CURRENT LITERATURE: BASIC SCIENCE
The Hypothalamus, Pain, and Primary Headaches he hypothalamus integrates a multitude of functions including endocrine and autonomic control, thermoregulation, sleep, appetite, emotional behavior and arousal, and governs the rhythmicity and timing of many body functions. Evidence is emerging from neuroimaging studies in man and animal experimental studies that the hypothalamus plays a crucial role in nociceptive processing, particularly in primary headache syndromes. This commentary focuses on the human studies implicating a role for the hypothalamus in primary headache syndromes.
EVIDENCE FOR HYPOTHALAMIC
INVOLVEMENT IN PRIMARY HEADACHE
The pathophysiologic basis of the aura and headache phases of migraine have recently been relatively well characterized. Cortical spreading depression is the basis of aura symptoms while dorsal pontine activation seems to play a fundamental role in the genesis of the headache phase. Nonetheless, the site of initiation of the migraine attack is poorly understood, though a central role for the hypothalamus has been suggested by clinical, endocrinological, and autonomic studies.
Premonitory symptoms that warn of the impending migraine aura and headache may precede the attack by up to 48 hours.
The types of symptoms reported during the premonitory phase provide us with an insight into their pathogenesis. Hypothalamic involvement has also been proposed on the basis that some migraineurs experience irritability, hunger, craving for food, difficulties with temperature control and somnolence; interestingly, a similar catalogue of symptoms is produced by lesions of the ventromedial nucleus of the hypothalamus in experimental animals.1
Other arguments for the hypothalamic initiation of attacks are the circadian rhythmicity of the onset of migraine attacks2 and the remarkable temporal relation of hormonal fluctuations and the onset of migraine in female patients (in whom migraine preferentially begins around puberty and fades after the menopause and attacks commonly occur around menstruation).3
Several endocrinological and autonomic function studies suggest involvement of the hypothalamus as well, although the interpretation of the results is not straightforward. Changes have
C 2007 the Authors
2007 American Headache Society
been found in melatonin excretion, beta-endorphin, and cortisol response to naloxone, and activation of the hypothalamus– pituitary–adrenal axis in patients with migraine, both related and unrelated to the menstrual cycle.4 Cardiovascular reflex tests, pupillometry, and sweating function suggest autonomic dysfunction between attacks.
Trigeminal Autonomic Cephalalgias.—
A central role for the hypothalamus has been implicated in the pathophysiology of the trigeminal autonomic cephalalgias
(TACs), which include cluster headache (CH), paroxysmal hemicrania (PH), and short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing (SUNCT).
Cluster Headache.—CH has a distinct circadian and circannual periodicity, with clock-like regularity of attacks, nocturnal attacks coinciding with rapid eye movement (REM) sleep, and peak and trough frequencies of cluster period onset in relation to photoperiod cues. The striking circadian and circannual periodicity seen in CH implicates a role for the suprachiasmatic nucleus of the hypothalamic gray matter, which is the area involved in the human biological clock system. Neuroendocrine studies provided the first evidence of deranged hypothalamic function in CH. It was initially demonstrated that plasma testosterone concentrations were altered during the CH period in men. Subsequently, it has been observed that there are abnormalities in the secretion of melatonin and cortisol, alterations in the secretion of luteinizing hormone