Neurostructural correlates of intolerance of uncertainty: Regional and network-level associations with general psychological distress

Intolerance of uncertainty (IU), which is characterized by an inability to endure aversive responses to uncertainty, is a transdiagnostic and transituational risk factor for general psychological distress (GPD). However, its neuroanatomical basis remains unclear. This study investigated the associations between IU and brain structure at both regional and network levels in 115 healthy university students, and explored whether IU mediates the brain-GPD association. Voxel-based morphometry revealed a positive correlation between IU and gray matter volume (GMV) in the right orbitofrontal cortex (OFC). Graph-based analysis of structural covariance networks showed that IU was positively associated with patterns of nodal local efficiency (reflecting local information processing capability) and nodal clustering coefficient (reflecting regional modular connectivity). The brain regions contributing to these network patterns were primarily located within the limbic network (LN) and default mode network (DMN), including the inferior frontal gyrus, middle temporal gyrus, and parahippocampal gyrus. Critically, mediation analyses demonstrated that IU significantly accounting for variance in the link of right OFC GMV and the two structural covariance network patterns with GPD. All findings remained robust after controlling for family socioeconomic status or general anxiety. These results reveal multilevel neuroanatomical features associated with IU, implicating the right OFC and structural covariance patterns of LN and DMN. They further highlight IU as a critical psychological mechanism linking these brain structural features to GPD, offering potential targets for neurobehavioral interventions.