Parametric characterization of the rat Hering-Breuer reflex evoked with implanted and non-invasive vagus nerve stimulation.

Vagus nerve stimulation (VNS) has rapidly gained interest as a treatment for a variety of disorders. A number of methods have been employed to stimulate the vagus nerve, but the most common relies on a cuff electrode implanted around the cervical branch of the nerve. Recently, two non-invasive methods have increased in popularity: transcutaneous cervical VNS (tcVNS) and transcutaneous auricular VNS (taVNS). Despite promising clinical results, there has been little direct comparison of these methods to stimulation delivered via an implanted device. In this study, we directly compared both non-invasive strategies to stimulation with an implanted cuff electrode on activation of the Hering-Breuer (HB) reflex, a non-invasive biomarker of A-fiber activation in the vagus. Stimulation was delivered across a wide range of parameters using tcVNS, taVNS, and an implanted cuff electrode in female rats. Activation of the HB reflex, changes in heart rate, and neck muscle twitch force were recorded. Consistent with low thresholds reported in previous studies, we found that the threshold to activate the HB reflex using an implanted cuff electrode was 0.406 ± 0.066 mA. tcVNS was capable of activating the HB reflex, but the threshold was 34.18 ± 1.86 mA, over 15 fold higher than the stimulation intensity that caused twitching of the neck muscles (2.09 ± 0.16 mA). No activation of the HB reflex was observed with taVNS at any parameters. These results describe activation of the HB reflex with each strategy and provide initial evidence regarding differences in the activation of the vagus nerve with invasive and non-invasive methods.