Microemboli may link spreading depression, migraine aura, and patent foramen ovale.

Migraine headaches are among the most common and debilitating conditions and occur in 10 to 12% of the general population.1 Migraine with aura accounts for 15% of cases, and the aura is characterized most commonly by visual or somatosensory symptoms that often anticipate the onset of headache by 20 to 40 minutes. Certain patients with migraine auras are at greater risk for stroke.2,3 Despite the multiplicity of potential mechanisms linking migraine aura and stroke,4 experimental evidence linking the triggering of migraine aura attacks to microvascular dysfunction is lacking. Cortical spreading depression (CSD) may be important to this link. CSD is a slowly propagating intense neuronal and glial depolarization that spreads at a characteristic rate of 3 to 5mm per minute. It is a property of all mammalian cortices, but varies in susceptibility between the rodent and more resistant human brain.5 A number of high- and low-resolution brain imaging studies have led to the conclusion that CSD causes migraine aura.6–8 For example, during visual aura, a slowly propagating wave of cerebral blood oxygenation level-dependent (BOLD) signal change was recorded in calcarine cortex in a migraineur using near continuous high-resolution functional magnetic resonance imaging (MRI).6 The observed perturbations of the BOLD signal were retinotopically congruent with the patient’s visual percept, and displayed several CSD characteristics (eg, typical blood flow response and velocity of propagation). In experimental animals, CSD triggers specific gene programs to precondition the brain and render it more resistant to subsequent tissue injury.9 In patients, slowly propagating depolarizations closely resembling CSD have now been well documented following ischemic stroke,10 intracerebral hematoma, subarachnoid hemorrhage, and brain trauma,11,12 further suggesting that human brain can sustain slowly spreading depolarizations very much like CSD. A pioneer of the vascular theory of migraine, Harold G. Wolff proposed that the neurological symptoms of migraine aura were caused by cerebral vasoconstriction and ischemia.13 Similarly, Van Harreveld and Stamm ascribed CSD to ischemia resulting from a spreading wave of vasoconstriction.14 Indeed, several vascular risk factors have been implicated in attacks of migraine aura.15 For example, migraine has been identified in several studies as an independent risk factor for ischemic stroke.3 Migraine with aura and stroke are also reportedly more common in patients with right-to-left cardiac shunts, usually in the setting of a patent foramen ovale (PFO),16 or less commonly, pulmonary arteriovenous malformations,17 although the strength of this relationship has been questioned recently.18 The mechanism for this association is not clear, but paradoxical embolization has been proposed as a possible explanation. To establish a mechanism linking migraine aura to blood components, blood vessels and intracardiac or arteriovenous shunts, we examined whether small microemboli injected into the carotid artery could evoke CSD in otherwise normal mouse brain. We hypothesized that the injection of minute amounts of air, polystyrene microspheres, or cholesterol crystals into carotid artery could trigger CSD, and that CSD in this context could develop without requisite tissue damage. This work was reported previously in preliminary form.19