Structure-function coupling alterations in adolescent depression correlate with neurotransmitter systems and cell-type-specific transcriptomics.

BACKGROUND

Adolescent major depressive disorder (AMDD) emerges during a period of significant neurobiological reorganization, yet its specific pathophysiological mechanisms remain poorly understood. This study investigated structural-functional brain coupling (SC-FC coupling) in AMDD and its relationship with neurotransmitter systems and molecular profiles.

METHODS

We examined 107 adolescents with AMDD and 78 healthy controls. Participants underwent multimodal neuroimaging (DTI, resting-state fMRI), clinical assessment, and cognitive testing. We analyzed regional SC-FC coupling abnormalities and their associations with neurotransmitter distributions. Gene expression profiles underlying coupling alterations were examined through partial least squares regression with Allen Human Brain Atlas data. Cell-type enrichment analysis was performed using established transcriptomic references, and developmental expression trajectories were mapped using BrainSpan developmental transcriptome atlas through CSEA tool.

RESULTS

AMDD was characterized by decoupling in the default mode network and hypercoupling in somatomotor networks. These alterations demonstrated significant potential for diagnostic classification (AUC = 0.83-0.85) and correlated with clinical symptom severity. The spatial distribution of coupling alterations was significantly associated with multiple neurotransmitter systems, most robustly with dopaminergic and serotonergic markers. At the transcriptomic level, these alterations were correlated with distinct gene expression profiles, which were further linked to cell-type-specific signatures: genes associated with decoupled regions were enriched in neuronal lineages, while those associated with hypercoupled regions showed enrichment in glial cells.

CONCLUSIONS

These findings suggest that SC-FC alterations in AMDD are linked to neurotransmitter systems and cell-type-specific gene expression. These associations may reflect developmentally sensitive mechanisms that could inform age-appropriate intervention strategies for adolescent depression.