Transcutaneous Auricular Vagus Nerve Stimulation at 20 Hz Improves Depression-Like Behaviors and Down-Regulates the Hyperactivity of HPA Axis in Chronic Unpredictable Mild Stress Model Rats.

Shaoyuan Li,Jinling Zhang,Yifei Wang,Liang Li,Guojian Gao,Yu Wang,Yongsheng Yang,Zixuan Zhang,Peijing Rong,Yue Zhang,Xiao Guo,Junying Wang

doi:10.3389/fnins.2020.00680

Abstract

Transcutaneous auricular vagus nerve stimulation (taVNS) has gained growing interest as a non-invasive and non-pharmacologic treatment option in various neurological and psychiatric disorders. Animal experiments and clinical trials confirm that taVNS at the auricular concha region has beneficial effects on depression. However, stimulation frequencies are selected empirically, and there is no evidence showing that any frequency is superior to the others. This study explores antidepressant-like effects of three frequencies of taVNS on rats subjected to chronic unpredictable mild stress (CUMS). Sprague-Dawley rats were randomly divided into five groups, i.e., the control, CUMS, 5 Hz-taVNS, 20 Hz-taVNS, and 100 Hz-taVNS groups. The three different frequencies were administered during the 30-min taVNS procedure once a day for 28 consecutive days. Rats exposed to CUMS showed signs of depression-like behaviors, including reduction in sucrose preference and increased immobility time in forced swimming and open field tests as well as significant dysfunction of the hypothalamic-pituitary-adrenal (HPA) axis as detected by plasma corticosterone and adrenocorticotropic hormone concentration. The 28 days’ taVNS sessions with three frequencies elicited quite different consequences. Although 20 Hz taVNS significantly reversed the depression-like behaviors and downregulated the hyperactivity of the HPA axis, neither 5 nor 100 Hz showed any antidepressant-like effect on CUMS-induced rat behavior. Based on these results, we propose that, out of the three frequencies for taVNS intervention on depression, 20 Hz may be the optimized frequency to have a better modulation effect on HPA axis function by activating the auricular vagus nerve.

Highlights

Depression is a frequent and prevalent clinical complaint
During the 21 days of the chronic unpredictable mild stress (CUMS) procedure without treatment, a loss in sucrose preference as a sign of depression-like behavior in rats was observed in the CUMS and CUMS with 5 Hz-transcutaneous auricular vagus nerve stimulation (taVNS), 20 Hz-taVNS, and 100 Hz-taVNS groups compared with the non-stressed control group
Starting with taVNS treatment from day 0, sucrose preference significantly increased until days 21 and 28 only in the 20 Hz group (P < 0.05 and P < 0.01) compared to other CUMS groups but was still below that of the control group

Summary

Introduction

Depression is a frequent and prevalent clinical complaint. In 2015, the proportion of the global population with depression was estimated to be 4.4% (World Health Organization, 2017). Inspired by the mechanism of VNS, we and other researchers have proven that transcutaneous auricular vagus nerve stimulation (taVNS), a non-invasive method, has a curative effect on depression (Rong et al, 2016; Wu et al, 2018). It is assumed that stimulation on the auricular vagus nerve can activate the inferior ganglion, which projects to the nucleus tractus solitarii (NTS) (He et al, 2013) and affects the activities of depression-related cortical-limbic-thalamic neural circuits through connections between NTS and other brain regions, such as the locus coeruleus, parabrachial nucleus, hypothalamus, thalamus, amygdala, hippocampus, anterior cingulate cortex, anterior insula, and lateral prefrontal cortex (Beekwilder and Beems, 2010). Previous studies have exhibited that taVNS is an effective treatment for depression (Hein et al, 2013; Rong et al, 2016), which significantly modulates the default mode network functional connectivity in patients with mild or moderate major depressive disorder (MDD) (Fang et al, 2016)

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Results

Conclusion