The impact of stroke on motor functioning is analyzed at different levels. ‘Impairment’ denotes the loss of basic characteristics of voluntary movement. ‘Activity limitation’ denotes the loss of normal capacity for independent execution of daily activities. Recovery from impairment is accomplished by ‘restitution’ and recovery from activity limitation is accomplished by the combined effect of ‘restitution’ and ‘compensation.’ We aimed to unravel the long-term effects of variation in lesion topography on motor impairment of the hemiparetic lower limb (HLL), and gait capacity as a measure of related activity limitation. Gait was assessed by the 3 m walk test (3MWT) in 67 first-event chronic stroke patients, at their homes. Enduring impairment of the HLL was assessed by the Fugl–Meyer Lower Extremity (FMA-LE) test. The impact of variation in lesion topography on HLL impairment and on walking was analyzed separately for left and right hemispheric damage (LHD, RHD) by voxel-based lesion-symptom mapping (VLSM). In the LHD group, HLL impairment tended to be affected by damage to the posterior limb of the internal capsule (PLIC). Walking capacity tended to be affected by a larger array of structures: PLIC and corona radiata, external capsule and caudate nucleus. In the RHD group, both HLL impairment and walking capacity were sensitive to damage in a much larger number of brain voxels. HLL impairment was affected by damage to the corona radiata, superior longitudinal fasciculus and insula. Walking was affected by damage to the same areas, plus the internal and external capsules, putamen, thalamus and parts of the perisylvian cortex. In both groups, voxel clusters have been found where damage affected FMA-LE and also 3MWT, along with voxels where damage affected only one of the measures (mainly 3MWT). In stroke, enduring ‘activity limitation’ is affected by damage to a much larger array of brain structures and voxels within specific structures, compared to enduring ‘impairment.’ Differences between the effects of left and right hemisphere damage are likely to reflect variation in motor-network organization and post-stroke re-organization related to hemispheric dominance. Further studies with larger sample size are required for the validation of these results.

Understanding the impact of variation in lesion topography on the expression of functional impairments following stroke is important, as it may pave the way to modeling structure–function relations in statistical terms while pointing to constraints for adaptive remapping and functional recovery. Multi‐perturbation Shapley‐value analysis (MSA) is a relatively novel game‐theoretical approach for multivariate lesion‐symptom mapping. In this methodological paper, we provide a comprehensive explanation of MSA. We use synthetic data to assess the method's accuracy and perform parameter optimization. We then demonstrate its application using a cohort of 107 first‐event subacute stroke patients, assessed for upper limb (UL) motor impairment (Fugl‐Meyer Assessment scale). Under the conditions tested, MSA could correctly detect simulated ground‐truth lesion‐symptom relationships with a sensitivity of 75% and specificity of ~90%. For real behavioral data, MSA disclosed a strong hemispheric effect in the relative contribution of specific regions‐of‐interest (ROIs): poststroke UL motor function was mostly contributed by damage to ROIs associated with movement planning (supplementary motor cortex and superior frontal gyrus) following left‐hemispheric damage (LHD) and by ROIs associated with movement execution (primary motor and somatosensory cortices and the ventral brainstem) following right‐hemispheric damage (RHD). Residual UL motor ability following LHD was found to depend on a wider array of brain structures compared to the residual motor ability of RHD patients. The results demonstrate that MSA can provide a unique insight into the relative importance of different hubs in neural networks, which is difficult to obtain using standard univariate methods.

Hemiparesis and spasticity are common co-occurring manifestations of hemispheric stroke. The relationship between impaired precision and force in voluntary movement (hemiparesis) and the increment in muscle tone that stems from dysregulated activity of the stretch reflex (spasticity) is far from clear. Here we aimed to elucidate whether variation in lesion topography affects hemiparesis and spasticity in a similar or dis-similar manner. Voxel-based lesion-symptom mapping (VLSM) was used to assess the impact of lesion topography on (a) upper limb paresis, as reflected by the Fugl-Meyer Assessment scale for the upper limb and (b) elbow flexor spasticity, as reflected by the Tonic Stretch Reflex Threshold, in 41 patients with first-ever stroke. Hemiparesis and spasticity were affected by damage to peri-Sylvian cortical and subcortical regions and the putamen. Hemiparesis (but not spasticity) was affected by damage to the corticospinal tract at corona-radiata and capsular levels, and by damage to white-matter association tracts and additional regions in the temporal cortex and pallidum. VLSM conjunction analysis showed only a minor overlap of brain voxels where the existence of damage affected both hemiparesis and spasticity, suggesting that control of voluntary movement and regulation of muscle tone at rest involve largely separate parts of the motor network.