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 chronic pain in disorders of gut-brain interaction. However, the role of accurate contingency awareness remains unclear. In a translational model of pain-related conditioning, we investigated the brain-behavior relationships that underlie contingency awareness and shape 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 assess the predictive value of neural activation patterns for accurate contingency awareness. High contingency awareness enhanced CS+ > CS- differentiation in dorsolateral prefrontal cortex (dlPFC) and parahippocampus, and CS- > CS+ induced widespread activation in fronto-parietal and limbic networks. Regression analyses showed that enhanced CS--related responses were associated with increased contingency accuracy 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 accurate contingency awareness highlights their relevance in shaping pain- and, particularly, safety-predictive cue properties. These results suggest distinct processes for fear acquisition and inhibition, with putative implications for exposure-based treatments of disorders of gut-brain interaction.