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.
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