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 (LIFE) limit their clinical utility. Furthermore, cuff electrodes typically record clear asynchronous neural activity in small animal models but not in human-scaled 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 performed cervical vagus nerve evoked compound action potential (ECAP) and spontaneous activity recordings 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 microelectrodes 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 microelectrodes 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 microelectrode was the only electrode to record distinct sensory evoked neural activity (p<0.01). Significance: The results suggest that microneurography microelectrodes could enable minimally invasive assessment of neural activity for individual subjects. This will further neuromodulation therapies by providing a real-time biomarker to adjust electrode placement and stimulation parameters to optimize the on- to off-target neural fiber engagement and study mechanisms of action.

Using neural biomarkers to personalize dosing of vagus nerve stimulation

“…Finally, using neural responses during VNS dosing would allow to reoptimize VNS therapies with less stress to the patient. While not used for VNS dosing today, IPGs with neural recording capabilities or minimally invasive techniques, such as microneurography (Ottaviani et al, 2020; Verma et al, 2022), could enable neural recordings to be used periodically as efficacy decreases in response to electrode movement, scarring, or habituation.…”

“…We consider the possibility of a causal connection between a neural and a physiological response to stimulation whenever the dose response curves (DRCs) agree in their points of onset and saturation (Verma et al, 2022;Blanz et al, 2022). We might term this approach the DRC alignment criterion for a potential causal connection between a specific fibre type activation and a specific physiological response.…”

“…The alignment of neural and physiological response curves can be used to highlight causal connections between physiological responses and eCAPs (Verma et al, 2022;Blanz et al, 2022).…”

Computational modeling of dorsal root ganglion stimulation using an Injectrode

“…Previous studies have illustrated that obtaining clean recordings from these small-diameter fibers often necessitates the removal of the epineurium, with recording electrodes placed directly on the fascicle [54]. Moreover, if muscle activation due to Aα-fiber activation and the corresponding electromyography activity is not accounted for, there might be incorrect estimation of Aδ-LTMR thresholds [55], which otherwise, as predicted by our computational models [5] and several previous experiments, is roughly an order of magnitude higher than Aβ-fiber activation thresholds [55][56][57][58].…”

A flexible adhesive surface electrode array capable of cervical electroneurography during a sequential autonomic stress challenge

“…Prior preclinical work demonstrate resting vagus nerve action potential recording with: (1) cuff electrodes in anesthetized rats during inflammatory cytokine injection 19 , (2) carbon nanotube yarn electrodes in anesthetized rats during chronic recording 20 , (3) multi-electrode recording cuff electrodes in regularly breathing anesthetized pigs 21 , (4) upon stimulation evoked compound action potentials 22 , and (5) inserting tungsten microelectrodes into the vagus nerve through ultrasound guidance in awake humans 23 . Further, recent work demonstrate vagus nerve action potentials uniformly synchronize with the respiratory cycle in porcine models 24 , 25 and in one recent human microelectrode study 23 , although synchronized respiratory and cardiac activity may reflect recording modality deployed 26 . Other preclinical work measured (via cuff electrode) superior cervical ganglion activity with hypertensive stress tests, i.e., injection of adrenaline 27 , 28 or during painful stimuli 29 .…”