Trait anxiety mediates the association between hippocampal-insula functional connectivity and anxiety symptom severity in adults with and without generalized anxiety disorder

Background: Trait anxiety is a vulnerability factor for the development of generalized anxiety disorder (GAD). The hippocampus has been implicated in trait anxiety in normal and GAD populations. However, the exact neural mechanism of hippocampal functional connectivity (FC) and its association with clinical symptoms and trait anxiety in GAD patients remains unknown. Methods: We recruited 68 participants (37 drug-naive non-comorbidity GAD patients and 31 matched healthy controls (HC)), assessed their trait and state anxiety, scanned them with structural and resting-state functional magnetic resonance imaging (fMRI), and compared their hippocampal FC and volumes. We explored the relationships between hippocampal FC, clinical symptoms, and trait anxiety using partial correlation analyses; we also investigated the mediating effects of trait anxiety on the association between hippocampal FC and GAD symptom severity. Results: The GAD group showed increased right hippocampal FC with left insula, which was positively correlated with the Self-Rating Anxiety Scale (SAS), State Anxiety Inventory (SAI), and Trait Anxiety Inventory (TAI). Trait anxiety mediated the relationship between hippocampal FC and anxiety levels. We found no significant difference in hippocampal volumes between GAD and HC. Limitations: The sample size was moderate. The exclusion of comorbidity may reduce the generalizability of our results in normal clinical settings. Conclusions: The GAD patients showed no structural change but had functional alterations in the hippocampus. More importantly, future psychotherapy for this disorder should consider that trait anxiety might play a crucial role in the altered hippocampal FC in GAD.