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

OPEN Citation: Transl Psychiatry (2016) 6, e810; doi:10.1038/tp.2016.80 www.nature.com/tp ORIGINAL ARTICLE Anhedonia and general distress show dissociable ventromedial prefrontal cortex connectivity in major depressive disorder CB Young1,2, T Chen1, R Nusslock2, J Keller1, AF Schatzberg1 and V Menon1,3,4 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. Translational Psychiatry (2016) 6, e810; doi:10.1038/tp.2016.80; published online 17 May 2016 INTRODUCTION Little is known about the neural underpinnings of individual symptoms of major depressive disorder (MDD), such as anhedonia, as the disorder has been primarily examined as a unitary construct. However, the research domain criteria framework highlights the growing recognition that complex psychiatric disorders such as MDD need to be more fully characterized by identifying potentially distinct neurobiological mechanisms associated with individual symptom clusters.1 Examining the relationships between specific symptoms and brain circuits, such as anhedonia and mesolimbic and cortical pathways involved in reward processing, has important implications for understanding the etiology of MDD symptoms and developing targeted treatments.1,2 Here, we take a research domain criteria-like approach1 to distinguish symptom features and investigate the functional brain circuits implicated in MDD and reward processing. Our primary goal was to investigate the specificity of neurofunctional pathways associated with anhedonia by conducting differential circuit analysis with task-based and resting-state functional magnetic resonance imaging (fMRI) in individuals with MDD. Our second goal was to examine whether connectivity patterns related to anhedonia are specific to distinct anatomical ventromedial prefrontal cortex (VMPFC) subregions. A third goal of this study was to investigate whether anhedonia-specific pathways observed in MDD are also present in healthy controls. A clinical diagnosis of MDD requires the presence of at least one of two symptoms: depressed mood and anhedonia, defined as diminished interest or pleasure in response to rewarding stimuli.3 Recent estimates suggest that approximately 37% of individuals with MDD experience clinically significant anhedonia.4 Anhedonia involves specific impairments in motivation and reward-based decision-making,5,6 and is linked to abnormal activity in the brain regions important for reward processing.7–9 Anhedonia is also a predictor of poor treatment response in MDD,10 and is especially difficult to treat both pharmacologically and psychosocially.11–19 Given the significance of anhedonia in MDD and its relationship with reward-processing deficits, it is critical to identify the brain regions and functional circuits that are specifically associated with this symptom in affected individuals. There have been relatively few neuroimaging studies examining anhedonia in MDD and fewer still have disentangled anhedonia from depression severity. Emerging evidence suggests that anhedonia is characterized by reduced activity in subcortical and ventromedial prefrontal cortex regions involved in reward processing and monitoring.7,8,20,21,22 Furthermore, the posterior VMPFC (pVMPFC) has been consistenty implicated in MDD in previous neuroimaging studies,23–27 as well as findings from 1 Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Stanford, CA, USA; 2Department of Psychology, Northwestern University, Evanston, IL, USA; 3Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA, USA and 4Stanford Neuroscience Institute, Stanford University School of Medicine, Stanford, CA, USA. Correspondence: CB Young or Professor V Menon, Stanford Cognitive and Systems Neuroscience Laboratory, Department of Psychiatry and Behavioral Sciences, Stanford University of Medicine, 1070 Arastradero Suite 220, Palo Alto, CA 94304, USA. E-mail: or Received 5 August 2015; revised 27 March 2016; accepted 31 March 2016 Anhedonia and vmPFC connectivity in MDD CB Young et al 2 psychopharmacology,24,28 psychotherapy29 and deep-brain stimulation treatments.30,31 Indeed, the pVMPFC is thought to be central to the pathophysiology of depression.18,32 However, the unique effects of anhedonia on the pVMPFC circuits are currently unknown. Understanding the pathophysiology of psychiatric disorders such as MDD requires better characterization of underlying taskmodulated and intrinsic resting-state functional circuits. A network of brain regions that includes the pVMPFC, specifically its BA25/32pl subdivision, is particularly relevant to MDD. Anatomical tracing studies have identified pVMPFC projections to regions in the mesolimbic reward system, including the nucleus accumbens (NAc).33,34 In addition, the pVMPFC has connections to limbic structures that are central to emotion-processing and hypothalamic regions that modulate autonomic reactivity.33 The animal models of depression have shown that optogenetic stimulation of medial prefrontal cortex cells that terminate in the NAc elicits antidepressant effects in mice,35 and these (...truncated)