Learning by experience? Visceral pain‐related neural and behavioral responses in a classical conditioning paradigm

Background Studies investigating mechanisms underlying nocebo responses in pain have mainly focused on negative expectations induced by verbal suggestions. Herein, we addressed neural and behavioral correlates of nocebo responses induced by classical conditioning in a visceral pain model. Methods In two independent studies, a total of 40 healthy volunteers underwent classical conditioning, consisting of repeated pairings of one visual cue (CSHigh) with rectal distensions of high intensity, while a second cue (CSLow) was always followed by low-intensity distensions. During subsequent test, only low-intensity distensions were delivered, preceded by either CSHigh or CSLow. Distension intensity ratings were assessed in both samples and functional magnetic resonance imaging data were available from one study (N=16). As a consequence of conditioning, we hypothesized CSHigh-cued distensions to be perceived as more intense and expected enhanced cue- and distension-related neural responses in regions encoding sensory and affective dimensions of pain and in structures associated with pain-related fear memory. Key Results During test, distension intensity ratings did not differ depending on preceding cue. Greater distension-induced neural activation was observed in somatosensory, prefrontal, and cingulate cortices and caudate when preceded by CSHigh. Analysis of cue-related responses revealed strikingly similar activation patterns. Conclusions & Inferences We report changes in neural activation patterns during anticipation and visceral stimulation induced by prior conditioning. In the absence of behavioral effects, markedly altered neural responses may indicate conditioning with visceral signals to induce hypervigilance rather than hyperalgesia, involving altered attention, reappraisal, and perceptual acuity as processes contributing to the pathophysiology of visceral pain.