Forebrain networks driving brainstem pain modulatory circuits during nocebo hyperalgesia in healthy humans

Prior experiences, conditioning cues, and expectations of improvement are essential for nocebo hyperalgesia expression. The neural circuits that communicate with brainstem pain modulatory nuclei during nocebo hyperalgesia responsivity are underexplored. In this study, we employed a classical conditioning and expectation model in 25 healthy human participants and measured brain activity using ultra-high field functional magnetic resonance imaging. We assessed forebrain activity changes as well as noxious stimulus-independent and -dependent connectivity changes with the lateral midbrain periaqueductal gray matter (lPAG). We found hyperalgesia-related signal increases in the orbitofrontal cortex, insula, and amygdala. In addition, we found stimulus-dependent lPAG connectivity changes with the orbitofrontal, anterior cingulate, and dorsolateral prefrontal cortices and stimulus-independent lPAG connectivity with the anterior cingulate cortex, dorsolateral prefrontal cortex, and nucleus accumbens during hyperalgesia. Whilst these connectivity changes are all associated with hyperalgesia, dynamic causal modelling analysis revealed that the dorsolateral prefrontal cortex was principally responsible for driving the lPAG. Overall, our results show that there is a complex relationship between forebrain activation and connectivity with brainstem pain modulation circuitry that results in the behavioural expression of nocebo hyperalgesia.