Neurobiology of Intolerance of Uncertainty: A Systematic Review

Author(s): Alexandria Greifenberger, Grace Hill, Elssa Toumeh, Sachinthya Lokuge, Kathryn Fotinos, Irvin Epstein, Tia Sternat, Martin A Katzman.

Intolerance of uncertainty (IU) has been identified as a key component of several psychiatric disorders; however, the neural mechanisms underlying IU remains unclear. Determining the role and neural predictors of IU in the pathophysiology of various anxiety disorders may better explain the high rate of comorbidity across these conditions, which may result in more effective and precise treatment for individual patients. Thus, this paper aims to present an up to date, comprehensive, and consolidated review of the neurobiology underlying IU. For this systematic review, we searched the PubMed database for studies published between database inception and February 2025. Studies published in peer-reviewed journals examining mechanisms of brain regions associated with intolerance of uncertainty were included. Results showed that clinical and non-clinical populations with higher IU directly correspond with alterations in regional brain activity compared to populations with lower IU. In general, limbic brain regions appeared to be hyperactive, while the prefrontal cortical regions were more often reported to be hypoactive among those with high IU. Differentiating and understanding the neural structures responsible for elevated IU is crucial in order to develop and assess the effectiveness of personalized treatment options targeting trans-diagnostic features underlying a range of psychiatric disorders