Connectomic-Guided Radiosurgical Thalamotomy for Chronic Pain

British Journal of Neurosurgery
ISSN: 0268-8697 (Print) 1360-046X (Online) Journal homepage: www.tandfonline.com/journals/ibjn20
Individualised connectomic-guided radiosurgical
thalamotomy for chronic pain
Eduardo Lovo, Flavia Venetucci Gouveia, Jurgen Germann, William Omar
Contreras, Eduardo Joaquim Lopes Alho, Claudia Cruz & Luis BermúdezGuzmán
To cite this article: Eduardo Lovo, Flavia Venetucci Gouveia, Jurgen Germann, William Omar
Contreras, Eduardo Joaquim Lopes Alho, Claudia Cruz & Luis Bermúdez-Guzmán (08 Sep 2025):
Individualised connectomic-guided radiosurgical thalamotomy for chronic pain, British Journal
of Neurosurgery, DOI: 10.1080/02688697.2025.2557210
To link to this article: https://doi.org/10.1080/02688697.2025.2557210
© 2025 The Author(s). Published by Informa
UK Limited, trading as Taylor & Francis
Group.
Published online: 08 Sep 2025.
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BRITISH JOURNAL OF NEUROSURGERY
https://doi.org/10.1080/02688697.2025.2557210
SHORT REPORT
Individualised connectomic-guided radiosurgical thalamotomy for chronic
pain
Eduardo Lovoa, Flavia Venetucci Gouveiab, Jurgen Germannc, William Omar Contrerasd, Eduardo Joaquim
�dez-Guzm�ang,h
Lopes Alhoe, Claudia Cruzf, and Luis Bermu
a
Neurosurgery, Gamma Knife Program, International Cancer Center, Diagnostic Hospital, San Salvador, El Salvador; bNeuroscience and
Mental Health, Hospital for Sick Children, Toronto, Canada; cCenter for Advancing Neurotechnological Innovation to Application
(CRANIA), Krembil Brain Institute, Toronto, Canada; dInternational Neuromodulation Center-NEMOD, UNAB University, Bucaramanga,
Colombia; eNeurocirurgia, Cl�ınica de Dor e Funcional, S~ao Paulo, Brazil; fAlgology, Pain Management Program, International Cancer
Center, Diagnostic Hospital, San Salvador, El Salvador; gCancer Research UK Cambridge Institute, University of Cambridge, Cambridge,
UK; hRobotic Radiosurgery Center, Costa Rican Oncology Center, San Jos�e, Costa Rica
ABSTRACT
ARTICLE HISTORY
Introduction: Radiosurgery targeting the thalamus has long been used to treat refractory
pain, with medial thalamotomy as a key approach. Traditionally, targeting relied on indirect
methods based on anatomical atlases, which do not account for individual variations in
brain connectivity. Recent advances in connectomic-guided stereotactic radiosurgery have
improved precision in the treatment of movement disorders, but their application to pain
management remains underexplored. This study evaluates the feasibility of connectomicguided radiosurgery for refractory pain using Brainlab Elements, integrating autosegmentation and manual contouring for patient-specific planning.
Methods: We analysed the thalamic target’s structural and functional connectivity using the
FMRIB Software Library and Advanced Normalisation Tools. The region of interest (ROI) was
mapped using diffusion tensor imaging and functional magnetic resonance imaging to
assess connectivity with pain-processing structures, including the periventricular grey (PVG)
and ventroposteromedial (VPM) nucleus. Connectivity analysis was performed with Brainlab
Elements and validated against independent connectomic studies. Dose-volume relation­
ships for PVG and VPM were retrospectively assessed in patients treated with radiosurgery
for chronic pain.
Results: Connectivity analysis showed that fibres within the ROI extend to primary motor
(M1) and sensory (S1) cortices, while descending fibres reach the periaqueductal gray (PAG).
Functional connectivity linked the ROI to key pain-processing regions, including the pre­
frontal cortex, insula, amygdala, and cerebellum. Retrospective dose-volume (DVs) analysis
revealed clear differences between the volumes receiving more than 20 Gy in the original
vs connectomic-based target. . The integration of Brainlab Elements facilitated connectomicguided targeting, enabling a patient-specific approach to radiosurgery.
Conclusion: Connectomic-guided radiosurgery is a feasible approach that enables precise,
patient-specific targeting pain management. Auto-segmentation of PVG and VPM allows
dose-volume assessment, potentially correlating with clinical outcomes. Standardising
connectomic-guided planning may enhance radiosurgical precision and support future clin­
ical research in refractory pain.
Received 13 May 2025
Revised 22 July 2025
Accepted 2 September 2025
Introduction
Radiosurgical thalamic targeting for refractory pain
dates back to Lars Leksell’s development of the
Gamma Knife.1 Traditional medial thalamotomy, typ­
ically involving the centromedian and parafascicular
CONTACT Luis Berm�udez-Guzm�an
Costa Rica
[email protected]
KEYWORDS
Connectomic-guided radio­
surgery; thalamotomy;
refractory pain; diffusion
tensor imaging (DTI)
complex, has been well-documented and used both
unilaterally and bilaterally for managing oncological
and non-oncological pain. Recently, its application has
expanded to include refractory trigeminal neuralgia,
chronic facial pain, and other neuropathic pain syn­
dromes, although the outcomes vary.2–9
Robotic Radiosurgery Center, Costa Rican Oncology Center, San Jos�e,
� 2025 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.
This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License (http://creativecommons.org/licenses/bync-nd/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited, and is not altered, transformed,
or built upon in any way. The terms on which this article has been published allow the posting of the Accepted Manuscript in a repository by the author(s) or with their
consent.
2
E. LOVO ET AL.
Despite these advances, all of these procedures have
relied on indirect anatomical targeting, localising
structures based on standard atlases, predefined
stereotactic coordinates, or anatomical landmarks.
This method does not account for interindividual ana­
tomical variability and does not incorporate functional
connectivity data, limiting its precision. Unlike inva­
sive procedures such as deep-brain stimulation or
high-intensity focused ultrasound, radiosurgery does
not allow for real-time physiological validation. A
more patient-specific targeting strategy is therefore
essential to improve precision and clinical efficacy.
Recent advances in functional and structural neuro­
imaging now permit the use of each patient’s unique
brain-connectivity maps to guide stereotactic plan­
ning. One pioneering application (recently introduced
for tremor treatment) retrospectively identified an
optimal lesion ‘sweet spot’ by correlating clinical out­
comes with connectivity to the primary motor
cortex.10 While connectivity-based targeting is gaining
traction in movement disorders, its potential applica­
tion in pain management remains largely unexplored.
In our previous work, we evaluated the outcomes
of unilateral radiosurgical thalamotomy using indirect
targeting in a cohort of 14 patients with refractory
pain, reporting a long-term success rate of 50%.2 That
study also generated three-dimensional models of the
target region (using the S~ao Paulo-W€
urzburg Atlas of
the Human Brain) to suggest an initial coordinate set
(X: 4–4.5 mm, Y: 4 mm, Z: þ4 mm relative to the
anterior commissure-posterior commissure line).
While this provided a useful starting framework, it
did not leverage patient-specific connectivity data to
refine the target further.
Building on that foundation and our later observa­
tions that the 20 Gy isodose can overlap with the med­
ial dorsal parvocellular nucleus (MDpc) (which may
modulate the affective/cognitive dimensions of pain),5
we refined our targeting by lowering the Z coordinate
by 2 mm, optimising coverage of the centromedianparafascicular (CM-Pf) complex, which aligns approxi­
mately with the 0 mm Z-axis (relative to the anterior
commissure-posterior commissure line). This refine­
ment was guided by the concept of a neuromodulatory
‘area of influence’, corresponding to the 20 Gy isodose
line.11 This threshold was selected based on preclinical
studies demonstrating neuronal spiking and metabolic
activity alterations at subnecrotic radiation doses,12 as
well as empirical clinical observations.13
More recently, we have integrated Brainlab Elements
(Brainlab, Munich, Germany) into our Gamma Knife
workflow to enable automated PVG/PAG and VPM
segmentation, as well as fibre-tracking within the ROI.
Critically, the connectomic analyses presented here con­
firmed that the irradiated thalamic region projects not
only to the primary motor (M1) and sensory (S1) corti­
ces via the corticospinal tract, but also to descending
pathways targeting the periaqueductal and periventricu­
lar grey. In addition, projections were observed to a
broad corticolimbic network, including the somatosen­
sory and premotor cortices, prefrontal regions, insula,
temporo-occipital junction, and posterior cingulate,
highlighting the PVG/PAG as a key node in pain
modulation.
This technical report details the incorporation of
connectomic data into the refinement of thalamic
radiosurgical targeting for pain, describing our current
patient workflow, connectivity analyses, and updated
targeting methodology. Additionally, we provide retro­
spective dose-volume comparisons for target struc­
tures, with radiation doses ranging from 100 to
140 Gy, which have demonstrated clinical efficacy2,5,6
in various forms of refractory pain, hopefully provid­
ing preliminary reference points for future target
adjustments based on such parameters.
Methods
Structural connectivity analysis
ROI segmentation and normalisation
Starting from the post-operative MRI of a patient
treated with a 140 Gy thalamotomy for pain, we first
segmented the contrast-enhancing lesion (the target
ROI) using FMRIB Software Library tools. This ROI
was then normalised to standard space (ICBM 2009b
NLIN asymmetric) using transformations derived
from rigid post-to-pre-operative image alignment and
full non-linear pre-operative to Montreal Neurological
Institute (MNI) space registration with Advanced
Normalisation Tools.
Tractography and fibre density mapping
Brain-wide structural connectivity was examined using a
12 million-fibre whole-brain tractography template. All
streamlines intersecting the ROI were identified, and
fibre density maps were generated and compared to the
XTRACT Human Connectome Project Probabilistic
Tract Atlas.
Functional connectivity analysis
Resting-State fMRI processing
Functional connectivity was assessed via resting-state
fMRI by analysing blood oxygen level-dependent
BRITISH JOURNAL OF NEUROSURGERY
(BOLD) signal correlations between the ROI and other
brain voxels. A whole-brain r-map was produced, con­
verted into a t-map using the known p-distribution,
and corrected for multiple comparisons (p < 0.05,
whole-brain voxel-wise Bonferroni correction).
Alternative connectivity analysis approach
ROI definition and ellipsoid generation
Based on the same data set from the MRI used for
structural connectivity analysis, the ROIs were defined
in MNI space by transforming stereotactic coordinates
into MNI (ICBM 152) coordinates (x ¼ ±4 mm, y ¼
−20 mm, z ¼ þ2 mm). A customised Python script
was used to generate ellipsoid ROIs based on the
diameters of the 50% isodose curve of the prescription
dose and the isodose line corresponding to 20 Gy.
These ROI masks were imported into DSI Studio soft­
ware (https://dsi-studio.labsolver.org/), where a group
connectome template, constructed from 1021 subjects,
was used for analysis.
Data acquisition and reconstruction
A multishell diffusion scheme was implemented with
b-values of 990/1985/2980 s/mm2, each with 90 diffu­
sion sampling directions. Imaging was acquired at an
in-plane resolution and slice thickness of 1.25 mm.
Diffusion data were reconstructed in MNI space using
q-space diffeomorphic reconstruction to obtain the
spin distribution function, employing a diffusion sam­
pling length ratio of 2.5 and an output resolution
of 1 mm.
Deterministic fibre-tracking
A deterministic fibre-tracking algorithm, incorporating
augmented tracking strategies, was used to enhance
reproducibility. Parameters included a randomly
selected anisotropy threshold between 0.5 and 0.7 (Otsu
threshold) and an angular threshold between 45� and
90� . Tracks shorter than 30 mm or longer than 200 mm
were excluded, with a total of 1,000,000 seed points
placed for tractography.
Connectivity-based treatment planning &
workflow
Pre-treatment imaging
One day before treatment, patients underwent axial T1weighted gadolinium-enhanced MRI (1 mm slice thick­
ness, no spacing), diffusion tensor imaging (DTI), and a
1-mm axial T2-weighted sequence covering the thalamic
region (from the corpus callosum to the trigeminal
3
nerve). Imaging was performed using a 1.5 Tesla
Siemens Avanto MRI scanner (Siemens, Erlangen,
Germany). A standard diagnostic computed tomography
(CT) scan of the head is also acquired with 1 mm slice
thickness.
Segmentation and co-registration
Connectivity planning using Brainlab Elements (https://
www.brainlab.com/) enabled clinical verification of the
ROI with patient-specific connectomics based on DTI
tract reconstruction. This process included automatic
segmentation of key anatomical structures such as the
PVG/PAG, VPM, M1, S1, amygdala, and cerebellum, as
well as manual contouring of the insular lobes.
Image fusion and distortion correction
On the day of treatment, we first aligned the planning
MRI and CT using Elements Image Fusion. We then
co-registered the DTI to the T1-weighted MRI and
ran Elements Distortion Correction Cranial, which
compares the MRI against the CT to flag any geomet­
ric distortions greater than 1 mm within the thalamic
volume. Although distortions above this threshold
were detected, we did not apply the correction, opting
instead to use the T1-weighted MRI as our distortionfree reference for all DTI and diffusion-weighted
sequences used in subsequent fibre tracking.
Treatment setup and verification
Using Elements Trajectory Planning, all images were
aligned to the anterior commissure-posterior commis­
sure (AC-PC) line. In the Elements Basal Ganglia
Atlas, auto-segmented structures (including the PVG/
PAG, VPM, M1, S1, amygdalae, and cerebellum) were
selected. Additional regions of interest (ROIs), such as
the insula, orbitofrontal cortex (OFC), and superior
frontal gyrus (SFG), were manually contoured. Small
ROIs were then placed bilaterally between the PVG
and VPM at 2 mm above the AC-PC line. These were
labelled as the left and right planning target volumes
(PTVs), although no specific volumes were defined at
this stage, as these ROIs served solely as connectivity
seeds.
In Elements FiberTracking, specific ROI combina­
tions were used to generate distinct connectivity
maps: OFC þ PVG, representing the descending pain
pathway; PVG alone, showing projections to the OFC
and M1; SFG þ ipsilateral PTV, or SFG alone, illus­
trating the medial pain pathway; M1 þ S1 þ VPM,
highlighting the lateral spinothalamocortical pathway;
PVG þ PTV þ VPM, providing a comprehensive con­
nectivity map of the target region.
4
E. LOVO ET AL.
The connectomic-defined target was identified at
the thickest and most central portion of the medial
spinothalamic tract, and its coordinates were recorded
for treatment planning. Once all imaging data and
segmentations were transferred to GammaPlan (GP),
the left and right PTVs, PVG/PAG, and VPM were
registered to the patient’s profile. The AC-PC line was
marked in GP, and functional targets were incorpo­
rated using the coordinates derived from Elements
software.
Dose prescription varied by clinical indication:
140 Gy (unilateral) or 120 Gy (bilateral) for benign
conditions such as chronic facial or neuropathic pain,
and 90 Gy (under a triple-strategy protocol) for onco­
logical pain, ensuring that the 20 Gy isodose line
encompassed part of both the PVG and VPM.
After final approval, the patient is positioned in the
GK suite, and a ‘time-out’ is conducted to confirm
identity, pathology, treatment team, and correct place­
ment of the Vantage frame (Elekta, Stockholm, Sweden)
under local anaesthesia. The patient is positioned at a
90� angle in the trunnion, and High-Definition Motion
Management is activated to halt treatment in the event
of frame slippage or cranial movement >1 mm.
A cone-beam CT scan is acquired and co-registered
to the planning CT. The neurosurgeon, radiation
oncologist, and physicist verify alignment before treat­
ment initiation. Following treatment, the frame is
removed, and patients are discharged with instructions
to take paracetamol (500 mg-1 g every 8 hours) for any
discomfort at pain sites. Patients maintain their base­
line pain medications and are followed daily for 15
days, then every 15 days thereafter to assess treatment
response.
somatosensory and premotor cortices, medial and
dorsolateral prefrontal cortices, insula, temporo-occipital
junction, and posterior cingulate cortex (Figure 1(C)).
These connectivity patterns align with our radiosurgi­
cal targeting strategy, which focuses on the parvocellular
section of the VPM nucleus and the centromedianparafascicular (CM-Pf) complex in the medial thalamus,
both implicated in relaying sensory signals related to
pain perception. We ensure that these regions receive
radiation doses exceeding 20 Gy within the treatment
zone, aiming to modulate thalamic activity and relieve
chronic pain. The convergence of anatomical, functional,
and treatment-planning data reinforces the ROI as a
therapeutically relevant target for pain management.
To further validate the targeting accuracy and net­
work engagement, we conducted a complementary
tractography-based analysis using the 20 Gy isodose
line volume as a seed. This analysis identified a total
of 1483 fibre tracts (Figure 2), with the majority pro­
jecting to the superior frontal gyrus (SFG; 669 tracts),
followed by the lateral orbital cortex (217 tracts), pars
orbitalis (60 tracts), pars triangularis (49 tracts), and
pre-central gyrus (M1) (26 tracts). Notably, no fibres
reached the post-central gyrus (S1). A more stringent
analysis using the inner 50% isodose level of 140 Gy
yielded 772 tracts, again showing dominant connectiv­
ity to the SFG (306 tracts), with additional projections
to the lateral orbital cortex (129 tracts) and pars orbi­
talis (39 tracts). These findings provide additional sup­
port for the functional integration of the target ROI
within pain-relevant cortical networks.
Results
Building on these anatomical and tractographic findings,
we translated connectivity insights into the clinical work­
flow through connectivity-guided treatment planning
and dose-volume analysis. One day before radiosurgery,
patients underwent axial T1-weighted gadoliniumenhanced MRI (1 mm slice thickness, no spacing), diffu­
sion tensor imaging (DTI), and a 1-mm axial T2weighted sequence covering the thalamic region (from
the corpus callosum to the trigeminal nerve). Integration
of Brainlab Elements into the clinical pipeline enabled
patient-specific connectomic validation of the ROI using
DTI-based tract reconstruction. Key pain-related struc­
tures (including the PVG/PAG, ventral posteromedial
nucleus (VPM), M1, S1, amygdala, and cerebellum) were
automatically segmented, with manual contouring per­
formed for additional regions such as the insula, orbito­
frontal cortex (OFC), and superior frontal gyrus (SFG).
Structural and functional connectivity analysis
Structural and functional connectivity mapping in stand­
ard space revealed that fibres originating from the target
region of interest (ROI) consistently extended to both
the primary motor cortex (M1) and primary sensory
cortex (S1) via the corticospinal tract (Figure 1(A)).
Additionally, descending projections, particularly M1,
were observed reaching the periaqueductal grey (PAG)
through the periventricular grey (PVG). Fibre density
maps (Figure 1(B)) confirmed strong white matter con­
nectivity with these regions, supporting the anatomical
relevance of the selected ROI in pain modulation.
Functional connectivity analysis further demonstrated
robust connections between the ROI and several cortical
and subcortical structures, including the cerebellum,
Connectivity-guided treatment planning and dosevolume analysis
BRITISH JOURNAL OF NEUROSURGERY
5
Figure 1. ROI and Structural and Functional Connectivity Analyses. (A) The target ROI (red) is shown in axial, coronal, and sagittal
views. (B) Structural connectivity analysis reveals fibres extending from the ROI (blue), travelling via the corticospinal tract, and
reaching the PAG. (C) Functional connectivity analysis identifies the cerebellum and multiple cortical areas as functionally con­
nected to the ROI. The lesion ROI and connectivity maps are overlaid on a high-resolution MRI template in MNI space.
Abbreviations: ROI: region of interest; PAG: periaqueductal grey; mPFC: medial prefrontal cortex; dlPFC: dorsolateral prefrontal cor­
tex; MNI: Montreal Neurological Institute.
PVG/PAG segmentation enabled dose-volume quantifica­
tion of the radiosurgical shot, while delineation of other
structures contributed critical data for refining treatment
parameters using the Gamma Knife Icon system and
GammaPlan.
To guide targeting within functionally relevant pain
networks, connectivity maps were generated to iden­
tify three principal pathways: the descending pain
pathway (PVG ¼ OFC þ M1), the lateral pain pathway
(M1 þ S1 þ VPM), and the medial pain pathway
(SFG þ ipsilateral planning target volume), providing
a comprehensive, patient-specific connectivity map to
support precise dose delivery (Figure 3).
To further enhance treatment precision, we refined
the initial target coordinates based on connectivity
data. Anatomically, the refined target aligns with the
thickest and most central portion of the medial
spinothalamic tract bundle, anchoring the isocentre
coordinates used during treatment (Figure 4(A)). After
image acquisition and segmentation, all relevant struc­
tures, including the left and right planning target vol­
umes (PTV), PVG/PAG, and VPM, are transferred
and registered within the GammaPlan system under
the patient’s profile. The anterior commissureposterior commissure line is defined, and functional
targets are added using connectomic-based coordinates
derived from Brainlab Elements (Figure 4(B)).
Dose prescription is adapted to clinical indication:
for benign conditions such as chronic facial or neuro­
pathic pain, a unilateral dose of 140 Gy or a bilateral
dose of 120 Gy is used; for oncological pain, a triplestrategy protocol of 90 Gy is applied. In all cases, the
20 Gy isodose line is shaped to encompass key struc­
tures within the PVG and VPM, ensuring optimal
6
E. LOVO ET AL.
Figure 2. A 3D Connectivity Analysis of the Radiosurgical Shot. (A) The shot is represented as a sphere from which fibres emanate,
with the SFG hidden to reveal connectivity to the OFC (pink). (B) The left pars orbitalis (light green) is included. (C) The SFG is dis­
played separately as the primary connectivity site. (D) All cortical connections related to the shot are visualised. Abbreviations: 3D:
three-dimensional; SFG: superior frontal gyrus; OFC: orbitofrontal cortex.
engagement of pain-modulating pathways (Figure
4(C,D)). Retrospective dose-volume analysis of a
patient treated for cancer pain revealed that this refine­
ment significantly increases the volume of the periaque­
ductal and periventricular grey (PVG/PAG) receiving
>20 Gy (Table 1).
After final approval, patients were positioned in
the Gamma Knife (GK) suite for treatment delivery
(Figure 5). A standardised ‘time-out’ procedure was per­
formed to confirm patient identity, pathology, and
correct placement of the Vantage frame (Elekta,
Stockholm, Sweden), applied under local anaesthesia.
Patients were aligned at a 90� angle within the trunnion,
and High-Definition Motion Management (HDMM)
was activated to automatically pause treatment in the
event of frame slippage or cranial motion exceeding
1 mm. A cone-beam CT scan was acquired and coregistered to the planning CT, allowing the neurosur­
geon, radiation oncologist, and physicist to verify align­
ment before treatment initiation. Following the
BRITISH JOURNAL OF NEUROSURGERY
7
Figure 3. Pathway generation in brainlab elements. (A) The OFC is manually delineated, while the PVG/PAG is auto-segmented.
These structures are added to the ‘Include Regions’ section, generating the descending pain pathway. (B) Lateral Spinothalamic
Tract Generation. The precentral and postcentral gyri (M1, S1) and the VPM are auto-segmented and selected in ‘Include Regions’,
automatically generating the lateral spinothalamic tract. (C) Medial Pain Pathway Generation. The SFG and a small region of inter­
est (PTV left) at 2 mm above the AC-PC line are manually drawn. The PVG/PAG and VPM are auto-segmented. These structures are
added to ‘Include Regions’, generating the medial pain pathway. D-E) Global connectivity from the ROI. Lateral 3D view of all fibres
extending from the ROI, which corresponds to a 5.6 mm diameter region at 2 mm above the AC-PC line, matching the 50% iso­
dose line (left). The same lateral view is shown, displaying all relevant structures involved in pain perception and regulation (right).
Abbreviations: M1: primary motor cortex; S1: primary sensory cortex; VPM: ventroposteromedial nucleus; 3D: three-dimensional.
OFC: orbitofrontal cortex; PVG: periventricular grey; PAG: periaqueductal grey. SFG: superior frontal gyrus; PTV: planning target vol­
ume; VPM: ventroposteromedial nucleus; AC-PC: anterior commissure-posterior commissure; ROI: region of interest.
procedure, the frame was removed, and patients were
discharged.
This patient-specific workflow enabled integration of
anatomical and connectivity data directly into the treat­
ment planning algorithm, refining coordinates for a fully
connectomic-driven targeting approach. Importantly, the
incorporation of PVG segmentation allowed for quantifi­
cation of dose-volume delivery to these key painmodulatory regions, an advancement not previously
feasible with standard radiosurgical protocols.
Verification of the clinical workflow showed that pretreatment imaging (MRI, DTI, CT) was successfully
fused and aligned to the AC-PC line, with geometric
distortion correction and co-registration ensuring accur­
ate spatial localisation. Intra-procedural assessments con­
firmed proper frame placement and minimal cranial
movement (<0.5 mm), validating the implementation of
refined target coordinates during GK treatment.
Collectively, both structural and functional connectivity
analyses confirmed that the region of interest (ROI)
8
E. LOVO ET AL.
Figure 4. Target Refinement in Brainlab Elements Trajectory Planning and GammaPlan Integration. (A) The refined target corre­
sponds to the thickest fibre bundle of the medial pain pathway (green), marked with an orange trajectory in sagittal and coronal
views, showing its relationship to the VPM and PVG. The tract is turned off to clearly visualise the coordinates before exporting to
GammaPlan (bottom part). (B) GammaPlan Integration. Axial, coronal, and sagittal screenshots of GammaPlan displaying AC-PC
alignment (green boxes) and imported elements from Brainlab software: VPM (red, lateral), PVG (blue, medial), and the expected
50% and 20 Gy isodose lines for a bilateral 4 mm, 90 Gy shot. Functional target selection in GammaPlan, with Brainlab-derived
coordinates marked by green crosshairs bilaterally, is also shown (bottom part). (C) Dose prescription Variations in gammaPlan.
Bilateral 4 mm shots prescribing 90 Gy DMax and Bilateral 4 mm shots prescribing 120 Gy DMax. (D) Unilateral shots prescribing
100 Gy and 120 Gy DMax, respectively. In all images, the outermost isodose line represents the 20 Gy threshold. Abbreviations:
VPM: ventroposteromedial nucleus; PVG: periventricular grey; AC-PC: anterior commissure-posterior commissure; PVG: periventricular
grey; DMax: maximum dose.
BRITISH JOURNAL OF NEUROSURGERY
9
Table 1. Retrospective calculation of dose-volume effects from connectomic target refinement in a patient treated with tripletarget radiosurgery for cancer pain.
Dose (Gy)
140
140
120
120
100
100
Coordinate
Original
Connectomic-based
Original
Connectomic-based
Original
Connectomic-based
PVG volume
receving
>20 Gy (cc)
0.012
0.023
0.009
0.021
0.007
0.018
% PVG receving
>20 Gy
50
96
39
89
27
76
Dmax
62.6
94
53.7
80.6
26
67
Median D
23
42
9
36
7.5
30
VPM volume
receving
>20 Gy (cc)
0.012
0.016
0.006
0.012
0.002
0.008
% VPM receiving
>20 Gy
12
15
6
11
2
7
Dmax
39
83
33.6
71
36.6
60
Median D
14
13.5
12.1
11.6
7.8
9.6
Abbreviations: PVG: Periventricular Gray; Dmax: Maximum dose; Median D: Median dose; VPM: Ventral posteromedial nucleus.
Figure 5. Patient positioning and motion tracking in gamma knife radiosurgery. (A) Frontal view of the patient with the Vantage
frame fixed to the skull and coupled to the trunnion at a 90� angle, with a CBCT scan in progress. A fiducial marker for HDMM is
placed on the patient’s nose. (B) Lateral view showing the Vantage frame, trunnion, and motion tracker. HDMM ensures movement
remains below 1 mm, typically <0.5 mm, throughout treatment. Abbreviations: CBCT: cone-beam computed tomography; HDMM:
high-definition motion monitoring.
maintains robust connections to pain-processing areas,
with the superior frontal gyrus (SFG) emerging as a pre­
dominant node. The connectivity-guided adjustment of
the Z coordinate improved dose distribution to the PVG/
PAG, enhancing modulation of pain pathways. The
revised, patient-specific workflow (incorporating advanced
segmentation, connectivity mapping, and dose-volume
quantification) underscores the potential clinical value of
a connectomic-guided radiosurgical strategy for chronic
pain management.
Discussion
Radiosurgical refinement in essential tremor has demon­
strated the value of combining anatomy with tractogra­
phy.12,14,15 Yet, thalamic radiosurgery for pain has
remained dependent on atlas-based, indirect targeting.
Pain engages a far more distributed and multilayered
network than tremor, and consensus on optimal radio­
surgical targets remains elusive. Most existing approaches
continue to rely on indirect atlas measurements, such as
the Schaltenbrand-Wahren microseries.2,3,7,8 Historically,
our own planning followed this convention, using sagittal
and axial placements derived from stereotactic atlases.
The functional and connectomic analyses presented here,
however, represent a pivotal shift: by mapping each
patient’s network, Brainlab Elements enables a move
from one-size-fits-all planning to truly individualised
treatment.
This shift is especially relevant in the context of
multiple-site targeting, a strategy increasingly explored
in pain radiosurgery. The principle first appeared in
post-herpetic trigeminal neuralgia, where three patients
received Gamma Knife treatment at two sites: 60–80 Gy
to the trigeminal nerve and 120–140 Gy to the centro­
median nucleus.4 Though preliminary, this series
10
E. LOVO ET AL.
illustrated that engaging both peripheral and central
nodes may enhance analgesia more effectively than
single-target approaches.
Our own experience supports this model. In a cohort
of 21 patients with chronic facial pain, we observed
rapid (>50% within seven days), dose-dependent relief
when the thalamus received 140 Gy, significantly out­
performing 120 Gy or lower, whereas trigeminal nerve
dosing showed no such correlation.6 This dual-target
strategy suggests that higher thalamic doses may more
effectively engage descending and lateral pain pathways
within the 20 Gy isodose ‘area of influence’. In contrast,
our recent triple-target approach for intractable cancer
pain used lower radiation doses (90 Gy) across the pitu­
itary and bilateral thalami, achieving substantial reduc­
tions in VAS scores and medication requirements, with
minimal side effects and improved quality of life.16
These findings highlight a critical insight: robust anal­
gesia may result from either higher doses to select
nodes or synergistic modulation across multiple circuits,
even at non-ablative levels.
These observations raise fundamental questions:
which target, or combination of targets, drives the
greatest clinical benefit? Does efficacy arise from a
dominant node, or concurrent modulation of several
interconnected structures? Prospective, comparative tri­
als that incorporate each patient’s connectome will be
essential to answer these questions and advance a truly
circuit-based intervention for pain. Our current meth­
odology suggests that connectomic-guided targeting
can increase the volume of the PVG and VPM receiv­
ing �20 Gy, potentially resulting in better outcomes.
The PVG/PAG is a well-established component of
the descending pain pathway17 while the VPM nucleus
of the thalamus is critical for relaying somatosensory
information, particularly from the face and head.18 Our
approach also provided insights into prefrontal con­
nectivity with the PVG/PAG, hippocampus, thalamus,
insula, and amygdala, regions integral to pain process­
ing and regulation.19 Ascending nociceptive afferents
pass through the PVG/PAG to the thalamus, while
descending modulation regulates dorsal horn activation
in response to peripheral stimuli. The thalamic region
between the PVG and VPM, where the shot is typically
centred, is also linked to the CM-Pf complex and the
medial pain pathway, which mediates the affectiveemotional dimensions of pain.2,5,20
While our current treatment algorithm does not expli­
citly target the PVG or VPM, the ability to retrospect­
ively assess dose-volume relationships and potentially
correlate them with clinical outcomes could represent an
important step towards refining connectomic-based
targeting. Reporting these values across various strategies
and doses provides a foundational dataset for future opti­
misation. Prospective validation using patient-specific,
connectivity-guided planning remains a critical direction
for future research.
Conclusions
Connectomic-based radiosurgery for pain is feasible
using the commercially available Brainlab Elements
software. Auto-segmentation and manual contouring
of brain regions enable patient-specific treatment
planning. We successfully correlated and validated our
current patient planning workflow with independent
functional connectomic studies, leading to its adoption
at our centre.
The ability to auto-segment the PVG and VPM
nucleus also allows for volume and dose measure­
ments, which may facilitate future correlations with
clinical outcomes. A key contribution of this technical
report is the establishment of a more standardised
approach to treatment planning and delivery, which
could help unify target selection across the radiosurgi­
cal community. This standardisation may, in turn,
stimulate further clinical research and trials on refrac­
tory oncological and non-oncological pain.
Current limitations include the restricted number
of thalamic structures that can be auto-segmented for
pain treatment. The addition of the CM-Pf complex
would be a valuable enhancement. Further research is
also needed to explore additional potential radiosur­
gery targets and determine the optimal radiation doses
for maximum therapeutic effectiveness.
Acknowledgements
We acknowledge and deeply appreciate Bogdam Valcu and
Rebecca Ljungqvist from Brainlab Elements for their critical
guidance on optimising the operation of the software
Elements.
Disclosure statement
No potential conflict of interest was reported by the
author(s).
Ethical approval
Written informed consent was obtained from the patients
for their anonymised information to be published in this
article. Ethical approval to report this series was obtained
from a local research ethics committee (Comit�e Nacional de
Etica de la Investigaci�
on en Salud - CNEIS/2022/10).
BRITISH JOURNAL OF NEUROSURGERY
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