Reduced caudate and nucleus accumbens response to rewards in unmedicated individuals with major depressive disorder
Open accessAbstract
OBJECTIVE: Major depressive disorder is characterized by impaired reward processing, possibly due to dysfunction in the basal ganglia. However, few neuroimaging studies of depression have distinguished between anticipatory and consummatory phases of reward processing. Using functional MRI (fMRI) and a task that dissociates anticipatory and consummatory phases of reward processing, the authors tested the hypothesis that individuals with major depression would show reduced reward-related responses in basal ganglia structures. METHOD: A monetary incentive delay task was presented to 30 unmedicated individuals with major depressive disorder and 31 healthy comparison subjects during fMRI scanning. Whole-brain analyses focused on neural responses to reward-predicting cues and rewarding outcomes (i.e., monetary gains). Secondary analyses focused on the relationship between anhedonic symptoms and basal ganglia volumes. RESULTS: Relative to comparison subjects, participants with major depression showed significantly weaker responses to gains in the left nucleus accumbens and the caudate bilaterally. Group differences in these regions were specific to rewarding outcomes and did not generalize to neutral or negative outcomes, although relatively reduced responses to monetary penalties in the major depression group emerged in other caudate regions. By contrast, evidence for group differences during reward anticipation was weaker, although participants with major depression showed reduced activation to reward cues in a small sector of the left posterior putamen. In the major depression group, anhedonic symptoms and depression severity were associated with reduced caudate volume bilaterally. CONCLUSIONS: These results suggest that basal ganglia dysfunction in major depression may affect the consummatory phase of reward processing. Additionally, morphometric results suggest that anhedonia in major depression is related to caudate volume.
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Decreased activity and connectivity of the ventral striatum and other reward-related regions has been found in MDD.
“By contrast, decreased activity and connectivity of the ventral striatum and other reward-related regions has been found in MDD, leading to decreased recruitment of saliency processing areas like the dorsal cingulate and anterior insula 102-106 .”
From Major depressive disorder (2016) · cites this paper as [105]
The Results (Functional MRI Data; page unavailable) report weaker responses to gains in the left nucleus accumbens and bilateral caudate in participants with MDD, supporting decreased reward-related activity. The paper does not establish decreased connectivity or that these findings lead to reduced recruitment of the dorsal cingulate or anterior insula. It also describes the nucleus accumbens difference as preliminary. (LLM, conf=0.88)
Experimental — accuracy not yet measuredAberrant activity in the dorsal striatum is implicated in the core symptoms of depression, such as anhedonia and psychomotor retardation.
“Aberrant activity in the dorsal striatum is implicated in the core symptoms of depression, such as anhedonia and psychomotor retardation.”
From The Role of Cortisol in Chronic Stress, Neurodegenerative Diseases, and Psychological Disorders (2023) · cites this paper as [126]
The Discussion (page unavailable) reports weaker reward responses in the caudate in participants with depression and relates caudate volume to anhedonia, supporting the dorsal-striatal and anhedonia portion of the claim. The paper does not link dorsal-striatal activity to psychomotor retardation; its Introduction mentions the basal ganglia’s role in motor control but does not establish that symptom-specific connection. (LLM, conf=0.86)
Experimental — accuracy not yet measuredMultiple studies support the idea that the severity of depression is associated with both increased levels of proinflammatory cytokines and with structural as well as functional alterations in the dorsal part of the striatum.
“Multiple studies support the idea that the severity of depression is associated with both increased levels of proinflammatory cytokines and with structural as well as functional alterations in the dorsal part of the striatum [124,125,126].”
From The Role of Cortisol in Chronic Stress, Neurodegenerative Diseases, and Psychological Disorders (2023) · cites this paper as [126]
The Results (Morphometric Data and Functional MRI Data; page numbers unavailable) associate greater depression severity with smaller caudate volume and report weaker reward-related caudate responses in the depressed group. They do not establish an association between severity and functional response, and the Limitations section notes that the volume association appeared on one depression scale but not another. The paper does not address proinflammatory cytokines. (LLM, conf=0.88)
Experimental — accuracy not yet measuredThe severity of depression in unmedicated patients is associated with increased levels of proinflammatory cytokines and with structural and functional alterations in the dorsal part of the striatum.
“Increasing evidence from clinical studies indicates that the severity of depression in unmedicated patients is associated not only with increased levels of proinflammatory cytokines, but also with the structural and functional alterations in the dorsal part of the striatum [21–23].”
From Chronic stress-induced depression requires the recruitment of peripheral Th17 cells into the brain (2022) · cites this paper as [23]
The Results (Morphometric Data; page unavailable) associate greater depression severity on the BDI with smaller bilateral caudate volume in unmedicated patients. The Results also report weaker caudate responses to rewards in patients than controls, but the Discussion (Limitations; page unavailable) says striatal activation was not correlated with symptoms. The paper does not address proinflammatory cytokines, and its structural severity correlation did not emerge for the HRSD. (LLM, conf=0.90)
Experimental — accuracy not yet measuredDepressed patients show an attenuated activation of the VTA-NAc pathway or the NAc itself when compared to normal patients in fMRI analyses.
“Depressed patients show an attenuated activation of the VTA-NAc pathway or the NAc itself when compared to normal patients in fMRI analyses (Epstein et al. 2006; Furman et al. 2011; Pizzagalli et al. 2009; Smoski et al. 2009).”
From Neurotrophic factors and neuroplasticity pathways in the pathophysiology and treatment of depression (2018) · cites this paper as Pizzagalli et al. 2009
Decreased frontoparietal connectivity has been found both at rest and in response to negative stimuli, but not in response to positive stimuli.
“Moreover, decreased frontoparietal connectivity has been found both at rest and in response to negative stimuli, but not in response to positive stimuli, suggesting that this network may contribute to inappropriate cognitive appraisals of negative events more specifically 100,105 .”
From Major depressive disorder (2016) · cites this paper as [105]
The Methods describe an fMRI monetary-incentive task, and the Results report basal-ganglia responses to gains and penalties (page numbers unavailable). Searching for frontoparietal connectivity, resting-state findings, and responses to negative versus positive stimuli found no passage addressing the claimed connectivity pattern. (LLM, conf=0.78)
Experimental — accuracy not yet measuredDepressed individuals or those with trait-like anhedonia display attenuated NAc reactivity to pleasurable stimuli, monetary rewards, and positive words.
“Additionally, depressed individuals or those with trait-like anhedonia display attenuated reactivity of the NAc to pleasurable stimuli (Harvey et al., 2007; Keedwell et al., 2005), monetary rewards (Pizzagalli et al., 2009; Wacker et al., 2009), and positive words (Epstein et al., 2006).”
From The role of inflammation in core features of depression: Insights from paradigms using exogenously-induced inflammation. (2018) · cites this paper as Pizzagalli et al., 2009
Executive function deficits, reductions in cortical thickness, and tonic cortical hypoactivation are mechanisms that explain the association of early deprivation with ADHD.
“EF deficits—particularly in working memory and inhibition, reductions in cortical thickness, and patterns of neural function reflecting tonic cortical hypo-activation are mechanisms that explain the association of early deprivation with ADHD.(122, 130, 141)”
From Neglect as a violation of species-expectant experience: neurodevelopmental consequences (2017) · cites this paper as [141]
Age, gender, intellectual ability and depression were included as regressors to exclude their effects.
“To exclude the effects of age, gender, intellectual ability and depression,31–33 we included these measures as regressors.”
From Ventral striatum dysfunction in children and adolescents with reactive attachment disorder: functional MRI study (2015) · cites this paper as [33]
Patients with major depressive disorder show reduced striatal responses to rewards.
“Moreover, patients with major depressive disorder also show reduced striatal responses to rewards.33”
From Ventral striatum dysfunction in children and adolescents with reactive attachment disorder: functional MRI study (2015) · cites this paper as [33]
Reduced mesolimbic activity in MDD is found during reward anticipation and outcomes in both adults and children, and during reward learning.
“Reduced mesolimbic activity in MDD has been found during reward anticipation and outcomes in both adults and children [210,219-227] and during reward learning [206].”
From Reward circuitry dysfunction in psychiatric and neurodevelopmental disorders and genetic syndromes: animal models and clinical findings (2012) · cites this paper as [224]
These MDD patients had less activation in response to gains in the left nucleus accumbens and the caudate nucleus in both hemispheres.
“These patients had less activation in response to gains in the left nucleus accumbens and the caudate nucleus in both hemispheres (130)”
From Localization of Dysfunction in Major Depressive Disorder: Prefrontal Cortex and Amygdala (2011) · cites this paper as [130]
Reduced activation during consummatory phase of reward in NAc and caudate in MDD vs HCs.
“Furthermore, reduced activation during the consummatory phase of reward was shown for the NAc and caudate in MDD patients compared with HCs (Pizzagalli et al., 2009; Redlich et al., 2015).”
From Circuit Mechanisms of Reward, Anhedonia, and Depression (2019) · cites this paper as Pizzagalli et al., 2009
Other studies show significantly reduced response to rewarding monetary outcomes in NAc and caudate and equally disrupted anticipatory and consummatory pleasure in daily activities in depressed patients, not supporting greater motivation deficits.
“However, this fact is not supported by other studies that showed significantly reduced response to rewarding monetary outcomes in the NAc and the caudate (Pizzagalli et al., 2009) and equally disrupted anticipatory and consummatory pleasure in daily activities in depressed patients (Wu et al., 2017).”
From Circuit Mechanisms of Reward, Anhedonia, and Depression (2019) · cites this paper as Pizzagalli et al., 2009
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- Authors
- Pizzagalli, D. A., Holmes, A. J., Dillon, D. G., Goetz, E. L., Birk, J. L., Bogdan, R., Dougherty, D. D., Iosifescu, D. V., Rauch, S. L., & Fava, M.
- Affiliations
- Harvard University (US)
- ORCID
- Venue
- American Journal of Psychiatry
- Published
- 2009-06
- Volume
- 166
- Issue
- 6
- Pages
- 702-710
- ISSN
- 0002-953X (ISSN-L)
- 1535-7228
- PMC
- PMC2735451
- OpenAlex
- W2100036649
- Semantic Scholar
- 45b8bf65fbe2e8899a84701a04da23c6e017feb9
- Cited by
- 1,232
- References
- 49
- Citations by year
- 2026: 35 · 2025: 66 · 2024: 65 · 2023: 95 · 2022: 89 · 2021: 79 · 2020: 96 · 2019: 77 · 2018: 58 · 2017: 82 · 2016: 76 · 2015: 99 · 2014: 90 · 2013: 60 · 2012: 62
- FWCI
- 26.13
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- American Journal of Psychiatry (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institute of Mental Health (R01MH068376, R21MH078979, R01 MH68376)
- National Center for Complementary and Integrative Health (R21AT002974, R01AT001638, R01 AT1638)
- Topics
- Life Sciences › Neuroscience › Cognitive Neuroscience › Neural and Behavioral Psychology Studies
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Health Sciences › Medicine › Pharmacology › Treatment of Major Depression
- Keywords
- major depressive disorder, reward processing, caudate nucleus, nucleus accumbens, basal ganglia, anhedonia, monetary incentive delay task, reward anticipation, posterior putamen, caudate volume, untreated depression
- MeSH terms
- Adult, Antidepressive Agents, Caudate Nucleus, Major Depressive Disorder, Female, Humans, Magnetic Resonance Imaging, Male, Nucleus Accumbens, Surveys and Questionnaires, Reaction Time, Reward, Severity of Illness Index, Citalopram, Diagnostic and Statistical Manual of Mental Disorders
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