Abstract
ObjectiveClinical data suggest that efficacious vagus nerve stimulation (VNS) is limited by side effects such as cough and dyspnea that have stimulation thresholds lower than those for therapeutic outcomes. VNS side effects are putatively caused by activation of nearby muscles within the neck, via direct muscle activation or activation of nerve fibers innervating those muscles. Our goal was to determine the thresholds at which various VNS-evoked effects occur in the domestic pig—an animal model with vagus anatomy similar to human—using the bipolar helical lead deployed clinically.ApproachIntrafascicular electrodes were placed within the vagus nerve to record electroneurographic (ENG) responses, and needle electrodes were placed in the vagal-innervated neck muscles to record electromyographic (EMG) responses.Main resultsContraction of the cricoarytenoid muscle occurred at low amplitudes (∼0.3 mA) and resulted from activation of motor nerve fibers in the cervical vagus trunk within the electrode cuff which bifurcate into the recurrent laryngeal branch of the vagus. At higher amplitudes (∼1.4 mA), contraction of the cricoarytenoid and cricothyroid muscles was generated by current leakage outside the cuff to activate motor nerve fibers running within the nearby superior laryngeal branch of the vagus. Activation of these muscles generated artifacts in the ENG recordings that may be mistaken for compound action potentials representing slowly conducting Aδ-, B-, and C-fibers.SignificanceOur data resolve conflicting reports of the stimulation amplitudes required for C-fiber activation in large animal studies (>10 mA) and human studies (<250 μA). After removing muscle-generated artifacts, ENG signals with post-stimulus latencies consistent with Aδ- and B-fibers occurred in only a small subset of animals, and these signals had similar thresholds to those that caused bradycardia. By identifying specific neuroanatomical pathways that cause off-target effects and characterizing the stimulation dose-response curves for on- and off-target effects, we hope to guide interpretation and optimization of clinical VNS.
Highlights
The cervical vagus nerve provides an entry point for modulating both visceral organ function and much of the brain
The electric field from an electrode source decreases rapidly with distance from the electrode (Plonsey & Barr, 1995). These principles combined suggest that the likely sources for off-target neck muscle activation are activated large diameter motor fibers either within the cervical vagus itself, or large diameter motor fibers located near the placement of the helical epineural cuff on the cervical vagus
It is well known that a subset of motor fibers within the cervical vagus eventually bifurcate into the recurrent laryngeal branch (RL) of the vagus and terminate in the cricoarytenoid muscle of the neck
Summary
The cervical vagus nerve provides an entry point for modulating both visceral organ function and much of the brain. Therapeutic vagus nerve stimulation (VNS) with implanted electrodes has grown over recent years for diverse conditions from epilepsy to heart failure (De Ferrari et al, 2017; Kimberley et al, 2018; Koopman et al, 2016; Morris et al, 2013; Ng et al, 2016; Tyler et al, 2017; Wheless et al, 2018). These side effects can limit tolerable stimulation amplitudes to below effective therapeutic levels. In an early study of VNS for epilepsy in humans, patients were unable to tolerate stimulation amplitudes higher than 1.3 mA on average using a μs pulse width at 30 Hz The average tolerable amplitude was 1.2 mA using a 300 μs pulse width at 20 Hz in a recent clinical trial, with only 12% of patients experienced targeted VNS-evoked heart rate changes 1 year post-implant (De Ferrari et al., 2017)
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