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 瘫痪和呼吸受损或衰竭。大约20%的CSCI患者将需要 呼吸机支持，康复的治疗选择很少。硬膜外 刺激已经成为一种恢复各种运动、感觉和自主神经的策略 在脊髓损伤后的实验和临床条件下的功能。尽管基础有限 机制已经提出，到目前为止对硬膜外刺激如何引起运动知之甚少。 在神经元水平上发挥作用。对硬膜外刺激的能力了解更少 促进长时间的脊柱可塑性以实现真正的设备独立性，迄今为止还没有研究 探索了引发呼吸道可塑性的可能性。指导这一点的基本假设 建议长期的、闭合的硬膜外刺激可以改善患者的功能 通过依赖活动的机制，持续刺激期间的横隔膜活动 BDNF/TrkB信号转导在膈运动神经元中的作用。初步数据令人振奋， 表明至少有一些短期的可塑性和较长的刺激期(4d)。我们设想 更慢性和更有针对性的刺激参数将导致更长的运动持续时间 恢复。这是首次提出在清醒、自由行为时进行慢性硬膜外刺激的研究。 动物处于特定的呼吸神经回路中。最终，来自该项目的数据将用于 关于硬膜外刺激机制基础的未来研究进展 疗效对于将治疗应用推广到许多运动系统是必不可少的，但 尤其是对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.