Uncertainty increases pain: evidence for a novel mechanism of pain modulation involving the periaqueductal gray
Open accessAbstract
Predictions about sensory input exert a dominant effect on what we perceive, and this is particularly true for the experience of pain. However, it remains unclear what component of prediction, from an information-theoretic perspective, controls this effect. We used a vicarious pain observation paradigm to study how the underlying statistics of predictive information modulate experience. Subjects observed judgments that a group of people made to a painful thermal stimulus, before receiving the same stimulus themselves. We show that the mean observed rating exerted a strong assimilative effect on subjective pain. In addition, we show that observed uncertainty had a specific and potent hyperalgesic effect. Using computational functional magnetic resonance imaging, we found that this effect correlated with activity in the periaqueductal gray. Our results provide evidence for a novel form of cognitive hyperalgesia relating to perceptual uncertainty, induced here by vicarious observation, with control mediated by the brainstem pain modulatory system.
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The basic psychological mechanisms underlying the formation of negative expectations and nocebo effects are anticipation of and information about negative outcomes, prior lack of therapeutic effectiveness, and observation of other patients' pain worsening.
“The basic psychological mechanisms underlying the formation of negative expectations and thus, nocebo effects, are anticipation of and information about negative outcomes,34,76 prior lack of therapeutic effectiveness,33,34 and observation of other patients' pain worsening.42,60,74,77,78”
From Nocebo and pain: an overview of the psychoneurobiological mechanisms (2017) · cites this paper as [78]
In a study of 97 women exposed to either a nocebo condition or control condition through observing a video portraying a female model, results demonstrated a significant difference in pain ratings as an effect of group condition and also as an effect of ointment applications within each condition.
“Results demonstrated a significant difference in the pain ratings as an effect of group condition, and also as an effect of ointment applications within each condition.”
From Nocebo and pain: an overview of the psychoneurobiological mechanisms (2017) · cites this paper as [78]
In this study, nocebo responses were correlated with hypochondriacal trepidations as well as somatic complaints in the control condition group but not in the nocebo group.
“In this study, nocebo responses were correlated with hypochondriacal trepidations as well as somatic complaints in the control condition group but not in the nocebo group.78”
From Nocebo and pain: an overview of the psychoneurobiological mechanisms (2017) · cites this paper as [78]
Ratings of pain were higher in the nocebo condition than in the control condition, suggesting a potentiated perception of pain related to social observation.
“Furthermore, ratings of pain were higher in the nocebo condition than that in the control condition, which suggests a potentiated perception of pain related to the social observation.”
From Nocebo and pain: an overview of the psychoneurobiological mechanisms (2017) · cites this paper as [78]
Women within both the nocebo and control conditions reported more pain with application of the ointment.
“Women within both the nocebo and control conditions reported more pain with application of the ointment.”
From Nocebo and pain: an overview of the psychoneurobiological mechanisms (2017) · cites this paper as [78]
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- Authors
- Yoshida, W., Seymour, B., Koltzenburg, M., & Dolan, R. J.
- Affiliations
- Wellcome Centre for Human Neuroimaging (GB)
- UCL Queen Square Institute of Neurology (GB)
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2013-03-27
- Volume
- 33
- Issue
- 13
- Pages
- 5638-5646
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC3701089
- OpenAlex
- W2085014216
- Cited by
- 165
- References
- 74
- Citations by year
- 2026: 11 · 2025: 13 · 2024: 23 · 2023: 25 · 2022: 12 · 2021: 7 · 2020: 7 · 2019: 14 · 2018: 10 · 2017: 14 · 2016: 7 · 2015: 11 · 2014: 9 · 2013: 2
- FWCI
- 6.66
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Neuroscience (publishedVersion, cc-by-nc-sa)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- UCL Discovery (University College London) (submittedVersion)
- Max Planck Digital Library (submittedVersion, other-oa)
- Cambridge University Engineering Department Publications Database (submittedVersion)
- MPG.PuRe (Max Planck Society) (submittedVersion, other-oa)
- Funders
- Wellcome Trust (091593, 078865/Z/05/Z, 078865, 098362, 098362/Z/12/Z, 091593/Z/10/Z)
- Ministry of Internal Affairs and Communications
- Medical Research Council (MR/K000608/1, MR/K015222/1)
- Topics
- Health Sciences › Medicine › Physiology › Pain Mechanisms and Treatments
- Life Sciences › Neuroscience › Cognitive Neuroscience › Pain Management and Placebo Effect
- Health Sciences › Medicine › Anesthesiology and Pain Medicine › Pain Management and Treatment
- Keywords
- pain perception, uncertainty, periaqueductal gray, predictive information, assimilation, thermal pain
- MeSH terms
- Brain Mapping, Computer Simulation, Female, Humans, Image Processing, Computer-Assisted, Magnetic Resonance Imaging, Male, Models, Biological, Oxygen, Pain, Pain Measurement, Periaqueductal Gray, Physical Stimulation, Pain Threshold, Uncertainty, Pain Perception
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