Negative expectations interfere with the analgesic effect of safety cues on pain perception by priming the cortical representation of pain in the midcingulate cortex.

It is well known that the efficacy of treatment effects, including those of placebos, is heavily dependent on positive expectations regarding treatment outcomes. For example, positive expectations about pain treatments are essential for pain reduction. Such positive expectations not only depend on the properties of the treatment itself, but also on the context in which the treatment is presented. However, it is not clear how the preceding threat of pain will bias positive expectancy effects. One hypothesis is that threatening contexts trigger fearful and catastrophic thinking, reducing the pain-relieving effects of positive expectancy. In this study, we investigated the disruptive influence of threatening contexts on positive expectancy effects while 41 healthy volunteers experienced laser-induced heat pain. A threatening context was induced using pain-threatening cues that preceded the induction of positive expectancies via subsequent pain-safety cues. We also utilised electroencephalography (EEG) to investigate potential neural mechanisms underlying these effects. Lastly, we used the Fear of Pain Questionnaire to address whether the disruptive effect of negative contexts on cued pain relief was related to the degree of fear of pain. As predicted, participants responded less to pain-safety cues (i.e., experienced more pain) when these were preceded by pain-threatening cues. In this threatening context, an enhancement of the N2 component of the laser-evoked potential was detected, which was more pronounced in fearful individuals. This effect was localised to the midcingulate cortex, an area thought to integrate negative affect with pain experience to enable adaptive behaviour in aversive situations. These results suggest that threatening contexts disrupt the effect of pain relief cues via an aversive priming mechanism that enhances neural responses in the early stages of sensory processing.