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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 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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Cites
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Nonconscious activation of placebo and nocebo pain responses
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Self-citationA systematic review of adverse events in placebo groups of anti-migraine clinical trials
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Self-citationPain, decisions, and actions: a motivational perspective
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“These findings suggest that the increased demand for attentional resources when the task is performed under pain can be compensated for until no more resources can be allocated; then the lack of resources becomes apparent as either compromised task performance or attenuated pain perception.”
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“Session 1 We used the first behavioral session to familiarize subjects with the rating scales and determine appropriate stimulus intensities using methods employed in our previous studies (Dougherty et al., 2008; Kong et al., 2005; Kong et al., 2008; Kong et al., 2006a; Kong et al., 2009; Kong et al., 2006b).”
InfluentialSelf-citationWhat’s in a word? How instructions, suggestions, and social information change pain and emotion
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“Studies in placebo and nocebo research have shown the dramatic power of the mind to alter physiology and underlying brain circuitry (Bingel et al., 2006; Colloca et al., 2008b; Craggs et al., 2007; Kong et al., 2008; Kong et al., 2006a; Lieberman et al., 2004; Petrovic et al., 2002; Price et al., 2007; Scott et al., 2…”
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Pain anticipation: An activation likelihood estimation meta‐analysis of brain imaging studies
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“Indeed, only a few studies have analyzed the nocebo phenomenon and importantly, only one of them has described cortical–subcortical circuitries related to the nocebo response using fMRI technique [Kong et al., 2008].”
MethodFacilitation of Pain in the Human Spinal Cord by Nocebo Treatment
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“Nocebo-induced hyperalgesia increases pain along with activity in cortical painprocessing areas (Kong et al., 2008; Rodriguez-Raecke et al., 2010).”
BackgroundA Neural Mechanism for Nonconscious Activation of Conditioned Placebo and Nocebo Responses
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“This session involved an expectancy manipulation model employed in some of our laboratory's previous studies (Kong et al., 2006, 2008, 2009a, 2009b).”
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“However, noxious stimuli can sometimes increase hippocampal activation [11,30], and hippocampal activity has been associated with anxiety-induced hyperalgesia [61] and nocebo-related increases in pain [41].”
BackgroundPlacebo 2.0: the impact of expectations on analgesic treatment outcome
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Carlino, E., Frisaldi, E., & Benedetti, F. (2014) · Nature Reviews Rheumatology · doi:10.1038/nrrheum.2014.17 · Cited by 112
Rethinking Explicit Expectations: Connecting Placebos, Social Cognition, and Contextual Perception
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“Nocebo hyperalgesia additionally elicited modulated blood oxygen level-dependent (BOLD) activity patterns in the hippocampus [47,48].”
Schmid, J., Langhorst, J., Gaß, F., Theysohn, N., Benson, S., Engler, H., Gizewski, E. R., Forsting, M., & Elsenbruch, S. (2014) · Gut · doi:10.1136/gutjnl-2013-306648 · Cited by 106
Different contexts, different pains, different experiences
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“such as the prefrontal cortex, anterior cingulate cortex and insula, along with the subjective rating of pain (Koyama et al., 1998; Chua et al., 1999; Ploghaus et al., 1999; Sawamoto et al., 2000; Porro et al., 2002, 2003; Koyama et al., 2005; Keltner et al., 2006; Kong et al., 2008).”
Sex similarities and differences in pain-related periaqueductal gray connectivity
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“To achieve an adequate sample size, we pooled data from 3 experiments [65,67,68] from our laboratory.”
MethodSelf-citationSchmid, J., Theysohn, N., Ga, F., Benson, S., Gramsch, C., Forsting, M., Gizewski, E. R., & Elsenbruch, S. (2013) · Pain · doi:10.1016/j.pain.2013.07.013 · Cited by 102
“Furthermore, learning or conditioning processes, which were not addressed in our study, have previously been found to induce nocebo responses [10,11,25,30] as well as conditioned pain-related fear [29], along with hippocampal activation.”
BackgroundResultInfluentialNocebo Hyperalgesia, Partial Reinforcement, and Extinction
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“However, increasing evidence indicates that placebo mechanisms can also amplify pain, referred to as nocebo hyperalgesia [5, 7, 14, 16, 28].”
BackgroundImaging pain: a potent means for investigating pain mechanisms in patients
Lee, M., & Tracey, I. (2013) · British Journal of Anaesthesia · doi:10.1093/bja/aet174 · Cited by 108
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Psychological Placebo and Nocebo Effects on Pain Rely on Expectation and Previous Experience
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Kong, J., Spaeth, R. B., Cook, A., Kirsch, I., Claggett, B. L., Vangel, M. G., Gollub, R. L., Smoller, J. W., & Kaptchuk, T. J. (2013) · PLoS ONE · doi:10.1371/journal.pone.0067485 · Cited by 99
“Studies have shown that expectation can significantly influence an individual’s perception of pain [15–17,21–28].”
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“In fact, only 2 studies have so far investigated nocebo effects in chronic pain patients and both found small, but nonsignificant nocebo effects [31,64], proposing that placebo and nocebo manipulations might exert differential effects in chronic pain conditions and/or that it may be more difficult to obtain nocebo eff…”
Mitsikostas, D., Chalarakis, N., Mantonakis, L., Delicha, E. M., & Sfikakis, P. P. (2011) · European Journal of Neurology · doi:10.1111/j.1468-1331.2011.03528.x · Cited by 97
Placebo Acupuncture Devices: Considerations for Acupuncture Research
Zhu, D., Gao, Y., Chang, J., & Kong, J. (2013) · Evidence-based Complementary and Alternative Medicine · doi:10.1155/2013/628907 · Cited by 92
Self-citationRodriguez‐Raecke, R., Doganci, B., Breimhorst, M., Stankewitz, A., Büchel, C., Birklein, F., & May, A. (2010) · Journal of Neuroscience · doi:10.1523/jneurosci.2197-10.2010 · Cited by 89
“The methodological differences between the study by Kong et al. (2008) and our study are manyfold, the most important one being that we investigated long-term rather than short-term intrasession effects and that the relative hyperalgesic effect in our study relied exclusively on the verbal…”
BackgroundInfluentialNocebo in clinical trials for depression: A meta-analysis
Mitsikostas, D. D., Mantonakis, L., & Chalarakis, N. (2013) · Psychiatry Research · doi:10.1016/j.psychres.2013.10.019 · Cited by 86
“Experimental human studies showed that nocebo is mediated by limbic system after affective and cognitive evaluation (Kong et al., 2008).”
Frisaldi, E., Piedimonte, A., & Benedetti, F. (2015) · American Journal of Clinical Hypnosis · doi:10.1080/00029157.2014.976785 · Cited by 93
“Kong et al. (2008) emphasized the effect of negative expectations about pain perception following sham acupuncture and compared fMRI responses following thermal stimuli of equal intensity delivered at control sites or at sites along the suggested course of an acupuncture meridian (nocebo).”
BackgroundZyloney, C. E., Jensen, K. B., Polich, G. R., Loiotile, R. E., Cheetham, A., LaViolette, P. S., Tu, P., Kaptchuk, T. J., Gollub, R. L., & Kong, J. (2010) · Molecular Pain · doi:10.1186/1744-8069-6-80 · Cited by 82
“Recent findings using fcMRI have significantly enhanced our understanding of the intrinsic functional and anatomical connections of the brain, including those that underlie pain perception [38] and modulation [39,40], and pathological changes in these connections that are associated with chronic pain in patients [41-4…”
BackgroundMethodSelf-citationNocebos in rheumatology: emerging concepts and their implications for clinical practice
Kravvariti, E., Kitas, G. D., Mitsikostas, D. D., & Sfikakis, P. P. (2018) · Nature Reviews Rheumatology · doi:10.1038/s41584-018-0110-9 · Cited by 80
Schafer, S. M., Geuter, S., & Wager, T. D. (2017) · Progress in Neurobiology · doi:10.1016/j.pneurobio.2017.10.008 · Cited by 79
“…found that hippocampus is needed to induce fear conditioned analgesia (Ford et al., 2011), and other conditioned associations (Kim and Fanselow, 1992; Selden et al., 1991), as well as nocebo hyperalgesia (Bingel et al., 2011; Dickenson et al., 1979; Kong et al., 2008; cf. Tinnermann et al., 2017).”
Yu, R., Gollub, R. L., Vangel, M. G., Kaptchuk, T. J., Smoller, J. W., & Kong, J. (2014) · Human Brain Mapping · doi:10.1002/hbm.22496 · Cited by 80
Self-citationThe role of hedonics in the Human Affectome
Becker, S., Bräscher, A., Bannister, S., Bensafi, M., Calma‐Birling, D., Chan, R. C. K., Eerola, T., Ellingsen, D., Ferdenzi, C., Hanson, J. L., et al. (2019) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2019.05.003 · Cited by 93
Hashmi, J. A., Kong, J., Spaeth, R. B., Khan, S., Kaptchuk, T. J., & Gollub, R. L. (2014) · Journal of Neuroscience · doi:10.1523/jneurosci.3155-13.2014 · Cited by 77
“We have used this scale for investigating placebo responses in several investigations that form the basis for this study (Kong et al., 2005, 2006a, 2008, 2009a,b).”
MethodSelf-citationExpectancy and conditioning in placebo analgesia: Separate or connected processes?
Kirsch, I., Kong, J., Sadler, P., Spaeth, R. B., Cook, A., Kaptchuk, T. J., & Gollub, R. L. (2014) · Psychology of Consciousness Theory Research and Practice · doi:10.1037/cns0000007 · Cited by 77
“These procedures were first developed by Voudouris and colleagues (Voudouris, Peck, & Coleman, 1985) and have been used in many fMRI studies of placebo analgesia (e.g., Kong et al., 2008; Kong et al., 2013; Kong et al., 2006; Wager et al., 2004).”
Self-citationChen, X., Spaeth, R. B., Freeman, S. G., Scarborough, D. M., Hashmi, J. A., Wey, H., Egorova, N., Vangel, M. G., Mao, J., Wasan, A. D., et al. (2015) · Molecular Pain · doi:10.1186/s12990-015-0071-9 · Cited by 76
Self-citationFear of pain potentiates nocebo hyperalgesia
Aslaksen, P. M., & Lyby, P. S. (2015) · Journal of Pain Research · doi:10.2147/jpr.s91923 · Cited by 76
“…on nocebo hyperalgesia have shown that negative emotional activation mediates the observed increase in pain 6,7 and that nocebo manipulations may affect physiological systems such as the hypothalamic– pituitary–adrenal axis, 8 cerebral pain systems, 9,10 and pain processing in the spinal cord.”
Questioning the Methodologic Superiority of ‘Placebo’ Over ‘Active’ Controlled Trials
Howick, J. (2009) · The American Journal of Bioethics · doi:10.1080/15265160903090041 · Cited by 72
Opposite effects of the same drug
Aslaksen, P. M., Zwarg, M. L., Eilertsen, H.-I. H., Gorecka, M. M., & Bjørkedal, E. (2015) · Pain · doi:10.1016/j.pain.0000000000000004 · Cited by 74
Marca, R. L., Nedeljković, M., Yuan, L., Maercker, A. R. A., & Ehlert, U. (2009) · Clinical Science · doi:10.1042/cs20090264 · Cited by 71
Elsenbruch, S., Schmid, J., Bäsler, M., Cesko, E., Schedlowski, M., & Benson, S. (2012) · Neurogastroenterology & Motility · doi:10.1111/j.1365-2982.2012.01950.x · Cited by 73
Simultaneous fMRI–PET of the opioidergic pain system in human brain
Wey, H., Catana, C., Hooker, J. M., Dougherty, D. D., Knudsen, G. M., Wang, D. J. J., Chonde, D. B., Rosen, B. R., Gollub, R. L., & Kong, J. (2014) · NeuroImage · doi:10.1016/j.neuroimage.2014.07.058 · Cited by 69
“Similar methods have been used in several studies from our lab (Kong et al., 2006a, 2006b, 2008).”
Self-citationNeural underpinnings of nocebo hyperalgesia in visceral pain: A fMRI study in healthy volunteers
Schmid, J., Bingel, U., Ritter, C., Benson, S., Schedlowski, M., Gramsch, C., Forsting, M., & Elsenbruch, S. (2015) · NeuroImage · doi:10.1016/j.neuroimage.2015.06.060 · Cited by 71
Yu, S., Li, W., Shen, W., Edwards, R. R., Gollub, R. L., Wilson, G., Park, J., Ortiz, A., Cao, J., Gerber, J. A., et al. (2020) · NeuroImage · doi:10.1016/j.neuroimage.2020.116969 · Cited by 73
Self-citationThe imagined itch: brain circuitry supporting nocebo-induced itch in atopic dermatitis patients
Napadow, V., Li, A., Loggia, M. L., Kim, J., Mawla, I., Desbordes, G., Schalock, P. C., Lerner, E. A., Tran, T. N., Ring, J., et al. (2015) · Allergy · doi:10.1111/all.12727 · Cited by 71
“Anxiety is thought to arise from negative expectation, and prior studies have shown that negative suggestions modulate expectations and heighten anxiety leading to greater pain report and hyperactivation in prefrontal and limbic brain regions thought to process cognitive and affective dimensions of pain (12, 43).”
BackgroundResultSelf-citationThe Biology of Placebo and Nocebo Effects on Experimental and Chronic Pain: State of the Art
Rossettini, G., Campaci, F., Bialosky, J. E., Huysmans, E., Vase, L., & Carlino, E. (2023) · Journal of Clinical Medicine · doi:10.3390/jcm12124113 · Cited by 69
“, 2008 [71] 20 (5, 8, 7) Healthy subjects Heat pain Neuroimaging (fMRI) Gracely Sensory and Affective Scales p < 0.”
BackgroundInfluentialMurray, D., & Stoessl, A. J. (2013) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2013.07.009 · Cited by 72
Gollub, R. L., Kirsch, I., Maleki, N., Wasan, A. D., Edwards, R. R., Tu, Y., Kaptchuk, T. J., & Kong, J. (2018) · Journal of Pain · doi:10.1016/j.jpain.2017.12.260 · Cited by 67
Self-citationLoggia, M. L., Jensen, K. B., Gollub, R. L., Wasan, A. D., Edwards, R. R., & Kong, J. (2011) · PLoS ONE · doi:10.1371/journal.pone.0027764 · Cited by 65
“In order to test our hypothesis we reanalyzed the fMRI activations in response to early and late stimuli in a series of repeated heat pain stimulations, using data from three previous experiments from our laboratory [20–22].”
MethodSelf-citationEgorova, N., Yu, R., Kaur, N., Vangel, M., Gollub, R. L., Dougherty, D. D., Kong, J., & Camprodon, J. A. (2015) · Pain · doi:10.1097/j.pain.0000000000000163 · Cited by 63
Self-citationReview of neuroimaging studies related to pain modulation
Knudsen, L., Petersen, G. L., Nørskov, K. N., Vase, L., Finnerup, N. B., Jensen, T. S., & Svensson, P. J. (2011) · Scandinavian Journal of Pain · doi:10.1016/j.sjpain.2011.05.005 · Cited by 68
Nocebo and the contribution of psychosocial factors to the generation of pain
Benedetti, F., Frisaldi, E., Barbiani, D., Camerone, E. M., & Shaibani, A. I. (2019) · Journal of Neural Transmission · doi:10.1007/s00702-019-02104-x · Cited by 69
Nocebo in Headaches: Implications for Clinical Practice and Trial Design
Mitsikostas, D. D. (2011) · Current Neurology and Neuroscience Reports · doi:10.1007/s11910-011-0245-4 · Cited by 58
Tian, T., Guo, L., Xu, J., Zhang, S., Shi, J., Liu, C., Qin, Y., & Zhu, W. (2016) · Scientific Reports · doi:10.1038/srep36030 · Cited by 57
Kessner, S. S., Forkmann, K., Ritter, C., Wiech, K., Ploner, M., & Bingel, U. (2014) · PLoS ONE · doi:10.1371/journal.pone.0109014 · Cited by 59
“These regions include brain areas known to be involved in pain processing (brainstem (3/235/217), thalamus (12/212/4), basal ganglia (8/14/210), posterior (48/2 4/16) and anteromedial (34/0/26) insula and secondary somatosensory cortex (49/219/18) [28]) and its modulation (subgenual (10/10/210) and dorsal (8/34/18) an…”
BackgroundShih, Y.-W., Tsai, H.-Y., Lin, F.-S., Lin, Y., Chiang, C.-Y., Lu, Z., & Tseng, M. (2018) · Journal of Neuroscience · doi:10.1523/jneurosci.2154-18.2018 · Cited by 61
“Importantly, the strength of the aIC– hippocampus connectivity under positive expectations showed a significant negative correlation with that of rACC–OFC connectivity under negative expectations (r 0.417; p 0.048; Fig.”
BackgroundInfluentialPlacebo-Induced Improvements: How Therapeutic Rituals Affect the Patient's Brain
Benedetti, F. (2012) · Journal of Acupuncture and Meridian Studies · doi:10.1016/j.jams.2012.03.001 · Cited by 61
“As for placebo analgesia, neuroimaging techniques have also brought important contributions to the knowledge of nocebo hyperalgesia [26].”
The nocebo effect: A clinicians guide
Data-Franco, J., & Berk, M. (2012) · Australian & New Zealand Journal of Psychiatry · doi:10.1177/0004867412464717 · Cited by 56
“A positron emission tomography study reported changes in μ-opioid and dopamine D2/D3 neurotransmission with the nocebo effect, and functional magnetic resonance imaging studies have suggested the involvement of specific brain structures, such as anterior cingulate, insula and the prefrontal cortex (Kong et al., 2008;…”
BackgroundUnravelling the Mystery of Pain, Suffering, and Relief With Brain Imaging
Lee, M., & Tracey, I. (2010) · Current Pain and Headache Reports · doi:10.1007/s11916-010-0103-0 · Cited by 55
Placebo, nocebo, and neuropathic pain
Vase, L., Skyt, I., & Hall, K. T. (2015) · Pain · doi:10.1097/j.pain.0000000000000445 · Cited by 56
“Interestingly, these findings show that placebo effects exert inhibitory effects on 3 measures that are likely to be associated with hyperalgesia and central sensitization: (1) maximum windup-like pain intensity, (2) area of secondary hyperalgesia, and (3) ongoing clinical pain.”
BackgroundRooney, T., Sharpe, L., Todd, J., Richmond, B., & Colagiuri, B. (2022) · Health Psychology Review · doi:10.1080/17437199.2022.2125894 · Cited by 52
“…do measure expectancy have found evidence that negative expectancies are induced by the nocebo manipulation (e.g., Colagiuri & Quinn, 2018; Elsenbruch et al., 2019; Kong et al., 2008), some have failed to observe this relationship (e.g., B ą bel et al., 2017; Mao et al., 2021; Quinn et al., 2017).”
BackgroundXiang, Y., Wang, Y., Gao, S., Zhang, X., & Cui, R. (2018) · Frontiers in Neuroscience · doi:10.3389/fnins.2018.00507 · Cited by 54
Human lesions and animal studies link the claustrum to perception, salience, sleep and pain
Atilgan, H., Doody, M., Oliver, D. K., McGrath, T., Shelton, A. M., Echeverria-Altuna, I., Tracey, I., Vyazovskiy, V. V., Manohar, S., & Packer, A. M. (2022) · Brain · doi:10.1093/brain/awac114 · Cited by 59
Manipulating placebo analgesia and nocebo hyperalgesia by changing brain excitability
Tu, Y., Wilson, G., Camprodon, J. A., Dougherty, D. D., Vangel, M. G., Benedetti, F., Kaptchuk, T. J., Gollub, R. L., & Kong, J. (2021) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2101273118 · Cited by 54
“S6), as previous studies have suggested that anxiety level could affect nocebo hyperalgesia (12, 13).”
BackgroundResultInfluentialSelf-citation
Metadata
- 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 (medical) › 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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