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Transl Psychiatry. 2016 May 17;6:e810. doi: 10.1038/tp.2016.80.

Anhedonia and general distress show dissociable ventromedial prefrontal cortex connectivity in major depressive disorder.

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Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Stanford, CA, USA.
Department of Psychology, Northwestern University, Evanston, IL, USA.
Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA, USA.
Stanford Neuroscience Institute, Stanford University School of Medicine, Stanford, CA, USA.


Anhedonia, the reduced ability to experience pleasure in response to otherwise rewarding stimuli, is a core symptom of major depressive disorder (MDD). Although the posterior ventromedial prefrontal cortex (pVMPFC) and its functional connections have been consistently implicated in MDD, their roles in anhedonia remain poorly understood. Furthermore, it is unknown whether anhedonia is primarily associated with intrinsic 'resting-state' pVMPFC functional connectivity or an inability to modulate connectivity in a context-specific manner. To address these gaps, a pVMPFC region of interest was first identified using activation likelihood estimation meta-analysis. pVMPFC connectivity was then examined in relation to anhedonia and general distress symptoms of depression, using both resting-state and task-based functional magnetic resonance imaging involving pleasant music, in current MDD and healthy control groups. In MDD, pVMPFC connectivity was negatively correlated with anhedonia but not general distress during music listening in key reward- and emotion-processing regions, including nucleus accumbens, ventral tegmental area/substantia nigra, orbitofrontal cortex and insula, as well as fronto-temporal regions involved in tracking complex sound sequences, including middle temporal gyrus and inferior frontal gyrus. No such dissociations were observed in the healthy controls, and resting-state pVMPFC connectivity did not dissociate anhedonia from general distress in either group. Our findings demonstrate that anhedonia in MDD is associated with context-specific deficits in pVMPFC connectivity with the mesolimbic reward system when encountering pleasurable stimuli, rather than a static deficit in intrinsic resting-state connectivity. Critically, identification of functional circuits associated with anhedonia better characterizes MDD heterogeneity and may help track of one of its core symptoms.

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Conflict of interest statement

AFS has served as a consultant to Bay City Capital, BrainCells, CeNeRx, Cervel, Clintara, Depomed, Eli Lilly, Forum (EnVivo), Genentech, Gilead, Jazz, Lundbeck/Takeda, McKinsey, Merck, MSI, Naurex, Neuronetics, Novadel, One Carbon, Pfizer, PharmaNeuroBoost, Sunovion, Synosia and Xhale. AFS has had equity in Amnestix, CeNeRx, Corcept (co-founder), Forest Labs, Merck, Neurocrine, Pfizer, PharmaNeuroBoost, Synosia, Titan and Xhale. He is a named inventor on pharmacogenetic use patents on prediction of antidepressant response and glucocorticoid antagonists in psychiatry. The remaining authors declare no conflict of interest.

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