Respiratory-gated auricular vagal afferent nerve stimulation (RAVANS) modulates brain response to stress in major depression

Ronald G Garcia; Justine E Cohen; Arielle D Stanford; Aileen Gabriel; Jessica Stowell; Harlyn Aizley; Riccardo Barbieri; David Gitlin; Vitaly Napadow; Jill M Goldstein

doi:10.1016/j.jpsychires.2021.07.048

Respiratory-gated auricular vagal afferent nerve stimulation (RAVANS) modulates brain response to stress in major depression

J Psychiatr Res. 2021 Oct:142:188-197. doi: 10.1016/j.jpsychires.2021.07.048. Epub 2021 Aug 2.

Authors

Affiliations

¹ Department of Psychiatry, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA; Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA; Innovation Center on Sex Differences in Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
² Department of Psychiatry, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA; Innovation Center on Sex Differences in Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
³ Translational Medicine, Alkermes Inc, Waltham, MA, USA.
⁴ Innovation Center on Sex Differences in Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
⁵ Department of Psychiatry, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
⁶ Department of Electronics, Information and Bioengineering, Politecnico di Milano, Milano, Italy; Department of Anesthesia and Critical Care, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
⁷ Department of Psychiatry, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
⁸ Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA; Innovation Center on Sex Differences in Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA; Department of Radiology, Logan University, Chesterfield, MO, USA.
⁹ Department of Psychiatry, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA; Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA; Innovation Center on Sex Differences in Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA. Electronic address: jill_goldstein@hms.harvard.edu.

Abstract

Background: Negative stress significantly impacts major depressive disorder (MDD), given the shared brain circuitry between the stress response and mood. Thus, interventions that target this circuitry will have an important impact on MDD. The aim of this study was to evaluate the acute effects of a novel respiratory-gated auricular vagal afferent nerve stimulation (RAVANS) technique in the modulation of brain activity and connectivity in women with MDD in response to negative stressful stimuli.

Methods: Twenty premenopausal women with recurrent MDD in an active episode were included in a cross-over experimental study that included two functional MRI visits within one week, randomized to receive exhalatory- (e-RAVANS) or inhalatory-gated (i-RAVANS) at each visit. Subjects were exposed to a visual stress challenge that preceded and followed RAVANS. A Factorial analysis was used to evaluate the effects of RAVANS on brain activity and connectivity and changes in depressive and anxiety symptomatology post-stress.

Results: Compared with i-RAVANS, e-RAVANS was significantly associated with increased activation of subgenual anterior cingulate, orbitofrontal and ventromedial prefrontal cortices and increased connectivity between hypothalamus and dorsolateral prefrontal cortex, and from nucleus tractus solitarii to locus coeruleus and ventromedial prefrontal cortex. Changes in brain activity and connectivity after e-RAVANS were significantly associated with a reduction in depressive and anxiety symptoms.

Conclusions: Our study suggests exhalatory-gated RAVANS effectively modulates brain circuitries regulating response to negative stress and is associated with significant acute reduction of depressive and anxiety symptomatology in women with recurrent MDD. Findings suggest a potential non-pharmacologic intervention for acute relief of depressive symptomatology in MDD.

Keywords: Major depression; Respiration; Stress response; Transcutaneous auricular vagus nerve stimulation; Vagus nerve; fMRI.

Publication types

Randomized Controlled Trial
Research Support, N.I.H., Extramural

MeSH terms

Brain / diagnostic imaging
Depression
Depressive Disorder, Major* / therapy
Female
Humans
Magnetic Resonance Imaging
Vagus Nerve Stimulation*

Abstract

Publication types

MeSH terms

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