Investigating the Neural Circuits of Spinal Cord Stimulation

研究脊髓刺激的神经回路

• 批准号: 9525493
• 负责人: Andrei D Sdrulla
• 金额: $ 19.39万
• 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 2023-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9525493
• 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; Nerve; 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; injured; insight; minimally invasive; mouse model; 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病 疼痛。据认为，SCS 通过电刺激 Aβ 纤维 (Aβ-ES) 介导疼痛缓解，然而详细的研究 对其生物学基础缺乏了解，特别是关于它如何影响脊髓伤害感受 途径。该提案的长期目标是描述 SCS 诱导的脊柱机制 镇痛，努力优化其治疗慢性疼痛的临床实施。总体目标 本申请的目的是剖析Aβ-ES对特定神经元微电路的影响，并测试其作用 Aβ-ES 镇痛作用的关键候选亚群。中心假设是 Aβ-ES 通过诱导位于脊髓中的特定脊髓神经元群的动态变化来实现镇痛 浅表背角（SDH）。该假设将通过追求三个具体目标来检验：1）确定 背根 Aβ-ES 调节序列调节高阈值（C 纤维）诱发活动的程度 幼稚和神经损伤的整体脊髓制剂中 SDH 中的兴奋性和抑制性神经元 老鼠。 2) 使用体内成像确定背柱 Aβ-ES 调节序列的程度 减弱浅表背角中兴奋性和抑制性神经元的外周诱发活动 和神经损伤的小鼠。 3)确定背柱Aβ-ES中生长抑素表达神经元的作用 介导镇痛。所提出的方法利用了最先进的离体和体内双光子 成像与光遗传学方法相结合，描绘 Aβ-ES 对特定神经元群的影响 实时。拟议的研究意义重大，因为详细了解 Aβ-ES 如何参与 背角将为增强 SCS 疗法提供直接的生物靶点，并具有良好的机制 基础。因此，这项工作将具有直接的转化相关性，因为它可能有助于优化脊髓刺激 计划并改善患者的治疗结果。 Andrei Sdrulla 博士是一位医学博士/博士临床医生科学家，其职业目标是成为一名成功的、独立的 资助疼痛研究员和神经调节领域的临床领导者。 Sdrulla 博士将与其密切合作 综合指导团队开发神经元群体体内定量成像专业知识 成像、慢性疼痛小鼠模型以及神经元群体行为的光遗传学操作 动物。这项培训将主要通过在他的监督下进行实验来完成 导师以及由教学、面对面指导和研讨会组成的结构化培训。斯德鲁拉博士 将在俄勒冈健康与科学大学麻醉学系进行研究 实验室，一个建立在共享资源和核心基础上的独特协作环境 卓越，这是早期职业调查员的理想选择。