Rethinking migraine with aura: Why cortical spreading depolarization (depression), not aura, causes headaches

Cortical spreading depolarization (depression) underlies migrainous aura and is posited to cause its headache. At times, aura may start before headache, auras may start at the same time as, or shortly after headache onset, or sometimes without any headache at all. We suggest that the extent of spread and not the spread limited to eloquent cortex, is the key variable in the genesis of headache. Consistent with this notion, a first human case studied electrophysiologically showed that cortical spreading depolarization spreads extensively and silently We propose a Buildup Hypothesis to explain headache generation in migraine with aura. Buildup occurs because cortical spreading depression releases noxious chemicals from cortical cells that accumulate in tissues and cerebrospinal fluid to reach levels sufficient to trigger pial afferents and cause pain. The extent of silent (or relatively silent) spread determines significant buildup. This Buildup Hypothesis helps to explain (1) typical and shorter latencies between end of aura and headache onset (approximately 0–20 minutes) and (2) why headache may not develop after aura (insufficient buildup), and also addresses temporal discrepancies such as headaches starting before an aura (i.e. subclinical spread with buildup in advance of aura). Hence, aura and headache are distinct consequences of cortical spreading depolarization.