Biophysics and Mechanisms of Spinal Cord Stimulation for Chronic Pain

Titus, Nathan D.; Gilbert, John E.; Grill, Warren M.

doi:10.1007/978-981-15-2848-4_99-2

“…Epidural spinal cord stimulation (SCS) for neuropathic pain is thought to engage inhibitory dorsal horn mechanisms, whether via synaptic activation following antidromic stimulation of dorsal column fibers, consistent with Gate Control Theory (Shealy et al, 1970), or through more subtle, slower acting mechanisms (Titus et al, 2021). Dorsal column stimulation is sensed by evoked electrical responses representing the summed activity of dorsal column (Ab ) axons, whose synchronous activation produces a propagating evoked compound action potential (ECAP) characterized by P1, N1, and P2 waves, with latencies ,2 ms proximal to the stimulation site (Cioni and Meglio, 1986;Parker et al, 2013;Cedeño et al, 2022;Dietz et al, 2022).…”

Section: Introductionmentioning

confidence: 99%

Novel Evoked Synaptic Activity Potentials (ESAPs) Elicited by Spinal Cord Stimulation

Sharma

¹

,

Bhaskar

²

,

Yang

³

et al. 2023

eNeuro

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Spinal cord stimulation (SCS) evokes fast epidural Evoked Compound Action Potential (ECAPs) that represent activity of dorsal column axons, but not necessarily a spinal circuit response. Using a multimodal approach, we identified and characterized a delayed and slower potential evoked by SCS that reflects synaptic activity within the spinal cord. Anesthetized female Sprague Dawley rats were implanted with an epidural SCS lead, epidural motor cortex stimulation electrodes, an epidural spinal cord recording lead, an intraspinal penetrating recording electrode array, and intramuscular electromyography (EMG) electrodes in the hindlimb and trunk. We stimulated the motor cortex or the epidural spinal cord and recorded epidural, intraspinal, and EMG responses. SCS pulses produced characteristic propagating ECAPs (composed of P1, N1, and P2 waves with latencies <2 ms) and an additional wave (“S1”) starting after the N2. We verified the S1-wave was not a stimulation artifact and was not a reflection of hindlimb/trunk EMG. The S1-wave has a distinct stimulation-intensity dose response and spatial profile compared to ECAPs. CNQX (a selective competitive antagonist of AMPA receptors) significantly diminished the S1-wave, but not ECAPs. Furthermore, cortical stimulation, which did not evoke ECAPs, produced epidurally detectable and CNQX-sensitive responses at the same spinal sites, confirming epidural recording of an evoked synaptic response. Finally, applying 50 Hz SCS resulted in dampening of S1-wave, but not ECAPs. Therefore, we hypothesize that the S1-wave is synaptic in origin, and we term the S1-wave type responses: Evoked Synaptic Activity Potentials (ESAPs). The identification and characterization of epidurally recorded ESAPs from the dorsal horn may elucidate SCS mechanisms.Significance StatementSpinal cord stimulation (SCS) is an established treatment for chronic pain and has applications to other disorders and neurorehabilitation. Notwithstanding decades of trials and research, questions remain about SCS mechanisms of action - and indicators thereof. Recent technological developments have enabled the detection of Evoked Compound Action Potential (ECAPs) – reflecting synchronous activity of the dorsal column axons activated by SCS. However, ECAP is not a direct measure of sensory processing in the dorsal horn. Here, we identify and characterize a novel electrophysiological signal that is evoked and detectable by epidural SCS electrodes and reflects spinal synaptic currents. This new signal, termed an Evoked Synaptic Activity Potential (ESAP), is thus a novel means with which to interrogate spinal gray matter circuits during SCS.

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“…Epidural spinal cord stimulation (SCS) for neuropathic pain is thought to engage inhibitory dorsal horn mechanisms, whether via synaptic activation following antidromic stimulation of dorsal column fibers, consistent with Gate Control Theory (Shealy et al, 1970), or through more subtle, slower acting mechanisms (Titus et al, 2021). Dorsal column stimulation is sensed by evoked electrical responses representing the summed activity of dorsal column (Aβ) axons, whose synchronous activation produces a propagating evoked compound action potential (ECAP) characterized by P1, N1, and P2 waves, with latencies <2 ms proximal to the stimulation site (Cedeño et al, 2022; Cioni and Meglio, 1986; Dietz et al, 2022; Parker et al, 2013).…”

Section: Introductionmentioning

confidence: 99%

Novel Evoked Synaptic Activity Potentials (ESAPs) elicited by Spinal Cord Stimulation

Sharma

¹

,

Bhaskar

²

,

Yang

³

et al. 2023

Preprint

View full text Add to dashboard Cite

Spinal cord stimulation (SCS) evokes fast epidural Evoked Compound Action Potential (ECAPs) that represent activity of dorsal column axons, but not necessarily a spinal circuit response. Using a multimodal approach, we identified and characterized a delayed and slower potential evoked by SCS that reflects synaptic activity within the spinal cord. Anesthetized female Sprague Dawley rats were implanted with an epidural SCS lead, epidural motor cortex stimulation electrodes, an epidural spinal cord recoding lead, an intraspinal penetrating recording electrode array, and intramuscular electromyography (EMG) electrodes in the hindlimb and back. We stimulated the motor cortex or the epidural spinal cord and recorded epidural, intraspinal, and EMG responses. SCS pulses produced characteristic propagating ECAPs (composed of P1, N1, and P2 waves with latencies <2 ms) and an additional wave (S1) starting after the N2. We verified the S1-wave was not a stimulation artifact and was not a reflection of hindlimb/back EMG. The S1-wave has a distinct stimulation-intensity dose response and spatial profile compared to ECAPs. CNQX (a selective competitive antagonist of AMPA receptors) significantly diminished the S1-wave, but not ECAPs. Furthermore, cortical stimulation, which did not evoke ECAPs, produced epidurally detectable and CNQX-sensitive responses at the same spinal sites, confirming epidural recording of an evoked synaptic response. Finally, applying 50 Hz SCS resulted in dampening of ESAPs, but not ECAPs. Therefore, we hypothesize that the S1-wave is synaptic in origin, and we term the S1-wave type responses: Evoked Synaptic Activity Potentials (ESAPs). The identification and characterization of epidurally recorded ESAPs from the dorsal horn may elucidate SCS mechanisms.

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“…One important consideration is the effect of anatomy. These experimental recordings were from the rat lumbar spinal cord, which notably differs from the relevant human anatomy in important factors including cerebrospinal fluid thickness and superficial dorsal horn depth, allowing greater penetration of the electric field into the gray matter [71], as well as differences in DC fiber diameters and dimensions of preclinical versus clinical SCS leads. Furthermore, it is impossible to verify that these amplitudes are subparesthetic in rodents, and observed effects may be driven trans-synaptically by activation of DC fibers.…”

Section: Comparison Of Modeling Results With Existing Experimental Ev...mentioning

confidence: 99%

Model-based analysis of subthreshold mechanisms of spinal cord stimulation for pain

Rogers,

Mirzakhalili,

Lempka

2023

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Objective. Spinal cord stimulation (SCS) is a common treatment for chronic pain. For decades, SCS maximized overlap between stimulation-induced paresthesias and the patient’s painful areas. Recently developed SCS paradigms relieve pain at sub-perceptible amplitudes, yet little is known about the neural response to these new waveforms or their analgesic mechanisms of action. Therefore, in this study, we investigated the neural response to multiple forms of paresthesia-free SCS. Approach. We used computational modeling to investigate the neurophysiological effects and the plausibility of commonly proposed mechanisms of three paresthesia-free SCS paradigms: burst, 1 kHz, and 10 kHz SCS. Specifically, in C- and Aβ-fibers, we investigated the effects of different SCS waveforms on spike timing and activation thresholds, as well as how stochastic ion channel gating affects the response of dorsal column axons. Finally, we characterized membrane polarization of superficial dorsal horn neurons. Main results. We found that none of the SCS waveforms activate nor modulate spike timing in C-fibers. Spike timing was modulated in Aβ-fibers only at suprathreshold amplitudes. Ion channel stochasticity had little effect on Aβ-fiber activation thresholds but produced heterogeneous spike timings at suprathreshold amplitudes. Finally, local cells were preferentially polarized in their axon terminals, and the magnitude of this polarization was dependent on cellular morphology and position relative to the stimulation electrodes. Significance. Overall, the mechanisms of action of subparesthetic SCS remain unclear. Our results suggest that no SCS waveforms directly activate C-fibers, and modulation of spike timing is unlikely at subthreshold amplitudes. We conclude that potential subthreshold neuromodulatory effects of SCS on local cells are likely to be presynaptic in nature, as axons are preferentially depolarized during SCS.

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Biophysics and Mechanisms of Spinal Cord Stimulation for Chronic Pain

Cited by 6 publications

References 201 publications

Novel Evoked Synaptic Activity Potentials (ESAPs) Elicited by Spinal Cord Stimulation

Novel Evoked Synaptic Activity Potentials (ESAPs) Elicited by Spinal Cord Stimulation

Novel Evoked Synaptic Activity Potentials (ESAPs) elicited by Spinal Cord Stimulation

Model-based analysis of subthreshold mechanisms of spinal cord stimulation for pain

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