Neuroimaging Studies of Reward Processing in Depression

Summary

Principal Investigator: Diego Pizzagalli
Affiliation: Harvard University
Country: USA
Abstract: The aim of this proposal is to investigate the functional neuroanatomy of depression. A promising strategy for parsing the heterogeneity of Major Depressive Disorder (MDD) is to identify phenotypes characterized by reliable functional brain abnormalities. Anhedonia, the lack of reactivity to pleasurable stimuli, is considered a trait marker for depression. Preclinical work suggests links among phenomena associated with depression - decreased hedonic responsiveness, exaggerated stress responsiveness, and dysfunction in the dopaminergic mesolimbic system - but in humans the neural underpinnings are largely unknown. Using behavioral, event-related potential (ERP), and functional magnetic resonance imaging (fMRI) techniques, this proposal aims to investigate these processes. A monetarily reinforced button-press task will be used to dissociate the neural circuitry involved in anticipation of and reactivity to reward or punishment. Experiment 1 addresses the spatio-temporal dynamics of brain mechanisms underlying anticipation of and reactivity to reward and punishment in subjects differing on objective measures of anhedonia, operationalized as decreased responsiveness to reward-related cues in a separate signal-detection task. Compared to controls, subjects with impaired reward responsiveness (n=20) are predicted to show lower activation in regions subserving reward processing (e.g., nucleus accumbens, medial prefrontal cortex) to reward-related, but not to punishment-related, cues. In the ERP data, decreased late frontal negativity wave to reward cues, and decreased medial-frontal negativity and P3 to reward feedbacks, are hypothesized. Experiment 2 extends this paradigm to subjects with a DSM-IV diagnosis of MDD. These subjects (n=23) are expected to show lower activation in regions subserving reward processing than controls (n=23) in response to reward-related cues, and higher activation in regions subserving processing of withdrawal-related cues. In the ERP data, medial-frontal negativity and P3 are predicted to differentiate the subject groups. Experiment 3 addresses the effects of mental stress on reward processing in MDD. Compared to controls (n=21), depressed subjects (n=21) are expected to show a larger stress-induced reduction of activation in regions subserving reward processing, and a larger activation in regions subserving punishment processing. Decreased gray matter density in medial and subgenual prefrontal regions, as assessed by voxel-based MRI morphometrical analyses, is expected to be associated with the detrimental effect of stress on reward responsiveness. Overall, the integration of techniques with high temporal (ERP) and spatial (fMRI) resolution will enhance understanding of the functional neuroanatomy of depression.
Funding Period: 2004-06-07 - 2009-04-30
more information: NIH RePORT

Top Publications

  1. pmc Toward an objective characterization of an anhedonic phenotype: a signal-detection approach
    Diego A Pizzagalli
    Department of Psychology, Harvard University, Cambridge, Massachusetts, USA
    Biol Psychiatry 57:319-27. 2005
  2. pmc Dissociable recruitment of rostral anterior cingulate and inferior frontal cortex in emotional response inhibition
    Pearl H Chiu
    Department of Psychology, Harvard University, Cambridge, MA 02138, USA
    Neuroimage 42:988-97. 2008
  3. pmc Response conflict and frontocingulate dysfunction in unmedicated participants with major depression
    Avram J Holmes
    Department of Psychology, Harvard University, Cambridge, MA 02138, USA
    Neuropsychologia 46:2904-13. 2008
  4. pmc Enhanced negative feedback responses in remitted depression
    Diane L Santesso
    Department of Psychology, Harvard University, Cambridge, Massachusetts 02138, USA
    Neuroreport 19:1045-8. 2008
  5. pmc Individual differences in reinforcement learning: behavioral, electrophysiological, and neuroimaging correlates
    Diane L Santesso
    Department of Psychology, Harvard University, 1220 William James Hall, 33 Kirkland Street, Cambridge, MA 02138, USA
    Neuroimage 42:807-16. 2008
  6. pmc Implicit depression and hopelessness in remitted depressed individuals
    Tiffany M Meites
    Harvard University, Psychology Department, 1220 William James Hall, 33 Kirkland Street, Cambridge, MA 02138, USA
    Behav Res Ther 46:1078-84. 2008
  7. pmc Single dose of a dopamine agonist impairs reinforcement learning in humans: evidence from event-related potentials and computational modeling of striatal-cortical function
    Diane L Santesso
    Department of Psychology, Harvard University, Cambridge, MA 02138, USA
    Hum Brain Mapp 30:1963-76. 2009
  8. pmc Neural activity and diurnal variation of cortisol: evidence from brain electrical tomography analysis and relevance to anhedonia
    Katherine M Putnam
    National Center for PTSD, VA Boston Healthcare Center, Department of Psychiatry, Boston University School of Medicine, Boston, Massachusetts 02130, USA katherine putnam va gov
    Psychophysiology 45:886-95. 2008
  9. pmc Electrophysiological evidence of attentional biases in social anxiety disorder
    E M Mueller
    Department of Psychology, Boston University, Boston, MA, USA
    Psychol Med 39:1141-52. 2009
  10. pmc Childhood adversity is associated with left basal ganglia dysfunction during reward anticipation in adulthood
    Daniel G Dillon
    Department of Psychology, Harvard University, Cambridge, Massachusetts 02138, USA
    Biol Psychiatry 66:206-13. 2009

Scientific Experts

  • Pearl H Chiu
  • Michele Candrian
  • C M Deveney
  • Diego Pizzagalli
  • Avram J Holmes
  • Daniel G Dillon
  • Diane L Santesso
  • Ryan Bogdan
  • Tiffany M Meites
  • E M Mueller
  • Jan Wacker
  • R Bogdan
  • Jeffrey L Birk
  • Katherine T Steele
  • Katherine M Putnam
  • Roy H Perlis
  • Jesen Fagerness
  • Michael J Frank
  • A E Meuret
  • S G Hofmann
  • Nancy Brooks
  • A Eden Evins
  • Erika C Schetter
  • S Bitran
  • Karlen Lyons-Ruth
  • D L Santesso
  • Ned H Kalin
  • Richard J Davidson
  • Erik M Mueller
  • Stefan G Hofmann
  • Elena Goetz
  • Kyle G Ratner
  • Lawrence L Wald
  • Allison L Jahn
  • Alicia E Meuret
  • Diane C Gooding
  • Etienne B Roesch

Detail Information

Publications28

  1. pmc Toward an objective characterization of an anhedonic phenotype: a signal-detection approach
    Diego A Pizzagalli
    Department of Psychology, Harvard University, Cambridge, Massachusetts, USA
    Biol Psychiatry 57:319-27. 2005
    ..Decreased approach-related behavior and anhedonia (lack of responsiveness to pleasure) are considered cardinal features of depression, but few studies have used laboratory-based measures to objectively characterize these constructs...
  2. pmc Dissociable recruitment of rostral anterior cingulate and inferior frontal cortex in emotional response inhibition
    Pearl H Chiu
    Department of Psychology, Harvard University, Cambridge, MA 02138, USA
    Neuroimage 42:988-97. 2008
    ....
  3. pmc Response conflict and frontocingulate dysfunction in unmedicated participants with major depression
    Avram J Holmes
    Department of Psychology, Harvard University, Cambridge, MA 02138, USA
    Neuropsychologia 46:2904-13. 2008
    ....
  4. pmc Enhanced negative feedback responses in remitted depression
    Diane L Santesso
    Department of Psychology, Harvard University, Cambridge, Massachusetts 02138, USA
    Neuroreport 19:1045-8. 2008
    ..The present findings suggest that abnormal responses to negative feedback extend to samples at increased risk for depressive episodes in the absence of current symptoms...
  5. pmc Individual differences in reinforcement learning: behavioral, electrophysiological, and neuroimaging correlates
    Diane L Santesso
    Department of Psychology, Harvard University, 1220 William James Hall, 33 Kirkland Street, Cambridge, MA 02138, USA
    Neuroimage 42:807-16. 2008
    ..Furthermore, these results highlight the importance of the dACC to probabilistic reward learning in humans...
  6. pmc Implicit depression and hopelessness in remitted depressed individuals
    Tiffany M Meites
    Harvard University, Psychology Department, 1220 William James Hall, 33 Kirkland Street, Cambridge, MA 02138, USA
    Behav Res Ther 46:1078-84. 2008
    ..Results extend prior IAT research by documenting the presence of a reduced tendency to associate the self with happiness in a sample at increased risk for depression...
  7. pmc Single dose of a dopamine agonist impairs reinforcement learning in humans: evidence from event-related potentials and computational modeling of striatal-cortical function
    Diane L Santesso
    Department of Psychology, Harvard University, Cambridge, MA 02138, USA
    Hum Brain Mapp 30:1963-76. 2009
    ..These preliminary findings offer important insights on the role of phasic DA signals on reinforcement learning in humans and provide initial evidence regarding the spatiotemporal dynamics of brain mechanisms underlying these processes...
  8. pmc Neural activity and diurnal variation of cortisol: evidence from brain electrical tomography analysis and relevance to anhedonia
    Katherine M Putnam
    National Center for PTSD, VA Boston Healthcare Center, Department of Psychiatry, Boston University School of Medicine, Boston, Massachusetts 02130, USA katherine putnam va gov
    Psychophysiology 45:886-95. 2008
    ..For the anhedonic group, the mPFC finding was absent. Anhedonia may be characterized by disruptions of mPFC-mediated neuroendocrine regulation, which could constitute a vulnerability to the development of stress-related disorders...
  9. pmc Electrophysiological evidence of attentional biases in social anxiety disorder
    E M Mueller
    Department of Psychology, Boston University, Boston, MA, USA
    Psychol Med 39:1141-52. 2009
    ..We used a dot-probe task in conjunction with high-density ERPs and source localization to investigate attentional biases in SAD...
  10. pmc Childhood adversity is associated with left basal ganglia dysfunction during reward anticipation in adulthood
    Daniel G Dillon
    Department of Psychology, Harvard University, Cambridge, Massachusetts 02138, USA
    Biol Psychiatry 66:206-13. 2009
    ..In animal models, early adversity is associated with dysfunction in basal ganglia regions involved in reward processing, but this relationship has not been established in humans...
  11. pmc Reduced caudate and nucleus accumbens response to rewards in unmedicated individuals with major depressive disorder
    Diego A Pizzagalli
    Department of Psychology, Harvard University, 1220 William James Hall, 33 Kirkland St, Cambridge, MA 02138, USA
    Am J Psychiatry 166:702-10. 2009
    ....
  12. pmc The role of the nucleus accumbens and rostral anterior cingulate cortex in anhedonia: integration of resting EEG, fMRI, and volumetric techniques
    Jan Wacker
    Department of Psychology, Philipps Universitaet, Marburg, Germany
    Neuroimage 46:327-37. 2009
    ..Taken together, these results help elucidate the neural basis of anhedonia and strengthen the argument for anhedonia as an endophenotype for depression...
  13. pmc The heritability of hedonic capacity and perceived stress: a twin study evaluation of candidate depressive phenotypes
    R Bogdan
    Department of Psychology, Harvard University, Cambridge, MA, USA
    Psychol Med 39:211-8. 2009
    ..The present proof-of-concept study assessed whether hedonic capacity and stress perception are heritable and whether their genetic and environmental contributions are shared...
  14. pmc Reduced hedonic capacity in major depressive disorder: evidence from a probabilistic reward task
    Diego A Pizzagalli
    Department of Psychology, Harvard University, 1220 William James Hall, 33 Kirkland Street, Cambridge, MA 02138, USA
    J Psychiatr Res 43:76-87. 2008
    ..The goal of the present study was to test the hypothesis that individuals with major depression are characterized by blunted reward responsiveness, particularly when anhedonic symptoms are prominent...
  15. ncbi Resting anterior cingulate activity and abnormal responses to errors in subjects with elevated depressive symptoms: a 128-channel EEG study
    Diego A Pizzagalli
    Department of Psychology, Harvard University, Cambridge, Massachusetts 02138, USA
    Hum Brain Mapp 27:185-201. 2006
    ..Because rostral ACC regions have been implicated in treatment response in depression, our findings provide initial insight into putative mechanisms fostering treatment response...
  16. ncbi Frontal brain asymmetry and reward responsiveness: a source-localization study
    Diego A Pizzagalli
    Department of Psychology, Harvard University, Cambridge, MA 02138, USA
    Psychol Sci 16:805-13. 2005
    ..8% of the variance in reward bias. These findings not only confirm that frontal EEG asymmetry modulates the propensity to engage in appetitively motivated behavior, but also provide anatomical details about the underlying brain systems...
  17. pmc Acute stress reduces reward responsiveness: implications for depression
    Ryan Bogdan
    Department of Psychology, Harvard University, 33 Kirkland Street, Cambridge, MA 02138, USA
    Biol Psychiatry 60:1147-54. 2006
    ..Stress, one of the strongest risk factors for depression, has been linked to "anhedonic" behavior and dysfunctional reward-related neural circuitry in preclinical models...
  18. pmc Task feedback effects on conflict monitoring and executive control: relationship to subclinical measures of depression
    Avram J Holmes
    Department of Psychology, Harvard University, Cambridge, MA 02138, USA
    Emotion 7:68-76. 2007
    ..These findings suggest that subclinical depression is associated with impairments in behavioral adjustments after internal (perceived failure) and external feedback about deficient task performance...
  19. pmc Dissociation of neural regions associated with anticipatory versus consummatory phases of incentive processing
    Daniel G Dillon
    Department of Psychology, Harvard University, Cambridge, Massachusetts 02138, USA
    Psychophysiology 45:36-49. 2008
    ..Although the study features several methodological improvements and helps clarify the neural basis of incentive processing, replications in larger samples are needed...
  20. pmc Increased perceived stress is associated with blunted hedonic capacity: potential implications for depression research
    Diego A Pizzagalli
    Department of Psychology, Harvard University, 1220 William James Hall, 33 Kirkland Street, Cambridge, MA 02138, USA
    Behav Res Ther 45:2742-53. 2007
    ..These findings are consistent with preclinical data highlighting links between stress and anhedonia, and offer promising insights into potential mechanisms linking stress to depression...
  21. pmc Single dose of a dopamine agonist impairs reinforcement learning in humans: behavioral evidence from a laboratory-based measure of reward responsiveness
    Diego A Pizzagalli
    Department of Psychology, Harvard University, 1220 William James Hall, 33 Kirkland Street, Cambridge, MA 02138, USA
    Psychopharmacology (Berl) 196:221-32. 2008
    ..Animal studies have emphasized the role of phasic dopamine (DA) signaling in reward-related learning, but these processes remain largely unexplored in humans...
  22. ncbi Perceived stress and cognitive vulnerability mediate the effects of personality disorder comorbidity on treatment outcome in major depressive disorder: a path analysis study
    Michele Candrian
    Depression Clinical and Research Program, Department of Psychiatry, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114, USA
    J Nerv Ment Dis 195:729-37. 2007
    ..Depressogenic cognitions might be continuously activated by chronic distress in MDD subjects reporting axis II pathology, leading to stress exacerbation and eventually poorer treatment outcome...
  23. pmc The cognitive consequences of emotion regulation: an ERP investigation
    C M Deveney
    Department of Psychology, Harvard University, Cambridge, Massachusetts 02138, USA
    Psychophysiology 45:435-44. 2008
    ..Results are discussed in the context of the developing ER literature, as well as theories of emotional incongruity (N400) and resource allocation (P300)...
  24. pmc Euthymic patients with bipolar disorder show decreased reward learning in a probabilistic reward task
    Diego A Pizzagalli
    Department of Psychology, Harvard University, Cambridge, MA 02138, USA
    Biol Psychiatry 64:162-8. 2008
    ..Our goal was to test the hypothesis that BPD is characterized by impairments in adjusting behavior as a function of prior reinforcement history, particularly in the presence of residual anhedonic symptoms...
  25. pmc Electrophysiological correlates of spatial orienting towards angry faces: a source localization study
    Diane L Santesso
    Department of Psychology, Harvard University, Cambridge, MA, USA
    Neuropsychologia 46:1338-48. 2008
    ..Results suggest that the earliest modulation of spatial attention by face stimuli is manifested in the P1 component, and provide insights about mechanisms underlying attentional orienting toward cues of threat and social disapproval...
  26. pmc Spatiotemporal dynamics of error processing dysfunctions in major depressive disorder
    Avram J Holmes
    Department of Psychology, Harvard University, Cambridge, MA 02138, USA
    Arch Gen Psychiatry 65:179-88. 2008
    ..Depression is characterized by executive dysfunctions and abnormal reactions to errors; however, little is known about the brain mechanisms that underlie these deficits...
  27. pmc Variation in TREK1 gene linked to depression-resistant phenotype is associated with potentiated neural responses to rewards in humans
    Daniel G Dillon
    Department of Psychology, Harvard University, Cambridge, Massachusetts 02138, USA
    Hum Brain Mapp 31:210-21. 2010
    ..Future studies in depressed samples should evaluate whether variation in neural responses to rewards may contribute to the association between TREK1 and antidepressant response in humans...