Meta-analysis links functional and structural brain networks in first-episode depression

A systematic meta-analysis of 82 neuroimaging studies identified convergent functional and structural brain-network alterations associated with first-episode major depressive disorder. The analysis covered 4,480 patients with the condition and 4,211 healthy controls, showing that the disorder’s imaging signature extends across several large-scale systems rather than a single brain region. Researchers extracted the coordinates of group differences reported in functional and structural neuroimaging studies, then applied coordinate-level coordinate network mapping.

A normative connectome dataset with n = 1,000 was used to derive depression-associated functional and structural networks. These networks were mapped onto canonical large-scale brain networks, allowing the investigators to interpret the meta-analytic results within established brain systems and quantify their spatial correspondence. Across both modalities, the depression-associated networks involved the hippocampus, insula, thalamus, precuneus, temporal cortex, middle frontal gyrus and cingulate cortex.

Their broader organization differed by imaging modality. The functional network predominantly aligned with the cingulo-opercular, somatomotor and posterior multimodal networks, whereas the structural network primarily aligned with the default mode, auditory and language networks. Despite these modality-specific patterns, the probability maps derived from functional and structural imaging showed substantial agreement across the whole brain.

The researchers reported a spatial correlation of r = 0.61 with p < 0.001. This convergence indicates that the two imaging approaches identified overlapping distributions of depression-associated network alterations, even though their assignments to canonical large-scale systems were not identical. The investigators also examined whether the spatial distribution of depression-associated probability maps corresponded with maps of neurotransmitter systems.

Significant spatial associations were observed for the dopamine transporter, N-methyl-D-aspartate receptor and vesicular acetylcholine transporter. Robustness analyses showed that the identified networks were broadly consistent when the researchers varied the number of random seeds, examined test–retest data, restricted the analysis to drug-naïve first-episode depression samples and performed leave-one-study-out analyses. Specificity was examined through parallel coordinate network mapping analyses of first-episode schizophrenia and drug-naïve obsessive–compulsive disorder.

The depression-associated networks showed relatively limited spatial overlap with those associated with the two comparison conditions, indicating that the pattern was not simply reproduced across all serious psychiatric disorders included in the analysis. Study-level coordinate network mapping also demonstrated high whole-brain spatial correspondence between functional and structural results, although the detailed topology of the functional network differed from the network obtained through the study-level approach. This distinction suggests that the broad spatial pattern was reproducible, but some structural features of the functional network were sensitive to the analytical method.

The findings offer a network-level characterization of brain alterations associated with early-stage major depressive disorder. Because coordinate network mapping synthesizes locations reported across separate studies rather than following individual participants over time, it identifies a shared pattern in the published literature but cannot establish when the alterations arise or whether they precede clinical symptoms.

Subject of Research: Functional and structural brain-network alterations in first-episode major depressive disorder

Article Title: Network-level convergence of functional and structural alterations in first-episode major depressive disorder

Article References: Han, Y., Yan, H., Guo, W., & Cao, H. (2026). Network-level convergence of functional and structural alterations in first-episode major depressive disorder. BMC Medicine. https://doi.org/10.1186/s12916-026-05348-z

Image Credits: AI Generated

DOI: 10.1186/s12916-026-05348-z

Keywords: first-episode depression, major depressive disorder, brain networks, functional neuroimaging, structural neuroimaging, coordinate network mapping, connectomics, neuroimaging meta-analysis, neurotransmitter maps, large-scale brain systems, Network-level, convergence