Cortical potentials evoked by stimulation of cervical vagus vs. auricular nerve: a comparative, parametric study in nonhuman primates

Stimulation of sensory vagal pathways is typically delivered via invasive, cervical vagus nerve stimulation (cVNS) or noninvasive, trans-auricular nerve stimulation (taNS). While both methods are investigated therapeutically, their effects on brain physiology remain poorly understood, hindering mechanistic understanding and stimulus optimization. In 6 awake nonhuman primates, we recorded cortical vagal-evoked potentials (VEPs) from subdural electrodes placed in prefrontal, sensorimotor and parietal cortical areas, in response to cVNS or taNS. Across 478 different taNS and cVNS protocols, we varied stimulation side, intensity, frequency, pulse count, and pulse width (PW) and assessed independent effects on amplitude and latency of early (EC; 30-100 ms), intermediate (IC; 101-200 ms) and late components (LC; 201-500 ms) of VEPs. Fixed and random effects of stimulation parameters and subjects, respectively, on VEP measurements, were assessed using a linear mixed-effects model. Overall, cVNS elicits more robust VEPs than taNS, with larger EC, IC and LC amplitudes in both hemispheres. cVNS-elicited ECs and LCs are largest in PFC and PC areas, whereas ICs are largest in SM areas. On the other hand, taNS generally does not elicit area-specific responses. cVNS-elicited ECs have slower latency than ta-NS elicited ECs. Higher stimulation frequencies and intensities and a longer pulse width elicit larger ECs and ICs for cVNS, and to some extent for taNS. Both short and long cVNS trains elicit stronger ECs, and long trains elicit slower ICs. Earlobe stimulation elicits VEPs that partially overlap with those from taNS. In conclusion, cVNS and taNS elicit cortical VEPs in a manner consistent with distinct engagement of ascending vagal pathways, and with similarities and differences in the effects of stimulation parameters on evoked responses.