Daniel G. Dillon

Reduced Caudate and Nucleus Accumbens Response to Rewards in Unmedicated Individuals With Major Depressive Disorder

OBJECTIVE Major depressive disorder 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 MRI (fMRI) and a task that dissociates anticipatory and consummatory phases of reward processing, the authors tested the hypothesis that individuals with major depression would show reduced reward-related responses in basal ganglia structures. METHOD A monetary incentive delay task was presented to 30 unmedicated individuals with major depressive disorder 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, participants with major depression showed significantly weaker responses to gains in the left nucleus accumbens and the caudate bilaterally. 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 the major depression group emerged in other caudate regions. By contrast, evidence for group differences during reward anticipation was weaker, although participants with major depression showed reduced activation to reward cues in a small sector of the left posterior putamen. In the major depression group, anhedonic symptoms and depression severity were associated with reduced caudate volume bilaterally. CONCLUSIONS These results suggest that basal ganglia dysfunction in major depression may affect the consummatory phase of reward processing. Additionally, morphometric results suggest that anhedonia in major depression is related to caudate volume.

The role of the nucleus accumbens and rostral anterior cingulate cortex in anhedonia: integration of resting EEG, fMRI, and volumetric techniques.

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 electroencephalography, functional magnetic resonance imaging, and volumetric analyses to probe putative associations between anhedonia and individual differences in key nodes of the brains 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 brains reward circuit. Taken together, these results help elucidate the neural basis of anhedonia and strengthen the argument for anhedonia as an endophenotype for depression.

Childhood Adversity is Associated with Left Basal Ganglia Dysfunction During Reward Anticipation in Adulthood

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: 1) cues signaling possible monetary rewards and losses; and 2) delivery of monetary gains and penalties, in 13 young adults who experienced maltreatment before age 14 years and 31 nonmaltreated control subjects. RESULTS Relative to control subjects, 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 might 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 might be useful for reducing the negative consequences of childhood adversity.

Dissociable effects of conscious emotion regulation strategies on explicit and implicit memory.

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.

Illness Progression, Recent Stress, and Morphometry of Hippocampal Subfields and Medial Prefrontal Cortex in Major Depression

BACKGROUND Longitudinal studies of illness progression in patients with 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 patients with MDD--especially in medial prefrontal cortex (mPFC) and the hippocampus--but few studies have investigated whether these changes are exacerbated by prior episodes. METHODS In a sample of 103 medication-free patients with depression and control subjects with no history of depression, structural magnetic resonance imaging was performed to examine relationships between number of prior episodes, current stress, hippocampal subfield volume and cortical thickness. Volumetric analyses of the hippocampus were performed using a recently validated subfield segmentation approach, and cortical thickness estimates were obtained using vertex-based methods. Participants were grouped on the basis of the number of prior depressive episodes and current depressive diagnosis. RESULTS Number of prior episodes was associated with both lower reported stress levels and reduced volume in the dentate gyrus. Cortical thinning of the left mPFC was associated with a greater number of prior depressive episodes but not current depressive diagnosis. 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.

Dissociation of event-related potentials indexing arousal and semantic cohesion during emotional word encoding

Event-related potential (ERP) studies have shown that emotional stimuli elicit greater amplitude late positive-polarity potentials (LPPs) than neutral stimuli. This effect has been attributed to arousal, but emotional stimuli are also more semantically coherent than uncategorized neutral stimuli. ERPs were recorded during encoding of positive, negative, uncategorized neutral, and categorized neutral words. Differences in LPP amplitude elicited by emotional versus uncategorized neutral stimuli were evident from 450 to 1000 ms. From 450 to 700 ms, LPP effects at midline and right hemisphere frontal electrodes indexed arousal, whereas LPP effects at left hemisphere centro-parietal electrodes indexed semantic cohesion. This dissociation helps specify the processes underlying emotional stimulus encoding, and suggests the need to control for semantic cohesion in emotional information processing studies.

Dynamic Resting-State Functional Connectivity in Major Depression

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.

Peril and Pleasure: An RDoC-inspired examination of threat responses and reward processing in anxiety and depression

As a step toward addressing limitations in the current psychiatric diagnostic system, the National Institute of Mental Health 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 the fourth section reviews new optogenetic data in rodents indicating 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.

Startle modulation during conscious emotion regulation is arousal-dependent.

Conscious regulation of negative emotion has been shown to affect human eyeblink startle responses, but whether these results depend on modulation of arousal- or valence-based processes is unknown. The authors presented participants with negative, neutral, and positive pictures and directed them to enhance, maintain, and suppress emotional responses. On emotional picture trials, startle responses decreased as a function of cue in the following order: enhance > maintain > suppress. Analysis of negative and positive picture trials separately revealed similar patterns of startle modulation by emotion regulation. There were no effects of emotion regulation on neutral trials. Results indicate that arousal, not valence, may be critical to startle modulation via conscious emotion regulation.

Evidence of successful modulation of brain activation and subjective experience during reappraisal of negative emotion in unmedicated depression.

Functional magnetic resonance imaging (fMRI) was used to examine cognitive regulation of negative emotion in 12 unmedicated patients with major depressive disorder (MDD) and 24 controls. The participants used reappraisal to increase (real condition) and reduce (photo condition) the personal relevance of negative and neutral pictures during fMRI as valence ratings were collected; passive viewing (look condition) served as a baseline. Reappraisal was not strongly affected by MDD. Ratings indicated that both groups successfully reappraised negative emotional experience. Both groups also showed better memory for negative vs. neutral pictures 2 weeks later. Across groups, increased brain activation was observed on negative/real vs. negative/look and negative/photo trials in left dorsolateral prefrontal cortex (DLPFC), rostral anterior cingulate, left parietal cortex, caudate, and right amygdala. Depressive severity was inversely correlated with activation modulation in the left DLPFC, right amygdala, and right cerebellum during negative reappraisal. The lack of group differences suggests that depressed adults can modulate the brain activation and subjective experience elicited by negative pictures when given clear instructions. However, the negative relationship between depression severity and effects of reappraisal on brain activation indicates that group differences may be detectable in larger samples of more severely depressed participants.