Harvard Catalyst Profiles

Brown University , Providence, RI	A.B.	05/1976	Psychological Anthropology
Columbia University School of Public Health, NY, NY	M.P.H	05/1979	Mental Health Evaluation
Columbia University Graduate School of Arts and Sciences, NY, NY	Ph.D.	05/1985	Epidemiology in Psychiatry
Harvard Medical School, Beth Israel & Massachusetts General Hospitals, Boston, MA	Postdoctoral	05/1994	Clinical Neuroscience
Harvard University, Cambridge, MA	Honorary M.A.	2004	In Honor of Harvard Professorship

Introduction: I have had a long-standing interest in sex differences in the brain and the roles of steroid hormones, genes, and markers of immune function in understanding sex differences in psychiatric disorders and their comorbidity with general medicine. I believe that an understanding of these pathways will provide knowledge for the development of novel sex-dependent therapeutic discovery. For >30 years at Harvard, I have been working with colleagues that span Harvard schools and departments and other collaborative institutions that integrate fields of study, methods of analysis, and levels of study from basic to clinical to tackle issues of sex differences in medicine and women's health. Relatively little is known about how sex differences in healthy brain development may or may not deviate in producing pathology and the impact on treatment. Further, clinical decisions based on research are primarily based on data from males that are often inappropriate for females, even for disorders (like depression) in which women predominate. Given the gap between the clinical and scientific importance of studying sex effects in medicine and the relative paucity of studies on these issues, the history of my work has contributed to moving this field forward.

History of Research: My laboratory, called the Clinical Neuroscience Laboratory of Sex Differences in the Brain, has been ongoing for >25 years (http://cnl-sd.mgh.harvard.edu). Our team consists of an interdisciplinary group of investigators, integrating structural and functional MRI studies, psychophysiology, steroid hormones, markers of immune function, genetics, and collaborative efforts with preclinical investigators modeling steroid hormones, genes, immune function, and the brain. The first disorder of interest was schizophrenia, a devastating illness for which men have a higher risk than women. Although in the 1980’s, the prevailing ideology was that it was similar in men and women, my team was instrumental in demonstrating that men have a significantly higher risk than women, the causes for which begin during mid-gestation, a key period of the sexual differentiation of the brain. Our studies of sex differences in cognitive functions identified specific domains in which women compared with men had relative preservation of function, i.e. language, executive functions, verbal memory, and olfaction. Using structural and functional MRI, my team identified brain abnormalities in schizophrenia in regions associated with sex differences in cognitive and affective functions. These brain regions, rich in gonadal hormone receptors, led to studies with basic neuroscience colleagues to map out prenatal stress and immune mechanisms associated with the dysregulation of the sexual differentiation of the brain during mid-gestation. We further demonstrated similar causal pathways for understanding sex differences in the risk for major depressive disorder, but for which women have a significantly higher risk than men.

Over the last 15 years, the lab has focused on sex differences in major depression and why it is highly comorbid with cardiovascular disease and risk for Alzheimer’s disease later in life. We continue to take a lifespan approach to understanding sex differences in the shared causes of these disorders of the heart and brain. Included in this work, I oversee a unique prenatal cohort study in which subjects have prospective data from pregnancy through their 60’s, including brain imaging, allowing us to investigate in a human population the fetal programming of adult onset disorders, a topic primarily studied in animals. Our work has contributed to identifying fetal stress-immune biomarkers that disrupt the sexual differentiation of the brain and that are retained and expressed in adulthood as sex differences in deficits in stress response circuitry, major depression, and comorbid physiologic and cardiac dysfunction. In 2018, I launched the Innovation Center on Sex Differences in Medicine (ICON), a collaborative effort between Massachusetts General Hospital and the Harvard T. H. Chan School of Public Health, partnering with WomenAgainstAlzheimers (http://icon.mgh.harvard.edu). ICON consists of collaborators across departments, fields and methodologies bringing together psychiatry, OB-GYN, cardiology, neurology, and public health. ICON’s primary mission is to leverage fundamental discoveries “from cells to society” about sex differences in the brain and heart into strategies to develop sex-dependent therapeutics and target them early for prevention. In addition, we are invested in educating the next generation of scientists, clinicians, and the public about sex differences in medicine and advocating for these issues at the national and global levels. In 2020, ICON was designated an NIH Specialized Center of Research Excellence (SCORE) for Sex Differences in Medicine, one of only 8 in the country.

Finally, I have spent my career educating the next generation of scientists and clinicians to study sex differences in health and disease across disciplines and methods and providing resources for their careers in women’s health and sex differences in medicine. In the service of this for >15 years, I have been the PI of a Harvard-wide junior faculty training program (ORWH-NICHD K12 HD051959-06) called Building Interdisciplinary Careers in Women's Health (BIRCWH) with ours targeted to "Hormones and Genes in Women's Health: From Bench to Bedside". With a translational focus, BIRCWH is training the next generation to investigate sex differences in medicine, and/or women's health specifically, and incorporate the knowledge into their academic and clinical careers in medicine.