Aberrant resting-state functional connectivity in medication-naïve generalized anxiety disorder: a whole-brain...

Generalized Anxiety Disorder (GAD), characterized by excessive worry and somatic symptoms. Although neuroimaging studies have identified alterations in functional connectivity (FC), structural integrity, and neural activation in GAD, most include medicated or psychotherapy-treated patients, limiting insights into the neurobiology of the untreated state. This study investigated resting-state FC (rsFC) abnormalities in medication-naïve GAD patients using a whole-brain, data-driven approach.

In this cross-sectional study, medication-naïve GAD patients (n = 85) and HCs (n = 82) underwent rs-fMRI at Guang'anmen Hospital on a Siemens 3.0T scanner. Data were analyzed using CONN toolbox (v22.v2407). After preprocessing, cluster-based rsFC was examined across 9, 453 connections in 138 ROIs (FSL Harvard-Oxford atlas, excl. cerebellum). Clusters correlated with HAMA scores; rsFC for 10 ROI pairs extracted via MATLAB; key ROIs seeded voxel-wise maps in SBC, controlling gender.

Significant group differences emerged in rsFC clusters, centered on connections between the posterior cingulate cortex (PCC) and right supramarginal gyrus (SMG). Compared to HCs, GAD patients exhibited hyper-connectivity in 5 connections and hypo-connectivity in 5 others within these clusters. Four connections showed positive correlations with HAMA scores.

The analysis of 9, 354 connections may have reduced statistical power, possibly obscuring additional relevant findings.

This study demonstrates aberrant resting-state functional connectivity in medication-naïve GAD patients, particularly enhanced PCC-SMG rsFC correlated with anxiety severity, suggesting a potential role for interoceptive hypersensitivity in GAD pathophysiology. These findings support the hypothesis of SMG-driven vigilance engaging PCC and mPFC to perpetuate anxiety cycles, warranting future validation with direct interoceptive measures and highlighting neural targets for interventions.