Placebos have been used ubiquitously throughout the history of medicine. Expectations and associative learning processes are important psychological determinants of placebo effects, but their underlying brain mechanisms are only beginning to be understood. We examine the brain systems underlying placebo effects on pain, autonomic, and immune responses. The ventromedial prefrontal cortex (vmPFC), insula, amygdala, hypothalamus, and periaqueductal gray emerge as central brain structures underlying placebo effects. We argue that the vmPFC is a core element of a network that represents structured relationships among concepts, providing a substrate for expectations and a conception of the situation—the self in context—that is crucial for placebo effects. Such situational representations enable multidimensional predictions, or priors, that are combined with incoming sensory information to construct percepts and shape motivated behavior. They influence experience and physiology via descending pathways to physiological effector systems, including the spinal cord and other peripheral organs.

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