Temporal Dynamics of Brain Mediation in Predictive Cue-induced Pain Modulation

Pain is not a mere reflection of noxious input. Rather, it is constructed through the dynamic integration of prior predictions with incoming sensory input. However, the temporal dynamics of the behavioral and neural processes underpinning this integration remain elusive. Here, we identified a series of brain mediators that integrated cue-induced expectations with noxious inputs into ongoing pain predictions using a semicircular scale designed to capture rating trajectories. Temporal mediation analysis revealed that during the early-to-mid stages of integration, the frontoparietal and dorsal attention network regions, such as the lateral prefrontal, premotor, and parietal cortex, mediated the cue effects. Conversely, during the mid-to-late stages of integration, the somatomotor network regions mediated the effects of stimulus intensity, suggesting that the integration occurs along the cortical hierarchy from transmodal to unimodal brain systems. Our findings advance the understanding of how the brain integrates prior and sensory information into pain experience over time.