Cortical responses to vagus nerve stimulation are modulated by brain state in non-human primates

Abstract

Vagus nerve stimulation (VNS) is tested as therapy for several brain disorders and as a means to modulate brain plasticity. Cortical effects of VNS, manifesting as vagal-evoked potentials (VEPs), are thought to arise from activation of ascending cholinergic and noradrenergic systems. However, it is unknown whether those effects are dependent on oscillatory brain activity underling different brain states. In 2 freely behaving macaque monkeys, we delivered trains of left cervical VNS, at different pulsing frequencies (5-300 Hz), while recording local field potentials (LFP) from sites in contralateral prefrontal, sensorimotor and parietal cortical areas, continuously over 11-16 hours. Different brain states were inferred from oscillatory components of LFPs and the presence of overt movement: active awake, resting awake, REM sleep and NREM sleep. VNS elicited VEPs comprising early (<70 ms), intermediate (70-250 ms) and late (>250 ms) components in all sampled cortical areas. The magnitude of only the intermediate and late components was modulated by brain state and pulsing frequency. These findings have implications for the role of ongoing brain activity in shaping cortical responses to peripheral stimuli, for the modulation of vagal interoceptive signaling by cortical states, and for the calibration of VNS therapies.