Beyond fear circuits: multiscale neurobiological architecture of panic disorder

Abstract Panic disorder is a prevalent and disabling condition marked by recurrent panic attacks and high treatment resistance. While previous research has focused on dysfunction within canonical fear circuits, the neurobiological basis of panic disorder may involve broader alterations across multiple brain systems. Here, we conducted a meta-analysis of functional neuroimaging experiments to identify consistent patterns of altered brain activity in panic disorder. We found increased activity in a prefrontal–hippocampus–brainstem axis, which was not confined to traditional fear-related regions. This pattern showed robust spatial associations with serotonergic and dopaminergic receptor distributions and was significantly explained by gene expression profiles of candidate genes, accounting for over one-third of the variance and supporting a polygenic model of the disorder. Further enrichment analyses revealed that the brain pattern is characterized by low neurodevelopmental and evolutionary expansion and reduced oxygen metabolism, consistent with theories of brainstem-based hypersensitivity. Functional annotation linked the identified brain pattern to emotional arousal, memory, learning, and goal-directed behavior, suggesting that panic disorder reflects psychophysiological interactions of higher-order cognitive systems and evolutionary older biological processes. These findings suggest that panic disorder involves widespread neural alterations beyond fear circuitry and highlight potential molecular and functional targets for future mechanistic and therapeutic research.