Brain hypoactivation, autonomic nervous system dysregulation, and gonadal hormones in depression: A preliminary study

Laura M. Holsen, Jong Hwan Lee, Sarah B. Spaeth, Lauren A. Ogden, Anne Klibanski, Susan Whitfield-Gabrieli, Richard P. Sloan, Jill M. Goldstein

Research output: Contribution to journalArticlepeer-review

42 Citations (Scopus)


The comorbidity of major depressive disorder (MDD) and cardiovascular disease (CVD) is among the 10th leading cause of morbidity and mortality worldwide. Thus, understanding the co-occurrence of these disorders will have major public health significance. MDD is associated with an abnormal stress response, manifested in brain circuitry deficits, gonadal dysfunction, and autonomic nervous system (ANS) dysregulation. Contribution of the relationships between these systems to the pathophysiology of MDD is not well understood.The objective of this preliminary study was to investigate, in parallel, relationships between HPG-axis functioning, stress response circuitry activation, and parasympathetic reactivity in healthy controls and women with MDD. Using fMRI with pulse oximetry [from which we calculated the high frequency (HF) component of R-R interval variability (HF-RRV), a measure of parasympathetic modulation] and hormone data, we studied eight women with recurrent MDD in remission and six controls during a stress response paradigm. We demonstrated that hypoactivations of hypothalamus, amygdala, hippocampus, anterior cingulate cortex (ACC), orbitofrontal cortex (OFC), and subgenual ACC were associated with lower parasympathetic cardiac modulation in MDD women. Estradiol and progesterone attenuated group differences in the effect of HF-RRV on hypoactivation in the amygdala, hippocampus, ACC, and OFC in MDD women. Findings have implications for understanding the relationship between mood, arousal, heart regulation, and gonadal hormones, and may provide insights into MDD and CVD risk comorbidity.

Original languageEnglish
Pages (from-to)57-61
Number of pages5
JournalNeuroscience Letters
Issue number1
Publication statusPublished - 2012 Apr 11

Bibliographical note

Funding Information:
This work was supported by grants from the National Institute of Health to J.M.G.: ORWH-NIMH P50 MH082679 and pilot funds for fMRI scans from NIH NCRR-GCRC M01 RR02635 at Brigham and Women's Hospital's General Clinical Research Center. Additional funding for support of Dr. Lee's effort is from the World Class University program through the National Research Foundation (NRF) of Korea, funded by the Ministry of Education, Science and Technology (R31-10008) and Basic Science Research Program, NRF grant of Korea (2011-0004794). We thank Drs. Tamara Gersh, Seung-Schik Yoo, and Matthew Jerram for help in earlier phases of the study, Harlyn Aizley, M.Ed. for clinical interviewing, and Jo-Ann Donatelli, Ph.D. for her contributions to diagnostic review. We also appreciate the input of Stuart Tobet, Ph.D. and Robert Handa, Ph.D. (Co-PIs on ORWH-NIMH P50 MH082679) for their comments on earlier drafts.


  • Autonomic nervous system
  • Estrogen
  • HPG-axis
  • Mood disorders
  • Progesterone
  • Sympathovagal balance

ASJC Scopus subject areas

  • General Neuroscience


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