Enhancing Recovery after Chronic Bilateral Cervical Spinal Cord Injury with Targeted Plasticity Therapy

项目摘要 脊髓损伤(SCI)是致残的主要原因，目前仅在美国就有27.6万人受到影响 全世界还有数以百万计的人。颈椎脊髓损伤(CSCI)占所有SCI的55%，通常会导致 上肢运动功能。大多数CSCI患者都有双侧脊髓损伤。 寻找和开发促进上肢功能恢复的康复疗法 双侧CSCI具有重要的临床意义。 我们建议评估一种使用精确定时刺激迷走神经的新型治疗干预方法。 神经与康复训练配对。迷走神经刺激(VNS)与运动相结合 可塑性神经调节系统及其导致大鼠运动高度特异、持久的神经可塑性 大脑皮层。基于这种可塑性的增强，我们最近的结果表明，VNS与 康复显著促进缺血性卒中大鼠前肢运动功能的恢复， 出血性中风和创伤性脑损伤。此外，我们的初步结果表明，VNS治疗是 对单侧脊髓损伤模型有效。为了在更准确地代表临床脊髓损伤的模型中测试这一点 在慢性双侧CSCI模型中，我们建议评估VNS与康复训练的配对。 并检查皮质和脊髓运动网络的神经可塑性，这可能是康复的基础。此外, 我们将确定两个关键的神经调节系统，胆碱能和去甲肾上腺素能系统在 脊髓损伤后的康复。我们假设VNS配合康复训练将支持功能性和 双侧颈脊髓损伤后下行运动网络的解剖可塑性促进功能恢复。 拟议的实验结果将澄清双侧颈椎损伤之间的关系， 神经可塑性、神经调节功能和上肢运动恢复。此外，这项提议将提供 迷走神经综合征结合康复训练促进前肢功能恢复的概念验证评价 在严重的双侧脊髓损伤后，并阐明支持恢复的机制。

PROJECT ABSTRACT Spinal cord injury (SCI) is a major cause of disability, currently affecting 276,000 individuals in the U.S. alone and millions more worldwide. Cervical SCI (cSCI) accounts for 55% of all SCIs and typically results in impaired upper extremity motor function. The majority of cSCI patients have bilateral damage to the spinal cord. Identifying and developing rehabilitative therapies that promote recovery of upper extremity function after bilateral cSCI is of great clinical importance. We propose to evaluate a novel therapeutic intervention which uses precisely timed stimulation of the vagus nerve paired with rehabilitative training. Pairing vagus nerve stimulation (VNS) with movement engages pro- plasticity neuromodulatory systems and results in highly specific, long-lasting neuroplasticity in rat motor cortex. Based on this enhancement of plasticity, our recent results demonstrate that VNS paired with rehabilitation significantly enhances recovery of forelimb motor function in rat models of ischemic stroke, hemorrhagic stroke, and traumatic brain injury. Moreover, our preliminary results suggest that VNS therapy is effective in a unilateral model of SCI. To test this in a model that more accurately represents the clinical SCI population, we propose to evaluate VNS paired with rehabilitative training in a model of chronic, bilateral cSCI and examine the neuroplasticity in cortical and spinal motor networks that may underlie recovery. In addition, we will define the role of two key neuromodulatory systems, the cholinergic and noradrenergic systems, in recovery after SCI. We hypothesize the VNS paired with rehabilitative training will support functional and anatomical plasticity in descending motor networks to enhance recovery of function after bilateral cSCI. The results of the proposed experiments will clarify the relationship between bilateral cervical spinal damage, neuroplasticity, neuromodulatory function, and upper limb motor recovery. Moreover, this proposal will provide a proof-of-concept evaluation of VNS paired with rehabilitative training to improve recovery of forelimb function after a severe bilateral SCI and elucidate the mechanisms that support recovery.