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Pain processing in patients with migraine: an event-related fMRI study during trigeminal nociceptive stimulation

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We explored the functional pattern of the pain-processing network in patients with migraine, in the interictal periods, during trigeminal noxious stimulation. Contact heat evoked potential stimulation induced thermal pain and functional magnetic resonance imaging were used to measure whole-brain activation in 16 patients with episodic migraine without aura and 16 age- and gender-matched healthy controls in response to a severe (53°C) noxious, a moderate (51°C) noxious, and a control (41°C) stimulus applied to the maxillary skin. When comparing the fMRI activation over the entire brain, patients with migraine, with respect to healthy controls, showed a significantly greater activation in the perigenual part of anterior cingulate cortex at 51°C and less activation in the bilateral secondary somatosensory cortex at 53°C. A group-by-stimulus interaction analysis revealed a region in the pons showing a divergent response in patients and healthy controls. Correlation analyses demonstrated that the pons activation correlated with higher headache-related disability in patients. Our findings demonstrate increased antinociceptive activity in patients with migraine, which may represent a compensatory reorganization to modulate pain perception at the same intensity of healthy controls.

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  1. Kim JH, Kim S, Suh SI et al (2010) Interictal metabolic changes in episodic migraine: a voxel-based FDG-PET study. Cephalalgia 30(1):53–61

    PubMed  CAS  Google Scholar 

  2. Messlinger K (2009) Migraine: where and how does the pain originate? Exp Brain Res 196(1):179–193

    Article  PubMed  Google Scholar 

  3. Coppola G, Pierelli F, Schoenen J (2007) Is the cerebral cortex hyperexcitable or hyperresponsive in migraine? Cephalalgia 27(12):1427–1439

    Article  PubMed  CAS  Google Scholar 

  4. Aderjan D, Stankewitz A, May A (2010) Neuronal mechanisms during repetitive trigemino-nociceptive stimulation in migraine patients. Pain 151(1):97–103

    Article  PubMed  Google Scholar 

  5. Welch KM, Nagesh V, Aurora SK et al (2001) Periaqueductal gray matter dysfunction in migraine: cause or the burden of illness? Headache 41(7):629–637

    Article  PubMed  CAS  Google Scholar 

  6. Aurora SK, Barrodale PM, Tipton RL et al (2007) Brainstem dysfunction in chronic migraine as evidenced by neurophysiological and positron emission tomography studies. Headache 47(7):996–1003 (discussion 1004–1007)

    Article  PubMed  Google Scholar 

  7. Moulton EA, Burstein R, Tully S et al (2008) Interictal dysfunction of a brainstem descending modulatory center in migraine patients. PLoS One 3(11):e3799

    Article  PubMed  Google Scholar 

  8. May A, Goadsby PJ (1999) The trigeminovascular system in humans: pathophysiologic implications for primary headache syndromes of the neural influences on the cerebral circulation. J Cereb Blood Flow Metab 19(2):115–127

    Article  PubMed  CAS  Google Scholar 

  9. Borsook D, Burstein R, Becerra L (2004) Functional imaging of the human trigeminal system: opportunities for new insights into pain processing in health and disease. J Neurobiol 61(1):107–125

    Article  PubMed  Google Scholar 

  10. Kovelowski CJ, Ossipov MH, Sun H et al (2000) Supraspinal cholecystokinin may drive tonic descending facilitation mechanisms to maintain neuropathic pain in the rat. Pain 87(3):265–273

    Article  PubMed  CAS  Google Scholar 

  11. Kim JH, Suh SI, Seol HY et al (2008) Regional grey matter changes in patients with migraine: a voxel-based morphometry study. Cephalalgia 28(6):598–604

    Article  PubMed  CAS  Google Scholar 

  12. Bahra A, Matharu MS, Buchel C et al (2001) Brainstem activation specific to migraine headache. Lancet 357(9261):1016–1017

    Article  PubMed  CAS  Google Scholar 

  13. Weiller C, May A, Limmroth V et al (1995) Brain stem activation in spontaneous human migraine attacks. Nat Med 1(7):658–660

    Article  PubMed  CAS  Google Scholar 

  14. Afridi SK, Giffin NJ, Kaube H et al (2005) A positron emission tomographic study in spontaneous migraine. Arch Neurol 62(8):1270–1275

    Article  PubMed  Google Scholar 

  15. Afridi SK, Matharu MS, Lee L et al (2005) A PET study exploring the laterality of brainstem activation in migraine using glyceryl trinitrate. Brain 128(Pt 4):932–939

    Article  PubMed  CAS  Google Scholar 

  16. Stankewitz A, Aderjan D, Eippert F et al (2011) Trigeminal nociceptive transmission in migraineurs predicts migraine attacks. J Neurosci 31(6):1937–1943

    Article  PubMed  CAS  Google Scholar 

  17. Roberts K, Papadaki A, Goncalves C et al (2008) Contact heat evoked potentials using simultaneous EEG and fMRI and their correlation with evoked pain. BMC Anesthesiol 8:8

    Article  PubMed  Google Scholar 

  18. Truini A, Galeotti F, Pennisi E et al (2007) Trigeminal small-fibre function assessed with contact heat evoked potentials in humans. Pain 132(1–2):102–107

    Article  PubMed  CAS  Google Scholar 

  19. Headache Classification Committee of the International Headache Society (2004) The international classification of headache disorders: 2nd edition. Cephalalgia 24(Suppl 1):9–160

    Google Scholar 

  20. Sauro KM, Rose MS, Becker WJ et al (2010) HIT-6 and MIDAS as measures of headache disability in a headache referral population. Headache 50(3):383–395

    Article  PubMed  Google Scholar 

  21. Bayliss MS, Dewey JE, Dunlap I et al (2003) A study of the feasibility of Internet administration of a computerized health survey: the headache impact test (HIT). Qual Life Res 12(8):953–961

    Article  PubMed  CAS  Google Scholar 

  22. Stankewitz A, Voit HL, Bingel U et al (2010) A new trigemino-nociceptive stimulation model for event-related fMRI. Cephalalgia 30(4):475–485

    PubMed  CAS  Google Scholar 

  23. Olesen J, Burstein R, Ashina M, Tfelt-Hansen P (2009) Origin of pain in migraine: evidence for peripheral sensitisation. Lancet Neurol 8(7):679–690

    Article  PubMed  Google Scholar 

  24. Friston KJ, Frith CD, Frackowiak RS et al (1995) Characterizing dynamic brain responses with fMRI: a multivariate approach. Neuroimage 2(2):166–172

    Article  PubMed  CAS  Google Scholar 

  25. Friston KJ, Holmes AP, Poline JB et al (1995) Analysis of fMRI time-series revisited. Neuroimage 2(1):45–53

    Article  PubMed  CAS  Google Scholar 

  26. Forman SD, Cohen JD, Fitzgerald M, Eddy WF et al (1995) Improved assessment of significant activation in functional magnetic resonance imaging (fMRI): use of a cluster-size threshold. Magn Reson Med 33(5):636–647

    Article  PubMed  CAS  Google Scholar 

  27. Peyron R, Laurent B, Garcia-Larrea L (2000) Functional imaging of brain responses to pain. A review and meta-analysis. Neurophysiol Clin 30(5):263–288

    Article  PubMed  CAS  Google Scholar 

  28. Brooks J, Tracey I (2005) From nociception to pain perception: imaging the spinal and supraspinal pathways. J Anat 207(1):19–33

    Article  PubMed  Google Scholar 

  29. Tracey I, Dunckley P (2004) Importance of anti- and pro-nociceptive mechanisms in human disease. Gut 53(11):1553–1555

    Article  PubMed  CAS  Google Scholar 

  30. May A (2006) A review of diagnostic and functional imaging in headache. J Headache Pain 7(4):174–184

    Article  PubMed  Google Scholar 

  31. Valfre W, Rainero I, Bergui M et al (2008) Voxel-based morphometry reveals gray matter abnormalities in migraine. Headache 48(1):109–117

    Article  PubMed  Google Scholar 

  32. Seifert F, Maihofner C (2009) Central mechanisms of experimental and chronic neuropathic pain: findings from functional imaging studies. Cell Mol Life Sci 66(3):375–390

    Article  PubMed  CAS  Google Scholar 

  33. Tessitore A, Russo A, Esposito F et al (2011) Interictal cortical reorganization in episodic migraine without aura: an event-related fMRI study during parametric trigeminal nociceptive stimulation. Neurol Sci 32(Suppl 1):S165–S167

    Article  PubMed  Google Scholar 

  34. Ferraro S, Grazzi L, Mandelli ML et al (2011) Pain processing in medication overuse headache: a functional magnetic resonance imaging (fMRI) study. Pain Med [Epub ahead of print]

  35. Rocca MA, Ceccarelli A, Falini A et al (2006) Brain gray matter changes in migraine patients with T2-visible lesions: a 3-T MRI study. Stroke 37:1765–1770

    Article  PubMed  Google Scholar 

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Correspondence to Gioacchino Tedeschi.

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A. Russo and A. Tessitore contributed equally to this work.

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Russo, A., Tessitore, A., Esposito, F. et al. Pain processing in patients with migraine: an event-related fMRI study during trigeminal nociceptive stimulation. J Neurol 259, 1903–1912 (2012).

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