Background & Aims

Electrically evoked compound action potentials (ECAPs) can be measured from the epidural space during spinal cord stimulation (SCS) in various species [1,2]. The effect of stimulus parameters on the excitability and nature of responding fibres, within the dorsal column (DC), has been extensively studied, but remains unclear [3,4]. Recent studies have shown that increasing SCS frequency without changing other stimulus parameters leads to a reduction in ECAP amplitude that may be linked to the loss of paraesthesia through asynchronous firing of DC axons [3,5]. This observation may have a significant implication for the understanding of mechanisms underlying SCS efficacy. We have therefore considered this finding in further development of our pre-clinical model of SCS [2,6] and aimed to investigate the effect that SCS stimulus parameters (frequency) have on the excitability and/or nature of responding DC fibres using sheep and rat SCS models.

Methods

Naïve adult male Sprague-Dawley rats (200-400g) were implanted with a custom-made 6-contact epidural lead, covering T12-L2. A specially designed Multi-Channel System was used to record ECAPs and apply SCS at the different stimulus parameters. In the first experiment (n=7), baseline recordings were measured at 2 Hz (40 µs), followed by high-frequency SCS (HF-SCS) applied for 15 minutes at 200 Hz (40 µs). After cessation of HF-SCS, the frequency was returned to 2 Hz (40 µs) to facilitate ECAP amplitude recovery. In the second separate experiment (n=8), frequencies of 50 Hz, 500 Hz and 1 kHz (all at 40 µs) were each applied for 5 minutes with 5-minute intervals of 2Hz (40 µs) between to aid ECAP amplitude recovery. Comparisons in ECAP amplitudes and conduction velocities were made between recordings at baseline and after HF-SCS. At the end of the experiments, no animals were allowed to recover from anaesthesia and were terminated. Experiments were approved by the UK Home Office.

Results

SCS applied at 50 Hz showed no significant change in ECAP amplitude and conduction velocity however, a significant reduction in ECAP amplitude was observed during stimulation at 200 Hz, both orthodromically and antidromically. Specifically, decreases from 0.670 ± 0.109mV and 0.526 ± 0.110mV, to 0.306 ± 0.031mV and 0.270 ± 0.039mV were observed respectively, but no significant change in conduction velocity was found. Returning the frequency to 2 Hz after cessation of 200 Hz showed a return to baseline ECAP amplitudes by the end of the recovery period (2 Hz). On average, the amplitude increased to 0.595 ± 0.092mV orthodromically, and 0.503 ± 0.114mV antidromically.  During 500 Hz, reductions in ECAP amplitude was observed both orthodromically and antidromically, along with a significant decrease in conduction velocity, antidromically. Significant increases in ECAP amplitude, orthodromically and antidromically, were observed by the end of the recovery period (2 Hz) after 500 Hz and 1 kHz.

Conclusions

Our data, in line with previous observations in other species [3,4], shows that HF-SCS compared to SCS applied at lower frequencies (50 Hz) results in a reduction in ECAP amplitude, both orthodromically and antidromically. This reduction may indicate that HF-SCS alters the excitability and/or nature of the activated DC fibres during the period of stimulation. However, we demonstrated that DC fibres are able to recover from the effects of HF-SCS, as ECAP amplitudes in our experiments returned to baseline when the frequency was lowered to 2 Hz after cessation of HF-SCS, albeit not immediately. This suggests that the effects HF-SCS has on the excitability of the activated DC fibres may be reversible and the fibres may be able to return to their original state of excitability, but there is a wash-in and wash-out effect which may vary with the time over which HF-SCS is delivered.

References

  1. Parker JL, Karantonis D.M, Single PS, Obradovic M, and Cousins MJ. Compound action potentials recorded in the human spinal cord during neurostimulation for pain relief. Pain. 2020;153(3):593–601.
  2. Dietz BE, Mugan D, Vuong QC, and Obara I. Electrically Evoked Compound Action Potentials in Spinal Cord Stimulation: Implications for Preclinical Research Models. Neuromodulation. 2022;25(1):64–74.
  3. Sagalajev B, et al. Absence of paresthesia during high-rate spinal cord stimulation reveals importance of synchrony for sensations evoked by electrical stimulation. Neuron. 2023.
  4. Schechter R, Yang F, Xu Q, Cheong Y-K, et al. Conventional and kilohertz-frequency spinal cord stimulation produces intensity- and frequency- dependent inhibition of mechanical hypersensitivity in a rat model of neuropathic pain. Anesthesiology. 2013;119(2):422-32.
  5. Gmel GE, Santos Escapa R, Benkohen TE, Mugan D, Parker JL, Palmisani S. Postsynaptic dorsal column pathway activation during spinal cord stimulation in patients with chronic pain. Frontiers in Neuroscience. 2023;17.
  6. Versantvoort EM, Dietz BE, Mugan D, Vuong QC, Luli S, and Obara I. Evoked compound action potential (ECAP)-controlled closed-loop spinal cord stimulation in an experimental model of neuropathic pain in rats. Bioelectronic Medicine. 2024;10(1).

Presenting Author

Ilona Obara

Poster Authors

Kimberley Ladner

BSc, MRes

Newcastle University

Lead Author

E-mail

Birte Dietz

PhD

Saluda Medical

Lead Author

E-mail

Eline Versantvoort

MSc

Newcastle University

Lead Author

E-mail

Quoc Vuong

PhD

Newcastle University

Lead Author

E-mail

Dave Mugan

MBA

Saluda Medical

Lead Author

E-mail

Charles Brooker

MBChB

Royal North Shore Hospital, Australia

Lead Author

E-mail

Dean Karantonis

Saluda Medical Pty Ltd

Lead Author

E-mail

Milan Obradovic

Saluda Medical Pty Ltd

Lead Author

E-mail

Robert Gorman

Saluda Medical Pty Ltd

Lead Author

E-mail

Ilona Obara

PhD

Newcastle University

Lead Author

E-mail

Topics

  • Models: Chronic Pain - Neuropathic