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Abstract

Migraine is a complex brain disorder where several neuronal pathways and neurotransmitters are involved in the pathophysiology. To search for a specific anatomical or physiological defect in migraine may be futile, but the hypothalamus, with its widespread connections with other parts of the central nervous system and its paramount control of the hypophysis and the autonomic nervous system, is a suspected locus in quo. Several lines of evidence support involvement of this small brain structure in migraine. However, whether it plays a major or minor role is unclear. The most convincing support for a pivotal role so far is the activation of the hypothalamus shown by positron emission tomography (PET) scanning during spontaneous migraine attacks. A well-known theory is that the joint effect of several triggers may cause temporary hypothalamic dysfunction, resulting in a migraine attack. If PET scanning had consistently confirmed hypothalamic activation prior to migraine headache, this hypothesis would have been supported. However, such evidence has not been provided, and the role of the hypothalamus in migraine remains puzzling. This review summarizes and discusses some of the clues.

Keywords

Hypothalamus migraine pathophysiology nociception triggering factors

Introduction

Migraine is characterized by episodes of headache and hypersensitivity to sensory stimuli. The prevailing theory is that migraine is a brain disorder, and that migraine aura is caused by the electrophysiological phenomenon cortical spreading depression (CSD) (1). Whether CSD triggers migraine pain is more controversial, but not beyond the realms of possibility (2). Brainstem activation during migraine attacks detected by neuroimaging has raised the possibility of a primary dysfunction in the midbrain and/or dorsal pons (3, 4). Thus, CSD may be an epi- or secondary phenomenon to perturbed sensory modulation in the branstem pathways that control afferent inputs (5).

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

The hypothalamus

The name ‘hypothalamus’ (Gr. hypo = below, thalamus = room, inner chamber) was introduced in the late 19th century (6). It denotes a small brain structure at the base of the brain. The hypothalamus weighs only 4–5 g and is only 4 cm³ in size (7). The anatomy is complex and borders are rather arbitrary. It is common to distinguish between the medial and the lateral hypothalamus. The former contains several distinct nuclei and may be divided into three regions (8) (Fig. 1): the anterior (chiasmatic or preoptic region), the cone-shaped tuberal region, and the posterior (mamillary) region. The lateral hypothalamus (LHT) is a diffuse structure where fibres from the medial forebrain bundle (MFB) are passing. Despite some distinct nuclei in hypothalamus, short association fibres abound, and there are widespread connections to other parts of the central nervous system. It is very difficult to study hypothalamic functions both clinically and experimentally. To regard specific nuclei as independent reflex centres for specialized functions would probably be incorrect.

Figure 1

Approximate topography of the hypothalamic nuclei based on Young and Stanton (9). The medial hypothalamus is commonly divided into an anterior, a medial, 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, paraventricular nucleus. 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 lateral maxillary nucleus is not shown.)

The hypothalamus has a multitude of functions. In the broadest sense, it maintains homeostasis by controlling the endocrine system, coordinating the activity of the sympathetic and parasympathetic nervous systems, and integrates psyche and soma. Insight into its role in organizing circadian rhythms and regulation of arousal has increased considerably in recent years. The hypothalamus also plays an important role in nociceptive processing.

It is beyond the scope of this review to discuss the anatomy of the hypothalamus in detail, but with respect to the subsequent text the following is worth mentioning.

The anterior part of hypothalamus contains the supraoptic nucleus and the paraventricular nucleus (PVN) that synthesize vasopressin and oxcytocin, and the master circadian clock, the suprachiasmatic nucleus (SCN). PVN has also been called the ‘master controller’ of the autonomic system. The tuberal part contains the luteinizing hormone-releasing hormone (LHRH) pulse generator that controls the menstrual cycle, and the arcuate nucleus which is, inter alia, involved in pain modulation (9). The posterior hypothalamic area is a poorly defined region that merges caudally with the mesencephalic reticular formation. Together with the caudal part of the lateral hypothalamic area and the mamillary bodies, this constitutes the posterior region. The mamillary bodies are the hypothalamic components of Papez circuit, a multinuclear pathway that plays a role in emotion (10).

Historical/anecdotal aspects

The first to suggest an important role of the hypothalamus in migraine is uncertain. In 1933 Henriksen treated 42 patients with the hypophysis extract Pituitrin (aqueous extract of the posterior lobe of the pituitary containing vasopressin and oxytocin), of whom 37 allegedly improved in their ailments (11). Daro et al. reported the same positive effect after treating a female migraineur in 1940 and another headache patient in 1959 (12). Later in the 1960s, migraine authorities made their contribution (13, 14). Pearce expressed it quite succinctly (14):

A periodic central disturbance of hypothalamic activity could account for the periodicity of the migraine attacks, and could also be related to emotional disturbances mediated by pathways from the limbic system to the hypothalamus.

A more recent report presented two patients who were promptly relieved from their migraine headache by intravenous oxytocin (15).

The central histaminergic system, the tuberomamillary complex (TMC) located in the posterior/lateral hypothalamus, is an area of recent interest in the pathophysiology of primary headaches (16–19). The TMC probably participates in several functions such as modulation of arousal state, circadian rhythms, stress, analgesia, cerebral circulation, etc. (7). A common statement about antihistamines in the treatment of migraine is that they are ineffective in the prevention of migraine headaches. However, first-generation H₁ receptor antagonists are often recommended in paediatric and pregnant patients for treating symptoms of migraine, such as nausea and vomiting. Most of these antihistamines are lipophilic compounds that readily penetrate into the brain, and cause both anti-nausea and sedative effects (20). However, there may be other central effects that may be beneficial in migraine. Two antihistamines (cinnarizine and cyproheptadine) that cross the blood–brain barrier and cause sedation (21) have been reported to be efficacious in migraine (22–24). Their efficacy has been ascribed other actions than antihistaminergic. Interestingly, meclizine, an antihistamine with a chemical structure similar to cinnarizine but with no effect on calcium channels, 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 in control of nociception (26). Electrical stimulation [deep brain stimulation (DBS)] of the hypothalamus, similar to stimulation of the raphe nucleus and the periaqueductal grey, reduces pain in experimental animals (27). The hypothalamus contains several opioid peptides, and the analgesia achieved by electrostimulation is traditionally presumed to be caused by the opioid system (28). The oxytocinergic mechanisms may however also be involved in long-term antinociception (29). In fact, several peptides associated with the hypothalamus, such as angiotensin II, vasopressin, calcitonin, somatostatin and others, may have antinociceptive effects (28). For example, somatostatin injected into the posterior hypothalamus of rats seems to have an antinociceptive effect on input from dural and facial structures (30). A novel growth hormone-releasing peptide, ghrelin, seems to reduce the pain threshold in mice (31). Interestingly, it has been found to decrease serotonin release in the dorsal raphe nucleus. Alteration of brain histamine levels has also been shown to influence nociception, and both the H₁ and H₂ receptors are probably involved (32). Even the H₃ receptor has been considered a potential new drug target in migraine (33), as have the orexin receptors (34). The potential role of vasopressin in migraine was reviewed a few years ago (35), and the orexinergic system recently (36).

As regards primary headaches, antinociception may perhaps be mediated by direct hypothalamic–trigeminal connections (37). It is almost orthodox to regard cluster headache a primary hypothalamic dysfunction and the effect of DBS of the posterior hypothalamus in this disorder as specific (38), but this is still not proven. Stimulation that may affect the LHT would influence axons in the MFB, and functional imaging has shown hypothalamic activation not only in several trigeminal autonomic cephalalgias (TACs), but also in migraine (39).

Features of migraine consistent with hypothalamic involvement

One of the main arguments why the explanation of migraine should be sought in hypothalamic networks is the sexual dimorphism of migraine. Migraine is a ‘female disorder’, with three times the prevalence of men after puberty (40), and it is probably the transition to puberty that causes this gender difference (41). In fact, migraine manifests for the first time at menarche in one-third of affected women (42), and the relative risk of having a migraine attack on days −2 to +3 of menstruation has been estimated to be about twice the risk of having an attack at other times of the month (43). Menstrually associated migraine is probably related to the decline in oestrogen that occurs at menstruation (44, 45), but the evidence for menstrual migraine prevention is scarce for oestrogen (46). It is a clear clinical experience that migraine is affected by pregnancy, as confirmed in prospective studies (47). As expressed by Fachinetti, the explanation of the sexual dimorphism of migraine might be sought in hypothalamic networks related to LHRH secretion (48). A number of hypothalamic sexually dimorphic structures have been found. The most prominent is the interstitial nucleus of the anterior hypothalamus-1, which is also called the sexually dimorphic nucleus of the preoptic area.

Another weighty argument for hypothalamic involvement in migraine is premonitory symptoms that have been recognized for centuries (49). Up to several hours before the migraine aura and the migraine headache, many patients experience vague symptoms like hunger, thirst, lassitude, tiredness, yawning and, on some occasions, a sense of oppression, desire to micturate, etc. By using an electronic diary system Giffin et al. showed that 97 selected patients were able to predict 72% of the attacks that were experienced in a 3-month period based on symptoms believed to represent the prodromal phase of migraine (50). Given the central role of the hypothalamus in maintaining homeostasis, one may claim that symptoms may reflect hypothalamic dysfunction that precedes a migraine attack. A significant decrease in urinary vasopressin associated with marked diuresis and natriuresis during migraine, but not prior to migraine headache, has been shown (51). However, given the multitude of precipitating factors in migraine, stress being the most common (52), symptoms may also reflect a normal hypothalamic response to different trigger factors. Stress may be defined as the physiological response to the perception of major threats or demands (10), and a pivotal role of the hypothalamus in psychosomatic interrelations has been acknowledged for decades (53). It seems that the main part of the extended amygdala (the bed nucleus of stria terminalis) with its connections to the PVN may mediate long-lasting behavioural responses during sustained stress. These responses persist for a long time after the termination of stress, which may perhaps explain why migraine may be triggered both during and after stress (54).

The role of the hypothalamus in regulating arousal in general has been scrutinized (55), and, as expressed by Brodal, ‘stress is a stimulus that increases arousal—with appurtenant EEG changes, increased attention … activation of part of the autonomic nervous system’, etc. (56). Compared with patients suffering from stress that was not related to headache, migraineurs had lower levels of noradrenalin in plasma and cerebrospinal fluid during attacks in one study (57), but studies of the autonomic nervous system in migraine are conflicting (58). The majority of studies, however, seem to support a sympathetic hypofunction (59). Evidence also tends to support hyperactivity of cranial parasympathetic nerves, via the trigeminal-parasympathetic reflex (60). Parasympathetic symptoms such as facial flushing, lacrimation and nasal stuffiness may accompany migraine attacks. The involvement of the parasympathetic system may also cause the well-known vasodilation of meningeal blood vessels.

In view of conflicting data, an interesting opinion of Kalsbeek and co-workers is that the major role of the SCN is control of the sympathetic/parasympathetic balance in autonomic nervous activity, and that a not well-entrained biological clock would predispose to diseases of modern life (61). In 1997 Zurack proposed that temporary dysfunction of the SCN could be the cause of migraine attacks (62). Actually, the circadian temporal pattern of migraine, with attacks occurring more frequently during the night and the early morning hours (63, 64), has been considered by some as strong indirect evidence for a pivotal role of the SCN in migraine pathophysiology (65–67). However, we may have been led astray by observations that reflect the exception 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 migraine to rapid eye movement (REM) and deep sleep (stages II and IV) (69–71). However, nocturnal migraine, having the majority of attacks during the night, is probably a minority phenomenon in general, and the circadian patterns of migraine strongly indicate a protective effect of sleep (72, 73) (Fig. 2).

Figure 2

The 24-h distribution of migraine attacks. The upper histogram shows the 24-h distribution of migraine attacks in a paediatric population (72) and the lower histogram shows the equivalent in an adult female population (73). A protective effect of sleep in migraine seems obvious.

Sleep is in fact excellent treatment for attacks, an observation made clearly by the 19th century neurologists (74). It is well known that patients with sleep disorders are prone to have morning headaches (75), as are probably patients with both chronic (76) and episodic (77) migraine. At the end of a sleep period, in the process of waking up, the TMC starts to fire, and histaminergic neurons have been proposed to be involved in the triggering of early-morning migraine (54). Triggering factors such as food and sleep deprivation may increase the activity of hypocretinergic neurons of the LHT, and these neurons may also be involved in the triggering of a migraine attack (54). Instead of regarding sleep as a common precipitator of migraine, we have to ask why sleep protects against attacks.

Migraine comorbidity and hypothalamic dysfunction

An alluring hypothalamic flip-flop switch mechanism that can explain the fast transitions between the waking state and sleep, and between REM and non-REM sleep, has been proposed (78). Principally, this mechanism is easy to understand and makes an excellent basis for the understanding of narcolepsy, but perhaps also for other episodic brain disorders such as migraine and cluster headache. The increased prevalence of migraine in narcolepsy (79), epilepsy (80) and somnambulism (81) at least supports that migraine is an arousal-related disorder. The strong association between migraine and mood and anxiety disorders, where hypothalamic neural circuits most certainly are involved (82), is also well documented (83). Headache associated with pituitary tumours is common, and the majority are migraine-like (84).

An association between migraine and obesity could implicate hypothalamic dysfunction in appetite regulation and energy homeostasis. Migraineurs do not have a higher body mass index than the normal population. However, an association between obesity and migraine attack frequency and chronic migraine has been shown (85). One recent study showed significantly lower levels of the protein leptin in a cohort of migraineurs compared with controls (86). Leptin is an adipose-derived hormone that mediates negative feedback to the hypothalamus, and causes reduction in body weight (7).

Findings in experimental models that support hypothalamic involvement in migraine

Fos protein immunoactivity can be used as a marker of nociception (87). Stimulation of the dura mater, a sort of modelling the pain in migraine, in rats produces Fos expression in the ventromedial, paraventricular and dorsomedial hypothalamic nuclei (88). Stimulation of the superior sagittal sinus in cats leads to increased Fos expression in the supraoptic and posterior hypothalamic nuclei (89).

Evidence for a pivotal hypothalamic role in migraine?

Hypothalamic dysfunction in both episodic (90) and chronic (91) migraine has been postulated based on deviation from the normal circadian patterns of hormones such as prolactin, cortisol and melatonin. In the only study of chronic migraine, the majority of patients suffered from insomnia, and the hypothalamus is certainly involved in sleep disorders. Similar neuroendocrine changes compatible with hypothalamic dysfunction have also been shown in cluster headache (90) and in trigeminal neuralgia (92), illustrating the lack of specificity in these neuroendocrine deviations.

Hypothalamic activation in spontaneous migraine attacks was recently shown for the first time by using positron emission tomography (PET) (39) (Fig. 3). This study shows that the hypothalamus is involved relatively early in the migraine attack. Hypothalamic activation may be secondary to the trigeminal pain, and to prove a pivotal role in generating an attack similar studies have to show consistent hypothalamic activation prior to the headache phase.

Figure 3

Hypothalamic activation in migraine. The picture is adapted from Denuelle et al. (39) with permission. The positron emission tomography (PET) images taken during a migraine attack show hypothalamic activation (at the point of intersection). 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.

To complete the story

Demonstrating enhanced or impaired activity in a neuroanatomical part of a complex network involved in migraine does not of course necessarily prove a ‘migraine generator’ or a specific ‘migraine defect’. However, the study of Denuelle et al. has shown that hypothalamic functions and networks have to be explored further to understand migraine fully. The interplay between hypothalamus, the trigeminovascular system and autonomic nuclei is essential in this, and Burstein and co-workers have made a substantial contribution to this understanding (37, 54, 88, 93–98).

Burstein and Jakubowski have proposed that various triggers of migraine activate different brain areas, especially limbic and hypothalamic, that impinge on the preganglionic parasympathetic neurons in the superior salivatory nucleus, which in turn activates postganglionic parasympathetic neurons in the sphenopalatine ganglion resulting in vasodilation and activation of meningeal nociceptors. The latter activates the trigeminovascular system, the fundamental process of migraine pain. In turn, ascending trigeminovascular projections reach and alter hypothalamus and limbic structures to mediate the accompanying symptoms of migraine (54). An example is loss of appetite common in migraine, and brief noxious dural stimulation has been shown to suppress food intake in rats. This effect is probably mediated via trigeminohypothalamic neurons (88). The theory is well founded, but why these mechanisms are unique to migraine is not clear.

Conclusions and remarks

With its extensive and multifarious functions in the brain, the hypothalamus is most certainly involved in migraine pathophysiology, but its exact role has still not been clarified. Several systems are probably involved in the construction and release of attacks. Lines of indirect evidence link several parts of the hypothalamus to migraine, both prior to, during and after the headache phase, but no evidence for a specific hypothalamic dysfunction or structural abnormality in migraine exists. A major hurdle in our understanding is the lack of experimental models that allow us to study distinct hypothalamic functions in a complex setting, which migraine in the highest degree is.

Current hypotheses on migraine and the role of the hypothalamus lack specificity. Several disorders are postulated to be of hypothalamic origin, and a common denominator in many of these is the episodic nature. An interesting view is that a compromised hypothalamic system is unable to stabilize an inherently unstable network and cause the transition from normal state to a state of illness (90). An acquired susceptibility to migraine attacks due to modern life (61) is not inconceivable. With respect to its role in the maintenance of homeostasis, it is plausible to suspect that the hypothalamus plays an important role in the start of an attack. In the future, patients who are able to predict their migraine attacks based on probable hypothalamic symptoms should be PET scanned when attacks are suspected. More experimental research should be done to find out how trigger factors exert their influence. The role of the circumventricular organs of the brain (areas strongly connected to the hypothalamus and important in maintenance of homeostasis (99)) has for example not quite been determined. In view of migraine as an arousal related disorder, more studies exploring the association between migraine, sleep and the circadian system should be done. The periodicity of migraine indicates that the master biological clock influences migraine attack susceptibility, but a pivotal role has not been proven. One previous open-label study of melatonin, a hormone that plays an important role in modulating the activity of the SCN and the circadian system via the hypothalamic–pineal axis (7, 100), has shown effects that certainly warrant a placebo-controlled study (101). Several systems associated with arousal and circadian rhythms like the orexinergic and the histaminergic may also perhaps be targets for future drugs for the treatment of migraine.

Its direct and hormonally mediated pain modulating role (102) links the hypothalamus automatically to a painful condition such as migraine. Whether neurostimulation of hypothalamic grey matter exerts only a pure analgesic effect, or exerts other effects that are specific for TACs, is still unclear (103), but it is reason to believe that migraine also could respond to such treatment. One can not exclude that attacks could be triggered directly by the hypothalamus, or that there could be inadequate modulation of other brain functions. Interestingly, pain-induced release of opioids from the periaqueductal grey and norepinephrine from the magnocellular nuclei act at the hypothalamus to produce increased levels of induced nitric oxide (iNO), which produces vasodilation within the hypothalamic median eminence and activates the hypothalamus–pituitary–adrenal system (102). NO-based mechanisms have long been suspected in migraine pathophysiology, and the effects need not be only vascular (34).

Finally, a coherent picture of the pathophysiology of migraine can not be given. Attempts at synthesis tend to ignore the role of the hypothalamus, but such an approach is hardly fruitful in the future understanding and prevention of migraine.

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Migraine and the Hypothalamus

Abstract

Keywords

Introduction

The hypothalamus

Historical/anecdotal aspects

Modulation of nociceptive processing

Features of migraine consistent with hypothalamic involvement

An arousal-related disorder?

Migraine comorbidity and hypothalamic dysfunction

Findings in experimental models that support hypothalamic involvement in migraine

Evidence for a pivotal hypothalamic role in migraine?

To complete the story

Conclusions and remarks

References