Effects of Stimulus Frequency, Intensity, and Sex on the Autonomic Response to Transcutaneous Vagus Nerve Stimulation

Abstract

This study aimed to determine how transcutaneous vagus nerve stimulation (tVNS) alters autonomic nervous activity by comparing the effects of different tVNS frequencies and current intensities. We also investigated the sex-dependent autonomic response to tVNS. Thirty-five healthy adult participants were stimulated using a tVNS stimulator at the left cymba conchae while sitting on a reclining chair; tVNS-induced waveform changes were then recorded for different stimulus frequencies (Experiment 1: 3.0 mA at 100 Hz, 25 Hz, 10 Hz, 1 Hz, and 0 Hz (no stimulation)) and current intensities (Experiment 2: 100 Hz at 3.0 mA, 1.0 mA, 0.2 mA (below sensory threshold), and 0 mA (no stimulation)) using an electrocardiogram. Pulse widths were set at 250 µs in both experiment 1 and 2. Changes in heart rate (HR), root-mean-square of the difference between two successive R waves (RMSSD), and the ratio between low-frequency (LF) (0.04–0.15 Hz) and high-frequency (HF) (0.15–0.40 Hz) bands (LF/HF) in spectral analysis, which indicates sympathetic and parasympathetic activity, respectively, in heart rate variability (HRV), were recorded for analysis. Although stimulation at all frequencies significantly reduced HR (p = 0.001), stimulation at 100 Hz had the most pronounced effect (p = 0.001) in Experiment 1 and was revealed to be required to deliver at 3.0 mA in Experiment 2 (p = 0.003). Additionally, participants with higher baseline sympathetic activity experienced higher parasympathetic response during stimulation, and sex differences may exist in the autonomic responses by the application of tVNS. Therefore, our findings suggest that optimal autonomic changes induced by tVNS to the left cymba conchae vary depending on stimulating parameters and sex.

Short-term transcutaneous vagus nerve stimulation increases pupil size but does not affect EEG alpha power: a replication

“…Whereas Sharon et al [31] examined only male participants, we tested mainly female participants. Although this difference could potentially account for the discrepancy between our EEG results, the limited available evidence suggests that female animals [10] and human participants [51] show larger effects of VNS than males, which is inconsistent with our null finding in a group of mainly female participants.…”

Optimization of respiratory-gated auricular vagus afferent nerve stimulation for the modulation of blood pressure in hypertension

“…In addition, the activity of LC was positively associated with increased cardiovagal indices, suggesting that the administration of RAVANS at higher frequencies has an optimized effect on strengthening vagal afference to brainstem autonomic circuitry and is associated with increased efferent regulation of peripheral cardiovascular activity. Our results of taVNS frequency-dependent effects on the modulation of cardiovascular function are also consistent with a recent report from Yokota et al (2022) that evaluated the effects of taVNS at different stimulation frequencies (1, 10, 25, and 100 Hz) on the autonomic response of 30 healthy participants. In this study, stimulation at 100 Hz had the most pronounced effect on the reduction of heart rate when compared to other frequencies.…”

“…A direct measurement of sympathetic activity was not obtained in this study and therefore we cannot confirm this hypothesis. However, previous studies have found greater effects of taVNS on the modulation of cardiac autonomic function in those individuals with higher baseline sympathetic activity (Deuchars et al, 2018;Bretherton et al, 2019;Yokota et al, 2022).…”

“…For instance, while many clinical applications of taVNS use 20-30 Hz stimulation, our group has found a significantly greater effect of high-frequency (100 Hz) stimulation on modulation of medullary vagal nuclei activity (Sclocco et al, 2020). Further, many of the brain regions modulated by vagal afference are morphologically and functionally sexually dimorphic (McEwen, 1983;Tobet and Hanna, 1997;Goldstein et al, 2001;Tobet et al, 2009), and therefore, taVNS actions could potentially be sex-dependent (i.e., an effect that is present in men and women but differs by sex), as suggested by previous publications (Yokota et al, 2022). Addressing these gaps in knowledge could provide valuable information for optimized stimulation protocols with improved clinical efficacy and compliance in hypertensive patients.…”

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

“…Although some conclusions have been drawn, future research should attempt to combine HRV parameters with other indicators to obtain more precise results [ 42 ]. Fourth, there is evidence that stimulation frequency and intensity can affect the extent of taVNS activation [ 43 , 44 ]; therefore, it is unclear whether the effects of stimulation timing and duration vary with other stimulation parameters. It is worth noting that the stimulation intensity used in this study was much higher than that used in the taVNS study of cymba concha, which may be the reason for the conflicting results of taVNS on HRV in the literature.…”