Bipolar disorder (BD) is a highly heritable condition characterized by recurrent shifts between manic and depressive states. Here we investigated the potential involvement of the habenula because it plays a central role in negative affect and behavioral regulation. We investigated bilateral habenular volume and seed-based resting-state functional connectivity in a discovery cohort (78 BD, 102 controls) and an independent replication cohort (72 BD, 85 controls). Associations among habenular features, clinical symptoms, and molecular correlates were examined by integrating pathway-specific polygenic risk scores and brain-wide gene expression data from the Allen Human Brain Atlas. Across both cohorts, BD was associated with reduced bilateral habenular volume and increased rs-FC between the habenula and right precentral gyrus. Habenular volume correlated positively with severity of mania symptoms and negatively with severity of symptoms of anxiety and somatization. Polygenic risk scores linked the altered volume to dopaminergic pathways and altered connectivity to serotonergic pathways, while transcriptomic data linked the altered connectivity to changes in expression of synaptic membrane structures, transporter complexes, and other proteins involved in synaptic transmission. Structural, functional and transcriptomic data identify the habenula as a critical neural hub in BD and therefore important for understanding pathogenesis and clinical manifestations. Not applicable.
Qiao et al. (Sat,) studied this question.