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.

摘要 人们对使用电刺激来促进感觉运动和运动功能的恢复越来越感兴趣 神经损伤后的自主神经功能。我们实验室和其他实验室之前的研究已经证明 刺激腰椎节段会激活中枢模式生成器，进而促进站立 还有走路。然而，尽管有大量的动物、临床前和临床数据检验了 腰椎刺激，将神经调节应用于上肢颈脊髓的研究非常有限。 在此，我们提出了在上肢神经调节领域存在的基本盲点，包括 在哪里进行解剖学上的刺激，如何给药，特别是作用机制。霍纳实验室已经 建立了一种临床相关的大鼠颈脊髓损伤模型，并设计了一种自给式硬膜外 一种可在行为自由的大鼠身上部署的刺激装置，以从多个角度刺激感觉运动回路 脊髓的表面。因此，我们处于有利地位，可以检验关于 颈椎刺激在恢复上肢功能中的作用。我们提供了令人兴奋的初步数据来演示 硬膜外刺激颈髓可以改善前肢功能。建议的理由是 研究表明，硬膜外刺激的部位提供了进入运动神经回路的独特通道。我们假设 电极的腹侧定位(VSS)将提供刺激运动回路的通路 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VSS结合时，可以放大恢复 DSS。为了验证这一假设，我们提出了以下目标：目标1：确定急性分子和生理 VSS治疗亚急性颈髓损伤的机制。目标2：确定功能影响 刺激部位及康复训练对早期慢性颈脊髓损伤康复的影响。目标3： 建立颈髓损伤后VSS和DSS联合应用的协同效应。这些研究将 探索一种令人兴奋的新方法来促进上肢的神经恢复，这是一个已经 调查有限，但仍是患者最关心的问题。我们的方法将严格确立 刺激部位对分子生理机制的生理和功能影响 上肢的可塑性。