Major Depressive Disorder (MDD) is a debilitating condition that places a significant burden on individuals and society. For individuals, MDD is associated with a range of symptoms, including feelings of hopelessness and guilt and extending to anhedonia, apathy, disturbances in appetite and sleep, and problems with concentration and memory. For society, the/burden of MDD is manifested in lost productivity and in significant costs associated with treatment. The heterogeneity of symptoms associated with depression presents a challenge to both researchers trying to understand the disorder and clinicians trying to treat it. However, two separate lines of research suggest a straightforward hypothesis: multiple aspects of depressive illness may fundamentally be a consequence of dysfunction in neural systems implicated in emotion regulation. First, research examining baseline neural activity and performance on cognitive tasks demonstrates that depression is associated with dysfunction in neural regions such as the prefrontal cortex (PFC), anterior cingulate cortex (ACC), and amygdala. Second, research with healthy participants shows that these same neural regions are directly implicated in emotion regulation. This proposal describes two experiments designed to integrate these lines of research. In both experiments, participants will attempt to regulate their responses to emotionally negative stimuli using reappraisal, an adaptive emotion regulation strategy supported by cortico-cingulate-amygdalar interactions. Electroencephalogram (EEG;Exp. 1) and functional magnetic resonance imaging (fMRI;Exp. 2) data will be collected during reappraisal attempts made by patients with MDD and healthy controls. In combination, the EEG and fMRI data will be used to generate a detailed spatiotemporal model of the brain mechanisms underlying reappraisal. These data will also be used to test the hypothesis that failures of emotion regulation in MDD are associated with dysfunction in specific neural regions, including lateral PFC, dorsal ACC, and the amygdala. PUBLIC HEALTH RELEVANCE: By identifying a core process-emotion regulation-implicated in depression and tying emotion regulation failures to dysfunction in specific neural circuits, the proposed studies will help clarify the pathophysiology of depression. Ultimately, this approach might contribute to improvements in diagnosis and treatment.