-2 adrenergic agonists clonidine and guanfacine both enhance working
memory performance in aged monkeys [240, 241] and
cognitive tasks mediated by prefrontal cortex, such as
Trails B, Word Fluency and Stroop tasks, are improved
by clonidine in patients with schizophrenia and Korsakoff ’s syndrome [242–244]. In patients with dementia of the frontal lobe type, EF may be selectively
enhanced by the alpha-2 adrenergic antagonist idazoxan [245].
In ADHD and TS, a variety of agents having important effects on the noradrenergic system, dopaminergic system, or both, may ameliorate features of both
DLPF (attentional/executive) and OF (inhibitory) dysfunction (see below). Such drugs include selegiline,
stimulant medications, low-dose tricyclic antidepressants, clonidine, and guanfacine [246–251].
The anterior cingulate syndrome: akinetic
mutism and apathy
In animals, a syndrome similar to akinetic mutism
(AM) was first demonstrated by bilateral or unilateral
injection of 6-hydroxydopamine into the SN, VTA, or
nigrostriatal tract within the medial forebrain bundles
of the lateral hypothalamus [252–254]. These behavioral deficits could be reversed by the direct DA agonist
apomorphine [255, 256], and blocked by pretreatment
with the DA receptor antagonist spiroperidol [257].
Similarly, in an early clinical report, AM following surgical removal of a tumor from the anterior
hypothalamus responded to the DA receptor agonists
lergotrile and bromocriptine but not to the presynaptic dopaminomimetics carbidopa/levodopa or
methylphenidate [258]. This suggested that akinesia
in this setting resulted from loss of dopaminergic
input to AC or other corticolimbic structures rather
than to the striatum. Clinico-pathologic correlations
have subsequently suggested that isolated damage
to any of the projections of brainstem dopaminergic
nuclear groups may result in AM [259]. Chronic AM
secondary to mesencephalic infarction, destroying
ventral tegmental DA neurons at their site of origin,
may also be reversed with DA agonists [260]. Where
DA receptors have been lost, however, as in patients
with lesions involving the AC gyri, response to direct
DA agonists is typically poor.
While requiring confirmation, a recent report suggests that AM may respond successfully to intramuscular olanzapine [261], a drug which may also ameliorate negative symptoms in schizophrenia. In addition to blockade of DA D2-receptors in the mesolimbic
pathway, olanzapine blocks serotonin 5HT2A receptors, leading to disinhibition of D2 receptors and
enhanced DA release in the mesocortical pathway.
73
Section I: Structural and Functional Neuroanatomy
A preponderance of the latter action might explain
observed increases in levels of DA in the medial prefrontal cortex in response to olanzapine administration [261].
Dopaminergic agents may also afford a clinically
significant and sustained improvement in apathetic
states encountered in a variety of neuropsychiatric
disorders including Wilson’s disease, PD and human
immunodeficiency virus (HIV)-associated dementia,
subcortical strokes and anterior communicating artery
aneurysm [209, 262–266]. Effective agents in such conditions may include direct DA agonists, particularly
pramipexole and ropinirole, which have some selectivity for D3 receptors, amantadine, selegiline, bupropion, amphetamine, and methylphenidate.
Apathy is the most commonly observed behavioral disturbance in Alzheimer’s disease (AD) and is
associated with AC hypoperfusion [267]. The documented improvement in AD-related apathy with
cholinesterase inhibitor therapy [268] may reflect partial correction of cholinergic disconnection of AC
structures. The latter include the basal nucleus of
the amygdala [51], innervated by cholinergic projections from basal forebrain structures, and the midline thalamic nuclei which receive input both from the
basal forebrain and from cholinergic pedunculopontine projections that form part of the ascending reticular activating system. Cholinesterase inhibitors may
also ameliorate apathy in traumatic brain injury [269,
270].
The orbitofrontal syndrome: personality change
A variety of pharmacologic agents may ameliorate, at
least partially, the disinhibited behavior of the patient
with OF circuit dysfunction [271]. Such drugs include
the major and minor tranquilizers, propranolol, buspirone, carbamazepine, sodium valproate, lithium,
clonidine, and selective serotonin reuptake inhibitors
(SSRIs).
Robust data, including studies using 5HT1B
receptor gene knockout mice [272], link behavioral
disinhibition with central serotonergic deficiency
[273–276]. The efficacy of serotonergic agonists,
including fluoxetine and clomipramine, for impulsive,
aggressive, or sexually disinhibited behaviors [275,
277, 278] may relate to the density of serotonin
receptors in the ventral striatum and other limbic
brain regions. Certain 5-HT1A agonists (“serenics”)
exert a dose-dependent decrease in aggression with
a concomitant increase in social interest in animal
74
paradigms [279]. In man, both propranolol and pindolol have agonist effects at limbic somato-dendritic
5-HT1A receptors at dosages used in the treatment of
aggressive behavior [280–282] and the partial 5-HT1A
agonist buspirone may also be effective in the treatment of aggression in a variety of neuropsychiatric
conditions. In addition to their dopaminergic activity,
neuroleptics may have a serotonergic mode of action
in the treatment of impulsive aggression by binding
to and down-regulating the 5-HT2 receptor [274],
which is represented in intermediate levels in the NAc
and striatum. Lithium’s mood-stabilizing action may
be mediated by effects both on the serotonin system
and on phosphoinositide [283, 284], which is selectively concentrated in striosomes of the medial and
ventral striatum [64], regions which receive dense OF
input.
Clonidine is an alpha-2 noradrenergic agonist,
which reduces central noradrenergic transmission by
stimulating presynaptic autoreceptors [285, 286]. Its
efficacy for OF syndrome is exemplified by the report
of a patient with OF dysfunction including mania secondary to bilateral OF contusions [105]. The rapid
response to clonidine in this case was attributed to
reduction of noradrenergic overactivity induced by
lesions of prefrontal areas projecting to noradrenergic
systems [287] which, in turn, innervate and modulate
prefrontal cortex [238, 239, 288]. Clonidine may also
successfully ameliorate symptoms characteristic of OF
circuit dysfunction, including distractibility, impulsivity and emotional lability, in children with ADHD and
TS [246, 248, 289].
Several classes of drugs thus have the potential to
favorably influence symptoms of OF circuit dysfunction, reflecting serotonergic, dopaminergic, and noradrenergic modulation of functions of the OF cortex
and connected brain regions.
Obsessive-compulsive disorder
Serotonin is robustly implicated in the pathophysiology of OCD and SSRIs are effective treatments for
this condition [290, 291]. The serotonergic innervation of the striatum is dense and is localized to those
basal ganglia regions which receive input from the
OF and AC cortices, via the ventromedial caudate
nucleus head and ventral striatum, respectively [62].
Glucose metabolic rates in the head of the caudate
nucleus diminish when OCD is treated successfully
with SSRIs, a result that may be attributable to the
action of serotonin afferents from the dorsal raphe on
Chapter 5: Frontal-subcortical circuits
caudate interneurons [130, 292]. The thalamofrontal
pathways, lesioned at different sites in anterior capsulotomy and subcaudate tractotomy (see below), contain both serotonergic and dopaminergic tracts [293].
The improvement in OCD that may be observed with
adjunctive DA receptor blockers, particularly in TS
[294], reflects the functionally coupled interactions
between brain 5-HT and DA systems [295].
Neurosurgical interventions
Obsessive-compulsive disorder and Tourette syndrome
Anterior cingulotomy or limbic leucotomy have been
used successfully in the past to treat disabling ritualistic behaviors in selected patients with OCD [296] and
TS [297–299]. The rationale for lesioning the anterior
cingulate in these disorders derives from its role as the
conduit for frontal cortex input to the Papez circuit and
limbic system [300, 301], while limbic leucotomy selectively targets both anterior cingulate cortex and frontothalamic projections. The beneficial effect of anterior
capsulotomy in OCD [302] would also be predicted by
the proposed models, as this procedure severs a pathway for reciprocal tracts interconnecting the OF cortex with the dorsomedial and related thalamic nuclei
[143, 303]. More recently this has been replaced effectively by DBS of the ventral anterior internal capsule
[304], a procedure which has been shown to modulate activity in the dorsal and ventral striatum, subgenual cingulate cortex, MOF cortex, and thalamus [191,
305, 306]. This demonstrates how the stimulation of a
single region can generate complex changes throughout the interconnected network [303]. Electrode placements in ventral caudate, STN, zona incerta (near the
STN), and ventral striatum have also been effective for
refractory OCD [98].
Deep brain stimulation of several targets has
been used effectively to treat severe pharmacologically refractory TS. These include the nucleus ventralis oralis, the motor and limbic portions of GPi
[307–311], NAc/anterior limb of the internal capsule
[312], and the centromedian parafascicular complex
of the median and intralaminar thalamic nuclei [311,
313–317], a unit which has significant projections into
motor striatum as well as limbic and associative areas
of the subthalamic nucleus [318]. Targeting of these
sites often results in at least 70% long-term reductions
in vocal or motor tics, with accompanying disappearance of the preceding sensory urge.
Depression
Five potential targets have been identified in the literature as potential surgical targets for DBS in treatmentresistant depression: (1) ventral striatum/NAc; (2) subgenual cingulate cortex (area 25); (3) inferior thalamic
peduncle; (4) rostral cingulate cortex (area 24a); and
(5) lateral habenula [319]. Although it has been suggested that the subgenual cingulate region may prove
to be most effective, based on its anatomic connectivity [189], further studies are required in larger patient
groups to assess both the safety and efficacy of these
targets.
Addiction
In the past, procedures such as cingulotomy, hypothalamotomy, and resection of the substantia innominata
and NAc have been recommended as treatments for
severe addictive disorders. With expansion of knowledge concerning its neurobiology, refractory addictive
states might also prove amenable to DBS of relevant
brain targets [320].
Conclusion
Frontal-subcortical circuits (FSCs) are effector mechanisms that allow the organism to act on the environment. The DLPF circuit allows the organization
of information to facilitate a response; AC circuitry
is required for motivated behavior; the LOF circuit allows the integration of limbic and emotional
information into contextually appropriate behavioral
responses; and mood regulation and integration of
information pertaining to emotions are functions,
respectively, of the subgenual cingulate and MOF circuits. Correspondingly, impaired EFs, apathy, impulsivity, and depression are hallmarks of FSC dysfunction. Movement disorders typically involve not only
the motor circuit but also other FSCs as they project
through the basal ganglia. A variety of other neuropsychiatric disorders may result from disturbances that
impact directly or indirectly on the integrity or functioning of these circuits. Examples of such conditions
include OCD and TS, ADHD, substance abuse and
impulse control disorders, BD and schizophrenia. The
circuits involve a number of transmitters, receptor subtypes, and second messengers that can be manipulated pharmacologically. In addition, for an increasing number of conditions, such as disabling OCD, TS
and depression, discrete neurosurgical approaches to
75
Section I: Structural and Functional Neuroanatomy
specific FSC dysfunctions are being explored more
actively, with advances in DBS showing particular
promise.
Acknowledgments
Special thanks are offered to John Nyquist for preparation of the figures.
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Section I
Structural and Functional Neuroanatomy
Chapter
Arousal
6
C. Alan Anderson, Christopher M. Filley, David B. Arciniegas,
and James P. Kelly
Arousal refers to the physiological state of wakefulness and alertness. Whereas the term has been used
interchangeably with consciousness, arousal in fact
has a more specific meaning as a neural foundation
of what is required to be conscious. Arousal denotes
the level of consciousness [1], which, in combination
with the content of consciousness (attention, language,
memory, praxis, gnosis, visuospatial skills, and executive function) creates the capacity for awareness and
behavior. The arousal system involves multiple distributed neural networks working in harmony to permit normal sleep–wake cycles, satisfy internal drive
states, and respond to environmental demands. Diseases and injuries that affect these systems represent
some of the most serious and devastating conditions
encountered in clinical medicine.
The assessment of arousal therefore is as crucial in patient care as the details of higher cognitive
function. Arousal represents a fundamental requirement for consciousness, providing the wakefulness
and alertness that enable all other cognitive operations. It makes no sense, for example, to describe a
patient as aphasic because of failure to produce meaningful language while he or she is asleep or in deep
coma. Disorders of arousal highlight this core function
of the brain while challenging the clinician to address
a host of medical, neurologic, ethical, and social
issues.
Neuroanatomy and neurophysiology
of arousal and awareness
Disorders of arousal typically involve pathology of the
brainstem, thalamus, or widespread areas of both cerebral hemispheres. This useful generalization structures
the consideration of how arousal is organized in the
normal brain. It has been long recognized that the
ascending reticular activating system in the brainstem
forms the foundation of the arousal system [2]. From
these early observations, the understanding of the
arousal system has been significantly refined through
expanded knowledge of its anatomy and physiology
(Figures 6.1 and 6.2).
Key features of the distributed neural networks
supporting arousal are their multiplicity and redundancy. These characteristics permit fine-tuning of
the organism’s response to its environment, as well
as provide protection against failure of any single
component [3]. A parallel series of distinct neural
networks using dopamine, histamine, serotonin,
acetylcholine, and norepinephrine as neurotransmitters originates in the brainstem or in the basal
forebrain [4]. The arousal systems then converge in
the thalamus, and from there support and modulate
arousal through widespread projections throughout
the cerebral cortex [3]. These distributed reticulocortical, reticulothalamic, and thalamocortical networks
are the foundation of consciousness, and comprise a
highly integrated anatomy that matches the level of
arousal to the requirements of the organism [5].
While there is a general level of arousal maintained
during waking states, these networks also serve to
modulate specific arousal states related to motivational
systems including hunger, thirst, pain, fear, and sexual
behavior [6]. The brainstem nuclei for these ascending
arousal systems receive afferent sensory input including somatosensory, auditory, vestibular, and gustatory
information. Somatosensory signals related to pain or
sexual signals are amplified as they reach arousal networks [3].
Other forms of sensory information modulating
arousal, however, enter the system through alternative
Behavioral Neurology & Neuropsychiatry, eds. David B. Arciniegas, C. Alan Anderson, and Christopher M. Filley.
C Cambridge University Press 2013.
Published by Cambridge University Press. 88
Chapter 6: Arousal
Figure 6.1. Key components of the ascending arousal system. A
major input to the relay and reticular nuclei of the thalamus
originates from cholinergic (ACh) cell groups in the upper pons, the
pedunculopontine (PPT) and laterodorsal tegmental nuclei (LDT).
These inputs facilitate thalamocortical transmission. A second
pathway activates the cerebral cortex to facilitate the processing of
inputs from the thalamus; this arises from neurons in the
monoaminergic cell groups, including the tuberomammillary
nucleus (TMN) containing histamine (His), ventral periaqueductal
gray (vPAG) dopamine-containing cell groups (DA), the dorsal and
median raphe nuclei containing serotonin (5-HT), and the
noradrenergic locus coeruleus (LC) containing noradrenaline (NA).
This pathway also receives contributions from peptidergic neurons
in the lateral hypothalamus (LH) containing orexin (ORX) or
melanin-concentrating hormone (MCH), and from basal forebrain
(BF) neurons that contain gamma-aminobutyric acid (GABA) or ACh.
Reproduced from Saper CB, Scammell TE, Lu J. Hypothalamic
regulation of sleep and circadian rhythms. Nature 2005;437(7063):
1257–63, with permission from Nature Publishing Group.
pathways. Olfactory input, for example, enters the system via the basal forebrain, which is tightly connected
to the amygdala and modulates arousal based on relevant odors and their associated emotional valence.
The visual system also has unique connections with
the arousal system and, given the importance of visual
input in humans, it is not surprising that multiple pathways exist by which vision can influence arousal. Projections from visual cortex to the superior colliculus
in the midbrain are relayed to thalamic nuclei including the reticular and medial cell groups as well as the
pulvinar [3]. Through widespread cortical connections
these thalamic cell groups modulate arousal based on
salient visual stimuli. Higher cortical processing of
Figure 6.2. A schematic drawing to show the key projections of
the ventrolateral preoptic nucleus (VLPO) to the main components
of the ascending arousal system. It includes the monoaminergic cell
groups such as the tuberomammillary nucleus (TMN), the A10 cell
group, the raphe cell groups and the locus coeruleus (LC). It also
innervates neurons in the lateral hypothalamus, including the
perifornical (PeF) orexin (ORX) neurons, and interneurons in the
cholinergic (ACh) cell groups, the pedunculopontine (PPT) and
laterodorsal tegmental nuclei (LDT). Additional abbreviations:
5-HT – serotonin; GABA – gamma-aminobutyric acid; gal – galanin;
NA – noradrenaline; His – histamine. Reproduced from Saper CB,
Scammell TE, Lu J. Hypothalamic regulation of sleep and circadian
rhythms. Nature 2005;437(7063):1257–63, with permission from
Nature Publishing Group.
visual input influences arousal in a top-down fashion
through reciprocal connections back to the thalamus
as well as to upper brainstem nuclei, thus tailoring an
appropriate level of arousal based on the biological significance of visual information [3, 7].
The ascending arousal systems include cholinergic, noradrenergic, dopaminergic, glutamatergic, and
histaminic nuclei [6]. The pendunculopontine and
laterodorsal tegmental nuclei in the brainstem send
cholinergic projections to the reticular nuclei of the
thalamus, forming the reticulothalamic component
of the ascending arousal system, and modulating
cortical engagement and information processing. Glutamatergic projections from the thalamus are broadly
distributed to the cerebral cortex, activating these areas
in preparation for information processing. Dopaminergic projections originating in the ventral tegmental
area of the midbrain project widely throughout the
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Section I: Structural and Functional Neuroanatomy
cerebral cortex and serve a similar activating function.
These connections are bidirectional, providing for
feedback in the system, and their bilateral distribution provides additional safety through redundancy
against the failure of any single component [6].
Brainstem projections from serotonergic nuclei in the
median and dorsal raphe nuclei, histamine-producing
neurons in the hypothalamus, noradrenergic nuclei
in the locus coeruleus, and additional cholinergic
projections originating in the ventral forebrain
nuclei also participate in the modulation of cortical
activation [6].
The combination of reticulothalamic and reticulocortical projections, as well as ascending tracts originating in the ventral forebrain, provide balance and
feedback mechanisms that help modulate the activity of diencephalic and cortical targets, and match
the overall level of arousal and awareness to the everchanging needs for self- and environmental awareness,
and behavior [4, 8]. The brainstem and basal forebrain
structures are so closely linked that some investigators consider the basal forebrain nuclei a rostral extension of the reticular activating system in the brainstem
rather than a separate functional entity [9].
The intralaminar and midline thalamic nuclei form
a critical relay of the arousal system, receiving ascending arousal fibers originating in the brainstem and in
turn projecting diffusely throughout the cerebral cortex [7, 10]. In addition to the input from the brainstem reticular activating system, thalamic intralaminar nuclei receive fibers from the spinothalamic tract
and cerebellum, and have reciprocal connections to
medial prefrontal and anterior cingulate cortex [10].
These nuclei serve more than a simple relay function. The thalamic nuclei are anatomically and functionally distinct, receiving targeted input from specific brainstem nuclei and projecting to specific sites
in the striatum and cerebral cortex, thus allowing the
integration of sensory input and internal drive states
[7]. As such, these nuclei serve as part of a thalamic
matrix that underlies cortical synchronization in support of awareness and higher cognitive functions [11].
In addition to their role in arousal and other cognitive functions, these thalamic nuclei modulate basal
ganglia function and participate in the transmission
of nociceptive inputs to the cerebral cortex [10]. Thus,
the thalamic nuclei are positioned to integrate internal drive states, cognitive function, somatic and external sensory information, and motor systems into the
modulation of arousal.
90
Disturbances at any level of this system can affect
arousal. A wide variety of pathological processes
including vascular disease, the compressive effects of
tumors or other mass lesions, and the direct mechanical effects of trauma can injure brainstem nuclei and
their ascending fibers. For example, white matter tracts
that interconnect cortical and subcortical structures
are particularly vulnerable to traumatic brain injury
(TBI) and anoxia. The midline and intralaminar nuclei
of the thalamus are also affected in TBI [10]. Hypoxic–
ischemic brain injury (HI–BI) can produce a wide
range of lesions involving the rostral brainstem [12],
the cerebral white matter (with special vulnerability in
areas between the major cerebral artery territories and
subcortical regions irrigated by the distal branches of
deep and superficial penetrating vessels), and the cerebral cortex, producing laminar necrosis that is usually
most severe in layers three, four, and five [13–15].
Disorders of arousal and awareness
Brain death
Brain death represents the most severe disturbance
of arousal, with total and irreversible cessation of
any brain function, including that associated with the
brainstem. In most of the USA, with the exception of
a few state governments that amended the Uniform
Determination of Death Act [16] to address physician
qualifications or religious considerations, an individual determined to meet the criteria for brain death is
clinically and legally dead. Determining the presence
of brain death is not just an academic exercise, since
once the diagnosis of brain death is established, it is
permissible to discontinue patient care [17]. Current
criteria for brain death include the absence of responsiveness, including any motor response to painful
stimulation, and the loss of all brainstem reflexes
(including respiratory drive). The diagnosis must be
made in the absence of confounding medical problems that could affect the evaluation, including centrally active medications and hypothermia [18]. Complicating the assessment, some patients meeting the
criteria for brain death are noted to retain autonomic
responses including sweating, blushing, and tachycardia, intact limb reflexes, and they may even have spontaneous limb movements.
Diagnostic studies used to confirm the diagnosis of
brain death include conventional angiography, transcranial Doppler ultrasonography, and radionuclide
Chapter 6: Arousal
brain scans used to establish the absence of cerebral
blood flow. Electroencephalographic (EEG) monitoring, typically for at least 30 minutes, can be performed
to demonstrate the absence of cerebral electrical activity. Similarly, the absence of somatosensory evoked
potentials with stimulation of the median nerve is a
confirmatory finding [18].
Once the diagnosis of brain death is established,
issues surrounding termination of care, the potential
suitability of the patient as an organ donor, and postmortem examination must be decided. The complexity of these considerations make the diagnosis and
management of brain death a challenging problem for
medical personnel, staff, families, and other parties
with vested interests in the outcome (e.g., organ transplant teams).
Moving beyond the complete cessation of brain
function constituting brain death, the discussion leads
to patients with severe impairments of arousal and
awareness but with at least some residual brain function. Coma, the vegetative state, and the minimally
conscious state are disorders of consciousness with disturbances in both arousal and awareness. All of these
states imply major brain dysfunction and, unlike typical portrayals in motion pictures and television programs, most patients with cardiac arrest, severe TBI,
or other severe insult to the brain remain comatose
for some time following the insult and their resuscitation. As patients begin the slow process of recovery, they emerge from coma and progress through levels of improving arousal and awareness; the eventual
outcome varies considerably and is largely dependent
on age, medical comorbidities, and the mechanism of
injury [19].
Coma
Coma is the state of neurological unconsciousness
exhibited by unarousable unawareness of the external environment that is due to extensive damage to
or depressed function of both cerebral hemispheres,
bilateral diencephalic structures, or the ascending
reticular activating system [1]. This state can last for
several weeks or a matter of seconds. The loss of
consciousness seen with concussion is due to rapid
and widespread neuronal depolarization across the
hemispheres, which resolves quickly but can initiate
a neurochemical cascade, which further impairs brain
function [20].
Coma patients typically (but not invariably) have
their eyes closed, are unresponsive to verbal or painful
physical stimuli, and lack sleep–wake cycles; while
there may be reflex motor activity or purposeless restless movements, they lack any goal-directed motor
activity [1, 21]. This state represents the effects of structural injury, pharmacologic effects, or metabolic disturbances of the brain’s arousal mechanisms, resulting
in an unconscious and unarousable clinical condition
[22].
In addition to making the diagnosis and recommending treatment, establishing the prognosis for
patients in coma is a frequent clinical question.
Depending on the mechanism and severity of the
insult that results in coma, some patients may progress
to higher levels of consciousness very quickly, while
others remain in coma for prolonged periods of time.
The setting where clinicians are most accurate in making prognostic determinations is in the aftermath of
hypoxic–ischemic events.
For example, validated neurological examination
and laboratory findings support early predictions,
within the first five to seven days after HI–BI, of
survival and neurological outcome following cardiac
arrest in adults [17, 23]. Established clinical markers
associated with death or unconsciousness at one
month, or unconsciousness or severe disability at six
months following the hypoxic–ischemic event, include
the absence of corneal reflexes or the pupillary light
response, an absent or extensor motor response to
noxious stimulation 72 hours following cardiac arrest,
and the presence of myoclonic status epilepticus.
Validated laboratory data predicting poor outcome
following hypoxic–ischemic events include a serum
neuron-specific enolase level of greater than 33 mcg
per liter and the absence of cortical somatosensory
evoked potentials performed at least 72 hours following resuscitation [23]. Prognosis based on these
clinical measures, however, may be influenced by
treatments administered as part of the resuscitation following cardiac arrest. Cooling protocols may
change the predictive value of diagnostic tests as well as
extend the time period for potential recovery [24, 25].
Coma in other settings – including trauma, infections, poisonings, metabolic disturbances, and hemorrhagic or ischemic cerebral vascular injury – presents
greater prognostic challenges, with more variability
in both short-term and long-term recovery. For these
conditions, the prognosis is largely determined by
the patient’s response to specific treatments aimed
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Section I: Structural and Functional Neuroanatomy
at addressing the underlying process. This additional
variable limits the development and application of
prognostic criteria similar to that available for anoxic
ischemic injury for these causes of coma.
Finally, regardless of the mechanism of injury,
accurate diagnosis, management, and prognostication
may be complicated by ongoing treatments including paralytics, sedation, mechanical ventilation, and
hypothermia, as well as the confounding effects of
comorbid injury and medical conditions.
Vegetative state
Vegetative states (VS) are distinguished from coma by
the presence of spontaneous eye opening and sleep–
wake cycles. Patients in VS demonstrate no response
to verbal, visual, or physical stimulation and no awareness of self or the environment [26]. Patients in VS
have no purposeful activity, and demonstrate no effort
(or ability) to communicate (e.g., express or comprehend language).
Diagnostic criteria have been established for VS
and include the absence of any awareness of self or
environment, the absence of purposeful voluntary
responses to external stimuli, the absence of language
expression or comprehension, adequate autonomic
function to survive with medical and nursing care,
bowel and bladder incontinence, the presence of
sleep–wake cycles, and variable preserved cranial
nerve and spinal reflexes [26]. Laboratory findings
among patients in VS include polymorphic delta or
theta activity on electroencephalogram (EEG), and
evidence of diffuse gray and white matter injury and
global volume loss on structural neuroimaging [27].
Progression from coma to VS represents recovery
of some or nearly all brainstem arousal mechanisms
with continued failure of the distal target networks;
the persistent dysfunction of rostral brain networks
can occur because of thalamic injury, disruption of
white matter tracts, and diffuse cortical injury, alone
or in combination. Positron emission tomography
(PET) measurements of cerebral blood flow in VS
patients demonstrate that there is actually hypermetabolism in the ascending reticular activating
system with impaired functional connectivity between
the brainstem arousal system and higher cortical
structures [28].
Pathologically, patients in VS demonstrate
variable findings, including injury in the upper
brainstem, the central thalamus, the subcortical white
92
matter (often diffuse axonal injury), and widespread
cortical injury, depending on the individual patient
and mechanism(s) of injury [29–31]. The degree of
brain injury in VS patients is typically greater than
that of other severely brain-injured patients who
demonstrate any degree of conscious behavior [30].
As described above, the diagnostic criteria for VS
are based on clinical observation, meaning the assessment of the patient for the absence of any form of
awareness, spontaneous communication, or responsiveness to the environment. This evaluation requires
careful serial examinations over a period of time, and
the recognition of subtle clinical signs can be difficult.
The diagnostic process is subject to error, and a
significant number of patients are incorrectly diagnosed [32]. Specific bedside assessment tools have
been developed to measure neurological function as
patients emerge from coma, which aids in the diagnosis, prognosis, and understanding of an individual
patient’s level of consciousness [33–35]. Of particular concern is misdiagnosis of VS among individuals
who are conscious and aware of their surroundings –
including those whose clinical conditions are most
accurately regarded as a “locked-in syndrome” (LIS)
[36]. A subset of individuals with LIS – in which consciousness and higher cognitive abilities are intact –
superficially appear to be in VS simply as a result of
lost capacity for a motor response [37–39]. Functional
magnetic resonance imaging (fMRI) and PET studies assessing language, facial recognition, and other
cognitive functions in patients with VS have demonstrated cortical regions of preserved activation in some
subjects [37].
The prognosis for patients in VS is to a large degree
dependent on the mechanism(s) of injury. Establishing
a prognosis in patients in VS has crucial medical–legal
implications. Important decisions regarding ongoing
care, end-of-life decisions including termination of
care, and withdrawal of nutritional support and hydration are commonly based on these prognostications
[40]. Whereas the overall prognosis for patients with
brain insult of this severity is poor, there are patients
who emerge from VS and recover to varying degrees
while others remain in VS indefinitely [1, 40]. This
condition has been referred to variably as a persistent
or a permanent VS (PVS); given that these terms are
not interchangeable, it is important to be clear in our
use of these terms.
Criteria for considering a patient to be in PVS is
controversial, with proposed criteria varying based on
Chapter 6: Arousal
the cause: 30 days is considered adequate for patients
following cardiac arrest and 12 months is required
after TBI [1, 40]. The recommendation of the Aspen
Neurobehavior Conference Working Group was to
limit the diagnosis to the indefinite term “vegetative
state” and include the cause of the injury (i.e., anoxic
versus metabolic versus TBI) and the length of time
that the patient had been in VS.
Whereas overall rates of recovery from VS are poor,
the likelihood of recovery is better for younger patients
and for those with TBI than for patients with HI–BI
[41]. The longer the time interval after onset of VS, the
less likely the patient will see any significant recovery.
It is unlikely for patients with TBI to return to consciousness after 12 months, and following non-TBI it
is unlikely to see a return to consciousness after three
months. While there are patients with late recovery
from VS, even years after the onset, these patients are
typically severely impaired neurologically [41].
Minimally conscious state
The minimally conscious state (MCS) differs from
VS by virtue of the patient having minimal and
inconsistent evidence for conscious behavior and
some awareness of self and the environment [40,
42]. While MCS represents a spectrum of severely
altered consciousness, patients with MCS demonstrate
inconsistent purposeful behavior including following
commands, responding to physical stimulation,
manifesting appropriate emotional responses, and
making efforts to initiate communication. When
patients begin to interact with their environment
and communicate consistently, even if still functionally severely impaired, they are considered to have
made the transition from MCS to a higher level of
consciousness. While VS is defined by the absence
of any purposeful behaviors, efforts to communicate,
and unresponsiveness to the environment, MCS is
defined by the presence of these features, albeit at an
inconsistent and minimal level.
Making the diagnosis of MCS requires careful
patient observation and examination as well as consideration of the confounding effect of specific cognitive
deficits including aphasia and apraxia to try to determine the true level of awareness for self and environment. This process is critical because the prognostic
implications of MCS are quite different from those of
the VS.
Because MCS includes a broader spectrum of
function as well as a wider range of injury producing
the condition, overall the prognosis is usually better
than for VS [43]. Patients in MCS show slightly higher
levels of cerebral metabolism compared to patients in
VS, and functional imaging studies assessing responsiveness to auditory and tactile stimuli demonstrate
large-scale activation of cortical networks in some
MCS patients, to a much greater extent than is typically
seen with similar paradigms applied to patients in VS
[19, 44]. This distinction in the level of consciousness
between MCS and VS has important medical–legal
ramifications for decisions about ongoing management as well as termination of care, including
withdrawal of nutritional support and hydration.
While the distinction between VS and MCS is clear
in principle, if not always clinically, it is still difficult
to determine when patients have emerged from
MCS. Similarly, given the severity of the cognitive
dysfunction, it is sometimes difficult to gauge clinical
improvement within the spectrum of MCS. In an
effort to clarify this issue, the Aspen Neurobehavior
Conference Working Group defined emergence
from MCS as the ability to consistently demonstrate
functional interactive communication, the functional
use of objects, or both [42]. It is not surprising that
the most useful prognostic measures for recovery
from MCS are the patient’s age, intact auditory evoked
potentials, functional level when evaluated, the duration of the condition, and the rate of improvement
shown by the patient up to that point [43, 45].
In contrast to VS, in which late recovery is rare, in
a recent study of patients with MCS, a third (including
both traumatic and non-traumatic etiologies) emerged
from MCS [43]. However, it is important to note
that despite their late improvement, they all remained
severely or totally disabled. The recent advances in
functional imaging of aspects of arousal and awareness demonstrate the limitations of our current clinical
approach to the assessment and prognosis of patients
with disorders of consciousness, and highlight the
need for better ways of evaluating and treating these
challenging patients [39].
In summary, much has been clarified recently
about the fundamental differences in arousal and
awareness that distinguish brain death, coma, VS, and
MCS. Brain death is the complete failure of brain function, including all aspects of cortical and brainstem
function. This condition implies the complete and irreversible loss of arousal and consciousness, as well as all
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Section I: Structural and Functional Neuroanatomy
other neurological functions of the brain and brainstem. In coma, elementary centrally mediated functions are preserved with an absence of arousal and
awareness. Vegetative state is defined by wakefulness
without any awareness of self or the environment and
the absence of any purposeful behaviors. With the
return of minimal awareness and interaction with the
environment, the patient is defined as being in MCS.
Principles of treatment in the
disorders of consciousness
Most of what is known about the disorders of consciousness considered in this chapter relates to etiology, diagnosis, and prognosis. Given the broad range
of clinical disorders that can produce these disturbances of arousal and awareness, there is a vast literature addressing specific interventions (i.e., the management of metabolic disorders, interventions for
ischemic stroke and intracranial hemorrhage, and
cooling protocols after cardiac arrest). Specific therapies aimed at the fundamental disturbance of arousal
and awareness, however, remain an understudied area
in clinical medicine.
Regardless of the mechanism of injury, it is important to identify and aggressively treat ongoing medical
problems, provide adequate nutritional support and
hydration, and limit as much as possible the use of
medications that reduce arousal (e.g., anticonvulsants,
antipsychotics, pain medications, and sedatives).
Because the diagnosis of the specific disorders of
consciousness described above depends on careful
assessments, and improvement, while clinically relevant, may be subtle, it is important to have systematic
serial examinations on which to base treatment
decisions. A number of clinical scales for use in
this setting are available. These include the Coma
Recovery Scale-Revised [46], the Coma–Near Coma
Scale [47], the Glasgow Coma Scale [48], and the
Rancho Los Amigos Levels of Cognitive Functioning
[49]. In our experience, the Coma Recovery Scale and
the Coma–Near Coma Scale have proved particularly
useful in the evaluation of treatment response and
recovery.
The available literature, much of it related to
patients with TBI, offers some evidence to help guide
pharmacologic interventions and specific rehabilitative strategies in patients with disorders of arousal
and consciousness. General considerations include
providing the best possible environment for their
94
ongoing care. Specific steps include optimizing light–
dark cycles, protecting time for sleep at night and
encouraging wakefulness throughout the day, and providing regularly scheduled meals (by whatever means
necessary, including tube feedings) in order to entrain
circadian rhythms, limit distractions and other sources
of unwanted stimulation such as treating pain and
minimizing painful procedures, and provide necessary
stimuli to help facilitate interaction with others and the
environment.
For coma patients, a specific rehabilitative strategy
is coma stimulation, in which structured sensory stimulation is administered for the purposes of improving sensory awareness and facilitating improvements
in arousal and awareness. A time-limited trial of this
therapy represents a specific intervention with limited
risk for patients in coma, and can also be considered
for those in VS and MCS. There is mounting evidence
supporting the use of this therapy when provided by
well-trained and competent therapists in the proper
setting [50].
The evidence for pharmacologic interventions in
disorders of consciousness is limited and it is important to note that at present there are no FDA-approved
treatment options for these patients. All proposed
treatment options are based on off-label uses of these
medications. Amantadine has been used in the treatment of severe disturbances of arousal, with two
double-blind, placebo-controlled studies suggesting
that it may be beneficial [45, 51]. A variety of other
medications have demonstrated benefit in small case
series and individual case reports. These medications include modafinil [52], methylphenidate [53–
55], bromocriptine [56], pramipexole [57], levodopa
[58], and zolpidem [58, 59]. These drugs represent
additional off-label treatment options as second-line
therapies in patients where amantadine was either not
tolerated or ineffective.
Deep brain stimulation (DBS), in common use
for the treatment of a variety of movement disorders, may offer an alternative to pharmacologic therapy in selected patients in the future. Deep brain stimulation targeting specific nuclei in the thalamus in a
patient in MCS following TBI led to improvement in
arousal, interactions with the environment, and the
ability to communicate [60]. Bilateral DBS leads were
placed in the anterior intralaminar nuclei and the adjacent paralaminar regions of the thalamus. This patient
was selected for the procedure because fMRI studies indicated that large-scale bihemispheric language
Chapter 6: Arousal
networks remained intact and responsive to activation despite the marked functional impairment. The
premise behind the DBS procedure was that increasing activation of neocortical and basal ganglia neurons through stimulation of the thalamus would compensate for the loss of arousal modulation normally
provided by these structures in the intact brain [31].
Whereas these studies suggest great potential for DBS
in this severely impaired population (in whom there
are limited therapeutic options), the available evidence
and experience with the procedure limits its application to selected research subjects. Whether the risks
and benefits of this procedure warrant broader application remains to be seen.
Conclusion
Arousal is a central function of the brain and, as such,
makes possible all the higher functions characterizing the human species and collectively known as consciousness. Disorders of arousal affect consciousness
at its most fundamental level, and serve well to illustrate how the capacity for wakefulness and awareness
is so critical for all conscious human behavior. For
clinicians engaged in the care of these severely compromised patients, clinical management commonly
involves not only complex neurologic issues but also
difficult medical–legal, ethical, and social concerns.
Although specific treatments for these disorders are
limited, a range of rehabilitative, pharmacologic, and
environmental strategies can improve outcomes. As
neuroscientific advances continue, a more informed
approach to the topic of arousal and its disorders can
be anticipated.
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97
Section I
Structural and Functional Neuroanatomy
Chapter
Sleep
7
Martin L. Reite
The core function of sleep in maintaining the integrity
of brain and bodily function in animals is still under
debate [1], but its absolute necessity in humans is
unequivocal. Total sleep deprivation leads to death
[2]. In humans, sleep restriction and insufficient sleep
lead to decreased cognitive and psychomotor performance [3], impaired antibody production following
immunizations [4], increased C-reactive protein [5],
decreased leptin, and increased grehlin production
with concomitant higher risk for insulin resistance and
type 2 diabetes [6, 7].
Recognition of the personal and economic cost of
disturbed sleep has contributed to the development of
the specialty of sleep medicine and improved the definition of the many sleep pathologies. Four major brain
systems, and two state switching mechanisms, underlie the appearance and control of sleep. The major systems are the arousal system, the non-rapid eye movement (REM) slow-wave sleep (SWS) system, the REM
sleep system, and the circadian timing system. The
switching mechanisms are bistable neurophysiological mechanisms, one of which controls the wake/SWS
transition, the other controlling the REM-on vs. REMoff state. A basic knowledge of these systems and
switching mechanisms provides an important background for assessment and treatment of most sleep
disorders.
In the parlance of sleep medicine, the sleep homeostatic systems are encompassed by the term Process S,
and the circadian timing systems by the term Process
C [8]. Most sleep pathologies can be conceptualized as
representing disturbances in Process S, Process C, or
both.
Historically, an important event in sleep medicine
was the encephalitis lethargica epidemic of 1917–
1918, which was associated with profound changes
in sleep behavior, including severe hypersomnia, and,
less frequently, profound insomnia. The Austrian neuropsychiatrist and World War I pilot Constantin von
Economo examined the brains of deceased patients
and found that lesions in the regions now known to
encompass the ascending reticular activating system
(ARAS) led to profound sleepiness and even coma,
whereas lesions in regions now known to encompass
the sleep-promoting ventrolateral pre-optic (VLPO)
region led to profound insomnia. The cause was never
found, and explanations ranged from viral to, more
recently, delayed destructive autoimmune responses
following streptococcal infection. Since that time,
much progress in the understanding of sleep has been
made.
In this chapter, the organization of human sleep
and the brain mechanisms that regulate it are reviewed,
and the manner in which disturbances in those mechanisms lead to specific sleep disorders is discussed.
For convenience we will group the sleep pathologies
into three broad categories: (1) the insomnias, (2) the
hypersomnias, and (3) the parasomnias. While there
is much overlap between syndromes, patients often
present with complaints representing these three categories (e.g., “I can’t sleep,” “I sleep too much,” or
“strange things happen while I sleep”).
Basic wake–sleep organization
and mechanisms
Wake-promoting systems
The ARAS lies in the upper brainstem and sends
projections rostrally through two major pathways,
one to the thalamus-activating thalamic relay neurons
Behavioral Neurology & Neuropsychiatry, eds. David B. Arciniegas, C. Alan Anderson, and Christopher M. Filley.
C Cambridge University Press 2013.
Published by Cambridge University Press. 98
Chapter 7: Sleep
which gate transmission of information to the cortex, and a second more direct system that bypasses
the thalamus and activates neurons in the hypothalamus, basal forebrain, and cerebral cortex. These pathways, when active, promote wakefulness. The first
pathway originates largely in cholinergic cell groups
active during wakefulness and REM sleep that are
located in the pedunculopontine (PPT) and laterodorsal tegmental (LDT) nuclei. Whereas downregulation
of this system during sleep might be thought to prevent sensory information from reaching the cortex,
clinical and laboratory evidence show otherwise. For
example, neurons in the auditory cortex respond to
auditory input during sleep [9], and complex parasomnia behavior including driving can occur during
sleep, indicating that the brain can respond appropriately to sensory input while not conscious of it.
Several additional regions in the upper brainstem,
predominantly monoaminergic, are involved in promoting wakefulness, including histaminergic nuclei
(important in maintaining vigilance, as discussed
below), the tubero-mammillary region (modulated by
orexin/hypocretin), and serotonergic influences (primarily from the raphe nuclei). The second branch
of the ARAS originates primarily in monoaminergic
neurons in the upper brainstem and caudal hypothalamus, including the noradrenergic locus coeruleus
(LC). The ARAS thus depends on acetylcholine (ACh),
monoamines, and some neuropeptide neurotransmitter systems for its function.
Overactivation of the ARAS leads to complaints
of insomnia, suggesting stress, anxiety, or the general state of hyperarousal thought to underlie primary insomnia. Agents that inhibit the ARAS promote
decreased arousal or sleep. It has been hypothesized
that disturbances in ARAS function may be related
to sleep–wake control problems found in a number
of neurological and mental disorders [10]. The neurophysiology of arousal is discussed in more detail in
Chapter 6.
Sleep-promoting systems
As noted above, von Economo described a small percentage of patients with encephalitis lethargica whose
response was to develop profound insomnia, sleeping
only a few hours each day. Autopsy studies demonstrated that these patients had lesions involving the
basal ganglia and adjacent hypothalamus. Subsequent
animal studies identified sleep-promoting neural systems located primarily in hypothalamic and contiguous regions, and emphasizing neuronal activity in the
median pre-optic nucleus (MnPN) and VLPO region
of the hypothalamus, the activity of which promotes
non-REM or SWS and inhibits wakefulness. VLPO
and MnPN neurons are primarily active during sleep,
and send inhibitory output to all major cell groups of
the hypothalamus and brainstem that participate in
arousal [11, 12].
These neuronal systems depend significantly on the
inhibitory neurotransmitter gamma-amino butyric
acid (GABA) and the inhibitory neuropeptide galanin.
They appear to be activated by preceding wakefulness,
and may be modulated by the build-up of adenosine
associated with the wakeful state. Adenosine appears
to be an important homeostatic sleep factor acting
through the adenosine (Ado) A1 and A2 receptors,
whose release is triggered by inducible nitric oxide
synthesis in the basal forebrain secondary to prolonged wakefulness [13]. Thus the longer one has been
awake, the more likely sleep will be triggered, and the
adenosine antagonist caffeine tends to prolong wakefulness.
The VLPO hypothalamic areas in humans is a sexually dimorphic region, with volume and cell number peaking about age 2–4 and declining thereafter. In
males, decreases do not begin until later in adulthood;
men between 45 and 60 years of age show a decrease
in cell number of about 3% per year until age 60, after
which further decreases are not noted. In females, cell
numbers decrease until the teen years, then remain
fairly stable until after age 50 when a gradual decrease
begins, dramatically increasing after age 75. Between
the ages of 75 and 85 years, cell number decreases in
females at a rate of 4–8% per year, leading to cell numbers only 10–15% of the peak seen between ages 2 and
4 [14].
These findings imply increasing difficulty in initiating and maintaining sleep in both men and women
beginning around age 50, stabilizing in men by 60, but
continuing to worsen in women with increasing age.
Paralleling these neuroanatomic changes, it is notable
that insomnia is a complaint that increases with age,
especially in women, leading Gaus and colleagues to
suggest that “ . . . shrinkage of the VLPO with advancing age may explain sleep deficits in elderly humans”
[15]. The genetic regulation of SWS is not yet well
understood, but advances are being made that should
illuminate this likely important area [16, 17].
99
Section I: Structural and Functional Neuroanatomy
Bi-stable wake/sleep switch
The ARAS and VLPO systems are mutually inhibitory,
and can therefore set up a self-reinforcing loop such
that activity in one decreases activity in the other, similar to electrical circuits termed “flip-flop” switches
[11]. Increasing activity in one side of the circuit
can abruptly switch the circuit and cause abrupt
sleep/wake transitions. This flip-flop switch may be
modulated by orexin neurons, which when depleted,
as in narcolepsy (see below), lead to instability of the
switch. Diminished strength of either side of the switch
can increase its instability, and thus elderly individuals
who have lost some VLPO neurons may also exhibit
more frequent wake/sleep transitions.
REM sleep
REM sleep is controlled independently by brainstem
oscillators whose activation leads to the multiple physiological accompaniments of the REM state, including
low-voltage fast, awake-like electroencephalographic
(EEG) patterns, skeletal muscle paralysis, rapid eye
movements, temporary suspension of thermoregulation, and EEG sharp waves termed PGO spikes, sharp
complexes arising in the pons and transmitted through
the lateral geniculate to the occipital cortex (hence
PGO). The REM state normally appears only during
SWS, although evidence suggests the underlying neurophysiological oscillator may run continuously. In
narcolepsy, the REM state can break into the waking
state with varying degrees of loss of skeletal muscle
tone, termed cataplexy; this disorder, often triggered
by emotional arousal, can result in the person falling
to the ground and entering a full-blown REM episode
complete with dream-like mentation.
Brainstem neuronal systems appear to account for
the periodic generation of the REM state in all mammals, including humans. Cholinergic systems residing
in the laterodorsal and pedunculopontine (LDT/PPT)
nuclei projecting to the mesencephalic and pontine
reticular formation (mPRF) appear to play a prominent role in activating REM sleep [18]. These systems
largely reside in the pontine tegmentum, and may constitute a separate component of the ARAS. The frequencies of these independent oscillators appear to
be a function of body size (the smaller the animal,
the faster the oscillator). Cholinergic systems appear
involved in activating REM states, and monoamines
in suppressing them. Agents that increase Ach activity, such as the Ach inhibitor physostigmine, increase
100
REM sleep, and agents that increase monoamine activity, such as certain antidepressants (most notably the
monoamine oxidase inhibitors) decrease REM sleep.
REM flip-flop switch
It has recently been suggested that a type of neurophysiological “flip-flop” switch also exists for controlling transitions into and out of the REM state
(the “REM-on/REM-off” switch), consisting of mutually inhibitory GABAergic neurons with independent
pathways mediating EEG and atonia effects [19]. In the
cat, the REM-on neurons are thought to be concentrated in the sublaterodorsal nucleus and modulated
by glutamatergic neurons in the lateral and ventrolateral periaqueductal gray. This switch is thought to be
subsidiary to the putative wake–sleep flip-flop switch,
preventing transitions into REM during wakefulness,
unless narcolepsy is present and leads to a weakened
wake side of the wake–sleep switch due to loss of orexin
neurons.
Dreaming
The dream is the unusual mental content that often
accompanies REM sleep. Thought by Freud to encompass significant symbolism, the explanation of Hobson
and McCarley that the dream is random mental content accompanying an activated cortex generated by
brainstem structures led to a fundamental re-thinking
of dreaming [20]. Several lines of evidence support
this idea. Selective activation of the amygdalae and
other emotion-generating limbic regions occurs
during REM sleep, along with deactivation of the
dorsolateral prefrontal cortex. Several aminergic
systems, including noradrenergic, serotonergic, and
histaminergic, are essentially shut down in REM sleep,
while dopaminergic systems remain active. With the
recognition that dopamine antagonists are used in the
treatment of psychosis, it has been suggested that the
relative predominance of dopamine activity during
REM sleep may account for the psychotic quality of a
typical dream [21].
Sleep timing regulation –
the circadian system
The primary body “clock” regulating circadian
rhythms is located in the suprachiasmatic nucleus
(SCN) of the hypothalamus, and has an intrinsic
Chapter 7: Sleep
rhythmicity of about 24 hours. This clock is primarily synchronized by light exposure. A set of
photoreceptors distinct from rods and cones contain
a vitamin A-based photoreceptor called melanopsin
and project via the retino-hypothalamic pathway to
the SCN to provide light information to the brain.
A number of factors that affect the role of light in
modulating circadian rhythms have been described,
including light intensity and duration (more photons
equals more activation), previous light exposure
(less previous light exposure increases the effect of
light, and vice versa) [22], timing (there is a phase
response curve), and frequency (short wavelength
more effective than longer wavelengths) of light [23].
Output from the SCN includes efferent projections
to contiguous hypothalamic regions, as well as a
major sympathetic pathway from the SCN via the
intermediolateral cell column of the spinal cord
and superior cervical ganglion to the pineal gland,
which regulates production of melatonin, the primary
circadian hormone. Melatonin production is activated
when light diminishes as day transitions to night.
Measurement of blood or salivary melatonin can assist
in deriving a metric termed dim-light melatonin onset
(DLMO), a primary circadian timing signal.
The circadian system is largely under genetic control [24]. A number of circadian clock genes have been
identified (e.g., Per1, Per2, Per3, Cry1, Cry2) that are
transcriptional regulators thought to underlie circadian rhythm generation at the cellular level, and may
also have a role in sleep homeostasis [25]. Disturbances
in the regulation of these genes is thought to underlie
many sleep disturbances [17].
Disturbances in circadian regulation, as seen in jet
lag or shift work, and the circadian rhythm sleep disorders (e.g., delayed and advanced sleep phase syndrome, and free-running rhythms in blind individuals) constitute an important component of sleep
medicine. These disorders usually present clinically as
insomnia, as discussed below.
Sleep morphology and architecture
The original Rechtschaffen and Kales sleep stage terminology [26] has recently been supplanted by a new
scoring system developed by the American Academy
of Sleep Medicine [27], which is used in this chapter.
The EEG, however, remains central to the characterization of sleep morphology and architecture (see
Chapter 28). Non-REM sleep typically progresses from
wakefulness to stage N1 (loss of alpha rhythm, lower
voltage theta with some sharp wave activity), to N2
(development of sleep spindles, K-complexes, increasing ⬍1 to ∼4 Hz delta activity), to N3 (greater than
20% delta activity with diminution of spindles and
K-complexes). The term SWS has been variably and
confusingly used to represent non-REM sleep, stage
N3 sleep, or sometimes simply delta activity ⬍2Hz.
Sleep spindles result from recurrent inhibitory circuits in the reticular thalamic nuclei leading to hyperpolarization of thalamocortical neurons [28]. Sleep
spindles can be divided into subtypes based upon both
frequency and topography. ∼12 Hz spindle activity
is dominant over precentral and frontal areas, and
∼14 Hz spindles are dominant post-centrally [29,
30]. Fast spindles have been related to visuomotor
learning [31].
K-complexes are large (high voltage), sharp wave
complexes, often followed by spindle bursts that are
maximally seen over high central and central parietal regions. They are thought to represent a type of
EEG “evoked response” triggered by external or internal stimuli, and may have, as their source, deeper brain
structures.
Spectral-based measurement of sleep EEG activity in the 0.75 Hz to 4.5 Hz band has been termed
slow wave activity (SWA) and has proven very useful
in measuring sleep homeostatic pressure. Slow wave
activity varies regionally over the brain as a function
of experience preceding sleep, suggesting a local regulation of SWA in addition to that relating to circadian timing and duration of wakefulness prior to sleep
[32].
Conceptually, the term “Process S” was coined by
Borbely and Achermann [8] to refer to the homeostatic
sleep drive. The strength of this homeostatic drive,
sometimes termed “sleep pressure,” is measured by
computing the amount of SWA in the sleep EEG following varying periods of wakefulness. Longer periods of wakefulness result in substantial increases in
SWA during the first several sleep cycles of recovery
sleep. Animal studies suggest that the adenosine receptor Ado A1 gene is involved in regulating the efficiency
of the SWA response and associated recovery of central
nervous system (CNS) function following sleep loss
[33].
Other EEG patterns are often seen during sleep,
but their significance is not well understood and
they are usually neither formally scored nor commented upon in typical clinical sleep recordings. One
101
Section I: Structural and Functional Neuroanatomy
such pattern is the cyclic alternating pattern (CAP),
which consists of spontaneous, periodic, somewhat
stereotypical interruptions of background activity during non-REM sleep and thought to be a measure of
sleep stability [34, 35]. It has been suggested that CAP
EEG waveforms may be related to learning [36], parasomnias in children [37], and sleep disturbances in
other disorders, including chronic fatigue [38], depression [39], and developmental disabilities [37].
The suggestion has been made that it may be more
meaningful to examine the wake and sleep EEG based
on the coalescence of complex oscillatory phenomena, a metric that might index neuronal interactions
in corticothalamic systems with greater neurobiological and functional meaning than that obtained with
most current sleep staging based on analytic methods
[40].
Local sleep
While earlier it was thought that sleep reflects a state
encompassing the entire brain, emerging evidence
suggests that this is not so. It is now thought that the
specific brain regions most used during the preceding period of wakefulness require a greater intensity
and/or duration of sleep during a subsequent sleep
period, thus sleep, especially SWS, will be differentially
distributed across brain regions in a use-dependent
fashion [41]. Krueger and colleagues suggest that sleep
may be a fundamental property of cortical networks,
dependent upon prior activity in each, and such difference may be expressed at the level of the cortical column [42].
Sleep physiology
As humans transition from wakefulness to sleep, characteristic physiological changes include decreases in
muscle tone (as measured by electromyographic activity), respiratory rate, heart rate, and blood pressure.
Body temperature also decreases, and this change is
related not only to the decreased metabolic activity
accompanying sleep but also to the central circadian
temperature regulation system. Sleep also modulates
hormonal secretion, with decreases in cortisol and thyrotropin and increases in prolactin and growth hormone production.
REM sleep is accompanied by increased variability in the heart rate, respiratory rate, and blood pressure. Adverse cardiac events such as arrhythmias and
infarctions seem to cluster in the early morning hours
102
when REM sleep is more prominent, possibly indicating an increased vulnerability of those with impaired
cardiac perfusion to this physiological activation and
variability. Body temperature regulation temporarily
ceases during REM sleep, and for a short time humans
become essentially poikilothermic animals. REM sleep
has other unique physiological signatures including
penile or clitoral tumescence and the characteristic
sharp occipital EEG waves called PGO spikes. Most
pronounced of all, perhaps, is the general paralysis
of descending skeletal muscle (with the exception of
the diaphragm) that accompanies REM sleep, which
not only prevents the acting out of dreams but also
increases the probability of apneas, hypopneas, and
hypoventilation because of hypotonia of the accessory
muscles of respiration (e.g., the intercostal muscles)
and the upper airway dilator muscles. Prominent disturbances in the regulation of REM sleep physiology
are also seen in narcolepsy and REM behavior disorder (see below).
Development of sleep across
the lifespan
Human sleep patterns change dramatically during
development (see [43] for review). At birth, sleep consists of two types, each occurring in 50% of sleep time:
active sleep, an immature form of REM sleep, and
quiet sleep, a prelude to non-REM SWS. Active sleep
rapidly decreases such that by 6 months of age it represents only 25% of total sleep, approaching adult REM
values.
The two major processes termed homeostatic and
circadian (Process S and Process C, respectively) are
not developed at birth. Process S in infants consists
of quiet sleep with gradual maturation into adult EEG
sleep patterns as the neocortex develops. Process C is
not apparent at birth, but begins to appear at about
16 weeks when a 24-hour sleep–wake cycle begins to
emerge with sleep being consolidated in the night and
waking in the day. At birth, quiet and active sleep are
interspersed, but by 3 months of age adult sleep cycle
patterns emerge and REM (active) sleep comes to constitute a greater percentage of later sleep periods, with
non-REM or SWS being more prominent in earlier
cycles. REMs are present at birth in active sleep; the
skeletal muscle inhibition of adult REM sleep begins
to appear at 6 months. Total sleep time is about 16–18
hours/day at birth, diminishing to 14–15 hours at one
year and to more adult values as maturation continues.
Chapter 7: Sleep
There is an increase in SWS sleep during adolescence, likely associated with the onset of programmed
synaptic pruning associated with brain maturation
during this period [44]. Recent experimental data
demonstrate the close association of SWA during sleep
supporting the synaptic plasticity (“pruning and tuning”) associated with learning and memory consolidation [45]. During the nocturnal sleep period, “sleep
cycles” usually beginning with non-REM sleep and
ending in a REM period, repeat with about a 90minute periodicity, to be repeated four to five times
during a typical night. Most SWS sleep occurs during the first several sleep cycles; REM periods become
longer as the night progresses. After a period of
sleep deprivation, SWS is the first sleep epoch to
recover.
Sleep morphology is generally reasonably stable
during adulthood (late adolescence to the mid-50s or
60s); however, changes are prominent in the elderly.
The amplitude of SWS diminishes such that formal criteria for Stage N3 may not be met, leaving primarily stages N1 and N2. The loss of VLPO neurons (see
above) and their support of Process S lead to sleep
fragmentation with frequent awakenings, less restorative sleep, and resultant insomnia complaints in the
elderly.
With respect to Process C, aging is accompanied by
a decrease in the amplitude of body temperature and
other circadian rhythms as well as a decrease in the
ability to synchronize the circadian system to changes
such as those associated with jet lag [46]. Adults over
the age of 65 have decreased sensitivity to the phasedelaying effects of bright light exposure [47]. The nocturnal production of melatonin also decreases with
age, so after age 60 this may be related to difficulties
with sleep onset [48]. These changes may relate to functional or structural alterations within the SCN itself
[46].
Complicating such sleep loss in the elderly is the
fact that those genetic mechanisms subserving recovery from sleep deprivation may also be impaired in
older individuals. Animal studies have shown that the
endoplasmic reticulum (ER) is a major component of a
quality control system that removes abnormal or misfolded proteins accumulated during the stress of sleep
deprivation. The adaptive response of the ER to coping
with these abnormal proteins appears to be attenuated
in older individuals, and thus they may be disproportionately impacted by sleep deprivation as a result of
impaired abnormal protein recovery systems [49].
Sleep disorders
Insomnias
The domain of the insomnias is the largest in terms
of sleep complaints, and benefits from thoughtful
differential diagnosis, as the causation may be both
multiple and obscure. The 2005 National Institutes of
Health (NIH) State-of-the-Science Conference on the
Manifestations and Management of Chronic Insomnia
in Adults estimated that 30% of people in the general
population experience symptoms consistent with
insomnia. Often essentially written off in the past with
the attitude that “no one dies from insomnia” this
disorder has been recently shown to be associated with
significant daytime functional decrements, emphasizing that it is a 24-hour disorder, not just a sleep
disorder. Problems include sleepiness and fatigue,
cognitive and psychomotor impairments, worsened
anxiety and depression, increased risk for some
medical disorders, activation of the hypothalamic–
pituitary–adrenal axis, impairment in immune
function, and impairment in global functioning
and/or quality of life. For a recent review of functional
impairments associated with insomnia see [50].
Our conceptualization of insomnia has undergone
a dramatic shift during the past few years, from being
an annoying but not particularly serious symptom to
the recognition that (1) sleep loss has serious consequences; (2) chronic insomnia and its associated
impaired sleep are highly comorbid with (or indeed
may cause) many other medical and psychiatric disorders; and (3) chronic insomnia in some cases may
represent a separate medical disorder of its own with
an independent neurobiological basis. Our primary
concern is not the transient and short-term insomnias, which are generally related to stress, short-term
illness, jet lag, or shift work (although clearly medically significant in its own right), but the chronic
insomnias that require a systematic differential diagnosis. The diagnosis of an insomnia complaint should
include a systematic review of the following areas,
some or all of which may be contributory: (1) medical
disorders and their treatments; (2) psychiatric disorders and substance misuse; (3) circadian rhythm disorders; (4) movement disorders; and (5) the conditioned
insomnia, sleep state misperception, primary insomnia group.
A systematic review of each of these categories is
likely to encompass the potential contributions to most
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insomnia complaints. It is important not to stop with
the first potential causation encountered, as more than
one cause is the rule rather than the exception. A brief
discussion of each area follows.
Medical disorders
The insomnia complaints that are comorbid with
medical disorders include both sleep disturbances
caused by medical symptoms (e.g., breathing difficulties, heartburn from gastroesophageal reflux disease, nocturia, pain), but also those sleep disturbances
caused by the pathophysiology underlying the medical condition. Major entries on this list include the
dementias, rheumatological disorders, chronic fatigue
syndrome (CFS), and fibromyalgia. Sleep complaints
are very common in CFS, and can include insomnia,
hypersomnia, non-restorative sleep, and sleeping at
the wrong time of the 24-hour period (e.g., circadian
rhythm abnormalities). Conventional polysomnogram (PSG) findings are generally non-specific and
include decreased sleep efficiency, decreased SWS,
increased sleep latency, and alpha-delta sleep EEG patterns. CFS-related disturbances in regulation of underlying sleep control mechanisms are supported by several studies. One recent study found an increase in
cyclic alternating pattern in the PSG of CFS patients
complaining of non-restorative sleep [38], and there
is also evidence of decreased sleep drive (Process S)
in CFS [51]. Sleep disturbances, usually insomnia and
non-restorative sleep, are also common components
of fibromyalgia, and are not entirely explained by the
pain and depression associated with this syndrome
[52]. Chronic pain is of special concern, as it has been
demonstrated that sleep loss lowers the pain threshold,
and self-reported restorative sleep is associated with
the resolution of pain complaints [53]. Treatments of
sleep complaints in these disorders has been challenging, although recently positive results have been found
in fibromyalgia using sodium hydroxybutyrate, which
enhances GABAergic activity and increases delta sleep.
Dementias including Alzheimer’s disease (AD) are
often associated with severe insomnia that is quite
disruptive to patients and families, and may be one
of the factors precipitating institutional care. Neuropathologic changes of AD in the sleep and circadian rhythm control centers of the hypothalamus
and SCN may contribute to this problem. Sleep is
also disturbed in dementia with Lewy bodies (DLB),
which has been found in up to 20% of dementia
cases referred to autopsy [54]. This disturbance often
104
takes the form of increased motor activity and suggests REM behavior disorder. Body temperature and
activity circadian rhythms can also be altered in the
dementing disorders as a result of characteristic brain
lesions. Alzheimer’s disease has been associated with
a phase delay in both body temperature and activity
rhythms, whereas frontotemporal dementia appears
to produce fragmented sleep with a phase advance
of the activity rhythm, apparently uncoupled from
the body temperature rhythm [55]. Degeneration of
cholinergic neurons in the nucleus basalis of Meynert may contribute to rest–activity disturbances and
the “sundowning” syndrome in AD patients [56].
Pharmacotherapy of AD may contribute as well to
sleep complaints, as tacrine and donepezil are centrally acting cholinesterase inhibitors, and may cause
insomnia.
Psychiatric disorders
Sleep complaints are very frequently comorbid with
psychiatric disorders. Most common is insomnia,
although hypersomnia may accompany atypical
depression. In the case of mood disorders, dysregulation of hypothalamic systems controlling mood likely
overlaps with systems controlling sleep. The striking
and rapid antidepressive response to sleep deprivation,
possibly due to a reduction in brain glutamatergic
systems involving the cingulate, demonstrates the
close relationship between sleep and mood regulation systems [57, 58]. Schizophrenia has also been
associated with a wide variety of sleep disorders,
including both Process S and Process C dysregulation
[17]. Sleep spindles have been found to be deficient
in schizophrenia, possibly reflecting dysfunction of
the thalamic reticular nucleus and thalamocortical
mechanisms [59].
Circadian rhythm disorders
The circadian rhythm disorders include a number of
phenotypes. Patients usually present with an insomnia complaint, but in fact these disorders are caused
by abnormal function of the circadian timing system. Most common is the delayed sleep phase syndrome (DSPS), with onset usually in adolescence or
early adulthood, significant difficulty getting to sleep
at a normal bedtime, and a tendency to sleep late in
the morning. If these patients are required to arise
early, they become sleep-deprived, and complain of
insomnia. Advanced sleep phase syndrome (ASPS),
more common in older persons, is associated with
Chapter 7: Sleep
early waking and early bedtime. Both DSPS and ASPS
are strongly familial, and to date, at least ten abnormalities in the clock genes regulating circadian timing have been found in these disorders [17]. Lack
of circadian entrainment (free-running rhythms) is
found in 50% of blind individuals, although light
can be utilized as a zeitgeber in cortical-blind individuals with intact retinas and retino-hypothalamic
tracts. Appropriately timed melatonin administration
may re-entrain many blind free-runners [60]. Circadian components of chronic insomnia complaints
should be independently identified and treated, primarily with proper sleep hygiene, light therapy, appropriately timed melatonin, or possibly the melatonin
receptor MT1 and MT2 agonist ramelteon. Typical
hypnotic agents are usually not particularly helpful.
Movement disorders
Restless leg syndrome (RLS) and periodic limb movements of sleep (PLMS) are usually considered sleep
disorders, but are perhaps more appropriately thought
of as movement disorders that interfere with sleep.
Restless leg syndrome is associated with both disordered brain iron homeostasis and altered CNS
dopaminergic systems, with genetic influences considered likely [61]. Restless leg syndrome can also be
secondary to a wide variety of other illnesses including renal failure, iron deficiency, neuropathy, pregnancy, multiple sclerosis, and other illnesses [62]. Periodic limb movements of sleep is closely associated
with RLS, but occurs widely in the general population
without sleep complaints, and may imply enhanced
spinal cord excitability [63]. Periodic limb movements
of sleep may be aggravated by a number of antidepressant agents, a point to be kept in mind during its
evaluation.
Conditioned insomnia, sleep state misperception,
and primary insomnia
Insomnia complaints that remain after evaluation and
treatment of the causes outlined above suggest a group
including conditioned insomnia, sleep state misperception syndrome (SSMS), and primary insomnia.
These disorders are grouped together under the term
“psychophysiological insomnia” in the latest International Classification of Sleep Disorders [64].
Conditioned insomnia is precisely as it sounds –
susceptible individuals are conditioned to arouse in
their normal sleep environment, whereas they may
sleep normally in a sleep laboratory. Sleep state misperception syndrome is sometimes termed “paradoxical insomnia,” since patients are unaware they have
been sleeping. Some evidence suggests an increase in
fast activity in the sleep EEG of SSMS patients [65,
66] might account for a preservation of some level of
awareness of mentation during sleep in these patients.
Primary insomnia includes those subjects with
insomnia complaints at least 30 days in duration, not
explained by any other etiology, and associated with
significant impairment of daytime function. Evidence
supporting the notion that primary insomnia represents a state of physiological hyperarousal comes from
a number of studies in such patients that include elevated metabolic activity [67], increased fast EEG activity during sleep [65, 68, 69], and auditory evoked
potential findings supportive of impaired inhibitory
mechanisms during sleep [70]. Additional evidence
includes increased evening cortisol levels [71], elevations in inflammatory markers [72], and increases in
waking whole-brain glucose metabolism [73]. Coortoos et al. have suggested that primary insomnia
might best be considered a state of hyperarousal
affecting both sleep and daytime function throughout
the entire 24-hour period and not just during sleep
[74].
Treatment considerations for the insomnias
Assuming comorbid conditions have been optimally
treated, and Process C components appropriately
addressed, two options remain for treatment of continuing insomnia: behavioral, primarily cognitive behavioral therapy (CBT), and pharmacologic. Cognitive
behavioral therapy has been reported as significantly
effective for many forms of insomnia, including primary insomnia, and should be considered wherever possible [75–78]. Pharmacologic treatments have
improved greatly over the years, with safe and effective medications now available. A decision should
be made as to whether pharmacologic efforts will
be directed at up-regulating the VLPO GABAergic
sleep control systems, down-regulating the ARAS, or
both. Unfortunately, adequate information is not yet
available to enable this decision without some trial
and error. GABAergic supplementation can be provided by benzodiazepine (BZ) hypnotics (triazolam,
temazepam, estazolam, flurazepam, and quazepam)
and newer non-BZ omega-1 agonists (zolpidem, zolpidem ER, zaliplon, and eszopiclone). With both BZ
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Section I: Structural and Functional Neuroanatomy
and non-BZ hypnotics, the half-life is a major consideration in choosing specific agents. Benzodiazepine
hypnotic agents are appropriate in patients who also
have anxiety; for primary insomnia, the newer non-BZ
agents have a better risk–benefit profile.
Other GABAergic agents have been shown to
influence sleep, but are not yet approved for use as
hypnotics. Sodium oxybate, approved for narcolepsy,
increases SWS. Tiagabine, a GABA reuptake inhibitor
that increases synaptic GABA through selective inhibition of the GAT-1 GABA transporter, and is approved
for epilepsy, has been shown to increase SWS in a
dose-dependent fashion in primary insomnia [79].
Gaboxadol is a selective extrasynaptic GABAa agonist, possibly working at the thalamic level, that has
been shown to improve sleep in a phase-advance
model of insomnia [80], but has many adverse side
effects.
Alternative strategies include down-regulation of
the ARAS. Sedative antidepressants have been used
at low doses likely for their antihistaminic and antiserotonergic properties, but have not formally been
studied as hypnotics and are used off-label. Promising drugs are histamine H1 antagonists such as lowdose (3–6 mg) doxepin, which improves sleep in primary insomnia, but has few anticholinergic or antinoradrenergic side effects at this dose [81]. Atypical
antipsychotic agents are used off-label at low doses
likely for the H1 and 5HT2a antagonism, but are probably not drugs of first choice. Several 5HT2a antagonists, which may actually increase SWS, are in clinical
trials, including epilvanserin, volinanserin, and pruvanserin [82]. Orexin antagonists are also in development as possible hypnotic agents [83], based upon the
yet unsubstantiated premise that since underactivity
of the orexin systems leads to hypersomnia with state
instability, overactivity of orexin systems may lead to
insomnia.
A good general rule is to consider GABAergic
hypnotics, and CBT, as first-line approaches for most
insomnias, and switching to and/or adding additional ARAS active sedative hypnotic agents is recommended only if the initial therapeutic response is
inadequate. It may be necessary to use more than one
agent, addressing different mechanisms (e.g., GABA
up-regulation as well as ARAS down-regulation) in
difficult cases. Using the lowest dose possible for
the shortest time possible is standard practice, but
considering the adverse consequences of sleep loss,
106
effective treatment should not be withheld when
necessary.
Hypersomnias
Excessive daytime sleepiness (EDS) is the primary
symptom of the hypersomnias. It is important to distinguish true EDS from fatigue, which can present with
EDS, although those complaining of fatigue will often
not demonstrate short sleep latency on the Multiple
Sleep Latency Test (MSLT). Any disorder (or lifestyle)
that interferes with adequate sleep, or results in fragmented sleep, may present with an EDS complaint,
but most germane to this chapter are the hypersomnia disorders that are thought to result from primary
CNS dysfunction, which include narcolepsy, primary
hypersomnia, and the periodic hypersomnias (e.g.,
Kleine–Levin syndrome). A number of neurological
disorders may have EDS as an associated complaint,
including Parkinson’s disease (PD) [84], and various
infectious diseases, possibly related to cytokine production [85].
The most common cause of EDS (aside from not
getting enough sleep at night – encountered surprisingly often) is a sleep-related breathing disorder, primarily obstructive sleep apnea (OSA). The
hypersomnia of OSA is not considered to be of central origin, but rather secondary to the physiological disturbances associated with repeated respiratory
obstructions. Decreased cerebrospinal fluid (CSF) histamine levels, a likely marker of central hypersomnia (see below), is not seen in OSA [86]. Evidence
of altered cognition or affective regulation associated with the breathing disorder may indicate CNS
involvement, but is more likely secondary to the OSA
syndrome.
Narcolepsy
Narcolepsy is a rare (worldwide prevalence estimated
at 0.02% with some racial and national variation)
but well-known cause of EDS. The primary characteristics of narcolepsy are EDS with uncontrollable
sleep attacks, and evidence of abnormal REM sleeprelated phenomena such as cataplexy, sleep paralysis, and hypnagogic hallucinations (the so-called narcoleptic tetrad). There are thought to be two forms of
narcolepsy, which have been termed idiopathic narcolepsy and symptomatic narcolepsy [87]. The more
common form, idiopathic narcolepsy, has been linked
Chapter 7: Sleep
to an orexin/hypocretin deficiency from neuronal loss
in the hypothalamus, possibly autoimmune in origin.
Narcolepsy is closely associated with the HLA system,
supporting a possible autoimmune basis. The main
predisposing allele is DQB1∗ 0602, which is found in
95% of patients who have narcolepsy with cataplexy
across all ethnic groups. However, this allele is neither necessary nor sufficient for developing narcolepsy
[16]. Genetic variants of narcolepsy with cataplexy also
exist with normal CSF hypocretin levels [88, 89].
Narcolepsy usually appears in late adolescence
or early adulthood in previously healthy individuals. Early symptoms often begin with EDS, and irresistible sleep attacks may occur in school or other
inappropriate places. Within several years episodes
of cataplexy may appear, with loss of skeletal muscle tone in response to anger or emotional excitement. Patients may collapse in a chair or fall to the
ground during a cataplectic episode, and if undisturbed a full-blown REM sleep episode may ensue.
Loss of orexin/hypocretin neurons in the hypothalamus may result in instability of the sleep/wake and
REM-on/REM-off bi-stable switches, thought to be
modulated by the orexins, such that stable wakefulness cannot be maintained, and REM onset may not
be restricted to non-REM sleep periods. Symptomatic
narcolepsy is rare and may accompany or be seemingly caused by a large number of other disturbances
of brain function [87].
The nocturnal sleep in most narcoleptic patients
is often significantly disrupted. Patients are prone to
frequent nocturnal spontaneous arousals as well as a
greater incidence of PLMS and sleep apnea. The sleep
disruption may be related to impaired function of the
sleep/wake and REM-off/REM-on neurophysiological
switches as a result of loss of the orexin/hypocretin
controlling system. Narcolepsy is diagnosed by history and a PSG followed by MSLT. The MSLT will
show decreased mean sleep latency (⬍5 minutes) and
requires two sleep-onset REM periods for diagnosis. Narcolepsy without cataplexy will not have symptoms of REM breakthrough, but will have similar
PSG/MSLT findings [90].
Histamine, a major contributor to vigilance, has
been shown to be deficient in the CSF in narcolepsy,
and may be related to the EDS. The histaminergic system is modulated by orexin/hypocretin, and loss of
neurons may result in decreased histamine and resultant EDS [86]. However, decreased CSF histamine has
also been found in narcolepsy without hypocretin deficiency, thus decreased histamine may also be an index
of central hypersomnia independent of hypocretins
[89].
There is at this time no cure for narcolepsy.
However, in most cases the symptoms can be adequately managed with alerting and, if necessary, wakepromoting agents [91].
Primary hypersomnia
Idiopathic hypersomnia (IH) is a syndrome of persistent daytime somnolence. Patients with this disorder note an increasingly irresistible need to sleep
during the day that leads to prolonged naps. These
naps are lengthy, often 60 minutes or longer, and not
very refreshing. When these patients are not sleeping, they are drowsy and have difficulty concentrating.
This excessive sleepiness occurs after sufficient or even
increased amounts of nocturnal sleep. Two forms of
IH have been described, IH with a long sleep time and
IH without a long sleep time. In the former, patients
have documented EDS in spite of sleep durations
greater than 10 hours, whereas in the latter, patients
have excessive sleepiness documented after a preceding night’s sleep duration of 6–10 hours. Patients with
either form of IH frequently have complaints of “sleep
drunkenness” on awakening.
Idiopathic hypersomnia can usually be differentiated from narcolepsy by the absence of cataplexy,
hypnagogic hallucinations, and sleep paralysis. A PSG
and MSLT are usually necessary to differentiate this
disorder from other causes of EDS. Patients with IH
will usually demonstrate short mean sleep latency
on the MSLT, but not sleep-onset REM periods as
commonly seen in narcolepsy. They also do not have
the HLA genetic markers of narcolepsy or decreased
CSF orexin/hypocretin levels, but they may have
low CSF histamine levels [86]. The etiology remains
obscure.
Periodic hypersomnias
Kleine–Levin syndrome is an uncommon periodic
hypersomnia disorder that is most common in males
and often begins in the teenage years. Typically, the
patient has one or more episodes yearly that are characterized by periods of excessive sleepiness often lasting for weeks. During these hypersomnolent periods
the patient can be aroused from sleep, but when awake,
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Section I: Structural and Functional Neuroanatomy
he or she is confused and agitated and has a loss of
sexual inhibitions [92]. While in this state, patients can
have insatiable appetites, especially when presented
with food. The patient has minimal recollection of the
hypersomnolent period after the episode clears, and
appears to function normally between attacks. Usually, this disorder spontaneously remits by age 40. The
etiology of Kleine–Levin syndrome is unknown, but
disorders of several brain regions, including the thalamus, brainstem, frontal lobes, and hypothalamus, have
been suggested [93]. Infections, trauma, and autoimmune conditions have also been proposed as etiologies
[94].
Electroencephalograms performed during the
wakeful portions of a hypersomnolent episode have
shown mild intermittent slowing of brain-wave
activity. Nocturnal sleep has been reported to lack
Stage III and Stage IV (N3) sleep. Also, shortened
REM latency has been reported, and even occasional
sleep-onset REM periods [95]. Although the results of
CSF analysis are usually normal in these patients, one
study reported that levels of 5-hydroxyindoleacetic
acid are elevated [96], and CSF hypocretin levels
appear normal in asymptomatic patients but were
reported as low in one patient while symptomatic
[97].
The periodic nature of the somnolence, along with
the abnormal behavior, confusion, and compulsive eating, differentiate Kleine–Levin syndrome from other
common causes of excessive somnolence. The clinician
should consider other psychiatric disorders (especially
bipolar disorder and schizophrenia), drug-induced
states, and metabolic and inflammatory disorders in
the differential diagnosis.
Because Kleine–Levin syndrome is self-limited,
many patients are not treated. Stimulant medication
has been useful to treat the somnolence but can worsen
the behavioral problems. Lithium has had some success in prophylaxis of the hypersomnolent episodes
[98].
Menstruation-associated hypersomnia is an
uncommon condition occurring in women who
become periodically hypersomnolent around the
time of their menses. They may awaken only for
bathroom visits and often act uncharacteristically
(e.g., exhibiting withdrawal, apathy, and irritability). After menstruation, these women resume their
regular behavior and daytime alertness. The etiology is not known, but hypothalamic dysfunction is
hypothesized.
108
Parasomnias
The third major category of sleep disorders is the parasomnias, or the strange things that happen during the
night. These events range from the mundane (e.g.,
bruxism (tooth grinding)) or sleeptalking, to the spectacular (e.g., the rare but well-publicized homicidal
incidents occurring during a somnambulistic state).
They clearly represent interesting and sometimes clinically significant yet peculiar interactions of brain function and behavior.
Parasomnias are often grouped into two major categories: (1) primary sleep parasomnias which include
both non-REM (e.g., bruxism, night terrors, somnambulism (sleepwalking)) and REM sleep-related parasomnias (e.g., nightmares, REM behavior disorder),
and (2) secondary parasomnias which represent disorders of function of other organ systems that manifest themselves during sleep. The former category is
emphasized in this chapter, as its underlying disordered sleep mechanisms are beginning to be understood.
Non-REM sleep parasomnias
The most common non-REM parasomnias – night
terrors, confusional arousals, and somnambulism –
are usually grouped together as “disorders of arousal”
(which should not be confused with the disorders of
consciousness discussed in Chapter 6) since they are
thought to reflect partial but not complete activation
of arousal systems such that complex motor behaviors
can occur without conscious awareness or intent [99].
These parasomnias occur mainly in Stage N3 sleep
and thus cluster during the first several hours of sleep.
Night terrors usually begin with a cry at the onset of
a period of intense agitation including motor behavior
(even jumping out of bed) and evidence of physiological arousal including sweating, tachycardia, increased
blood pressure, and dilated pupils. These disorders
of arousal are more common in the immature CNS.
Night terrors begin in early childhood, and somnambulism later in childhood, with most of both resolving
by adulthood, although it is estimated that up to 5%
of normal adults may still experience occasional parasomnias. Recall for such events is usually lacking, and
they are not accompanied by typical complex dream
imagery. Sleepwalking is highly hereditary; if both parents sleepwalk, there is a 60% chance that any child
of the couple will sleepwalk [100]. If only one parent
sleepwalks, the risk is still 45%.
Chapter 7: Sleep
Grillner suggested the term “central pattern generators” (CPG) for ensembles of neurons located
in the mesencephalon, pons, and spinal cord, that
subserve complex behavioral patterns, both motoric
and emotional, when activated [101]. Tassinari and
colleagues have suggested that such CPG neuronal
systems, normally under the control of neocortical
inhibition, may be released with suppression of neocortical inhibition, such as during sleep parasomnias
and epileptic seizures [102]. Such a mechanism may
help explain phenomena such as bruxism, sleep terrors
and somnambulism, although the more complex parasomnias, i.e., those involving driving a car, are clearly
also associated with modulation of motor activity by
concurrent sensory input, even in the absence of consciousness.
Treatment of most disorders of arousal remains in
the domain of protecting the patient from injury, alerting others if possible, and avoiding factors known to
increase frequency (e.g., sleep deprivation, sedatives
such as alcohol). Anticipatory awakenings have been
effectively used in children [103].
Considerable recent interest has been shown in the
“night eating syndrome” first reported by Stunkard
over half a century ago [104]. Two types are described:
the night eating syndrome (NES), characterized by
evening hyperphagia, nocturnal eating, and morning
anorexia, and sleep-related eating disorder (SRED),
characterized by recurrent episodes of eating after
arousal from nighttime sleep with or without amnesia
[105]. Night eating syndrome is thought to represent
an abnormality in the circadian rhythm of meal timing with preservation of normal timing of sleep onset,
rather than a true parasomnia, and has been reported
to respond to sertraline [106]. Sleep-related eating disorder often accompanies other parasomnias, has been
associated with use of zolpidem as well as other sedative hypnotic agents, and has been reported to respond
to topiramate [105].
REM sleep parasomnias
Nightmares are the most common REM sleep parasomnia, but REM behavior disorder is the most
serious. Nightmares are frightening dreams usually
accompanied by intense fear and anxiety. They are
most common in children, and tend to decrease in
frequency with age. They are seen in about 5–8% of
the general adult population, and are more common
in women. Some recent evidence has suggested that
persons with low serum lipid levels (total cholesterol,
LDL, and triglycerides) may be especially susceptible
to nightmares [107].
Severe cases may qualify for a diagnosis of nightmare disorder, and nightmares are common accompaniments of the post-traumatic stress disorder (PTSD)
syndrome. Pharmacologic management has not been
systematically evaluated, although recent evidence
suggests prazosin [108], and possibly topiramate
[109], to be effective in some cases. A manualized
CBT program for chronic nightmares has recently
been described with positive long-term results [110].
Imagery rehearsal therapy has also been described as
successful in treatment of PTSD-induced nightmares
[111, 112].
Of more concern is REM behavior disorder (RBD),
representing an impairment of the descending skeletal
muscle inhibition normally accompanying REM sleep
such that affected individuals may sit up or jump out
of bed and engage in vigorous physical activity during
REM sleep as though they are acting out their dreams.
Such motor activity may result in injury to themselves or others. REM behavior disorder is most commonly encountered in older men. A careful history will
help in differential diagnosis to distinguish RBD from
seizure disorders or non-REM disorders of arousal, as
dream content synonymous with the unusual behavior can usually be elicited. Polysomnogram evidence of
increased motor activity during REM sleep is required
for definitive diagnosis, however. Boeve and colleagues
have recently proposed a pathophysiology of RBD as
indicative of an impairment in the operation of the
putative flip-flop switch involved in REM sleep control
[113].
REM behavior disorder has been associated with
a variety of neurological disorders (e.g., autoimmune,
neoplastic, vascular, infectious), often following the
onset of the other disorder to suggest a pathophysiological commonality. Of concern is the evidence that
RBD can frequently be a harbinger of a subsequent
neurodegenerative disorder, most often PD or DLB,
with an estimated risk of developing one of these disorders of 40% at 10 years [114]. Neurological evaluation and close follow-up may be warranted in these
cases.
Secondary parasomnias
There are a number of additional so-called “secondary parasomnias” that will not be considered here,
including phenomena such as vascular headaches,
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Section I: Structural and Functional Neuroanatomy
“exploding head syndrome,” “hypnic headache syndrome,” and several cardiopulmonary and gastrointestinal parasomnias that interested readers can find
described in more comprehensive textbooks.
Conclusion
This chapter provided a review of the basic neurophysiological mechanisms of wake/sleep systems,
and discussed the relationships between disorders in
the functioning of these complex systems and sleep
pathologies observed in clinical medicine. If disorders
of sleep are approached from the standpoint of the
basic system disturbances that may be contributing
to the phenomenology at issue, more rational treatment programs may be developed that can improve
on approaching the problems from the standpoint of
symptom alleviation alone.
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Section I
Structural and Functional Neuroanatomy
Chapter
Attention
8
Joshua Cosman and Matthew Rizzo
The ability to effectively deal with the overwhelming
amount of information present in the environment
at any given time requires humans to focus on some
things and ignore others. For example, imagine
attempting to read a book in a crowded public place.
This requires the reader to focus on the words on
the page and ignore the sounds of conversations
going on in the background, allowing an effective
focus on the task at hand. The process by which
people can both select relevant and suppress irrelevant
environmental information refers to a number of
processes collectively referred to as “attention.” From
an information-processing standpoint, attention
can be conceptualized as operating not as a single,
monolithic process, but rather a group of more
fragmented, domain-specific processes. For instance,
in the example above, attention is required to select or
suppress information across more than one sensory
modality. In addition, attention can select information
based on its location in space, its identity, or its
relevance to current goals. For this reason, research in
the cognitive and brain sciences has typically focused
on specific subcomponents of attentional processing.
One broad distinction that has been made in the
study of attention has been between the control of
attention (i.e., how attention selects stimuli) and the
subsequent effects of attention (i.e., what is the fate of
stimuli once attended to). Within the domain of control, attentional selection can occur as the result of
cognitive (top-down) or stimulus-driven (bottom-up)
processes. In turn, these selection processes can bias
the way in which information provided by the environment is interpreted. Since the majority of research on
attention has focused on the visual system, the discussion of attention in this chapter will center primarily
on the control of different aspects of visual attention.
However, many of the principles discussed below hold
true for the selection of information across other sensory domains. This chapter will outline relevant behavioral measures related to the control of attention, and
functional theories of attention based on such measures. The major focus will be on the control of visual
attention in both normal and neurologically impaired
individuals, mapping functional theories of attention
onto what is known about the cerebral structures subserving this process.
Control of attention
One of the most important issues in attention research
concerns how attention is controlled. At a basic level,
attention can be considered a sensory gatekeeper,
allowing humans to select and act upon only the subset of sensory information that is most relevant to carrying out specific goals. A familiar example illustrates
this point. When conversing with a friend in a noisy
room, one is able to carry on a normal conversation
despite the milieu of irrelevant sensory information –
in other words, to selectively attend to the conversation. However, if another friend shouts one’s name
from across the room, attention is captured in a nearly
automatic manner, putting on hold the conversation in
which one was engaged.
This scenario highlights two ways in which attention can be controlled. On one hand, you are able to
voluntarily attend to a conversation with your friend –
an example in which you exercise “goal-directed,” or
top-down, control of attention. However, this voluntary focus of attention can be overridden if a sufficiently important stimulus (in this case, the shouting
of your name by another friend) is detected in the environment – a case of “stimulus-driven,” or bottom-up,
Behavioral Neurology & Neuropsychiatry, eds. David B. Arciniegas, C. Alan Anderson, and Christopher M. Filley.
C Cambridge University Press 2013.
Published by Cambridge University Press. 115
Section I: Structural and Functional Neuroanatomy
(A)
(B)
Ti
m
Reaction time (milliseconds)
Reaction time (milliseconds)
e
Valid
Invalid
Cue validity
Valid
Invalid
Cue validity
Figure 8.1. The order of events in Posner’s spatial cueing
paradigm. Observers are asked to detect the appearance of a target
that has been validly or invalidly pre-cued. (A) Peripheral pre-cue
that automatically summons spatial attention to the cued region,
and typical results. (B) Central, symbolic pre-cue that can be used to
voluntarily shift spatial attention to the cued region, and typical
results. Note that in both cases, subjects respond more quickly to
targets that have been validly cued. However, central pre-cues
typically elicit a slower response to the target, reflecting the
voluntary nature of the attentional orienting produced by such
cues.
factors controlling the allocation of attention. This distinction between the bottom-up and top-down control of attention has served as an important concept
informing the study of attention in both cognitive psychology and neuroscience. The following section will
outline the concepts of bottom-up and top-down control of attention, their interaction, and their consequences for subsequent sensory processing.
Bottom-up vs. top-down selection: evidence
from spatial cueing and visual search
Two experimental paradigms have contributed the
most to the understanding of the control of visual
attention: visual search and spatial cueing. In a spatial
cueing paradigm, a stimulus or instruction precedes
the presentation of a target stimulus. This stimulus or
instruction is referred to as a “cue,” and this cue typically either predicts or does not predict the location of
a subsequently presented target stimulus. One widely
used spatial cueing task is that developed by Posner
[1]. In Posner’s cueing task, depicted in Figure 8.1, each
trial begins with a cue intended to orient an observer’s
116
attention to one of several possible locations. The cue
can take the form of either a peripherally presented
“flicker” appearing in a location where a subsequent
target may appear, or may appear as a centrally presented symbol such as an arrow, or a directionally
related word (“left”). After a delay, a target is presented
and observers indicate that they detect the target (e.g.,
by pressing a button as soon as the target appears) or
they discriminate among several targets (e.g., reporting if the target is a “T” or an “L”). On “valid” trials, the cue correctly predicts the target’s location; on
“invalid” trials, the cue is misleading. Observers typically respond to valid trials fastest and invalid trials
slowest, representing a “validity effect” of the cue.
Each of the cues mentioned above are designed to
direct attention to locations in space, but each does
so through different mechanisms. Specifically, peripherally presented cues tap bottom-up attentional control processes, whereas centrally presented cues recruit
top-down processes. This distinction allows for the
examination of bottom-up and top-down influences
on attention independently of one another, and data
from these types of cueing tasks have provided useful
information regarding differences between these two
types of attentional control:
(1) Observers typically cannot ignore peripheral
cues, and these cues attract attention to the cued
location more or less automatically. However,
observers can ignore central cues when
instructed, demonstrating that central cues do
not direct attention in a stimulus-driven manner
and are instead under voluntary control.
(2) Peripheral cues operate more quickly than central
cues, with reaction time differences between
validly and invalidly cued trials emerging sooner
with peripheral cues. This phenomenon reflects
greater processing time required to use central
cues, indicating that these cues require voluntary
and effortful cognitive control.
(3) Peripheral cues have the capacity to interrupt
attentional orienting produced by a central cue,
but central cues exert little effect on orienting
from peripheral cues. This observation indicates
that peripheral cues attract attention more or less
automatically, in a stimulus-driven manner.
(4) Studies that use central cues tend to present more
valid than invalid trials, in an effort to encourage
observers to attend to locations predicted by the
cue. For example when using central cues, 75% of
Chapter 8: Attention
(C)
(D)
Reaction time (milliseconds)
(B)
Reaction time (milliseconds)
(A)
0
4
8
12
Set size (# of items)
0
4
8
12
Set size (# of items)
Figure 8.2. (A, B) Visual search displays and (C, D) typical results
from a visual search task. Panel C shows an efficient search for a
target that differs from distracters on a single feature dimension,
such as color (A). D shows an inefficient search for a target that
differs from distracters on two feature dimensions (B).
trials may include a valid cue, with only 25% of
cues being invalid. By contrast, peripheral cues
attract attention to a location regardless of
validity, even if valid trials are less frequent than
invalid (e.g., 25% valid, 75% invalid). Again,
peripheral cues are shown to summon attention
in an automatic manner.
The other paradigm that has provided insight into
the control of visual attention is the visual search task
(Figure 8.2). Visual search refers to the act of looking for a visual target among distracters – similar to
the process encountered when trying to “find Waldo”
in the popular book series. In a typical visual search
task, the number of distracters, or “set size,” is varied across trials, and reaction time (RT) to detect a
target item is measured as a function of the set size.
An “efficient” visual search results in shallow search
slopes (i.e., set size has little influence on an efficient search), and “inefficient” searches result in steep
search slopes (i.e., set size affects the time taken to
detect a target). These differences in search functions
can be conceptualized as representing the differential
recruitment of bottom-up, stimulus-driven attention
mechanisms and top-down, goal-directed attention
mechanisms.
In the case of an efficient search, the target is typically perceptually distinct from the distracter items.
An example of an efficient search would be a case
where observers are asked to search for a red bar
among green distracters (Figure 8.2A). In this case,
attention would be attracted more or less automatically to the target based on bottom-up factors – in this
example, the bar’s distinctive color. Since the target is
defined on the basis of a distinct perceptual attribute,
this type of search would remain efficient regardless of
the number of distracters present in the array, resulting
in the characteristic shallow slope seen during efficient
search. By contrast, in the case of an inefficient search,
the target is typically less perceptually distinct from the
distracter items. For instance, if an observer were asked
to search for a target based on a conjunction of multiple features (i.e., a red vertical bar among red horizontal and green vertical distracters, Figure 8.2B), the
observer would be forced to carry out a more effortful
search, requiring a greater amount of cognitive control. In this case, bottom-up information is not sufficient to define a target, and observers are required
to adopt a strategy in which each item in the display is treated as a possible target, with each item or
a subset of items being examined until the target is
identified.
Functional models of attentional control
An early explanation for the differential efficiency during visual search was based on serial and parallel processing models, with efficient searches being classified
as “parallel” and inefficient searches “serial.” This conceptualization of search being either serial or parallel
is the core of Treisman and Gelade’s [2] feature integration theory of visual search. In their original model
[2], these investigators proposed that during an efficient search, all items in the array are processed preattentively in parallel – all incoming visual sensory information is processed simultaneously, and the target is
detected in a more or less automatic manner, “popping out” based on its bottom-up salience. This “parallel search” would lead to the shallow search slopes
described during efficient search, since all items in
the display could be processed simultaneously regardless of the number of distracters present. Conversely,
a search in which bottom-up information alone is not
sufficient to identify the target requires subjects to perform a more effortful “serial search.” It was hypothesized that during inefficient searches, observers are
forced to direct attention to each item in the display, with attention to each item being required to
“bind” the two features and identify the stimulus [3].
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Section I: Structural and Functional Neuroanatomy
“Feature maps”
Vertical
Orientation
Horizontal
“Saliency map”
Black
Top-down information
Color
White
“Search for black vertical bar”
Consequently, set size would have a large impact on
target detection RTs, as increasing the number of serially searched items theoretically increases RTs with
each distracter item added to the array.
Although this feature integration model of visual
search provides a straightforward account of search
slope differences between efficient and inefficient
searches, it does not fully account for some findings
in the visual search literature. Specifically, it has been
shown that some “serial” looking processes can arise
from parallel processing mechanisms. For instance, RT
patterns that resemble those seen in serial search can
be produced by limited capacity parallel search mechanisms.
To illustrate this point, imagine that multiple items
in a display can be processed in parallel. However, due
to capacity limitations not all items in the display can
be processed at once. Since not all items in the display
can be searched through in parallel, searching through
many items (large set size) in a display takes longer
than searching through only a few items (small set
size), producing RT slopes that resemble those seen
in “serial” searches. In addition, searches that would
be deemed “serial” by feature integration theory can
be surprisingly efficient, resulting in RT slopes that
resemble parallel searches [4]. Therefore, search is typically discussed with respect to its efficiency, where efficient search leads to shallow search functions (slopes
⬍10 ms/item) and inefficient search leads to steeper
search functions (slopes ⬎20 ms/item), rather than in
terms of serial or conjunction search.
118
Figure 8.3. An illustration of the visually
guided search model of attentional
allocation during visual search. In this
model of attentional control, observers
organize bottom-up information from the
environment into “feature maps” that
code for the identity and location of
features in visual space. This information
regarding stimulus features present in a
scene is combined with top-down
information based on the goals of the
observer to create a “saliency map.” The
saliency map then provides information
on which areas of space are most likely to
contain a particular stimulus in the
environment, preferentially directing
attention to these areas over others. This
model allows the interaction of
bottom-up and top-down information to
bias the control of attention toward
relevant visual stimuli.
To account for results that appeared to be inconsistent with feature integration theory, Wolfe [4, 5] proposed a two-stage “guided search” model of attentional
control (Figure 8.3). As with feature integration theory, the initial stage of processing is carried out preattentively and in parallel across the entire visual field.
From this processing, independent parallel representations of items in the search array are created based
on basic visual features such as color, shape, or orientation. These representations are termed “feature maps,”
and code for all of the features that are present in a
given visual scene. Importantly, these maps also code
for the location that the different features occupy. For
example, if a subject were asked to search for a red bar
among green distracters, all items in the display would
be preattentively processed in parallel. From this processing, a feature map for “color” would be generated
that included representations for items that were both
red and green (since both types of items are present in
the display). In addition to this color information, the
location at which this information was detected would
be represented in the map, providing the observer with
a spatial map of features present in the scene.
In contrast to feature integration theory, in the second stage of processing the bottom-up information
represented in the feature map is combined with topdown information based on the goals of the observer.
This combination, in turn, serves to bias attention
toward particular elements of a visual scene [6]. In the
case of the simple feature search described above, topdown information regarding target identity (i.e., the
Chapter 8: Attention
target is red) is combined with bottom-up information
regarding the location of red items in the display. This
produces an “activation map” or “saliency map” that is
used to direct the limited capacity resources of attention to a location or locations that are most likely to
contain the target item.
The guided search model is important for three
reasons. First, it clears up the serial vs. parallel issues
that are not easily explained by feature integration theory, providing a more plausible explanation of the control of attention during search. Second, the underlying
mechanisms of the model are made explicit and can
be studied empirically. Third, and most importantly,
the model is transparent at a neural level: although
it is based on behavioral research and computer simulation, it maps well onto what is known about the
structural organization of brain regions involved in
attentional control (to be discussed in detail later).
This point illustrates an important principle in neuroscientific research, which is that functional accounts
of cognition should correspond with what is known
about the anatomy of cognitive functions and vice
versa. The following section will focus on the major
forms of attention, and how functional accounts of
these constructs map on to neuropsychological and
neuroanatomical data.
Major types of attention
Having considered how attention is controlled, it is
now important to turn to the types of information
that attention can select. In this section, four different classes of selection will be considered: (1) spatial
attention, in which stimuli are selected based on their
position in space; (2) object-based attention, in which
stimuli are selected based on their identity; (3) attentional selection in visual working memory, in which
attention selects items that will be remembered; and
(4) executive attention, in which attention is involved
in choosing which task or behavior an observer will
perform.
Spatial attention
Attention can be selectively directed toward different
regions in space, a concept traditionally referred to
as “spatial attention.” Spatial attention selects stimuli based on their location in space, allowing stimuli at a particular location to receive further processing. One of the first and most widely used paradigms
in the study of spatial attention is the spatial cueing
task mentioned in the previous section. Recall that
when observers are directed to a specific location in
space, subsequent stimuli appearing in this location
are detected or discriminated better than those appearing in other locations. This phenomenon suggests that
once attention selects a location, stimuli appearing in
that location receive processing benefits over other
stimuli.
One way that spatial attention may exert an influence on stimulus processing at particular locations is
by prioritizing these locations, so that stimuli located
within a particular region are processed before those
in other regions. In a standard spatial cueing task,
the pre-cue draws attention to a particular location,
putting stimuli falling within that region first in line
for further processing. This sequence would result in
the response time patterns seen in spatial cueing trials,
with validly cued targets being detected or discriminated more quickly than those at invalidly cued locations based on the priority settings established by the
cues.
Another way that spatial attention may exert an
influence on stimulus processing at particular locations is by enhancing the perceptual representation of
stimuli at those locations. Since there is a great deal of
noise in the visual system, effective selection of incoming stimuli requires a mechanism that increases the
signal-to-noise ratio in favor of relevant sensory information. At a neural level, this perceptual enhancement
may be achieved through increased firing amplitude
of neurons coding for stimuli at the selected location.
In other words, attention acts as a sensory gain control that effectively “turns up” the neural representation of stimuli in an attended location versus those in
unattended locations, causing these attended stimuli
to stand out [7].
For example, spatial attention has been shown to
change the appearance of items, actually making them
more perceptible. Carrasco and colleagues [8] showed
that directing attention to a location in a display effectively increased contrast for the item falling within
the attended region, thus leading to increased performance on a visual discrimination task. From this
observation it was concluded that attention intensified
the sensory representation of the attended item, producing a stronger sensory impression of the stimulus.
In this way, spatial attention can actually alter the phenomenological perception of objects occupying a particular location.
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Section I: Structural and Functional Neuroanatomy
Figure 8.4. Diagram indicating the region of the brain in which
damage most commonly results in symptoms of visual neglect, the
temporoparietal junction.
It has also been demonstrated that spatial attention
can influence what information is allowed into visual
working memory. If the appearance of multiple visual
objects must be retained in working memory during
a delay period, entry into visual working memory is
necessary for these items to be remembered following
the delay. If the location of one of the visual objects
is cued either before or directly following its presentation, it is more easily remembered than other, uncued
items [9]. Thus it appears that by directing attention to
the location of one of the objects in a display, working
memory is better able to encode the objects for later
recall.
These effects of spatial attention are contingent
on the ability of the attention system to effectively
orient to particular locations in space. This process
has been shown to be deficient in patients with focal
cerebral damage, and these patients have enabled the
study of spatial attention defects. More recently, these
investigations have been complemented by functional
imaging studies, shedding further light on the neural mechanisms responsible for the control of spatial
attention.
The parietal lobes, spatial attention, and neglect
One of the most extensively studied cortical regions
contributing to spatial attention processes is the posterior parietal lobe. Unilateral damage to the human
parietal lobe, especially in the vicinity of the temporoparietal junction (or TPJ, see Figure 8.4), results
in a profoundly disabling syndrome referred to as
neglect or hemineglect [10, 11]. Because neglect
120
most often follows right parietal damage, clinical
symptoms are most evident for the left side of
extrapersonal space or the left side of the patient (i.e.,
left hemineglect). Neglect has been known to occur
following focal lesions to areas other than the parietal lobes, such as the frontal lobes, but most studies of attention in patient populations have focused on
damage to parietal lobe structures. Within the parietal
lobe, there has been debate over what regions are most
crucial to the control of attention. A number of studies have implicated damage to the TPJ in neglect, but
others have associated symptoms of neglect with damage to the superior parietal lobe (SPL). Friedrich and
colleagues [11] directly compared the effects of focal
damage to either the TPJ or the SPL, and showed that
patients with damage to the TPJ were more likely to
display symptoms characteristic of neglect, supporting a central role of the TPJ in the control of spatial
attention.
Patients with neglect typically fail to attend to stimuli falling within the region of space contralateral to
the lesion (the contralesional side of space). In many
cases, individuals with neglect will fail to read words
on the left side of the page, eat food on the left side
of the plate, or shave the left side of the face. Importantly, this failure to attend to stimuli in the hemifield
opposite to the lesion is not the result of visual sensory deficits such as scotoma or hemianopia. Patients
with sensory disturbances alone are aware of their
defects, and therefore will orient to a contralesional
hemifield stimulus in order to compensate for their
impairment. However, patients with hemineglect are
generally unaware of their deficit, and if confronted
with a defect on the impaired side (such as a hemiparesis) may even deny it, a phenomenon known as
anosognosia.
Insights into the nature of the attentional impairments seen in neglect have come from studies using
the attention paradigms discussed above. Posner and
colleagues [12] were among the first to study patients
with right parietal lobe damage using the guidance of
an explicit cognitive theory of attention. Using a spatial
cueing task, they found asymmetries in attentional orienting in patients with right parietal lobe damage, who
were slower to detect invalidly cued targets presented
in the contralesional field. In other words, patients
with right parietal damage were slower to detect targets
appearing in the left hemifield following an invalid cue
in the right hemifield than they were to detect targets
Chapter 8: Attention
Target in right hemifield
Neglect subjects
Normal subjects
Reaction time (milliseconds)
Reaction time (milliseconds)
Target in left hemifield
Valid
Invalid
Cue validity
Valid
Invalid
Cue validity
Figure 8.5. Hypothetical data depicting a typical “disengage” pattern of results on a spatial cueing task. Compared with normal subjects,
patients with parietal lobe damage show slightly slower overall reaction times to targets. Importantly, these patients show a disproportionate
slowing in their reaction time to invalidly cued targets following cues presented in their intact hemifield (note the disproportionate cost of
invalid cues when the subsequent target appeared in the damaged hemifield). These results have been taken as evidence for a role of the
parietal lobe in the disengagement of attention.
appearing in their right hemifield following an invalid
cue in the left hemifield field (Figure 8.5). However,
these patients were nearly as fast to detect validly cued
targets in their contralateral hemifield as they were to
detect targets in their ipsilesional hemifield, suggesting
a disproportionate cost for reorienting attention following invalid cues in the ipsilesional hemifield. Based
on this response asymmetry, Posner and colleagues
[12] suggested that the parietal lobes allow disengagement of attention and that right parietal lesions cause
a “disengage deficit,” that hinders disengagement from
the ipsilesional visual field. Thus, when a cue appears
in the ipsilesional field and a target follows in the contralesional field, a right parietal lobe patient would
have difficulties detecting the target.
This interpretation would predict that patients with
damage to both the left and right parietal lobes would
be equally likely to show symptoms of neglect. However, as discussed above, this is not the case, and severe
or lasting neglect typically results only from damage
to the right parietal lobe. Therefore, alternative theories of the deficits present in neglect have emphasized
competitive interactions between left and right parietal
regions and how this competition affects the control of
attention.
For example, Cohen and colleagues [13] presented
a neural network model as an alternative explanation
of the disengage deficit (Figure 8.6). In their model
[13], neural representations of each visual hemifield
compete with each other for attentional selection.
If the representation of the left field is damaged, it
competes less effectively with the representation of
the right field. As a consequence, when attention is
directed to the right (good) field, a target appearing in
the left (damaged) field is at a competitive disadvantage. Thus, detecting an invalidly cued target appearing in the left field would be difficult. In contrast, when
attention is directed to the disordered left field, a target
appearing in the intact right field could compete effectively for attention, allowing this target to be detected
relatively quickly. Under this account, no mention of
“attentional disengaging” is required. Patients’ behavior appears as though there is a disengagement of
attention, but the mechanism underlying the patients’
behavior is based on competition between damaged
and intact representations of space, not on an “attentional disengager.”
Effects of right parietal damage on visual search are
consistent with results from spatial cueing paradigms.
Eglin and colleagues [14] asked patients with parietal
damage to perform a conjunction search (e.g., color
and shape, see Figure 8.2B) across a number of set
sizes. The patients were much slower to detect target items when the distracters appeared in the ipsilesional field compared with when they appeared in the
contralesional field. In the context of Cohen and colleagues’ model, the presence of ipsilesional distracters
may have prevented the contralesional representation
of the target from competing effectively for attention.
Taken together, these data suggest that the attention deficits seen following parietal lobe damage are
the result of impaired processing of bottom-up inputs
to the attention system. This interpretation does not
necessarily mean that neglect is an elemental sensory
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Section I: Structural and Functional Neuroanatomy
Response
unit
Attention units
(left hemispace)
Perception units
(left hemispace)
Attention units
(right hemispace)
Inhibitory connections
responsible for competition
Perception units
(right hemispace)
Figure 8.6. An illustration based on the neural network that simulates the “disengage deficit” seen in patients with damage to the parietal
lobe by performing a simulated version of Posner’s spatial cueing task. The perception units provide parallel input to both attention units and
a response unit. Spatial cues and targets are presented as input to the model by “turning on” one of the perception units. This activation
propagates through the network and activates the attention and response units. Thus, if a target is then presented to the right perception
unit – an invalidly cued target – the model takes a long time to respond because the right pool of attention units has been inhibited. This
model shows a disengage-like pattern of results because damage to one of the attentional pools impairs these units’ ability to compete with
the intact pool of attentional units. If the right pool of attention units is damaged (e.g., in parietal damage) a spatial cue on the left (which
activates the left pool of attention units) is able to inhibit the right pool of attention units more than if the model was undamaged.
deficit, but rather that it may involve an inability of
the attention system to effectively use bottom-up sensory information in the allocation of attention. Recall
Wolfe’s guided search model, where bottom-up and
top-down inputs are combined to create a salience
map of the visual environment. If the attention system is less able to use bottom-up information from
contralesional space, salient items in that portion of
the visual environment would be less able to compete
for attentional selection. As a result, these items would
not be readily detected and it would take the observer
with neglect longer to respond to them, resulting in
the types of search and detection deficits outlined
above. Therefore, rather than conceptualizing the posterior parietal lobe as an “attentional disengager,” it
may be more accurate to think of this region as being
responsible for detecting salient aspects of the environment, allowing the attention system to reorient toward
them.
Frontal lobe influences on spatial attention
Although neglect has typically been studied in patients
with parietal lobe damage, neglect can also occur in
patients with damage to areas of the frontal lobes.
Specifically, damage to the regions of the dorsolateral prefrontal cortex (DLPFC) has been implicated
in neglect [15, 16]. Husain and colleagues [17] performed a lesion overlap analysis on lesion information
122
from patients with focal frontal lobe damage who
showed symptoms of neglect. The region of greatest
overlap in this analysis was located in a specific area
of the DLPFC, the frontal eye field (FEF). This region
has been implicated in both overt attentional orienting
(attention requiring eye movements) and covert orienting (attentional orienting that does not require eye
movements).
Many studies of damage to the FEF have focused
on the ability of patients with lesions to this region to
overtly direct attention in space. Typically, directing
the eyes to a region of space is preceded by directing
covert spatial attention to the target region [18], and
lesions to the FEF seem to disrupt particular types of
eye movements. In a study by Henik and colleagues
[19], performance on a spatial cueing task was compared between a group of patients with damage to the
FEF and a group of patients with frontal lobe damage that did not include the FEF. In one portion of
the experiment, patients performed a “saccade task”
in which they were instructed to make eye movements
to a peripheral location, indicated by either a central
cue (an arrow) or a peripheral cue (a brief peripherally
located flicker). In another portion of the experiment,
patients performed a detection task in which they were
told to respond to a target by pressing a particular
key, without making saccades. As in the first task, subjects were presented with either a central arrow cue
Chapter 8: Attention
or a peripheral flicker cue, which in this task was followed by the presentation of a target, which observers
responded to with a button press. In both tasks, half of
the cues (central and peripheral) were valid and half
were neutral; there were no invalid cues.
It was shown that FEF lesions disrupted eye movements to peripheral locations, but not all eye movements were disrupted equally [19]. The FEF patients
were slower to make eye movements into the contralesional field than into the ipsilesional field following
central cues. Conversely, following peripheral cues, the
patients with frontal damage that included the FEF
made faster eye movements into the contralesional
field than into the ipsilesional field. However, frontal
lobe patients with an intact FEF made eye movements
into the contra- and ipsilesional field approximately
equally following both central and peripheral cues. The
results from the FEF patients indicate that overt, voluntary orienting to central cues is impaired in this
group, as these patients are only slowed in directing eye movements to the contralesional field following the symbolic arrow cue. Thus the FEF appears to
play a role in the voluntary, or top-down, orienting of
attention.
Further evidence implicating the frontal lobes in
the voluntary orienting of attention comes from a
study by Vecera and Rizzo [20]. In this study patient
E.V.R., a well-known patient with bilateral frontal lobe
damage, performed two spatial cueing tasks. In both
tasks, E.V.R. was instructed to press a key as quickly as
possible in response to the detection of a target appearing on either the left or right side of the screen. In one
task, peripheral cues were used to direct attention to
the location of the target, on either the left or right
side of the display. In the other task, central word cues
(left, right) were used to direct attention to the target
location. It was shown that E.V.R. could use peripheral cues, as evidenced by quicker reaction times to
validly vs. invalidly cued target locations. However,
performance in the central cue task did not reflect any
reaction time differences between validly and invalidly
cued trials, indicating that E.V.R. could not use the
directional information provided by the central cue.
These results suggest that regions of the frontal lobes
are critical for voluntary, top-down attentional control,
with the FEFs being particularly important.
Functional imaging of spatial attention
As already mentioned, top-down or “goal-directed”
attentional processes are those that rely on an
observer’s knowledge about the environment to guide
attention. This knowledge can include previously
learned information (e.g., looking for a friend’s face
in a crowd) or can be based on a particular goal state
(e.g., searching for an empty chair in a crowded auditorium). Conversely, bottom-up, “stimulus-driven”
attentional processes rely on the properties of the
stimuli present in a scene and attract attention on
the basis of some unique visual quality rather than
any cognitive factors. Whereas the patient studies discussed above provided early insights into brain regions
involved in the control of attention, a number of recent
functional imaging investigations have attempted to
more precisely elucidate the mechanisms involved
in both stimulus-driven and goal-directed attentional
orienting.
In an early event-related functional magnetic resonance imaging (fMRI) study by Hopfinger and colleagues [21], hemodynamic responses of observers
were recorded while they performed a cueing task
that used a central cue. In this study, observers were
presented with a central arrow cue that always indicated the location of the target to-be-discriminated.
By using a predictive central cue, it was possible to
isolate the activation of brain structures involved in
voluntary allocation of attention in space. Analyses of
hemodynamic responses to these stimuli revealed that
a number of discrete regions of parietal and frontal
cortex were differentially active during attentional orienting and response. Specifically, regions in superior
frontal and parietal cortex showed increased activity
in response to the presentation of the central cue. This
increased activity was greatest for the FEF and intraparietal sulcus (IPs), suggesting that these regions were
linked in controlling the voluntary orienting of attention to locations indicated by the cue. In contrast to
the more dorsal activation in response to the top-down
information provided by cue, ventral regions of the
prefrontal and parietal cortex showed greater activation in response to the presentation of the target. In
particular, the inferior frontal gyrus (IFG) and inferior parietal lobule (IPL) showed greater activity during target presentation, indicating that these regions
may be involved in the selective processing of stimuli
and subsequent response processes rather than attentional orienting in general.
Further evidence for a dorsal-ventral distinction
between structures supporting voluntary attentional
orienting and stimulus detection comes from a
study in which the neural activity in response to
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Section I: Structural and Functional Neuroanatomy
peripheral and central cues was directly compared.
Kincade and colleagues [22] used a spatial cueing task
in which observers monitored a display for a target
letter appearing on either the left or right side of the
display, responding to the identity of the letter once
presented. Before target presentation, a spatial cue
was presented that could be either valid or invalid
with respect to the subsequent target presentation.
Critically, across blocks of trials the cue could be
peripheral, central, or neutral (no cue), allowing for a
comparison between cues that relied on voluntary and
stimulus-driven shifts of attention. When central cues
were used to direct attention, there was significantly
higher activation in bilateral areas of the FEF and IPs
than in conditions where either peripheral or neutral
cues were presented, consistent with previously discussed findings. Moreover, these same dorsal regions
showed greater activation in response to peripheral
cues as well, suggesting that this dorsal frontoparietal
network mediates both stimulus-driven (bottomup) and goal-directed (top-down) allocation of
attention.
Object-based attention
To this point, our discussion has focused on the control of attention in space. However, attention also may
be directed toward objects. In particular situations,
object selection can take place regardless of where
the object appears, suggesting that object-based and
space-based attention are dissociable processes. When
studying object-based attention, it is important to use
designs that rule out selection by spatial attention,
since by necessity objects occupy locations in space.
For this reason, most studies of object-based attention
have used experimental designs that eliminate or hold
constant the spatial separation between objects.
Although a number of object-based attention
paradigms have been employed in the attention literature, this discussion will be limited to two of the
most widely used tasks. In the “object attribute” task
developed by Duncan [23], observers view a stimulus which includes two overlapping objects: a box and
a line (Figure 8.7). Each object has two features: the
box can be tall or short, and has a gap on either the
left or the right side; the line can be either dashed
or dotted, and can be tilted either to the left or the
right. A box/line stimulus is presented briefly (∼100
ms) and followed by a masking stimulus that disrupts
perception. Observers are asked to report two of the
124
Figure 8.7. An illustration of stimuli used to study object-based
attention. Participants report features from the same object (e.g.,
box height and side of gap) or from different objects (e.g., box
height and line tilt).
four features mentioned above, and the features can
come from the same object (e.g., box height and side of
gap) or from different objects (e.g., box height and type
of line). Observers are typically more accurate when
reporting two features from the same objects than
when reporting two features from different objects.
A second paradigm developed for studies of objectbased attention uses an adaptation of the spatial cueing method already discussed. In a task developed by
Egly and colleagues [24], observers view two rectangles, and the end of one of the rectangles is cued with a
brief flash (i.e., a peripheral cue), followed by a target
item (Figure 8.8). On most trials, the cue is valid and
the target appears in the same location as the cue. Critically, on some trials the target appears at an uncued
location, either within the same object that was cued or
in another, uncued object. Even when uncued targets
appear at the same distance from the cued region of
the rectangle, observers are faster to respond to targets
appearing in the uncued end of the cued rectangle than
at any location in the uncued rectangle. This seems to
suggest that attention automatically spreads across an
entire object, conferring the benefits of attention to any
region located within an attended object.
Results from these studies suggest that space- and
object-based attention can be dissociated from one
another at the behavioral level. A number of patient
and functional imaging studies seem to support this
dissociation, although it appears that portions of the
same attention system responsible for carrying out
space-based attention are recruited during objectbased attention. The next section reviews relevant data
from patient populations and functional imaging studies regarding the neural mechanisms of object-based
selection.
Chapter 8: Attention
e
m
Ti
or
Invalid same object Invalid diff. object
Reaction time (milliseconds)
Valid
or
Figure 8.8. An illustration of the object
cueing paradigm and typical results.
Following a pre-cue, a target appears at
either the cued location (left), at an
un-cued location in the same (cued)
object (center), or at an un-cued location
in the other (un-cued) object (right).
Response times are faster to targets that
appear in the cued object (Invalid Same)
than in the un-cued object (Invalid
Different [Diff.]), even though these two
locations are the same spatial distance
from the cued region.
Valid
Invalid same Invalid diff.
Cue validity
Object-based attention in neglect
As discussed above, patients with neglect due to parietal lobe damage often fail to attend to stimuli falling
within the region of space contralateral to the lesion,
neglecting to read words on the left side of the page
or eat food on the left side of the plate. In addition to
deficits in spatial attention, patients with neglect may
also show deficits in object-based attention. Although
it is possible that some object-based attention deficits
in neglect patients arise as a secondary effect of their
spatial attention deficits, a number of studies have
shown that these deficits can be dissociated in these
patients.
An early study of object-based attention in parietal patients was carried out by Egly and colleagues
[24], as a portion of the study described above. In their
study, patients were placed into two groups based on
the laterality of their parietal lobe lesion; one group
consisted of patients with damage to the left parietal
lobe, and the other group had damage to the right parietal lobe. With the use of a cued detection task identical to that described above (see Figure 8.8), objectbased attention effects were measured between the two
groups. Results showed that the two groups exhibited
different types of attentional impairment in the task.
Both groups showed evidence of impaired disengagement following invalid cues, which would be expected
based on the site of their lesions. However, the two
groups differed in their object-based results. Patients
with damage to the right parietal lobe showed a typical object effect, responding faster to invalid targets
appearing in the cued object than those appearing in
the uncued object. In contrast, patients with damage
to the left parietal lobe showed a larger object effect
in their contralesional field than in their ipsilesional
field, indicating that they had trouble shifting attention between objects when the objects fell within their
contralesional field. The authors suggested that the
performance differences between patients with damage to left and right parietal lobes was due to differential recruitment of left and right parietal lobes during
object-based attentional selection. Specifically, it was
hypothesized that the right parietal lobe may be more
involved in spatial attention processes (since damage
here results in space- but not object-based attention
effects), whereas the left parietal lobe may be more
involved in object-based attention processes.
Functional imaging of object-based attention
The neural mechanisms underlying object-based
attention effects have received a great deal of study
using functional imaging in recent years. In many of
these studies, locations of to-be-attended items are
held constant, as described above, allowing the control
125
Section I: Structural and Functional Neuroanatomy
processes responsible for attention to objects to be
isolated from those involved in attention to spatial
locations. In a functional imaging study reported
by Serences and colleagues [25], observers viewed
a continuous stream of superimposed houses and
faces, presented in the same location at the center
of the display. Observers were asked to selectively
attend to either the house stream or the face stream,
monitoring the streams for one of four possible
targets (two houses, two faces). One of the face or
house targets signaled that attention should remain
on the current stream of objects (the “hold” condition), and the other target signaled that attention
should be shifted to the other object stream (the
“shift” condition). By comparing activations in the
hold and shift conditions, it was possible to isolate
regions involved in object-based shifts of attention.
It was shown that relative to the hold condition,
there was increased activity in bilateral regions of
the superior parietal lobule (SPL) during trials that
required a shift of attention between object streams.
The authors concluded that this response reflected a
transient signal that indicated an object-based shift of
attention.
Further support for the involvement of the SPL in
object-based shifts of attention comes from another
study using an object-based cueing task similar to
that in Figure 8.8 [26]. Observers viewed two rectangles oriented perpendicular to each other, with a
color patch located in both ends of each rectangle,
and were initially instructed to attend to a single
color patch. The color patches changed in color synchronously every 250 ms, and observers were asked
to monitor the stream for one of three particular target colors. One color indicated that observers should
hold attention on the current patch, another indicated
that they should shift attention to the color patch at
the other end of the same object, and another indicated that they should shift attention to the color patch
at the same end of the other object. Overall, activation in bilateral SPL regions was greater for shift trials versus hold trials, consistent with the results of Serences and colleagues [25]. In addition, activation in
the left SPL showed object-based modulation; in trials
that required within object shifts, left SPL activations
were increased relative to trials requiring betweenobject shifts. These data indicate that regions of the left
SPL may be specifically involved in object-based shifts
of attention, a finding consistent with that reported
126
in Egly and colleagues’ [24] study of object-based
attention in a patient with left parietal lobe damage.
Taken together, these results show that some parietal
regions involved in spatial attention processes may also
be responsible for mediating object-based attention.
Additionally, there appears to be a bias toward regions
in the left SPL in mediating the control of attention to
objects.
Attention and visual working memory
Both spatial and object attention involve selection of
perceptual characteristics that do not persist beyond
the duration of the attentional operation. Visual working memory provides a mechanism for the storage of
three to four objects in a more durable form over a
longer period of time [9]. Recent research suggests
that attention is vital for allowing information to enter
into visual working memory, gating incoming sensory
information, and keeping the working memory system
from becoming overloaded.
Evidence for this function of attention – as a gatekeeper for working memory – comes from studies of
an event referred to as the “attentional blink.” In a
typical attentional blink task, observers are presented
with a rapid serial visual presentation (RSVP) of stimuli in which they are asked to detect two targets from
the stream, responding at the end of the stream [27].
Figure 8.9 depicts a typical attentional blink task. In
this example, observers are asked to identify two letters within a stream of numbers, with letter one being
target one (T1) and letter two being target two (T2).
There is a window of time following the detection of
target one where observers fail to detect the presentation of a second target (see Figure 8.9A). However,
if T2 is presented a sufficient time after T1, observers
typically have little problem detecting the target (see
Figure 8.9B). The period of time following the presentation of T1 where subjects are unable to detect
T2 is referred to as the attentional blink because, as
in an eyeblink, there is a brief period during which
targets cannot be detected. Typical results from an
attentional blink task are shown in Figure 8.9C. Note
that the recognition of T2 depends upon the occurrence of T1. If no T1 target appears, observers are
accurate at reporting T2, and there is no attentional
blink.
These results suggest that the attentional blink
arises from an inability to store T2 in visual working
Chapter 8: Attention
(A)
(B)
+
+
F
e
m
Ti
T1
T1
A
A
T
C
C
F
X
T2
X
T
Percent reported
(C)
T2
Figure 8.9. Attentional blink paradigm
and typical results from this paradigm. In
this example, subjects are asked to
monitor the stream of letters and respond
to two targets – the letters A and X. (A)
shows a rapid serial visual presentation
(RSVP) stream of letters and numbers, with
T1 and T2 separated by a single item. (B)
shows the same RSVP task, but T1 and T2
are separated by a greater number of
intervening letters. (C) shows a typical
attentional blink result: After identifying
the first target digit (T1), observers fail to
correctly identify the second target digit
(T2) when it appears shortly after T1, as in
(A). However, if T2 is presented sufficiently
long after T1, as in (B), observers can
correctly identify both targets.
T1
80
70
60
50
T2
40
30
1
2
3
4
5
Number of items presented between T1 and T2
memory. This incapacity is due to the fact that attending to T1 delays the allocation of attention to the second target for a short period of time. Therefore, if
the second target is presented soon after the first, it
cannot be immediately processed and decays before
being stored in working memory. However, as the time
between T1 and T2 increases, processing of T1 is more
likely to be completed by the time T2 appears, allowing
attention resources to be allocated to T2 and resulting
in detection of the second target.
The attentional blink paradigm has been used
in patient populations to shed light on the neural
structures responsible for the type of memory-based
attention outlined above. For example, Husain and
colleagues [17] showed that an increased attentional blink can accompany visual neglect. Eight
subjects with a mean age of 64 years were studied
one month (on average) after a right hemisphere
stroke affecting IPL, ventral frontal cortex (VFC),
or the basal ganglia. All had clinically defined visual
neglect and performed an attentional blink task
similar to that in Figure 8.9. It was shown that the
neglect patients could not identify the second target
in the visual stream until 1.4 s had elapsed after the
identification of the first target, an attentional blink
that was nearly twice that of non-brain-damaged
subjects (540 ms). Based on these results, the authors
concluded that visual neglect is a disorder that affects
the patient’s ability to direct attention in time as well
as space. Furthermore, this study implicated the same
cortical regions involved in attention in space and
attention to objects in higher-level memory-based
attention.
However, Rizzo and colleagues [28] provided
further details in 13 subjects with chronic focal brain
lesions on MRI and nine control subjects without
neurological impairments performing an RSVP task
that used letters as targets. The results showed that
an abnormal attentional blink could occur with
lesions in either hemisphere and persist for years. The
abnormality affected both length and magnitude of
the attentional blink; did not require a lesion in the
parietal lobe, frontal lobe, or basal ganglia; occurred
independently of spatial neglect, and persisted after
spatial neglect resolved. The authors concluded that
an increased attentional blink has no special status
127
Section I: Structural and Functional Neuroanatomy
in neglect, and that the neural mechanisms of spatial
attention that are disrupted in the visual hemineglect
syndrome differ from the neural mechanisms that
underlie the attentional blink. Elucidation of the
neural structures responsible for the type of temporal selection seen during the attentional blink is
an active area of research, with a number of recent
functional imaging studies providing insights into the
neural correlates of memory-based attentional control
[29].
Executive attention and task selection
The last form of attentional selection to be discussed
is the selection of one task from among many possible ones, which also implicates the coordination of
multiple tasks [30, 31]. In all of the paradigms discussed above, observers perform the same attention
task throughout, yet in real life, humans often perform different tasks concurrently or in series, such as
rehearsing a phone number that was looked up, dialing the phone number, and conversing with the person
just called. In general, executive functions control the
focus of attention [32] and the executive system permits the awareness of marked changes in an object or
a scene.
The failure of executive control over attention
has important real-world implications for noticing
changes in the environment, particularly when information load is high. For example, automobile drivers
navigating through complex driving environments
with high traffic and visual clutter would be required
to use the executive system to recognize and cope with
changes in the driving environment [33, 34]. Driver
errors occur when attention is focused away from a
critical roadway event in which vehicles, traffic signals, and signs are seen but not acted upon, or are
missed altogether [35]. Sometimes eye gaze is captured
by irrelevant distracters [36] that may prevent a driver
from seeing a critical event [37], such as an incurring
vehicle or a child chasing a ball. Drivers with cerebral
lesions disrupting the executive system are liable to be
“looking but not seeing” despite low information load
[38, 39].
Considering the multiple tasks involved in a complex task such as driving, executive control is needed
to switch the focus of attention between various critical tasks such as tracking the road terrain, monitoring the changing locations of neighboring vehicles,
128
reading signs, maps, traffic signals, and dashboard displays, and checking the mirrors. This requires switching attention between disparate spatial locations, local
and global object details, and different visual tasks.
Drivers must also switch attention between modalities when they drive while conversing with other vehicle occupants, listening to the radio, using a mobile
phone, and interacting with in-vehicle devices [40].
These attentional abilities can fail in drivers with visual
processing impairments caused by cerebral lesions or
fatigue [32, 41].
Neural systems involved in the
control of attention
Before the advent of functional imaging techniques,
research on patients with focal brain damage provided
a great deal of evidence for brain regions involved in
the control of attention. From this work, a number
of cortical areas involved in attentive processing were
revealed, allowing an early classification of the neural
systems involved in the control of attention [12, 42].
These theories paved the way for functional imaging
studies that attempted to classify the large-scale operations of attention systems involved in the performance
of specific attention-demanding tasks. To this point,
the account has focused on distinct regions of the brain
that play a role in the control of attention. This section
will center on the relationships between these various
regions, describing how specific brain areas directly
interact to form large-scale neural systems responsible
for the control of attention.
A useful organizing concept is Corbetta and Shulman’s [43] model of selective attention, which was
developed by synthesizing large amounts of data from
patient and functional imaging studies, as well as information from early models of attentional selection.
Based on this information, Corbetta and colleagues
have developed a theoretical framework for the neural
mechanisms of attentional selection. In their model,
two separate attentional systems are posited that rely
on differential frontoparietal connectivity, each system being involved in a different aspect of attentional
control. The bilateral dorsal frontoparietal system is
hypothesized to be involved in the overall control of
attention, and consists of the IPs-FEF network shown
to be responsible for the voluntary orienting of attention in response to relevant top-down information.
This system is complemented by a right-lateralized
Chapter 8: Attention
IPs/SPL
FEF
VFC
(IFg/MFg)
TPJ
(IPL/STG)
Top-down control
L FEF
R FEF
Novelty
R VFC
L VFC
Circuit
breaker
Stimulusresponse
selection
L TPJ
R IPs
L IPs
R TPJ
Behavioral
valence
Visual areas
Stimulus-driven control
Figure 8.10. Illustration of a neuroanatomic model of attentional control. Top: diagram indicating brain regions involved in the control of
attention. Bottom: Schematic of the mechanisms of a model of attentional control [43]. The dorsal network (IPs-FEF), indicated by the black
arrows, is involved in the top-down, or “goal-directed,” control of attention. The ventral network (TPJ-VFC), indicated by the gray arrows, is
involved in bottom-up, or “stimulus-driven,” control of attention. The dorsal system is also modulated by bottom-up information, with the TPJ
communicating with the IPs and acting as a “circuit breaker” allowing salient bottom-up information to interrupt voluntary, top-down
orienting, in turn reorienting attention to salient aspects of the environment. Abbreviations: IPs: intraparietal sulcus; SPL: superior parietal
lobule; FEF: frontal eye field; TPJ: temporoparietal junction; IPL: inferior parietal lobule; STG: superior temporal gyrus; VFC: ventral frontal cortex;
IFg: inferior frontal gyrus: MFg: middle frontal gyrus; L: left; R: right. Adapted from Corbetta M, Shulman GL. Control of goal-directed and
stimulus-driven attention in the brain. Nat Rev Neurosci. 2002;3(3):201–15, with permission from Macmillan Publishers Ltd. This figure is
presented in color in the color plate section.
ventral-frontoparietal system that includes regions of
VFC and the TPJ. The ventral-frontoparietal system is
involved in the detection of salient or novel bottomup information, especially with regard to behaviorally
relevant stimuli, and can act as a circuit breaker for
the dorsal system. Specifically, it is hypothesized that
the right TPJ is involved in detecting task-relevant or
salient stimuli outside of the focus of processing, and
through interactions with the IPs in the dorsal system
can cause attention to re-orient in response to these
stimuli (Figure 8.10).
To illustrate this model, consider another familiar
example. Imagine searching the night sky for a particular constellation. In an example such as this, one
uses previously learned information such as the constellation’s location or the way that it typically appears
to guide one’s search. At a neural level, this process
would rely on structures in the dorsal-frontoparietal
circuit. Now imagine that, suddenly, a shooting star
appears in the corner of one’s eye, capturing attention. This event would be detected by structures in
the ventral-frontoparietal circuit, and a signal would
be sent to the IPs to re-orient attention toward the
shooting star. By this account, the dorsal attention system is responsible for the overall control of attention,
but the ventral-frontoparietal system acts as an environmental sensor that picks up on relevant bottom-up
information.
129
Section I: Structural and Functional Neuroanatomy
An appealing feature of this neural model of attentional control is that it maps well onto Wolfe’s guided
search model of attentional control during visual
search [4, 5]. Recall that according to guided search
theory, salient bottom-up information from the visual
field is represented by category-specific feature maps,
with separate maps for features such as color and orientation. In addition, these maps include not only
information about physical features present in the
visual field, but also for the locations of these features,
marking possible areas of interest for the allocation
of attention. This information is combined with topdown information regarding current goals or previous knowledge, forming an overall salience map of the
entire visual scene. This salience map is then used to
guide attention to regions of a scene most likely to
include stimuli of interest.
In the context of Corbetta and Shulman’s model,
the ventral frontoparietal system may act as a saliency
detector that, through reciprocal connections with
visual and association cortices, uses bottom-up information to alert the dorsal system to salient aspects
of the environment. This arrangement would allow
the ventral system to direct attention in a stimulusdriven manner to highly salient stimuli in the visual
field through its interactions with the dorsal system.
Based on the functional imaging findings discussed
above, Kincade and colleagues [22] hypothesized that
the dorsal frontoparietal system is an ideal candidate
for the saliency map described in guided search theory. Through interactions with the ventral system, this
map receives bottom-up information from the environment. In addition, its involvement in goal-directed
attentional control indicates that it directly uses topdown information to direct attention. Therefore, in
the context of guided search components, the dorsal
system (especially the FEF) appears to be a candidate
region responsible for overall saliency coding, representing a possible neural correlate of the saliency map
[44].
Dorsal and ventral attention systems
and neglect
As we have already described in detail, damage to
regions of the parietal lobe, particularly on the right,
results in profound neglect of contralesional space.
How does Corbetta and Shulman’s model of attention
map onto the deficits seen in patients with neglect?
130
Mesulam [45] has hypothesized that the deficits seen
in neglect result from damage to regions that control
the deployment of attention in response to top-down
signals, which in the context of Corbetta and Shulman’s model would imply that neglect arises following damage to the FEF or IPs, or the dorsal attention system. However, data previously discussed show
that neglect is most often the result of damage to the
TPJ [11], a component of the ventral attention system.
Therefore, Corbetta and Shulman have suggested that
neglect more likely reflects damage to the ventral TPJVFC system, an assertion based on the following findings from neglect studies:
(1) Neglect most often arises following damage to
regions of the TPJ, which is part of the ventral
attention circuit [11, 46].
(2) Neglect is more frequent, severe, and lasting
following right parietal lesions. Recall that the
functions of the ventral TPJ-VFC system are right
lateralized, whereas the functions of the dorsal
system are bilateral. The stronger association of
neglect with right parietal damage is consistent
with ventral-system damage.
(3) Neglect patients show impaired inability to
effectively use bottom-up information in the
control of attention, as evidenced by the
“disengage” deficits described above – a function
attributed to the ventral system. However, they
retain the ability to effectively use top-down
information to guide attention, indicating an
intact dorsal attention system [47].
Although this model fits many of the data regarding the deficits seen during neglect, one point of divergence from the literature should be noted. In this
model the ventral frontoparietal system is hypothesized to be right lateralized, with no homologous function attributed to the TPJ-VFC system in the left hemisphere. Therefore, damage to this system would predict bilateral deficits in attentional orienting to salient
bottom-up sensory information by the dorsal IPs-FEF
system.
However, this is not typically the case: there is a
disproportionate deficit in directing attention to stimuli appearing in contralesional space, with a relative
sparing of the ability to orient to stimuli in the ipsilesional field. It is possible that damage to the right TPJ
or underlying white matter could impair communication between the ventral saliency detector and dorsal
Chapter 8: Attention
orienting system, resulting in a functional inactivation
of the right dorsal IPs-FEF system. This would lead to
the same types of “disengage” deficits described above,
with the intact left dorsal attention system more effectively competing for attentional resources. Although
Corbetta and Shulman’s model is tentative, it provides
an intuitive framework for understanding the allocation of attention in response to bottom-up and topdown information. Importantly, this model maps well
onto a widely accepted functional theory of attention,
and is supported by a large amount of converging evidence from patient and functional imaging studies.
Conclusion
Attention is required for focusing on relevant information in the environment, simultaneously suppressing
irrelevant information. By restricting what stimuli are
and are not processed, attention acts as a gating system
that allows us to function efficiently in a highly complex, ever-changing environment. Although the term
attention has traditionally been considered to represent a single, monolithic process, it is clear that attention can and does operate across a number of different functionally defined levels. Whereas it is evident
from the above discussion that many forms of attention have been defined, further research is needed to
better understand both the functional and anatomic
mechanisms involved in the control of these processes.
Using behavioral techniques provided by cognitive psychology, the processes of attention can be
studied rigorously across these multiple domains. By
using well-defined behavioral measures in conjunction
with neuropsychological and neurophysiological techniques, it is also possible to study the multiple components of attention at a structural level, providing further insights into how the brain carries out attentive
processing. This chapter has provided evidence for a
number of cerebral sites that appear to be involved in
the overall control of attention. Understanding how
these sites interact and how they relate to functional
theories of attentional control will greatly increase our
understanding of normal and disordered attentional
control processes.
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Section I
Structural and Functional Neuroanatomy
Chapter
Motivation
9
Brian D. Power and Sergio E. Starkstein
The English term “motivation” was first recorded in
1873, and is defined as “the (conscious or unconscious) stimulus for action towards a desired goal”
[1]. In neurobiological terms, motivation refers to
the behaviorally relevant process that helps to regulate the organism’s internal (e.g., thirst, loneliness)
and external environment (e.g., proximity to water,
proximity to people) [2]. Motivation implies activation of the organism by external or internal stimuli resulting in goal-directed behaviors (e.g., drinking, companionship) [3]. A scheme for the motivated
behavior is considered to involve the following steps:
(a) formulating a goal and an intention to act; (b)
response selection; (c) programming; and (d) initiation that precedes the execution of an action [4].
Cognitive operations of motivated behavior consist of
the following necessary components: (1) attention and
conscious awareness; (2) choice and control; and (3)
intentionality.
Disorders of motivation in humans have been
reported since the nineteenth century [5]. Loss of
motivation constitutes the core symptom of apathy,
a syndrome frequently found among patients with
acute or chronic neurological conditions such as
stroke, traumatic brain injury, and dementia. This
chapter will discuss the neurobiological basis of
motivation. We will first review the most important
findings obtained from animal research (mostly
in rodents and non-human primates) and also
discuss the putative mechanism of motivation in
humans. We will then discuss conceptual issues
that underlie the study of motivation in humans,
and finish with a brief discussion of disorders of
motivation.
Neurobiological basis of motivation
The mechanism of motivated behavior is based on neural structures that attach salience (i.e., allocate importance) and valence (i.e., allocate positive or negative
value) to a given stimulus, and activate and direct
an appropriate behavior in response to that stimulus [6]. Goal-oriented behavior is thought to mostly
depend on the neural connectivity of three relevant
brain regions – the amygdala, nucleus accumbens,
and the prefrontal cortex – with the neurotransmitter dopamine exerting an important influence on the
activity of this neural circuitry [6]. This section will
address the proposed role of each of these neural networks in motivation; before doing so, consideration
will be given to some of the general concepts of the
organization of these networks.
First, it is important to note that motivation or
intentional behavior does not depend on a single brain
structure. Stimulation of a localized brain region may
elicit a variety of motivated behaviors, which is partially related to contextual cues, individual predisposition, and exposure to previous events [7]. For instance,
Berridge [8] demonstrated that motivated behavior
evoked by brain stimulation may be changed gradually by manipulating the animal’s experiences during
the stimulation process [7].
Second, with regard to the hierarchy of structures
involved in motivation, the forebrain is considered to
mediate the “higher” motivational functions and to
interact with “lower” centers in the brainstem that
mediates core functions, such as locomotion, autonomic changes, and emotional responses [9]. Given
the complexity of re-entrant loops in forebrain limbic
Behavioral Neurology & Neuropsychiatry, eds. David B. Arciniegas, C. Alan Anderson, and Christopher M. Filley.
C Cambridge University Press 2013.
Published by Cambridge University Press. 134
Chapter 9: Motivation
Figure 9.1. Schema showing the
mesolimbic and mesocortical DA systems.
wiring [10], Berridge [8] suggested that the relationship is likely to be more complex than the connections
explained by a hierarchical system (e.g., from cortical
centers to subcortical effectors), and proposed a heterarchical organization (i.e., non-hierarchical) to accommodate those circuits involved in motivated behavior.
Dopaminergic systems in the
mechanism of motivation
Dopaminergic systems in the brain have been implicated in numerous neurological and psychiatric disorders, from Parkinson’s disease to schizophrenia.
Dopamine (DA) is considered to play a central role
in the mechanism of motivation and regulation of
effort-related processes, despite the fact that significant discussion is presently underway on the hypotheses related to DA function in this domain [2]. Below we
shall discuss the structure and function of dopaminergic systems and how they relate to the neural circuitry
of motivation.
Brainstem reticular formation and
monoaminergic systems
The brainstem in humans is a small structure that lies
between the spinal cord and diencephalic structures
(including the thalamus, where all sensory modalities,
with the exception of olfaction, feature a synaptic
connection between the periphery and the cerebral
cortex). The brainstem could be considered as a more
sophisticated spinal cord, for it contains somatic and
visceral sensory and motor fibers, as well as the nuclei
of the cranial nerves that primarily subserve the head
and neck. However, surrounding the major tracts and
nuclei of the brainstem are the cells of the reticular
formation that make more extensive connections, and
which confer on the brainstem a functional importance that far outweighs its small size. Within the
reticular formation are three major monoaminergic
systems – the noradrenergic, serotonergic, and
dopaminergic systems – whose efferent axons have
widespread connections with most parts of the
neuraxis.
Although the serotonergic system is the most
extensive monoaminergic system in the brainstem, the
dopaminergic neurons are by far more numerous than
noradrenergic neurons. Further, dopaminergic cells
are highly organized topographically, and, on the basis
of their efferent projections, are classified into two
main systems, as illustrated in Figure 9.1. The mesostriatal system consists of dopaminergic cell bodies
located in the retrorubal nucleus, substantia nigra, and
ventral tegmental area (VTA), which project to striatal and related structures, including the caudate, putamen, subthalamic nucleus, and nucleus accumbens.
135
Section I: Structural and Functional Neuroanatomy
The mesolimbocortical system consists of dopaminergic cell bodies in the VTA, which project to limbic and
cortical areas such as the habenula, amygdala, locus
coeruleus, cingulate cortex, and piriform and entorhinal cortices. Dopaminergic neurons are also found in
other parts of the central nervous system, such as the
zona incerta, hypothalamus, the olfactory bulb, the
retina, and pre-optic areas.
It is postulated that dopaminergic neurons in the
VTA are activated in response to a motivationally relevant event [11]. The dopaminergic system is therefore thought to have an enhancing or energizing effect
on goal-oriented behavior by affecting the target structures innervated by the mesolimbic, mesocortical, and
mesostriatal pathways, thereby placing the behavioral
responses in a state of preparedness [12]. Further, it
is thought that the release of DA at these sites facilitates cellular changes that establish learned associations with the event, thereby reinforcing the behavioral
response should the event re-occur [13].
Experimental work in animals implicating
dopaminergic systems in motivation
The classical studies linking DA to motivation were
based on stereotaxic injections of neurotoxin into the
afferent projections of the mesolimbic and mesocortical pathways, which produced severe aphagia and
adipsia [14]. Since the time of these studies, numerous
means (e.g., pharmacologic, electrophysiological) have
been used to study the effects of altering DA systems on
motivated behaviors, such as hunger, thirst, and sex;
some data remain inconclusive, while the interpretation of other results is the focus of much debate (see
[15], [2], and [16] for review).
Pharmacologic studies suggest a role for DA
in motivation. Pharmacologic enhancement of DA
release in the ventral striatum has been shown to
increase the control by the animal over behavior
exerted by conditioned reinforcing stimuli previously
paired in a Pavlovian fashion with appetite reinforcement [17]. Other pharmacologic studies that implicate DA in motivation include infusion of DA into the
nucleus accumbens altering animal approach behaviors [18], blockade of DA receptors by neuroleptics
impairing intracranial self-stimulation by the animal
[19], and observations of DA increases occurring during goal-directed behaviors for cocaine and natural
reinforcers [20]. It should be noted, however, that there
136
is no clear evidence that antagonism of DA receptors blocks drug-induced euphoria [21]. Brain dialysis studies of DA in the nucleus accumbens and prefrontal cortex (i.e., sampling DA efflux over minutes)
showed an increase in DA efflux in both of these structures before contact with food [22] or sexual reward
stimuli [23].
Electrophysiological studies also suggest a role for
DA in motivation. Neurons in the VTA projecting
to the nucleus accumbens fire selectively in response
to the presentation of reward cues [24]. Animals are
shown to emit very high rates of responding for
intracranial self-stimulation of the VTA [25], eliciting
DA release in the nucleus accumbens [26], and self
stimulation is suppressed by the injection of DA antagonist drugs [27]. Using a combination of electrochemistry, electrophysiology, and iontophoresis, Cheer and
colleagues [28] demonstrated changes in firing and
increased DA release in the nucleus accumbens shell,
occurring for cues signaling award availability, and this
was functionally linked to DA receptor activation.
Further data supporting the role of DA in motivation are the findings that the ventral subiculum powerfully increases DA neuronal activity and elevates DA in
terminal regions of the nucleus accumbens, prefrontal
cortex, and amygdala, possibly via its connections with
the prefrontal cortex [29].
Nucleus accumbens
The nucleus accumbens (originally named, for its
physical location in the brain, the nucleus accumbens
septi, meaning the nucleus leaning against the septum), together with adjacent parts of the caudate and
putamen, constitutes a striatal subdivision termed the
ventral striatum. Whereas the dorsal striatum is considered to be involved in motor processes, the ventral
striatum is considered to be involved in affective and
goal-related behavior [15]. The nucleus accumbens
may be regarded as a striatal nucleus with predominantly limbic connections, and hence a critical structure linking motor and motivational processes [2].
The nucleus accumbens seems to mediate the primary
motivational characteristics of feeding and reproductive behavior as well as reward-motivated behaviors
[30].
The nucleus accumbens contains two functionally
distinct sectors, designated the shell and core [31]. The
shell is connected to the hypothalamus and the VTA,
Chapter 9: Motivation
and plays an important role in unconditioned motivated behavior [32]. For instance, rises of dopamine
in the accumbal shell has been found to precede
goal-directed behavior [33]. On the other hand, the
core is connected with the anterior cingulate and the
orbitofrontal cortex, and may mediate the expression
of learned behaviors in response to stimuli predicting
motivationally relevant events [31].
Depletion of DA in the nucleus accumbens
can interfere with instrumental behaviors in some
conditions, including feeding [2], sexual behavior
[34], and maternal behavior [35]. Further evidence
from animal experimentation implicating the nucleus
accumbens in motivation includes electrophysiological recordings of neurons that were shown to
react to novel and previously reinforced stimuli,
and the fact that DA release increases more robustly
in the nucleus accumbens during reward anticipation
than during reward consumption [36]. Neurons in
the nucleus accumbens show response to impending
rewards that are altered in DA receptor knock-out
mice [37], and by VTA inactivation [38]. Further, DA
efferents from the VTA to the nucleus accumbens
become active with a motivationally relevant event
[39]. Lesions of the nucleus accumbens have been
shown to impair the ability of the animal to increase
the rate of food-reinforced instrumental responding
to a conditioned stimulus previously paired with food
[36].
Taken together, these findings suggest that the
nucleus accumbens plays a pivotal role in the motivation circuits, such as mediating the primary motivational characteristics of feeding and reproductive
behavior as well as reward-motivated behaviors.
Prefrontal cortex
Another critical region in the neural circuit of motivation is the prefrontal cortex, mainly the anterior
cingulate and the orbitofrontal cortices [6]. To better understand the role of the prefrontal cortex in
motivation, one must first consider some of the
wiring paradigms that have been defined, the socalled frontal-subcortical circuits. Frontal-subcortical
circuits are thought to form the main network by
which motor activity and behavior in humans are
mediated, and help explain the similarity of behavioral
changes in frontal cortical and subcortical disorders
[40].
Anterior cingulate
Cortex
Gyrus rectus/
medial orbital gyrus
Striatum
Nucleus
accumbens
Globus pallidus
substantia nigra
Globus pallidus/
substantia nigra
Ventral
pallidum
Ventral
anterior
Thalamus
nucleus
Mediodorsal
Ventral
striatum
Figure 9.2. Schema showing frontal-subcortical loops related to
motivation.
There are five well-defined frontal-subcortical circuits named according to their function or site of origin in the cortex: the motor circuit, the oculomotor
circuit, the dorsolateral prefrontal circuit, the lateral
and medial orbitofrontal circuit, and the anterior cingulate circuit (see Chapter 5). The circuits share many
features in common. For instance, they originate in
the prefrontal cortex, project to the striatum (caudate,
putamen, and ventral striatum); connect to the globus
pallidus and substantia nigra, project to the thalamus,
and are finally closed via projections back to the frontal
cortex. There are also open-loop connections of each
of these circuits, which are thought to integrate information from functionally related sites. Within each of
these circuits there are both direct and indirect pathways, which can modulate input to the thalamus, the
function of which is thought to modulate overall circuit activities in response to different inputs [40].
Limbic system connections involve both the
anterior cingulate and medial orbitofrontal cortex
(Figure 9.2). The anterior cingulate circuit originates
in the anterior cingulate cortex and projects to the
ventral striatum (ventromedial caudate, ventral putamen, nucleus accumbens, and olfactory tubercle).
Efferents from this limbic part of the striatum go
to the rostromedial globus pallidus interna, ventral
pallidum, and rostrodorsal substantia nigra. The
ventral pallidum in turn projects to the ventral
anterior nucleus of the thalamus, and from the thalamus, neurons project back to the anterior cingulate
cortex, thus closing the loop. The open connections
137
Section I: Structural and Functional Neuroanatomy
of the anterior cingulate circuit include inputs from
the perirhinal area and hippocampus, and outputs
to the substantia nigra, lateral hypothalamus, and
subthalamic nucleus. The medial orbitofrontal circuit
originates in the gyrus rectus and the medial orbital
gyrus, and projects to the nucleus accumbens, ventral
pallidum, and the mediodorsal thalamic nucleus in
a closed loop fashion; open connections include the
ventral striatum and amygdala.
This prefrontal cortical region has a primary role
in goal-directed behavior and affective processing [41].
More specifically, the prefrontal cortex may regulate
the motivational salience of stimuli and determine the
type of behavioral response [42]. Furthermore, the
nucleus accumbens and the prefrontal cortex have
reciprocal connections by which the prefrontal cortex may engage the nucleus accumbens to process
motivationally salient stimuli [43]. Ventura and coworkers [44] demonstrated that norepinephrine projections from the prefrontal cortex modulate DA levels
in the nucleus accumbens, which, in conjunction with
the DA mesolimbic system, may play an important role
in attaching motivational attribution to award- and
aversion-related stimuli.
Amygdala
The amygdala (derived from the Greek word for
“almond” and named for its size and shape) is a collection of nuclei originally considered to be part of the
basal ganglia, as in the temporal lobe it is adjacent to
striatal structures (the tail of the caudate is continuous
with the amygdala, which in turn is continuous with
the putamen). Although the amygdala does have
some connectivity with the striatum, its pattern of
connectivity is more typical of limbic structures, and
the amygdala forms one of the central components of
the so-called lateral limbic system. The amygdala is
situated below the uncus, at the anterior end of the
hippocampus, and at the inferior horn of the lateral
ventricle. It receives its main afferents from the inferior
visual temporal cortex, the superior temporal auditory
cortex, the cortex of the temporal pole (involved in
the regulation of behavior), as well as from taste and
auditory cortical centers. The main efferents of the
amygdala are to the hypothalamus, autonomic centers
of the medulla oblongata, the nucleus accumbens
in the ventral striatum, and areas of the temporal
insular and orbitofrontal cortices. The amygdala is
138
thus positioned to receive polymodal information
from sensory regions and influence motor, autonomic,
and endocrine systems. These connections allow the
amygdala to influence drive-related behaviors and the
subjective feelings that accompany them.
Experimental data obtained from animal models
support the role of the amygdala in motivation, with
lesions of the central nucleus impairing the acquisition
of learned orienting response to visual conditioned
stimuli paired with food [45], and impairing the ability of a cue previously paired with food to increase the
rate of food-reinforced instrumental responding [46].
Further, inactivation of the basolateral amygdala abolishes the increase in nucleus accumbens DA resulting
from presentation of a stimulus previously associated
with a reward [47].
The amygdala is thus considered a relevant region
in the mechanism of goal-oriented behavior [6], and
is traditionally considered to be primarily involved
in fear-motivated behavior. The amygdala may mediate those processes that associate motivationally relevant events with otherwise neutral stimuli, which later
become predictors of that specific event (i.e., the conditioned stimuli) [48]. The role of the amygdala in
motivated behaviors may be inferred by the behavioral
manifestations of the Klüver–Bucy syndrome produced by bilateral lesions of the amygdala, which usually results in tameness and lack of emotional responsivity.
The physiology of motivation
Jahanshahi and Frith [4] proposed a “willed action
route,” through which “goals and plans lead to formulation of intentions, which result in initiation of
appropriate actions . . . and production of a response.”
The dorsolateral prefrontal cortex, the anterior cingulate, and the supplementary motor area were suggested
as the key cortical components of this route, with the
thalamus and basal ganglia as its main subcortical
components.
Using functional magnetic resonance imaging
(fMRI), Epstein and co-workers [12] found that
depressed patients had less activation of ventral striatal regions compared with healthy individuals, and
there was a significant correlation between patients’
failure to show brain activation to positive stimuli and
loss of interest and motivation. The authors speculated
Chapter 9: Motivation
that the relatively low ventral activation in depressed
patients may be related to deficits translating motivational information into behavior.
Habib [49] proposed that a subset of the basal ganglia may subserve motivational functions in humans
through previously described frontal-subcortical
loops underlying motor acts, emotional expression,
and cognitive activity. The main circuit considered
to be involved in human motivation consists of
projections from the anterior cingulate to the ventral
striatum, the ventral globus pallidus, the dorsomedial
thalamus, and back to the anterior cingulate. This
striato-pallidal circuit is considered “an interface
between motivation and action” [50], as well as the
site of “conversion of motivational processes into
behavioural output” [51]. Habib suggested that the
crucial role of the “limbic striatopallidum” depends
on relevant inputs from the amygdala (involved in
“emotional labelling” of sensory stimuli) and the
hippocampus (involved with comparing new information with biographical data). In turn, output from
the striato-pallidum projects to sections of the basal
ganglia involved in initiating and organizing motor
behavior.
Habib [49] explained loss of spontaneous action
and poverty of thinking (which he labeled “athymormia”) as due to cortico-subcortical lesions disconnecting the anterior striatum from cortical afferents.
The main connection runs from the anterior cingulate to the nucleus accumbens, and lesions of these
structures may result in loss of initiative and spontaneous action, decreased interest and drive, and emotional blunting [52]. Bilateral lesions of the thalamus
may also result in loss of motivation, but this is usually
accompanied by cognitive deficits [49].
Laplane and Dubois used the term “loss of psychic auto-activation” [53] to refer to a deficit in spontaneous activation of mental processing, observed
in behavioral, cognitive or affective domains, which
can be totally reversed by external stimulation that
activates normal patterns of response. Brown and
Pluck [54] stressed that loss of motivation in humans
does not result from lesions in any single structure,
given that motivated behavior results from complex
cortico-subcortical networks. They suggested that the
auto-activation deficit usually results from damage to
pathways linking the ventral striatum to the anterior cingulate, caudate nucleus, and the orbitofrontal
cortex.
Limitations of current models of the
neurobiology of motivation
The fronto-subcortical circuit proposed to mediate
motivation is not fully segregated, and connections
between different circuits are the rule. Complex reentrant loops connect the nucleus accumbens, ventral pallidum, hypothalamus, amygdala, septum, hippocampus, VTA, cingulate and prefrontal cortex, with
other forebrain limbic structures [8].
From a conceptual standpoint, it is important to
consider how internal and external triggers “motivate”
behavior. This interaction may not be problematic for
basic or instinctive behaviors (e.g., feeding and sexual
behaviors), although these behaviors are better considered reflex or automatic rather than motivated. More
difficult is to conceptualize how complex goals and
projects may engage a “motivation system,” given that
goals, plans, and projects are all psychological concepts while behavior is instantiated by complex neural
networks. Another concern is that motivation circuits
should be in close functional association with systems
mediating mood and arousal, given the well-known
impact of mood and anxiety disorders upon motivated behavior. However, little is yet known about this
association.
Loss of motivation
Diminished motivation is a common finding of the
aging process and neurodegenerative brain conditions.
In 1991, Robert Marin [55] reported a series of patients
with stroke, Parkinson’s disease, or Alzheimer’s disease who had comorbid loss of motivation in the
absence of depression. He proposed apathy as an independent syndrome characterized by (1) deficits in
goal-directed behaviors [55] as manifested by lack of
effort, initiative, and productivity, (2) reduced goaldirected cognition, as manifested by decreased interests, lack of plans and goals, and lack of concern about
one’s own health or functional status, and (3) reduced
emotional concomitants of goal-directed behaviors, as
manifested by flat affect, emotional indifference, and
restricted emotional responses to important life events
[55]. Starkstein organized these symptoms into a set
of diagnostic criteria, which were validated for use in
Alzheimer’s disease and stroke [56] (Box 9.1). Similarly, van Reekum and co-workers divided apathy into
emotional, cognitive, and behavioral domains [57].
139
Section I: Structural and Functional Neuroanatomy
Box 9.1 Diagnostic criteria for apathy. Adapted
from Starkstein SE, Leentjens AF. The nosological
position of apathy in clinical practice. J Neurol
Neurosurg Psychiatry 2008;79(10):1088–92, with
permission from BMJ Publishing Group Ltd.
A. Lack of motivation relative to the patient’s
previous level of functioning or the standards of
his or her age and culture, as indicated either by
subjective account or observation by others.
B. Presence for at least four weeks, during most of
the day, of at least one symptom belonging to
each of the following three domains:
Diminished goal-directed behavior
1. Lack of effort or energy to perform everyday
activities.
2. Dependency on prompts from others to structure
everyday activities.
Diminished goal-directed cognition
1. Lack of interest in learning new things, or in new
experiences.
2. Lack of concern about one’s personal problems.
Diminished concomitants of goal-directed behavior
1. Unchanging or flat affect
2. Lack of emotional responsivity to positive or
negative events.
A. The symptoms cause clinically significant distress
or impairment in social, occupational, or other
important areas of functioning.
B. The symptoms are not due to diminished level of
consciousness or the direct physiological effects
of a substance.
Diagnosis of loss of motivation
One of the main limitations to the diagnosis of apathy is that structured clinical interviews and valid
diagnostic criteria have only recently been developed.
Thus, most assessments of apathy in clinical samples use scales to measure the severity of this condition. The Apathy Evaluation Scale was developed by
Marin and co-workers [58], and consists of three sections, rated by an informant, the examiner, and the
patient. The Apathy Scale developed by Starkstein and
co-workers [59] is an examiner-rated scale based on
Marin’s instrument. Robert and co-workers developed
140
the Apathy Inventory [60], which is structured similar
to the Neuropsychiatric Inventory [61] and has been
used to rate apathy in Parkinson’s disease. Strauss and
Sperry developed the Dementia Apathy Interview and
Rating [62] to assess apathy among individuals with
cognitive decline. To our knowledge, the Structured
Clinical Interview for Apathy [63] is the only standardized assessment for this condition. This instrument is assessed with the patient and an appropriate
informant, but information from other sources, such
as patients’ medical records or information from other
medical providers, is also considered. This instrument
has been validated for use in dementia, but it is currently used in Parkinson’s disease and stroke as well.
Finally, diagnosis of apathy may be carried out using
the diagnostic criteria proposed by Marin and modified by Starkstein and Leentjens [64] (Box 9.1). This
set of criteria has been already validated for use in
dementia.
Conclusion
Motivation is a complex construct that is expressed
in a wide variety of behaviors, ranging from instinctive behavior in mammals (e.g., feeding, fight or flight
reactions), to complex human behaviors. The neuroanatomy of motivation is being increasingly clarified. Critical regions for motivation include the amygdala, nucleus accumbens, and prefrontal cortex, and
the neurotransmitter dopamine plays an important
role. Loss of motivation is a cardinal symptom of
depression, but is also a conspicuous finding in many
acute and chronic neuropsychiatric disorders such as
traumatic brain injury, stroke, dementia, and Parkinson’s disease. The diagnosis of apathy is still fraught
with methodological limitations, but valid and reliable structured interviews and diagnostic criteria are
now being developed. A better knowledge of the
brain mechanisms of motivation coupled with adequate diagnostic instruments will enhance the search
for better treatments for this condition.
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Section I
Structural and Functional Neuroanatomy
Chapter
Perception and recognition
10
Benzi M. Kluger and Gila Z. Reckess
The wind was flapping a temple flag. Two monks were
arguing about it. One said the flag was moving; the
other said the wind was moving. Arguing back and
forth they could come to no agreement. The Sixth
Patriarch said, “It is neither the wind nor the flag that
is moving. It is your mind that is moving.” The two
monks were struck with awe.
Zen Koan
In this chapter we will discuss the processes by
which we come to know the environment, namely sensation, perception, and recognition. Although seemingly effortless, these computational tasks are remarkably complex. For instance, we can recognize the face
of a friend in the midst of a crowd or distinguish their
voice despite significant background noise. While we
typically take these abilities for granted, there are many
symptoms and syndromes in Behavioral Neurology &
Neuropsychiatry (BN&NP) in which specific aspects
of perception or recognition are disrupted.
The study of perceptual processes is historically
one of the oldest fields of inquiry within psychology
and neuroscience, and thus is one of the most highly
developed. A comprehensive overview of what is currently known about perception would not be feasible
within the confines of a single chapter. Therefore, we
have endeavored to provide a concise, broad overview
of the functional anatomy underlying perception and
recognition within each of the five primary perceptual
systems. To facilitate discussion of each system, we
will first begin with an overview of shared terminology
and general organizational principles, followed by
an introduction to classes of perceptual disorders.
Clinical cases have provided valuable insight into
normal and pathologic mechanisms subserving
each sensory system. Conversely, understanding
the structural architecture of sensory systems and
behavioral correlates of normal and abnormal connectivity is essential for localizing anatomic and
behavioral abnormalities. Therefore, for each sensory system we will first review the general functional
neuroanatomy, followed by an overview of related syndromes that readers may encounter in the literature or
clinic.
Defining perception and recognition
Rather than engaging in a philosophical or semantic debate about the definitions of perception and
recognition, we define these processes on the basis
of their relatively concrete neuroanatomic and neuropsychological elements. The first of these is sensation, which involves transduction of external stimuli
to neural signals and transmission of this information
to the central nervous system (CNS). Basic sensory
information includes stimulus timing (onset and offset), magnitude, location, and basic qualitative information related to the sensory modality. Perception
builds upon basic sensation by extracting more complex attributes from sensory elements. For example,
visual perception includes the ability to detect motion,
differentiate colors, and distinguish basic forms. Primary sensation, however, is not a necessary precondition for perception, as demonstrated by internally generated perceptual phenomena such as hallucinations
or imagery.
Recognition involves identification of a sensory
stimulus via access to and integration of stored representations of previously encountered stimuli. Recognition may be seen as a form of memory, and clearly
involves learning and access to prior knowledge [1].
Behavioral Neurology & Neuropsychiatry, eds. David B. Arciniegas, C. Alan Anderson, and Christopher M. Filley.
C Cambridge University Press 2013.
Published by Cambridge University Press. 144
Chapter 10: Perception and recognition
Moreover, the role of learning in perception requires a
certain degree of plasticity within these systems, which
may allow for improved rehabilitation strategies [2].
We purposefully avoid conscious awareness as a
criterion for our definitions of perception and recognition given that stimuli do not have to be consciously perceived in order to influence behavior or
other neurophysiologic outcomes. Perceptual priming, for example, is a well-established phenomenon in
which behavior is influenced by stimuli that are not
consciously perceived [3]. Many aspects of perception
and recognition are not passive, however, and require
active allocation of attention and coordination of perceptual and motor systems. For example, the ability to
recognize complex objects such as faces requires elaborate visual scanning to identify both global and local
features [4]. In contrast, autistic individuals have a disorganized scanning pattern and spend less time fixating on critical facial areas such as the eyes [5].
Organizational principles
All of our sensory and perceptual systems share certain
organizational principles. Knowledge of these principles is helpful in understanding both the basic neuroscience of these systems, as well as understanding
pathological syndromes. Sensation begins with the
transduction of energy (in the case of hearing and
vision), pressure (in the case of touch) or the detection of molecules (in the case of chemosensation –
i.e., taste and smell) to neural signals by specialized
receptor neurons. These receptor neurons then transmit sensory information to the CNS. This information is quantitatively coded in that stimuli of larger
magnitudes typically induce higher firing rates (also
known as frequency coding). It is also qualitatively
coded based on the location of the receptor type that
originated the signal (also known as location coding).
This is true across modalities as well as within modalities. For example, sensory pathways mediating light
touch remain distinct from those mediating vibration
from peripheral neurons all the way through the primary sensory cortex.
At the earliest stages of perception, sensory input
is refined through center-surround inhibition. For
example, if a beam of light hits the retina, stimulated
cells will also inhibit neighboring cells. This mechanism allows for detection of edges (in vision and
touch), fine-tuning of sensory input, and progressive refinement of accuracy. Neurons at progressively
higher levels of the CNS are tuned to detect more
complex features, typically through combining input
from multiple lower level neurons. For instance, while
retinal neurons may detect light in a particular area,
their projections in primary visual cortex are tuned to
detect lines in a particular orientation anywhere on the
retina.
Sensory input is typically transmitted via a combination of serial and parallel circuitry. Most sensory
systems project to the contralateral thalamus en route
to primary cortical sensory areas. Mesulam [6] proposed a schema for dividing cortical areas into primary
sensory cortex, unimodal cortex, and transmodal cortex (including heteromodal, limbic, and paralimbic
cortices). In this model, the primary sensory cortices
are the entry point of sensory information into cortical circuits and initiate modality specific perceptual
processing. Information then travels in parallel to multiple unimodal association specialized to accomplish
a particular perceptual or recognition task. Transmodal processing areas receive input from multiple
sensory modalities to accomplish higher-order recognition, emotional or behavioral goals. In this chapter
we will focus primarily on primary sensory and unimodal cortex. Examples of transmodal cortex include
Wernicke’s area, the entorhinal-hippocampal complex,
and posterior parietal cortices.
Although traditional texts suggest that information
flow is unidirectional in sensory systems, progressing
from sensory neurons through polymodal association
areas, more recent evidence demonstrates that there
are multiple layers of both top-down and bottom-up
reciprocal communication between primary sensory
and unimodal areas [7]. Similarly, top-down influences from the prefrontal cortex have been demonstrated to modify many aspects of perception and
recognition [8].
In addition to specialized cortical modules dedicated to certain perceptual or sensory functions, there
are extensive connections between these modules. As
we will discuss below, perceptual dysfunction may
occur without damage to modules but from their disconnection from either afferent sensory input or efferent output to higher-order stores of verbal and nonverbal information [9, 10]. More recent research suggests that certain forms of information processing
depend not only on the basic architecture of intermodal circuitry, but also on its temporal properties.
For example, lesions that disrupt the timing of reciprocal communication between cortical areas, or cortical
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Section I: Structural and Functional Neuroanatomy
and subcortical areas, may be sufficient to disturb normal perception and recognition. These clinical observations are consistent with basic research on the binding problem, which asks how functionally and structurally modular perceptual systems become integrated
[11, 12].
Disorders of perception and
recognition
Acquired brain damage and developmental abnormalities may affect each level of processing discussed
above, including primary sensation, cortically mediated perception, or higher-order aspects of perception or recognition. A useful distinction can be made
between negative syndromes, those in which there is a
failure to correctly perceive some element of the environment, and positive syndromes, those in which a
patient perceives stimuli or stimulus features in the
absence of associated external sensory input.
Although relatively rare, the agnosias are among
the more extensively studied negative perceptual syndromes and have provided invaluable insight into the
functional neuroanatomy of perception and recognition. Agnosias are characterized by profound impairment in perceiving, identifying, and/or recognizing
stimuli in the context of relatively unimpaired language, attention, and primary sensation. Therefore, an
important part of making this diagnosis is to exclude
other more general causes of perceptual disturbances.
Additionally, agnosias are most commonly modality
specific, which allows one to demonstrate that higherorder cortical processes are intact. For instance, a
patient with a tactile agnosia may be unable to recognize a key placed in their hand but can recognize the
sound of jangling keys or a picture of a key.
Lissauer [13] drew a distinction between apperceptive agnosias, in which patients are limited by perceptual disturbances, and associative agnosias, in which
patients are unable to attach appropriate concepts or
meaning to perceptual objects. These syndromes are
often difficult to distinguish, but can be differentiated
if one tests the perceptual abilities necessary for recognition. For example, patients with visual associative
agnosia can copy drawings of objects but cannot identify, name, or categorize objects; those with apperceptive agnosia are often unable to even copy simple object
drawings, or do so in a manner that disregards the
natural groupings of parts of objects. Lissauer’s initial model continues to form the basis of theories on
146
agnosia. However, it is now clear that this dichotomous
distinction is an oversimplification. For example, there
is now considerable evidence of perceptual deficits in
patients with associative agnosia as well [14].
A further categorization of agnosias is integrative agnosias, characterized by a recognition deficit
attributed to the inability to incorporate the parts of an
object into a global percept. A classic example is simultanagnosia (as seen in Balint’s syndrome), in which
patients with bilateral lesions of the occipitoparietal
cortices are able to identify individual objects but
are unable to recognize a larger scene. For example, when shown a picture of a picnic they may
report seeing a blanket, a sandwich, or ants. There
is some controversy about a final class of agnosia,
termed category-specific agnosias, such as selective
recognition impairment for living versus non-living
things. Determining the characteristics of objects
affected by category-specific agnosias remains elusive,
as patients with agnosia for “living things” often have
difficulties with musical instruments but not body
parts [15].
Positive symptoms may be classified as either illusions, which are misinterpretations of existing stimuli, or hallucinations, which are perceptions that arise
independently of external stimuli. Some authors further distinguish between hallucinations and pseudohallucinations, the latter of which are associated with
preserved insight into the hallucination’s disconnection from objective reality; however, pseudohallucinations is not a universally accepted term. Hallucinations
may be divided into release hallucinations, which are
believed to arise from the release of perceptual areas
from inhibitory input, and hyperexcitable or irritative hallucinations, which arise from excessive stimulation. Based on recent, sophisticated physiological
models, Behrendt and Young [16] proposed that hallucinations are due to aberrant thalamocortical communications, leading to under-constrained perceptual processing. Release hallucinations may arise from
destructive lesions at any level of the CNS, ranging
from environmental sensory deprivation and peripheral nerve lesions to higher-cortical transmodal areas.
Irritative hallucinations classically arise in the setting
of ictal phenomena in epilepsy. Similar principles may
apply to the balance of excitatory and inhibitory neurotransmitters impinging on perceptual areas in the
setting of psychiatric disorders and pharmacologically
induced hallucinations [17]. From a clinical standpoint, ictal hallucinations are characterized by their
Chapter 10: Perception and recognition
brevity (seconds to a few minutes), stereotypic nature,
and frequent association with other alterations in consciousness or post-ictal confusion; in contrast, release
hallucinations are of longer duration, more variable
with regard to their content, and may be associated
with other fixed perceptual deficits.
Although we will not discuss the physiology of
perception in dreams, there appears to be a strong
relationship between alterations in sleep and arousal
systems and hallucinations. In peduncular hallucinosis, patients with strokes in the midbrain develop
hallucinations (predominantly visual) in association
with disturbances of arousal [18]. Similarly, hallucinations may be associated with primary sleep disorders (including narcolepsy) [19], secondary sleep disorders as in the setting of Parkinson’s disease (PD) [20],
and even in normal individuals who are sleep-deprived
[21].
Vision
The paramount importance and inherent complexity
of visual perception is evident in the sheer magnitude
of cortical representation of this sensory system. More
than one quarter of the cerebral cortex is involved in
vision and vision-related processes, and more than 30
cortical areas with vision-related function had been
identified by 1991 [22], only some of which will be
highlighted in this section.
Multiple systems of nomenclature are often used in
reference to subregions within the visual cortex. Brodmann’s area (BA) 17, located along the banks of the
calcarine fissure, is the primary visual cortex. It is also
referred to as striate cortex due to the visibly pale striation of myelinated axons within the fourth of its six
principal cortical layers. Consequently, visual association areas (BA18 and 19), which do not contain myelinated striations, are collectively referred to as extrastriate cortex. Additionally, subdivisions within
human visual cortex are often referenced based on
functional mapping studies in macaque monkeys,
although the functional and structural correspondence of these areas may not be conserved across
species [23]. Based on functional mapping, BA17 is
equivalent to V1, BA18 includes V2 and V3, and BA19
includes V3a, V4, and V5.
The primary visual pathway
The central, or primary, visual pathway refers to the
series of connections through which input is relayed
from the retina to the visual cortex. Stimulus-initiated,
or veridical, visual perception begins when light passes
through the cornea, iris, and lens and is detected by
photoreceptors (rods and cones) in the outermost layer
of the retina. Visual input is inverted and reversed
by the lens as it is projected onto the retina. Therefore, cells in the lower left portion of each retina process light from the upper-right portion of visual space.
There is considerable overlap between the visual fields
of each eye, which enables binocular vision and facilitates depth perception.
Axons of retinal ganglion cells exit the retina via
the optic disk and form the optic nerve (though technically not a “nerve” since the retina is actually part
of the CNS). Axons from the medial half of each
retina, or nasal hemiretina, decussate at the optic chiasm and project to the opposite cerebral hemisphere;
axons from the temporal hemiretina (lateral to the
fovea) do not cross. As a result, each cerebral hemisphere receives visual input from both eyes, with each
hemisphere exclusively processing information from
the opposite visual field.
Posterior to the optic chiasm, retinal ganglion
fibers are referred to as the optic tract. The majority of these fibers terminate in the lateral geniculate nucleus (LGN) of the thalamus as part of the
central visual pathway. Although traditionally viewed
as a simple relay station, the LGN may itself have
a more active role in perception [24]. In fact, retinal input only accounts for 10–20% of input to the
LGN [25]. Optic tract fibers also project to at least
nine other targets [26] that contribute to functions,
such as regulation of circadian rhythms (the hypothalamus), pupillary reflexes (Edinger–Westphal nucleus
of midbrain) and oculomotor functions (superior colliculus). Extra-geniculate visual pathways have also
been implicated in some visual functions, including
collicular contribution to visually guided action [27]
and visual motion detection functions in the pulvinar
[28].
Within the geniculostriate pathway, axons of postsynaptic neurons in the LGN form the optic radiations,
which arc around the lateral ventricles. The inferior
radiations (also known as Meyer’s loop) transmit input
from the superior visual field through the temporal
lobe while the superior radiations transmit information from the inferior visual field through the parietal
lobe. As its name implies, the geniculostriate pathway
terminates in striate cortex (area V1), typically considered to be the final point along the central visual
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Section I: Structural and Functional Neuroanatomy
pathway. Visual input from LGN to V1 maintains
general topographic integrity such that input from
the upper-right visual field is transmitted to the leftinferior portion of V1. Note, however, that the relative
dimensions of this retinotopic map are not preserved.
A disproportionately large portion (25–50%) of V1 is
devoted to the very small amount of visual input processed by the fovea. V1 relays visual input to extrastriate visual areas for further processing. Additionally,
evidence suggests that V1 also projects to subcortical
regions, including the superior colliculus and feedback
fibers to the LGN [29].
Functional specialization within the
visual system
In 1890, Lissauer proposed that there are three perceptual processes – color, motion, and form – that
are differentially affected by brain damage and that
therefore are functionally and neuroanatomically
distinct (see [30] for review). These three functional
distinctions correspond to input from at least three
parallel pathways, beginning with distinct classes
of retinal ganglion cells [31]. M ganglion cells are
relatively large and respond to gross visual features,
including luminance contrast, temporal frequency,
and movement. P cells comprise the vast majority
(approximately 80%) of ganglion cells and are most
sensitive to finer visual details, including spatial
frequency and stimulus orientation. Additionally,
there appear to be two subdivisions within the P cell
pathway, one of which transmits color input, whereas
the other contributes to form/shape perception.
Although some cross-projections have been identified, the M and P pathways remain largely segregated
throughout the visual system, including formation of
synapses within different layers of the LGN (e.g., magnocellular and parvocellular layers) and projection to
different portions of primary and association cortices
[32].
M and P pathways also serve as bases for
the distinct ventral (“what”) and dorsal (“where”)
visual streams originally proposed by Ungerleider and
Mishkin [33]. V1 and V2 are the largest visual cortical subregions and contribute to early processing for
both dorsal and ventral visual systems, although evidence suggests that each is also involved in higherorder functions [34]. The ventral visual stream processes object properties such as color and shape and
is closely associated with the two P pathways [35].
148
Within extrastriate cortex, the ventral system includes
V4, located in the lingual and fusiform gyri, and
adjacent area V8, both of which are highly sensitive to chromatic input and serve as the main
loci for color perception [36]. The fusiform gyrus,
located anterior to V8, is also part of the ventral
visual stream and contributes to object and form
perception.
Movement and spatially relevant visual features
relayed via the M pathway predominantly contribute
to the dorsal visual system [35]. Motion perception
in the extrastriate cortex is largely attributed to areas
V5 (motion-sensitive middle temporal cortex in
humans, designated hMT+) [37] and V3, followed by
projection through the medial superior temporal area
(MST, or V5a). The dorsal stream projects through
the parietal cortex, bridging between the visual and
sensorimotor cortices. Although colloquially referred
to as the “where” pathway due to its role in spatial
perception [33, 38], the complex and nuanced functions of the parietal portion of the dorsal visual stream
continue to be a matter of debate. Milner and Goodale
[39] emphasized the system’s contribution to visually
guided action and contrasted this with the ventral
visual stream’s more perceptually based function.
Jeannerod [40] characterized the dorsal stream as
“pragmatic” and proposed that the parietal portion
serves multiple visually related functions [41]. The
authors argue that these functional distinctions correspond to differentiable contributions of superior and
inferior parietal lobules, such that the superior lobule
contributes to non-lateralized visuomotor processing
whereas the inferior lobule subserves visuospatial perception (right hemisphere) and goal-directed action
(left hemisphere). Rizzolatti and Matelli [42] also
suggest that the dorsal visual stream is comprised of
two functionally independent subsystems: the dorsodorsal and ventro-dorsal streams both contribute
to coordination of action but only the ventrodorsal stream plays a pivotal role in visuospatial
perception.
At the level of recognition, both dorsal and ventral visual streams project to the medial temporal lobe,
where visual information is translated into stored representations for future access. However, even at this
point, spatial and object input appear to remain largely
segregated in primates, such that dorsal visual input
projects to the parahippocampal cortex whereas ventral visual input primarily projects to the perirhinal
cortex [43].
Chapter 10: Perception and recognition
Disorders of visual perception and
recognition
Visual field cuts (anopsias) may result from lesions at
any point within the central visual pathway, and, based
on the serial trajectory, visual field defects often facilitate localization of CNS lesions. Lesions to the optic
nerve result in monocular visual loss; damage affecting the optic chiasm classically results in bitemporal
hemianopia; and lesions posterior to the optic chiasm
result in loss of vision in the contralateral visual field
(contralateral homonymous hemianopia). Unilateral
lesions within superior or inferior V1 or V2 result in
contralateral homonymous quadrantanopia [44].
Cortically mediated vision loss is not functionally
identical to vision loss from peripheral visual pathway
lesions. Severe bilateral damage to V1 results in cortical blindness. This syndrome often presents as Anton’s
syndrome, which, unlike direct retinal damage, is
accompanied by anosognosia and confabulation of
visual experiences [45]. Patients with visual cortical
lesions may also present with blindsight, a curious
combination of impaired conscious visual perception
despite residual implicit visual abilities, including
localization of visual stimuli. Recall that a minority of
retinal ganglion cells do not synapse within the LGN,
and instead project to other structures including the
hypothalamus, superior colliculus, and pretectal areas.
Functions subserved by these additional pathways
are not necessarily disrupted by damage at the level
of V1. In a recent review [46], Weiskrantz provides
compelling evidence that blindsight cannot be simply
explained as degraded vision. Rather, it is most likely
that residual vision-related functions are attributable
to unaffected cortical and subcortical brain regions
with vision-related functionality, including collicular
input to the dorsal visual stream [27].
In contrast to lesions of V1 and V2, extrastriatal
damage may result in apperceptive agnosias that predominantly affect perception of one aspect of visual
input. Patients with akinetopsia consequent to damage
in V5 demonstrate selectively impaired motion perception relative to intact color and form perception
[47, 48]. In contrast, lesions to V4 typically result in
selective impairment of color perception, called central achromatopsia. Since V4 is located within the inferior visual cortex, central achromatopsia is characteristically accompanied by visual field defects restricted
to the superior visual field. Both color and motion perception can also be impaired consequent to lesions
elsewhere in the brain. For example, achromatopsia
may result from central visual pathway damage [49],
and motion perception may be impaired in patients
with cerebellar, midbrain, or vestibular lesions [48].
Another category of visual deficit is simultanagnosia, which refers to impaired perception or recognition of a stimulus or group of stimuli despite comparatively unimpaired processing of subcomponents
of the stimulus or array. Although features of simultanagnosia can be associated with ventral damage [14],
it most commonly occurs in the context of bilateral occipitoparietal (dorsal) lesions. Simultanagnosia
is a hallmark feature of Balint’s syndrome, which is
additionally characterized by optic ataxia (impaired
visually guided reaching) and oculomotor apraxia
(impaired voluntary saccadic movement to visual targets).
Ventral visual stream lesions may result in associative visual object agnosias characterized by impaired
object identification, categorization and naming,
despite relatively unimpaired visual object perception.
Prosopagnosia was originally considered to be an
example of a category-specific associative agnosia for
faces and resulting from damage to the fusiform face
area in the medial occipitotemporal gyrus, analogous
to inferotemporal cortex (area IT) in non-human primates [50]. Deficits no longer appear to be constrained
to face perception/recognition, and may include other
aspects of configural processing and non-face exemplars [51]. Multiple variants of prosopagnosia also
have been identified, including both apperceptive
and associative forms [50]. Additionally, other brain
regions appear to contribute to facial perception and
recognition, including the left inferior occipital gyrus
(i.e., “occipital face area”) and the right posterior
superior temporal sulcus [52]. Recent evidence also
suggests that category-specific representations within
the ventral visual pathway may not be vision-specific,
but rather represent object forms based on multi
modal input [53].
All of the above are examples of negative symptoms, or deficits, resulting from damage to stimulusinduced (veridical) sensory-perceptual systems. In
contrast, non-veridical, or positive, perceptual abnormalities are not directly triggered by external stimulation of the retina. Visual hallucinations are less common in psychosis than their auditory counterparts,
but they are prominent features in numerous other
disorders ranging from neurodegenerative dementias to migraines and epilepsy [54, 55]. Simple, or
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elementary, hallucinations typically arise from pathology within the occipital lobe or central visual pathway and are characterized by nondescript (e.g.,
phosphenes) and/or simple geometric visual experiences. Visual auras with migraines and ictal visual phenomena in occipital lobe epilepsy typically present as
elementary visual hallucinations, although evidence
suggests they can be clinically differentiated based,
for example, on the tendency for visual seizures to be
shorter in duration, more frequent, and characterized
by circular, colored patterns [56]. Complex, or formed,
hallucinations include perception of complete objects,
animals, or people. The nature of complex hallucinations strongly implicates aberrant neuronal activity within visual association cortex, particularly within
the temporal lobe. For example, Bien and colleagues
[57] found that complex hallucinations occurred in
temporal lobe epilepsy patients but not in patients with
occipital lobe seizure onset. Complex hallucinations
can also occur in the context of lesions to early visual
pathways (e.g., retina and optic nerve), as is the case of
the Charles Bonnet syndrome [58].
Finally, neurodegenerative disorders may also lead
to visual symptoms. Posterior cortical atrophy (PCA)
is a progressive neurodegenerative disease characterized by prominent visual deficits that affect higherorder visual functions over time, eventually leading to
deficits including Balint’s syndrome, Gerstmann’s syndrome, and/or visual object agnosia [59]. This clinical
profile has been identified most often as a variant of
Alzheimer’s disease (AD), and a visual variant of AD
associated with asymmetric cortical degeneration has
been proposed [54]; however PCA also develops as a
result of other neurological diseases, including progressive subcortical gliosis [60]. Consistent with the
role of subcortical regions in visual processing, neurodegenerative disorders with subcortical pathology
may also result in positive or negative visual abnormalities. For example, up to 60% of patients with PD experience positive visual abnormalities including complex
hallucinations [61].
Audition
Auditory pathways are activated when sound waves are
transmitted to the cochlea through the temporal bone
and the tympanic membrane and ossicles of the inner
ear. The cochlea is a fluid-filled structure shaped like a
snail’s shell. Separating the cochlea into two chambers
150
is the basilar membrane, which is a specialized structure designed to mechanically capture sound on the
basis of pitch and loudness. This is accomplished by the
physical characteristics of the basal membrane, which
vary from a broad flexible quality at its base to a narrower more rigid quality at the apex. Sound is transduced to neural signals in the organ of Corti, which lies
along the basilar membrane. The organ of Corti contains hair cells that have mechanically gated ion channels activated when their region of the basilar membrane is moved by a sound wave (see [62] for additional
details). Thus there is an inherent spatial organization
to pitch even at the level of the cochlea, and this tonotopic organization is maintained even at the level of the
primary auditory cortex.
Hair cells transmit information to neurons of the
cochlear (i.e., spiral) ganglion, which, in turn, reaches
the CNS as the eighth cranial nerve and terminates
in the cochlear nucleus at the pontomedullary junction. From here information is transmitted to the
superior olivary complex in the ventral pons (via the
trapezoid body), the nucleus of the lateral lemniscus
in the superior pons, and the inferior colliculus (via
the lateral lemniscus). The superior olivary complex
is notably important in sound localization. The inferior colliculus is important in some multisensory processing, including the startle reflex, and may also be
important in auditory vigilance [63]. From the inferior colliculus, information passes to the medial geniculate nucleus (MGN) of the thalamus and then to the
primary auditory cortex (also known as A1 or Brodmann’s areas 41 and 42) located in the superior temporal gyrus or Heschl’s gyrus. The primary auditory
cortex is organized tonotopically, with low frequencies
located anterolateral to higher frequencies and with
segregated but bilateral representation of sound from
both ears. Two other tonotopic maps exist in the temporal cortex adjacent to A1, namely areas R (rostrolateral to A1), which receives direct input from the MGN,
and CM (centromedial), which is dependent on A1 for
auditory and tonal information [64].
Similar to visual processing, there is increasing evidence in primates and humans of distinct “what” and
“where” pathways of higher unimodal cortices that
lie adjacent to primary auditory cortex (often referred
to as belt and parabelt regions as they form a belt
around A1). The “where” auditory system is primarily involved in sound localization, although it may play
some role in other auditory tasks including language,
Chapter 10: Perception and recognition
and is located posteriorally to primary auditory areas
[65]. The “what” auditory system is involved primarily in sound discrimination, including speech. Functional imaging studies and lesion studies in humans
suggest that the “what” pathway proceeds anterolaterally from A1, with higher-order discrimination of
speech being processed in the left superior temporal
gyrus (STG), and higher-order pitch discrimination in
both speech and music being processed in the right
STG. Results from both functional imaging and lesion
studies suggest that posterior portions of the middle
temporal gyrus, particularly on the right, are involved
in the recognition of environmental sounds [66].
Disorders of auditory perception
and recognition
As with the visual system, negative perceptual symptoms involving hearing may affect primary sensory
processes, secondary perceptual abilities, or recognition. Hearing loss or deafness may occur on the basis
of either peripheral or central lesions. Because of the
extensive crossing of tracts in the brainstem, most
cases of unilateral deafness reflect peripheral causes or
brainstem lesions at the level of the cochlear nucleus.
However, subtle signs of decreased auditory discrimination can be detected contralateral to temporal lobe
lesions [67]. Cases of cortical deafness typically involve
bilateral damage to the temporal cortex and frequently
extend beyond A1. In fact, the majority of cases of
bilateral lesions to auditory cortices have auditory
agnosias rather than true cortical deafness as demonstrated by intact hearing abilities [68]. Analogous to
blindsight, two patients have been reported to demonstrate “deaf-hearing” through either acoustic startle
responses [69] or the ability to determine tone onset
and offset when specifically directed to do so [70]. In
one patient, these abilities appeared to be mediated by
residual temporal cortex and prefrontal cortex when
studied using functional imaging [70].
Cortical auditory disorder or auditory agnosia
refers to a non-specific loss of the ability to discriminate both speech and environmental auditory stimuli. As noted above, this is a more frequent outcome
from bilateral damage to auditory cortices. Pure word
deafness (PWD) or auditory verbal agnosia is a rare
disorder that refers to the specific loss of the ability to
discriminate auditory speech in the face of otherwise
intact language and ability to recognize non-speech
sounds. Lesions typically involve bilateral temporal
cortex, although isolated left STG lesions [71] suggest
that this area may have a unique contribution to speech
analysis. Similarly, isolated left subcortical lesions have
been described, which presumably interrupted auditory input to Wernicke’s area [72]. Auditory sound or
auditory object agnosia refers to a deficit in the ability
to recognize environmental sounds in the face of intact
speech recognition. Pure auditory object agnosia has
been reported most frequently with right temporal
lesions, although bilateral and left-sided lesions have
also been reported [73].
Phonagnosia refers to the loss of the ability to recognize or discriminate voices, similar to prosopagnosia for faces. Van Lancker and colleagues [74] have
distinguished between an inability to discriminate
between unfamiliar voices, associated with lesions of
the STG, and the ability to recognize familiar voices,
which occurs with lesions of the right inferior parietal
lobe. Receptive amusia refers to impairments in the
ability to recognize or appreciate music. Music appreciation is a complex function that depends on the subject’s level of musical expertise and the precise aspects
of music that are assessed. In general, research suggests that global aspects of music (such as melody) are
mediated through the right hemisphere, while more
local aspects (such as rhythm) are related to the left
hemisphere. However, lesion analyses only partially
support this division (showing a disruption of rhythm
with left hemisphere lesions) and there are increasing
data to suggest that music perception relies on crosshemispheric networks [75]. While basic science studies support the notion of auditory “what” and “where”
systems, deficits of sound localization in humans do
not reliably localize to these “where” pathways [76].
The complexity of the auditory agnosias is further displayed by observations that, in addition to cortical
lesions, subcortical [77], thalamic [78], and brainstem
lesions [79] may also be responsible.
Positive auditory symptomatology includes palinacusis, tinnitus, and auditory hallucinations. Palinacusis refers to an auditory illusion in which an external
sound is perseverated internally, typically for seconds
but occasionally as long as hours. It is most frequently
associated with temporal lobe seizures and may be
an aura, ictal event, or post-ictal event [80]. Tinnitus,
which is experienced most commonly as ringing in the
ears, may be associated with peripheral lesions or damage to the ear. However, increasing evidence suggests
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that most chronic tinnitus results from neuroplastic
changes within primary and secondary auditory pathways; these models of chronic tinnitus are analogous
to those proposed as explanations for chronic central pain [81]. Chronic tinnitus is frequently difficult
to treat and may have severe neuropsychiatric sequelae including impaired attention, depression, and an
increased risk for suicide. Recent studies have suggested the repetitive transcranial magnetic stimulation
to the primary auditory cortex may have some potential for treating this condition [82].
Whereas auditory hallucinations are one of the
classic symptoms of schizophrenia, they may also be
seen in many other psychiatric disorders as well as
with lesions of the peripheral and central auditory
pathways. Similar to the Charles Bonnet syndrome in
vision, hearing loss from any cause may result in auditory release hallucinations [17]. With regard to central
etiologies, Lampl and colleagues [83] reviewed over
600 stroke cases and found four patients with acute
auditory hallucinations following right temporal lobe
infarcts. This phenomenon may be due to release of
the left temporal lobe, which may be more strongly
associated with auditory hallucinations in schizophrenia [84], and which may be the site of auditory hallucinations associated with negative affect in epilepsy
[85]. As for musical hallucinations, these may be seen
in psychiatric disease, hearing loss, epilepsy and focal
brain lesions of either hemisphere, mostly involving
the temporal lobes [86].
Somatosensation
Although “touch” is considered colloquially to be
one of the five main senses, it is just one element of a group of sensations processed by somesthesis (also referred to as somatic sensation or
somatosensation). Somesthesis is unique in that
it incorporates mechanical, thermal, and chemical
sensory transduction, and receptors are distributed
throughout the body rather than within one discrete
organ/location. Tactile (or haptic) sensation is one
of three primary cutaneous senses, along with temperature (thermoreception) and pain (nociception).
Another prominent somatic sense is proprioception,
which includes perception of static limb and body
position, and perception of limb movement (kinesthesia). Dorsal root ganglion neurons serve as the primary sensory receptor for each modality, although
there is a range of receptor subtypes. For example,
152
mechanoreceptors mediate proprioception and fine
touch via large, myelinated fibers whereas nociceptors
transmit pain via small myelinated or unmyelinated
fibers.
Regarding serial connectivity, most somesthesis
is accomplished via a three-neuron system: primary
afferent fibers from skin, muscles, joints, and internal organs relay sensory input to second-order neurons, which then synapse within the contralateral thalamus. Post-synaptic, tertiary neurons project to four
cytoarchitecturally differentiable regions within the
primary somatosensory cortex (S-I), including BA 1,
2, 3a, and 3b. In addition to internal cross-projections,
S-I projects to the secondary somatosensory cortex
(S-II).
Central somatosensory pathways also include parallel circuitry. Input with high spatial and temporal
resolution, including proprioception and some aspects
of tactile sensation (e.g., discriminative (fine) touch
and vibration), is relayed via the dorsal column-medial
lemniscal pathway; crude touch, pain, temperature,
and visceroreception are transmitted via the anterolateral pathways, which include the spinothalamic tract.
Both pathways terminate in the ventral posterior lateral (VPL) nucleus, and the spinothalamic tract also
projects to medial and intralaminar thalamic nuclei.
Tactile sensation is relayed by multiple pathways and
this redundancy ensures that selective damage to one
pathway does not result in complete loss of haptic sensation. Somatosensory input from the face is transmitted from the trigeminal nerve (cranial nerve V) and
ascends to the ventral posterior medial (VPM) nuclei
of the thalamus via the ventral trigeminal thalamic
tract (VTTT).
Segregation by submodality and by input location
appears to be conserved throughout the ascending
pathways and within primary somatosensory cortex
(S-I). Each of the four subdivisions of S-I (BA 1, 2, 3a,
and 3b) contains a full somatotopic representation of
input (homunculus), with proportional allocation of
cortical and subcortical maps based on density of input
receptors. Areas 1 and 3b process cutaneous input,
whereas proprioceptive information is processed in
areas 2 and 3a [87].
Both S-I and S-II project to the posterior parietal and insular cortices, which are both involved
in higher-order and multimodal sensory processing.
Dijkerman and Haan [88] recently proposed that the
posterior parietal and posterior insular cortices receive
projections from the anterior parietal cortex via two
Chapter 10: Perception and recognition
somatosensory processing streams, similar to the differentiation between dorsal and ventral visual streams.
In this model, the stream projecting to posterior insular cortex is akin to the ventral visual stream and
primarily contributes to object perception and recognition. In contrast, the role of the posterior parietal cortex in somesthesis is closely related to its role
in visual perception, including spatial and actionoriented functions.
In addition to direct pathways to somatosensory
cortex, there are also indirect pathways through which
spinal afferents project to areas other than primary
somatosensory cortex, some of which also have somesthetic functions. For example, proprioceptive input to
the cerebellum relayed via the spinocerebellar tracts
was traditionally thought to subserve motor planning
and/or reflexive action, but recent evidence suggests
that it may also contribute to tactile perception and
non-motor sensory support functions [89]. Visual cortical regions have also been implicated in tactile perception in healthy individuals, including haptic shape
discrimination [90] and gating orientation discrimination [91, 92]. Evidence for occipital involvement in tactile perception is even more compelling in early blind
individuals, including recent evidence for somatotopic
representation of tactile finger sensations in early blind
Braille readers [93].
Disorders of somatosensory perception
and recognition
Sensory loss may arise from damage at any point
within the somatosensory system. Since afferents
decussate within the spinal cord or brainstem and
synapse within the contralateral thalamus, lesions
within or above the level of the thalamus result in
contralateral deficits. Cortical sensory loss is classically associated with “cortical sensory deficits,” namely
agraphesthesia (impaired recognition of numbers or
letters traced on the palm or fingers) and astereognosis (impaired spatiotemporal discrimination, typically evaluated via recognition and discrimination of
objects placed in the hand). These deficits are frequently associated with stroke but may also present
in the context of neurodegenerative disorders, most
notably corticobasal degeneration [94]. Bauer and
Demery [49] suggest that astereognosis is primarily a deficit in perception and may be differentiated from associative forms of tactile agnosia in
which marked object recognition deficits occur in
the absence of notable somatosensory impairment.
Agraphesthesia and astereognosis may also be found
consequent to damage elsewhere in the dorsal columnlemniscal system, including damage restricted to the
dorsal columns. Somatosensation is critically important for normal motor function, and thus lesions
affecting somatosensory systems are often associated
with motor deficits as well.
Positive somatic symptoms, called paresthesias,
also may develop consequent to lesions at any level
within the somatosensory systems. The Dejerine–
Roussy syndrome is characterized by contralateral
pain associated with unilateral thalamic lesions. Tactile, or haptic, hallucinations are physical sensations in
the absence of cutaneous input. Formications are one
subtype of tactile hallucinations, and are characterized
by the sensation of insects or snakes crawling along
the skin. In the general population, one study found
that haptic hallucinations were the most frequent form
of hypnagogic (while falling asleep) and hypnopompic (while waking up) hallucinations, and the prevalence of daytime haptic hallucinations was 2.6% [95].
Haptic hallucinations may also occur in the context of
neurological or neuropsychiatric dysfunction, including substance withdrawal and lesions affecting the thalamus or parietal cortex.
Phantom limb sensations are present in the vast
majority of amputees, a subset of whom also experience pain in the amputated or deafferented body part.
The precise etiology of these phantom phenomena is
not known, but clinical and animal studies suggest
possible contributory roles throughout the somatosensory pathway, including injured nerve endings, abnormal activity within the dorsal root ganglia, and both
spinal and supraspinal CNS mechanisms. Additionally, research suggests that the S-I undergoes neuroplastic changes after amputation or deafferentation of
a limb, and phantom sensations at least in part reflect
invasion of cortical regions previously dedicated to
perceptual processes for the amputated limb (for a
review, see [96]).
The proximity and overlap of higher-order
somatosensory processing with the dorsal visual
stream may have clinical implications as well. In
addition to its role in somesthesis, the posterior
parietal cortex is involved in spatial perception and
visuomotor integration (see Vision section above),
and evidence suggests that it contributes to attention
orientation [97]. Hemineglect consequent to posterior
parietal lesions may therefore present with tactile
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Section I: Structural and Functional Neuroanatomy
symptoms, including tactile extinction (impaired
tactile perception during simultaneous, bilateral
stimulation).
Finally, clinical symptoms may arise from deficient integration of somatosensory modalities and/or
coordination with motor execution. For example,
movement disorders primarily characterized by motor
impairment may present with features of somatic
abnormalities as well. Aberrant somatosensory evoked
potentials have been demonstrated in patients with
Parkinson’s disease (PD) or Huntington’s disease, and
patients with dystonia often present with sensory
symptoms in addition to their primary motor impairment [98].
Chemosensation: olfaction and
gustation
Olfaction begins with specialized neurons in the olfactory epithelium of the nose. These neurons are unique
in that they have a relatively short lifespan (30–60
days) and are continuously being replaced by basal
cells in the olfactory epithelium. Olfactory neurons
project cilia into the nasal cavity. On the surface of
these cilia are specialized odor receptors that detect
specific molecular configurations and cause depolarization through a second messenger system. Each
olfactory neuron expresses one of approximately 350
unique odorant receptor genes [99]. Unlike other sensory modalities, these neurons do not have a relay in
the thalamus, but proceed to an area directly above
the olfactory epithelium on the ventral surface of the
prefrontal cortex known as the olfactory bulb. Some
authors, however, have argued that the olfactory bulb
serves many functions similar to those of the thalamus, including inhibitory modulation and oscillatory
communication with higher olfactory cortical areas
[100]. From the olfactory bulb, information is transmitted to several structures including the primary
olfactory cortex (the piriform and peri-amygdaloid
cortex), the amygdala, the olfactory tubercle, and the
anterior entorhinal cortex. From these structures there
are direct projections to the orbitofrontal cortex (OFC)
olfactory area, as well as indirect projections that
pass through the mediodorsal nucleus of the thalamus. Similar to other sensory systems, the olfactory
system has several higher-order functions including
odor discrimination and odor localization [101]. In
154
humans, odor discrimination appears to rely mainly
on the piriform cortex and OFC. At least one functional imaging study suggests that in humans there
may be hemispheric asymmetry such that the right
OFC is more strongly associated with higher-order
odor discrimination [102]. With regard to localization
of odors, functional imaging studies in humans suggest a role for the piriform cortex (left greater than
right) and in the posterior superior temporal gyrus
near areas previously identified in the dorsal visual
stream [103]. The strong connections and proximity of olfactory cortex to limbic and paralimbic areas
seem to facilitate the ability of olfactory stimuli to trigger both autobiographical memories and emotional
reactions [104].
Taste is a complex sensation that incorporates stimuli not only from primary taste receptors (taste buds),
but also from olfaction and somatosensory information including the presence of capsaicin (found in
spicy hot foods such as chili peppers), and the temperature and consistency of ingested food or liquids.
Basic taste begins with taste cells, which are located
primarily within taste buds on the tongue but also
the pharynx and upper esophagus. Microvilli from
taste cells interact with chemicals in foods and liquids either through specific receptors and second messenger systems (e.g., sweet) or ion channels (e.g., salt)
that then lead to depolarization of the taste cell [105].
These interactions result in the five primary tastes of
humans: sweet, salt, bitter, sour, and umami (derived
from the combined Japanese words umai (delicious)
and mi (taste), and translated into English as “savory,”
this taste is related to glutamate in many high-protein
foods such as meat). The facial, glossopharyngeal,
and vagal nerves carry taste information to the rostral portion of the nucleus tractus solitarius (NTS).
Somatosensory information from the trigeminal nerve
also converges on the NTS. From the NTS information travels to the ventroposterior medial parvicellular (VPMpc) portion of the thalamus and from the
VPMpc to the primary taste cortex, which lies just
anterior to the face areas of the post-central gyrus as
well as the anterior insula. Unlike other primary sensory modalities, there is evidence of polymodal integration (e.g., olfaction and taste) in the anterior insula.
From the primary taste cortex, information is transmitted to the amygdala, hypothalamus, and the secondary taste cortex located in the caudolateral OFC.
Pathways exist from all of these secondary taste areas
Chapter 10: Perception and recognition
to the NTS, and are able to modulate brainstem taste
function [106].
Disorders of olfactory and gustatory
perception and recognition
Although disorders of olfaction are rarely brought to
medical attention, they may affect nutritional status
through their interaction with taste and are often associated with neuropsychiatric diseases. Anosmia refers
to the loss of smell and is most frequently associated
with diseases of the nasal cavity. Hyposmia refers to
an incomplete deficit in olfaction. The term olfactory
agnosia is rarely used as most researchers test only
for odor discrimination ability, rather than other primary aspects of smell such as stimulus onset/offset or
intensity. Anosmia or hyposmia is frequently seen following traumatic brain injury as a result of shearing
injury of the olfactory nerve at the cribriform plate,
as well as possible secondary injuries to other nasal
structures or the olfactory cortex in the basal forebrain. Deficits in olfactory discrimination are seen following lesions of the temporal lobe, particularly the
uncinate region. Jones-Gotman and colleagues [107]
reported that olfactory dysfunction is common in
patients who have had temporal lobe resection for
intractable epilepsy. Consistent with the functional
imaging literature, lesions of the right OFC have also
been associated with central anosmia [108]. Olfactory deficits may also be seen in other neuropsychiatric disorders that affect the medial temporal lobe
and olfactory bulbs including AD and mild cognitive impairment [109], PD [110], and schizophrenia
[111]. The easy accessibility of neural tissue and neural
stem cells within the olfactory epithelium has spurred
efforts to use nasal biopsies as a means of diagnosing
neuropsychiatric conditions with pathological specimens including Creutzfeldt–Jakob disease [112], AD
[113], and PD [114]. Olfactory testing is also being
studied as a means of determining preclinical risk for
AD, which involves mediotemporal olfactory cortex
as an early event, and PD, which affects the olfactory bulbs [109, 114]. Olfactory hallucinations are typically unpleasant and have been described with temporal lobe epilepsy (uncinate fits), AD, parkinsonism, schizophrenia, post-traumatic stress disorder, and
depression [115].
Ageusia and hypogeusia refer to lack and loss
of taste respectively. In addition to changes in
olfactory function, these syndromes may be associated with peripheral lesions, brainstem lesions
interrupting ascending pathways from the NTS [116],
and occasionally from medications (notably phenytoin and chemotherapy). Gustatory agnosia has rarely
been reported with one case demonstrating bilateral
anterior medial temporal lobe lesions [117]. Gustatory hallucinations have been noted in schizophrenia,
temporal lobe lesions, and temporal lobe epilepsy
[17].
Crossmodal integration
Humans typically do not experience the world in
terms of individual sensory modalities, but rather
as a seamlessly integrated whole based on information from multiple sensory sources. Crossmodal
integration may change perception within a sensory modality through information from a separate
modality, as may be seen through the influence of
visual information on our sense of taste or smell
[118]. Alternatively, crossmodal integration may be
necessary to accomplish a truly multisensory task
such as sound localization or lip reading. Crossmodal integration depends on the communication
between unimodal and transmodal sensory areas, particularly the OFC, hippocampal-entorhinal complex,
and posterior parietal lobe. Although patients with
lesions in these areas do not typically present with
deficits in crossmodal integration, these deficits may
be demonstrated through neuropsychological testing
[119]. Many conditions in BN&NP, including AD
[120] and schizophrenia [121], demonstrate crossmodal integration deficits when clinical examinations
sensitive to such impairments are performed.
Synesthesia refers to a phenomenon in which a
stimulus presented in one sensory modality automatically invokes a distinct perception in a secondary sensory modality. This condition is most commonly seen
in otherwise normal (and often artistic) individuals,
although a case of “feeling sounds” has been reported
following a thalamic stroke [122]. The most common
type of synesthesia involves the linking of graphemic
forms (often numbers) with the experience of particular colors. Other types of synesthesia may involve
crossmodal perception, as in seeing the color of certain auditory tones. Experiments in individuals with
synesthesia have demonstrated that synesthesia occurs
at relatively early perceptual processing stages and is
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Section I: Structural and Functional Neuroanatomy
not dependent on conscious associations. Synesthesia is proposed to arise from abnormal connectivity
between either unimodal perceptual areas or within
transmodal cortex (see [123] for an excellent review).
Self-perception and recognition
A final topic of importance to BN&NP is the unique
human ability to recognize self-generated actions,
sounds, images, and touch as distinct from environmental stimuli from other sources. This ability involves
the generation of a feed-forward or efferent copy of our
motor actions to be sent to transmodal sensory areas
to tag the ensuing stimuli as self-generated. Research
from both lesion and functional imaging studies in
humans implicates a predominantly right cerebral network for feelings of agency for actions, particularly the
inferior parietal lobule and anterior cingulate cortex
[124], and a predominantly left cerebral network for
the perception of agency regarding inner voice, particularly the left inferior frontal lobe [125]. Disturbances
in these networks have been hypothesized to underlie
several neuropsychiatric symptoms, particularly hallucinations and delusions of control [126]. Support for
this hypothesis comes from functional imaging studies demonstrating disruptions within these networks
in individuals with hallucinations and passivity experiences, as well as the surprising ability of these individuals to tickle themselves [127].
Conclusion
The study of perceptual processes is among the oldest fields of inquiry in neurology and also one of
the most highly developed. In this chapter, a concise, broad overview of the functional neuroanatomy
underlying perception and recognition within each of
the five primary perceptual systems was provided. Perception and recognition were defined in terms of their
neuroanatomic and neuropsychological elements. The
organizational principles common to all human sensory and perceptual processes were reviewed, and the
general types of perception and recognition disorders were presented. Specific discussion of the neuroanatomy and neuropsychology of vision, audition,
somatosensation, and chemosensation (i.e., olfaction
and gustation) was offered, and specific types of perception and recognition disturbances for each sensory
modality were presented. Finally, the importance of
crossmodal integration as well as self-perception and
recognition were discussed. Throughout this review,
156
understanding the structural architecture of sensory
systems and behavioral correlates of normal and
abnormal connectivity was emphasized and identified
as prerequisite knowledge for clinical examination and
lesions localization of persons with disorders of perception and recognition.
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Section I
Structural and Functional Neuroanatomy
Chapter
Memory
11
Felipe DeBrigard, Kelly S. Giovanello, and Daniel I. Kaufer
Human memory consists of several functional systems
that collectively support the acquisition, retention,
and subsequent retrieval of information. Much of
what is known about different memory processes
has been gleaned from experiments in non-human
primates and other mammals, which allow for direct
manipulation of experimental conditions but provide
limited information about the human condition.
Complementing animal lesion experimental data
are individual case studies in a few human subjects
uniquely affected with specific lesions that isolate
different memory systems. Data generated from these
select individuals have widely influenced current
theories of memory function by yielding inferences
regarding component processes and anatomical
substrates based on brain–behavioral correlation.
More recently, high-resolution structural and functional imaging methods have greatly facilitated the
investigation of structure–function relationships
associated with different human memory functions.
In particular, functional magnetic resonance imaging (fMRI) allows for assaying neural circuitry in
real-time during the performance of various memory
tasks.
Memory systems are classified according to the
temporal duration (short- vs. long-term memory)
or the qualitative nature of the information being
retained (Figure 11.1). Short-term memory (STM)
generally refers to the retention of information over
brief periods of time, on the order of seconds. Working memory (WM) is a form of STM that entails a
temporary storage buffer for information that undergoes further processing; long-term memory (LTM)
involves the acquisition and retention of information
over longer intervals of time. Long-term memory can
be further subdivided into declarative memory, which
Figure 11.1. A framework for understanding memory and its
subtypes.
refers to the acquisition and retention of knowledge,
and non-declarative memory, reflecting experienceinduced changes in performance.
In a clinical context, the temporal aspects of learning and memory are parsed into immediate recall
(processing and recitation over a period of seconds),
recent memory (anterograde learning over a period
of minutes), and remote memory (retrograde recall of
previously learned information). These terms reflect
stages of information processing (encoding, storage,
retrieval) that form the basis of standard clinical tests
of verbal episodic memory (e.g., word-list or paragraph recall).
This chapter will review the clinical context and
describe the functional–anatomic architecture of
multiple memory systems including WM, declarative memory (i.e., semantic memory and episodic
memory), and non-declarative memory (i.e., implicit
Behavioral Neurology & Neuropsychiatry, eds. David B. Arciniegas, C. Alan Anderson, and Christopher M. Filley.
C Cambridge University Press 2013.
Published by Cambridge University Press. 161
Section I: Structural and Functional Neuroanatomy
memory and procedural memory). The account will
be based on neuropsychological and functional neuroimaging studies of normal individuals and clinical
populations.
Clinical overview
The anatomical substrates of memory include distributed networks of cortical and subcortical nuclei
interconnected by white matter projection pathways.
For example, the Papez circuit – comprising the
entorhinal complex, hippocampal formation, fornix,
mammillary bodies, and anterior/dorsomedial thalamus, and the cingulate gyrus – contributes to learning
new information; lesions affecting any of these structures may interfere with this process, resulting in a
learning or storage deficit [1]. Although susceptible
to injury from a variety of insults, these structures
are particularly susceptible to the effects of hypoxicischemic, hypoglycemic, or other metabolic injury
(i.e., CA1 region of the hippocampus), increased glucose metabolism in the setting of thiamine deficiency
(i.e., mammillary bodies and thalamus), trauma (i.e.,
hippocampus and fornix), and Alzheimer’s disease
(AD) (i.e., entorhinal complex–hippocampal formation). By contrast, injury to frontal–subcortical systems is more often associated with difficulty retrieving
recently learned information (producing a retrieval
deficit). Accordingly, lesions associated with traumatic
brain injury, cerebrovascular disease, multiple sclerosis, HIV/AIDS, and other conditions may have a deleterious effect on frontal-subcortical circuits and are
common causes of impaired memory retrieval. Degenerative conditions such as Parkinson’s disease (PD)
and Huntington’s disease (HD) that affect basal ganglia
and cerebellar structures involved in perceptual-motor
processing may cause impairments in WM and procedural memory [2]. From a therapeutic perspective,
research on memory functions has focused on remediating “core” cognitive deficits (i.e., short-term episodic
memory deficits) in the setting of AD, and WM deficits
in the context of attention-deficit disorder (ADD) and
schizophrenia.
Memory impairment is the most common reason for seeking a cognitive evaluation, and this problem has multiple possible causes. In most cases, memory impairments are comorbid with other cognitive
and neurobehavioral problems. Disorders such as herpes encephalitis, which has a predilection for limbic and paralimbic cortical regions, may cause an
162
amnestic syndrome associated with other neurobehavioral features, such as personality change and seizures.
Alcohol amnestic disorder (also known as Korsakoff ’s
syndrome or Korsakoff ’s psychosis), transient global
amnesia (TGA), and amnestic mild cognitive impairment (MCI) are the most common causes of isolated
impairment of declarative memory. Although well
known to be associated with Korsakoff ’s syndrome, an
amnestic syndrome in which a tendency to confabulate
features prominently also may develop after rupture
of an anterior cerebral artery aneurysm. Secondary
memory impairments may develop as complications
of electroconvulsive therapy (ECT), epileptic seizures
(i.e., complex partial or generalized seizures), or severe
alcohol intoxication (“alcoholic blackouts”). A variety
of nutritional, metabolic, endocrine, and toxic conditions may impair memory function directly or indirectly via compromise in attentional systems, as with
an acute confusional state or delirium.
Multiple memory systems
Memory is not a unitary function, but instead denotes
a large and diverse set of psychological processes and
neural systems involved in learning and retrieving
information. These processes include, among others,
WM, declarative (episodic, semantic) memory, and
non-declarative (implicit, procedural) memory, each
of which will be considered in the following sections
of this chapter.
Working memory
Working memory refers to the retention of information over brief intervals of time, typically on the order
of seconds. It involves the temporary online storage
and manipulation of information that can be used for
immediate behavior, without being directly available
to the senses. It is different from the notion of STM
in that it is not merely a relaying stage prior to the
storage of information in LTM. Rather, WM encompasses an array of cognitive processes. The amount of
information WM can handle is both limited in time
(approximately 20 seconds) and in capacity (approximately four to nine items), and is somewhat flexible.
By actively rehearsing an informational item, one can
keep information in WM for extended periods of time.
Similarly, by grouping different items into meaningful
chunks of information, WM capacity can increase substantially [3]. The limited capacity of WM allows cognitive scientists to study its nature using a dual-task
Chapter 11: Memory
methodology. This research strategy is based on the
assumption that if two activities are conducted in tandem and neither is impaired, then the processes do not
depend on the same system. However, if performance
on one task decreases as a function of being carried out
along with the other task, then both tasks depend upon
the same mnemonic system.
This methodology has been widely used by Alan
Baddeley in shaping his WM model [4]. The model
comprises four components: three material-specific
slave systems and one central executive. One slave
system is called the “phonological loop.” It mediates
the temporal storage and rehearsal of phonemes and
sounds. As such, it is essential for language production and comprehension, as well as for the temporary
storage of numeric and other symbolic representations. Experimental studies have shown that rehearsal
and retrieval of information processed by the phonological loop is sensitive to phono-articulatory characteristics. It has been suggested, for instance, that
the phonological loop stores information in a phonetic format, as evidenced by the phonological similarity effect in which recall is poorer for sequences of
phonologically similar items [5]. Similarly, it has been
suggested that phonological rehearsal involves highlevel activation of speech-motor planning processes
[6]. This claim finds support in the word length effect,
which states that serial recall accuracy is correlated
with length of phonological articulation – the longer
and more complex the word, the longer it takes to
rehearse.
Neuroimaging and neuropsychological studies
support dissociation between phonological storage
and rehearsal [7–9]. On the one hand, patients with
damage to the left supramarginal gyrus of the inferior parietal cortex exhibit poor repetition, produce
phonemic paraphasias, and have reduced auditory
verbal span, deficits indicative of an impaired phonological store [10, 11]. On the other hand, patients
with damage to the left inferior frontal gyrus display
output deficits characterized by diminished phrase
length and poor articulation, findings indicative of
impaired articulatory rehearsal [11, 12]. Importantly,
functional neuroimaging studies have shown that
storage and maintenance of information involves
interactions between posterior buffer regions and
anterior rehearsal mechanisms. For example, verbal
WM appears to be mediated by the left posterior
parietal cortex, which subserves the phonological
store, as well as Broca’s area, the left premotor area,
and the left supplementary area, which are involved in
articulatory rehearsal [13].
Another slave system is the visuospatial sketchpad,
which stores and manipulates visual and spatial information. The visuospatial sketchpad is independent of
the phonological loop, as it is associated with activity in
the right – and not the left – cerebral hemisphere [14].
Additionally, it is selectively disrupted by concurrent
activities that do not influence the phonological loop
[15]. It is also thought to involve two different components: a visual store that preserves perceptual features
of objects, and a spatial or sequential component that
may serve a rehearsal function.
Neuropsychological findings offer strong support
for this dissociation. Patients with occipital and temporal damage exhibit impaired visual storage, but preserved spatial WM [16]. In contrast, patients with parietal deficits show impaired spatial storage, but preserved visual WM [17, 18]. Recent research has also
revealed that eye-movements play a key role in the
maintenance of spatial, but not object, representations
in the visuospatial sketchpad [19].
The final slave system, the episodic buffer, is the
most recent addition to the model [20]. The function
of this buffer is to represent and integrate inputs from
all subcomponents of WM, as well as LTM, in a multimodal neural code. As such, it is thought to process
multidimensional information that will later be consolidated or reconsolidated in episodic memory. Moreover, the episodic buffer is thought to link semantic
information from the visuospatial sketchpad and the
phonological loop in order to integrate this information into complex episodic representations via modulation by the central executive. The observation that
amnestic patients can produce coherent episodic narratives despite profound deficits in LTM supports the
postulated role of the episodic buffer. Although the
precise neural correlates of this episodic buffer remain
unspecified, preliminary fMRI evidence suggests that
the right frontal lobe may play a key role [21].
Each of the aforementioned slave systems depends
on a central executive system. This system, which is
also limited in capacity, plays a fundamental role in
complex memory span tasks (e.g., random digit generation) and it is closely linked to attentional control. Indeed, Baddeley [22] suggested that the central executive may in fact correspond to Shallice’s [23]
supervisory attentional system. It is thought to regulate the flow of information with WM, and the retrieval
of material from more permanent LTM into WM.
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In addition, the central executive permits attentional
shifts between tasks as well as selective attention and
inhibition.
Neuropsychological evidence suggests that there
are two main types of dysexecutive syndrome, each
reflecting dysfunction in the central executive system. One type involves marked perseveration, indicating decreased ability to disengage and shift attention,
whereas the other is characterized by excessive distractibility, which reflects impairments in attentional
inhibition. It has been observed that individuals with
AD and frontotemporal dementias are impaired when
performing concurrent multiple tasks, indicating that
the frontal and prefrontal cortices may be selectively
involved in the functioning of the executive system
[24]. Furthermore, neuroimaging studies indicate that
executive control processes are mediated by the cingulate and dorsolateral prefrontal cortices [25, 26].
Finally, it is worth noting that despite the influence of Baddeley’s WM model, other models have
been suggested. Of note is Nelson Cowan’s [27] model,
which unlike Baddeley’s model, suggests that WM and
LTM process the same types of memory representations. According to Cowan’s model, there are not different kinds of systems operating upon different kinds
of WM representations, but rather a unique executive
system activating and deactivating memory representations via attentional modulation. Further research is
needed to assess the relative virtues of these different
models.
Declarative memory
Declarative memory encompasses the acquisition,
long-term retention, and retrieval of events, facts, and
concepts [28]. Such knowledge can be retrieved at will
and used in a variety of contexts. Declarative memory can be subdivided depending on whether memories are concerned with personally relevant events (i.e.,
episodic memory) or impersonal information (i.e.,
semantic memory).
Episodic memory
Episodic memory enables individuals to recollect
conscious experiences from their personal past (e.g.,
remembering what one had for breakfast this morning). According to Tulving [29], episodic memories
are characterized by a sense of subjective awareness
of having experienced the remembered events in the
past.
164
To tap into this particular feeling or “recollective
experience,” Tulving developed the so-called remember/know paradigm. In this paradigm, participants are
first presented with stimulus material and then asked
to retrieve this information on a memory test. During recall, participants are asked whether they remember the studied event – that is, whether they can picture it in their minds with some detail – or, instead, if
they only know that they have studied it (i.e., a sense of
knowing something without being able to conjure up
additional informational details).
This widely implemented paradigm has produced
robust results, suggesting two different mnemonic processes: recollection and familiarity. As later suggested
by Tulving [30], the hallmark of recollection is a sense
of autonoetic (self-awareness) consciousness accompanying the recollective experience; it pertains, therefore, to episodic memory. On the other hand, the
absence of autonoetic consciousness during familiarity evidences a different sort of processing, this time
related to semantic memory. Although the nature
and exact relation between recollection and familiarity is a matter of debate [31] convergent evidence
suggests that episodic memory is a distinct memory
system.
A pervasive deficit in episodic memory is dramatically exemplified in patients with anterograde amnesia, who are unable to acquire and retrieve any events
or episodes from their personal life that occurred since
the onset of their amnesia. This phenomenon was first
documented in patient H.M., a man who, in 1953,
underwent surgery for treatment of refractory seizures
[32]. The surgery involved bilateral resection of the
medial temporal region, which reportedly included
removal of the amygdala, anterior two-thirds of the
hippocampus, and hippocampal gyrus. Although the
surgery was successful in substantially reducing H.M.’s
seizures, the procedure produced a pervasive impairment of memory that was termed “global amnesia”
[33]. From the time of his surgery at the age of 27 until
his death in 2008, H.M. was unable to consciously learn
and remember new episodic information.
Patients with global amnesia also manifest retrograde amnesia (i.e., the loss of memory for experienced
events that occurred prior to brain injury onset). Frequently, remote memories are better preserved than
memories for events that occurred shortly before brain
injury. This effect, which was described over a century
ago by Théodule Ribot [34] and referred subsequently
to as Ribot’s law, is only now coming to be understood,
Chapter 11: Memory
as cognitive neuroscientists investigate how the hippocampus and surrounding medial-temporal structures contribute to the enduring storage of episodic
memories.
Although there is general agreement that the hippocampus is critical for memory consolidation (i.e.,
the permanent laying down) of information, memory
theorists disagree as to the role the hippocampus
plays in the storage of consolidated memories. The
traditional view suggests that the medial temporal lobes are not the ultimate repositories for new
memories [35, 36]. Rather, storage of new memories
requires interaction between medial-temporal and
neocortical areas. The hippocampus receives input
from distributed neocortical sites about an event to be
remembered and forms a compressed representation
that binds together the information from different
sites that form a complete representation of that
event. Partial reinstatement of the activation pattern
associated with that event leads to a spreading of
activation, whereby the initial pattern of neocortical
activation is regenerated. Whenever a neocortical pattern is reinstated, the functional connections between
constituent sites are reinforced. Over time, permanent
cortico-cortical connections are established, allowing
a memory to be retrieved without mediation from
the limbic system. As a result, information that is
not fully consolidated is vulnerable to partial or
complete loss in the setting of hippocampal damage,
whereas fully consolidated (i.e., older, representationally stable) memories are able still to be retrieved
successfully.
More recently, alternative views have been proposed in which the hippocampus plays a more permanent role in the retrieval of episodic memories.
One such theory, known as the Multiple Trace Theory
[37], suggests that recollection of episodic memories
always depends on the hippocampus, and that every
time one recollects an episodic memory, a new memory trace is created. Thus, episodic memories that are
more frequently remembered have been coded in multiple traces, rendering them less vulnerable to damage.
Other views suggest that the hippocampus is always
required for recollection, but not for familiarity [38,
39], insofar as it permits the recombination of episodic
components into a single memory event [40]. Finally,
some views suggest that the hippocampus stores allocentric (i.e., non-self-centered) representations of spatial context, which allow humans and other mammals
not only to navigate their immediate surroundings, but
also to mentally access the spatio-temporal content of
their memories. Further research is needed to fully
understand the specific role of the hippocampus and
the medial temporal lobes in retrieval.
Neuroimaging studies provide additional evidence
for the role of the medial temporal lobes in episodic
memory. Activation of the medial temporal region
is observed during both initial registration of novel
events and also during retrieval of recently acquired
information [41, 42]. Medial temporal lobe activity is
greater during the encoding of experiences that are
later remembered versus those that are later forgotten
[43, 44].
Episodic memory also depends on frontal lobe
function. Although patients with frontal lobe lesions
may demonstrate normal performance on tasks of
recognition memory, prose recall, and some cued
recall tasks, they typically show impairments on free
recall, memory for temporal order, and source memory tasks [45]. These latter tasks depend on elaboration
of information at encoding, as well as monitoring and
decision processes at retrieval – strategic processes
proposed to be mediated by frontal regions. On
recognition tests, some patients with frontal lesions
(primarily in the right hemisphere) make an unusually
high number of errors in which items are designated
as “old” when they in fact are “new” (i.e., false alarms)
[46, 47]. Additionally, Levine and collaborators [48]
reported the case of M.L., who after suffering closed
head trauma, experienced a severe episodic retrograde
amnesia: he was unable to remember any autobiographical experiences prior to the accident. Interestingly, M.L. did not experience anterograde amnesia,
as he was still able to encode and further recall events
occurring after the accident. M.L.’s pathology was
restricted to the right ventral frontal lobe, including
the uncinate fasciculus, while his hippocampus was
intact. Taken together, these cases indicate that while
the hippocampus is essential for encoding episodic
information, the frontal lobes are essential for episodic
recollection.
Finally, the most recent conceptual development
in our understanding of episodic memory is the relationship between remembering the past and imagining
the future. When studying patient K.C. – an individual whose case offers the clearest known example of
a dissociation between episodic memory and semantic memory [49] – researchers noted his inability to
remember the past in concert with his inability to envision himself in the future. The capacity to think about
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Section I: Structural and Functional Neuroanatomy
one’s future is related to the capacity to remember previous episodes from one’s life [50]; more specifically,
these capacities share the same neural underpinnings
[51–54] and are phenomenologically [55] and ontogenetically related [56].
Semantic memory
Semantic knowledge encompasses a wide range of
information, including facts about the world, the
meanings of words and concepts, and the names
attached to objects and people. Unlike episodic memories, semantic memories can be retrieved without associated information regarding the context in which they
were acquired.
By virtue of its diverse nature, not all forms
of semantic knowledge share the same properties.
Some forms of knowledge can be acquired after a
single exposure (e.g., knowledge that Lisbon is the
capital of Portugal), whereas other forms may be
gradually acquired across multiple repetitions (e.g.,
understanding the concept “website”). Additionally,
semantic information, when first encountered, may
vary in the extent to which it is truly novel. For
instance, semantic learning may involve establishing
new associations between pre-existing representations
in memory (e.g., learning that William Shakespeare
wrote Romeo and Juliet) or acquiring a new label for
information already represented in memory (e.g.,
foreign-language learning). Finally, a new label and
a novel set of properties may be linked to each other
(e.g., learning the meaning of the word “microbrew”).
Neuropsychological studies of semantic memory
have focused on brain lesions that selectively impair
different stages of information processing (i.e., acquisition, storage, or retrieval) as well as the organization of knowledge. Evidence for the neural structures
subserving the acquisition of new semantic knowledge
has come primarily from studying patients with amnesia. Patients with extensive medial temporal lesions,
such as amnesic H.M., are unable to acquire the meanings of words that entered the language after the onset
of their amnesia [57, 58]. Some findings suggest that
the integrity of structures surrounding the hippocampus (subhippocampal cortices) may be critical for new
semantic learning. Vargha-Khadem and collaborators
[59] reported three young amnestic individuals who
sustained severe bilateral hippocampal atrophy as a
result of anoxia. Importantly, their deficit appeared to
be confined to episodic memory, as they were unable to
remember or encode any specific events of their lives,
166
while their capacity to remember and learn new facts
was preserved. Inspection of available neuroanatomic
data revealed that in all three children, damage was
limited to the hippocampus proper with sparing of
subhippocampal cortices. These cases suggest that
while the hippocampus is necessary for episodic memory, subhippocampal cortices may mediate semantic memory. Consistent with these findings, an adult
patient with hippocampal and subhippocampal damage demonstrated profoundly impaired episodic and
semantic learning, whereas another adult patient with
only hippocampal damage had disproportionately preserved semantic learning [60].
Whereas subhippocampal cortices appear critical
for acquiring new semantic information, these areas
are not implicated in information storage. Studies
of patients with semantic dementia or focal temporal lobe lesions suggest that semantic knowledge is
stored/represented in the lateral temporal lobes in a
distributed network of information [61, 62].
Memory retrieval requires interaction between
retrieval cues and stored representations so as to trigger cortical storage sites to provide memory output. This retrieval process is thought to be mediated
by inferolateral frontal and temporopolar regions, as
patients with lesions in these areas, especially in the left
hemisphere, have significant difficulty retrieving old
semantic memories [63]. Neuroimaging studies also
have shown activation in these areas when normal subjects make semantic judgments about objects or words
[64].
Insight into the organization of semantic memory
has come from investigating patients with circumscribed lesions who demonstrate category-specific
knowledge deficits. An especially striking dissociation
has been observed between knowledge of living
and non-living things. Some patients have impaired
knowledge of living things (e.g., animals and vegetables), but preserved knowledge of non-living things
(e.g., tools and furniture), whereas other patients
show the reverse pattern [65, 66]. One interpretation of category-specific deficits is that semantic
memory is represented in the brain according to
taxonomic categories. Another interpretation is that
categories differ in their reliance on knowledge from
different sensorimotor modalities, with living things
known predominately by their visual attributes and
non-living things by their function. Accordingly,
category-specific knowledge deficits for living and
non-living things may reflect impairments in the
Chapter 11: Memory
representation of visual and functional knowledge,
respectively.
Consistent with the neuropsychological literature,
pioneering neuroimaging studies showed differential activations for category-specific stimuli. Using
positron emission tomography (PET) scans, Martin
and collaborators [67] found greater activation in left
medial occipital cortex during naming pictures of animals relative to pictures of tools. In contrast, naming pictures of tools revealed greater activation in left
premotor and middle temporal cortices. Additionally,
several neuroimaging studies showed activation in left
prefrontal cortices during semantic retrieval [68].
Perhaps the stronger piece of evidence supporting the observation that left-lateralized damage to the
anterior temporal cortex affects semantic rather than
episodic memory comes from patients suffering from
semantic dementia. One of the best-documented cases
of semantic dementia is patient A.M. [69]. Upon examination, A.M. showed severe difficulty remembering
the names of things (anomia), even though his speech
and prosody remained largely intact. Further testing revealed intact non-verbal episodic retrieval, evidenced by normal performance during tasks such as
copying the Rey complex figure. More recently, Davies
and collaborators [70], using post-mortem data from
a group of seven individuals with semantic dementia cases, discovered that, relative to controls, semantic dementia was associated with anterior temporal
atrophy, including parts of the perirhinal cortex, and
preservation of adjacent areas in the temporal lobe.
The extent to which other brain areas are implicated
in semantic memory, as well as the nature of semantic
representations in memory, remains an area of active
scientific research.
Non-declarative memory
Non-declarative memory refers to a variety of forms
of memory in which learning is expressed as enhanced
performance [71]. In this chapter, we focus on two
forms of non-declarative memory: implicit memory
and procedural memory.
Implicit memory
Implicit memory describes a type of non-declarative
memory in which previous experiences aid task
performance without any requirement for conscious
awareness of those previous experiences [72]. One
well-studied form of implicit memory is repetition
priming (referred to as “priming” hereafter). A typical
priming task is comprised of study and test phases.
During the study phase, participants are exposed to
a series of words, pictures, or objects. For example,
they might see a word list that contains the word
“turnip.” During the test phase, participants perform
a seemingly unrelated task. For example, they might
have to identify briefly flashed words or generate as
many words as possible when cued with the semantic
category “vegetable.” Priming is measured as the
facilitation in task performance induced by recent
exposure to task stimuli (e.g., enhanced accuracy
in identifying or generating the word “turnip”), as
compared with a baseline condition in which that
word had not appeared on the prior study list.
Studies in normal participants have identified two
types of priming: perceptual priming, which requires
analysis of the perceptual attributes of a stimulus (e.g.,
identification of perceptually degraded stimuli), and
conceptual priming, which requires analysis of the
meaning of a stimulus (e.g., category exemplar generation) [73]. Importantly, these two types of priming
are differentially affected by experimental manipulations that vary the amount of overlap between study
and test phases. A change in the perceptual format
between study and test reduces perceptual priming,
but has no impact on conceptual priming. Alternatively, enhanced conceptual priming occurs with elaborate processing of stimuli at study versus when only
shallow processing occurs; this processing manipulation has no effect on perceptual priming.
Neuropsychological investigations indicate that
globally amnesic patients show intact performance
on perceptual and conceptual priming tasks [74].
This finding suggests that the mnemonic operations
involved in priming are not dependent on the medial
temporal and diencephalic structures implicated in
global amnesia. Like globally amnesic patients, AD
patients have pathologic changes in limbic structures and show impairments on declarative memory
tasks. Unlike amnesic patients, however, those with
AD also have extensive neocortical pathology, particularly in frontal, temporal, and parietal association
areas [75], and show impaired conceptual priming
despite preserved perceptual priming [76, 77]. This
pattern of impaired and preserved priming in AD
suggests that conceptual priming processes may be
localized to frontal, temporal, and parietal association
areas that are compromised in AD. In contrast, perceptual priming processes may be localized to early
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Section I: Structural and Functional Neuroanatomy
modality-specific cortices that are relatively spared in
AD. Further neuropsychological evidence that perceptual priming is mediated by modality-specific cortices
comes from patients with focal occipital lobe lesions
who show impaired priming on visual perceptual tasks
and preserved priming on conceptual tasks [78, 79].
Taken together, these findings lend strong support to
the notion that perceptual and conceptual priming are
mediated by separable neural substrates.
Neuroimaging studies aimed at localizing priming processes are generally consistent with findings
from clinical studies [80]. Visual perceptual priming
is mediated by visual association areas, whereas conceptual priming is mediated by more anterior cortices
(e.g., superior temporal and anterior frontal regions).
Furthermore, these studies have demonstrated that the
facilitation resulting from repeated processing of a
stimulus is associated with decreased neural activation
(also called response suppression) for repeated stimuli relative to new stimuli. Depending on the technique, the reduction in hemodynamic response can
be measured as decreased regional cerebral blood flow
(using PET) or as decreased blood oxygen-level dependent (BOLD) signal (using fMRI). Using event-related
fMRI, Henson, Shallice and Dolan [81] presented a
series of familiar faces and familiar symbols while subjects were instructed to search for a target. Simply
viewing repeated faces or symbols was associated with
decreased neural activation in the fusiform gyrus. Such
decreases in neural activity have been interpreted to
map onto the behavioral priming effect, as the facilitated, more efficient processing of previously perceived
stimuli (see [82] for a thoughtful discussion of this
issue).
According to one model [83], such decreased activation reflects a neural tuning, or sharpening mechanism, in which only the neurons that respond best to
the stimulus are recruited for reprocessing that stimulus at a later time (but see [82, 84] for important caveats
with regard to this model). Neural priming is typically
evident in areas of stimulus- or concept-specific processing, such as extrastriate cortex of the occipital lobe
(for visually perceived stimuli), fusiform cortex (for
object or face stimuli), primary auditory cortex in lateral temporal lobe (for aurally perceived stimuli), or
inferior frontal gyrus (for priming of semantic information).
More recently, Schacter and colleagues [85]
reviewed numerous studies reporting reductions
in cortical activity during priming. Their review
168
yielded several observations. First, prefrontal regions
demonstrate sensitivity to both conceptual- and
stimulus-decision mapping components of repetition
priming. Robust correlations have been observed
between the magnitude of behavioral priming and
neural priming in this region, and trancranial magnetic stimulation (TMS) applied to the left prefrontal
cortex (PFC) during semantic classification tasks
disrupts subsequent behavioral priming. Second,
regions in the lateral temporal cortex demonstrate
sensitivity to conceptual components of repetition
priming and, similar to prefrontal regions, respond
amodally. Third, perceptual cortices demonstrate
sensitivity to perceptual components of priming
and tend not to be correlated with behavior during
tasks that encourage conceptual or semantic priming.
Neural priming in these regions demonstrates a
gradient of stimulus specificity such that the degree of
stimulus-specific priming decreases as one proceeds
from early (posterior) to late (anterior) regions with
the perceptual system, and there is a laterality effect
(i.e., less specific in the left than right hemisphere)
across later visual regions.
Procedural memory
Procedural memory is involved in the acquisition of
skills and habits, results from repeated practice, and is
relatively impervious to the effects of decay or interference. Research studies investigating the acquisition
of new perceptual-motor skills have employed simple
tasks, such as mirror tracing or rotary pursuit. During
mirror tracing, a participant uses a metal stylus to trace
a geometric pattern seen in a mirror, while the geometric pattern and the individual’s hand are obscured from
view by a board. Learning is measured by the reduction
in time to complete tracing of the pattern, as well as the
number of errors committed. During rotary pursuit, a
participant is given a metal stylus that must be kept in
contact with a revolving disk. Learning occurs as the
individual becomes more proficient at matching his or
her motor movement with the movement of the disk.
Early studies of patient H.M. were among the
first to establish that globally amnesic patients could
acquire and retain new motor skills [33, 86]. Such findings are especially significant given that these patients
are frequently unaware of having been previously
exposed to the tasks. These results suggest that procedural memory is mediated by neural structures outside
the medial temporal-diencephalic region.
Chapter 11: Memory
In contrast to amnesic patients, other neurological
populations, such as PD and HD patients, have poor
rotary pursuit learning [87]. Based on these data, it
appears that the basal ganglia, which are compromised
by these diseases, play a critical role in motor skill
learning. However, basal ganglia lesions do not impair
all motor skill tasks to the same extent; for example, Gabrieli and colleagues observed that HD patients
demonstrate normal mirror tracing despite impaired
rotary pursuit learning [88]. In contrast, patients with
cerebellar lesions show impaired mirror tracing [89].
These observations suggest that the basal ganglia and
cerebellum both contribute to motor skill learning but
do so differentially: the basal ganglia are critical for
sequence learning whereas the cerebellum is involved
in error correction [88].
The perceptual skill that has been studied most
extensively in neurological patients is learning to read
text that has been geometrically transformed (such
as reading mirror-reversed words). Current interest
in perceptual skill learning was driven by the classic
study of Cohen and Squire [90] in which they examined the performance of amnesic patients on the mirror reading task. The results of the study showed that
the amnesic patients were able to learn to read mirrorreversed text as well as age-matched control participants, despite having poor declarative memory for the
practice episodes and stimuli. Subsequent studies have
replicated these findings in other groups of amnesic
patients [91, 92].
Evidence for the role of the basal ganglia in perceptual skill learning comes from patients with HD, who
show a mild impairment in mirror reading, despite
good declarative memory for the words read [91].
Studies of mirror reading in patients with PD have
been mixed, however, with some studies reporting
impaired learning [93–95] and other studies reporting
intact learning [96, 97].
Perceptual learning studies in healthy adults have
used psychophysical tasks such as contrast detection, orientation, and visual search [98, 99]. This
research suggests that perceptual learning proceeds
in two stages: an initial learning stage, characterized
by unskilled and effortful performance, that reflects
establishment of task-specific processing routines; and
a subsequent stage, ultimately leading to skilled performance, reflecting modification of representations
within the processing system [100].
Accordingly, functional imaging studies have
demonstrated different neural contributions in the
early versus later stages of skill learning. For instance,
a study of mirror-reversed reading in normal subjects
demonstrated that skill acquisition was accompanied
by decreasing activation in regions including both
occipital and right superior parietal cortices during
initial learning, and increasing activation in regions
including the left inferior temporal cortex later on
[101]. On the basis of these results, it was proposed
that learning to read mirror-reversed text may reflect
a transition from right hemisphere visuospatial processing of mirror-reversed stimuli to left hemisphere
object recognition areas involved in establishing
new representations of mirror-reversed letters [101,
102]. Interestingly, in a follow-up study, Poldrack
and Gabrieli [103] found that the caudate was active
during initial mirror-reading and showed a significant
learning-related increase in activation, consistent with
the reported impairment of HD and PD patients in
learning the mirror-reading task.
In an analogous manner, studies investigating
the acquisition of new motor skills have revealed
that prefrontal and cerebellar regions are primarily
activated early in the course of learning [104, 105]. As
task proficiency increases, this activation gives way to
a slowly evolving, long-term, experience-dependent
reorganization of primary motor cortex [106]. More
recent studies have further delineated the roles of
prefrontal, cerebellar, and motor cortices during
motor skill learning, as well as the parameters under
which new motor skill learning occurs. For example,
using fMRI and a motor sequence task, Doyon and
colleagues [107] found evidence for an experienceinduced shift from the cerebellar cortex to the dentate
nucleus during early learning, and from cerebellarcortical to striatal-cortical networks with extended
practice; these findings suggest that intrinsic modulation within the cerebellum, together with activation of
motor-related cortical activations, serves to establish a
procedurally acquired sequence of movements. More
recently, Doyon and colleagues [108] investigated the
contribution of sleep to consolidation of two motor
skills: finger tapping sequence learning (FTSL) and
visuomotor adaptation (VMA). They demonstrated
that the consolidation processes involved in the FTSL
task benefited from sleep (even a short nap) while
the simple passage of time was as effective as sleep
time for the consolidation of VMA to occur. Such
findings point to important task differences in the
study of motor skill learning. Finally, Rozanov, Keren
and Karni [109] examined the specificity of memory
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Section I: Structural and Functional Neuroanatomy
for a highly trained finger movement sequence. Their
results demonstrated that the gains attained in the
performance of a well-trained sequence of motor
movements can be expressed only when the order of
the movements is exactly as practiced. These results
may have important implications for the transfer of
new motor skills in patient populations, particularly
in neurorehabilitation efforts directed at improving
motor functions impaired by injury or disease.
Conclusion
Multiple human memory systems subserve the retention of knowledge, skills, experience, and emotions
over a time frame that spans seconds to decades. Neural pathways that encode information within these
overlapping systems are being elucidated with structural and functional brain imaging techniques and
sophisticated cognitive test paradigms. Such work is
enriching our understanding of component memory
processes and has great potential for informing clinical diagnostic and therapeutic efforts. Translating
research advancements in the cognitive neuroscience
of memory into practical clinical assessments and
interventions will be greatly facilitated by increased
collaboration among basic scientists, clinical investigators, and clinicians.
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Section I
Structural and Functional Neuroanatomy
Chapter
Language
12
Mario F. Mendez
Language is the distinctive human facility for communication through symbols. The expression of language includes all symbolic communication, including speech, reading and writing, sign language, Braille,
Morse code, and even musical notation. Language
evolved during the last 2.5 million years from a primitive system of individual sounds with concrete referents to strings or sequences of symbols with abstract
and generalizable meanings. The main processes of
language are the decoding and encoding of sequences
of symbols and associating them with concepts and
meanings [1].
How is language organized in the brain? Our
basic understanding of the neuroanatomy of language
and the brain is based on a classical lesion model
derived from the study of brain-injured patients in
the nineteenth and early twentieth centuries. Clinicians identified the existence of dedicated language
centers from the observation of different language
impairments after brain lesions in these areas or their
interconnecting fiber tracts. Today, we know that the
elements of language are not as fixed as defined by
the classical lesion model, and that the neuroanatomy
of language is complex. Rapid advances in cognitive
neuroscience indicate the existence of mental lexicons or dictionaries and processes for phonology,
morphology, syntax, semantics, and other features,
all interacting in a rapid, large-capacity system. In
this neurocomputational system composed of rapid
processing streams, there is simultaneous activation
at multiple levels and top-down, as well as bottom-up,
influences on language production and language comprehension. This chapter describes the neuroanatomy
of language beginning with the foundation in the
classical lesion model and concludes with an updated
view of language-brain organization.
Figure 12.1. Brain of Paul Broca’s original patient M. Leborgne,
commonly known as “Tan Tan.” Reproduced from Dronkers NF,
Plaisant O, Iba-Zizen MT, Cabanis EA. Paul Broca’s historic cases: high
resolution MR imaging of the brains of Leborgne and Lelong. Brain
2007;130(Pt 5):1432–41, with permission from Oxford University
Press.
Classical lesion model of language
and the brain
Clinical aphasia or language impairments from brain
lesions have been the window to localization of language in the brain. In 1861, Paul Broca inaugurated
the modern study of language with a description of
his patient “Tan Tan” who had lost the ability to speak
from a focal brain injury in the inferior frontal region
(see Figure 12.1) [2].
Later, Broca reported on the association of
impaired verbal fluency with left inferior frontal
damage in what came to be known as “Broca’s area”
(see Figure 12.2). In 1874, Karl Wernicke described
aphasia from loss of language comprehension consequent to left superior temporal injury. He then
elaborated a group of specialized and interconnected
Behavioral Neurology & Neuropsychiatry, eds. David B. Arciniegas, C. Alan Anderson, and Christopher M. Filley.
C Cambridge University Press 2013.
Published by Cambridge University Press. 174
Chapter 12: Language
Figure 12.2. Lateral view of the left hemisphere indicating the perisylvian area. The illustration shows Broca’s area in the frontal operculum
and Wernicke’s area in the superior temporal gyrus and the corresponding Brodmann’s areas. Reprinted with permission from Mark Dubin,
PhD, Department of Molecular, Cellular & Developmental Biology, University of Colorado at Boulder
(http://spot.colorado.edu/∼dubin/talks/brodmann/brodmann.html). This figure is presented in color in the color plate section.
language regions in the left perisylvian region. The
early work of Broca, Wernicke, and others established
the dominance of the left hemisphere for language
and demonstrated an anterior-posterior dichotomy
around the Sylvian fissure, with two hubs, Broca’s area
(Brodmann’s area [BA] 44, 45) for language production in the inferior frontal region and Wernicke’s area
(BA 22) for language comprehension in the superior
temporal gyrus (Figure 12.2). Norman Geschwind
subsequently described how disconnection of cortical
centers, such as Broca’s and Wernicke’s, can produce
distinct language and other syndromes [3, 4]. This
localization concept is embodied in the classical lesion
or “Wernicke–Geschwind” model of language and the
corresponding aphasia syndromes [5] (Figure 12.3).
Each classic aphasic syndrome suggests a neuroanatomical association of a specific language
function (Table 12.1). Broca’s aphasics are non-fluent
and have difficulty encoding language, using grammar,
and articulating words and sentences. This profile
suggests that Broca’s area processes grammatical
structure, including syntactic rules and grammatical
morphemes, rather than elements of language that
have content or specific meaning. It also suggests
that a major role of Broca’s area is the articulation of
language. Wernicke’s aphasics, on the other hand, are
fluent but have difficulty decoding and understanding
language. This suggests that Wernicke’s area selects
and uses elements of language with concrete meaning,
including content words. Conduction aphasia is a
175
Section I: Structural and Functional Neuroanatomy
Table 12.1. The aphasia syndromes and their characteristics.
Aphasia syndrome
Fluency
Auditory
comprehension
Repetition
Naming
Reading
comprehension
Writing
Broca’s
Abnormal
Relatively normal
Abnormal
Abnormal
Normal or abnormal
Abnormal
Wernicke’s
Normal, paraphasic
Abnormal
Abnormal
Abnormal
Abnormal
Abnormal
Global
Abnormal
Abnormal
Abnormal
Abnormal
Abnormal
Abnormal
Conduction
Normal, paraphasic
Relatively normal
Abnormal
Usually
abnormal
Relatively normal
Abnormal
Transcortical motor
Abnormal
Relatively normal
Relatively
normal
Abnormal
Relatively normal
Abnormal
Transcortical sensory
Normal, echolalic
Abnormal
Relatively
normal
Abnormal
Abnormal
Abnormal
Mixed transcortical
Abnormal, echolalic
Abnormal
Relatively
normal
Abnormal
Abnormal
Abnormal
Anomic
Normal
Relatively normal
Normal
Abnormal
Normal or abnormal
Normal or
abnormal
Transcortical
motor
aphasia
Broca’s
aphasia
Concepts
Motor
patterns
Figure 12.3. Wernicke–Geschwind
model. The diagram illustrates the
organization of language and
corresponding aphasia syndromes in the
left hemisphere.
Transcortical
sensory
aphasia
Auditory
images
Wernicke’s
aphasia
Conduction
aphasia
m
third perisylvian aphasia, and is due to the disconnection of Broca’s and Wernicke’s areas. This disorder
features a prominent disturbance in repetition out of
proportion to any other language disturbance. Most
cases of conduction aphasia have neuropathology
involving the anterior inferior parietal lobe, including the arcuate fasciculus and the supramarginal
gyrus [6].
Additional syndromes localize outside of the perisylvian region in the Wernicke–Geschwind model
[7]. Transcortical motor and transcortical sensory
aphasias have relative preservation of the ability to
repeat spoken language in the presence of language
impairments otherwise consistent with Broca’s aphasia
176
a
or Wernicke’s aphasia, respectively. The neuropathologic lesion underlying transcortical motor aphasia is
in the supplementary motor area of the left hemisphere
or between that area and Broca’s area. The neuropathologic lesion underlying transcortical sensory aphasia is
in the left angular gyrus in the parietal region or in the
left posterior superior or middle temporal gyri.
Subcortical aphasias can result from lesions in the
left basal ganglia, the anterolateral nuclei of the thalamus, or white matter [8]. Language impairment from
the basal ganglia may resemble transcortical motor
aphasia, and language impairment from the thalamus may resemble transcortical sensory aphasia. With
these “subcortical” aphasias, cortical involvement or
Chapter 12: Language
distal hypometabolism is probably necessary for permanent language changes [9, 10].
Alexias are characterized by the inability to read
with or without accompanying agraphia, the inability
to write. Alexia with agraphia can result from left angular gyrus lesions, and alexia without agraphia from
lesions in the left visual occipital region combined with
damage to the splenium of the corpus callosum.
Finally, frontal lesions involving motor areas
impair speech, or the motor aspects of verbal communication, and can produce dysarthria, apraxia of
speech, reiterative speech disorders, and even mutism.
Problems with the classical lesion model
The classical lesion model does not address a number
of critical aspects of language organization and the
brain. The model does not formally consider basic
linguistic elements such as phonology (the sound
pattern of language), morphology (the combination
of language’s smallest meaningful units), syntax (the
structure of sentences), semantics (the relationship
of language to meaning), and pragmatics (intonation,
gesture, and other aspects of discourse). In addition,
the model does not consider the speed with which
children acquire language and the related suggestion
by Chomsky that there is a brain region or process
that restricts the set of possible human grammars and
thereby facilitates language acquisition [11]. Finally,
the classical lesion model does not consider brain
plasticity or the effects of age, sex, and handedness.
The greatest challenge to the classical lesion model,
however, comes from advances in neuroimaging and
related methodologies. For a long time, information
about how the brain processed language could only
come from the study of the effects of neurological
disease in humans. In the last few decades, many
imaging technologies have expanded our understanding of language and the brain, and moved us beyond
dependency on the lesion model. These include voxelbased morphometry, positron and single photon
emission tomography, functional magnetic resonance
imaging, special analyses of electroencephalograms,
magnetoencephalography, and transcortical magnetic
stimulation. These methodologies have dramatically
expanded our understanding of the neuroanatomic
relationships and functional connectivity of language
organization in the brain [12, 13] (Figure 12.4).
Using these methodologies, investigators have
challenged the basic assumptions of the classical lesion
model. First, damage to more than Broca’s area is
needed to cause Broca’s aphasia. Although Broca’s area
does participate in syntactic processing and the execution of articulatory movements, lesions confined to
Broca’s area may not result in language production
deficits [14]. Lesions of the two sections of Broca’s
area, the pars triangularis (BA 44) and the pars opercularis (BA 45), are not sufficient or necessary for Broca’s
aphasia. In fact, a re-analysis of the preserved brains
of Broca’s two original patients confirmed that their
lesions extended well beyond BA 44 and 45, deep into
the white matter, and involved the insula and the superior longitudinal fasciculus [2]. The anterior insula,
which is implicated in the labored articulation and
non-fluency, or apraxia of speech, is evident in Broca’s
aphasia [15]. This suggests that the complete Broca’s
aphasia syndrome is predicated on injury not only to
Broca’s area but also to the white matter underlying
Broca’s area and to the anterior insula.
Second, Wernicke’s aphasia requires more than
damage to Wernicke’s area alone. Although Wernicke’s
area plays a role in word comprehension, isolated
destruction of this area does not necessarily result
in decreased auditory comprehension. Involvement of
the underlying white matter and adjacent areas, such
as the supramarginal and angular gyri in the inferior parietal region, is necessary for a complete disturbance of auditory verbal comprehension [16]. So,
neither Broca’s area lesions nor Wernicke’s area lesions
are necessary or sufficient for Broca’s aphasia and Wernicke’s aphasia, respectively, challenging the usefulness
of the classical lesion model of aphasia.
Current views on language
and the brain
New data support some of the aspects of the classical lesion model of aphasia but dispute or modify
others. There is continued support for a left hemispheric specialization for language in the perisylvian
region. Recent studies, however, have modified the
classic role of Broca’s area. Similarly, recent studies
have also modified the classic role of Wernicke’s area.
Additionally, more recent characterizations of uncommon language disorders add to our understanding of
language and the brain. Finally, lesion re-analysis and
functional neuroimaging point to a new organization
based on a neurocomputational model of rapid processing streams in which language areas are embedded
within complex and highly interconnected networks.
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Section I: Structural and Functional Neuroanatomy
Figure 12.4. Examples of language mapping in the frontal lobe (A) and the combined temporal and parietal lobes (B). Yellow and green
circles represent numbered electrocortical stimulation mapping (ESM) language sites and clean ESM sites, respectively. Red boxes represent
expression fMR imaging activations. Blue boxes represent comprehension fMR imaging activations. The frontal lobe slices are shown with an
ESM radius of 5 mm (determined to produce the highest sensitivity with the least cost to specificity) and temporoparietal lobe slices are
shown with an ESM radius of 9 mm. A: For frontal lobe mapping, these brain slices demonstrate that red (expression) activations tend to
overlap with, or are adjacent to, essential (yellow) ESM sites, but avoid non-essential (green) ESM sites. Blue activations in the frontal lobe also
appear predictive. B: In most cases of temporoparietal lobe mapping, such as the one illustrated here, comprehension fMR imaging
178
Chapter 12: Language
Hemispheric specialization
The perisylvian area of the language-dominant hemisphere most closely approximates a “language organ”
in the human brain. Broca suggested an association
between the dominant hand and the dominant hemisphere for language [17], and almost all right-handed
persons are left hemisphere dominant for language.
Among aphasics, left hemisphere lesions occur in 92%
or more of all patients, nearly 100% if they are righthanded, but only about 63% if they are left-handed.
Most non-right-handed (left-handed and ambidextrous) persons are also left hemisphere language dominant, although they usually have additional language
representation in the right hemisphere. The greater
bilaterality of language in most left-handers decreases
the clinical value of the classic aphasia syndromes in
these patients. Henri Hecaen distinguished familial
left-handers with a decreased left hemisphere predominance of language and a greater likelihood of hemispheric symmetry for language compared with righthanders [18].
Neuroanatomic evidence for this organization is
the relative absence of hemisphere asymmetry of the
planum temporale, which contains Wernicke’s area,
in familial left-handers. The planum temporale, an
enlargement located on the posterior surface of the
temporal lobe, is larger on the left in 65 of 100
post-mortem brains [19]. Most right-handers have a
larger planum temporale in the left hemisphere compared with the right, and this asymmetry is evident
at about 30 weeks of gestation. In contrast to the
left hemisphere, the right hemisphere has a dominant role for emotional features, including determining the emotional prosodic aspects of communication
and the emotional state of a speaker from tone of voice
[20].
There is increased metabolic activity, cerebral
blood flow, and neural activity in perisylvian areas
of the left hemisphere when subjects are using
language [21]. In comparison, language is temporarily disrupted with sodium amytal injection into the left
carotid artery or with electrical charges sent to certain
areas of the left hemisphere [22]. Patients who have
undergone a “split-brain” procedure with transection
of the corpus callosum cannot name objects visible
only in the left visual field or held in their left hand
[23]. In addition, normal individuals perceive spoken
words or phonemes better in the right ear than in the
left [24].
Alternative role for Broca’s area
Rather than a static seat of grammar or speech articulation, Broca’s area is part of a processing stream of
lexical integration that forms sentences. It appears to
be a node through which linguistic units are combined
and broken down, selected and compared, and also
through which integration of the syntactic, semantic,
and phonological elements into sentences is accomplished prior to their expression. First, Broca’s area
(BA 44, 45) engages other brain areas in which mental
lexicon (or dictionary) is represented and facilitates
selections of words of interest (lexical selection). Second, it assigns and constructs grammatical structures
(“lemmas” or grammatical morphological aspect
of words) so as to relate words to each other. This
process occurs at the word level, with grammatical
morphemes and function words, and at the sentence
level with syntax [25]. The words require semantic
integration into the context of preceding words in a
sentence for the sequences of words to have meaning.
Third, Broca’s area constructs a phonological output
lexicon. Phonological encoding involves activating
word sounds (phonemes, syllables) and monitoring
and segmenting them. Through this phonological
encoding, Broca’s area plays a role in speech perception, and phoneme, syllable, and word discrimination
and identification [14]. Fourth, phonetic encoding
precedes actual articulation. This information is
←
Figure 12.4. (cont.)
activations matched well with ESM language sites (yellow) in the temporoparietal lobes and did not overlap with clean ESM sites (green). Very
little expression fMR imaging activations are seen in the temporoparietal lobe region and the reason why such tasks as verbal object naming
and word generation do not accurately predict language sites in these regions. C: These maps were obtained in an individual case in which
preoperative fMR imaging was the least effective at accurately predicting whether a given cortical area would be involved in language
function. In this case, only two of the three essential ESM sites overlapped with fMR imaging activations, and only two of seven of the clean
ESM sites completely avoided fMR imaging activations. Reproduced from Pouratian N, Bookheimer SY, Rex DE, Martin NA, Toga AW. Utility of
preoperative functional magnetic resonance imaging for identifying language cortices in patients with vascular malformations. J Neurosurg.
2002;97(1):21–32, with permission of Journal of Neurosurgery Publishing Group. This figure is presented in color in the color plate section.
179
Section I: Structural and Functional Neuroanatomy
conveyed to motor areas including the anterior insula
and supplementary motor area. The cortex just in
front of the face part of the motor strip is involved
in the control of movements of the mouth, jaw,
tongue, palate, larynx and other articulators that are
needed for speech, and the anterior insula functions
to select and sequence phonemes. Finally, other
dorsolateral and ventromedial frontal areas participate in short-term memory for language, retrieval
and manipulation of semantic representations, and
social elements of discourse such as topic initiation,
turn-taking, and personal references.
The alternative role of Broca’s area explains many
problems seen among persons with Broca’s aphasia.
These individuals do not use action words (verbs),
function words, and inflections correctly, and they
have difficulty connecting morphemes to build words
[26]. When comprehension is dependent on understanding the syntactical information in a sentence,
individuals with Broca’s aphasia demonstrate comprehension impairments and difficulty integrating
words into the context of a sentence [14]. They also
demonstrate difficulty discriminating or identifying
phonemes or speech syllables and pronouncing new or
unfamiliar words, reflecting problems with the phonological output lexicon [27].
Alternative role for Wernicke’s area
Wernicke’s area is part of a processing stream that
accesses and selects from the mental lexicon, which
in turn, activates related concepts or semantics. First,
prelexical acoustic or phonetic analysis takes place
bilaterally in the left superior temporal gyrus [14].
This region partially segregates different vowel categories suggestive of initial stages of speech sound
mapping [28]. These acoustic or phonetic percepts are
mapped as a phonological input code in the left midsuperior temporal gyrus. In reading, letters and the
orthographic input code are also integrated in the left
superior temporal cortex [29]. Second, word recognition requires lexical access and selection from the
phonological input lexicon or the best-fitting auditory word forms in the left superior temporal sulcus.
The left ventral mid-superior temporal sulcus appears
to discriminate speech sounds (words, pseudo-words,
reversed speech) from non-speech sounds. Third,
word recognition further requires activated word form
representations that are subsequently combined with
180
grammatical features (lemma). Fourth, these lexicalphonological elements access a semantic network of
contextual and background knowledge. The left midinferior temporal gyrus and anterior temporal pole
store and retrieve these semantic word representations. Some individuals with lesions in Wernicke’s area
have preserved phoneme discrimination and identification (phonological information) but impaired access
to semantics, possibly from damage in the left posterior inferior temporal region (BA 37). Finally, there is
a working memory capacity specific to sentence processing that is different for that tapped by span tasks.
The alternative role of Wernicke’s area explains
many of the language problems experienced by persons with Wernicke’s aphasia. These individuals perceive speech sounds normally but are unable to access
the phonological input lexicon and/or auditory word
forms. Consequently, they produce erroneous but
well-articulated words, paraphasic errors, or neologisms rather than appropriate content words. In Wernicke’s aphasia, content words tend to be absent or
replaced by general terms or associations based on
context.
Contributions of other language disorders
Clarification of several uncommon conditions has
added to our understanding of language and the brain.
Pure word deafness is a pre-language disturbance from
bilateral or unilateral lesions undercutting Wernicke’s
area and causing impaired comprehension of speech
sounds but not of most non-speech sounds. This disorder suggests that there are different systems for speech
and non-speech auditory perception [14]. Patients
with pure word deafness have deficits at the level of
extracting the acoustic cues to speech due to difficulty
in perceiving rapid changes in complex pitch patterns.
Pure word deafness further indicates that speech perception depends on the ability to perceive rapid temporal changes.
Pure anomia or “word-selection” anomia is a disturbance from left inferior, posterior temporal (BA 37)
lesions causing confrontation naming difficulty with
intact word comprehension. This disorder suggests
that this region is crucial for the retrieval of phonological word forms, and that these word forms are dissociable from semantic knowledge [14].
Progressive non-fluent aphasia results from left
frontotemporal atrophy and presents with gradual
Chapter 12: Language
Figure 12.6. Diffusion tensor imaging pathways in conduction
aphasia. Reproduced from Catani M, Jones DK, Ffytche DH.
Perisylvian language networks of the human brain. Ann Neurol.
2005;57(1):8–16, with permission from John Wiley & Sons, Inc. This
figure is presented in color in the color plate section.
input lexicon, and associated with posterior temporalinferior parietal dysfunction [34].
Figure 12.5. MRI (T2) images of a patient with semantic aphasia.
There is bilateral anterior temporal atrophy disproportionately
affecting the left temporal lobe.
progression of non-fluency, agrammatism, and articulation difficulty [30, 31]. Recent information indicates
that much of the non-fluency may be apraxia of speech
from extension of the atrophy to the underlying left
anterior insular cortex [15].
Semantic dementia includes semantic aphasia and
is associated with atrophy in the anterior, infero-lateral
temporal lobe; in this dementia, the aphasia involves
impaired understanding of word meaning, often
disproportionately affecting specific word categories
[32, 33] (Figure 12.5). This profile indicates that the
semantic system is organized and coordinated from
the anterior temporal poles. On reading, these patients
also demonstrate “surface dyslexia,” or the inability to
read irregularly spelled words but preserved ability to
sound them out, emphasizing the dual route model of
reading.
Deep dyslexia is a reading disorder from large left
hemisphere lesions resulting in residual reading for
meaning only. Deep dyslexia, with its access to semantics but difficulty in single-word repetition, supports
independent phonological input and output lexicons.
Finally, investigators recently described a “logopenic”
form of aphasia characterized by difficulty with a
phonological store, possibly a part of the phonological
Neurocomputational model
Language is organized in a complex and highly interconnected network engaged in successive integration of information. Linguistic functions result from
distributed groups of connected neurons organized
around two processing hubs, Broca’s area and Wernicke’s area, in the perisylvian region of the languagedominant hemisphere. These areas form a central axis
of interconnected nodes enabling nearly simultaneous iterative computation of the “best fit” needed for
a linguistic task, depending on top-down, as well as
bottom-up, influences [35, 36].
An example of processing distributed between
hubs rather than localized with specific centers is
conduction aphasia: the clinical manifestations of
this aphasia vary with the specific inter-hub pathway
between Broca’s and Wernicke’s areas that is interrupted [37] (Figure 12.6). Some investigators suggest
that, similar to the visual system, there are two main
processing streams for language, a ventral stream and
a dorsal stream [38]. A bilaterally organized ventral
processing stream mediates speech signals for comprehension, and a left-sided dorsal processing stream
mediates speech signals for articulation.
Language also depends on the production and
detection of precise time intervals. Both speech production and detection are unusually fast processes,
181
Section I: Structural and Functional Neuroanatomy
and precise timing is needed for both aspects of language. Quick temporal variants characterize language
sounds, the processing of which appears to be essential
to a correct perception of speech. Speech sounds can be
continuously varied, but a subject only hears categories
(categorical perception; i.e., no “in between” representations); this auditory “chunking” mechanism facilitates the speed at which such sounds are processed.
Fast-changing temporal cues seem to elicit preponderant activation in the auditory system of the dominant hemisphere, and the superior temporal gyrus in
that hemisphere is particularly sensitive to the rate of
change over time in speech signals. A neuroanatomical correlate of this dominant-hemisphere temporal
advantage in processing speed is the greater amount of
white matter and myelination in the dominant vs. nondominant temporal lobe [39]. A further important factor for effective speech production is the rapid syntactic organization provided by the left inferior frontal
region [40].
Conclusion
Current information modifies the classical Wernicke–
Geschwind model of language to incorporate the contributions of perisylvian processing hubs that participate in sequential, neurocomputational operations on
language-related information. The human brain has
the innate capacity to manipulate complex symbol systems such as language, and in childhood the structure
of the brain allows for the rapid and efficient acquisition of language. The left perisylvian areas are predisposed for fast timing of strings of symbols organized
on a syntactic scaffolding. Broca’s area and Wernicke’s
area are critical hubs for rapid processing streams that
integrate steps from the extraction of phonetic features
to lexical-phonological representations to semantic
representations and so on, eventually to articulation
and motor speech. Recent and continuing advances
in neuroimaging and related technologies offer great
promise of clarifying further the structural and functional neuroanatomy of language.
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Section I
Structural and Functional Neuroanatomy
Chapter
Affective prosody
13
Elliott D. Ross
In humans, vocal–acoustic communication is a highly
evolved behavior. Although lower animals have wellestablished systems of vocal–acoustic communication,
humans possess a communication system of complexity and flexibility sufficient to qualify as language: this
system encompasses the ability to store and cognitively
modulate vast numbers of verbal-semantic representations, to produce intricate patterns of articulation,
and to generate syntactical relationships with nearly
infinite flexibility [1–9]. It has been assumed therefore,
that human language is an evolutionary adaptation
related to the marked expansion of prefrontal and
temporoparietooccipital heteromodal neocortex [10–
17]. This gradual encephalization leads, in turn, to
the corticalization and resultant cognitization [18–23]
of communication systems that in lower animals are
heavily represented in non-neocortical areas, including the basal ganglia, thalamus, limbic system, paralimbic mesocortex, brainstem, and cerebellum
[24–34].
Based on the fundamental discoveries of Broca [35,
36], Wernicke [37], and Lichtheim [38] in the late
1800s that focal lesions in the left but not right hemisphere (in strongly right-handed individuals) may produce deficits in the verbal-linguistic aspects of language resulting in various aphasic syndromes [39], language is viewed as a dominant and highly lateralized
function of the left hemisphere [9]. Because language
is a distinguishing feature of humans, the right hemisphere has been relegated inappropriately to the role of
the non-dominant or “minor” hemisphere [40].
Nevertheless, the very first functional imaging
study of language [41], which was expected to show
predominantly left-sided activation, showed instead
that both hemispheres were activated in a relatively
homologous pattern that included the posterior and
anterior opercular regions and the medial surfaces of
the frontal lobes. In fact, all subsequent functional
imaging research that has probed various aspects of
language, including verbal-linguistic and paralinguistic functions has shown robust bilateral activations on
initial data acquisition that, at minimum, involve the
posterior perisylvian regions [9, 42–49]. Thus, modern
functional imaging data overwhelmingly support the
concept that human language is, in fact, a distributed
process that actively engages both hemispheres [9].
This chapter considers the topic of affective prosody as
an important aspect of language that appears to be lateralized to the right hemisphere.
Constituents of language
and communication
Human language is composed of various basic elements that are classified as being either linguistic
or paralinguistic [2, 50]. The linguistic or propositional elements are characterized by words (vocabulary, lexicon) and syntactical relationships (grammar) that convey meaning based on word sequences.
The basic acoustical features underlying word production (phonology) and comprehension (phonetics) are
called segments, and these have distinctive acoustical
signatures associated with various consonants, vowels, and syllables. It is these word-related constituents
of language that are primarily disrupted by focal lefthemisphere injury that causes aphasic syndromes [9,
39].
In contrast, paralinguistic aspects of language
are accessory to words, and include prosody and
kinesics. The acoustical features underlying prosody
include pitch, intonation (variation of pitch over time),
melody, cadence, loudness, timbre (voice quality),
Behavioral Neurology & Neuropsychiatry, eds. David B. Arciniegas, C. Alan Anderson, and Christopher M. Filley.
C Cambridge University Press 2013.
Published by Cambridge University Press. 184
Chapter 13: Affective prosody
stress, and pauses. As will be described in subsequent sections of this chapter, there are various levels of prosodic communication that convey linguistic, affective (attitudinal and emotional), dialectical,
and idiosyncratic information [50]. Kinesics refers to
facial, limb, and body movements associated with language and communications [51]. Movements that are
used for standard, well-defined communication (semiotics), such as the thumbs down sign for displeasure
or the “V” for “victory” sign, are classified as pantomime whereas movements used to color, emphasize,
and embellish communication are classified as gestures. Most spontaneous kinesic activity often blends
gestures and pantomime into a single movement.
Prosody
Monrad-Krohn [52] initiated the modern clinical
study of prosody after caring for a native Norwegian woman during WWII who sustained a shrapnel wound to the left frontal area that precipitated
acute Broca’s aphasia. The woman made an excellent
recovery except that she acquired a foreign accent.
The acquired accent caused her considerable emotional distress during the Nazi occupation of Norway
because she was mistaken for being a German and,
consequently, socially ostracized. Although her speech
had preserved melody, as evidenced by her ability to
sing, intone, and emote, she had inappropriate application of stresses and pauses to her speech giving it
the patina of a foreign accent. Based on this patient
and others, Monrad-Krohn [53] divided prosody into
four major components: intrinsic (or linguistic), intellectual (or attitudinal), emotional, and inarticulate.
Intrinsic (or linguistic) prosody enhances and clarifies the linguistic aspects of a language through judicious use of stress pauses and intonation without altering either words or word order. For example, raising
the intonation at the end of a statement by a halfoctave transforms a statement into a question. Altering word stress and timing may clarify word meaning, i.e., “the Redcoats are coming” (British regulars)
versus “the red-coats are coming” (red-colored coats)
or changing the stress on certain words and altering
the pausal structure of the sentence may clarify potentially ambiguous syntax, i.e., “The man . . . and woman
dressed in black . . . came to visit” (only the woman was
dressed in black) versus “The man and woman dressed
in black . . . came to visit” (both were dressed in black)
[54, 55].
Intellectual (or attitudinal) prosody imparts attitudinal information to discourse that may drastically
alter meaning. For example, if the sentence “He is
smart” is spoken with emphatic stress on “is,” then it
becomes a resounding acknowledgment of the person’s
ability. If, instead, the emphasis resides on “smart” with
a terminal rise in intonation, then sarcasm is communicated.
Emotional prosody infuses speech with primary
types of emotions such as happiness, sadness, fear,
and anger. In modern terminology, the term affective
prosody refers to the combination of Monrad-Krohn’s
intellectual and emotional prosody [50].
Inarticulate prosody is the use of certain paralinguistic non-verbal elements, such as grunts and sighs,
to embellish discourse. In addition, there is also dialectical (or regional) prosody that belies a speaker’s origin and idiosyncratic prosody that gives rise to voice
patterns and qualities that are unique to an individual.
Both these subclassifications can be considered as part
of intrinsic prosody.
Monrad-Krohn [53] also described various clinical disorders of prosody caused by brain injury or
disease. Dysprosody is a change in voice quality that
may result in a foreign accent syndrome [56–58]. It
is encountered primarily in patients with reasonably
good recovery from non-fluent aphasias due to left
hemisphere lesions that alter the patient’s dialectical and idiosyncratic aspects of prosody. Aprosody is
the general lack of attitudinal and emotional prosody
observed, for example, in patients with Parkinson’s disease as part of their bradykinesia, masked facies, and
softly monotonous voice. Hyperprosody refers to the
excessive use of prosody that occurs in acutely manic
or psychotic patients, or in Broca’s or global aphasics
who have very few words at their disposal but use them
vehemently to convey their emotional states, an observation first made by Hughlings Jackson in the nineteenth century [59].
Although Monrad-Krohn did not attribute disorders of prosody specifically to focal right brain damage, he did predict that, in addition to aprosodic
speech, disturbed prosodic comprehension should
also be encountered after brain damage. Indeed, publications over the last three decades, discussed below,
establish that focal lesions of the right hemisphere lead
to fundamental disturbances in the production and/or
comprehension of affective prosody. The resulting syndromes have been termed aprosodias, and research
has shown that functional-anatomic correlations of
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Section I: Structural and Functional Neuroanatomy
the aprosodias in the right hemisphere are similar
to those of the aphasias in the left hemisphere [60–
62]. Lastly, the syndrome of phonagnosia has been
described [63, 64] in which patients with lesions of the
right parietal region lose the ability to identify familiar
individuals by their voice characteristics alone, similar to the syndrome of prosopagnosia [65] (the inability to identify familiar individuals by facial features
alone).
Kinesics
Disturbances in pantomime, involving both production and comprehension, have been linked to left brain
damage [66–72]. Goodglass and Kaplan [66] proposed
that disorders of pantomime in aphasics with significant comprehension deficits may be related to their
inability to comprehend symbols whereas disorders of
pantomime in aphasics without significant comprehension deficits are associated with ideomotor apraxia.
Although other investigators have not shown such
tight correlation of a specific pantomimal disturbance
with a specific linguistic disturbance [68, 69, 71, 72],
disorders of pantomime are almost always associated
with left hemisphere damage that usually results in
aphasia, unless corpus callosum injury is the responsible lesion [73].
Gestural kinesics, however, is often preserved in
aphasic patients [51, 59]. In 1979, Ross and Mesulam
[74] reported two right-handed patients with ischemic
infarctions of the right frontoparietal operculum who,
in addition to affectively flat speech, had a general
loss of spontaneous gestural activity that involved the
non-paralyzed right face and limbs. Neither patient
had disturbances in ideomotor praxis. Based on these
patients, it was suggested that gestural as opposed to
pantomimal behavior was a dominant and lateralized
function of the right hemisphere. Subsequent studies
lend further support to this hypothesis by showing
that the right hemisphere is not only specialized for
producing gestures but also for comprehending their
meaning [75–86].
In summary, affective prosody, gestures, and other
paralinguistic features of language impart vitality to
human discourse that is essential for overall communication competency [54, 86–90]. These features are
also important for enabling the experience of satisfactory psychosocial interactions, and for overall emotional well-being in both children and adults [91–95].
In fact, all the index cases that provided insights into
186
the potential role of the right hemisphere in dominantly modulating the affective aspects of communication, which in turn initiated contemporary programs of research, presented clinically because of psychosocial discord [96–98]. Although affective prosody
is considered a paralinguistic or subservient feature of
language, it is crucial to emphasize that if the affectiveprosodic message of a statement is at variance with
its verbal-linguistic message, such as encountered in
irony or sarcasm, adults and most children will overwhelmingly believe the affective-prosodic intent [55,
87, 90, 99, 100].
The role of the right hemisphere in
language and communication
The first clinician to suggest a lateralized role for
the right hemisphere in communication was Hughlings Jackson in his 1879–1880 publication [59]. He
observed that patients with dense aphasias were often
still able to communicate intent through gestures and
vocalizations using the few words available to them.
Thus, he suggested that the emotional aspects of language and communication might be dominant functions of the right hemisphere. Clinicians, however,
did not formally investigate his observations, until the
1970s when Heilman and colleagues [100–105] and
Ross and colleagues [60–62, 74, 106] published a series
of papers describing loss of the affective-prosodic
aspects of language following focal brain damage.
In 1975, Heilman and colleagues [101] tested 12
right-handed patients with temporoparietal lesions on
their ability to comprehend affective prosody by presenting verbally neutral sentences with various emotional intonations. Six had left brain damage (LBD)
and six had right brain damage (RBD). The patients
with LBD had minimal aphasic deficits that did not
interfere with testing. Patients with RBD scored near
chance in their ability to detect emotions compared to
controls and LBD patients. In a follow-up study [102],
LBD and RBD patients with temporoparietal injuries
were tested for their ability to repeat verbally neutral
sentences with various emotional intonations. Once
again, the RBD patients were severely impaired on the
task compared with controls and LBD patients.
In 1979, Ross and Mesulam [74] published a
report describing two patients with computed tomography (CT)-verified ischemic lesions of the right frontoparietal operculum. Both of these patients had left
hemiplegia. They displayed markedly flattened affect
Chapter 13: Affective prosody
Table 13.1. The aprosodias. Note: (∗ ) Indicates types of aprosodias with functional–anatomic correlations in the right hemisphere that
are similar to the aphasias resulting from left hemisphere lesions that are predominantly cortical in location (9, 39, 60–62, 110–113, 138,
186). Agesic (aprosodia) (187) is similar to anomic aphasia (188).
Spontaneous
Comprehension
Repetition of
affective
of affective
Type of aprosodia communication affective prosody prosody
Comprehension Lesion location in
of gestures
right hemisphere
Motor ∗
Poor
Poor
Good
Good
Frontoparietal
operculum
Sensory ∗
Good
Poor
Poor
Poor
Temporoparietal
operculum
Conduction
Good
Poor
Good
Good
(insufficient cases)
Global ∗
Poor
Poor
Poor
Poor
Perisylvian
Transcortical Motor ∗
Poor
Good
Good
Good
Medial frontal
Transcortical Sensory ∗ Good
Good
Poor
Poor
Temporal parasylvian
Mixed Transcortical
Poor
Good
Poor
Poor
(insufficient cases)
Agesic
Good
Good
Good
Poor
(insufficient cases)
because they could not project emotions into their
speech or kinesic behaviors, yet retained the ability
to comprehend affect in the speech of others. Both
patients were right-handed and neither demonstrated
aphasic or apraxic deficits.
Based on these cases and those published by Heilman and colleagues [101, 102], it was hypothesized
that the affective aspects of communication, as originally proposed by Hughlings Jackson [59], were dominant and lateralized functions of the right hemisphere, and that the functional–anatomic organization of affective prosody in the right hemisphere was
similar to that of propositional language in the left
hemisphere. An issue not resolved in the paper, however, was whether all prosodic aspects of language
were impaired by RBD. Subsequent studies [93, 103,
107–109] have carefully examined this issue, and the
composite data indicate that the linguistic features of
prosody may be impaired by either LBD or RBD.
Based on the hypothesized organization of affective prosody in the right hemisphere [74], Ross [60]
studied ten patients with focal RBD due to stroke.
The patients were tested within four weeks of their
event, except for one patient tested at 10 months
after stroke, and the lesions were localized by CT.
The patients underwent a bedside assessment of their
ability to modulate affective prosody and gestures
in a manner similar to methods utilized for assessing propositional language. The patients were examined qualitatively for their ability to: (1) spontaneously
project affect into their speech (affective prosody) and
display kinesic behaviors (gestures) during discourse;
(2) repeat verbally neutral sentences with different
emotional intonations, i.e., happiness, sadness, surprise, disinterest, and anger; (3) comprehend affective prosody auditorily; and (4) comprehend gestures
visually. When analyzed for functional–anatomic relationships, all patients with opercular lesions bordering
the right Sylvian fissure had some disorder of affective communication with loss of affective repetition.
Transcortical syndromes were also observed in which
patients retained the ability to repeat with affective
variation but had flattened affect and/or loss of the
ability to comprehend affective prosody and gestures.
The specific combinations of affective-prosodic
deficits following localized lesions in the right
hemisphere appeared to be reasonably analogous
to the functional–anatomic relationships of aphasic deficits observed after focal left brain damage.
Thus, the syndromes associated with RBD were called
“aprosodias,” and the same modifiers used for classifying the aphasias were adopted for descriptive purposes
(Table 13.1). In a follow-up study, using blinded evaluations of affective communication in patients with
ischemic infarctions localized by CT, Gorelick and
Ross [61] corroborated the proposed aprosodia classifications and their functional–anatomic relationships
in the right hemisphere. They also reported that the
prevalence of aprosodic syndromes following RBD
was equal to the prevalence of aphasic syndromes
following LBD, underscoring that the aprosodias are
common syndromes.
187
Section I: Structural and Functional Neuroanatomy
Using quantitative testing methods, including
acoustical analysis of voice, and magnetic resonance
imaging (MRI) to localize lesions in patients with
ischemic infarctions, Ross and Monnot [62] confirmed
robustly that RBD patients with loss of the ability to
produce affective prosody in their spontaneous speech
had, at minimum, lesions that involved the right posterior frontal operculum or homolog of Broca’s area,
whereas RBD patients with loss of the ability to comprehend affective prosody had, at minimum, lesions
that involved the right posterior temporal operculum
or homolog of Wernicke’s area. These localizations
have also been confirmed by other investigators [110–
113].
However, these functional–anatomic relationships
only hold for acute brain damage for the time period
immediately post-injury because of long-term recovery of function due to neural re-organization [9, 62].
Reports that have not confirmed these functional–
anatomic relationships have either studied patients
many months to years after brain injury or used
patients with mixed etiologies of brain injury [62,
114–119]. In addition, patients with slowly progressive
lesions such as brain tumors may not show expected
aprosodic deficits, as noted by Lebrun and colleagues
[120]; as the tumor gradually destroys cerebral tissue,
the brain has time to re-organize itself and functional–
anatomic relationships change accordingly [9, 62].
This phenomenon was first noted and conceptualized by Hughlings Jackson ([59] see pp. 343–5) as the
“Momentum of Lesions” [121].
Similar to the aphasias, strictly subcortical lesions
that involve right basal ganglia structures and thalamus have also been reported to cause aprosodias
[9, 60–62, 117, 122–125]. There has also been a case
report of crossed aprosodia, in which a strongly righthanded patient becomes aprosodic but not aphasic
following a left hemisphere stroke, similar to cases
of crossed aphasia, in which a strongly right-handed
patient becomes aphasic following a right hemisphere
stroke [126].
When functional imaging studies are performed
probing the affective-prosodic aspects of language,
bilateral activations are always observed that, at minimum, involve the posterior perisylvian regions, analogous to the results of functional imaging studies probing the semantic, phonetic, or phonologic aspects of
language [9, 41–49]. However, if the stimuli are manipulated by incrementally reducing the articulatory–
verbal content, asymmetries in the intensity of the
188
bilateral perisylvian activations occur with a relative
shift to the right hemisphere [49, 127–129], supporting
the concept that affective prosody is a lateralized and
dominant function of the right hemisphere. Nevertheless, aprosodic deficits have been described following
LBD [111, 119] bringing into question the concept that
affective prosody is always a lateralized and dominant
function of the right hemisphere [104].
Hemispheric lateralization of
affective prosody
The terms “dominant” and “lateralized” are used interchangeably in the literature even though they have different neurological implications regarding brain functions. If a unilateral lesion produces a behavioral deficit
that affects both sides of space, then the function is
considered dominant [9, 106], a criterion met easily
by the various aphasic and aprosodic syndromes. If a
behavioral function is also strongly lateralized, then
it must be shown that the behavioral deficit does not
occur following lesions of the opposite hemisphere,
as exemplified by the aphasias. A behavioral function
may be lateralized but not necessarily dominant, as
exemplified by forebrain lesions that cause contralateral but not ipsilateral paralysis.
Unlike the aphasias, the lateralization of affective
prosody has been more difficult to resolve because various publications have documented affective-prosodic
disturbances among patients with left hemisphere
damage with and without aphasic deficits [106, 111,
119]. In patients with dense aphasias, the ability to
comprehend affective prosody correlates positively
with the severity of aphasic deficits [130, 131], suggesting that the presence of moderate to severe propositional language impairments may interfere with the
ability of examiners to assess affective prosody [106].
However, patients with left hemisphere damage may
develop affective-prosodic impairments that are not
aphasic [106, 111, 118, 119]. Thus, some investigators
call into question whether affective prosody is truly a
lateralized dominant function of the right hemisphere
[111, 119]. There is, however, another possible explanation for these findings [106].
If one assumes that affective prosody is a dominant
and lateralized function of the right hemisphere and
propositional language is a dominant and lateralized
function of the left hemisphere, then considerable
inter-hemispheric interaction must occur to ensure
that the articulatory-verbal and affective-prosodic
Chapter 13: Affective prosody
elements of speech are temporally and behaviorally
coherent [106, 122, 132, 133]. For example, if a speaker
wishes to express anger, the right hemisphere must
be apprised by the left hemisphere of what words
will be articulated and their temporal pace, so that
the right hemisphere can properly time the insertion
of affective-prosodic information into the spoken
sentence or phrase. Conversely, in order for the right
hemisphere to insert attitudinal information such as
sarcasm or irony into a sentence, certain syllables may
need to be prolonged to obtain the correct temporal
pace [87, 134–136]. Thus, left hemisphere damage
could alter the inter-hemispheric coordination of
language functions, causing an indirect disruption of
affective prosody.
This possibility was explored by Ross and colleagues [62, 106] in a series of patients with RBD and
LBD due to ischemic infarction localized by MRI. The
patients were tested within 6 weeks of their stroke
using the Aprosodia Battery, in which the verbalarticulatory demands are reduced incrementally when
assessing comprehension and production of affective
prosody; that is, stimuli were presented with varying
affects carried either by a fully articulated sentence
(“I am going to the other movies”), a repeated monosyllabic utterance (“ba ba ba ba ba ba”), or an asyllabic utterance (“aaaaaaaaaah”). Among LBD patients,
reducing the verbal articulatory demands caused a
robust incremental improvement in their ability to
comprehend and repeat affective prosody compared
with controls, whereas the similar maneuver among
RBD patients led to either no improvement or worsening of performance compared with controls. In addition, the affective prosodic deficits of LBD patients
were not correlated to the presence, severity, or type
of aphasic deficits or the cortical location of lesions
[62, 106]. However, lesions involving the paracallosal
white matter located below the supplementary motor
area and cingulate gyrus best predicted loss of spontaneous affective prosody and affective prosodic repetition in LBD patients. In contrast, affective prosodic
deficits were highly correlated with the cortical location of lesions among patients with RBD [62].
These findings suggested that the predominant
mechanism underlying affective-prosodic deficits following LBD is loss of interhemispheric integration of
the dominant and lateralized language functions represented in each hemisphere (the LBD/Callosal profile). In contrast, the predominant mechanism underlying affective prosodic deficits following RBD is loss
of the ability to directly modulate affective prosody
(the RBD/Aprosodic profile), a finding supporting
the hypothesis of Blonder and colleagues [104] and
Bowers and colleagues [105] that RBD causes loss of
affective-communicative representations as the theoretical basis for the aprosodias, similar to LBD causing
loss of semantic-syntactic representations as the theoretical basis for the aphasias.
Bedside assessment of affective
communication
Although quantitative acoustical and neuropsychological test batteries are available for assessing affective prosody such as the Aprosodia Battery [62, 106]
and the Florida Affective Battery [137, 138], clinicians
can readily incorporate an examination of aprosodic
deficits into their bedside neurological examination.
This procedure is similar to the assessment commonly
used for aphasic deficits [39, 50].
Spontaneous affective prosody
and gesturing
When interviewing patients, the examiner should
observe whether or not they gesture or impart affect
into their spontaneous conversation. Also, patients
should be asked questions that are emotionally laden,
such as those probing their reactions to the current illness or past emotional experiences. Attention should
also be devoted to how well patients insert appropriate
affective prosody and gestures into their discourse.
Repetition of affective prosody
This process involves patients imitating the examiner
immediately after being presented with an emotionally
neutral sentence or a repeated monosyllable using different affects, such as happy, sad, angry, surprised, disinterested, or neutral. The key observation is how well
patients insert the appropriate affective prosody and
gestures into their imitation. In an attempt to imitate
surprise (terminal rise in intonation of ∼2 octaves),
some patients may slightly raise their voice at the end
of the repetition (terminal rise in intonation of ∼1/2
octave). This is not a correct response because they are
attempting to imitate surprise using linguistic prosody
by converting the repetition from a statement into a
question.
189
Section I: Structural and Functional Neuroanatomy
Comprehension of affective prosody
After patients are presented with an emotionally neutral sentence or a repeated monosyllable using different vocal affects, such as happy, sad, angry, surprised, disinterested, or neutral, they are immediately
asked to identify the affect verbally. If needed, multiple choices can be presented. Standing behind patients
during this assessment avoids giving them visual clues
to the intended affect.
Comprehension of gestures
The examiner stands in front of patients and mimes a
particular emotion using only gestural activity involving the face and limbs. As with affective-prosodic comprehension, patients are requested to verbally identify
the mimed emotion. Again, if needed, multiple choices
can be presented.
Affective prosody in other
clinical settings
Congenital or early childhood lesions involving the
right hemisphere have been associated with aberrant
psychosocial development, including excessive shyness, poor eye contact, and deficient modulation of
affective prosody and gestures. These deficits have been
conceptualized as right hemisphere learning disability [91–93], similar to dyslexia being considered a left
hemisphere learning disability.
Recent studies by Monnot and colleagues [139,
140] using the Aprosodia Battery have examined the
effects of ethanol exposure and abuse on comprehension of affective prosody. A highly robust relationship
with age of ethanol exposure was found (r = 0.88 and
r2 = 0.78, explaining 78% of the data variance), such
that the earlier the exposure to ethanol, the more devastating the deficit. Individuals who were exposed to
ethanol in utero, even if they were not alcohol abusers
themselves, had mean comprehension score of −5.0
standard deviations below controls, essentially performing at chance. Yet these individuals did not meet
criteria for either fetal alcohol syndrome or fetal alcohol effects, and had no other cognitive or language
deficits [139]. In contrast, patients whose exposure and
ethanol abuse began as adults (⬎24 years of age) did
not have impaired comprehension of affective prosody.
From these data, it was postulated that early exposure to alcohol may cause a developmental disorder
190
that preferentially affects affective rather than propositional communication systems.
Affective prosody has also been studied in normal elderly individuals. Comprehension appears to
deteriorate with advancing age [141–144]. In patients
with Alzheimer’s disease, affective prosodic comprehension is impaired well before the onset of anomicaphasic deficits, a finding thought to reflect an aging
effect [145, 146]. Orbelo and colleagues [143, 144]
used the Aprosodia Battery in normal elders and
observed that the pattern of comprehension deficit fits
the RBD/Aprosodic profile, but is less severe and not
explainable by hearing loss. Thus the findings lend support to the hypothesis that cognitive aging is due primarily or, at least initially, to right hemisphere decline
[147–149].
In addition, aging substantially impairs the comprehension of attitudinal prosody [143]. In this regard,
a common occurrence in dementia clinics is that
elderly patients and their spouses, whether cognitively
impaired or not, often fail to appreciate jokes, sarcasm,
double entendres, witticisms, or irony (unpublished
observation). These individuals may react negatively to
comments meant to put them at ease because they tend
to interpret conversations literally. This clinical observation and the documented age-associated loss of the
ability to comprehend attitudinal prosody [143] suggest that interaction with elderly patients should strive
to employ literal communication whenever possible.
One of the cardinal aspects of schizophrenia is
flattening of affect [150–152], which includes loss
of the ability to modulate affective prosody [153–
155]. Using the Aprosodia Battery, Ross and colleagues [156] examined 45 patients with medically stable schizophrenia to ascertain if the pattern of deficit
suggested left, right, or mixed hemispheric dysfunction. The results showed that 84% of the patients
had an aprosodic syndrome with 58% having significant deficits in comprehension. The pattern of deficits
for both comprehension and repetition was statistically identical to the RBD/Aprosodic pattern, but not
related statistically to other cardinal symptom clusters
associated with schizophrenia. This suggests that loss
of affective prosodic comprehension could be a core
deficit contributing to the psychosocial impoverishment characteristic of the disease. Deficits in spontaneous affective prosody, however, were associated with
avolition, apathy, and asociality.
Most recently, Freeman and colleagues [157] used
the comprehension portion of the Aprosodia Battery
Chapter 13: Affective prosody
to assess patients with well-documented chronic posttraumatic stress disorder (PTSD) [158]. This research
was initiated because some of the symptoms of PTSD
suggest right hemisphere dysfunction; that is, patients
often have a restricted range of affect and family
members often report difficulty in reading their emotions. In addition, an intriguing case report documented that nightmares and intrusive recollections of
combat experience associated with PTSD, were ameliorated after a right frontal stroke [159], and there
is preliminary evidence that low-frequency repetitive right transcranial magnetic stimulation, causing
cortical inhibition, improves PTSD symptoms [160,
161]. Eleven patients with PTSD were evaluated [157].
Every patient had deficient comprehension of affective prosody compared with age-matched controls. As
in schizophrenia [156], the performance was identical statistically to the RBD/Aprosodic profile found
in patients with RBD. Ethanol was not found to
contribute to the findings because, if ethanol abuse
occurred, it began, with one exception, after age 23.
The authors surmised that without evidence for RBD it
was unlikely that an affective-prosodic comprehension
deficit could be acquired as a result of PTSD. Rather,
the individuals may have had a pre-existing developmental deficit in processing affective prosody, making
them vulnerable to chronic PTSD when exposed to
combat.
Affective prosody, gestures, and the
neurology of emotions
The aprosodias are disturbances in the modulation
of graded emotional behaviors associated with language and communication that are organized predominantly, but not exclusively, in the neocortex [9,
62]. As such, the aprosodias represent disruptions of
cognitive functions that can be manipulated for psychosocial purposes and ulterior motives as part of the
social emotional system [162–164]. Other aspects of
emotions, such as the experience of an emotion or
the display of coarse, all or none, emotional behaviors, such as laughing, crying, and anger, may be
unaffected by lesions causing aprosodias because they
are organized predominantly by the limbic system
and related descending pathways via the hypothalamus and brainstem [163–166]. Because of this neuroanatomic arrangement, paradoxical behaviors may
occur during clinical interactions that may interfere
with arriving at a correct diagnosis.
A dramatic example involves the challenge of diagnosing depression in patients with focal brain lesions
[167]. For example, patients with motor types of
aprosodia will exhibit a flat affect even when discussing
highly emotional issues, such as depression or suicide [167, 168]. Consequently, clinicians may discount
their verbal reports of emotional distress and not diagnose or treat their depression. Patients with RBD, in
addition to being aprosodic, may have neglect and
denial of illness causing them to verbally deny that
they are depressed even though they have appropriate behavioral, vegetative, and neuroendocrine indicators of melancholic depression that will respond to
antidepressant medications. Patients with motor or
global aprosodia may be able to display appropriate
emotional behaviors during very sad, happy, or angry
situations even though they have an otherwise flat
affect during normal discourse [60, 61]. However, if
the emotional displays are excessive and inappropriate
to the psychosocial situation, similar to patients with
pathologic regulation of affect due to pseudobulbar
palsy [163, 164, 169, 170], then the patient may have
an underlying depression [167, 168]. The pathological
regulation of affect responds very quickly to antidepressant medications, in contrast to other symptoms
associated with depression, especially mood [168].
Other contributions of the
right hemisphere to language
and communication
Although this chapter has focused on affective prosody
and disorders of affective communication, the right
hemisphere makes other contributions to language
and communication that are not well appreciated by
clinicians [9]. Some functions contribute to higherorder semantic-linguistic competency and include:
(1) the comprehension of connotative, non-standard
(third and fourth order) word meaning as opposed
to denotative or standard word meaning; (2) comprehension of metaphor; (3) thematic comprehension,
i.e., understanding communicative intent conveyed by
paragraphs and chapters as opposed to words and sentences; and (4) comprehension of complex linguistic
relationships [171–181]. In addition, the right hemisphere is involved in the comprehension of non-literal,
idiomatic, types of expressions that are not semantically or literally feasible [182–184], e.g., “he is walking
191
Section I: Structural and Functional Neuroanatomy
on clouds,” and the modulation of semantically emotional words and curses [59, 76, 185].
Conclusion
This chapter considered the topic of the right hemisphere’s contribution to language and communication, with special emphasis on affective prosody and
gestures. The various levels of prosodic communication that convey linguistic, dialectical, and idiosyncratic information were also reviewed. Formal methods for assessing disturbances of affective prosody,
and a brief description of the bedside assessment of
affective prosody were provided in order to enhance
the clinical skill set of BN&NP subspecialists. Finally,
the clinical conditions in which disturbances of affective prosody occur commonly were reviewed, thereby
illuminating the contexts in which it may be productive for clinicians to undertake assessment for
aprosodic defects [91–93, 139–146, 156, 157, 167,
168].
Acknowledgments
This work was supported, in part, by grants from
the Merit Review Board, Medical Research Service,
Department of Veterans Affairs, Washington, DC. I am
indebted to Marilee Monnot, PhD, for suggestions to
improve the manuscript.
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Section I
Structural and Functional Neuroanatomy
Chapter
Praxis
14
Kenneth M. Heilman
There are two major cognitive control systems that
help the human program movements. One system
helps determine when to move and the other how
to move. Akinesia, or hypokinesia, is a disorder in
the “when” or “action-intentional system.” Some of
the other disorders of the action-intentional system
include motor impersistence, defective response inhibition, and motor perseveration. Although these disorders are caused by brain damage and are terribly disabling, this chapter will focus on the disorders of the
“how” system. The term apraxia was originally used
by Steinthal in 1871 [1] to describe a misuse of tools
and objects, a disorder of the “how” system. Although
the term apraxia, derived from Greek, literally means
“without action,” the word akinesia is used currently to
describe the failure to initiate an action in the absence
of weakness.
The term apraxia has been used for a variety of
how-movement disorders including disorders of gait,
speech and eye control, but this chapter will focus on
apraxia of the upper limbs. Apraxia of the forelimbs
can be task specific or general. Task-specific apraxias
include dressing apraxia and constructional apraxia;
these specific forms of apraxia will not be discussed in
this chapter, which instead will focus on the general
forms of apraxia.
As noted by Geschwind [2, 3], who helped to
re-establish interest in apraxia, these disorders are
in part defined by what they are not. For example,
there are many sensory, motor and cognitive disorders
that might impair a person’s ability to correctly make
skilled purposeful movements, including: weakness,
sensory loss, abnormal and involuntary movements
such as tremors, dystonia, chorea, ballismus, athetosis,
myoclonus, loss of coordination such as ataxia, as well
as seizures. Patients with severe cognitive, memory
and attentional disorders may also have difficulty performing skilled acts, because they do not understand,
forget, or get distracted. The presence of these more
elemental motor, sensory and cognitive disorders do
not, however, preclude that a patient can also have limb
apraxia. Unfortunately, the presence of these disorders
might prevent the examiner from adequately testing
for apraxia.
Clinical relevance
Apraxia often goes unrecognized by patients as well as
physicians and there are several possible reasons for
its poor recognition. In regard to the patient, apraxia
is often associated with left hemispheric injury such as
that produced by diseases such as stroke. Since many
of these patients have a hemiparesis of their preferred
right arm and hand, when these patients attempt to
perform skilled acts with their non-preferred left arm
and learn that they are impaired, they may attribute
their poor performance to pre-morbid clumsiness
of their non-dominant left forelimb. However, many
apraxic patients who do not have a right hemiplegia but who are impaired when attempting to perform learned skilled movement with their preferred
right upper limb still fail to recognize their deficits;
this unawareness of deficits appears to be a form of
anosognosia.
Not only do patients often fail to complain about
the deficits associated with apraxia, but many health
professionals also fail to test for limb apraxia. Limb
apraxia has been noted to be a heterogeneous group
of disorders with a variety of different clinical presentations; unfortunately, there is a paucity of standardized clinical tests that can be used to assess for these
disorders.
Behavioral Neurology & Neuropsychiatry, eds. David B. Arciniegas, C. Alan Anderson, and Christopher M. Filley.
C Cambridge University Press 2013.
Published by Cambridge University Press. 199
Section I: Structural and Functional Neuroanatomy
For many years neurologists, neuropsychologists,
speech pathologists, and other clinicians thought that
limb apraxia was a rare disorder seen only in the
laboratory by a handful of academicians, and that
these disorders did not interfere with performing
activities of daily living or instrumental activities.
However, it is now widely recognized that apraxia is
a major cause of disability which can interfere with a
patient’s ability to perform both basic and instrumental activities of daily living. Additionally, apraxia can
occur with a variety of diseases that cause damage to
the brain, the most common perhaps being stroke and
degenerative dementias, such as Alzheimer’s disease
(AD), Parkinson’s disease (PD) and tauopathies, such
as corticobasal degeneration.
The apraxias
Hugo Liepmann, a student of Carl Wernicke, made
important contributions to the understanding of
apraxia that parallel the paradigm shifts made by Wernicke in the study of aphasia. In a series of papers
written between 1900 and 1920, Liepmann described
three major forms of apraxia: ideomotor apraxia,
which was also called ideo-kinetic apraxia in Liepmann’s terminology [4]; ideational apraxia; and limbkinetic apraxia, also referred to by some investigators
as melokinetic or innervatory apraxia.
Studies in our laboratory introduced two other
forms: conceptual apraxia and dissociation apraxia.
We have discussed each of these forms of apraxia elsewhere [5], discussing the means of their testing, the
abnormal behaviors that characterize them, and their
pathophysiology. In this chapter, we also discuss the
signs and pathophysiology of these apraxic disorders
but use a processing approach. Like many other cognitive activities, performing skilled purposeful movements requires the sequential and/or parallel activation of distributed modular networks. Degradation
of the different modules or disconnections between
modules in these networks induces specific forms of
apraxia, and these forms of apraxia will be discussed
in the following sections.
Conceptual apraxia
Definition and description
Human forelimbs perform several functions of major
importance, interacting and altering the environment
as well as helping to take care of others and oneself. In
200
order to be successful at these motor-action endeavors,
a person must have motives and goal-oriented behaviors. Apathy, abulia, and akinesia are major causes
of disability but, as mentioned earlier, these actionintentional system (i.e., “when”) disorders will not be
discussed here.
When attempting to alter the environment, one
needs to decide what needs to be altered and “how”
it will be altered. Thus, a person has to know if he
or she will need a tool-implement to help accomplish
their goals, the type of tool that would be needed, and
how this tool will be moved by the person to accomplish this goal. In regard to tool knowledge, patients
with conceptual apraxia might not know the mechanical advantage afforded by specific tools and implements. For example, an individual may be shown a nut
on a bolt that is not fully tightened; when that individual next is shown a hammer, handsaw, chisel, pliers, and wrench and asked to select the correct tool
to complete the job, he or she might incorrectly select
the handsaw. Some patients with a milder form of
conceptual apraxia might be able to select the correct tool (e.g., wrench); however, if this tool is not
present in their tool chests and they therefore must
use another tool, they might then select the incorrect tool. For example, an individual might be presented with a wooden board in which a nail has been
driven partially and with a tool chest in which there
is no hammer; instead of selecting pliers or wrench
to pound in this nail, the individual might select the
handsaw. In general, the highest level of tool conceptual knowledge allows individuals to create a new tool
to solve a mechanical problem; conceptual apraxia is
characterized in some patients by the loss of this ability
[6, 7].
After a person is given, correctly selects, or devises
a tool to use for a task, he or she then must select
and perform the action that is associated with that
tool. For example, if a person wants to insert a nail
into a board then that person has to make pounding
motions, not slicing or sawing movements; if, instead,
a person wants to cut something then he or she must
make slicing rather than pounding movements. As will
be discussed below, patients with ideomotor apraxia
make movement errors but the clinician can usually
detect that the intent of the movement is correct.
In contrast, patients with conceptual apraxia make
content-movement errors, such that when asked to
pantomime a specific transitive movement and shown
a partially driven-in nail, the patient pantomimes the
Chapter 14: Praxis
movements associated with using another tool, such as
slicing. Some patients with severe conceptual apraxia
will make errors even when given the tool; for example, even when shown a hammer or even when holding
the hammer the patient makes slicing movements.
Testing
Unfortunately, there is a paucity of standardized tests
that are available to assess for conceptual apraxia. The
Florida Action Recall Test (FLART) [8], developed to
assess conceptual apraxia, consists of 45 line drawings
of objects or scenes for which an action with a tool
is required. First, the patient must decide what in the
scene needs to be altered. Next, the subject must imagine the proper tool with which to make these alterations and then pantomime its use. There are several
types of errors that may be made by patients. They
may fail to know which elements of the scene need to
be altered, which tool allows a person to make those
alterations, and/or the correct actions associated with
the use of a tool. For example, a patient shown a partially driven-in nail might make no movement and
state “I do not know what to do” or instead make
slicing movement rather than pounding movements.
Both of these errors are conceptual errors. However, a
patient might make pounding movements but either
hold his hand in an incorrect posture or fail to make
flexion-extension or radial-ulnar movements at the
wrist. These latter errors are considered evidence for
an ideomotor apraxia (discussed below) and not a sign
of conceptual apraxia.
In today’s “bean counter” controlled practice of
medicine, physicians and neuropsychologists often
cannot afford to observe patients when they are performing basic or instrumental activities of daily living; however, observations of these activities often best
allow the clinician to detect the presence of conceptual apraxia. For example, we observed a patient with
a hemispheric stroke after he was brought a meal on
a tray that was placed next to his bed [9]. Before the
patient got his tray, we placed some extra implements,
such as a toothbrush, on his tray along with the silverware. The first thing this patient did was to take
a sugar packet, tear it open, and pour it into his iced
tea. Although there was a long teaspoon on his tray, he
picked up a knife and placed it in his glass of tea. Rather
than stirring the sugar by moving the knife he instead
rotated the glass. While unorthodox, these actions did
allow him to accomplish his mission. On his dinner
plate there was creamed corn; when he attempted to
eat his creamed corn, he picked up the toothbrush,
rather than a fork, and was unsuccessful, leading him
to use his fingers to get this item into his mouth. In
order to make certain that this patient did not have a
visual agnosia (which could have interfered with his
object and food item recognition), we asked him to
name all the utensils on his tray – he had no difficulty
doing so.
Pathophysiology
Conceptual apraxia is reported among persons with
degenerative dementias such as Alzheimer’s disease
(AD) [6] and in the semantic dementia subtype of
frontotemporal lobar degeneration [10]. In addition,
a study of patients with right and left hemisphere
strokes revealed that right-handed patients with left
hemisphere strokes may demonstrate conceptual
apraxia [7].
Mechanical knowledge, at least in part, is learned
throughout life and thus is likely to be a form of
memory. Warrington and Shallice [11] reported that
whereas some patients had degradation of semantic
memories of living things, others had degradation
of semantic memories of non-living things. In our
study of patients with conceptual apraxia due to
stroke, many of the participants with left hemisphere
lesions who demonstrate conceptual apraxia had
intact verbal comprehension, an observation suggesting that tool-action semantic representations
are independent of lexical-semantics. Unfortunately,
when we attempted to localize the region of the left
hemisphere that when damaged was most likely to
lead to conceptual apraxia, we were unable to localize
it [7]. Some of the patients with conceptual apraxia
following left hemisphere strokes had temporoparietal
injury, others had frontal injury, and still others a
combination of frontal and temporoparietal injury.
Failure to find a significant specific locus for conceptual apraxia suggests that either we had an insufficient
number of subjects or that mechanical knowledge is
widely distributed neuroanatomically. Support for the
latter possibility comes from a functional magnetic
resonance imaging study of conceptual mechanical
knowledge in normal subjects [12], in which investigators observed activation in multiple areas of the left
hemisphere, including the parietal-temporal-occipital
junction, inferior frontal and anterior dorsal premotor
areas.
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Section I: Structural and Functional Neuroanatomy
If mechanical knowledge is stored in the left hemisphere of right-handed people, then disconnection of
the cerebral hemispheres due to a callosal lesion in
a right-handed person might produce signs of conceptual apraxia when that individual attempts to use
his left hand to solve mechanical problems. Liepmann
and Maas reported patient Ochs [13], an individual
who appeared to have a callosal disconnection and
whose many left upper extremity errors appeared to
be content errors. Unfortunately, Ochs had a right
hemiparesis from a brainstem lesion and thus the
performance of his right and left hand could not be
compared. The patient reported by Watson and Heilman [14], who sustained an infarction of her corpus callosum, initially made content errors with her
left but not her right hand and arm. If the content errors performed by this woman’s left forelimb
were only in response to verbal commands it might
have suggested that language speech commands could
not get access to the right hemisphere; however, this
woman also made content errors when holding the
actual tools or implements in her left hand. Her right
hand performance, in these same conditions, however,
was flawless.
Ideational apraxia
Definition and description
The term ideational apraxia has been used to describe
many different forms of apraxic disorders. For
example, De Renzi and Lucchelli [15] defined
ideational apraxia as failure to correctly use actual
tools and implements. In their article entitled
“Ideational Apraxia,” they noted that patients with
lesions of their left inferior parietal lobe made spatial
errors when attempting to use actual tools and implements. However, Poizner et al. [16] demonstrated that
patients with ideomotor apraxia are often impaired
when using tools and objects. Unfortunately, when
Heilman first described dissociation apraxia he called
it ideational apraxia; conceptual apraxia also has
been called ideational apraxia [9, 12]. Despite the
overlapping use of these terms, these are presently
recognized as distinct types of apraxia. The latter type
of apraxia was described in the preceding section of
this chapter and dissociation apraxia will be discussed
later in this chapter. The remainder of this section
focuses specifically on ideational apraxia.
202
Many goal-oriented behaviors require that a person perform a series of acts to accomplish a goal. For
example, a person making a ham and cheese sandwich to bring to work for lunch ordinarily follows a
series of steps when doing so. First, two slices of bread
are cut from the loaf. Mustard and/or mayonnaise are
then put on the slices of bread. Next, the ham, cheese,
and lettuce are placed on one slice of this bread, and
then covered with the other piece of bread. Finally, the
sandwich is cut in half and put into a vinyl sandwich
bag. According to Liepmann’s definition [17], a person
with ideation apraxia demonstrates problems properly
sequencing these acts; for example, cutting the bread
before placing the mustard, ham, and cheese on it.
Pathophysiology
Patients with frontal lobe injuries often have trouble
with sequencing; however, De Renzi and co-workers
[18] noted that this sequencing disorder was more
commonly associated with left inferior parietal than
frontal injury. After degeneration of the medial temporal lobes, AD involves degeneration of the inferior
parietal lobes; consistent with the findings of De Renzi
and colleagues [18], Crutch et al. [19] observed that
patients with AD often had ideational apraxia.
Ideomotor apraxia
Definition and description
After a person decides what tool or implement they
need to use to accomplish each act in a goal, the next
step is to use this tool or implement to accomplish the
desired task. In order to correctly perform the required
actions, an individual needs to know: (1) how to hold
the tool; (2) how to direct the tool to the location where
the action of the tool is required; (3) how to move their
forelimb through space so that the tool-implement can
correctly move on the target upon which it is acting;
(4) how fast to move the tool; and (5) how much force
with which to use the tool.
After having selected the correct tool for the job
and upon knowing the type of action needed to use
the tool effectively to accomplish the goal, a patient
with ideomotor apraxia might: (1) fail to hold her hand
correctly (i.e., make a postural error); (2) fail to move
her forelimb to the target of the tool’s action or fail to
maintain the correct spatial orientation; (3) move the
incorrect joints of the limb involved or not properly
Chapter 14: Praxis
coordinate multiple joint movements; and (4) use the
incorrect speed or force.
Testing
When testing patients for ideomotor apraxia, if possible, both the right and the left forelimbs should be
tested. In general, there are two types of gestures or
movements that a person can make with their forelimb, transitive and intransitive. Transitive movements
are those that are used with tools and implements.
Intransitive movements are those usually used to communicate with others. For example, when standing at
the side of the road, if a person makes a fist and points
his thumb in the direction to which he wants to travel
then that is understood as a sign that he is requesting someone to stop and give him a ride (hitchhiking). This is an intransitive gesture. When the policeman puts his open hand up in the air with his palm
facing a driver it means that he wants the driver to stop
his car. This is another intransitive gesture. In contrast,
asking a person to pretend she is using a pair of scissors
to cut in half a piece of paper she will be pantomiming a transitive act. In general, when assessing patients
for ideomotor apraxia, testing patients by asking them
to pantomime transitive acts is much more likely to
detect ideomotor apraxia then testing them performing intransitive acts.
While having patients pantomime transitive acts
is the most sensitive means of assessing for ideomotor apraxia, patients should be asked to imitate the
examiner performing both meaningful and meaningless gestures. Additionally, being allowed to see pictures of tools or even to hold actual tools or objects and
to demonstrate how to use these tools and implements
is valuable. It also is valuable to determine whether a
patient can name transitive pantomimes made by the
examiner and is able to discriminate between well- and
poorly performed transitive pantomimes made by the
examiner.
Patients with ideomotor apraxia may produce
several types of movement errors, including postural, allocentric orientation, and egocentric movement
errors. Each of these is considered further here.
can be observed in these patients: postural or internal configuration errors, spatial movement errors, and
errors of spatial orientation.
When using a tool or implement, the hand has to
be held in a certain posture. Goodglass and Kaplan
[20] noted that when patients with ideomotor apraxia
are asked to perform a pantomime of a transitive act
they often use a body part, such as the finger or the
hand, as the tool. For example, when patients with
ideomotor apraxia are asked to show the examiner
how they would use a screwdriver they might use their
forefinger as the shaft of the screwdriver; when asked
to pantomime using a pair of scissors, they may use
their fingers as if they were the blades. These movements are emblems of the tool and are not the correct
pantomime.
When given the command to pretend that they
are using a pair of scissors, many normal people
make similar “body part as tool” errors. Thus, it
is important that patients be instructed not to use
a body part as a tool. We have found that, unlike
normal subjects who improve with these instructions, patients with ideomotor apraxia often continue using their body parts as tools [21]. However,
when patients can be convinced not to use their
body parts as tools, patients with ideomotor apraxia
often fail to correctly position their arms, hands, and
fingers.
Allocentric orientation errors
When asked to pantomime the use of the tool (e.g.,
“show me how you would cut a piece of paper in half by
using a pair of scissors”) normal individuals orient the
pantomimed tool to an imaginary target of the tool’s
action. Patients with ideomotor apraxia often fail to
correctly orient their forelimbs to an imaginary target.
For example, when pantomiming the use of scissors
to cut a piece of paper in half, most normal subjects
will keep the blades of the scissor oriented in a sagittal plane; in contrast, patients with ideomotor apraxia
may orient the scissors laterally so that they are in the
coronal plane or even fail to maintain any consistent
plane of movement [22].
Egocentric movement errors
Postural errors
When attempting to perform skilled transitive acts,
patients with ideomotor apraxia primarily make spatial errors. There are three types of spatial errors that
A tool must be moved in certain directions with
respect to the object upon which this tool is acting
in order for this tool to perform its intended action.
When attempting to pantomime or even use actual
203
Section I: Structural and Functional Neuroanatomy
tools, patients with ideomotor apraxia often incorrectly move the tool through space. The core concept of
the movement may be correct, but other, more refined,
elements are incorrect. For example, when patients
with ideomotor apraxia are asked to pantomime hammering a nail into a board, these patients will often
demonstrate pounding-like movements by flexing and
extending their arm at the elbow and shoulder. However, correctly using a hammer to pound a nail into a
board requires when extending the arm at the elbow
to also flex or ulnar-deviate the wrist; failing to move
the wrist results in the head of the hammer not coming
down upon the nail [22, 23].
Some egocentric movement errors associated with
ideomotor apraxia are the result of incorrectly stabilizing some joints and moving the incorrect joints.
For example, by trying to rotate a screwdriver on
axis by using only the wrist joint, the screwdriver
will not rotate on axis and instead makes circular movements. However, many transitive movements
require the coordinated movements of multiple joints
(e.g., slicing) and patients with ideomotor apraxia
often have difficulty coordinating these multiple joint
movements.
Pathophysiology
Callosal disconnection
One of the first people to intensively investigate the
pathophysiology of ideomotor apraxia was Hugo
Liepmann. In one of his most important reports,
Liepmann and Maas [13] described a 70-year-old man
whose post-mortem examination revealed an infarction in the distribution of the left anterior cerebral
artery which damaged the anterior two-thirds of the
corpus callosum. Unfortunately, this patient also had a
lesion of his left pons that caused a right hemiparesis.
Prior to this patient’s death, Liepmann and Maas
noted that when attempting to write or perform skilled
movements to command with his left hand this patient
demonstrated an inability to correctly perform skilled
movements. Liepmann was a student of Carl Wernicke
and was aware that the left hemisphere mediated language. Thus, injury to the corpus callosum, the major
interhemispheric connecting system, could have
isolated the left hemisphere language systems from
the motor systems in the right hemisphere that control
the left hand and arm. Liepmann and Maas, however,
rejected this language disconnection hypothesis
204
because this patient was unable not only to correctly
perform skilled purposeful gestures to command
but also to use real implements/tools with his left
forelimb. Based on these observations, Liepmann and
Maas posited that the left hemisphere of right-handed
people not only mediates language-speech but also
contains movement formulae, the spatial-temporal
movement representations that are important for
programming purposeful learned skilled movements.
They therefore suggested that the callosal injury
sustained by their patient prevented movement representations in his left hemisphere from gaining access
to the motor systems in his right hemisphere.
Liepmann and Maas’ callosal disconnection study
played an important role in developing an understanding of the role of the corpus callosum in interhemispheric communication as well as the role of the
left hemisphere in the control of movements of the
ipsilateral left forelimb. Unfortunately the case they
described was less than optimal for this purpose. Their
patient’s stroke, which appeared to be in the distribution of the anterior cerebral artery, not only damaged
the anterior portion of the corpus callosum but also
damaged the superior and medial portions of the left
frontal lobe. As we will discuss below, damage to the
left medial frontal lobe, including the supplementary
motor area, can induce an ideomotor apraxia of both
the right and left hands [24]. To demonstrate that the
patient reported by Liepmann and Maas had a ideomotor apraxia of his left hand because he had a callosal disconnection, Liepmann and Maas needed to
demonstrate that their patient did not have an ideomotor apraxia of his right forelimb; unfortunately, this
patient also had a brainstem infarction that caused a
right hemiparesis and thus he could not be tested for
this finding.
Another major problem with Liepmann and Maas’
report is that their patient (who had a callosal lesion)
often made what appeared to be content errors; as
discussed above, content errors suggest a conceptual
apraxia rather than an ideomotor apraxia.
Another patient with apraxia from a callosal disconnection was described by Geschwind and Kaplan
[25]. Their patient had a left hemisphere glioblastoma and in the peri-operative period he developed an
infarction in the distribution of the anterior cerebral
artery that injured the anterior four-fifths of his corpus
callosum. This patient was able to use his right hand
flawlessly, but could not correctly use his left hand in
Chapter 14: Praxis
response to verbal commands. He was, however, able
to imitate and use actual objects normally with his
left forelimb; thus, he could not be classified as having
an ideomotor apraxia but instead appeared to have a
verbal dissociation apraxia. The signs and mechanism
of dissociation apraxia are discussed in a subsequent
section.
Gazzaniga and his co-workers [26] studied several
epileptic patients who had surgical disconnection of
their corpus callosum. Like Geschwind and Kaplan’s
patient, these patients were able to imitate and use
actual implements with their left forelimb. Thus, these
investigators concluded that callosal damage induced
a language disconnection. Gazzaniga et al. [26] suggested that if patients had impaired imitation and trouble using actual objects this apraxia would be the result
of extracallosal damage.
Watson and Heilman [14] reported a woman with
a subarachnoid hemorrhage who appeared to contradict the assertion of Gazzaniga et al. [26] that extracallosal damage induces ideomotor apraxia with impairment of imitation and actual object use. This woman’s
subarachnoid hemorrhage caused a spasm of the anterior cerebral artery, which caused an infarction of
the body of her corpus callosum. Magnetic resonance
imaging of this patient’s brain revealed no evidence
of any extracallosal damage [27]. Unlike Geschwind
and Kaplan’s [25] patient, who was only impaired in
pantomiming commands with his left forelimb, this
woman was impaired in performing transitive pantomimes and intransitive movements with her left
upper limb to command, but she also had trouble imitating the examiner and using actual objects with her
left forelimb. In addition, her spatial movement errors
were typical of those observed with ideomotor apraxia.
In contrast to the apraxia observed when she was using
her left forelimb, her ability to pantomime transitive
movements and to imitate and use actual objects with
her right forelimb was flawless. Graff-Radford et al.
[28] and Lausberg et al. [29] have reported patients
that replicated the finding of Watson and Heilman [14,
27]. These patients with callosal disconnection also
demonstrated left, but not right, ideomotor apraxia
making spatial errors with pantomimes, imitation, and
actual object use.
The patients with callosal disconnection reported
by Watson and Heilman [14, 27], Graff-Radford et al.
[28], and Lausberg et al. [29] might have differed
from those reported by Geschwind and Kaplan [25]
and Gazzaniga et al. [26] because these two groups of
patients had differences in their brain organizationlaterality. Liepmann [17] reported that left hemisphere
lesions are most likely to cause ideomotor apraxia
in right-handed individuals. However, Liepmann also
noted that whereas about 95% of patients with large left
hemisphere lesions are aphasic, only about 50% have
ideomotor apraxia [17]. The fact that there are a lower
percentage of left hemisphere-damaged patients who
have ideomotor apraxia than have aphasia suggests
that a substantial percentage of right-handed people
either have movement representations stored in both
hemispheres or instead have movement representations stored in the right hemisphere. Apraxia in righthanded patients from right hemisphere injury has
been reported [30]; however, this is rare. The majority of people who do not have apraxia from a large left
hemisphere lesion therefore probably have movement
representations stored in both hemispheres.
When a patient has movement representations in
both hemispheres and they have an injury to the anterior portions of their corpus callosum, he or she should
have the clinical picture described by Geschwind and
Kaplan [25]: when using the left forelimb to pantomime to command, the movement is impaired as a
result of disconnection of the language-dominant left
hemisphere from the left hand-controlling right hemisphere. However, the left hand is able to be used by
such individuals to perform imitation and to use actual
objects because these actions can be performed without language and because the movement representations necessary for their performance are stored in
their right hemispheres.
In contrast, the patients reported by Watson and
Heilman [14, 27], Graff-Radford et al. [28], and Lausberg et al. [29] appear to have their movement representation restricted to their left hemisphere; thus,
callosal disconnection prevented both language and
movement formulae from reaching the right hemisphere. These patients therefore made errors when
pantomiming to command, imitating, and using actual
objects, i.e., they demonstrated unilateral ideomotor
apraxia.
Intrahemispheric disconnection
As mentioned above, Liepmann [17] noted that about
50% of patients with large left hemisphere damage
will have an ideomotor apraxia. Unlike patients with
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Section I: Structural and Functional Neuroanatomy
callosal lesions (who have this apraxia restricted to
their left forelimb), ideomotor apraxia can be observed
in both hands among patients without a hemiparesis. Both Liepmann [17] and Geschwind [2, 3] noted
that it was primarily lesions in the region of the left
supramarginal gyrus that induce ideomotor apraxia.
To account for the development of ideomotor apraxia
following injury to this region, Geschwind [2, 3] proposed a disconnection hypothesis. In the subcortical
white matter of the supramarginal gyrus is the arcuate
fasciculus. This fasciculus is the white matter pathway
that connects Wernicke’s area, important in language
comprehension, to the left hemisphere’s convexity premotor areas. The premotor cortex of the left hemisphere projects to the right hemisphere’s premotor cortex and both premotor cortices project to the motor
cortex on the same side. According to Geschwind’s [2,
3] disconnection model, injury to the region of the
supramarginal gyrus interrupts the arcuate fasciculus;
thus, when a person with injury to this region hears
a command, he is unable to transfer this information
to the premotor cortices and hence unable to correctly
carry out the command.
Inferior parietal lobe
Geschwind’s [2, 3] verbal disconnection hypothesis
cannot explain why patients with lesions in the region
of the supramarginal gyrus cannot correctly imitate or
correctly use actual objects. An alternative explanation
is that the region of the inferior parietal lobe contains
the multimodal (visuo-kinesthetic) movement representations (spatial-temporal movement representations) and that degradation of these representations
of skilled movements induces apraxia [31, 32]. Unlike
Geschwind’s [2, 3] disconnection hypothesis, this representational hypothesis can account for why injury to
this area would also impair imitation and the use of
actual objects.
If a patient has a degradation of a movement representation, then – in addition to being unable to produce the behavior that this representation programs –
such a patient also should have trouble discriminating
correctly versus incorrectly performed pantomimes.
Therefore, we tested this representation hypothesis of
ideomotor apraxia by assessing the ability of apraxic
patients, who suffered with anterior versus posterior
left hemisphere strokes, to discriminate correctly
from incorrectly performed pantomimes of transitive
movements. We found that patients with anterior left
206
hemisphere lesions could correctly discriminate
between pantomimes of these types whereas those
with posterior lesions were impaired, thereby supporting the representational hypothesis. Recently,
functional imaging studies have also provided converging evidence that movement representations are
stored in the inferior parietal lobe [33].
Lissauer [34] noted that patients with ventral
temporal-occipital lesions had trouble identifying
objects (visual object agnosia) and Balint [35] noted
that patients with dorsal parietal-occipital lesions have
trouble determining the position of objects in relation
to the body (optic ataxia and psychic paralysis of gaze).
Ungerleider and Haxby [36] called these the “what”
and “where” visual systems. Watson et al. [37] suggested and provided support for the postulate that in
humans the integration of the areas important in stimulus localization (e.g., the dorsal visual [“where”] system) and stimulus identification (the ventral [“what”]
system) takes place in the inferior parietal lobe. The
synthesis of these systems would appear to be critical
for developing the correct postures and body-centered
(egocentric) joint movements when pantomiming the
use of a tool or implements as well as for directing the
subject’s hand and arm to the location where the action
is directed. Injury to the left inferior parietal cortex
would impair these functions and patients with inferior parietal injuries do demonstrate both postural and
orientation errors [22].
Premotor cortex
The movement representations we discussed above
that are stored in the inferior parietal lobe are stored
in a polymodal (visual-kinesthetic) three-dimensional
spatial-temporal code [5]. In some respects, this code
could be considered similar to sheet music. Sheet
music provides the piano player with a program that
denotes the sequences of spatial movements required
to be made by the pianist’s fingers and the duration of
each movement as well as the duration between movements. The corticospinal neurons, found primarily in
Brodmann’s area 4 (primary motor cortex), might be
thought of as being similar to the piano keys. These
corticospinal neurons activate the motor nerves in
the spinal cord, which in the metaphor we have been
using might be the felt hammers in the piano. The
felt hammer hits the wires that make the sound and
the motor nerves when active make specific muscle
groups contract.
Chapter 14: Praxis
At one time it was thought that each site of the
motor cortex activated one muscle that moved a
joint in a specific direction, but more recent studies
show the primary motor cortex can influence the
speed or movement as well as its direction through
space [38]. Other investigators have suggested that it
might be joint angle that is coded and programmed
in the primary motor cortex [39]. For the purpose of
our discussion of ideomotor apraxia, the functional
organization of the corticospinal system is not critical.
However, in order for the corticospinal system to
provide the motor units with the correct firing patterns, this system must get instructions from another
portion of the brain. Thus, the spatial-temporal
knowledge (sheet music) stored in the parietal lobe
that guides purposeful voluntary movements have
to be transformed into motor programs (the piano
player) and these motor programs have to activate the
motor cortex using specific firing patterns.
The premotor cortex, which is anterior to the
motor cortex, can be divided into two major divisions:
a lateral portion and a medial portion. Each of these
major subdivisions of the premotor area can also be
further divided into subunits. These subunits include
rostral and caudal subregions. Medially, the premotor
cortex is divided into the caudally situated supplementary motor area (SMA) and the rostrally located
pre-SMA. The lateral portions of the premotor cortex
are divided into ventral and dorsal subregions, and
each of these dorsal and ventral subregions is divided
further into caudal and rostral portions. Picard and
Strick [40] noted that the more rostral portions do not
have strong direct connections with the motor cortex
and appear to be heavily connected with regions of the
prefrontal cortex. According to these investigators,
the role of the rostral premotor area is primarily
executive-planning functions rather than motor
control. In contrast, the more caudal portions (such
as SMA and caudal lateral premotor cortex) appear
to play a critical role in mediating and programming
skilled movements. Whereas electrical stimulation of
the primary motor cortex induces simple movements
such as flexion of the thumb, stimulation of the supplementary motor area induces complex movements
that may include the entire forelimb.
The role of the lateral versus medial caudal premotor cortex (SMA) in controlling purposeful skilled
movements has still not been entirely elucidated. There
is, however, evidence for the hypothesis that SMA
primarily programs the aspects of skilled movement
that are entirely internally initiated (self-directed
actions) whereas the lateral premotor cortex is more
involved with movements that are directed by external
sensory (e.g., visual) stimuli [41]. Some investigators
find that the lateral premotor cortex also might activate
these movements [42]. Thus, the medial premotor cortex (SMA) may be more important in programming
the egocentric aspects of skilled movements and the
lateral premotor cortex the allocentric (target) aspects.
The connectivity of the SMA also places it in a good
anatomic position to act as the piano player. It receives
projections from parietal neurons, which contain the
spatial temporal movement representations (the sheet
music) and project to corticospinal motor neurons (the
piano keys). Physiological studies have revealed that
the neurons in the SMA discharge before neurons in
the primary motor cortex [43]. Functional imaging
studies (measuring alterations of blood flow, which
indirectly reflects synaptic activity), revealed that single simple repetitive movements such as finger flexion increase activation of the primary motor cortex
contralateral to the finger that is flexing. In contrast,
blood flow increases in both the contralateral motor
cortex and in the supplementary motor area when subjects make complex purposeful movements. Finally,
when normal subjects think about/plan making complex movements but do not make actual movements,
blood flow increases in the SMA but not the primary
motor cortex [44, 45]. This series of studies provide
evidence that in normal subjects the SMA is critical
in programming complex purposeful voluntary movements – in the metaphor begun earlier in this section,
SMA is the pianist.
In regard to ideomotor apraxia, Watson et al. [24]
reported several patients with left-sided medial frontal
lesions involving the SMA who demonstrated an ideomotor apraxia when tested with either arm. Unlike
patients with parietal lesions, these patients with SMA
injury could discriminate between well and incorrectly
performed pantomimes.
Patients with corticobasal degeneration often suffer with an ideomotor apraxia and Leiguarda et al.
[46] suggested that these patients’ deficits may also
be related to dysfunction of the supplementary motor
area. Imaging studies appear to support this hypothesis [47]. We observe that most of our patients with corticobasal degeneration are able to discriminate wellperformed from incorrectly performed pantomimes of
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Section I: Structural and Functional Neuroanatomy
transitive movements, supporting the hypothesis that
these patients’ movement representations are intact
and that their disability might be related to dysfunction of the supplementary or convexity premotor areas.
Returning to our metaphor, it appears that information from the sheet music gets to the pianist by
means of vision; how then does the spatial-temporal
movement information needed to perform transitive
acts get from the parietal lobe to the premotor areas?
Additionally, can a disconnection between these two
regions also induce an ideomotor apraxia?
Based on the work of Schmahmann et al. [48], the
pathway that connects the supramarginal gyrus and
premotor cortex is the superior longitudinal fasciculus. Although Schmahmann et al. [48] described this
white matter pathway in rhesus monkeys, studies in
humans using diffusion tensor imaging tractography
[49] also appear to demonstrate a similar white matter
pathway.
If the white matter connections between these two
critical areas are interrupted then these patients should
also have an ideomotor apraxia. Pramstaller and Marsden [50] reviewed the reports of 82 patients with
apraxia from subcortical lesions. These investigators
found that the majority of these patients sustained
large lesions with damage to the basal ganglia and/or
thalamus together with the white matter. The injured
portions of white matter included the internal capsule as well as the periventricular and peristriatal white
matter, interrupting association fibers in the superior
longitudinal fasciculus.
Discrimination between correctly and incorrectly
performed pantomimes might be performed by a
visuo-spatial analysis that does not require motor
programming. Thus, a disconnection between the
stored spatial-temporal movement representations in
the parietal lobe and the regions that translate these
representations to movement programs in the premotor cortex should induce an ideomotor apraxia
with intact discrimination. Hanna-Pladdy et al. [51]
compared the performance on praxis performance
and discrimination tasks in patients with left hemisphere cortical and subcortical lesions. The patients
with cortical lesions demonstrated production deficits,
as well as impaired gesture discrimination. Whereas
the patients with subcortical injuries also exhibited
apraxic production deficits they had normal discrimination. Unfortunately, at the time the Hanna-Pladdy
et al. study was performed the exact white matter
pathways that induced these deficits could not be
208
determined, but now with diffusion tensor imaging
the white matter pathways that when damaged induce
ideomotor apraxia can be examined.
Dissociation apraxia
Definition, description, and testing
In some circumstances, a person might be required to
perform a learned action in response to a command,
or by seeing a tool, or by observing another person
perform an action. There are patients who are unable
to correctly pantomime transitive movements to command using either forelimb, but who are able to correctly pantomime when seeing the tool or implement,
to imitate normally, and to use actual objects normally.
As mentioned, this disorder is now called verbal dissociation apraxia [5].
De Renzi et al. [52] also reported similar patients,
but also described patients who were unable to correctly pantomime transitive gestures in response to
seeing tools but who were able to do so in response
to commands. Heilman et al. [5] suggested that verbal
dissociation apraxia was induced by dissociation
between lexical-semantic language representations
and movement representations and that visual-object
dissociation apraxia reported by De Renzi et al. [52]
was caused by a functional dissociation between object
recognition units and movement representations.
However, in both disorders the movement representations and their connections to premotor and motor
cortex were intact. These are not common disorders, and the loci of lesion that induces these forms of
intrahemispheric dissociation apraxias are not known.
Patients with ideomotor apraxia typically are more
impaired when performing to command than when
imitating. When a patient has degraded movement
representations, observing an examiner make movements provides patients with movement information that is not available from their own degraded
movement representations. However, there are several reports of patients who were more impaired when
imitating an examiner perform a gesture than when
performing to command or actually using tools and
implements [53–56]. Whereas some patients demonstrated that the imitation of novel gestures was more
impaired than previously learned gestures [53], other
patients were more impaired when imitating meaningful gestures than meaningless gestures [57]. Some
aphasic patients have more problems with imitation
Chapter 14: Praxis
than spontaneous speech, and this disorder has been
called conduction aphasia; since patients with this
form of apraxia have more problems with visual
imitation of gesture than performing gestures to
command, this disorder has been called conduction
apraxia [56]. However, another term that describes
these modality-specific dissociation disorders would
be “visual-imitative dissociation apraxia.”
The mechanism of this visual-motor imitative disorder is not known. When patients with this disorder perform to commands their pantomimes are relatively intact, suggesting that there is no degradation of
their movement representations and that their premotor areas do have the ability to translate these visualkinesthetic movement representations into motor programs and thereby to innovate the motor cortex. Thus,
the inability to imitate viewed gestures might suggest a
failure of the visual perceptual systems to successfully
access the areas of the brain that program movements.
Support for this postulate comes from the report
of Merians et al. [58], who wrote about a patient with
a left occipital and inferior temporal lobe lesion that
spared the inferior parietal cortex. This patient performed well to verbal command but was impaired
when imitating. In contrast, three patients with ideomotor apraxia whose lesions included the left parietal
cortex had the most severe deficits when pantomiming
to verbal command and improved pantomime performance with imitation.
The observation that there is, in some patients,
dissociation between imitation of meaningful and
meaningless gestures suggest that there are at least
two routes for imitation. Meaningful and previously
learned movement might be imitated by accessing
movement representations and meaningless movements might directly access the premotor areas that
alter this visual input into motor programs.
As mentioned, Geschwind and Kaplan [25]
reported a patient with a corpus callosum disconnection who, when performing pantomimes to verbal
command with his left forelimb, was apraxic but was
able to perform normally with the right forelimb. This
patient could imitate and use actual objects normally
with both hands. Although this patient’s behavior
is similar to the patients with the intrahemispheric
verbal dissociation apraxia described above, unlike
the patients with intrahemispheric verbal dissociation
apraxia that involves both forelimbs, the callosal
verbal dissociation apraxia seen in this patient only
involved the left forelimb.
Limb-kinetic apraxia
Definition, description, and testing
Limb-kinetic apraxia is characterized by a loss of dexterity or deftness such that patients with this disorder are impaired at making precise, independent but
coordinated finger movements. One of the simplest
and most sensitive means of testing patients for limbkinetic apraxia is to have the patients attempt to rotate
a coin, such as a nickel, between the forefinger, middle
finger and thumb, as rapidly as possible. Many patients
with ideomotor apraxia will be unable to rotate the
coin, others will drop it frequently, and still others perform this movement slowly [59].
Again using the metaphor begun earlier in this
chapter, after the piano player reads the music and
hits the proper piano keys in the proper sequence and
duration, the piano key must move the hammers that
hit the strings. If the sheet music is the movement program stored in the parietal lobe, the piano player is
the motor program performed by the supplementarypremotor area, the hammer is the motor neurons, and
the strings are the muscles, then the piano keys, which
activate the hammers (lower motor neurons), is the
corticospinal system.
Pathophysiology
Lawrence and Kuypers [60] demonstrated that
destruction of the pyramidal neurons in the brainstem (corticospinal tract) in monkeys did not cause
paralysis but did induce a loss of deftness, in this case
independent and precise finger movement –which are
the signs of a limb-kinetic apraxia. Other investigators
report that damage to the primary motor area or its
projections to the motor neurons in the spinal cord
does not cause a paralysis, and instead results in a
specific deficit in fine manual actions –what Liepmann
[17] termed limb-kinetic apraxia [61–64].
Hannah-Pladdy and co-workers [59] found that
right-handed patients with left hemisphere lesions
not only demonstrated a limb-kinetic apraxia of their
right (contralateral) hand but also frequently exhibit
a loss of deftness of their ipsilateral (left) hand. In
contrast, patients with right hemisphere lesions may
have a limb-kinetic apraxia of their left hand but usually perform normally with their right (ipsi-lesional)
hand. Thus, it appears that in right-handed people
the left hemisphere corticospinal system influences the
deftness of the left hand more than vice versa, but the
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Section I: Structural and Functional Neuroanatomy
means by which this asymmetry of control is mediated
is not fully known. It is possible that the left hemisphere’s motor cortex influences the right hemisphere
by transferring information by way of the corpus
callosum or influences the left hand by means of ipsilateral pathways. Support for the callosal hypothesis
comes from the report of a right-handed man who
infarcted the anterior and middle parts of his corpus
callosum [65]. This man lost agility and deftness in
his left hand, including the ability to make fast and
nimble finger movements of his left hand, and these
investigators thought that this patient had a melokinetic (limb-kinetic) apraxia induced by a hemispheric
disconnection.
Treatment
Recently, a consensus conference was held to review
the treatment for limb apraxia [66]. The investigators
and clinicians participating in this conference concluded, “despite evidence that several types of limb
apraxia significantly impact functional abilities, surprisingly few studies have focused on development of
treatment paradigms.”
The successful therapies for ideomotor apraxia as
reviewed by Buxbaum et al. [66] used a variety of different strategies including: multiple cues, error correction, conductive education, where treatment is focused
on a task analysis of the movements with articulationverbalization of the task elements, the use of compensatory strategies to help perform activities of daily living, and imitation with errorless learning.
In regard to limb-kinetic apraxia, Quencer and coworkers [67] demonstrated that patient with Parkinson’s disease (PD) often demonstrate limb-kinetic
apraxia. Gebhardt et al. [68] demonstrated that
whereas dopaminergic agents improve the bradykinesia associated with PD, the limb-kinetic apraxia
Figure 14.1. Cartoon of the praxis system and the injuries that can induce the different forms of apraxia. The right hemisphere is
on the top half and the left hemisphere on the bottom half of this cartoon of the brain. O-R-U = Object recognition units. These visual
representations are stored in the ventral occipital-temporal cortex. L-S = The lexical-semantic network. The other modular networks are
labeled. The arrows represent the pathways that connect these modular networks. The lines with letters attached represent either damage to
a network or disconnection between the networks. Damage to the different networks and their connections induce different forms of apraxia,
including: A = ideomotor apraxia with impaired pantomime to command, imitation, tool-implement use and impaired discrimination; B =
intrahemispheric disconnection ideomotor apraxia, with intact discrimination; C = premotor ideomotor apraxia with same symptoms as B; D
= callosal (disconnection) interhemispheric ideomotor apraxia and/or callosal interhemispheric conceptual apraxia; E = intrahemispheric
limb-kinetic apraxia; F = interhemispheric disconnection limb-kinetic apraxia; G = visual intrahemispheric dissociation apraxia; H = verbal
intrahemispheric dissociation apraxia; I = conceptual apraxia. Some patients have movement representations in both hemispheres (right
hemisphere movement representations are illustrated in this cartoon as a cloud). In these patients a callosal disconnection, J = verbal
dissociation apraxia of the left, but not right, hand.
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Chapter 14: Praxis
does not improve with this treatment. A search of
PubMed did not reveal any other studies where investigators attempted to treat limb-kinetic apraxia. In
addition, there are at present no studies demonstrating treatments of either conceptual or ideational
apraxia.
Conclusion
In this chapter, several types of limb apraxia were discussed. The cartoon in Figure 14.1 displays the systems that mediate purposeful, skilled movements and
the injuries that can induce the different forms of limb
apraxia discussed in this review. Patients with conceptual apraxia have lost the knowledge of the mechanical advantage offered by tools and might make errors
such as selecting the wrong tool for a specific task,
using the incorrect action with a tool, and be unable to
correctly use alternative tools, as well as being unable
to create tools. Patients with ideational apraxia are
impaired at sequencing a series of independent acts
that lead to a goal (e.g., making a sandwich). Patients
with ideomotor apraxia primarily make spatial errors.
The errors may be postural, or may consist of egocentric and allocentric movement errors. There are several
forms of dissociation apraxia in which patients cannot
perform correct purposeful movements in response
to a stimulus in a specific modality (speech commands), but can correctly perform these movements in
response to a stimulus in another modality (e.g., seeing
the object with which a tool interacts). Finally, limbkinetic (melokinetic, innervatory) apraxia is characterized by a loss of hand–wrist deftness. Within each
of these five major categories of limb apraxia there are
subtypes. For example, there are patients with ideomotor apraxia who cannot discriminate well-performed
movements from incorrectly performed movements
and there are other patients who can normally discriminate. Some of these forms and subtypes of apraxia can
be caused by disconnection and others by degradation
or destruction of critical brain representations.
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Section I
Structural and Functional Neuroanatomy
Chapter
Visuospatial function
15
Doron Merims and Morris Freedman
In this chapter, we discuss the neuroanatomy underlying visuospatial function. Our focus will include
the anatomical organization of visuospatial processing, visuospatial syndromes relevant to clinical disorders, as well as specific neurologic diseases affecting
visuospatial function.
Visuospatial processing
The organization of visual processing in the brain
involves two general components. The first of these
transmits information from the retina to the striate
cortex, and the second includes neurons that leave
the striate cortex to project to various regions in the
interconnected hierarchical network of extrastriate
cortical areas [1]. The first component of the visual
system starts with the optic nerves, which consist
mainly of axons originating in the ganglion layer of
the retina. The optic nerves converge to form the optic
chiasm. The fibers lying medially in the optic nerves
cross the chiasm and continue in the optic tract on
the contralateral side of the brain, while the lateral
fibers do not cross and continue in the optic tract on
the ipsilateral side. The optic tract ends in the lateral
geniculate body of the thalamus. Visual information
continues along the geniculocalcarine tract (optic
radiation) to the striate cortex [2]. The primary visual
area, also called the striate cortex, corresponds to
Brodmann’s area (BA) 17 and is located in the depths
of the calcarine fissure, mainly on the medial surface
of the occipital lobe. The primary visual area contains
well-developed outer and internal granular layers (II
and IV). The internal granular layer of the primary
visual area receives fibers from the lateral geniculate body via the optic radiation [2]. The unimodal
visual association areas in the human brain occupy
peristriate cortex that corresponds to BA 18 and
19 and parts of the fusiform, inferior temporal and
middle temporal gyri (BA 37, 20 and 21) [3].
Lesions in the pathway to the striate cortex result in
a contralateral visual field defect that affects all aspects
of vision. The deficits are thus specific for location but
not for modality. Lesions in the areas that receive projections from the striate cortex may cause impairment
in different modalities of the visual system and are less
specific for location [1].
Schneider [4] described two different types of
visual impairment in the hamster due to cortical and
tectal ablations. Ablating the superior colliculus abolished the ability to orient toward an object, but not the
ability to identify it, while ablation of the visual cortical
areas (BA 17 and 18) had the opposite effect. Ungerleider and Mishkin [5] distinguished between two different visual pathways originating in the occipital cortex,
the ventral and dorsal streams. The superior longitudinal fasciculus follows a dorsal path, traversing the posterior parietal region in its course to the frontal lobes.
The dorsal stream is responsible for spatial localization (i.e., object location) and is alternatively known
as the “where” stream. The inferior longitudinal fasciculus projects to the inferior temporal area; this ventral stream has a role in visual object recognition, and
is known as the “what” stream. In their theory of perception and action, Goodale and Milner [6] proposed
that the ventral stream plays a major role in perceptual identification of objects, whereas the dorsal stream
mediates the required sensorimotor transformations
for visually guided actions directed at these objects.
The role of right and left hemispheres in visuospatial function was investigated by Delis and colleagues
[7]. They compared the performance of patients
with left hemisphere damage to patients with right
Behavioral Neurology & Neuropsychiatry, eds. David B. Arciniegas, C. Alan Anderson, and Christopher M. Filley.
C Cambridge University Press 2013.
Published by Cambridge University Press. 214
Chapter 15: Visuospatial function
hemisphere lesions and normal controls. Patients and
normal controls were asked to remember visual hierarchical stimuli consisting of larger forms constructed
of smaller forms. An example of a stimulus was a large
letter (“M”) created out of many copies of a small letter (“z”). The major difference between the groups was
their ability to remember the two levels of hierarchical stimuli on a forced-choice recognition test. Patients
with right hemisphere damage made significantly
more errors than control subjects in remembering the
larger forms relative to the smaller forms. In contrast,
patients with left hemisphere damage made significantly more errors than control subjects in remembering the smaller forms relative to the larger forms.
Ng and colleagues [8] supported the concept that
both hemispheres participate in visuospatial processing in a study using functional magnetic resonance
imaging (fMRI) in ten right-handed normal volunteers, as well as lesion analyses in patients with focal
parietal damage. The fMRI was done while the normal
volunteers were performing a spatial processing task
and showed robust bilateral cortical activation in both
superior parietal lobes. However, the right parietal
lobe showed earlier and stronger signal change. Lesion
analysis of 17 patients indicated that damage to either
the right or left parietal lobe led to impaired judgment
of line orientation, but relatively greater difficulty was
found in the right parietal lesion sample. These studies support the conclusion that the right cerebral hemisphere, and in particular the parietal lobe, plays a special role in visuospatial function.
Visuospatial clinical syndromes
Neglect
Neglect is a failure to report, respond or orient to novel
or meaningful stimuli presented to the side opposite
a brain lesion, when this failure cannot be attributed
to sensory or motor dysfunction [9]. Neglect reflects
a lateralized disruption of spatial attention. The left
neglect syndrome is characterized by a reduction of
neural resources that can be mobilized by sensory
events located on the left and by motor plans directed
towards the left. When neglect is severe, the patient
may behave as if half the environment has ceased to
exist [10].
Neglect can be either sensory or motor. Sensory
neglect manifests by a deficit in awareness of stimuli
contralateral to a lesion that does not involve sensory
projection systems or the primary cortical sensory
areas to which they project. Motor neglect is characterized by failure to respond to a stimulus even though
the patient is aware of the stimulus and has the strength
to respond [9]. Patients with neglect may be slower to
initiate a motor response to targets appearing in left
hemispace (directional hypokinesia).
Patients with directional hypokinesia were found
to have a lesion involving the ventral lateral putamen,
the claustrum, and the white matter subjacent to the
frontal lobe [11]. Ghacibeh and colleagues [12] examined the effect of repetitive transcranial magnetic stimulation (rTMS) on the right frontal and right parietal
areas during a line bisection task in healthy volunteers.
They used a task that dissociated motor-intentional
from sensory-attentional neglect. Right frontal rTMS
caused motor-intentional neglect, whereas right parietal rTMS caused sensory-attentional neglect.
Lesions in other brain areas also may cause neglect.
The area that is most commonly involved is the right
posterior parietal lobe, especially the inferior parietal
area. The most common cause is stroke [13, 14] and
thus a major portion of the data regarding the neuroanatomy of neglect is derived from patients who
have had focal cerebral infarcts.
The anatomical correlates of visual neglect were
investigated in 110 right-handed stroke patients with
lesions confined to the right hemisphere. Neglect was
found to be associated more frequently with lesions
posterior to the Rolandic fissure, as compared with
frontal lesions. When the cerebral lesion is confined to
deep structures, neglect occurs more frequently when
nuclei such as the thalamus and the basal ganglia are
damaged. Conversely, lesions limited to the subcortical
white matter are rarely associated with neglect [13].
Using intra-operative direct electrical stimulation
during tumor resection, Thiebaut de Schotten and
colleagues [15] described two patients who underwent surgical resection of a low-grade glioma. In one
patient, the glioma was centered on the caudal part
of the right temporal lobe. In the second patient, the
glioma was centered on the right inferior parietal lobule. Both patients showed a rightward deviation on line
bisection upon stimulation of two cortical sites: the
supramarginal gyrus (SMG) and the caudal portion
of the superior temporal gyrus (cSTG). In addition,
the second patient showed a maximal rightward deviation upon stimulation of a restricted subcortical region
on the floor of the surgical cavity that corresponded
to a portion of the superior occipitofrontal fasciculus
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Section I: Structural and Functional Neuroanatomy
connecting the parietal to the frontal lobe. The findings
suggest that the SMG, the cSTG, and a poorly known
parietal-frontal pathway, the superior occipitofrontal
fasciculus, but not the rostral superior temporal gyrus,
are critical to the symmetrical processing of the visual
scene in humans.
Watson and Heilman [16] described three patients
with right thalamic hemorrhage, contralateral motor
neglect, and limb akinesia. These patients also had
anosognosia and emotional flattening. Ischemic stroke
to the right medial thalamus may also cause hemispatial neglect [17].
Mort and colleagues [18] used high-resolution
MRI protocols to map the lesions of 35 patients with
neglect and either right middle cerebral artery (MCA)
or right posterior cerebral artery (PCA) stroke. For
patients with MCA stroke, the critical area involved
in all patients with neglect was the angular gyrus on
the lateral surface of the inferior parietal lobe. The
superior temporal gyrus was involved only in half of
these patients. Eight MCA neglect patients had frontal
involvement, with lesions overlapping in the inferior
frontal gyrus, but the same overlap region was also
involved in four MCA patients without neglect.
Park and colleagues [19] examined 45 patients with
right or left PCA territory infarctions. The overall
frequency of hemispatial neglect was 42.2% and did
not significantly differ between right (48.0%) and left
(35.0%) PCA groups, but the severity of neglect was
significantly greater in those with right PCA territory lesions. Isolated occipital lesions did not cause
neglect; however, injury to both the occipital lobe and
the splenium of the corpus callosum did produce this
syndrome. Bird and colleagues [20] showed that, in
patients with neglect after right PCA territory infarction, the region maximally involved was the white matter of the occipital lobe, but there also was a high
degree of overlap extending anteriorly into the ventral
medial temporal lobe.
Using MRI, Committeri and colleagues [21]
demonstrated the anatomical segregation of personal
and extrapersonal neglect. They found that awareness
of extrapersonal space is based on the integrity of right
frontal and superior temporal regions whereas the
right inferior parietal regions (supramarginal gyrus,
post-central gyrus, and especially the white matter
medial to them) are crucial areas for the awareness
of personal space. Common but less crucial regions
for both personal and extrapersonal awareness were
located in the temporo-perisylvian cortex.
216
The presence of visual neglect in the studies cited
above was identified primarily by patient performance
on “pencil and paper” tests such as line bisection [22]
and cancellation tasks [3]. On the line bisection task,
the patient is asked to divide a line by placing a mark
at its central point. Patients with neglect displace the
mark ipsilateral to their lesion. On cancellation tests,
patients are asked to cross out letters, numbers, or
symbols, such as stars. The severity of neglect can
be quantified by the number of target objects that
are missed [22, 23]. The presence of neglect can also
be determined by performance on different drawing
tasks such as drawing a clock or a flower. On these
tasks, patients with neglect ignore the left side of
the image. On clock drawing, for example, left hemiinattention often results in omission of numbers on the
left [24].
Simultanagnosia
Simultanagnosia is a disorder characterized by the
inability to see more than one object at a time [25].
Patients have difficulty describing a complex scene
and may report only one or a few components of
the visual array. Simultanagnosia is one of the three
components of Balint’s syndrome, which also includes
optic ataxia (deficient visually guided reaching), and
oculomotor apraxia (impaired visual scanning) [26].
Simultanagnosia typically occurs following bilateral
lesions in the superior occipitoparietal regions. Rizzo
and Hurtig [27] described three patients with simultanagnosia caused by bilateral superior occipital lobe
strokes. These patients had no abnormalities in visual
acuity or visual fields to explain their impairment.
A striking example of this syndrome was recently
reported by Smith and colleagues [28] in an 87-yearold artist who had a presumed top of the basilar stroke
secondary to atrial fibrillation. During the first 4 weeks
following her stroke, there was a change in her drawings, with selective attention to the left lower quadrant and important aspects of the whole image missing. Subsequently, she improved to the point where
there was no major difference from her style of painting compared with before the stroke. The authors interpreted her changed paintings post-stroke as showing selective inattention to the whole of the object.
This transient inability to perceive the overall figure or
scene was thought to represent simultanagnosia. The
localization of her lesion was not determined by neuroimaging.
Chapter 15: Visuospatial function
Transient Balint’s syndrome was reported in a
74-year-old woman who received non-ionic contrast
media during renal angiography. The contrast material was noted in the bilateral parietooccipital cortices
on the initial computed tomography (CT) scan and
disappeared after clinical resolution of the symptoms
[29]. Coslett and Lie [25] described a patient with profound simultanagnosia and optic ataxia in the presence of bilateral posterior parietal infarcts and white
matter hyperintensities. The patient could not report
more than one attribute of an object; for example, he
could not name the color of the ink in which words
were written despite being able to name the word correctly. These investigators suggested that, in patients
with simultanagnosia, the inability to offer explicit
information about object identity, attributes, or location reflects a failure to link spatial representations
computed in the parietal lobe to information about
object identity and perceptual attributes stored in the
temporal lobe. They suggested the presence of at least
two subtypes of dorsal simultanagnosia: one characterized by an early visual attention impairment that
may be related to lesions involving the superior parietooccipital junction bilaterally, and another reflecting impairments in the binding of information computed in the dorsal and ventral visual streams. Patients
with this “binding deficit” simultanagnosia may have
lesions involving the inferior parietal lobes bilaterally. Another group of patients with simultanagnosia
appear to have a lesion restricted to the left occipitotemporal junction [30].
Simultanagnosia may also be a feature of degenerative brain disorders such as posterior cortical atrophy [31, 32], corticobasal degeneration [33], and
Alzheimer’s disease (AD) [34]. In addition to simultanagnosia following ischemic stroke [28, 35], the syndrome may appear after brain hemorrhage [36], with
brain tumors [37], and with infections including progressive multifocal leukoencephalopathy associated
with acquired immunodeficiency syndrome (AIDS)
and subacute sclerosing panencephalitis [38].
Visuospatial memory
Studies on visuospatial memory have distinguished
between visuospatial working memory and memory
for visuospatial information. With regard to working
memory, an fMRI study in 11 healthy subjects suggested that an area in the superior frontal sulcus plays
a predominant role in visuospatial working memory
[39]. Other studies, using positron emission tomography (PET) in humans, suggest that the neural systems involved in working memory for spatial location
and object identification are functionally segregated,
with a dorsal frontal region being important for spatial location and a more ventral region (involving the
middle, inferior, and orbital frontal areas) being critical for object identification [40].
A widely known study of memory for visuospatial information is that of Maguire and colleagues [41].
These investigators examined 16 London taxi drivers,
who, through their daily work, acquired a substantial amount of large-scale spatial information (as evidenced by passing the licensing examinations). These
taxi drivers were compared with a group of comparison subjects who did not drive taxis. The volume of the
posterior hippocampus (as assessed using quantitative
MRI) was larger among the taxi drivers whereas anterior hippocampal volume was larger among the comparison subjects. Additionally, posterior hippocampal
volume correlated with the amount of time spent as a
taxi driver.
In another study, Iaria and colleagues [42] used a
virtual radial maze task and fMRI to investigate the
modulation of brain activity while healthy subjects
spontaneously adopted different navigational strategies. Subjects were categorized as using a non-spatial
strategy if they associated the arms of the maze with
numbers or letters, or they counted the arms clockwise
or counterclockwise from a single starting point. They
were categorized as using a spatial memory strategy if
they used at least two landmarks and did not mention
a non-spatial strategy. Subjects using a spatial memory
strategy showed activation of the right hippocampus in
the early phase of performance, whereas those using
a non-spatial strategy showed a sustained increase in
activity within the caudate nucleus in the later stages
and no increase in hippocampal activity.
In a subsequent study, Bohbot and colleagues
[43] used voxel-based morphometry to identify brain
regions co-varying with the navigational strategies
used by healthy subjects. They used the MRI scans
of subjects tested previously in the study by Iaria and
colleagues [42] and found that those who adopted
a spatial memory strategy had significantly more
gray matter in the hippocampus and less gray matter
in the caudate nucleus compared with those who
used a non-spatial strategy. In addition, the gray
matter in the hippocampus was negatively correlated
with the gray matter of the caudate nucleus. The
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Section I: Structural and Functional Neuroanatomy
authors suggested that a competitive interaction exists
between the hippocampus and the caudate, one or the
other being optimal for different tasks. Gray matter
regions anatomically connected to the hippocampus,
such as the amygdala, parahippocampal, perirhinal,
entorhinal, and orbitofrontal cortices were found to
co-vary with gray matter in the hippocampus. Bohbot
and colleagues [43] suggested that the correspondence
between navigational strategies and gray matter density found in their study has implications for clinical
intervention aimed at recovering function in patients
with hippocampal or caudate dysfunction.
Another dissociation, supported by lesion studies,
divides visuospatial memory into two categories: allocentric and egocentric. The allocentric system refers to
the spatial location of objects in relation to each other.
It has been suggested that the hippocampus is involved
in allocentric spatial memory, and functions to consolidate allocentric information into long-term memory
[44]. The egocentric system, which refers to the location of an object in relation to the observer, is thought
to be mediated by the posterior parietal cortex [45].
The amygdala also may be involved in visuospatial memory. In one study, quantitative MRI measurement of hippocampal sclerosis in patients suffering
from temporal lobe epilepsy failed to find a correlation between the right hippocampus and visuospatial
memory. Instead, a correlation was found between the
volume of the right amygdala and visuospatial memory [46].
Depth perception and stereopsis
Depth perception can be achieved, to a certain degree,
with monocular vision by use of depth cues such as
motion parallax (a depth cue that results from one’s
motion) and the obscuration of distant objects by
nearer ones. However, for maximal three-dimensional
visuospatial processing, the brain uses the difference
between both eyes (disparity) as a cue for evaluation of
depth [47]. Stereopsis is the perception of depth arising from these small differences between the images in
the two eyes.
Tsao and colleagues [48] used fMRI to show that
a cluster of areas at the parietooccipital junction is
specialized for stereopsis. Similarly, Merboldt and colleagues [49] showed with fMRI that stereoscopic depth
perception relies on the recruitment of neuronal populations in higher-order visual areas of the parietal cortex rather than in primary visual areas. The finding that
218
transient activity caused by the recognition of a minor
change (view angle) of the visual percept is localized to
the intraparietal sulcus suggests that this process represents an early search for binocular disparity, which
precedes or even initiates depth perception.
Cerebral akinetopsia
Akinetopsia is the inability to perceive visual motion
[50] and like many visuospatial deficits can be
functionally disturbing. Blanke and colleagues [51]
reported a 41-year-old patient with akinetopsia
accompanied by dog phobia. MRI showed bilateral
parietal lobe strokes, more evident on the left and with
extension toward the occipital lobe. The patient could
recognize a dog, but would constantly misperceive
its position and direction of motion. However, the
patient also had difficulty walking on or crossing a
crowded street even without dogs present, and his
functional impairment could not be solely attributed
to dog phobia. The lesion was largely restricted to
the parietal lobes, a component of the dorsal stream
of the visual system that is responsible for spatial
processing.
Using focal electrical stimulation in a patient
undergoing invasive monitoring for epilepsy, Blanke
and colleagues [52] studied whether extrastriate cortex
was involved in the unidirectional motion blindness.
Findings suggested that unilateral electrical stimulation in the posterior temporal lobes, more specifically
the middle temporal gyrus (area hMT+, also referred
to as V5), may diminish the capacity to discriminate
motion in the contralateral visual field. Beckers and
Zeki [53] studied the effect of deactivation of areas V1
and V5 in normal subjects using transcranial magnetic
stimulation (TMS). Stimulation of V5 induced severe
impairment in perception of the direction of motion.
TMS of V1 also showed impairment in motion
perception but to a lesser degree than was apparent
in V5.
Neurological conditions and
visuospatial dysfunction
This section will consider visuospatial impairment in
common neurologic diseases such as AD and Parkinson’s disease (PD). Less common disorders such as
Huntington’s disease (HD) and Williams syndrome
(WMS) will also be described to emphasize the variety
of etiologies that may affect the visuospatial system.
Chapter 15: Visuospatial function
Alzheimer’s disease
Basal ganglia lesions
Although memory loss is the most prominent feature
of AD, visuospatial function is also impaired, even
in the early stages of the disease [54]. Using PET and
tests to assess spatial vision and object recognition,
Fujimori and colleagues [55] showed that visuospatial
disturbances were significantly correlated with lower
metabolic rate of both inferior parietal lobules in
patients with mild to moderate AD. More specifically,
object recognition deficits were significantly correlated with lower metabolic rate in the right middle
temporal gyrus and the right inferior parietal lobule.
Grossi and colleagues [56] performed a longitudinal
study of a patient with selective, progressive impairment of topographical orientation. Six years after the
onset of this disturbance, and three years after the first
evaluation, the patient developed typical cognitive
impairments of AD with PET findings of bilateral
hypoperfusion in parietotemporal areas. Although
not an autopsy-proven case of AD, this patient may
represent a highly focal variant of AD, with visuospatial impairment as the dominant and presenting
symptom.
Su and colleagues [61] studied 37 patients with basal
ganglia hemorrhage and found that visuospatial function and memory were the most affected cognitive
domains. The explanation for visuospatial dysfunction
associated with basal ganglia disorders may be disruption of the cortical-striatal circuits involving parietal
and temporal cortices that may lead to impairment
in visuospatial analysis [62]. In addition, striatal damage has been found to selectively impair performance
based on egocentric (body-centered) rather than allocentric (object-centered) spatial cues [63].
Lineweaver and colleagues [64] compared the
visuospatial performance of patients with HD, a disease that primarily affects the basal ganglia, to performance in patients with AD. Speed, but not accuracy, of
mental rotation decreased with increasing angle of orientation in patients with HD. In contrast, accuracy but
not speed of rotation decreased with increasing angle
of orientation in patients with AD. The slowing exhibited by HD patients may be mediated by damage to the
basal ganglia, whereas the spatial manipulation deficit
of AD patients may reflect pathology in parietal and
temporal lobe cortices important for visuospatial processing [64].
Lawrence and colleagues [65] showed that patients
with HD exhibited deficits on tests of spatial recognition and impaired reaction times on visual search.
HD patients were also impaired on spatial but not
visual object working memory, and showed impaired
pattern–location associative learning. On two visuospatial recognition memory tasks, one assessing memory for hand positions (egocentric) and the other
assessing memory for spatial locations (allocentric),
HD patients were impaired relative to matched healthy
controls on both. Correlation analyses indicated that
performance of HD patients on the Hand Position
Memory task, but not the Spatial Location Memory
task, was associated with global cognitive impairment
[66].
Posterior cortical atrophy
Posterior cortical atrophy (PCA) is a clinically homogeneous but pathologically heterogeneous syndrome
in which the onset of a progressive dementia is characterized by visual deficits. AD is the most common
pathological correlate of PCA [57], although this syndrome is also associated with progressive subcortical
gliosis and Creutzfeldt–Jakob disease [58].
McMonagle and colleagues [59] compared cognitive performance of patients with PCA with that
of patients with probable AD and normal controls.
Patients were included in the PCA group if they
showed gradual onset of progressive cognitive impairment with prominent visuospatial dysfunction. The
PCA patients had marked impairment on visuospatial
tasks with poor reading and writing in the presence of
relatively preserved memory, in striking contrast to the
patients with AD. The most common visual symptoms
among PCA patients were simultanagnosia and optic
ataxia; complete Balint’s syndrome was detected in five
individuals. Unilateral neglect and visual field defects
were found less commonly. PET studies in patients
with PCA have shown hypometabolism in the occipitoparietal cortices, more prominent on the right [60].
Dementia with Lewy bodies and Parkinson’s
disease with dementia
Dementia with Lewy bodies (DLB) and Parkinson’s
disease with dementia (PDD) can be considered to lie
on the same spectrum of neurodegeneration, and their
cognitive impairments have much in common. In particular, visual perception impairments are similar in
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Section I: Structural and Functional Neuroanatomy
patients with DLB and PDD [67]. In both diseases,
visual perception is more impaired if visual hallucinations are present [68].
Dementia with Lewy bodies
In contrast to their relatively mild episodic memory
deficits, the visuospatial abilities of patients with DLB
are profoundly impaired, and significantly worse than
those of patients with AD [69, 70]. Tiraboschi and colleagues [71] collected first-visit data of 23 pathologically proven DLB and 94 AD cases. Whereas visual
hallucinations at presentation were more specific for
DLB (99%), visuospatial impairment was observed in
74% of the DLB cases and found to be the most sensitive symptom. Visual hallucinations at presentation
were the best positive predictor of DLB at autopsy,
and lack of visuospatial impairment was the best negative predictor. The best model for differentiating DLB
from AD in the earliest stages of disease was found to
include visual hallucinations and visuospatial dysfunction but not extrapyramidal symptoms.
Lobotesis and colleagues [72] compared regional
cerebral blood flow (rCBF) using single-photon emission computed tomography (SPECT) in DLB patients,
AD patients, and normal age-matched control subjects. Both DLB and AD subjects had significantly
reduced rCBF in parietal and temporal regions compared with control subjects. A significant difference
between DLB and AD was in the occipital regions, with
the DLB patients showing a greater rCBF deficit. Harding and colleagues [73] studied the pathology of 63
cases with Lewy body (LB) pathology and described
consistent association between the presence of visual
hallucinations and cortical pathology. The overall LB
burden was significantly greater in the parahippocampal and inferior temporal cortices in cases with early
hallucinations. Higher LB densities were found in the
inferior temporal cortex in cases with DLB than in
cases with PDD. Cases with hallucinations had significantly more LB/field on average than those without hallucinations in the parahippocampus and amygdala, but not in the frontal, anterior cingulate or inferior temporal cortices. Abnormalities in the occipital
and temporoparietal areas in patients with DLB may
explain the prominent visuospatial deficits in these
patients.
Parkinson’s disease with dementia
Visuospatial deficits in PD are clearly related to
dementia and progression of the disease [74]. Witt and
220
colleagues [75] evaluated the influence of the subthalamic nucleus (STN) in extrapersonal space orientation using STN deep brain stimulation (DBS) in PD as
a reversible model of functional ablation. They examined 12 patients with PD one year after implantation of
DBS electrodes in the STN after overnight withdrawal
of L-dopa. Patients were tested with both stimulators
turned on, the right only, the left only, or none at
all. No asymmetries in spatial orientation were found
when both stimulators were off, when both stimulators were on, and when only the right stimulator was
on. When only the left subthalamic stimulation was
switched on, the reaction times of both hands to visual
stimuli in left extra-personal hemispace increased significantly, and the line bisection test showed a significant shift to the right. These results lead to the
conclusion that the STN and its cortical projections
may influence the network involved in visuospatial
orientation.
Williams syndrome
WMS is a rare genetic condition characterized by
mild to moderate cognitive and behavioral abnormalities including unusually heightened drive toward
social interaction. In addition, there are distinctive
facial features, growth delay, cardiovascular anomalies, and occasional hypercalcemia. The etiology relates
to microdeletions on chromosome 7q11.23 [76, 77].
The main visuospatial deficit in WMS is in spatial
localization [78, 79]. Paul and colleagues [78] showed
that patients with WMS perform markedly worse than
healthy controls on a location-matching task. However, their performance on a face-matching task was
similar to controls. These investigators suggested that
patients with WMS might have selective involvement
of the dorsal stream of visual processing.
Chiang and colleagues [80] compared 3D
T1-weighted brain MRI scans of patients with WMS
with healthy controls and found marked volume
reductions of the parietal and occipital lobes, thalamus, basal ganglia, and midbrain in WMS. Using fMRI
in WMS patients, Meyer-Lindenberg and colleagues
[81] found isolated hypoactivation in the parietal portion of the dorsal visual stream with normal activation
in the ventral visual stream. Using high-resolution
structural MRI, they also found symmetrical reduction in gray matter; one such area, the parietooccipital
region/intraparietal sulcus, is immediately adjacent to
the dorsal visual stream. The authors suggested that the
Chapter 15: Visuospatial function
visuoconstructive deficit in WMS could be attributed
to impaired input from this structurally altered region.
Mitochondrial myopathies
Mitochondrial myopathies are clinically heterogeneous disorders that can affect multiple organ systems. The Kearns–Sayre syndrome (KSS) is the bestknown example of a mitochondrial myopathy, and
is characterized by onset before age 15, progressive
external ophthalmoplegia, and pigmentary degeneration of the retina, with other systemic manifestations
[82]. Chronic progressive external ophthalmoplegia
(CPEO) is a closely related disorder.
KSS and CPEO patients were compared with
healthy control subjects matched for age, sex, and education with a neuropsychological test battery covering verbal skills, verbal and visual memory, visuospatial perception, visual construction, attention, abstraction, and flexibility [83]. The patients with KSS or
CPEO did not have dementia, but there was evidence
of neuropsychological dysfunction, suggesting selective impairment of visuospatial perception and executive function. A specific pattern of cognitive deficits
implicating parietooccipital and prefrontal dysfunction was suggested [83]. In an earlier study by Turconi and colleagues [84], 16 patients with mitochondrial encephalomyopathy showed no global cognitive
impairment but did score lower on non-verbal versus
verbal tasks. Visuospatial skills and short-term memory were selectively impaired. SPECT scans were carried out on 12 of the patients, and the most frequent
finding was hypoperfusion in both temporal lobes
[84].
Conclusion
Impairment of visuospatial function is common with
focal brain lesions, as well as more widespread disorders such as neurodegenerative diseases. Knowledge of
the neuroanatomy underlying deficits in visuospatial
function is critical for understanding the mechanisms
leading to the disability experienced by patients with
visuospatial dysfunction. This understanding may in
turn provide insights for better assessment and management strategies of affected patients.
Acknowledgments
During the preparation of this work, M. Freedman
held a research grant from the Ontario Mental Health
Foundation and was supported by the Saul A. Silverman Family Foundation, Toronto, Ontario, Canada,
as part of a Canada International Scientific Exchange
Program (CISEPO) project.
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224
(A)
(B)
(C)
(D)
(E)
Figure 2.1. General structure of the brain (A). Major areas considered in this chapter include the brainstem and cerebellum (B),
diencephalon (C), limbic and paralimbic structures (D), basal ganglia (see Figure 2.5), and cerebral cortex (E).
Corpus callosum
Cingulate
gyrus
Orbital and medial
prefrontal cortex
Cut edge
of midbrain
Parahippocampal
gyrus
Temporal
lobe
Mammillothalamic
tract
Anterior nucleus
of the thalamus
Fornix
Medial dorsal
nucleus of the thalamus
Anterior
commissure
Ventral basal
ganglia
Hypothalamus
Optic chiasm
Amygdala
Mammillary
body
Hippocampus
Figure 2.6. Limbic and paralimbic areas
(green shading) viewed parasagittally. The
top panel depicts these areas as if viewed
through the left hemisphere. The bottom
panel illustrates these areas in greater
detail. Reprinted from Purves D,
Augustine GJ, Fitzpatrick D et al. (editors),
Neuroscience, 2nd edition; 2001, with
permission from Sinauer Associates.
Figure 2.8. Lobar divisions of the cerebral hemispheres (left lateral
view).
Figure 2.9. Brodmann’s areas in the human brain. Reprinted with permission from Mark Dubin, PhD, Department of Molecular, Cellular &
Developmental Biology, University of Colorado at Boulder (http://spot.colorado.edu/∼dubin/talks/brodmann/brodmann.html).
Figure 2.11. Orthogonal frontal projection of the cerebral and
cerebellar arteries in situ, together with some bony landmarks and
the lateral ventricles. Labeled structures include: 1 – Calvaria (inner
border). 2 – Medial occipital artery, parieto-occipital branch.
3 – Trunk of the corpus callosum. 4 – Lateral ventricle. 5 – Insula.
6 – Medial occipital artery. 7 – Superior cerebellar artery, medial
branch. 8 – Lateral occipital artery. 9 – Free margin of the lesser wing
of the sphenoid bone. 10 – Middle meningeal artery, intraosseous
part (in-constant). 11 – Middle meningeal artery, frontal branch. 12 –
Middle meningeal artery, parietal branch.
13 – Superior margin of petrous part of the temporal bone.
14 – Superior cerebellar artery, lateral branch. 15 – Posterior cerebral
artery. 16 – Superior cerebellar artery. 17 – Basilar artery.
18 – Anterior inferior cerebellar artery. 19 – Posterior inferior
cerebellar artery, medial branch. 20 – Posterior inferior cerebellar
artery, lateral branch. 21 – Posterior inferior cerebellar artery.
22 – Vertebral artery, intracranial part. 23 – Maxillary artery, pterygoid
part. 24 – Middle meningeal artery. 25 – Superficial temporal artery.
26 – Maxillary artery, manidibular part. 27 – Vertebral artery, atlantal
part. 28 – External carotid artery. 29 – Facial artery. 30 – Vertebral
artery, cervical part. 31 – Paracentral artery. 32 – Pericallosal artery.
33 – Callosomarginal artery. 34 – Middle cerebral artery, terminal
part. 35 – Middle cerebral artery, insular part. 36 – Anterior cerebral
artery, post-communicating part. 37 – Anterior communicating
artery. 38 – Anterior cerebral artery, pre-communicating part.
39 – Middle cerebral artery, sphenoid part. 40 – Internal carotid
artery, cavernous part. 41 – Internal carotid artery, petrous part.
42 – Internal carotid artery, cervical part. 43 – Common carotid
artery. Reprinted from Nieuwenhuys R, Voogd J, Huijzen CV. The
Human Central Nervous System. 4th edition. New York, NY: Springer;
2008, with permission from Springer Science+Business Media.
Figure 2.12. Orthogonal lateral projection of the cerebral and cerebellar arteries, together with external and bony landmarks. Some neural
structures are illustrated in outline; in the center, two lines tangential to the anterior and posterior commisures (AC and PC, respectively) are
seen: the one passing above the AC and beneath the PC is part of the bicommissural line of Talairach (BC); the other tangent is part of the
upper horizontal line of Krönlein (CH). Additional abbreviations include: CM – canthus-meatus line; FH – horizontal line of Frankfurt;
GI – glabella-inion line; VCA – vertical tangent to anterior commissure; and VCP – vertical tangent to posterior commissure. Labeled structures
include: 1 – Central sulcus. 2 – Pericallosal artery. 3 – Callosomarginal artery. 4 – Corpus callosum. 5 – Outline of ventricles. 6 – Outline of
insula. 7 – Anterior cerebral artery. 8 – Middle cerebral artery, frontal trunk. 9 – Anterior commissure. 10 – Middle cerebral artery, parietal trunk.
11 – Middle cerebral artery, temporal trunk. 12 – Posterior commissure. 13 – Medial occipital artery. 14 – Lateral occipital artery. 15 – Superior
cerebellar artery, medial branch. 16 – Superior cerebellar artery, lateral branch. 17 – Superior cerebellar artery. 18 – Posterior cerebral artery.
19 – Posterior communicating artery. 20 – Internal carotid artery, cerebral part. 21 – Internal carotid artery, cavernous part. 22 – Siphon point.
23 – Middle cerebral artery, sphenoid part. 24– Ektocanthion (Canthus externus). 25 – Glabella. 26 – Orbital (on infraorbital margin).
27 – Internal carotid artery, petrous part. 28 – Basilar artery. 29 – Superior margin of petrous part of the temporal bone. 30 – Anterior inferior
cerebellar artery. 31 – Porion (on supramental margin). 32 – Fourth ventricle. 33– Posterior inferior cerebellar artery, medial branch.
34 – Posterior inferior cerebellar artery, lateral branch. 35 – Posterior inferior cerebellar artery. 36 – Vertebral artery, intracranial part.
37 – Vertebral artery, atlantal part. 38 – Internal carotid artery, cervical part. 39 – Maxillary artery. 40 – Middle meningeal artery. 41 – External
carotid artery. 42 – Vertebral artery, cervical part. 43 – Common carotid artery. 44 – Spinal cord. 45 – Inion (external occipital protuberance).
Reprinted from Nieuwenhuys R, Voogd J, Huijzen CV. The Human Central Nervous System. 4th edition. New York, NY: Springer; 2008, with
permission from Springer Science+Business Media.
Figure 2.13. The ventricular system, including the lateral ventricles
(dark blue, rostral), third ventricle (purple), cerebral aqueduct (green),
fourth ventricle (light blue, caudal), and choroid plexus (red).
Adapted from 3D Brain from G2C Online (www.g2conline.org),
produced by the Dolan DNA Learning Center, Cold Spring Harbor
Laboratory.
(A)
(B)
(C)
(F)
(D)
(G)
(E)
(H)
Figure 3.1. A, Posterior, and B, right lateral surface reconstructions of the human cerebellum derived from MRI images. The named fissures
are demarcated in color, and the fissures and lobules are identified. C, Surface reconstruction of the cerebellum seen from the oblique
posterior view, with lobules demarcated. Parasagittal images of human cerebellum on MRI 2 mm lateral to midline in D, and 18 mm lateral to
midline in E. Fissures are color coded according to the convention used in A and B, and the lobules are designated. F, Superior (SCP), middle
(MCP), and inferior (ICP) cerebellar peduncles in human identified with diffusion spectrum imaging, overlaid on diffusion-weighted image of
cerebellum and brainstem. G, Cryosection image of post-mortem human cerebellum in the coronal plane 52 mm behind the anterior
commissure – posterior commissure (AC-PC), with deep cerebellar nuclei identified: D – dentate nucleus, E – emboliform nucleus, F – fastigial
nucleus, G – globose nucleus. H, Diagram of a single cerebellar folium is shown sectioned in its longitudinal axis (diagram right) and
transversely (left) to depict the histology of the cerebellar cortex. Purkinje cells are red; superficial and deep stellate, basket, and Golgi cells are
black; granule cells and ascending axons and parallel fibers are yellow; mossy and climbing fibers are blue. Also shown are the glomeruli with
mossy fiber rosettes, claw-like dendrites of granule cells, and Golgi axons. (A, B, D, E, G reproduced from Schmahmann JD, Doyon J, Toga A,
Evans A, Petrides M. MRI Atlas of the Human Cerebellum. San Diego, CA: Academic Press; Copyright Elsevier, 2000, with permission from
Elsevier; C from Makris N, Schlerf JE, Hodge SM et al. MRI-based surface-assisted parcellation of human cerebellar cortex: an anatomically
specified method with estimate of reliability. Neuroimage 2005;25(4):1146–60, with permission from Academic Press; F reproduced from
Granziera C, Schmahmann JD, Hadjikhani N et al. Diffusion spectrum imaging shows the structural basis of functional cerebellar circuits in the
human cerebellum in vivo. PLoS One 2009;4(4):e5101, with permission; H reproduced from Williams PL, Bannister LH, Berry MM et al. (editors).
Gray’s Anatomy. 38th edition. New York, NY: Churchill Livingstone; 1995; Copyright Elsevier, 1995, with permission from Elsevier. Redrawn
from Eccles JC, Ito M, Szentágothai J. The Cerebellum as a Neuronal Machine. Berlin: Springer-Verlag; Copyright Elsevier, 1967.
(A)
(D)
(B)
(C)
Figure 3.2. Activation Likelihood Estimation (ALE) activation maps for the domains of A, spatial cognition, B, motor tapping with the right
hand, and C, language tasks drawn from a meta-analysis of functional imaging studies [26]. The right cerebellum is depicted on the right. The
results are overlaid upon an image of the cerebellum in the coronal plane at y = −70 from the MRI Atlas of the Human Cerebellum [7], and
the cerebellar fissures and lobules at this level are identified in D. Reproduced from Schmahmann JD, Doyon J, Toga A, Evans A, Petrides M.
MRI Atlas of the Human Cerebellum. San Diego, CA: Academic Press; Copyright Elsevier, 2000, with permission of Elsevier; and with permission
of Academic Press from Stoodley CJ, Schmahmann JD. Functional topography in the human cerebellum: a meta-analysis of neuroimaging
studies. Neuroimage 2009;44(2):489–501.
Figure 3.3. Representative rostral (y = −44) to caudal (y = −76) coronal sections through a human cerebellum showing activation patterns
in a functional magnetic resonance imaging experiment in a single subject [28]. Tasks investigated sensorimotor function (finger tapping,
red), language (verb generation, blue), spatial cognition (mental rotation, green), working memory (n-back task, purple), and emotional
processing (viewing images from the International Affective Picture System, yellow). Lobules V, VI, Crus I (Cr I), Crus II (Cr II), VIIB and VIII are
labeled. The right and left cerebellar hemispheres are as indicated. Reproduced with permission of Masson Spa from Stoodley CJ,
Schmahmann JD. Evidence for topographic organization in the cerebellum of motor control versus cognitive and affective processing. Cortex
2010;48(7):831–844.
Figure 4.2. Diffusion tensor image showing the arcuate fasciculus.
Note the additional fascicle extending to Geschwind’s territory in the
inferior parietal cortex, not recognized by traditional neuroanatomic
investigation. Reproduced from Catani M, Jones DK, Ffytche DH.
Perisylvian language networks of the human brain. Ann Neurol.
2005;57(1):8–16, with permission from John Wiley & Sons, Inc.
IPs/SPL
FEF
VFC
(IFg/MFg)
TPJ
(IPL/STG)
Top-down control
L FEF
R FEF
Novelty
R VFC
L VFC
Circuit
breaker
Stimulusresponse
selection
L TPJ
R IPs
L IPs
R TPJ
Behavioral
valence
Visual areas
Stimulus-driven control
Figure 8.10. Illustration of a
neuroanatomic model of attentional
control. Top: diagram indicating brain
regions involved in the control of
attention. Bottom: Schematic of the
mechanisms of a model of attentional
control [43]. The dorsal network (IPs-FEF),
indicated by the black arrows, is involved
in the top-down, or “goal-directed,”
control of attention. The ventral network
(TPJ-VFC), indicated by the gray arrows, is
involved in bottom-up, or
“stimulus-driven,” control of attention. The
dorsal system is also modulated by
bottom-up information, with the TPJ
communicating with the IPs and acting as
a “circuit breaker” allowing salient
bottom-up information to interrupt
voluntary, top-down orienting, in turn
reorienting attention to salient aspects of
the environment. Abbreviations: IPs:
intraparietal sulcus; SPL: superior parietal
lobule; FEF: frontal eye field; TPJ:
temporoparietal junction; IPL: inferior
parietal lobule; STG: superior temporal
gyrus; VFC: ventral frontal cortex; IFg:
inferior frontal gyrus: MFg: middle frontal
gyrus; L: left; R: right. Adapted from
Corbetta M, Shulman GL. Control of
goal-directed and stimulus-driven
attention in the brain. Nat Rev Neurosci.
2002;3(3):201–15, with permission from
Macmillan Publishers Ltd.
Figure 12.2. Lateral view of the left hemisphere indicating the perisylvian area. The illustration shows Broca’s area in the frontal operculum
and Wernicke’s area in the superior temporal gyrus and the corresponding Brodmann’s areas. Reprinted with permission from Mark Dubin,
PhD, Department of Molecular, Cellular & Developmental Biology, University of Colorado at Boulder (http://spot.colorado.edu/∼dubin/talks/
brodmann/brodmann.html).
(A)
(B)
(C)
Figure 12.4. Examples of language mapping in the frontal lobe (A) and the combined temporal and parietal lobes (B). Yellow and green
circles represent numbered electrocortical stimulation mapping (ESM) language sites and clean ESM sites, respectively. Red boxes represent
expression fMR imaging activations. Blue boxes represent comprehension fMR imaging activations. The frontal lobe slices are shown with an
ESM radius of 5 mm (determined to produce the highest sensitivity with the least cost to specificity) and temporoparietal lobe slices are
shown with an ESM radius of 9 mm. A: For frontal lobe mapping, these brain slices demonstrate that red (expression) activations tend to
overlap with, or are adjacent to, essential (yellow) ESM sites, but avoid non-essential (green) ESM sites. Blue activations in the frontal lobe also
appear predictive. B: In most cases of temporoparietal lobe mapping, such as the one illustrated here, comprehension fMR imaging
activations matched well with ESM language sites (yellow) in the temporoparietal lobes and did not overlap with clean ESM sites (green). Very
little expression fMR imaging activations are seen in the temporoparietal lobe region and the reason why such tasks as verbal object naming
and word generation do not accurately predict language sites in these regions. C: These maps were obtained in an individual case in which
preoperative fMR imaging was the least effective at accurately predicting whether a given cortical area would be involved in language
function. In this case, only two of the three essential ESM sites overlapped with fMR imaging activations, and only two of seven of the clean
ESM sites completely avoided fMR imaging activations. Reproduced from Pouratian N, Bookheimer SY, Rex DE, Martin NA, Toga AW. Utility of
preoperative functional magnetic resonance imaging for identifying language cortices in patients with vascular malformations. J Neurosurg.
2002;97(1):21–32, with permission of Journal of Neurosurgery Publishing Group.
Figure 12.6. Diffusion tensor imaging pathways in conduction
aphasia. Reproduced from Catani M, Jones DK, Ffytche DH.
Perisylvian language networks of the human brain. Ann Neurol.
2005;57(1):8–16, with permission from John Wiley & Sons, Inc.
(a)
(b)
Figure 16.5. White matter tractography
may be used to label brain voxels
according to the white matter structure
of which they form a part. (a) Image
tractograms of the projection (green),
association (red) and callosal (blue) fibers
are mapped into the brain space,
indicating their position with respect to
other brain regions, and include the
anterior region of corona radiata (acr),
external capsule (ec), internal capsule (ic),
and posterior region of corona radiata
(pcr). (b) A similar procedure has been
used to label various white matter tracts,
including the corpus callosum (purple),
superior longitudinal fasciculus (yellow),
cingulum (green), uncinate fasciculus
(dark red), inferior occipito-frontal
fasciculus (orange), inferior longitudinal
fasciculus (brown), corticobulbar tract
(light blue), corticospinal tract (white),
fornix and stria terminalis (light yellow).
Tract positions are shown in several
sagittal and axial slices. Reprinted from
Lazar M. Mapping brain anatomical
connectivity using white matter
tractography. NMR Biomed
2010;23:821–35, with permission of John
Wiley & Sons Ltd.
(A)
(B)
(C)
(D)
(E)
(F)
Figure 18.1. Graphic illustrations of relationships between mood and affect. In each panel, the Y-axis represents the valence of emotion and
emotional feeling and the X-axis represents time (days to weeks or longer). Mood is represented by a thick solid line and affect is represented
by a thin dotted line. The amplitude of each line reflects the intensity of emotion and emotional feeling. (A) Mood is euthymic (from Greek eu
“normal” + thymia “state of mind”) – that is, the emotional climate is temperate and stable over days to weeks. Affect varies around that
mood, with clearly identifiable shifts between positive (e.g., happiness) and negative (e.g., irritation, frustration, anger) of modest intensity
occurring during any given day. (B) Mood is dysphoric (from Greek dusphoros “hard to bear”), i.e., persistently sad or sad/irritable most of the
day nearly every day for several weeks. Affect continues to vary around that mood, but it is restricted to emotions and emotional feelings that
are predominantly negative and whose amplitudes are attenuated. (C) Mood varies from persistently and excessively positive (i.e., euphoric
and expansive) for a week or longer to excessively negative (i.e., sad). Affect is labile and intense when superimposed on persistently and
excessively positive mood and its valence and amplitude are more restricted when superimposed on persistently and excessively negative
mood. (D) Moderate affective lability superimposed on euthymic mood. (E) Severely pathological affect (i.e., pathological laughing and crying)
superimposed on euthymic mood. (F) Severely pathological affect (i.e., pathological laughing and crying) superimposed on dysphoric mood
(i.e., major depressive episode).
Figure 18.2. Graphic illustrations of several types of mood and affect. The Y-axis represents the valence of emotion and emotional feeling
and the X-axis represents time (days to weeks or longer). Moods are represented by thick solid lines and affects are represented by thin dotted
lines, the intensity of which are reflected by their amplitudes. This graphic offers a visual representation of the concepts of mood and affect:
mood is a slow-frequency phenomenon (background, emotional “climate”) and affect is a fast frequency phenomenon (foreground,
emotional “weather”).
Figure 18.5. A schematic representation of many of the structures and circuits supporting emotional generation, expression, experience,
and control and their functional relationships. Glutamatergic, presumed excitatory projections are shown in green, GABAergic projections are
shown in orange, and modulatory projections in blue. In the model proposed here, dysfunction in the amygdala and/or the medial prefrontal
network results in dysregulation of transmission throughout an extended brain circuit that stretches from the cortex to the brainstem,
generating emotion and its expression through motoric, visceral, autonomic, endocrine, and neurochemical effectors. Intra-amygdaloid
connections link the basal and lateral amygdaloid nuclei to the central and medial nuclei of the amygdala. Parallel and convergent efferent
projections from the amygdala and the medial prefrontal network to the hypothalamus, periaqueductal gray, nucleus basalis, locus coeruleus,
dorsal raphe, and medullary vagal nuclei organize neuroendocrine, autonomic, neurotransmitter and behavioral responses to stressors and
emotional stimuli. Structures of the default system (or network) support emotional experience. The amygdala and medial prefrontal network
interact with the cortico-striatal-pallidal-thalamic loop, through prominent connections both with the accumbens nucleus and medial
caudate, and with the mediodorsal and paraventricular thalamic nuclei, to control and limit responses. Abbreviations: 5-HT – serotonin; ACh –
acetylcholine; BNST – bed nucleus of the stria terminalis; Cort. – corticosteroid; CRH – corticotrophin releasing hormone; Ctx – cortex;
NorAdr – norepinephrine; PAG – periaqueductal gray; PVH – paraventricular nucleus of the hypothalamus; PVZ – periventricular zone of
hypothalamus; VTA – ventral tegmental area. Reprinted from Price JL, Drevets WC. Neurocircuitry of mood disorders.
Neuropsychopharmacology 2010;35(1):192–216, with permission.
(A)
(B)
Figure 26.3. An example of diffusion tensor imaging (DTI) as
applied to the study of traumatic brain injury (TBI) (axial
T1-weighted image with DTI overlaid). White matter tractography
using TBI is used here to visualize the anterior forceps of the corpus
callosum in a male who experienced multiple concussions due to
blast forces. This case is provided courtesy and with the permission
of Dr. Rajendra Morey, Duke University and Mid-Atlantic Mental
Illness Research, Education and Clinical Center, Veterans Integrated
Service Network 6, Durham, North Carolina.
Figure 18.6. Results from a study
examining the effects on brain activation
and emotion of systematic variations in
the goal and content of reappraisal
strategies. A: Regardless of whether the
goal is to increase or decrease emotion,
lateral prefrontal and anterior cingulate
cortices are activated. B: When the goal is
to decrease emotion, right dorsolateral
and ventrolateral prefrontal as well as
right orbitofrontal cortex is more active
than are left-hemispheric structures (left
panel). By contrast, when the goal of
control is to increase emotion, left lateral
and dorsomedial prefrontal cortical
regions are differentially recruited when
imagining worsening experiences and
outcomes (right panel). Abbreviations:
LPFC, lateral prefrontal cortex; MPFC,
medial prefrontal cortex; ACC, anterior
cingulate cortex; OFC, orbitofrontal
cortex. Adapted from Ochsner KN, Gross
JJ. The cognitive control of emotion.
Trends Cogn Sci. 2005;9(5):242–9, with
permission.
Figure 27.1. Functional magnetic resonance imaging (fMRI) using
a light pain stimulation paradigm, which produced bilateral
thalamic activation.
(A)
(B)
Figure 27.2. Magnetic resonance
imaging (MRI) of a man with remote
traumatic brain injury (TBI).
High-resolution T2-weighted imaging (A),
diffusion tensor imaging (DTI) with
color-coded fractional anisotropy (FA)
mapping (B), and fiber tracking (C) based
on the identification of the region of
interest (boxed area in A).
(C)
Figure 27.4. Functional magnetic resonance imaging (fMRI) of a
visual task. In this example, a 40-year-old subject was asked to fixate
on a small fixation cross while concentric circles expanded from this
central point at a rate of 8 Hz for 20 seconds. This 20-second period
was followed by a rest condition when the subject was presented
the same stimulus with eyes closed. This cycle was repeated three
times.
(A)
(B)
(C)
(E)
(F)
(G)
(D)
Figure 27.6. Examples of various
diffusion tensor images generated using
data acquired from a 30-year-old healthy
adult.
Figure 27.7. Typical patterns of cerebral metabolism as imaged using fluorodeoxyglucose positron emission tomography (FDG-PET)
among persons with mild, moderate, and severe Alzheimer’s disease (AD). FDG-PET scans are displayed as three-dimensional stereotactic
surface projection (SSP) maps normalized to pons generated with the software program Neurostat. Maps are shown with relative cerebral
metabolism or statistical significance increasing on the color scale from the lowest values shown in blue to the highest values in red and
white. For orientation, a reference brain is shown in row A with regions of interest in dementia evaluations in color; orange areas usually
hypometabolic in AD, blue and purple areas typically hypometabolic in frontotemporal dementia. Row B shows the pattern of metabolism in
27 normal elderly subjects. This is used for statistical comparisons with metabolism in individual patients (rows D, F, and H). There are
increasing severity and extent of cerebral glucose hypometabolism as AD progresses from mild (rows C and D) and moderate (rows E and F)
to severe (rows G and H). Reproduced from Foster NL, Wang AY, Tasdizen T et al. Realizing the potential of positron emission tomography
with 18F-fluorodeoxyglucose to improve the treatment of Alzheimer’s disease. Alzheimers Dement. 2008;4(1 Suppl. 1):S29–36, with
permission from Elsevier.
Figure 27.8. Statistical parametric mapping of metabolic activity using fluorodeoxyglucose positron emission tomography (FDG-PET) in
patients with relatively common neurodegenerative disorders. Statistical parametric mapping of regions of decreased metabolic activity
(relative to the global mean, thresholded at p ⬍ 0.001 with cluster cut-off of 20 voxels) are overlaid onto a single subject T1 magnetic
resonance image. Abbreviations: PD – Parkinson’s disease; MSA – multisystem atrophy; PSP – progressive supranuclear palsy; CBD –
corticobasal degeneration; DLB – dementia with Lewy bodies; AD – Alzheimer’s disease; FTD – frontotemporal dementia. Reproduced from
Teune LK, Bartels AL, de Jong BM et al. Typical cerebral metabolic patterns in neurodegenerative brain diseases. Mov Disord.
2010;25(14):2395–404, with permission from John Wiley and Sons.
Figure 28.4. Sleep architecture presented in a bipolar montage. The stages of sleep are identified by their typical EEG findings and cycle
throughout the night among lighter (Stages 1 and 2) and deeper (Stages 3, 4, and REM) stages of sleep. Stage 1 sleep (top left) is characterized
by loss of the posterior dominant rhythm, further diminishment of movement and muscle artifact and increasing diffuse slowing of
background activity. Stage 2 sleep (top right) is characterized by the appearance of sleep spindles and K-complexes. Stages 3 and 4 sleep
(bottom left) are characterized by various percentages of higher amplitude delta range activity. REM sleep (bottom right) is characterized by a
low-voltage, irregular background with multiple rapid eye movements. Muscle artifact is virtually absent during normal REM sleep.
Figure 28.5. Normal posterior
dominant rhythm with attenuation upon
eye opening (black arrow) and
reappearance with eye closure (purple
arrow).
Figure 28.7. Widespread, or diffuse,
beta activity.
Figure 28.14. Photoparoxysmal response.
Figure 29.4. Scalp topography of posterior-dominant alpha. A flat
projection of the top of the head is shown and the circles indicate
approximate electrode locations (nose is up in figure). The power
distribution across electrodes exhibits a typical posterior dominance
for alpha, mapped at 10 Hz.
Figure 29.8. Time, frequency, and
time–frequency representations. The
signal in the left column is a mixture of
two pure tones (20 and 80 Hz). The signal
in the right column is the same complex
tone as the left, but amplitude modulated
at 5 Hz. Top panels: Time domain; Bottom
panels: Frequency domain (FFT); Middle
panels: Time–frequency domain
(Short-Time Fourier Transform). The reds in
the color scale indicate greater spectral
power. Note that for the stationary signal
on the left, a simple frequency
representation (middle panel) conveys as
much information as the time–frequency
representation (bottom). For the
non-stationary signal on the right,
however, the amplitude modulation effect
is lost in the FFT (middle panel), but
captured effectively in the time–frequency
representation (bottom panel).
Figure 29.9. Examples of
time–frequency transformations. Top
panel: Original signal in the time domain.
The signal is linearly decreasing in
frequency across time (i.e., it is a chirp
signal). Middle panel: Short-time Fourier
Transform of chirp. Bottom panel:
Pseudo-Wigner Distribution of chirp. Note
the increased frequency resolution of the
Pseudo-Wigner Distribution. Reds in the
color scale indicate greater spectral
power.
Figure 29.10. Magnetic response to visually cued index finger flexions. Top panel: Averaged evoked field (EF) (101 trials) from a single
channel over the right hemisphere. Time zero indicates movement onset. The evoked responses seen in the immediate post-movement
period are known as motor evoked fields (MEF, or MEP for EEG recordings) and reflect the somatosensory feedback from motor cortex and
from the peripheral sensation of movement. Bottom panel: Wavelet-based time-frequency transformation of same trials in same channel
used to create averaged EF (color scale: blues indicate event-related de-synchronization (ERD) and reds indicate event-related
synchronization (ERS)). Note the prominent beta-band changes in the panel, including ERD in the pre- and peri-movement period and then
ERS following the ERD. The power increase from the evoked response in the top panel is evident immediately following movement onset at
the lower frequencies (⬍10 Hz). The ERD/ERS in the beta-band is difficult to visualize in the averaged evoked response, although a small
change in amplitude may be discerned.
Figure 29.11. Subdividing the spectral
response into evoked and induced
components. The data illustrated in
Figure 29.10 are shown here, focusing
more clearly on the relevant time and
frequency windows. Top panel: evoked
power, relative to pre-movement baseline
period (−3 to −2 s); Middle panel: relative
induced power; Bottom panel:
phase-locking factor. Color scales: reds
indicates greater power (top two panels)
or phase-locking (bottom panel) – blues
indicate lower power or phase-locking.
Figure 29.12. Distributed source analysis of the visual evoked
magnetic field and electric potential at 100 ms (M/P100) produced
by averaging EEG and MEG data to repeated presentations of a
central visual fixation crosshair. A cortically constrained minimum
norm solution was used for source reconstruction in this case.
Figure 29.14. Independent component
analysis of a 248-channel MEG dataset
from a child with medial temporal lobe
epilepsy. The first 20 (of 248) ICA
components are illustrated (top:
waveforms; bottom: topography).
Component 14 shows a spike at
approximately 232 seconds from the
initiation of recording. The spike shows a
dipole-like phase-reversal over the left
temporal cortex in the topography.
Follow-on source analysis revealed a
hippocampal origin. Also of interest are
component 16, which reflects eyeblinks,
and component 19, a
magnetocardiographic artifact (note the
broad phase-reversal over the left and
right sensors reflecting a very distant
source). A significant amount of slowing in
the MEG record (mixed delta/theta) is also
seen in the first 10 components. Color
scale: reds are positive and blues negative
component values.
(A)
(B)
(C)
(D)
Figure 31.1. Lymphomatosis cerebri. A: Coronal brain autopsy sections showed no mass lesions or hemorrhages, and no obvious
abnormalities of the white matter except for very subtle discoloration best seen in the left inferior frontal gyrus (arrow). B: Whole mount
sections stained with hematoxylin and eosin (H&E) (left) and CD45 for lymphocytes (right) showed that the densest lymphoma cell infiltrates
were found in this same abnormal left inferior frontal gyrus, where they filled the subgyral white matter, with relative sparing of the overlying
cortical gray matter. C: High-power photomicrograph of the white matter showing clusters of lymphoma cells that permeated, splayed, and
disrupted the myelinated fibers, seen as elongate linear strands (Luxol fast blue-periodic acid Schiff (LFB-PAS)). D: High-power
photomicrograph of the white matter from the same area as seen in Figure 31.1C, showing better preservation of axons. Anti-neurofilament
immunostaining with light hematoxylin counterstain.
(A)
(B)
(C)
(D)
(E)
(F)
Figure 31.2. Lymphomatosis cerebri. A: Low-power photomicrograph illustrating that less-dense lymphomatous infiltrates could also be
found in the cerebellar white matter (WM), where they again favored white matter over the cerebellar gray matter (GM) or molecular layer
(ML). Meningeal involvement was focally identified (arrow). Hematoxylin and eosin (H&E) stain. B: Low power photomicrograph showing that
in the subcortical gray matter areas the preference of the cells for white matter over gray matter still existed. Note extensive involvement of
the white matter, with virtual stoppage cells where the gray matter of the putamen (P) meets the adjacent white matter (arrows); H&E stain
used in this photomicrograph. C: High-power photomicrograph illustrates that while some degree of perivascular accumulation of lymphoma
cells was found, individual cell permeation by the cytologically malignant cells (D: arrows) was more typical. E: Lymphoma cells were
immunoreactive for CD20, a B-cell marker; CD20 immunostaining with light hematoxylin counterstain. F: Only a few accompanying
non-neoplastic T-cells were identified; CD3 immunostaining with light hematoxylin counterstain.
(A)
(B)
(C)
(D)
(E)
(F)
(G)
(H)
Figure 31.3. Mycosis fungoides. A:
Low-power photomicrograph of the skin
from the lower extremities demonstrated
increased numbers of lymphocytes
within the upper dermis that were
cytologically atypical, features diagnostic
for mycosis fungoides. Hematoxylin and
eosin (H&E) stain. B: At the same
magnification and in the same region, the
atypical lymphocytes are easily
highlighted by their strongly positive
reaction for CD8, an immunomarker for
suppressor T-cells. Cases of mycosis
fungoides with CD8+ predominance are
far fewer than those with CD4+ strong
staining. CD8 immunostaining with light
hematoxylin counterstain. C: Same region
of skin immunostained with CD4 shows
that CD4-positive helper T-cells are far
less frequent. CD4 immunostaining with
light hematoxylin counterstain. D: Low
power photomicrograph taken from the
white matter of the cerebral hemispheres
shows cytologically atypical lymphocytes
that percolate through the white matter,
yielding only subtle hypercellularity and
only focal angiocentric arrangement
(arrow). H&E stain. E: High-power
magnification revealed the individual
neoplastic T-cells of mycosis fungoides
with classic “cerebriform,” folded and
grooved nuclei (arrow). H&E stain. F:
Immunohistochemical staining for CD8
highlighted these individual tumor cells
far better in the white matter than did
routine H&E staining. G: High-power
photomicrograph of one of the mycosis
fungoides cells in white matter
immunostained for CD8. H:
Leptomeningeal involvement could also
be discerned in some areas. H&E stain.
(A)
(B)
(C)
(D)
(E)
(F)
Figure 31.4. Intravascular lymphoma.
A: Magnetic resonance imaging (MRI)
performed soon after diagnosis reveals
multiple bilateral areas of increased T2
signal in the cerebral white matter
(illustrated) as well as in the pons and
cerebellar hemispheres. B:
Fluid-attenuated inversion recovery
(FLAIR) imaging similarly demonstrates
multiple foci with ill-defined borders
scattered throughout the supratentorial
region. The lesions principally occupy the
white matter, but some cortical
involvement is also present. Probable
restrictive diffusion was noted, with
definitive enhancement (not shown).
C: T2-weighted MRI scan performed
hours prior to demise shows even more
extensive white matter lesions; these
proved to be white matter infarctions
devoid of intravascular tumor cells at the
time of autopsy. D: FLAIR (pictured),
diffusion, and post-contrast images prior
to demise are similar in appearance to the
MRI performed soon after diagnosis,
despite the absence of tumor cells at
autopsy. E and F: Coronal brain autopsy
sections at the level of the mamillary
bodies (E) and occipital horns (F) showed
no mass lesions or hemorrhages,
although obvious abnormalities of the
white matter were seen bilaterally in the
cerebral white matter as grayish areas of
partial cavitation, indicative of multifocal
white matter infarctions (arrows).
(A)
(B)
(C)
(D)
(E)
(F)
(G)
(H)
Figure 31.5. Intravascular lymphoma. A:
Low-power photomicrograph of the
pre-mortem brain biopsy revealed that
vessels of all sizes were packed with
lymphoma cells; lymphoma was confined
to the intralumenal space. Hematoxylin
and eosin (H&E) stain. B: Medium-power
photomicrograph shows that even
individual small capillaries contained
single lymphoma cells; no infarction of
surrounding brain was found on the small
biopsy sections (H&E stain). C: High-power
photomicrograph illustrates the extreme
cytological atypia of the individual
lymphoma cells within blood vessels (H&E
stain). D: These cells, including those in
capillaries, were highlighted by their
strong immunoreactivity for CD20 (CD20
immunostaining for B-cell lymphocytes,
with light hematoxylin counterstain).
E: Whole-mount section of the cerebral
white matter discloses the discrete white
matter areas of pallor and infarction (H&E
stain). F: Whole-mount section of the
lower spinal cord revealed multifocal
areas of infarction, correlating with the
patient’s lower extremity weakness noted
in life (luxol fast blue-periodic acid Schiff
stain for myelin). G: On lower power
microscopic sections, infarcted white
matter lesions could be recognized by
their vacuolization, partial cavitation, and
pallor (upper left in photograph; H&E
stain). H: On high-power magnification,
nearby blood vessels (seen at low power
in block G) contained no residual
intralumenal lymphoma cells after the
patient’s chemotherapy treatment. Only
reactive, perivascular non-neoplastic
lymphocytes remained at autopsy near
the infarcts.
Section I
Structural and Functional Neuroanatomy
Chapter
Executive function
16
David B. Arciniegas
Executive function refers to a complex set of processes
that manage and control other, relatively basic, cognitive functions [1, 2] and that support purposeful goaldirected behaviors [2–5]. These processes are engaged
most fully when confronting novel problems or situations for which no previously established routines exist
[5, 6]. By facilitating pattern identification, strategy
development, and problem solving, executive function
enables an individual to respond flexibly and adaptively to the environment, to develop goals and anticipate their consequences, and to direct cognition, emotion, and behavior in the service of goal attainment
[7, 8].
The broad anatomic areas contributing to the networks upon which executive functions are predicated
render them vulnerable to disruption by many conditions affecting the brain [2, 9–17]. When the function
of these networks is compromised, executive dysfunction ensues. This dysfunction may manifest as limited
conceptualization and abstraction, cognitive inflexibility, impaired control of attention, working memory, declarative memory, language, praxis, calculation,
and visuospatial function and other cognitive abilities, impaired decision-making and judgment (including impulsivity, disinhibition, and carelessness), difficulty setting goals, organizing, maintaining, and shifting plans, and difficulty with error detection and correction [5].
Deficits in executive function compromise an individual’s ability to meet the demands of everyday life
in a flexible and adaptive manner, even when basic
cognitive functions are relatively preserved [18–20].
Accordingly, an understanding of the phenomenology
and neuropathophysiology of executive function and
dysfunctions is required of subspecialists in Behavioral
Neurology & Neuropsychiatry (BN&NP) [21]. Toward
that end, this chapter reviews conceptual issues and
definitions of executive function. It is argued that executive function is a multidimensional construct and it is
suggested that subspecialists in BN&NP regard executive function principally as a cognitive domain. The
neuroanatomy and neurochemistry of executive function is reviewed, beginning with early formulations of
frontal lobe functioning and ending with a description
of the distributed neural networks supporting executive function. Finally, neuropsychological tests and
bedside assessments of executive function are identified and discussed briefly.
Conceptual issues and definitions
The referents of executive function offered in the medical and psychology literatures are diverse [5, 22] and
consensus is lacking on a definition of this cognitive domain [2, 5, 22]. Royall et al. (2002) [2], writing on behalf of the American Neuropsychiatric Association Committee on Research (ANPA CoR), suggest that the historical foundations for the concept
of executive function derive from the application of
systems engineering descriptions of the 1960s to the
study of human cognitive processes [23] and the seminal analyses of higher cortical function performed by
Luria [24, 25]. Among the earliest and clearest descriptions of this area of cognition is Luria’s (1962) [24]
characterization of the prefrontal cortices as regions
of the brain responsible for integrating and attaching
informative or regulatory significance to selected elements of incoming stimuli (i.e., establishing “the provisional basis of action”). He suggested that this information is processed “with the intimate participation of
the frontal lobes” in a manner that fosters “complex
Behavioral Neurology & Neuropsychiatry, eds. David B. Arciniegas, C. Alan Anderson, and Christopher M. Filley.
C Cambridge University Press 2013.
Published by Cambridge University Press. 225
Section I: Structural and Functional Neuroanatomy
programs of behavior; the constant monitoring of the
performance of these programs and the checking of
behavior with comparison of actions performed and
the original plans; [and] the provision of a system of
“feedback” on the basis of which complex forms of
behavior are regulated” (translated in [26], p. 248).
This system was conceptualized as supporting the
“general organization of behavior” [26] through programming, regulation, and verification [25].
Over the following decades, general descriptions
of executive functions arose in the context of theories describing the psychological mechanisms and
cerebral loci of control over specific cognitive processes. Norman and Shallice (1986) [6, 27] described
a “supervisory system” for attentional control (i.e.,
executive control of attention) that is used in situations in which routine or automatic processes are
inadequate (contention scheduling). Building upon
the filter model proposed by Broadbent (1958) [28],
it was suggested that the supervisory attentional system facilitates target selection from amongst multiple
competing inputs, monitors for and corrects errors,
and resolves response conflicts. Posner and Rothbart
(1998, 2009) [29, 30], reviewing the literature on attention and self-regulation from a developmental perspective, extended this view to include effortful control
of mental events (i.e., a category of mental events that
is contrasted with those that are automatically, or nonvolitionally, activated by internal or external stimuli).
The concept of a supervisory (executive) system subsequently expanded to encompass cognitive processes
responsible for supplanting automatic responses with
strategies necessary for volitional goal-directed behavior, especially in novel or complex circumstances, and
for monitoring their effectiveness [5].
Baddeley (1986) [31] posited a role for a “central executive” that regulates and manipulates information held in working memory (i.e., the phonological loop, the visuospatial “sketchpad,” and the episodic
buffer that integrates short- and long-term memory).
Mesulam (2000) [32] suggests that the role of the central executive applies most directly to the volitional
manipulation of information held in working memory,
reflecting the “top-down” influence (i.e., supramodal
role) of lateral prefrontal cortices on the orchestration of working memory in all domains of information
processing. The referent of the central executive was
subsequently clarified by Stuss and Alexander. (2007)
[33] as several separate processes: facilitation (energizing) of neural systems involved in decision-making
226
(contention scheduling), response initiation, monitoring of task activity and timing (e.g., error detection),
and adjustment of behavior.
In the context of developing a conceptual model
of attention-deficit hyperactivity disorder, Barkley
(1997) [34] integrated definitions of executive function offered by others [35–38]. He suggests that
executive function comprises self-directed (cognitive)
actions, the organization of behavioral contingencies
across time, the use of self-directed speech, rules, or
plans, deferred gratification, and goal-directed, futureoriented, purposive or intentional actions.
These domain- or condition-specific control
functions form the background for broader, albeit
still cognitively focused, models of executive function.
Zelazo et al. (1997) [39] describe executive function as a macro-construct that spans four phases of
problem solving: representation, planning, execution,
and evaluation. Similarly, the American Psychiatric
Association (1994, 2000) [40, 41] describes executive
function as involving conceptualization (i.e., thinking
abstractly) and the ability to plan, initiate, sequence,
monitor, and stop complex behavior. Miyake et al.
(2000) [42] describe executive function as the processes involved in the continuous monitoring and
modification of information in working memory
(updating), the capacity to supersede automatic
responses (inhibition), and the capacity to flexibly
alternate between different tasks or mental states
(shifting). Baron (2004) [8] suggests that executive functions are metacognitive capacities that
facilitate stimulus perception, adaptive responding,
flexibility (i.e., changing responses), anticipating
future goals and consequences integrating responses
rationally, and using such capacities to achieve
goals.
More recently, Banich (2009) [43] described executive function as a multidimensional construct encompassing the set of abilities required to guide effortful behavior toward a goal in non-routine situations.
These abilities include prioritizing and sequencing
behavior, inhibiting familiar or stereotyped behaviors,
generating and maintaining an attentional set focused
on contextually relevant information, providing resistance to distracting or task-irrelevant information,
switching between goals, using information in the service of decision-making, categorization and abstraction, and managing novel information and/or situations. These executive functions are organized into a
“cascade-of-control” model involving four distinct and
Chapter 16: Executive function
interactive information-processing steps mediated by
discrete prefrontal cortices: establishing a bias toward
task-relevant processes, biasing to task-relevant representations, selecting information that guides responding, and evaluating responses.
The concept of executive function, or at least
the language used to describe it, sometimes extends
beyond cognition to include volition [4], initiation
[2, 44], emotional evaluation and regulation [45–47],
insight [48–53] and theory of mind (i.e., insight into
thoughts and feelings of other people) [47, 54, 55]. For
example, Lezak (1995, 2004) [4, 56] suggests that there
are at least four general components of executive function: volition, planning, purposive active, and effective
performance. In this view, executive function explains
not “what” or “how much” an individual does something (e.g., a cognitive task, a behavior) but instead
“whether” and “how” it is done. Royall et al. (2002)
[2] suggest that this simple dichotomy usefully divides
the broad array of cognitive, emotional, and behavioral
functions in which prefrontal systems participate into
executive and non-executive types.
A more recent multi-perspective approach undertaken by Packwood et al. (2011) [22] reviewed 60 studies on executive function. Although all of the studies reviewed purported to study “executive function,”
the authors identified 68 sub-components (i.e., specific
processes) referred to by this term. Latent semantic
analysis (to account for semantic overlap) and hierarchical cluster analysis (to account for psychometric
overlap) reduced the referents of executive function to
18 clusters of clinically identifiable processes and abilities (Table 16.1). They suggested that this relatively
large number of abilities comprising executive function reflects a tendency in the clinical neuropsychological literature to rest definitions of executive functions on behaviors (or deficits) revealed by test performances. Even if these 18 clusters can be organized
into a smaller number of core abilities, such as those
described by Lezak [4, 56], this analysis makes clear
that executive function is not a unidimensional construct – i.e., there is no single “central executive” or
simple homunculus-like supervisory system [22, 33,
46, 57].
Defining executive function for
clinical practice
The cognitive neuroscience literature, from which
much of the preceding review is drawn, takes a broad
Table 16.1. Clusters of executive functions and their
constituents as described by Packwood et al. (2011) [22].
Cluster
Elements
1
Working memory, efficient retrieval of works from
memory, temporal coding, concentration,
performing a sequence of actions
2
Strategy generation, conceptualization,
attentional set formation, set maintenance
3
Executive memory (as demonstrated by verbal
and non-verbal fluency tasks)
4
Goal-setting, “central executive” function
5
Impulsivity
6
Initiation
7
Inhibition, interference control, response control,
mental control, visual search, sustained attention
(vigilance)
8
Freedom from/resistance to distraction
9
Problem solving, controlling actions
10
Planning/goal management, developing a plan,
executing a plan
11
Organization
12
Strategy use, self-generative behavior,
self-monitoring, selective attention, set shifting,
attentional control (shifting attention),
cue-directed attention
13
Cognitive flexibility
14
Concept formation
15
Abstraction
16
Spontaneous verbal formation, fluency, response
generation, response control (i.e., response
suppression, response modulation), verbal
efficiency
17
Information processing, sequencing
18
Perseveration, reasoning
view of executive function. By many of these accounts
[2, 4, 22, 29, 30, 34, 44–47], initiation, emotional regulation, comportment, and behavioral control all fall
within the category of executive function. For academic purposes (i.e., studying information processing
and control systems in theory and in the human brain),
such a broad view of executive function is useful to the
extent that it facilitates identification of general mechanisms of control over information processing in the
human brain.
Clinicians, especially subspecialists in BN&NP,
also recognize that cognitive control processes
contribute to emotional and behavioral regulation.
However, regulation of non-cognitive functions is
227
Section I: Structural and Functional Neuroanatomy
conceptualized [58–64] and assessed separately from
cognition [65–69]. Similarly, cognitive impairments
commonly co-occur with disturbances of emotion and
behavior, but disturbances of emotion and behavior
(e.g., disorders of motivation, disorders of mood and
affect, impaired comportment, impulsivity, agitation,
aggression) are diagnosed separately from cognitive
disorders, including the dysexecutive syndrome [14,
41, 70, 71].
In clinical practice, executive function is regarded
as a cognitive domain, understood to be a multidimensional (i.e., non-unitary) construct, and assessed separately from emotion and behavior [41, 72–75] (see
Chapter 23). Within the domain of executive function are complex sets of cognitive processes involved in
the management and control of other, relatively basic,
aspects of information processing. These processes
and their outcomes support purposeful goal-directed
behaviors, especially those required to address novel
problems or situations for which no previously established routines exist, and interact with the processes
and outcomes of systems involved in the regulation of
emotion and behavior.
The merits of “splitting” control processes into cognitive (i.e., executive) and non-cognitive (i.e., emotional and behavioral) types are debatable and are subjects of disagreement within and between researchers
and clinicians. Additional theoretical and experimental research is needed to determine whether a unified account of cognitive, emotional, and behavioral
control process in the human brain is tenable [2, 22,
43, 75]. Since a widely accepted, theoretically comprehensive, and experimentally supported account that
integrates control processes across cognition, emotion,
and behavior is not available presently, executive function is considered in this chapter and volume to be a
domain of cognition.
Neuroanatomy of executive function
There is a longstanding tradition amongst clinicians
and neuroscientists of attributing executive function
to the frontal lobes, describing them as “frontal lobe
functions,” and referring to their disturbances as
“frontal lobe syndromes” or “frontal lobe disorders”
[2, 9, 20, 24, 26, 32, 43, 75, 76]. Neuroanatomic and
neuroimaging studies performed over the last several decades suggest that this tradition requires reconsideration. Executive function requires the integrated
actions of the frontal-subcortical circuits, open-loop
228
connections to other neocortical areas, limbic and
paralimbic structures, thalamic nuclei, pontocerebellar networks, modulatory neurochemical projections
from mesencephalic and ventral forebrain structures,
and the white matter connections within and between
all of these areas [2, 32, 75, 77–80] (see also Chapter 5). As such, executive dysfunction is more accurately understood as dysfunction within or across
these networks [81]. Understanding this revised view
of the neuroanatomy of executive function necessitates
reviewing briefly the history of ideas on this subject
and findings from modern neuroanatomic studies.
Early observations on frontal function
In his review of disturbances associated with lesions of
the frontal region, Luria (1962, 1980) [24, 26] credits
Gratiolet (1861) [82] with first describing the frontal
lobes as the site of the “regulating mind.” He then
describes decades of research in the late 1800s and
early 1900s involving stimulation and extirpation of
the frontal lobes in animals, and identifies Jackson
[83], Bianchi [84, 85], Bekheterev [86], and Pavlov
[87] as key contributors to the foundation upon which
modern views of the neuroanatomy of executive function rests.
Jackson (1884) [83] identified the prefrontal
regions as the highest and most complex motor
centers that indirectly represent movements of all
parts of the body. Bianchi (1895, 1920) [84, 85],
through ablation studies of animals, identified the
role of the frontal lobes in coordinating motor and
sensory elements, using the products of the sensory
zones to create mental syntheses (i.e., integrative
function), and relate to sensorimotor zones in the
same manner that motor systems relate to subcortical
nuclei. He observed that bilateral extirpation (i.e.,
lesion or resection) of the frontal lobes results in
behavioral disorganization and lack of adaptation to
new conditions.
Bekhterev (1907) [86], summarizing observations
begun in the 1880s, observed disintegration of goaldirected behavior following extirpation of the frontal
lobes, including loss of the regulatory activity required
to correctly evaluate external impressions and purposively direct movements in accordance with the evaluation. Pavlov (1949) [87], through studies involving extirpation of the frontal lobes in dogs, regarded
the prefrontal cortices as integrators of goal-directed
movement. He introduced the concept of the “motor
Chapter 16: Executive function
analyzer,” referring to the cortical motor areas that
served as an afferent analyzing apparatus of impulses
received from all other parts of the brain, especially
the kinesthetic signals providing information on the
course of a movement and its effects. He regarded the
frontal lobes as an essential component, and the most
complex aspect, of the cortical division of the motor
analyzer and hypothesized that they facilitate the selection of goal-directed movements.
Pavlov’s concept of a “motor analyzer” informed
subsequent works (summarized in [24, 26]) on the
regulatory functions served by the prefrontal cortices. These works identified the prefrontal cortices as
subserving complex forms of motor operations and
the evaluating of the effects of action, and suggested
that their destruction precludes selective goal-directed
behavior. The works of Gratiolet (1861) [82], Jackson
(1884) [83], Bianchi (1895, 1920) [84, 85], Bekhterev
(1907) [86], Pavlov (1949) [87] and other investigators [24, 26] established the importance of the prefrontal cortices in the integration, coordination, and
inhibitory functions as well as evaluation (i.e., selfobservation) of movements and bodily activities.
Prefrontal cortices
Luria (1962, 1980) [24, 26] emphasized connections
between prefrontal cortices and other areas as illuminating their role in the functional organization of the
cerebral hemispheres. He anchored his review of the
functional anatomy of the prefrontal cortices to the
work of Brodmann (1909, 1914) [88, 89] (Figure 16.1).
He recognized that the prefrontal divisions of the cortex differ in a number of respects from the motor and
premotor areas, including the structure of the second
and their association layers, in which giant pyramidal Betz cells are absent (Figure 16.2), as well as the
system of vertical connections between the prefrontal
divisions of the cortex and the thalamus. He identified
Brodmann’s areas (BA) 9, 10, 11, 24, 44, 45, and 46 as
subdivisions of the prefrontal cortices possessing specific afferent-efferent conn