Morphological and genetic signatures of hypomania: A multisite exploration of reward circuitry and transcriptomic...

Hypomania, characterized by elevated mood, impulsivity, and heightened social vitality, is closely linked to alterations in the brain's reward circuitry. However, the relationship between reward circuitry and hypomanic traits, particularly in terms of structural and molecular mechanisms, remains unclear.

A total of 742 participants with varying proneness to hypomania were recruited across four sites. Hypomanic proneness was assessed using psychometric scales. Structural MRI data were analyzed with voxel-based morphometry and inter-subject representational similarity analysis (IS-RSA) to examine morphological volume and patterns in striatal subregions. Transcriptomic associations with neural patterns were identified using Gene Annotation for Modular Brain Analysis (GAMBA), Enrichment analysis and cell-type expression analyses.

Whole-brain and ROIs analyses consistently revealed that proneness to hypomania, including social vitality and mood volatility, was positively correlated with morphological volume and its patterns in the reward circuitry (e.g., NAcc). Transcriptomic analysis identified overlapping 1583 genes linked to morphological patterns related to three sub-dimensions of hypomania, with upregulated genes enriched in neural development pathways, while downregulated genes linked to synaptic signaling. Furthermore, these genes were predominantly expressed in astrocytes (upregulated) and excitatory/inhibitory (downregulated) neurons. GAMBA analysis revealed opposing correlations between these genes and the limbic network functions, mood disorders, and emotion processing. Spatiotemporal analysis highlighted peak expression related to upregulated but not downregulated genes in the striatum during middle-late childhood and adolescence.

This study provides a deeper understanding of hypomania's biological basis, emphasizing the role of the reward system in emotional dysregulation and suggesting potential molecular targets for therapeutic interventions.