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Novel Form of Vagus Nerve Stimulation Promising for Treatment of Major Depressive Disorder

Key findings

  • In this study, functional MRI was used to evaluate the effects of respiratory-gated auricular vagal afferent nerve stimulation (RAVANS), a novel form of transcutaneous auricular vagus nerve stimulation developed at Massachusetts General Hospital
  • Specifically, the researchers compared delivery of transcutaneous auricular vagus nerve stimulation during the exhalation phase of respiration as opposed to the inhalation phase in 20 women with recurrent major depressive disorder, primarily unmedicated
  • Regional brain activations and their connectivities with exhalatory-gated RAVANS were associated with greater acute reductions in depressive and anxiety symptomatology compared with inhalatory-gated RAVANS
  • The level of improvement suggested clinical relevance
  • This is the first study to show fast-acting effects of transcutaneous auricular vagus nerve stimulation, emphasizing the potential clinical utility of exhalatory-gated RAVANS for major depressive disorder

The vagus nerve, as the main component driving the parasympathetic nervous system, is involved in regulating mood. Implanting electrodes to stimulate the vagus nerve in the neck can be useful in managing treatment-resistant major depressive disorder (MDD), but significant side effects and surgical morbidity are possible.

A newer, noninvasive variant of vagus nerve stimulation, called transcutaneous auricular vagus nerve stimulation (taVNS), targets a branch of the vagus that extends to an easily accessible location in the ear. Previous studies of taVNS have shown promising antidepressant effects, but responses varied substantially.

Ronald G. Garcia, MD, PhD, an instructor in the Department of Psychiatry at Massachusetts General Hospital and team member at the Innovation Center on Sex Differences in Medicine (ICON), Jill M. Goldstein, PhD, founder and executive director of ICON, and the Helen T. Moerschner Endowed MGH Research Institute Chair in Women's Health, and colleagues have implemented a novel taVNS technique called respiratory-gated auricular vagal afferent nerve stimulation (RAVANS).

In the Journal of Psychiatric Research, they describe RAVANS and report promising effects on symptoms of both depression and anxiety in women with MDD.


In taVNS, auricular information flows to the nucleus tractus solitarii (NTS) in the brainstem. The NTS receives an inhibitory drive from the ventral respiratory group medullary neurons during inhalation and a facilitatory input during exhalation.

The Mass General team previously reported in Brain Stimulation that stimulating a specific location in the auricular branch of the vagus nerve during exhalation enhanced NTS modulation. RAVANS is a taVNS technique aimed at using a person's own respiratory activity to improve activation of brain areas that regulate mood.


The participants in this initial study were 20 women who had recurrent MDD and were experiencing an active episode. 85% (n=17) were unmedicated and three had been on stable antidepressant doses for at least eight weeks.

The participants were randomly assigned to receive 30 minutes of exhalatory-gated RAVANS (e-RAVANS) or inhalatory-gated RAVANS (i-RAVANS), then cross over to the opposite condition within one week. Functional MRI was used to evaluate the effects on the brain, and while in the scanner the participants completed three runs of an adapted version of the International Affective Picture System (IAPS), a mild visual stress test.

Just before and after scanning, the participants completed the Beck Depression Inventory-II (BDI-II) and the State-Trait Anxiety Inventory (STAI).

Clinical Results

The differences between pre- and post-scan scores were:

  • BDI-II: −8.21 with e-RAVANS vs. −3.58 with i-RAVANS (P=0.03)
  • Twelve (60%) of women after e-RAVANS presented a clinically important change in depressive mood symptomatology (>5-point reduction in BDI-II scores from baseline) compared to 5 (25%) women following i-RAVANS administration (P=0.01)
  • Exhalatory-gated RAVANS was associated with a medium to large effect size (Cohen's d=0.73) on reduction of depressive symptomatology
  • STAI: −7.36 vs. −1.76 (P=0.06)
  • IAPS negative arousal: 4.72 vs. 5.28 (P=0.41)
  • IAPS negative valence: 7.29 vs. 7.58 (P=0.46)

The reductions in depressive and anxiety symptoms were at a level suggesting clinical relevance. All participants tolerated auricular electrical stimulation.

fMRI Results

Compared with i-RAVANS, e-RAVANS was significantly associated with:

  • Increased activation of the subgenual anterior cingulate, orbitofrontal and ventromedial prefrontal cortices
  • Increased connectivity between the hypothalamus and the dorsolateral prefrontal cortex
  • Increased connectivity from the NTS to the locus coeruleus and ventromedial prefrontal cortex

These changes in brain activity and connectivity after e-RAVANS were significantly associated with the reductions in depressive and anxiety symptoms.

Unique Demonstration of Acute Effects

Previous research into taVNS for MDD involved daily treatment over two to four weeks. This is the first study to show fast-acting effects, emphasizing the potential clinical utility of e-RAVANS for MDD. Currently, the only treatment for MDD that has acute effects is ketamine, a dissociative anesthetic that has hallucinogenic effects.

The team is now studying e-RAVANS comparing men with women with recurrent MDD and e-RAVANS for men and women with hypertension.

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