Bipolar disorder (BD) is present in about 1% of the population. Suffering is great for individuals with BD, their families and communities, as episodes can lead to relationship loss, economic hardship, and a high suicide risk. The peak onset in adolescence suggests that understanding the development of brain abnormalities during this period may be pivotal to understanding the biology of BD; yet, studies of BD in adolescents are rare. Furthermore, diagnosis and treatment of BD in adolescents are extrapolated from adults; yet, it is not known whether brain abnormalities differ between adolescents and adults with BD. Thus, study of brain development in adolescents with BD is important because it could provide information key to elucidating its pathophysiology, and improvements in early detection and treatment and therefore prognosis. The amygdala and orbitofrontal cortex are brain structures that work together to process emotions and that are implicated by preclinical, brain lesion, imaging and postmortem studies in adult BD. Our cross-sectional pilot work suggests that amygdala deficits are present by early adolescence and are sustained into adulthood in BD, but that orbitofrontal deficits progress over adolescence paralleling the normal regional sequence of brain development. The proposed study employs structural and functional magnetic resonance imaging to measure longitudinal changes (over 2 years) in amygdala and orbitofrontal cortex in 40 adolescents with BD, compared to 40 healthy controls. We will also extend our pilot investigation which provides evidence for modifying influences of allelic variation in the genes encoding catechoI-O-methyl transferase and a serotonin transporter promotor protein on the amygdala in BD. To the best of our knowledge this is the first work of its kind. Innovations include: testing a novel neurodevelopmental hypothesis supported by significant cross sectional work, with the first prospective longitudinal study of adolescent BD; and integrated neuroimaging and genetic study of modifying influences of allelic variation in genes implicated in BD on brain abnormalities.