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

项目摘要/摘要 脊髓损伤(SCI)后的呼吸衰竭损害了受伤患者的健康，呼吸衰竭 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治疗 通风，使用机械泵来促进空气与肺部的交换。机械通风 是侵入性的、昂贵的、限制性的，并伴随着并发症和死亡的高风险。机械通风 提供了一种不响应生理需求的恒定的通风模式；它不 重述一下正常的呼吸。正常呼吸在自愿和非自愿的情况下都是一种复杂的行为 神经控制；它对病人的生理状态做出反应(在毫秒或更短的时间内)。恢复 完全整合的自然呼吸将是呼吸衰竭治疗的重大进步。 追随SCI。为了治疗目的而进入神经网络进行呼吸的主要障碍是 控制呼吸的神经机制位于脑干深处，通过手术进入是危险的。 最近，我们阐明了脊髓中一种新的呼吸途径，它可以通过电调节。 刺激颈椎，这是一个可以通过手术到达的区域。我们汇编了重要的数据， 刺激颈椎可以恢复或增加呼吸。临床批准的硬膜外脊髓 刺激器是用来治疗疼痛的，而这些刺激器也可以用来刺激颈椎恢复 呼吸功能。该项目的主要目的是证明颈段硬膜外麻醉的概念 刺激可改善呼吸机依赖脊髓损伤患者的呼吸功能并确定刺激 最有效地恢复正常呼吸的参数。这个为期5年的项目的可交付成果包括 建立硬膜外刺激用于脊髓损伤患者呼吸康复的安全性和可行性，并提供 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，我们预计将使用硬膜外刺激部分或完全 使每位SCI患者摆脱机械通气，这将立即产生好处-增加 独立，提高生活质量，降低与机械通风相关的成本和风险。 传统的想法是，一旦脊髓受伤，功能恢复几乎或根本不可能。这可怕的事 不可逆性的感觉与我们对脊髓神经调节的研究不一致，这表明 硬膜外脊髓可显著恢复自主手和上肢功能 刺激。一种类似的神经调节策略可用于增强或恢复患者的呼吸功能 和SCI一起。如果成功，这种恢复呼吸功能的神经调节策略可能会开启一个新的时代 呼吸神经康复治疗脊髓损伤，以及潜在的其他神经疾病，并改变我们的 了解支配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.