It is very likely that spontaneous oscillations of complex networks involving the hypothalamus, brainstem, and dopaminergic networks lead to changes in susceptibility thresholds that ultimately start but also terminate headache attacks. We will review clinical and neuroscience evidence that puts the hypothalamus in the center of scientific attention when attack generation is discussed.

This has been intensely discussed in the last decades and the advent of modern imaging studies refined the involvement of rostral parts of the pons in acute migraine attacks, but more importantly suggested a predominant role of the hypothalamus and alterations in hypothalamic functional connectivity shortly before the beginning of migraine headaches. This was shown in the NO-triggered and also in the preictal stage of native human migraine attacks. Another headache type that is clinically even more suggestive of hypothalamic involvement is cluster headache, and indeed a structure in close proximity to the hypothalamus has been identified to play a crucial role in attack generation.

The clinical picture, but also neuroimaging findings, suggested the brainstem and midbrain structures as possible driving or generating structures in migraine.

References

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

Google Scholar SAGE Journals | ISI

2. Lance, JW . Headache . Ann Neurol 1981 ; 10: 1 – 10 .

Google Scholar Crossref | Medline | ISI

3. Headache Classification Committee of the International Headache Society (IHS) . The International Classification of Headache Disorders, 3rd edition . Cephalalgia 2018 ; 38: 1 – 211 .

Google Scholar SAGE Journals

4. Snoer, A, Lund, N, Beske, R, et al. Pre-attack signs and symptoms in cluster headache: Characteristics and time profile . Cephalalgia 2017 ; 38: 1128 – 1137 .

Google Scholar SAGE Journals

5. Pringsheim, T . Cluster headache: Evidence for a disorder of circadian rhythm and hypothalamic function . Can J Neurol Sci 2002 ; 29: 33 – 40 .

Google Scholar Crossref | Medline | ISI

6. Strittmatter, M, Hamann, GF, Grauer, M, et al. Altered activity of the sympathetic nervous system and changes in the balance of hypophyseal, pituitary and adrenal hormones in patients with cluster headache . Neuroreport 1996 ; 7: 1229 – 1234 .

Google Scholar Crossref | Medline | ISI

7. May, A . Pearls and pitfalls: Neuroimaging in headache . Cephalalgia 2013 ; 33: 554 – 565 .

Google Scholar SAGE Journals | ISI

8. Matharu, M, May, A. Functional and structural neuroimaging in trigeminal autonomic cephalalgias . Curr Pain Headache Rep 2008 ; 12: 132 – 137 .

Google Scholar Crossref | Medline | ISI

9. Leone, M, Bussone, G. A review of hormonal findings in cluster headache. Evidence for hypothalamic involvement . Cephalalgia 1993 ; 13: 309 – 317 .

Google Scholar SAGE Journals | ISI

10. Blau, JN . Migraine: Theories of pathogenesis . Lancet 1992 ; 339: 1202 – 1207 .

Google Scholar Crossref | Medline | ISI

11. Laurell, K, Artto, V, Bendtsen, L, et al. Premonitory symptoms in migraine: A cross-sectional study in 2714 persons . Cephalalgia 2016 ; 36: 951 – 959 .

Google Scholar SAGE Journals | ISI

12. Giffin, NJ, Ruggiero, L, Lipton, RB, et al. Premonitory symptoms in migraine: An electronic diary study . Neurology 2003 ; 60: 935 – 940 .

Google Scholar Crossref | Medline | ISI

13. Kelman, L . The premonitory symptoms (prodrome): A tertiary care study of 893 migraineurs . Headache 2004 ; 44: 865 – 872 .

Google Scholar Crossref | Medline | ISI

14. Quintela, E, Castillo, J, Muñoz, P, et al. Premonitory and resolution symptoms in migraine: A prospective study in 100 unselected patients . Cephalalgia 2006 ; 26: 1051 – 1060 .

Google Scholar SAGE Journals | ISI

15. Schoonman, GG, Evers, DJ, Terwindt, GM, et al. The prevalence of premonitory symptoms in migraine: A questionnaire study in 461 patients . Cephalalgia 2006 ; 26: 1209 – 1213 .

Google Scholar SAGE Journals | ISI

16. Cuvellier, J-C, Mars, A, Vallée, L. The prevalence of premonitory symptoms in paediatric migraine: A questionnaire study in 103 children and adolescents . Cephalalgia 2009 ; 29: 1197 – 1201 .

Google Scholar SAGE Journals | ISI

17. Schulte, LH, Jürgens, TP, May, A. Photo-, osmo- and phonophobia in the premonitory phase of migraine: Mistaking symptoms for triggers? J Headache Pain 2015 ; 16: 14 – 14 .

Google Scholar Crossref | Medline | ISI

18. Giffin, NJ, Lipton, RB, Silberstein, SD, et al. The migraine postdrome: An electronic diary study . Neurology 2016 ; 87: 309 – 313 .

Google Scholar Crossref | Medline

19. Bose, P, Goadsby, PJ. The migraine postdrome . Curr Opin Neurol 2016 ; 29: 299 – 301 .

Google Scholar Crossref | Medline | ISI

20. Kelman, L . The postdrome of the acute migraine attack . Cephalalgia 2006 ; 26: 214 – 220 .

Google Scholar SAGE Journals | ISI

21. May, A . Understanding migraine as a cycling brain syndrome: Reviewing the evidence from functional imaging . Neurol Sci 2017 ; 38: 125 – 130 .

Google Scholar Crossref | Medline

22. Dahlem, MA, Kurths, J, Ferrari, MD, et al. Understanding migraine using dynamic network biomarkers . Cephalalgia 2014 ; 35: 627 – 630 .

Google Scholar SAGE Journals

23. Stankewitz, A, May, A. Cortical excitability and migraine . Cephalalgia 2007 ; 27: 1454 – 1456 .

Google Scholar SAGE Journals | ISI

24. Güven, B, Güven, H, Çomoğlu, SS. Migraine and yawning . Headache 2018 ; 58: 210 – 216 .

Google Scholar Crossref | Medline

25. Alstadhaug, K, Salvesen, R, Bekkelund, S. Insomnia and circadian variation of attacks in episodic migraine . Headache 2007 ; 47: 1184 – 1188 .

Google Scholar Crossref | Medline | ISI

26. Silberstein, S, Merriam, G. Sex hormones and headache 1999 (menstrual migraine) . Neurology 1999 ; 53: S3 – S13 .

Google Scholar Medline | ISI

27. Charbit, AR, Akerman, S, Goadsby, PJ. Dopamine: What’s new in migraine? Curr Opin Neurol 2010 ; 23: 275 – 281 .

Google Scholar Crossref | Medline | ISI

28. Mayanagi, Y, Hori, T, San, K. The posteromedial hypothalamus and pain, behavior, with special reference to endocrinological findings . Appl Neurophysiol 1978 ; 41: 223 – 231 .

Google Scholar Medline

29. Buller, KM . Neuroimmune stress responses: Reciprocal connections between the hypothalamus and the brainstem . Stress 2003 ; 6: 11 – 17 .

Google Scholar Crossref | Medline

30. Bartsch, T, Levy, MJ, Knight, YE, et al. Inhibition of nociceptive dural input in the trigeminal nucleus caudalis by somatostatin receptor blockade in the posterior hypothalamus . Pain 2005 ; 117: 30 – 39 .

Google Scholar Crossref | Medline | ISI

31. Holland, P, Goadsby, PJ. The hypothalamic orexinergic system: Pain and primary headaches . Headache 2007 ; 47: 951 – 962 .

Google Scholar Crossref | Medline | ISI

32. Tso, AR, Goadsby, PJ. New targets for migraine therapy . Curr Treat Options Neurol 2014 ; 16: 318 – 318 .

Google Scholar Crossref | Medline

33. Hoffmann, J, Supronsinchai, W, Akerman, S, et al. Evidence for orexinergic mechanisms in migraine . Neurobiol Dis 2015 ; 74: 137 – 143 .

Google Scholar Crossref | Medline

34. Bartsch T, Levy MJ, Knight YE, et al. Differential modulation of nociceptive dural input to [hypocretin] orexin A and B receptor activation in the posterior hypothalamic area. Pain 2004; 109: 367–378.

Google Scholar

35. Akerman, S, Goadsby, PJ. Dopamine and migraine: Biology and clinical implications . Cephalalgia 2007 ; 27: 1308 – 1314 .

Google Scholar SAGE Journals | ISI

36. Cerbo, R, Barbanti, P, Buzzi, MG, et al. Dopamine hypersensitivity in migraine: Role of the apomorphine test . Clin Neuropharmacol 1997 ; 20: 36 – 41 .

Google Scholar Crossref | Medline | ISI

37. Del Zompo, M, Lai, M, Loi, V, et al. Dopamine hypersensitivity in migraine: Role in apomorphine syncope . Headache 1995 ; 35: 222 – 224 .

Google Scholar Crossref | Medline | ISI

38. Blin, O, Azulay, JP, Masson, G, et al. Apomorphine-induced yawning in migraine patients: Enhanced responsiveness . Clin Neuropharmacol 1991 ; 14: 91 – 95 .

Google Scholar Crossref | Medline | ISI

39. Del Bene, E, Poggioni, M, De Tommasi, F. Video assessment of yawning induced by sublingual apomorphine in migraine . Headache 1994 ; 34: 536 – 538 .

Google Scholar Crossref | Medline | ISI

40. Ferraro, S, Nigri, A, Bruzzone, MG, et al. Defective functional connectivity between posterior hypothalamus and regions of the diencephalic-mesencephalic junction in chronic cluster headache . Cephalalgia 2018 ; 38: 1910 – 1918 .

Google Scholar SAGE Journals | ISI

41. Eken, C . Critical reappraisal of intravenous metoclopramide in migraine attack: A systematic review and meta-analysis . Am J Emerg Med 2015 ; 33: 331 – 337 .

Google Scholar Crossref | Medline | ISI

42. Ellis, GL, Delaney, J, DeHart, DA, et al. The efficacy of metoclopramide in the treatment of migraine headache . Ann Emerg Med 1993 ; 22: 191 – 195 .

Google Scholar Crossref | Medline | ISI

43. Factor, SA, Jankovic, J, Friedman, BW, et al. Randomized trial of IV valproate vs metoclopramide vs ketorolac for acute migraine . Neurology 2014 ; 83: 1388 – 1389 .

Google Scholar Crossref | Medline

44. Gaffigan, ME, Bruner, DI, Wason, C, et al. A randomized controlled trial of intravenous haloperidol vs. intravenous metoclopramide for acute migraine therapy in the emergency department . J Emerg Med 2015 ; 49: 326 – 334 .

Google Scholar Crossref | Medline

45. Talabi, S, Masoumi, B, Azizkhani, R, et al. Metoclopramide versus sumatriptan for treatment of migraine headache: A randomized clinical trial . J Res Med Sci 2013 ; 18: 695 – 698 .

Google Scholar Medline

46. Tek, DS, McClellan, DS, Olshaker, JS, et al. A prospective, double-blind study of metoclopramide hydrochloride for the control of migraine in the emergency department . Ann Emerg Med 1990 ; 19: 1083 – 1087 .

Google Scholar Crossref | Medline | ISI

47. Kagan, R, Kainz, V, Burstein, R, et al. Hypothalamic and basal ganglia projections to the posterior thalamus: Possible role in modulation of migraine headache and photophobia . Neuroscience 2013 ; 248C: 359 – 368 .

Google Scholar Crossref

48. Malick, A, Strassman, RM, Burstein, R, et al. Trigeminohypothalamic and reticulohypothalamic tract neurons in the upper cervical spinal cord and caudal medulla of the rat . J Neurophysiol 2000 ; 84: 2078 – 2112 .

Google Scholar Crossref | Medline | ISI

49. Holland, P, Goadsby, PJ. The hypothalamic orexinergic system: Pain and primary headaches . Headache 2007 ; 47: 951 – 962 .

Google Scholar Crossref | Medline | ISI

50. Barloese, M, Jennum, P, Lund, N, et al. Reduced CSF hypocretin-1 levels are associated with cluster headache . Cephalalgia 2015 ; 35: 869 – 876 .

Google Scholar SAGE Journals | ISI

51. Schürks, M, Kurth, T, Geissler, I, et al. Cluster headache is associated with the G1246A polymorphism in the hypocretin receptor 2 gene . Neurology 2006 ; 66: 1917 – 1919 .

Google Scholar Crossref | Medline | ISI

52. Schürks, M, Kurth, T, Geissler, I, et al. The G1246A polymorphism in the hypocretin receptor 2 gene is not associated with treatment response in cluster headache . Cephalalgia 2007 ; 27: 363 – 367 .

Google Scholar SAGE Journals | ISI

53. Chabi, A, Zhang, Y, Jackson, S, et al. Randomized controlled trial of the orexin receptor antagonist filorexant for migraine prophylaxis . Cephalalgia 2015 ; 35: 379 – 388 .

Google Scholar SAGE Journals | ISI

54. Wei, DY, Jensen, RH. Therapeutic approaches for the management of trigeminal autonomic cephalalgias . Neurotherapeutics 2018 ; 15: 346 – 360 .

Google Scholar Crossref | Medline

55. May, A, Ashburner, J, Büchel, C, et al. Correlation between structural and functional changes in brain in an idiopathic headache syndrome . Nat Med 1999 ; 5: 836 – 838 .

Google Scholar Crossref | Medline | ISI

56. May, A, Bahra, A, Büchel, C, et al. Hypothalamic activation in cluster headache attacks . Lancet 1998 ; 352: 275 – 278 .

Google Scholar Crossref | Medline | ISI

57. Sprenger, T, Boecker, H, Tolle, TR, et al. Specific hypothalamic activation during a spontaneous cluster headache attack . Neurology 2004 ; 62: 516 – 517 .

Google Scholar Crossref | Medline | ISI

58. May, A, Bahra, A, Büchel, C, et al. PET and MRA findings in cluster headache and MRA in experimental pain . Neurology 2000 ; 55: 1328 – 1335 .

Google Scholar Crossref | Medline | ISI

59. Leone, M, Franzini, A, Bussone, G. Stereotactic stimulation of posterior hypothalamic gray matter in a patient with intractable cluster headache . N Engl J Med 2001 ; 345: 1428 – 1429 .

Google Scholar Crossref | Medline | ISI

60. Leone, M . Deep brain stimulation in headache . Lancet Neurol 2006 ; 5: 873 – 877 .

Google Scholar Crossref | Medline | ISI

61. Akram, H, Miller, S, Lagrata, S, et al. Ventral tegmental area deep brain stimulation for refractory chronic cluster headache . Neurology 2016 ; 86: 1676 – 1682 .

Google Scholar Crossref | Medline

62. Nowacki, A, Moir, L, Owen, SLF, et al. Deep brain stimulation of chronic cluster headaches: Posterior hypothalamus, ventral tegmentum and beyond . Cephalalgia 2019 ; 39: 1111 – 1120 .

Google Scholar SAGE Journals

63. Seijo-Fernandez, F, Saiz, A, Santamarta, E, et al. Long-term results of deep brain stimulation of the mamillotegmental fasciculus in chronic cluster headache . Stereotact Funct Neurosurg 2018 ; 96: 215 – 222 .

Google Scholar Crossref | Medline

64. May, A, Leone, M, Boecker, H, et al. Hypothalamic deep brain stimulation in positron emission tomography . J Neurosci 2006 ; 26: 3589 – 3593 .

Google Scholar Crossref | Medline | ISI

65. Lodi, R, Pierangeli, G, Tonon, C, et al. Study of hypothalamic metabolism in cluster headache by proton MR spectroscopy . Neurology 2006 ; 66: 1264 – 1266 .

Google Scholar Crossref | Medline | ISI

66. Wang, S-J, Lirng, J-F, Fuh, J-L, et al. Reduction in hypothalamic H-MRS metabolite ratios in patients with cluster headache . J Neurol Neurosurg Psychiatry 2006 ; 77: 622 – 625 .

Google Scholar Crossref | Medline | ISI

67. Burstein, R, Yamamura, H, Malick, A, et al. Chemical stimulation of the intracranial dura induces enhanced responses to facial stimulation in brain stem trigeminal neurons . J Neurophysiol 1998 ; 79: 964 – 982 .

Google Scholar Crossref | Medline | ISI

68. Malick, A, Strassman, RM, Burstein, R. Trigeminohypothalamic and reticulohypothalamic tract neurons in the upper cervical spinal cord and caudal medulla of the rat . J Neurophysiol 2000 ; 84: 2078 – 2112 .

Google Scholar Crossref | Medline | ISI

69. Malick, A, Burstein, R. Cells of origin of the trigeminohypothalamic tract in the rat . J Comp Neurol 1998 ; 400: 125 – 144 .

Google Scholar Crossref | Medline | ISI

70. Burstein, R, Cliffer, KD, Giesler, GJ. Cells of origin of the spinohypothalamic tract in the rat . J Comp Neurol 1990 ; 291: 329 – 344 .

Google Scholar Crossref | Medline | ISI

71. Cliffer, KD, Burstein, R, Giesler, GJ. Distributions of spinothalamic, spinohypothalamic, and spinotelencephalic fibers revealed by anterograde transport of PHA-L in rats . J Neurosci 1991 ; 11: 852 – 868 .

Google Scholar Crossref | Medline | ISI

72. Vandewalle, G, Maquet, P, Dijk, D-J. Light as a modulator of cognitive brain function . Trends Cogn Sci 2009 ; 13: 429 – 438 .

Google Scholar Crossref | Medline | ISI

73. Herrera, CG, Cadavieco, MC, Jego, S, et al. Hypothalamic feedforward inhibition of thalamocortical network controls arousal and consciousness . Nat Neurosci 2016 ; 19: 290 – 298 .

Google Scholar Crossref | Medline | ISI

74. Bernard, JF, Peschanski, M, Besson, JM. A possible spino (trigemino)-ponto-amygdaloid pathway for pain . Neurosci Lett 1989 ; 100: 83 – 88 .

Google Scholar Crossref | Medline | ISI

75. Kannan, H, Osaka, T, Kasai, M, et al. Electrophysiological properties of neurons in the caudal ventrolateral medulla projecting to the paraventricular nucleus of the hypothalamus in rats . Brain Res 1986 ; 376: 342 – 350 .

Google Scholar Crossref | Medline

76. Pan, B, Castro-Lopes, JM, Coimbra, A. Central afferent pathways conveying nociceptive input to the hypothalamic paraventricular nucleus as revealed by a combination of retrograde labeling and c-fos activation . J Comp Neurol 1999 ; 413: 129 – 145 .

Google Scholar Crossref | Medline

77. Person, RJ . Somatic and vagal afferent convergence on solitary tract neurons in cat: Electrophysiological characteristics . Neuroscience 1989 ; 30: 283 – 295 .

Google Scholar Crossref | Medline

78. Zhang, X, Fogel, R, Renehan, WE. Physiology and morphology of neurons in the dorsal motor nucleus of the vagus and the nucleus of the solitary tract that are sensitive to distension of the small intestine . J Comp Neurol 1992 ; 323: 432 – 448 .

Google Scholar Crossref | Medline

79. Cechetto, DF, Standaert, DG, Saper, CB. Spinal and trigeminal dorsal horn projections to the parabrachial nucleus in the rat . J Comp Neurol 1985 ; 240: 153 – 160 .

Google Scholar Crossref | Medline

80. Saper, CB, Loewy, AD. Efferent connections of the parabrachial nucleus in the rat . Brain Res 1980 ; 197: 291 – 317 .

Google Scholar Crossref | Medline | ISI

81. Slugg, RM, Light, AR. Spinal cord and trigeminal projections to the pontine parabrachial region in the rat as demonstrated with Phaseolus vulgaris leucoagglutinin . J Comp Neurol 1994 ; 339: 49 – 61 .

Google Scholar Crossref | Medline | ISI

82. Menétrey, D, Basbaum, AI. Spinal and trigeminal projections to the nucleus of the solitary tract: A possible substrate for somatovisceral and viscerovisceral reflex activation . J Comp Neurol 1987 ; 255: 439 – 450 .

Google Scholar Crossref | Medline | ISI

83. Ricardo, JA, Koh, ET. Anatomical evidence of direct projections from the nucleus of the solitary tract to the hypothalamus, amygdala, and other forebrain structures in the rat . Brain Res 1978 ; 153: 1 – 26 .

Google Scholar Crossref | Medline | ISI

84. Beitz, AJ . The organization of afferent projections to the midbrain periaqueductal gray of the rat . Neuroscience 1982 ; 7: 133 – 159 .

Google Scholar Crossref | Medline | ISI

85. Eberhart, JA, Morrell, JI, Krieger, MS, et al. An autoradiographic study of projections ascending from the midbrain central gray, and from the region lateral to it, in the rat . J Comp Neurol 1985 ; 241: 285 – 310 .

Google Scholar Crossref | Medline

86. Lima, D, Coimbra, A. Morphological types of spinomesencephalic neurons in the marginal zone (lamina I) of the rat spinal cord, as shown after retrograde labelling with cholera toxin subunit B . J Comp Neurol 1989 ; 279: 327 – 339 .

Google Scholar Crossref | Medline | ISI

87. Liu, RP . Laminar origins of spinal projection neurons to the periaqueductal gray of the rat . Brain Res 1983 ; 264: 118 – 122 .

Google Scholar Crossref | Medline

88. Lima, D, Mendes-Ribeiro, JA, Coimbra, A. The spino-latero-reticular system of the rat: Projections from the superficial dorsal horn and structural characterization of marginal neurons involved . Neuroscience 1991 ; 45: 137 – 152 .

Google Scholar Crossref | Medline

89. Sawchenko, PE, Swanson, LW. Central noradrenergic pathways for the integration of hypothalamic neuroendocrine and autonomic responses . Science 1981 ; 214: 685 – 687 .

Google Scholar Crossref | Medline | ISI

90. Bernardis, LL, Bellinger, LL. The dorsomedial hypothalamic nucleus revisited: 1998 update . Proc Soc Exp Biol Med 1998 ; 218: 284 – 306 .

Google Scholar SAGE Journals | ISI

91. Norgren, R . Gustatory responses in the hypothalamus . Brain Res 1970 ; 21: 63 – 77 .

Google Scholar Crossref | Medline

92. Peyron, C, Tighe, DK, van den Pol, AN, et al. Neurons containing hypocretin (orexin) project to multiple neuronal systems . J Neurosci 1998 ; 18: 9996 – 10015 .

Google Scholar Crossref | Medline | ISI

93. Sherin, JE, Shiromani, PJ, McCarley, RW, et al. Activation of ventrolateral preoptic neurons during sleep . Science 1996 ; 271: 216 – 219 .

Google Scholar Crossref | Medline | ISI

94. Kai, Y, Oomura, Y, Shimizu, N. Responses of rat lateral hypothalamic neurons to periaqueductal gray stimulation and nociceptive stimuli . Brain Res 1988 ; 461: 107 – 117 .

Google Scholar Crossref | Medline

95. Hamba, M . Effects of lesion and stimulation of rat hypothalamic arcuate nucleus on the pain system . Brain Res Bull 1988 ; 21: 757 – 763 .

Google Scholar Crossref | Medline

96. Hamamura, M, Shibuki, K, Yagi, K. Noxious inputs to supraoptic neurosecretory cells in the rat . Neurosci Res 1984 ; 2: 49 – 61 .

Google Scholar Crossref | Medline

97. Hilton SM. Hypothalamic control of the cardiovascular responses in fear and rage. Sci Basis Med Annu Rev 1965; 217–238.

Google Scholar

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

Google Scholar Crossref | Medline | ISI

99. Matharu, MS, Bartsch, T, Ward, N, et al. Central neuromodulation in chronic migraine patients with suboccipital stimulators: A PET study . Brain 2004 ; 127: 220 – 230 .

Google Scholar Crossref | Medline | ISI

100. Kröger, IL, May, A. Pharmacological neuroimaging in headache and pain . Curr Opin Neurol 2013 ; 26: 254 – 261 .

Google Scholar Crossref | Medline

101. Bahra, A, Matharu, MS, Buchel, C, et al. Brainstem activation specific to migraine headache . Lancet 2001 ; 357: 1016 – 1017 .

Google Scholar Crossref | Medline | ISI

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

Google Scholar Crossref | Medline | ISI

103. Schulte, LH, May, A. The migraine generator revisited: Continuous scanning of the migraine cycle over 30 days and three spontaneous attacks . Brain J Neurol 2016 ; 139: 1987 – 1993 .

Google Scholar Crossref | Medline | ISI

104. Maniyar, FH, Sprenger, T, Monteith, T, et al. Brain activations in the premonitory phase of nitroglycerin-triggered migraine attacks . Brain J Neurol 2014 ; 137: 232 – 241 .

Google Scholar Crossref | Medline | ISI

105. Sherman, SM . Thalamic relays and cortical functioning . Prog Brain Res 2005 ; 149: 107 – 126 .

Google Scholar Crossref | Medline | ISI

106. Sherman, SM, Guillery, RW. On the actions that one nerve cell can have on another: Distinguishing “drivers” from “modulators” . Proc Natl Acad Sci USA 1998 ; 95: 7121 – 7126 .

Google Scholar Crossref | Medline | ISI

107. McCormick, DA . Neurotransmitter actions in the thalamus and cerebral cortex and their role in neuromodulation of thalamocortical activity . Prog Neurobiol 1992 ; 9: 337 – 388 .

Google Scholar Crossref

108. Steriade, M, McCormick, DA, Sejnowski, TJ. Thalamocortical oscillations in the sleeping and aroused brain . Science 1993 ; 262: 679 – 685 .

Google Scholar Crossref | Medline | ISI

109. Guillery, RW, Sherman, SM. Thalamic relay functions and their role in corticocortical communication: Generalizations from the visual system . Neuron 2002 ; 33: 163 – 175 .

Google Scholar Crossref | Medline | ISI

110. Kaneko, T, Mizuno, N. Immunohistochemical study of glutaminase-containing neurons in the cerebral cortex and thalamus of the rat . J Comp Neurol 1988 ; 267: 590 – 602 .

Google Scholar Crossref | Medline

111. McCormick, DA, von Krosigk, M. Corticothalamic activation modulates thalamic firing through glutamate “metabotropic” receptors . Proc Natl Acad Sci USA 1992 ; 89: 2774 – 2778 .

Google Scholar Crossref | Medline

112. Noseda, R, Jakubowski, M, Kainz, V, et al. Cortical projections of functionally identified thalamic trigeminovascular neurons: Implications for migraine headache and its associated symptoms . J Neurosci 2011 ; 31: 14204 – 14217 .

Google Scholar Crossref | Medline | ISI

113. Noseda, R, Kainz, V, Borsook, D, et al. Neurochemical pathways that converge on thalamic trigeminovascular neurons: Potential substrate for modulation of migraine by sleep, food intake, stress and anxiety . PloS One 2014 ; 9: e103929 – e103929 .

Google Scholar Crossref | Medline | ISI

114. McCarley, RW, Benoit, O, Barrionuevo, G. Lateral geniculate nucleus unitary discharge in sleep and waking: State- and rate-specific aspects . J Neurophysiol 1983 ; 50: 798 – 818 .

Google Scholar Crossref | Medline

115. Steriade, M, Deschenes, M. The thalamus as a neuronal oscillator . Brain Res 1984 ; 320: 1 – 63 .

Google Scholar Crossref | Medline

116. Steriade, M, Domich, L, Oakson, G. Reticularis thalami neurons revisited: Activity changes during shifts in states of vigilance . J Neurosci 1986 ; 6: 68 – 81 .

Google Scholar Crossref | Medline

117. McCormick, DA, Bal, T. Sleep and arousal: Thalamocortical mechanisms . Annu Rev Neurosci 1997 ; 20: 185 – 215 .

Google Scholar Crossref | Medline | ISI

118. Govindaiah, G, Wang, Y, Cox, CL. Dopamine enhances the excitability of somatosensory thalamocortical neurons . Neuroscience 2010 ; 170: 981 – 991 .

Google Scholar Crossref | Medline

119. Pape, HC, McCormick, DA. Noradrenaline and serotonin selectively modulate thalamic burst firing by enhancing a hyperpolarization-activated cation current . Nature 1989 ; 340: 715 – 718 .

Google Scholar Crossref | Medline

120. Lüthi, A, McCormick, DA. Periodicity of thalamic synchronized oscillations: The role of Ca2+-mediated upregulation of Ih . Neuron 1998 ; 20: 553 – 563 .

Google Scholar Crossref | Medline | ISI

121. Lüthi, A, McCormick, DA. H-current: Properties of a neuronal and network pacemaker . Neuron 1998 ; 21: 9 – 12 .

Google Scholar Crossref | Medline

122. Robinson, RB, Siegelbaum, SA. Hyperpolarization-activated cation currents: From molecules to physiological function . Annu Rev Physiol 2003 ; 65: 453 – 480 .

Google Scholar Crossref | Medline | ISI

123. McCormick, DA, Williamson, A. Modulation of neuronal firing mode in cat and guinea pig LGNd by histamine: Possible cellular mechanisms of histaminergic control of arousal . J Neurosci 1991 ; 11: 3188 – 3199 .

Google Scholar Crossref | Medline

124. Govindaiah, G, Cox, CL. Modulation of thalamic neuron excitability by orexins . Neuropharmacology 2006 ; 51: 414 – 425 .

Google Scholar Crossref | Medline

125. Elias, CF, Lee, CE, Kelly, JF, et al. Characterization of CART neurons in the rat and human hypothalamus . J Comp Neurol 2001 ; 432: 1 – 19 .

Google Scholar Crossref | Medline