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The neuroscience of placebo effects: connecting context, learning and health

Key Points

  • Placebo effects are effects of the context surrounding medical treatment. They can have meaningfully large impacts on clinical, physiological and brain outcomes.

  • Effects of placebo treatments are consistent across studies from different laboratories. These effects include reduced activity in brain areas associated with pain and negative emotion, and increased activity in the lateral and medial prefrontal cortex, ventral striatum and brainstem.

  • Placebo effects in pain, Parkinson disease, depression and emotion are enabled by engagement of common prefrontal–subcortical motivational systems, but the similarity across domains in the way these systems are engaged has not been directly tested.

  • Meaningfully large placebo effects are likely to require a mixture of both conceptual belief in the placebo and prior experiences of treatment benefit, which engage brain learning processes.

  • In some cases, placebo effects are self-reinforcing, suggesting that they change symptoms in a way that precludes extinction. The mechanisms that drive these effects remain to be uncovered, but doing so could have profound translational implications.

Abstract

Placebo effects are beneficial effects that are attributable to the brain–mind responses to the context in which a treatment is delivered rather than to the specific actions of the drug. They are mediated by diverse processes — including learning, expectations and social cognition — and can influence various clinical and physiological outcomes related to health. Emerging neuroscience evidence implicates multiple brain systems and neurochemical mediators, including opioids and dopamine. We present an empirical review of the brain systems that are involved in placebo effects, focusing on placebo analgesia, and a conceptual framework linking these findings to the mind–brain processes that mediate them. This framework suggests that the neuropsychological processes that mediate placebo effects may be crucial for a wide array of therapeutic approaches, including many drugs.

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Figure 1: Elements of treatment context.
Figure 2: Paradigms for assessing placebo effects.
Figure 3: The neurophysiology of placebo analgesia.
Figure 4: Concepts, associations and the representation of context.

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Acknowledgements

The authors thank J. Sills and E. Hitchcock for research support, the members of the Cognitive and Affective Neuroscience Lab, S. Maier and L. Watkins for helpful discussions, and L. Ruzic for help with the summary in Figure 3. This work was funded by grants NIMH 2R01MH076136 and R01DA027794 (to T.D.W.). This work was also supported in part by the Intramural Research Program of the US National Institutes of Health's National Center for Complementary and Integrative Health.

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Glossary

Context

The combination of all of the elements surrounding a given event that can be psychologically meaningful, including interpersonal dynamics, situational features owing to a place or location, memories, goals for the future and internal body or brain states.

Cues

Stimuli that signify the occurrence, or evoke a representation, of another stimulus or internal experience.

Emotions

Coordinated responses to biologically relevant events (such as threats and opportunities) that involve changes in multiple systems, including peripheral physiology.

Nocebo effects

Deleterious outcomes (for example, an increase in pain or an increase in negative side effects) owing to beliefs about the treatment context.

Placebo responders

Individuals who show an improvement in symptoms after receiving inert treatments (that is, placebos).

Placebo analgesia

A reduction in pain that can be attributed to the treatment context.

Response conditioning

The process of associating neutral stimuli with biologically meaningful outcomes, through which neutral stimuli may begin to induce anticipatory responses that are associated with the outcomes themselves.

Expectancy

A conscious, conceptual belief about the future occurrence of an event. It is a subclass of predictive processes, which may be conscious or unconscious.

Analgesia

Pain relief, which can be caused by many factors, including medical treatments (for example, opioid analgesia), features of the treatment context (placebo analgesia) and affective states (for example, stress-induced analgesia).

Nociceptive

Receiving input from stimuli that can cause damage to tissues.

Descending pain modulation systems

Endogenous, biological mechanisms for suppressing ascending nociceptive information at the level of the spinal cord.

Pre-cognitive associations

Links between events and/or objects that exist outside conscious awareness. These links are generally created through conditioning procedures or innate (evolutionarily afforded) associations.

Conceptual processes

Processes that depend on an interpretation of the situational context and its relationship to prior information (for example, memories and rules), including interoceptive cues from the body, and which can be updated in response to verbally presented or symbolic information.

Schema

A conceptual, 'situational' pattern — inferred from a combination of sensory cues, internal motivation, interoceptive information and thoughts — that can activate scripts that guide behaviour based on the nature of the situation rather than any single cue.

Attributions

Inferred causality; the process of assigning an observed effect (for example, a symptom) to an underlying cause or mechanism.

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Wager, T., Atlas, L. The neuroscience of placebo effects: connecting context, learning and health. Nat Rev Neurosci 16, 403–418 (2015). https://doi.org/10.1038/nrn3976

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