Cognitive heterogeneity in major depressive disorder: Neuroimaging, transcriptomic, and neurotransmitter profiles.

BACKGROUND: Major depressive disorder (MDD) is often accompanied by cognitive impairment; however, the cognitive heterogeneity of MDD and its neurobiological context remain poorly understood. METHODS: A total of 198 participants with MDD and 275 HCs underwent multi-domain cognitive assessments and multi-modal MRI acquisition. A semi-supervised approach was applied to identify cognitive dimensions of MDD, and individual-level structural-enriched functional networks (SFNs) were constructed. Network-based statistics were applied to characterize network-level associations between structural-functional coupling deviation and cognitive dimensions. Furthermore, the correlations between the spatial pattern of SFN deviation and meta-analytic neurocognitive terms, cortical transcriptome, and neurotransmitter density distribution maps were detected. RESULTS: In the MDD group, 103 individuals were assigned to Cluster 1, presenting widespread cognitive impairments, whereas 95 were assigned to Cluster 2, presenting cognitive preservations. An abnormally enhanced SFN subnetwork (PPerm = 0.042) was identified, which showed significant spatial correlation with meta-analytic neurocognitive maps (r = 0.181, P < 0.001). The SFN deviation pattern was spatially associated with 2458 genes enriched primarily in neuronal and synaptic function, and these genes also showed enrichment for pathways annotated to neurodegenerative diseases (PFDR < 0.05). In addition, SFN deviation was spatially associated with three neurotransmitter maps, including N-methyl-D-aspartate receptor, cannabinoid type-1 receptor, and norepinephrine transporter (PFDR = 0.028). CONCLUSIONS: The study provides a data-driven characterization of cognitive heterogeneity in MDD, identifying two cognitive dimensions spanning from relative preservation to widespread impairment. By integrating structural-functional coupling deviations with transcriptomic and neurotransmitter maps, these findings provide preliminary biological context for interpreting cognitive heterogeneity in MDD.