SPARC: Neural elements mediating side effects during cervical vagus nerve stimulation in the pig

Abstract

Vagus nerve stimulation (VNS) is FDA‐approved and CE‐marked for a diverse set of conditions including epilepsy, depression, heart failure, and others. Despite widespread adoption and perceived efficacy, a post‐hoc analysis of patients treated for heart failure using VNS revealed that only 12% of patients showed stimulation evoked heart rate changes one‐year post‐implant. This finding is not unexpected given that A‐type nerve fibers have the lowest activation thresholds, and they innervate neck muscles, causing contractions that patients will not tolerate. Therefore, muscle responses at lower amplitudes may have prevented application of higher amplitudes required to achieve cardiac effects in clinical trials of VNS for heart failure. Understanding therapy‐limiting side effects to VNS and finding ways to mitigate them are critical for optimizing VNS for clinical therapies.We developed a swine model of VNS which closely approximates the size and fascicular organization of the cervical vagus nerve observed in humans. The clinical LivaNova stimulation electrode was used as advised by a practicing neurosurgeon. We hypothesized that neck muscle responses are mediated by somatic branches of the vagus nerve as opposed to direct electrical activation of the muscle fibers. Further, we hypothesized that stimulation evoked responses depend on the location of the stimulation electrode on the vagus nerve. We measured compound nerve action potentials using intrafascicular electrodes placed within the vagus to identify activation of different nerve fiber types by conduction velocity. The downstream effects of nerve fiber activation, i.e. changes in heart rate and neck muscle responses (EMG), were measured using an arterial catheter and intramuscular electrodes, respectively. We then used a neuromuscular junction blocking agent, as well as systematic transection of somatic vagus nerve branches, to specifically identify the pathways causing neck muscle contractions.Two pathways contributed to VNS‐evoked neck muscle responses: activation of nerve fibers in the recurrent laryngeal branch of the cervical vagus nerve at low amplitudes and in the superior laryngeal branch at higher amplitudes. Lesser activation of the superior laryngeal branch could be achieved by moving the stimulation electrode caudally down the length of the vagus. This work represents a step towards mitigating intolerable side effects of VNS, thereby allowing maximization of intended target engagement and therapeutic benefit.Support or Funding InformationThe Defense Advanced Research Projects Agency (DARPA) Biological Technologies Office (BTO) Targeted Neuroplasticity Training Program under the auspices of Doug Weber and Tristan McClure‐Begley through the Space and Naval Warfare Systems Command (SPAWAR) Systems Center with (SSC) Pacific grants no. N66001‐17‐2‐4010, and the NIH SPARC Program Award OT2 OD025340.