Skip to main content

Physiopathology of Migraine: What Have We Learned from Functional Imaging?

Abstract

Purpose of Review

This review aims to provide an overview of the most recent and significant functional neuroimaging studies which have clarified the complex mechanisms underlying migraine pathophysiology.

Recent Findings

The recent data allow us to overcome the concept of a migraine generator suggesting that functional networks abnormalities may lead to changes in different brain area activities and consequent reduced migraine thresholds susceptibility, likely associated with higher migraine severity and burden.

Summary

Although functional magnetic resonance imaging studies have allowed recognition of several migraine mechanisms, its pathophysiology is not completely understood and is still a matter of research. Nevertheless, in recent years, functional magnetic resonance imaging studies have allowed us to implement our knowledge of migraine pathophysiology. The pivotal role of both the brainstem and the hippocampus in the first phase of a migraine attack, the involvement of limbic pathway in the constitution of a migrainous pain network, the disrupted functional connectivity in cognitive brain networks, as well as the abnormal function of the visual network in patients with migraine with aura are the main milestones in migraine imaging achieved through functional imaging advances. We believe that further studies based on combined functional and structural techniques and the investigation of the different phases of migraine cycle may represent an efficient methodological approach for comprehensively looking into the migrainous brain secrets.

This is a preview of subscription content, access via your institution.

Fig. 1

References

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

  1. 1.

    Olesen J, Larsen B, Lauritzen M. Focal hyperemia followed by spreading oligemia and impaired activation of rCBF in classic migraine. Ann Neurol. 1981;9(4):344–52.

    CAS  Article  PubMed  Google Scholar 

  2. 2.

    Tedeschi G, Russo A, Tessitore A. Functional neuroimaging in migraine: usefulness for the clinical neurologist. Neurol Sci. 2012;33(Suppl. 1):S91–4.

    Article  PubMed  Google Scholar 

  3. 3.

    May A. A review of diagnostic and functional imaging in headache. J Headache Pain. 2006;7(4):174–84.

    Article  PubMed  PubMed Central  Google Scholar 

  4. 4.

    Sprenger T, Henriksen G, Valet M, et al. Positron emission tomography in pain research. From the structure to the activity of the opiate receptor system. Schmerz. 2007;21:503–13.

    CAS  Article  PubMed  Google Scholar 

  5. 5.

    Sprenger T, Ruether KV, Boecker H, et al. Altered metabolism in frontal brain circuits in cluster headache. Cephalalgia. 2007;27:1033–42.

    CAS  Article  PubMed  Google Scholar 

  6. 6.

    Sprenger T, Willoch F, Miederer M, et al. Opioidergic changes in the pineal gland and hypothalamus in cluster headache: a ligand PET study. Neurology. 2006;66:1108–10.

    CAS  Article  PubMed  Google Scholar 

  7. 7.

    Weiller C, May A, Limmroth V, et al. Brainstem activation in spontaneous human migraine attacks. Nat Med. 1995;1(7):658–60.

    CAS  Article  PubMed  Google Scholar 

  8. 8.

    Afridi SK, Giffin NJ, Kaube H, et al. A positron emission tomographic study in spontaneous migraine. Arch Neurol. 2005;62(8):1270–5.

    Article  PubMed  Google Scholar 

  9. 9.

    Denuelle M, Fabre N, Payoux P, et al. Hypothalamic activation in spontaneous migraine attacks. Headache. 2007;47(10):1418–26.

    PubMed  Google Scholar 

  10. 10.

    Russo A, Tessitore A, Giordano A, et al. The pain in migraine beyond the pain of migraine. Neurol Sci. 2012;33(Suppl. 1):S103–6.

    Article  PubMed  Google Scholar 

  11. 11.

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

    Article  PubMed  Google Scholar 

  12. 12.

    Maniyar FH, Sprenger T, Monteith T, et al. Brain activations in the premonitory phase of nitroglycerin-triggered migraine attacks. Brain. 2014;137(Pt 1):232–41.

    Article  PubMed  Google Scholar 

  13. 13.

    • Maniyar FH, Sprenger T, Schankin C, et al. The origin of nausea in migraine—a PET study. J Headache Pain. 2014;15:84. The results demonstrate that nausea is a centrally driven symptom in migraine due to activation of brain structures known to be involved in nausea independently from pain and trigeminal activation.

    Article  PubMed  PubMed Central  Google Scholar 

  14. 14.

    Shin JH, Kim YK, Kim HJ, Kim JS. Altered brain metabolism in vestibular migraine: comparison of interictal and ictal findings. Cephalalgia. 2014;34(1):58–67.

    Article  PubMed  Google Scholar 

  15. 15.

    Chabriat H, Tehindrazanarivelo A, Vera P, et al. 5HT2 receptors in cerebral cortex of migraineurs studied using PET and 18F-fluorosetoperone. Cephalalgia. 1995;15(2):104–8.

    CAS  Article  PubMed  Google Scholar 

  16. 16.

    Chugani DC, Niimura K, Chaturvedi S, et al. Increased brain serotonin synthesis in migraine. Neurology. 1999;53(7):1473–9.

    CAS  Article  PubMed  Google Scholar 

  17. 17.

    Demarquay G, Lothe A, Royet JP, et al. Brainstem changes in 5-HT1A receptor availability during migraine attack. Cephalalgia. 2011;31(1):84–94.

    CAS  Article  PubMed  Google Scholar 

  18. 18.

    •• Coppola G, Di Renzo A, Tinelli E, et al. Resting state connectivity between default mode network and insula encodes acute migraine headache. Cephalalgia. 2017;1:333102417715230.The authors demonstrated a reduced DMN-insula connectivity related with an increased pain perception during attacks in migraine, unlike what has been observed in other chronic extra-cephalic pain disorders.

    Google Scholar 

  19. 19.

    Tedeschi G, Russo A, Tessitore A. Relevance of functional neuroimaging studies for understanding migraine mechanisms. Expert Rev Neurother. 2013;13(3):275–85.

    CAS  Article  PubMed  Google Scholar 

  20. 20.

    Nascimento TD, DosSantos MF, Lucas S, et al. μ-Opioid activation in the midbrain during migraine allodynia—brief report II. Ann Clin Transl Neurol. 2014;1(6):445–50.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  21. 21.

    Da Silva AF, Nascimento TD, DosSantos MF, et al. Association of μ-opioid activation in the prefrontal cortex with spontaneous migraine attacks—brief report I. Ann Clin Transl Neurol. 2014;1(6):439–44.

    Article  Google Scholar 

  22. 22.

    •• DaSilva AF, Nascimento TD, Love T, et al. 3D-neuronavigation in vivo through a patient’s brain during a spontaneous migraine headache. J Vis Exp. 2014;(88). This study investigated, for the first time, using a novel 3D interactive neuronavigation approach, the endogenous μ-opioid transmission in the brain during a migraine attack.

  23. 23.

    Leao AAP. Spreading depression of activity in cerebral cortex. J Neurophysiol. 1944;7(6):359–90.

    Google Scholar 

  24. 24.

    Smith JM, Bradley DP, James MF, Huang CL. Physiological studies of cortical spreading depression. Biol Rev Camb Philos Soc. 2006;81(4):457–81.

    Article  PubMed  Google Scholar 

  25. 25.

    Olesen J, Friberg L, Olsen TS, et al. Timing and topography of cerebral blood flow, aura, and headache during migraine attacks. Ann Neurol. 1990;28(6):791–8.

    CAS  Article  PubMed  Google Scholar 

  26. 26.

    Hadjikhani N, Sanchez del Rio M, Wu O, et al. Mechanisms of migraine aura revealed by functional MRI in human visual cortex. Proc Natl Acad Sci U S A. 2001;98(8):4687–92.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  27. 27.

    Ayata C. Cortical spreading depression triggers migraine attack: pro. Headache. 2010;50(4):725–30.

    Article  PubMed  Google Scholar 

  28. 28.

    Sprenger T, Goadsby PJ. What has functional neuroimaging done for primary headache and for the clinical neurologist? J Clin Neurosci. 2010;17(5):547–53.

    Article  PubMed  Google Scholar 

  29. 29.

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

    Article  PubMed  PubMed Central  Google Scholar 

  30. 30.

    Moulton EA, Becerra L, Maleki N, et al. Painful heat reveals hyperexcitability of the temporal pole in interictal and ictal migraine states. Cereb Cortex. 2011;21:435–48.

    CAS  Article  PubMed  Google Scholar 

  31. 31.

    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. 2012;259:1903–12.

    Article  PubMed  Google Scholar 

  32. 32.

    Stankewitz A, May A. Increased limbic and brainstem activity during migraine attacks following olfactory stimulation. Neurology. 2011;77(5):476–82.

    Article  PubMed  Google Scholar 

  33. 33.

    •• Schulte LH, Allers A, May A. Hypothalamus as a mediator of chronic migraine: evidence from high-resolution fMRI. Neurology. 2017;88(21):2011–6. The study results confirm the key role of the anterior part of the hypothalamus in the pathophysiology of migraine chronification.

    Article  PubMed  Google Scholar 

  34. 34.

    •• Russo A, Esposito F, Conte F, et al. Functional interictal changes of pain processing in migraine with ictal cutaneous allodynia. Cephalalgia. 2017;37(4):305–14. These findings suggest that ictal cutaneous allodynia may be subtended by both a dysfunctional analgesic compensatory mechanism and an abnormal internal representation of pain in migraine patients.

    Article  PubMed  Google Scholar 

  35. 35.

    •• Schwedt TJ, Chong CD, Chiang CC, et al. Enhanced pain-induced activity of pain-processing regions in a case-control study of episodic migraine. Cephalalgia. 2014;34(12):947–58. The study underlines that the enhanced cognitive pain processing might reflect cerebral hypersensitivity related to high expectations and hypervigilance for pain in migraine patients.

    Article  PubMed  PubMed Central  Google Scholar 

  36. 36.

    •• Schulte LH, May A. The migraine generator revisited: continuous scanning of the migraine cycle over 30 days and three spontaneous attacks. Brain. 2016;139(Pt 7):1987–93. In this elegant study, the hypothalamus shows altered functional coupling with the spinal trigeminal nuclei and the region of the brainstem, suggesting that the real driver of attacks might be the functional changes in hypothalamo-brainstem connectivity.

    Article  PubMed  Google Scholar 

  37. 37.

    Boulloche N, Denuelle M, Payoux P, Fabre N, Trotter Y, Géraud G. Photophobia in migraine: an interictal PET study of cortical hyperexcitability and its modulation by pain. J Neurol Neurosurg Psychiatry. 2010;81(9):978–84.

    Article  PubMed  Google Scholar 

  38. 38.

    Martín H, Sánchez del Río M, de Silanes CL, et al. Photoreactivity of the occipital cortex measured by functional magnetic resonance imaging-blood oxygenation level dependent in migraine patients and healthy volunteers: pathophysiological implications. Headache. 2011;51(10):1520–8.

    Article  PubMed  Google Scholar 

  39. 39.

    Datta R, Aguirre GK, Hu S, et al. Interictal cortical hyperresponsiveness in migraine is directly related to the presence of aura. Cephalalgia. 2013;33:365–74.

    Article  PubMed  PubMed Central  Google Scholar 

  40. 40.

    •• Hougaard A, Amin FM, Hoffmann MB, et al. Interhemispheric differences of fMRI responses to visual stimuli in patients with side-fixed migraine aura. Hum Brain Mapp. 2014;35(6):2714–23. These findings suggest that an advanced visual system hyperexcitability characterizes the hemispheres involved in the aura phenomenon also during the interictal phase.

    Article  PubMed  Google Scholar 

  41. 41.

    Stankewitz A, Voit HL, Bingel U, Peschke C, May A. A new trigemino-nociceptive stimulation model for event-related fMRI. Cephalalgia. 2010;30:475–85.

    CAS  PubMed  Google Scholar 

  42. 42.

    •• Russo A, Marcelli V, Esposito F, et al. Abnormal thalamic function in patients with vestibular migraine. Neurology. 2014;82(23):2120–6. A novel evidence for abnormal thalamic functional response to vestibular stimulation in patients with VM has been demonstrated for the first time, suggesting that functional abnormalities in central vestibular processing may contribute to VM pathophysiology.

    Article  PubMed  Google Scholar 

  43. 43.

    May A, Kaube H, Büchel C, et al. Experimental cranial pain elicited by capsaicin: a PET study. Pain. 1998;74(1):61–6.

    CAS  Article  PubMed  Google Scholar 

  44. 44.

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

    Article  PubMed  Google Scholar 

  45. 45.

    Maizels M, Aurora S, Heinricher M. Beyond neurovascular: migraine as a dysfunctional neurolimbic pain network. Headache. 2012;52(10):1553–65.

    Article  PubMed  Google Scholar 

  46. 46.

    May A. Understanding migraine as a cycling brain syndrome: reviewing the evidence from functional imaging. Neurol Sci. 2017;38(Suppl 1):125–30.

    Article  PubMed  Google Scholar 

  47. 47.

    Main A, Dowson A, Gross M. Photophobia and phonophobia in migraineurs between attacks. Headache. 1997;37:492–5.

    CAS  Article  PubMed  Google Scholar 

  48. 48.

    Vanagaite J, Pareja JA, Storen O, et al. Light-induced discomfort and pain in migraine. Cephalalgia. 1997;17:733–41.

    CAS  Article  PubMed  Google Scholar 

  49. 49.

    Wober-Bingol C, Wober C, Karwautz A, et al. Clinical features of migraine: a cross-sectional study in patients aged three to sixty-nine. Cephalalgia. 2004;24:12–7.

    CAS  Article  PubMed  Google Scholar 

  50. 50.

    Cao Y, Aurora SK, Nagesh V, et al. Functional MRI-BOLD of brainstem structures during visually triggered migraine. Neurology. 2002;59(1):72–8.

    CAS  Article  PubMed  Google Scholar 

  51. 51.

    Denuelle M, Boulloche N, Payoux P, et al. A PET study of photophobia during spontaneous migraine attacks. Neurology. 2011;76(3):213–8.

    CAS  Article  PubMed  Google Scholar 

  52. 52.

    Sarchielli P, Tarducci R, Presciutti O, et al. Functional 1H-MRS findings in migraine patients with and without aura assessed interictally. NeuroImage. 2005;24(4):1025–31.

    Article  PubMed  Google Scholar 

  53. 53.

    Headache Classification Committee of the International Headache Society (IHS). The international classification of headache disorders, 3rd edition (beta version). Cephalalgia. 2013;33(9):629–808.

    Article  Google Scholar 

  54. 54.

    Zanchin G, Dainese F, Trucco M, et al. Osmophobia in migraine and tension-type headache and its clinical features in patients with migraine. Cephalalgia. 2007;27(9):1061–8.

    CAS  Article  PubMed  Google Scholar 

  55. 55.

    De Carlo D, Toldo I, Dal Zotto L, et al. Osmophobia as an early marker of migraine: a follow-up study in juvenile patients. Cephalalgia. 2012;32(5):401–6.

    Article  PubMed  Google Scholar 

  56. 56.

    Demarquay G, Royet JP, Mick G, et al. Olfactory hypersensitivity in migraineurs: a H(2)(15)O-PET study. Cephalalgia. 2008;28(10):1069–80.

    CAS  Article  PubMed  Google Scholar 

  57. 57.

    Borsook D, Burstein R. The enigma of the dorsolateral pons as a migraine generator. Cephalalgia. 2012;32(11):803–12.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  58. 58.

    Espinosa-Sanchez JM, Lopez-Escamez JA. New insights into pathophysiology of vestibular migraine. Front Neurol. 2015;6:12.

    Article  PubMed  PubMed Central  Google Scholar 

  59. 59.

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

    CAS  Article  PubMed  Google Scholar 

  60. 60.

    Mainero C, Boshyan J, Hadjikhani N. Altered functional magnetic resonance imaging resting-state connectivity in periaqueductal gray networks in migraine. Ann Neurol. 2011;70(5):838–45.

    Article  PubMed  PubMed Central  Google Scholar 

  61. 61.

    Tessitore A, Russo A, Giordano A, et al. Disrupted default mode network connectivity in migraine without aura. J Headache Pain. 2013;14:89.

    Article  PubMed  PubMed Central  Google Scholar 

  62. 62.

    Russo A, Tessitore A, Giordano A, et al. Executive resting-state network connectivity in migraine without aura. Cephalalgia. 2012;32(14):1041–8.

    Article  PubMed  Google Scholar 

  63. 63.

    •• Tessitore A, Russo A, Conte F, et al. Abnormal connectivity within executive resting-state network in migraine with aura. Headache. 2015;55(6):794–805. The study demonstrates disrupted executive control network functional connectivity in patients with migraine with and without aura, during the interictal period, although in the absence of clinically relevant executive deficits.

    Article  PubMed  Google Scholar 

  64. 64.

    •• Tedeschi G, Russo A, Conte F, et al. Increased interictal visual network connectivity in patients with migraine with aura. Cephalalgia. 2016;36(2):139–47. The results support that the increased functional connectivity of the visual network represents a functional biomarker that could differentiate patients experiencing the aura phenomenon from patients with migraine without aura, even between attacks.

    Article  PubMed  Google Scholar 

  65. 65.

    Niddam DM, Lai KL, Fuh JL, et al. Reduced functional connectivity between salience and visual networks in migraine with aura. Cephalalgia. 2015;36(1):53–66.

  66. 66.

    Hougaard A, Amin FM, Magon S, et al. No abnormalities of intrinsic brain connectivity in the interictal phase of migraine with aura. Eur J Neurol. 2015;22(4):702–e46.

    CAS  Article  PubMed  Google Scholar 

  67. 67.

    Zhao L, Liu J, Dong X, et al. Alterations in regional homogeneity assessed by fMRI in patients with migraine without aura stratified by disease duration. J Headache Pain. 2013;14:85.

    Article  PubMed  PubMed Central  Google Scholar 

  68. 68.

    Moulton EA, Becerra L, Johnson A, et al. Altered hypothalamic functional connectivity with autonomic circuits and the locus coeruleus in migraine. PLoS One. 2014;9(4):e95508.

    Article  PubMed  PubMed Central  Google Scholar 

  69. 69.

    Hadjikhani N, Ward N, Boshyan J, et al. The missing link: enhanced functional connectivity between amygdala and visceroceptive cortex in migraine. Cephalalgia. 2013;33(15):1264–8.

    Article  PubMed  PubMed Central  Google Scholar 

  70. 70.

    Colombo B, Rocca MA, Messina R, et al. Resting-state fMRI functional connectivity: a new perspective to evaluate pain modulation in migraine? Neurol Sci. 2015;36(Suppl 1):41–5.

    Article  PubMed  Google Scholar 

  71. 71.

    Maleki N, Becerra L, Borsook D. Migraine: maladaptive brain responses to stress. Headache. 2012;52(Suppl 2):102–6.

    Article  PubMed  PubMed Central  Google Scholar 

  72. 72.

    Borsook D, Maleki N, Becerra L, et al. Understanding migraine through the lens of maladaptive stress responses: a model disease of allostatic load. Neuron. 2012;73(2):219–34.

    CAS  Article  PubMed  Google Scholar 

  73. 73.

    Ellerbrock I, Engel AK, May A. Microstructural and network abnormalities in headache. Curr Opin Neurol. 2013;26(4):353–9.

    Article  PubMed  Google Scholar 

  74. 74.

    Zhao L, Liu J, Yan X, et al. Abnormal brain activity changes in patients with migraine: a short-term longitudinal study. J Clin Neurol. 2014;10(3):229–35.

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Author information

Affiliations

Authors

Corresponding author

Correspondence to Alessandro Tessitore.

Ethics declarations

Conflict of Interest

Antonio Russo, Marcello Silvestro, Gioacchino Tedeschi, and Alessandro Tessitore declare no conflict of interest.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

Additional information

This article is part of the Topical Collection on Neuroimaging

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Russo, A., Silvestro, M., Tedeschi, G. et al. Physiopathology of Migraine: What Have We Learned from Functional Imaging?. Curr Neurol Neurosci Rep 17, 95 (2017). https://doi.org/10.1007/s11910-017-0803-5

Download citation

Keywords

  • Migraine
  • Functional neuroimaging
  • PET
  • fMRI
  • Resting-state network
  • Trigeminal stimulation