Central and Peripheral Neuromodulation during Activity to Synergistically Augment Stroke Recovery

Durham Va Medical Center, Durham NC

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Abstract

Stroke is a common disorder amongst veterans, with >15,000 veterans hospitalized each year for stroke, 85% of which are ischemic strokes, and the incidence is significantly exacerbated in elderly patients and those with PTSD. Even with early treatment of ischemic stroke with reperfusion most aged patients experience significant residual deficits. Potentially synergistic phases of stroke recovery include early prevention of progression and later recovery enhancement. Neural recovery can include enhanced axonal collaterals from both ipsilesional and contralesional cortex to regain control of extremity function, which may be enhanced by neuromodulation approaches of the central and peripheral nerve system. Vascular recovery includes initial latent collateral opening as well as new vessel formation after ischemia, as measured with either laser speckle imaging [LSI] or indocyanine green [ICG] cerebral blood flow imaging [CBF]. A basic principle of stroke rehabilitation is that neural and vascular recovery require co-activation of neuromodulation together with intent to use the extremity. However, after stroke, both exercise and activity are limited by severe functional deficits, which may be potentially overcome with peripheral stimulation as a surrogate for intent to move. Co-activation with multiple neuromodulation modalities applied during behavior (ie, sensory and motor activation) may further enhance recovery based on both neuronal and vascular mechanisms. Stroke recovery may be augmented through a wide range of neuromodulation techniques, including central stimulation through transcranial approaches (ie, transcranial alternating current [tACS] or magnetic stimulation [TMS]), vagal nerve stimulation, and sensory stimulation (of the wrist and hand), as well as high intensity exercise. We have recently shown that tACS can enhance CBF in a rapid, dose-dependent manner and a common mechanism underlying these central and peripheral neuromodulation techniques may be heightened CBF around the stroke region together with neuronal activation. We propose concurrent neuromodulation with tACS and peripheral activation together with active behavior to enhance mouse stroke recovery. Our treatment hypothesis is that combined neuromodulation at both central and peripheral sites during intentional activity will augment stroke recovery in aged mice through enhanced neural plasticity and collateral blood flow. To address this hypothesis we will combine daily, focused tACS around a photothrombotic stroke in motor cortex in aged male and female mice (18 months) together with peripheral neuromodulation (sensory input via electrical stimulation) during activity and exercise, beginning at 3 days after stroke induction for 4 weeks. We will compare animal groups with each neuromodulation approach and activity alone to the synergistic combination by analyzing at 4 weeks: 1) dose-response curves of integrated EMG in the forelimb contralateral to the stroke region to assess neural plasticity; 2) cortical LSI and fluorescent ICG angiograms to evaluate CBF for vascular ingrowth, collateral formation, and hemodynamic responses to sensory stimulation in the stroke region over time; 3) cognitive performance on the novel object recognition task; and 4) motor performance of the contralateral forelimb. These translational experiments will provide a novel approach to stroke rehabilitation through a clinically feasible protocol.