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）是一种用于治疗难治性神经病的微创疗法