Elderly Patients with Ongoing Migraine Show Reduced Gray Matter Volume in Second Somatosensory Cortex

Aims: To identify structural changes in gray matter in suspected migraine generators (the hypothalamus and/or brainstem nuclei) and pain pathways and to evaluate whether structural changes in migraine are definitive or resolve with age. Methods: Voxel-based morphometry (VBM) was used to assess differences in gray matter between 39 healthy controls (HC), 25 episodic migraine (EM) subjects, and 37 subjects with a history of migraine (HM). In addition, morphometric changes were specifically investigated in suspected migraine generators and/or pain pathways. For statistical analyses, t tests between the groups were performed, and a correction for multiple comparisons was used. Results: Whole-brain analysis did not reveal any gray or white matter changes. However, when the analysis was limited to the pain matrix, a lower gray matter volume was observed in the left second somatosensory (SII) cortex in EM subjects compared to HC subjects. This volume was significantly reduced in the EM group compared to the HC group and to the HM group, but not in the HM group compared to the HC group. Conclusion: Morphometric abnormalities in the SII in subjects with ongoing migraine but not in subjects with a resolved migrainous disease are likely to characterize a migrainous state rather than be a marker of brain susceptibility to migraine.

brain morphology;elderly;migraine;past migraine

1. Olesen J, Steiner TJ. The International Classification of Headache Disorders, ed 2 (ICDH-II). J Neurol Neurosurg Psychiatry 2004;75:808–811.

2. Merikangas KR. Contributions of epidemiology to our under- standing of migraine. Headache 2013;53:230–246.

3. Lantéri-Minet M, Valade D, Géraud G, Chautard MH, Lucas C. Migraine and probable migraine-Results of FRAMIG 3, a French nationwide survey carried out according to the 2004 IHS classification. Cephalalgia 2005;25:1146–1158.

4. Martins KM, Bordini CA, Bigal ME, Speciali JG. Migraine in the elderly: A comparison with migraine in young adults. Headache 2006;46:312–316.

5. Kelman L. Migraine changes with age: IMPACT on migraine classification. Headache 2006;46:1161–1171.

6. Haan J, Hollander J, Ferrari MD. Migraine in the elderly: A re- view. Cephalalgia 2007;27:97–106.

7. Borsook D, Hargreaves R. Brain imaging in migraine research. Headache 2010;50:1523–1527.

8. Donnet A, Daniel C, Milandre L, Berbis J, Auquier P. Migraine with aura in patients over 50 years of age: The Marseille’s reg- istry. J Neurol 2012;259:1868–1873.

9. Lakhan SE, Avramut M, Tepper SJ. Structural and function- al neuroimaging in migraine: Insights from 3 decades of re- search. Headache 2013;53:46–66.

10. Hougaard A, Amin FM, Ashina M. Migraine and structural ab- normalities in the brain. Curr Opin Neurol 2014;27:309–314.

11. Bilgiç B, Kocaman G, Arslan AB, et al. Volumetric differences suggest involvement of cerebellum and brainstem in chronic migraine. Cephalalgia 2016;36:301–308.

12. Akerman S, Holland PR, Goadsby PJ. Diencephalic and brainstem mechanisms in migraine. Nat Rev Neurosci 2011;12:570–584.

13. Noseda R, Burstein R. Migraine pathophysiology: Anatomy of the trigeminovascular pathway and associated neurological symptoms, cortical spreading depression, sensitization, and modulation of pain. Pain 2013;154(suppl):s44–s53.

14. Bashir A, Lipton RB, Ashina S, Ashina M. Migraine and structural changes in the brain: A systematic review and meta-analysis. Neurology 2013;81:1260–1268.

15. Kruit MC, van Buchem MA, Hofman PA, et al. Migraine as a risk factor for subclinical brain lesions. JAMA 2004;291:427–434.

16. Kurth T, Mohamed S, Maillard P, et al. Headache, migraine, and structural brain lesions and function: Population based epide- miology of vascular ageing-MRI study. BMJ 2011;342:c7357.

17. Kurth T, Diener HC. Migraine and stroke: Perspectives for stroke physicians. Stroke 2012;43:3421–3426.

18. Kim JH, Suh SI, Seol HY, et al. Regional grey matter changes in patients with migraine: A voxel-based morphometry study. Cephalalgia 2008;28:598–604.

19. Obermann M, Wurthmann S, Steinberg BS, Theysohn N, Diener HC, Naegel S. Central vestibular system modulation in vestibular migraine. Cephalalgia 2014;34:1053–1061.

20. Schmidt-Wilcke T, Gänssbauer S, Neuner T, Bogdahn U, May A. Subtle grey matter changes between migraine patients and healthy controls. Cephalalgia 2008;28:1–4.

21. Schmitz N, Admiraal-Behloul F, Arkink EB, et al. Attack fre- quency and disease duration as indicators for brain damage in migraine. Headache 2008;48:1044–1055.

22. Schmitz N, Arkink EB, Mulder M, et al. Frontal lobe structure and executive function in migraine patients. Neurosci Lett 2008;440:92–96.

23. Valfrè W, Rainero I, Bergui M, Pinessi L. Voxel-based mor- phometry reveals gray matter abnormalities in migraine. Headache 2008;48:109–117.

24. Liu J, Lan L, Li G, et al. Migraine-related gray matter and white matter changes at a 1-year follow-up evaluation. J Pain 2013;14:1703–1708.

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

26. Matharu MS, Good CD, May A, Bahra A, Goadsby PJ. No change in the structure of the brain in migraine: A voxel-based morphometric study. Eur J Neurol 2003;10:53–57.

27. Russo A, Tessitore A, Giordano A, et al. Executive resting-state network connectivity in migraine without aura. Cephalalgia 2012;32:1041–1048.

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

29. Tessitore A, Russo A, Conte F, et al. Abnormal connectivity within executive resting-state network in migraine with aura. Headache 2015;55:794–805.

30. Jin C, Yuan K, Zhao L, et al. Structural and functional ab- normalities in migraine patients without aura. NMR Biomed 2013;26:58–64.

31. Dai Z, Zhong J, Xiao P, et al. Gray matter correlates of migraine and gender effect: A meta-analysis of voxel-based morphome- try studies. Neuroscience 2015;299:88–96.

32. Barthélémy JC, Pichot V, Dauphinot V, et al. Autonomic ner- vous system activity and decline as prognostic indicators of cardiovascular and cerebrovascular events: The 'PROOF' study. Study design and population sample. Associations with sleep-related breathing disorders: The 'SYNAPSE' study. Neuroepidemiology 2007;29:18–28.

33. Ashburner J, Friston KJ. Unified segmentation. Neuroimage 2005;26:839–851.

34. Ashburner J. A fast diffeomorphic image registration algorithm. Neuroimage 2007;38:95–113.

35. Maizels M, Aurora S, Heinricher M. Beyond neurovascu- lar: Migraine as a dysfunctional neurolimbic pain network. Headache 2012;52:1553–1565.

36. Eickhoff SB, Stephan KE, Mohlberg H, et al. A new SPM tool- box for combining probabilistic cytoarchitectonic maps and functional imaging data. Neuroimage 2005;25:1325–1335.

37. Maldjian JA, Laurienti PJ, Kraft RA, Burdette JH. An automated method for neuroanatomic and cytoarchitectonic atlas-based interrogation of fMRI data sets. Neuroimage 2003;19: 1233–1239.

38. Tzourio-Mazoyer N, Landeau B, Papathanassiou D, et al. Automated anatomical labeling of activations in SPM us- ing a macroscopic anatomical parcellation of the MNI MRI single-subject brain. Neuroimage 2002;15:273–289.

39. Hubbard CS, Khan SA, Keaser ML, Mathur VA, Goyal M, Seminowicz DA. Altered brain structure and function correlate with disease severity and pain catastrophizing in migraine pa- tients. eNeuro 2014;1:e20.14.

40. Hu W, Guo J, Chen N, Guo J, He L. A meta-analysis of voxel-based morphometric studies on migraine. Int J Clin Exp Med 2015;8:4311–4319.

41. Datta R, Detre JA, Aguirre GK, Cucchiara B. Absence of changes in cortical thickness in patients with migraine. Cephalalgia 2011;31:1452–1458.

42. Good CD, Johnsrude IS, Ashburner J, Henson RN, Friston KJ, Frackowiak RS. A voxel-based morphometric study of ageing in 465 normal adult human brains. Neuroimage 2001;14:21–36.

43. Salat DH, Buckner RL, Snyder AZ, et al. Thinning of the cere- bral cortex in aging. Cereb Cortex 2004;14:721–730.

44. Géraud G, Denuelle M, Fabre N, Payoux P, Chollet F. Positron emission tomographic studies of migraine [in French]. Rev Neurol (Paris) 2005;161:666–670.

45. Borsook D, Burstein R. The enigma of the dorsolateral pons as a migraine generator. Cephalalgia 2012;32:803–812.

46. Bahra A, Matharu MS, Buchel C, Frackowiak RS, Goadsby PJ. Brainstem activation specific to migraine headache. Lancet 2001;357:1016–1017.

47. Afridi SK, Giffin NJ, Kaube H, et al. A positron emission tomo- graphic study in spontaneous migraine. Arch Neurol 2005;62: 1270–1275.

48. Frot M, Mauguière F. Dual representation of pain in the operculo-insular cortex in humans. Brain 2003;126:438–450.

49. Mazzola L, Faillenot I, Barral FG, Mauguière F, Peyron R. Spatial segregation of somato-sensory and pain activations in the hu- man operculo-insular cortex. Neuroimage 2012;60:409–418.

50. Peyron R. Functional brain imaging: what has it brought to our understanding of neuropathic pain? A special focus on allody- nic pain mechanisms. Pain 2016;157(suppl):s67–s71.

51. Segerdahl AR, Mezue M, Okell TW, Farrar JT, Tracey I. The dorsal posterior insula is not an island in pain but subserves a fundamental role— Response to: “Evidence against pain spec- ificity in the dorsal posterior insula” by Davis et al. F1000Res 2015;4:1207.

52. Frot M, Magnin M, Mauguière F, Garcia-Larrea L. Human SII and posterior insula differently encode thermal laser stimuli. Cereb Cortex 2007;17:610–620.

53. Russo A, Esposito F, Conte F, et al. Functional interictal chang- es of pain processing in migraine with ictal cutaneous allodyn- ia. Cephalalgia 2017;37:305–314.

54. Brooks JC, Zambreanu L, Godinez A, Craig AD, Tracey I. Somatotopic organisation of the human insula to painful heat studied with high resolution functional imaging. Neuroimage 2005;27:201–209.

55. Eickhoff SB, Amunts K, Mohlberg H, Zilles K. The human pari- etal operculum. II. Stereotaxic maps and correlation with func- tional imaging results. Cereb Cortex 2006;16:268–279.

56. Vogel H, Port JD, Lenz FA, Solaiyappan M, Krauss G, Treede RD. Dipole source analysis of laser-evoked subdural potentials recorded from parasylvian cortex in humans. J Neurophysiol 2003;89:3051–3060.

57. Huang RS, Chen CF, Tran AT, Holstein KL, Sereno MI. Mapping multisensory parietal face and body areas in humans. Proc Natl Acad Sci U S A 2012;109:18114–18119.

58. Afif A, Hoffmann D, Minotti L, Benabid AL, Kahane P. Middle short gyrus of the insula implicated in pain processing. Pain 2008;138:546–555.

59. Mazzola L, Isnard J, Peyron R, Guénot M, Mauguière F. Somatotopic organization of pain responses to direct electrical stimulation of the human insular cortex. Pain 2009;146:99–104.

60. Burstein R, Noseda R, Borsook D. Migraine: Multiple process- es, complex pathophysiology. J Neurosci 2015;35:6619–6629.

61. DaSilva AF, Granziera C, Snyder J, Hadjikhani N. Thickening in the somatosensory cortex of patients with migraine. Neurology 2007;69:1990–1995.

62. Maleki N, Becerra L, Brawn J, Bigal M, Burstein R, Borsook D. Concurrent functional and structural cortical alterations in migraine. Cephalalgia 2012;32:607–620.

63. Kim JH, Kim JB, Suh SI, Seo WK, Oh K, Koh SB. Thickening of the somatosensory cortex in migraine without aura. Cephalalgia 2014;34:1125–1133.

64. Chong CD, Dodick DW, Schlaggar BL, Schwedt TJ. Atypical age-related cortical thinning in episodic migraine. Cephalalgia 2014;34:1115–1124.

65. Wessman M, Kaunisto MA, Kallela M, Palotie A. The molecular genetics of migraine. Ann Med 2004;36:462–473.

66. Rodriguez-Raecke R, Niemeier A, Ihle K, Ruether W, May A. Brain gray matter decrease in chronic pain is the consequence and not the cause of pain. J Neurosci 2009;29:13746–13750.

67. Obermann M, Nebel K, Schumann C, et al. Gray matter chang- es related to chronic posttraumatic headache. Neurology 2009;73:978–983.