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Brain activity associated with pain, hyperalgesia and allodynia: an ALE meta-analysis

  • Basic Neurosciences, Genetics and Immunology - Original Article
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Abstract

The use of functional brain imaging techniques offers the possibility of uncovering the cerebral processing of the human pain experience. In recent years, many imaging studies have focused on defining a network of brain structures involved in the processing of normal pain. Additionally, it has been shown that stimulus-evoked pain, which is a frequent symptom of neuropathic pain, causes distinct patterns of brain activation. In the present study, we quantitatively analyzed the data of previous functional imaging studies. Studies were thus collected by means of a MEDLINE query. A meta-analysis using the activation-likelihood estimation method was conducted to quantify the acquired results. We then used this data to summarize and compare the cerebral activations of (i) normal and stimulus-evoked pain, (ii) thermal and mechanical pain, (iii) different types of stimulus-evoked pain (hyperalgesia, allodynia), and (iv) clinical neuropathic and experimental pain. The results suggest the existence of distinct, although overlapping, neuronal networks related to these different types of pain.

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References

  • Apkarian AV, Shi T (1994) Squirrel monkey lateral thalamus I. Somatic nociresponsive neurons and their relation to spinothalamic terminals. J Neurosci 14:6779–6795

    PubMed  CAS  Google Scholar 

  • Apkarian AV, Bushnell MC, Treede RD, Zubieta JK (2005) Human brain mechanisms of pain perception and regulation in health and disease. Eur J Pain 9:463–484

    Article  PubMed  Google Scholar 

  • Baron R, Baron Y, Disbrow E, Roberts TP (1999) Brain processing of capsaicin-induced secondary hyperalgesia: a functional MRI study. Neurology 53:548–557

    PubMed  CAS  Google Scholar 

  • Bingel U, Quante M, Knab R, Bromm B, Weiller C, Buchel C (2003) Single trial fMRI reveals significant contralateral bias in responses to laser pain within thalamus and somatosensory cortices. Neuroimage 18:740–748

    Article  PubMed  CAS  Google Scholar 

  • Bingel U, Lorenz J, Schoell E, Weiller C, Buchel C (2006) Mechanisms of placebo analgesia: rACC recruitment of a subcortical antinociceptive network. Pain 120:8–15

    Article  PubMed  CAS  Google Scholar 

  • Bingel U, Schoell E, Herken W, Buchel C, May A (2007) Habituation to painful stimulation involves the antinociceptive system. Pain 131:21–30

    Article  PubMed  CAS  Google Scholar 

  • Chein JM, Fissell K, Jacobs S, Fiez JA (2002) Functional heterogeneity within Broca’s area during verbal working memory. Physiol Behav 77:635–639

    Article  PubMed  CAS  Google Scholar 

  • Coghill RC, Sang CN, Maisog JM, Iadarola MJ (1999) Pain intensity processing within the human brain: a bilateral, distributed mechanism. J Neurophysiol 82:1934–1943

    PubMed  CAS  Google Scholar 

  • Collins DL, Neelin P, Peters TM, Evans AC (1994) Automatic 3D intersubject registration of MR volumetric data in standardized Talairach space. J Comput Assist Tomogr 18:192–205

    Article  PubMed  CAS  Google Scholar 

  • Disbrow E, Roberts T, Krubitzer L (2000) Somatotopic organization of cortical fields in the lateral sulcus of Homo sapiens: evidence for SII and PV. J Comp Neurol 418:1–21

    Article  PubMed  CAS  Google Scholar 

  • Ducreux D, Attal N, Parker F, Bouhassira D (2006) Mechanisms of central neuropathic pain: a combined psychophysical and fMRI study in syringomyelia. Brain 129:963–976

    Article  PubMed  Google Scholar 

  • Eickhoff SB, Laird AR, Grefkes C, Wang LE, Zilles K, Fox PT (2009) Coordinate-based activation likelihood estimation meta-analysis of neuroimaging data: a random-effects approach based on empirical estimates of spatial uncertainty. Hum Brain Mapp 30:2907–2926

    Article  PubMed  Google Scholar 

  • Farrell MJ, Laird AR, Egan GF (2005) Brain activity associated with painfully hot stimuli applied to the upper limb: a meta-analysis. Hum Brain Mapp 25:129–139

    Article  PubMed  Google Scholar 

  • Forss N, Raij TT, Seppa M, Hari R (2005) Common cortical network for first and second pain. Neuroimage 24:132–142

    Article  PubMed  Google Scholar 

  • Fox PT, Parsons LM, Lancaster JL (1998) Beyond the single study: function/location metanalysis in cognitive neuroimaging. Curr Opin Neurobiol 8:178–187

    Article  PubMed  CAS  Google Scholar 

  • Geha PY, Baliki MN, Wang X, Harden RN, Paice JA, Apkarian AV (2008) Brain dynamics for perception of tactile allodynia (touch-induced pain) in postherpetic neuralgia. Pain 138:641–656

    Article  PubMed  CAS  Google Scholar 

  • Hoffman HG, Richards TL, Coda B, Bills AR, Blough D, Richards AL, Sharar SR (2004) Modulation of thermal pain-related brain activity with virtual reality: evidence from fMRI. Neuroreport 15:1245–1248

    Article  PubMed  Google Scholar 

  • Iadarola MJ, Berman KF, Zeffiro TA, Byas-Smith MG, Gracely RH, Max MB, Bennett GJ (1998) Neural activation during acute capsaicin-evoked pain and allodynia assessed with PET. Brain 121(Pt 5):931–947

    Article  PubMed  Google Scholar 

  • Jensen TS, Baron R (2003) Translation of symptoms and signs into mechanisms in neuropathic pain. Pain 102:1–8

    Article  PubMed  Google Scholar 

  • Jung P, Baumgartner U, Stoeter P, Treede RD (2009) Structural and functional asymmetry in the human parietal opercular cortex. J Neurophysiol 101:3246–3257

    Article  PubMed  Google Scholar 

  • Kenshalo DR Jr, Isensee O (1983) Responses of primate SI cortical neurons to noxious stimuli. J Neurophysiol 50:1479–1496

    PubMed  Google Scholar 

  • Koltzenburg M, Torebjork HE, Wahren LK (1994) Nociceptor modulated central sensitization causes mechanical hyperalgesia in acute chemogenic and chronic neuropathic pain. Brain 117(Pt 3):579–591

    Article  PubMed  Google Scholar 

  • Kupers R, Kehlet H (2006) Brain imaging of clinical pain states: a critical review and strategies for future studies. Lancet Neurol 5:1033–1044

    Article  PubMed  Google Scholar 

  • Laird AR, Fox PM, Price CJ, Glahn DC, Uecker AM, Lancaster JL, Turkeltaub PE, Kochunov P, Fox PT (2005) ALE meta-analysis: controlling the false discovery rate and performing statistical contrasts. Hum Brain Mapp 25:155–164

    Article  PubMed  Google Scholar 

  • Lebel A, Becerra L, Wallin D, Moulton EA, Morris S, Pendse G, Jasciewicz J, Stein M, Aiello-Lammens M, Grant E, Berde C, Borsook D (2008) fMRI reveals distinct CNS processing during symptomatic and recovered complex regional pain syndrome in children. Brain 131:1854–1879

    Article  PubMed  CAS  Google Scholar 

  • Lorenz J, Cross D, Minoshima S, Morrow T, Paulson P, Casey K (2002) A unique representation of heat allodynia in the human brain. Neuron 35:383–393

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • Lui F, Duzzi D, Corradini M, Serafini M, Baraldi P, Porro CA (2008) Touch or pain? Spatio-temporal patterns of cortical fMRI activity following brief mechanical stimuli. Pain 138:362–374

    Article  PubMed  CAS  Google Scholar 

  • Maihofner C, Handwerker HO (2005) Differential coding of hyperalgesia in the human brain: a functional MRI study. Neuroimage 28:996–1006

    Article  PubMed  Google Scholar 

  • Maihofner C, Schmelz M, Forster C, Neundorfer B, Handwerker HO (2004) Neural activation during experimental allodynia: a functional magnetic resonance imaging study. Eur J Neurosci 19:3211–3218

    Article  PubMed  Google Scholar 

  • Maihofner C, Forster C, Birklein F, Neundorfer B, Handwerker HO (2005) Brain processing during mechanical hyperalgesia in complex regional pain syndrome: a functional MRI study. Pain 114:93–103

    Article  PubMed  Google Scholar 

  • Maihofner C, Herzner B, Otto Handwerker H (2006) Secondary somatosensory cortex is important for the sensory-discriminative dimension of pain: a functional MRI study. Eur J Neurosci 23:1377–1383

    Article  PubMed  Google Scholar 

  • Maihofner C, Ringler R, Herrndobler F, Koppert W (2007) Brain imaging of analgesic and antihyperalgesic effects of cyclooxygenase inhibition in an experimental human pain model: a functional MRI study. Eur J Neurosci 26:1344–1356

    Article  PubMed  Google Scholar 

  • Melzack R (1999) From the gate to the neuromatrix. Pain Suppl 6:S121–126

    Google Scholar 

  • Merskey H, Bogduk N (1994) Classification of chronic pain: descriptions of chronic pain syndromes and definition of pain terms, 2nd edn. IASP Press, Seattle

  • Mohr C, Leyendecker S, Helmchen C (2008) Dissociable neural activity to self- vs. externally administered thermal hyperalgesia: a parametric fMRI study. Eur J Neurosci 27:739–749

    Article  PubMed  CAS  Google Scholar 

  • Moisset X, Bouhassira D (2007) Brain imaging of neuropathic pain. Neuroimage 37(Suppl 1):S80–S88

    Article  PubMed  Google Scholar 

  • Neumann J, von Cramon DY, Lohmann G (2008) Model-based clustering of meta-analytic functional imaging data. Hum Brain Mapp 29:177–192

    Article  PubMed  Google Scholar 

  • Ochoa JL, Yarnitsky D (1993) Mechanical hyperalgesias in neuropathic pain patients: dynamic and static subtypes. Ann Neurol 33:465–472

    Article  PubMed  CAS  Google Scholar 

  • Ochoa JL, Yarnitsky D (1994) The triple cold syndrome. Cold hyperalgesia, cold hypoaesthesia and cold skin in peripheral nerve disease. Brain 117(Pt 1):185–197

    Article  PubMed  Google Scholar 

  • Petrovic P, Ingvar M, Stone-Elander S, Petersson KM, Hansson P (1999) A PET activation study of dynamic mechanical allodynia in patients with mononeuropathy. Pain 83:459–470

    Article  PubMed  CAS  Google Scholar 

  • Peyron R, Garcia-Larrea L, Gregoire MC, Convers P, Lavenne F, Veyre L, Froment JC, Mauguiere F, Michel D, Laurent B (1998) Allodynia after lateral-medullary (Wallenberg) infarct. A PET study. Brain 121(Pt 2):345–356

    Article  PubMed  Google Scholar 

  • Peyron R, Laurent B, Garcia-Larrea L (2000) Functional imaging of brain responses to pain. A review and meta-analysis (2000). Neurophysiol Clin 30:263–288

    Article  PubMed  CAS  Google Scholar 

  • Qiu Y, Noguchi Y, Honda M, Nakata H, Tamura Y, Tanaka S, Sadato N, Wang X, Inui K, Kakigi R (2006) Brain processing of the signals ascending through unmyelinated C fibers in humans: an event-related functional magnetic resonance imaging study. Cereb Cortex 16:1289–1295

    Article  PubMed  Google Scholar 

  • Rogers R, Wise RG, Painter DJ, Longe SE, Tracey I (2004) An investigation to dissociate the analgesic and anesthetic properties of ketamine using functional magnetic resonance imaging. Anesthesiology 100:292–301

    Article  PubMed  CAS  Google Scholar 

  • Salimi-Khorshidi G, Smith SM, Keltner JR, Wager TD, Nichols TE (2009) Meta-analysis of neuroimaging data: a comparison of image-based and coordinate-based pooling of studies. Neuroimage 45:810–823

    Article  PubMed  Google Scholar 

  • Schlereth T, Baumgartner U, Magerl W, Stoeter P, Treede RD (2003) Left-hemisphere dominance in early nociceptive processing in the human parasylvian cortex. Neuroimage 20:441–454

    Article  PubMed  Google Scholar 

  • Schmelz M, Schmid R, Handwerker HO, Torebjork HE (2000) Encoding of burning pain from capsaicin-treated human skin in two categories of unmyelinated nerve fibres. Brain 123(Pt 3):560–571

    Article  PubMed  Google Scholar 

  • Schmidt R, Schmelz M, Forster C, Ringkamp M, Torebjork E, Handwerker H (1995) Novel classes of responsive and unresponsive C nociceptors in human skin. J Neurosci 15:333–341

    PubMed  CAS  Google Scholar 

  • Schoedel AL, Zimmermann K, Handwerker HO, Forster C (2008) The influence of simultaneous ratings on cortical BOLD effects during painful and non-painful stimulation. Pain 135:131–141

    Article  PubMed  Google Scholar 

  • Schweinhardt P, Glynn C, Brooks J, McQuay H, Jack T, Chessell I, Bountra C, Tracey I (2006) An fMRI study of cerebral processing of brush-evoked allodynia in neuropathic pain patients. Neuroimage 32:256–265

    Article  PubMed  Google Scholar 

  • Seifert F, Maihofner C (2009) Central mechanisms of experimental and chronic neuropathic pain: findings from functional imaging studies. Cell Mol Life Sci 66:375–390

    Article  PubMed  CAS  Google Scholar 

  • Seifert F, Jungfer I, Schmelz M, Maihofner C (2007) Representation of UV-B-induced thermal and mechanical hyperalgesia in the human brain: a functional MRI study. Hum Brain Mapp

  • Seifert F, Jungfer I, Schmelz M, Maihofner C (2008) Representation of UV-B-induced thermal and mechanical hyperalgesia in the human brain: a functional MRI study. Hum Brain Mapp 29:1327–1342

    Article  PubMed  Google Scholar 

  • Seminowicz DA, Davis KD (2007) Interactions of pain intensity and cognitive load: the brain stays on task. Cereb Cortex 17:1412–1422

    Article  PubMed  Google Scholar 

  • Seminowicz DA, Mikulis DJ, Davis KD (2004) Cognitive modulation of pain-related brain responses depends on behavioral strategy. Pain 112:48–58

    Article  PubMed  CAS  Google Scholar 

  • Smith SM, Fox PT, Miller KL, Glahn DC, Fox PM, Mackay CE, Filippini N, Watkins KE, Toro R, Laird AR, Beckmann CF (2009) Correspondence of the brain’s functional architecture during activation and rest. Proc Natl Acad Sci USA 106:13040–13045

    Article  PubMed  CAS  Google Scholar 

  • Sprenger T, Valet M, Woltmann R, Zimmer C, Freynhagen R, Kochs EF, Tolle TR, Wagner KJ (2006) Imaging pain modulation by subanesthetic S-(+)-ketamine. Anesth Analg 103:729–737

    Article  PubMed  CAS  Google Scholar 

  • Symonds LL, Gordon NS, Bixby JC, Mande MM (2006) Right-lateralized pain processing in the human cortex: an FMRI study. J Neurophysiol 95:3823–3830

    Article  PubMed  Google Scholar 

  • Talairach J, Tournoux P (1988) Co-planar stereotaxic atlas of the human brain. Thieme Medical Publishers, Germany, pp 1–122

  • Tracey I (2008) Imaging pain. Br J Anaesth 101:32–39

    Article  PubMed  CAS  Google Scholar 

  • Treede RD, Kenshalo DR, Gracely RH, Jones AK (1999) The cortical representation of pain. Pain 79:105–111

    Article  PubMed  CAS  Google Scholar 

  • Turkeltaub PE, Eden GF, Jones KM, Zeffiro TA (2002) Meta-analysis of the functional neuroanatomy of single-word reading: method and validation. Neuroimage 16:765–780

    Article  PubMed  Google Scholar 

  • Wager TD, Jonides J, Reading S (2004a) Neuroimaging studies of shifting attention: a meta-analysis. Neuroimage 22:1679–1693

    Article  PubMed  Google Scholar 

  • Wager TD, Rilling JK, Smith EE, Sokolik A, Casey KL, Davidson RJ, Kosslyn SM, Rose RM, Cohen JD (2004b) Placebo-induced changes in FMRI in the anticipation and experience of pain. Science 303:1162–1167

    Article  PubMed  CAS  Google Scholar 

  • Wager TD, Lindquist M, Kaplan L (2007) Meta-analysis of functional neuroimaging data: current and future directions. Soc Cogn Affect Neurosci 2:150–158

    Article  PubMed  Google Scholar 

  • Wager TD, Lindquist MA, Nichols TE, Kober H, Van Snellenberg JX (2009) Evaluating the consistency and specificity of neuroimaging data using meta-analysis. Neuroimage 45:S210–S221

    Article  PubMed  Google Scholar 

  • Wagner KJ, Sprenger T, Kochs EF, Tolle TR, Valet M, Willoch F (2007) Imaging human cerebral pain modulation by dose-dependent opioid analgesia: a positron emission tomography activation study using remifentanil. Anesthesiology 106:548–556

    Article  PubMed  CAS  Google Scholar 

  • Wiech K, Seymour B, Kalisch R, Stephan KE, Koltzenburg M, Driver J, Dolan RJ (2005) Modulation of pain processing in hyperalgesia by cognitive demand. Neuroimage 27:59–69

    Article  PubMed  Google Scholar 

  • Witting N, Kupers RC, Svensson P, Arendt-Nielsen L, Gjedde A, Jensen TS (2001) Experimental brush-evoked allodynia activates posterior parietal cortex. Neurology 57:1817–1824

    PubMed  CAS  Google Scholar 

  • Witting N, Kupers RC, Svensson P, Jensen TS (2006) A PET activation study of brush-evoked allodynia in patients with nerve injury pain. Pain 120:145–154

    Article  PubMed  Google Scholar 

  • Woolf CJ, Mannion RJ (1999) Neuropathic pain: aetiology, symptoms, mechanisms, and management. Lancet 353:1959–1964

    Article  PubMed  CAS  Google Scholar 

  • Xu X, Fukuyama H, Yazawa S, Mima T, Hanakawa T, Magata Y, Kanda M, Fujiwara N, Shindo K, Nagamine T, Shibasaki H (1997) Functional localization of pain perception in the human brain studied by PET. Neuroreport 8:555–559

    Article  PubMed  CAS  Google Scholar 

  • Youell PD, Wise RG, Bentley DE, Dickinson MR, King TA, Tracey I, Jones AK (2004) Lateralisation of nociceptive processing in the human brain: a functional magnetic resonance imaging study. Neuroimage 23:1068–1077

    Article  PubMed  Google Scholar 

  • Ziegler EA, Magerl W, Meyer RA, Treede RD (1999) Secondary hyperalgesia to punctate mechanical stimuli. Central sensitization to A-fibre nociceptor input. Brain 122(Pt 12):2245–2257

    Article  PubMed  Google Scholar 

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Acknowledgments

This study was supported by the German Research Network “Neuropathic Pain” of the German Federal Ministry of Education and Research (Bundesministerium für Bildung und Forschung; BMBF) and the German Research Foundation (DFG, KFO 130).

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Correspondence to Christian Maihöfner.

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Stefan Lanz and Frank Seifert contributed equally to this work.

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Lanz, S., Seifert, F. & Maihöfner, C. Brain activity associated with pain, hyperalgesia and allodynia: an ALE meta-analysis. J Neural Transm 118, 1139–1154 (2011). https://doi.org/10.1007/s00702-011-0606-9

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