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

Wager, Tor D.; Atlas, Lauren Y.

doi:10.1038/nrn3976

Cited by 844Pain Management and Placebo EffectPain Mechanisms and TreatmentsTranscranial Magnetic Stimulation Studies

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

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Wager, Tor D., Atlas, Lauren Y.·2015·Nature Reviews Neuroscience

DOI 10.1038/nrn3976PMC PMC6013051

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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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Expectations could modulate reinforcement signals, and if such manipulations affect the reinforcement signal used in calculating prediction errors, it would short-circuit learning by suppressing cue-inconsistent prediction errors.
“If these manipulations affect the reinforcement signal used in calculating prediction errors, it would short-circuit learning by suppressing cue-inconsistent prediction errors.”
From Social information creates self-fulfilling prophecies in judgments of pain, vicarious pain, and cognitive effort (2026) · cites this paper as [44]
In “Understanding the role of conceptual processes” (page unavailable), the paper says prior beliefs shape reward learning and suggestions may influence credit assignment. “Self-reinforcing placebo effects?” (page unavailable) proposes that experiences inconsistent with prior beliefs may be discarded. These passages support the general idea of suppressing disconfirmatory feedback, but do not establish that the manipulations alter the reinforcement signal used to calculate prediction errors. (LLM, conf=0.82)
Experimental — accuracy not yet measured
dlPFC is especially important for top-down regulation of treatment and placebo expectancies, whereas mPFC plays a key role in encoding value of expected outcomes.
“In particular, dlPFC regions appear especially important for exerting top-downregulation of treatment and placebo expectancies, whereas mPFC regions play a key role in encoding value of expected outcomes [218,219].”
From Prefrontal cortex and depression (2022) · cites this paper as [218]
In “Placebos engage endogenous pain modulation circuitry” (page unavailable), the review links dlPFC activity and stimulation to placebo analgesia, but does not specifically assign dlPFC a role in top-down regulation of treatment and placebo expectancies. In “Different mechanisms for different outcomes?” (page unavailable), it links vmPFC responses to valuation and beliefs, but does not establish that mPFC encodes the value of expected outcomes as stated. (LLM, conf=0.84)
Experimental — accuracy not yet measured
lOFC has been activated in several placebo treatment studies, often in co-activation with rACC.
“The lOFC has been activated in several placebo treatment studies (often in co-activation with rACC) as indicated by meta-analysis (Atlas and Wager, 2014; Wager and Atlas, 2015; Figure 6A) including placebo analgesia (Petrovic et al., 2002; Lieberman et al., 2004; Wager et al., 2004) and emotional placebo (Petrovic et al., 2005).”
From Top-Down Dysregulation—From ADHD to Emotional Instability (2016) · cites this paper as Wager and Atlas, 2015
The Neuroimaging evidence section reports placebo-related increases in the mid-lateral OFC across several pain studies and also identifies increases in the rostral cingulate. It does not establish that the two regions were often co-activated in the same studies, or extend the lateral-OFC finding to emotional placebo studies. (LLM, conf=0.82)
Experimental — accuracy not yet measured
In placebo analgesia, expecting low pain decreases pain perception and associated brain activity.
“For example, in placebo analgesia, expecting low pain decreases pain perception and associated brain activity6–11.”
From Boundary effects of expectation in human pain perception (2019) · cites this paper as [11]
Placebo effects involve the expectation or belief that a sham treatment is effective in changing response without relying on top-down control processes.
“Placebo effects involve the expectation or belief that a sham treatment is effective in changing the way one will respond to a stimulus without relying on top-down control processes to cause placebo-related changes in response to a stimulus (Wager and Atlas, 2015).”
From Explicit and implicit emotion regulation: a multi-level framework (2017) · cites this paper as Wager and Atlas, 2015

Placebo treatment is accompanied by reductions in activity in pain-sensitive brain regions including medial thalamus, anterior insula, dACC, periaqueductal gray and secondary somatosensory cortex-dorsal posterior insula.
“Accompanying these activity increases are reductions in activity in pain-sensitive brain regions including the medial thalamus, anterior insula, and dACC, periaqueductal gray and secondary somatosensory cortex-dorsal posterior insula (Wager and Atlas, 2015).”
From Explicit and implicit emotion regulation: a multi-level framework (2017) · cites this paper as Wager and Atlas, 2015
Placebo treatment is generally accompanied by increased recruitment of vmPFC, dlPFC, lateral OFC, ventral striatum and periaqueductal gray.
“In the brain (Figure 3), placebo treatment is generally accompanied by increased recruitment of several regions, including vmPFC, dlPFC, lateral OFC, ventral striatum and periaqueductal gray, with activity in these regions thought to support the maintenance of information about the context and the creation of placebo-related expectations/appraisals (Wager and Atlas, 2015).”
From Explicit and implicit emotion regulation: a multi-level framework (2017) · cites this paper as Wager and Atlas, 2015
Placebo effects are shaped by the desire for personal well-being and expectations of efficacy of inert treatment.
“Placebo effect refers to health benefits induced by the use of inert treatment and is shaped by the desire for personal well-being and expectations of efficacy of inert (but believed active) treatment (1, 2).”
From Placebo treatment facilitates social trust and approach behavior (2018) · cites this paper as [2]
Placebo effects are often found on dimensions that are sensitive to an individual's internal thoughts.
“As placebo effects are often found on dimensions that are sensitive to an individual’s internal thoughts (2)”
From Placebo treatment facilitates social trust and approach behavior (2018) · cites this paper as [2]
Placebo treatment reduces pain and negative emotion through a top-down modulation, with high-level expectation driving downstream changes in sensory feelings and affective physiology.
“It has been recognized that placebo treatment reduces pain and negative emotion through a top-down modulation, with “high-level” expectation driving the downstream changes in one’s own sensory feelings and affective physiology (2, 46, 47).”
From Placebo treatment facilitates social trust and approach behavior (2018) · cites this paper as [2]

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Research works printed but not linked: 3

[1]Committee on Advancing Pain Research, Care, and Education Relieving Pain in America: A Blueprint for Transforming Prevention, Care, Education, and Research Institute of Medicine of the National Academies 1 350 The National Academies Press 2011 22553896
[103]Atlas LY Wager TD Placebo Benedetti F Enck P Frisaldi E Schedlowski M 37 69 Springer 2014
[119]Heinricher M Fields H Wall & Melzack’s Textbook of Pain McMahon S Koltzenburg M Tracey I Turk DC 129 142 Elsevier Health Sciences 2013

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Self-citation

Authors: Wager, T. D., & Atlas, L. Y.
Affiliations: University of Colorado Boulder (US)
National Institutes of Health (US)
Corresponding author: Wager, Tor D.
ORCID: Wager, Tor D.
Atlas, Lauren Y.
Venue: Nature Reviews Neuroscience
Publisher: Springer Science and Business Media LLC
Published: 2015-06-19
Volume: 16
Issue: 7
Pages: 403-418
ISSN: 1471-003X (ISSN-L)
1471-0048
DOI: 10.1038/nrn3976
PMC: PMC6013051
OpenAlex: W1518596071
Cited by: 844
References: 224
Citations by year: 2026: 86 · 2025: 105 · 2024: 98 · 2023: 71 · 2022: 89 · 2021: 96 · 2020: 79 · 2019: 73 · 2018: 69 · 2017: 45 · 2016: 28 · 2015: 4
FWCI: 4.84
Type: journal article
Language: en
Open access: green
europepmc.org
Licence: www.springer.com/tdm (tdm)
Locations: Nature reviews. Neuroscience (publishedVersion)
PubMed (publishedVersion)
Europe PMC (PubMed Central) (acceptedVersion)
PubMed Central (acceptedVersion)
Funders: National Institutes of Health
National Institute of Mental Health (R01MH076136)
National Institute on Drug Abuse (R01DA027794)
National Center for Complementary and Integrative Health
Topics: Life Sciences › Neuroscience › Cognitive Neuroscience › Pain Management and Placebo Effect
Health Sciences › Medicine › Physiology › Pain Mechanisms and Treatments
Life Sciences › Neuroscience › Neurology › Transcranial Magnetic Stimulation Studies
Keywords: placebo effect, placebo analgesia, expectations, learning, social cognition, opioids, dopamine, brain systems
MeSH terms: Brain, Humans, Learning, Mental Processes, Neural Pathways, Neurosciences, Placebo Effect, Pain Management

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

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