Neuroimaging and Depression Current Status and Unresolved Issues Ian H. Gotlib and J. Paul Hamilton Stanford University ABSTRACT—Major depression is among the most debilitat- ing, prevalent, and recurrent of all psychiatric disorders. Over the past decade, investigators have examined the neural mechanisms associated with this disorder. In this article we present an overview of neuroimaging research that has assessed the structure and functioning of the amygdala, subgenual anterior cingulate cortex, and dorso- lateral prefrontal cortex in major depression. We then describe results of studies that have attempted to elucidate the nature of the relations among these brain structures. The picture that emerges from these investigations is one in which heightened activity in limbic structures that un- derlie the experience and expression of emotion dampens activation in dorsal cortical structures that are involved in affect regulation, reducing their ability to influence limbic activation. We conclude by highlighting unresolved issues concerning the roles of these structures in depression and their relation to specific symptoms of this disorder. KEYWORDS—depression; neuroimaging; fMRI; amygdala; ACC; DLPFC Major Depressive Disorder (MDD) is among the most prevalent of all psychiatric disorders. MDD is characterized by sad mood and/or a loss of interest or pleasure in almost all daily activities, as well as by several associated symptoms such as weight loss or gain, sleep disturbance, psychomotor agitation or retardation, fatigue, and concentration difficulties. Depression is both widespread, with up to 20% of the general population experi- encing at least one episode of depression during their lifetime, and recurrent, with a relapse rate of over 80%. This high prev- alence and recurrence of depression, combined with its sig- nificant personal and societal costs, makes it imperative that we identify and elucidate factors that are involved in the onset and maintenance of MDD and in recovery from this disorder. Over the past 15 years, investigators have used neuroimaging techniques to examine the neural substrates of depression. In this review, we briefly summarize findings from this work, em- phasizing key regions of the brain that have been implicated in MDD. We then discuss these findings in the context of an integrative formulation of the neural substrates of depression. We conclude by highlighting important unresolved issues in this field and by suggesting directions for future research that will help to add specificity and breadth to neural models of depres- sion. DEPRESSION AND THE BRAIN Even before the advent of structural and functional neuro- imaging research on MDD, there were strong indications that neural abnormalities play a crucial role in depression. Foremost among these is the fact that depressive disorders are responsive to a diverse set of brain-based interventions. In addition to showing positive outcome following drug treatment, for example, a significant subset of depressed individuals also respond favorably to electroconvulsive therapy, in which seizure-in- ducing current is applied to the temples, as well as to surgeries that sever neural fiber tracts or destroy brain regions that are postulated to be involved in the maintenance of depression. The specific symptoms that make up the syndrome of MDD also implicate the functioning of particular brain structures. Depression is primarily a disorder of emotion and its regulation; indeed, hallmark symptoms of depression are pervasive sad mood and an inability to inhibit the processing of negative in- formation, exacerbating the experience of negative affect. Over the past decade, neuroscientists examining the ‘‘emotion cir- cuitry’’ of the brain have documented the involvement of the limbic system, a complex of structures including the amygdala, hippocampus, insula, and parts of the anterior cingulate cortex (ACC), in the experience and expression of emotional states (see Davidson et al., 2002, for a review). Among these structures, the amygdala and the ventral (i.e., bottom) aspect of the ACC, most often referred to as the subgenual ACC, have received the most attention from investigators interested in depression. Whereas the amygdala has been shown to play a prominent role in Address correspondence to Ian H. Gotlib, Department of Psychology, Bldg. 420, Jordan Hall, Stanford University, Stanford, CA 94305; e-mail: ian.gotlib@stanford.edu. CURRENT DIRECTIONS IN PSYCHOLOGICAL SCIENCE Volume 17—Number 2 159 Copyright r 2008 Association for Psychological Science