Since the beginning of this project we have screened over 3000 subjects for this study. We have enrolled approximately 215 youth with bipolar disorder (BD), 320 subjects at risk for BD because they have a parent or sibling with the illness, and 120 adults with BD. This year, approximately 15 new subjects were enrolled. This year we continued our work designed to identify the brain mechanisms underlying BD in children; compare brain function in youth and adults with BD in order to begin to understand how the illness develops over time; and compare brain function in youth at familial risk for BD to those with BD and those at low risk, in order to facilitate the eventual development of preventive interventions. Regarding our work on the brain mechanisms mediating BD, much of that work consists of, not only comparing youth with BD to healthy youth, but also comparing youth with BD to those with severe, chronic irritability (the so-called Disruptive Mood Dysregulation, or DMDD, population, see Annual Intramural Research Report ZIAMH002786). It is important to compare youth with BD and those with DMDD because, particularly before the inclusion of DMDD in the DSM-5, irritable children frequently received the diagnosis of BD in the community, despite not having a history of manic episodes. This potential misdiagnosis is important because, compared to severe, chronic irritability, BD in youth is treated with medications with high side-effect burden. While it is possible that the addition of DMDD to DSM-5 has decreased the extent to which irritable children are misdiagnosed as having BD, nonetheless it is important to differentiate the brain mechanisms underlying each of these clinical presentations, because differences between the diagnoses may be relevant to treatment approaches. Across our bipolar disorder-related groups (adults with BD, youth with BD, youth at risk for BD), face emotion processing has been a major focus of our work. This is because deficits labeling face emotions accurately, as well as deficits in face emotion memory, are present, not only in patients with BD, but also in youth at risk for the disorder. These findings indicate that such deficits in face emotion labeling and memory are potential endophenotypes for BD. Last year we published a paper demonstrating that, when youth with BD and DMDD labeled emotional faces, the neural mechanisms associated with irritability differed across diagnoses. This year, we conducted a study whose results are currently being analyzed. This study was designed to replicate the prior work, while also studying eye tracking patterns across the groups. Specifically, subjects complete the face emotion labeling paradigm in the scanner one day, and the next day complete it while doing eye tracking. In previously published work, we found that youth with BD, and those at risk for the illness, had a decreased tendency to focus on the eye region while labeling emotional faces. Results for the DMDD group were equivocal. Our goal is to replicate both our previous imaging and eye tracking findings; to examine potential associations between eye tracking patterns and neural activity; and to determine whether youth with DMDD have an eye tracking deficit. Our research on pediatric bipolar disorder has been productive. Our accomplishments include demonstrating that severe, chronic irritability is not a pediatric presentation of BD, but that youth with BD, like adults with the illness, experience definable episodes of mania. We identified face emotion labeling and increased variability in reaction time as potential heritable biomarkers of BD, and explored the brain mechanisms mediating each. However, we have decided to terminate this project and devote all of our resources to the study of chronic irritability in youth (see Annual Report ZIAMH002786). The reasons for this are multiple, including the fact that irritability is significantly more common in youth than is BD; there is a marked paucity of research on irritability; and there are very few evidence-based treatments for irritability.