Middle East Journal of Family Medicine

M. Bashir Abiad, BS Biology

ABSTRACT

Migraine is a neurovascular disorder characterized by a unilateral mild or severe headache lasting from a few hours to as long as three days. It has been recently shown in many studies that this disorder has a firm and complicated genetic background that exposes individuals to a higher susceptibility to migraine attacks. Old theories used to focus on the vascular changes and the subsequent blood flow alterations in the brain to explain the different symptoms occurring during migraines. New theories on the other hand are shedding more light on the involvement of the nervous system in the brain, primarily the trigeminal nerve in the brain stem, considering it the primary cause for the initiation of migraine attacks. Changes in blood vessels in the brain are believed to be an epiphenomenon only.

In this article, the pathophysiology of a migraine attack is explained on the basis of the unified theory that tries to integrate all the available scientific data about migraine.

Migraine is best defined as a chronic disorder of the central nervous system. It is characterized by a series of events beginning with the abnormal over-excitement of certain nerve cells in the brain. These neurons release a pool of chemicals that stimulate the brain's blood vessels to swell (vasodilation), and create an inflammatory reaction in the affected area. As a result, the person suffers from a severe and pulsating unilateral headache, accompanied by nausea, vomiting, visual and auditory problems, tingling of the face and extremities, as well as fatigue, drowsiness and yawning^[1].

Migraine attacks may be triggered by many different factors, including hormonal changes (observed in menstrual cycles, with oral contraception or estrogen replacement therapy, which explains why nearly 74% of migraine sufferers in the United States are females^[2]). Other triggers involve dietary factors (like chocolate; alcohol; cheese; yoghurt; fermented, decayed or marinated meat and anything that may contain tyramine, a monoamine which is produced by the decarboxylation of tyrosine during fermentation or decay and that causes the release of stored monoamines (dopamine, epinephrine or norepinephrine)^[3]. Changes in sleep patterns, emotional disturbances (like excitement, fear, anxiety, anger, and stress), allergic reactions, and environmental factors (like weather changes, bright light, loud noise, certain odors and perfumes) may also trigger migraine attacks^[4]. Each person, with his/her unique genetic background, is at a certain threshold of neuronal excitability in his/her brain. In fact, specific allele mutations have been recently discovered to be involved in exposing the individual to higher risks to migraine attacks: four different missense mutations in the

_1A subunit of the P/Q - type of voltage-gated Ca²⁺ on chromosome 19 affect the release of serotonin, a vasoconstrictor, in midbrain^[5][6][7] ATP1A2 gene, found on chromosome 1q23, is also linked to migraine attacks. This gene codes for the

₂ subunit of the Na⁺/K⁺ ATPase^[8]. Moreover, the dopamine D2 receptor gene is found to be responsible also for increasing the susceptibility to migraine recurrence^[9].

When exposed to the migraine triggers listed above, the ones with low threshold (i.e. higher susceptibility to migraine attacks) will experience a short wave of neural depolarization in the brain due to the initial release of potassium and glutamate in the occipital lobe and then propagate throughout the whole cortex at a speed ranging between 3 and 6 mm/min. This wave is followed by a longer one of neural depression known as cortical spreading depression, or simply CSD^[1]. These consecutive alterations in the neural activity in the brain stimulate the vasoconstriction of specific blood vessels in the brainstem. If the decrease in the blood flow goes below a critical value, the different symptoms observed during the aura phase (e.g. blurred vision, weakness, tingling or numbness of the face and extremities) may be initiated^[10].

It should be noted that one third only of migraine sufferers pass through the aura symptoms. The rest two third, despite the electrical wave disturbances, have what we call migraine without aura because the decrease in blood flow in their brain is not so critical^[11]. Some studies have shown that the disruption of the normal electric status of the brain might affect the performance of the hypothalamus causing the different prodromal signs observed several hours (or even days) before the migraine, like mood disturbances, food cravings, drowsiness, thirst, and yawning^[12].

Once the CSD is terminated, the brain cells synthesize many vasodilators but most importantly nitric oxide (NO), which diffuses to the cortical area and stimulates the peripheral blood vessels at the meninges to swell. These vessels are highly innervated by the peripheral trigeminal nerves; also know as the trigeminal afferents. Once the stretch receptors found in the walls of the meningeal vessels are activated upon the dilation of these vessels, the trigeminal afferents will send specific sensory input to the trigeminal nucleus in the brain stem^[13]. In a pseudo-reflex pathway, motor trigeminal nerves release at their axonal terminals many neurotransmitters and neuropeptides near the dilated vessels. The most important chemicals are substance P, which is mainly responsible for mediating the pain impulses to the appropriate nociceptors in the brain, and neurokinin A which promotes protein extravasations from the blood plasma to the neighboring tissue. Both of the latter, with the neuropeptide calcitonin gene-related peptide (CGRP) induce vasodilation of more peripheral arteries, worsening the pain. Other chemicals like the vasoactive intestinal peptide (VIP), nitric oxide (NO), serotonin (5-HT), and dopamine (D) are also involved. This pool of chemicals will cause a local inflammatory reaction, termed sterile neurogenic perivascular inflammation^[13].

It is suggested as well that the thalamus plays an important role in directly stimulating the cortical pain areas situated in higher centers of the CNS, which produce pain of the headache^[11]. Note also that several aminergic brain stem nuclei are directly involved in the migraine attack. Dorsal Raphe nucleus for instance is involved in changing the levels of serotonin in the brain^[12]. This neurotransmitter is crucial for mood control, pain sensation, sexual behavior, sleep, as well as dilation and constriction of the blood vessels, which might trigger a migraine [14]. Locus Ceruleus causes changes in epinephrine level, which explains the activation of the sympathetic nervous system in the body during or around a migraine attack. This activity in the intestine causes nausea, vomiting, and diarrhea. Sympathetic activity also delays emptying of the stomach into the small intestine and thereby prevents oral medications from entering the intestine and being absorbed. The impaired absorption of oral medications is a common reason for the ineffectiveness of medications taken to treat migraine headaches. The increased sympathetic activity also decreases the circulation of blood, and this leads to pallor of the skin as well as cold hands and feet. The sensitivity to light and sound as well as blurred vision are also consequences for the increased sympathetic activity^[15].

Till now, the complete phenomenon of migraine initiation was not well understood. In fact more research and studies are required in order to reveal the whole pathway triggering this disorder. Once this stage is reached, the "perfect" treatment for migraine would be easily synthesized.