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

脊髓神经调节促进受损脊髓的生理和分子可塑性

• 批准号: 10805726
• 负责人: Philip J Horner
• 金额: $ 46.94万
• 依托单位: METHODIST HOSPITAL RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-20 至 2028-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10805726
• 关键词: Acute; Anatomy; Animal Experiments; Animals; Area; Biology; Cervical; Cervical spinal cord injury; Cervical spinal cord structure; Chronic; Clinical; Clinical Data; Clinical Research; Contusions; Data; Devices; Dorsal; Dose; Effectiveness; Electric Stimulation; Electrodes; Engineering; Family; Fiber; Forelimb; Future; Gene Expression; Genetic Transcription; Hour; Informatics; Injury; Investigation; Lesion; Locomotion; Maps; Methods; Modeling; Molecular; Motor; Muscle; Neuronal Plasticity; Paralysed; Pathway interactions; Patients; Pattern; Performance; Persons; Physiological; Physiology; Positioning Attribute; Publishing; Quadriplegia; Quality of life; Rattus; Recovery; Recovery of Function; Rehabilitation therapy; Reporting; Research; Retinal blind spot; Rodent; Role; Sensory; Site; Speed; Spinal; Spinal Cord; Spinal cord injury; Stroke; Surface; Testing; Time; Training; Traumatic Brain Injury; Upper Extremity; Vertebral column; Walking; Work; candidate identification; central pattern generator; clinically relevant; cost; experience; experimental study; functional improvement; functional plasticity; gene regulatory network; hand rehabilitation; improved; innovation; insight; interest; intraspinal microstimulation; motor recovery; nerve injury; neural; neuroinflammation; neuroregulation; novel; novel strategies; pre-clinical; restoration; transcriptomics

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.

抽象的 人们越来越关注使用电刺激来促进感觉运动和感觉运动的恢复 神经损伤后的自主神经功能。我们实验室和其他人之前的研究表明 刺激脊柱腰段会激活中央模式发生器，从而促进站立 和步行。然而，虽然有大量的动物、临床前和临床数据检验了 腰部刺激，将神经调节应用于上肢颈脊髓的研究非常有限。 在这里，我们提出上肢神经调节领域存在基本盲点，包括 在哪里进行解剖学刺激、如何剂量，尤其是作用机制。霍纳实验室有 开发了临床相关的颈脊髓损伤大鼠模型，并设计了独立的硬膜外麻醉 刺激装置可以部署在自由行为的大鼠身上，以刺激多个感觉运动电路 脊髓表面。因此，我们有能力测试关于以下角色的至关重要的假设： 颈部刺激恢复上肢功能。我们提供令人兴奋的初步数据证明 颈脊髓的硬膜外刺激可改善前肢功能。拟议的理由 研究表明，硬膜外刺激部位提供了进入运动回路的独特途径。我们假设 腹侧定位电极（VSS）将提供刺激部位运动电路的通道 通过更常见的背侧入路 (DSS) 无法到达的病变。此外，我们建议 VSS 将产生新的功能可塑性机制，与 决策支持系统。为了检验这一假设，我们提出以下目标： 目标 1：确定急性分子和生理学 VSS应用于亚急性颈脊髓损伤的机制。目标 2：确定功能影响 刺激部位和康复训练对早期慢性颈脊髓损伤恢复的影响。目标 3： 建立颈髓损伤后联合 VSS 和 DSS 的协同效应。这些研究将 探索一种令人兴奋的新方法来促进上肢神经恢复，这是一个研究领域 调查有限，但仍然是患者主要关心的问题。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 上肢可塑性。