Effects of Sub-threshold Transcutaneous Auricular Vagus Nerve Stimulation on Cingulate Cortex and Insula Resting-state Functional Connectivity

Abstract

Transcutaneous auricular vagus nerve stimulation (taVNS), a non-invasive alternative to vagus nerve stimulation (VNS) with implantable devices, has shown promise in treating disorders such as depression, migraine, and insomnia. Studies of these disorders with resting-state functional magnetic resonance imaging (MRI) (rsfMRI) have found sustained changes in resting-state functional connectivity (rsFC) in patients treated with low frequency (1–20 Hz) taVNS. A recent study has reported reductions in pain scores in patients with rheumatoid arthritis after a 12-week treatment of high-frequency (20 kHz) sub-threshold taVNS. However, no studies to date have examined the effects of high-frequency sub-threshold taVNS on rsFC. The objective of this study was to determine whether high-frequency sub-threshold taVNS induces changes in rsFC using seed regions from the cingulate cortex and insula, brain regions that play a key role in interoception and processing of pain. With a single-blind placebo-controlled repeated measures experimental design, rsfMRI scans were acquired before and after 15 min of either sub-threshold taVNS treatment or a sham control. Significant taVNS-related changes in functional connections to the cingulate cortex were detected between the anterior cingulate cortex and right superior temporal gyrus and between the midcingulate cortex and right inferior parietal lobule. In addition, significant changes in functional connections to the insula were detected between the posterior insula and right precuneus and between the anterior insula and right cuneus gyrus. These results suggest that high-frequency sub-threshold taVNS can lead to sustained effects on the rsFC of brain regions involved in interoception and processing of pain in a cohort of healthy subjects. This study lays the foundation for future rsfMRI studies of high-frequency sub-threshold taVNS in clinical populations.

Structural and functional changes of anterior cingulate cortex subregions in migraine without aura: relationships with pain sensation and pain emotion

“…Furthermore, researches have suggested that the left sACC is a key region for pain activation and may be closely related to pain sensation in migraine, which is consistent with our findings ( Schulz-Stübner et al. 2004 ; Mao et al. 2022 ).…”

“…The ACC plays a vital role in integrating and regulating the multidimensional clinical manifestations of migraines ( Lee et al. 2022 ; Mao et al. 2022 ; Journée et al.…”

Enhancing the selective electrical activation of human vagal nerve fibers: a comparative computational modeling study with validation in a rat sciatic model

“…Finally, it is worth noting that values reported in human experiments in the absence of a recording electrode are perceptual thresholds, whereas activation of individual nerve fibers can occur sub-perceptually. Indeed, subperceptual threshold VNS is beginning to be explored as an alternative to conventional VNS, which uses amplitudes titrated from perception [41,42].…”

Orally Ingested Self‐Powered Stimulators for Targeted Gut–Brain Axis Electrostimulation to Treat Obesity and Metabolic Disorders

“…This imaging technique is commonly used to identify functional connectivity within the brain and spatially distributed networks by measuring changes in blood oxygenation levels. [62][63][64] Figure 4e shows 16 consecutive slices of brain functional images in a transversal view acquired using a gradient-echo echo planar imaging sequence. The regions of interest (ROIs) used for analyzing rs-fMRI signals are illustrated in Figure 4f.…”