Familial hemiplegic migraine type 1 (FHM1) is an autosomal dominant subtype of migraine with aura that is associated with hemiparesis. As with other types of migraine, it affects women more frequently than men. FHM1 is caused by mutations in the CACNA1A gene, which encodes the α 1A subunit of Ca v 2.1 channels; the R192Q mutation in CACNA1A causes a mild form of FHM1, whereas the S218L mutation causes a severe, often lethal phenotype. Spreading depression (SD), a slowly propagating neuronal and glial cell depolarization that leads to depression of neuronal activity, is the most likely cause of migraine aura. Here, we have shown that transgenic mice expressing R192Q or S218L FHM1 mutations have increased SD frequency and propagation speed; enhanced corticostriatal propagation; and, similar to the human FHM1 phenotype, more severe and prolonged post-SD neurological deficits. The susceptibility to SD and neurological deficits is affected by allele dosage and is higher in S218L than R192Q mutants. Further, female S218L and R192Q mutant mice were more susceptible to SD and neurological deficits than males. This sex difference was abrogated by ovariectomy and senescence and was partially restored by estrogen replacement, implicating ovarian hormones in the observed sex differences in humans with FHM1. These findings demonstrate that genetic and hormonal factors modulate susceptibility to SD and neurological deficits in FHM1 mutant mice, providing a potential mechanism for the phenotypic diversity of human migraine and aura.

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...

SUMMARY Peri-infarct depolarizations (PIDs) are seemingly spontaneous spreading depression-like waves that negatively impact tissue outcome in both experimental and human stroke. Factors triggering PIDs are unknown. Here, we show that somatosensory activation of peri-infarct cortex triggers PIDs when the activated cortex is within a critical range of ischemia. We show that the mechanism involves increased oxygen utilization within the activated cortex, worsening the supply-demand mismatch. We support the concept by clinical data showing that mismatch predisposes to PIDs in human stroke as well. Conversely, transient worsening of mismatch by episodic hypoxemia or hypotension also reproducibly triggers PIDs. Therefore, PIDs are triggered upon supply-demand mismatch transients in metastable peri-infarct hot zones due to increased demand or reduced supply. Based on the data, we propose that minimizing sensory stimulation and hypoxic or hypotensive transients in stroke and brain injury would reduce PID incidence and their adverse impact on outcome.