A failed top-down control from the prefrontal cortex to the amygdala in generalized anxiety disorder: Evidence from resting-state fMRI with Granger causality analysis

In generalized anxiety disorder (GAD), abnormal top-down control from the prefrontal cortex (PFC) to the amygdala is a widely accepted hypothesis through which an "emotional dysregulation model" may be explained. However, whether and how the PFC directly exerts abnormal top-down control on the amygdala remains largely unknown. We aimed to investigate the amygdala-based effective connectivity by using Granger causality analysis (GCA). Thirty-five drug-naive patients with GAD and thirty-six healthy controls (HC) underwent resting-state functional MR imaging. We used seed-based Granger causality analysis to examine the effective connectivity between the bilateral amygdala and the whole brain. The amygdala-based effective connectivity was compared between the HC and GAD groups. The results showed that, in the HC group, the left middle frontal gyrus exerted an inhibitory influence on the right amygdala, while in the GAD group, this influence was disrupted (single voxel P < 0.001, Gaussian random field corrected with P < 0.01). Our findings support and advance the "insufficient top-down control" hypothesis by identifying a failed top-down control from the prefrontal cortex to the amygdala in GAD.