Spinal Neuromodulation to Promote Physiologic and Molecular Plasticity in theInjured Spinal Cord

摘要 人们对使用电刺激来促进感觉运动和神经功能的恢复越来越感兴趣。 神经损伤后的自主神经功能。我们实验室和其他人以前的研究已经证明， 脊髓腰段的刺激激活了中枢模式发生器，这反过来又促进了站立 还有走路然而，尽管有大量的动物、临床前和临床数据研究了 腰椎刺激，将神经调节应用于上肢颈脊髓的研究非常有限。 在这里，我们提出，基本盲点存在于上肢神经调制领域，包括 从解剖学的角度去刺激哪里，如何给药，尤其是作用机制。霍纳实验室 开发了一种临床相关的颈髓损伤大鼠模型，并设计了一种独立的硬膜外 刺激装置，其可以部署在自由行为的大鼠中，以刺激来自多个神经元的感觉运动回路， 脊髓的表面。因此，我们完全有能力测试关于 颈部刺激恢复上肢功能。我们提供了令人兴奋的初步数据， 颈髓的硬膜外刺激可以改善前肢功能。建议的理由 研究表明，硬膜外刺激的部位提供了通向运动回路的独特通道。我们假设 电极的腹侧定位（VSS）将提供在以下部位刺激运动电路的通路： 更常见的背侧入路（DSS）无法触及的病变。此外，我们建议， VSS将产生新的功能可塑性机制，当与 安保部为了验证这一假设，我们提出了以下目标：目的1：确定急性分子和生理 VSS应用于亚急性颈髓损伤的机制。目标2：确定功能影响 早期慢性颈脊髓损伤后的康复训练。目标3： 建立VSS和DSS联合应用在颈髓损伤后的协同作用。这些研究将 探索一种令人兴奋的新方法来促进上肢的神经恢复，这一研究领域已经 调查有限，但仍然是患者的主要问题。我们的方法将严格建立 刺激部位对分子和生理机制的生理和功能影响 上肢的可塑性

Abstract There is growing interest in the use of electrical stimulation to promote the recovery of sensorimotor and autonomic function after neural injury. Previous research from our lab and others has demonstrated that stimulation of spinal lumbar segments activates central pattern generators, which, in turn, facilitates standing and walking. However, while there is extensive animal, pre-clinical, and clinical data examining the impact of lumbar stimulation, studies that apply neuromodulation to the cervical spinal cord for upper limb are very limited. Here, we propose that fundamental blind spots exist in the field of neuromodulation for upper limb, including where to stimulate anatomically, how to dose and, especially, mechanisms of action. The Horner lab has developed a clinically relevant rat model of cervical spinal cord injury and engineered a self-contained epidural stimulation device that can be deployed in freely behaving rats to stimulate sensorimotor circuitry from multiple surfaces of the spinal cord. Hence, we are well positioned to test critically important hypotheses on the role of cervical stimulation in the restoration of upper limb function. We present exciting preliminary data demonstrating that epidural stimulation of the cervical spinal cord improves forelimb function. The rationale for the proposed research is that the site of epidural stimulation provides unique access to motor circuitry. We hypothesize that ventral positioning of electrodes (VSS) will provide access to stimulate motor circuitry at the site of lesion that are inaccessible from the more common dorsal approach (DSS). Further, we propose that VSS will produce novel mechanisms of function plasticity that can amplify recovery when combined with DSS. To test this hypothesis, we propose the following aims: Aim 1: Determine acute molecular and physiological mechanisms of VSS when applied to subacute cervical spinal cord injury. Aim 2: Establish the functional impact of site of stimulation and rehabilitative training on recovery from early chronic cervical spinal cord injury. Aim 3: Establish the synergistic effects of combined VSS and DSS after cervical spinal cord injury. These studies will explore an exciting new approach to promote neural recovery of the upper limb, an area of research that has had limited investigation, but remains a primary concern for the patient. Our approach will rigorously establish the physiological and functional effects of the site of stimulation on the molecular and physiological mechanisms of upper limb plasticity.