It has a one-year prevalence of 15-18% worldwide ( 536, 539), if both episodic and chronic migraine are included, and has a huge financial burden on global economies, costing the United States $19.6 ( 757) and the European Union €27 billion ( 43) annually. Unfortunately, its ranking is increasing with time ( 620, 827). Migraine is a severe and disabling brain condition ( 340), listed as the sixth most disabling disorder globally by the World Health Organization, and the most disabling of all neurological disorders ( 303). Investment in understanding migraine has been very successful and leaves us at a new dawn, able to transform its impact on a global scale, as well as understand fundamental aspects of human biology. Understanding the biology of migraine through careful bench-based research has led to major classes of therapeutics being identified: triptans, serotonin 5-HT 1B/1D receptor agonists gepants, calcitonin gene-related peptide (CGRP) receptor antagonists ditans, 5-HT 1F receptor agonists, CGRP mechanisms monoclonal antibodies and glurants, mGlu 5 modulators with the promise of more to come.

In the first, premonitory, phase that precedes headache, brain stem and diencephalic systems modulating afferent signals, light-photophobia or sound-phonophobia, begin to dysfunction and eventually to evolve to the pain phase and with time the resolution or postdromal phase. When: migraine attacks emerge due to a disorder of brain sensory processing that itself likely cycles, influenced by genetics and the environment. How: the now classical trigeminal durovascular afferent pathway has been explored in laboratory and clinic interrogated with immunohistochemistry to functional brain imaging to offer a roadmap of the attack. It could be said there are three questions: why, how, and when? Why: migraine is largely accepted to be an inherited tendency for the brain to lose control of its inputs. The pathophysiology of migraine has emerged from a historical consideration of the “humors” through mid-20th century distraction of the now defunct Vascular Theory to a clear place as a neurological disorder. Plaguing humans for more than two millennia, manifest on every continent studied, and with more than one billion patients having an attack in any year, migraine stands as the sixth most common cause of disability on the planet.

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