Experimental placebo analgesia changes resting-state alpha oscillations
Nathan T M Huneke, Christopher A Brown, Edward Burford, Alison Watson, Nelson J Trujillo-Barreto, Wael El-Deredy, Anthony K P Jones, Nathan T M Huneke, Christopher A Brown, Edward Burford, Alison Watson, Nelson J Trujillo-Barreto, Wael El-Deredy, Anthony K P Jones
Abstract
The lack of clear understanding of the pathophysiology of chronic pain could explain why we currently have only a few effective treatments. Understanding how pain relief is realised during placebo analgesia could help develop improved treatments for chronic pain. Here, we tested whether experimental placebo analgesia was associated with altered resting-state cortical activity in the alpha frequency band of the electroencephalogram (EEG). Alpha oscillations have been shown to be influenced by top-down processes, which are thought to underpin the placebo response. Seventy-three healthy volunteers, split into placebo or control groups, took part in a well-established experimental placebo procedure involving treatment with a sham analgesic cream. We recorded ongoing (resting) EEG activity before, during, and after the sham treatment. We show that resting alpha activity is modified by placebo analgesia. Post-treatment, alpha activity increased significantly in the placebo group only (p < 0.001). Source analysis suggested that this alpha activity might have been generated in medial components of the pain network, including dorsal anterior cingulate cortex, medial prefrontal cortex, and left insula. These changes are consistent with a cognitive state of pain expectancy, a key driver of the placebo analgesic response. The manipulation of alpha activity may therefore present an exciting avenue for the development of treatments that directly alter endogenous processes to better control pain.
Conflict of interest statement
Competing Interests: The authors have declared that no competing interests exist.
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References
- Phillips C, Main C, Buck R, Aylward M, Wynne-Jones G et al. (2008) Prioritising pain in policy making: the need for a whole systems perspective. Health Policy 88: 166–175. doi:10.1016/j.healthpol.2008.03.008. PubMed: .
- College Royal of General Practitioners (1995) Morbidity statistics from general practice. Fourth national study. London: HMSO; pp. 1991-1992.
- Goldenberg DL (2007) Pharmacological treatment of fibromyalgia and other chronic musculoskeletal pain. Best Pract Res Clin Rheumatol 21: 499–511. doi:10.1016/j.berh.2007.02.012. PubMed: .
- Clauw DJ (2010) Pain management: Fibromyalgia drugs are “as good as it gets” in chronic pain. Nat Rev Rheumatol 6: 439–440. doi:10.1038/nrrheum.2010.120. PubMed: .
- Frymoyer JW, Newberg A, Pope MH, Wilder DG, Clements J et al. (1984) Spine radiographs in patients with low-back pain. An epidemiological study in men. J Bone Joint Surg Am 66: 1048–1055. PubMed: .
- Jensen MC, Brant-Zawadzki MN, Obuchowski N, Modic MT, Malkasian D et al. (1994) Magnetic Resonance Imaging of the Lumbar Spine in People without Back Pain. N Engl J Med 331: 69–73. doi:10.1056/NEJM199407143310201. PubMed: .
- Bedson J, Croft PR (2008) The discordance between clinical and radiographic knee osteoarthritis: a systematic search and summary of the literature. BMC Musculoskelet Disord 9: 116. doi:10.1186/1471-2474-9-116. PubMed: .
- Natvig B, Bruusgaard D, Eriksen W (2001) Localized low back pain and low back pain as part of widespread musculoskeletal pain: two different disorders? A cross-sectional population study. J Rehabil Med 33: 21–25. doi:10.1080/165019701300006498. PubMed: .
- Picavet HSJ, Schouten JSAG (2003) Musculoskeletal pain in the Netherlands: prevalences, consequences and risk groups, the DMC(3)-study. Pain 102: 167–178. doi:10.1016/s0304-3959(02)00372-x. PubMed: .
- Kamaleri Y, Natvig B, Ihlebaek CM, Bruusgaard D (2008) Localized or widespread musculoskeletal pain: does it matter? Pain 138: 41–46. doi:10.1016/j.pain.2007.11.002. PubMed: .
- Mease PJ, Hanna S, Frakes EP, Altman RD (2011) Pain mechanisms in osteoarthritis: understanding the role of central pain and current approaches to its treatment. J Rheumatol 38: 1546–1551. doi:10.3899/jrheum.100759. PubMed: .
- Schmidt-Wilcke T, Clauw DJ (2011) Fibromyalgia: from pathophysiology to therapy. Nat Rev Rheumatol 7: 518–527. doi:10.1038/nrrheum.2011.98. PubMed: .
- Jones AKP, Kulkarni B, Derbyshire SWG (2003) Pain mechanisms and their disorders. Br Med Bull 65: 83–93. doi:10.1093/bmb/ldg65.083. PubMed: .
- Fields H (2004) State-dependent opioid control of pain. Nat Rev Neurosci 5: 565–575. doi:10.1038/nrn1431. PubMed: .
- Schmidt-Wilcke T, Clauw DJ (2011) Fibromyalgia: from pathophysiology to therapy. Nat Rev Rheumatol 7: 518–527. doi:10.1038/nrrheum.2011.98. PubMed: .
- Petrovic P, Kalso E, Petersson KM, Ingvar M (2002) Placebo and opioid analgesia-- imaging a shared neuronal network. Science 295: 1737–1740. doi:10.1126/science.1067176. PubMed: .
- Eippert F, Bingel U, Schoell ED, Yacubian J, Klinger R et al. (2009) Activation of the opioidergic descending pain control system underlies placebo analgesia. Neuron 63: 533–543. doi:10.1016/j.neuron.2009.07.014. PubMed: .
- Benedetti F, Carlino E, Pollo A (2011) How placebos change the patient’s brain. Neuropsychopharmacology 36: 339–354. doi:10.1038/npp.2010.81. PubMed: .
- Meissner K, Bingel U, Colloca L, Wager TD, Watson A et al. (2011) The placebo effect: Advances from different methodological approaches. J Neurosci 31: 16117–16124. doi:10.1523/JNEUROSCI.4099-11.2011. PubMed: .
- Klimesch W (1999) EEG alpha and theta oscillations reflect cognitive and memory performance: a review and analysis. Cogn Brain Res 29: 169–195. PubMed: .
- Klimesch W, Sauseng P, Hanslmayr S (2007) EEG alpha oscillations: the inhibition-timing hypothesis. Brain Res Rev 53: 63–88. doi:10.1016/j.brainresrev.2006.06.003.
- Morton DL, Brown CA, Watson A, El-Deredy W, Jones AKP (2010) Cognitive changes as a result of a single exposure to placebo. Neuropsychologia 48: 1958–1964. doi:10.1016/j.neuropsychologia.2010.03.016. PubMed: .
- Trujillo-Barreto NJ, Aubert-Vázquez E, Valdés-Sosa PA (2004) Bayesian model averaging in EEG/MEG imaging. Neuroimage 21: 1300–1319. doi:10.1016/j.neuroimage.2003.11.008. PubMed: .
- Evans A, Collins D, Mills S, Brown E, Kelly R et al. (1993) 3D statistical neuroanatomical models from 305 MRI volumes. In: Proc IEEE-Nuclear Science Symposium and Medical Imaging Conference. London: MTP Press Vol. 95. pp. 1813–1817
- Benjamini Y, Hochberg Y (1995) Controlling false discovery rate. J R Stat Soc 57: 289–300.
- Carlino E, Pollo A, Benedetti F (2011) Placebo analgesia and beyond: a melting pot of concepts and ideas for neuroscience. Curr Opin Anaesthesiol 24: 540–544. doi:10.1097/ACO.0b013e328349d0c2. PubMed: .
- Watson A, El-Deredy W, Vogt BA, Jones AKP (2007) Placebo analgesia is not due to compliance or habituation: EEG and behavioural evidence. Neuroreport 18: 771–775. doi:10.1097/WNR.0b013e3280c1e2a8. PubMed: .
- Chen AC, Dworkin SF, Drangsholt MT (1983) Cortical power spectral analysis of acute pathophysiological pain. Int J Neurosci 18: 269–278. doi:10.3109/00207458308987371. PubMed: .
- Chen ACN, Rappelsberger P (1994) Brain and Human pain: Topographic EEG amplitude and coherence mapping. Brain Topogr 7: 129–140. doi:10.1007/BF01186771. PubMed: .
- Babiloni C, Brancucci A, Babiloni F, Capotosto P, Carducci F et al. (2003) Anticipatory cortical responses during the expectancy of a predictable painful stimulation. A high-resolution electroencephalography study. Eur J Neurosci 18: 1692–1700. doi:10.1046/j.1460-9568.2003.02851. PubMed: .
- Babiloni C, Brancucci A, Del Percio C, Capotosto P, Arendt-Nielsen L et al. (2006) Anticipatory electroencephalography alpha rhythm predicts subjective perception of pain intensity. J Pain 7: 709–717. doi:10.1016/j.jpain.2006.03.005. PubMed: .
- Franciotti R, Ciancetta L, Della Penna S, Belardinelli P, Pizzella V et al. (2009) Modulation of alpha oscillations in insular cortex reflects the threat of painful stimuli. Neuroimage 46: 1082–1090. doi:10.1016/j.neuroimage.2009.03.034. PubMed: .
- Nir R-R, Sinai A, Moont R, Harari E, Yarnitsky D (2012) Tonic pain and continuous EEG: prediction of subjective pain perception by alpha-1 power during stimulation and at rest. Clin Neurophysiol 123: 605–612. doi:10.1016/j.clinph.2011.08.006. PubMed: .
- Başar E, Schürmann M, Başar-Eroglu C, Karakaş S (1997) Alpha oscillations in brain functioning: an integrative theory. Int J Psychophysiol 26: 5–29. doi:10.1016/S0167-8760(97)00753-8. PubMed: .
- De Luca M, Beckmann CF, De Stefano N, Matthews PM, Smith SM (2006) fMRI resting state networks define distinct modes of long-distance interactions in the human brain. NeuroImage 29: 1359–1367. doi:10.1016/j.neuroimage.2005.08.035. PubMed: .
- Damoiseaux JS, Rombouts SARB, Barkhof F, Scheltens P, Stam CJ et al. (2006) Consistent resting-state networks across healthy subjects. Proc Natl Acad Sci U S A 103: 13848–13853. doi:10.1073/pnas.0601417103. PubMed: .
- Cooper NR, Croft RJ, Dominey SJJ, Burgess AP, Gruzelier JH (2003) Paradox lost? Exploring the role of alpha oscillations during externally vs. internally directed attention and the implications for idling and inhibition hypotheses. Int J Psychophysiol 47: 65–74. doi:10.1016/S0167-8760(02)00107-1. PubMed: .
- Cooper NR, Burgess AP, Croft RJ, Gruzelier JH (2006) Investigating evoked and induced electroencephalogram activity in task-related alpha power increases during an internally directed attention task. Neuroreport 17: 205–208. doi:10.1097/01.wnr.0000198433.29389.54. PubMed: .
- Knyazev GG, Slobodskoj-Plusnin JY, Bocharov AV, Pylkova LV (2011) The default mode network and EEG alpha oscillations: an independent component analysis. Brain Res 1402: 67–79. doi:10.1016/j.brainres.2011.05.052. PubMed: .
- Klimesch W, Doppelmayr M, Schwaiger J, Auinger P, Winkler T (1999) “Paradoxical” alpha synchronization in a memory task. Cogn Brain Res 7: 493–501. doi:10.1016/S0926-6410(98)00056-1.
- Jensen O, Gelfand J, Kounios J, Lisman JE (2002) Oscillations in the alpha band (9-12 Hz) increase with memory load during retention in a short-term memory task. Cereb Cortex 12: 877–882. doi:10.1093/cercor/12.8.877. PubMed: .
- Sauseng P, Klimesch W, Doppelmayr M, Pecherstorfer T, Freunberger R et al. (2005) EEG alpha synchronization and functional coupling during top-down processing in a working memory task. Hum Brain Mapp 26: 148–155. doi:10.1002/hbm.20150. PubMed: .
- Jones AK, Brown WD, Friston KJ, Qi LY, Frackowiak RS (1991) Cortical and subcortical localization of response to pain in man using positron emission tomography. Proc Biol Sci 244: 39–44. doi:10.1098/rspb.1991.0048. PubMed: .
- Talbot J, Marrett S, Evans A, Meyer E, Bushnell M et al. (1991) Multiple representations of pain in human cerebral cortex. Science 251: 1355–1358. doi:10.1126/science.2003220.
- Treede RD, Kenshalo DR, Gracely RH, Jones AKP (1999) The cortical representation of pain. Pain 79: 105–111.
- Hsieh JC, Stone-Elander S, Ingvar M (1999) Anticipatory coping of pain expressed in the human anterior cingulate cortex: a positron emission tomography study. Neurosci Lett 262: 61–64. doi:10.1016/S0304-3940(99)00060-9. PubMed: .
- Lieberman MD, Jarcho JM, Berman S, Naliboff BD, Suyenobu BY et al. (2004) The neural correlates of placebo effects: a disruption account. NeuroImage 22: 447–455. doi:10.1016/j.neuroimage.2004.01.037. PubMed: .
- Wager TD, Rilling JK, Smith EE, Sokolik A, Casey KL et al. (2004) Placebo-induced changes in FMRI in the anticipation and experience of pain. Science 303: 1162–1167. doi:10.1126/science.1093065. PubMed: .
- Kong J, Gollub RL, Polich G, Kirsch I, Laviolette P et al. (2008) A functional magnetic resonance imaging study on the neural mechanisms of hyperalgesic nocebo effect. J Neurosci 28: 13354–13362. doi:10.1523/JNEUROSCI.2944-08.2008. PubMed: .
- Schreckenberger M, Siessmeier T, Viertmann A, Landvogt C, Buchholz H-G et al. (2005) The unpleasantness of tonic pain is encoded by the insular cortex. Neurology 64: 1175–1183. doi:10.1212/01.WNL.0000156353.17305.52. PubMed: .
- Ploghaus A, Tracey I, Gati JS, Clare S, Menon RS et al. (1999) Dissociating Pain from Its Anticipation in the Human Brain. Science 284: 1979–1981. doi:10.1126/science.284.5422.1979.
- Sawamoto N, Honda M, Okada T, Hanakawa T, Kanda M et al. (2000) Expectation of pain enhances responses to nonpainful somatosensory stimulation in the anterior cingulate cortex and parietal operculum/posterior insula: an event-related functional magnetic resonance imaging study. J Neurosci 20: 7438–7445. PubMed: .
- Porro CA, Baraldi P, Pagnoni G, Serafini M, Facchin P et al. (2002) Does anticipation of pain affect cortical nociceptive systems? J Neurosci 22: 3206–3214. PubMed: .
- Brown CA, Seymour B, El-Deredy W, Jones AKP (2008) Confidence in beliefs about pain predicts expectancy effects on pain perception and anticipatory processing in right anterior insula. Pain 139: 324–332. doi:10.1016/j.pain.2008.04.028. PubMed: .
- Hsieh JC, Stone-Elander S, Ingvar M (1999) Anticipatory coping of pain expressed in the human anterior cingulate cortex: a positron emission tomography study. Neurosci Lett 262: 61–64. doi:10.1016/S0304-3940(99)00060-9. PubMed: .
- Knudsen L, Petersen GL, Nørskov KN, Vase L, Finnerup N et al. (2011) Review of neuroimaging studies related to pain modulation. Scandinavian Journal of Pain 2: 108–120. doi:10.1016/j.sjpain.2011.05.005.
- Petrovic P, Dietrich T, Fransson P, Andersson J, Carlsson K et al. (2005) Placebo in emotional processing--induced expectations of anxiety relief activate a generalized modulatory network. Neuron 46: 957–969. doi:10.1016/j.neuron.2005.05.023. PubMed: .
- Nemoto H, Nemoto Y, Toda H, Mikuni M, Fukuyama H (2007) Placebo analgesia: a PET study. Experimental Brain Research 179: 655–664. doi:10.1007/s00221-006-0821-z. PubMed: .
- Seifert F, Bschorer K, De Col R, Filitz J, Peltz E et al. (2009) Medial prefrontal cortex activity is predictive for hyperalgesia and pharmacological antihyperalgesia. J Neurosci 29: 6167–6175. doi:10.1523/JNEUROSCI.4654-08.2009. PubMed: .
- Watson A, El-Deredy W, Iannetti GD, Lloyd D, Tracey I et al. (2009) Placebo conditioning and placebo analgesia modulate a common brain network during pain anticipation and perception. Pain 145: 24–30. doi:10.1016/j.pain.2009.04.003. PubMed: .
- Lorenz J, Minoshima S, Casey KL (2003) Keeping pain out of mind: the role of the dorsolateral prefrontal cortex in pain modulation. Brain 126: 1079–1091. doi:10.1093/brain/awg102. PubMed: .
- Varela F, Lachaux JP, Rodriguez E, Martinerie J (2001) The brainweb: phase synchronization and large-scale integration. Nat Rev Neurosci 2: 229–239. doi:10.1038/35067550. PubMed: .
- Hardt JV, Kamiya J (1978) Anxiety change through electroencephalographic alpha feedback seen only in high anxiety subjects. Science 201: 79–81. doi:10.1126/science.663641. PubMed: .
- Fell J, Elfadil H, Klaver P, Röschke J, Elger CE et al. (2002) Covariation of spectral and nonlinear EEG measures with alpha biofeedback. Int J Neurosci 112: 1047–1057. doi:10.1080/00207450290026049. PubMed: .
- Grant JA, Courtemanche J, Duerden EG, Duncan GH, Rainville P (2010) Cortical thickness and pain sensitivity in zen meditators. Emotion 10: 43–53. doi:10.1037/a0018334. PubMed: .
- Jensen KB, Kosek E, Wicksell R, Kemani M, Olsson G et al. (2012) Treatment with Cognitive Behavioral Therapy increases pain-evoked activation of the prefrontal cortex in patients suffering from chronic pain. Pain 153: 1495–1503. doi:10.1016/j.pain.2012.04.010. PubMed: .
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