ABSTRACT Depression is the leading cause of disability worldwide, and despite the fact that several treatments have been developed, only a minority of patients (<40%) respond and sustain that response for a year, regardless of which treatment they receive. Sustained response rates beyond one year are lower still. Thus, there is a vital public health need to better target the enduring quality of depressive symptoms and to improve longer-term outcomes. Negative self-evaluations, a core characteristic of depressive illness, appear to contribute to the enduring nature of depression. Negative self-evaluations are not only linked directly to the persistence of depressive symptoms, but for many, negative self-evaluations persist even after otherwise effective treatments, increasing the risk of relapse. Although much is known about the cognitive deficits and negative information processing biases in memory and attention among adults with depression, very little is known about the specific disruptions in information processing and brain function that cause depressed adults to make overly negative self-evaluations either during or following episodes of depression. We argue that we can substantially improve longer-term outcomes by identifying the underlying pathology that leads to these negative self-evaluations so that better targeted and more enduring treatments can be developed. Building on our preliminary data, and the work of others, the goal of this short-term project is to provide the first test of a novel hypothesis about the neural mechanisms that lead to dysfunctional self-evaluations in current and remitted depressed adults and to begin to examine the real-world consequences of that pathology for future symptoms and functioning. To test our hypotheses, we will evaluate behavioral and neuroimaging markers of abnormal processing during self- evaluation in 30 currently depressed, 30 remitted depressed, and 30 healthy adults. Participants will complete baseline clinical and functional magnetic resonance imaging (fMRI) assessments, as well as three weeklong daily diary protocols (over the span of four months) that will assess symptoms, self-evaluations in daily life, and real-world functioning. The project will examine processes leading to the abnormal engagement of the autobiographical memory (Aim 1) and social-cognitive (Aim 2) networks among depressed adults when evaluating self-relevant material, and it will examine whether abnormalities in brain function during self- evaluation prospectively predict psychiatric symptoms and poorer interpersonal and work functioning in daily life (Exploratory Aim). The aims of the project match well with the strategic goals of the National Institute of Mental Health, and the results of this study have the potential to lead to new, brain-based treatment strategies to target the identified mechanisms underlying negative self-evaluations to improve longer-term outcomes.