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...

Cortical spreading depression (CSD) evokes a large cerebral blood flow (CBF) increase in normal rat brain. In contrast, in focal ischemic penumbra, CSD-like periinfarct depolarizations (PID) are mainly associated with hypoperfusion. Because PIDs electrophysiologically closely resemble CSD, we tested whether conditions present in ischemic penumbra, such as tissue hypoxia or reduced perfusion pressure, transform the CSD-induced CBF response in nonischemic rat cortex. Cerebral blood flow changes were recorded using laser Doppler flowmetry in rats subjected to hypoxia, hypotension, or both. Under normoxic normotensive conditions, CSD caused a characteristic transient CBF increase (74±7%) occasionally preceded by a small hypoperfusion (À4±2%). Both hypoxia (pO 2 45 ± 3 mm Hg) and hypotension (blood pressure 42 ± 2 mm Hg) independently augmented this initial hypoperfusion (À14±2% normoxic hypotension; À16±6% hypoxic normotension; À21 ± 5% hypoxic hypotension) and diminished the magnitude of hyperemia (44±10% normoxic hypotension; 43±9% hypoxic normotension; 27±6% hypoxic hypotension). Hypotension and, to a much lesser extent, hypoxia increased the duration of hypoperfusion and the DC shift, whereas CSD amplitude remained unchanged. These results suggest that hypoxia and/or hypotension unmask a vasoconstrictive response during CSD in the rat such that, under nonphysiologic conditions (i.e., mimicking ischemic penumbra), the hyperemic response to CSD becomes attenuated resembling the blood flow response during PIDs.

Cutting spinal nerves just distal to the dorsal root ganglion (DRG) triggers, with rapid onset, massive spontaneous ectopic discharge in axotomized afferent A-neurons, and at the same time induces tactile allodynia in the partially denervated hindlimb. We show that secondary transection of the dorsal root (rhizotomy) of the axotomized DRG, or suppression of the ectopia with topically applied local anesthetics, eliminates or attenuates the allodynia. Dorsal rhizotomy alone does not trigger allodynia. These observations support the hypothesis that ectopic firing in DRG A-neurons induces central sensitization which leads to tactile allodynia. The question of how activity in afferent A-neurons, which are not normally nociceptive, might induce allodynia is discussed in light of the current literature.