Individual differences in intolerance of uncertainty is primarily linked to the structure of inferior frontal regions.

Increased intolerance of uncertainty (IU), or distress felt when encountering situations with unknown outcomes, occurs transdiagnostically across various forms of psychopathology and is targeted in therapeutic intervention. Increased intolerance of uncertainty shows overlap with symptoms of internalizing disorders, such as depression and anxiety, including negative affect and anxious apprehension (worry). While neuroanatomical correlates of IU have been reported, previous investigations have not disentangled the specific neural substrates of IU above and beyond any overlapping relationships with aspects of internalizing psychopathology. The current study did so in a sample of 42 adults and 79 adolescents, who completed questionnaires assessing IU and internalizing symptoms, and underwent structural MRI. When controlling for internalizing symptoms, across adults and adolescents, specific associations of IU were found with the structure of the inferior frontal cortex and orbitofrontal cortex, regions implicated in cognitive control and emotional valuation/regulation. In addition, in adolescents, associations were observed with rostral middle frontal cortex and portions of the cingulate cortex. No associations were observed with threat-related regions, such as the amygdala. Potential cognitive/emotional mechanisms that might explain the association between individual differences in intolerance of uncertainty and morphology of the inferior frontal cortex are discussed.