TRANScranial direct current stimulation for POst-stroke motor Recover - a phase II sTudy (TRANSPORT 2)

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Stroke is a leading cause of disability, with motor deficit as the most common complication after stroke. Recovery of motor function after a stroke has been primarily attributed to the structural and/or functional degree of injury to the descending motor pathways. In addition, various forms of neuroplasticity also contribute to the recovery process, including unmasking of pre-existing connections, the establishment of new synaptic contacts through axonal sprouting, reorganization of peri-lesional and homologous contralesional regions, and modulation of stroke-induced abnormal interhemispheric interactions. Transcranial direct current stimulation (tDCS), a non-invasive brain stimulation technique, has been shown to promote and enhance brain plasticity and to modulate the excitatory and inhibitory interhemispheric imbalance that developed after a stroke. When combined with a peripheral rehabilitation therapy, tDCS can enhance synaptic plasticity and motor skill acquisition/consolidation by increasing or modulating afferent inputs to the cortex while concurrently receiving central stimulation. Furthermore, meta-analyses have demonstrated a dose-response relationship between current density and motor impairment reduction. A recently published phase I current escalation study has shown that up to 4mA is safe and tolerable for stroke patients. It is a logical step to conduct a dose selection phase II study while continuing to monitor safety and tolerability issue. Modified CIMT(mCIMT), a peripheral therapy, overcomes a learned non-use phenomenon in stroke patients. The protocol is effective, standardized and quantifiable. The primary aim of this proposal is to determine whether there is an overall treatment effect among the three dosing groups (sham+mCIMT, 2 mA+mCIMT and 4 mA+mCIMT) immediately after 2-week intervention in the Fugl-Myer Upper-Extremity Scale (a measure of motor impairment). Additional outcome measures include the Wolf Motor Function Test Time Score (a measure of functional motor activity), and the Stroke Impact Scale Hand Subscale (a measure of the quality of life). The sustained benefit is assessed at 1 month as well as 3 months post-intervention. Secondary aims will assess safety, tolerability, and feasibility to implement this combined approach in a multi-site trial. An exploratory aim will examine whether weighted corticospinal tract- lesion load (wCST-LL, structural assessment of integrity of descending motor tract) or Motor Evoked Potentials (MEPs, functional assessment of integrity of descending motor tract) or a combination of both are correlated with changes in FM-UE scale, and evaluate the utility of these measures as biomarkers for patient selection criteria in future confirmatory Phase III study.