From Nerve to Brain: Toward a Mechanistic Understanding of Spinal Cord Stimulation in Human Subjects

从神经到大脑：对人类受试者脊髓刺激的机制理解

• 批准号: 10518516
• 负责人: ROY FREEMAN
• 金额: $ 711.47万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-22 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10518516
• 关键词: Algorithms; Anesthesia procedures; Axon; Biological Markers; Brain; Brain Stem; Clinical Trials; Clinical Trials Design; Collection; Cross-Over Studies; Crossover Design; Data; Development; Device Designs; Devices; Electrodes; Fiber; General Hospitals; Gills; Goals; Hospitals; Hour; Human; Implant; Inflammatory; Interneurons; Intractable Pain; Israel; Location; Longitudinal Studies; Magnetic Resonance Imaging; Maintenance; Massachusetts; Measurement; Measures; Mechanoreceptors; Medial lemniscus; Methods; Modeling; Movement; Nerve; Nerve Fibers; Neuraxis; Neuroglia; Neurons; Neurostimulation procedures of spinal cord tissue; Nociceptors; Outcome; Pain; Pain Clinics; Pain Research; Patient Selection; Patients; Pattern; Peptides; Peripheral; Peripheral Nerves; Phenotype; Physiologic pulse; Physiology; Plasma; Positron-Emission Tomography; Process; Psychometrics; Reproducibility; Research; Role; Sensory; Signal Transduction; Spinal; Spinal Cord; Spinal Cord Tract; Spinal Ganglia; Statistical Data Interpretation; Subgroup; System; Testing; Therapeutic; Woman; Work; afferent nerve; biomarker development; candidate marker; chemokine; clinical practice; cytokine; dorsal column; epidural space; human subject; implantable device; implantation; improved; innovation; instrument; nerve conduction study; neuroimaging; neuroinflammation; neurophysiology; pain outcome; pain reduction; pain score; painful neuropathy; pharmacodynamic biomarker; predicting response; predictive marker; preimplantation; primary outcome; prospective; psychologic; recruit; response; secondary outcome; tool; trial design

PROJECT SUMMARY Spinal cord stimulators (SCS) and related devices are commonly used to treat refractory pain conditions, although mechanisms underlying pain reduction remain unclear. Improved understanding of SCS and the development of biomarkers are critical for improving device design and stimulation patterns and optimizing patient selection for device treatment. The main hypothesis of this proposal is that SCS devices reduce pain by modulating the excitability of peripheral sensory nerve fibers that project within the spinal dorsal columns, and this effect can be leveraged for biomarker development. The rationale for this hypothesis is that first order low-threshold mechanoreceptors project from the periphery through the dorsal column/medial lemniscus system to the brainstem. These are the neurons that (1) have closest proximity to the epidural space, the location of stimulation, and (2) have processes in both the periphery and spinal cord tracts. We will apply specialized tests of peripheral nerve excitability, threshold tracking nerve conduction studies, to detect changes in the excitability exerted on these neurons by SCS. We will also perform secondary measurements to determine other potential mechanisms of SCS in the peripheral and central nervous systems: microneurography, to detect modulation of primary nociceptor neuron excitability; PET-MRI, to measure changes in brain neuroinflammation; plasma cytokines and chemokines, to detect systemic neuroinflammatory effects due to SCS. We will perform sensory phenotyping to identify mechanisms in specific subgroups and pain and psychometric instruments to quantify responses. Aim 1 will use a multiple crossover design in subjects who have stably implanted SCS devices, and SCS settings will be toggled between therapeutic and minimal settings. Crossover intervals will include both two-week periods and rapid two-hour periods between setting changes. Aim 2 will consist of a prospective assessment of subjects prior and after implantation of new SCS devices, with a goal of identifying predictors of pain reduction response. The successful completion of this study will yield new mechanisms by which SCS reduces pain, relevant biomarkers, and further development of promising outcomes for broad pain research.

项目摘要 脊髓刺激器（SCS）和相关装置通常用于治疗顽固性疼痛状况， 尽管减轻疼痛的潜在机制仍不清楚。加深对《能力标准说明》和 生物标志物的开发对于改进设备设计和刺激模式以及优化 选择患者进行器械治疗。该提案的主要假设是SCS器械可减轻疼痛 通过调节在脊髓背侧内投射的外周感觉神经纤维的兴奋性 柱，并且这种效应可以用于生物标志物开发。这一假设的基本原理是 第一级低阈值机械感受器从外周通过背柱/内侧 丘系系统到脑干。这些神经元（1）最接近硬膜外 空间，刺激的位置，和（2）在外周和脊髓束都有突起。我们 将应用周围神经兴奋性的专门测试，阈值跟踪神经传导研究， 检测SCS对这些神经元施加的兴奋性的变化。我们还将执行第二次 测量以确定SCS在外周和中枢神经系统中的其他潜在机制 系统：显微神经造影术，检测初级伤害感受器神经元兴奋性的调制; PET-MRI， 测量大脑神经炎症的变化;血浆细胞因子和趋化因子，以检测全身性 SCS引起的神经炎症效应。我们将进行感觉表型分析以确定 具体的亚组和疼痛和心理测量工具，以量化反应。Aim 1将使用倍数 交叉设计适用于稳定植入SCS器械的受试者，并将切换SCS设置 介于治疗和最低设置之间。交叉间隔将包括两个星期的时间和快速 两个小时的时间间隔。目标2将包括对受试者进行前瞻性评估， 以及植入新SCS器械后，目的是确定疼痛缓解反应的预测因子。 本研究的成功完成将产生SCS减轻疼痛的新机制， 生物标志物，并进一步发展广泛的疼痛研究的有希望的结果。