Peripherally Induced Reconditioning of the Central Nervous System: A Proposed Mechanistic Theory for Sustained Relief of Chronic Pain with Percutaneous Peripheral Nerve Stimulation

Abstract

Peripheral nerve stimulation (PNS) is an effective tool for the treatment of chronic pain, although its efficacy and utilization have previously been significantly limited by technology. In recent years, purpose-built percutaneous PNS devices have been developed to overcome the limitations of conventional permanently implanted neurostimulation devices. Recent clinical evidence suggests clinically significant and sustained reductions in pain can persist well beyond the PNS treatment period, outcomes that have not previously been observed with conventional permanently implanted neurostimulation devices. This narrative review summarizes mechanistic processes that contribute to chronic pain, and the potential mechanisms by which selective large diameter afferent fiber activation may reverse these changes to induce a prolonged reduction in pain. The interplay of these mechanisms, supported by data in chronic pain states that have been effectively treated with percutaneous PNS, will also be discussed in support of a new theory of pain management in neuromodulation: Peripherally Induced Reconditioning of the Central Nervous System (CNS).

Keywords: chronic pain; cortical plasticity; mechanism of action; neuromodulation; peripheral nerve stimulation; peripherally induced reconditioning.

Conflict of interest statement

TRD has consulted for Abbott, Axonics, Cornerloc, Ethos, Flowonix, Nalu, Saluda, SpineThera, Stimgenics, SI Bone, Medtronic, PainTeq, Vertiflex (Boston Scientific), Nevro, Vertos, and SPR Therapeutics. He has received research support from Vertiflex, Vertos, Abbott, Mainstay, Saluda, SPR Therapeutics. He holds minor equity in Bioness, Cornerloc, Ethos, Vertiflex, Vertos, Nalu, SpineThera, Saluda, and SPR Therapeutics. SE has consulted for Medtronic, Inc, Mainstay Medical, Boston Scientific Corp, Saluda, and Abbott. He has received research support from the National Institute of Health Research, Medtronic, Inc, and Nevro Corp. SMF has consulted for Abbott, Medtronic, Nevro, Saluda Medical, SPR Therapeutics, and Vertiflex (Boston Scientific). He has received research support from Abbott, Biotronik, Medtronic, Nuvectra, and Saluda Medical. He holds stock options in SpineThera, SPR Therapeutics, Stimgenics, Cornerloc, and Thermaquil, and has equity interest in Saluda Medical. MAH has consulted for SPR, Saluda and Mainstay Medical. PSS has consulted for Abbott, Nevro, Medtronic, and SPR Therapeutics. He has received research support from Boston Scientific, Abbott, Vertos, Nevro, Saluda and Grunenthal Halyard. He is in the Clinical Advisory Board for AIS Therapeutics. He has stock or equity interest in SPR Therapeutics, Nalu and electroCore. IRC, NDC, and JWB are employees of SPR Therapeutics. NDC and JWB report systems and methods for sustained relief of chronic pain patent pending. The authors report no other conflicts of interest in this work.

© 2021 Deer et al.

Figures

Figure 1

Two percutaneous PNS approaches have demonstrated sustained relief of chronic pain. Stimulation is delivered from a system with open-coiled leads designed to be placed remote from the nerve to selectively activate Aα/β fibers while avoiding Aδ/C fiber activation (ie, remote selective targeting). The activation zones are shown for Aα/β fibers (blue) and Aδ/C fibers (orange). (A) Stimulation of mixed nerves at 100 Hz (1) can selectively activate the largest sensory afferents (many of which are larger than muscle efferents147). (2) Stimulation activates the large diameter muscle and tactile afferents while avoiding activation of muscle efferents and nociceptive afferents. (3) Directly induced large diameter afferent action potentials enter the spinal dorsal horn at the rate of the stimulation frequency (100 Hz) to engage the gating mechanism, typically producing comfortable sensations in the innervated region. (B) Stimulation of mixed nerves at 12 Hz (1) at a sufficient intensity can also activate muscle efferent fibers. (2) Stimulation activates large diameter fibers, including cutaneous afferents, muscle afferents, and muscle efferents while avoiding nociceptive afferents. (3) Orthodromic firing of muscle efferents causes muscle contraction, generating physiological activation of muscle afferent fibers. (4) Large diameter afferent action potentials (directly induced by stimulation and indirectly through muscle contraction) enter the spinal dorsal horn to collectively engage the gating mechanism.

Figure 2

Pain circuitry in the spinal dorsal horn. Four primary sub-circuits are represented: (1) post-synaptic inhibition of nociceptive projection neurons, (2) pre-synaptic inhibition of nociceptive projection neurons, (3) basally inhibited PKCγ excitatory interneurons, and (4) polysynaptically excited nociceptive projection neurons. (A) In a healthy case there is a balance between nociceptive and non-nociceptive afferent input and dorsal horn circuit strengths, resulting in minimal activation of nociceptive projection neurons. (B) In the case of chronic pain, peripheral nerve damage/inflammation elevates firing of nociceptive afferent fibers. Additionally, GABAergic and glycinergic drive from inhibitory interneurons are reduced, resulting in: (1) reduction in post-synaptic inhibition, (2) reduction in pre-synaptic inhibition, (3) disinhibition of PKCγ interneurons, enabling allodynia-producing circuits, and (4) sensitization of nociceptive projection neurons, characterized by increased excitability and decreased inhibition. (C) Neurostimulation is believed to cause elevated firing of Aα/β afferent fibers, counteracting many of the circuit-level effects of chronic pain. Specifically, high rates of Aα/β firing induce: (1) elevated post-synaptic inhibition, (2) elevated pre-synaptic inhibition (3) return of inhibition to the PKCγ cells, reducing allodynia, and (4) elevated inhibition and reduction of nociceptive drive to the nociceptive projection neurons.

Figure 3

Remote selective targeting promotes activation of large diameter fibers while avoiding activation of small diameter fibers using PNS systems and open coil leads designed for placement distant to the nerve. Large diameter fibers have lower activation thresholds than smaller diameter fibers, and thresholds also increase with electrode-to-fiber distance. The activation zones are shown for Aα/β fibers (blue) and Aδ/C fibers (orange). (A) For a conventional PNS electrode placed intimate to the nerve, a limited number of Aα/β fibers may be activated. (B) Increasing the intensity to activate a larger proportion of Aα/β fibers begins to concurrently activate Aδ/C fibers or motor fibers, causing unintended discomfort. (C) A system using a percutaneous open-coil electrode placed remotely from the nerve (eg, 0.5–3 cm) is designed to selectively activate a larger proportion of Aα/β fibers without concomitant activation of Aδ/C fibers.

Figure 4

Varying degrees of cortical activation using different stimulation methods. Optimal induction of cortical remapping requires selective activation of a large number of afferent fibers (ie, robust activation) that is generated focally (ie, from the region of pain). The activation zones are shown for Aα/β fibers (blue) and Aδ/C fibers (orange). (A) SCS activates a small number of fibers in the superficial dorsal column before reaching discomfort thresholds due to dorsal root activation, and the dorsal column fibers it does activate are commonly spread across multiple dermatomes. The afferent input to S1 is thus neither robust nor focal. Conventional DRGS (B) or PNS (C) can more focally target the dermatome and/or nerve innervating the specific region of pain, though DRGS often involves multi-level stimulation, but limitations with conventional systems and stimulation strategies curb the degree of large diameter fiber activation before reaching discomfort thresholds due to small diameter nociceptor activation. The afferent input to S1 is thus more focal than SCS but not robust. (D) Percutaneous PNS with remote selective targeting enables both focal and robust activation of the target nerves, potentially resulting in optimal cortical input to induce activity-dependent remapping and sustained analgesia, facilitating reconditioning of the CNS.