Neuroimaging of Pain

  • S. Espinoza
  • C. HabasEmail author
Part of the Contemporary Clinical Neuroscience book series (CCNE)


Advanced neuroimaging techniques (fMRI, PET, and MEG) have led to the identification of a set of neural networks jointly and dynamically recruited during pain processing. These techniques allow also to better characterize cerebral anatomo-functional impairments underlying chronic pain. If a “pain matrix” (PM) was characterized as the first encephalic circuit processing location and intensity of nociceptive afferents, it turns out that several potentially collaborative networks underlie specific vegetative, motor, emotional, motivational, mnesic, and executive aspects of the integrated painful experience. In other words, all brain areas engaged in pain sensation do not belong to a unique, well-delineated pain-specific network but represent a “pain signature” across distinct networks (Tracey and Mantyh Neuron 55: 377–391, 2007). In this vein, if activation of the PM is always elicited either by nociceptive stimuli or by (pathological) endogenous mechanisms, placebo, hypnosis, or empathy can be accompanied by activity in PM and pain-recruited networks. Structural, functional, and metabolic neuroimaging has shed light on neuroplastic aberrant reshaping of large-scale circuits underlying chronic pain. Furthermore, specific areas of PM and associated pain modulatory networks, which are well-delineated by fMRI, can be targeted by several noninvasive brain stimulation methods, such as transcranial direct current stimulation (tDCS) or transcranial magnetic stimulation (TMS), in order to alleviate pain symptoms, as well as real-time fMRI-based neurofeedback.


Pain Chronic pain Pain matrix Analgesia Insula Anterior cingulate cortex Prefrontal cortex Canonical networks Salience network Default mode network fMRI ASL PET scan Spectroscopy Voxel-based morphometry Aversive learning Neurofeedback Neurostimulation 


  1. 1.
    Garcia L, Peyron R (2013) Pain matrices and neuropathic pain matrices : a review. Pain., elsevier 154(Suppl 1):S29–S43CrossRefGoogle Scholar
  2. 2.
    Baliki MN, Geha PY, Apkarian AV (2009) Parsing pain perception between nociceptive representation and magnitude estimation. J Neurophysiol 101(2):875–887CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Peyron R, Laurent B, Garcia-Larrea L (2000) Functional imaging of brain responses to pain. A review and meta-analysis. Neurophysiol Clin 30:263–288CrossRefPubMedGoogle Scholar
  4. 4.
    Vogt BA, Derbyshire S, Jones AKP (1996) Pain processing in four regions of human cingulate cortex localized with coregistered PET and fMRI imaging. Eur J Neurosci 8:1461–1473CrossRefPubMedGoogle Scholar
  5. 5.
    Peyron R, Garcia-Larrea L, Gregoire MC, Costes N, Converts P, Lavenne F, Maugière F, Michel D, Laurent B (1999) Haemodynamic brain responses to acute pain in humans : sensory and attentional networks. Brain 122(9):1765–1780CrossRefPubMedGoogle Scholar
  6. 6.
    Craig AD (2009) How do you feel-now ? The anterior insula and human awareness. Nat Rev Neurosci 10(1):59–70CrossRefPubMedGoogle Scholar
  7. 7.
    Ploner M, Lee MC, Wiech K, Bingel U, Tracey I (2010) Prestimulus functional connectivity determines pain perception in humans. PNAS 107(1):355–360CrossRefPubMedGoogle Scholar
  8. 8.
    Mouraux A, Diukova A, Lee MC, Wise RG, Lannetti GD (2011) A multisensory investigation of the functional significance of the « pain matrix». NeuroImage 54:2237–2249CrossRefPubMedGoogle Scholar
  9. 9.
    Wiech K, Lin C-S, Brodersen KH, Bingel U, Ploner M, Tracey I (2010) Anterior insula integrates information about salience into perceptual decisions of pain. J Neurosci 30(48):16324–16331CrossRefPubMedGoogle Scholar
  10. 10.
    Neugebauer V, Li W, Bird GC, Han JS (2004) The amygdala and persistent pain. Neuroscientist 10:221–234CrossRefPubMedGoogle Scholar
  11. 11.
    Benuzzi F, Lui F, Duzzi D, Nichelli PF, Porro CA (2008) Does it look painful or disgusting ? Ask your parietal and cingulate cortex. J Neurosci 28(4):923–931CrossRefPubMedGoogle Scholar
  12. 12.
    Bingel U, Quante M, Knab R, Bromm B, Weiller C, Büchel C (2002) Subcortical structures involved in pain processing : evidence from single-trial fMRI. Pain 1(2):313–321CrossRefGoogle Scholar
  13. 13.
    Atlas LY, Bolger N, Lindquist MA, Wager T (2010) Brain mediators of predictive cue effects on perceived pain. J Neurosci 30(39):12964–12977CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Baliki MN, Geha PY, Fileds HL, Apkarian AV (2010) Predicting value of pain and analgesia : nucleus accumbens response to noxious stimuli changes in the presence of chronic pain. Neuron:66.
  15. 15.
    Moulton EA, Schmahmann JD, Becerra L, Borsook D (2010) The cerebellum and pain : passive integrator or active participator. Brain Res Rev 65(1):14–27CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Helmchen C, Mohr C, Erdmann C, Petersen D, Nitschke MF (2003) Differential cerebellar activation related to perceived pain intensity during noxious thermal stimulation in humans : a functional magnetic resonance imaging study. Neurosci Lett 335(3):202–206CrossRefPubMedGoogle Scholar
  17. 17.
    Mclver TA, Kornelsen J, Stroman PW (2017) Diversity in the emotional modulation of pain perception : an account of individual variability. Eur J Pain. Version of Record online: 20 SEP 2017.
  18. 18.
    Bantick SJ, Wise RG, Ploghaus A, Clare S, Smith SM, Tracey I (2002) Imaging how attention modulates pain in humans using functional MRI. Brain 125(2):310–319CrossRefPubMedGoogle Scholar
  19. 19.
    Valet M, Sprenger T, Boeker H, Willoch F, Rummeny E, Conrad B, Erhard P, Tolle TR (2004) Distraction modulates connectivity of the cingulo-frontal cortex and the midbrain during pain-an fMRI analysis. Pain 109(3):399–408CrossRefPubMedGoogle Scholar
  20. 20.
    Lorenz J, Minoshima S, Casey KL (2003) Keeping pain out of mind : the role of the dorsolateral prefrontal cortex in pain modulation. Brain 126(5):1079–1091CrossRefPubMedGoogle Scholar
  21. 21.
    Wiech K, Kalisch R, Weiskopf N, Pleger B, Stephan KE, Dolan RJ (2006) Anterolateral prefrontal cortex mediates the analgesic effect of expected and perceived control over pain. J Neurosci 26(44):11506–11509CrossRefGoogle Scholar
  22. 22.
    Bräscher A-K, Becker S, Hoeppllo M-E, Schweinhardt P (2016) Different brain circuitries mediating controllable and uncontrollable pain. J Neurosci 36(18):5013–5025CrossRefPubMedGoogle Scholar
  23. 23.
    Fairhurst M, Wiech K, Duncley P, Tracey I (2007) Anticipatory brainstem activity predicts neural processing of pain in humans. Pain 128(1–2):101–110CrossRefPubMedGoogle Scholar
  24. 24.
    Stroman PW, Khan HS, Bosma RL, Cotoi AI, Leung RL, Cadotte DW, Fehlings MG (2016) Changes in pain processing in the spinal cord and brainstem after injury characterized by functional magnetic resonance imaging. J Neurotrauma 33:1450–1460CrossRefPubMedGoogle Scholar
  25. 25.
    Tracey I (2010) Getting the pain you expect : mechanisms of placebo, nocebo and reappraisal effects in human. Nat Med 16(11):1277–1283CrossRefPubMedGoogle Scholar
  26. 26.
    Wagner TD, Rilling JK, Smith EE, Sokolik A, Casey KL, Davidson RJ, Kosslyn SM, Rose RM, Cohen JD (2004) Placebo-induced changes in fMRI in the anticipation and experience of pain. Science 303:1163–1166Google Scholar
  27. 27.
    Eckert MA, Menon V, Walczak A, Ahlstrom J, Denslow S, Horwitz A, Dubno JR (2009) At the heart of the ventral attention system : the right anterior insula. Hum Brain Mapp 30(8):2530–2541CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Loggia ML, Kim J, Gollub RL, Vangel MG, Kirsch J, Wasan AD, Napadow V (2013) Default mode network connectivity encodes clinical pain : an arterial spin labeling study. Pain 154(1):24–33CrossRefPubMedGoogle Scholar
  29. 29.
    Taylor KS, Seminowicz DA, Davis KD (2009) Two systems of resting state connectivity between the insula and cingulate cortex. Hum Brain Mapp 30:2731–2745CrossRefPubMedGoogle Scholar
  30. 30.
    Uddin LQ (2014) Salience processing and insular cortical function and dysfunction. Nat Neurosci 16(1):55–61CrossRefGoogle Scholar
  31. 31.
    Seminowicz DA, Moayedi M (2017) The dorsolateral prefrontal cortex in acute and chronic pain. J Pain 18(9):1027–1035CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Menon V, Uddin LQ (2010) Saliency, switching, attention and control : a network model of insula function. Brain Struct Funct 214(5–6):655–667CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Lee MC, Tracey I (2013) Imaging pain : a potent means for investigating pain mechanisms in patients. Br J Anaesth 111(1):64–72CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Akaparian AV, Hashmi JA, Baliki MN (2011) Pain and the brain : specificity of the brain in clinical chronic pain. Pain 152(3 Suppl):S49–S64CrossRefGoogle Scholar
  35. 35.
    Schmidt-Wilcke T (2015) Neuroimaging of chronic pain. Best Pract Res Clin Rheumatol 29:29–41CrossRefPubMedGoogle Scholar
  36. 36.
    Apkarian AV, Baliki MN, Geha PY (2009) Towards a theory of chronic pain. Prog Neurobiol 87(2):81–97CrossRefPubMedGoogle Scholar
  37. 37.
    Tracey I, Mantyh PW (2007) The cerebral signature for pain perception and its modulation. Neuron 55(3):377–391CrossRefPubMedGoogle Scholar
  38. 38.
    Baliki MN, Chialvo DR, Geha PY, Levy RM, Harden LR, Parrish TB, Apkarian AV (2006) Chronic pain and emotional brain : specific brain activity associated with spontaneous fluctuations of intensity of chronic back pain. J Neurosci 22(47):12165–12173CrossRefGoogle Scholar
  39. 39.
    Apkarian AV, Sosa Y, Sonty S, Levy RM, Harden RN, Parrish TB, Gitelman DR (2004) Chronic back pain associated with decreased prefrontal and thalamic grey matter density. J Neurosci 24:10410–10415CrossRefPubMedGoogle Scholar
  40. 40.
    Baliki MN, Petre B, Torbey S, Herrmann KM, Huang L, Schnitzer TJ, Fields HL, Apkarian AV (2012) Corticostriatal functional connectivity predicts transition to chronic back pain. Nat Neurosci 15(8):1117–1119CrossRefPubMedPubMedCentralGoogle Scholar
  41. 41.
    Baliki MN, Geha PY, Apkarian VA, Chialvo DR (2008) Beyond feeling : chronic pain hurts the brain, disrupting the default-mode network dynamics. J Neurosci 28(6):1398–1403CrossRefPubMedGoogle Scholar
  42. 42.
    Baliki MN, Mansour AR, Baria AT, Apkarian AV (2014) Functional reorganization of the default mode network across chronic pain conditions. PLoS.
  43. 43.
    Kucyi A, Moayedi M, Weissman-Fogel I, Goldberg MB, Freeman BV, Tenenbaum HC, Davis KD (2014) Enhanced medial prefrontal-default mode network functional connectivity in chronic pain and its association within pain rumination. J Neurosci 34(11):3969–3975CrossRefPubMedGoogle Scholar
  44. 44.
    Otti A, Guendel H, Wohlschläger A, Zimmer C, Noll-Hussong M (2013) Frequency shifts in the anterior default mode network and the salience network in chronic pain. BMC Psychiatry 13:84CrossRefPubMedPubMedCentralGoogle Scholar
  45. 45.
    Kim J-Y, Kim S-H, Seo J, Kim S-H, Han SW, Nam EJ, Kim S-K, Lee HJ, Lee S-J, Kim Y-T, Chang Y (2013) Increased power spectral density in resting-state pain related brain networks in fibromyalgia. Pain 154:1792–1797CrossRefPubMedGoogle Scholar
  46. 46.
    Balenzuela P, Chernomoretz A, Fraiman D, Cifre I, Sitges C, Ontoya P, Chialvo DR (2010) Modular organization of brain resting state networks in chronic back pain patients. Front Neuroinform 1:116Google Scholar
  47. 47.
    Mills EP, DiPietro F, Alshelh Z, Peck CC, Murray GM, Vickers ER, Henderson LA (2017) Brainstem pain control circuitry connectivity in chronic neuropathic pain. J Neurosci:1647–1617.
  48. 48.
    Lorenz J, Cross DJ, Minoshima S, Morrow TJ, Paulson PE, Casey JL (2002) A unique representation of heat allodynia in the human brain. Neuron 35(2):383–393CrossRefPubMedGoogle Scholar
  49. 49.
    Schwedt TJ, Larson-Prior L, Coalson RS, Nolan T, Mar S, Ances BM, Benzinger T, Schlaggar BL (2014) Allodynia and descending pain modulation in migraine : a resting state functional connectivity analysis. Pain Med 15(1):154–165CrossRefPubMedGoogle Scholar
  50. 50.
    Seminowicz DA, Davis KD (2005) Cortical responses to pain in healthy individuals depends on pain catastrophizing. Pain 120:297–306CrossRefGoogle Scholar
  51. 51.
    Cauda F, Palermo S, Costa T, Torta R, Duca S, Vercelli U, Geminiani G, Torta DME (2014) Gray matter alterations in chronic pain : a network-oriented meta-analytic approach. Neuroimage Clin 4:676–686CrossRefPubMedPubMedCentralGoogle Scholar
  52. 52.
    Mansour A, Baliki MN, Huang L, Torbey S, Herrmann K, Schnitzer TJ, Apkarian AV (2013) Brain white matter structural properties predict transition to chronic pain. Pain 154(10):2160–2168CrossRefPubMedPubMedCentralGoogle Scholar
  53. 53.
    Lutz J, Jäger L, de Quervain D, Krauseneck T, Padberg F, Wichnalek M, Beyer A, Stahl R, Zirngibl B, Reiser M, Schelling G (2008) White and grey matter abnormalities in the brain of patients with fibromyalgia : a diffusion-tensor and volumetric imaging study. Arthritis Rheum 58(12):3960–3969CrossRefPubMedGoogle Scholar
  54. 54.
    Hotta J, Zhou G, Harno H, Forss N, Hari R (2017) Complex regional pain syndrome : the matter of white matter ? Brain Behav 7(5):e00647. eCollection 2017 MayCrossRefPubMedPubMedCentralGoogle Scholar
  55. 55.
    Farmer MA, Baliki MN, Apkarian AV (2012) A dynamical network perspective of chronic pain. Neurosci Lett 520(2):197–203CrossRefPubMedPubMedCentralGoogle Scholar
  56. 56.
    Chapin H, Bagarinao E, Mackey S (2012) Real-time applied to pain management. Neurosci Lett 520(2):174–181CrossRefPubMedPubMedCentralGoogle Scholar
  57. 57.
    Sulzer J, Haller S, Scharnowski F, Weiskopf N, Birbaumer N, Blefari ML, Bruehl AB, Cohen LG, deCharms RC, Gassert R, Goebel R, Herwig U, LaConte S, Linden D, Luft A, Seifritz E, Sitaram R (2013) Real-time fMRI neurofeedback : progress and challenges. NeuroImage 73:386–399CrossRefGoogle Scholar
  58. 58.
    deCharms RC, Maeda F, Glover GH, Ludlow D, Pauly JM, Soneji D, Gabrieli JDE, Mackey SC (2005) Control over brain activation and pain learned by using real-time functional MRI. PNAS 102(51):18627–18631CrossRefGoogle Scholar
  59. 59.
    Emmert K, Breimhorst M, Bauermann T, Birklein F, Van De ville D, Haller S (2014 .; 8 article) Comparison of anterior cingulate vs insular cortex as targets for real-time fMRI regulation during pain stimulation. Front Behav Neurosci 350:1–13Google Scholar
  60. 60.
    Rance M, Ruttorf M, Nees F, Schad LR, Flor H (2014) Real time fMRI feedback of the anterior cingulate and posterior insular cortex in the processing of pain. Hum Brain Mapp 35(12):5784–5798CrossRefPubMedGoogle Scholar
  61. 61.
    Emmert K, Kopel R, Sulzer J, Brühl AB, Berman BD, Linden DEJ, Horovitz SG, Caria A, Frank S, Johnston LZL, Paret C, Robineau F, Veit R, Bartsch A, Beckmann CF, Van De Ville D, Haller S (2016) Meta-analysis of real-time fMRI neurofeedback studies using individual participant data : how is brain regulation mediated ? NeuroImage 124:806–812CrossRefPubMedGoogle Scholar
  62. 62.
    Jensen MP, Day MA, Miro J (2014) Neuromodulatory treatments for chronic pain : efficacy and mechanisms. Nat Rev Neurol 10:167–178CrossRefPubMedPubMedCentralGoogle Scholar
  63. 63.
    Landry M, Lifshitz M, Raz A (2017) Brain correlates of hypnosis : a systematic review and meta-analytic exploration. Neurosci Biobehav Rev 81:75–98CrossRefPubMedGoogle Scholar
  64. 64.
    Lutz A, McFarlin DR, Perlman DM, Salomons TV, Davidson RJ (2013) Altered anterior insula activation during anticipation and experience of painful stimuli in expert meditators. NeuroImage 64:538–546CrossRefPubMedGoogle Scholar
  65. 65.
    Fregni F, freedman S, Pascual-Leone A (2007) Recent advances in the treatment of chronic pain with non-invasive brain stimulation techniques. Lancet Neurol 6:188–191CrossRefPubMedGoogle Scholar
  66. 66.
    Siebner HR, Bergmann TO, Nestmann S, Massimini M et al (2009) Consensus paper : combining transcranial stimulation with neuroimaging. Brain Stimul 2:58–80CrossRefPubMedGoogle Scholar
  67. 67.
    Klooster DCW, de Louw AJA, Aldenkamp AP, Besseling RMH, Mestrom RMC, Carette S, Zinger S, bergmans JWM, Mess WH, Vonck K, Carrette E, Breuer LEM, Bernas A, Tijuis AG, Boon P (2016) Technical aspects of neurostimulation : focus on equipment, electric field modeling and stimulation protocols. Neurosci Biobehav Rev 65:113–141CrossRefPubMedGoogle Scholar
  68. 68.
    Luedtke K, Rushton A, Wright C, Geiss B, Juergens TP, May A (2012) Transcranial direct current stimulation for the reduction of clinical and experimentally induced pain : a systematic review and meta-analysis. Clin J Pain 28(5):452–461CrossRefPubMedGoogle Scholar
  69. 69.
    O'Connell NE, Wand BM, Marston L, Spencer S, Desouza LH (2011) Non-invasive brain stimulation techniques for a chronic pain. A report of a Cochrane systematic review and meta-analysis. Eur J Phys Rehabil Med 47(2):309–326PubMedGoogle Scholar
  70. 70.
    Vaseghi B, Zoghi M, Jaberzadeh S (2014) Does anodal transcranial direct current stimulation modulate sensory perception and pain? A metaanalysis study. Clinical Neurophysiol 125(9):1847–1858CrossRefPubMedGoogle Scholar
  71. 71.
    DosSantos MF, Love TM, Martikainen IK, Nascimento TD, Fregni F, Cummiford C, Deboer MD, Zubieta J-K, DaSilva AFM (2012) Immediate effects of tDCS on the μ-opioid system of a chronic pain patient. Front Psych 3:93Google Scholar
  72. 72.
    Lang N, Siebner HR, Ward NS, Lee L, Nitsche MA, Paulus W, Rothwell JC, Lemon RN, rackowiak RS (2005) How does trans-cranial DC stimulation of the primary motor cortex alter regional neuronal activity in the human brain ? Eur J Neurosci 22(2):495–504CrossRefPubMedPubMedCentralGoogle Scholar
  73. 73.
    Peyron R, Faillenot I, Mertens P, Laurent B, Garcia-Larrea L (2007) Motor cortex stimulation in neuropathic pain. Correlations between analgesic effect and hemodynamic changes in the brain. A PET study. NeuroImage 34(1):310–321CrossRefPubMedGoogle Scholar
  74. 74.
    Jin Y, Xing G, Li G, Wang A, Feng S, Tang Q, Liao X, Guo Z, McClure MA, Mu Q (2015) High frequency repetitive transcranial magnetic stimulation therapy for chronic neuropathic pain : a meta-analysis. Pain Physician 18(6):E1029–E1046PubMedGoogle Scholar
  75. 75.
    Lefaucheur J-P, Antal A, Ahdab R, Ciampi de Andrade D, Fregni F, Khedr EM, Nitsche M, Paulus W (2008) The use of repetitive transcranial magnetic stimulation (rTMS) and transcranial direct current stimulation (tDCS) to relieve pain. Brain Stimul 1:337–344CrossRefPubMedGoogle Scholar
  76. 76.
    André-Obadia N, Mertens P, Gueguen A, Peyron R, Garcia-Larrea L (2008) Pain relief by rTMS. Differential effect of current flow but no specific action on pain subtypes. Neurology 71(11):833CrossRefPubMedGoogle Scholar
  77. 77.
    Hou WH, Wang TY, Kang JH (2016) The effects of add-on non-invasive brain stimulation in fibromyalgia : a meta-analysis and meta-regression of randomized controlled trials. Rheumatology (Oxford) 55(8):1507–1517CrossRefGoogle Scholar
  78. 78.
    Maleki N, Brawn J, Barmetter G, Borsook D, Becerra L (2013) Pain responses measured with arterial spin labelling. NMR Biomed 26(6):664–673PubMedPubMedCentralGoogle Scholar
  79. 79.
    Segerdahl AR, Mezue M, Okell TW, Farrar JT, Tracey I (2015) The dorsal posterior insula subserves a fundamental role in human pain. Nat Neurosci 18(4):499–500CrossRefPubMedGoogle Scholar

Copyright information

© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Service de NeuroImagerieParisFrance

Personalised recommendations