Neural underpinnings of nocebo hyperalgesia in visceral pain: A fMRI study in healthy volunteers.

Despite the clinical relevance of nocebo effects, few studies have addressed their underlying neural mechanisms in clinically-relevant pain models. We aimed to address the contribution of nocebo effects and their underlying neural circuitry to central pain amplification in visceral pain, as it may develop over repeated painful experiences due to negative pain-related expectations. Healthy volunteers received verbal suggestions of pain sensitization (nocebo group, N=28) or neutral instructions (control group, N=16). fMRI was used to investigate changes in neural responses during cued pain anticipation and painful rectal distensions delivered in successive fMRI sessions. Pain intensity was rated trial-by-trial, and expected pain intensity, state anxiety and tension were assessed prior to each session. Behavioral analyses demonstrated significantly greater increases in both expected and perceived pain in the nocebo group. The fMRI analysis performed on nocebo-responders only (N=14) revealed that these behavioral changes were associated with increased activation within the secondary somatosensory cortex and amygdala during pain anticipation and within the thalamus, insula and amygdala during painful stimulation when compared to controls. A subsequent psycho-physiological interaction analysis of the pain phase showed increased functional connectivity between the anterior insula, which was set-up as seed region based on group results, and midcingulate cortex as a function of negative expectations. These findings support that negative pain-related expectations can play a crucial role in pain amplification of visceral pain, which is mediated, at least in part, by a neural up-regulation of pain-associated areas and their connectivity. These findings may have implications for the pathophysiology and treatment of chronic abdominal pain.