Cortical spreading depression as a site of origin for migraine: Role of CGRP

Abstract

Premise Migraine is a complex neurologic disorder that leads to significant disability, yet remains poorly understood. Problem One potential triggering mechanism in migraine with aura is cortical spreading depression, which can activate the trigeminal nociceptive system both peripherally and centrally in animal models. A primary neuropeptide of the trigeminal system is calcitonin gene-related peptide, which is a potent vasodilatory peptide and is currently a major therapeutic target for migraine treatment. Despite the importance of both cortical spreading depression and calcitonin gene-related peptide in migraine, the relationship between these two players has been relatively unexplored. However, recent data suggest several potential vascular and neural connections between calcitonin gene-related peptide and cortical spreading depression. Conclusion This review will outline calcitonin gene-related peptide-cortical spreading depression connections and propose a model in which cortical spreading depression and calcitonin gene-related peptide act at the intersection of the vasculature and cortical neurons, and thus contribute to migraine pathophysiology.

CGRP and the Trigeminal System in Migraine

“…[22][23][24] As described in a recent review, some investigators hold that cortical spreading depression (CSD) can initiate a migraine attack. 25 This view is not inconsistent with studies showing excitation of cortical and subcortical structures preceding or concomitant with migraine attacks, and supports the concept that migraine is due in part to cortical hyperexcitability. 26,27 However, whether CSD has a role in the initiation of a migraine attack has not been demonstrated definitively, and the role of CSD in migraine remains a topic of vigorous debate.…”

“…As described in a recent review, some investigators hold that cortical spreading depression (CSD) can initiate a migraine attack . This view is not inconsistent with studies showing excitation of cortical and subcortical structures preceding or concomitant with migraine attacks, and supports the concept that migraine is due in part to cortical hyperexcitability .…”

“…CSD in animal studies in induced by damaging stimuli applied to the cortex. Clinically, CSD may be observed with traumatic brain injury or infarct, and is associated with progression of ischemia and of brain injury, and worsening of patient outcomes . There is no evidence of injury or trauma to cause CSD in migraine .…”

“…Clinically, CSD may be observed with traumatic brain injury or infarct, and is associated with progression of ischemia and of brain injury, and worsening of patient outcomes . There is no evidence of injury or trauma to cause CSD in migraine . Spontaneous CSD was inferred in one study, where functional magnetic resonance imaging (fMRI) performed in a patient with migraine with aura induced by strenuous exercise and photostimulation showed changes in blood oxygenation level‐dependent (BOLD) signal suggestive of CSD …”

“…25 There is no evidence of injury or trauma to cause CSD in migraine. 25,120 Spontaneous CSD was inferred in one study, where functional magnetic resonance imaging (fMRI) performed in a patient with migraine with aura induced by strenuous exercise and photostimulation showed changes in blood oxygenation level-dependent (BOLD) signal suggestive of CSD. 121 Also, in a study of patients with migraine using magnetoencephalographic waveforms, patients with migraine with aura induced by a visual stimulus showed spreading depression-like neuroelectric event.…”