Connors-BRI Symposium

Incorporating Sex as Biologic Variable to Advance Health

May 24, 2021 | 3-5PM

Virtual Event

Ronald Garcia, MD, PhD

Massachusetts General Hospital


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.


3PM – Welcome Remarks
3:05PM – Keynote Address
3:45PM – Featured Short Talks
4:20PM – Lightning Talks
4:50PM – Closing Remarks

Keynote Speaker

Janine Austin Clayton, MD

Janine Austin Clayton, M.D., Associate Director for Research on Women’s Health and Director of the Office of Research on Women’s Health (ORWH) at the National Institutes of Health (NIH), is the architect of the NIH policy requiring scientists to consider sex as a biological variable across the research spectrum. This policy is part of NIH’s initiative to enhance reproducibility through rigor and transparency. As co-chair of the NIH Working Group on Women in Biomedical Careers with NIH Director Dr. Francis Collins, Dr. Clayton also leads NIH’s efforts to advance women in science careers.

Prior to joining the ORWH, Dr. Clayton was the Deputy Clinical Director of the National Eye Institute (NEI) for seven years. A board-certified ophthalmologist, Dr. Clayton’s research interests include autoimmune ocular diseases and the role of sex and gender in health and disease. She is the author of more than 120 scientific publications, journal articles, and book chapters.
Dr. Clayton, a native Washingtonian, received her undergraduate degree with honors from Johns Hopkins University and her medical degree from Howard University College of Medicine. She completed a residency in ophthalmology at the Medical College of Virginia. Dr. Clayton completed fellowship training in cornea and external disease at the Wilmer Eye Institute at Johns Hopkins Hospital and in uveitis and ocular immunology at NEI.

Dr. Clayton has received numerous awards, including the Senior Achievement Award from the Board of Trustees of the American Academy of Ophthalmology in 2008 and the European Uveitis Patient Interest Association Clinical Uveitis Research Award in 2010. She was selected as a 2010 Silver Fellow by the Association for Research in Vision and Ophthalmology. In 2015, she was awarded the American Medical Women’s Association Lila A. Wallis Women’s Health Award and the Wenger Award for Excellence in Public Service. Dr. Clayton was granted the Bernadine Healy Award for Visionary Leadership in Women’s Health in 2016. She was also selected as an honoree for the Woman’s Day Red Dress Awards and the American Medical Association’s Dr. Nathan Davis Awards for Outstanding Government Service in 2017.