BackgroundDysfunction 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.Methods70 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.ResultsOf 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.ConclusionOur 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.

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.

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.

Migraine is a common primary headache disorder. Transcutaneous auricular vagus nerve stimulation (taVNS) has been verified to be effective in patients with migraine without aura (MWoA). However, there are large interindividual differences in patients’ responses to taVNS. This study aimed to explore whether pretreatment fractional amplitude of low frequency fluctuation (fALFF) features could predict clinical outcomes in MWoA patients after 4-week taVNS. Sixty MWoA patients and sixty well-matched healthy controls (HCs) were recruited, and migraineurs received 4-week taVNS treatment. Resting-state functional magnetic resonance imaging (rs-fMRI) data were collected, and the significant differences of fALFF were detected between MWoA patients and HCs using two-sample t-test. A mask of these significant regions was generated and used for subsequent analysis. The abnormal fALFF in the mask was used to predict taVNS efficacy for MWoA using a support vector regression (SVR) model combining with feature select of weight based on the LIBSVM toolbox. We found that (1) compared with HCs, MWoA patients exhibited increased fALFF in the left thalamus, left inferior parietal gyrus (IPG), bilateral precentral gyrus (PreCG), right postcentral gyrus (PoCG), and bilateral supplementary motor areas (SMAs), but decreased in the bilateral precuneus and left superior frontal gyrus (SFG)/medial prefrontal cortex (mPFC); (2) after 4-week taVNS treatment, the fALFF values significantly decreased in these brain regions based on the pretreatment comparison. Importantly, the decreased fALFF in the bilateral precuneus was positively associated with the reduction in the attack times (r = 0.357, p = 0.005, Bonferroni correction, 0.05/5), whereas the reduced fALFF in the right PoCG was negatively associated with reduced visual analog scale (VAS) scores (r = −0.267, p = 0.039, uncorrected); (3) the SVR model exhibited a good performance for prediction (r = 0.411, p < 0.001),which suggests that these extracted fALFF features could be used as reliable biomarkers to predict the treatment response of taVNS for MWoA patients. This study demonstrated that the baseline fALFF features have good potential for predicting individualized treatment response of taVNS in MWoA patients, and those weight brain areas are mainly involved in the thalamocortical (TC) circuits, default mode network (DMN), and descending pain modulation system (DPMS). This will contribute to well understanding the mechanism of taVNS in treating MWoA patients and may help to screen ideal patients who respond well to taVNS treatment.

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