Effective Connectivity Reveals Hippocampal Disruptions in Adolescent Anxiety

Anxiety disorders peak during adolescence alongside rapid neural development, yet the neural mechanisms underlying adolescent threat learning remain unclear. Using fMRI and dynamic causal modeling, we mapped effective connectivity during threat conditioning and extinction in 87 adolescents (ages 11-17), focusing on the amygdala, hippocampus, and posterior ventromedial prefrontal cortex (p-vmPFC) circuit. The adolescent brain showed distinct circuit strategies for threat versus safety learning: threat learning (CS+) initially engaged only amygdala and p-vmPFC excitatory coupling without hippocampal involvement, while early safety learning (CS-) recruited hippocampal inhibition of threat-processing regions. By late conditioning, bidirectional inhibitory connectivity emerged between amygdala and p-vmPFC for both stimulus types, suggesting homeostatic regulation once associations consolidated. During extinction, the network transitioned from complex mutual amygdala-hippocampus inhibition during early CS+ trials to streamlined hippocampal-prefrontal pathways by late extinction, reflecting safety consolidation. Adolescents with higher trait anxiety demonstrated stronger hippocampal to p-vmPFC connectivity during early conditioning and altered hippocampal modulation during extinction, revealing temporally dynamic disruptions in directional signaling. This study provides the first effective connectivity map of adolescent threat learning and identifies neural mechanisms that may confer risk for anxiety disorders during this vulnerable developmental period.