Stimulation of novel spinal respiratory circuit to restore breathing in ventilator-dependent patients with SCI.

项目总结/摘要 脊髓损伤（SCI）后的呼吸衰竭损害了受伤患者的健康， 是脊髓损伤患者死亡的主要原因。呼吸衰竭的治疗包括机械性 通气，其中使用机械泵来促进与肺的空气交换。机械通气 是侵入性的、昂贵的、限制性的，并且伴随着并发症和死亡的高风险。机械通气 提供不响应生理需求的不变的通气模式;它不 重现正常呼吸。正常的呼吸是一种复杂的行为，在自愿和非自愿的情况下 神经控制;它对病人的生理状态有反应（毫秒或更少）。恢复 完全整合的自然呼吸将代表呼吸衰竭治疗的重大进步 SCI之后。为了治疗目的而访问用于呼吸的神经网络的主要障碍是， 控制呼吸的神经机制存在于脑干深处，这对于外科手术来说是危险的。 最近，我们阐明了一种新的呼吸途径，在脊髓，可以调制的电 刺激颈椎，这是一个手术可触及的区域。我们收集了大量数据， 刺激颈椎可以恢复或增强呼吸。临床批准的硬膜外脊髓 刺激器的存在是为了治疗疼痛，这些刺激器也可以用来刺激颈椎恢复 呼吸功能本项目的主要目的是提供证据的概念，颈部硬膜外 刺激可以改善呼吸机依赖性SCI患者的呼吸功能， 最有效地恢复更正常呼吸的参数。这个五年计划的成果包括 确立硬膜外刺激用于脊髓损伤呼吸康复的安全性和可行性， 选择最佳刺激变量以增强每个患者的呼吸活动的算法（例如， 刺激部位、剂量和时机）。如果成功，我们预计使用硬膜外刺激部分或完全 让每一位SCI患者脱离机械通气，这将有直接的好处-增加 独立性，提高生活质量，降低与机械通气相关的成本和风险。 传统的想法是，一旦脊髓受伤，很少或没有功能恢复是可能的。这种可怕 这种可逆性的感觉与我们在脊髓神经调节方面的研究不一致，我们的研究表明， 硬脊膜外脊髓可使随意手和上肢功能得到实质性恢复 刺激.类似的神经调节策略可用于增强或恢复患者的呼吸功能 关于SCI如果成功，这种恢复呼吸功能的神经调节策略可能会迎来一个新的时代， 呼吸神经功能障碍的SCI，和潜在的其他神经系统疾病，并改变我们的 了解控制呼吸的神经回路和脊柱损伤状态的可塑性。

PROJECT SUMMARY/ABSTRACT Respiratory failure after spinal cord injury (SCI) impairs the health of the injured patients, and respiratory failure is the leading cause of death in patients with SCI. Treatment of respiratory failure consists of mechanical ventilation, in which a mechanical pump is used to facilitate air exchange with the lungs. Mechanical ventilation is invasive, costly, limiting, and carries with it a high risk of complications and death. Mechanical ventilation provides an unvarying pattern of ventilation that is not responsive to physiological demands; it does not recapitulate normal breathing. Normal breathing is a complex behavior under both voluntary and involuntary neural control; it is responsive (in milliseconds or less) to the physiological state of the patient. Restoration of fully integrated, naturalistic breathing would represent a significant advance in the treatment of respiratory failure following SCI. The main hurdle to accessing the neural network for breathing for therapeutic purposes is that the neural mechanisms controlling respiration reside deep in the brainstem, which is dangerous to access surgically. Recently, we elucidated a novel breathing pathway in the spinal cord that can be modulated by electrical stimulation of the cervical spine, an area that is surgically accessible. We have compiled significant data that stimulating the cervical spine can restore or augment breathing. Clinically approved epidural spinal cord stimulators exist to treat pain, and these stimulators can also be used to stimulate the cervical spine to restore respiratory function. The main objective of this project is to provide proof of the concept that cervical epidural stimulation can improve respiratory function in ventilator-dependent patients with SCI and define the stimulation parameters that most effectively restore more normal breathing. The deliverables for this 5-year project include establishing the safety and feasibility of epidural stimulation for respiratory rehabilitation in SCI and providing an algorithm to select the optimum stimulation variables to augment respiratory activity in each patient (e.g., stimulation site, dose, and timing). If successful, we anticipate using epidural stimulation to partially or completely wean each patient with SCI off mechanical ventilation, which would have immediate benefits — increased independence, improved quality of life, and decreased costs and risks associated with mechanical ventilation. Conventional thinking is that once the spinal cord is injured, little or no functional recovery is possible. This dire sense of irrreversibility is at odds with our research in spinal cord neuromodulation, which has shown that substantial recovery of voluntary hand and upper extremity function can result from epidural spinal cord stimulation. A similar neurmodulatory strategy may be used to augment or restore respiratory function in patients with SCI. If successful, this neuromodulatory strategy to restore respiratory function may usher in a new era of respiratory neurorehabiltitation for SCI, and potentially other neurological disorders, and transform our understanding of neural circuits governing respiration and the plasticity of injured states of the spine.