Microemboli may link spreading depression, migraine aura, and patent foramen ovale.
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 (10 microm) or cholesterol crystals (<70 microm) 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.


CONCLUSIONS
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.
Stroke and Neurovascular Regulation Laboratory, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USA.
Ala
A
Nozari
Ergin
E
Dilekoz
Inna
I
Sukhotinsky
Thor
T
Stein
Katharina
K
Eikermann-Haerter
Christina
C
Liu
Yumei
Y
Wang
Matthew P
MP
Frosch
Christian
C
Waeber
Cenk
C
Ayata
Michael A
MA
Moskowitz
D000818:Animals; D002560:Cerebrovascular Circulation / Q000502:physiology*; D013181:Cortical Spreading Depression / Q000502:physiology*; D004195:Disease Models, Animal; D004569:Electroencephalography / Q000379:methods; D004617:Embolism / Q000150:complications*; D054092:Foramen Ovale, Patent / Q000209:etiology*; D007839:Functional Laterality / Q000502:physiology; D008279:Magnetic Resonance Imaging / Q000379:methods; D051379:Mice; D008810:Mice, Inbred C57BL; D008833:Microcirculation / Q000502:physiology*; D020325:Migraine with Aura / Q000209:etiology*; D009460:Neurologic Examination / Q000379:methods