NEUROIMAGING data from six large population studies have revealed that depression is linked to reduced grey matter in frontal and insular brain regions, while surprisingly showing no significant subcortical involvement, challenging decades of assumptions about the condition’s neural basis.
Depression has been linked to reduced size of subcortical regions and abnormal functional connectivity in frontal and default mode networks in prior research. However, recent meta-analyses have failed to identify significant converging correlates of depression across the literature, and a conclusive mapping of its neuroimaging correlates has remained elusive despite more than 11,000 papers published on the topic to date.
Researchers analysed structural and resting-state functional neuroimaging data from 23,417 participants across six large-scale population datasets. Each dataset was analysed separately for parcellated structural and functional correlates of depression, and estimates were then meta-analytically combined to establish the most reliable neuroimaging correlates robust to sampling variability, phenotypic definitions, and regional bias. The analysis distinguished between correlates associated with depression symptom severity and those associated with personality-based susceptibility phenotypes.
The strongest and most robust reductions in grey matter volume and cortical surface area associated with depression were found in the frontal cortex, anterior cingulate, and insula, including the superior frontal, middle frontal, orbitofrontal, and rostral anterior cingulate regions.
Significant reductions were also identified in somatomotor and visual regions not commonly associated with depression, including the paracentral, postcentral, precentral, fusiform, and pericalcarine regions. By contrast, none of the 16 subcortical regions examined showed significant associations with depression severity or susceptibility.
Depression susceptibility was associated with increased functional connectivity between the right anterior temporal cortex and right medial prefrontal cortex, and between the left medial and left ventral prefrontal cortices.
No significant associations were found for cortical thickness, and full correlation functional connectivity showed more extensive significant associations than partial connectivity, particularly during development compared with ageing.
These findings have substantially updated understanding of the neuroimaging correlates of depression, highlighting the relative importance of structural over functional associations and uncovering previously underappreciated contributions from somatomotor and visual brain regions.
As this was an observational, cross-sectional analysis, causality cannot be established. The authors have suggested that future research should further map how functional connectivity correlates of depression change across the lifespan.
Hamilton KM et al. The neuroimaging correlates of depression established across six large-scale population datasets. Nat Mental Health.2026;4:1329-41.
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