Phase-Amplitude Coupling in Response to Transcutaneous Vagus Nerve Stimulation: Focus on Regions Implicated in Mood and Memory

OBJECTIVE: This study aimed to investigate whether transcutaneous vagus nerve stimulation (tVNS) at different frequencies affects phase-amplitude coupling among regions of the brain linked to mood and memory disorders using simultaneous magnetoencephalography (MEG) in healthy participants. MATERIALS AND METHODS: Phase-amplitude coupling was measured among brain areas in response to different stimulation frequencies of tVNS using concurrent MEG and tVNS in 17 healthy participants. The 4 protocols were: 24 Hz cymba concha, 1 Hz cymba concha, PFM cymba concha, and 24 Hz ear lobe. A driven autoregressive method was used to estimate the coupling among brain areas in different physiological frequency bands in response to these protocols. RESULTS: Different tVNS stimulation protocols led to alterations in phase-amplitude coupling among multiple brain regions linked to mood and memory, notably the prefrontal cortex, hippocampus, and temporal pole. Stimulation delivered at 24 Hz was observed to decrease delta-gamma coupling within the temporal pole and cingulate cortex when contrasted with 24-Hz sham stimulation. Increased alpha-gamma coupling was observed between the hippocampus and prefrontal cortex when contrasting 24 Hz with pulse-frequency-modulated stimulation. Finally, a comparison of 24-Hz with low-frequency 1-Hz stimulation showed an increase in theta-gamma coupling within the prefrontal cortex. SIGNIFICANCE: To our knowledge, this study represents the first attempt to quantify phase-amplitude coupling in response to tVNS and suggests that different stimulation frequencies can modulate coupling between different areas of the brain. Abnormal phase-amplitude coupling has been linked to multiple mood and memory disorders. Further investigations using different stimulation frequencies of tVNS to alter phase-amplitude coupling may lead to the development of tVNS as a therapeutic option for different medical conditions.