Objective Major depressive disorder (MDD) is characterized by impaired reward processing, possibly due to dysfunction in the basal ganglia. However, few neuroimaging studies of depression have distinguished between anticipatory and consummatory phases of reward processing. Using functional magnetic resonance imaging (fMRI) and a task that dissociates anticipatory and consummatory phases of reward processing, the authors tested the hypothesis that MDD participants would show reduced reward-related responses in basal ganglia structures. Method A monetary incentive delay task was presented to 30 unmedicated MDD subjects and 31 healthy comparison subjects during fMRI scanning. Whole-brain analyses focused on neural responses to reward-predicting cues and rewarding outcomes (i.e., monetary gains). Secondary analyses focused on the relationship between anhedonic symptoms and basal ganglia volumes. Results Relative to comparison subjects, MDD participants showed significantly weaker responses to gains in the left nucleus accumbens and bilateral caudate. Group differences in these regions were specific to rewarding outcomes and did not generalize to neutral or negative outcomes, although relatively reduced responses to monetary penalties in MDD emerged in other caudate regions. By contrast, evidence for group differences during reward anticipation was weaker, although MDD subjects showed reduced activation to reward cues in a small sector of the left posterior putamen. Among MDD subjects, anhedonic symptoms and depression severity were associated with reduced bilateral caudate volume. Conclusions These results indicate that basal ganglia dysfunction in MDD may affect the consummatory phase of reward processing. Additionally, morphometric results suggest that anhedonia in MDD is related to caudate volume.

Background-Difficulties in defining and characterizing phenotypes has hindered progress in psychiatric genetics and clinical neuroscience. Decreased approach-related behavior and anhedonia (lack of responsiveness to pleasure) are considered cardinal features of depression, but few studies have employed laboratory-based measures to objectively characterize these constructs.

Rationale-The investigation of putative effects of early life stress (ELS) in humans on later behavior and neurobiology is a fast developing field. While epidemiological and neurobiological studies paint a somber picture of negative outcomes, relatively little attention has been devoted to integrating the breadth of findings concerning possible cognitive and emotional deficits associated with ELS. Emerging findings from longitudinal studies examining developmental trajectories of the brain in healthy samples may provide a new framework to understand mechanisms underlying ELS sequelae.Objective-The goal of this review was two-fold. The first was to summarize findings from longitudinal data on normative brain development. The second was to utilize this framework of normative brain development to interpret changes in developmental trajectories associated with deficits in cognitive and affective function following ELS.Results-Five principles of normative brain development were identified and used to discuss behavioral and neural sequelae of ELS. Early adversity was found to be associated with deficits in a range of cognitive (cognitive performance, memory, and executive functioning) and affective (reward processing, processing of social and affective stimuli, and emotion regulation) functions. Conclusion-Three general conclusions emerge:(1) higher-order, complex cognitive and affective functions associated with brain regions undergoing protracted postnatal development are particularly vulnerable to the deleterious effects of ELS; (2) the amygdala is particularly sensitive to early ELS; and (3) several deficits, particularly those in the affective domain, appear to persist years after ELS has ceased and may increase risk for later psychopathology.

Large-scale network dysfunction in major depressive disorder: metaanalysis of resting-state functional connectivity. JAMA Psychiatry.

Depression is a significant public health problem, but its etiology and pathophysiology remain poorly understood. Such incomplete understanding likely arises from the fact that depression encompasses a heterogeneous set of disorders. To overcome these limitations, renewed interest in intermediate phenotypes (endophenotypes) has resurfaced, and anhedonia has emerged as one of the most promising endophenotypes of depression. Here, a heuristic model is presented postulating that anhedonia arises from dysfunctional interactions between stress and brain reward systems. To this end, we review and integrate three bodies of independent literature investigating the role of (1) anhedonia, (2) dopamine, and (3) stress in depression. In a fourth section, we summarize animal data indicating that stress negatively affect mesocorticolimbic dopaminergic pathways critically implicated in incentive motivation and reinforcement learning. In the last section, we provide a synthesis of these four literatures, present initial evidence consistent with our model, and discuss directions for future research.

Objective-Anhedonia, the lack of reactivity to pleasurable stimuli, is a cardinal feature of depression that has received renewed interest as a potential endophenotype of this debilitating disease. The goal of the present study was to test the hypothesis that individuals with major depression are characterized by blunted reward responsiveness, particularly when anhedonic symptoms are prominent.Methods-A probabilistic reward task rooted within signal-detection theory was utilized to objectively assess hedonic capacity in 23 unmedicated subjects meeting DSM-IV criteria for major depressive disorder (MDD) and 25 matched control subjects recruited from the community. Hedonic capacity was defined as reward responsiveness -i.e., the participants' propensity to modulate behavior as a function of reward.Results-Compared to controls, MDD subjects showed significantly reduced reward responsiveness. Trial-by-trial probability analyses revealed that MDD subjects, while responsive to delivery of single rewards, were impaired at integrating reinforcement history over time and expressing a response bias toward a more frequently rewarded cue in the absence of immediate reward. This selective impairment correlated with self-reported anhedonic symptoms, even after considering anxiety symptoms and general distress.Conclusions-These findings indicate that MDD is characterized by an impaired tendency to modulate behavior as a function of prior reinforcements, and provides initial clues about which aspects of hedonic processing might be dysfunctional in depression.

Depression is a disorder of the representation and regulation of mood and emotion. The circuitry underlying the representation and regulation of normal emotion and mood is reviewed, including studies at the animal level, human lesion studies, and human brain imaging studies. This corpus of data is used to construct a model of the ways in which affect can become disordered in depression. Research on the prefrontal cortex, anterior cingulate, hippocampus, and amygdala is reviewed and abnormalities in the structure and function of these different regions in depression is considered. The review concludes with proposals for the specific types of processing abnormalities that result from dysfunctions in different parts of this circuitry and offers suggestions for the major themes upon which future research in this area should be focused.

Increased rostral anterior cingulate cortex (rACC) activity has emerged as a promising predictor of treatment response in depression, but neither the reliability of this relationship nor the mechanisms supporting it have been thoroughly investigated. This review takes a three-pronged approach to these issues. First, I present a meta-analysis demonstrating that the relationship between resting rACC activity and treatment response is robust. Second, I propose that the rACC plays a key role in treatment outcome because of its 'hub' position in the default network. Specifically, I hypothesize that elevated resting rACC activity confers better treatment outcomes by fostering adaptive self-referential processing and by helping to recalibrate relationships between the default network and a 'task-positive network' that comprises dorsolateral prefrontal and dorsal cingulate regions implicated in cognitive control. Third, I support this hypothesis by reviewing neuropsychological, electrophysiological, and neuroimaging data on frontocingulate dysfunction in depression. The review ends with a discussion of the limitations of current work and future directions.