Reduced right ventrolateral prefrontal cortex activity while inhibiting positive affect is associated with improvement in hedonic capacity after 8 weeks of antidepressant treatment in major depressive disorder

Abstract

Background: Anhedonia, a reduced ability to experience pleasure, is a chief symptom of major depressive disorder and is related to reduced frontostriatal connectivity when attempting to upregulate positive emotion. The present study examined another facet of positive emotion regulation associated with anhedonia-namely, the downregulation of positive affect-and its relation to prefrontal cortex (PFC) activity.

Methods: Neuroimaging data were collected from 27 individuals meeting criteria for major depressive disorder as they attempted to suppress positive emotion during a positive emotion regulation task. Their PFC activation pattern was compared with the PFC activation pattern exhibited by 19 healthy control subjects during the same task. Anhedonia scores were collected at three time points: at baseline (time 1), 8 weeks after time 1 (i.e., time 2), and 6 months after time 1 (i.e., time 3). Prefrontal cortex activity at time 1 was used to predict change in anhedonia over time. Analyses were conducted utilizing hierarchical linear modeling software.

Results: Depressed individuals who could not inhibit positive emotion-evinced by reduced right ventrolateral prefrontal cortex activity during attempts to dampen their experience of positive emotion in response to positive visual stimuli-exhibited a steeper anhedonia reduction slope between baseline and 8 weeks of treatment with antidepressant medication (p < .05). Control subjects showed a similar trend between baseline and time 3.

Conclusions: To reduce anhedonia, it may be necessary to teach individuals how to counteract the functioning of an overactive pleasure-dampening prefrontal inhibitory system.

Trial registration: ClinicalTrials.gov NCT00909155.

Conflict of interest statement

Financial Disclosures: Sharee N. Light, Aaron S. Heller, Tom Johnstone, Michael J. Peterson, Gregory G. Kolden and Richard J. Davidson reported no biomedical financial interests or potential conflicts of interest. Dr. Ned H. Kalin is a consultant related to the development of psychotropic agents (or serves on the Scientific Advisory Board) for the following companies: Astra Zeneca, Bristol-Myers-Squibb, CeNeRx Biopharma, Corcept, Cyberonics, Forest Laboratories, General Electric Corp., Jazz Pharmaceuticals, Eli Lilly, Neuronetics, Sanofi Syntholabs, and Wyeth Pharmaceuticals. Wyeth Pharmaceuticals funded this study. Dr. Ned H. Kalin has stock options in Corcept and CeNeRx and is principal owner of Promoter Neurosciences.

Copyright © 2011 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.

Figures

Figure 1

(A) Repeated Measures ANOVA. A main effect of group (p<.001) and a main effect of time (p<.001) emerged. Furthermore, the group × time interaction was significant (p<.001). Controls had lower anhedonia scores relative to individuals with MDD at all 3 time points (all ps<.05). Individuals with MDD exhibited a significant reduction in anhedonia from T1 to T2 (ps<.01), but not from T2 to T3 (ps>.10). (B) RVLPFC cluster derived from the MDD group “positive suppress” – “positive maintain” contrast (MNI coordinates: x=25, y=−29, z=−16; 1034 voxels). There was a significant regulation effect (F(1,45)=28.01; p=.001), a group effect (F(1,45=4.0; p=.05), and a non-significant group × regulation effect (F(1,45)=1.27; p=.27). Greater RVLPFC activity during the “positive suppress” condition vs. the “positive maintain” condition may reflect cognitive control processes and the inhibition of the pre-potent response to freely experience positive emotion. The disruption of this process is associated with reductions in anhedonia.

Figure 2

Examples of actual anhedonia trajectories for depressed individuals who exhibited high (those depressed individuals with the top 4 percent signal change scores) and low (those depressed individuals with the bottom 4 percent signal change scores) RVLPFC activity during the “positive suppress” condition relative to the “positive maintain” condition. This graph depicts the finding of the HLM model and is provided for illustrative purposes only.

Figure 3

In controls, the less RVLPFC activity shown at T1 during the “positive suppress” condition relative to the “positive maintain” condition, the greater the reduction in anhedonia from T1 to T3 (p=.05; r2=26%).