Circadian stage-dependent and stimulation duration effects of transcutaneous auricular vagus nerve stimulation on heart rate variability.

Transcutaneous auricular vagus nerve stimulation (taVNS) can improve autonomic nerve function and is currently undergoing extensive clinical research; however, its efficacy heterogeneity has caused great controversy. Heart rate variability (HRV), a biomarker reflecting autonomic function, exhibits a time-varying pattern with circadian rhythms, which may be the main reason for the inconsistent stimulation effects. To test this conjecture, we performed isochronous acute stimulation experiments at intervals of 12 h. The results showed that HRV indicators representing vagal nerve activity significantly increased when stimulation was performed in the morning, and the enhancement of high frequency continued into the recovery period. However, the evening stimulation did not yield similar results. In addition, we found that improvements in the measures of autonomic balance were more pronounced in the presence of lower vagal activity. By increasing the stimulation duration, we also found that the effect of taVNS on HRV was not regulated by duration; in other words, HRV changes only had the best effect at the beginning of stimulation. These studies allowed us to determine the optimal stimulation phase and duration and potentially screen the optimal candidates for taVNS.