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

Major depressive disorder (MDD) is often accompanied by cognitive impairment; however, the cognitive heterogeneity of MDD and its neurobiological context remain poorly understood.

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.

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 (P_Perm = 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 (P_FDR < 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 (P_FDR = 0.028).

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.