Ronald Garcia, MD, PhD

Background: Sex-dependent alterations of the stress response circuitry (SRC) have been implicated in major depression and associated with dysregulation of steroid hormones and cardiac physiology. The development of novel interventions at the neural-cardiac interface may have significant positive impacts on clinical and physiological functioning in depression. We developed a study oriented to identify sex differences in SRC activity associated with depressed mood, steroid hormones, and cardiac autonomic dysregulation in depression (Discovery phase). These results were then used in a second study to guide the evaluation of a novel, non-invasive, respiratory-gated auricular vagal afferent nerve stimulation (RAVANS) on the modulation of SRC activity and peripheral autonomic dysregulation in major depression (Translational phase).

Methods: Study 1 included 50 subjects (28 females, 45.5±5.0 years), in which functional magnetic resonance imaging (fMRI) was used to evaluate associations between SRC activity and cardiovagal activity in response to negative affective stimuli, dependent on depressed mood and sex. Study 2 included 20 women (30.3±4.7 years) with recurrent major depression who attended two fMRI visits in which expiratory-gated (eRAVANS) and inspiratory-gated (iRAVANS) effects on SRC activity, depressive symptoms and cardiovagal activity were evaluated.

Results: Activation of hypothalamus and amygdala and their reduced connectivity with orbitofrontal cortex (OFC) were significantly associated with impaired cardiovagal activity, particularly in women with depressed mood vs. men. eRAVANS effectively modulated OFC and connectivity between subgenual anterior cingulate and ventrolateral prefrontal cortex in the depressed women, resulting in reduction of depressive symptomatology and increased cardiovagal activity.

Conclusion: RAVANS effectively modulated sex-dependent brain alterations involved in mood and cardiac autonomic dysregulation in depression. We argue this novel neuromodulatory technique has important treatment implications for comorbid depression and cardiovascular disease that differs by sex.

Brief description of how this work applies to sex difference, gender biology, or women’s health research:
Many of the brain regions involved in the regulation of mood and cardiovascular function are morphologically and functionally sexually dimorphic beginning in prenatal development, which predispose for sex differences in the susceptibility for mental disorders and increased risk for cardiovascular disease. For example, women have twice the risk of men for developing comorbidity of depression and cardiometabolic disorders leading to a 3–5-fold risk of death from heart disease in depressed women.

We propose that the evaluation of the mechanisms linking these conditions should be informed by a sex-dependent lens in order to develop more precise and efficacious therapeutics. For instance, the translation of our findings showing the effects of a novel transcutaneous vagus nerve stimulation device on the modulation of sex-dependent alterations of the stress response circuitry may enhance target engagement in the brain and associated physiology for optimization of the technology and maximization of its therapeutic effects.