Multimodal Abnormalities of Brain Structure and Function in Major Depressive Disorder: A Meta-Analysis of Neuroimaging Studies
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OBJECTIVE: Imaging studies of major depressive disorder have reported structural and functional abnormalities in a variety of spatially diverse brain regions. Quantitative meta-analyses of this literature, however, have failed to find statistically significant between-study spatial convergence, other than transdiagnostic-only effects. In the present study, the authors applied a novel multimodal meta-analytic approach to test the hypothesis that major depression exhibits spatially convergent structural and functional brain abnormalities. METHODS: This coordinate-based meta-analysis included voxel-based morphometry (VBM) studies and resting-state voxel-based pathophysiology (VBP) studies of blood flow, glucose metabolism, regional homogeneity, and amplitude of low-frequency fluctuations (ALFF) and fractional ALFF (fALFF). Input data were grouped into three primary meta-analytic classes: gray matter atrophy, increased function, and decreased function in patients with major depression relative to healthy control subjects. In secondary meta-analyses, the data were grouped across primary categories, and in tertiary analyses, by medication status and absence of psychiatric comorbidity. Activation likelihood estimation was used for all analyses. RESULTS: A total of 92 publications reporting 152 experiments were identified, collectively representing 2,928 patients with major depressive disorder. The primary analyses detected no convergence across studies. The secondary analyses identified portions of the subgenual cingulate cortex, hippocampus, amygdala, and putamen as demonstrating convergent abnormalities. The tertiary analyses (clinical subtypes) showed improved convergence relative to the secondary analyses. CONCLUSIONS: Coordinate-based meta-analysis identified spatially convergent structural (VBM) and functional (VBP) abnormalities in major depression. The findings suggest replicable neuroimaging features associated with major depression, beyond the transdiagnostic effects reported in previous meta-analyses, and support a continued research focus on the subgenual cingulate and other selected regions' role in depression.
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An early meta-analysis of 64 structural MRI studies reported that frontal regions showed the largest volumetric reductions in major depressive disorder, particularly in the anterior cingulate cortex and bilateral orbitofrontal cortex.
“An early meta-analysis (64 structural MRI studies) reported that frontal regions showed the largest volumetric reductions in MDD [78], particularly in the ACC and bilateral OFC, although distinct subregions were not investigated (see also [79]).”
From Prefrontal cortex and depression (2022) · cites this paper as [79]
The Results report 97 studies, not 64 structural MRI studies. The Results section on all patients says the gray-matter-volume analysis found no significant region of convergent abnormality, rather than the largest reductions occurring in frontal regions. The Discussion identifies a subgenual anterior cingulate abnormality in the multimodal analysis, but does not report the claimed bilateral orbitofrontal volumetric reductions. Page numbers were not available in our copy. (LLM, conf=0.88)
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Experimental — accuracy not yet measuredRecent meta-analyses have yielded surprisingly few structural abnormalities linked to major depressive disorder.
“First, recent meta-analyses have yielded surprisingly few structural abnormalities linked to MDD [79].”
From Prefrontal cortex and depression (2022) · cites this paper as [79]
Convergence across studies on cerebral blood flow changes in depression is not strong.
“but convergence across studies is not strong (Gray et al., 2020).”
From The orbitofrontal cortex: reward, emotion and depression (2020) · cites this paper as Gray et al., 2020
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Rolls, E. T., Cheng, W., & Feng, J. (2020) · Brain Communications · doi:10.1093/braincomms/fcaa196 · Cited by 474 · see citing works
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- Authors
- Gray, J. P., Müller, V. I., Eickhoff, S. B., & Fox, P. T.
- Affiliations
- The University of Texas at San Antonio Health Science Center (US)
- Venue
- American Journal of Psychiatry
- Published
- 2020-05-01
- Volume
- 177
- Issue
- 5
- Pages
- 422-434
- ISSN
- 0002-953X (ISSN-L)
- 1535-7228
- PMC
- PMC7294300
- OpenAlex
- W3007560027
- Cited by
- 449
- References
- 84
- Citations by year
- 2026: 53 · 2025: 69 · 2024: 147 · 2023: 73 · 2022: 54 · 2021: 45 · 2020: 8
- FWCI
- 6.08
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- American Journal of Psychiatry (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institute of Mental Health (R01MH074457, R56MH074457)
- Topics
- Life Sciences › Neuroscience › Cognitive Neuroscience › Functional Brain Connectivity Studies
- Health Sciences › Medicine › Pharmacology › Treatment of Major Depression
- Life Sciences › Neuroscience › Cognitive Neuroscience › Neural and Behavioral Psychology Studies
- Keywords
- major depressive disorder, structural brain abnormalities, functional brain abnormalities, multimodal neuroimaging, subgenual anterior cingulate cortex, hippocampus, amygdala, putamen, gray matter atrophy, regional homogeneity, amplitude of low-frequency fluctuation
- MeSH terms
- Brain, Major Depressive Disorder, Depressive Disorder, Major, Humans, Functional Neuroimaging
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