Cingulate atrophy as a shared structural basis for cognitive and functional brain impairments in GAD, PD, and OCD: Links to shared gene expression and treatment implications.

BACKGROUND

Structural brain deficits associated with generalized anxiety disorder (GAD), panic disorder (PD), and obsessive-compulsive disorder (OCD) have been documented, but their integration within a unified framework remains unexplored. This study investigates, in anxiety and anxiety-related disorders, whether they share neurophysiological bases, whether structural changes (SCs) are linked to common genes, whether shared SCs co-occur with similar functional brain impairments, and whether brain morphometry can serve as biomarkers for diagnosis and treatment prediction.

METHODS

Participants included 100 individuals with GAD, 58 with PD, 45 with OCD, and 85 healthy controls, all drug-free. Structural and resting-state functional magnetic resonance imaging scans and clinical assessments were conducted before and after 4 weeks of paroxetine monotherapy. Analyses included voxel-based and surface-based morphometry; functional connectivity (FC) and Granger causality analysis (GCA) with shared SCs as regions of interest; associations between clinical assessments and neuroimaging metrics; associations between gene expression profiles and SCs; and machine learning.

RESULTS

Cingulate atrophy (CA) emerged as a common SC, with disorder-specific atrophy in gray matter volume (GMV) and cortical surface. Transcriptome-neuroimaging correlations identified shared genetic associations with GMV alterations, with negatively correlated genes enriched in neurodevelopment and cellular growth regulation (ND-CGR). Cingulate GMV was positively correlated with cognitive performance in GAD and PD patients. FC and GCA showed CA disrupted networks governing emotional regulation and cognitive control, characterized by overactive top-down influence and reduced bottom-up feedback. Machine learning demonstrated strong performance in classification and treatment response prediction, with cingulate morphometry contributing significantly.

CONCLUSIONS

CA is a shared neural substrate in GAD, PD, and OCD, linked to genetic disruptions in ND-CGR, cognitive impairments, and functional brain deficits. Cingulate morphometry holds promise as a biomarker for diagnosis and treatment response in these conditions.