Mechanisms of Action of Peripheral Nerve Stimulation for the Treatment of Chronic Neuropathic Pain

近年来，随着现代经皮周围神经刺激（PNS）系统的出现，PNS治疗难治性慢性神经性疼痛（CNP）的疗效呈指数级增长。PNS通过靠近目标周围神经的皮下电极传递电流。尽管有重大的技术创新，但PNS如何调节疼痛处理仍然未知。我们的跨学科团队在PNS植入物、疼痛临床试验、心理评估、定量感觉测试（QST）和先进的疼痛分子成像方面拥有深厚的专业知识，具有独特的资质。我们的建议直接针对HEAL RFA-NS-23-003，优化PNS作为非成瘾性CNP治疗。我们的主要假设是PNS对电脉冲的响应减少了异位放电，导致初级感觉传入的潜伏期增加、镇痛和中枢致敏性降低。我们的总体目标是确定PNS疼痛缓解的中枢和外周神经系统机制，并表征治疗反应的生物心理社会预测因子。我们对134例下肢CNP-PI患者进行了一项机制性随机对照试验，随机分为稳定的常规医疗管理（CMM）或CMM和PNS联合治疗（PNS+CMM）。所有参与者将接受基线和每月远程评估长达1年。定量感觉测试（QST）将在基线、30天和3个月时对所有参与者进行，在6个月时对植入PNS的患者进行额外的QST测试。慢性疼痛中S1R的局部表达允许外周疼痛产生者的可视化，我们已经开发了一种新的PET放射性示踪剂，高度选择性地与局部受体密度和疼痛症状相关的S1R。78例患者（每组39例）将在基线时进行[18F]FTC-146 PET/ MRI下肢检查，并在3个月时进行[18F]FTC-146 PET/CT检查。我们将描述治疗与参与者属性和基线QST疼痛敏感性的相互作用，以预测治疗反应；检查抑郁和身体功能作为治疗反应的中介；比较不同治疗期间的纵向疼痛、抑郁症状、疼痛大化、身体功能和QST轨迹，比较稳定植入后PNS对急性QST的反应，并确定外周成像标志物是否与基线疼痛和治疗反应相关。该项目将为精确的PNS治疗提供信息，确定CNP-PI的表型和PNS治疗反应以及与治疗反应相关的可修改因素。在CNP治疗过程中，pns诱导的中枢神经系统修复可能会导致神经刺激时间（即更早或更晚）的显著范式转变。鉴定CNP- pi的诊断性成像生物标志物和PNS治疗的预测/反应性成像生物标志物将显著推进CNP的诊断成像方法。

With advent of modern, percutaneous peripheral nerve stimulation (PNS) systems in the last few years, there has been exponential use of PNS for the treatment of refractory chronic neuropathic pain (CNP) with reported efficacy. PNS delivers electrical current through subcutaneous electrodes in proximity to a target peripheral nerve. Despite major technical innovations, exactly how PNS modulates pain processing remains unknown. Our interdisciplinary team is uniquely qualified for this cohesive project with deep expertise in PNS implant, pain clinical trials, psychological assessments, quantitative sensory testing (QST), and advanced molecular imaging for pain. Our proposal directly addresses HEAL RFA-NS-23-003 to optimize PNS as a nonaddictive CNP treatment. Our main hypothesis is that PNS induces reduced ectopic firing in response to electrical pulses, with resulting increased latency of primary sensory afferents, analgesia, and decreased central sensitization. Our overall goal is to identify central and peripheral nervous system mechanisms of PNS pain relief and to characterize the biopsychosocial predictors of treatment response. We propose a mechanistic RCT of 134 patients with lower extremity CNP-PI randomized to stable conventional medical management (CMM) or combined CMM and PNS therapy (PNS+CMM). All participants will undergo baseline and monthly remote assessments for up to 1 year. Quantitative sensory testing (QST) will be performed in all participants at baseline, 30 days, and 3 months, with an additional QST session in PNS implanted patients at 6 months. The local expression of S1R in chronic pain allows for visualization of peripheral pain generators, and we have developed a novel PET radiotracer highly selective for the S1R correlating with local receptor density and pain symptoms. 78 patients (39 in each arm) will undergo [18F]FTC-146 PET/ MRI of the lower extremities at baseline and [18F]FTC-146 PET/CT at 3 months. We will characterize treatment interactions with participant attributes and baseline QST pain sensitivity measures in predicting treatment response; examine depression and physical function as mediators of treatment response; compare longitudinal pain, depressive symptom, pain catastrophizing, physical function, and QST trajectories across treatments, compare acute QST responses to PNS after stable implantation, and determine whether peripheral imaging markers correlate with baseline pain and treatment response. This project will inform precision PNS therapy identifying phenotypes of CNP-PI and PNS treatment response and modifiable factors associated with therapeutic response. Demonstration of PNS-induced reconditioning of the CNS may result in significant paradigm shifts regarding the timing of neurostimulation (i.e. earlier vs. later) in the course of CNP treatment. Identification of a diagnostic imaging biomarker of CNP-PI and predictive/response imaging biomarkers of PNS therapy will significantly advance the diagnostic imaging approach to CNP.