In reference to the extracranial vessels, Iversen and associates, by means of ultrasonography, documented a dilatation of the superior temporal artery on the side of the migraine during the headache period. The same dilatation in the middle cerebral arteries has been inferred from observations with transcranial Doppler insonation. The complication of cerebral infarction is also in keeping with a vascular hypothesis, but it involves only a tiny proportion of migraineurs. The vascular hypothesis for migraine must be regarded as uncertain, but, clearly, there is frequently a reduction in posterior cortical blood flow during an aura. What is not established is whether the blood flow changes are fundamental or simply the result in a reduction in cortical activity. The original opinion expressed by Wolff that a vascular element is responsible for the cranial pain of migraine is also unconfirmed.
The relationship between the vascular changes and evolving neurologic symptoms of migraine are noteworthy. Lashley, who as noted earlier (see Fig. 9-1) plotted his own visual aura, calculated that the cortical impairment progressed at a rate of 2 to 3 mm/min over the surface of the brain. The site of activity putatively begins in one occipital lobe and extends forward slowly (2.2 mm/min) as a wave of “spreading oligemia” that does not respect arterial boundaries (Lauritzen and Olesen). Both of these events are intriguingly similar to the above-mentioned phenomenon of “spreading cortical depression,” observed by Leão in experimental animals. He demonstrated that a noxious stimulus applied to the rat cortex was followed by vasoconstriction and slowly spreading waves of inhibition of the electrical activity of cortical neurons, moving at a rate of approximately 3 mm/min. Lauritzen and Olesen attribute both the aura and spreading oligemia to the spreading cortical depression, and considerable work since then has corroborated this idea. These observations, however, apply only to the aura.
An alternative, but not necessarily exclusive hypothesis links the aura and the painful phase of migraine through a neural mechanism originating in the trigeminal nerve as proposed by Moskowitz. This is based on the innervation of extracranial and intracranial vessels by small unmyelinated fibers of the trigeminal nerve that subserve both pain and autonomic functions (the “trigeminovascular” complex). This model provides an explanation for migraine pain as originating in the trigeminal ganglion. Activation of these fibers releases substance P, calcitonin gene-related peptide (CGRP), and other peptides into the vessel wall, which serves to sensitize the trigeminal system to the pulsatility of cranial vessels, and to increase their permeability, thereby promoting an inflammatory response. The small molecules released from nerve endings adjacent to the cortex would then incite spreading depression in this model. Against this hypothesis is the occurrence of headache as often as not on the side opposite the side of generation of the aura and the lack of clinical effect of drugs that work in this experimental model. Most likely, both neural and vascular mechanisms are operative and they interact.
In part to address the action of the serotonin agonist drugs on migraine (see below), a body of evidence has been assembled that serotonin (5-HT) acts as a humoral mediator in the neural and vascular components of migraine headache. Serotonin is discharged from platelets at the onset of headache and the headache is reduced by the injection of 5-HT. This led to the development by Humphrey of sumatriptan, which acted selectively on 5-HT1B/D receptors so as to reduce side effects. This was the forerunner of the large group of “triptans.” More recently, nitric oxide generated by endothelial cells has been implicated as the cause of the pain of migraine headache, but the reason for its release and the relationship to changes in blood flow is unclear.