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REVIEW

Migraine and the hypothalamus

KB Alstadhaug

Department of Neurology, Nordlandssykehuset Bod, Norway

Alstadhaug KB. Migraine and the hypothalamus. Cephalalgia 2009. London.ISSN 0333-1024

Migraine is a complex brain disorder where several neuronal pathways andneurotransmitters are involved in the pathophysiology. To search for a specificanatomical or physiological defect in migraine may be futile, but the hypothala-mus, with its widespread connections with other parts of the central nervoussystem and its paramount control of the hypophysis and the autonomic nervoussystem, is a suspected locus in quo. Several lines of evidence support involve-ment of this small brain structure in migraine. However, whether it plays a majoror minor role is unclear. The most convincing support for a pivotal role so faris the activation of the hypothalamus shown by positron emission tomography(PET) scanning during spontaneous migraine attacks. A well-known theory isthat the joint effect of several triggers may cause temporary hypothalamicdysfunction, resulting in a migraine attack. If PET scanning had consistentlyconfirmed hypothalamic activation prior to migraine headache, this hypothesiswould have been supported. However, such evidence has not been provided,and the role of the hypothalamus in migraine remains puzzling. This reviewsummarizes and discusses some of the clues. Hypothalamus, migraine, patho-physiology, nociception, triggering factors

Karl B. Alstadhaug MD, PhD, Department of Neurology, Prinsensgt 164,Nordlandssykehuset Bod, 8011 Bod, Norway. E-mail [email protected] 6 June 2008, accepted 22 October 2008

Introduction

Migraine is characterized by episodes of headacheand hypersensitivity to sensory stimuli. The prevail-ing theory is that migraine is a brain disorder, andthat migraine aura is caused by the electrophysi-ological phenomenon cortical spreading depression(CSD) (1). Whether CSD triggers migraine pain ismore controversial, but not beyond the realms of

possibility (2). Brainstem activation during migraineattacks detected by neuroimaging has raised thepossibility of a primary dysfunction in the midbrainand/or dorsal pons (3, 4). Thus, CSD may be an epi-or secondary phenomenon to perturbed sensorymodulation in the branstem pathways that controlafferent inputs (5).

However, where and why attacks are triggered,the primum movens of migraine, is not known. Thekey may be the hypothalamus.

The hypothalamus

The name hypothalamus (Gr. hypo = below,thalamus = room, inner chamber) was introduced inthe late 19th century (6). It denotes a small brainstructure at the base of the brain. The hypothala-mus weighs only 45 g and is only 4 cm 3 in size (7).The anatomy is complex and borders are ratherarbitrary. It is common to distinguish between the

medial and the lateral hypothalamus. The formercontains several distinct nuclei and may be dividedinto three regions (8) (Fig. 1): the anterior (chias-matic or preoptic region), the cone-shaped tuberalregion, and the posterior (mamillary) region. Thelateral hypothalamus (LHT) is a diffuse structurewhere fibres from the medial forebrain bundle(MFB) are passing. Despite some distinct nuclei inhypothalamus, short association fibres abound, andthere are widespread connections to other parts of

doi:10.1111/j.1468-2982.2008.01814.x

1 Blackwell Publishing Ltd Cephalalgia, 2009
mailto:[email protected]:[email protected]

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the central nervous system. It is very difficult tostudy hypothalamic functions both clinically andexperimentally. To regard specific nuclei as inde-pendent reflex centres for specialized functions

would probably be incorrect.The hypothalamus has a multitude of functions.In the broadest sense, it maintains homeostasis bycontrolling the endocrine system, coordinating theactivity of the sympathetic and parasympatheticnervous systems, and integrates psyche and soma.Insight into its role in organizing circadian rhythmsand regulation of arousal has increased consider-ably in recent years. The hypothalamus also playsan important role in nociceptive processing.

It is beyond the scope of this review to discussthe anatomy of the hypothalamus in detail, butwith respect to the subsequent text the following is

worth mentioning.The anterior part of hypothalamus contains the

supraoptic nucleus and the paraventricularnucleus (PVN) that synthesize vasopressin andoxcytocin, and the master circadian clock, thesuprachiasmatic nucleus (SCN). PVN has also beencalled the master controller of the autonomicsystem. The tuberal part contains the luteinizinghormone-releasing hormone (LHRH) pulse genera-tor that controls the menstrual cycle, and the

arcuate nucleus which is, inter alia, involved inpain modulation (9). The posterior hypothalamicarea is a poorly defined region that merges cau-dally with the mesencephalic reticular formation.Together with the caudal part of the lateral hypo-thalamic area and the mamillary bodies, this con-stitutes the posterior region. The mamillary bodiesare the hypothalamic components of Papez circuit,a multinuclear pathway that plays a role inemotion (10).

Historical/anecdotal aspects

The first to suggest an important role of the hypo-thalamus in migraine is uncertain. In 1933 Henrik-sen treated 42 patients with the hypophysis extractPituitrin (aqueous extract of the posterior lobe ofthe pituitary containing vasopressin and oxytocin),of whom 37 allegedly improved in their ailments

(11). Daro et al. reported the same positive effectafter treating a female migraineur in 1940 andanother headache patient in 1959 (12). Later in the1960s, migraine authorities made their contribution(13, 14). Pearce expressed it quite succinctly (14):

A periodic central disturbance of hypothalamic activ-ity could account for the periodicity of the migraineattacks, and could also be related to emotional distur-bances mediated by pathways from the limbic systemto the hypothalamus.

A more recent report presented two patients whowere promptly relieved from their migraine head-ache by intravenous oxytocin (15).

The central histaminergic system, the tubero-mamillary complex (TMC) located in theposterior/lateral hypothalamus, is an area ofrecent interest in the pathophysiology of primaryheadaches (1619). The TMC probably participatesin several functions such as modulation of arousalstate, circadian rhythms, stress, analgesia, cerebralcirculation, etc. (7). A common statement aboutantihistamines in the treatment of migraine is thatthey are ineffective in the prevention of migraine

headaches. However, first-generation H1 receptorantagonists are often recommended in paediatricand pregnant patients for treating symptoms ofmigraine, such as nausea and vomiting. Most ofthese antihistamines are lipophilic compoundsthat readily penetrate into the brain, and causeboth anti-nausea and sedative effects (20).However, there may be other central effects thatmay be beneficial in migraine. Two antihistamines(cinnarizine and cyproheptadine) that cross the

Anterior region

Lamina

terminalis

Opticchiasm

Mammilary

body

Posterior region Tuberal region

Infundibular

stalk

II

14

13

12

10

11

7

8

9

5

6

1

2

3

4

Figure 1 Approximate topography of the hypothalamicnuclei based on Young and Stanton (9). The medialhypothalamus is commonly divided into an anterior, amedial, and a posterior region. Anterior region: 1,suprachiasmatic nucleus; 2, supraoptic nucleus; 3,

interstitial nucleus of the anterior hypothalamus -1(INAH-1); 4, INAH-3; 5, INAH-4; 6, paraventricularnucleus. Tuberal region: 7, arcuate nucleus; 8,ventromedial nucleus; 9, dorsolateral nucleus; 10,tuberomamillary nucleus; 11, lateral tuberal nucleus.Posterior region: 12, medial mamillary nucleus; 13,supramamillary nucleus; 14, mamillary body. (The lateralmaxillary nucleus is not shown.)

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bloodbrain barrier and cause sedation (21) havebeen reported to be efficacious in migraine (2224). Their efficacy has been ascribed other actionsthan antihistaminergic. Interestingly, meclizine, anantihistamine with a chemical structure similar tocinnarizine but with no effect on calcium chan-nels, has not been rigorously tested in migraine,but favourable effects were reported in the 1950s(25).

Modulation of nociceptive processing

The hypothalamus plays an important role incontrol of nociception (26). Electrical stimulation[deep brain stimulation (DBS)] of the hypothala-mus, similar to stimulation of the raphe nucleusand the periaqueductal grey, reduces pain inexperimental animals (27). The hypothalamus con-tains several opioid peptides, and the analgesia

achieved by electrostimulation is traditionally pre-sumed to be caused by the opioid system (28). Theoxytocinergic mechanisms may however also beinvolved in long -term antinociception (29). In fact,several peptides associated with the hypothalamus,such as angiotensin II, vasopressin, calcitonin,somatostatin and others, may have antinociceptiveeffects (28). For example, somatostatin injected intothe posterior hypothalamus of rats seems to havean antinociceptive effect on input from dural andfacial structures (30). A novel growth hormone-releasing peptide, ghrelin, seems to reduce the pain

threshold in mice (31). Interestingly, it has beenfound to decrease serotonin release in the dorsalraphe nucleus. Alteration of brain histamine levelshas also been shown to influence nociception,and both the H1 and H2 receptors are probablyinvolved (32). Even the H3 receptor has been con-sidered a potential new drug target in migraine(33), as have the orexin receptors (34). The potentialrole of vasopressin in migraine was reviewed a fewyears ago (35), and the orexinergic system recently(36).

As regards primary headaches, antinociceptionmay perhaps be mediated by direct hypothalamic

trigeminal connections (37). It is almost orthodoxto regard cluster headache a primary hypotha-lamic dysfunction and the effect of DBS of theposterior hypothalamus in this disorder as specific(38), but this is still not proven. Stimulation thatmay affect the LHT would influence axons in theMFB, and functional imaging has shown hypotha-lamic activation not only in several trigeminalautonomic cephalalgias (TACs), but also inmigraine (39).

Features of migraine consistent withhypothalamic involvement

One of the main arguments why the explanation ofmigraine should be sought in hypothalamic net-works is the sexual dimorphism of migraine.Migraine is a female disorder, with three times theprevalence of men after puberty (40), and it isprobably the transition to puberty that causes thisgender difference (41). In fact, migraine manifestsfor the first time at menarche in one-third ofaffected women (42), and the relative risk of havinga migraine attack on days -2 to +3 of menstruationhas been estimated to be about twice the risk ofhaving an attack at other times of the month (43).Menstrually associated migraine is probably relatedto the decline in oestrogen that occurs at menstrua-tion (44, 45), but the evidence for menstrualmigraine prevention is scarce for oestrogen (46). It

is a clear clinical experience that migraine isaffected by pregnancy, as confirmed in prospectivestudies (47). As expressed by Fachinetti, the expla-nation of the sexual dimorphism of migraine mightbe sought in hypothalamic networks related toLHRH secretion (48). A number of hypothalamicsexually dimorphic structures have been found.The most prominent is the interstitial nucleus of theanterior hypothalamus-1, which is also called thesexually dimorphic nucleus of the preoptic area.

Another weighty argument for hypothalamicinvolvement in migraine is premonitory symptoms

that have been recognized for centuries (49). Up toseveral hours before the migraine aura and themigraine headache, many patients experiencevague symptoms like hunger, thirst, lassitude, tired-ness, yawning and, on some occasions, a sense ofoppression, desire to micturate, etc. By using anelectronic diary system Giffin et al. showed that 97selected patients were able to predict 72% of theattacks that were experienced in a 3-month periodbased on symptoms believed to represent the pro-dromal phase of migraine (50). Given the centralrole of the hypothalamus in maintaining homeosta-sis, one may claim that symptoms may reflect hypo-

thalamic dysfunction that precedes a migraineattack. A significant decrease in urinary vasopressinassociated with marked diuresis and natriuresisduring migraine, but not prior to migraine head-ache, has been shown (51). However, given themultitude of precipitating factors in migraine, stressbeing the most common (52), symptoms may alsoreflect a normal hypothalamic response to differenttrigger factors. Stress may be defined as the physi-ological response to the perception of major threats

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or demands (10), and a pivotal role of the hypo-thalamus in psychosomatic interrelations has beenacknowledged for decades (53). It seems that themain part of the extended amygdala (the bednucleus of stria terminalis) with its connections tothe PVN may mediate long-lasting behaviouralresponses during sustained stress. These responsespersist for a long time after the termination ofstress, which may perhaps explain why migrainemay be triggered both during and after stress (54).

The role of the hypothalamus in regulating arousalin general has been scrutinized (55), and, asexpressed by Brodal, stress is a stimulus thatincreases arousalwith appurtenant EEG changes,increased attention . . . activation of part of the auto-nomic nervous system, etc. (56). Compared withpatients suffering from stress that was not related toheadache, migraineurs had lower levels of norad-renalin in plasma and cerebrospinal fluid during

attacks in one study (57), but studies of the auto-nomic nervous system in migraine are conflicting(58). The majority of studies, however, seem tosupport a sympathetic hypofunction (59). Evidencealso tends to support hyperactivity of cranialparasympathetic nerves, via the trigeminal-parasympathetic reflex (60). Parasympathetic symp-toms such as facial flushing, lacrimation and nasalstuffiness may accompany migraine attacks. Theinvolvement of the parasympathetic system mayalso cause the well-known vasodilation of meningealblood vessels.

In view of conflicting data, an interesting opinionof Kalsbeek and co-workers is that the major roleof the SCN is control of the sympathetic/parasympathetic balance in autonomic nervousactivity, and that a not well-entrained biologicalclock would predispose to diseases of modern life(61). In 1997 Zurack proposed that temporary dys-function of the SCN could be the cause of migraineattacks (62). Actually, the circadian temporal patternof migraine, with attacks occurring more frequentlyduring the night and the early morning hours (63,64), has been considered by some as strong indirectevidence for a pivotal role of the SCN in migraine

pathophysiology (6567). However, we may havebeen led astray by observations that reflect theexception and not the rule.

An arousal-related disorder?

Migraine attacks have a tendency to recur in a daily,weekly, monthly and even a seasonal pattern (68),but for the time being the evidence for a retino-hypothalamic-pineal hypothesis is lacking. In the

1970s Dexter advocated a relationship of migraineto rapid eye movement (REM) and deep sleep(stages II and IV) (6971). However, nocturnalmigraine, having the majority of attacks during thenight, is probably a minority phenomenon ingeneral, and the circadian patterns of migrainestrongly indicate a protective effect of sleep (72, 73)(Fig. 2).

Sleep is in fact excellent treatment for attacks, anobservation made clearly by the 19th century neu-rologists (74). It is well known that patients withsleep disorders are prone to have morning head-aches (75), as are probably patients with both chronic(76) and episodic (77) migraine. At the end of a sleepperiod, in the process of waking up, the TMC startsto fire, and histaminergic neurons have been pro-posed to be involved in the triggering of early-morning migraine (54). Triggering factors such asfood and sleep deprivation may increase the activity

of hypocretinergic neurons of the LHT, and theseneurons may also be involved in the triggering of amigraine attack (54). Instead of regarding sleep as acommon precipitator of migraine, we have to askwhy sleep protects against attacks.

Figure 2 The 24-h distribution of migraine attacks. Theupper histogram shows the 24-h distribution of migraineattacks in a paediatric population (72) and the lowerhistogram shows the equivalent in an adult femalepopulation (73). A protective effect of sleep in migraineseems obvious.

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Migraine comorbidity andhypothalamic dysfunction

An alluring hypothalamic flip-flop switch mecha-nism that can explain the fast transitions betweenthe waking state and sleep, and between REM andnon-REM sleep, has been proposed (78). Principally,this mechanism is easy to understand and makes anexcellent basis for the understanding of narcolepsy,but perhaps also for other episodic brain disorderssuch as migraine and cluster headache. Theincreased prevalence of migraine in narcolepsy (79),epilepsy (80) and somnambulism (81) at least sup-ports that migraine is an arousal-related disorder.The strong association between migraine and moodand anxiety disorders, where hypothalamic neuralcircuits most certainly are involved (82), is also welldocumented (83). Headache associated with pitu-itary tumours is common, and the majority are

migraine-like (84).An association between migraine and obesity

could implicate hypothalamic dysfunction in appe-tite regulation and energy homeostasis. Migraineursdo not have a higher body mass index than thenormal population. However, an associationbetween obesity and migraine attack frequency andchronic migraine has been shown (85). One recentstudy showed significantly lower levels of theprotein leptin in a cohort of migraineurs comparedwith controls (86). Leptin is an adipose-derivedhormone that mediates negative feedback to the

hypothalamus, and causes reduction in body weight(7).

Findings in experimental models thatsupport hypothalamic involvementin migraine

Fos protein immunoactivity can be used as a markerof nociception (87). Stimulation of the dura mater, asort of modelling the pain in migraine, in rats

produces Fos expression in the ventromedial,paraventricular and dorsomedial hypothalamicnuclei (88). Stimulation of the superior sagittal sinusin cats leads to increased Fos expression in thesupraoptic and posterior hypothalamic nuclei (89).

Evidence for a pivotal hypothalamic rolein migraine?

Hypothalamic dysfunction in both episodic (90)and chronic (91) migraine has been postulatedbased on deviation from the normal circadian pat-terns of hormones such as prolactin, cortisol andmelatonin. In the only study of chronic migraine,the majority of patients suffered from insomnia,and the hypothalamus is certainly involved in sleepdisorders. Similar neuroendocrine changes compat-ible with hypothalamic dysfunction have also beenshown in cluster headache (90) and in trigeminal

neuralgia (92), illustrating the lack of specificity inthese neuroendocrine deviations.

Hypothalamic activation in spontaneous migraineattacks was recently shown for the first time by usingpositron emission tomography (PET) (39) (Fig. 3).This study shows that the hypothalamus is involvedrelatively early in the migraine attack. Hypothalamicactivation may be secondary to the trigeminal pain,and to prove a pivotal role in generating an attacksimilar studies have to show consistent hypotha-lamic activation prior to the headache phase.

To complete the storyDemonstrating enhanced or impaired activity in aneuroanatomical part of a complex networkinvolved in migraine does not of course necessarilyprove a migraine generator or a specific migrainedefect. However, the study of Denuelle et al. hasshown that hypothalamic functions and networkshave to be explored further to understand migrainefully. The interplay between hypothalamus, the

Figure 3 Hypothalamic activation in migraine. The picture is adapted from Denuelle et al. (39) with permission. Thepositron emission tomography (PET) images taken during a migraine attack show hypothalamic activation (at the point ofintersection). The localization is more anterior than described in cluster headaches and trigemino-autonomic cephalalgias.The resolution for PET studies is not large enough to localize the exact structure involved, and sometimes even not the side.



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trigeminovascular system and autonomic nuclei isessential in this, and Burstein and co-workers havemade a substantial contribution to this understand-ing (37, 54, 88, 9398).

Burstein and Jakubowski have proposed thatvarious triggers of migraine activate different brainareas, especially limbic and hypothalamic, that im-pinge on the preganglionic parasympathetic neuronsin the superior salivatory nucleus, which in turnactivates postganglionic parasympathetic neurons inthe sphenopalatine ganglion resulting in vasodila-tion and activation of meningeal nociceptors. Thelatter activates the trigeminovascular system, thefundamental process of migraine pain. In turn,ascending trigeminovascular projections reach andalter hypothalamus and limbic structures to mediatethe accompanying symptoms of migraine (54). Anexample is loss of appetite common in migraine, andbrief noxious dural stimulation has been shown to

suppress food intake in rats. This effect is probablymediated via trigeminohypothalamic neurons (88).The theory is well founded, but why these mecha-nisms are unique to migraine is not clear.

Conclusions and remarks

With its extensive and multifarious functions in thebrain, the hypothalamus is most certainly involvedin migraine pathophysiology, but its exact role hasstill not been clarified. Several systems are probablyinvolved in the construction and release of attacks.

Lines of indirect evidence link several parts of thehypothalamus to migraine, both prior to, duringand after the headache phase, but no evidence for aspecific hypothalamic dysfunction or structuralabnormality in migraine exists. A major hurdle inour understanding is the lack of experimentalmodels that allow us to study distinct hypothalamicfunctions in a complex setting, which migraine inthe highest degree is.

Current hypotheses on migraine and the role ofthe hypothalamus lack specificity. Several disordersare postulated to be of hypothalamic origin, and acommon denominator in many of these is the epi-

sodic nature. An interesting view is that a compro-mised hypothalamic system is unable to stabilize aninherently unstable network and cause the transitionfrom normal state to a state of illness (90). Anacquired susceptibility to migraine attacks due tomodern life (61) is not inconceivable. With respect toits role in the maintenance of homeostasis, it isplausible to suspect that the hypothalamus plays animportant role in the start of an attack. In the future,patients who are able to predict their migraine

attacks based on probable hypothalamic symptomsshould be PET scanned when attacks are suspected.More experimental research should be done to findout how trigger factors exert their influence. The roleof the circumventricular organs of the brain (areasstrongly connected to the hypothalamus and impor-tant in maintenance of homeostasis (99)) has forexample not quite been determined. In view ofmigraine as an arousal related disorder, more studiesexploring the association between migraine, sleepand the circadian system should be done. The peri-odicity of migraine indicates that the master biologi-cal clock influences migraine attack susceptibility,but a pivotal role has not been proven. One previousopen-label study of melatonin, a hormone that playsan important role in modulating the activity of theSCN and the circadian system via the hypothalamicpineal axis (7, 100), has shown effects that certainlywarrant a placebo-controlled study (101). Several

systems associated with arousal and circadianrhythms like the orexinergic and the histaminergicmay also perhaps be targets for future drugs for thetreatment of migraine.

Its direct and hormonally mediated pain modu-lating role (102) links the hypothalamus auto-matically to a painful condition such as migraine.Whether neurostimulation of hypothalamic greymatter exerts only a pure analgesic effect, or exertsother effects that are specific for TACs, is still unclear(103), but it is reason to believe that migraine alsocould respond to such treatment. One can not

exclude that attacks could be triggered directly bythe hypothalamus, or that there could be inadequatemodulation of other brain functions. Interestingly,pain-induced release of opioids from the periaque-ductal grey and norepinephrine from the magnocel-lular nuclei act at the hypothalamus to produceincreased levels of induced nitric oxide (iNO), whichproduces vasodilation within the hypothalamicmedian eminence and activates the hypothalamuspituitaryadrenal system (102). NO-based mecha-nisms have long been suspected in migrainepathophysiology, and the effects need not be onlyvascular (34).

Finally, a coherent picture of the pathophysiologyof migraine can not be given. Attempts at synthesistend to ignore the role of the hypothalamus, butsuch an approach is hardly fruitful in the futureunderstanding and prevention of migraine.

References

1 Lauritzen M. Pathophysiology of the migraine aura. Thespreading depression theory. Brain 1994; 117:199210.

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2 Bolay H, Reuter U, Dunn AK, Huang Z, Boas DA,Moskowitz MA. Intrinsic brain activity triggers trigemi-nal meningeal afferents in a migraine model. Nat Med2002; 8:13642.

3 Weiler C, May A, Limmroth V, Juptner M, Kaube H, vanSchayck R et al. Brain stem activation in spontaneoushuman migraine attacks. Nat Med 1995; 1:65860.

4 Bahra A, Matharu S, Buchel C, Frackowiak RSJ, GoadsbyPJ. Brainstem activation specific to migraine headache.Lancet 2001; 357:101617.

5 Alstadhaug KB, Salvesen R. Migrainemechanisms andconsequences for treatment. Tidsskr Nor Laegeforen2007; 127:30648.

6 Louis ED, Stapf C. Unraveling the neuron jungle: the18791886 publications by Wilhelm His on the embryo-logical development of the human brain. Arch Neurol2001; 58:19325.

7 Amionff MJ, Boller F, Swaab DF, eds. Handbook ofclinical neurology, Vol. 79. The human hypothalamus:

basic and clinical aspects. Part I. Amsterdam, London:Elsevier 2003.

8 Young JK, Stanton GB. A three-dimensional reconstruc-

tion of the hypothalamus. Brain Res Bull 1994; 35:3237.

9 Sun YG, Gu XL, Lundeberg T, Yu LC. An antinocicep-tive role of galanin in the arcuate nucleus of hypothala-mus in intact rats and rats with inflammation. Pain 2003;106:14350.

10 Eggers AE. Redrawing Papez cicuit: a theory about howacute stress becomes chronic and causes disease. MedHypothesis 2007; 69:8527.

11 Henriksen KZ. Migraine, its pathogenesis and treatmentwith hypophysis extract. Acta Psychiatrica Scandinavica1933; 8:70121.

12 Daro AF, Harvey AG, Samos FH. The tranquilizingeffect of posterior pituitary extract. J Int Coll Surg 1964;

41:297300.13 Selby G, Lance JW. Observations on 500 cases of

migraine and allied vascular headache. J Neurol Psy-chiatry 1960; 23:2332.

14 Pearce J. Migraine: clinical features, mechanisms andmanagement. Springfield, IL: Charles C. Thomas 1969.

15 Philips WJ, Ostrovsky O, Galli RL, Dickey S. Relief ofacute migraine headache with intravenous oxytocin:report of two cases. J Pain Palliat Care Pharmacother2006; 20:258.

16 Montagna P. Hypothalamus, sleep and headaches.Neurol Sci 2006; 27 (Suppl. 2):S13843.

17 Holland PR, Akerman S, Goadsby PJ. Modulation ofnociceptive dural input to the trigeminal nucleus cau-

dalis via activation of the orexin 1 receptor in the rat.Eur J Neurosci 2006; 24:282533.

18 Holland P, Goadsby PJ. The hypothalamic orexinergicsystem: pain and primary headaches. Headache 2007;47:95162.

19 Vetrugno R, Pierangeli G, Leone M, Bussone G, FranziniA, Brogli G et al. Effect on sleep of posterior hypothala-mus stimulation in cluster headache. Headache 2007;47:108590.

20 Parsons ME, Ganellin RC. Histamine and its receptors.Br J Pharmacol 2006; 147 (Suppl. 1):S12735.

21 Togha M, Ashrafian H, Tajik P. Open-label trial ofcinnarizine in migraine prophylaxis. Headache 2006;46:498502.

22 Rossi P, Fiermonte G, Pierelli F. Cinnarizine in migraineprophylaxis: efficacy, tolerability and predictive factorsfor therapeutic responsiveness. An open-label pilot trial.Funct Neurol 2003; 18:1559.

23 Togha M, Ashrafian H, Tajik P. Open-label trial ofcinnarizine in migraine prophylaxis. Headache 2006;46:498502.

24 Rao BS, Das DG, Taraknath VR, Sarma Y. A double blindcontrolled study of propranolol and cyproheptadine inmigraine prophylaxis. Neurol India 2000; 48:2236.

25 Kutscher AH. Meclizine and headache: a case report.American practitioner and digest of treatment 1955;6:150911.

26 Jacob J, Vidal C. The relevance of the hypothalamus andof the hypophysis in the control of nociception. Possibleinvolvement in cephalees and migraine. PanminervaMed 1982; 24:7780.

27 Carstens E. Hypothalamic inhibition of rat dorsal hornneuronal responses to noxious skin heating. Pain 1986;

25:95107.28 Amionff MJ, Boller F, Swaab DF. Pain and addiction. In:

Amionff MJ, Boller F, Swaab DF, eds. Handbook ofclinical neurology, Vol. 80. The human hypothalamus:

basic and clinical aspects. Part II. Amsterdam, London:Elsevier 2004.

29 Lund I, Ge Y, Yu LC, Uvnas-Moberg K, Wang J, Yu Cet al. Repeated massage-like stimulation induces long-term effects on nociceptioncontribution of oxytociner-gic mechanisms. Eur J Neurosci 2002; 16:3308.

30 Bartsch T, Levy MJ, Knight PJ, Goadsby PJ. Inhibition ofnociceptive dural input in the trigeminal nucleus cau-dalis by somatostatin receptor blockade in the posteriorhypothalamus. Pain 2005; 117:309.

31 Kutlu S, Ozcan M, Canpolat S, Sandal S, Aydin M,Kelestimur H. Effect of Ghrelin on pain threshold inmice. Firat Tip Dergisi 2005; 10:8991.

32 Haas H, Panula P. The role of histamine and the tubero-mamillary nucleus in the nervous system. Nat Rev 2003;4:12130.

33 Leurs R, Bakker RA, Timmermann H, de Esch IJP. Thehistamine H3 receptor: from gene cloning to H3 receptordrugs. Nat Rev 2005; 4:10720.

34 Goadsby PJ. Can we develop neurally acting drugsfor the treatment of migraine? Nat Rev 2005; 4:74150.

35 Gupta VK. A clinical review of the adaptive roleof vasopressin in migraine. Cephalalgia 1997; 17:5619.

36 Holland P, Goadsby PJ. The hypothalamic orexinergicsystem: pain and primary headaches. HeadacheCurrents 2007; 95162.

37 Malick A, Strassman AM, Burnstein R. Trigeminohypo-thalamic and reticulohypothalamic tract neurons in theupper cervical spinal cord and caudal medulla of the rat.

J Neurophysiol 2000; 84:2078112.38 May A, Leone M, Boecker H, Sprenger T, Juergens T,

Bussone G et al. Hypothalamic deep brain stimulationin positron emission tomography. J Neurosci 2006;29:358993.



7/29/2019 Hipotalam

8/9

39 Denuelle M, Fabre N, Payoux P, Chollet F, GeraudG. Hypothalamic activation in spontaneous migraineattacks. Headache 2007; 47:141826.

40 Stewart WF, Shechter A, Rasmussen BK. Migraineprevalence: a review of population-based studies. Neu-rology 1994; 44 (Suppl. 4):S1723.

41 Sillanpaa M. Changes in the prevalence of migraine andother headaches during the first seven school years.Headache 1983; 23:1519.

42 Epstein MT, Hockaday JM, Hockaday TD. Migraine andreproductive hormones throughout the menstrual cycle.Lancet 1975; 1:5438.

43 MacGregor EA, Hackshaw A. Prevalence of migraine oneach day of the natural menstrual cycle. Neurology 2004;63:3513.

44 Silberstein SD, Elkind AH, Schreiber C, Keywood C. Arandomized trial of frovatriptan for the intermittentprevention of menstrual migraine. Neurology 2004;63:2619.

45 Lichten EM, Lichten JB, Whitty A, Pieper D. Theconfirmation of a biochemical marker for womenshormonal migraine: the depo-estradiol challenge test.

Headache 1996; 35:36771.46 Brandes JL. The influence of estrogen on migraine.

JAMA 2006; 295:18249.47 Sances G, Granella F, Nappi RE, Fignon A, Ghiotto N,

Polatti F et al. Course of migraine during pregnancy andpostpartum: a prospective study. Cephalalgia 2003;23:197205.

48 Facchinetti F, Sgarbi L, Piccinini F. Hypothalamic reset-ting at puberty and the sexual dimorphism of migraine.Funct Neurol 2000; 15 (Suppl. 3):13742.

49 Fordyce J. Historia febris miliaris et de hemicrania dis-sertatio. Londini: apud D. Wilson & T. Durham 1758.[WWW document]. URL http://web2.bium.univ-paris5.fr/livanc/?cote=30797&do=chapitre (accessed 21 May

2008).50 Giffin NJ, Ruggiero L, Lipton RB, Silberstein SD,

Tvedskov JF, Olesen J et al. Premonitory symptoms inmigraine. An electronic diary study. Neurology 2003;60:93540.

51 Poole CJM, Lightman SL. Inhibition of vasopressinsecretion during migraine. J Neurol Neurosurg Psychia-try 1988; 51:14414.

52 Lawrence R. Precipitating factors in migraine: a retro-spective review of 494 patients. Headache 1994; 34:21416.

53 Grinker RR. Hypothalamic functions in psychosomaticinterrelations. Psychosom Med 1939; 1:1947.

54 Burstein R, Jakubowski M. A unitary hypothesis for

multiple triggers of the pain and strain of migraine. JComp Neurol 2005; 493:914.

55 Saper CB, Scammell TE, Lu J. Hypothalamic regulationof sleep and circadian rhythms. Nature 2005; 437:125763.

56 Brodal P. Sentralnervesystemet, 4th edn. Oslo, Norway:Universitetsforlaget 2006.

57 Martinez F, Castillo J, Pardo J, Lema M, NoyaM. Catecholamine levels in plasma and CSF inmigraine. J Neurol Neurosurg Psychiatry 1993; 56:111921.

58 Ludwig J, Bartsch T, Wasner G, Baron R. Autonomicdysfunction in migraines. In: Olesen J, Goadsby PJ,Ramadan NM, Tfelt-Hansen P, Welch KMA, eds. Theheadaches, 3rd edn. Philadelphia, PA: Lippincot Will-iams & Wilkins 2006:37784.

59 Perotuka SJ. Migraine: a chronic sympathetic nervoussystem disorder. Headache 2004; 44:5364.

60 Avnon Y, Nitzan M, Sprecher E, Rogowski Z, YarnitskyD. Different patterns of parasympathetic activation inuni- and bilateral migraineurs. Brain 2003; 126:166070.

61 Kalsbeek A, Palm IF, La Fleur SE, Scheer FAJL, Perreau-Lenz S, Ruiter M et al. SCN outputs and the hypotha-lamic balance of life. J Biol Rhythms 2006; 21:45869.

62 Zurak N. Role of the suprachiasmatic nucleus in thepathogenesis of migraine attacks. Cephalalgia 1997;17:7238.

63 Solomon GD. Circadian rhythms and migraine. CleveClin J Med 1992; 59:3269.

64 Fox AW, Davies RL. Migraine chronobiology. Headache1998; 38:43641.

65 Cortelli P, Pierangeli G. Hypothalamus and headaches.Neurol Sci 2007; 28:S198S202.

66 Matharu MS. The hypothalamus, pain, and primaryheadaches. Headache 2007; 47:9638.

67 Gourineni R, Zee PC. The hypothalamus and primaryheadache disorders. Headache Curr 2005; 4:7780.

68 Alstadhaug KB. Periodicity of migraine. In: Clarke LB,ed. Migraine disorders research trends. New York: NovaScience 2007:10744.

69 Dexter JD, Wetzman ED. The relationship of nocturnalheadaches to sleep stage patterns. Neurology 1970;20:51318.

70 Dexter JD, Riley TL. Studies in nocturnal migraine.Headache 1975; 15:5162.

71 Dexter JD. The relationship between stage III + Iv + REMsleep and arousals with migraine. Headache 1979;

19:3649.72 Soriani S, Fiumana E, Manfredini R, Boari B, Battistella

PA, Canetta E et al. Circadian and seasonal variationof migraine attacks in children. Headache 2006; 46:15714.

73 Alstadhaug KB, Salvesen R, Bekkelund S. 24-hour dis-tribution of migraine. Headache 2008; 48:95100.

74 Lieving E. On megrim, sick-headache, and some allieddisorders: a contribution to the pathology of nerve-storms. London: Churchill 1873:1467.

75 Sahota P. Morning headaches in patients with sleepdisorders. Sleep Med 2003; 4:377.

76 Kelman L, Rains JC. Headache and sleep: examination ofsleep patterns and complaints in a large clinical sample

of migraineurs. Headache 2005; 45:90410.77 Alstadhaug K, Salvesen R, Bekkelund S. Insomnia and

circadian variation of attacks in episodic migraine.Headache 2007; 47:11848.

78 Lu J, Sherman D, Devor M, Saper CB. A putative flip-flop switch for control of REM sleep. Nature 2006;441:58994.

79 Dahmen N, Kasten M, Wieczorek S, Gencik M, EpplenJT, Ullrich B. Increased frequency of migraine in narco-leptic patients: a confirmatory study. Cephalalgia 2003;23:1419.

8 KB Alstadhaug

http://web2.bium.univ-paris5/http://web2.bium.univ-paris5/

7/29/2019 Hipotalam

9/9

80 Haut SR, Bigal ME, Lipton RB. Chronic disorders withepisodic manifestations: focus on epilepsy and migraine.Lancet Neurol 2006; 5:14857.

81 Casez O, Dananchet Y, Besson G. Migraine and som-nambulism. Neurology 2005; 65:13346.

82 Ressler KJ, Mayberg HS. Targeting abnormal neuralcircuits in mood and anxiety disorders: from the labo-ratory clinic. Nat Neurosci 2007; 10:111624.

83 Oedegaard KJ, Neckelmann D, Mykletun A, Dahl AA,Zwart JA, Hagen K, Fasmer OB. Migraine with andwithout aura: association with depression and anxietydisorder in a population-based study. The HUNT Study.Cephalalgia 2006; 26:16.

84 Levy MJ, Matharu MS, Meeran K, Powell M, GoadsbyPJ. The clinical characteristics of headache in patientswith pituitary tumours. Brain 2005; 128:192130.

85 Bigal ME, Lipton RB, Holland PR, Goadsby PJ. Obesity,migraine, and chronic migrainepossible mechanismsof interaction. Neurology 2007; 68:185161.

86 Guldiken B, Guldiken S, Demir M, Turgut N, Tugrul A.Low leptin levels in migraine: a case control study.Headache 2008; 48:11037.

87 Hunt SP, Pini A, Evan G. Introduction of c-fos likeprotein in spinal cord neurons following sensory stimu-lation. Nature 1987; 328:1686704.

88 Malick A, Jakubowski M, Elmquist JK, Saper CB,Burstein R. A neurohistochemical blueprint for pain-induced loss of appetite. Proc Natl Acad Sci USA2001; 98:99305.

89 Benjamin L, Levy MJ, Lasalandra MP, Knight YE,Akerman S, Classey JD et al. Hypothalamic activationafter stimulation of the superior sagittal sinus in the cat:a Fos study. Neurobiol Dis 2004; 16:5005.

90 Overem S, van Vliet JA, Lammers GJ, Zitman FG, SwaabDF, Ferrari MD. The hypothalamus in episodic braindisorders. Lancet Neurol 2002; 1:43744.

91 Peres MF, Sanchez del Rio M, Seabra ML, Tufik S,Abucham J, Cipolla-Neto J et al. Hypothalamic involve-ment in chronic migraine. J Neurol Neurosurg Psychia-try 2001; 71:74751.

92 Strittmatter M, Grauer MT, Fischer C, Hamann G,

Hoffmann KH, Blaes F, Schimrigk K. Autonomicnervous system and neuroendocrine changes in patientswith idiopathic trigeminal neuralgia. Cephalalgia 1996;16:47680.

93 Burstein R, Cliffer KD, Giesler GJ. Direct somatosensoryprojections from the spinal cord to the hypothalamusand telencephalon. J Neurosci 1987; 7:415964.

94 Burstein R, Cliffer KD, Giesler GJ. Cells of origin of thespinohypothalamic tract in the rat. J Comp Neurol 1990;291:32944.

95 Cliffer KD, Burstein R, Giesler GJ. Distributions ofspinothalamic, spinohypothalamic and spinotelencepha-lic fibers revealed by anterograde transport of PHA-L inrats. J Neurosci 1991; 11:85268.

96 Burstein R, Falkowsky O, Borsook D, Strassman A.Distinct lateral and medial projections of the spinohy-pothalamic tract of the rat. J Comp Neurol 1996;373:54974.

97 Burstein R, Yamamura H, Malick A, Strassman AM.Chemical stimulation of the intracranial dura inducesenhanced responses to facial stimulation in brainstemtrigeminal neurons. J Neurophysiol 1998; 79:96482.

98 Malick A, Burstein R. Cells of origin of the trigemino-hypothalamic tract in the rat. J Comp Neurol 1998;400:12544.

99 Vgh B, Manzano e Silva MJ, Frank CL, Vincze C, CzirokSJ, Szab A et al. The system of cerebrospinal fluid-contacting neurons. Its supposed role in the nonsynapticsignal transmission of the brain. Histol Histopathol 2004;19:60728.

100 Kalsbeek A, Palm IF, La Fleur SE, Scheer FAJL, Perreau-Lenz S, Ruiter M et al. SCN outputs and the hypotha-lamic balance of life. J Biol Rhythms 2006; 21:45869.

101 Peres MF, Zukerman E, da Cunha Tanuri F, Moreira FR,Cipolla-Neto J. Melatonin 3 mg, is effective for migraineprevention. Neurology 2004; 63:757.

102 Giordano J. The neurobiology of nociceptive and anti-nociceptive systems. Pain Physician 2005; 8:27790.

103 Goadsby PJ. Neurostimulation in primary headache syn-dromes. Expert Rev Neurother 2007; 7:17859.



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