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

缺血性中风是导致死亡和严重长期残疾的主要原因 是最常见的并发症之一。尽管做出了巨大的努力， 战略仍然缺乏。经颅交流电刺激（tACS）是一种有前途的非电刺激疗法。 与运动任务训练相结合侵入性脑刺激技术可以促进 神经可塑性和运动学习。然而，对神经生理学的理解有限， 作用、剂量反应关系、卒中后运动结果、安全性和耐受性问题， 阻碍了tACS在康复环境中的成功应用。的个体变异规律 侧支血管密度是影响卒中结局的关键因素，但可能会改变脑 血流量（CBF）和活动依赖性可塑性机制，支持电路重塑， 中风后的运动恢复因此，我们假设，监测 运动康复训练、tACS和CBF恢复可以促进卒中后康复干预。到 解决侧支循环和CBF在恢复中的作用，我们将评估 tACS（10 Hz），以改善同基因系小鼠（雄性和雌性，6 和12月龄），并将其与没有广泛侧支血管系统的小鼠进行比较。具体 目的1：在卒中后干预的四周内，我们将评估局部CBF的影响 对tACS的反应增加与长期运动康复训练相结合 使用局部CBF作为神经元激活和剂量反应的替代标记的功能 WT和侧支缺陷型Rabep 2-KO小鼠中的关系。具体目标2。的效果进行评估 tACS神经元和血管可塑性与卒中结局的关系 运动康复方案对脑卒中后脑功能的影响 WT和Rabep 2-KO小鼠中神经可塑性与神经和认知功能的关系。 对于我们的中风模型，我们将使用远端大脑中动脉闭塞（MCAO）加 采用同侧颈总动脉结扎（CCA）24小时后再灌注模型， 适合用于研究年轻成年和老年小鼠长期卒中结局的模型。而这 反过来，结果在一致的梗死面积和显着的长期感觉运动障碍。康复 将开始模拟传统早期上肢运动恢复+/-tACS的训练h（2个给药组） 中风后72小时。研究的长期恢复机制包括评估运动功能 性能，这将与中风后神经血管可塑性，神经和 认知功能本研究的成功完成将确定TACS对以下患者的治疗效果： 脑卒中后长期运动功能恢复和脑血流作为颅内生物标志物用于确定 有效的刺激方案。

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.