Different modulation effects of 1 Hz and 20 Hz transcutaneous auricular vagus nerve stimulation on the functional connectivity of the periaqueductal gray in patients with migraine

Jin Cao, Yue Zhang, Hui Li, Zhaoxian Yan, Xian Liu, Xiaoyan Hou, Weicui Chen, Sierra Hodges, Jian Kong, Bo Liu, Jin Cao, Yue Zhang, Hui Li, Zhaoxian Yan, Xian Liu, Xiaoyan Hou, Weicui Chen, Sierra Hodges, Jian Kong, Bo Liu

Abstract

Background: A growing body of evidence suggests that transcutaneous auricular vagus nerve stimulation (taVNS) may relieve symptoms of migraineurs. Frequency is one of the key stimulation parameters. The aim of this study is to investigate the modulation effect of taVNS frequency on the descending pain modulation system (DPMS) in patients with migraine.

Methods: Twenty-four episodic migraineurs without aura (21 females) were recruited for the single-blind, crossover, functional magnetic resonance imaging (fMRI) study. Each participant attended two separate fMRI scan sessions, one for 1 Hz and another for 20 Hz taVNS, in a random order. Seed-based functional connectivity analysis was applied using the ventrolateral periaqueductal gray (PAG) as the region of interest.

Results: Compared with the pre-taVNS resting state, continuous 1 Hz taVNS (during) produced a significant increase in functional connectivity between the PAG and the bilateral middle cingulate cortex (MCC), right precuneus, left middle frontal gyrus (MFG), and left cuneus. Compared with 20 Hz taVNS, 1 Hz taVNS produced greater PAG connectivity increases with the MCC, right precuneus/posterior cingulate cortex, left insula, and anterior cingulate cortex (ACC). A significant negative correlation was observed between the number of migraine attacks in the previous 4 weeks and the PAG-MCC functional connectivity in the pre-taVNS resting-state before 1 Hz taVNS.

Conclusions: Our findings suggest that taVNS with different frequencies may produce different modulation effects on the descending pain modulation system, demonstrating the important role of stimulation frequency in taVNS treatment.

Keywords: Descending pain modulation network; Frequency; Functional connectivity; Periaqueductal gray; Transcutaneous auricular vagus nerve stimulation.

Conflict of interest statement

Jian Kong has a disclosure to report (holding equity in a startup company, MNT, and a patent to develop new neuromodulation devices) but declares no conflict of interest. All other authors declare no competing interests.

© 2021. The Author(s).

Figures

Fig. 1
Fig. 1
Overview of study procedure and taVNS sites. A Study procedure. B taVNS sites
Fig. 2
Fig. 2
vlPAG based connectivity results. A Compared to pre-taVNS resting-state, 1 Hz taVNS had significantly greater connectivity with the MCC, precuneus, Cuneus, and left MFG (not present in the figure). B Significant negative correlation was observed in migraine attacks and vlPAG-MCC connectivity in pre-taVNS resting-state preceding to the 1 Hz taVNS. Bonferroni correction was applied, and the significance threshold was adjusted to p < 0.0125 because four significant clusters were identified. C Compared to 20 Hz, 1 Hz taVNS had significant connectivity increases (stimulation minus pre-taVNS resting-state) with the MCC, precuneus, ACC, and left insula. FC functional connectivity, vlPAG ventrolateral periaqueductal gray, MCC middle cingulate cortex, PCu precuneus, MFG middle frontal gyrus, ACC anterior cingulate cortex, INS insula

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