Transcranial Electrical Stimulation Promotes Cerebral Blood Flow, Enhancing Cognitive and Motor Recovery with Concurrent Rehab Training after Stroke

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Ischemic stroke is a leading cause of death and serious long-term disability with motor impairment as one of most common complication. Despite significant efforts, effective motor rehabilitation strategies are still lacking. Transcranial alternating current stimulation (tACS) is a promising non- invasive brain stimulation technique that combined with motor task training can facilitates neuroplasticity and motor learning. However, limited understanding of the neurophysiological effects, dose-response relationship, post-stroke motor outcome, safety, and tolerability issue have prevented the successful application of tACS in rehabilitation settings. Individual variation of collateral vessel density it is a critical factor that influence stroke outcome, but likely alters cerebral blood flow (CBF) and activity-dependent plasticity mechanism that support circuit remodeling and motor recovery after stroke. Therefore, we hypothesize that monitoring the interaction between motor rehab training, tACS, and CBF recovery can advance post-stroke rehab intervention. To address the role of the collateral circulation and CBF in recovery, we will assess the ability of tACS (10Hz) to improve motor performance in isogenic strains of mice (males and females at 6 and 12 months of age) and compare it with mice without extensive collateral vasculature. Specific Aim 1: During the four weeks of post-stroke intervention, we will assess the effects of local CBF increase in response to tACS in conjunction with motor rehabilitation training on long-term motor function using local CBF as surrogate maker of neuronal activation and dose-response relationship in WT and collateral-deficient Rabep2-KO mice. Specific Aim 2. To assess the effect of tACS neuronal and vascular plasticity in relationship with stroke outcome We will compare the effects of the motor rehabilitation protocol with and without tACS on post-stroke brain neuroplasticity in relationship to neurological and cognitive function in WT and Rabep2-KO mice. For our model of stroke, we will use a distal middle cerebral artery occlusion (MCAO) plus ipsilateral common carotid artery ligation (CCA) model with reperfusion after 24hr, which is a suitable model for the study of long-term stroke outcomes in young adult and older mice. This, in turn, results in consistent infarct size and significant long-term sensorimotor impairment. Rehab training h to mimic traditional early upper limb motor recovery +/-tACS, (2 dosing groups) will start 72hr after stroke. Long-term recovery mechanisms to be studied include an assessment of motor performance, which will be correlated with post-stroke neurovascular plasticity, neurological and cognitive function. Successful completion of this study will determine treatment effect of TACS on long-term post-stroke motor recovery and utility of CBF as intracranial biomarker for determining effective stimulation protocol.