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

项目总结 脊髓刺激器(SCS)和相关设备通常用于治疗顽固性疼痛情况， 尽管减轻疼痛的机制仍不清楚。提高了对SCS和 生物标志物的开发对改进设备设计和刺激模式以及优化至关重要 设备治疗的患者选择。这项提议的主要假设是SCS设备可以减轻疼痛 通过调节投射在脊髓背侧的外周感觉神经纤维的兴奋性 柱，这一效应可用于生物标记物的开发。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/内侧投射 丘疹系统连接到脑干。这些是(1)最接近硬膜外的神经元 (2)在外周和脊髓束均有突起。我们 将应用专门的周围神经兴奋性测试，阈值跟踪神经传导研究，以 检测SCS对这些神经元的兴奋性的变化。我们还将执行第二次 确定外周和中枢神经SCS其他潜在机制的测量 系统：显微神经学，以检测初级伤害性感受器神经元兴奋性的调制；PET-MRI，以 测量脑神经炎症；血浆细胞因子和趋化因子的变化，以检测全身性 SCS引起的神经炎性反应。我们将进行感觉表型鉴定，以确定 具体的亚组和疼痛和心理测量工具，以量化反应。目标1将使用倍数 稳定植入SCS装置的受试者的交叉设计，以及SCS设置将被切换 介于治疗性环境和最小环境之间。交叉间隔将包括两周和快速 设置更改之间的两个小时间隔。目标2将包括事先对受试者的前瞻性评估 并在植入新的SCS设备后，目标是确定疼痛减轻反应的预测因素。 这项研究的成功完成将产生SCS减轻疼痛的新机制，相关 生物标志物，以及在广泛的疼痛研究中有希望的结果的进一步发展。

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.