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（SC）和相关设备通常用于治疗难治性疼痛条件， 尽管减轻疼痛的机制尚不清楚。提高了对SC和 生物标志物的开发对于改善设备设计和刺激模式和优化至关重要 患者选择设备治疗。该提议的主要假设是SCS设备减轻疼痛 通过调节脊柱背在脊柱内的外周感官纤维的兴奋性 列，这种效果可以利用生物标志物的发展。该假设的理由是 一阶低阈值机械感受器从外围通过背侧柱/内侧项目 Lemniscus系统到脑干。这些是（1）与硬膜外最接近的神经元 空间，刺激的位置以及（2）在外围和脊髓区域都有过程。我们 将应用外周神经兴奋性的专业测试，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。我们还将执行次要 测量以确定周围和中枢神经中SC的其他潜在机制 系统：微功能学，以检测原发性伤害感受器神经元兴奋性的调节； Pet-Mri，到 测量脑神经炎症的变化；血浆细胞因子和趋化因子，以检测全身性 SCS引起的神经炎症作用。我们将执行感官表型来识别机制 特定的亚组，疼痛和心理测量工具，以量化反应。 AIM 1将使用多个 在稳定植入SCS设备和SCS设置的受试者中的跨界设计将被切换 在治疗和最小设置之间。跨界间隔将包括两周和快速的时间 设置更改之间的两个小时的时间。 AIM 2将包括对主题的预期评估 在植入新的S​​CS设备之后，目的是识别减轻疼痛反应的预测指标。 这项研究的成功完成将产生新的机制，而SC可以减轻疼痛，相关 生物标志物，以及进一步发展有希望的结果，以进行广泛的疼痛研究。