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.

中风是退伍军人中的常见疾病，每年有超过 15,000 名退伍军人因中风住院，其中 85% 其中缺血性中风，在老年患者和患有糖尿病的患者中发病率明显加剧 创伤后应激障碍。即使对缺血性中风进行再灌注的早期治疗，大多数老年患者也会经历显着的症状 剩余赤字。中风恢复的潜在协同阶段包括早期预防进展和 后期恢复增强。神经恢复可包括增强同病灶的轴突侧支 和对侧皮层以重新获得对四肢功能的控制，这可以通过神经调节来增强 中枢和周围神经系统的途径。血管恢复包括初始潜在的侧支循环 缺血后的开口以及新血管形成，通过激光散斑成像 [LSI] 或 吲哚菁绿 [ICG] 脑血流成像 [CBF]。中风康复的基本原则是 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，运动和活动都会受到严重功能缺陷的限制，这可能是 通过外周刺激作为移动意图的替代品，可能会克服这一障碍。与多个共激活 在行为（即感觉和运动激活）过程中应用的神经调节方式可能会进一步增强 基于神经元和血管机制的恢复。 中风恢复可以通过多种神经调节技术来增强，包括中枢神经调节技术 通过经颅方法进行刺激（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。我们最近表明，tACS 可以以快速、剂量依赖的方式增强 CBF，并且 这些中枢和周围神经调节技术的共同机制可能会得到加强 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 结合 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，将通过增强神经功能来促进老年小鼠中风的恢复 可塑性和侧支血流。为了解决这个假设，我们将围绕以下问题结合每日、集中的 tACS： 老年雄性和雌性小鼠（18 个月）运动皮层的光血栓性中风以及外周 活动和锻炼期间的神经调节（通过电刺激的感觉输入），从术后 3 天开始 中风诱导4周。我们将比较动物组与每种神经调节方法和活动 通过在 4 周时分析，将单独用药与协同组合进行比较：1) 综合肌电图的剂量反应曲线 中风区域对侧的前肢以评估神经可塑性； 2）皮质LSI和荧光ICG 血管造影评估 CBF 的血管向内生长、侧枝循环形成和血流动力学反应 随着时间的推移，中风区域的感觉刺激； 3）新物体识别的认知表现 任务; 4）对侧前肢的运动性能。这些转化实验将提供 通过临床可行的方案进行中风康复的新方法。