Cortical microstructural alterations in first-episode and recurrent depression and their associations with gene...

Onset of major depressive disorder is associated with cortical microstructural changes. However, differences in cortical microstructure between first-episode depression (FED) and recurrent-episode depression (RED) remain unclear.

We recruited 236 participants (54 FED patients, 138 RED patients, 44 healthy controls). Diffusion tensor imaging was used to measure cortical mean diffusivity (cMD) and T1-weighted imaging assessed cortical thickness and gray matter volume. Depression and anxiety severity were evaluated using the Hamilton Rating Scales (HAMD, HAMA). Group differences between patients and controls were analyzed, and spatial cMD patterns were correlated with gene expression data from the Allen Human Brain Atlas. Genetic and cell-enrichment analyses were conducted to identify biological underpinnings.

cMD was more sensitive than cortical thickness and gray matter volume in detecting cortical abnormalities in FED and RED patients. Increased cMD in FED patients was predominantly confined to prefrontal cortex, whereas in FED patients, elevations extended into frontal, temporal, and parietal regions (Cohen's d = 0.42-1.35). Elevated cMD in RED patients correlated positively with HAMD and HAMA in the right pars opercularis. Both tissue-level and extracellular free water abnormalities contributed to cMD elevations. Cell enrichment analysis revealed abnormal cMD regions were linked to oligodendrocyte-enriched genes, showing overexpression in FED but underexpression in RED.

Cortical microstructural alterations represent a sensitive neuroimaging phenotype reflecting stage-specific oligodendrocyte disruption in depression. These findings provide insights into biological mechanisms underlying progression from first to recurrent depressive episodes and highlight potential therapeutic targets.