Non-invasive Access to the Vagus Nerve Central Projections via Electrical Stimulation of the External Ear: fMRI Evidence in Humans

Abstract

Background: Tract-tracing studies in cats and rats demonstrated that the auricular branch of the vagus nerve (ABVN) projects to the nucleus tractus solitarii (NTS); it has remained unclear as to whether or not the ABVN projects to the NTS in humans.

Objective: To ascertain whether non-invasive electrical stimulation of the cymba conchae, a region of the external ear exclusively innervated by the ABVN, activates the NTS and the "classical" central vagal projections in humans.

Methods: Twelve healthy adults underwent two fMRI scans in the same session. Electrical stimulation (continuous 0.25ms pulses, 25Hz) was applied to the earlobe (control, scan #1) and left cymba conchae (scan #2). Statistical analyses were performed with FSL. Two region-of-interest analyses were performed to test the effects of cymba conchae stimulation (compared to baseline and control, earlobe, stimulation) on the central vagal projections (corrected; brainstem P < 0.01, forebrain P < 0.05), followed by a whole-brain analysis (corrected, P < 0.05).

Results: Cymba conchae stimulation, compared to earlobe (control) stimulation, produced significant activation of the "classical" central vagal projections, e.g., widespread activity in the ipsilateral NTS, bilateral spinal trigeminal nucleus, dorsal raphe, locus coeruleus, and contralateral parabrachial area, amygdala, and nucleus accumbens. Bilateral activation of the paracentral lobule was also observed. Deactivations were observed bilaterally in the hippocampus and hypothalamus.

Conclusion: These findings provide evidence in humans that the central projections of the ABVN are consistent with the "classical" central vagal projections and can be accessed non-invasively via the external ear.

Keywords: Neuromodulation; Non-invasive vagus stimulation; Nucleus of the solitary tract; Vagus nerve auricular branch; fMRI; t-VNS.

Conflict of interest statement

Conflict of Interest: Funding for this research (e.g., fMRI scan costs and honoraria to research participants) was provided by a grant from Cerbomed, GmbH, Erlangen, Germany. Cerbomed, the manufacturer of the ear stimulator, provided the instruments for this study. JE was the Chief Medical Officer of Cerbomed during the early part of this study; he is no longer affiliated with the company. BRK is a paid consultant and member of the Advisory Board of Cerbomed. EF received financial compensation from Cerbomed to support the fMRI data analysis. No contractual relations or proprietary considerations exist that restrict the dissemination of our findings.

Copyright © 2015 Elsevier Inc. All rights reserved.

Figures

Figure 1

a. The left external ear indicating the regions referred to in the Introduction and Stimulation Procedure section; b. Position of the earpiece during the control condition (earlobe stimulation); c. Position of the earpiece during the experimental condition (cymba conchae stimulation); d. Detail of the earpiece and the pair of titanium electrodes.

Figure 2

Selected vagal projections (“masked” in green) for the ROI analyses designed to test the hypothesis. a. Mask for the brainstem analysis. b. Masks for the forebrain analysis: thalamus, hypothalamus, amygdala, nucleus accumbens, insula (pictured in coronal slice), and (included but not pictured in coronal slice) paracentral lobule and hippocampus.

Figure 3

Medulla oblongata activations: cymba conchae > earlobe. Serial axial slices (location indicated by top left sagittal image, MNI152 z-coordinates: z = 4–12) showing the regions that were significantly active during cymba conchae stimulation compared to earlobe (control) stimulation. The left schematic diagrams from the Naidich et al. [42] atlas indicate the location of the corresponding labeled nuclei. Color-coding: solitary nucleus = orange; hypoglossal nucleus = blue; spinal trigeminal nucleus = green. Compass: R = rostral; C = caudal; L = left; Ri = right; D = dorsal; V = ventral. a. Coronal section indicating widespread left (ipsilateral) NTS activation. This and all the following figures are based upon group data, N=12. Top right colored bar indicates the z-score range. The z-score convention is the same for all the following figures.

Figure 4

Pons and lower midbrain activations: cymba conchae > earlobe. Conventions are the same as in Figure 2 with the exception of the color-coding: principal sensory trigeminal nucleus = orange; locus coeruleus = blue; parabrachial area = green. MNI152 z-coordinates: z = 19–26.

Figure 5

Midbrain activations: cymba conchae > earlobe. Conventions are the same as in Figure 2 with the exception of the color-coding: red nuclei = orange; substantia nigra = blue; dorsal raphe nuclei = yellow; periaqueductal gray = green. MNI152 z-coordinates: z = 27–33.

Figure 6

Mean effects of cymba conchae stimulation and post-stimulation in the brainstem. Labeled regions were each significantly activated. MNI152 z-coordinates: a. z = 31, b. z = 27, c. z = 23, d. z = 8, e. z = 29, f. z = 24, g. z = 6, h. z = 5.

Figure 7

Mean effects of cymba conchae stimulation in the forebrain. Labeled regions were each significantly activated.

Figure 8

a. Mean effects of cymba conchae stimulation on the primary somatosensory cortex; b. Mean effects of earlobe (control) stimulation on the primary somatosensory cortex; c. Three-dimensional composite of the sensory cortical response to stimulation of cymba conchae (orange) and earlobe (green). Compass: R = right; L = left; A = anterior; P = posterior; D = dorsal; V = ventral.

Figure 9

Significant deactivations of cymba conchae stimulation. Note the deactivation sites dispersed in hippocampus and parahippocampal gyrus. Deactivation occurred also in hypothalamus.

Figure 10

Brainstem activations for the control condition. a. Earlobe (control) stimulation > cymba conchae stimulation; b. Mean effects of earlobe (control) stimulation. Activations were significant only in the regions of the medulla oblongata that are labeled. We found no evidence of significant activation of solitary nucleus or its projections. MNI152 z-coordinates: a. and b. z = 6.

Figure 11

Mean effects of earlobe (control) stimulation in the forebrain.

Figure 12

Time-course analysis of the percent change of the BOLD signal for each significantly active region compared to the initial 2 minutes of rest (baseline). Note the gradual increase in activity during the 7 minutes of cymba conchae stimulation. For most regions, the activity peaked then persisted after cessation of the stimulation.