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.

Peripheral nerve stimulation (PNS) is a promising, non-addictive, non-pharmacologic intervention for the treatment of chronic neuropathic pain (CNP) with demonstrated efficacy. Despite major technical advances with advent of dedicated percutaneous PNS systems, much remains unknown regarding the underlying mechanisms of pain relief. We propose to identify the biopsychosocial predictors of PNS treatment response and characterize parallel longitudinal changes in central and peripheral pain processing induced by PNS to advance the evidence-base for PNS in the treatment of CNP in a mechanistic randomized trial comparing combined PNS therapy and conventional medical management (CMM) to CMM alone.