246 discontinued, only the first few extinction trials can be considered to distinctly represent nocebo evocation. One solution that would allow future studies to examine brain activity during evocation, before extinction occurs, is to reinforce nocebo associations throughout extinction. Some nocebo studies employed such continued reinforcement paradigms and achieved persistent nocebo responding that may have been less contaminated by extinction effects 92,94. Additionally, while we conducted our power analysis for this study based on the behavioral-pharmacological primary outcome, a sample of 25 participants per group is considered a minimum required sample for fMRI analyses, and this may have led to some of the imaging results for smaller brain clusters being underpowered 95,96. This study also had other limitations that future research should address. It is important to note that the generalizability of our results may be limited, due to the recruitment of a healthy, young participant sample. Results of this study may not represent pain processing correlates in patients or individuals who have experienced severe or chronic pain, as their neurophysiology may differ from that of healthy people 97. It is imperative for future research to replicate our findings both in patient populations and in more realistic clinical contexts. Albeit the pharmacological manipulation using a partial NMDA receptor agonist did not affect nocebo responses, this study provided important support for the integration of specific cognitive-emotional and sensory processes in nocebo hyperalgesia. The acquisition of nocebo hyperalgesia was primarily characterized by increased activation in brain regions that cognitively integrate and modulate pain inputs. We showed that cognitive-emotional processing of pain signals in the operculum and ACC may integrate prior negative experiences. Understanding the intricate relationship of learning and sensory modulation in the formation of negative pain associations is highly relevant for the effective management of pain.
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