Treatment-related changes in functional connectivity of anterior cingulate cortex subregions and their genetic associations in bipolar disorder.

BACKGROUND

Bipolar disorder (BD) is characterized by abnormalities in large-scale brain networks, yet subregional functional alterations of the anterior cingulate cortex (ACC), their treatment-related changes, and underlying molecular mechanisms remain unclear.

METHODS

Resting-state functional magnetic resonance imaging (rs-fMRI) was acquired from 82 patients with BD and 88 healthy controls (HCs). A subset of patients (n = 38) completed a three-month longitudinal follow-up after pharmacological treatment. Seed-based functional connectivity (FC) analyses were conducted using anatomically defined ACC subregions. Baseline group differences were identified using voxel-wise two-sample t tests with multiple-comparison correction, and longitudinal changes were evaluated in those connections showing significant baseline differences. Imaging-transcriptomic associations were examined by integrating FC alterations with regional gene expression data from the Allen Human Brain Atlas using partial least squares analysis.

RESULTS

At baseline, patients with BD showed increased FC between the left caudal ACC and bilateral precuneus/cuneus, and decreased FC between perigenual and subgenual ACC subregions and limbic-prefrontal regions. After treatment, caudal ACC-precuneus/cuneus hyperconnectivity was significantly reduced, indicating partial normalization of ACC-default mode network coupling. Changes in caudal ACC-precuneus connectivity were negatively associated with symptom improvement, although these correlations did not survive multiple-comparison correction. Transcriptomic analyses revealed that ACC-related FC alterations were linked to genes enriched in synaptic signaling and neurodevelopmental pathways.

CONCLUSIONS

These findings demonstrate subregion-specific ACC connectivity abnormalities in BD and suggest that treatment-related network normalization is associated with molecular pathways involved in synaptic and neurodevelopmental processes.