The chief goal of this study is to identify the components of the spectrum of mood disorders using the methods of genetic epidemiology, developmental psychopathology and clinical psychiatry/psychology. One of the chief issues addressed in our work is identifying the core clinical and biologic factors underlying mood disorder spectrum and migraine that run in families. The phases of implementation of this research include: (1) development of measures of the spectrum of mood and anxiety disorders in adults and children, and structured interviews for the key components of the study phenotypes including mood, sleep and headache;(2) sampling and recruitment of probands from both clinical and community settings and enrollment and evaluation of the relatives;(3) selection and implementation of core features and endophenotypes for mood disorders and migraine;and (4) establishment of a high risk cohort to study the evolution of these disorders and the specificity of vulnerability markers and endophenotypes prior to clinical onset of these conditions. Phase I: Development of Measures We have now completed the first phase of our study in both adults and children. Phase II: Recruitment We recruit participants into our study from both clinical settings (Suburban Hospital, the NIH Clinical Center, and Childrens National Medical Center) and the greater Washington, D.C. community. The community recruitment helps create an unbiased sample of probands and controls for our family study to further enhance the generalizability of our study findings to the population. To date, we have enrolled 329 participants into the study from the community, and 209 from clinical sources. Our total enrollment from all sources combined is 682 probands and 788 relatives, including 77 children. Over the past year 56 probands and 195 relatives have been recruited. Probands represent a range of disorders including: 22% with bipolar disorder, 34% with depression, 51% with anxiety, 44% with migraine, and 34.2% are controls. Phase III: Clinical Components and Endophenotypes In order to identify the core features of mood and anxiety disorders and their overlap with cardiovascular diseases and migraine, we have established a set of clinical, psychophysiological and neuropsychological measures. Most of these studies are conducted at the NIH Clinical Center. Current measures include: biologic rhythms, prospective measures of diet, activity, life stress, and health, and 1.5 t Magnetic Resonance Imaging (MRI). Potential trait markers include: psychophysiological measures, sensory thresholds and the physiological stress response through evaluation of endocrine system and cardiovascular system. First, we collect data on biologic rhythms including sleep, eating, and physical activity (as measured by actigraphy). Electronic diaries (experiential sampling) are used to query symptoms of headache, mood and anxiety multiple times daily as well as current life activities. The use of electronic diaries in combination with actigraphy is unique and novel in that it is a method of validating anecdotal associations that have previously been based on retrospective reports that are prone to individual interpretation and bias. The data we have collected to date provides some exciting findings regarding the extent to which physical activity can actually reduce depressed mood. More than 200 probands have had 1.5t MRIs and in collaboration with Drs. Karen Berman, Wayne Drevets, and Nicholas Patronas we have completed independent ratings of white matter hyperintensities (WMHs), and other brain structures that have been shown to be associated with migraine and depression. Preliminary results suggest that there are a greater number of WMHs in people with a history of depression. In this study we are also measuring the endocrine, autonomic, cardiovascular, and immune systems and their role in the physiological stress response. Because deficits in processing sensory information have repeatedly been associated with migraine, we have also included several psychophysiological measures including the nociceptive eye-blink reflex, startle reflex conditioning and prepulse inhibition in this study. The auditory startle reflex is a sensitive probe to emotional states and is especially interesting, because it can be elicited in many species. We have established a new fear potentiated startle paradigm can be used in adults and we have shown that it is well tolerated by children and adolescents. These measures are crucial mechanisms for the understanding of anxiety disorders and their development. In collaboration with Raquel Gur, M.D., Ph.D., and Ruben Gur, Ph.D. at the University of Pennsylvania, we have developed and administered a computerized battery of neuropsychological measures assessing attention, memory, perception, decision making, and general cognitive function in our participants. Deficits and abnormalities in these domains have been long associated with migraine, mood, and anxiety disorders. Ascertaining such an extensive neuropsychological profile in a family study setting gives us added power that is unique to our study and allows us to better understand the disorders in question. The preliminary findings of these studies have been presented at several local and international conferences, as well as the NIH research festival. During the next year, we will have sufficient numbers to conduct preliminary analyses of familial aggregation of the spectrum of disorders as well as to evaluate whether these measures discriminate between diagnostic subgroups. We can then examine the specificity of these measures in the relatives and offspring. Overall, the combination of these clinical, neuropsychological and psychophysiological measures within families will allow us an in-depth analysis of the biological mechanisms crucial for migraine and mood and anxiety disorders and the common diathesis underlying these domains. This will not only lead to a better understanding of these conditions, and assist in identifying common genetic mechanisms, but may also lead to the development of novel treatment options and possible strategies for prevention and early intervention in those with elevated risk for these conditions. Phase IV: High Risk Study of Offspring Major progress has been achieved during the past year in developing the high risk component of our research. We completed adaptation of the adult clinical and biologic measures for children, and recruited and enrolled 77 youth and their parents in the study. The two sources of recruitment include offspring under age 18 of parents already enrolled in our family study, as well as a new collaboration with the Department of Neurology at the National Childrens Medical Center where we recruit children seeking treatment for headache, and a comparable sample of children from pediatric practices. We are conducting parallel studies of children in the same domains that are being assessed in the adult probands including clinical, psychiatric, physical, neurocognitive, perception, and genetic evaluations. The purpose of the high risk study is to target and recruit offspring of parents with mood spectrum disorders in order to better identify and characterize early signs and symptoms of clinical conditions. Enhancing current understanding of the initial biological and psychological signs of clinical disorder will enable more timely and effective identification and treatment of children at risk.