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Blunted neural responses to reward in remitted major depression: A high-density event-related potential study.

ABSTRACT: Major depressive disorder (MDD) is a highly recurrent condition, and improving our understanding of the abnormalities that persist in remitted MDD (rMDD) may provide insight into mechanisms that contribute to relapse. MDD has been characterized by reward learning deficits linked to dysfunction in frontostriatal regions. Although initial behavioral evidence of reward learning deficits in rMDD has recently emerged, it is unclear whether these reflect impairments in neural reward processing that persist into remission.We examined behavioral reward learning and 128-channel event-related potentials (ERP) during a well-validated probabilistic reward task in 26 rMDD individuals and 34 never-depressed controls. Temporo-spatial principal components analysis (PCA) was used to separate overlapping ERP components, and group differences in neural activity in a priori regions were examined using low-resolution electromagnetic tomography (LORETA).Individuals with rMDD displayed reduced behavioral reward learning, as well as blunted ERP amplitude to reward feedback. Importantly, the reduction in ERP amplitude occurred at a PCA factor that peaked during the time at which phasic reward feedback-related signaling - hypothesized to originate in the striatum and project to the anterior cingulate cortex (ACC) - are thought to modulate scalp-recorded activity. Consistent with this, LORETA analyses revealed reduced activity in the ACC in the rMDD group, and this blunting correlated with poorer reward learning.These findings suggest that the reward learning impairment observed in acute MDD persists into full remission and that these impairments may be attributable to abnormalities in the neural processes that support reward feedback monitoring, particularly within the ACC.

SUBMITTER: Whitton AE

PROVIDER: S-EPMC4743048 | biostudies-literature | 2016 Jan

REPOSITORIES: biostudies-literature

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Blunted neural responses to reward in remitted major depression: A high-density event-related potential study.

Whitton Alexis E AE Kakani Pragya P Foti Dan D Van't Veer Ashlee A Haile Anja A Crowley David J DJ Pizzagalli Diego A DA

Biological psychiatry. Cognitive neuroscience and neuroimaging 20160101 1

<h4>Background</h4>Major depressive disorder (MDD) is a highly recurrent condition, and improving our understanding of the abnormalities that persist in remitted MDD (rMDD) may provide insight into mechanisms that contribute to relapse. MDD has been characterized by reward learning deficits linked to dysfunction in frontostriatal regions. Although initial behavioral evidence of reward learning deficits in rMDD has recently emerged, it is unclear whether these reflect impairments in neural reward ...[more]

PMID: 26858994

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Project description:Major depressive disorder is a leading cause of disability and significant mortality, yet mechanistic understanding remains limited. Over the past decade evidence has accumulated from case-control studies that depressive illness is associated with blunted reward activation in the basal ganglia and other regions such as the medial prefrontal cortex. However it is unclear whether this finding can be replicated in a large number of subjects. The functional anatomy of the medial prefrontal cortex and basal ganglia has been extensively studied and the former has excitatory glutamatergic projections to the latter. Reduced effect of glutamatergic projections from the prefrontal cortex to the nucleus accumbens has been argued to underlie motivational disorders such as depression, and many prominent theories of major depressive disorder propose a role for abnormal cortico-limbic connectivity. However, it is unclear whether there is abnormal reward-linked effective connectivity between the medial prefrontal cortex and basal ganglia related to depression. While resting state connectivity abnormalities have been frequently reported in depression, it has not been possible to directly link these findings to reward-learning studies. Here, we tested two main hypotheses. First, mood symptoms are associated with blunted striatal reward prediction error signals in a large community-based sample of recovered and currently ill patients, similar to reports from a number of studies. Second, event-related directed medial prefrontal cortex to basal ganglia effective connectivity is abnormally increased or decreased related to the severity of mood symptoms. Using a Research Domain Criteria approach, data were acquired from a large community-based sample of subjects who participated in a probabilistic reward learning task during event-related functional MRI. Computational modelling of behaviour, model-free and model-based functional MRI, and effective connectivity dynamic causal modelling analyses were used to test hypotheses. Increased depressive symptom severity was related to decreased reward signals in areas which included the nucleus accumbens in 475 participants. Decreased reward-related effective connectivity from the medial prefrontal cortex to striatum was associated with increased depressive symptom severity in 165 participants. Decreased striatal activity may have been due to decreased cortical to striatal connectivity consistent with glutamatergic and cortical-limbic related theories of depression and resulted in reduced direct pathway basal ganglia output. Further study of basal ganglia pathophysiology is required to better understand these abnormalities in patients with depressive symptoms and syndromes.

Project description:One of the core symptoms of major depressive disorder is anhedonia, an inability to experience pleasure. In patients with major depressive disorder, a dysfunctional reward-system may exist, with blunted temporal difference reward-related learning signals in the ventral striatum and increased temporal difference-related (dopaminergic) activation in the ventral tegmental area. Anhedonia often remains as residual symptom during remission; however, it remains largely unknown whether the abovementioned reward systems are still dysfunctional when patients are in remission. We used a Pavlovian classical conditioning functional MRI task to explore the relationship between anhedonia and the temporal difference-related response of the ventral tegmental area and ventral striatum in medication-free remitted recurrent depression patients (n = 36) versus healthy control subjects (n = 27). Computational modelling was used to obtain the expected temporal difference errors during this task. Patients, compared to healthy controls, showed significantly increased temporal difference reward learning activation in the ventral tegmental area (PFWE,SVC = 0.028). No differences were observed between groups for ventral striatum activity. A group × anhedonia interaction [t(57) = -2.29, P = 0.026] indicated that in patients, higher anhedonia was associated with lower temporal difference activation in the ventral tegmental area, while in healthy controls higher anhedonia was associated with higher ventral tegmental area activation. These findings suggest impaired reward-related learning signals in the ventral tegmental area during remission in patients with depression. This merits further investigation to identify impaired reward-related learning as an endophenotype for recurrent depression. Moreover, the inverse association between reinforcement learning and anhedonia in patients implies an additional disturbing influence of anhedonia on reward-related learning or vice versa, suggesting that the level of anhedonia should be considered in behavioural treatments.

Project description:ImportanceMajor depressive disorder (MDD) is associated with deficits in representing reward prediction errors (RPEs), which are the difference between experienced and predicted reward. Reward prediction errors underlie learning of values in reinforcement learning models, are represented by phasic dopamine release, and are known to affect momentary mood.ObjectiveTo combine functional neuroimaging, computational modeling, and smartphone-based large-scale data collection to test, in the absence of learning-related concerns, the hypothesis that depression attenuates the impact of RPEs.Design, setting, and participantsFunctional magnetic resonance imaging (fMRI) data were collected on 32 individuals with moderate MDD and 20 control participants who performed a probabilistic reward task. A risky decision task with repeated happiness ratings as a measure of momentary mood was also tested in the laboratory in 74 participants and with a smartphone-based platform in 1833 participants. The study was conducted from November 20, 2012, to February 17, 2015.Main outcomes and measuresBlood oxygen level-dependent activity was measured in ventral striatum, a dopamine target area known to represent RPEs. Momentary mood was measured during risky decision making.ResultsOf the 52 fMRI participants (mean [SD] age, 34.0 [9.1] years), 30 (58%) were women and 32 had MDD. Of the 74 participants in the laboratory risky decision task (mean age, 34.2 [10.3] years), 44 (59%) were women and 54 had MDD. Of the smartphone group, 543 (30%) had a depression history and 1290 (70%) had no depression history; 918 (50%) were women, and 593 (32%) were younger than 30 years. Contrary to previous results in reinforcement learning tasks, individuals with moderate depression showed intact RPE signals in ventral striatum (z = 3.16; P = .002) that did not differ significantly from controls (z = 0.91; P = .36). Symptom severity correlated with baseline mood parameters in laboratory (ρ = -0.54; P < 1 × 10-6) and smartphone (ρ = -0.30; P < 1 × 10-39) data. However, participants with depression showed an intact association between RPEs and happiness in a computational model of momentary mood dynamics (z = 4.55; P < .001) that was not attenuated compared with controls (z = -0.42; P = .67).Conclusions and relevanceThe neural and emotional impact of RPEs is intact in major depression. These results suggest that depression does not affect the expression of dopaminergic RPEs and that attenuated RPEs in previous reports may reflect downstream effects more closely related to aberrant behavior. The correlation between symptom severity and baseline mood parameters supports an association between depression and momentary mood fluctuations during cognitive tasks. These results demonstrate a potential for smartphones in large-scale computational phenotyping, which is a goal for computational psychiatry.

Dataset Information

Blunted neural responses to reward in remitted major depression: A high-density event-related potential study.

Publications

Blunted neural responses to reward in remitted major depression: A high-density event-related potential study.

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