Investigating the Neural Circuits of Spinal Cord Stimulation

研究脊髓刺激的神经回路

• 批准号: 10263824
• 负责人: Andrei D Sdrulla
• 金额: $ 2.16万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-03-01 至 2021-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10263824
• 关键词: Absence of pain sensation; Amyloid beta-Protein; Analgesics; Anesthesiology; Animals; Attenuated; Behavior; Biological; C Fiber; Cells; Chronic; Clinical; Complex; Coupled; Development; Doctor of Philosophy; Electric Stimulation; Fiber; Foundations; Funding; Goals; Health; Health Sciences; Implant; Instruction; Laboratories; Long-Term Depression; Mediating; Mentors; Mentorship; Mission; Modality; Mus; Neurons; Neurostimulation procedures of spinal cord tissue; Nociception; Oregon; Pain; Pathway interactions; Patient-Focused Outcomes; Patients; Peripheral; Peripheral Nerve Stimulation; Population; Population Heterogeneity; Posterior Horn Cells; Preparation; Public Health; Refractory; Research; Research Personnel; Resource Sharing; Role; Scientist; Somatostatin; Spinal; Spinal Cord; Structure; Supervision; Synapses; Testing; Time; Training; Transcutaneous Electric Nerve Stimulation; United States National Institutes of Health; Universities; Work; awake; career; chronic pain; chronic painful condition; clinical implementation; collaborative environment; conditioning; control theory; dorsal column; dorsal horn; excitatory neuron; experience; experimental study; human disease; improved; in vivo imaging; in vivo two-photon imaging; inhibitory neuron; insight; minimally invasive; mouse model; nerve injury; neural circuit; neuronal circuitry; neuroregulation; nociceptive response; novel; optogenetics; pain relief; painful neuropathy; personalized medicine; programs; quantitative imaging; response; selective expression; sound; spinal nerve posterior root; synaptic depression; treatment program

Spinal cord stimulation (SCS) is a minimally invasive therapy used for the treatment of refractory neuropathic pain. It is believed that SCS mediates pain relief by electrical stimulation of Aβ fibers (Aβ-ES), however a detailed understanding of its biological basis is lacking, particularly concerning how it engages spinal cord nociceptive pathways. The long-term goals of this proposal are to delineate the spinal mechanisms of SCS-induced analgesia in an effort to optimize its clinical implementation for the treatment of chronic pain. The overall objective of the present application is to dissect the influence of Aβ-ES on defined neuronal microcircuits, and test the role of a critical candidate subpopulation for the analgesic effects of Aβ-ES. The central hypothesis is that Aβ-ES achieves analgesia by inducing dynamic changes in specific populations of spinal cord neurons residing in the superficial dorsal horn (SDH). This hypothesis will be tested by pursuing three specific aims: 1) Determine the extent to which a conditioning train of dorsal root Aβ-ES modulates high-threshold (C-fiber) evoked activity of excitatory and inhibitory neurons in the SDH in an en bloc spinal cord preparation from naïve and nerve-injured mice. 2) Use in vivo imaging to determine the extent to which a conditioning train of dorsal column Aβ-ES attenuates peripherally evoked activity of excitatory and inhibitory neurons, in the superficial dorsal horn, in naïve and nerve-injured mice. 3) Determine the role of somatostatin expressing neurons in dorsal column Aβ-ES mediated analgesia. The proposed approach takes advantage of state-of-the-art ex vivo and in vivo two-photon imaging coupled with optogenetic approaches to delineate the effects of Aβ-ES on defined neuronal populations in real time. The proposed research is significant because a detailed understanding of how Aβ-ES engages the dorsal horn will provide a direct biological target for enhancements to SCS therapies with a sound mechanistic basis. This work will thus have direct translational relevance, as it may help optimize spinal cord stimulation programs and improve patient outcomes. Dr. Andrei Sdrulla is a MD/PhD clinician-scientist whose career goals are to become a successful, independently funded pain researcher and a clinical leader in the field of neuromodulation. Dr. Sdrulla will work closely with his comprehensive mentorship team to develop expertise in quantitative imaging of neuronal populations, in vivo imaging, mouse models of chronic pain and optogenetic manipulation of neuronal populations in behaving animals. This training will be accomplished primarily via performing experiments under supervision from his mentors, as well as structured training consisting of didactics, face-to-face instruction and seminars. Dr. Sdrulla will be conducting his research within Oregon Health & Science University’s Department of Anesthesiology Laboratories, a uniquely collaborative environment constructed on a foundation of shared resources and core excellence, which is ideal for an early career investigator.

脊髓刺激（SCS）是一种微创疗法，用于治疗难治性神经性疗法 疼痛。据信，SCS通过Aβ纤维（Aβ-Es）的电刺激来缓解疼痛，但是详细 缺乏对其生物学基础的理解，尤其是关于它如何吸引脊髓伤害感受的 途径。该提案的长期目标是描述SCS引起的脊柱机制 镇痛为了优化其临床实施以治疗慢性疼痛。总体目标 本应用的目的是剖析Aβ-E对定义的神经元微电路的影响，并测试该作用 Aβ-E的镇痛作用的关键候选亚群。中心假设是Aβ-E 通过诱导位于 表面角（SDH）。该假设将通过追求三个具体目标来检验：1）确定 背根Aβ-E的调节列车调节高阈值（C纤维）诱发活性的程度 SDH中的兴奋性和抑制性神经元在整体的脊髓制备中，由幼稚和神经受伤 老鼠。 2）使用体内成像来确定背侧Aβ-ES条件列的程度 在浅表背角中，刺激和抑制性神经元的外周诱发活性，幼稚 和神经损害的小鼠。 3）确定表达神经元在背圆柱Aβ-ES中的表达神经元的作用 介导的镇痛。所提出的方法利用了最新的离体和体内两光子 成像与光遗传学方法相结合，以描绘Aβ-E对定义神经元种群的影响 实时。拟议的研究很重要，因为对Aβ-E如何参与的详细理解 背喇叭将提供直接的生物学目标，以增强具有声音机械的SCS疗法 基础。因此，这项工作将具有直接的翻译相关性，因为它可能有助于优化脊髓刺激 计划并改善患者的预后。 Andrei Sdrulla博士是医学博士/博士学位临床科学家，其职业目标是成为一个成功的，独立的 资助的疼痛研究人员和神经调节领域的临床领导者。 Sdrulla博士将与他的 全面的质体团队在体内发展神经元人群的定量成像方面的专业知识 成像，慢性疼痛的小鼠模型以及对行为中神经元种群的光遗传操纵 动物。该培训将主要通过在他的监督下进行实验来完成 导师以及包括教学，面对面指令和下水道组成的结构化培训。 Sdrulla博士 将在俄勒冈健康与科学大学的麻醉学系中进行研究 实验室，一个独特的协作环境，建于共享资源和核心的基础上 卓越，这是早期职业调查员的理想选择。