Central and Peripheral Neuromodulation during Activity to Synergistically Augment Stroke Recovery

活动期间的中枢和外周神经调节可协同增强中风恢复

• 批准号: 10588544
• 负责人: DENNIS Alan TURNER
• 金额: --
• 依托单位: DURHAM VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-10-01 至 2024-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10588544
• 关键词: Address; Affect; Age Months; Aging; Anesthesia procedures; Angiography; Animals; Astrocytes; Axon; Behavior; Blood Vessels; Blood flow; Brain; Cephalic; Cerebrovascular Circulation; Chronic; Clinical; Contralateral; Disease; Dose; Early treatment; Electric Stimulation; Electrodes; Exercise; FDA approved; Female; Forelimb; Gait; Goals; Growth; Hand; Hospitalization; Image; Implant; Implantation procedure; Incidence; Individual; Indocyanine Green; Ischemia; Ischemic Stroke; Laser Speckle Imaging; Limb structure; Magnetism; Measures; Modality; Motion; Motor; Motor Cortex; Movement; Mus; Nerve; Neuronal Plasticity; Neurons; Outcome; Output; Patients; Performance; Peripheral; Peripheral Nerves; Phase; Post-Traumatic Stress Disorders; Prevention; Procedures; Protocols documentation; Recovery; Reperfusion Therapy; Reproducibility; Residual state; Scalp structure; Sensory; Signal Transduction; Site; Stroke; System; Techniques; Testing; Time; Veterans; Wrist; aged; awake; balance recovery; cognitive performance; cranium; density; electric field; exercise intensity; experience; experimental study; foot; grasp; hemodynamics; improved; in vivo; indexing; male; mouse model; neural; neuroprotection; neuroregulation; novel; novel strategies; object recognition; older patient; post stroke; response; sensory input; stroke intervention; stroke recovery; stroke rehabilitation; translational clinical trial; wireless

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.

中风是退伍军人中常见的疾病，每年有超过15，000名退伍军人因中风住院，85% 其中缺血性卒中，老年患者和患有 创伤后应激障碍即使早期治疗缺血性卒中伴再灌注，大多数老年患者仍存在显著的 剩余赤字。中风恢复的潜在协同阶段包括早期预防进展， 后期恢复增强。神经恢复可以包括增强的轴突侧支， 和对侧皮质，以恢复对肢体功能的控制，这可以通过神经调节来增强 中枢和外周神经系统的方法。血管恢复包括最初的潜在侧支 开放以及缺血后新血管形成，用激光散斑成像[LSI]或 吲哚菁绿色[ICG]脑血流显像[CBF]。中风康复的基本原则是， 神经和血管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，运动和活动都受到严重功能缺陷的限制，这可能是 潜在地用外周刺激作为移动意图的替代来克服。与多种药物共激活 在行为过程中应用的神经调节方式（即，感觉和运动激活）可以进一步增强 基于神经和血管机制的恢复。 中风恢复可以通过广泛的神经调节技术来增强，包括中枢神经调节技术。 经颅刺激（即经颅交流电[tACS]或磁刺激 [TMS]）、迷走神经刺激和感觉刺激（手腕和手），以及高强度 锻炼的我们最近发现tACS可以快速、剂量依赖性地增强CBF， 这些中枢和外周神经调节技术下的共同机制可以被提高 中风区域周围的CBF以及神经元激活。我们建议同时进行神经调节 用tACS和外周激活以及主动行为来增强小鼠中风恢复。 我们的治疗假设是中枢和外周部位的联合神经调节 在有意识的活动期间，将通过增强的神经功能来增强老年小鼠的中风恢复。 可塑性和侧支血流。为了解决这一假设，我们将联合收割机每天，集中tACS周围 老年雄性和雌性小鼠（18个月）运动皮质中的光血栓性卒中以及外周 在活动和锻炼期间的神经调节（通过电刺激的感觉输入），在施用后3天开始， 中风诱导4周。我们将比较每种神经调节方法和活动的动物组 通过在4周时分析：1）单独使用与协同组合的组合中整合EMG的剂量-反应曲线， 脑卒中区对侧前肢评估神经可塑性; 2）皮质LSI和荧光ICG 血管造影以评价CBF的血管向内生长、侧支形成和血流动力学反应， 感觉刺激在脑卒中区域随时间的变化; 3）对新物体识别的认知表现 任务;和4）对侧前肢的运动性能。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。