Past research has demonstrated that pain experience can be manipulated through non-specific effects. Placebo analgesia (PA) is known to be sensitive to an individual’s expectations of pain relief. This study aimed to investigate the relationship between the spinal cord, midbrain, and cortical regions commonly associated with expectancy-induced PA. Fifty healthy participants underwent separate brain and spinal fMRI scans involving application of painful heat in four conditions: baseline, placebo analgesia (PA), placebo match (PM; i.e., stimulus adjusted to match PA pain intensity), and repeated baseline (RB). PA was induced through a verbal expectation manipulation with an inert cream. Pain-related functional connectivity (FC) between the dorsolateral prefrontal cortex and periaqueductal gray (PAG), as well as right dorsal C6 and PAG, was calculated. Pain-related functional activation in right dorsal C6 and PAG was also characterized. Results demonstrated a significant placebo analgesic response with decreased pain intensity from baseline to PA conditions. Spinal cord FC revealed greater activation in the periaqueductal gray (PAG) and right dorsal C6 during PA compared to baseline. PAG-C6 FC was significant in all conditions except baseline and was positively associated with pain intensity and expected pain in the PA condition. Double mediation analysis indicated an indirect effect of expected pain on pain intensity through PAG-C6 FC in the PA condition. These findings highlight the critical role of the midbrain-spinal cord pathway in translating expectancy-based placebo into a reduction of perceived pain intensity and underscore the importance of considering cortico-midbrain-spinal mechanisms in understanding placebo analgesia.

Prior neuroimaging studies suggest placebo-related pain reduction is an active pain modulatory process. However, these studies typically do not integrate both spinal and brain fMRI within the same cohort. Combining modalities, our results suggest an important role for midbrain-spinal connectivity as a mediator of expectancy-based placebo analgesia.