Central and Peripheral Neuromodulation during Activity to Synergistically Augment Stroke Recovery

中风是退伍军人中的一种常见疾病，每年有15000名退伍军人因中风住院，占85% 其中缺血性中风，在老年患者和那些有 创伤后应激障碍。即使早期治疗缺血性卒中并再灌注，大多数老年患者仍有明显的 剩余赤字。卒中康复的潜在协同阶段包括早期预防进展和 后来的恢复增强。神经恢复可以包括增强的轴突侧支来自双侧 和对侧皮质，以恢复对肢体功能的控制，这可能通过神经调节来增强 中枢神经系统和周围神经系统的入路。血管恢复包括最初的潜在抵押品 用激光散斑成像[LSI]或 吲哚青绿[ICG]脑血流显像[CBF]中风康复的一个基本原则是 神经和血管的恢复需要神经调节的共同激活以及使用肢体的意图。 然而，中风后，锻炼和活动都受到严重功能缺陷的限制，这可能是 可能会被外周刺激克服，作为移动意图的替代品。与多个 在行为过程中应用神经调节方式(即，感觉和运动激活)可能会进一步增强 基于神经和血管机制的康复。 中风的恢复可以通过广泛的神经调节技术来增强，包括中枢神经系统 经颅入路刺激(即经颅交流电刺激或磁刺激 [TMS])，迷走神经刺激，感觉刺激(手腕)，以及高强度 锻炼身体。我们最近发现，Tacs可以快速、剂量依赖的方式增加脑血流量，并且 这些中枢和外周神经调节技术的共同机制可能会得到加强 卒中区域周围的CBF与神经元的激活一起。我们建议同时进行神经调节。 通过Tacs和外周激活以及主动行为来增强小鼠中风的恢复。 我们的治疗假说是中枢和外周两个部位的联合神经调节 在有意识的活动中将通过增强神经功能促进老龄小鼠中风的恢复 可塑性和侧支循环。为了解决这一假设，我们将结合日常的、重点关注的TAC 老年雄性和雌性小鼠(18月龄)及外周运动皮质中的光栓性卒中 活动和锻炼期间的神经调节(通过电刺激的感觉输入)，从3天后开始 卒中诱导4周。我们将比较每一种神经调节方法和活动的动物组 4周后通过分析：1)整合肌电的剂量-反应曲线 卒中区域对侧前肢评估神经可塑性；2)皮质LSI和荧光ICG 血管造影术评估CBF对血管生长、侧支形成和血流动力学反应的影响 卒中区域感觉刺激随时间的变化；3)对新物体识别的认知表现 任务；4)对侧前肢的运动能力。这些翻译实验将提供一个 通过临床可行的方案进行中风康复的新方法。

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.