Exacerbation of Pain by Anxiety Is Associated with Activity in a Hippocampal Network
Open accessAbstract
It is common clinical experience that anxiety about pain can exacerbate the pain sensation. Using event-related functional magnetic resonance imaging (FMRI), we compared activation responses to noxious thermal stimulation while perceived pain intensity was manipulated by changes in either physical intensity or induced anxiety. One visual signal, which reliably predicted noxious stimulation of moderate intensity, came to evoke low anxiety about the impending pain. Another visual signal was followed by the same, moderate-intensity stimulation on most of the trials, but occasionally by discriminably stronger noxious stimuli, and came to evoke higher anxiety. We found that the entorhinal cortex of the hippocampal formation responded differentially to identical noxious stimuli, dependent on whether the perceived pain intensity was enhanced by pain-relevant anxiety. During this emotional pain modulation, entorhinal responses predicted activity in closely connected, affective (perigenual cingulate), and intensity coding (mid-insula) areas. Our finding suggests that accurate preparatory information during medical and dental procedures alleviates pain by disengaging the hippocampus. It supports the proposal that during anxiety, the hippocampal formation amplifies aversive events to prime behavioral responses that are adaptive to the worst possible outcome.
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Ploghaus et al.'s functional magnetic resonance imaging study indicated that activation in the entorhinal cortex of the hippocampal formation differed depending on whether pain intensity was increased by the anxiety manipulation.
“Results indicated that activation in the entorhinal cortex of the hippocampal formation differed depending on whether pain intensity was increased by the anxiety manipulation.”
From Psychological aspects of persistent pain: Current state of the science (2004) · cites this paper as [94]
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 Ploghaus et al., 2001
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Self-citation
- Authors
- Ploghaus, A., Narain, C., Beckmann, C. F., Clare, S., Bantick, S., Wise, R., Matthews, P. M., Rawlins, J. N. P., & Tracey, I.
- Affiliations
- John Radcliffe Hospital (GB)
- University of Oxford (GB)
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2001-12-15
- Volume
- 21
- Issue
- 24
- Pages
- 9896-9903
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC6763058
- OpenAlex
- W1828259239
- Cited by
- 822
- References
- 99
- Citations by year
- 2026: 8 · 2025: 20 · 2024: 27 · 2023: 37 · 2022: 32 · 2021: 42 · 2020: 32 · 2019: 40 · 2018: 32 · 2017: 36 · 2016: 35 · 2015: 47 · 2014: 48 · 2013: 48 · 2012: 35
- FWCI
- 11.18
- 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)
- ORCA Online Research @Cardiff (Cardiff University) (acceptedVersion)
- Topics
- Life Sciences › Neuroscience › Cognitive Neuroscience › Pain Management and Placebo Effect
- Health Sciences › Medicine › Physiology › Pain Mechanisms and Treatments
- Life Sciences › Neuroscience › Cognitive Neuroscience › Memory and Neural Mechanisms
- Keywords
- pain modulation, hippocampal formation, entorhinal cortex, noxious thermal stimulation, pain intensity, insula, anticipatory anxiety, emotional pain
- MeSH terms
- Adult, Anxiety, Behavior, Brain Mapping, Conditioning, Classical, Heart Rate, Hot Temperature, Hippocampus, Humans, Hyperalgesia, Magnetic Resonance Imaging, Male, Nerve Net, Pain, Physical Stimulation, Entorhinal Cortex, Parahippocampal Gyrus
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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