Evaluation of the Neuromodulatory Mechanisms of Vagus Nerve Stimulation to Improve Motor Rehabilitation after Stroke

项目摘要 中风是导致残疾的主要原因，在美国每年估计有795，000例。多达70% 的中风患者表现出上肢运动功能的长期损伤。的 制定康复策略以改善运动功能的恢复至关重要。 神经可塑性被认为有助于中风后的恢复;因此， 可能会增加恢复。在运动训练中刺激迷走神经， 大鼠运动皮层的神经可塑性。最近的证据表明，迷走神经刺激（VNS）提供 在康复训练期间显著改善多种中风模型中前肢功能的恢复， 但是没有定义VNS依赖的恢复增强的基础机制。胆碱能和 去甲肾上腺素能神经调节系统参与VNS，并代表了潜在的途径， VNS可以支持恢复。我们建议通过以下方法来描述神经调节通路和机制： 其中VNS用于增加中风后前肢运动功能的恢复。研究的第一个目标是 确定VNS依赖性增强是否需要胆碱能和去甲肾上腺素能系统 中风后的恢复本研究的第二个目的是评估是否直接刺激胆碱能神经元， 或去甲肾上腺素能系统在康复训练期间足以增强恢复。第三个目标 一项提案将研究VNS是否能增强下行运动网络的解剖重组 支持功能恢复的治疗。 本实验的结果将描述神经调节通路和机制， 迷走神经刺激配合康复训练可促进卒中后的恢复。从这些研究中获得的见解将 有助于确定是否常见的疾病相关和药理因素，影响这些 神经调节系统可能干扰VNS的有益作用。最终，这项研究的结果 将提高VNS治疗中风患者成功转化的可能性。

PROJECT ABSTRACT Stroke is a leading cause of disability, with an estimated 795,000 cases in the US each year. As many as 70% of patients who suffer a stroke exhibit long-term impairment in upper extremity motor function. The development of rehabilitative strategies to improve the recovery of motor function is of key importance. Neuroplasticity is believed to support recovery after stroke; therefore, manipulations that enhance plasticity may increase recovery. Stimulation of the vagus nerve during motor training drives robust, specific neuroplasticity in rat motor cortex. Recent evidence indicates that vagus nerve stimulation (VNS) delivered during rehabilitative training significantly improves recovery of forelimb function in multiple models of stroke, but the mechanisms underlying VNS-dependent enhancement of recovery are not defined. The cholinergic and noradrenergic neuromodulatory systems are engaged by VNS and represent potential pathways through which VNS may support recovery. We propose to delineate the neuromodulatory pathways and mechanisms by which VNS acts to increase recovery of forelimb motor function after stroke. The first aim of the study will determine whether the cholinergic and noradrenergic systems are required for VNS-dependent enhancement of recovery after stroke. The second aim of the study will evaluate whether direct stimulation of the cholinergic or noradrenergic systems during rehabilitative training is sufficient to enhance recovery. The third aim of the proposal will examine whether anatomical reorganization in descending motor networks is enhanced by VNS therapy to support functional recovery. The results of the proposed experiments will delineate the neuromodulatory pathways and mechanisms by which VNS paired with rehabilitative training enhances recovery after stroke. Insights from these studies will help to determine whether common disease-related and pharmacological factors that influence these neuromodulatory systems may interfere with the beneficial effects of VNS. Ultimately, results from this study will improve the likelihood of successful translation of VNS therapy for stroke patients.