Objective-Patent foramen ovale and pulmonary arteriovenous shunts are associated with serious complications such as cerebral emboli, stroke, and migraine with aura. The pathophysiological mechanisms that link these conditions are unknown. We aimed to establish a mechanism linking microembolization to migraine aura in an experimental animal model. Methods-We introduced particulate or air microemboli into the carotid circulation in mice to determine whether transient microvascular occlusion, insufficient to cause infarcts, triggered cortical spreading depression (CSD), a propagating slow depolarization that underlies migraine aura.Results-Air microemboli reliably triggered CSD without causing infarction. Polystyrene microspheres (10μm) or cholesterol crystals (<70μm) triggered CSD in 16 of 28 mice, with 60% of the mice (40% of those with CSD) showing no infarcts or inflammation on detailed histological analysis of serial brain sections. No evidence of injury was detected on magnetic resonance imaging examination (9.4T; T2 weighted) in 14 of 15 selected animals. The occurrence of CSD appeared to be related to the magnitude and duration of flow reduction, with a triggering mechanism that depended on decreased brain perfusion but not sustained tissue damage.Interpretation-In a mouse model, microemboli triggered CSD, often without causing microinfarction. Paradoxical embolization then may link cardiac and extracardiac right-to-left shunts to migraine aura. If translatable to humans, a subset of migraine auras may belong to a spectrum of hypoperfusion disorders along with transient ischemic attacks and silent infarcts. 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][7][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 displaye...

Background Migraine is an independent risk factor for stroke. Mechanisms underlying this association are unclear. Familial hemiplegic migraine (FHM), a migraine subtype that also carries an increased stroke risk, is a useful model for common migraine phenotypes because of shared aura and headache features, trigger factors, and underlying glutamatergic mechanisms. Methods and Results Here, we show that FHM type 1 (FHM1) mutations in CaV2.1 voltage-gated Ca2+ channels render the brain more vulnerable to ischemic stroke. Compared to wild-type, two FHM1 mutant mouse strains developed earlier onset of anoxic depolarization and more frequent peri-infarct depolarizations, associated with rapid expansion of infarct core on diffusion-weighted MRI and larger perfusion deficits on laser speckle flowmetry. Cerebral blood flow required for tissue survival was higher in the mutants, leading to infarction with milder ischemia. As a result, mutants developed larger infarcts and worse neurological outcomes after stroke, which were selectively attenuated by a glutamate receptor antagonist. Conclusions We propose that enhanced susceptibility to ischemic depolarizations akin to spreading depression predisposes migraineurs to infarction during mild ischemic events, thereby increasing the stroke risk.