Pathophysiology

Several theories on the pathogenesis of migraine exist. A clinically relevant model of migraine pathophysiology may explain several phenomena that both clinicians and patients have noted:

Dietary, sleep, and hormonal changes can trigger a migraine.
Migraine has a circadian rhythm similar to several diseases of vasoconstriction, such as myocardial infarction, angina pectoris, and ischemic stroke.
Sleep is effective in aborting many migraines.
Cerebral blood flow is decreased during migraine aura.
Both generalized systemic vasoconstriction and local cerebrovascular vasodilation occur on the side where head pain occurs.
Platelets release serotonin during a migraine attack.
Levels of calcitonin gene-related peptide (CGRP), and probably substance P, are elevated during a migraine attack.

Some migraine models use the following concepts to explain the above phenomena.

Similar to other internal organs, the brain has a pain system to signal tissue injury. The trigeminovascular system acts as a warning system, causing migraines to help "protect" the brain against insults such as ischemia, toxins, and intrinsic disease, just as angina pectoris "protects" the heart against ischemia.
Neuronal and chemical activators – including prostaglandins, serotonin, and histamine – can stimulate the trigeminal nerve. Migraine triggers work either directly to alter these chemical mediators (e.g., fluctuating estrogen levels altering prostaglandins during menses), or indirectly through neural mediators (e.g., rapid eye movement [REM] sleep eliminating serotonin release from the dorsal raphe nucleus).
When stimulated, the trigeminal nerve releases substance P and CGRP into dural and meningeal blood vessels. The release of substance P causes the degranulation of mast cells and the attraction of polymorphonuclear leukocytes. This leads to mast cell release of histamine and platelet release of serotonin, with consequent vasodilation and exudation of plasma into the tissues. The resulting inflammation and swelling of the blood vessels represents the so-called sterile arteritis that H. Wolff described half a century ago.
The neurogenic inflammation and release of substance P causes both distention of cranial arteries and headache pain. It is likely that nitric oxide mediates the vasodilation and may also act as a nociceptive neurotransmitter.
Trigger factors either have direct actions on vasomotor tone (e.g., tyramine in certain foods) or mediate neurochemical release (e.g., sleep alters serotonin release from the dorsal raphe nucleus; stress modifies catecholamine levels). Platelet changes, neurochemical mediators, and ischemia can also trigger the trigeminovascular system.
Increases in platelet activity and catecholamine levels and in serotonin release from the dorsal raphe nucleus occur in the early morning. Because these changes may trigger the trigeminovascular system, either directly or through ischemia, this might at least partially explain the circadian rhythm of migraine.
REM sleep inhibits the release of serotonin from the dorsal raphe nucleus, and sleep may abort a migraine attack by inhibiting the serotonin-mediated stimulation of the trigeminovascular system.

Common Theories of Migraine Pathogenesis

Theories on the pathogenesis of migraine include:

the vascular theory
the cortical spreading depression theory
the neurovascular hypothesis
the serotonergic abnormalities hypothesis
the integrated hypothesis.

The Vascular Theory

H. Wolff developed the vascular theory of migraine pathogenesis during the 1940s and 1950s. According to this theory, migraine is a vasospastic disorder that is initiated by vasoconstriction in the cranial vasculature. The vasoconstriction stage appears to be associated with migraine aura.

Following the early vasoconstrictive stage, intracranial or extracranial blood vessels dilate. Whereas most of the brain is insensitive to pain, meningeal blood vessels show a high level of innervation. Thus, blood vessel dilation activates the trigeminal sensory nerves that surround the meningeal blood vessels, causing pain. Activation of trigeminal nerves also causes the release of vasoactive neuropeptides that further contribute to dilation and worsen pain.

Studies have documented the occurrence of oligemia during the aura phase of a migraine, and an increase in blood flow during the headache phase. Moreover, when a patient with a headache is given a vasodilator such as a nitrate, the headache intensifies, whereas when a patient is given a vasoconstrictor such as a 5-HT agonist, the headache is usually alleviated. These studies lend support to the vascular theory.

However, some researchers have questioned whether the measured decreases in cerebral blood flow during the aura phase are sufficient to cause the aura symptoms (e.g., visual disturbances) that some migraineurs experience. Furthermore, vasodilation alone cannot explain the local swelling and tenderness of the head that generally accompany migraine.

The Cortical Spreading Depression Theory

Cortical spreading depression (CSD) is a relatively short-lasting wave of depolarization that spreads across the surface of the brain, moving from the back (occipital region) of the cerebral cortex toward the front at about 3-5 mm/minute (see figure below). This electrical phenomenon can be induced in animals with noxious stimuli, and is frequently referred to in the literature as the "spreading depression of Leao."

Cortical Spreading Depression

Adapted from Lauritzen [1987]; with permission.
Click on image for animation/larger version.

According to the theory, CSD begins with a brief wave of excitation, followed by a prolonged period of neuronal depression, which is associated with disturbances in nerve cell metabolism and regional reductions in blood flow. It has been suggested that migraine aura results from this spreading depression that suppresses neuronal activity as it passes forward over the cerebral cortex. During migraine without aura, cerebral blood flow abnormalities usually are not seen, but recent data suggest that this may not always be the case.

Although CSD has been demonstrated only in animals, support for the CSD theory comes from observations that, in patients who have migraine with aura, a gradual spread of reduced blood flow that mimics the rate of progression of CSD in animals can be measured during the aura phase. One researcher who mapped his own scintillation scotomas noticed a relationship between the development and spread of the visual disturbance and the organization of the visual cortex of the brain. Thus, the aura symptoms were consistent with a wave of intense excitation developing in the visual cortex, followed by a longer period of inhibition.

The Neurovascular Hypothesis

Fibers from the trigeminal nerve innervate blood vessels in the meninges, the extracranial arteries, and those in the circle of Willis. These nerve fibers contain nociceptors that are capable of generating pain impulses, and the endings of these nerve fibers contain peptide neurotransmitters (see figure below).

The Trigeminovascular System

Click on image for larger version.

The neurovascular hypothesis proposes that either migraine triggers or CSD can activate trigeminal nerve axons, which then release neuropeptides (such as substance P, neurokinin A, and CGRP) from axon terminals near the meningeal and other blood vessels. Substance P and neurokinin A cause vasodilation and promote the extravasation of plasma proteins and fluid from nearby meningeal blood vessels. Although CGRP does not promote plasma extravasation, it is a potent vasodilator. Together, these neuropeptides produce an inflammatory response in the area around the innervated blood vessels. This response is termed sterile neurogenic perivascular inflammation.

The neuropeptides may also sensitize nerve endings, providing a mechanism for sustaining the headache. When activated, the trigeminal nerve also transmits pain impulses to the trigeminal nucleus caudalis, which relays pain impulses to higher centers of the brain.

According to the neurovascular theory, vasodilation is not the cause of migraine headaches but is an accompanying phenomenon attributable to trigeminal nerve activation. Although the cause of this activation is not known, it may be due to ionic and metabolic disturbances in brain function, such as those associated with CSD. It has also been proposed that abnormal activity in brain stem sensory nuclei may cause antidromic activation of trigeminal sensory pathways.

The Serotonergic Abnormalities Hypothesis

Observations that both plasma and platelet levels of serotonin fluctuate during a migraine attack suggest that serotonin may be involved in the pathogenesis of migraine. When platelets are activated, they aggregate and release serotonin, thus increasing the plasma serotonin level. An increase in plasma serotonin level would be expected to cause vasoconstriction, whereas a decrease in serotonin would promote vasodilation.

Platelet serotonin levels may drop precipitously during the headache phase of migraine. Also, urine levels of serotonin and its metabolites rise during headaches, suggesting that there is a large release of serotonin during such attacks. Moreover, drugs such as reserpine that cause the release and depletion of serotonin from tissue storage sites may precipitate migraine headaches.

An initial surge in plasma serotonin levels may cause constriction of cerebral blood vessels and a reduction in cerebral blood flow. If the blood flow is sufficiently reduced, migraine aura may result. A subsequent depletion and drop in serotonin levels may then lead to a marked dilation of extracranial and intracranial arteries, precipitating migraine pain.

Several questions regarding the serotonin abnormalities hypothesis remain unanswered. It seems unlikely that changes in blood serotonin levels are solely responsible for the development of migraine. For instance, global changes in plasma serotonin levels do not explain the unilateral nature of migraine pain, and serotonin levels in patients with migraine may remain depressed long after the headache has resolved. It may be, however, that changes in plasma serotonin levels reflect more important disturbances in brain serotonin levels.

One brain stem structure that has a high concentration of serotonin receptors is the dorsal raphe nucleus. This nucleus contains many serotonin-secreting neurons that terminate on cerebral blood vessels and various other brain areas that are involved in the production of migraine symptoms. It has been suggested that the raphe nucleus, which is responsive to changes in serotonin levels, may serve as a "migraine generator."

The Integrated Hypothesis

The integrated hypothesis of migraine pathogenesis is an attempt to consolidate various theories and explain several observations related to migraine pain. The following video is an animation demonstration video. According to this theory, triggers such as stress, glare, noise, the patient's internal clock, the dilation of the internal or external carotid arteries, or other factors may activate specific centers in the brain stem.

One such center, the locus ceruleus, causes changes in epinephrine levels. Another center, the dorsal raphe nucleus, affects serotonin levels in the brain.

Constriction of cerebral blood vessels may cause a localized deficiency in blood flow, provoking CSD, which may, in turn, stimulate trigeminovascular fibers, eliciting neurogenic inflammation and headache pain.

Nerve fibers from the locus ceruleus, the dorsal raphe nucleus, and the trigeminal nerve cause a stimulation of cranial nerves that dilate both cerebral and extracranial blood vessels. The dilation of meningeal vessels contributes to pain generation.

The locus ceruleus also sends fibers to higher centers of the cerebral cortex, where it influences a person’s state of arousal and awareness, and descending projections interact with the body’s pain control mechanisms.

Likewise, the dorsal raphe nucleus sends multiple fibers to blood vessels and upward toward the cerebral cortex. These serotonin-secreting fibers help regulate sleep and neuroendocrine functions. Other connections are made with lower brain stem areas and with the hypothalamus.

A disruption in the normal function of the hypothalamus may be responsible for prodromal signs and symptoms of migraine such as mood changes, food cravings, drowsiness, thirst, and yawning. These signs and symptoms may occur several hours, or even as long as 1 day, before headache pain begins.

Reference

Lauritzen M. Cerebral blood flow in migraine and cortical spreading depression. Acta Neurol Scand Suppl. 1987;76:1-40.

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