Personality Heterogeneity Shapes the Neural Organization of Conditioned Threat Learning

How individual differences in personality structure relate to the neural mechanisms of fear conditioning remains an important question for precision psychiatry. Here, combining multidimensional personality profiling with spatiotemporal neuroimaging analyses in a multi-site cohort, we show that personality-defined heterogeneity is associated with distinct neural organization of conditioned threat learning. Rather than reflecting exaggerated neural responses to threat, elevated neuroticism was characterized by a reduced capacity to differentiate conditioned threat from safety signals. This pattern was reflected in reduced threat-related responses within a distributed set of regions, including the ventromedial prefrontal cortex (vmPFC), subgenual anterior cingulate cortex (sgACC), and posterior cingulate cortex (PCC). Complementing the brain activation findings, personality-related differences were also observed in threat–safety dynamic functional connectivity differentiation, including connections between the PCC and centromedial amygdala (cmAMY), precentral cortex and middle frontal gyrus (MFG), and dorsal anterior cingulate cortex (dACC) and orbitofrontal cortex (OFC), as well as broader interactions involving the dorsal attention network (DAN), cerebellum network (CEM) frontoparietal control network (CON), and sensorimotor network (SMN). Symptom analyses revealed that the high-neuroticism subgroup showed elevated trait-related anxiety measures, whereas state anxiety and subjective fear-learning behavior did not differ between groups. Cross-validated predictive analyses further showed that fear-learning-related neural features significantly predicted anxiety sensitivity only within the high-neuroticism subgroup, suggesting personality-dependent brain–symptom coupling. These findings indicate that personality-defined heterogeneity is associated with both the neural organization of conditioned threat learning and the mapping between neural threat representations and anxiety vulnerability, highlighting the importance of incorporating personality structure into neurobiological models of anxiety vulnerability and precision psychiatry frameworks.