Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.

Science 20 February 2004:
Vol. 303. no. 5661, pp. 1162 - 1167
DOI: 10.1126/science.1093065
Prev | Table of Contents | Next

Research Articles

Placebo-Induced Changes in fMRI in the Anticipation and Experience of Pain

Tor D. Wager,1*{dagger} James K. Rilling,2 Edward E. Smith,1 Alex Sokolik,3 Kenneth L. Casey,3 Richard J. Davidson,4 Stephen M. Kosslyn,5 Robert M. Rose,6 Jonathan D. Cohen2,7

The experience of pain arises from both physiological and psychological factors, including one's beliefs and expectations. Thus, placebo treatments that have no intrinsic pharmacological effects may produce analgesia by altering expectations. However, controversy exists regarding whether placebos alter sensory pain transmission, pain affect, or simply produce compliance with the suggestions of investigators. In two functional magnetic resonance imaging (fMRI) experiments, we found that placebo analgesia was related to decreased brain activity in pain-sensitive brain regions, including the thalamus, insula, and anterior cingulate cortex, and was associated with increased activity during anticipation of pain in the prefrontal cortex, providing evidence that placebos alter the experience of pain.

1 Department of Psychology, University of Michigan, 525 East University, Ann Arbor, MI 48109–1109, USA.
2 Center for the Study of Brain, Mind and Behavior, Princeton University, Princeton, NJ 08544, USA.
3 Department of Neurology, Veterans Affairs Medical Center, University of Michigan, Ann Arbor, MI 48109, USA.
4 Department of Psychology, University of Wisconsin, Madison, WI 53706, USA.
5 Department of Psychology, Harvard University, Cambridge, MA 02138, USA.
6 Mind Brain Body and Health Initiative, University of Texas Medical Branch, Galveston, TX 77555, USA.
7 Department of Psychology, Princeton University, Princeton, NJ 08544, USA.



{dagger} Present address: Department of Psychology, Columbia University, 1190 Amsterdam Avenue, New York, NY 10027, USA.

* To whom correspondence should be addressed. E-mail: torw{at}umich.edu, tor{at}paradox.psych.columbia.edu

Read the Full Text


THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES:
Cerebral and spinal modulation of pain by emotions.
M. Roy, M. Piche, J.-I. Chen, I. Peretz, and P. Rainville (2009)
PNAS 106, 20900-20905
   Abstract »    Full Text »    PDF »
Cerebral Representation of the Relief of Itch by Scratching.
V. Vierow, M. Fukuoka, A. Ikoma, A. Dorfler, H. O. Handwerker, and C. Forster (2009)
J Neurophysiol 102, 3216-3224
   Abstract »    Full Text »    PDF »
When seeing outweighs feeling: a role for prefrontal cortex in passive control of negative affect in blindsight.
S. Anders, F. Eippert, S. Wiens, N. Birbaumer, M. Lotze, and D. Wildgruber (2009)
Brain 132, 3021-3031
   Abstract »    Full Text »    PDF »
Affective Neuroscience: Past, Present, and Future.
T. Dalgleish, B. D. Dunn, and D. Mobbs (2009)
Emotion Review 1, 355-368
   Abstract »    PDF »
Changes in Rapid Eye Movement Sleep Associated with Placebo-Induced Expectations and Analgesia.
D. Laverdure-Dupont, P. Rainville, J. Montplaisir, and G. Lavigne (2009)
J. Neurosci. 29, 11745-11752
   Abstract »    Full Text »    PDF »
Low-frequency pulsed electromagnetic field exposure can alter neuroprocessing in humans.
J. A. Robertson, J. Theberge, J. Weller, D. J. Drost, F. S. Prato, and A. W. Thomas (2009)
J R Soc Interface
   Abstract »    Full Text »    PDF »
Down-Regulation of Insular Cortex Responses to Dyspnea and Pain in Asthma.
A. von Leupoldt, T. Sommer, S. Kegat, F. Eippert, H. J. Baumann, H. Klose, B. Dahme, and C. Buchel (2009)
Am. J. Respir. Crit. Care Med. 180, 232-238
   Abstract »    Full Text »    PDF »
The effect of group-based exercise on cognitive performance and mood in seniors residing in intermediate care and self-care retirement facilities: a randomised controlled trial.
A K Brown, T Liu-Ambrose, R Tate, and S R Lord (2009)
Br. J. Sports Med. 43, 608-614
   Abstract »    Full Text »    PDF »
Electrophysiological properties of thalamic, subthalamic and nigral neurons during the anti-parkinsonian placebo response.
F. Benedetti, M. Lanotte, L. Colloca, A. Ducati, M. Zibetti, and L. Lopiano (2009)
J. Physiol. 587, 3869-3883
   Abstract »    Full Text »    PDF »
Acupuncture: What Underlies Needle Administration?.
T. Liu (2009)
Evid. Based Complement. Altern. Med. 6, 185-193
   Abstract »    Full Text »    PDF »
Decreased Gray Matter Volumes in the Cingulo-Frontal Cortex and the Amygdala in Patients With Fibromyalgia.
M. Burgmer, M. Gaubitz, C. Konrad, M. Wrenger, S. Hilgart, G. Heuft, and B. Pfleiderer (2009)
Psychosom Med 71, 566-573
   Abstract »    Full Text »    PDF »
Medial Prefrontal Cortex Activity Is Predictive for Hyperalgesia and Pharmacological Antihyperalgesia.
F. Seifert, K. Bschorer, R. De Col, J. Filitz, E. Peltz, W. Koppert, and C. Maihofner (2009)
J. Neurosci. 29, 6167-6175
   Abstract »    Full Text »    PDF »
Initial Evidence of a Failure to Activate Right Anterior Insula During Affective Set Shifting in Posttraumatic Stress Disorder.
A. Simmons, I. A. Strigo, S. C. Matthews, M. P. Paulus, and M. B. Stein (2009)
Psychosom Med 71, 373-377
   Abstract »    Full Text »    PDF »
The Anatomy of the Mesolimbic Reward System: A Link between Personality and the Placebo Analgesic Response.
P. Schweinhardt, D. A. Seminowicz, E. Jaeger, G. H. Duncan, and M. C. Bushnell (2009)
J. Neurosci. 29, 4882-4887
   Abstract »    Full Text »    PDF »
Anticipatory Activation in the Amygdala and Anterior Cingulate in Generalized Anxiety Disorder and Prediction of Treatment Response.
J. B. Nitschke, I. Sarinopoulos, D. J. Oathes, T. Johnstone, P. J. Whalen, R. J. Davidson, and N. H. Kalin (2009)
Am J Psychiatry 166, 302-310
   Abstract »    Full Text »    PDF »
Morphological and functional reorganization of rat medial prefrontal cortex in neuropathic pain.
A. E. Metz, H.-J. Yau, M. V. Centeno, A. V. Apkarian, and M. Martina (2009)
PNAS 106, 2423-2428
   Abstract »    Full Text »    PDF »
The Rebirth of Neuroscience in Psychosomatic Medicine, Part II: Clinical Applications and Implications for Research.
R. D. Lane, S. R. Waldstein, H. D. Critchley, S. W. G. Derbyshire, D. A. Drossman, T. D. Wager, N. Schneiderman, M. A. Chesney, J. R. Jennings, W. R. Lovallo, et al. (2009)
Psychosom Med 71, 135-151
   Abstract »    Full Text »    PDF »
Exercise and cognition in older adults: is there a role for resistance training programmes?.
T Liu-Ambrose and M G Donaldson (2009)
Br. J. Sports Med. 43, 25-27
   Abstract »    Full Text »    PDF »
A Link between Serotonin-Related Gene Polymorphisms, Amygdala Activity, and Placebo-Induced Relief from Social Anxiety.
T. Furmark, L. Appel, S. Henningsson, F. Ahs, V. Faria, C. Linnman, A. Pissiota, O. Frans, M. Bani, P. Bettica, et al. (2008)
J. Neurosci. 28, 13066-13074
   Abstract »    Full Text »    PDF »
A Functional Magnetic Resonance Imaging Study on the Neural Mechanisms of Hyperalgesic Nocebo Effect.
J. Kong, R. L. Gollub, G. Polich, I. Kirsch, P. LaViolette, M. Vangel, B. Rosen, and T. J. Kaptchuk (2008)
J. Neurosci. 28, 13354-13362
   Abstract »    Full Text »    PDF »
Physiology and Treatment of Pain.
J. E. Helms and C. P. Barone (2008)
Crit. Care Nurse 28, 38-49
   Full Text »    PDF »
Imaging CNS Modulation of Pain in Humans.
U. Bingel and I. Tracey (2008)
Physiology 23, 371-380
   Abstract »    Full Text »    PDF »
Association of Major Depressive Disorder With Altered Functional Brain Response During Anticipation and Processing of Heat Pain.
I. A. Strigo, A. N. Simmons, S. C. Matthews, A. D. Craig, and M. P. Paulus (2008)
Arch Gen Psychiatry 65, 1275-1284
   Abstract »    Full Text »    PDF »
Placebo effects: clinical aspects and neurobiology.
B. S. Oken (2008)
Brain 131, 2812-2823
   Abstract »    Full Text »    PDF »
The Importance of Placebo in Headache Research.
H-C Diener, C. Schorn, U Bingel, and D. Dodick (2008)
Cephalalgia 28, 1003-1011
   Abstract »    Full Text »    PDF »
Dissociable Roles for the Hippocampus and the Amygdala in Human Cued versus Context Fear Conditioning.
A. Marschner, R. Kalisch, B. Vervliet, D. Vansteenwegen, and C. Buchel (2008)
J. Neurosci. 28, 9030-9036
   Abstract »    Full Text »    PDF »
The Roles of Physiological and Subjective Stress in the Effectiveness of a Placebo on Experimentally Induced Pain.
P. M. Aslaksen and M. A. Flaten (2008)
Psychosom Med 70, 811-818
   Abstract »    Full Text »    PDF »
The placebo treatments in neurosciences: New insights from clinical and neuroimaging studies.
N. J. Diederich and C. G. Goetz (2008)
Neurology 71, 677-684
   Abstract »    Full Text »    PDF »
Imaging pain.
I. Tracey (2008)
Br. J. Anaesth. 101, 32-39
   Abstract »    Full Text »    PDF »
Your pain or mine? Common and distinct neural systems supporting the perception of pain in self and other.
K. N. Ochsner, J. Zaki, J. Hanelin, D. H. Ludlow, K. Knierim, T. Ramachandran, G. H. Glover, and S. C. Mackey (2008)
Soc Cogn Affect Neurosci 3, 144-160
   Abstract »    Full Text »    PDF »
Where dopamine meets opioids: a meta-analysis of the placebo effect in restless legs syndrome treatment studies.
S. Fulda and T. C. Wetter (2008)
Brain 131, 902-917
   Abstract »    Full Text »    PDF »
Relief of Dyspnea Involves a Characteristic Brain Activation and a Specific Quality of Sensation.
C. Peiffer, N. Costes, P. Herve, and L. Garcia-Larrea (2008)
Am. J. Respir. Crit. Care Med. 177, 440-449
   Abstract »    Full Text »    PDF »
THE AUTHOR REPLIES.
H. Hemila (2008)
Am. J. Epidemiol. 167, 501-502
   Full Text »    PDF »
Placebo and Nocebo Effects Are Defined by Opposite Opioid and Dopaminergic Responses.
D. J. Scott, C. S. Stohler, C. M. Egnatuk, H. Wang, R. A. Koeppe, and J.-K. Zubieta (2008)
Arch Gen Psychiatry 65, 220-231
   Abstract »    Full Text »    PDF »
Opioid-Mediated Placebo Responses Boost Pain Endurance and Physical Performance: Is It Doping in Sport Competitions?.
F. Benedetti, A. Pollo, and L. Colloca (2007)
J. Neurosci. 27, 11934-11939
   Abstract »    Full Text »    PDF »
Altered Metabolism in Frontal Brain Circuits in Cluster Headache.
T Sprenger, K. Ruether, H Boecker, M Valet, A Berthele, V Pfaffenrath, A Woller, and T. Tolle (2007)
Cephalalgia 27, 1033-1042
   Abstract »    Full Text »    PDF »
Topiramate Reduces Headache Days in Chronic Migraine: A Randomized, Double-Blind, Placebo-Controlled Study.
H-C Diener, G Bussone, J. V. Oene, M Lahaye, S Schwalen, P. Goadsby, and on behalf of the TOPMAT-MIG-201(TOP-CHROME) Study (2007)
Cephalalgia 27, 814-823
   Abstract »    Full Text »    PDF »
Physiology and Neurobiology of Stress and Adaptation: Central Role of the Brain.
B. S. McEwen (2007)
Physiol Rev 87, 873-904
   Abstract »    Full Text »    PDF »
Placebo effects on human {micro}-opioid activity during pain.
T. D. Wager, D. J. Scott, and J.-K. Zubieta (2007)
PNAS 104, 11056-11061
   Abstract »    Full Text »    PDF »
Threatening a rubber hand that you feel is yours elicits a cortical anxiety response.
H. H. Ehrsson, K. Wiech, N. Weiskopf, R. J. Dolan, and R. E. Passingham (2007)
PNAS 104, 9828-9833
   Abstract »    Full Text »    PDF »
Embodiment and Our Immersion With Others: Commentary On Fonagy and Target.
R. N. Emde (2007)
J Am Psychoanal Assoc 55, 485-492
   PDF »
Interactions of Pain Intensity and Cognitive Load: The Brain Stays on Task.
D. A. Seminowicz and K. D. Davis (2007)
Cereb Cortex 17, 1412-1422
   Abstract »    Full Text »    PDF »
Memory Traces of Pain in Human Cortex.
M.-C. Albanese, E. G. Duerden, P. Rainville, and G. H. Duncan (2007)
J. Neurosci. 27, 4612-4620
   Abstract »    Full Text »    PDF »
Recent Neuroimaging Techniques in Mild Traumatic Brain Injury.
H. G. Belanger, R. D. Vanderploeg, G. Curtiss, and D. L. Warden (2007)
J Neuropsychiatry Clin Neurosci 19, 5-20
   Abstract »    Full Text »    PDF »
Acupuncture of LI-4 in Anesthetized Healthy Humans Decreases Cerebral Blood Flow in the Putamen Measured with Positron Emission Tomography.
L. Schlunzen, M. S. Vafaee, and G. E. Cold (2007)
Anesth. Analg. 104, 308-311
   Abstract »    Full Text »    PDF »
Chronic Pain and the Emotional Brain: Specific Brain Activity Associated with Spontaneous Fluctuations of Intensity of Chronic Back Pain..
M. N. Baliki, D. R. Chialvo, P. Y. Geha, R. M. Levy, R. N. Harden, T. B. Parrish, and A. V. Apkarian (2006)
J. Neurosci. 26, 12165-12173
   Abstract »    Full Text »    PDF »
The Biochemical and Neuroendocrine Bases of the Hyperalgesic Nocebo Effect..
F. Benedetti, M. Amanzio, S. Vighetti, and G. Asteggiano (2006)
J. Neurosci. 26, 12014-12022
   Abstract »    Full Text »    PDF »
Anterolateral Prefrontal Cortex Mediates the Analgesic Effect of Expected and Perceived Control over Pain..
K. Wiech, R. Kalisch, N. Weiskopf, B. Pleger, K. E. Stephan, and R. J. Dolan (2006)
J. Neurosci. 26, 11501-11509
   Abstract »    Full Text »    PDF »
Context-dependent human extinction memory is mediated by a ventromedial prefrontal and hippocampal network..
R. Kalisch, E. Korenfeld, K. E. Stephan, N. Weiskopf, B. Seymour, and R. J. Dolan (2006)
J. Neurosci. 26, 9503-9511
   Abstract »    Full Text »    PDF »
Studying mind and brain with fMRI.
M. G. Berman, J. Jonides, and D. E. Nee (2006)
Soc Cogn Affect Neurosci 1, 158-161
   Abstract »    Full Text »    PDF »
Enhanced Presynaptic Neurotransmitter Release in the Anterior Cingulate Cortex of Mice with Chronic Pain..
M.-G. Zhao, S. W Ko, L.-J. Wu, H. Toyoda, H. Xu, J. Quan, J. Li, Y. Jia, M. Ren, Z. C. Xu, et al. (2006)
J. Neurosci. 26, 8923-8930
   Abstract »    Full Text »    PDF »
Reply: Orbitofrontal cortex hypometabolism, medication overuse headache, substance abuse and migraine: key pathophysiological issues.
A. Fumal, R. Kupers, and J. Schoenen (2006)
Brain 129, E53
   Full Text »    PDF »
Neural correlates of antinociception in borderline personality disorder..
C. Schmahl, M. Bohus, F. Esposito, R.-D. Treede, F. Di Salle, W. Greffrath, P. Ludaescher, A. Jochims, K. Lieb, K. Scheffler, et al. (2006)
Arch Gen Psychiatry 63, 659-666
   Abstract »    Full Text »    PDF »
Neurobiological substrates of dread..
G. S. Berns, J. Chappelow, M. Cekic, C. F. Zink, G. Pagnoni, and M. E. Martin-Skurski (2006)
Science 312, 754-758
   Abstract »    Full Text »    PDF »
Isolating the modulatory effect of expectation on pain transmission: a functional magnetic resonance imaging study..
J. R. Keltner, A. Furst, C. Fan, R. Redfern, B. Inglis, and H. L. Fields (2006)
J. Neurosci. 26, 4437-4443
   Abstract »    Full Text »    PDF »
Mechanisms of central neuropathic pain: a combined psychophysical and fMRI study in syringomyelia.
D. Ducreux, N. Attal, F. Parker, and D. Bouhassira (2006)
Brain 129, 963-976
   Abstract »    Full Text »    PDF »
Sham device v inert pill: randomised controlled trial of two placebo treatments.
T. J Kaptchuk, W. B Stason, R. B Davis, A. R T Legedza, R. N Schnyer, C. E Kerr, D. A Stone, B. H. Nam, I. Kirsch, and R. H Goldman (2006)
BMJ 332, 391-397
   Abstract »    Full Text »    PDF »
Alterations in blood-brain barrier ICAM-1 expression and brain microglial activation after {lambda}-carrageenan-induced inflammatory pain.
J. D. Huber, C. R. Campos, K. S. Mark, and T. P. Davis (2006)
Am J Physiol Heart Circ Physiol 290, H732-H740
   Abstract »    Full Text »    PDF »
Brain Activity Associated with Expectancy-Enhanced Placebo Analgesia as Measured by Functional Magnetic Resonance Imaging.
J. Kong, R. L. Gollub, I. S. Rosman, J. M. Webb, M. G. Vangel, I. Kirsch, and T. J. Kaptchuk (2006)
J. Neurosci. 26, 381-388
   Abstract »    Full Text »    PDF »
Placebo-Induced Changes in Spinal Cord Pain Processing.
D. Matre, K. L. Casey, and S. Knardahl (2006)
J. Neurosci. 26, 559-563
   Abstract »    Full Text »    PDF »
Control over brain activation and pain learned by using real-time functional MRI.
R. C. deCharms, F. Maeda, G. H. Glover, D. Ludlow, J. M. Pauly, D. Soneji, J. D. E. Gabrieli, and S. C. Mackey (2005)
PNAS 102, 18626-18631
   Abstract »    Full Text »    PDF »
Neurobiological Mechanisms of the Placebo Effect.
F. Benedetti, H. S. Mayberg, T. D. Wager, C. S. Stohler, and J.-K. Zubieta (2005)
J. Neurosci. 25, 10390-10402
   Full Text »    PDF »
Investigating Acupuncture Using Brain Imaging Techniques: The Current State of Play.
G. T. Lewith, P. J. White, and J. Pariente (2005)
Evid. Based Complement. Altern. Med. 2, 315-319
   Abstract »    Full Text »    PDF »
Placebo Effects Mediated by Endogenous Opioid Activity on {micro}-Opioid Receptors.
J.-K. Zubieta, J. A. Bueller, L. R. Jackson, D. J. Scott, Y. Xu, R. A. Koeppe, T. E. Nichols, and C. S. Stohler (2005)
J. Neurosci. 25, 7754-7762
   Abstract »    Full Text »    PDF »
The Neural Bases of Placebo Effects in Pain.
T. D. Wager (2005)
Current Directions in Psychological Science 14, 175-179
   Abstract »    Full Text »    PDF »
Hypnotic suggestion reduces conflict in the human brain.
A. Raz, J. Fan, and M. I. Posner (2005)
PNAS 102, 9978-9983
   Abstract »    Full Text »    PDF »
Alcohol Misuse and Mood Disorders Following Traumatic Brain Injury.
R. E. Jorge, S. E. Starkstein, S. Arndt, D. Moser, B. Crespo-Facorro, and R. G. Robinson (2005)
Arch Gen Psychiatry 62, 742-749
   Abstract »    Full Text »    PDF »
Placebo.
H J McQuay and R A Moore (2005)
Postgrad. Med. J. 81, 155-160
   Abstract »    Full Text »    PDF »
Brain correlates of subjective reality of physically and psychologically induced pain.
T. T. Raij, J. Numminen, S. Narvanen, J. Hiltunen, and R. Hari (2005)
PNAS 102, 2147-2151
   Abstract »    Full Text »    PDF »
Separate Neural Systems Value Immediate and Delayed Monetary Rewards.
S. M. McClure, D. I. Laibson, G. Loewenstein, and J. D. Cohen (2004)
Science 306, 503-507
   Abstract »    Full Text »    PDF »


To Advertise     Find Products

Science. ISSN 0036-8075 (print), 1095-9203 (online)