Functional Imaging for Interpretation of Pain Pathways: Current Clinical Application/Relevance and Future Initiatives

Anesthetic Techniques in Pain Management (KA Williams, Section editor)
Part of the following topical collections:
  1. Topical Collection on Anesthetic Techniques in Pain Management


Functional imaging of the central nervous system has been utilized since the 1970s focusing on the concept that neural functioning is coupled to regional cerebral blood flow. This has allowed for extensive mapping of the neural pathways associated with pain, the “pain-matrix.” The study of the functional anatomy utilizes positron electron tomography and 2 magnetic resonance imaging techniques known as arterial spin labeling and blood oxygen dependent imaging. This area of study has greatly improved in recent years in being able to assist in the diagnosis of conditions and support in the creation of targeted therapies. The goal of this review is to educate the reader on the evolution of functional imaging and its application to the study of pain and furthermore to highlight the advances in this field that may allow for further clinical applications of this modality.


Functional imaging Arterial spin labeling Blood oxygen level dependent Positron emission tomography Chronic pain Pain 



CFM Clarke: receives honoraria from Pfizer Pharma as invited lecturer; K St. Lawrence: none.


Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. 1.
    Toyama H, Lio M, Lisaka J, Chiba K, Yamada H, Matsui K, et al. Color functional images of the cerebral blood flow. J Nucl Med. 1976;17:953–8.PubMedGoogle Scholar
  2. 2.
    Peyron R, Laurent B, Garcia-Larrea L. Functional imaging of brain responses to pain. A review and meta-analysis. Neurophysiol Clin. 2000;30:263–88.PubMedGoogle Scholar
  3. 3.
    Apkarian AV, Bushnell MC, Treede RD, Zubieta JK. Human brain mechanisms of pain perception and regulation in health and disease. Eur J Pain. 2005;9:463–84.PubMedGoogle Scholar
  4. 4.
    Di Piero V, Jones AK, Iannotti F, Powell M, Perani D, Lenzi GL, et al. Chronic pain: a PET study of the central effects of percutaneous high cervical cordotomy. Pain. 1991;46:9–12.PubMedGoogle Scholar
  5. 5.
    Hsieh JC, Belfrage M, Stone-Elander S, Hansson P, Ingvar M. Central representation of chronic ongoing neuropathic pain studied by positron emission tomography. Pain. 1995;63:225–36.PubMedGoogle Scholar
  6. 6.
    Xu X, Fukuyama H, Yazawa S, Mima T, Hanakawa T, Magata Y, et al. Functional localization of pain perception in the human brain studied by PET. Neuroreport. 1997;8:555–9.PubMedGoogle Scholar
  7. 7.
    Davis KD, Kwan CL, Crawley AP, Mikulis DJ. Event-related fMRI of pain: entering a new era in imaging pain. Neuroreport. 1998;9:3019–23.PubMedGoogle Scholar
  8. 8.
    Chen AC. New perspectives in EEG/MEG brain mapping and PET/fMRI neuroimaging of human pain. Int J Psychophysiol. 2001;42:147–59.PubMedGoogle Scholar
  9. 9.
    Bingel U, Tracey I. Imaging CNS modulation of pain in humans. Physiology. 2008;23:371–80.PubMedGoogle Scholar
  10. 10.
    Owen DG, Bureau Y, Thomas AW, Prato FS, St Lawrence KS. Quantification of pain-induced changes in cerebral blood flow by perfusion MRI. Pain. 2008;136:85–96.PubMedGoogle Scholar
  11. 11.
    •• Owen DG, Clarke CF, Ganapathy S, Prato FS, St Lawrence KS. Using perfusion MRI to measure the dynamic changes in neural activation associated with tonic muscular pain. Pain. 2010;148:375–86. This study demonstrated that ASL can be applied to studies of prolonged pain since it becomes increasingly more sensitive than BOLD to changes in neural over time. It further supported that ASL can capture dynamic activation patterns during prolonged pain periods.PubMedGoogle Scholar
  12. 12.
    Colombo B, Dalla Costa G, Dalla Libera D, Comi G. From neuroimaging to clinical setting: what have we learned from migraine pain? Neurol Sci. 2012;33 Suppl 1:S95–7.PubMedGoogle Scholar
  13. 13.
    Tedeschi G, Russo A, Tessitore A. Functional neuroimaging in migraine: usefulness for the clinical neurologist. Neurol Sci. 2012;33 Suppl 1:S91–4.PubMedGoogle Scholar
  14. 14.
    • Gracely RH, Ambrose KR. Neuroimaging of fibromyalgia. Best Pract Res Clin Rheumatol. 2011;25:271–84. This paper reviews historical work performed in the investigation of fibromyalgia and how functional imaging has demonstrated that this disease is its own distinct, legitimate clinical entity.PubMedGoogle Scholar
  15. 15.
    •• Borsook D, Upadhyay J, Klimas M, Schwarz AJ, Coimbra A, Baumgartner R, et al. Decision-making using fMRI in clinical drug development: revisiting NK-1 receptor antagonists for pain. Drug Discov Today. 2012;17:964–73. doi: 10.1016/j.drudis.2012.05.004. This review highlights how functional imaging may be utilized as a cost effective tool to assist in the prediction of valid targets for drug design success in the therapeutic domain.
  16. 16.
    Chapin H, Bagarinao E, Mackey S. Real-time fMRI applied to pain management. Neurosci Lett. 2012;520:174–81.PubMedGoogle Scholar
  17. 17.
    Oluigbo C, Abduljalil A, Yang X, Kalnin A, Knopp MV, Rezai AR. 156 Neuroimaging biomarkers of chronic neuropathic pain and its modulation: resting state fMRI signals during spinal cord stimulation. Neurosurgery. 2012;71:E562.Google Scholar
  18. 18.
    • Borsook D, Becerra L. How close are we in utilizing functional neuroimaging in routine clinical diagnosis of neuropathic pain? Curr Pain Headache Rep. 2011;15:223–9. This paper serves as an excellent review of the socio-economic and clinical issues that surround the advancement of functional imaging into common place within the current medical environment.PubMedGoogle Scholar
  19. 19.
    Takemura Y, Yamashita A, Horiuchi H, Furuya M, Yanase M, Niikura K, et al. Effects of gabapentin on brain hyperactivity related to pain and sleep disturbance under a neuropathic pain-like state using fMRI and brain wave analysis. Synapse. 2011;65:668–76.PubMedGoogle Scholar
  20. 20.
    Scrivani S, Wallin D, Moulton EA, Cole S, Wasan AD, Lockerman L, et al. A fMRI evaluation of lamotrigine for the treatment of trigeminal neuropathic pain: pilot study. Pain Med. 2010;11:920–41.PubMedGoogle Scholar
  21. 21.
    • Sharma HA, Gupta R, Olivero W. fMRI in patients with lumbar disc disease: a paradigm to study patients over time. J Pain Res. 2011;4:401–5. This study demonstrates the successful use of a clinical paradigm integrating the use of functional imaging and clinical exam to study patients with low back pain and leg pain including lumbar radiculopathy over time.PubMedGoogle Scholar
  22. 22.
    Egloff N, Sabbioni ME, Salathe C, Wiest R, Juengling FD. Nondermatomal somatosensory deficits in patients with chronic pain disorder: clinical findings and hypometabolic pattern in FDG-PET. Pain. 2009;145:252–8.PubMedGoogle Scholar
  23. 23.
    Davis KD. Neuroimaging of pain: what does it tell us? Curr Opin Support Palliat Care. 2011;5:116–21.PubMedGoogle Scholar
  24. 24.
    Wang YT, Huang G. Is FDG PET/CT cost-effective for pre-operation staging of potentially operative non-small cell lung cancer? From Chinese healthcare system perspective. Eur J Radiol. 2012;81:e903–9.PubMedGoogle Scholar
  25. 25.
    Mohr C, Leyendecker S, Mangels I, Machner B, Sander T, Helmchen C. Central representation of cold-evoked pain relief in capsaicin induced pain: an event-related fMRI study. Pain. 2008;139:416–30.PubMedGoogle Scholar
  26. 26.
    Aguirre GK, Detre JA, Zarahn E, Alsop DC. Experimental design and the relative sensitivity of BOLD and perfusion fMRI. NeuroImage. 2002;15:488–500.PubMedGoogle Scholar
  27. 27.
    Kim SG. Quantification of relative cerebral blood flow change by flow-sensitive alternating inversion recovery (FAIR) technique: application to functional mapping. Magn Reson Med. 1995;34:293–301.PubMedGoogle Scholar
  28. 28.
    Thunberg J, Lyskov E, Korotkov A, Ljubisavljevic M, Pakhomov S, Katayeva G, et al. Brain processing of tonic muscle pain induced by infusion of hypertonic saline. Eur J Pain. 2005;9:185–94.PubMedGoogle Scholar
  29. 29.
    Wang J, Aguirre GK, Kimberg DY, Roc AC, Li L, Detre JA. Arterial spin labeling perfusion fMRI with very low task frequency. Magn Reson Med. 2003;49:796–802.PubMedGoogle Scholar
  30. 30.
    Yongbi MN, Fera F, Yang Y, Frank JA, Duyn JH. Pulsed arterial spin labeling: comparison of multisection baseline and functional MR imaging perfusion signal at 1.5 and 3.0 T: initial results in six subjects. Radiology. 2002;222:569–75.PubMedGoogle Scholar
  31. 31.
    Bushnell MC, Duncan GH, Hofbauer RK, Ha B, Chen JI, Carrier B. Pain perception: is there a role for primary somatosensory cortex? Proc Natl Acad Sci U S A. 1999;96:7705–9.PubMedGoogle Scholar
  32. 32.
    Vogt BA, Berger GR, Derbyshire SW. Structural and functional dichotomy of human midcingulate cortex. Eur J Neurosci. 2003;18:3134–44.PubMedGoogle Scholar
  33. 33.
    Peyron R, Frot M, Schneider F, Garcia-Larrea L, Mertens P, Barral FG, et al. Role of operculoinsular cortices in human pain processing: converging evidence from PET, fMRI, dipole modeling, and intracerebral recordings of evoked potentials. NeuroImage. 2002;17:1336–46.PubMedGoogle Scholar
  34. 34.
    Becerra LR, Breiter HC, Stojanovic M, Fishman S, Edwards A, Comite AR, et al. Human brain activation under controlled thermal stimulation and habituation to noxious heat: an fMRI study. Magn Reson Med. 1999;41:1044–57.PubMedGoogle Scholar
  35. 35.
    Casey KL, Minoshima S, Morrow TJ, Koeppe RA. Comparison of human cerebral activation pattern during cutaneous warmth, heat pain, and deep cold pain. J Neurophysiol. 1996;76:571–81.PubMedGoogle Scholar
  36. 36.
    Schreckenberger M, Siessmeier T, Viertmann A, Landvogt C, Buchholz HG, Rolke R, et al. The unpleasantness of tonic pain is encoded by the insular cortex. Neurology. 2005;64:1175–83.PubMedGoogle Scholar
  37. 37.
    Teutsch S, Herken W, Bingel U, Schoell E, May A. Changes in brain gray matter due to repetitive painful stimulation. NeuroImage. 2008;42:845–9.PubMedGoogle Scholar
  38. 38.
    Jenkins WM, Merzenich MM, Ochs MT, Allard T, Guic-Robles E. Functional reorganization of primary somatosensory cortex in adult owl monkeys after behaviorally controlled tactile stimulation. J Neurophysiol. 1990;63:82–104.PubMedGoogle Scholar
  39. 39.
    •• Wrigley PJ, Press SR, Gustin SM, Macefield VG, Gandevia SC, Cousins MJ, et al. Neuropathic pain and primary somatosensory cortex reorganization following spinal cord injury. Pain. 2009;141:52–9. This study demonstrates that, just as with phantom limb pain, the amount of S1 reorganization in subjects with spinal cord injury is correlates significantly with on-going pain intensity levels. Thus strategies aimed at reversing somatosensory cortical reorganization following spinal cord injury may have therapeutic potential.PubMedGoogle Scholar
  40. 40.
    Maihofner C, Handwerker HO, Neundorfer B, Birklein F. Patterns of cortical reorganization in complex regional pain syndrome. Neurology. 2003;61:1707–15.PubMedGoogle Scholar
  41. 41.
    Fukumoto M, Ushida T, Zinchuk VS, Yamamoto H, Yoshida S. Contralateral thalamic perfusion in patients with reflex sympathetic dystrophy syndrome. Lancet. 1999;354:1790–1.PubMedGoogle Scholar
  42. 42.
    Flor H, Denke C, Schaefer M, Grusser S. Effect of sensory discrimination training on cortical reorganisation and phantom limb pain. Lancet. 2001;357:1763–4.PubMedGoogle Scholar
  43. 43.
    Flor H. Cortical reorganisation and chronic pain: implications for rehabilitation. J Rehabil Med. 2003;41(Suppl):66–72.PubMedGoogle Scholar
  44. 44.
    Sprenger T, Boecker H, Tolle TR, Bussone G, May A, Leone M. Specific hypothalamic activation during a spontaneous cluster headache attack. Neurology. 2004;62:516–7.PubMedGoogle Scholar
  45. 45.
    • Leone M, Franzini A, Cecchini AP, Bussone G. Efficacy of hypothalamic stimulation for chronic drug-resistant cluster headache. Cephalalgia. 2012;32:267–8. This study reviews work performed by this group on hypothalamic stimulation for headache. A theory originally proposed following discovery of hypothalamic activation changes noted during functional imaging in patients with chronic headache.PubMedGoogle Scholar
  46. 46.
    Matharu MS, Cohen AS, Frackowiak RS, Goadsby PJ. Posterior hypothalamic activation in paroxysmal hemicrania. Ann Neurol. 2006;59:535–45.PubMedGoogle Scholar
  47. 47.
    May A, Bahra A, Buchel C, Turner R, Goadsby PJ. Functional magnetic resonance imaging in spontaneous attacks of SUNCT: short-lasting neuralgiform headache with conjunctival injection and tearing. Ann Neurol. 1999;46:791–4.PubMedGoogle Scholar
  48. 48.
    Bartsch T, Falk D, Knudsen K, Reese R, Raethjen J, Mehdorn HM, et al. Deep brain stimulation of the posterior hypothalamic area in intractable short-lasting unilateral neuralgiform headache with conjunctival injection and tearing (SUNCT). Cephalalgia. 2011;31:1405–8.PubMedGoogle Scholar
  49. 49.
    Walcott BP, Bamber NI, Anderson DE. Successful treatment of chronic paroxysmal hemicrania with posterior hypothalamic stimulation: technical case report. Neurosurgery. 2009;65:E997. discussion E997.PubMedGoogle Scholar
  50. 50.
    Afridi SK, Matharu MS, Lee L, Kaube H, Friston KJ, Frackowiak RS, et al. A PET study exploring the laterality of brainstem activation in migraine using glyceryl trinitrate. Brain. 2005;128(Pt 4):932–9.PubMedGoogle Scholar
  51. 51.
    Afridi SK, Giffin NJ, Kaube H, Friston KJ, Ward NS, Frackowiak RS, et al. A positron emission tomographic study in spontaneous migraine. Arch Neurol. 2005;62:1270–5.PubMedGoogle Scholar
  52. 52.
    Denuelle M, Fabre N, Payoux P, Chollet F, Geraud G. Posterior cerebral hypoperfusion in migraine without aura. Cephalalgia. 2008;28:856–62.PubMedGoogle Scholar
  53. 53.
    Mainero C, Boshyan J, Hadjikhani N. Altered functional magnetic resonance imaging resting-state connectivity in periaqueductal gray networks in migraine. Ann Neurol. 2011;70:838–45.PubMedGoogle Scholar
  54. 54.
    Baliki MN, Geha PY, Jabakhanji R, Harden N, Schnitzer TJ, Apkarian AV. A preliminary fMRI study of analgesic treatment in chronic back pain and knee osteoarthritis. Mol Pain. 2008;4:47.PubMedGoogle Scholar
  55. 55.
    Giesecke T, Gracely RH, Grant MA, Nachemson A, Petzke F, Williams DA, et al. Evidence of augmented central pain processing in idiopathic chronic low back pain. Arthritis Rheum. 2004;50:613–23.PubMedGoogle Scholar
  56. 56.
    Maihofner C, Neundorfer B, Birklein F, Handwerker HO. Mislocalization of tactile stimulation in patients with complex regional pain syndrome. J Neurol. 2006;253:772–9.PubMedGoogle Scholar
  57. 57.
    Maihofner C, Handwerker HO, Neundorfer B, Birklein F. Cortical reorganization during recovery from complex regional pain syndrome. Neurology. 2004;63:693–701.PubMedGoogle Scholar
  58. 58.
    Gustin SM, Schwarz A, Birbaumer N, Sines N, Schmidt AC, Veit R, et al. NMDA-receptor antagonist and morphine decrease CRPS-pain and cerebral pain representation. Pain. 2010;151:69–76.PubMedGoogle Scholar
  59. 59.
    •• Schwenkreis P, Maier C, Tegenthoff M. Functional imaging of central nervous system involvement in complex regional pain syndrome. AJNR. 2009;30:1279–84. This paper utilized functional imaging to demonstrate reorganization in central somatosensory and motor networks in CRPS. Indicating that a significant amount of clinical findings of CRPS are related to central rather than peripheral changes.Google Scholar
  60. 60.
    Zambreanu L, Wise RG, Brooks JC, Iannetti GD, Tracey I. A role for the brainstem in central sensitisation in humans. Evidence from functional magnetic resonance imaging. Pain. 2005;114:397–407.PubMedGoogle Scholar
  61. 61.
    Seifert F, Bschorer K, De Col R, Filitz J, Peltz E, Koppert W, et al. Medial prefrontal cortex activity is predictive for hyperalgesia and pharmacological antihyperalgesia. J Neurosci. 2009;29:6167–75.PubMedGoogle Scholar
  62. 62.
    Maihofner C, Handwerker HO, Birklein F. Functional imaging of allodynia in complex regional pain syndrome. Neurology. 2006;66:711–7.PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2012

Authors and Affiliations

  1. 1.Department of Anesthesiology and Perioperative Medicine, Western UniversityLawson Health Research InstituteLondonCanada
  2. 2.Departments of Medical Imaging and Medical BiophysicsLawson Health Research InstituteLondonCanada

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