An investigation in the neuromodulation of olfactory function using non-invasive vagus nerve stimulation

In the existing literature, invasive direct vagus nerve stimulation (VNS) using high frequencies has shown to be effective in modulating the activity of the olfactory bulb in animal models. Under indirect vagus nerve stimulation, stimulation via peripheral nerves (such as median nerve stimulation-MNS) using low frequencies alleviates nausea, which indicates a potential contribution of the olfactory system. However, there is no research that assessed the effects of median nerve stimulation (either high- or low frequency) or high frequencies VNS on olfactory function in humans. The present study aimed to, therefore test the potential effects of non-invasive, direct and indirect stimulation of the vagus nerve (VN), using high- and low frequencies in humans. Two separate experiments were performed. In the first experiment, healthy adult male participants (n = 20) performed an odour threshold test (OTT), before and after receiving either, high-, low frequency MNS (indirect VNS) or placebo. Data from olfactory tests were analysed using paired parametric and non-parametric statistical tests (dependent on the presence or absence of normal distribution in the normality test using Shapiro-Wilk correction). Stimulation of the median nerve (MN) (indirect VNS) through high or low frequencies displayed no improvements in the performance of the OTT in healthy, adult male participants. The second experiment explored the effects of non-invasive, direct VNS through the auricular branch of the vagus nerve (AbVN). Healthy, adult male participants (n = 18) performed an OTT and supra-threshold test (STT), before and after receiving either, high-, low frequency VNS or placebo. Supplementary exploration of bilateral orbitofrontal cortex (OFC) was performed using near-infrared spectroscopy (NIRS). NIRS data of separate stimulation parameters were statistically analysed using repeated-measures ANOVA across all stages of the experiment. Data from the olfactory tests were analysed using paired parametric and non-parametric statistical tests. Only direct auricular VNS under high frequency stimulation displayed improvements in olfactory function of the healthy participants in the STT (p:0.021, Wilcoxon sign-ranked test), with significant differences in the NIRS recordings of the right hemispheric, OFC (p:0.014, post-hoc test with Bonferroni correction). Overall, the results of the present study demonstrated that non-invasive auricular VNS using high frequency stimulation can improve STT performance in healthy humans for the first time in the existing literature. Findings from this study provide important insights into the potential effects of high frequency VNS over the olfactory function via the OFC. Further studies are needed to investigate the entire network of olfactory system that responds to high frequency VNS. In addition, the results of the present study also underline a potential beneficial effect of high frequency VNS on early progression of olfactory impairments in Alzheimer’s and Parkinson’s disease, which, in this context, future studies are also needed to investigate this potential