Our research takes place at the University of North Carolina at Chapel Hill Hospitals and is supported by the National Institute of Mental Health, the Foundation of Hope, the North Carolina Translational and Clinical Sciences Institute, and the Brain and Behavior Research Foundation.


Neuroendocrine Mechanisms of Reproductive Hormone Related Affective Dysfunction

PIs: David Rubinow, MD and Crystal Schiller, PhD

Affective disorders, such as postpartum depression (PPD) and other reproductive-related mood disorders, are common and constitute a significant burden for women, children, and society. However, little is known about the neurobiological mechanisms underlying depressive disorders in women. The long-term goal of this research is to 1) advance our understanding of the biological mechanisms underlying both the triggering of and susceptibility to depressive disorders in women; and 2) permit the prediction of those at risk for PPD. The objective of the current project is to examine whether those with a past episode of PPD (at "high risk" for recurrence) show differences in emotional arousal and reward processing domains relative to healthy control women (without a history of PPD) under baseline and hormone withdrawal-precipitated conditions. Our central hypothesis is that reproductive hormone changes are associated with dysregulation of the neural circuits underlying emotional arousal and reward processing and consequent depressive symptoms in high-risk women. The rationale for the proposed study is that employing a scaled down model of puerperal hormonal events in high-risk women permits the identification of a group of individuals homogeneous for reproductive related affective dysfunction and, hence, the best opportunity for disentangling the specific changes in brain function due to reproductive hormones from those accompanying reproductive hormone-precipitated affective dysfunction. Moreover, identifying a neurophysiologic biomarker for hormone-related affective dysfunction provides a clear pathway for examining mechanisms of susceptibility to affective dysfunction across disorders. We plan to accomplish the objectives of this application by pursuing the following specific aims: 1) to assess the effects of simulated postpartum reproductive hormone withdrawal, compared to baseline, on corticolimbic circuit activation in high-risk and control women; and 2) to examine the effects of reproductive hormone withdrawal, compared to baseline, on reward circuit activation in high-risk and control women. An additional exploratory aim is to identify a neural biomarker, characterized by corticolimbic and reward circuit dysfunction, that can be used to predict the onset of PPD. The proposed study involves experimentally manipulating reproductive hormones in euthymic women to create a scaled down version of the changes that occur at the puerperium. This endocrine manipulation paradigm will be used to examine the neurocircuitry underlying the regulation of affect and reward processing under baseline and hormone withdrawal-precipitated conditions among women who are expected to experience hormone-related affective dysregulation (n=15) and controls (n=15). The expected outcome is the identification of neural circuits underlying both the susceptibility to and mediation of hormone-related affective dysfunction. Understanding these neurobiological mechanisms will subsequently improve our ability to identify those at risk for PPD, which may strengthen prevention efforts and ultimately prevent the deleterious effects of maternal depression on offspring.

Understanding the neural and biological mechanisms by which reproductive hormones influence mood is critically important for public health given that postpartum depression is the leading cause of morbidity and mortality associated with childbirth and has negative effects on infants. Using a hormone-withdrawal challenge to precipitate mood symptoms will improve our ability to identify the biological mechanisms underlying both the triggering of and susceptibility to depressive disorders in women; and will permit the prediction of those at risk for PPD and other reproductive-related mood disorders.

Effects of Estradiol on the Neural Reward System and Depression in the Perimenopause

PI: Crystal Schiller, PhD

Despite decades of research, affective disorders are prevalent and associated with significant morbidity and mortality. Unraveling the pathophysiology of affective disorders has been uniquely challenging because depressive syndromes are heterogeneous and have diverse etiologies. We propose to address this problem by studying perimenopausal major depressive disorder (MDD), a more homogeneous depression subtype with an established trigger (i.e., estradiol withdrawal). Focusing on perimenopausal MDD will therefore increase the likelihood of identifying meaningful neurobiological markers. One of the most powerful tools for understanding the neurobiological mediators of MDD is brain imaging. Prior research suggests that the frontostriatal reward system is regulated by estradiol and implicated in MDD. However, the neural pathophysiology of perimenopausal MDD has never been studied. We will use functional magnetic resonance imaging (fMRI) at baseline and following estradiol treatment to 1) measure the frontostriatal response to reward in perimenopausal MDD and test the effects of estradiol on neural activation in perimenopausal women; 2) quantify behavioral responses to reward at baseline and following estradiol administration in perimenopausal women with and without MDD; and 3) measure the psychological correlates of the frontostriatal response to reward in women with perimenopausal MDD at baseline and following estradiol administration. This study design will allow us to explore the neural pathophysiology of perimenopausal MDD, the effects of estradiol on the neural reward system, and the degree to which neural reward system dysfunction predicts the antidepressant effects of estradiol. This research will support my primary career goal to become an independently funded clinical scientist with the expertise necessary to conduct state-of-the-art mechanistic research on the neuroendocrinology of reproductive mood disorders. My long-term research objectives are to 1) advance our understanding of the effects of ovarian hormones on the brain and how these effects contribute to the triggering of and susceptibility to reproductive-related mood disorders; and 2) to identify neural and endocrine markers of depression risk, thereby improving our ability to prevent affective illness in women. The training and research plan outlined in this proposal are designed to supplement my previous experience with a novel, clinically relevant program of research at the intersection of behavioral endocrinology and neuroscience. The specific objectives to meet my career goal are to 1) obtain focused training in neuroscience and fMRI data acquisition and analysis; 2) develop expertise in neuroendocrinology and hormone administration; 3) gain experience with conducting clinical research in perimenopausal women; and 4) obtain expertise and pilot data to support an interdisciplinary research program principally funded by NIH R01 grants. This career development application represents the critical next step in my academic and research training. Although the ultimate measure of successful training will be the attainment of independent funding by the end of the award period, benchmarks that will be used to determine progress toward my training and research goals include participant enrollment, creation of a data analysis pipeline, manuscript preparation, conference presentations, and grant writing. The proposed training and research activities will prepare me to lead an independently funded research program focused on the neuroendocrine pathophysiology of reproductive mood disorders. In addition to supporting my career development objectives, the proposed research represents the first step in characterizing neural mechanisms of reproductive hormone-related affective dysfunction during the perimenopausal period. The impact of this research is expected to be an improved understanding of the neuroendocrine pathophysiology of perimenopausal MDD. Future directions for this work will include identifying neural biomarkers that predict reproductiv mood disorder susceptibility and response to hormonal interventions, and exploring neuroendocrine etiological pathways that may help to explain the preponderance of depression in women.

This study is currently recruiting participants.  This research study is seeking women with current depression and those who have never experienced depression to participate in the study. The study involves wearing a low-dose estrogen patch for 3 weeks, having 2 fMRI brain scans, and coming to UNC for a total of 6 appointments.  For this research study, participants will receive a total of $500, and participants are responsible for their own transportation costs.

To see if you would be a good fit, please visit PEERSstudy.org or call 919-966-5243.