Introduction: I have had a long-standing interest in sex differences in brain development and their implications for adult brain structure and function, the roles of adrenal and gonadal hormones and genes in understanding these sex differences, and how these factors relate to understanding sex differences in psychiatric disorders. I believe that an understanding of these hormonal and genetic pathways will provide knowledge for the development of novel sex-specific therapeutic discovery for these disorders. In my roles as Director of Research for the Connors Center for Women’s Health and Gender Biology at BWH, P.I. of a Harvard-wide ORWH-NICHD K-award training grant entitled, “Hormones and Genes in Women’s Health: From Bench to Bedside”, in addition to a number of cross-institutional, interdisciplinary grants, I have been working with a team of colleagues that span Harvard schools and departments and outside collaborative institutions that integrate fields of study, methods of analysis, and levels of study from basic to clinical. 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 and current team efforts have been to contribute to move 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. I began my career by demonstrating empirically that sex differences in schizophrenia were not an artifact of diagnosis and one’s sex may provide clues to the illness etiology. For >25 years, I have been investigating the hypothesis that men may be at higher risk for a more severe form of schizophrenia than women. Trained originally as a psychiatric epidemiologist, my work focused on identifying how men and women differed in their symptomatology, premorbid history and age at onset, course, genetic transmission, and incidence.
My team, among others, demonstrated that schizophrenia’s origins are most likely in fetal/perinatal periods of brain development. Thus, I hypothesized that explanatory mechanisms regarding sex differences involved understanding sex differences in brain development. Beginning in 1989, I received NIMH and NARSAD awards to support supplemental training in clinical neuroscience (neuroanatomy and brain imaging) to provide me with the ability to investigate this. My studies of sex differences in cognitive functions resulted in several publications identifying specific domains in which women had relative preservation of function, i.e. language, executive functions, verbal memory, and olfaction. Using sophisticated structural MRI techniques, my team showed that cortical brain regions implicated in the processing of these domains showed sex differences in brain volume in schizophrenia. Further, based on animal studies, the brain regions implicated were rich in gonadal hormone receptors compared with other brain regions. This work suggested that the effects of gonadal hormones on the brain during fetal and/or perinatal development would contribute to understanding sex differences in schizophrenia and normal sex differences in the adult brain, with implications for sex differences in brain function and activity in adulthood. Current studies are focusing on the associations between hormonal dysregulation and brain activity deficits in the stress response circuitry and in memory and working memory in major psychiatric disorders. My research program, called the Clinical Neuroscience Laboratory of Sex Differences in the Brain, has been ongoing for over 20 years (cnl-sd.bwh.harvard.edu; mddscor.bwh.harvard.edu).
Current Studies: My team’s current studies are identifying the role of pre-and perinatal risk factors in understanding differential brain abnormalities in men and women with major psychiatric disorders, such as schizophrenia and affective disorders, the role of gonadal and adrenal hormones and genes in the etiology and functional course of these abnormalities, and better identifying normal sex differences in brain structure and function in order to understand how the brain goes awry differentially in men and women with adult onset psychiatric disorders but whose origins begin during fetal development. I am also investigating the shared fetal antecedents to sex differences in the co-morbidity of psychiatric disorders with general medical disorders, such depression and cardiovascular disease and endocrine dysfunction. My research team consists of an interdisciplinary team of investigators, integrating structural and functional MRI studies, psychophysiological responses, neuroendocrine studies of adrenal and gonadal hormones, inflammatory factors, geneticists, and collaborative efforts with animal investigators of steroid hormones, genes, inflammatory factors, and the brain. Included in this work, I oversee a unique birth cohort study in which subjects have prospective data from pregnancy through their late 40’s, including brain imaging, thus drawing on my combined expertise in epidemiology and clinical neuroscience. This work is contributing to understanding the nature of major psychiatric disorders, the impact of sex, and normal properties of the male and female brain in the face of disease.
Finally, as Director of Research at the Connors-BRI Center, I have been building a research infrastructure at BWH 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 gender biology.