Research report
fMRI of alterations in reward selection, anticipation, and feedback in major depressive disorder

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Abstract

The purpose of the present investigation was to evaluate reward processing in unipolar major depressive disorder (MDD). Specifically, we investigated whether adults with MDD demonstrated hyporesponsivity in striatal brain regions and/or hyperresponsivity in cortical brain regions involved in conflict monitoring using a Wheel of Fortune task designed to probe responses during reward selection, reward anticipation, and reward feedback. Functional magnetic resonance imaging (fMRI) data indicated that the MDD group was characterized by reduced activation of striatal reward regions during reward selection, reward anticipation, and reward feedback, supporting previous data indicating hyporesponsivity of reward systems in MDD. Support was not found for hyperresponsivity of cognitive control regions during reward selection or reward anticipation. Instead, MDD participants showed hyperresponsivity in orbitofrontal cortex, a region associated with assessment of risk and reward, during reward selection, as well as decreased activation of the middle frontal gyrus and the rostral cingulate gyrus during reward selection and anticipation. Finally, depression severity was predicted by activation in bilateral midfrontal gyrus during reward selection. Results indicate that MDD is characterized by striatal hyporesponsivity, and that future studies of MDD treatments that seek to improve responses to rewarding stimuli should assess striatal functioning.

Introduction

Anhedonia, a lack of interest or pleasure in normally rewarding experiences, is a defining symptom of major depressive disorder (MDD; American Psychiatric Association, 1994). Anhedonia is also a central feature of a number of theories of MDD, particularly neurobiologic perspectives stating that deficits in emotional and motivational responses to affective stimuli are key to the disorder (e.g., Tomarken and Keener, 1998). Despite the centrality of anhedonia to MDD, the capacity of depressed individuals to experience anticipation of pleasurable events and enjoyment of pleasure during reward presentation has received little empirical attention, and the neurobiology of anhedonia in depression remains to be delineated.

Two non mutually-exclusive neurobiological mechanisms may contribute to anhedonia in MDD: hyporesponsivity of structures within mesolimbic dopamine system related to processing rewards; and hyperresponsivity in cortical regions associated with conflict monitoring. In support of the former hypothesis, lower activation in mesolimbic regions were observed in response to positive stimuli in MDD (Schaefer et al., 2006, Epstein et al., 2006, Keedwell et al., 2005). However, these studies exclusively examined responses to reward presentation, and thus the contributions of mesolimbic/striatal hyporesponsivity during anticipation of rewards were unclear. In support of the cortical hyperresponsivity hypothesis, dorsal anterior cingulate cortex (dACC) activation has been implicated under conditions of uncertainty and affective conflict during the anticipation of potential positive outcomes (Botvinick et al., 1999, Carter et al., 1998). To the extent that individuals with MDD are less confident of potential positive outcomes (Beck and Clark, 1988), heightened dACC activation may be expected during reward anticipation. Knutson et al. (2008) employed a Monetary Incentive Delay (MID) task to differentiate brain responses during reward anticipation and positive reward feedback. They reported that activation of the striatum, including the nucleus accumbens (NAc), did not differentiate MDD and control samples during monetary anticipation or during receipt of monetary rewards. Depressed participants did, however, exhibit dorsal anterior cingulate cortex (dACC) hyperactivation during anticipation of monetary rewards. The authors concluded that MDD may not be characterized by hypoactive anticipatory pleasure states during reward anticipation, but rather by increased affective conflict during anticipation of gains.

This key investigation by Knutson et al. (2008) warrants replication and further examination for at least two reasons: First, in the MID task, reward anticipation and preparation to engage in a behavior with potential reward (i.e., a speeded button press) occur simultaneously. Thus, brain functioning in MDD to a reward anticipation phase devoid of behavioral preparation has not been examined. Second, the MID task does not incorporate decision-making based on risk/reward trade-offs. Thus, it is unknown if MDD hyperactivity in regions associated with conflict monitoring extends to decision-making processes related to risk/reward behaviors, or, conversely, is purely linked to reward anticipation. Given the direct relevance of behavioral initiation/avoidance to the clinical presentation of MDD (Jacobson et al., 2001), a greater understanding of reward system activity while selecting a response option is of strong interest.

In the present investigation we employed a Wheel of Fortune (WoF) task to assess the functional neural correlates of reward selection, reward anticipation, and reward feedback in adults with MDD and in a matched adult control sample. The WoF has been shown to elicit activation in both striatum and ACC during reward anticipation (Ernst et al., 2004). Based on the existing literature showing relatively lower levels of response in mesolimbic dopamine regions to positive stimuli in MDD (Schaefer et al., 2006, Epstein et al., 2006, Keedwell et al., 2005), we hypothesized hyporesponsivity in striatal regions across all three phases of the task, but most critically during reward anticipation because of preclinical evidence that reward-seeking behaviors are mediated by striatal structures (Salamone et al., 1994, Swerdlow and Koob, 1987). As highlighted earlier, Knutson et al. (2008) did not find striatal hypoactivation during reward anticipation, but we hypothesized that the anticipatory phase devoid of a motor preparatory components may be more sensitive to anticipatory hedonic deficits in MDD. In addition, consistent with the findings of Knutson et al. (2008), we hypothesized hyperresponsivity of conflict monitoring regions, including dorsal ACC, during both the reward selection and reward anticipation phases.

Section snippets

Participants

Study participants were recruited through the Duke Cognitive Behavioral Research and Treatment Program and advertisements at Duke University Medical Center and the University of North Carolina, Chapel Hill. In addition, nondepressed participants were recruited from lists maintained at the Duke-UNC Brain Imaging and Analysis Center. Potential participants received a Structured Clinical Interview for DSM-IV (SCID) conducted by licensed clinical psychologists or trained research assistants to

In-scanner choices

Selection choices, confidence ratings, outcome valence ratings, and reaction times to respond were analyzed. Unless otherwise noted, 2 (Group: MDD, control) × 3 (Condition: safe, 50/50, risky) repeated measure MANOVAs were performed. For the sake of brevity, non-significant main effects and interaction terms are omitted. Reaction times to respond did not differ by group or condition in any phase.

To test for group differences in the propensity to make risky versus safe selections, a 2 (Group: MDD,

Discussion

The goal of the present study was to map brain regions differentially recruited by individuals with and without MDD during reward selection, anticipation, and feedback. A primary question was the degree to which MDD is characterized by hyporesponsivity of mesolimbic structures related to reward processing, and/or hyperresponsivity in cortical regions associated with conflict monitoring across the phases of the reward response. Relative to affectively healthy control adults, MDD participants

Role of funding source

This research was supported by MH078145 to G. Dichter. Assistance for this study was provided by the Neuroimaging Core of the UNC Neurodevelopmental Disorders Research Center. M. Smoski was supported by NIMH T32-MH070448, a NARSAD Young Investigator award, and a career development award from Duke University Medical Center, NICHD K12 HD043446. G. Dichter was supported by Postdoctoral Research in Neurodevelopmental Disorders, a NARSAD Young Investigator award, NICHD T32-HD40127, a career

Conflict of interest

All authors declare that they have no conflicts of interest.

Acknowledgements

The authors would like to thank Chris Petty, Todd Harshbarger, and Syam Gadde for assistance with image analysis, Allen Song, Aysenil Belger, Prue Cuper, Shian Ling Keng, Andrew Ekblad, and Justin Woodlief for assistance with various aspects of this project, and MRI technologists Susan Music, Natalie Goutkin, and Talaignair Venkatraman for assistance with data acquisition.

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