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Accumulating neuroimaging studies implicate widespread brain structural alterations in patients with generalized anxiety disorder (GAD), but little is known regarding the temporal information of these changes and their causal relationships. In this study, a morphometric analysis was performed on T1-weighted structural images, and the progressive changes in the gray matter volume (GMV) in GAD were simulated by dividing the patients into different groups from low illness duration to high illness duration. The duration was defined as the interval between the onset of GAD and the time for magnetic resonance imaging collection. Then, a causal structural covariance network analysis was conducted to describe the causal relationships of the brain structural alterations in GAD. With increased illness duration, the GMV reduction in GAD originated from the subgenual anterior cingulate cortex (sgACC) and propagated to the bilateral ventromedial prefrontal cortex, right dorsomedial prefrontal cortex, left inferior temporal gyrus, and right insula. Intriguingly, the sgACC and the right insula had positive causal effects on each other. Moreover, both sgACC and right insula exhibited positive causal effects on the parietal cortex and negative effects on the posterior cingulate cortex, dorsolateral prefrontal cortex, visual cortex, and temporal lobe. The opposite causal effects were noted on the somatosensory and the ventrolateral prefrontal cortices. In conclusion, patients with GAD show gradual GMV reduction with increasing ilness duration. Furthermore, the causal effects of the sgACC and the right insula GMV reduction with shifts of duration may provide an important new avenue for understanding the pathological anomalies in GAD.

Progressive brain structural alterations assessed via causal analysis in patients with generalized anxiety disorder