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Contemporary Concepts of Migraine Pathogenesis
K.M.A. Welch
Posted: June 2005  
Neurology 2003;61(Suppl 4):S2-S8

The pathogenesis of migraine is incompletely understood. Recent discoveries have shed light on the neuronal events mediating both the aura and the headache phases of migraine, identifying a cerebral cortical origin of migraine aura, susceptibility to attacks based on cortical hyperexcitability, and headache originating in the trigeminovascular system and its central projections. Abnormal modulation of brain nociceptive systems, at first transient but becoming permanent with continuing illness and, predisposing to central sensitization, may explain the prolonged headache of the migraine attack and the shift of the migraine phenotype from episodic to chronic headache. Migraine attacks might also originate in abnormal nociceptive neuromodulator centers in the brainstem.

The Interictal Status in Migraine: The concept that migraine attacks originate in the brain and can be triggered under various conditions argues in favor of a threshold that governs the incidence of attacks. The nature of the final common pathway with which these factors interact probably constitutes the true cause of migraine. In this regard, transient or persistently exaggerated excitability of neurons in the cerebral cortex, especially the occipital region, has received strong consideration. Transcranial magnetic stimulation (TMS) of the occipital cortex required to produce phosphene generation was significantly lower in patients with migraine who experienced aura between their headaches than it was in normal controls. Using the same technology, but with different paradigms, other studies have added consistent data that support cortical hyperexcitability, although not all agree. Furthermore, Battelli et al. were the first to report a significantly lower phosphene threshold for TMS delivered over V5 in migraineurs, indicating that hyperexcitability of the visual cortex in migraine goes beyond the primary visual cortical area (V1). Further corroboration was found in a study in which there was an association between reduced excitability and the clinical effectiveness of valproic acid. Observation of phosphenes is a subjective experience, however, and is one drawback of these studies. Nevertheless, visual activation monitored by magnetoencephalography and functional MRI-BOLD has confirmed abnormal excitability of widespread regions of the occipital, occipitotemporal, and occipitoparietal cortex, with consequent triggering of the neuroelectric accompaniments of aura symptoms.

Headache Mechanisms: As described above, migraine headache may originate from dilatation of the large cranial vessels and dura mater, which are innervated by the trigeminal nerve as part of the trigeminovascular system. The vasodilator peptides calcitonin gene-related peptide (CGRP), substance P, and neurokinin A are found in the cell bodies of trigeminal neurons. CGRP has been implicated most in the headache of migraine. This vasoactive peptide is present in nonmyelinated fibers in the trigeminal ganglion, and CGRP-like immunoreactivity has been identified in regions of the trigeminal nuclei known to receive primary afferent terminals. The sensory role of CGRP in the trigeminal system is unclear but may involve vascular nociception. Stimulation of the ganglion released CGRP in cats and humans, and CGRP (but not substance P) was detected in jugular venous blood during a migraine attack. Furthermore, IV infusion of CGRP into susceptible individuals elicited migraine-like headache. The neurogenic inflammation theory of migraine proposed that CGRP released from trigeminal sensory afferents causes vasodilatation and plasma extravasation from dural vessels, a point of controversy because it is unclear whether such effects occur in humans during migraine. Triptans, acting as 5-HT agonists, block these responses. Although triptans are effective, they are not invariably so, and their profile of adverse events limits their use in patients with vascular risk factors or established cardiovascular disease. It remains to be determined if specific CGRP antagonists are effective in alleviating migraine attacks. Accordingly, the search continues for new drug targets.

Neuromodulation, central sensitization, and headache: Patients frequently offer evidence for central sensitization of the trigeminal system during migraine attacks, such as pain returning on head movement or scalp pressure after attacks have subsided, allodynia of the head, and even allodynia and pain of the upper trunk and limbs that suggests supraspinal origins of sensitization. Central sensitization may account for the severe, prolonged pain of migraine headache. Assessment of allodynia during a migraine attack by Burstein et al. has confirmed sensitization of the trigeminal system at a second- or third-order neuron level. Studies using neurophysiologic tools, e.g., a noniceptive-sensitive blink reflex, have proved equally substantive of the concept. Abnormal supraspinal pain modulation is in keeping with dysfunction of the PAG and aberrance of its balanced nociceptive facilitatory or inhibitory functions. The critical importance of central sensitization has been underlined most recently, again from work of Burstein et al., by a report that triptans may decrease in efficacy after allodynia is established, emphasizing the importance of early acute treatment.