The impact of contingency awareness on the neurocircuitry underlying pain-related fear and safety learning

Visceral pain-related fear, shaped by associative learning, drives maladaptive emotional reactions and may contribute to the chronicity of pain in disorders of gut-brain interaction. However, the role of contingency awareness remains unclear. In a translational model of pain-related conditioning, we investigated the brain-behavior relationships underlying contingency awareness in shaping the neural circuitry involved in visceral pain-related fear and safety learning. Data from 75 healthy individuals undergoing differential conditioning were acquired in two functional magnetic resonance imaging studies. Visceral pain as unconditioned stimulus (US) was paired with a visual cue as conditioned stimulus (CS+) while another cue (CS-) remained unpaired. Differential neural responses to predictive cues were analyzed using a full factorial model and regression analyses to evaluate the predictive value of neural activation patterns based on contingency awareness. Analyses revealed a significant interaction between CS-type and contingency awareness involving dorsolateral prefrontal cortex (dlPFC) and parahippocampus, driven by an enhanced CS+>CS- differentiation in highly aware participants. The reverse contrast revealed widespread activation in fronto-parietal and limbic networks, more pronounced in the highly aware group. Regression analyses showed that enhanced CS--related were associated with increased contingency awareness and CS- valence change, while no activation clusters predictive of behavioral responses were found for CS+. The recruitment of emotional arousal and executive control networks as a function of contingency awareness highlights its relevance in shaping pain- and, particularly, safety-predictive cue properties. These results suggest distinct processes for fear acquisition and inhibition, with significant implications for exposure-based treatments of disorders of gut-brain interaction.