Abstract
The formation and persistence of negative pain-related expectations by classical conditioning remain incompletely understood. We elucidated behavioural and neural correlates involved in the acquisition and extinction of negative expectations towards different threats across sensory modalities. In two complementary functional magnetic resonance imaging studies in healthy humans, differential conditioning paradigms combined interoceptive visceral pain with somatic pain (study 1) and aversive tone (study 2) as exteroceptive threats. Conditioned responses to interoceptive threat predictors were enhanced in both studies, consistently involving the insula and cingulate cortex. Interoceptive threats had a greater impact on extinction efficacy, resulting in disruption of ongoing extinction (study 1), and selective resurgence of interoceptive CS-US associations after complete extinction (study 2). In the face of multiple threats, we preferentially learn, store, and remember interoceptive danger signals. As key mediators of nocebo effects, conditioned responses may be particularly relevant to clinical conditions involving disturbed interoception and chronic visceral pain.
Highlights
The formation and persistence of negative pain-related expectations by classical conditioning remain incompletely understood
Adaptive human behaviour in complex environments with multiple threats is guided by evolutionary-driven survival strategies that are preserved across species
In the face of imminent threat, learning from experience is fundamental to the ability to identify and remember predictors of danger to facilitate avoidance or escape
Summary
The formation and persistence of negative pain-related expectations by classical conditioning remain incompletely understood. Despite broad clinical implications of nocebo effects reaching far beyond chronic pain[13,14,15], the formation and persistence of negative pain-related expectations by classical conditioning remain incompletely understood, especially with respect to neurobiological mechanisms and their possible specificity to threat modality. Conditioned negative expectations may be markedly resistant to extinction, as suggested by studies involving somatic pain stimuli[33,34] This may be the case for interoceptive memory traces, as suggested by early classical interoceptive conditioning studies carried out by soviet psychologists[35], complemented by modern approaches on fear learning of interoceptive and exteroceptive cues[36] and on the partially distinct neural representation of aversive visceral signals[37]. Impaired extinction efficacy and other phenomena related to memory processes can reportedly facilitate the return of fear and increase the risk of relapse[38], with broad implications for the chronicity and treatment of pain and fear-related disorders[39]
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