Anisotropy of descending motor pathways has repeatedly been linked to the severity of motor impairment following stroke-related damage to the corticospinal tract. Despite promising findings consistently tying anisotropy of the ipsilesional corticospinal tract to motor outcome, anisotropy is not yet utilized as a biomarker for motor recovery in clinical practice as several methodological constraints hinder a conclusive understanding of degenerative processes in the ipsilesional corticospinal tract and compensatory roles of other descending motor pathways. These constraints include estimating anisotropy in voxels with multiple fiber directions, sampling biases, and confounds due to aging-related atrophy. The present study addressed these issues by combining diffusion spectrum imaging with a novel compartmentwise analysis approach differentiating voxels with one dominant fiber direction (one-directional voxels) from voxels with multiple fiber directions. Compartmentwise anisotropy for bihemispheric corticospinal and extrapyramidal tracts was compared between 25 chronic stroke patients, 22 healthy age-matched controls, and 24 healthy young controls and its associations with motor performance of the upper and lower limbs were assessed. Our results provide direct evidence for Wallerian degeneration along the entire length of the ipsilesional corticospinal tract reflected by decreased anisotropy in descending fibers compared to age-matched controls, while aging-related atrophy was observed more ubiquitously across compartments. Anisotropy of descending ipsilesional corticospinal tract voxels showed highly robust correlations with various aspects of upper and lower limb motor impairment, highlighting the behavioral relevance of Wallerian degeneration. Moreover, anisotropy measures of two-directional voxels within bihemispheric rubrospinal and reticulospinal tracts were linked to lower limb deficits, while anisotropy of two-directional contralesional rubrospinal voxels explained gross motor performance of the affected hand. Of note, the relevant extrapyramidal structures contained fibers crossing the midline, fibers potentially mitigating output from brain stem nuclei, and fibers transferring signals between the extrapyramidal system and the cerebellum. Thus, specific parts of extrapyramidal pathways seem to compensate for impaired gross arm and leg movements incurred through stroke-related corticospinal tract lesions, while fine motor control of the paretic hand critically relies on ipsilesional corticospinal tract integrity. Importantly, our findings suggest that the extrapyramidal system may serve as a compensatory structural reserve independent of post-stroke reorganization of extrapyramidal tracts. In summary, compartment-specific anisotropy of ipsilesional corticospinal tract and extrapyramidal tracts explained distinct aspects of motor impairment, with both systems representing different pathophysiological mechanisms contributing to motor control post-stroke. Considering both systems in concert may help to develop diffusion imaging biomarkers for specific motor functions after stroke.

ObjectiveAlthough ample evidence highlights that the ipsilesional corticospinal tract (CST) plays a crucial role in motor recovery after stroke, studies on cortico‐cortical motor connections remain scarce and provide inconclusive results. Given their unique potential to serve as structural reserve enabling motor network reorganization, the question arises whether cortico‐cortical connections may facilitate motor control depending on CST damage.MethodsDiffusion spectrum imaging (DSI) and a novel compartment‐wise analysis approach were used to quantify structural connectivity between bilateral cortical core motor regions in chronic stroke patients. Basal and complex motor control were differentially assessed.ResultsBoth basal and complex motor performance were correlated with structural connectivity between bilateral premotor areas and ipsilesional primary motor cortex (M1) as well as interhemispheric M1 to M1 connectivity. Whereas complex motor skills depended on CST integrity, a strong association between M1 to M1 connectivity and basal motor control was observed independent of CST integrity especially in patients who underwent substantial motor recovery. Harnessing the informational wealth of cortico‐cortical connectivity facilitated the explanation of both basal and complex motor control.InterpretationWe demonstrate for the first time that distinct aspects of cortical structural reserve enable basal and complex motor control after stroke. In particular, recovery of basal motor control may be supported via an alternative route through contralesional M1 and non‐crossing fibers of the contralesional CST. Our findings help to explain previous conflicting interpretations regarding the functional role of the contralesional M1 and highlight the potential of cortico‐cortical structural connectivity as a future biomarker for motor recovery post‐stroke. ANN NEUROL 2023