Cervical Epidural Stimulation and Respiratory Motor Plasticity

项目摘要 超过一半的创伤性脊髓损伤（SCI）发生在颈椎水平，导致 瘫痪和呼吸衰竭。大约20%的cSCI患者需要 呼吸机支持，对于其恢复的治疗选择非常少。硬膜外 刺激已经作为一种恢复各种运动、感觉和自主神经的策略而出现 在SCI后的实验和临床条件下发挥作用。虽然基础有限， 机制已被提出，但到目前为止，很少有人知道硬膜外刺激如何促进运动 在神经元水平发挥作用。关于硬膜外刺激的能力， 促进持久的脊柱可塑性，实现真正的器械独立性，迄今为止， 探索激发呼吸可塑性的潜力。指导这一研究的基本假设 建议长期闭环硬膜外刺激有助于改善 通过活动依赖性机制持续超过刺激期的隔膜活动 涉及膈运动神经元中的BDNF/TrkB信号。初步数据显示， 这表明在较长刺激周期下至少有一些短期可塑性（4D）。我们设想 更多的慢性和有针对性的刺激参数将导致更长的运动持续时间， 复苏这是第一个提出慢性硬膜外刺激清醒，自由行为的研究。 动物在一个明确的呼吸神经回路。最终，该项目的数据将有助于 为硬膜外刺激机制基础的未来研究提供信息 对于推进许多运动系统的治疗应用至关重要， 尤其是控制呼吸的神经系统。

Project Summary More than half of traumatic spinal cord injuries (SCI) occur at the cervical level, leading to paralysis and respiratory compromise or failure. Approximately 20% of cSCI patients will require ventilator support for which there are very few therapeutic options for recovery. Epidural stimulation has emerged as a strategy to restore a variety of motor, sensory, and autonomic functions in both experimental and clinical conditions after SCI. Though limited underlying mechanisms have been proposed, to date little is known how epidural stimulation elicits motor function at the neuronal level. Even less is known about the capacity for epidural stimulation to promote long-lasting spinal plasticity for true device-independence and to date no studies have explored the potential for eliciting respiratory plasticity. The fundamental hypothesis guiding this proposal is that long-term, closed-loop epidural stimulation elicits functional improvement in diaphragm activity that outlasts the period of stimulation via activity-dependent mechanisms involving BDNF/TrkB signaling in phrenic motor neurons. Preliminary data are promising and indicate at least some short-term plasticity with longer periods of stimulation (4d). We envision that more chronic and targeted stimulation parameters will result in longer persistence of motor recovery. This is the first study to propose chronic epidural stimulation in awake, freely-behaving animals in a defined respiratory neural circuit. Ultimately, data from this project will serve to inform development of future investigations of the mechanistic basis of epidural stimulation efficacy essential for advancing the therapeutic applications to many motor systems but especially to the neural system controlling breathing.