A functional magnetic resonance imaging study on the neural mechanisms of hyperalgesic nocebo effect
Open accessAbstract
Previous studies suggest that nocebo effects, sometimes termed “negative placebo effects,” can contribute appreciably to a variety of medical symptoms and adverse events in clinical trials and medical care. In this study, using a within-subject design, we combined functional magnetic resonance imaging (fMRI) and an expectation/conditioning manipulation model to investigate the neural substrates of nocebo hyperalgesia using heat pain on the right forearm. Thirteen subjects completed the study. Results showed that, after administering inert treatment, subjective pain intensity ratings increased significantly more on nocebo regions compared with the control regions in which no expectancy/conditioning manipulation was performed. fMRI analysis of hyperalgesic nocebo responses to identical calibrated noxious stimuli showed signal increases in brain regions including bilateral dorsal anterior cingulate cortex (ACC), insula, superior temporal gyrus; left frontal and parietal operculum, medial frontal gyrus, orbital prefrontal cortex, superior parietal lobule, and hippocampus; right claustrum/putamen, lateral prefrontal gyrus, and middle temporal gyrus. Functional connectivity analysis of spontaneous resting-state fMRI data from the same cohort of subjects showed a correlation between two seed regions (left frontal operculum and hippocampus) and pain network including bilateral insula, operculum, ACC, and left S1/M1. In conclusion, we found evidence that nocebo hyperalgesia may be predominantly produced through an affective–cognitive pain pathway (medial pain system), and the left hippocampus may play an important role in this process.
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Previous neuroimaging studies have shown that nocebo effects are mediated by the hippocampus and regions involved in anticipatory anxiety processing.
“Previous neuroimaging studies have also shown that nocebo effects are mediated by the hippocampus and regions involved in anticipatory anxiety processing (Bingel et al., 2011; Kong et al., 2008; Ploghaus et al., 2001).”
From Distinct neural representations of placebo and nocebo effects (2015) · cites this paper as Kong et al., 2008
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Self-citation
- Authors
- Kong, J., Gollub, R. L., Polich, G., Kirsch, I., LaViolette, P., Vangel, M., Rosen, B., & Kaptchuk, T. J.
- Affiliations
- Harvard University (US)
- Massachusetts General Hospital (US)
- University of Hull (GB)
- ORCID
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2008-12-03
- Volume
- 28
- Issue
- 49
- Pages
- 13354-13362
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC2649754
- OpenAlex
- W2143071887
- Cited by
- 263
- References
- 59
- Citations by year
- 2026: 3 · 2025: 10 · 2024: 15 · 2023: 5 · 2022: 15 · 2021: 16 · 2020: 16 · 2019: 16 · 2018: 11 · 2017: 11 · 2016: 14 · 2015: 19 · 2014: 23 · 2013: 26 · 2012: 19
- FWCI
- 7.48
- 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)
- Funders
- National Institutes of Health (RR14075)
- National Center for Complementary and Alternative Medicine
- National Center for Research Resources (RR 14075, M01RR001066, P41RR014075)
- National Center for Complementary and Integrative Health (K24AT004095, R21AT001922, R21AT000949, P01AT002048, K01AT003883)
- Topics
- Life Sciences › Neuroscience › Cognitive Neuroscience › Pain Management and Placebo Effect
- Health Sciences › Medicine › Physiology › Pain Mechanisms and Treatments
- Health Sciences › Medicine › Anesthesiology and Pain Medicine › Pain Management and Treatment
- Keywords
- nocebo effect, hyperalgesia, thermal pain, pain anticipation, dorsal anterior cingulate cortex, insula, hippocampus, frontal operculum, resting-state functional connectivity, pain network
- MeSH terms
- Adult, Brain, Brain Mapping, Cognition, Conditioning, Psychological, Female, Hippocampus, Humans, Hyperalgesia, Illusions, Functional Laterality, Magnetic Resonance Imaging, Male, Nerve Net, Neuropsychological Tests, Pain, Pain Measurement, Physical Stimulation, Placebo Effect, Pain Threshold, Young Adult
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