Anxiety disorders are prevalent and cause substantial disability. An important risk factor for anxiety disorders is inhibited temperament, the tendency to be shy and to avoid new situations. Inhibited adults have heightened amygdala activation and less flexible engagement of the prefrontal cortex (PFC); however, it remains unknown whether these brain alterations are present in inhibited children before the onset of anxiety disorders.

A total of 37 children (18 inhibited and 19 uninhibited), 8 to 10 years of age, completed a task testing anticipation and viewing of threat stimuli and social stimuli in the magnetic resonance imaging (MRI) scanner. Brain activation and functional connectivity were measured.

During the anticipation of threat stimuli, inhibited children failed to show the robust PFC engagement observed in the uninhibited children. In contrast, when viewing social stimuli, inhibited children had increased medial PFC and dorsolateral PFC activation. Connectivity analyses revealed a pattern of reduced connectivity between prefrontal and limbic regions and among distinct PFC regions in the inhibited group. The medial PFC emerged as a key hub of the altered PFC circuitry in inhibited children.

This study provides new evidence of a neural signature of vulnerability to anxiety disorders. By investigating both anticipation and response to images, we identified that high-risk, inhibited children have widespread alterations in PFC function and connectivity, characterized by an inability to proactively prepare for social threat combined with heightened reactivity to social stimuli. Thus, children at high risk for anxiety show significantly altered prefrontal cortical function and connectivity before the onset of anxiety disorders.