Crystal E. Schiller, Ph.D. - US grants

DESCRIPTION (provided by applicant): 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.

? DESCRIPTION (provided by applicant): 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.

Irritability, defined as a predisposition to exhibit anger, is a prominent, defining symptom of perinatal depression (PND) and many other neuropsychiatric disorders. Despite the near ubiquity of irritability across disorders, the neural dysfunction underlying the vulnerability to, onset of, and exacerbation of irritability is understudied and poorly understood. The proposed study involves experimentally manipulating reproductive hormones in nonpregnant, euthymic women to create a scaled down version of the changes that occur during pregnancy and the postpartum period. This endocrine manipulation paradigm, which we have shown provokes irritability in past studies, will be used to examine the neurocircuitry underlying irritability under baseline and hormone challenge conditions among women who are hormone sensitive (HS+; n=15) and non-hormone sensitive (HS-; n=15). The long-term goal of this research is to advance our understanding of the neural systems underlying both the triggering of and susceptibility to irritability in women. The objective of the current project is to examine whether HS+ show differences in the behavioral activation system relative to HS- under baseline and hormone challenge conditions using functional magnetic resonance imaging (fMRI) and behavioral tests. Our central hypothesis is that reproductive hormone changes are associated with dysregulated threat and reward processing and consequent irritability in HS+. The rationale for the proposed study is that employing a scaled down model of puerperal hormonal events permits the identification of a group of individuals homogeneous for hormone sensitivity (HS+), hence creating the best opportunity for disentangling the specific changes in brain function due to reproductive hormones (i.e., HS-) from those accompanying reproductive hormone-precipitated affective dysfunction (i.e., HS+). Because women will act as their own controls across time, this study design also allows for a powerful evaluation of state and trait variables that may contribute to irritability, including both threat and reward processing. Identifying both state and trait markers of irritability, and disentangling them from the effects of reproductive hormones on brain and behavior, will allow for the identification of neural substrates of irritability susceptibility that can be investigated across neuropsychiatric disorders. We plan to accomplish the objectives of this application by pursuing the following specific aims: to determine the extent to which irritability is characterized by 1) dysfunctional threat processing and 2) dysfunctional reward processing during reproductive hormone challenge relative to baseline in HS+ and HS-. We expect that, relative to baseline, HS+ women will show greater behavioral approach during threat and frustration as well as dysregulation in brain regions responsible for threat and reward processing during hormone challenge, relative to baseline, compared with HS-. The expected outcome of this research is the identification of neural circuits underlying both the susceptibility to and mediation of irritability.