Phrenic motoneuron activation usingtemporal interference

摘要 为了响应NINDS PA-18-358（与神经系统疾病相关的“探索性和创新性项目”），我们 提出了一个为期两年的项目，以开发一种新的方法，电刺激脊髓。目的是 在急性或慢性通气不足期间恢复呼吸肌激活和呼吸， 阿片类药物过量或神经创伤基于脑深部电刺激数据，该方法被称为时间 干扰（T-I）刺激。前提是针对脊髓用两种，高频，但低频 振幅电波形。这些波形以千赫兹的频率传输， 直接刺激神经元的值。两个波形的频率偏移少量（例如，1- 100%）。 5 Hz），并且当两个电场在组织中相加时，神经元群与 的偏移。我们的总体假设是，T-I刺激可以用于将能量靶向腹侧颈 脊髓以最小的脱靶效应调节横膈膜激活。对于这个应用程序，我们进行了 使用阿片类药物过量和颈脊髓损伤大鼠模型的概念验证初步实验 （SCI）。我们首先检查了通过简单的皮下颈部电极传递的T-I刺激， 急性阿片类药物过量其基本原理是，一种快速和容易应用的维持呼吸的方法可能是 用于在紧急临床情况下维持通气。值得注意的是，T-I刺激使用亚- 颈部的皮肤导联能够引起膈肌运动募集， 通过改变两个刺激波形之间的偏移频率来调节。据我们所知， 方法已经能够诱导有节奏的隔膜收缩即，“起搏”与微创 刺激方法另外的初步实验集中在颈椎的硬膜外刺激， 线.其基本原理是硬膜外刺激作为恢复躯体和/或神经功能的一种手段正在获得牵引力。 脊髓损伤后的自主运动功能，并显示出激活横膈膜的希望。中间的电极- 颈部背侧硬膜外表面用于在KHz频率下传递两个波形。T-I双波 硬膜外刺激在激活和调节膈肌运动单位方面非常有效。相比 单波硬膜外刺激，我们预测T-I将提供的优点包括：1）改善疗效后， 不完全和/或慢性病变; 2）能够产生广泛的膈肌运动单位募集 具有更自然的“爆发”包络的模式，以及3）能够更集中地将刺激瞄准腹侧 号角.将通过评估和优化通过以下方式递送的T-I刺激来检验总体假设： 皮下（目标1）或硬膜外电极（目标2）。该项目是创新的，因为双波形T-I 刺激以前没有被探索作为激活呼吸肌的手段。PI Dr. Fuller Otto博士是一位具有20多年经验的生物医学工程师， 具有中枢神经系统电刺激经验，包括电极设计。

ABSTRACT In response to NINDS PA-18-358 (“exploratory and innovative projects” related to neurological disorders), we propose a 2-yr project to develop a novel method to electrically stimulate the spinal cord. The purpose is to restore respiratory muscle activation and breathing during acute or chronic hypoventilation associated with opioid overdose or neurotrauma. Based on deep brain stimulation data, the method is called temporal interference (T-I) stimulation. The premise is to target the spinal cord with two, high frequency, but low amplitude electrical waveforms. The waveforms are delivered at kilohertz frequencies that are well above values that directly stimulate neurons. The frequency of the two waveforms is offset by a small amount (e.g. 1- 5 Hz), and where the two electrical fields sum in the tissue, neuronal populations are recruited in phase with the offset. Our overall hypothesis is that T-I stimulation can be used to target energy to the ventral cervical spinal cord to regulate diaphragm activation with minimal off target effects. For this application, we conducted proof-of-concept preliminary experiments using rat models of opioid overdose and cervical spinal cord injury (SCI). We initially examined T-I stimulation delivered via simple sub-cutaneous neck electrodes following acute opioid overdose. The rationale is that a rapid and easily applied method to sustain breathing could be useful to sustain ventilation in emergency clinical situations. Remarkably, T-I stimulation delivered using sub- cutaneous leads in the neck region was able to evoke diaphragm motor recruitment, and the discharge could be regulated by varying the offset frequency between the two stimulus waveforms. To our knowledge, no prior methods have been able to induce rhythmic diaphragm contractions i.e., “pacing” with a minimally invasive stimulation approach. Additional preliminary experiments focused on epidural stimulation of the cervical spinal cord. The rationale is that epidural stimulation is gaining traction as a means of restoring somatic and/or autonomic motor function after SCI and shows promise for activating the diaphragm. Electrodes on the mid- cervical dorsal epidural surface were used to deliver two waveforms at KHz frequencies. The T-I dual wave epidural stimulation was remarkably effective at activating and regulating diaphragm motor units. Compared to single wave epidural stimulation, we predict that T-I will offer advantages including 1) improved efficacy after incomplete and/or chronic lesions; 2) ability to produce a wide range of diaphragm motor unit recruitment patterns with more natural “burst” envelope, and 3) ability to more focally target the stimulus to the ventral horn. The overall hypothesis will be tested by evaluating and optimizing T-I stimulation delivered via subcutaneous (Aim 1) or epidural electrodes (Aim 2). The project is innovative since dual waveform T-I stimulation has not previously been explored as a means of activating the respiratory muscles. PI Dr. Fuller has extensive experience with rodent models of SCI and Co-I Dr. Otto is a biomedical engineer with 20+ years of experience in electrical stimulation of the central nervous system including electrode design.