Biology subjects

Esteller, R.

Publications and source records attributed to Esteller, R..

3 recordsLinked to original sources

bioRxiv2023

Spinal Cord Stimulation using time-dynamic pulses achieves faster and longer reversal of allodynia compared to tonic pulses in a rat model of neuropathic pain

Spinal cord stimulation (SCS) utilizing time-dynamic pulses (TDPs) is an emergent field of neuromodulation that continuously and automatically modulates pulse parameters. We previously demonstrated that TDPs delivered for 60 min at sub-paresthesia amplitudes significantly reversed allodynia in a rat model of neuropathic pain. Because we observed these anti-allodynic effects persisted post-cessation, we investigated the extended temporal dynamics of SCS-induced analgesia. We hypothesized that TDPs achieve a longer duration of analgesia than tonic stimulation. Both TDPs and tonic stimulation reversed PWT to near pre-chronificiation levels within 30 minutes. Most TDPs exhibited significantly slower ramp-up slope (analgesia wash-in rates) compared to tonic stimulation (amplitude modulation: 0.16{+/-}0.03 min-1, pulse width modulation: 0.18{+/-}0.05 min-1, stochastic modulation: 0.17{+/-}0.04 min-1, tonic: 0.31{+/-}0.06 min-1). All TDPs showed slower wind-down slopes (analgesia wash-out rates) compared to tonic (-0.29{+/-}0.07 min-1), with pulse width modulation (-0.11{+/-}0.02 min-1) reaching significance. Extending SCS from 60 to 90 minutes revealed all TDPs maintain analgesic efficacy longer than tonic stimulation, which decreased significantly at both 75 and 90 minutes (from 13.8{+/-}0.5 g to 12.3{+/-}0.9 g and to 11.0{+/-}0.5 g, respectively). Although TDPs and tonic stimulation comparably mitigated allodynia, TDPs generally exhibited slower temporal dynamics, suggesting longer-lasting analgesic effects and potentially different mechanisms of action.

neuroscience↗

bioRxiv2023

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

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. 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.

neuroscience↗

bioRxiv2023

Paresthesia during spinal cord stimulation depends on synchrony of dorsal column axon activation

Spinal cord stimulation (SCS) reduces chronic pain. Conventional (40-60 Hz) SCS engages spinal inhibitory mechanisms by activating low-threshold mechanoreceptive afferents with axons in the dorsal columns (DCs). But activating DC axons typically causes a buzzing sensation (paresthesia) that can be uncomfortable. Kilohertz-frequency (1-10 kHz) SCS produces analgesia without paresthesia and is thought, therefore, not to activate DC axons, leaving its mechanism unclear. Here we show in rats that kilohertz-frequency SCS activates DC axons but causes them to spike less synchronously than conventional SCS. Spikes desynchronize because axons entrain irregularly when stimulated at intervals shorter than their refractory period, a phenomenon we call overdrive desynchronization. Effects of overdrive desynchronization on evoked compound action potentials were verified in simulations, rats, pigs, and a chronic pain patient. Whereas synchronous spiking in DC axons is necessary for paresthesia, asynchronous spiking is sufficient to produce analgesia. Asynchronous activation of DC axons thus produces paresthesia-free analgesia.

neuroscience↗