85 - Peripherally Induced Reconditioning of the Central Nervous System: Proposed Mechanisms for Sustained Relief of Chronic Pain with Percutaneous Peripheral Nerve Stimulation

¹The Spine and Nerve Center of the Virginias, Charleston, WV, USA. ²The James Cook University Hospital, Middlesbrough, United Kingdom. ³Neurosurgical Associates of Lancaster, Lancaster, PA, USA. ⁴Virginia Commonwealth University Medical Center, Richmond, VA, USA. ⁵Premier Pain Centers, Shrewsbury, NJ, USA. ⁶SPR Therapeutics, Cleveland, OH, USA

Purpose
Chronic pain is associated with peripheral and central sensitization processes that result in abnormal pain processing and hypersensitivity throughout pain pathways in the periphery and CNS. Supraspinal circuits play a major role in the processing of pain and have been implicated in centrally mediated chronic pain. Specifically in the somatosensory cortex, which encodes the sensory-discriminative aspects of pain, the nociceptive representational zones exhibit a sensitized state characterized by expansion and/or shifting of pain representations, reduced GABAergic inhibition, and stronger response to activation, while non-nociceptive representational zones may diminish in size and response to activation. These maladaptive shifts in the balance of sensory processing are likely due to activity-dependent cortical remapping caused by the relative increases in nociceptive and decreases in non-nociceptive information coming from the region of pain.
Peripheral nerve stimulation (PNS) can be an effective tool for the treatment of chronic pain, though its utilization has previously been limited by available technology. Recent years have seen the advancement of various PNS features and techniques intended to overcome many of the limitations of conventional neurostimulation. Several key advances have enabled the development and adoption of improved neurostimulation systems designed specifically for use in the periphery including the development of minimally-invasive percutaneous implantation techniques, advancements in ultrasound imaging to guide lead placement, renewed focus on non-opioid treatment alternatives for pain, observation of long term efficacy when a temporary percutaneously implanted lead is employed without an implanted pulse generator or receiver, and the incorporation of open coil leads designed to enable more secure percutaneous peripheral placement with lower rates of infection. Recent clinical evidence suggests significant and sustained reductions in pain often persist well beyond the stimulation period following short-term (up to 60-day) PNS treatments, outcomes which have not previously been observed with conventional permanently implanted neurostimulation devices. This review summarizes the potential mechanisms by which selective large diameter afferent fiber activation may reverse maladaptive CNS changes associated with chronic pain to induce a prolonged reduction in pain.
Methods
This review is based on searches of published literature on PubMed, Google Scholar, and Web of Science and the authors' familiarity with the published literature in their respective fields, including preclinical and clinical articles related to chronic pain, neurostimulation, peripheral nerve stimulation, and cortical plasticity.
Results
The somatotopic representation map in the primary somatosensory cortex (S1) is dynamic and can substantially change as a result of shifts in afferent input, with expansion of regions that experience stronger and more frequent input than those around them and contraction of regions that have reduced inputs. Activity-dependent cortical remapping requires that the peripheral input to the cortex be robust, since sufficient signal strength is needed to drive the plasticity, and that it is focally derived from within a specific region, since functional plasticity also requires a low level of relative activity in surrounding cortical regions. Preclinical and clinical studies suggest that conventional PNS is limited by the use of small electrodes placed in close contact with target neural structures, resulting in a narrow therapeutic window that prevents selective, robust, and/or focal activation of large diameter fibers.
It has been hypothesized that one way to overcome the limitations of conventional, “intimate” electrode placement is to use percutaneous PNS systems designed to enable remote selective targeting. The goal of remote selective targeting is to activate a greater proportion of large diameter fibers while avoiding the unwanted activation of nociceptive afferents to produce a robust non-nociceptive peripheral signal. The relationships between stimulation strength, electrode characteristics, electrode-fiber distance, and fiber diameter are predicted to result in a greater separation of activation thresholds between large and small diameter fibers when using a PNS system designed to enable electrode placement up to several centimeters away (e.g., 0.5-3 cm) and deliver stimulation at therapeutic parameters more selective for large diameter fibers. Leads designed for remote selective targeting have large monopolar electrodes such that the generated electric fields, which decay exponentially across distance, are broad and relatively homogeneous at remote distances and have the potential to activate large diameter fibers throughout the entire cross-section of a nerve while avoiding activation of smaller fibers. Remote selective targeting may enable more robust activation of large diameter fibers (i.e., a larger proportion of targeted fibers) while avoiding small diameter fibers by optimizing the strength-distance and strength-diameter relationships that govern the activation of nerve fibers. It is theorized that activation of non-nociceptive, large diameter afferent fibers via percutaneous PNS with remote selective targeting could widen the therapeutic window for both focal and robust activation of Aα/β fibers to optimally recondition the S1 cortex and produce pain relief that long outlasts a temporary (e.g., up to 60-day) PNS treatment.

Conclusions
Advancements in imaging and neurostimulation technology have enabled innovation in PNS for pain relief in recent years. Studies of percutaneous PNS systems utilizing remote selective targeting have suggested the ability to produce clinically meaningful sustained reductions in pain following temporary (up to 60-day) treatment periods across a variety of chronic pain conditions. Mechanistically, it is theorized that these results may be the result of a widened therapeutic window for stimulation that enables robust and selective activation of Aα/ βfibers focally from the region of pain, leading to multiple analgesic mechanisms from the periphery to the dorsal horn and cortex. These diverse effects may be explained in a new neuromodulation theory of pain management, Peripherally Induced Reconditioning of the CNS, involving stimulation-evoked reversal of the central sensitized state that contributed to the chronic pain.