Patients with recurrent major depression have abnormalities in a broad array of emotional and cognitive functions. Recently functional imaging studies have developed emotional tasks to elicit brain activation responses under standardized conditions. These studies implicate a circuit including the amygdala, the affective division of the anterior cingulate (ACad) and dorsolateral prefrontal cortex (DLPFC) in emotional regulation. The amygdala detects critical emotional information, especially threats. The ACad assesses salience of motivational cues, particularly based on amygdala input, detects conflict and regulates emotional responses. The DLPFC has a critical role in supporting a wide range of cognitive control functions. The goal of the current project is to determine which elements of the emotional circuit are dysfunctional in major depression. We propose to use functional magnetic resonance imaging (fMRI) in depressed (n = 50) and matched control (n = 50) subjects studied before and after a course of antidepressant treatment. We will use two standard cognitive paradigms in which emotion is manipulated to help elucidate the cognitive-emotional interace: a 2-back emotional working memory task and a matching task producing emotional conflict. We will determine whether depression involves a primary dysfunction in amygdala, ACad, or DLPFC. In addition, we hypothesize that depressed subjects will have normalization of abnormal brain activation with treatment. The proposed study has the potential to substantially advance our understanding of the precise nature and mechanisms underlying cognitive-emotional dysregulation in major depression. [unreadable] [unreadable]