Microneurography as a minimally invasive method to assess target engagement during neuromodulation

Abstract

Objective. Peripheral neural signals recorded during neuromodulation therapies provide insights into local neural target engagement and serve as a sensitive biomarker of physiological effect. Although these applications make peripheral recordings important for furthering neuromodulation therapies, the invasive nature of conventional nerve cuffs and longitudinal intrafascicular electrodes (LIFEs) limit their clinical utility. Furthermore, cuff electrodes typically record clear asynchronous neural activity in small animal models but not in large animal models. Microneurography, a minimally invasive technique, is already used routinely in humans to record asynchronous neural activity in the periphery. However, the relative performance of microneurography microelectrodes compared to cuff and LIFE electrodes in measuring neural signals relevant to neuromodulation therapies is not well understood.

Approach. To address this gap, we recorded cervical vagus nerve (cVN) electrically evoked compound action potentials (ECAPs) and spontaneous activity in a human-scaled large animal model – the pig. Additionally, we recorded sensory evoked activity and both invasively and non-invasively evoked CAPs from the great auricular nerve (GAN). In aggregate, this study assesses the potential of microneurography electrodes to measure neural activity during neuromodulation therapies with statistically powered and pre-registered outcomes (https://osf.io/y9k6j).

Main results. The cuff recorded the largest ECAP signal (p<0.01) and had the lowest noise floor amongst the evaluated electrodes. Despite the lower signal to noise ratio, microneurography electrodes were able to detect the threshold for neural activation with similar sensitivity to cuff and LIFE electrodes once a dose-response curve was constructed. Furthermore, the microneurography electrodes recorded distinct sensory evoked neural activity.

Significance. The results show that microneurography electrodes can measure neural signals relevant to neuromodulation therapies. Microneurography could further neuromodulation therapies by providing a real-time biomarker to guide electrode placement and stimulation parameter selection to optimize local neural fiber engagement and study mechanisms of action.

Epidural Spinal Cord Recordings (ESRs): Sources of Artifact in Stimulation Evoked Compound Action Potentials

“…As the recording sites were sampled across the array, closer to the stimulating pair, the latency of this feature decreased, as expected, given the evoked action potential should arrive at closer recording sites more quickly. The amplitude of this recorded evoked response tended to decrease slightly and becomes more diffuse as distance increased from the stimulating contacts, consistent with previous observations of the behavior of ECAPs based on recording distance (Andreis et al, 2021;Verma, Knudsen, et al, 2023). At recording sites progressively closer to the stimulating pair (contacts 3-6) this evoked feature moved visibly closer to the stimulation artifact until partially overlapped, and for the closest recording sites, was no longer visible.…”

“…In addition, recording electrodes are very susceptible to motion artifact, in which the capacitive Helmholtz layer established at the electrode-tissue interface is disturbed by motion, creating an artifactual recording signal coincident with the source of motion (Giancoli, 1998;Ludwig et al, 2006Ludwig et al, , 2009Michelson et al, 2018;E. Nicolai et al, 2018;Tam & Webster, 1977;Verma, Knudsen, et al, 2023;Wartzek et al, 2011). Consequently, we hypothesized that both the A-beta signal and EMG bleed-through recorded in the SCS ECAPs may vary cyclically as a function of motion due to breathing and heartbeat.…”

“…These studies have demonstrated that ECAP recordings are susceptible to multiple sources of artifact, including post-stimulation capacitive artifact and electromyography (EMG) bleed-through into the recordings from nearby activated muscle (Bahmer et al, 2010;Blanz et al, 2022;Miller et al, 1999;E. N. Nicolai et al, 2020;Verma, Knudsen, et al, 2023;Yoo et al, 2013). Despite these known difficulties in recording ECAPs spanning diverse stimulation targets for other therapies, a rigorous evaluation of sources of artifact in spinal cord ECAPs in a large animal model has yet to be performed.…”

“…ECAPs have been proposed as a method to identify these changes and to provide a control signal for closed-loop SCS. However, recording electrode arrays have been shown to be very sensitive to periods of motion, which can create a large transient artifact (Giancoli, 1998;Ludwig et al, 2006Ludwig et al, , 2009Michelson et al, 2018;Tam & Webster, 1977;Verma, Knudsen, et al, 2023;Wartzek et al, 2011). This artifact is due to the relative motion of the electrode disturbing the Helmholtz layer formed by charged molecules in tissue that can appear surprisingly similar to recorded neural signals (Bard et al, 1980;Giancoli, 1998;Merrill et al, 2005;Michelson et al, 2018;E.…”

“…Prior acute neuromodulation studies used a series of controls to identify and differentiate artifacts from neural signals, but these controls have yet to be adopted into common practice for ESRs (Blanz et al, 2022;E. N. Nicolai et al, 2020;Verma, Knudsen, et al, 2023). In this study, we characterized the sources of artifacts in a swine model during epidural spinal cord stimulation using clinical SCS leads, to address the potential artifacts confounding the interpretation of ESRs.…”