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Cited by 116Pain Management and Placebo EffectPain Mechanisms and TreatmentsPain Management and Treatment

Distinct neural representations of placebo and nocebo effects

Open access
Freeman, Sonya, Yu, Rongjun, Egorova, Natalia, Chen, Xiaoyan, Kirsch, Irving, Claggett, Brian, Kaptchuk, Ted J., Gollub, Randy L. +1 more·2015·NeuroImage
DOI 10.1016/j.neuroimage.2015.03.015PMC PMC4408248
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Abstract

Expectations shape the way we experience the world. In this study, we used fMRI to investigate how positive and negative expectation can change pain experiences in the same cohort of subjects. We first manipulated subjects' treatment expectation of the effectiveness of three inert creams, with one cream labeled "Lidocaine" (positive expectancy), one labeled "Capsaicin" (negative expectancy) and one labeled "Neutral" by surreptitiously decreasing, increasing, or not changing respectively, the intensity of the noxious stimuli administered following cream application. We then used fMRI to investigate the signal changes associated with administration of identical pain stimuli before and after the treatment and control creams. Twenty-four healthy adults completed the study. Results showed that expectancy significantly modulated subjective pain ratings. After controlling for changes in the neutral condition, the subjective pain rating changes evoked by positive and negative expectancies were significantly associated. fMRI results showed that the expectation of an increase in pain induced significant fMRI signal changes in the insula, orbitofrontal cortex, and periaqueductal gray, whereas the expectation of pain relief evoked significant fMRI signal changes in the striatum. No brain regions were identified as common to both "Capsaicin" and "Lidocaine" conditioning. There was also no significant association between the brain response to identical noxious stimuli in the pain matrix evoked by positive and negative expectancies. Our findings suggest that positive and negative expectancies engage different brain networks to modulate our pain experiences, but, overall, these distinct patterns of neural activation result in a correlated placebo and nocebo behavioral response.

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Crossref · 10.1016/j.neuroimage.2015.03.015

Cites

76 of 76 references verified0 citation errors · 0 not checkable

Statistics

Claims the paper makes

0 of 49 cited sources checked · 0 supported · 0 flagged

  • Findingown data

    In the Lidocaine condition, pain ratings fell.

    “within-condition t-tests indicated that pain ratings decreased in the “Lidocaine” condition, t(23) = −4.83, p < .001”
    Quote in the paperNot a substantial claim
  • Findingown data

    In the 'Capsaicin' condition, the post > pre contrast showed activation in bilateral insula, right OPFC, and PAG.

    “The opposite contrast in the “Capsaicin” condition (post > pre) showed activation in the bilateral insula, and right OPFC and PAG (Figure 6).”
    Quote in the paperSubstantial claim
  • Findingnone given

    In the present study, after the expectancy manipulation in Session 2, participants believed that the inert 'Lidocaine' cream could reduce their pain sensation.

    “In the present study, after the expectancy manipulation in Session 2, participants believed that the inert “Lidocaine” cream could reduce their pain sensation.”
    Quote in the paperSubstantial claim
  • Findingown data

    Expecting more pain produced significant fMRI signal changes in the insula, orbitofrontal cortex, and periaqueductal gray.

    “fMRI results showed that the expectation of an increase in pain induced significant fMRI signal changes in the insula, orbitofrontal cortex, and periaqueductal gray”
    Quote in the paperSubstantial claim
  • Findingown data

    Pain rating changes under Capsaicin correlated significantly with those under the neutral cream.

    “We found a significant correlation between the “Capsaicin” and neutral cream (r = 0.56, p = 0.006)”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The neutral cream condition provides a valid control for nonspecific changes in pain ratings and fMRI signal over time.
  • May combine two claims. 16
  • Classified as probably not a substantial claim. 19

  • May combine two claims.

    Findingown data

    Beta values from those regions showed significant fMRI signal decreases in the 'Lidocaine' condition and signal increases in the 'Capsaicin' condition.

    “We extracted the beta values from those brain regions and found significant fMRI signal decreases in the “Lidocaine” condition and signal increases in the “Capsaicin” condition (Figure 4).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Left anterior insula and right DLPFC had comparable pre-treatment activation in the two conditions, which diverged post-treatment with increased activation after 'Capsaicin' and decreased after 'Lidocaine'.

    “In contrast, the left anterior insula and right DLPFC showed comparable pre-treatment activation in the two conditions that diverged post-treatment in the direction consistent with the response of the pain responsive networks, e.g. increased after “Capsaicin” and decreased after “Lidocaine.””
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Inert 'Capsaicin' cream with expectancy of pain enhancement evoked a significant increase in subjective pain ratings and fMRI signal changes in the insula, OFC, and PAG.

    “In the present study, using a within-subject design, we found that the application of inert “Lidocaine” cream with expectation of pain relief evoked a significant reduction in subjective pain ratings and fMRI signal changes in the striatum, whereas inert “Capsaicin” cream with expectancy of pain enhancement evoked a significant increase in subjective pain ratings and fMRI signal changes in the ins”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    In the present study, inert 'Lidocaine' cream with expectation of pain relief evoked a significant reduction in subjective pain ratings and fMRI signal changes in the striatum.

    “In the present study, using a within-subject design, we found that the application of inert “Lidocaine” cream with expectation of pain relief evoked a significant reduction in subjective pain ratings and fMRI signal changes in the striatum, whereas inert “Capsaicin” cream with expectancy of pain enhancement evoked a significant increase in subjective pain ratings and fMRI signal changes in the ins”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Both positive and negative expectancy effects were correlated with changes in reported pain intensity in the neutral cream condition, suggesting reliable individual differences in response biases across the three conditions.

    “We found that both positive and negative expectancy effects were correlated with changes in reported pain intensity in the neutral cream condition, suggesting reliable individual differences in response biases across the three conditions.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Pearson correlation among the three conditions found a non-significant trend for association between 'Capsaicin' and neutral conditions (r = .35, p = .093), but no other correlations approached significance.

    “We found a non-significant trend for the association between “Capsaicin” and neutral conditions (r = .35, p = .093), but no other correlations approached significance.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    The dACC showed enhanced activation in pre-treatment 'Lidocaine' relative to pre-treatment 'Capsaicin', and this pattern reversed after treatment.

    “Interestingly, the dACC region showed a unique pattern of enhanced activation in the pre-treatment “Lidocaine” condition relative to the pre-treatment “Capsaicin” condition that reversed post treatment.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Expectancy ratings fell after the Session 3 post-treatment test, returning to a level statistically indistinguishable from before conditioning.

    “did not change significantly until after the post-treatment test in Session 3 when they decreased (p < .001) to a level that was not significantly different from pre-conditioning expectancy ratings.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    None of the four conjunction analyses revealed significant activation, indicating no common brain regions were observed between these contrasts.

    “None of these four conjunction analyses revealed any significant activation, indicating that no common brain regions were observed between these contrasts.”
    • Also stated in: § Discussion · plain
      “No overlapping brain regions were identified in response to both the “Capsaicin” and “Lidocaine” conditions at the threshold we set.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Premisecitation

    The context surrounding treatment delivery can allow placebo effects to improve care benefits.

    “There is an increasing body of literature suggesting that placebo effects can enhance the therapeutic benefits of care through the context in which the treatment is administered (Brody and Miller, 2011; Cleophas, 1995; de la Fuente-fernandex et al., 2002; Di Blasi et al., 2001; Finniss et al., 2010; Kaptchuk, 1998; Price et al., 2008; Thomas, 1994).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Brody and Miller, 2011 source

      Not checked in the free run.

    • cites Cleophas, 1995 source

      Not checked in the free run.

    • cites de la Fuente-fernandex et al., 2002 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    A recent study found that the ventral striatum might not be causally involved in placebo analgesia, but rather linked to phenomena associated with placebo analgesia, such as reward processing and learning.

    “This result is consistent with a recent study, in which Wrobel and colleagues (Wrobel et al., 2014) found that the ventral striatum might not be causally involved in placebo analgesia, but rather linked to phenomena associated with placebo analgesia, such as reward processing and learning.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Wrobel et al., 2014 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationcitation

    The observed main effects match earlier reports of neural activation and deactivation caused by pain.

    “These main effects are consistent with previous findings on the patterns of pain-elicited neural activation and deactivation (Kong et al., 2010a).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Kong et al., 2010a

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Premisenone given

    In the first stage, before pain is experienced, expectation or anticipation of pain relief or enhancement can modulate perception of subsequent pain stimuli.

    “In the first stage, prior to the experience of pain, the expectation or anticipation of pain relief/enhancement can modulate the perception of subsequent pain stimuli.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Dopamine-related measurements including baseline ventral striatum coherence, functional variation in the COMT gene, and openness to experience together could predict conditioning cue responses in healthy individuals, highlighting a strong link between placebo responsiveness and brain reward processing.

    “One of our previous studies (Yu et al., 2014) showed that dopamine-related measurements including baseline ventral striatum coherence, functional variation in the COMT gene, and openness to experience together could predict conditioning cue responses in healthy individuals, which highlights a strong link between placebo responsiveness and brain reward processing.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Yu et al., 2014

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductown data

    The analysis included every one of the 24 participants who finished the third session.

    “Data from all 24 subjects who completed Session 3 were included in the analysis.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Study design and conductnone given

    Participants had to show, through average pain ratings, that they could tell apart pre- and post-treatment stimuli in the Lidocaine and Capsaicin areas before they could remain in the study.

    “Only subjects who could distinguish between the pre- and post-treatment stimuli on the “Lidocaine” and “Capsaicin” regions, as indicated by average pain ratings, were permitted to continue with the study.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Study design and conductreasoning

    The study used a within-subject design, which allowed direct comparison of how positive and negative expectancy modulate the subjective experience of pain.

    “One of the strengths of the present study is that we used a within subject design, which allowed a direct comparison of how positive and negative expectancy can modulate the subjective experience of pain.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    The paper's findings suggest that while self-reported placebo and nocebo responses are highly associated, this association does not exist in corresponding brain activity changes in pain-related brain regions; positive and negative expectancy appear to engage different brain networks to modulate pain.

    “Our findings suggest that while self-reported placebo and nocebo responses are highly associated, this association does not exist in the corresponding brain activity changes in pain-related brain regions; positive and negative expectancy seem to engage different brain networks to modulate the experience of pain.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: fMRI mainly assesses phasic, stimulus-evoked responses.
    • Rests on an assumption: Brain responses in pain-related brain regions to calibrated heat pain only represent the response in one stage.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    In the second stage, during administration of painful stimuli, an inert treatment may inhibit or enhance incoming noxious signals.

    “In the second stage, during administration of painful stimuli, an inert treatment may inhibit/enhance the incoming signals of noxious stimuli.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationown data

    Despite separate neural activation patterns, placebo and nocebo behavioral responses are correlated.

    “but, overall, these distinct patterns of neural activation result in a correlated placebo and nocebo behavioral response.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Individual variation in ventral striatal response to reward expectation accounted for 28% of the variance in the magnitude of placebo analgesia.

    “It has been shown that individual variation in ventral striatal response to reward expectation accounted for 28% of the variance in the magnitude of placebo analgesia (Scott et al., 2007).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Scott et al., 2007 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    An inert treatment could function through three interrelated processes to produce placebo and nocebo effects.

    “Theoretically, an inert treatment could function through three interrelated processes to produce placebo and nocebo effects (Amanzio et al., 2013; Kong et al., 2007).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Amanzio et al., 2013 source

      Not checked in the free run.

    • cites Kong et al., 2007 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    The design made it possible to examine how placebo and nocebo effects relate and to compare their neural networks without any active drug.

    “This experimental design allowed us to investigate the association between the placebo and nocebo effects and directly compare the brain networks between these two important clinical phenomena in the absence of active medication.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Interpretationreasoning

    The anxiety level evoked in this study may be weaker compared to the previous experiment.

    “Thus, the anxiety level evoked in this study may be weaker compared to our previous experiment.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Anxiety is associated with functional connectivity between the amygdala and the insula, as well as coupling between the amygdala and the OFC.

    “Investigators have previously shown that anxiety is associated with the functional connectivity between the amygdala and the insula (Baur et al., 2013; Shah et al., 2009; Stein et al., 2007) as well as the coupling between the amygdala and the OFC (Hahn et al., 2011; Sladky et al., 2013).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites Baur et al., 2013 source

      Not checked in the free run.

    • cites Shah et al., 2009

      Not checked in the free run.

    • cites Stein et al., 2007 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Previous studies suggest that the descending pain modulatory system is involved in placebo analgesia.

    “This result is partly consistent with previous studies (Eippert et al., 2009; Wager et al., 2004) suggesting that the descending pain modulatory system is involved in placebo analgesia.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Eippert et al., 2009 source

      Not checked in the free run.

    • cites Wager et al., 2004 source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Premisecitation

    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).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Bingel et al., 2011 source

      Not checked in the free run.

    • cites Kong et al., 2008 source

      Not checked in the free run.

    • cites Ploghaus et al., 2001 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductown data

    Because the study did not have an anticipation stage, it could not explore brain networks associated with anticipation.

    “Additionally, since we did not have an anticipation stage in our study, we were not able to explore brain networks associated with anticipation.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Premisecitation

    Previous studies have shown that outcome processing is highly sensitive to the range of possible outcomes from which the final outcome is selected.

    “Previous studies have shown that outcome processing is highly sensitive to the range of possible outcomes from which the final outcome is selected (Akitsuki et al., 2003; Nieuwenhuis et al., 2005).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Akitsuki et al., 2003 source

      Not checked in the free run.

    • cites Nieuwenhuis et al., 2005 source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Interpretationreasoning

    In this within-subject design, the perception of the neutral condition might have been context-dependent.

    “In this within-subject design, the perception of a neutral condition might have been context-dependent.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Activity in the PAG and OFC has often been related to processing of anxiety associated with anticipating nociceptive stimuli.

    “The activity in the PAG and the OFC has also been often related to the processing of anxiety associated with anticipating nociceptive stimuli (Brodersen et al., 2012; Fairhurst et al., 2007).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Brodersen et al., 2012 source

      Not checked in the free run.

    • cites Fairhurst et al., 2007 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationreasoning

    This activation might be due to the unique design in which all participants experienced nocebo, neutral, and placebo conditions.

    “This might be due to the unique design we used in which all participants experienced nocebo, neutral, and placebo conditions.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductreasoning

    One potential limitation of the study is that the creams were colored and the color-coding was not randomized.

    “One potential limitation of this study is that creams were colored and that this color-coding was not randomized.”
    Quote in the paperNot a substantial claim
33 of 33

  • The paper relies on this without support.

    In pain perception, positive expectations can produce analgesia and negative expectations can produce hyperalgesia.

    “In the context of pain perception, positive expectations of treatment can elicit analgesia while negative expectation can elicit hyperalgesia.”

  • The paper relies on this without support.

    The neutral cream condition provides a valid control for nonspecific changes in pain ratings and fMRI signal over time.

    “After controlling for changes in the neutral condition, the subjective pain rating changes evoked by positive and negative expectancy were significantly associated.”
    “With neutral cream ratings controlled, the partial correlation between the “Lidocaine” response and the “Capsaicin” response was −.54 (p = .008)”

  • The paper relies on this without support.

    It remains unclear whether any or all proposed mechanisms for positive and negative pain modulation contribute, alone or together.

    “It is not yet clear whether any or all of the mechanisms that have been proposed to account for positive and negative modulation of pain perception are contributory, singly or in combination.”

  • The paper relies on this without support.

    Consensus is lacking about whether the same bidirectional mechanisms drive placebo analgesia and nocebo hyperalgesia, or whether the two are fully separable cognitive constructs.

    “Moreover, there is no clear consensus on whether bidirectional mechanisms contribute to placebo analgesia and nocebo hyperalgesia or whether they are completely separable cognitive constructs.”

  • The paper relies on this without support.

    No prior study has directly compared placebo and nocebo responses in the absence of an active treatment in the same cohort of subjects.

    “However, no study has directly compared placebo and nocebo responses in the absence of an active treatment in the same cohort of subjects.”

  • The paper relies on this without support.

    During expectation of high pain at the nocebo site, subjects are likely to feel anxious.

    “During expectation of high pain at the nocebo site, subjects are likely to feel anxious.”

  • The paper relies on this without support.

    fMRI mainly assesses phasic, stimulus-evoked responses.

    “Since the brain responses in the pain-related brain regions to calibrated heat pain only represent the response in one stage, fMRI mainly assesses phasic, i.e. stimulus-evoked, responses.”

  • The paper relies on this without support.

    Brain responses in pain-related brain regions to calibrated heat pain only represent the response in one stage.

    “Since the brain responses in the pain-related brain regions to calibrated heat pain only represent the response in one stage, fMRI mainly assesses phasic, i.e. stimulus-evoked, responses.”

  • The paper relies on this without support.

    The extent to which each stage contributes varies under different circumstances and by individual.

    “The extent to which each stage contributes varies under different circumstances and by individual.”
9 of 9

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • 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 [42]

  • Social modeling through multiple media outlets, such as internet medical information, social media, pharmacological advertisements, and television warnings, is strongly involved in socially induced nocebo effects.

    “Social modeling through multiple media outlets, such as medical information retrieved from the internet and shared among social media, as well as pharmacological advertisements and descriptions of health-related environmental factors and warnings through television channels are strongly involved in socially induced nocebo effects.42”

    From Nocebo and pain: an overview of the psychoneurobiological mechanisms (2017) · cites this paper as [42]

Statistics recomputed

Every reported test result, recomputed from its test statistic and degrees of freedom. A result shows as not adding up only once an independent check has confirmed it.

  • ConsistentF(1, 23) = 22.83reported p < .001 · recomputed p < .001

    “F (1,23) = 22.83, p < .001”

  • ConsistentF(2, 46) = 26.37reported p < .001 · recomputed p < .001

    “F(2,46) = 26.37, p < .001”

  • Consistentt(23) = -4.83reported p < .001 · recomputed p < .001

    “t(23) = −4.83, p < .001”

  • Consistentt(23) = 3.18reported p = .004 · recomputed p = .004

    “t(23) = 3.18, p = .004”

  • ConsistentF(4, 92) = 26.6reported p < .001 · recomputed p < .001

    “F (4,92) = 26.60, p < .001”

  • Consistentt(23) = 2.1reported p = .047 · recomputed p = .047

    “t(23) = 2.10, p = .047”

6 of 6

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • Pain-activation threshold differs from the stated analysis threshold

    Minor

    The methods specify p<0.005 and 25 contiguous voxels for non-ROI regions, but the pain-activation results report p>0.005 and 20 contiguous voxels. Both the inequality and cluster-size threshold differ.

  • Condition effect has the wrong numerator degrees of freedom

    Minor

    The ANOVA has three conditions, so an uncorrected main effect of condition has 3 − 1 = 2 numerator degrees of freedom, not 1. No degrees-of-freedom correction is stated.

    Reported 1 · recomputed 2

2 of 2

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Related

Authors
Freeman, S., Yu, R., Egorova, N., Chen, X., Kirsch, I., Claggett, B., Kaptchuk, T. J., Gollub, R. L., & Kong, J.
Affiliations
  • Harvard University (US)
  • Beth Israel Deaconess Medical Center (US)
  • Massachusetts General Hospital (US)
Corresponding author
Kong, Jian
ORCID
Venue
NeuroImage
Publisher
Elsevier BV
Published
2015-05
Volume
112
Pages
197-207
ISSN
1053-8119 (ISSN-L)
DOI
10.1016/j.neuroimage.2015.03.015
PMC
PMC4408248
OpenAlex
W2078116672
Cited by
116
References
78
Citations by year
2026: 2 · 2025: 6 · 2024: 15 · 2023: 7 · 2022: 7 · 2021: 25 · 2020: 10 · 2019: 13 · 2018: 13 · 2017: 9 · 2016: 5 · 2015: 4
FWCI
6.21
Type
journal article
Language
en
Open access
Licence
www.elsevier.com/tdm/userlicense/1.0/ (tdm)
Locations
  • NeuroImage (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
  • National University of Singapore (submittedVersion)
Funders
NCCAM (R01AT006364, R01AT005280, P01 AT006663)
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
placebo effect, nocebo effect, pain anticipation, pain perception, insula, orbitofrontal cortex, periaqueductal gray, striatum, pain matrix, noxious stimuli
MeSH terms
Adult, Anesthetics, Local, Capsaicin, Cerebral Cortex, Female, Hot Temperature, Humans, Lidocaine, Magnetic Resonance Imaging, Male, Middle Aged, Nervous System, Pain, Periaqueductal Gray, Reward, Set, Psychology, Placebo Effect, Young Adult, Pain Perception, Nocebo Effect

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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.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-09-28.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-09-28.

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