Functional Neuroimaging of Major Depressive Disorder: A Meta-Analysis and New Integration of Baseline Activation and Neural Response Data
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OBJECTIVE: Functional neuroimaging investigations of major depressive disorder can advance both the neural theory and treatment of this debilitating illness. Inconsistency of neuroimaging findings and the use of region-of-interest approaches have hindered the development of a comprehensive, empirically informed neural model of major depression. In this context, the authors sought to identify reliable anomalies in baseline neural activity and neural response to affective stimuli in major depressive disorder. METHOD: The authors applied voxel-wise, whole-brain meta-analysis to neuroimaging investigations comparing depressed to healthy comparison groups with respect to baseline neural activity or neural response to positively and/or negatively valenced stimuli. RESULTS: Relative to healthy subjects, those with major depression had reliably higher baseline activity, bilaterally, in the pulvinar nucleus. The analysis of neural response studies using negative stimuli showed greater response in the amygdala, insula, and dorsal anterior cingulate cortex and lower response in the dorsal striatum and dorsolateral prefrontal cortex in individuals with major depressive disorder than in healthy subjects. CONCLUSIONS: The meta-analytic results support an elegant and neuroanatomically viable model of the salience of negative information in major depressive disorder. In this proposed model, high baseline pulvinar activity in depression first potentiates responding of the brain's salience network to negative information; next, and owing potentially to low striatal dopamine levels in depression, this viscerally charged information fails to propagate up the cortical-striatal-pallidalthalamic circuit to the dorsolateral prefrontal cortex for contextual processing and reappraisal.
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A meta-analysis of MRI data by the ENIGMA working group detected significantly lower volumes in the hippocampus (but no other subcortical structures) as well as cortical thinning in the orbitofrontal cortex, anterior and posterior cingulate, insula and temporal lobes in MDD patients.
“A meta-analysis of MRI data from more than a dozen independent research samples by the ENIGMA working group detected significantly lower volumes in the hippocampus (but no other subcortical structures) 95 as well as cortical thinning in the orbitofrontal cortex, anterior and posterior cingulate, insula and temporal lobes in MDD patients 96 .”
From Major depressive disorder (2016) · cites this paper as [95]
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Experimental — accuracy not yet measuredMDD patients show lower activity of dorsolateral prefrontal cortex in resting state analyses.
“studies seemed consistent in showing a lower activity of dorsolateral PFC in resting state analyses of MDD patients”
From Neurotrophic factors and neuroplasticity pathways in the pathophysiology and treatment of depression (2018) · cites this paper as Hamilton et al. 2012
The Results (fMRI Meta-Analysis; page not provided) report lower dorsolateral prefrontal cortex activation in MDD patients in response to negative stimuli. The resting-state analysis (Results, rCBF Meta-Analysis; page not provided) instead reports reliably greater activity in the pulvinar nuclei; it does not establish lower resting-state dorsolateral prefrontal activity. (LLM, conf=0.89)
Experimental — accuracy not yet measuredIn response to negative stimuli, acute MDD episodes are often characterized by reduced engagement of cognitive control in brain regions such as the dorsolateral prefrontal cortex, but elevated engagement of salience detection in medial prefrontal cortex.
“In response to negative stimuli, acute MDD episodes are often characterized by reduced engagement of cognitive control in brain regions such as the dorsolateral prefrontal cortex (PFC), but elevated engagement of salience detection in medial PFC (Hamilton et al., 2012, Hamilton et al., 2013).”
From Static and treatment-responsive brain biomarkers of depression relapse vulnerability following prophylactic psychotherapy: Evidence from a randomized control trial (2022) · cites this paper as Hamilton et al., 2012
Prevailing theories of MDD mechanisms highlight an imbalance between an overactive salience network (putamen, amygdala, anterior cingulate) and decreased responsiveness in contextual processing regions (dorsal striatum and DLPFC).
“These data have informed prevailing theories of the mechanisms of MDD, which highlight an imbalance between an overactive salience network (involving in the putamen, amygdala, and anterior cingulate) and decreased responsiveness in regions involved in contextual processing (dorsal striatum and dorsolateral prefrontal cortex — DLPFC) (Hamilton et al., 2012).”
From Widespread reductions in gray matter volume in depression (2013) · cites this paper as Hamilton et al., 2012
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“, a bias toward the perception of negative rather than positive stimuli in MDD are generally accepted alterations in depression (14), with several models seeking to explain the underlying alterations on a neural level (7, 15, 16).”
BackgroundRepetition-Related Reductions in Neural Activity during Emotional Simulations of Future Events
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- Authors
- Hamilton, J. P., Etkin, A., Furman, D. J., Lemus, M. G., Johnson, R. F., & Gotlib, I. H.
- Affiliations
- VA Palo Alto Health Care System (US)
- Venue
- American Journal of Psychiatry
- Published
- 2012-07
- Volume
- 169
- Issue
- 7
- Pages
- 693-703
- ISSN
- 0002-953X (ISSN-L)
- 1535-7228
- PMC
- PMC11889638
- OpenAlex
- W2136148200
- Cited by
- 866
- References
- 86
- Citations by year
- 2026: 52 · 2025: 41 · 2024: 100 · 2023: 49 · 2022: 55 · 2021: 101 · 2020: 53 · 2019: 54 · 2018: 60 · 2017: 59 · 2016: 74 · 2015: 79 · 2014: 51 · 2013: 30 · 2012: 7
- Type
- conference abstract
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- American Journal of Psychiatry (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institute of Mental Health (F32MH079651, MH079651, MH59259, R01MH059259)
- Topics
- Life Sciences › Neuroscience › Cognitive Neuroscience › Neural and Behavioral Psychology Studies
- Health Sciences › Medicine › Pharmacology › Treatment of Major Depression
- Life Sciences › Neuroscience › Cognitive Neuroscience › Functional Brain Connectivity Studies
- Keywords
- major depressive disorder, pulvinar, amygdala, insula, dorsal anterior cingulate cortex, dorsal striatum, dorsolateral prefrontal cortex, salience network, striatal dopamine
- MeSH terms
- Brain, Major Depressive Disorder, Emotions, Humans, Models, Neurological, Neural Pathways, Functional Neuroimaging
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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