Sources of Off-Target Effects of Vagus Nerve Stimulation Using the Helical Clinical Lead in Domestic Pigs

Cervical vagus nerve stimulation (VNS) with a surgically implanted electrode is a Food and Drug Administration (FDA)-approved treatment for epilepsy and depression. Additionally, VNS is in clinical trials for diverse conditions such as hypertension, heart failure, rheumatoid arthritis, tinnitus, and stroke rehabilitation. Despite the growing use of VNS therapies, clinical data suggest that efficacious stimulation is often limited by side effects such as cough and dyspnea that have stimulation thresholds lower than those for specific therapeutic outcomes. The therapy-limiting side effects are putatively caused by activation of nearby muscles within the neck, either via direct muscle activation or through activation of the nerve fibers innervating those muscles. Our goal was to determine the thresholds at which various VNS effects occur in the domestic pig - the animal model most similar to humans in terms of vagus nerve size, complexity of fascicular organization, and relative anatomy - using the bipolar helical lead deployed clinically. Intrafascicular 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. Contraction of the cricoarytenoid muscle occurred at relatively low amplitudes (~0.3 mA), and resulted from activation of motor nerve fibers in the cervical vagus trunk within the electrode cuff which eventually became part of 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 more slowly conducting A{delta}-, B-, and C-fibers. These data resolve conflicting reports of the stimulation amplitudes required for C-fiber activation in large animal studies (>10 mA) and human studies (<250 A). After removing these artifacts, ENG signals with post-stimulus latencies consistent with A{delta}- and B-fibers occurred in a small subset of animals, and these signals had thresholds similar 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, these data will help guide interpretation and optimization of clinical VNS.