Vagus Nerve Stimulation Paired with Rehabilitative Training to Enhance Plasticity

描述（由申请人提供）：中风是导致残疾的主要原因，在美国每年估计有795,000例报告。多达70%的中风患者表现出上肢运动功能的长期损伤。许多中风患者表现出相关的危险因素，这些因素会损害功能的恢复，例如高龄。在老年背景下，发展康复策略以改善运动功能的恢复是至关重要的。我们建议评估一种新的早期治疗方法，利用迷走神经刺激与康复训练相结合来改善中风的恢复。迷走神经刺激（VNS）与运动配对可使大鼠初级运动皮层具有高度特异性、持久的神经可塑性。此外，在康复期间给予VNS可改善年轻成年大鼠运动皮质缺血性损伤后前肢速度和力量的恢复。为了评估VNS与物理康复相结合是否对脑卒中患者有用，我们建议在更准确地代表临床人群的模型中测试该疗法。由于高龄是中风的主要危险因素，可能会限制可塑性，因此本提案中描述的实验将在高龄中风模型中评估VNS。本研究的第一个目的是评估VNS配合康复训练对老年大鼠缺血性卒中后运动功能恢复的改善能力。本提案的第二个目的是研究中风后恢复的结构可塑性机制。本研究的第三个目的是评估VNS配合体育训练对老年大鼠运动皮层地图可塑性的增强能力。我们假设，在老年大鼠中，VNS与体育训练相结合可以改善功能恢复，增加结构可塑性，增强地图可塑性，而不仅仅是体育训练。本实验结果将阐明高龄与脑卒中运动功能恢复之间的关系。从这些研究中获得的见解将有助于描述VNS与物理康复相结合可能带来治疗益处的临床人群，并提高治疗成功转化的可能性。

DESCRIPTION (provided by applicant): Stroke is a leading cause of disability, with an estimated 795,000 cases reported in the US each year. As many as 70% of patients who suffer a stroke display a long-term impairment in upper extremity motor function. Many stroke patients exhibit associated risk factors which can impair recovery of function, such as advanced age. The development of rehabilitative strategies to improve the recovery of motor function in the context of advanced age is of key importance. We propose to evaluate a novel early stage therapy to improve stroke recovery which utilizes stimulation of the vagus nerve paired with rehabilitative training. Pairing vagus nerve stimulation (VNS) with movement results in highly specific, long-lasting neuroplasticity in rat primary motor cortex. Furthermore, VNS delivered during rehabilitation improves recovery of forelimb speed and strength after an ischemic lesion of the motor cortex in young adult rats. To evaluate if VNS paired with physical rehabilitation may be useful in stroke patients, we propose to test the therapy in a model that more accurately represents the clinical population. Because advanced age is a leading risk factor for stroke and may limit plasticity, the experiments described in this proposal will evaluate VNS in a model of stroke at an advanced age. The first aim of the study will assess the ability of VNS paired with rehabilitative training to improve recovery of motor function after ischemic stroke in aged rats. The second aim of this proposal will examine structural plasticity mechanisms that underlie recovery after stroke. The third aim of the study will assess the ability of VNS paired with physical training to enhance map plasticity in motor cortex of aged rats. We hypothesize that in aged rats, VNS paired with physical training will result in improved recovery of function, increased structural plasticity, and enhanced map plasticity beyond physical training alone. The results of the proposed experiments will clarify the relationship between advanced age and recovery of motor function are stroke. Insights from these studies will help to delineate the clinical population for which VNS paired with physical rehabilitation is likely to confer therapeutc benefits and improve the likelihood of successful translation of the therapy.