Research article

The role of the contralesional primary motor cortex in upper limb recovery after stroke: A scoping review following PRISMA-ScR guidelines

Peerapat Suputtitada^1*, Valton Costa^2,3, Felipe Fregni³

^1* School of Biomedical Sciences, Faculty of Medical Sciences, Newcastle University, Newcastle Upon Tyne, UK

²Laboratory of Neurosciences and Neurological Rehabilitation, Physical Therapy Department, Federal University of Sao Carlos, Sao Carlos, SP, Brazil.

³Neuromodulation Center and Center for Clinical Research Learning, Spaulding Rehabilitation Hospital and Massachusetts General Hospital, Harvard Medical School, Boston, USA.

The corresponding author : Peerapat Suputtitada

School of Biomedical Sciences, Faculty of Medical Sciences, Newcastle University, Newcastle Upon Tyne, UK

email: peerapat8181@gmail.com

Abstract

Background

Stroke often results in motor impairments, with recovery involving complex interactions between the lesioned (ipsilesional) and non-lesioned (contralesional) hemispheres. This scoping review investigates the role of the contralesional primary motor cortex (M1) in motor recovery of the paretic upper limb following stroke, examining its structural and functional changes and compensatory roles.

Methods

A systematic search for scoping review was conducted in PubMed, Embase, Web of Science, and Google Scholar following PRISMA-ScR guidelines. Studies examining contralesional M1 contributions to upper limb recovery in humans and animal models were included. Data were extracted, synthesized qualitatively, and assessed for risk of bias using SYRCLE and Cochrane tools.

Results

A total of 38 studies were included in the analysis, consisting of 34 focused on stroke patients and 4 utilizing animal models. The findings revealed the dual and task-specific role of the contralesional primary motor cortex (M1) in upper limb recovery after stroke. In patients with severe motor impairments, contralesional M1 supported recovery through compensatory mechanisms, such as increased neuronal recruitment and functional reorganization. However, in cases with mild impairments, its activation was associated with inhibitory effects on ipsilesional reorganization, potentially delaying optimal recovery. Animal studies provided evidence of structural and functional plasticity, including dendritic remodeling and enhanced neuronal connectivity, which paralleled improvements in motor function. In human studies, contralesional M1 activation was task-dependent, with pronounced engagement during demanding tasks and unimanual movements. Ipsilateral motor deficits, including reduced dexterity, strength, and coordination, were commonly reported and underscored the disrupted interhemispheric dynamics influencing recovery. Neuromodulation techniques showed promise in modulating interhemispheric interactions and enhancing motor outcomes. These results emphasize the complex interplay between compensatory and inhibitory processes mediated by contralesional M1 in stroke recovery.

Conclusion

The contralesional M1 plays a complex, task-specific role in upper limb recovery after stroke, acting as both a compensatory resource and a potential inhibitory factor. Future research should stratify patients by impairment severity to refine therapeutic approaches.

Keywords:

Contralesional motor cortex

Stroke recovery

Ipsilateral motor deficits

Interhemispheric dynamics

Neuromodulation

Task-specific training

Functional reorganization

Upper limb motor control

Scoping review

1. Introduction

Understanding how the brain controls motor functions in the human body is essential and complex topic, encompassing the interaction of cortical and subcortical networks, hierarchical processing, and dynamic neuroplastic mechanisms. Since the emergence of modern neuroimaging techniques, a whole world of possibilities for exploring the brain, both anatomically and physiologically, has become available.

This has provided much information that was previously dependent on animal studies. Regarding sensorimotor functions, such as the movements of the extremities and the axial control of posture, the cerebral hemispheres exhibit a primarily contralateral control of the upper and lower limbs through descending motor pathways, including the pyramidal (corticospinal) tract. Sensory inputs, however, are transmitted via afferent pathways to the central nervous system. [1].

The motor system is a complex biological network encompassing hierarchical levels of processing, specialized cortical areas, and interconnected afferent and efferent pathways, making it intricate and adaptable. These hierarchical levels include cortical motor areas (e.g., primary motor cortex [M1] [2], supplementary motor area [SMA], premotor cortex [PM], and cingulate motor area [CMA]), subcortical structures (e.g., basal ganglia, cerebellum), and spinal motor neurons. These regions are responsible for the planning, modulation, and execution of motor commands, which are transmitted through descending tracts to subcortical structures, spinal cord segments, and the opposite hemisphere via the corpus callosum [3, 4]. Non-motor cortical and subcortical areas, including frontal and parietal associative regions, support motor functions by providing sensory, mnemonic, and cognitive inputs, enhancing the system’s adaptability to varying demands and circumstances.

Contralateral hemispheric motor control means that the right hemisphere predominantly controls the muscles and movements of the left side of the body and receives sensory inputs from it, whereas the left hemisphere does the opposite. Although this has been the standard view in physiological and clinical studies of the nervous system, decades of research have demonstrated divergent evidence showing the existence of contralesional pathways potentially involved in the planning and execution of motor outputs. This evidence highlights redundant and complementary features of the motor system, which are relevant for the complex and coordinated motor skills observed especially in higher primates. These features are of paramount importance for functional recovery after brain damage [2, 3].

1.1 Ipsilateral motor pathways to the upper limb

From primate studies, we have learned that approximately 10% of corticospinal fibers project from different contralesional primary and secondary motor areas downstream to the contralesional side of the spinal cord through ventromedial and dorsolateral projections, in addition to the denser contralateral crossed pyramidal fibers. Both corticospinal tracts converge in intermediate zones, where they can influence groups of interneurons and spinal laminae involved in the direct control of motor neurons that govern limb movements [1, 3, 5]. In addition to uncrossed contralesional corticospinal projections, other contralesional descending pathways, such as the reticulospinal, rubrospinal, and propriospinal tracts, receive inputs from the motor cortex [6, 7]. These projections were historically associated mainly with axial and proximal postural control in preparation for and during distal limb movements. However, direct excitatory monosynaptic connections via reticulospinal projections to neurons responsible for intrinsic hand muscles in the ventral horn of the cervical spine have demonstrated the role of these projections in distal motor control, beyond proximal postural adjustments [8, 9].

1.2 Ipsilateral limb representations and evoked motor responses

Research has established beyond doubt that the contralesional motor cortex maintains independent representations of both upper limbs, as observed through functional imaging during unilateral and bilateral movements. These representations share approximately 50% of neuronal substrate and exhibit different dynamics depending on the area being activated, being less stable in the premotor (PM) and supplementary motor areas (SMA). This likely reflects the broader motor planning and coordination roles of premotor areas, which integrate sensory inputs, select motor actions based on external and internal cues, and prepare movement sequences, compared to the more discrete role of the primary motor cortex (M1) in executing motor commands and controlling specific muscle contractions [10, 11]. Interestingly, during bimanual movements, contralateral activity appears to suppress contralesional activity, which is thought to reduce interlimb interference from bilateral representations of the same limb and facilitate interlimb coordination [12, 13]. These contralesional representations encode independent muscle and movement patterns, enabling the prediction of contralateral limb movements, thus demonstrating that these representations maintain a bilateral mirror-like activity [14, 15].

Activity in M1 is modulated by contralesional upper limb movements, and intracortical microstimulation (ICMS) of M1 elicits contralesional hand movements in non-human primates [16]. In humans, contralesional motor responses vary and are rare in relaxed distal muscles. However, at about 50% muscle contractions, contralesional motor evoked potentials (MEPs) can be elicited in some individuals, albeit at longer latencies than those elicited contralaterally [17, 18]. Both cortical and pontomedullary reticular formation stimulation elicit motor responses that follow a gradient from proximal to distal. MEPs are easily elicited in axial muscles, vary in proximal muscles, and are rarely elicited in wrist and hand muscles, even less commonly for the reticular formation, in healthy adults. This likely reflects the distribution of contralesional and contralateral muscle control [18, 19].

Two main hypotheses are generally proposed to explain the contralesional activity in motor cortical areas during contralesional upper limb movement or the evocation of contralesional motor evoked potentials (MEPs) and muscle contractions. Some researchers advocate for the potential of corticospinal projections to produce motor outputs, while others attribute the cortical and motor activities to interhemispheric mechanisms, such as the inhibitory influence of one hemisphere over the other during unilateral limb movements [20].

Interestingly, transcranial magnetic stimulation (TMS) of cortical arm and hand areas evokes distinctive contralesional and contralateral MEPs in typical participants and participants with agenesis of the corpus callosum. This suggests that TMS may activate different pathways, including both interhemispheric mechanisms and potentially non-crossed corticofugal motor fibers, such as the contralesional corticospinal and reticulospinal tracts [17].

Overall, these findings highlight the role of motor areas in contralesional motor control, bimanual control, and interlimb coordination. Together, these findings suggest that while contralateral dominance remains a fundamental principle of motor control, its extent may be weaker than broadly assumed. The evidence highlights the significant contributions of both hemispheres to skilled, dissociated, and coordinated unilateral and bilateral limb movements. After stroke, the role of the contralesional hemisphere in motor control may increase substantially, reflecting a dynamic reorganization of motor networks.

Most of the evidence regarding the existence of contralesional motor pathways, including the density and relative importance of motor outputs, comes from lesion models and simulations in animal studies. This limits the generalization of findings, as significant differences exist in motor system organization and the relevance of some areas and pathways between non-primates, non-human primates, and humans. Human cases of motor system damage offer opportunities to study the function of the motor cortex and its descending pathways, as well as to clarify the relative importance of these structures for recovery after lesions, whether self-inflicted or induced by rehabilitation.

1.3 Objective of this review

The objective of this scoping review is to comprehensively examine and synthesize the current knowledge on the role of the contralesional motor cortex in the motor function of the contralesional upper limb following a stroke. Specifically, this review aims to:

Provide an overview of the existing evidence regarding the motor cortex's role in contralesional upper limb control after stroke, addressing the challenges posed by unilateral arm and hand function impairment caused by central lesions.

Enhance the understanding of the contralesional motor system by integrating insights from previous animal and clinical research, clarifying its function, and identifying potential therapeutic targets for improved stroke rehabilitation.

2. Methodology

This scoping review was conducted following the recommendations of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews (PRISMA-ScR) guidelines [20]. This method was chosen to comprehensively review and synthesize the topic and identify relevant gaps to be addressed in subsequent systematic reviews and clinical trials. To ensure the review adhered to all 22 PRISMA-ScR items, which are outlined below.

2.1 Identification of the research question

The primary question guiding the search for relevant records, as well as their subsequent selection and synthesis, was: What is the current state of knowledge regarding the role of the contralesional motor cortex in motor function of the contralesional upper limb after stroke? To answer this broad question, studies from both neurophysiological and clinical research domains were reviewed.

2.2 Search strategy

A comprehensive and systematic electronic search was conducted using PubMed, EMBASE, and Web of Science, with supplementary searches performed in Google Scholar to ensure broader coverage. Additionally, the reference lists of relevant papers were reviewed to identify further studies. The review methodology followed the PRISMA Extension for Scoping Reviews (PRISMA-ScR) [20], as illustrated in Fig. 1. The patient/population, intervention, comparison and outcomes (PICO) framework [21] was utilized to determine the inclusion criteria, specifically targeting stroke patients with the role of the contralesional motor cortex in motor function of the contralesional upper limb after stroke in human and animal models. The search strategy, based on the research question, covered literature up to March 2024. Search terms included variations and synonyms for "primary motor cortex" (e.g., M1, motor cortex, motor system), "contralesional upper limb" (e.g., contralesional hand, upper extremity), and "stroke" (e.g., cerebrovascular disease, brain infarct). MeSH terms were adapted to each database to ensure the retrieval of relevant records.

2.3 Study criteria and selection

The inclusion criteria covered case-control studies, cohort studies, randomized controlled trials, and observational studies, encompassing both animal and human research. Titles and abstracts were initially screened to exclude duplicates, reviews, background articles, non-English publications, and studies unrelated to the topic. Full texts of potentially eligible studies were independently reviewed by two authors to confirm relevance. The selected papers were then discussed among all authors based on their relevance to the research question.

Eligibility Criteria (PRISMA-ScR Application)

Studies were included if they evaluated the role of the contralesional primary motor cortex (M1) in upper limb recovery after stroke in human or animal models. Both neurophysiological and clinical studies were considered. Finally, the data was extracted and synthesized descriptively.

2.4 Data extraction and synthesis

Important information for the characterization of the studies was derived from each record, such as the author's names, year of publication, country, study design, and research settings. Additional data were extracted based on the type of publication.

Data Extraction (PRISMA-ScR Application)

Data were extracted using a standardized template, capturing information on study design, population characteristics, interventions, outcomes, and key findings.

Cochrane Risk-of-Bias Assessment

To evaluate the quality of included studies, the Cochrane Risk of Bias Tool [22, 23] was applied to human studies, and the SYRCLE Risk of Bias Tool [24] was adapted for animal studies. These assessments examined biases in selection, performance, detection, attrition, and reporting, with discrepancies resolved by consensus.

Synthesis of Results (PRISMA-ScR Application)

Findings were synthesized descriptively, categorizing studies based on methodology (e.g., human vs. animal studies) and neurophysiological techniques employed. The synthesis focused on key mechanisms and roles of the contralesional M1 in motor recovery.

3. Results

Through the implemented search strategy, a total of 259 records were identified on the databases and 9 were found through manual search. Out of these, 81 papers were selected based on title and abstract and 38 for full-text analysis. We identified 4 studies concerning the function of the motor cortex on contralesional upper limb control in animal models and in 34 studies regarding contralesional motor control after stroke. Cochrane risk-of-bias assessments were performed, and findings were synthesized qualitatively (summarized in Table 1A and Table 1B). Table 1A summarizes findings from animal models, while Table 1B details findings from clinical studies, including key outcomes and risk-of-bias results. The whole process is depicted in Fig. 1. constructed in accordance with the PRISMA-ScR checklist.

Fig. 1

PRISMA flow chart showing the literature search and study selection process.

Table 1

A: Key findings from animal models investigating contralesional motor cortex contributions to stroke recovery
Authors/Year	Study Design/Sample	Objectives	Methods	Main Findings	SYRCLE Risk of Bias
Liu et al., 2019 [25]	Rat model with focal ischemic brain injury. Constraint-induced movement therapy (CIMT) applied post-stroke.	Investigate the role of CIMT in promoting structural and functional neuroplasticity oriented toward the contralesional hemisphere.	Structural imaging to assess neuroplastic changes and functional recovery metrics during post-stroke rehabilitation.	CIMT significantly enhanced contralesional neuroplasticity, evidenced by increased dendritic arborization and functional connectivity. Bihemispheric coordination improved, highlighting contralesional adaptation during motor recovery.	Moderate risk: Sample size calculation not detailed; blinding during assessments not explicitly mentioned.
Gonzalez et al., 2004 [26]	Rat model with motor cortex and lateral frontal cortex lesions.	Assess bilateral contributions to skilled forelimb movements after contralesional and ipsilesional cortical lesions.	Observations of skilled forelimb reaching tasks pre- and post-lesion, focusing on recovery patterns in both the contralesional and ipsilesional limbs.	Lesions in motor cortex resulted in significant bilateral reaching deficits, underscoring the role of contralesional structures in skilled motor control. Recovery mechanisms indicated interplay between hemispheres for motor compensation.	Low risk: Blinding and randomization were followed; adequate controls were included.
Biernaskie et al., 2005 [27]	Rat model with focal ischemic brain injury.	Explore the bi-hemispheric contributions to motor recovery of the affected forelimb.	Behavioral assessments and neuroimaging to track functional recovery and cortical activity in both hemispheres post-injury.	Recovery of affected forelimb function was strongly associated with compensatory bi-hemispheric activity. Contralesional plasticity was more prominent in cases of severe ipsilesional damage.	Moderate risk: Limited discussion on potential confounding factors such as variability in ischemic lesion size.
Kaeser et al., 2010 [28]	Monkey model with unilateral motor cortex lesions.	Evaluate the impact of motor cortex lesions on the ipsilesional hand’s reach and grasp performance.	Quantitative kinematic analysis of reach and grasp performance in both ipsilesional and contralesional hands. Neural activity mapping in motor-related areas.	Ipsilesional hand movements showed marked deficits post-lesion, while recovery of contralesional hand function correlated with the contralesional hemisphere's adaptation. Plasticity in contralesional motor areas played a pivotal role in restoring skilled motor tasks.	Low risk: Comprehensive kinematic analysis conducted with robust experimental controls.

Table 1

B. Characterization and main findings of studies regarding the role of the ipsilateral motor cortex after stroke.
Authors/ Year	Objectives	Methods	Outcome Measures	Main Findings	Cochrane Risk of Bias Assessment	Clinical Implications
Yarosh, Hoffman, and Strick, 2004²⁹	To assess step-tracking wrist movements ipsilaterally to the hemispheric lesion.	Observational; 7 subacute to chronic patients (cortical and subcortical stroke, wrist MRC range = 0–4) and 7 healthy controls.	Step-tracking movements of the wrist (duration); EMG of four hand muscles.	Ipsilateral movements significantly were reduced to controls; the errors were due to inappropriate temporal sequencing of muscle activity regardless of hemispheric dominance.	A high risk of bias in randomization due to its observational nature. Objective measurements (EMG, kinematics) ensure low measurement bias. Missing data risks are minimal, but selective reporting concerns remain due to unregistered protocols. Overall, the study demonstrates robust methodology despite limitations.	Distal ipsilateral limb movements get impaired after stroke; muscle sequencing is impaired.
Baskett et al., 1996³⁰	To investigate ipsilateral sensorimotor deficits early after stroke.	Observational; 20 subacute patients (Motor Assessment Scale mean = 34.5) and 41 healthy controls.	Sensorimotor assessments.	Only subjects with a right hemisphere infarct showed reduced sensorimotor performance ipsilaterally in comparison to controls.	A high bias risk due to lack of randomization and potential selection bias from exclusion criteria. Objective and standardized tools reduce measurement bias. Missing data concerns are minimal, but unregistered protocols raise selective reporting risks. Overall, the study has moderate risk of bias.	Ipsilateral sensorimotor impairment may happen after a stroke.
Noskin et al., 2008³¹	To assess ipsilateral motor dysfunction after stroke.	Observation; Longitudinal; 30 acute patients (subcortical and cortical stroke, NIHSS range = 3–14).	Dynamometry (strength) and 9HPT (dexterity) at 24–48 h, 1 week, 3 months and 1 year following stroke.	Ipsilateral dexterity dysfunction was present at each time point and correlated with initial impairment; this was not found for hand strength.	A low-to-moderate risk of bias. Systematic inclusion and standardized assessments reduced randomization and measurement bias. Follow-up data were well-documented. However, the absence of pre-registration raises concerns about selective reporting. Overall, the study demonstrates strong methodology with some limitations in generalizability.	Ipsilateral motor impairment is present after stroke and persists to chronic stages;
Volz et al., 2017³²	To assess the role of contralesional M1 during recovery of mild to moderate affected UE.	Experimental; 12 subacute to chronic patients (NIHSS mean = 4.1) and 14 healthy controls.	Repetitive TMS over unaffected hemisphere or control site during three tasks (simple reaction, maximum finger tapping, grip strength) in the early acute phase and after 3 months.	In the early phase, there were improvements in the task (finger tapping frequency only) during disruptive stimulation; after 3 months, stimulation did not interfere with task performance, similar to healthy controls.	A moderate risk of bias. Concerns include limited sample size, potential selection bias, and lack of blinding in the analysis of fMRI data. Confounding factors, such as variability in rehabilitation and time since stroke, may influence outcomes. Reporting bias appears low, ensuring transparency.	Contralesional M1 may have a task- and time-specific influence on motor performance of the affected hand.
Schaefer et al., 2007³³	To determine whether different features of UE control could characterize ipsilesional motor deficits.	Experimental; 10 right-handed patients with left- or right-hemisphere stroke (UP FMA mean: left = 86.2 and right = 61.0 ± 32.4) and 16 healthy controls.	Assessment of targeted single-joint elbow movements (reaching) with the UE ipsilateral to the affected hemisphere.	Patients with left (dominant) hemisphere damage showed reduced modulation of acceleration amplitude ipsilaterally whereas patients with right (nondominant) hemisphere damage showed significantly larger errors in the final position, which corresponded to reduced modulation of acceleration duration.	A moderate risk of bias. Objective kinematic measures reduced measurement bias, and missing data were minimal. However, the lack of randomization and pre-registration raises concerns about selective reporting and generalizability. Methodological consistency ensures reliability within the study's observational design framework.	Support the idea that each hemisphere contributes differentially to the control of initial trajectory and final position and that ipsilesional deficits following stroke reflect this lateralization in control.
Lewis and Perreault, 2007³⁴	To determine how stroke lesion side influences motor performance in bimanual tasks.	Experimental; 15 chronic patients (cortical and subcortical stroke, FMA mean = 42) and 9 healthy controls.	Assessment of unimanual and symmetric and asymmetric bimanual tasks; TMS during isometric muscle activation.	Patients with left hemiparesis showed a stronger advantage for symmetric bimanual tasks compared to asymmetric. Interlimb coupling was stronger during homologous activation of muscles in the unaffected limb. These results were not seen in patients with right hemiparesis (left hemisphere damage).	A low risk of measurement and data bias due to standardized TMS protocols and clear task instructions. However, the lack of randomization, small sample size, and absence of pre-registration raise concerns about selection and reporting biases, limiting the generalizability of its findings.	The left hemisphere seems to have a specific role in controlling bimanual symmetric movements.
Yelnik et al., 1996³⁵	To analyze ipsilateral behavioral adaptation during a complex manual task.	Observational; 36 subacute patients (cortical stroke) and 86 healthy controls.	Two manual complex tasks: Pig-Tail and 9HPT (errors, duration).	Patients were worse than controls regardless of the side of the lesion.	A high risk of bias due to its observational design and lack of randomization. Objective measures like task performance metrics reduced measurement bias. Missing data risks are minimal, but selective reporting concerns arise due to the absence of pre-registration. Overall, moderate bias.	Ipsilateral motor disturbances during complex tasks happen after a stroke.
Colebatch and Gandevia, 1989³⁶	To determine the distribution of upper motor neuron weakness.	Observational; 16 subacute to chronic patients and 14 healthy controls.	Myometer and dynamometry for 12 UE muscles and hand grip.	In patients the strength of muscles ipsilateral to the lesion was reduced compared with controls; weakness was more markedly in distal wrist and finger flexors and hand grip.	A moderate risk of bias. While it used objective kinematic analysis to reduce measurement bias, the observational design, lack of randomization, and potential selection bias are concerns. The absence of pre-registration raises risks of selective reporting, though methodology was consistent.	Ipsilesional weakness is predominantly present distally in the ipsilateral arm.
Sunderland, 2000³⁷	To assess ipsilateral motor recovery 6 months after stroke.	Observational; 24 subacute patients (cortical stroke) and 34 healthy controls.	Dynamometry (grip strength), dexterity (JHFT bean spooning), and motor function tests (Extended Motricity Index and Action Imitation).	Recovery occurred on all outcomes; left hemisphere patients remained impaired in ipsilateral dexterity	A moderate risk of bias. While objective measures like grip strength and dexterity tests reduced measurement bias, the lack of randomization and pre-registration raises concerns about selection and reporting biases. Missing data from 20% of participants may also influence generalizability of findings.	Ipsilateral impairment recovers throughout 6 months with more persistent severity in left-hemisphere damage; ipsilateral impairment has a small impact on functionality.
Hermsdörfer, Blankenfeld, and Goldenberg, 2003³⁸	To evaluate the consequences of left and right brain damage for discrete aiming movements of the ipsilateral hand.	Observational; 24 subacute to chronic patients (cortical stroke).	Pointing task; imitation of meaningless gestures; ultrasonic motion measurement.	Patients with left hemisphere damage showed ipsilateral impaired pointing movements, exacerbated when high accuracy was required.	A moderate risk of bias. Standardized kinematic assessments reduced measurement bias, but the lack of randomization and pre-registration raises concerns about selective reporting. Missing data were minimal, though observational design limits generalizability. Findings align with objectives but warrant cautious interpretation	This reinforces the role of the left hemisphere in motor programming and execution of ipsilateral movements which increases with demand.
Hermsdörfer and Goldenberg, 2002³⁹	To evaluate the consequences of left and right brain damage for elementary 13diadochokineti14c moveme15nts of the 16ipsilateral 17hand.	Observational; 38 subacute to chronic patients (cortical and subcortical stroke).	Three diadochokinetic hand movements: forearm prono-supination, hand and index finger tapping; ultrasonic motion measurement.	Diadochokinetic movements were more impaired in left-hemisphere-damaged patients, especially during forearm movements.	A moderate risk of bias. Standardized diadochokinetic tasks and ultrasonic motion tracking ensured low measurement bias. Missing data were negligible, but the lack of randomization and pre-registration raises concerns about selection and reporting bias, limiting generalizability of findings to broader populations.	This reinforces the dominant role of the left hemisphere to control alternating ipsilateral arm movements after a stroke.
Chollet et al., 1991⁴⁰	To explore brain activation changes after 16recovery fro17m stroke.	Observational; 6 recovered patients.	Measurements of cerebral blood flow by positron tomography at rest and during finger movements of the recovered hand and contralateral hand.	Cerebral blood flow increased significantly in the contralateral primary SMC and the ipsilateral cerebellar hemisphere during the unaffected hand movements; Significant cerebral blood flow increases were observed in both the contralateral and ipsilateral primary sensorimotor cortex and in both cerebellar hemispheres during the movement of the recovered hand.	A moderate risk of bias. Objective PET imaging and consistent motor tasks reduced measurement bias, and no missing data were reported. However, the lack of randomization and pre-registration raises concerns about selection and reporting biases, limiting the generalizability of findings.	This supports the idea that ipsilateral motor pathways may play a role in the recovery of motor function after ischemic stroke.
Metrot et al., 2013⁴¹	To investigate time-related changes in motor performance of the UE ipsilateral to the affected hemisphere.	Observational; 19 subacute patients (supratentorial stroke, mild to severe) and 9 healthy controls.	Clinical (FMA, BBT, 9HPT, Barthel Index) and kinematic (during the reach-to-grasp task) weekly assessments between 6 weeks and 3 months after study inclusion.	Recovery of ipsilesional UE capacities increased over time and leveled off after 6 weeks of rehabilitation (9 weeks poststroke). At discharge, patients demonstrated similar ipsilesional clinical scores to controls but exhibited less smooth reaching movements. No hemispheric lesion side effect was found.	A low-to-moderate risk of bias. Systematic inclusion criteria and validated clinical and kinematic measures reduced bias risks. Missing data were appropriately managed. However, the observational design and absence of pre-registration raise concerns about randomization and selective reporting, limiting generalizability of findings.	Long-term ipsilesional UE dysfunction persists at least three months after stroke.
Riecker et al., 2010⁴²	To 18test the assump19tion that 20functionally relevant areas within the ipsilateral motor system would be coupled with the demand of a hand task.	Experimental; 8 chronic well-recovered patients (subcortical stroke) and 8 healthy controls.	fMRI and acoustically paced index finger tapping movements at increasing frequencies with the recovering right hand.	Hemodynamic response increased linearly in patients and controls (left SMA and the left primary SMC). In contrast, a linear increase of the hemodynamic response with higher tapping frequencies in the right PM and the right SMC was only seen in patients.	A moderate risk of bias due to a small sample size, potential detection bias from unblinded fMRI analysis, and inadequate control for confounders like rehabilitation history. However, transparent reporting and appropriate experimental design mitigate selective reporting concerns, supporting cautious interpretation of results regarding adaptive plasticity.	Enhanced bihemispheric recruitment of motor areas during a demanding task likely reflects adaptive plasticity.
Lotze et al., 2006⁴³	To explore the functional relevance of contralesional cortical areas.	Experimental; 7 well-recovered chronic patients (subcortical stroke, NIHSS = 1, MRC = 5).	Repetitive TMS over PMd, M1, and superior parietal lobe (SPL) during sequential finger movement performance in the paretic hand.	Repetitive TMS resulted in significant interference with recovered task performance in patients in terms of timing errors (PMd, M1) and timing and accuracy deficits (SPL).	A moderate risk of bias due to its small sample size, potential detection bias from unblinded analysis of neuroimaging data, and confounding factors like individual differences in stroke severity and recovery. However, transparent reporting reduces concerns about selective reporting bias, supporting cautious interpretation.	The persistent contralesional activity after recovery indicates a beneficial role of the contralesional PMd, M1, and SPL on some aspects of complex motor behavior.
Ferris et al., 2018⁴⁴	To investigate differences between affected and unaffected hemispheric plasticity after stroke.	Experimental; 22 chronic patients (stroke, FMA mean = 40).	Sensorimotor assessment (FMA); Paired Associative Stimulation (PAS).	PAS in the contralesional hemisphere caused an increase in corticospinal tract excitability, varying as a function of UE impairment severity; no changes after PAS in the ipsilesional hemisphere.	A moderate risk of bias due to convenience sampling, lack of blinding during TMS data analysis, and inadequate control for confounding factors like prior rehabilitation. However, selective reporting bias appears low, supporting cautious interpretation of results within its methodological constraints.	Contralesional hemisphere plasticity compensation depends on the extension of damaged ipsilesional corticospinal tracts.
Antelis et al., 2017⁴⁵	To investigate neural decoding of the attempt to move the paralyzed UE from unaffected hemisphere signals.	Experimental; 6 chronic patients.	EEG-EMG during a unilateral am task (reaching).	Greater event-related power desynchronization/synchronization activity during ipsilaterally affected arm movement. Decoding movement information from the unaffected hemisphere was possible.	A moderate risk of bias due to unclear patient selection criteria, potential detection bias from limited blinding, and possible confounding factors like stroke severity or rehabilitation differences. Additionally, reporting bias and unvalidated EEG decoding methods could influence the study's reliability and generalizability	The unaffected hemisphere has movement representations of the affected UE.
Bestmann et al., 2010⁴⁶	To explore how contralesional PMd might support motor function after stroke.	Experimental; 12 chronic patients (subcortical stroke, MRC ≤ 4+).	Paired-pulse TMS at rest (contralesional PMd-ipsilesional M1); TMS over contralesional PMd and fMRI (during hand grip and rest).	PMd influence became less inhibitory/more facilitatory in patients associated with greater impairment; fMRI activity was increased in posterior parts of the ipsilesional sensorimotor cortex during hand grip.	A moderate risk of bias. Limitations include a small sample size, potential detection bias from unblinded TMS-fMRI analysis, and unaddressed confounding factors like differences in stroke severity and recovery trajectories. However, thorough reporting minimizes selective reporting bias, supporting cautious interpretation of the findings.	Contralesional PMd seems to support recovered function through modulation of ipsilesional sensorimotor areas.
Marshall et al., 2000⁴⁷	To follow cortical activation throughout motor recovery.	Observational, longitudinal; 8 acute patients (subcortical stroke) and 6 healthy controls.	Serial fMRI during a finger-thumb opposition task, a few days, and 3 and 6 months after stroke.	Bilateral activations were seen in patients and controls. Yet, patients showed greater activation in ipsilateral sensorimotor, posterior parietal, and bilateral prefrontal regions than controls. The ratio of contralateral to ipsilateral activation increased over time in the function of hand motor recovery.	A moderate risk of bias. Small sample size, no randomization, and potential selection bias, but rigorous PET imaging and consistent protocols minimize measurement bias.	Increased activation of the ipsilateral unaffected hemisphere is associated with the recovery process.
Gould et al., 2021⁴⁸	To investigate the underlying mechanisms for the left hemiparesis after the subsequent left 21hemisphere lesion.	Case report; 61-year-old woman with a first right frontal stroke and a left recovered hemiparesis, and a subsequent left subdural hematoma leading to further left hemiparesis.	fMRI, Diffusion Tensor Imaging (DTI), and intraoperative cortical stimulation.	Expected contralateral activation for right-sided motor tasks but bilateral activation for left-sided tasks. DTI showed normal corticospinal and spinothalamic tracts. Intracortical stimulation elicited ipsilateral responses in some areas.	As a case report of a single individual, the study carries a high risk of bias in terms of generalizability. Findings from one person’s unique medical history and response to injury may not apply broadly to other cases.	Suggestive reorganization after the first stroke with left M1 perhaps taking over the left-side motor function.
Bütefisch et al., 2005⁴⁹	To investigate the bihemispheric activation during strictly unilateral movement of the paretic hand.	Experimental; 8 subacute patients with good hand recovery (motricity index = 75) and 9 healthy controls.	fMRI at rest and task (finger movements); EMG (extensor digitorum communis muscles); hand function tested before and after 8 weeks of neurorehabilitation.	Bilateral recruitment of M1 and premotor areas was evident in five well-recovered patients with strictly unilateral performance.	A moderate risk of bias. A small sample size limits generalizability, and the lack of blinding during fMRI analysis could introduce detection bias. Additionally, potential confounders, such as variations in neurorehabilitation, were not thoroughly addressed. However, reporting bias is minimal, supporting cautious interpretation.	The bilateral increased cortical recruitment in motor areas suggests an adaptive response.
Kwon BM, et als. Brain Neurorehabil. 2022⁵⁰	To investigate the relationship between ipsilesional upper extremity (UE) motor function and the integrity of the corpus callosum in stroke patients.	Retrospective observational study. 20 stroke patients (10 with left lesions, 10 with right lesions) with ipsilesional upper extremity motor deficits. -Unilateral stroke onset within 3 months. -Ipsilesional Jebsen-Taylor Hand Function Test (JHFT) score < 91. - Mini-Mental State Examination (MMSE-K) score > 18.	Motor Performance: JHFT total score and subtests (e.g., simulated feeding, lifting objects). 9HPT completion time (hand dexterity). Grip and pinch strength (mean of three trials). Neuroimaging: Fractional anisotropy (FA) values from DTI for five corpus callosum subregions: Region I: Prefrontal area. Region II: Premotor and supplementary motor cortices. Region III: Primary motor cortex. Region IV: Primary sensory cortex. Region V: Parietal, temporal, and occipital cortices.	Left callosal region I FA values correlated with ipsilesional UE motor function in the left-lesioned group. Right-lesioned group showed no significant correlations.	Moderate: No randomization, small sample size, retrospective design; however, validated tools and clear methodology minimized bias.	Highlights the role of callosal integrity in ipsilesional motor recovery, emphasizing tailored rehabilitation strategies for specific lesion profiles.
Schwerin et al., 2008⁵¹	To evaluate the presence and magnitude of ipsilateral and contralateral projections to the pectoralis major.	10 chronic patients (subcortical stroke, FMA UE range = 14–58, CMSA range = 2–7).	TMS-elicited MEP over ipsilesional and contralesional hemispheres during shoulder adduction (Biodex system).	Ipsilateral MEPs were more common in patients with moderate to severe impairments; the magnitude of ipsilateral projections correlated with impairment level and the extension of synergy in 24the arm, but not with strength.	A moderate risk of bias. Limitations include a small sample size and potential detection bias due to a lack of blinding in analyzing cortical motor projections. Confounding factors, such as variation in stroke chronicity and rehabilitation, were not fully addressed. Reporting bias appears minimal.	Increased ipsilateral projections excitability to the proximal arm may contribute to the expression of abnormal synergy after stroke.
Netz, Lammers, and Hömberg, 1997⁵²	To assess ipsilateral affected hand muscle responses to unaffected hemisphere stimulation.	Observational; 15 chronic patients (cortical and subcortical stroke) and 12 healthy controls.	TMS-MEP.	Ipsilateral MEPs were elicited only in two control subjects (at maximal intensities); in patients, they were recorded only in poor recovery at lower thresholds, but not in patients with good recovery. These responses were longer in latency than contralateral responses; ipsilateral silent periods were longer and contralateral unaffected hand thresholds were elevated than in controls.	A moderate risk of bias. The small sample size and lack of blinding during TMS-MEP analysis may introduce detection bias. Additionally, limited control of confounding factors like stroke location and recovery interventions affects the validity. However, reporting bias appears minimal, supporting cautious interpretation.	Though ipsilateral projections are unmasked after stroke, they are of little relevance for motor recovery.
Klomjai et al., 2022.⁵³	To investigate the role of ipsilateral corticospinal pathways in affected UE spinal neuron networks.	Experimental (sham-controlled); 21 subacute to chronic patients (cortical and subcortical stroke).	Anodal tDCS was applied over the unaffected M1 combined with monosynaptic H-reflex (reciprocal inhibition in wrist flexors and extensors).	Anodal tDCS decreased reciprocal inhibition in wrist flexors in both arms; results suggest ipsilateral control unmasking from the unaffected hemisphere onto spinal motor networks.	A moderate risk of bias. Key concerns include a small sample size, lack of blinding during tDCS application and data analysis, and potential confounding factors such as variability in stroke severity and prior rehabilitation. However, Mixed model analysis used to control for variables- Some data missing due to participant availability	Stimulation of the undamaged cortex induces modulation of ipsilateral motor networks controlling the hemiparetic side.
Caramia et al., 2000⁵⁴	To investigate ipsilateral activation of the unaffected hemisphere during recovery.	Observational, longitudinal; 14 acute patients (subcortical strokes, NIHSS range = 7–13) and 20 healthy controls.	TMS and Transcranial Doppler (TCD) of M1 at 48 h and 6 months after stroke; thumb to finger opposition task.	Ipsilateral MEPs from hand muscles were found in recovered patients; in 8 controls MEPs with smaller amplitudes were obtained by left hemisphere stimulation; TCD revealed increased blood flow velocity ipsilaterally to the recovering hand.	A moderate risk of bias. Limitations include a small sample size and potential detection bias from the lack of blinding during TMS and TCD data interpretation. Additionally, variability in stroke severity and recovery may act as confounders. Reporting bias appears low, supporting careful analysis.	Ipsilateral MEPs at rest can be elicited in the unaffected hemisphere; It is possible to elicit ipsilateral TMS responses in some healthy controls.
Werhahn et al., 2003⁵⁵	To test if disruption of the non-lesioned hemisphere would generate ipsilateral abnormal motor behavior.	Experimental; 20 chronic patients (cortical and subcortical stroke, FMA UE mean = 66.3, MCR mean = 3.6) and 10 healthy controls.	Repetitive TMS over motor cortex during a finger tapping task.	TMS over the intact hemisphere resulted in delayed simple reaction times (RTs) in the contralateral healthy but not in the ipsilateral paretic hand, whereas stimulation of the lesioned hemisphere led to a marked delay in RT in the contralateral paretic hand but not in the ipsilateral unaffected hand.	A moderate risk of bias. Key concerns include a small sample size, potential detection bias due to lack of blinding in neuroimaging and TMS data analysis, and possible confounding from variability in chronic stroke recovery. Transparent reporting reduces the risk of selective reporting bias.	The recovered motor function of the paretic hand may rely on reorganization within the motor areas of the affected hemisphere.
Zhang et al., 2024⁵⁶	Experimental, RCT; 35 subacute to chronic patients (FMA UE range = 4–46) and 16 healthy controls.	To explore brain reorganization after mirror therapy (including recruitment of ipsilateral motor pathways).	Resting-state fMRI; motor function assessment (FMA).	Improvement in the mirror therapy group was associated with a compensatory increase in the fractional amplitude of low-frequency fluctuations in M1 and enhanced functional connectivity between bilateral M1 regions.	A moderate risk of bias. Potential concerns include a small sample size, unblinded analysis of resting-state fMRI data, and confounding factors such as variability in stroke severity and rehabilitation history. However, comprehensive reporting minimizes the risk of selective reporting bias, supporting cautious interpretation.	MT likely achieved motor rehabilitation primarily by recruitment of the ipsilateral motor pathways.
Delvaux et al., 2003⁵⁷	To test prospectively corticospinal excitability changes and reorganization of FDI muscle.	Observational, longitudinal; 31 acute patients (mostly cortical strokes, MCR = 0–2) and 20 healthy controls.	Clinical assessment (MRC, Rankin, NIHSS, and Barthel Index) and focal M1 TMS at day 1, 8, 30, 90, 180, and 360 after stroke.	Persistence of MEP on the affected side at day 1 was a strong predictor of good recovery and was significantly smaller than the opposite side or healthy controls; At day 1, amplitudes of MEPs obtained in unaffected FDI were significantly larger than later.	A moderate risk of bias. The small sample size and lack of blinding in TMS data analysis introduce potential detection bias. Additionally, confounding factors such as individual differences in stroke severity and rehabilitation interventions were not fully addressed. Reporting bias appears low, ensuring transparency.	Findings indicate that the brain insult induces a transient (a few days after stroke) hyperexcitability of the contralesional M1.
Bütefisch et al., 2003⁵⁸	To investigate remote changes in intracortical excitatory and inhibitory activity are present in the non-affected hemisphere of recovering patients.	Experimental; 13 patients with good recovery and 5 patients with poor recovery of hand function (cortical and subcortical stroke) and 13 healthy controls.	Paired-pulse TMS over non-affected hemisphere (M1 on FDI muscle).	Patients with good recovery and healthy subjects had similar inhibitory effects at low conditioning stimulus intensities; in the recovering patients there was an increase in conditioned MEP amplitude at higher conditioning stimulus 33intensities; suggesting that in the patients' contralesional M1, the balance of excitatory and inhibitory activity was shifted towards an increase of excitatory activity (in neuronal circuits tested at interstimulus interval of 2 and 3 ms).	A moderate risk of bias. Concerns include a small sample size, lack of blinding in assessing cortical excitability, and potential confounding factors such as variability in stroke chronicity and prior treatments. However, thorough reporting minimizes selective reporting bias, supporting cautious interpretation of the findings.	This finding may guard similarities with re-organizational processes after experimental brain injury and may have an impact on functional recovery as indicated by the absence of changes in cortical excitability in patients with poor recovery.
Murase et al., 2004⁵⁹	To test if the lesioned M1 would receive abnormal inhibitory influences from the intact M1 during a task performed with the paretic hand.	Experimental; 9 chronic patients (subcortical stroke) and 8 healthy controls.	Reaction time task (finger press); Paired-pulse TMS (IHI).	IHI was similar between patients and healthy subjects at rest. Close-to-movement onset controls displayed a switch to facilitation, whereas patients exhibited sustained inhibition from the intact to the lesioned hemisphere, which 30correlated with poorer motor performance.	A moderate risk of bias due to a small sample size and potential detection bias from unblinded analysis of interhemispheric interactions using TMS. Variability in chronic stroke recovery and confounding factors such as rehabilitation were not fully addressed. Reporting was transparent, minimizing reporting bias.	These results document an abnormally high interhemispheric inhibitory drive from M1(intact hemisphere) to M1(lesioned hemisphere) in the process of generation of a voluntary movement by the paretic hand, which could adversely influence motor recovery in some patients.
Xu et al., 2019⁶⁰	To investigate the evolution of premovement IHI over the first year after stroke concerning hand function.	Observational, longitudinal; 22 acute patients (FMA UE range = 4–65) and 11 matched healthy controls.	Paired-pulse TMS (IHI) during rest and movement preparation (reaction-time task).	Premovement IHI was normal during the acute/subacute period but turned abnormal at the chronic stage (being kept in pre-movement and movement onset); as motor recovery improved IHI increased;	A moderate risk of bias. While it employs advanced neuroimaging and robust statistical methods, limitations include a small sample size, potential selection bias, and unblinded analysis of interhemispheric interactions. Confounding factors such as variability in stroke severity were not comprehensively addressed. Reporting bias appears low.	IHI imbalance might not be a cause of poor motor recovery but a consequence of underlying recovery processes.
Zimerman et al., 2012⁶¹	To test the capacity of cathodal tDCS over the contralesional hemisphere to enhance task acquisition and retention.	Experimental; cross-over; 12 well-recovered chronic patients (subcortical stroke) with mild impairment (FMA UE mean = 64, MRC mean = 29).	Cathodal or sham tDCS over contralesional M1 at two training sessions of a complex finger task (reassessed 90 min. and 24 h after intervention).	tDCS facilitated the acquisition of motor skill with better task retention; a significant correlation was observed between improvement during the training and intracortical inhibition.	A moderate risk of bias due to a small sample size, lack of blinding during tDCS application, and potential confounding from baseline motor variability and rehabilitation histories. However, transparent reporting of methods and results mitigates concerns, 27supporting careful interpretation of findings.	Inhibition of contralesional M1 can improve motor learning and performance after stroke.
Rehme et al., 2011⁶²	To in18vestigate the p19attern and ti20me course of acute stroke-induced changes in motor system activity.	Observational, longitudinal; 11 acute patients (cortical and subcortical stroke, NIHSS = 4, ARAT = 35).	fMRI and motor function assessments (action research arm test, maximum grip force) were performed 3 times during the first 2 weeks starting within 72 hours after stroke.	Bihemispheric increases of activity in M1, PMd, PMv, and SMA significantly correlated with motor recovery. These changes depended upon the degree of initial motor impairment: patients with mild deficits did not differ from healthy subjects. In contrast, patients with severe deficits were characterized by a global reduction of task-related activity, followed by increases in ipsilesional and contralesional motor areas.	A moderate risk of bias. Standardized fMRI protocols and objective motor function assessments minimized measurement bias. Missing data were negligible, but the lack of randomization and pre-registration raises concerns about selection and reporting biases, affecting the generalizability of findings.	Gradually increasing activity in contralesional motor areas correlates with improved functional recovery, indicating an early cortical reorganization supporting hand function recovery.

Baseline motor function data reported in the second column refer to the motor function of the UE of the hemiparetic side. FMA, Fugl-Meyer Assessment; UE, upper extremity; fMRI, Functional Magnetic Resonance Imaging; TMS, Transcranial Magnetic Stimulation; JHFT, Jebsen-Taylor hand function test; 9HPT, Nine-Hole Peg test; IHI, Interhemispheric Inhibition; EEG, Electroencephalography; EMG, Electromyography; NIHSS, National Institute of Health Stroke Scale; BBT, Box and Block Test; MRC, Medical Research Council; ARAT, Action Research Arm Test; M1, primary motor cortex; PM, premotor cortex, dorsal (PMd), ventral (PMv); SMA, supplementary motor area; SMC, sensorimotor cortex; CMSA, Chedoke-McMaster Stroke Assessment; MEP, motor-evoked potential; FDI, first dorsal interosseous.

3.1 Summary of main findings

3.1.1 Findings from animal models of stroke

Animal studies demonstrated significant contributions of the contralesional motor cortex to ipsilateral motor recovery. Following middle cerebral artery occlusion (MCAO), the contralesional motor cortex undergoes significant reorganization, including increased dendritic length, sprouting, neuronal recruitment, and synaptic formation in sensorimotor cortex and the red nucleus. These changes were paralleled by improvements in forelimb function, suggesting activity-dependent recovery [25, 26]. Constraint-induced movement therapy (CIMT): In one study, restricting the unaffected limb during recovery amplified cortical plasticity, mimicking the effects of constraint-induced movement therapy, led to pronounced reorganization within the contralesional hemisphere [25]. The role of the contralesional motor cortex was further validated through transient inactivation experiments. Lidocaine hydrochloride injection reinstated impairments in animals with large lesions, whereas animals with small lesions showed only partial deficits. These findings highlight the dependency of contralesional compensation on lesion size [27]. In primates, motor cortex lesions caused deficits in contralesional hand function. Recovery of the paretic hand correlated with contralesional hand performance, emphasizing the role of the contralesional hemisphere in motor recovery [28].

3.1.2 Findings from individuals after stroke

Research on the role of the contralesional motor cortex in post-stroke recovery focuses on understanding the reorganization of brain functions and the compensatory neural mechanisms that aid motor recovery. Various studies have employed different methodologies, including functional Magnetic Ressonance Imaging (fMRI), Transcranial Magentic Stimulation (TMS) either single, paired-pulse, paired associative, or repetitive stimulation, Diffusion Tensor Imaging (DTI), and clinical assessments and experimental tasks, to explore how the contralesional motor cortex contributes to the recovery of motor functions [29].

Ipsilateral motor deficits

Several studies documented persistent motor impairments in the upper limb ipsilateral to the lesioned hemisphere after stroke. These deficits primarily included reduced dexterity, strength, and movement sequencing, persisting into chronic stages. For instance, Baskett et al. [30] observed coordination deficits during bimanual tasks. Similarly, Noskin et al. [31] reported diminished fine motor control in the ipsilateral upper limb during chronic recovery. Volz et al. [32] found impairments in smoothness of reaching movements that persisted up to one year after stroke, while Schaefer et al. [33] noted deficits in strength and trajectory control in the ipsilateral limb. The nature of these impairments varied based on lesion laterality, with left hemisphere lesions affecting symmetrical bilateral coordination studied by Yarosh et al [29] and right hemisphere lesions disrupting acceleration modulation found by Lewis and Perreaul [34].

Yelnik et al. [35] added evidence of impaired proprioception in the ipsilateral upper limb during both acute and chronic phases, linking sensory deficits to decreased motor precision. Colebatch and Gandevia [36] demonstrated altered cortical control mechanisms in the ipsilateral upper limb, suggesting that these changes result from compensatory activity in the contralesional motor cortex. These findings expand on the understanding of ipsilateral motor deficits by emphasizing the role of disrupted sensorimotor integration.

Additional findings by Sunderland [37] showed significant impairments in hand dexterity and coordination during bilateral tasks. Hermsdörfer, Blankenfeld, and Goldenberg [38] further identified disruptions in movement sequencing and grip control, with Hermsdörfer and Goldenberg [39] emphasizing that these deficits were task-dependent and most evident in complex movements. Chollet et al. [40] demonstrated that left hemisphere lesions resulted in more pronounced ipsilateral motor deficits, likely reflecting the lateralized control of fine motor functions. Metrot et al.[41] found that these deficits were amplified during precision tasks, underscoring the challenges faced by patients during recovery.

Contralesional motor cortex recruitment

Neuroimaging studies highlighted the role of the contralesional motor cortex in motor recovery, particularly in patients with severe impairments. Riecker et al. [42] demonstrated increased contralesional activation in M1, premotor areas (PM), and supplementary motor areas (SMA), which correlated positively with motor recovery. This bihemispheric activation was task-dependent and linear in nature, as confirmed by Lotze et al. [43], who reported enhanced hemodynamic responses during more complex tasks. Similarly, Ferris et al. [44] observed that increased contralesional cortical activity predicted kinematic aspects of paretic hand movement. Antelis et al. [45] further validated these findings, showing contralesional cortical decoding capabilities during voluntary motor tasks. In chronic recovery, Bestmann et al. [46] found that contralesional motor cortex activity was predominantly recruited during high-demand tasks, especially in proximal muscle movements.

Added findings include Marshall et al. [47], who noted that contralesional motor activity was prominent during early recovery phases but decreased as ipsilesional motor function improved. Gould et al. [48] confirmed the dynamic and adaptive nature of contralesional recruitment, highlighting its importance during early recovery. Bütefisch et al. [49] found that excessive contralesional activation in milder impairments delayed ipsilesional motor reorganization, reflecting its dual role in recovery.

Kwon BM, et al. [50] highlighted the efficacy of repetitive transcranial magnetic stimulation (rTMS) in modulating contralesional motor activity, improving motor performance in severely impaired patients. This study demonstrated that contralesional recruitment can be targeted and enhanced through neuromodulation, providing a promising avenue for therapeutic interventions.

Ipsilateral motor pathways

The activation of ipsilateral corticospinal and reticulospinal pathways emerged as a consistent finding across multiple studies. Ipsilateral motor-evoked potentials (MEPs) were elicited more frequently in recovering patients, particularly in those with poor recovery, suggesting unmasking of these pathways. Schwerin et al. [51] and Netz, Lammers, and Hömberg [52] reported lower thresholds for ipsilateral MEPs in paretic hand muscles, indicating heightened activity in ipsilateral corticospinal tracts. However, ipsilateral responses were weaker and slower than contralateral responses, found by Klomjai et al. [53] and Caramia et al. [54]. Proximal muscles, such as the pectoralis major, showed stronger ipsilateral responses, correlating with the severity of motor impairments and the extent of abnormal synergy, reported by Werhahn et al.[55]; Volz et al.[32].

Zhang et al. [56] demonstrated that ipsilateral pathways were more active during tasks requiring significant proximal muscle engagement, reflecting their compensatory role in maintaining gross motor function. Delvaux et al. [57] and Bütefisch et al. [58] further highlighted the task-specific activation of these pathways, correlating with the severity of motor impairments.

Interhemispheric dynamics

The balance of interhemispheric inhibition (IHI) emerged as a critical factor influencing recovery. Studies like Murase et al. [59] found that excessive contralesional inhibition delayed recovery in the ipsilesional motor cortex, particularly in patients with milder impairments. Conversely, in patients with severe deficits, enhanced contralesional excitability facilitated compensatory mechanisms studied by Xu et al.[60]. These findings were echoed by Zimerman et al.[61], who reported that reducing IHI via cathodal transcranial direct current stimulation (tDCS) improved task performance in the paretic hand. Rehme et al.[62] further demonstrated that the degree of contralesional facilitation was proportional to the extent of ipsilesional damage, emphasizing the adaptive nature of contralesional motor cortex activation.

Neuromodulation and task-specific training

Neuromodulation approaches, including tDCS and repetitive transcranial magnetic stimulation (rTMS), showed promising but varied effects on contralesional motor activity. Klomjai et al. [53] and Zimerman et al. [61] demonstrated that anodal tDCS enhanced ipsilateral corticospinal activity, leading to improvements in wrist flexor function in the paretic hand. Conversely, repetitive TMS disrupted task accuracy and timing in well-recovered patients, particularly during complex motor tasks [39]. Task-specific training approaches, such as constraint-induced movement therapy (CIMT) and mirror therapy, promoted bilateral motor coordination and engaged contralesional motor areas effectively reported by Lotze et al.[36] and Metrot et al.[49].

Structural and functional plasticity

Contralesional motor areas underwent significant structural and functional reorganization after stroke. Studies by Bütefisch et al.[50] revealed increased dendritic arborization and synaptic remodeling in the contralesional cortex. These changes were associated with enhanced ipsilateral motor performance, particularly in patients with severe ipsilesional damage. Ferris et al. [44] further demonstrated that these adaptations were task-specific, underscoring the importance of targeted rehabilitation strategies. Chollet et al. [38] highlighted the role of structural adaptations in supporting motor recovery, while Delvaux et al. [54] emphasized their significance in maintaining functional outcomes.

Role of ipsilateral descending pathways

Ipsilateral corticospinal and reticulospinal pathways played a compensatory role in upper limb recovery. Zhang et al. [56] and Rehme et al. [62] found these pathways to be more active during tasks requiring proximal muscle engagement. Their activity increased in proportion to impairment severity, supporting the hypothesis that these pathways compensate for contralesional corticospinal deficits. Caramia et al. [54] and Netz et al. [52] suggested that this unmasking of ipsilateral pathways is critical for maintaining motor function in severely impaired patients.

4. Discussion

This scoping review synthesizes evidence from animal and human studies to explore the role of the contralesional primary motor cortex in upper limb recovery after stroke. The findings highlight a dual role of the contralesional motor cortex: compensatory in cases of severe impairments and potentially maladaptive in milder impairments. Ipsilateral corticospinal and reticulospinal pathways, once considered secondary to contralateral pathways, appear to play a critical role in stroke motor recovery, particularly in the context of structural and functional plasticity. This discussion integrates these findings into the broader framework of stroke recovery mechanisms, therapeutic strategies, and remaining research gaps.

Contralesional motor cortex: Adaptive and maladaptive roles

Adaptive plasticity in severe impairments

In patients with severe motor impairments, the contralesional motor cortex demonstrates strong compensatory mechanisms. Studies by Riecker et al.[42] and Ferris et al.[44] revealed Increased contralesional M1 activation during voluntary motor tasks, particularly for proximal muscles. This enhanced activation was associated with improved motor recovery, likely due to the recruitment of ipsilateral corticospinal and reticulospinal tracts. These pathways, while weaker than their contralateral counterparts, are sufficient to support proximal and gross motor function. Animal studies certify this, showing dendritic arborization, synaptic remodeling, and increased excitability in contralesional motor areas after middle cerebral artery occlusion (MCAO) [26–28]

Maladaptive dynamics in mild impairments

In contrast, excessive reliance on contralesional motor activity can hinder recovery in cases of mild impairments. Murase et al. [59] and Xu et al. [60] highlighted the role of interhemispheric inhibition (IHI) in this maladaptive process. Elevated IHI from the contralesional to the ipsilesional motor cortex delays the reorganization required for fine motor recovery. This is particularly evident in studies where repetitive transcranial magnetic stimulation (rTMS) over the contralesional motor cortex disrupted task performance in well-recovered patients [46]. These findings suggest that therapeutic interventions must balance contralesional and ipsilesional activity based on the severity of motor impairments.

Ipsilateral motor pathways: A compensatory mechanism

The unmasking of ipsilateral corticospinal and reticulospinal pathways emerges as a pivotal compensatory mechanism after stroke. Evidence from human studies demonstrates that ipsilateral motor-evoked potentials (MEPs) are more frequently elicited in recovering patients, especially in proximal muscles like the pectoralis major reported by Schwerin et al. [51] and Netz, Lammers, and Hömberg [52]. This activity is amplified in patients with severe impairments, suggesting that these pathways compensate for deficits in contralateral corticospinal tract function. However, the reliance on ipsilateral pathways comes with limitations, as they are less adept at controlling fine motor movements and finger individuation, studied by Caramia et al.[54] and Klomjai et al.[53].

Animal studies further support the role of ipsilateral pathways, showed that task-specific reorganization in ipsilateral descending tracts correlates with motor recovery in rodent models. Interestingly, when contralesional motor areas were transiently inhibited in animal models, impairments in paretic forelimb function re-emerged, underscoring the functional importance of these pathways[.

Interhemispheric dynamics in recovery

The balance between contralesional and ipsilesional motor cortex activity is critical for recovery. During normal motor function, interhemispheric inhibition ensures coordinated activity between hemispheres. After stroke, this balance is disrupted, with the contralesional motor cortex exerting excessive inhibitory control over the lesioned hemisphere, studied by Murase et al.[59] and Xu et al.[60]. This phenomenon is particularly detrimental during early recovery phases, as it delays the plasticity required for ipsilesional motor reorganization.

However, not all contralesional activity is maladaptive. Studies like Zimerman et al. [61] and Rehme et al.[62] highlight the adaptive potential of contralesional motor cortex activation, particularly in patients with extensive ipsilesional damage. Enhanced contralesional excitability may represent a compensatory mechanism to sustain motor output in the absence of sufficient ipsilesional recovery. These findings suggest that interhemispheric interactions are dynamic and context-dependent, requiring tailored therapeutic strategies.

Therapeutic implications

Neuromodulation

Non-invasive brain stimulation techniques, such as transcranial direct current stimulation (tDCS) and rTMS, offer promising avenues for modulating contralesional motor activity. Zimerman et al. [61] demonstrated that cathodal tDCS over the contralesional motor cortex reduces maladaptive activity, enhancing motor function in the paretic hand. Conversely, Klomjai et al. [53] found that anodal tDCS facilitated ipsilateral corticospinal activity, improving wrist flexor function in patients with severe impairments. These findings underscore the importance of tailoring neuromodulation approaches based on impairment severity and recovery stage.

Task-specific training

Task-specific training approaches, including constraint-induced movement therapy (CIMT) and mirror therapy, engage both hemispheres in recovery processes. Volz et al. [32] and Metrot et al.[41] reported that such training enhances bilateral motor coordination and promotes plasticity in contralesional motor areas. These approaches are particularly effective when combined with neuromodulation, creating a synergistic effect that optimizes recovery outcomes.

Timing of interventions

The timing of therapeutic interventions is crucial. Early modulation of contralesional activity may prevent maladaptive dynamics and support ipsilesional plasticity, while later interventions may enhance compensatory mechanisms in cases of severe impairments. Longitudinal studies are needed to determine the optimal timing and combination of therapies for different patient populations.

Challenges and future directions

Despite significant advancements, several questions remain unanswered as the followings:

Variability in recovery mechanisms: Why do some patients rely more on contralesional compensatory mechanisms while others depend on ipsilesional reorganization? Understanding this variability is essential for personalized rehabilitation.

Mechanisms of ipsilateral pathway activation: The precise mechanisms underlying the unmasking of ipsilateral pathways remain unclear. Are these pathways directly modulated by contralesional motor activity, or do they reflect intrinsic plasticity?

Interhemispheric inhibition: The role of interhemispheric dynamics in different stages of recovery is poorly understood. Future studies should explore how IHI changes over time and how it influences motor outcomes.

Long-term effects of neuromodulation: While short-term benefits of tDCS and rTMS are well-documented, their long-term efficacy and safety remain uncertain. More longitudinal studies are needed to address this gap.

Integration of advanced technologies: Emerging tools like real-time functional MRI (fMRI) and paired-pulse TMS could provide deeper insights into neuroplasticity mechanisms, enabling more targeted interventions.

Clinical implications

This review highlights the importance of stratified therapeutic approaches. Patients with severe impairments may benefit from interventions that enhance contralesional activity and ipsilateral pathway engagement, while those with mild impairments require strategies to suppress maladaptive contralesional activity and promote ipsilesional reorganization. The integration of neuromodulation, task-specific training, and advanced imaging techniques offers a promising path forward.

Conclusion

The contralesional motor cortex plays a dynamic role in stroke recovery, acting as both a compensatory and maladaptive system depending on impairment severity. Therapeutic strategies must balance these dynamics to optimize outcomes. By addressing the remaining research gaps, future studies can refine our understanding of stroke motor recovery and pave the way for more effective, personalized interventions.

Declarations

Ethics approval and consent to participate:

Not applicable.

Consent to publication:

Not applicable.

Data availability statement:

The datasets generated during and/or analyzed during the current study are not publicly available, but are available from the corresponding author on reasonable request.

Conflict of interest:

The authors have no relevant financial or non-financial interests to disclose.

Clinical trial number

not applicable.

Funding:

No funding.

Acknowledgements:

We would like to thank the School of Biomedical Sciences, Faculty of Medical Sciences, Newcastle University, UK and the Principles and Practice of Clinical Research (PPCR) Program, Harvard T.H. Chan School of Public Health, Harvard Medical School, Boston, Massachusetts, USA. Valton Costa is a fellow of the Institutional Internationalization Program (CAPES/PrInt/UFSCar) supported by the Brazilian Federal Agency for Support and Evaluation of Graduate Education (CAPES)/Ministry of Education of Brazil.

Author Contribution

P.S.: conceptualization, methodology development and optimization, strategic search and articles search with collection, articles analysis, data analysis and synthesis , writing the original manuscript, and writing the revised manuscript based on the editor and reviewers' comments ; V.C.: methodology development and optimization, strategic search, data analysis and synthesis, and writing of the manuscript; F.F.: supervision and resources, articles analysis, validation, and manuscript editing. All authors approved the final manuscript.

References

Lacroix S, Havton LA, McKay H, Yang H, Brant A, Roberts J, Tuszynski MH. Bilateral corticospinal projections arise from each motor cortex in the macaque monkey: a quantitative study. J Comp Neurol. 2004;473(2):147–61. 10.1002/cne.20051.

Strick PL, Dum RP, Rathelot JA. The Cortical Motor Areas and the Emergence of Motor Skills: A Neuroanatomical Perspective. Annu Rev Neurosci. 2021;44:425–47. 10.1146/annurev-neuro-070918-050216.

Dum RP, Strick PL. Spinal cord terminations of the medial wall motor areas in macaque monkeys. J Neurosci. 1996;16(20):6513–25. 10.1523/JNEUROSCI.16-20-06513.1996.

Kaas JH, Stepniewska I, Gharbawie O. Cortical networks subserving upper limb movements in primates. Eur J Phys Rehabil Med. 2012;48(2):299–306. Epub 2012 Mar 12.

Nathan PW, Smith MC, Deacon P. The corticospinal tracts in man. Course and location of fibres at different segmental levels. Brain. 1990;113(Pt 2):303–24. 10.1093/brain/113.2.303.

Kuypers HG, Lawrence DG. Cortical projections to the red nucleus and the brain stem in the Rhesus monkey. Brain Res. 1967;4(2):151–88. 10.1016/0006-8993(67)90004-2.

Keizer K, Kuypers HG. Distribution of corticospinal neurons with collaterals to the lower brain stem reticular formation in monkey (Macaca fascicularis). Exp Brain Res. 1989;74(2):311–8. 10.1007/BF00248864.

Riddle CN, Edgley SA, Baker SN. Direct and indirect connections with upper limb motoneurons from the primate reticulospinal tract. J Neurosci. 2009;29(15):4993–9. 10.1523/JNEUROSCI.3720-08.2009.

LAWRENCE, DG, KUYPERS HG. PYRAMIDAL AND NON-PYRAMIDAL PATHWAYS IN. MONKEYS: ANATOMICAL AND FUNCTIONAL CORRELATION. Science. 1965;148(3672):973–5. 10.1126/science.148.3672.973.

10.

Tanji J, Okano K, Sato KC. Relation of neurons in the nonprimary motor cortex to bilateral hand movement. Nat 1987 Jun 18–24;327(6123):618–20. 10.1038/327618a0

11.

Cisek P, Crammond DJ, Kalaska JF. Neural activity in primary motor and dorsal premotor cortex in reaching tasks with the contralateral versus ipsilesional arm. J Neurophysiol. 2003;89(2):922–42.

12.

Cross KP, Heming EA, Cook DJ, Scott SH. Maintained Representations of the Ipsilateral and Contralateral Limbs during Bimanual Control in Primary Motor Cortex. J Neurosci. 2020;40(35):6732–47. 10.1523/JNEUROSCI.0730-20.2020.

13.

Rokni U, Steinberg O, Vaadia E, Sompolinsky H. Cortical representation of bimanual movements. J Neurosci. 2003;23(37):11577–86. 10.1523/JNEUROSCI.23-37-11577.2003.

14.

Heming EA, Cross KP, Takei T, Cook DJ, Scott SH. Independent representations of ipsilateral and contralateral limbs in primary motor cortex. Elife. 2019;8:e48190. 10.7554/eLife.48190.

15.

Steinberg O, Donchin O, Gribova A, Cardosa de Oliveira S, Bergman H, Vaadia E. Neuronal populations in primary motor cortex encode bimanual arm movements. Eur J Neurosci. 2002;15(8):1371–80. 10.1046/j.1460-9568.2002.01968.x.

16.

Montgomery LR, Herbert WJ, Buford JA. Recruitment of ipsilateral and contralateral upper limb muscles following stimulation of the cortical motor areas in the monkey. Exp Brain Res. 2013;230(2):153–64. 10.1007/s00221-013-3639-5. Epub 2013 Jul 14.

17.

Ziemann U, Ishii K, Borgheresi A, et al. Dissociation of the pathways mediating ipsilesional and contralateral motor-evoked potentials in human hand and arm muscles. J Physiol. 1999;518(Pt 3):895–906. 10.1111/j.1469-7793.1999.0895p.x. (Pt 3)(.

18.

Bawa P, Hamm JD, Dhillon P, Gross PA. Bilateral responses of upper limb muscles to transcranial magnetic stimulation in human subjects. Exp Brain Res. 2004;158(3):385–90. 10.1007/s00221-004-2031-x. Epub 2004 Aug 13.

19.

Palmer E, Ashby P. Corticospinal projections to upper limb motoneurones in humans. J Physiol. 1992;448:397–412. 10.1113/jphysiol.1992.sp019048.

20.

Tricco AC, Lillie E, Zarin W, O'Brien KK, Colquhoun H, Levac D, et al. PRISMA Extension for Scoping Reviews (PRISMA-ScR): Checklist and Explanation. Ann Intern Med. 2018;169(7):467–73.

21.

Eriksen MB, Frandsen TF. The impact of patient, intervention, comparison, outcome (PICO) as a search strategy tool on literature search quality: a systematic review. J Med Libr Assoc. 2018;106(4):420–431. 10.5195/jmla.2018.345. Epub 2018 Oct 1.

22.

Sterne JAC, Savović J, Page MJ, Elbers RG, Blencowe NS, Boutron I, Cates CJ, Cheng HY, Corbett MS, Eldridge SM, Emberson JR, Hernán MA, Hopewell S, Hróbjartsson A, Junqueira DR, Jüni P, Kirkham JJ, Lasserson T, Li T, McAleenan A, Reeves BC, Shepperd S, Shrier I, Stewart LA, Tilling K, White IR, Whiting PF, Higgins JPT. RoB 2: a revised tool for assessing risk of bias in randomised trials. BMJ. 2019;366:l4898. 10.1136/bmj.l4898.

23.

Bero L, Chartres N, Diong J, Fabbri A, Ghersi D, Lam J, Lau A, McDonald S, Mintzes B, Sutton P, Turton JL, Woodruff TJ. The risk of bias in observational studies of exposures (ROBINS-E) tool: concerns arising from application to observational studies of exposures. Syst Rev. 2018;7(1):242. 10.1186/s13643-018-0915-2.

24.

Hooijmans CR, Rovers MM, de Vries RB, Leenaars M, Ritskes-Hoitinga M, Langendam MW. SYRCLE's risk of bias tool for animal studies. BMC Med Res Methodol. 2014;14:43. 10.1186/1471-2288-14-43.

25.

Liu P, Li C, Zhang B, Zhang Z, Gao B, Liu Y, Wang Y, Hua Y, Hu J, Qiu X, Bai Y. Constraint induced movement therapy promotes contralesional-oriented structural and bihemispheric functional neuroplasticity after stroke. Brain Res Bull. 2019;150:201–6. 10.1016/j.brainresbull.2019.06.003.

26.

Gonzalez CL, Gharbawie OA, Williams PT, Kleim JA, Kolb B, Whishaw IQ. Evidence for bilateral control of skilled movements:contralesional skilled forelimb reaching deficits and functional recovery in rats follow motor cortex and lateral frontal cortex lesions. Eur J Neurosci. 2004;20(12):3442–52. 10.1111/j.1460-9568.2004.03751.x.

27.

Biernaskie J, Szymanska A, Windle V, Corbett D. Bi-hemispheric contribution to functional motor recovery of the affected forelimb following focal ischemic brain injury in rats. Eur J Neurosci. 2005;21(4):989–99. 10.1111/j.1460-9568.2005.03899.x.

28.

Kaeser M, Wyss AF, Bashir S, Hamadjida A, Liu Y, Bloch J, Brunet JF, Belhaj-Saif A, Rouiller EM. Effects of unilateral motor cortex lesion on ipsilesional hand's reach and grasp performance in monkeys: relationship with recovery in the contralesional hand. J Neurophysiol. 2010;103(3):1630–45. 10.1152/jn.00459.2009. Epub 2010 Jan 13.

29.

Yarosh CA, Hoffman DS, Strick PL. Deficits in movements of the wrist ipsilateral to a stroke in hemiparetic subjects. J Neurophysiol. 2004;92(6):3276–85. 10.1152/jn.00549.2004. Epub 2004 Aug 4.

30.

Baskett JJ, Marshall HJ, Broad JB, Owen PH, Green G. The good side after stroke: ipsilateral sensory-motor function needs careful assessment. Age Ageing. 1996;25(3):239–44. 10.1093/ageing/25.3.239.

31.

Noskin O, Krakauer JW, Lazar RM, Festa JR, Handy C, O'Brien KA, Marshall RS. Ipsilateral motor dysfunction from unilateral stroke: implications for the functional neuroanatomy of hemiparesis. J Neurol Neurosurg Psychiatry. 2008;79(4):401–6. 10.1136/jnnp.2007.118463. Epub 2007 Jul 17.

32.

Volz LJ, Vollmer M, Michely J, Fink GR, Rothwell JC, Grefkes C. Time-dependent functional role of the contralesional motor cortex after stroke. Neuroimage Clin. 2017;16:165–74. 10.1016/j.nicl.2017.07.024.

33.

Schaefer SY, Haaland KY, Sainburg RL. Ipsilesional motor deficits following stroke reflect hemispheric specializations for movement control. Brain. 2007;130(Pt 8):2146–58. 10.1093/brain/awm145. Epub 2007 Jul 11.

34.

Lewis GN, Perreault EJ. Side of lesion influences bilateral activation in chronic, post-stroke hemiparesis. Clin Neurophysiol. 2007;118(9):2050–62. 10.1016/j.clinph.2007.06.010. Epub 2007 Jul 23.

35.

Yelnik A, Bonan I, Debray M, Lo E, Gelbert F, Bussel B. Changes in the execution of a complex manual task after ipsilateral ischemic cerebral hemispheric stroke. Arch Phys Med Rehabil. 1996;77(8):806–10. 10.1016/s0003-9993(96)90261-0.

36.

Colebatch JG, Gandevia SC. The distribution of muscular weakness in upper motor neuron lesions affecting the arm. Brain. 1989;112(Pt 3):749–63. 10.1093/brain/112.3.749.

37.

Sunderland A. Recovery of ipsilateral dexterity after stroke. Stroke. 2000;31(2):430–3. 10.1161/01.str.31.2.430.

38.

Hermsdörfer J, Blankenfeld H, Goldenberg G. The dependence of ipsilesional aiming deficits on task demands, lesioned hemisphere, and apraxia. Neuropsychologia. 2003;41(12):1628–43. 10.1016/s0028-3932(03)00097-6.

39.

Hermsdörfer J, Goldenberg G. Ipsilesional deficits during fast diadochokinetic hand movements following unilateral brain damage. Neuropsychologia. 2002;40(12):2100–15. 10.1016/s0028-3932(02)00048-9.

40.

Chollet F, DiPiero V, Wise RJ, Brooks DJ, Dolan RJ, Frackowiak RS. The functional anatomy of motor recovery after stroke in humans: a study with positron emission tomography. Ann Neurol. 1991;29(1):63–71. 10.1002/ana.410290112.

41.

Metrot J, Froger J, Hauret I, Mottet D, van Dokkum L, Laffont I. Motor recovery of the ipsilesional upper limb in subacute stroke. Arch Phys Med Rehabil. 2013;94(11):2283–90. 10.1016/j.apmr.2013.05.024. Epub 2013 Jun 22.

42.

Riecker A, Gröschel K, Ackermann H, Schnaudigel S, Kassubek J, Kastrup A. The role of the unaffected hemisphere in motor recovery after stroke. Hum Brain Mapp. 2010;31(7):1017–29. 10.1002/hbm.20914.43.

43.

Lotze M et al. The role of multiple contralesional motor areas for complex hand movements after internal capsular lesion. J neuroscience: official J Soc Neurosci 26,22 (2006): 6096–102. 10.1523/JNEUROSCI.4564-05.2006

44.

Ferris JK, Neva JL, Francisco BA, Boyd LA. Bilateral Motor Cortex Plasticity in Individuals With Chronic Stroke, Induced by Paired Associative Stimulation. Neurorehabil Neural Repair. 2018;32(8):671–81. 10.1177/1545968318785043.

45.

Antelis JM, Montesano L, Ramos-Murguialday A, Birbaumer N, Minguez J. Decoding Upper Limb Movement Attempt From EEG Measurements of the Contralesional Motor Cortex in Chronic Stroke Patients. IEEE Trans Biomed Eng. 2017;64(1):99–111. 10.1109/TBME.2016.2541084. Epub 2016 Mar 24.

46.

Bestmann S, Swayne O, Blankenburg F, Ruff CC, Teo J, Weiskopf N, Driver J, Rothwell JC, Ward NS. The role of contralesional dorsal premotor cortex after stroke as studied with concurrent TMS-fMRI. J Neurosci. 2010;30(36):11926–37. 10.1523/JNEUROSCI.5642-09.2010.

47.

Marshall RS, Perera GM, Lazar RM, Krakauer JW, Constantine RC, DeLaPaz RL. Evolution of cortical activation during recovery from corticospinal tract infarction. Stroke. 2000;31(3):656–61. 10.1161/01.str.31.3.656.

48.

Gould L, Kress S, Neudorf J, Gibb K, Persad A, Meguro K, Norton J, Borowsky R. An fMRI, DTI and Neurophysiological Examination of Atypical Organization of Motor Cortex in Ipsilesional Hemisphere Following Post-Stroke Recovery. J Stroke Cerebrovasc Dis. 2021;30(3):105593. 10.1016/j.jstrokecerebrovasdis.2020.105593.

49.

Bütefisch CM, Kleiser R, Körber B, Müller K, Wittsack HJ, Hömberg V, Seitz RJ. Recruitment of contralesional motor cortex in stroke patients with recovery of hand function. Neurology. 2005;64(6):1067–9. 10.1212/01.WNL.0000154603.48446.36.

50.

Kwon BM, Lee Y, Lee HH, Ko N, Kim H, Kim BR, Moon WJ, Lee J. Relationship Between Ipsilesional Upper Extremity Motor Function and Corpus Callosum Integrity in Patients With Unilateral Stroke: A Diffusion Tensor Imaging Study. Brain Neurorehabil. 2022;15(1):e7. 10.12786/bn.2022.15.e7.

51.

Schwerin S, Dewald JP, Haztl M, Jovanovich S, Nickeas M, MacKinnon C. Ipsilateral versus contralateral cortical motor projections to a shoulder adductor in chronic hemiparetic stroke: implications for the expression of arm synergies. Exp Brain Res. 2008;185(3):509–19. 10.1007/s00221-007-1169-8. Epub 2007 Nov 8.

52.

Netz J, Lammers T, Hömberg V. Reorganization of motor output in the non-affected hemisphere after stroke. Brain. 1997;120(Pt 9):1579–86. 10.1093/brain/120.9.1579.

53.

Klomjai W, Giron A, Mounir El Mendili M, Aymard C, Pradat-Diehl P, Roche N, Katz R, Bayen E, Lackmy-Vallee A. Anodal tDCS of contralesional hemisphere modulates ipsilateral control of spinal motor networks targeting the paretic arm post-stroke. Clin Neurophysiol. 2022;136:1–12. Epub 2022 Jan 20.

54.

Caramia MD, Palmieri MG, Giacomini P, Iani C, Dally L, Silvestrini M. Ipsilateral activation of the unaffected motor cortex in patients with hemiparetic stroke. Clin Neurophysiol. 2000;111(11):1990–6. 10.1016/s1388-2457(00)00430-2.

55.

Werhahn KJ, Conforto AB, Kadom N, Hallett M, Cohen LG. Contribution of the ipsilateral motor cortex to recovery after chronic stroke. Ann Neurol. 2003;54(4):464 – 72. 10.1002/ana.10686. Erratum in: Ann Neurol. 2004;55(1):148.

56.

Zhang K, Ding L, Wang X, Zhuang J, Tong S, Jia J, Guo X. Evidence of mirror therapy for recruitment of ipsilateral motor pathways in stroke recovery: A resting fMRI study. Neurotherapeutics. 2024;21(2):e00320. 10.1016/j.neurot.2024.e00320. Epub 2024 Jan 22.

57.

Delvaux V, Alagona G, Gérard P, De Pasqua V, Pennisi G, de Noordhout AM. Post-stroke reorganization of hand motor area: a 1-year prospective follow-up with focal transcranial magnetic stimulation. Clin Neurophysiol. 2003;114(7):1217–25. 10.1016/s1388-2457(03)00070-1.

58.

Bütefisch CM, Netz J, Wessling M, Seitz RJ, Hömberg V. Remote changes in cortical excitability after stroke. Brain. 2003;126(Pt 2):470–81. 10.1093/brain/awg044.

59.

Murase N, Duque J, Mazzocchio R, Cohen LG. Influence of interhemispheric interactions on motor function in chronic stroke. Ann Neurol. 2004;55(3):400–9. 10.1002/ana.10848.

60.

Xu J, Branscheidt M, Schambra H, Steiner L, Widmer M, Diedrichsen J, Goldsmith J, Lindquist M, Kitago T, Luft AR, Krakauer JW, Celnik PA, SMARTS Study Group. Rethinking interhemispheric imbalance as a target for stroke neurorehabilitation. Ann Neurol. 2019;85(4):502–13. 10.1002/ana.25452. Epub 2019 Mar 19.

61.

Zimerman M, Heise KF, Hoppe J, Cohen LG, Gerloff C, Hummel FC. Modulation of training by single-session transcranial direct current stimulation to the intact motor cortex enhances motor skill acquisition of the paretic hand. Stroke. 2012;43(8):2185–91. 10.1161/STROKEAHA.111.645382. Epub 2012 May 22.

62.

Rehme AK, Fink GR, von Cramon DY, Grefkes C. The role of the contralesional motor cortex for motor recovery in the early days after stroke assessed with longitudinal FMRI. Cereb Cortex. 2011;21(4):756–68. 10.1093/cercor/bhq140. Epub 2010 Aug 26.

Table 1A: Key findings from animal models investigating contralesional motor cortex contributions to stroke recovery

Authors/Year	Study Design/Sample	Objectives	Methods	Main Findings	SYRCLE Risk of Bias
Liu et al., 2019 [25]	Rat model with focal ischemic brain injury. Constraint-induced movement therapy (CIMT) applied post-stroke.	Investigate the role of CIMT in promoting structural and functional neuroplasticity oriented toward the contralesional hemisphere.	Structural imaging to assess neuroplastic changes and functional recovery metrics during post-stroke rehabilitation.	CIMT significantly enhanced contralesional neuroplasticity, evidenced by increased dendritic arborization and functional connectivity. Bihemispheric coordination improved, highlighting contralesional adaptation during motor recovery.	Moderate risk: Sample size calculation not detailed; blinding during assessments not explicitly mentioned.
Gonzalez et al., 2004 [26]	Rat model with motor cortex and lateral frontal cortex lesions.	Assess bilateral contributions to skilled forelimb movements after contralesional and ipsilesional cortical lesions.	Observations of skilled forelimb reaching tasks pre- and post-lesion, focusing on recovery patterns in both the contralesional and ipsilesional limbs.	Lesions in motor cortex resulted in significant bilateral reaching deficits, underscoring the role of contralesional structures in skilled motor control. Recovery mechanisms indicated interplay between hemispheres for motor compensation.	Low risk: Blinding and randomization were followed; adequate controls were included.
Biernaskie et al., 2005 [27]	Rat model with focal ischemic brain injury.	Explore the bi-hemispheric contributions to motor recovery of the affected forelimb.	Behavioral assessments and neuroimaging to track functional recovery and cortical activity in both hemispheres post-injury.	Recovery of affected forelimb function was strongly associated with compensatory bi-hemispheric activity. Contralesional plasticity was more prominent in cases of severe ipsilesional damage.	Moderate risk: Limited discussion on potential confounding factors such as variability in ischemic lesion size.
Kaeser et al., 2010 [28]	Monkey model with unilateral motor cortex lesions.	Evaluate the impact of motor cortex lesions on the ipsilesional hand’s reach and grasp performance.	Quantitative kinematic analysis of reach and grasp performance in both ipsilesional and contralesional hands. Neural activity mapping in motor-related areas.	Ipsilesional hand movements showed marked deficits post-lesion, while recovery of contralesional hand function correlated with the contralesional hemisphere's adaptation. Plasticity in contralesional motor areas played a pivotal role in restoring skilled motor tasks.	Low risk: Comprehensive kinematic analysis conducted with robust experimental controls.

Table 1B. Characterization and main findings of studies regarding the role of the ipsilateral motor cortex after stroke.

Authors/ Year	Objectives	Methods	Outcome Measures	Main Findings	Cochrane Risk of Bias Assessment	Clinical Implications
Yarosh, Hoffman, and Strick, 2004²⁹	To assess step-tracking wrist movements ipsilaterally to the hemispheric lesion.	Observational; 7 subacute to chronic patients (cortical and subcortical stroke, wrist MRC range = 0–4) and 7 healthy controls.	Step-tracking movements of the wrist (duration); EMG of four hand muscles.	Ipsilateral movements significantly were reduced to controls; the errors were due to inappropriate temporal sequencing of muscle activity regardless of hemispheric dominance.	A high risk of bias in randomization due to its observational nature. Objective measurements (EMG, kinematics) ensure low measurement bias. Missing data risks are minimal, but selective reporting concerns remain due to unregistered protocols. Overall, the study demonstrates robust methodology despite limitations.	Distal ipsilateral limb movements get impaired after stroke; muscle sequencing is impaired.
Baskett et al., 1996³⁰	To investigate ipsilateral sensorimotor deficits early after stroke.	Observational; 20 subacute patients (Motor Assessment Scale mean = 34.5) and 41 healthy controls.	Sensorimotor assessments.	Only subjects with a right hemisphere infarct showed reduced sensorimotor performance ipsilaterally in comparison to controls.	A high bias risk due to lack of randomization and potential selection bias from exclusion criteria. Objective and standardized tools reduce measurement bias. Missing data concerns are minimal, but unregistered protocols raise selective reporting risks. Overall, the study has moderate risk of bias.	Ipsilateral sensorimotor impairment may happen after a stroke.
Noskin et al., 2008³¹	To assess ipsilateral motor dysfunction after stroke.	Observation; Longitudinal; 30 acute patients (subcortical and cortical stroke, NIHSS range = 3–14).	Dynamometry (strength) and 9HPT (dexterity) at 24–48 h, 1 week, 3 months and 1 year following stroke.	Ipsilateral dexterity dysfunction was present at each time point and correlated with initial impairment; this was not found for hand strength.	A low-to-moderate risk of bias. Systematic inclusion and standardized assessments reduced randomization and measurement bias. Follow-up data were well-documented. However, the absence of pre-registration raises concerns about selective reporting. Overall, the study demonstrates strong methodology with some limitations in generalizability.	Ipsilateral motor impairment is present after stroke and persists to chronic stages;
Volz et al., 2017³²	To assess the role of contralesional M1 during recovery of mild to moderate affected UE.	Experimental; 12 subacute to chronic patients (NIHSS mean = 4.1) and 14 healthy controls.	Repetitive TMS over unaffected hemisphere or control site during three tasks (simple reaction, maximum finger tapping, grip strength) in the early acute phase and after 3 months.	In the early phase, there were improvements in the task (finger tapping frequency only) during disruptive stimulation; after 3 months, stimulation did not interfere with task performance, similar to healthy controls.	A moderate risk of bias. Concerns include limited sample size, potential selection bias, and lack of blinding in the analysis of fMRI data. Confounding factors, such as variability in rehabilitation and time since stroke, may influence outcomes. Reporting bias appears low, ensuring transparency.	Contralesional M1 may have a task- and time-specific influence on motor performance of the affected hand.
Schaefer et al., 2007³³	To determine whether different features of UE control could characterize ipsilesional motor deficits.	Experimental; 10 right-handed patients with left- or right-hemisphere stroke (UP FMA mean: left = 86.2 and right = 61.0 ± 32.4) and 16 healthy controls.	Assessment of targeted single-joint elbow movements (reaching) with the UE ipsilateral to the affected hemisphere.	Patients with left (dominant) hemisphere damage showed reduced modulation of acceleration amplitude ipsilaterally whereas patients with right (nondominant) hemisphere damage showed significantly larger errors in the final position, which corresponded to reduced modulation of acceleration duration.	A moderate risk of bias. Objective kinematic measures reduced measurement bias, and missing data were minimal. However, the lack of randomization and pre-registration raises concerns about selective reporting and generalizability. Methodological consistency ensures reliability within the study's observational design framework.	Support the idea that each hemisphere contributes differentially to the control of initial trajectory and final position and that ipsilesional deficits following stroke reflect this lateralization in control.
Lewis and Perreault, 2007³⁴	To determine how stroke lesion side influences motor performance in bimanual tasks.	Experimental; 15 chronic patients (cortical and subcortical stroke, FMA mean = 42) and 9 healthy controls.	Assessment of unimanual and symmetric and asymmetric bimanual tasks; TMS during isometric muscle activation.	Patients with left hemiparesis showed a stronger advantage for symmetric bimanual tasks compared to asymmetric. Interlimb coupling was stronger during homologous activation of muscles in the unaffected limb. These results were not seen in patients with right hemiparesis (left hemisphere damage).	A low risk of measurement and data bias due to standardized TMS protocols and clear task instructions. However, the lack of randomization, small sample size, and absence of pre-registration raise concerns about selection and reporting biases, limiting the generalizability of its findings.	The left hemisphere seems to have a specific role in controlling bimanual symmetric movements.
Yelnik et al., 1996³⁵	To analyze ipsilateral behavioral adaptation during a complex manual task.	Observational; 36 subacute patients (cortical stroke) and 86 healthy controls.	Two manual complex tasks: Pig-Tail and 9HPT (errors, duration).	Patients were worse than controls regardless of the side of the lesion.	A high risk of bias due to its observational design and lack of randomization. Objective measures like task performance metrics reduced measurement bias. Missing data risks are minimal, but selective reporting concerns arise due to the absence of pre-registration. Overall, moderate bias.	Ipsilateral motor disturbances during complex tasks happen after a stroke.
Colebatch and Gandevia, 1989³⁶	To determine the distribution of upper motor neuron weakness.	Observational; 16 subacute to chronic patients and 14 healthy controls.	Myometer and dynamometry for 12 UE muscles and hand grip.	In patients the strength of muscles ipsilateral to the lesion was reduced compared with controls; weakness was more markedly in distal wrist and finger flexors and hand grip.	A moderate risk of bias. While it used objective kinematic analysis to reduce measurement bias, the observational design, lack of randomization, and potential selection bias are concerns. The absence of pre-registration raises risks of selective reporting, though methodology was consistent.	Ipsilesional weakness is predominantly present distally in the ipsilateral arm.
Sunderland, 2000³⁷	To assess ipsilateral motor recovery 6 months after stroke.	Observational; 24 subacute patients (cortical stroke) and 34 healthy controls.	Dynamometry (grip strength), dexterity (JHFT bean spooning), and motor function tests (Extended Motricity Index and Action Imitation).	Recovery occurred on all outcomes; left hemisphere patients remained impaired in ipsilateral dexterity	A moderate risk of bias. While objective measures like grip strength and dexterity tests reduced measurement bias, the lack of randomization and pre-registration raises concerns about selection and reporting biases. Missing data from 20% of participants may also influence generalizability of findings.	Ipsilateral impairment recovers throughout 6 months with more persistent severity in left-hemisphere damage; ipsilateral impairment has a small impact on functionality.
Hermsdörfer, Blankenfeld, and Goldenberg, 2003³⁸	To evaluate the consequences of left and right brain damage for discrete aiming movements of the ipsilateral hand.	Observational; 24 subacute to chronic patients (cortical stroke).	Pointing task; imitation of meaningless gestures; ultrasonic motion measurement.	Patients with left hemisphere damage showed ipsilateral impaired pointing movements, exacerbated when high accuracy was required.	A moderate risk of bias. Standardized kinematic assessments reduced measurement bias, but the lack of randomization and pre-registration raises concerns about selective reporting. Missing data were minimal, though observational design limits generalizability. Findings align with objectives but warrant cautious interpretation	This reinforces the role of the left hemisphere in motor programming and execution of ipsilateral movements which increases with demand.
Hermsdörfer and Goldenberg, 2002³⁹	To evaluate the consequences of left and right brain damage for elementary 13diadochokineti14c moveme15nts of the 16ipsilateral 17hand.	Observational; 38 subacute to chronic patients (cortical and subcortical stroke).	Three diadochokinetic hand movements: forearm prono-supination, hand and index finger tapping; ultrasonic motion measurement.	Diadochokinetic movements were more impaired in left-hemisphere-damaged patients, especially during forearm movements.	A moderate risk of bias. Standardized diadochokinetic tasks and ultrasonic motion tracking ensured low measurement bias. Missing data were negligible, but the lack of randomization and pre-registration raises concerns about selection and reporting bias, limiting generalizability of findings to broader populations.	This reinforces the dominant role of the left hemisphere to control alternating ipsilateral arm movements after a stroke.
Chollet et al., 1991⁴⁰	To explore brain activation changes after 16recovery fro17m stroke.	Observational; 6 recovered patients.	Measurements of cerebral blood flow by positron tomography at rest and during finger movements of the recovered hand and contralateral hand.	Cerebral blood flow increased significantly in the contralateral primary SMC and the ipsilateral cerebellar hemisphere during the unaffected hand movements; Significant cerebral blood flow increases were observed in both the contralateral and ipsilateral primary sensorimotor cortex and in both cerebellar hemispheres during the movement of the recovered hand.	A moderate risk of bias. Objective PET imaging and consistent motor tasks reduced measurement bias, and no missing data were reported. However, the lack of randomization and pre-registration raises concerns about selection and reporting biases, limiting the generalizability of findings.	This supports the idea that ipsilateral motor pathways may play a role in the recovery of motor function after ischemic stroke.
Metrot et al., 2013⁴¹	To investigate time-related changes in motor performance of the UE ipsilateral to the affected hemisphere.	Observational; 19 subacute patients (supratentorial stroke, mild to severe) and 9 healthy controls.	Clinical (FMA, BBT, 9HPT, Barthel Index) and kinematic (during the reach-to-grasp task) weekly assessments between 6 weeks and 3 months after study inclusion.	Recovery of ipsilesional UE capacities increased over time and leveled off after 6 weeks of rehabilitation (9 weeks poststroke). At discharge, patients demonstrated similar ipsilesional clinical scores to controls but exhibited less smooth reaching movements. No hemispheric lesion side effect was found.	A low-to-moderate risk of bias. Systematic inclusion criteria and validated clinical and kinematic measures reduced bias risks. Missing data were appropriately managed. However, the observational design and absence of pre-registration raise concerns about randomization and selective reporting, limiting generalizability of findings.	Long-term ipsilesional UE dysfunction persists at least three months after stroke.
Riecker et al., 2010⁴²	To 18test the assump19tion that 20functionally relevant areas within the ipsilateral motor system would be coupled with the demand of a hand task.	Experimental; 8 chronic well-recovered patients (subcortical stroke) and 8 healthy controls.	fMRI and acoustically paced index finger tapping movements at increasing frequencies with the recovering right hand.	Hemodynamic response increased linearly in patients and controls (left SMA and the left primary SMC). In contrast, a linear increase of the hemodynamic response with higher tapping frequencies in the right PM and the right SMC was only seen in patients.	A moderate risk of bias due to a small sample size, potential detection bias from unblinded fMRI analysis, and inadequate control for confounders like rehabilitation history. However, transparent reporting and appropriate experimental design mitigate selective reporting concerns, supporting cautious interpretation of results regarding adaptive plasticity.	Enhanced bihemispheric recruitment of motor areas during a demanding task likely reflects adaptive plasticity.
Lotze et al., 2006⁴³	To explore the functional relevance of contralesional cortical areas.	Experimental; 7 well-recovered chronic patients (subcortical stroke, NIHSS = 1, MRC = 5).	Repetitive TMS over PMd, M1, and superior parietal lobe (SPL) during sequential finger movement performance in the paretic hand.	Repetitive TMS resulted in significant interference with recovered task performance in patients in terms of timing errors (PMd, M1) and timing and accuracy deficits (SPL).	A moderate risk of bias due to its small sample size, potential detection bias from unblinded analysis of neuroimaging data, and confounding factors like individual differences in stroke severity and recovery. However, transparent reporting reduces concerns about selective reporting bias, supporting cautious interpretation.	The persistent contralesional activity after recovery indicates a beneficial role of the contralesional PMd, M1, and SPL on some aspects of complex motor behavior.
Ferris et al., 2018⁴⁴	To investigate differences between affected and unaffected hemispheric plasticity after stroke.	Experimental; 22 chronic patients (stroke, FMA mean = 40).	Sensorimotor assessment (FMA); Paired Associative Stimulation (PAS).	PAS in the contralesional hemisphere caused an increase in corticospinal tract excitability, varying as a function of UE impairment severity; no changes after PAS in the ipsilesional hemisphere.	A moderate risk of bias due to convenience sampling, lack of blinding during TMS data analysis, and inadequate control for confounding factors like prior rehabilitation. However, selective reporting bias appears low, supporting cautious interpretation of results within its methodological constraints.	Contralesional hemisphere plasticity compensation depends on the extension of damaged ipsilesional corticospinal tracts.
Antelis et al., 2017⁴⁵	To investigate neural decoding of the attempt to move the paralyzed UE from unaffected hemisphere signals.	Experimental; 6 chronic patients.	EEG-EMG during a unilateral am task (reaching).	Greater event-related power desynchronization/synchronization activity during ipsilaterally affected arm movement. Decoding movement information from the unaffected hemisphere was possible.	A moderate risk of bias due to unclear patient selection criteria, potential detection bias from limited blinding, and possible confounding factors like stroke severity or rehabilitation differences. Additionally, reporting bias and unvalidated EEG decoding methods could influence the study's reliability and generalizability	The unaffected hemisphere has movement representations of the affected UE.
Bestmann et al., 2010⁴⁶	To explore how contralesional PMd might support motor function after stroke.	Experimental; 12 chronic patients (subcortical stroke, MRC ≤ 4+).	Paired-pulse TMS at rest (contralesional PMd-ipsilesional M1); TMS over contralesional PMd and fMRI (during hand grip and rest).	PMd influence became less inhibitory/more facilitatory in patients associated with greater impairment; fMRI activity was increased in posterior parts of the ipsilesional sensorimotor cortex during hand grip.	A moderate risk of bias. Limitations include a small sample size, potential detection bias from unblinded TMS-fMRI analysis, and unaddressed confounding factors like differences in stroke severity and recovery trajectories. However, thorough reporting minimizes selective reporting bias, supporting cautious interpretation of the findings.	Contralesional PMd seems to support recovered function through modulation of ipsilesional sensorimotor areas.
Marshall et al., 2000⁴⁷	To follow cortical activation throughout motor recovery.	Observational, longitudinal; 8 acute patients (subcortical stroke) and 6 healthy controls.	Serial fMRI during a finger-thumb opposition task, a few days, and 3 and 6 months after stroke.	Bilateral activations were seen in patients and controls. Yet, patients showed greater activation in ipsilateral sensorimotor, posterior parietal, and bilateral prefrontal regions than controls. The ratio of contralateral to ipsilateral activation increased over time in the function of hand motor recovery.	A moderate risk of bias. Small sample size, no randomization, and potential selection bias, but rigorous PET imaging and consistent protocols minimize measurement bias.	Increased activation of the ipsilateral unaffected hemisphere is associated with the recovery process.
Gould et al., 2021⁴⁸	To investigate the underlying mechanisms for the left hemiparesis after the subsequent left 21hemisphere lesion.	Case report; 61-year-old woman with a first right frontal stroke and a left recovered hemiparesis, and a subsequent left subdural hematoma leading to further left hemiparesis.	fMRI, Diffusion Tensor Imaging (DTI), and intraoperative cortical stimulation.	Expected contralateral activation for right-sided motor tasks but bilateral activation for left-sided tasks. DTI showed normal corticospinal and spinothalamic tracts. Intracortical stimulation elicited ipsilateral responses in some areas.	As a case report of a single individual, the study carries a high risk of bias in terms of generalizability. Findings from one person’s unique medical history and response to injury may not apply broadly to other cases.	Suggestive reorganization after the first stroke with left M1 perhaps taking over the left-side motor function.
Bütefisch et al., 2005⁴⁹	To investigate the bihemispheric activation during strictly unilateral movement of the paretic hand.	Experimental; 8 subacute patients with good hand recovery (motricity index = 75) and 9 healthy controls.	fMRI at rest and task (finger movements); EMG (extensor digitorum communis muscles); hand function tested before and after 8 weeks of neurorehabilitation.	Bilateral recruitment of M1 and premotor areas was evident in five well-recovered patients with strictly unilateral performance.	A moderate risk of bias. A small sample size limits generalizability, and the lack of blinding during fMRI analysis could introduce detection bias. Additionally, potential confounders, such as variations in neurorehabilitation, were not thoroughly addressed. However, reporting bias is minimal, supporting cautious interpretation.	The bilateral increased cortical recruitment in motor areas suggests an adaptive response.
Kwon BM, et als. Brain Neurorehabil. 2022⁵⁰	To investigate the relationship between ipsilesional upper extremity (UE) motor function and the integrity of the corpus callosum in stroke patients.	Retrospective observational study. 20 stroke patients (10 with left lesions, 10 with right lesions) with ipsilesional upper extremity motor deficits. -Unilateral stroke onset within 3 months. -Ipsilesional Jebsen-Taylor Hand Function Test (JHFT) score < 91. - Mini-Mental State Examination (MMSE-K) score > 18.	Motor Performance: JHFT total score and subtests (e.g., simulated feeding, lifting objects). 9HPT completion time (hand dexterity). Grip and pinch strength (mean of three trials). Neuroimaging: Fractional anisotropy (FA) values from DTI for five corpus callosum subregions: Region I: Prefrontal area. Region II: Premotor and supplementary motor cortices. Region III: Primary motor cortex. Region IV: Primary sensory cortex. Region V: Parietal, temporal, and occipital cortices.	Left callosal region I FA values correlated with ipsilesional UE motor function in the left-lesioned group. Right-lesioned group showed no significant correlations.	Moderate: No randomization, small sample size, retrospective design; however, validated tools and clear methodology minimized bias.	Highlights the role of callosal integrity in ipsilesional motor recovery, emphasizing tailored rehabilitation strategies for specific lesion profiles.
Schwerin et al., 2008⁵¹	To evaluate the presence and magnitude of ipsilateral and contralateral projections to the pectoralis major.	10 chronic patients (subcortical stroke, FMA UE range = 14–58, CMSA range = 2–7).	TMS-elicited MEP over ipsilesional and contralesional hemispheres during shoulder adduction (Biodex system).	Ipsilateral MEPs were more common in patients with moderate to severe impairments; the magnitude of ipsilateral projections correlated with impairment level and the extension of synergy in 24the arm, but not with strength.	A moderate risk of bias. Limitations include a small sample size and potential detection bias due to a lack of blinding in analyzing cortical motor projections. Confounding factors, such as variation in stroke chronicity and rehabilitation, were not fully addressed. Reporting bias appears minimal.	Increased ipsilateral projections excitability to the proximal arm may contribute to the expression of abnormal synergy after stroke.
Netz, Lammers, and Hömberg, 1997⁵²	To assess ipsilateral affected hand muscle responses to unaffected hemisphere stimulation.	Observational; 15 chronic patients (cortical and subcortical stroke) and 12 healthy controls.	TMS-MEP.	Ipsilateral MEPs were elicited only in two control subjects (at maximal intensities); in patients, they were recorded only in poor recovery at lower thresholds, but not in patients with good recovery. These responses were longer in latency than contralateral responses; ipsilateral silent periods were longer and contralateral unaffected hand thresholds were elevated than in controls.	A moderate risk of bias. The small sample size and lack of blinding during TMS-MEP analysis may introduce detection bias. Additionally, limited control of confounding factors like stroke location and recovery interventions affects the validity. However, reporting bias appears minimal, supporting cautious interpretation.	Though ipsilateral projections are unmasked after stroke, they are of little relevance for motor recovery.
Klomjai et al., 2022.⁵³	To investigate the role of ipsilateral corticospinal pathways in affected UE spinal neuron networks.	Experimental (sham-controlled); 21 subacute to chronic patients (cortical and subcortical stroke).	Anodal tDCS was applied over the unaffected M1 combined with monosynaptic H-reflex (reciprocal inhibition in wrist flexors and extensors).	Anodal tDCS decreased reciprocal inhibition in wrist flexors in both arms; results suggest ipsilateral control unmasking from the unaffected hemisphere onto spinal motor networks.	A moderate risk of bias. Key concerns include a small sample size, lack of blinding during tDCS application and data analysis, and potential confounding factors such as variability in stroke severity and prior rehabilitation. However, Mixed model analysis used to control for variables- Some data missing due to participant availability	Stimulation of the undamaged cortex induces modulation of ipsilateral motor networks controlling the hemiparetic side.
Caramia et al., 2000⁵⁴	To investigate ipsilateral activation of the unaffected hemisphere during recovery.	Observational, longitudinal; 14 acute patients (subcortical strokes, NIHSS range = 7–13) and 20 healthy controls.	TMS and Transcranial Doppler (TCD) of M1 at 48 h and 6 months after stroke; thumb to finger opposition task.	Ipsilateral MEPs from hand muscles were found in recovered patients; in 8 controls MEPs with smaller amplitudes were obtained by left hemisphere stimulation; TCD revealed increased blood flow velocity ipsilaterally to the recovering hand.	A moderate risk of bias. Limitations include a small sample size and potential detection bias from the lack of blinding during TMS and TCD data interpretation. Additionally, variability in stroke severity and recovery may act as confounders. Reporting bias appears low, supporting careful analysis.	Ipsilateral MEPs at rest can be elicited in the unaffected hemisphere; It is possible to elicit ipsilateral TMS responses in some healthy controls.
Werhahn et al., 2003⁵⁵	To test if disruption of the non-lesioned hemisphere would generate ipsilateral abnormal motor behavior.	Experimental; 20 chronic patients (cortical and subcortical stroke, FMA UE mean = 66.3, MCR mean = 3.6) and 10 healthy controls.	Repetitive TMS over motor cortex during a finger tapping task.	TMS over the intact hemisphere resulted in delayed simple reaction times (RTs) in the contralateral healthy but not in the ipsilateral paretic hand, whereas stimulation of the lesioned hemisphere led to a marked delay in RT in the contralateral paretic hand but not in the ipsilateral unaffected hand.	A moderate risk of bias. Key concerns include a small sample size, potential detection bias due to lack of blinding in neuroimaging and TMS data analysis, and possible confounding from variability in chronic stroke recovery. Transparent reporting reduces the risk of selective reporting bias.	The recovered motor function of the paretic hand may rely on reorganization within the motor areas of the affected hemisphere.
Zhang et al., 2024⁵⁶	Experimental, RCT; 35 subacute to chronic patients (FMA UE range = 4–46) and 16 healthy controls.	To explore brain reorganization after mirror therapy (including recruitment of ipsilateral motor pathways).	Resting-state fMRI; motor function assessment (FMA).	Improvement in the mirror therapy group was associated with a compensatory increase in the fractional amplitude of low-frequency fluctuations in M1 and enhanced functional connectivity between bilateral M1 regions.	A moderate risk of bias. Potential concerns include a small sample size, unblinded analysis of resting-state fMRI data, and confounding factors such as variability in stroke severity and rehabilitation history. However, comprehensive reporting minimizes the risk of selective reporting bias, supporting cautious interpretation.	MT likely achieved motor rehabilitation primarily by recruitment of the ipsilateral motor pathways.
Delvaux et al., 2003⁵⁷	To test prospectively corticospinal excitability changes and reorganization of FDI muscle.	Observational, longitudinal; 31 acute patients (mostly cortical strokes, MCR = 0–2) and 20 healthy controls.	Clinical assessment (MRC, Rankin, NIHSS, and Barthel Index) and focal M1 TMS at day 1, 8, 30, 90, 180, and 360 after stroke.	Persistence of MEP on the affected side at day 1 was a strong predictor of good recovery and was significantly smaller than the opposite side or healthy controls; At day 1, amplitudes of MEPs obtained in unaffected FDI were significantly larger than later.	A moderate risk of bias. The small sample size and lack of blinding in TMS data analysis introduce potential detection bias. Additionally, confounding factors such as individual differences in stroke severity and rehabilitation interventions were not fully addressed. Reporting bias appears low, ensuring transparency.	Findings indicate that the brain insult induces a transient (a few days after stroke) hyperexcitability of the contralesional M1.
Bütefisch et al., 2003⁵⁸	To investigate remote changes in intracortical excitatory and inhibitory activity are present in the non-affected hemisphere of recovering patients.	Experimental; 13 patients with good recovery and 5 patients with poor recovery of hand function (cortical and subcortical stroke) and 13 healthy controls.	Paired-pulse TMS over non-affected hemisphere (M1 on FDI muscle).	Patients with good recovery and healthy subjects had similar inhibitory effects at low conditioning stimulus intensities; in the recovering patients there was an increase in conditioned MEP amplitude at higher conditioning stimulus 33intensities; suggesting that in the patients' contralesional M1, the balance of excitatory and inhibitory activity was shifted towards an increase of excitatory activity (in neuronal circuits tested at interstimulus interval of 2 and 3 ms).	A moderate risk of bias. Concerns include a small sample size, lack of blinding in assessing cortical excitability, and potential confounding factors such as variability in stroke chronicity and prior treatments. However, thorough reporting minimizes selective reporting bias, supporting cautious interpretation of the findings.	This finding may guard similarities with re-organizational processes after experimental brain injury and may have an impact on functional recovery as indicated by the absence of changes in cortical excitability in patients with poor recovery.
Murase et al., 2004⁵⁹	To test if the lesioned M1 would receive abnormal inhibitory influences from the intact M1 during a task performed with the paretic hand.	Experimental; 9 chronic patients (subcortical stroke) and 8 healthy controls.	Reaction time task (finger press); Paired-pulse TMS (IHI).	IHI was similar between patients and healthy subjects at rest. Close-to-movement onset controls displayed a switch to facilitation, whereas patients exhibited sustained inhibition from the intact to the lesioned hemisphere, which 30correlated with poorer motor performance.	A moderate risk of bias due to a small sample size and potential detection bias from unblinded analysis of interhemispheric interactions using TMS. Variability in chronic stroke recovery and confounding factors such as rehabilitation were not fully addressed. Reporting was transparent, minimizing reporting bias.	These results document an abnormally high interhemispheric inhibitory drive from M1(intact hemisphere) to M1(lesioned hemisphere) in the process of generation of a voluntary movement by the paretic hand, which could adversely influence motor recovery in some patients.
Xu et al., 2019⁶⁰	To investigate the evolution of premovement IHI over the first year after stroke concerning hand function.	Observational, longitudinal; 22 acute patients (FMA UE range = 4–65) and 11 matched healthy controls.	Paired-pulse TMS (IHI) during rest and movement preparation (reaction-time task).	Premovement IHI was normal during the acute/subacute period but turned abnormal at the chronic stage (being kept in pre-movement and movement onset); as motor recovery improved IHI increased;	A moderate risk of bias. While it employs advanced neuroimaging and robust statistical methods, limitations include a small sample size, potential selection bias, and unblinded analysis of interhemispheric interactions. Confounding factors such as variability in stroke severity were not comprehensively addressed. Reporting bias appears low.	IHI imbalance might not be a cause of poor motor recovery but a consequence of underlying recovery processes.
Zimerman et al., 2012⁶¹	To test the capacity of cathodal tDCS over the contralesional hemisphere to enhance task acquisition and retention.	Experimental; cross-over; 12 well-recovered chronic patients (subcortical stroke) with mild impairment (FMA UE mean = 64, MRC mean = 29).	Cathodal or sham tDCS over contralesional M1 at two training sessions of a complex finger task (reassessed 90 min. and 24 h after intervention).	tDCS facilitated the acquisition of motor skill with better task retention; a significant correlation was observed between improvement during the training and intracortical inhibition.	A moderate risk of bias due to a small sample size, lack of blinding during tDCS application, and potential confounding from baseline motor variability and rehabilitation histories. However, transparent reporting of methods and results mitigates concerns, 27supporting careful interpretation of findings.	Inhibition of contralesional M1 can improve motor learning and performance after stroke.
Rehme et al., 2011⁶²	To in18vestigate the p19attern and ti20me course of acute stroke-induced changes in motor system activity.	Observational, longitudinal; 11 acute patients (cortical and subcortical stroke, NIHSS = 4, ARAT = 35).	fMRI and motor function assessments (action research arm test, maximum grip force) were performed 3 times during the first 2 weeks starting within 72 hours after stroke.	Bihemispheric increases of activity in M1, PMd, PMv, and SMA significantly correlated with motor recovery. These changes depended upon the degree of initial motor impairment: patients with mild deficits did not differ from healthy subjects. In contrast, patients with severe deficits were characterized by a global reduction of task-related activity, followed by increases in ipsilesional and contralesional motor areas.	A moderate risk of bias. Standardized fMRI protocols and objective motor function assessments minimized measurement bias. Missing data were negligible, but the lack of randomization and pre-registration raises concerns about selection and reporting biases, affecting the generalizability of findings.	Gradually increasing activity in contralesional motor areas correlates with improved functional recovery, indicating an early cortical reorganization supporting hand function recovery.

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The role of the contralesional primary motor cortex in upper limb recovery after stroke: A scoping review following PRISMA-ScR guidelines