Cerebellar activation in human placebo analgesia: Bridging findings from mice to humans

Abstract Placebo analgesia has traditionally been explained by top–down cortical regulation of brainstem and spinal pathways. Recent circuit-level work in animal models identified a rostral anterior cingulate–pontine–cerebellar pathway that contributes to expectation-based analgesia, implicating cerebellum circuits in placebo effects 1 . Building on these findings, we examined pontine and cerebellar contributions within a large individual-participant meta-analysis of human neuroimaging studies of placebo analgesia 2 ( n = 603). We found that the effects of human pain and placebo converge in cerebellar territories embedded in higher-order cognitive 3,4 and action-mode networks 5 . These regions exhibit placebo-induced anticipatory increases and reduced responses during painful stimulation, which correlate with the magnitude of placebo analgesia, consistent with predictive configuration of the system. Pontine responses also correlate with individual differences in placebo analgesia. In independent Human Connectome Project data ( n = 820), pontine activity is functionally connected with cingulate and cerebellar regions implicated in placebo analgesia. Together, these findings support a model in which expectation effects are implemented via predictive configuration of a cortico–pontine–cerebellar system.