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 (hyposensitivity to rewards) and negative bias (hypersensitivity to punishments) are core features of major depressive disorder (MDD), which could stem from abnormal reinforcement learning. Emerging evidence highlights blunted reward learning and reward prediction error (RPE) signaling in the striatum in MDD, although inconsistencies exist. Preclinical studies have clarified that ventral tegmental area (VTA) neurons encode RPE and habenular neurons encode punishment prediction error (PPE), which are then transmitted to the striatum and cortex to guide goal-directed behavior. However, few studies have probed striatal activation, and functional connectivity between VTA-striatum and VTA-habenula during reward and punishment learning respectively, in unmedicated MDD. To fill this gap, we acquired fMRI data from 25 unmedicated MDD and 26 healthy individuals during a monetary instrumental learning task and utilized a computational modeling approach to characterize underlying neural correlates of RPE and PPE. Relative to controls, MDD individuals showed impaired reward learning, blunted RPE signal in the striatum and overall reduced VTA-striatal connectivity to feedback. Critically, striatal RPE signal was increasingly blunted with more major depressive episodes (MDEs). No group differences emerged in PPE signals in the habenula and VTA or in connectivity between these regions. However, PPE signals in the habenula correlated positively with number of MDEs. These results highlight impaired reward learning, disrupted RPE signaling in the striatum (particularly among individuals with more lifetime MDEs) as well as reduced VTA-striatal connectivity in MDD. Collectively, these findings highlight reward-related learning deficits in MDD and their underlying pathophysiology.

This study examined the effects of reappraising stress arousal on affective displays, physiological responses, and social performance during an evaluative situation. Participants were sampled from across the social anxiety spectrum and instructed to reappraise arousal as beneficial or received no instructions. Independent raters coded affective displays, nonverbal signaling, and speech performance. Saliva samples collected at baseline and after evaluation were assayed for salivary alpha-amylase (sAA), a protein that indexes sympathetic activation. Arousal reappraisal participants exhibited less shame and anxiety, less avoidant nonverbal signaling, and performed marginally better than no instruction controls. Reappraisal participants also exhibited increased levels of sAA and increased appraisals of coping resources compared with controls. Furthermore, stress appraisals mediated relationships between reappraisal and affective displays. This research indicates that reframing stress arousal can improve behavioral displays of affect during evaluative situations via altering cognitive appraisals.

Objective Major Depressive Disorder is characterized by reduced reward-related striatal activation and dysfunctional reward learning, putatively reflecting decreased dopaminergic signaling. The goal of this study was to test whether a pharmacological challenge designed to facilitate dopaminergic transmission can enhance striatal responses to reward and improve reward learning among depressed individuals. Method In a double-blind placebo-controlled design, 46 unmedicated depressed participants and 43 healthy controls were randomized to receive either placebo or a single low dose (50 mg) of the D2/D3 antagonist amisulpride, which was believed to increase dopamine signaling through presynaptic autoreceptor blockade. To investigate the effects of increased dopaminergic transmission on reward-related striatal function and behavior, a monetary incentive delay task (in conjunction with functional magnetic resonance imaging) and a probabilistic reward learning task were administered at absorption peaks of amisulpride. Results Depressed participants selected previously rewarded stimuli less frequently than controls, indicating reduced reward learning, but this effect was not modulated by amisulpride. Relative to depressed participants receiving placebo (and controls receiving amisulpride), depressed participants receiving amisulpride exhibited increased striatal activation and potentiated corticostriatal functional connectivity between the nucleus accumbens and midcingulate cortex in response to monetary rewards. Stronger corticostriatal connectivity in response to rewards predicted better reward learning among depressed individuals receiving amisulpride as well as among controls receiving placebo. Conclusions Acute enhancement of dopaminergic transmission potentiated reward-related striatal activation and corticostriatal functional connectivity in depressed individuals (but had no behavioral effects), suggesting that targeted pharmacological treatments may normalize neural correlates of reward processing in depression. Thus, despite acute effects on neural function, behavioral modification may require more chronic exposure, fitting prior reports that antidepressant effects of amisulpride in depression emerged after sustained administration. ClinicalTrials.gov Protocol 2010-P001568