Transcriptional substrates of cortical thickness alterations in anhedonia of major depressive disorder.

Background: Anhedonia is a core symptom of major depressive disorder (MDD), which has been shown to be associated with abnormalities in cortical morphology. However, the correlation between cortical thickness (CT) changes with anhedonia in MDD and gene expression remains unclear.

Methods: We investigated the link between brain-wide gene expression and CT correlates of anhedonia in individuals with MDD, using 7 Tesla neuroimaging and a publicly available transcriptomic dataset. The interest-activity score was used to evaluation MDD with high anhedonia (HA) and low anhedonia (LA). Nineteen patients with HA, nineteen patients with LA, and twenty healthy controls (HC) were enrolled. We investigated CT alterations of anhedonia subgroups relative to HC and related cortical gene expression, enrichment and specific cell types. We further used Neurosynth and von Economo-Koskinas atlas to assess the meta-analytic cognitive functions and cytoarchitectural variation associated with anhedonia-related cortical changes.

Results: Both patient subgroups exhibited widespread CT reduction, with HA manifesting more pronounced changes. Gene expression related to anhedonia had significant spatial correlations with CT differences. Transcriptional signatures related to anhedonia-associated cortical thinning were connected to mitochondrial dysfunction and enriched in adipogenesis, oxidative phosphorylation, mTORC1 signaling pathways, involving neurons, astrocytes, and oligodendrocytes. These CT alterations were significantly correlated with meta-analytic terms involving somatosensory processing and pain perception. HA had reduced CT within the somatomotor and ventral attention networks, and in agranular cortical regions.

Limitations: These include measuring anhedonia using interest-activity score and employing a cross-sectional design.

Conclusions: This study sheds light on the molecular basis underlying gene expression associated with anhedonia in MDD, suggesting directions for targeted therapeutic interventions.