commentaries

Deciphering migraine
Takahiro Takano and Maiken Nedergaard
Division of Glial Disease and Therapeutics, Center for Translational Neuromedicine, Department of Neurosurgery, University of Rochester, Rochester, New York, USA.

Migraine is an episodic headache disorder affecting as many as 10% of people worldwide. Familial hemiplegic migraine (FHM) is an autosomal dominant subtype of severe migraine accompanied by visual disturbances known as aura. Migrainous aura is caused by cortical spreading depression (CSD) a slowly advancing wave of tissue depolarization in the cortex. More than half of FHM cases are caused by mutations in the CACNA1A gene, which encodes a neuronal Cav2.1 Ca2+ channel, resulting in increased Ca2+ flow into dendrites and excessive release of the excitatory neurotransmitter glutamate. In this issue of the JCI, Eikermann-Haerter et al. show that transgenic mice with FHM-associated mutations in Cacna1a have increased susceptibility to CSD compared with wild-type animals, likely due to augmentation of excitatory neurotransmission (see the related article beginning on page 99). Additional as-yet-undefined channel mutations may similarly render the migraine brain more susceptible to the initiation of CSD, with implications not only for the genesis of migraine but also for the hypoxic injury that accompanies its worst manifestation, complicated migraine.
Cortical spreading depression as a trigger of migraine pain Writtenaccountsofmigrainearenearlyas oldaswritingitself.Descriptionsofheadaches,datingtoroughly3000BCE,have been found in the ruins of the ancient Sumeriancivilization.Whenpeoplelacked the understanding of the human body thatmodernmedicinegrantsus,migraine painwasascribedtothewillofevilspirits ormalevolentgodsdoctorsofthetime recommendedcranialtrepanationasaway toreleaseunholyforces.Intheearlyseventeenthcentury,Europeancliniciansfirst proposedthevascularhypothesis,which long dominated our views of migraine. Patientsdescriptionsofthepulsatingcharacterofmigrainepainledtotheconceptthat thevasculaturemightplayacentralrolein thesevereheadachetypicalofmigraine(1). ItwastheCanadianpsychologistPeter Milnerwho,in1958,firstnotedthestrikingsimilaritiesbetweentheprogression of migraine aura and cortical spreading depression (CSD). CSD is a self-propagatingwaveoftissuedepolarizationthat migrateswithoutalossindepolarization
Conflict of interest:Theauthorshavedeclaredthatno conflictofinterestexists. Nonstandard abbreviations used:BOLD,bloodoxygenleveldependent;CACNA1A,voltage-gatedCav2.1 Ca2+channel,a1Asubunit;CSD,corticalspreading depression;FHM,familialhemiplegicmigraine. Citation for this article:J. Clin. Invest.119:1619 (2009).doi:10.1172/JCI38051.
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amplitudeandisfollowedbyaprolonged periodofsuppressedneuralactivity(2). Milnersawtheconnectionbetweenthis and the migraine aura, because it was known that the scintillating scotomata (oftenmanifestingasflashesoflightina geometricpatternthatslowlymoveacross thevisualfield)thatprecedeandaccompanymigrainepainpropagateatarateof about3mm/minthroughthevisualcortex (3).ItisnowgenerallyacceptedthatCSD constitutesthebiologicalbasisofmost,if notall,typesofmigraine.Approximately 30%ofmigrainepatientsexperiencethis aura(4).TheideathatCSDistheendogenoustriggerofmigrainewasinitiallymet withconsiderableskepticism;onearticle ofthetimecalledthistheoryingenious, ifabsurd(quotedinref.5).Oneobvious issuenotedwasthatthebrainitselfisnot capableofsensingpain.Thus,howmight atransientwaveofcorticaldepolarization giverisetotheprolongedstateofpainthat clearly involves the vasculature? Insight camefromMoskowitzandcoworkers,who showed that CSD induces long-lasting changesinextracranialbloodflow,including dilatation of the middle meningeal arteryandextravasationofplasmaprotein (6). In short, CSD disrupted the bloodbrainbarrier,resultinginMMP9-dependentpathwaymediatedextravasationof blood-bornefactors,whichinturnactivatedthenociceptivenerveafferentfibers aroundmeningealvessels(6)(Figure1).

Additional pathways, including those involving gap junctions, cytokines, and NOrelease,maycontributetotheactivationoftrigeminalganglionnerveafferents andtotheprolongedpainassociatedwith migraineheadaches(7,8).Migrainewithoutauramayresultfromadvancementof CSDwavesinregions(suchascerebellum) wherethetissuedepolarizationisnotperceivedbythepatient. TheinitialskepticismsurroundingCSD asanendogenoustriggerofmigrainepain hasvanishedinrecentyears,becausefunctionalMRIimagingofchangesinblood oxygen leveldependent (BOLD) signal haveshownthatthevisualauraofmigraine istemporallylinkedtoaslowlyadvancing wave of BOLD signal, which propagates across the visual cortex. The pattern of changesofBOLDsignalsapatientexperiencedduringvisualauraprovedidentical tothosethatwereobservedinexperimentallyelicitedCSD(9).Additionalevidence wasobtainedbymagnetoencephalography, whichdocumentedthatvisualscotomata wereaccompaniedbyslowchangesinthe cortical magnetic field, and these were indistinguishablefromthoserecordedduringCSD(10).Animportantquestiontherebyarose:Whatisthenatureofthetrigger forspontaneouswavesofCSD,antecedent tooraccompanyingamigraineepisode? Experimentally,strongfocalstimulationis neededtoevokeCSD.Variousapproaches havebeenused,includinginsertinganeedle intotheexposedcortex,electricalstimulation,ortopicalapplicationofhighK+concentrations or glutamate agonists (e.g., NMDA, a-amino-3-hydroxy-5-methyl-4isoxazolepropionicacid[AMPA])(11).It isalsoknownthatmultiplewavesofCSD oftenarespontaneouslyelicitedinthesettingofacuteneurologicalinjury,including strokeorheadtrauma(12).Interestingly, theCSDwaveslastlongerintheischemic brain,andthefrequencywithwhichthey aregeneratedcorrelateswiththedegreeof ischemicdamage(13).However,strokeor headtraumaisnotresponsiblefortheCSD wavesinpatientswithmigraine,makingit difficulttoexplainhowandwhyCSDisinitiatedintheabsenceoffocalstimulation.

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Figure 1
The link between CSD and migraine pain. CSD is most often initiated in the occipital cortex of patients with visual migraine aura. It is believed that CSD is ignited by local elevation of extracellular K+ levels in pockets of intense excitatory transmission. When K+ levels reach a critical threshold of 1012 mM, a self-propagating CSD wave is initiated and advances across the cortex with a slow velocity of 3 mm/min. The threshold for CSD initiation is reduced in FHM patients with mutations in the Cav2.1 Ca2+ channel because the higher Ca2+ level in dendrites facilitates glutamate release and thereby increases the likelihood that K+ levels will reach the CSD threshold. A combination of stress and food intake may be sufficient to ignite CSD in patients with FHM, whereas stronger stimulation is required in the rest of the population. The lower diagram depicts the cortical events linking CSD to migraine pain. The high extracellular K+ level at the edge of the CSD wavefront is key for wave propagation. K+ is normalized within minutes, but the restoration of normal membrane potential of neurons and glial cells is a high energydemanding process. The cortical tissue experiences a minutes-lasting period of severe reduction of tissue O2 tension (hypoxia) during CSD because O2 consumption transiently exceeds the vascular supply of O2. This hypoxia has several consequences: (a) Neurons exhibit severe morphological distortions, swelling, and transient loss of dendritic spines. Normal dendritic structures are reestablished 1520 minutes later, coinciding with the reappearance of a normal EEG pattern. This hypoxic phase is followed by prolonged vasoconstriction and reduction of local blood flow. (b) The CSD wave activates MMP9, resulting in opening of the blood-brain barrier (BBB) and extravasation of plasma protein. The leakage of blood-borne factors activates nociceptive afferent neurons from trigeminal ganglion innervating meningeal arteries, connecting to trigeminal nucleus caudalis, triggering the migraine pain. (c) CSD triggers preconditioning an endogenous mechanism of neuroprotection that raises ischemic tolerance.

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commentaries
Strong genetic component of migraine Analysisofgeneticdatafrompatientswith familial hemiplegic migraine (FHM), an autosomaldominantsubtypeofmigraine with aura associated with hemiparesis (weakeningorparalysisofonesideofthe body),hasinrecentyearsproventobea powerfultooltodeterminewhyCSDtypicallymanifestsinpatientswithmigraines. FHMisaheterogeneousgeneticdisease,but upto50%ofthepatientshaveamutation intheCACNA1Agene,whichencodesthe a1Asubunitoftheneuronal,voltage-gated Cav2.1Ca2+channel(14).Cav2.1channels areprimarilylocatedinpresynapticterminalsandareimportantregulatorsofneurotransmitterreleaseinexcitatorysynapses (7).Ananalysisofthesingle-channelpropertiesof8typesofmutantCav2.1channels reportedinindividualswithFHMshowed thatchannelactivationincerebellargranulecellswasshiftedtolowervoltagesasa resultofallmutations,resultinginagreater influx of Ca2+ in cerebellar granule cells (15).Althoughthefunctionalsignificance ofthesechangesintheintactbrainisnot completely understood, a likely scenario isthattheincreasedCa2+influxaugments releaseoftheneurotransmitterglutamate fromexcitatoryneuronsinFHMpatients, thusincreasingthelikelihoodoftriggering CSD.Infact,inaknock-inmousemodel carryingtheR192QmutationinCacna1a (thesamemutationobservedinindividuals withFHM),theanimalsexhibitedareduced thresholdforexperimentallyelicitedCSD; in addition, the waves propagated faster onceevoked(16). The study by Eikermann-Haerter and coworkers in this issue of the JCI sheds lightonseveralkeyaspectsofthebasicbiologyofmigraineheadaches(17).Theauthors describewhatisbelievedtobeanovelphenotypeintransgenicmiceexpressingthe R192Q or S218L mutations in Cacna1a, bothofwhichareassociatedwithhuman FHM.PatientswiththeR192Qmutation sufferfromFHMonly,whereastheS218L mutationisassociatedwithnotonlysevere migrainebutalsoriskofdevelopingexcessive edema in the setting of minor head injury(18).Eikermann-Haerteretal.show thatbothmutationsdecreasedthethresholdforelicitingCSDinmice,whileincreasingitsrateofpropagation,andthissusceptibilitywasmodulatedbyalleledosage(i.e., homozygotes>heterozygotes>wild-type). Bothmutationsloweredthethresholdfor theCav2.1channelopeningandprolonged
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channelinactivation,buttheS218Lmutationwasassociatedwithmoreseverealterationsinbothchannelactivityandneurological deficits, compared with changes associatedwiththeR192Qmutation.Interestingly,corticostriatalpropagationofCSD wasobservedinthemajorityofmutantmice, andmoreseriousandprolongedpost-CSD neurological deficits followed, compared withthoseobservedinwild-typemice.Moreover,thehigherprevalenceofmigrainein femaleswasreplicatedinthemutantmice. Femalemutantmiceweremoresusceptible toCSD,andtheirneurologicaldeficitsmanifestedmoreseverelythanthoseintheirmale equivalents.Thesexdifferencewaseliminatedbyovariectomyandpartiallyrestored byestrogenreplacement,suggestingthat differencesinCSDsusceptibilitybetween malesandfemalesinvolvetheeffectofovarianhormones.Likeanyimportantstudy, thisnewworkraisesanumberofquestions: OnlyexperimentallyinducedCSDwasstudied,anditistemptingtoaskwhetherthe mutantmiceexperiencespontaneouswaves ofCSD.Moreover,FHMisararedisease,and thecurrentstudydoesnotdirectlyaddress thepathogenesisofmigrainewithorwithoutaura.Commonmigraineisamultifactorialpolygeneticdisease,andageneticcomponentcanonlybeenidentifiedinabout 50%ofindividualswithmigraine.Inthese patients,recentgenome-widescreenshave pointedtoseveralsusceptibilityloci,butno causativegeneshavebeenidentified(7). Long-term effect of migraine Painisanunpleasantandnoteasilyoverriddensensationofpotentialoractualdangertothebody.Doesmigrainepainsignify thatthebrainisinpotentialdanger?Perhaps.Recentstudiesshowthatcorticaltissueexperiencesashort-lastingepisodeof hypoxiaduringCSD,whichmaybesimilar tothatexhibitedduringatransientischemic attack(Figure1)(19).Thehypoxiaiscaused notbyareductioninbloodflow,butbythe enormousincreaseinO2utilizationthatis requiredtorestoreionhomeostasisfollowing CSD. Neuronal and glial membrane potentialsarealmostzerofollowingawave ofCSD,andtheclearanceofthehighlevel ofextracellularK+isassociatedwithasharp increase in O2 consumption. As a consequence,neuronsandgliacanexperience12 minutesofhypoxiaduringCSD;tissueO2 tensionlevelfallsbelow4mmHg,resulting indendriticswellingandatransientlossof dendriticspines,likelycontributingtothe prolongeddepressionofEEGactivityafter

CSD(19).Thechangesinneuronalstructure arereversible,andneuronsdorecover,but whetherrepeatedepisodesofmigrainemight causepermanentneuronaldamageremains anunansweredquestion.Severalprospective studieshaveshownthatmigrainepatientsdo notexperiencecognitivedecline(20,21).Itis interestingtonote,however,thatallstudies publishedtodatedocumentthatlong-term migraineursconsistentlyscorelowerthan matchedcontrolsintheprocessingofvisual information(22,23).Thus,visualaura,which isinitiatedandadvancesthroughtheoccipitalcortex,mayimpaircorticalnetworkfunctionlocally.Alternatively,theimpairmentof visualprocessingandthelowerthreshold forCSDmightbesomehowcoassociated throughacommonetiology. A recent study suggested that women with a lifetime history of migraine performedbetteroncognitiveteststhandid subjectswithoutmigraines(24).Onepossibleexplanationisthatthemigrainepain, similartoothertypesofpain,warnedthe patientsandreinforcedahealthierlifestyle thatnotonlyreducedmigraineattackbut alsoprotectedmemory.Anotherpossible explanationisthatalthoughthehypoxiaassociatedCSDrepresentsanimmediate danger, the long-term effect might be a strengtheningofcorticalcircuits.Alarge bodyofliteraturedocumentsthatCSDisa preconditioningstimulus,similartoshortlasting episodes of ischemia (25). Thus, exposuretoawaveofCSDmightconfer tolerance,allowingcorticalneuronstosurviveanotherwiselethalsubsequentepisode ofischemia.ThemechanismbywhichCSD increasesischemictoleranceismultifactorialandincludesreleaseofwell-knowntrophicfactors,includingbrain-derivedneurotrophicfactor(26).Thus,itisplausiblethat thebeneficialeffectofincreasedneuronal tolerancemay,overthelongterm,outweigh thehypoxicstressassociatedwithCSD. Acknowledgments The authorsare supported by theNIH/ NationalInstituteofNeurologicalDisordersandStroke(NINDS)andNewYork State.WethankStevenGoldmanforcommentsonthemanuscriptandMaryAnn Ballouforexpertlibrarysupport. Addresscorrespondenceto:MaikenNedergaard,UniversityofRochester,601Elmwood Avenue, Box 605, MRB 1-9915B, Rochester,NewYork14642,USA.Phone: (585)273-2868;Fax:(585)275-0550;E-mail: nedergaard@urmc.rochester.edu.

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