STROKEAHA.121.034218

Stroke
ORIGINAL CONTRIBUTION
Rehabilitation of Cognitive Deficits Poststroke:
Systematic Review and Meta-Analysis of
Randomized Controlled Trials
Mairead O'Donoghue , BSc; Siobhan Leahy , PhD; Pauline Boland , PhD; Rose Galvin , PhD;
John McManus, MD; Sara Hayes , PhD
BACKGROUND: Despite the prevalence of cognitive impairment poststroke, there is uncertainty regarding interventions to
improve cognitive function poststroke. This systematic review and meta-analysis evaluate the effectiveness of rehabilitation
interventions across multiple domains of cognitive function.
METHODS: Five databases were searched from inception to August 2019. Eligible studies included randomized controlled
trials of rehabilitation interventions for people with stroke when compared with other active interventions or standard care
where cognitive function was an outcome.
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RESULTS: Sixty-four randomized controlled trials (n=4005 participants) were included. Multiple component interventions
improved general cognitive functioning (MD, 1.56 [95% CI, 0.69–2.43]) and memory (standardized MD, 0.49 [95% CI, 0.27–
0.72]) compared with standard care. Physical activity interventions improved neglect (MD, 13.99 [95% CI, 12.67–15.32])
and balance (MD, 2.97 [95% CI, 0.71–5.23]) compared with active controls. Noninvasive brain stimulation impacted neglect
(MD, 20.79 [95% CI, 14.53–27.04) and functional status (MD, 14.02 [95% CI, 8.41–19.62]) compared with active controls.
Neither cognitive rehabilitation (MD, 0.37 [95% CI, −0.94 to 1.69]) nor occupational-based interventions (MD, 0.45 [95%
CI, −1.33 to 2.23]) had a significant effect on cognitive function compared with standard care.
CONCLUSIONS: There is some evidence to support multiple component interventions, physical activity interventions, and
noninvasive brain stimulation improving cognitive function poststroke. Findings must be interpreted with caution given the
overall moderate to high risk of bias, heterogeneity of interventions, and outcome measures across studies.
GRAPHIC ABSTRACT: A graphic abstract is available for this article.
Key Words: activities of daily living ◼ brain ◼ cognition ◼ meta-analysis ◼ stroke ◼ systematic review
S
troke is one of the leading causes of death and disability worldwide.1 Cognitive impairment is reported
in up to 57% of ischemic stroke survivors at 6
months poststroke2 and is shown to be independently
associated with lower quality of life,3 higher rates of mortality and institutionalization,4 increased carer burden,5
and increased healthcare costs.6
A priority-setting partnership in the United Kingdom
identified that cognitive impairment poststroke was
among the top 10 research priorities for people living with stroke.7 Recent international consensus-based
core recommendations identify cognitive function poststroke as an area of unmet need for people poststroke.8
However, much rehabilitation focus is placed on motor
deficits, often neglecting hidden cognitive deficits.9,10
For example, a meta-summary of qualitative studies
exploring stroke survivors’ experiences of rehabilitation
found that an emphasis is placed on the rehabilitation of
Correspondence to: Mairéad O’Donoghue, BSc, Physiotherapy Department, School of Allied Health, University of Limerick, Ireland, V94 T9PX. Email mairead.
[email protected]
Supplemental Material is available at https://www.ahajournals.org/doi/suppl/10.1161/STROKEAHA.121.034218.
For Sources of Funding and Disclosures, see page xxx.
© 2022 American Heart Association, Inc.
Stroke is available at www.ahajournals.org/journal/str
Stroke. 2022;53:00–00. DOI: 10.1161/STROKEAHA.121.034218
May 2022 1
Original Contribution
Donoghue et al
Nonstandard Abbreviations and Acronyms
MoCA
Montreal Cognitive Assessment
NIBS
noninvasive brain stimulation
rTMSrepetitive transcranial magnetic
stimulation
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physical deficits over nonphysical needs such as social
reintegration.11
As illustrated by the diversity and range of neuropsychological assessments, cognition is not a unitary concept.12,13 Cognitive impairment poststroke encompasses
a variety of deficits across multiple domains and typically
includes memory, attention, executive function, language,
and visuoperceptual ability.14 Various cognitive domains
enable complex mental processes to occur, which allow
an individual to select and process information within
their environment.15
Cognitive rehabilitation is defined as “a systematic functionally orientated intervention of therapeutic cognitive activities based on the assessment and
understanding of the patient’s brain behavior deficits”.15
Previous Cochrane reviews have explored the effectiveness of cognitive rehabilitation interventions on a specific
domain of cognitive function poststroke, such as attention, memory, executive function, limb apraxia, neglect,
and perception.16–21
An overview by Gillespie et al22 synthesized evidence
across these Cochrane reviews and reported favorable
outcomes of cognitive rehabilitation across the domains
of attention, spatial neglect, and motor apraxia immediately postintervention, but these improvements are not
likely to persist in the long term and do not improve the
everyday functioning of the individual poststroke.22
Focusing on outcomes relating to any single domain
of cognitive function poststroke may be overly simplistic, given the often diffuse and interconnected cognitive impairments present in individuals poststroke.23
Studies focusing on the rehabilitation of single cognitive domains fail to capture the interrelated and highly
overlapping nature of cognitive domains.12,23,24 There
remains a need to move beyond the narrow scope of
specific cognitive rehabilitation interventions focusing
on one specific domain of cognitive function. A breadth
of intervention modalities impact cognitive function for
people living with stroke, including virtual reality training, physical activity interventions and neuro-feedback
therapy,25–27 and many more. Given the known interactions of cognitive domains required for optimal function and quality of life poststroke, alongside the broad
range of possible interventions, the effects of interventions across all domains of cognitive function poststroke requires examination.
2 May 2022
Rehabilitation of Cognitive Deficits Poststroke
To our knowledge, there is no systematic review that
has examined the effectiveness of all types of rehabilitation interventions, across multiple domains of cognitive
function poststroke. Therefore, in addition to general
cognitive function, this review includes outcomes on cognitive deficits across the domains of attention, memory,
executive function, perception, limb apraxia, and neglect,
and examines the effectiveness of nonpharmacological rehabilitation interventions across these multiple
domains of cognitive function poststroke.
METHODS
Study Design
This systematic review and meta-analysis were conducted in
accordance with the Preferred Items for Systematic Reviews
Meta-Analyses statement.28 The review protocol was registered with the International Prospective Register of Systematic
Reviews (https://www.crd.york.ac.uk/PROSPERO/; Unique
identifier: CRD42019125289) and has been published previously.29 Data available on request from the authors.
Eligibility Criteria
Types of Study
Randomized controlled trials and quasi-randomized control
trials, as defined by the Cochrane Handbook for Systematic
Reviews of Interventions were included.30 Feasibility studies
and pilot studies were also included. Studies published in the
English language with full text available were included.
Participants
Studies that included adults aged 18 years or older with a clinical diagnosis of ischemic or hemorrhagic stroke, in the acute,
subacute, or chronic stage poststroke were included. As outlined in the review protocol, people poststroke with a confirmed
cognitive impairment were to be included. However, the current
review includes individuals poststroke with or without a confirmed cognitive impairment. Mixed cause studies (eg, traumatic brain injury and stroke mix) were included only if separate
data for people poststroke was extractable.
Interventions
Interventions of which the primary or secondary aim is
to improve cognitive function after stroke were included.
Interventions of any duration or conducted at any time since
stroke were included. Pharmacological interventions (including
over-the-counter medications) were excluded.
Controls
Studies comparing an intervention that affects cognitive function poststroke with standard care, no treatment control, waitlist
control, or active control were included.
Outcomes
Change in cognitive function postintervention in individuals
poststroke was the primary outcome of interest. Outcome
measures that focused on general cognitive status, or ≥1
domain-specific aspects of cognition such as executive function, attention, memory, perception, limb apraxia, and neglect
Stroke. 2022;53:00–00. DOI: 10.1161/STROKEAHA.121.034218
Donoghue et al
Search
The following databases were searched: PubMed, Embase,
CENTRAL, PsycInfo, and CinAHL. The Vista and ClinicTrials.
gov databases were also searched for potentially eligible
ongoing clinical trials. The search was carried out from inception to October 2019. For details of the search strategy, see
the Supplemental Material.
Screening
The searches were exported and saved in a master reference
management library (Clarivate Analytics Endnote X7) and
duplicates were removed. Titles, abstracts, and full texts were
screened independently by 2 review authors (M.O.D. and S.H.,
P.B., or R.G.). Any disagreements regarding full-text eligibility
were resolved by discussion among all authors.
Data Extraction
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Data, including author, study design, sample size, population
characteristics (age, type of stroke, time since stroke), intervention characteristics (intervention type, intervention content,
duration of intervention, setting of intervention), control group
(standard care, waitlist control or active control), primary and
secondary outcomes postintervention were extracted and
entered into a standardized recording data extraction form.
Study authors were contacted for missing data or further information. Data were recorded as mean and SD where possible
for studies at postintervention and follow-up.
group (standard control, active control, or waitlist control).
Where studies presented data from multiple intervention/ control groups, all relevant interventions/control groups were combined into a single group and analyzed accordingly.30
Subgroup analysis was performed where pooled studies
included participants that were <3 months poststroke, between
3 and 6 months poststroke, and >6 months poststroke. We previously outlined that a narrative synthesis would be provided on
studies not included in the meta-analysis.29 However, due to the
number of studies identified and range of outcome measures
used, the characteristics of all studies (n=64) were reported
but a narrative synthesis of studies that did not provide data for
the meta-analysis was not performed.
Outcomes are listed according to general cognitive functioning and the following cognitive domains: attention, memory,
executive function, perception, apraxia, neglect. The impact of
heterogeneity on results was assessed using the I2 statistic.
When the I2 was <50% there was little concern about statistical heterogeneity.30 Random-effects models were used where
there was statistical heterogeneity≥50%.30
RESULTS
Searches yielded a total of 66 578 studies, with 25 215
duplicates removed, resulting in 41 363 titles and
abstracts screened for eligibility. Following title and
abstract screening, 277 full-text studies were screened
for eligibility. Out of these full texts, 64 studies met the
inclusion criteria, with 42 of these studies having suitable data for meta-analysis (Figure 1). The additional
22 studies were unsuitable for meta-analysis and so
descriptive data is available for these studies. Please
see the Supplemental Material.
Risk of Bias
Two authors (M.O.D. and either S.H., S.L., or R.G.) independently
assessed the validity of studies using the Cochrane Risk of Bias
Tool. Bias was assessed as low, unclear, or high for individual
components from 5 domains: selection bias, performance bias,
attrition bias, reporting bias, and other bias. Disagreements
were resolved by group consensus.
Data Synthesis
Separate analyses were performed for trials comparing
cognitive interventions with a standard care control, or with
a waitlist control intervention, and trials comparing 2 active
interventions. Interventions were classified into 6 categories
for analysis as follows: multiple component interventions,
cognitive rehabilitation interventions, physical activity interventions, noninvasive brain stimulation protocols (NIBS),
occupational-based interventions, and other interventions. For
details on the categorization of these interventions, please
see the Supplemental Material.
Meta-analyses were conducted using the Cochrane Review
Manager software (RevMan 5.3). For continuous data, the
treatment effect was calculated using standardized mean differences (SMD) and 95% CI where different studies used different scales to assess the same outcome and using mean
differences (MD) and 95% CI where studies used the same
scales to measure relevant outcomes. Analyses are presented
according to the type of intervention compared with a control
Stroke. 2022;53:00–00. DOI: 10.1161/STROKEAHA.121.034218
Characteristics of Included Studies
Of the 64 studies included in this review, 21 were multiple
component interventions, 16 were cognitive rehabilitation interventions, 11 were physical activity interventions,
6 were NIBS protocols, 5 were occupational-based
interventions, and 5 were other interventions. For the
characteristics of included studies, please see the Supplemental Material.
The 64 included studies yielded a total of 4005
participants. Sample sizes ranged from nine participants to 225 participants. The mean age of participants was 62.5 years, ranging from 45 years to 76
years. The mean time since stroke onset was 20.03
months, ranging from 48 hours since stroke onset to
6.25 years poststroke.
Twenty studies (31%) were conducted in the acute
phase (≤3 months poststroke), 12 studies (19%) were
conducted in the subacute phase (>3-6 months poststroke), 18 studies (28%) were conducted during the
chronic stage (>6 months poststroke), and 14 studies
(22%) had no data relating to time since stroke.
Twenty-five studies (39%) included both ischemic and
hemorrhagic types of stroke, 8 studies (12.5 %) reported
May 2022 3
Original Contribution
in line with Australian Clinical Guidelines for Stroke (2020)
were included. Cognitive outcome measures related to cognitive domains other than those listed were excluded. Cognitive
screening tools were also included. Secondary outcome measures included quality of life, using stroke-specific or generic
quality of life measures, functional abilities, mobility, balance,
and depression.
Rehabilitation of Cognitive Deficits Poststroke
Rehabilitation of Cognitive Deficits Poststroke
Original Contribution
Donoghue et al
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Figure 1. PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) flow chart of study selection.
*The characteristics of all studies (n=64) were reported but a narrative synthesis of studies that did not provide data for the meta-analysis was not
performed (n=22).
on ischemic stroke only, 8 studies (12.5%) reported on
left-sided/ right-sided stroke, and 23 studies (36%) had
no data relating to type of stroke.
4 May 2022
Twenty-four studies (38%) recruited their participants from an inpatient acute setting, 15 studies (23%)
recruited from a rehabilitation setting, 18 studies (28%)
Stroke. 2022;53:00–00. DOI: 10.1161/STROKEAHA.121.034218
Donoghue et al
I2=0%). For figures of these results, please see the Supplemental Material.
Multiple Component Interventions
Memory
Four studies reported a measure of memory using the
forward digital span test, the letter-number sequencing
test, and the Digital Span test post multiple component
intervention compared with a standard control. There
was an effect in favor of the intervention group (SMD,
0.49 [95% CI, 0.27–0.72]; I2= 0%; Figure 3). Subgroup
analysis demonstrated that studies >6 months did not
show an effect in favor of the intervention group (SMD,
0.32 [95% CI, −0.03 to 0.67]; I2=0%).
Two studies, one between 3 and 6 months poststroke
and one >6 months poststroke, reported a measure of
spatial and visual memory using the forward Visual Span
Test post multiple component intervention compared
with a standard control. There was an effect in favor of
the intervention group (MD, 0.98 [95% CI, 0.33–1.64];
I2=0%). For figures of these results, please see the Supplemental Material.
There was no evidence of an effect in favor of
multiple component interventions compared with a
standard control group for the cognitive domains of
general cognitive function as measured by the MiniMental State Examination (MD, 1.20 [95% CI, −0.28
to 2.67]), attention (MD, 0.01 [95% CI, −0.08 to 0.11]),
perception (SMD, 0.14 [95% CI, −0.16 to 0.45]), and
on secondary outcomes of depression (SMD, −0.26
[95% CI, −0.57 to 0.06]) and quality of life (SMD, 0.19
[95% CI, −0.24 to 0.63]).
There was no evidence of an effect in favor of multiple component interventions compared with an active
control for the domain of neglect (MD, 4.98 [95% CI,
−33.29 to 43.24]).
General Cognitive Function
Three studies reported a measure of general cognitive
function using the Montreal Cognitive Assessment, post
multiple component intervention compared with standard control. There was a significant effect in favor of
the intervention group (MD, 1.56 [95% CI, 0.69–2.43];
I2=30%; Figure 2). This effect was maintained for studies
<3 months poststroke (MD, 2.38 [95% CI, 0.97–3.80];
Secondary Outcomes
Four studies reported a measure of functional status
using the Barthel Index, the modified Barthel Index, and
the Functional Independence Measure post multiple
component intervention compared with a standard control. An effect was found in favor of the intervention group
(SMD, 0.33 [95% CI, 0.05–0.62]; I2=61%). Subgroup
analysis did not show an effect for studies that were <3
Risk of Bias
The risk of bias in the 64 included studies was generally
mixed, with a high risk of performance bias due to incomplete blinding of participants or personnel in 22 studies, a
high risk of other bias due to inadequate sample sizes or
conflicts of interest in 15 studies, a high risk of detection
bias due to lack of blinded outcome assessment in nine
studies, a high risk of attrition bias due to incomplete outcome data in 6 studies, a high risk of reporting bias associated with selective reporting of outcomes in 2 studies,
and a high risk of selection bias associated with random
sequence generation in one study. For complete Cochrane
Risk of Bias results, please see the Supplemental Material.
Effect of Interventions
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Results of the meta-analysis are presented below
according to intervention type. Data have been pooled in
accordance with each intervention classification as follows: multiple component interventions, cognitive rehabilitation interventions, physical activity interventions,
NIBS protocols, occupational-based interventions, and
other interventions.
Figure 2. Forest plot of general cognitive function outcomes, multiple component intervention vs standard control.
Stroke. 2022;53:00–00. DOI: 10.1161/STROKEAHA.121.034218
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Original Contribution
recruited from an outpatient service, and 7 studies (11%)
recruited from both an inpatient and outpatient setting.
Forty-one studies (64%) recruited their participants
from an inpatient acute setting, 13 studies (20%) recruited
from an outpatient service, whereas 4 studies (6.5%)
recruited from both an inpatient and outpatient setting. Six
studies (9.5%) recruited from community settings.
Rehabilitation of Cognitive Deficits Poststroke
Rehabilitation of Cognitive Deficits Poststroke
Original Contribution
Donoghue et al
Figure 3. Forest plot of memory outcomes, multiple component intervention vs standard control.
months poststroke or >6 months poststroke. For figures
of these results, please see the Supplemental Material.
Cognitive Rehabilitation Interventions
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There was no evidence of an effect in favor of cognitive rehabilitation interventions when compared with a
standard control for general cognitive function (MD, 0.37
[95% CI, −0.94 to 1.69]), memory (MD, 1.54 [95% CI,
−1.90 to 4.98]), executive function (MD, 0.44 [95% CI,
−1.94 to 2.82]), neglect (SMD, 0.26 [95% CI, −0.18 to
0.71]), or on secondary outcomes of quality of life (SMD,
0.17 [95% CI, −0.18 to 0.52]).
There was no evidence of an effect in favor of cognitive rehabilitation interventions when compared with an
active control for general cognitive functioning (MD, 0.83
[95% CI, −1.04 to 2.71]), memory (MD, −2.27 [95% CI,
−6.06 to 1.52]), executive function (MD, −53.45 [95%
CI, −148.26 to 41.36]), or attention (SMD, −0.05 [95%
CI, −1.02 to 0.91]).
There was no evidence of an effect in favor of cognitive rehabilitation interventions when compared with
a waitlist control for the cognitive domain of memory
(SMD, 0.63 [95% CI, −0.27 to 1.52]).
Physical Activity Interventions
Neglect
Two studies, both <3 months poststroke, reported a measure of neglect using the Star Cancellation Test when
comparing a physical activity intervention to an active
control group of sham mirror therapy. There was an
effect in favor of the control group (MD, 13.99 [95% CI,
12.67–15.32]; I2=0%)(Figure 4).
Secondary Outcomes
Two studies, both >6 months poststroke, reported a
measure of balance using the Berg Balance Scale when
compared with an active control group (stretching group).
There was an effect in favor of the intervention group
(MD, 2.97 [95% CI, 0.71–5.23]; I2=0%). For figures of
these results, please see the Supplemental Material.
There was no evidence of an effect of physical activity interventions when compared with an active control
for the cognitive domains executive function (MD, –1.92
[95% CI, –28.68 to 24.84]).
NIBS Interventions
Neglect
Three studies reported a measure of neglect using the
line bisection test when compared with an active control of sham repetitive transcranial magnetic stimulation therapy (rTMS). There was an effect in favor of
the intervention group (MD, 20.79 [95% CI, 14.53–
27.04]; I2=79%)(Figure 5). Subgroup analysis of studies between 3-6 months also found an effect in favor
of the intervention group (MD, 18.74 [95% CI, 11.50–
25.99]; I2=78%). For figures of these results, please
see the Supplemental Material.
Two studies, one <3 months poststroke and one
between 3 and 6 months poststroke reported a measure
of neglect using the Star Cancellation Test when compared with an active control of sham rTMS therapy. There
was an effect in favor of the active control group (MD,
−5.57 [95% CI, −8.53 to −2.61]; I2=99%; Figure 6).
Secondary Outcomes
Two studies, one <3 months poststroke and one >6
months poststroke, reported a measure of functional status using the Modified Barthel Index and the Korean version of the Modified Barthel Index when compared with
an active control of rTMS therapy. There was an effect
in favor of the intervention group (MD, 14.02 [95% CI,
8.41–19.62]; I2=0%). For figures of these results, please
see the Supplemental Material.
Figure 4. Forest plot of neglect outcomes, physical activity (mirror therapy) intervention vs sham mirror therapy.
6 May 2022
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Donoghue et al
Rehabilitation of Cognitive Deficits Poststroke
Occupational-Based Interventions
There was no evidence of an effect of occupationalbased interventions when compared with a standard control for general cognitive functioning (MD, 0.45 [95% CI,
−1.33 to 2.23]) or the secondary outcome of functional
status (SMD, 0.31 [95% CI, −0.03 to 0.65]). Subgroup
analysis revealed that studies <3 months poststroke
showed an effect in favor of the intervention group for
general cognitive functioning (MD, 0.39 [95% CI, 0.02–
0.76]; I2=0%). For figures of these results, please see the
Supplemental Material.
Other Interventions
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There was no evidence of an effect of other interventions, that is, prism adaptation therapy, when compared
with an active control group for the cognitive domain of
neglect (SMD, 0.40 [95% CI, −0.06 to 0.85]).
DISCUSSION
This comprehensive systematic review examined the
totality of evidence regarding the effectiveness of nonpharmacological interventions on cognitive deficits poststroke. Findings exhibited the range of rehabilitation
approaches that may be effective in improving cognitive
deficits poststroke. Multiple component interventions
demonstrated favorable effects on outcomes of general
cognitive functioning and memory when compared with
standard care. Physical activity interventions and NIBS
protocols were also effective on a range of cognitive and
secondary outcomes. Despite research involving over
4000 individuals across 64 randomized controlled trials,
the evidence base presented in this review demonstrated
several methodological shortcomings and unanswered
questions regarding the optimal design and delivery of
interventions to rehabilitate cognitive deficits poststroke.
Furthermore, the overall moderate certainty of evidence
and high risk of bias for various methodological domains
must be acknowledged.
The most consistent evidence in this review supported multiple component interventions, with significant improvement demonstrated for general cognitive
function and memory. Evidence from three pooled studies using multiple component interventions indicated a
positive effect in general cognitive functioning. Within
this analysis of multiple component interventions, cognitive rehabilitation training was used in conjunction with a
form of physical activity, such as systemic coordination
training,31 conventional occupational therapy/physiotherapy,32 or an acupuncture treatment.33 However, given the
very low clinically meaningful effect of this outcome,34
the practical and clinical importance of multiple component interventions on outcomes of general cognitive
function should be interpreted with caution.
Evidence from 2 pooled studies indicated a large
effect for spatial and visual memory outcomes post computerized cognitive rehabilitation,35 in conjunction with
traditional rehabilitation therapy consisting of physical
therapy and occupational therapy.36 Previous evidence
suggests that a combination of physical activity and cognitive rehabilitation may facilitate greater improvements in
relation to cognitive impairment in both older adults and
individuals poststroke, respectively.37,38 Although there
is relatively limited literature regarding the use of multiple component interventions in individuals poststroke,
combined cognitive interventions and physical activity
have shown positive effects on cognitive functioning in
persons with dementia39 and traumatic brain injury.40 In
their review of evidence-based cognitive rehabilitation,
Cicerone et al40 recommended that programs of comprehensive, holistic neuropsychological rehabilitation can
improve outcomes relating to community integration and
Figure 6. Forest plot of neglect outcomes (Star Cancellation Test), repetitive transcranial magnetic stimulation (rTMS) protocol
vs sham rTMS protocol.
Stroke. 2022;53:00–00. DOI: 10.1161/STROKEAHA.121.034218
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Original Contribution
Figure 5. Forest plot of neglect outcomes (line bisection test), repetitive transcranial magnetic stimulation (rTMS) vs sham rTMS.
Original Contribution
Donoghue et al
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functional independence and recommends that such
programs be provided to reduce both cognitive and
functional impairments. However, it should be noted that
these recommendations were based on studies examining a mixed cohort of individuals poststroke and posttraumatic brain injury and should be extrapolated with
caution. Furthermore, given the heterogeneity of interventions across studies in the current review, it remains
difficult to make recommendations regarding the optimal
design and delivery of a multiple component intervention for individual’s poststroke. Nevertheless, the provision of two or more interventions may be more effective
compared with usual care and as such, a combination is,
therefore, more likely than many single-component interventions to reduce cognitive dysfunction poststroke.
In addition to the benefits of physical activity when
combined with a form of cognitive training, this review
found favorable results of single-component physical activity interventions. Trials by Pandian et al41 and
Thieme et al42 found a significant improvement on outcomes of neglect post mirror therapy interventions of 4
and 5 weeks duration respectively. Both these studies
were conducted in the acute to subacute phases poststroke and were in comparison with an active control
group of sham mirror therapy. Mirror therapy is a feasible
and effective intervention that can facilitate both motor
and sensory improvements in the acute, subacute, and
chronic phases poststroke.43 It remains unclear whether
the intensity of exercise training affects cognitive outcomes poststroke.26
The benefits of physical activity on cognitive function
are widely known in older adult populations.44,45 Physical activity and exercise prescription are recommended
in the management of not only multiple physical but
also psychosocial domains poststroke.46 However,
uncertainty remains regarding the effects of such interventions specifically on cognitive function poststroke.
A review by Cumming et al26 evaluated the effect of
increased physical activity on cognitive functioning in
individuals poststroke. Although this review demonstrated a significant effect favoring the use of physical activity interventions compared with active control
groups on outcomes of neglect and balance, there was
large variability between trials regarding the optimal
frequency, intensity, timing, and type of physical activity
intervention provided. Moreover, the assessment of cognitive function was rarely the primary outcome measure
of these trials. Given the methodological shortcomings
and small pool of studies within this review by Cumming
et al,26 there was insufficient evidence to support clear
recommendations for clinical practice. In their updated
review examining the effects of fitness training poststroke, Saunders et al47 noted that outcomes of cognitive function in particular lack investigation, despite
being ranked as the most important research priority
relating to life after stroke.7
8 May 2022
Rehabilitation of Cognitive Deficits Poststroke
Although meta-analytic evidence from the current
review failed to demonstrate favorable effects of cognitive rehabilitation interventions on cognitive or secondary outcomes, Cicerone et al40 recommend external
compensation strategies as a practice standard for the
rehabilitation of memory deficits poststroke. However,
in their updated review of cognitive rehabilitation for
memory deficits poststroke, das Nair et al17 report insufficient evidence for memory rehabilitation due to poor
methodological quality of current studies. Similar to the
current review, das Nair et al17 noted lack of long-term
effects of cognitive intervention on memory outcomes. In
their updated meta-analysis, Loetscher et al48 examined
6 randomized controlled trials comparing cognitive rehabilitation with a standard care control group on outcomes
of attention. Although there were no significant improvements in global attentional measures, the domain of
divided attention improved significantly, but these effects
did not persist long-term.48 Their review highlighted
insufficient data to determine whether outcomes varied
according to the frequency, intensity, or type of intervention.48 Given the key features of intervention design. that
is, frequency, intensity, time, and type of cognitive rehabilitation interventions have yet to be established,8 it is
unclear whether the intensity and duration of these interventions were justified.
Meta-analytic evidence from this review suggests that
NIBS protocols have a favorable effect on outcomes of
neglect and performance in activities of daily living poststroke. NIBS, specifically rTMS, was found to have a large
effect on neglect outcomes in the acute and subacute
phase poststroke when compared with a sham stimulation group.49–51 Two of these studies combined NIBS with
another treatment such as conventional therapy or sensory cueing respectively.49,51 Our review adds to the existing body of evidence and supports the findings of Salazar
et al52 where NIBS, specifically rTMS and transcranial
direct current stimulation, in conjunction with other therapies (such as visuospatial scanning training, conventional
rehabilitation treatment, or feedback training) improved
neglect in the acute and subacute phase poststroke. Thus,
this combined approach, much like that of multiple component interventions, may result in more favorable clinical improvements on symptoms of neglect in individuals
poststroke. However, this effect is limited as a result of
the large heterogeneity observed in these analyses, suggesting that further studies are needed to determine the
effects of NIBS protocols on outcomes of neglect.
Subgroup analysis demonstrated favorable results
of occupational-based interventions conducted less
than 3 months poststroke on general cognitive functioning. Individual trials included in this review by Ntsiea
et al53 and Skidmore et al54 found favorable effects in
functional ability after a specific workplace intervention and a strategy training intervention respectively.
These interventions incorporated goal setting and
Stroke. 2022;53:00–00. DOI: 10.1161/STROKEAHA.121.034218
Donoghue et al
Stroke. 2022;53:00–00. DOI: 10.1161/STROKEAHA.121.034218
that the MoCA displays excellent sensitivity but poor
specificity.60 To this end, the MoCA may be particularly
useful in people poststroke given the diffuse nature of
cognitive impairment poststroke while also showing to
have acceptable responsiveness and criterion validity in
people poststroke receiving rehabilitation.34
Furthermore, it is not clear whether improvements
in cognitive functioning lead to improvements in daily
functioning or quality of life for the person poststroke.
Nine out of the 42 included studies in our metaanalysis demonstrated improved measures of quality
of life and/ or daily functioning outcomes, along with
improved cognitive outcomes. Given the relatively small
number of trials that reported improvements in these
measures, there are insufficient trials to support or
refute the use of the above interventions to improve
quality of life and functional outcomes poststroke while
simultaneously improving cognitive function. Although
it is important to show the functional significance of
these rehabilitation interventions, a causative effect
of improved cognitive outcomes leading to improved
quality of life or daily functioning outcomes cannot be
assumed from these results.
Strengths and Limitations
To our knowledge, this is the first systematic review that
examined all types of rehabilitation interventions across
multiple domains of cognitive function for people poststroke. This review complied with the Preferred Items
for Systematic Reviews and Meta-Analyses guidelines28
and employed a comprehensive search and screening
strategy of peer-reviewed research. Unlike previous
research which has focused on outcomes within a specific cognitive domain, we have included six domains of
cognitive function, as outlined in the Australian Clinical
Guidelines for Stroke (2020), as well as general cognitive functioning. Moreover, the comprehensive intervention categorization of included studies provides more
in-depth analysis of the effectiveness of a breadth of
rehabilitation approaches.
This review has several important limitations. Concerning the domains of cognition examined, this review
did not capture the multi-dimensional constructs of each
cognitive domain. For example, the domain of memory
can be subclassified into working memory, episodic
memory, procedural memory, semantic memory, and
prospective memory.61 Although we recognize the interconnected neural network and hierarchical structure of
cognitive performance,23 the analysis of inter-domain
interactions occurring during recovery poststroke was
beyond the scope of this review. Furthermore, findings
need to be interpreted with caution and considered in the
context of high risk of bias across the following domains
of bias: selection bias, performance bias, detection bias,
attrition bias, reporting bias, and other biases.
May 2022 9
Original Contribution
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self-management strategies. These findings are in contrast to a previous Cochrane review of occupational
therapy poststroke which found no differences between
groups for outcomes of general cognitive functioning
or basic activities of daily living as assessed using the
Barthel Index.55 However, it is of note that only one trial
met the criteria for inclusion in this review.55
Unlike previous research in this area, meta-analytic
evidence from the current systematic review evaluated an extensive range of rehabilitation interventions,
including multiple component interventions, physical
activity interventions, cognitive rehabilitation interventions, NIBS protocols, occupational interventions, and
other interventions such as art therapy, prism adaptation,
and music therapy. Given the breadth of interventions
included in this review, there was extensive heterogeneity in relation to the intervention content, the duration, and dose of the intervention, the delivery of the
intervention, and the domain of cognition targeted. To
address this, we categorized intervention type accordingly and limited the heterogeneity in the meta-analyses.
Furthermore, many of the included studies employed a
standard care control group, with few studies describing
the actual standard treatment delivered to the control
group. This variation between studies raises challenges
when aiming to determine the effectiveness of these
types of rehabilitation interventions on cognitive deficits poststroke. Studies should provide a comprehensive
description of intervention design to facilitate reliable
intervention implementation and also to allow for replication in subsequent research.56 Future trialists should
consider the Template for Intervention Description and
Replication checklist to guide comprehensive and systematic reporting of interventions.57
Another factor adding to the diversity across studies was the lack of consensus between trials regarding assessment of cognitive impairment poststroke.
The recent consensus-based recommendations from
the Stroke Recovery and Rehabilitation Roundtable
highlighted that no consensus was reached regarding
a single approach to assessment of cognitive function
poststroke.8 The need for assessments that are easily
implementable and target the assessment of cognition
across multiple cognitive domains was advocated.8 The
National Institute for Neurological Disorders and Stroke
and the Canadian Stroke Network recommend the use
of common protocols for neuropsychological assessment
in stroke-related research,58 which would address a current methodological limitation within stroke rehabilitation
trials when such assessments cannot be compared.22 In
the current review, there was substantial variability in both
the quality and the types of cognitive outcome measures
used. The MoCA assesses 6 cognitive domains including episodic memory, working memory, attention/ concentration, executive function, language, and visuospatial
ability.59 Pooled data from a recent review demonstrated
Rehabilitation of Cognitive Deficits Poststroke
Original Contribution
Donoghue et al
The comprehensive and pragmatic intervention categorization of included studies provides an in-depth analysis of the effectiveness of rehabilitation approaches.
However, the possibility of misclassification of intervention categorization within the analyses is acknowledged.
Furthermore, the variation across trials also limited further possible analyses and although we are adding to
the novelty of this evidence base, the existence of few
homogeneous trials is a limitation.
Rehabilitation of Cognitive Deficits Poststroke
3.
4.
5.
6.
Conclusions
The evidence regarding the effects of rehabilitation interventions to improve cognitive impairment poststroke
remains uncertain. The evidence base presented demonstrates moderate and high risk of bias and suggests
there is insufficient evidence to support or refute the
effectiveness of rehabilitation interventions on cognitive
impairment poststroke. Multiple component interventions,
particularly those with a physical activity component, seem
to have a favorable effect on memory and overall cognitive functioning. There is some evidence in r of physical
activity interventions and NIBS protocols on the cognitive
domains of memory and neglect. However, these findings
must be interpreted with caution given the moderate certainty of evidence and high risk of bias for various methodological domains, extensive heterogeneity of interventions
as well as outcome measures included in these studies.
7.
8.
9.
10.
11.
12.
13.
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14.
ARTICLE INFORMATION
Received January 15, 2021; final revision received August 25, 2021; accepted
October 29, 2021.
15.
Affiliations
School of Allied Health, Ageing Research Centre, Faculty of Education and Health
Sciences, Health Research Institute, University of Limerick, Ireland (M.O.D., S.L.,
P.B., R.G., S.H.). Geriatric and Stroke Medicine, University Hospital Limerick, Ireland (J.M.).
Acknowledgments
This work was funded by a PhD stipend from the School of Allied Health, University of Limerick.
16.
17.
18.
Sources of Funding
None.
Disclosures
None.
Supplemental Material
Tables S1–S4
Figures S1–S5
References 1–69
19.
20.
21.
22.
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