Intraoperative laryngeal muscle and heart rate responses to implanted vagus nerve stimulation

Objectives: Implanted cervical vagus nerve stimulation (VNS) is used to treat refractory epilepsy, depression, stroke sequelae and rheumatoid arthritis. The therapeutic efficacy of VNS is limited by stimulation-induced side effects, including hoarseness, coughing, and voice alteration. We quantified VNS-evoked laryngeal muscle activation (EMG; indicating side effects) and changes in heart rate (HR; proxy for activation of therapeutic fibers) in participants undergoing VNS implant surgery. Methods: We recruited adult participants (7F/3M) with treatment-resistant epilepsy who were receiving a new VNS implant (″acute″) or replacement of an implanted VNS pulse generator (″chronic″). During these procedures, we delivered VNS across pulsewidths (50, 250, and 1000 μs/phase) and stimulation amplitudes (0.05-28 mA) while recording laryngeal EMG and HR. Results: The median stimulation amplitudes to evoke 50% of maximal laryngeal EMG response were 1.32, 0.49, and 0.34 mA for pulsewidths of 50, 250, and 1000 μs/phase, respectively; thresholds were comparable between EMG electrodes placed endotracheally and subcutaneously. The median stimulation amplitudes to cause a 10% decrease in HR were 13.39 and 3.53 mA at 50 and 250 μs/phase, respectively—i.e., ~6 to 63x higher than the 50% EMG thresholds. We did not observe a difference in EMG or HR responses between sexes, acute/chronic, or stimulation polarities. For each subject in the chronic implant group, clinician-selected stimulation amplitudes were higher than the 50% EMG thresholds and lower than the 10% HR thresholds. Conclusions: Thresholds to evoke bradycardia were ~2x higher than clinician-selected stimulation amplitudes. This indicates that the target fibers of VNS for epilepsy may be larger diameter than those projecting to the heart. Alternatively, the therapeutic effect in refractory epilepsy may be evoked with less fiber activation than is required to produce bradycardia.