Microstructural integrity within the damaged region of the residual corticofugal projection from primary motor cortex predicts the effect of noninvasive neuromodulation targeting the spinal cord in chronic stroke

Distal limb impairment after neurological injury is largely a consequence of damage to descending tracts that structurally and functionally connect cortical motor areas with spinal motor neuron pools. Noninvasive neuromodulation strategies that aim to enhance cortico-spinal connectivity via spike timing-dependent mechanisms in the spinal cord rely on transmission of descending volleys across the residual tract. Whether variation in the aftereffects of noninvasive neuromodulation depends on the overall volume or microstructural integrity of fibers that survive injury is unknown. Here, paired corticospinal-motoneuronal stimulation (PCMS) was administered to increase cortico-spinal connectivity of the residual tract in humans with longstanding hand impairment due to stroke. Diffusion MRI was used to reconstruct the residual corticofugal projection from primary motor cortex. We found that fractional anisotropy of fibers within the region directly damaged by stroke accounted for 49.2 ​% of the variance in facilitation of motor-evoked potentials elicited by single-pulse transcranial magnetic stimulation. White matter volume within the damaged region was only weakly correlated with the observed change. Microstructure in caudal portions of the residual tract subject to secondary degeneration strongly predicted voluntary and stimulation-evoked activation of spinal motor neurons pools innervating the paretic hand but were unrelated to PCMS aftereffects. Our findings provide preliminary evidence to indicate that microstructural integrity of fibers directly damaged by stroke, and not the overall volume that remains, predicts the effect of noninvasive neuromodulation mediated downstream in the spinal cord.