Regional structural-functional coupling in generalized anxiety disorder and association with neurotransmitter and gene signature.

BACKGROUND

Generalized anxiety disorder (GAD) is a common psychiatric disorder frequently accompanied by somatic symptoms. Previous studies have been confined to isolated functional or structural connections. This study focuses on abnormal structural-functional coupling (SC-FC coupling) in GAD and its underlying genetic and molecular mechanisms, aiming to elucidate subtle alterations in disease-related brain activity.

METHODS

We enrolled 36 GAD patients with somatic symptoms and 36 healthy controls (HCs). We examined abnormal SC-FC coupling and constructed a support vector machine (SVM) model to evaluate the coupling's diagnostic and symptom-predictive value. We also explored associations with neurotransmitter distribution and gene expression.

RESULTS

Compared to HCs, GAD patients showed significant abnormalities in SC-FC coupling across multiple brain regions, mainly within the default mode network (DMN), dorsal and ventral attention networks, frontoparietal network, subcortical network, and sensorimotor network. The SVM model constructed based on the different brain regions (p < 0.01, false discovery rate (FDR) -corrected) demonstrated good predictive performance (AUC = 0.857, ACC = 0.792). SC-FC coupling changes were associated with the distribution of five neurotransmitter systems (serotonin 1B receptor, metabotropic glutamate receptor type 5, noradrenaline transporter, vesicular acetylcholine transporter, and kappa opioid receptor) and with specific gene expression patterns (p < 0.05, FDR-corrected). These genes were enriched in excitatory and inhibitory neurons, glial cells, and pathways related to cellular metabolism and synaptic signaling.

CONCLUSION

This study identified the diagnostic significance of abnormal SC-FC coupling in this patient cohort and its associations with neurotransmitters and gene expression, providing new clues for understanding the disease mechanism and guiding targeted interventions.