Repetitive transcranial magnetic stimulation of the contralesional dorsal premotor cortex for upper extremity motor improvement in severe stroke: Study protocol for a pilot randomized clinical trial

Up to 50% of stroke survivors have persistent, severe upper extremity paresis even after receiving rehabilitation. Repetitive transcranial magnetic stimulation (rTMS) can augment the effects of rehabilitation by modulating corticomotor excitability, but the conventional approach of facilitating excitability of the ipsilesional primary motor cortex (iM1) fails to produce motor improvement in stroke survivors with severe loss of ipsilesional substrate. Instead, the undamaged, contralesional dorsal premotor cortex (cPMd) may be a more suitable target. CPMd can offer alternate, bi-hemispheric and ipsilateral connections in support of paretic limb movement. This pilot, randomized clinical trial seeks to investigate whether rTMS delivered to facilitate cPMd in conjunction with rehabilitation produces greater gains in motor function than conventional rTMS delivered to facilitate iM1 in conjunction with rehabilitation in severely impaired stroke survivors. Twenty-four chronic (≥6 months) stroke survivors with severe loss of ipsilesional substrate (defined by the absence of physiologic evidence of excitable residual pathways tested using TMS) will be included. Participants will be randomized to receive rTMS to facilitate cPMd or iM1 in conjunction with task-oriented upper limb rehabilitation given for 2 sessions/week for 6 weeks. Assessments of primary outcome related to motor impairment (upper extremity Fugl- Meyer [UEFM]), motor function, neurophysiology, and functional neuroimaging will be made at baseline and at 6-week end-of-treatment. An additional assessment of motor outcomes will be repeated at 3-month follow-up to evaluate retention. The primary endpoint is 6-week change in UEFM. This pilot trial will provide preliminary evidence on the effects and mechanisms associated with facilitating intact cPMd in chronic severe stroke survivors. The trial is registered on clinicaltrials.gov, NCT03868410.