Differential cerebral white matter tract alterations in generalized anxiety disorder revealed by ultra-high-field 7 T diffusion-weighted imaging.

Generalized anxiety disorder (GAD) is characterized by chronic worry and emotional dysregulation, yet its underlying white matter (WM) microstructural alterations remain unclear owing to inconsistent findings and technical limitations in prior neuroimaging studies. To address this gap, we employed ultra-high-field 7-Tesla (7 T) diffusion tensor imaging (DTI) and advanced correlational tractography to characterize WM alterations in GAD, examine their associations with symptom burden, and evaluate their diagnostic utility. Eighty-eight young participants (27 with GAD and 61 healthy controls [HCs]) underwent 7 T DTI at 1.5-mm isotropic resolution. Whole-brain correlational tractography was applied to identify WM tracts exhibiting significant group differences in diffusion indices. Associations of identified WM tracts with Hamilton Anxiety Rating Scale (HAM-A) and Penn State Worry Questionnaire (PSWQ) scores were examined, and machine learning-based models were used to assess the diagnostic utility of the WM features. Two right-hemispheric tract alterations were identified in GAD. First, fractional anisotropy (FA) in the right cingulum was significantly elevated in GAD (PFDR < 0.001), particularly in the anterior portion of the tract. This elevated FA was positively correlated with HAM-A and PSWQ scores (PFDR < 0.001 for both), indicating that greater microstructural coherence was associated with more severe anxiety and worry. Second, lower FA was observed in the right prefrontal pathway (PFDR = 0.039), whereas this effect did not survive adjustment for medication use (PFDR = 0.133). Combining WM features with clinical scores improved diagnostic classification. These findings reveal tract-specific microstructural correlates of emotional dysregulation in GAD and provide new insight into its neurobiological mechanisms.