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 Childhood adversity increases the risk of psychopathology, but the neurobiological mechanisms underlying this vulnerability are not well-understood. In animal models, early adversity is associated with dysfunction in basal ganglia regions involved in reward processing, but this relationship has not been established in humans. Methods Functional magnetic resonance imaging was used to examine basal ganglia responses to (a) cues signaling possible monetary rewards and losses, and (b) delivery of monetary gains and penalties, in 13 young adults who experienced maltreatment before age 14 and 31 non-maltreated controls. Results Relative to controls, individuals exposed to childhood adversity reported elevated symptoms of anhedonia and depression, rated reward cues less positively, and displayed a weaker response to reward cues in the left globus pallidus. There were no group differences in right hemisphere basal ganglia response to reward cues, or in basal ganglia response to loss cues, no-incentive cues, gains, or penalties. Conclusions Results indicate that childhood adversity in humans is associated with blunted subjective responses to reward-predicting cues as well as dysfunction in left basal ganglia regions implicated in reward-related learning and motivation. This dysfunction may serve as a diathesis that contributes to the multiple negative outcomes and psychopathologies associated with childhood adversity. The findings suggest that interventions that target motivation and goal-directed action may be useful for reducing the negative consequences of childhood adversity.

Major depressive disorder (MDD) is characterized by abnormal resting-state functional connectivity (RSFC), especially in medial prefrontal cortical (MPFC) regions of the default network. However, prior research in MDD has not examined dynamic changes in functional connectivity as networks form, interact, and dissolve over time. We compared unmedicated individuals with MDD (n=100) to control participants (n=109) on dynamic RSFC (operationalized as SD in RSFC over a series of sliding windows) of an MPFC seed region during a resting-state functional magnetic resonance imaging scan. Among participants with MDD, we also investigated the relationship between symptom severity and RSFC. Secondary analyses probed the association between dynamic RSFC and rumination. Results showed that individuals with MDD were characterized by decreased dynamic (less variable) RSFC between MPFC and regions of parahippocampal gyrus within the default network, a pattern related to sustained positive connectivity between these regions across sliding windows. In contrast, the MDD group exhibited increased dynamic (more variable) RSFC between MPFC and regions of insula, and higher severity of depression was related to increased dynamic RSFC between MPFC and dorsolateral prefrontal cortex. These patterns of highly variable RSFC were related to greater frequency of strong positive and negative correlations in activity across sliding windows. Secondary analyses indicated that increased dynamic RSFC between MPFC and insula was related to higher levels of recent rumination. These findings provide initial evidence that depression, and ruminative thinking in depression, are related to abnormal patterns of fluctuating communication among brain systems involved in regulating attention and self-referential thinking.

Anhedonia, the reduced propensity to experience pleasure, is a promising endophenotype and vulnerability factor for several psychiatric disorders, including depression and schizophrenia. In the present study, we used resting electroencephalograms, functional magnetic resonance imaging, and volumetric analyses to probe putative associations between anhedonia and individual differences in key nodes of the brain's reward system in a non-clinical sample. We found that anhedonia, but not other symptoms of depression or anxiety, was correlated with reduced nucleus accumbens (NAcc) responses to rewards (gains in a monetary incentive delay task), reduced NAcc volume, and increased resting delta current density (i.e., decreased resting activity) in the rostral anterior cingulate cortex (rACC), an area previously implicated in positive subjective experience. In addition, NAcc reward responses were inversely associated with rACC resting delta activity, supporting the hypothesis that delta might be lawfully related to activity within the brain's reward circuit. Taken together, these results help elucidate the neural basis of anhedonia and strengthen the argument for anhedonia as an endophenotype for depression.

Background Longitudinal studies of illness progression in Major Depressive Disorder (MDD) indicate that the onset of subsequent depressive episodes becomes increasingly decoupled from external stressors. A possible mechanism underlying this phenomenon is that multiple episodes induce long-lasting neurobiological changes that confer increased risk for recurrence. Prior morphometric studies have frequently reported volumetric reductions in MDD—especially in medial prefrontal cortex (mPFC) and the hippocampus— but few studies have investigated whether these changes are exacerbated by prior episodes. Methods We used structural magnetic resonance imaging (sMRI) to examine relationships between number of prior episodes, current stress, and brain volume and cortical thickness in a sample of 103 medication-free depressed patients and never-depressed controls. Volumetric analyses of the hippocampus were performed using a recently-validated subfield segmentation approach, while cortical thickness estimates were obtained using Vertex-Based Cortical Thickness (VBCT). Participants were grouped on the basis of the number of prior depressive episodes as well as current depressive state. Results Number of prior episodes was associated with both lower reported stress levels as well as reduced volume in the dentate gyrus. Cortical thinning of the left medial prefrontal cortex (mPFC) was associated with a greater number of prior depressive episodes, but not current depressive state. Conclusions Collectively, these findings are consistent with preclinical models suggesting that the dentate gyrus and mPFC are especially vulnerable to stress exposure, and provide evidence for morphometric changes that are consistent with stress-sensitization models of recurrence in MDD.

The authors manipulated emotion regulation strategies at encoding and administered explicit and implicit memory tests. In Experiment 1, participants used reappraisal to enhance and decrease the personal relevance of unpleasant and neutral pictures. In Experiment 2, decrease cues were replaced with suppress cues that directed participants to inhibit emotion-expressive behavior. Across experiments, using reappraisal to enhance the personal relevance of pictures improved free recall. By contrast, attempting to suppress emotional displays tended to impair recall, especially compared to the enhance condition. Using reappraisal to decrease the personal relevance of pictures had different effects depending on picture type. Paired with unpleasant pictures, the decrease cue tended to improve recall. Paired with neutral stimuli, the decrease cue tended to impair recall. Emotion regulation did not affect perceptual priming. Results highlight dissociable effects of emotion regulation on explicit and implicit memory, as well as dissociations between regulation strategies with respect to explicit memory.Keywords: affect, cognitive control, emotion, emotion regulation, memory On a daily basis, lives are shaped by emotions, including joy at successes, sadness due to losses, and fear in the face of threats. However, emotions are often not experienced passively. Instead, individuals engage in emotion regulation (Gross, Richards, & John, 2006), attempting to modulate the behavioral, experiential, or physiological components of emotions (Gross, 1998b). Successful emotion regulation is associated with positive outcomes, including development of social competence (Eisenberg, Fabes, Guthrie, & Reiser, 2000) and improved subjective well-being (Larsen & Prizmic, 2004), whereas emotion dysregulation figures prominently in psychopathology (Gross & Munoz, 1995) and may be a precursor to problematic behaviors, including violence (Davidson, Putnam, & Larson, 2000).Various emotion regulation strategies have different behavioral effects, as demonstrated by investigations of reappraisal and expressive suppression. Reappraisal refers to cognitive attempts to change the meaning of stimuli, while expressive suppression refers to inhibition of emotionally expressive behavior (Gross, 1998b). Several studies have examined the effects of these strategies on stimulus encoding. Reappraising gruesome films as less distressing reduces self-reported negative emotion and physiological arousal (Lazarus & Alfert, 1964). Furthermore, using reappraisal to enhance and decrease responses to unpleasant pictures leads to increased and reduced startle responses, respectively (Jackson, Malmstadt, Larson, & Davidson, 2000), as well as increased and reduced activity in the amgydala (Ochsner et al., 2004). Less is known about the neural correlates of expressive suppression, but this strategy leads to increased sympathetic nervous system activity and does not effectively modulate unpleasant emotional experience (Gross, 1998a;Gross & Levenson, 1993.Thus, reappraisal and e...

As a step toward addressing limitations in the current psychiatric diagnostic system, the NIMH recently developed the Research Domain Criteria (RDoC) to stimulate integrative research—spanning self-report, behavior, neural circuitry, and molecular/genetic mechanisms—on core psychological processes implicated in mental illness. Here, we use the RDoC conceptualization to review research on threat responses, reward processing, and their interaction. The first section of the manuscript highlights the pivotal role of exaggerated threat responses—mediated by circuits connecting the frontal cortex, amygdala, and midbrain—in anxiety, and reviews data indicating that genotypic variation in the serotonin system is associated with hyperactivity in this circuitry, which elevates the risk for anxiety and mood disorders. In the second section, we describe mounting evidence linking anhedonic behavior to deficits in psychological functions that rely heavily on dopamine signaling, especially cost/benefit decision-making and reward learning. The third section covers recent studies that document negative effects of acute threats and chronic stress on reward responses in humans. The mechanisms underlying such effects are unclear, but new optogenetic data in rodents indicate that GABAergic inhibition of midbrain dopamine neurons, driven by activation of the habenula, may play a fundamental role in stress-induced anhedonia. In addition to its basic scientific value, a better understanding of interactions between the neural systems that mediate threat and reward responses may offer relief from the burdensome condition of anxious depression.

The neural bases of inhibitory function are reviewed, covering data from paradigms assessing inhibition of motor responses (antisaccade, go/nogo, stop-signal), cognitive sets (e.g., Wisconsin Card Sort Test), and emotion (fear extinction). The frontal cortex supports performance on these paradigms, but the specific neural circuitry varies: response inhibition depends upon fronto-basal ganglia networks, inhibition of cognitive sets is supported by orbitofrontal cortex, and retention of fear extinction reflects ventromedial prefrontal cortexamygdala interactions. Inhibition is thus neurobiologically heterogeneous, although right ventrolateral prefrontal cortex may support a general inhibitory process. Dysfunctions in these circuits may contribute to psychopathological conditions marked by inhibitory deficits.