PROJECT SUMMARY/ABSTRACT Approximately 1 in 3 reproductive aged women and girls suffer from migraine, the most disabling disease of this demographic worldwide. Affective disorders are 2-3 times more common among migraineurs, and migraineurs with psychiatric comorbidity report more functional impairment and worse quality of life than migraineurs without psychiatric conditions. Despite the high prevalence of this comorbidity and evidence of shared pathophysiology, the association between migraine and affective disorders remains largely unexplored. Fluctuations in female sex hormone levels play a significant role in migraine and affective disorder presentations and are particularly volatile across the menstrual cycle and during reproductive life transitions (puberty, postpartum, menopause); however, the longitudinal relationship between migraines and affective disorders across the life course has not been studied. Up to two-thirds of female migraineurs experience menstrual migraine and half of women with affective disorders report premenstrual exacerbation of anxiety and depression. However, migraine has not been studied as a risk factor for premenstrual syndrome/premenstrual dysphoric disorder or as a marker of increased hormonal sensitivity among women with anxiety or depression. The objective of this research is to collect and analyze detailed longitudinal data on migraine and mental health symptoms to establish migraineurs as a unique phenotype of individuals with affective disorders due to their vulnerability to hormonal fluctuations. In Aim 1, Dr. Crowe will determine the longitudinal association between migraine and affective disorders across the lifespan with an emphasis on hormonal transitions using data from the Nurses’ Health Study cohorts. In Aims 2 and 3, she will focus her work on hormonal fluctuations across the menstrual cycle. She will design and implement a sub-study in the Nurses’ Health Study 3 and Growing Up Today Study cohorts using smartphone data and ecological momentary analysis to estimate the relationship between migraine (menstrual and overall) and premenstrual syndrome/premenstrual dysphoric disorders (Aim 2). Dr. Crowe will also collect data on affective disorder symptom variability across the menstrual cycle among migraineurs, compared to non-migraineurs (Aim 3). To carry out this research, Dr. Crowe will receive training and mentorship from a team with expertise in epidemiological measurement of affective disorders, smartphone digital phenotyping, and modeling of high-dimensional longitudinal data. She will also draw on the myriad professional resources available at Brigham and Women’s Hospital, Harvard Medical School, and Harvard T.H. Chan School of Public Health. Altogether, the proposed research and training will improve affective disorder risk assessment and screening, inform treatment for those with comorbid affective disorders and migraine and prepare Dr. Crowe with the skills and preliminary data to become an...