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.

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.

Transcutaneous auricular vagus nerve stimulation (taVNS) for migraine: an fMRI study.

BACKGROUND: Dysfunction of the thalamocortical connectivity network is thought to underlie the pathophysiology of the migraine. This current study aimed to explore the thalamocortical connectivity changes during 4 weeks of continuous transcutaneous vagus nerve stimulation (taVNS) treatment on migraine patients. METHODS: 70 migraine patients were recruited and randomized in an equal ratio to receive real taVNS or sham taVNS treatments for 4 weeks. Resting-state functional MRI was collected before and after treatment. The thalamus was parceled into functional regions of interest (ROIs) on the basis of six priori-defined cortical ROIs covering the entire cortex. Seed-based functional connectivity analysis between each thalamic subregion and the whole brain was further compared across groups after treatment. RESULTS: Of the 59 patients that finished the study, those in the taVNS group had significantly reduced number of migraine days, pain intensity and migraine attack times after 4 weeks of treatment compared with the sham taVNS. Functional connectivity analysis revealed that taVNS can increase the connectivity between the motor-related thalamus subregion and anterior cingulate cortex/medial prefrontal cortex, and decrease the connectivity between occipital cortex-related thalamus subregion and postcentral gyrus/precuneus. CONCLUSION: Our findings suggest that taVNS can relieve the symptoms of headache as well as modulate the thalamocortical circuits in migraine patients. The results provide insights into the neural mechanism of taVNS and reveal potential therapeutic targets for migraine patients.

The Instant Effects of Continuous Transcutaneous Auricular Vagus Nerve Stimulation at Acupoints on the Functional Connectivity of Amygdala in Migraine without Aura: A Preliminary Study.

Background: A growing body of evidence suggests that both auricular acupuncture and transcutaneous auricular vagus nerve stimulation (taVNS) can induce antinociception and relieve symptoms of migraine. However, their instant effects and central treatment mechanism remain unclear. Many studies proved that the amygdalae play a vital role not only in emotion modulation but also in pain processing. In this study, we investigated the modulation effects of continuous taVNS at acupoints on the FC of the bilateral amygdalae in MwoA. Methods: Thirty episodic migraineurs were recruited for the single-blind, crossover functional magnetic resonance imaging (fMRI) study. Each participant attended two kinds of eight-minute stimulations, taVNS and sham-taVNS (staVNS), separated by seven days in random order. Finally, 27 of them were included in the analysis of seed-to-voxel FC with the left/right amygdala as seeds. Results: Compared with staVNS, the FC decreased during taVNS between the left amygdala and left middle frontal gyrus (MFG), left dorsolateral superior frontal gyrus, right supplementary motor area (SMA), bilateral paracentral lobules, bilateral postcingulum gyrus, and right frontal superior medial gyrus, so did the FC of the right amygdala and left MFG. A significant positive correlation was observed between the FC of the left amygdala and right SMA and the frequency/total time of migraine attacks during the preceding four weeks. Conclusion: Continuous taVNS at acupoints can modulate the FC between the bilateral amygdalae and pain-related brain regions in MwoA, involving the limbic system, default mode network, and pain matrix, with obvious differences between the left amygdala and the right amygdala. The taVNS may produce treatment effects by modulating the abnormal FC of the amygdala and pain networks, possibly having the same central mechanism as auricular acupuncture.

Transcutaneous auricular vagus nerve stimulation at 1 Hz modulates locus coeruleus activity and resting state functional connectivity in patients with migraine: An fMRI study.

BACKGROUND: Migraine is a common episodic neurological disorder. Literature has shown that transcutaneous auricular vagus nerve stimulation (taVNS) at 1 Hz can significantly relieve migraine symptoms. However, its underlying mechanism remains unclear. This study aims to investigate the neural pathways associated with taVNS treatment of migraine. METHODS: Twenty-nine patients with migraine were recruited from outpatient neurology clinics. Each patient attended two magnetic resonance imaging/functional magnetic resonance imaging (MRI/fMRI) scan sessions separated by one week. Each session included a pre-stimulation resting state fMRI scan, fMRI scans during real or sham 1 Hz taVNS (with block design), and a post-stimulation resting state fMRI scan. RESULTS: Twenty-six patients were included in the final analyses. Real taVNS evoked fMRI signal decreases in brain areas belonging to the default mode network (DMN) and brain stem areas including the locus coeruleus (LC), raphe nuclei, parabrachial nucleus, and solitary nucleus. Sham taVNS evoked fMRI signal decreases in brain areas belonging to the DMN. Compared to sham taVNS, real taVNS produced greater deactivation at the bilateral LC. Resting state functional connectivity (rsFC) analysis showed that after taVNS, LC rsFC with the right temporoparietal junction and left secondary somatosensory cortex (S2) significantly increased compared to sham taVNS. The increased rsFC of the left LC-left S2 was significantly negatively associated with the frequency of migraine attacks during the preceding month. CONCLUSION: Our results suggest that taVNS at 1 Hz can significantly modulate activity/connectivity of brain regions associated with the vagus nerve central pathway and pain modulation system, which may shed light on the neural mechanisms underlying taVNS treatment of migraine.