ABSTRACT: This RFA-MH-17-405 “Adult Maturational Changes and Dysfunctions in Emotion Regulation” R01 proposal is designed to study age-related changes in structure and function of a ventral prefrontal cortex (VPFC) neural system, that subserves emotion processing and regulation, during mid to later adulthood in individuals with bipolar disorder (BD), compared to healthy control (HC). The emotional dysregulation of BD, from the extreme positive mood states of manias to negative of depressions, is associated with a great deal of suffering for those affected and their families, with early mortality owing to one of the highest rates of suicide in any disorder. Progress has been made by our and other research groups in the identification of abnormalities in the VPFC brain circuitry that subserves emotional regulation as central to the disorder and its emotional dysregulation. BD is chronic and often progresses during middle to late adulthood, with an increase in emotional dysregulation, episode frequency and severity, and symptoms that can become increasingly refractory to current treatments, increasing suicide risk. However, there has been little previous study of the brain circuitry changes that underlie this progression. Our exciting new preliminary data implicate progressive decreases with age in older adults with BD within emotional brain circuitry in the structural integrity of gray matter regions and their white matter connections, and the ability of nodes within the circuitry to work well together to regulate emotional responses. In the first such work we are aware of, we plan to build on our previous neuroimaging and behavioral research in BD to study these age-related emotional brain circuitry changes in older adults. We propose a 5-year study of age-related changes in mood, emotion regulation and related symptoms and behaviors using multimodality imaging measures [structural magnetic resonance imaging (MRI) of gray matter, diffusion tensor imaging (DTI) of white matter, and functional MRI (fMRI) measures of functional connectivity and of brain responses during implicit and explicit emotion regulation] comparing BD and HC groups (N=80/group), ages 40-79 years, 50% female;; 64 individuals/group will be reassessed and rescanned after 2 years to study brain and associated behavioral changes over time. We will explore relationships between brain aging with sex differences, and with risk factors implicated in progression including genes and stress, as well as adverse outcomes of progression such as suicide ideation and behavior. As there has been little study of effects of aging of the VPFC emotional circuitry in healthy individuals, findings could provide new insights into brain circuitry and emotional regulation in older adults. In addition to the importance of contributing to understanding BD, as BD is unique in having both elevated and depressive episodes, its study can provide a model for understanding prog...