Vagus Nerve Stimulation Unequally Disturbs Circadian Variation of Cardiac Rhythms in Male and Female Rats

Vagus nerve stimulation (VNS) is a neurostimulation therapy for epilepsy and severe depression and has been recently shown to be effective for other conditions. Despite its demonstrated safety and efficacy, long-term and off-target effects of VNS remain to be fully determined. One of the complications reported in epilepsy is stimulation-induced sleep abnormalities. As epilepsy itself can impact sleep quality, contribution of VNS alone in such off-target effects remain mainly unknown. In this study, we analyzed data from long-term VNS experiments in rats to characterize effects of VNS on circadian rhythms derived from heart rate and heart rate variability (HRV). We have also explored possible sex differences in long-term effects of VNS on intrinsic biological rhythms. Compared with control animals, significant VNS-induced changes in circadian rhythms were observed particularly in female rats over 24h and 6h light cycles (1PM-7PM). These findings enhance our understanding of VNS contribution and biological sex role on sleep difficulties reported by using VNS therapy.