Background: The capacity to reacquire motor skills lost after a stroke is crucial to promote upper-limb motor recovery but the impact of lesion location on motor skill acquisition and the underlying neurophysiological mechanisms remain uncertain. Methods: We used transcranial magnetic stimulation to investigate associations between excitatory and inhibitory cortico-spinal excitability measures and the capacity to acquire a novel motor skill with the most affected hand in 103 individuals with cortical (n=34) or subcortical (n=69) lesions. Results: Both groups showed similar motor skill acquisition, but subcortical lesions exhibited more impairment in the most affected hand and lower excitability in the ipsilesional hemisphere. In cortical lesions, motor skill acquisition was associated with lower motor thresholds (?=-0.25, 95% CI [-0.47,-0.03]; p=0.024) and higher intracortical inhibition (?=-3.93, 95% CI [-6.89,-0.98]; p=0.011) in the ipsilesional hemisphere. In contrast, in subcortical lesions motor skill acquisition was associated with smaller motor evoked potentials (?=-4.46, 95% CI [-8.54,-0.38]; p=0.033), less intracortical inhibition (?=3.45, 95% CI [0.34,6.56]; p=0.030) and higher facilitation (?=1.34,95% CI [0.15,2.54]; p= 0.028) ipsilesionally. Sensitivity analyses revealed that associations with intracortical inhibition and facilitation in the subcortical group were driven by lesions affecting the corticospinal tract. No associations were found in the contralesional hemisphere. Conclusions: Reinforcing the existence of lesion-specific neurophysiological patterns, individuals with cortical and subcortical lesions show divergent associations between cortico-spinal excitability and motor skill acquisition. The use of cortico-spinal excitability as a biomarker to predict upper-limb recovery post-stroke or guide motor recovery interventions such as non-invasive brain stimulation should consider lesion location.

The authors have declared no competing interest.

NCT03614585, NCT05076747

This study is funded by an operating grant from the Canadian Institutes of Health Research (CIHR) (388320) and a Grant from The Canadian Partnership for Stroke Recovery (CPSR). Kevin Moncion is supported by a CANTRAIN post-doctoral Fellowship. Lynden Rodrigues is supported by a Doctoral Scholarship from the Fonds Recherche Santé Québec (FRQS). Janice Eng is supported by the Canada Research Chairs program. MR is supported by a Salary Award (Junior II) from Fonds de Recherche Santé Québec (FRQS).

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Ethics committee of Centre de Recherche de Readaptation du Montreal gave ethical approval for this work (CRIR-1265-0817) Hamilton Integrated Research Board gave ethical approval for this work (HIREB 4713)

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