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

Abstract

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...

Imaging Reveals the Focal Area of Spreading Depolarizations and a Variety of Hemodynamic Responses in a Rat Microembolic Stroke Model

“…Because TTC staining may not be sensitive enough to detect microinfarcts, 20 5-mm-thick paraffin sections of the TTC-stained slices were obtained, stained with hematoxylin/eosin (H&E), and examined with optical microscopy. The sections were digitally recorded with a microscope slide scanner (Zeiss Mirax Midi Slide Scanner, Carl Zeiss MicroImaging GmbH, Jena, Germany).…”

“…The present study focused on the first hour after embolization, during which the achieved perfusion deficit may cause initial microinfarctions, 18 rather than obvious, extensive infarcted regions. 20 …”

“…It is possible that microinfarcts too small for detection with imaging were associated with SD events. 20 However, supportive evidence suggests that the focus of ischemia-induced SD does not necessarily fall near the ischemic core or the thin penumbra embracing it, 28 and milder ischemic insults are able to trigger SD. 29 Finally, tissue at SD foci displaying a transient shift in membrane potential was involved in the propagation of subsequent SDs in our experiments, which indicates Type of red IOS signature Rank of SD in sequence functional recovery from the primary ionic imbalance.…”

Diffusion-weighted lesions in acute ischaemic stroke patients with migraine

“…CSD is the probable biological substrate of migrainous aura, and ischaemia is a known trigger of CSD (12)(13)(14). To investigate the role of CSD in the migrainestroke association, we aim to investigate whether acute ischaemic stroke (AIS) patients with migraine have a different pattern of diffusion weighted imaging (DWI) lesions compared to patients without migraine.…”

Migraine in the era of precision medicine

“…Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a monogenic-inherited form systemic vasculopathy linked to mutations in the Notch3 gene (located on chromosome 19p13.2-p13.1), which encodes a cell surface receptor (53). The incidence of migraine with aura in CADASIL is five times greater compared with the general population (54,55).…”