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Predicting Individual Differences in Placebo Analgesia: Contributions of Brain Activity during Anticipation and Pain Experience
Open accessAbstract
Recent studies have identified brain correlates of placebo analgesia, but none have assessed how accurately patterns of brain activity can predict individual differences in placebo responses. We reanalyzed data from two fMRI studies of placebo analgesia (N= 47), using patterns of fMRI activity during the anticipation and experience of pain to predict new subjects' scores on placebo analgesia and placebo-induced changes in pain processing. We used a cross-validated regression procedure, LASSO-PCR, which provided both unbiased estimates of predictive accuracy and interpretable maps of which regions are most important for prediction. Increased anticipatory activity in a frontoparietal network and decreases in a posterior insular/temporal network predicted placebo analgesia. Patterns of anticipatory activity across the cortex predicted a moderate amount of variance in the placebo response (∼12% overall, ∼40% for study 2 alone), which is substantial considering the multiple likely contributing factors. The most predictive regions were those associated with emotional appraisal, rather than cognitive control or pain processing. During pain, decreases in limbic and paralimbic regions most strongly predicted placebo analgesia. Responses within canonical pain-processing regions explained significant variance in placebo analgesia, but the pattern of effects was inconsistent with widespread decreases in nociceptive processing. Together, the findings suggest that engagement of emotional appraisal circuits drives individual variation in placebo analgesia, rather than early suppression of nociceptive processing. This approach provides a framework that will allow prediction accuracy to increase as new studies provide more precise information for future predictive models.
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“Pain relief produced by these cognitive techniques are associated with significant reductions in pain-related brain activation (i.e., SI, SII, posterior insula, parietal operculum) and activation in higher-order brain regions, such as the ACC, PFC, and insula.86, 89, 98–110”
From Mindfulness meditation-based pain relief: a mechanistic account (2016) · cites this paper as [103]
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“and a recent study found that vmPFC activity was correlated with the strength of both expectations of analgesia and pain relief [62].”
From Ventromedial prefrontal–subcortical systems and the generation of affective meaning (2012) · cites this paper as [62]
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“While placebo studies often involve conditioning procedures, these may often serve primarily to alter expectations and the meaning of pain in context [60,61], and a recent study found that vmPFC activity was correlated with the strength of both expectations of analgesia and pain relief [62].”
From Ventromedial prefrontal–subcortical systems and the generation of affective meaning (2012) · cites this paper as [62]
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The integration of negative affect, pain and cognitive control in the cingulate cortex
Shackman, A. J., Salomons, T. V., Slagter, H. A., Fox, A. S., Winter, J. J., & Davidson, R. J. (2011) · Nature Reviews Neuroscience · doi:10.1038/nrn2994 · Cited by 2,082
Ochsner, K. N., Silvers, J. A., & Buhle, J. T. (2012) · Annals of the New York Academy of Sciences · doi:10.1111/j.1749-6632.2012.06751.x · Cited by 1,879
An fMRI-Based Neurologic Signature of Physical Pain
Wager, T. D., Atlas, L. Y., Lindquist, M. A., Roy, M., Woo, C.-W., & Kross, E. (2013) · New England Journal of Medicine · doi:10.1056/nejmoa1204471 · Cited by 1,597
Self-citationBuilding better biomarkers: brain models in translational neuroimaging
Woo, C.-W., Chang, L. J., Lindquist, M. A., & Wager, T. D. (2017) · Nature Neuroscience · doi:10.1038/nn.4478 · Cited by 1,056
Self-citationVentromedial prefrontal–subcortical systems and the generation of affective meaning
Roy, M., Shohamy, D., & Wager, T. D. (2012) · Trends in Cognitive Sciences · doi:10.1016/j.tics.2012.01.005 · Cited by 856
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Metadata
- Authors
- Wager, T. D., Atlas, L. Y., Leotti, L. A., & Rilling, J. K.
- Affiliations
- University of Colorado Boulder (US)
- Columbia University (US)
- Rutgers, The State University of New Jersey (US)
- Emory University (US)
- Corresponding author
- Wager, Tor D.
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2011-01-12
- Volume
- 31
- Issue
- 2
- Pages
- 439-452
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC3735131
- OpenAlex
- W2158440149
- Cited by
- 328
- References
- 96
- Citations by year
- 2026: 11 · 2025: 19 · 2024: 25 · 2023: 26 · 2022: 13 · 2021: 16 · 2020: 22 · 2019: 18 · 2018: 20 · 2017: 27 · 2016: 18 · 2015: 24 · 2014: 23 · 2013: 29 · 2012: 24
- FWCI
- 14.28
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Neuroscience (publishedVersion, cc-by-nc-sa)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- Journal of Neuroscience Nursing
- Funders
- John D. and Catherine T. MacArthur Foundation
- Kohlberg Foundation
- National Institutes of Health (MH076136)
- National Institute of Mental Health (MH076136, R01MH076136, R37MH076136)
- National Institute on Drug Abuse (RC1DA028608, R01DA027794)
- Topics
- Life Sciences › Neuroscience › Cognitive Neuroscience › Pain Management and Placebo Effect
- Health Sciences › Medicine › Physiology (medical) › Pain Mechanisms and Treatments
- Health Sciences › Medicine › Anesthesiology and Pain Medicine › Pain Management and Treatment
- Keywords
- placebo analgesia, individual differences, pain experience, emotional appraisal, frontoparietal network, posterior insula, paralimbic regions, pain processing, nociception
- MeSH terms
- Analgesia, Analgesics, Brain, Cerebral Cortex, Data Interpretation, Statistical, Humans, Individuality, Magnetic Resonance Imaging, Nerve Net, Pain, Regression Analysis, Placebo Effect, Cluster Analysis, Anticipation, Psychological
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