Non-Invasive Brain Stimulation for Moderate-to-Severe Upper-Extremity Motor Impairment After Stroke: Neural Targets and Stimulation Responsiveness

Abstract

Extensive damage to corticospinal tract (CST) fibers originating from the ipsilesional primary motor cortex (iM1) post stroke leads to contralesional moderate-to-severe upper-extremity (UE) motor impairment. CST integrity is assessed using single-pulse transcranial magnetic stimulation (TMS) over the iM1 to elicit motor-evoked potentials (MEPs). Individuals who fail to elicit MEPs are presumed to have limited recovery potential and are routinely excluded from neuromodulatory trials. However, MEP absence may reflect insufficient activation of residual iM1 neurons by single-pulse TMS, rather than complete CST disruption. Thus, it is important to investigate: (1) non-primary motor areas as potential targets when iM1 is severely damaged; (2) alternative TMS paradigms to enhance MEP detection. This dissertation had two aims. First, we conducted a scoping review to summarize the roles of non-primary and primary motor areas in UE muscle recovery in individuals with moderate- to-severe UE impairment. Findings indicate that proximal recovery involves the contralesional M1 and dorsal premotor cortex, while distal recovery involves M1, premotor areas, dorsolateral prefrontal cortex, and intraparietal sulcus. The contralesional intraparietal sulcus exerts maladaptive effects early post-stroke, whereas the contralesional dorsal premotor cortex supports chronic-phase recovery. Second, we characterized clinical, biomechanical, and neurophysiological outcomes across TMS-responsiveness profiles and examined relationships between MEP amplitude and these outcomes in this population. This aimed to explore whether CST function exists on a continuum,

potentially reducing misclassification of recovery potential and expanding trial eligibility. We defined profiles by the lowest TMS protocol eliciting consistent MEPs: single-pulse at rest (SP_Rest), paired-pulse at rest (PP_Rest), or paired-pulse during active motor threshold contraction (PP_AMT). A consistent pattern emerged: PP_AMT responders had the most severe UE impairment, followed by the PP_Rest and SP_Rest responders. PP_Rest TMS revealed CST function in individuals considered MEP-absent using SP_Rest. Furthermore, MEP amplitude demonstrated moderate to good relationship with neurophysiological (rs=−.58 to −.62), clinical (rs=.52 to .57), and force outcomes (rs=. 61). These findings may inform personalized stimulation protocols for neuromodulation-based rehabilitation. Future studies should consider: (1) how time since stroke influences non-primary motor areas’ contributions to UE recovery when selecting stimulation sites and (2) applying paired-pulse stimulation to optimize detection of residual CST function.