BOLD fMRI effects of transcutaneous vagus nerve stimulation in patients with chronic tinnitus

Abstract

Objective: Vagus nerve stimulation (VNS) is a neuromodulation method used for treatment of epilepsy and depression. Transcutaneous VNS (tVNS) has been gaining popularity as a noninvasive alternative to VNS. Previous tVNS neuroimaging studies revealed brain (de)activation patterns that involved multiple areas implicated in tinnitus generation and perception. In this study, functional magnetic resonance imaging (fMRI) was used to explore the effects of tVNS on brain activity in patients with tinnitus.

Methods: Thirty-six patients with chronic tinnitus received tVNS to the inner tragus, cymba conchae, and earlobe (sham stimulation).

Results: The locus coeruleus and nucleus of the solitary tract in the brainstem were activated in response to stimulation of both locations compared with the sham stimulation. The cochlear nuclei were also activated, which was not observed in healthy subjects with normal hearing. Multiple auditory and limbic structures, as well as other brain areas associated with generation and perception of tinnitus, were deactivated by tVNS, particularly the parahippocampal gyrus, which was recently speculated to cause tinnitus in hearing-impaired patients.

Conclusions: tVNS via the inner tragus or cymba conchae suppressed neural activity in the auditory, limbic, and other tinnitus-related non-auditory areas through auditory and vagal ascending pathways in tinnitus patients. The results from this study are discussed in the context of several existing models of tinnitus. They indicate that the mechanism of action of tVNS might be involved in multiple brain areas responsible for the generation of tinnitus, tinnitus-related emotional annoyance, and their mutual reinforcement.

Fig 1. Activations (red) and deactivations (blue) induced by tVNS at the tragus, cymba conchae, and earlobe (p < 0.05, cluster corrected for multiple comparisons).

tVNS: transcutaneous vagus nerve stimulation; ACC/MCC/PCC: anterior/middle/posterior cingulate cortex; Amyg: amygdala; AnG: angular gyrus; CC: corpus callosum; CBLL: cerebellum; FuG: fusiform gyrus; Hip: hippocampus; LiG: lingual gyrus; MOG: middle orbital gyrus; MTG/STG: middle/superior temporal gyrus; PCu: precuneus; PoG/PrG: postcentral/precentral gyrus; SFG: superior frontal gyrus; TMP: temporal pole.

Fig 2

Spatial maps showing differences between the active stimulation locations and the sham stimulation location, corrected (A) and uncorrected (B) for multiple comparisons. CBLL: cerebellum, CC: corpus callosum, CN: cochlear nucleus, IFG: inferior frontal gyrus, LC: locus coeruleus, MTG: middle temporal gyrus, NTS: nucleus of solitary tract, PrG: precentral gyrus, SMC: supplementary motor cortex, SMG: supramarginal gyrus, Tha: thalamus.

Fig 3. Results of ROIs analysis in tinnitus patients: number of voxels, average t-value, and PSC in the auditory, limbic, and vagal brainstem structures for each electrode location.

Error bars represent standard error. ROIs; regions of interest; PSC: percent signal change; CN: cochlear nucleus; HG: Heschl’s gyrus; LC: locus coeruleus; NTS: nucleus of solitary tract; PHG: parahippocampal gyrus; STG: superior temporal gyrus. No significant differences were found among the locations.

Fig 4. Activations (red) and deactivations (blue) induced by tVNS at the tragus and cymba conchae for NORM and TINN after matching the number of functional volumes (p < 0.05, cluster corrected for multiple comparisons).

NORM: normal subjects; TINN: tinnitus patients; AnG: angular gyrus; CC: corpus callosum; Hip: hippocampus; MCC/PCC: middle/posterior cingulate cortex; MTG/STG: middle/superior temporal gyrus; PCu: precuneus; PoG/PrG: postcentral/precentral gyrus; SFG: superior frontal gyrus.

Fig 5. Spatial maps of the differences between the NORM and TINN datasets (p < 0.05, cluster corrected for multiple comparisons).

NORM: normal subjects; TINN: tinnitus patients; AnG: angular gyrus; PCu: precuneus; PoG/PrG: postcentral/precentral gyrus; SFG: superior frontal gyrus; STG: superior temporal gyrus; TMP: temporal lobe.

Fig 6. Results from the ROIs analysis in NORM and TINN.

The number of voxels, average t-value, and PSC of each ROI for NORM and TINN after matching the number of functional volumes. ROIs: regions of interest; NORM: normal subjects; TINN: tinnitus patients; PSC: percent signal change; HG: Heschl’s gyrus; PHG: parahippocampal gyrus; STG: superior temporal gyrus. *: p < 0.05 (paired t-test, Bonferroni-corrected for multiple comparisons).