Approach-Avoidance Conflict in Major Depressive Disorder: Congruent Neural Findings in Humans and Nonhuman Primates
Open accessAbstract
Background Maladaptive approach-avoidance behavior has been implicated in the pathophysiology of major depressive disorder (MDD), but the neural basis of these abnormalities in decision making remains unclear. Capitalizing on recent preclinical findings, we adapted an approach-avoidance conflict task from nonhuman primate research for use in human functional magnetic resonance imaging (fMRI).Methods Forty-two female participants, including 18 unmedicated individuals with current MDD (mean age 25.2 ± 5.1 years) and 24 psychiatrically healthy control subjects (mean age 26.3 ± 7.6 years) completed the adapted approach-avoidance task during fMRI. To probe potential mechanistic factors underlying the observed behavioral and fMRI findings and to inform interpretation of putative group differences, we examined electrophysiological data from 2 female Macaca mulatta monkeys performing the approach-avoidance conflict task mimicked in the fMRI study.Results Findings demonstrated congruent neural correlates of approach-avoidance conflict and aversive responsiveness in the anterior cingulate cortex, including the pregenual cortex, of human subjects and macaques (humans: p < .05 whole-brain corrected; macaques: p < .05). The MDD group exhibited aberrant task-related activations in the anterior cingulate cortex, prefrontal cortex, and striatum (all ps < .05). Neural effects in the MDD group were cross-sectionally associated with stress and depressive symptoms. Importantly, they also prospectively predicted stress at 6-month follow-up (all ps < .05).Conclusions Findings indicate that there is conservation of anterior cingulate activation across species and that frontal and striatal regions, in unmedicated humans with MDD, are abnormally responsive during cost-benefit decision making. We suggest that these disruptions could be valuable candidates for translational biomarkers.
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In MDD, reduced approach-related dlPFC activation correlated with increasing perceived stress.
“In MDD, reduced approach-related dlPFC activation correlated with increasing perceived stress.”
From Prefrontal cortex and depression (2022) · cites this paper as [42]
The Discussion reports reduced approach-related DLPFC activation in MDD. However, the correlation with higher perceived stress is reported for DLPFC activation during non-conflict trials, not specifically for approach-related activation (Results, Imaging Results; page not provided). (LLM, conf=0.88)
Experimental — accuracy not yet measuredRelative to controls, unmedicated adults with MDD were less sensitive to reward.
“Relative to controls, unmedicated adults with MDD were less sensitive to reward.”
From Prefrontal cortex and depression (2022) · cites this paper as [42]
Unmedicated adults with MDD showed reduced approach-related activation in the dlPFC and reduced avoidance-related pgACC activation.
“Moreover, they showed reduced approach-related activation in the dlPFC and, surprisingly, reduced avoidance-related pgACC activation.”
From Prefrontal cortex and depression (2022) · cites this paper as [42]
A region bordering area 32 within the pgACC of macaques is implicated in negative bias in decision making.
“A region bordering area 32 within the pgACC of macaques [39] has also been implicated in negative bias in decision making using a task subsequently adapted to assess negative biases in MDD [42].”
From Prefrontal cortex and depression (2022) · cites this paper as [42]
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- Authors
- Ironside, M., Amemori, K.-I., McGrath, C. L., Pedersen, M. L., Kang, M. S., Amemori, S., Frank, M. J., Graybiel, A. M., & Pizzagalli, D. A.
- Affiliations
- Harvard University (US)
- McGovern Institute for Brain Research (US)
- McLean Hospital (US)
- Brown University (US)
- Corresponding author
- Pizzagalli, Diego A.
- ORCID
- Venue
- Biological Psychiatry
- Publisher
- Elsevier BV
- Published
- 2020-03
- Volume
- 87
- Issue
- 5
- Pages
- 399-408
- ISSN
- 0006-3223 (ISSN-L)
- PMC
- PMC7007869
- OpenAlex
- W2971467968
- Cited by
- 75
- References
- 56
- Citations by year
- 2026: 13 · 2025: 13 · 2024: 14 · 2023: 12 · 2022: 9 · 2021: 11 · 2020: 3
- FWCI
- 3.34
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Biological Psychiatry (acceptedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- DSpace@MIT (Massachusetts Institute of Technology) (submittedVersion, cc-by-nc-nd)
- Funders
- Office of Naval Research
- Army Research Office
- Japan Society for the Promotion of Science
- CHDI Foundation
- National Institute of Mental Health
- Topics
- Life Sciences › Neuroscience › Cognitive Neuroscience › Neural and Behavioral Psychology Studies
- Health Sciences › Medicine › Pharmacology › Treatment of Major Depression
- Social Sciences › Psychology › Experimental and Cognitive Psychology › Anxiety, Depression, Psychometrics, Treatment, Cognitive Processes
- Keywords
- major depressive disorder, approach-avoidance conflict, cost-benefit decision making, anterior cingulate cortex, pregenual anterior cingulate cortex, prefrontal cortex, striatum, stress, translational biomarkers
- MeSH terms
- Animals, Brain, Brain Mapping, Depressive Disorder, Major, Major Depressive Disorder, Female, Gyrus Cinguli, Humans, Magnetic Resonance Imaging, Primates
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