Migraine Pathophysiology

Until the 1980s, the accepted explanation for migraine attacks was the vascular theory of migraine, which suggested that migraine headache was caused by the dilation of cranial blood vessels, while the aura of migraine resulted from vasoconstriction. The vascular theory was based on four observations: (1) the only effective treatment of acute migraine at the time, ergotamine, was a potent vasoconstrictor; (2) nitroglycerin, a vasodilating agent, caused headaches; (3) the classic observation that branches of the external carotid arteries often became distended and pulsated during a migraine attack; and (4) finding that stimulation of intracranial vascular structures (but not the brain) in awake patients undergoing surgical procedures caused headache. However, this vascular theory did not appear to account for all of the elements of migraine pathophysiology.

A neurogenic theory evolved next, suggesting that the migraine aura was caused by a cortical wave of neuronal and glial depolarization, referred to as cortical spreading depression (CSD). From its cerebral cortical origin, this CSD wave spreads across the cortex at a rate of 3 to 5 mm/min, a rate similar to the estimated speed of visual aura of migraine as it progresses across the primary visual cortex. In experimental CSD, there are characteristic cerebral blood flow changes, with an initial increase in blood flow (hyperemia), followed by a decrease in blood flow (oligemia) and relative tissue hypoxia. Imaging studies using functional magnetic resonance imaging (MRI) seem to corroborate these hemodynamic changes in migraineurs during visual aura. In addition to contributing to aura, CSD may also act as a trigger for the headache pain. Experimental evidence demonstrates that CSDs may result both in activation of nociceptive second-order neurons within the medullary trigeminal nucleus caudalis and in changes within the vessel caliber of dural vessels innervated with pain-sensitive neurons. This mechanism might certainly account for activation of the headache in patients who experience the migraine aura, but would not explain headache in migraine patients without aura. It has been suggested that migraine without aura occurs when CSD takes place in noneloquent brain areas (such as the cerebellum), where depolarization is not consciously perceived; however, there is insufficient evidence to support this possibility at this time.

The headache of migraine likely arises upon activation of nociceptive neurons in the trigeminovascular system (TVS). The TVS consists of small-caliber pseudounipolar sensory neurons arising from the trigeminal ganglion and upper cervical dorsal roots and project to innervate pial vessels, dura mater, large cerebral vessels, and venous sinuses. Once activated, the neurons transmit the nociceptive information to the trigeminal nucleus caudalis of the medulla, where they synapse on second-order neurons.

From the trigeminal nucleus caudalis, neurons that are involved in localization of pain project to the thalamus and then to the sensory cortex, where pain reaches consciousness. Central signals can be modulated by projections from several sources, including the periaqueductal gray, the nucleus raphe magnus in the rostral ventromedial medulla, and by descending cortical inhibitory systems. Other activated second-order neurons within the trigeminal nucleus caudalis project to numerous subcortical nuclei and to limbic areas of the brain involved in the emotional and vegetative responses to pain.

There is ongoing debate as to whether initial activation of primary afferent neurons is necessary for the occurrence of migraine headaches. The fact that increases in measured levels of CGRP, a neuropeptide known to be released by activated first-order neurons, are observed in external jugular venous blood during migraine in humans implicates activation of primary afferents neurons. However, logically, it would seem the abnormal activation or lack of regulating inhibitory tone could result in the propensity of a migraine attack in some individuals.

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