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 over 30 years at Harvard Medical School, 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. Little is known about how sex differences in healthy brain development may or may not deviate in producing neuropsychiatric 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: Schizophrenia is a devastating, costly illness, economically and socially. In the early 1980’s, the prevailing ideology was that schizophrenia was similar in men and women. The assumption was that some women with schizophrenia were misclassified as affective disorder patients. My career began by demonstrating empirically that sex differences in schizophrenia were not an artifact of diagnosis (see bibliography #10-16), and one’s sex may provide clues to the illness etiology (#14, 16). For ~30 years, I investigated the hypothesis that men were at higher risk for a more severe form of schizophrenia than women. Trained originally as a psychiatric epidemiologist, the work focused on identifying how men and women differed in their symptomatology (#10, 13, 14), premorbid history and age at onset (#10, 13, 14, 22, 25, 43), course (#8, 11, 12, 13, 15, 20), genetic transmission (#16, 18, 19, 68), and incidence (#86).
My team, among others, demonstrated that schizophrenia’s origins are most likely in fetal/perinatal periods of brain development (#42, 43, 94). Thus, I hypothesized that explanatory mechanisms regarding sex differences involved understanding sex differences in brain development. Beginning in 1989, I received NIH grants to support additional training in clinical neuroscience (neuroanatomy and brain imaging). Our studies of sex differences in cognitive functions identified specific domains in which women had relative preservation of function, i.e. language, executive functions, verbal memory, and olfaction (#25, 30, 31, 37,65). Using sophisticated structural MRI techniques, my team showed that brain regions implicated in these domains showed sex differences in brain volumes in schizophrenia (#40, 46, 48). These brain regions were rich in gonadal hormone receptors, suggesting that the effects of gonadal hormones on the brain during fetal development contributed to understanding sex differences in schizophrenia in brain (#46, 48, 69), sex differences in the adult healthy brain (#38, 46,62,76), and sex differences in adult brain function and activity (#61,62,76). This led to a series of studies that focused on associations between hormonal dysregulation and brain activity deficits in stress response circuitry and memory circuitries across major psychiatric disorders (#64, 85). More recently, this work on memory extended to investigations of the fetal programming of sex differences in the risk for memory decline and Alzheimer’s disease risk with aging.
My research program, called the Clinical Neuroscience Laboratory of Sex Differences in the Brain, has been ongoing for over 25 years (http://cnl-sd.mgh.harvard.edu). The team’s current studies are identifying shared causes of sex differences in the comorbidity of depression, cardiovascular disease and Alzheimer’s disease, taking a lifespan approach beginning in fetal development. Our team consists of an interdisciplinary group of investigators, integrating structural and functional MRI studies, psychophysiological responses, neuroendocrine studies of steroid hormones, markers of immune function, genetics, and collaborative efforts with preclinical investigators modeling associations between steroid hormones, genes, immune function, and the brain. Included in this work, I oversee a unique prenatal cohort study in which subjects have prospective data from pregnancy through their 50’s, including brain imaging, thus drawing on my combined expertise in epidemiology, psychiatry, and clinical neuroscience. My lab has contributed to identifying fetal stress-immune biomarkers that disrupt the healthy sexual differentiation of the brain that are retained and expressed in adulthood as sex differences in deficits in stress circuitry, major depression, and comorbid physiologic and cardiac dysfunction.
In 2018, I was recruited back to MGH to launch the Women, Heart and Brain Global Initiative (WHBGI), a collaborative effort between MGH and the Harvard T. H. Chan School of Public Health, partnering with WomenAgainstAlzheimers. Our goals are to: enhance discovery of shared causes of sex differences that contribute to explaining comorbidity of depression, CVD and Alzheimer’s disease; translate findings into sex-selective therapeutics, programs and policies; educate the next generation of scientists, clinicians, and public as to the importance of sex differences in medicine; and advocate at the national and global levels. The WHBGI is a collaborative effort across departments and fields and methodologies bringing together psychiatry, OB-GYN, cardiology, neurology, and public health.
Finally, I have spent my career building research and educational infrastructure to foster collaborative efforts to understand mechanisms that explain sex differences in health and disease across disciplines and methods of study and to provide a source of knowledge and training for future young scientists and clinicians in women’s health and sex differences in medicine. In the service of this, 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". The translational focus is training the next generation to investigate and incorporate our knowledge of sex differences in medicine, and/or women's health specifically, into their academic and clinical careers in medicine.