Microemboli May Link Spreading Depression, Migraine Aura, and Patent Foramen Ovale

Overview

Journal Ann Neurol

Specialty Neurology

Date 2010 Mar 13

PMID 20225282

Citations 121

Authors

Ala Nozari

Ergin Dilekoz

Inna Sukhotinsky

Thor Stein

Katharina Eikermann-Haerter

Christina Liu

Yumei Wang

Matthew P Frosch

Christian Waeber

Cenk Ayata

Michael A Moskowitz

Affiliations

Soon will be listed here.

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 (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.

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.

Citing Articles

Stroke etiology and white matter burden in women with and without migraine.

Wilms A, van der Weerd N, van Harten T, Linstra K, van Os H, de Boer I J Headache Pain. 2025; 26(1):37.

PMID: 39972322 PMC: 11841335. DOI: 10.1186/s10194-025-01975-8.

Headaches attributed to cranial and cervical artery dissections.

Doukhi D, Debette S, Mawet J J Headache Pain. 2025; 26(1):28.

PMID: 39915731 PMC: 11800537. DOI: 10.1186/s10194-025-01958-9.

Effects of patent foramen ovale in migraine: a metabolomics-based study.

Dong B, Li X, Zhang L, Liang G, Zheng W, Gui L J Physiol. 2025; 603(4):809-835.

PMID: 39838589 PMC: 11826071. DOI: 10.1113/JP286772.

Short-term efficacy of right-to-left shunt closure in patients with vestibular migraine.

Lang Y, Zhang S, Xie P, Wang Y, Wang C, Wang W Front Neurol. 2024; 15:1500918.

PMID: 39734627 PMC: 11672335. DOI: 10.3389/fneur.2024.1500918.

Field-testing the explicit diagnostic criteria for transient ischemic attack: a diagnostic accuracy study.

Scutelnic A, Auf der Maur S, Branca M, Beyeler M, Horvath T, Bucke P J Neurol. 2024; 272(1):79.

PMID: 39680237 PMC: 11649740. DOI: 10.1007/s00415-024-12733-2.

References

Moskowitz M . The neurobiology of vascular head pain. Ann Neurol. 1984; 16(2):157-68. DOI: 10.1002/ana.410160202. View

Woods R, Iacoboni M, Mazziotta J . Brief report: bilateral spreading cerebral hypoperfusion during spontaneous migraine headache. N Engl J Med. 1994; 331(25):1689-92. DOI: 10.1056/NEJM199412223312505. View

Lamy C, Giannesini C, Zuber M, Arquizan C, Meder J, Trystram D . Clinical and imaging findings in cryptogenic stroke patients with and without patent foramen ovale: the PFO-ASA Study. Atrial Septal Aneurysm. Stroke. 2002; 33(3):706-11. DOI: 10.1161/hs0302.104543. View

Post M, Letteboer T, Mager J, Plokker T, Kelder J, Westermann C . A pulmonary right-to-left shunt in patients with hereditary hemorrhagic telangiectasia is associated with an increased prevalence of migraine. Chest. 2005; 128(4):2485-9. DOI: 10.1378/chest.128.4.2485. View

STEINER M, Di Tullio M, Rundek T, Gan R, Chen X, Liguori C . Patent foramen ovale size and embolic brain imaging findings among patients with ischemic stroke. Stroke. 1998; 29(5):944-8. DOI: 10.1161/01.str.29.5.944. View

Eikermann-Haerter K, Dilekoz E, Kudo C, Savitz S, Waeber C, Baum M . Genetic and hormonal factors modulate spreading depression and transient hemiparesis in mouse models of familial hemiplegic migraine type 1. J Clin Invest. 2008; 119(1):99-109. PMC: 2613474. DOI: 10.1172/JCI36059. View

Michiels J, Berneman Z, Schroyens W, Koudstaal P, Lindemans J, Neumann H . Platelet-mediated erythromelalgic, cerebral, ocular and coronary microvascular ischemic and thrombotic manifestations in patients with essential thrombocythemia and polycythemia vera: a distinct aspirin-responsive and coumadin-resistant arterial.... Platelets. 2006; 17(8):528-44. DOI: 10.1080/09537100600758677. View

Olesen J, Thomsen L, Iversen H . Nitric oxide is a key molecule in migraine and other vascular headaches. Trends Pharmacol Sci. 1994; 15(5):149-53. DOI: 10.1016/0165-6147(94)90075-2. View

Del Sette M, Angeli S, Leandri M, Ferriero G, Bruzzone G, Finocchi C . Migraine with aura and right-to-left shunt on transcranial Doppler: a case-control study. Cerebrovasc Dis. 1998; 8(6):327-30. DOI: 10.1159/000015875. View

10.

Post M, Thijs V, Herroelen L, Budts W . Closure of a patent foramen ovale is associated with a decrease in prevalence of migraine. Neurology. 2004; 62(8):1439-40. DOI: 10.1212/01.wnl.0000120756.25236.37. View

11.

HANINGTON E, Jones R, Amess J, Wachowicz B . Migraine: a platelet disorder. Lancet. 1981; 2(8249):720-3. DOI: 10.1016/s0140-6736(81)91049-7. View

12.

Andersen A, Friberg L, Olsen T, Olesen J . Delayed hyperemia following hypoperfusion in classic migraine. Single photon emission computed tomographic demonstration. Arch Neurol. 1988; 45(2):154-9. DOI: 10.1001/archneur.1988.00520260040017. View

13.

Shammas N, Dippel E, Harb G, Egts S, Jerin M, Stoakes P . Interatrial septal defect closure for prevention of cerebrovascular accidents: impact on recurrence and frequency of migraine headaches. J Invasive Cardiol. 2007; 19(6):257-60. View

14.

Etminan M, Takkouche B, Caamano Isorna F, Samii A . Risk of ischaemic stroke in people with migraine: systematic review and meta-analysis of observational studies. BMJ. 2004; 330(7482):63. PMC: 543862. DOI: 10.1136/bmj.38302.504063.8F. View

15.

Strong A, Fabricius M, Boutelle M, Hibbins S, Hopwood S, Jones R . Spreading and synchronous depressions of cortical activity in acutely injured human brain. Stroke. 2002; 33(12):2738-43. DOI: 10.1161/01.str.0000043073.69602.09. View

16.

Diener H, Tfelt-Hansen P, Dahlof C, Lainez M, Sandrini G, Wang S . Topiramate in migraine prophylaxis--results from a placebo-controlled trial with propranolol as an active control. J Neurol. 2004; 251(8):943-50. DOI: 10.1007/s00415-004-0464-6. View

17.

Jensen R, Brinck T, Olesen J . Sodium valproate has a prophylactic effect in migraine without aura: a triple-blind, placebo-controlled crossover study. Neurology. 1994; 44(4):647-51. DOI: 10.1212/wnl.44.4.647. View

18.

Dinia L, Roccatagliata L, Bonzano L, Finocchi C, Del Sette M . Diffusion MRI during migraine with aura attack associated with diagnostic microbubbles injection in subjects with large PFO. Headache. 2007; 47(10):1455-6. DOI: 10.1111/j.1526-4610.2007.00948.x. View

19.

Matsushima K, Schmidt-Kastner R, Hogan M, Hakim A . Cortical spreading depression activates trophic factor expression in neurons and astrocytes and protects against subsequent focal brain ischemia. Brain Res. 1998; 807(1-2):47-60. DOI: 10.1016/s0006-8993(98)00716-1. View

20.

Friberg L, Olsen T, Roland P, Lassen N . Focal ischaemia caused by instability of cerebrovascular tone during attacks of hemiplegic migraine. A regional cerebral blood flow study. Brain. 1987; 110 ( Pt 4):917-34. DOI: 10.1093/brain/110.4.917. View