The Cognitive Neuroscience of Placebo Effects: Concepts, Predictions, and Physiology

Abstract

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.

Functional dissociation of stimulus intensity encoding and predictive coding of pain in the insula

“…The anterior insula could thus represent a mediator between somatosensory signals in posterior insula and contextual representations in prefrontral cortex, integrating those representations for perceptual decisions and behavioral responses (Kong et al, 2006; Seminowicz and Davis, 2007; Baliki et al, 2009). Integration of multiple information streams in this brain region could thus be crucial for the construction of pain experiences that are shaped by learning and external feedback (Wiech, 2016; Geuter et al, 2017). …”

What’s in a word? How instructions, suggestions, and social information change pain and emotion

“…Thus, we speculate that it might be crucial to translate more abstract instructed state representations into a self-referential space of expectations and conceptual meaning. The vmPFC may also be important for linking those expectations to changes in descending autonomic and physiological systems (Bingel et al, 2006; Geuter et al, in press; Roy et al, 2012). …”

Challenges of differential placebo effects in contemporary medicine: The example of brain stimulation

“…Opioid, dopamine, cholecystokinin, cannabinoid, cyclo-oxygenase, neuroendocrine, and neuro-immunological pathways have all been implicated in placebo effects. 53,54 In fact, recent studies suggest that the neural mechanisms underlying placebo effects may be the same or similar to those targeted by active pharmaceutical interventions. Placebo analgesia and the opioid system is the most well understood example.…”