Abstract Heightened responding to uncertain threat is considered a hallmark of anxiety disorder pathology. Here, we sought to determine if individual differences in self-reported intolerance of uncertainty (IU), a key transdiagnostic dimension in anxiety-related pathology, underlies differential recruitment of neural circuitry during instructed outcome uncertainty of threat ( n = 42). In an instructed threat of shock task, cues signalled uncertain threat of shock (50%) or certain safety from shock outcomes. Ratings of arousal and valence, skin conductance response (SCR) and functional magnetic resonance imaging were acquired. Overall, participants displayed greater ratings of arousal and negative valence, SCR, and amygdala activation to uncertain threat vs. safe cues. IU was not associated with greater arousal ratings, SCR or amygdala activation to uncertain threat vs. safe cues. However, we found that high IU was associated with greater ratings of negative valence and greater activity in the medial prefrontal cortex and dorsomedial rostral prefrontal cortex to uncertain threat vs safe cues. These findings suggest that during instructed outcome uncertainty of threat, individuals high in IU rate uncertain threat as aversive and engage prefrontal cortical regions known to be involved in safety-signalling and conscious threat appraisal. Taken together, these findings highlight the potential of IU in modulating safety-signalling and conscious appraisal mechanisms in situations with instructed outcome uncertainty of threat, which may be relevant to models of anxiety-related pathology.

Intolerance of uncertainty is associated with heightened responding in the prefrontal cortex during instructed outcome uncertainty of threat