Migrena z aurą
Patofizjologia i mechanizm

Migrena z aurą dotyka około 12% populacji, z czego 25-30% doświadcza aury, będącej wynikiem korowego szerzącego się zahamowania (CSD) – fali depolaryzacji neuronów i komórek glejowych rozprzestrzeniającej się po korze mózgowej z prędkością 2-6 mm/min. CSD inicjuje zmiany naczyniowe (początkowa hiperemia, następnie oligemia), aktywuje aferentne neurony nerwu trójdzielnego i prowadzi do neurogennego zapalenia opon mózgowych poprzez uwalnianie neuropeptydów, zwłaszcza peptydu związanego z genem kalcytoniny (CGRP). Na poziomie molekularnym obserwuje się wzrost ekspresji COX-2, TNF-alfa, IL-1β, IL-6 oraz glutaminianu, który odgrywa kluczową rolę w propagacji CSD. Migrena z aurą ma silniejszy komponent genetyczny, z mutacjami w genach CACNA1A, ATP1A2 i SCN1A, które zwiększają pobudliwość neuronów i sprzyjają CSD. Dodatkowo, mikroembolizacja i przetrwały otwór owalny (PFO) są potencjalnymi czynnikami wyzwalającymi migrenę z aurą, co podkreśla rolę zaburzeń naczyniowych w patogenezie tego schorzenia.

  1. Patofizjologia migreny z aurą
    1. Korowe szerzące się zahamowanie (depresja rozprzestrzeniająca się)
    2. Aktywacja układu trójdzielno-naczyniowego
    3. Mechanizmy molekularne i związki biochemiczne
    4. Predyspozycje genetyczne i mikroembolizacja
    5. Rola pnia mózgu i wzorce aktywności mózgu
  2. Modele mechanizmów patofizjologicznych
    1. Teoria wyzwalania bólu głowy przez CSD
    2. Teoria zdarzeń równoległych
    3. Teoria ping-pong
  3. Implikacje kliniczne i nowe kierunki terapeutyczne
    1. Zwiększone ryzyko udaru
    2. Potencjalne cele terapeutyczne
    3. Nowe mechanizmy i odkrycia
  4. Wniosek
    1. Kolejne rozdziały

Patofizjologia migreny z aurą

Migrena z aurą (Migrena z aurą) to powszechne zaburzenie bólowe głowy dotykające około 12% populacji ogólnej, przy czym około 25-30% przypadków doświadcza zlokalizowanych objawów sensorycznych zwanych aurą. Obecne badania sugerują, że pierwotna dysfunkcja neuronalna prowadzi do sekwencji zmian wewnątrzczaszkowych i pozaczaszkowych, które wywołują migrenę. Zrozumienie złożoności patofizjologii migreny z aurą ma kluczowe znaczenie dla skutecznego leczenia tego schorzenia.123

Korowe szerzące się zahamowanie (depresja rozprzestrzeniająca się)

Centralne znaczenie w patogenezie migreny z aurą ma zjawisko korowego szerzącego się zahamowania (ang. Cortical Spreading Depression, CSD), opisanego przez Leo. Jest to samopropagująca fala depolaryzacji neuronów i komórek glejowych, która rozprzestrzenia się po korze mózgowej z prędkością 2-6 mm/min, zazwyczaj rozpoczynając się w korze potylicznej. CSD stanowi podłoże zarówno objawów aury, jak i bólu głowy związanego z migreną.1234

CSD charakteryzuje się intensywną depolaryzacją neuronalną związaną z odwracalnym zaburzeniem homeostazy jonowej i przejściowym zahamowaniem aktywności neuronalnej. Neurony ulegają depolaryzacji w wyniku lokalnego wzrostu stężenia potasu pozakomórkowego, a zaburzone gradienty jonowe błony komórkowej charakteryzują się napływem sodu i wapnia oraz uwalnianiem glutaminianu. Początkowa akumulacja potasu pozakomórkowego występuje w wyniku powtarzającej się depolaryzacji i repolaryzacji nadpobudliwych neuronów w korze mózgowej, a nagromadzenie to dodatkowo depolaryzuje komórki, z których uwalniany jest potas.123

Za rozprzestrzenianiem się CSD podąża fala zmian naczyniowych charakteryzująca się początkowo hiperemią (przekrwieniem), a następnie długotrwałą oligemią (zmniejszonym przepływem) korową. Te zmiany w przepływie krwi mózgowej i utlenowaniu, wraz ze zwiększonymi potrzebami metabolicznymi związanymi z CSD, prowadzą do niedopasowania podaży i popytu, a normalne mechanizmy homeostazy naczyń mózgowych zostają przeciążone.123

Aktywacja układu trójdzielno-naczyniowego

CSD aktywuje neurony aferentne nerwu trójdzielnego, co prowadzi do kaskady zdarzeń prowadzących do bólu głowy. Depolaryzacja neuronów i komórek glejowych rozprzestrzeniająca się po korze mózgowej prowadzi do indukcji aury migreny, aktywacji aferentów nerwu trójdzielnego i modyfikacji przepuszczalności bariery krew-mózg poprzez aktywację i regulację w górę metaloproteinaz macierzy.12

Aktywacja neuronów aferentnych nerwu trójdzielnego powoduje zmiany zapalne w oponach wrażliwych na ból, przyczyniając się do bólu głowy związanego z migreną. Zakończenia nerwu trójdzielnego zawierają neuropeptydy wazoaktywne, takie jak peptyd związany z genem kalcytoniny (CGRP), substancja P, wazoaktywny peptyd jelitowy i neurokinina A. Aktywacja tych neuronów wyzwala uwalnianie neuropeptydów, szczególnie CGRP, prowadząc do zapalenia neurogennego i rozszerzenia naczyń oponowych i naczyń opony miękkiej.12

CGRP jest neuropeptydem występującym w nerwach zwojów trójdzielnych, który działa jako silny wazodilatator naczyń mózgowych i oponowych i odgrywa kluczową rolę w patogenezie migreny. Badania kliniczne potwierdzające tę teorię obejmują: podwyższone poziomy CGRP w krążeniu podczas napadów migreny, rozwój bólów głowy podobnych do migreny po eksperymentalnym wstrzyknięciu CGRP oraz skuteczność selektywnych antagonistów receptora CGRP w leczeniu migreny.11

Serotonina (5-HT), uwalniana z jąder serotoninergicznych pnia mózgu, może również odgrywać rolę w migrenie, choć dokładny charakter tej roli jest przedmiotem debaty. Receptor serotoninowy (5-HT) jest uważany za najważniejszy receptor w szlaku bólu głowy.12

Mechanizmy molekularne i związki biochemiczne

Na poziomie molekularnym CSD powoduje regulację w górę genów, takich jak te kodujące cyklooksygenazę 2 (COX-2), czynnik martwicy nowotworów alfa (TNF-alfa), interleukinę-1beta, galaninę i metaloproteinazy. Markery stanu zapalnego i stresu oksydacyjnego zostały powiązane z migreną w kilku badaniach. Cytokiny prozapalne, takie jak interleukina-1 (IL-1) i interleukina-6 (IL-6), zostały zaangażowane w ten stan. Stwierdzono, że poziom IL-1α jest podwyższony we krwi dzieci cierpiących na migrenę z aurą. Podobnie, u dorosłych z migreną z aurą stwierdzono wyższe poziomy IL-1β w osoczu w okresach bez bólu głowy i we wczesnych stadiach ataków w porównaniu z osobami cierpiącymi na migrenę bez aury.12

Glutaminian odgrywa kluczową rolę w CSD. Uwalnianie glutaminianu w CSD jest procesem regeneracyjnym, a późniejsza aktywacja presynaptycznych receptorów NMDA wywołuje dalsze uwalnianie glutaminianu. Ostatnie badania wykazały, że olbrzymie smugi glutaminianu, kluczowego neuroprzekaźnika, narastające w mózgu, mogą pomóc wyjaśnić wystąpienie migreny z aurą. Te smugi przewidują początek rozprzestrzeniania się depolaryzacji, a zapobieganie smugom hamuje je.12

Tlenek azotu (NO) również odgrywa rolę w CSD. Przekrwienie korowe i oligemia w CSD są połączone ze zmianami NO, które są znacznie osłabione przez zahamowanie syntazy tlenku azotu (NOS).1

Predyspozycje genetyczne i mikroembolizacja

Migrena z aurą wydaje się mieć silniejszy komponent genetyczny niż migrena bez aury. Chociaż mutacje w pojedynczym genie mogą powodować niektóre zaburzenia migrenowe, inne wynikają z polimorfizmów w wielu genach. Geny zaangażowane w aurę wpływają na sposoby działania neuronów i zwykle sprawiają, że są one bardziej pobudliwe.12

Najlepiej zbadanym monogenetycznym zespołem migreny z aurą jest migrena hemiplegiczna. U pacjentów z migreną hemiplegiczną aury obejmują osłabienie motoryczne oprócz innych ogniskowych objawów neurologicznych powszechnie obserwowanych u pacjentów z migreną z aurą. Sekwencjonowanie DNA genów kandydujących w regionach genomowych dzielonych przez członków rodzin dotkniętych tą chorobą, zidentyfikowało mutacje przyczynowe w trzech genach migreny hemiplegicznej: CACNA1A (FHM1), ATP1A2 (FHM2), SCN1A (FHM3).1

Mutacje FHM1 w genie CACNA1A, który koduje podjednostkę α1 kanału wapniowego CaV2.1, zwiększają pobudliwość tych kanałów poprzez obniżenie progu ich aktywacji, tym samym zwiększając napływ wapnia do zakończeń presynaptycznych. Wynikające z tego podwyższenie napływu wapnia sprzyja nadmiernemu uwalnianiu glutaminianu, przyspieszając CSD, podstawowy mechanizm leżący u podstaw przejściowych zaburzeń wzrokowych charakterystycznych dla aury migrenowej.12

Interesującym elementem patogenezy migreny z aurą jest zjawisko mikroembolizacji. Niedawne dane eksperymentalne u myszy wskazują, że mikroembolia mózgowa wyzwala CSD, biologiczny substrat aury migrenowej, bez powodowania wymaganego uszkodzenia tkanki. Jeśli ta możliwość jest prawdziwa u ludzi, zaburzenia naczyń krwionośnych i przepływu krwi byłyby wtedy uznane za wyzwalacze migreny, a przyczyny naczyniowe i czynniki ryzyka migreny z aurą byłyby bardziej agresywnie poszukiwane.1

Związek między migreną z aurą a przetrwałym otworem owalnym (PFO) i innymi przeciekami prawo-lewo został dobrze udokumentowany. U osób z migreną z aurą występuje zwiększona częstość występowania PFO niż u osób z grupy kontrolnej, ale osoby z migreną bez aury nie mają zwiększonej częstości występowania PFO. Sugerujemy, że u pacjentów z PFO, krótkie okresy lokalnego i łagodnego hipoperfuzji rozwijają się w konsekwencji mikroembolii powstających z krążenia żylnego, lub mogą rozwinąć się w innych warunkach w odpowiedzi na uraz ściany naczynia, lokalne uwalnianie substancji wazoaktywnych, zwiększoną lepkość krwi, krążące kompleksy immunologiczne, dysfunkcję śródbłonka, zwiększoną interakcję płytek krwi i śródbłonka lub interakcję płytek krwi i leukocytów.12

Rola pnia mózgu i wzorce aktywności mózgu

Badania sugerują, że pień mózgu może odgrywać kluczową rolę w patogenezie migreny z aurą. Wczesna aktywacja pnia mózgu/podwzgórza prawdopodobnie pośredniczy w objawach zapowiadających, w tym nieprawidłowym przetwarzaniu sensorycznym i podatności na różne czynniki ryzyka, i może prowadzić zarówno do aktywacji nocycepcji trójdzielno-naczyniowej, jak i do wyzwolenia aury/CSD. Odkrycia te podkreślają potencjalną rolę pnia mózgu jako czynnika napędzającego podatność na CSD i zaangażowanie wstępujących dróg z pnia mózgu do kory mózgowej w inicjacji CSD/aury.1

Nieprawidłowości w mocy i symetrii rytmu alfa, obecność spowolnienia i zwiększony przepływ informacji w szerokim zakresie pasm częstotliwości często charakteryzują spontaniczną aktywność EEG w migrenie z aurą. Ponieważ większość nieprawidłowości elektrofizjologicznych była częściej obecna i miała większą amplitudę w migrenie z aurą niż w migrenie bez aury, techniki neurofizjologiczne okazały się bardzo pomocne w poszukiwaniu patofizjologicznych podstaw aury migrenowej.1

Wzorzec neurofizjologiczny, który charakteryzuje pacjentów z migreną z aurą poprzez nieprawidłową korową aktywność rytmiczną, zwiększoną reaktywność korową i deficyt hamowania bocznego, może być przypisany dysrytmii wzgórzowo-korowej (TCD). Na poparcie tego teoretycznego wyjaśnienia, niektórzy autorzy stwierdzili tendencję do redukcji lub pełnej redukcji amplitudy presynaptycznej salwy aktywności oscylacyjnej o wysokiej częstotliwości osadzonej w zwykłych SSEP odzwierciedlających aktywność wzgórzowo-korową u pacjentów z migreną z aurą między atakami.1

Modele mechanizmów patofizjologicznych

Istnieje kilka modeli teoretycznych wyjaśniających relację między aurą migrenową a bólem głowy, a badacze nadal debatują nad dokładną sekwencją zdarzeń.

Teoria wyzwalania bólu głowy przez CSD

Jedna z teorii sugeruje, że CSD może bezpośrednio aktywować nocycepcję trójdzielną i tym samym wyzwalać ból głowy migrenowy. Badanie przeprowadzone na szczurach dostarczyło bezpośrednich dowodów, że aury, przypuszczalnie wywoływane przez fale depresji spontanicznej aktywności elektrycznej, które powoli rozprzestrzeniają się przez płat potyliczny kory mózgowej, mogą wyzwalać aktywację nocyceptorów oponowych.1

Opóźniona aktywacja neuronalna obserwowana w tych badaniach może być istotna dla typowego opóźnienia między początkiem aury a początkiem bólu głowy migrenowego, chociaż podstawowe mechanizmy pozostają nieznane. Trwała aktywacja nocyceptorów oponowych może być wynikiem albo krótkotrwałego uwalniania cząsteczek bólowych podczas CSD, które promuje ostrą aktywację nocyceptora i powoduje trwającą uczulenie, które zazwyczaj utrzymuje się dłużej niż bodziec o 30-60 minut, albo ciągłego uwalniania cząsteczek bólowych przez okres do 1 godziny podczas CSD.1

Ponieważ ten okres trwałej aktywacji nocyceptorów oponowych może nie być wystarczający sam w sobie, aby wyjaśnić 4- do 72-godzinny czas trwania fazy bólu głowy migreny, badacze zaproponowali, że czas trwania aktywacji nocyceptora może być wystarczający do promowania ciągłej aktywności centralnych neuronów trójdzielno-naczyniowych, które ostatecznie stają się niezależne od przychodzących sygnałów z nocyceptorów i mogą trwać wiele godzin.1

Teoria zdarzeń równoległych

Alternatywny pogląd uważa aurę/CSD i ból głowy za niezależne równoległe zdarzenia, oba wynikające z globalnej dysfunkcji mózgu podczas fazy prodromalnej ataku migreny. Dane kliniczne dotyczące zmiennej relacji między wystąpieniem aury i bólu głowy podczas ataków migreny podważyły przyczynowy związek tych 2 zjawisk.1

Według tej teorii, wczesna aktywacja pnia mózgu/międzymózgowia prawdopodobnie pośredniczy w objawach zapowiadających, w tym nieprawidłowym przetwarzaniu sensorycznym i podatności na różne czynniki ryzyka, i może prowadzić zarówno do aktywacji nocycepcji trójdzielno-naczyniowej, jak i do wyzwolenia aury/CSD.1

Teoria ping-pong

Kolejna teoria, znana jako teoria ping-pong, sugeruje, że migrena może również wyzwalać aurę, być może dlatego, że zapalenie migrenowe wyzwala falę elektryczną. Według tej teorii, mechanizm aury to fala elektryczna zwana korowym szerzącym się zahamowaniem, natomiast mechanizm migreny to zapalenie wokół nerwów czuciowych i aktywacja różnych ośrodków wewnątrz mózgu.1

Implikacje kliniczne i nowe kierunki terapeutyczne

Zrozumienie patofizjologii migreny z aurą ma istotne implikacje kliniczne, szczególnie w kontekście zwiększonego ryzyka udaru i rozwoju nowych opcji terapeutycznych.

Zwiększone ryzyko udaru

Osoby z migreną z aurą mają zwiększone ryzyko udaru (3 do 4 razy więcej niż populacja ogólna). Ale to ryzyko dotyczy głównie osób poniżej pięćdziesiątego roku życia, których bazowe ryzyko udaru jest bardzo niskie. Liczne badania, w tym pięć meta-analiz, powiązały migrenę, szczególnie migrenę z aurą, ze zwiększonym ryzykiem udaru niedokrwiennego. Względne ryzyko udaru niedokrwiennego jest podwojone u osób z migreną z aurą w porównaniu z osobami bez migreny.12

Związek między migreną a udarem niedokrwiennym jest silniejszy dla kobiet, kobiet poniżej 45 roku życia, kobiet stosujących doustne środki antykoncepcyjne i kobiet palących. Ryzyko jest większe dla osób z aktywną migreną (tj. atak migreny w ciągu ostatnich 12 miesięcy) i wyższą częstotliwością ataków.12

Dokładne mechanizmy, przez które migrena jest powiązana z udarem, są nieznane i prawdopodobnie wieloczynnikowe. Migrena z aurą jest związana z niższym progiem wyzwalania korowego szerzącego się zahamowania, czyniąc mózg podatny na migrenę bardziej podatnym na niedokrwienie mózgu.1

Potencjalne cele terapeutyczne

Wraz z lepszym zrozumieniem patofizjologii migreny, uwaga badaczy przesunęła się w kierunku podejść opartych na celach. W tym kontekście szlak CGRP wyłonił się jako jeden z głównych mediatorów migreny. W ostatnich latach kilka przeciwciał monoklonalnych ukierunkowanych na szlak CGRP zostało przebadanych i zatwierdzonych w wybranych regionach globalnych do profilaktycznego leczenia migreny epizodycznej i przewlekłej.1

Ponieważ CGRP okazał się realnym celem interwencji terapeutycznych w migrenie, badacze coraz częściej rozważają jego możliwą rolę w CSD i aurze migrenowej. Mimo sukcesu (z przeciwciałami blokującymi CGRP), to gdzie i jak CGRP powoduje migrenę pozostaje w dużej mierze nieznane. Spekulowano, że może istnieć połączenie między CGRP a CSD, i że możliwe jest, że działania naczyniowe CGRP mogą przyczyniać się do CSD.12

Inne cele neurofizjologiczne oceniane pod kątem potencjalnej interwencji w CSD obejmują 2 miejsca bramkowania kanałów jonowych, kanały jonowe wrażliwe na kwasy (ASICs) i kanały przejściowego potencjału receptorowego ankirynowego typu 1 (TRPA1). Dane silnie sugerują, że dezaktywacja kanałów TRPA1 i blokada CGRP miałyby korzyści terapeutyczne w zapobieganiu migrenie z aurą.1

Glutaminian również odgrywa pierwotną rolę w CSD. Uwalnianie glutaminianu w CSD jest procesem regeneracyjnym, a późniejsza aktywacja presynaptycznych receptorów NMDA wywołuje dalsze uwalnianie glutaminianu. Ta obserwacja może być najbardziej obiecująca klinicznie, ponieważ interwencja podczas fazy aury z lekami, które blokowałyby opóźnioną indukcję aktywacji neuronalnej, mogłaby potencjalnie zapobiec wystąpieniu bólu głowy migrenowego.12

Lamotrigina jest lekiem przeciwpadaczkowym, blokującym kanały sodowe, zdolnym do wywołania pośredniego zahamowania uwalniania glutaminianu neuronalnego, blokując w ten sposób rozprzestrzenianie się CSD po korze mózgowej, jak pokazano w modelu eksperymentalnym CSD. Badania sugerują, że lamotrigina może być skuteczna w leczeniu migreny z aurą. W porównaniu z topiramatem, innym lekiem przeciwpadaczkowym zatwierdzonym jako lek pierwszego rzutu do profilaktyki migreny, lamotrigina wykazała podobną skuteczność w zmniejszaniu miesięcznej częstotliwości ataków migreny oraz lepszy profil tolerancji, co czyni ją potencjalnym lekiem z wyboru, szczególnie u pacjentów zgłaszających przedłużoną aurę i którzy nie reagują, mają przeciwwskazania lub przerywają leczenie topiramatem z powodu działań niepożądanych.123

Nowe mechanizmy i odkrycia

Ostatnio odkryto wcześniej nieznany mechanizm, w którym białka z mózgu są przenoszone do określonej grupy nerwów czuciowych, co powoduje ataki migreny. Badacze odkryli, że białka te aktywują grupę ciał komórek nerwów czuciowych u podstawy czaszki, tzw. zwój trójdzielny, który można opisać jako bramę do obwodowego czuciowego układu nerwowego czaszki.1

U podstawy zwoju trójdzielnego brak bariery, która zwykle zapobiega wnikaniu substancji do nerwów obwodowych, co umożliwia substancjom w płynie mózgowo-rdzeniowym wnikanie i aktywowanie nerwów czuciowych sygnalizujących ból, czego rezultatem są bóle głowy. Oznacza to, że gdy białka są uwalniane, są przenoszone do zwoju trójdzielnego przez wspomniane szlaki sygnałowe, gdzie wiążą się z receptorem nerwu czuciowego sygnalizującego ból, aktywując nerw i wyzwalając atak migreny następujący po objawach aury.12

Co więcej, większość pacjentów doświadcza jednostronnych bólów głowy, a ten szlak sygnałowy może pomóc wyjaśnić dlaczego. Badanie sposobu transportu białek z mózgu pokazuje, że substancje nie są przenoszone do całej przestrzeni wewnątrzczaszkowej, ale głównie do układu czuciowego po tej samej stronie, co powoduje jednostronne bóle głowy.1

Wniosek

Migrena z aurą to złożone zaburzenie neurologiczne, którego patofizjologia obejmuje szeroką gamę mechanizmów, od korowego szerzącego się zahamowania po aktywację układu trójdzielno-naczyniowego. Rosnąca wiedza na temat tych mechanizmów przyczyniła się do opracowania ukierunkowanych terapii i lepszego zrozumienia związku między migreną a innymi schorzeniami naczyniowymi, takimi jak udar mózgu. Dalsze badania nad patofizjologią migreny z aurą mogą prowadzić do jeszcze bardziej skutecznych strategii profilaktycznych i terapeutycznych dla osób cierpiących na tę wyniszczającą chorobę.1

Kolejne rozdziały

Zapraszamy do dalszego czytania naszego leksykonu.

Wybierz kolejny rozdział z menu poniżej, aby otworzyć nową podstronę kompedium wiedzy i uzyskać szczegółowe informację o leku, substancji lub chorobie.

  1. 09.04.2026
  2. www.leksykon.com.pl

Materiały źródłowe

  • #1 Migraine With Aura – StatPearls – NCBI Bookshelf
    https://www.ncbi.nlm.nih.gov/books/NBK554611/
    Migraine syndrome with aura is a prevalent headache disorder affecting approximately 12% of the general population, with nearly 25% of cases experiencing localized sensory symptoms or auras. […] This activity discusses the underlying pathophysiology, and clinicians gain insight into the mechanisms driving migraine attacks, moving beyond outdated theories about cranial blood vessel changes. […] Understanding the intricacies of the pathophysiology, presentation, assessment, and management of migraine with aura is crucial for healthcare professionals. […] Current knowledge indicates that primary neuronal dysfunction leads to a sequence of intracranial and extracranial changes that cause migraines. Cortical spreading depression of Leo, a self-propagating wave of neuronal and glial depolarization that spreads across the cerebral cortex, underlies the etiology of both the headache and aura associated with migraine.
  • #1 Aura and the Mechanism of Migraine: The Next Treatment Target?
    https://www.neurologylive.com/view/aura-and-the-mechanism-of-migraine-the-next-treatment-target/1000
    Dodick described CSD as a self-propagating wave of transient neuronal depolarization, a form of intense neuronal excitation associated with reversible breakdown of ion homeostasis and transient depression of neuronal activity. […] Neurons are depolarized by local elevations in extracellular potassium, and the disrupted cell membrane ionic gradients are marked by the influx of sodium and calcium and the release of glutamate. […] Dodick suggested that initial accumulations of extracellular potassium occur as a result of repeated depolarization and repolarization of hyperexcitable neurons in the cortex, and the accumulation then further depolarizes the cells from which the potassium is released. […] He also pointed to evidence from animal studies that supports the proposition that CSD can activate trigeminal nociception and thereby trigger migraine headache.
  • #1 Aura and the Mechanism of Migraine: The Next Treatment Target?
    https://www.neurologylive.com/view/aura-and-the-mechanism-of-migraine-the-next-treatment-target/1000
    The propagation of CSD is still not fully understood, and several hypotheses exist, Dodick indicated. […] In addition to inhibition of cortical activity that follows the slowly propagating wave (2-6 mm/min) of CSD in neuronal and glial cell membranes, CSD is associated with a wave of hyperemia followed by a prolonged phase of cortical oligemia. […] These changes in cerebral blood flow and oxygenation, as well as the increased metabolic needs associated with CSD, lead to a mismatch of supply and demand, and normal mechanisms of cerebrovascular homeostasis are overwhelmed, Russo and colleagues observed. […] Clinical data on the variable relationship between aura and headache occurrence during migraine attacks have challenged the causative link of the 2 phenomena, Vinogradova added. […] An alternative view considers aura/CSD and headache as independent parallel events, both resulting from global brain dysfunction during the prodromal phase of the migraine attack.
  • #1 Migraine With Aura – StatPearls – NCBI Bookshelf
    https://www.ncbi.nlm.nih.gov/books/NBK554611/
    The pathophysiology of migraine involves the cortical spreading depression of Leo and activation of the trigeminovascular system. […] The depolarization of neuronal and glial cells spreads across the cerebral cortex, leading to induction of the migraine aura, activation of trigeminal nerve afferents, and modification of blood-brain barrier permeability through matrix metalloproteinase activation and upregulation. […] Activation of the trigeminal nerve’s afferent neurons brings about inflammatory changes in the pain-sensitive meninges, contributing to the headache associated with migraine. […] CGRP is a neuropeptide expressed in trigeminal ganglia nerves that serves as a potent vasodilator of cerebral and dural vessels and plays an essential role in the pathogenesis of migraine. […] Serotonin, released from the brainstem serotonergic nuclei, may play a role in migraine, although the precise nature of this role is subject to debate.
  • #1 Modern understanding of the pathophysiology of migraine | CnsBytes US
    https://www.cnsbytes.us/migraine/modern-understanding-of-the-pathophysiology-of-migraine/
    Trigeminal nerve endings contain vasoactive neuropeptides such as calcitonin gene-related peptide (CGRP), substance P, neurokinin A, and pituitary adenylate-cyclase activating peptide (PACAP). Activation of these neurons triggers the release of the neuropeptides, especially CGRP, leading to neurogenic inflammation, and vasodilation of dural and pial vessels. While vasodilation does not directly cause migraine, and neurogenic inflammation is unlikely to be a major migraine trigger, the latter may be involved in the sensitization of peripheral nociceptors. CGRP is also likely involved in central nociceptive sensitization. Although the exact mechanism of migraine onset remains to be elucidated, CGRP is clearly involved in modulating nociceptive input to the TCC. […] Several studies in the past two decades have shown that CGRP plays a key role in migraine pathogenesis. Clinical evidence supporting this conclusion includes: elevated levels of CGRP in the circulation during migraine attacks; development of migraine-like headaches after experimental injection of CGRP; and effectiveness of selective CGRP receptor antagonists in the treatment of migraine. In addition to nociceptive modulation and pain perception, CGRP is likely involved in other migraine phases and phenomena, such as photophobia and migraine aura. The mechanism through which CGRP causes migraine aura is believed to be related to its critical role in cortical spreading depression (CSD).
  • #1 Migraine Headache: Practice Essentials, Background, Pathophysiology
    https://emedicine.medscape.com/article/1142556-overview
    Activation of the trigeminovascular system by CSD stimulates nociceptive neurons on dural blood vessels to release plasma proteins and pain-generating substances such as calcitonin gene-related peptide, substance P, vasoactive intestinal peptide, and neurokinin A. […] The initial cortical hyperperfusion in CSD is partly mediated by the release of trigeminal and parasympathetic neurotransmitters from perivascular nerve fibers, whereas delayed meningeal blood flow increase is mediated by a trigeminal-parasympathetic brainstem connection. […] In addition, through a variety of molecular mechanisms, CSD upregulates genes, such as those encoding for cyclo-oxygenase 2 (COX-2), tumor necrosis factor alpha (TNF-alpha), interleukin-1beta, galanin, and metalloproteinases. […] The serotonin receptor (5-hydroxytryptamine [5-HT]) is believed to be the most important receptor in the headache pathway.
  • #1 Aura and the Mechanism of Migraine: The Next Treatment Target?
    https://www.neurologylive.com/view/aura-and-the-mechanism-of-migraine-the-next-treatment-target/1000
    We have speculated that there could be a connection between CGRP and CSD, [and] I think its possible that the vascular actions of CGRP could contribute to CSD, Russo added. […] The case for a primary role of glutamate in CSD was presented by Andrew Charles, MD, of the department of neurology at the David Geffen School of Medicine at the University of California, Los Angeles, and colleague Jan Hoffman, MD, PhD, of Kings College London. […] They described the release of glutamate in CSD as a regenerative process, with the subsequent activation of presynaptic NMDA receptors eliciting further release of glutamate. […] Akerman and colleagues noted that the cortical hyperemia and oligemia in CSD are accompanied with NO changes and that these are significantly attenuated with NOS inhibition.
  • #1 Migraine with Aura: An Overview – Migraine Canada
    https://migrainecanada.org/posts/the-migraine-tree/roots/migraine-categories/migraine-with-aura-an-overview/
    Migraine with aura is a unique and often perplexing condition that affects many individuals, including Shelly, whose experiences offer a glimpse into the complexities of this neurological phenomenon. […] An aura is a neurological symptom (vision, speech, sensation, motor function) that is caused by a wave of electricity on the surface of the brain. The wave moves gradually and eventually resolves. The aura symptoms often are progressive (though not always), and also resolve. […] Migraine with aura tend to be more genetic than migraine without aura. Many genes are involved. Hemiplegic migraine has been associated with three genes that can be tested. The genes involved in auras influence the ways the neurons work and usually make them more excitable. Some genes cause auras with paralysis.
  • #1 Genetics of migraine aura: an update | The Journal of Headache and Pain | Full Text
    https://thejournalofheadacheandpain.biomedcentral.com/articles/10.1186/s10194-020-01125-2
    Another explanation for the missing heritability could be epigenetic processes. […] Until now successful identification of genetic factors relevant to migraine with aura almost exclusively came from investigating rare monogenetic syndromes. […] The most investigated monogenetic migraine with aura syndrome is hemiplegic migraine. […] In patients with hemiplegic migraine, the auras include motor weakness in addition to other focal neurological features commonly seen in migraine with aura patients. […] DNA sequencing of candidate genes in genomic regions shared by affected family members, have identified causal mutations in three hemiplegic migraine genes: CACNA1A (FHM1), ATP1A2 (FHM2), SCN1A (FHM3). […] The identification of causal genes for such syndromes is more straightforward than for polygenic disorders, already because the hunt is for a single genetic factor that is sufficient to cause disease in a patient.
  • #1 fMRI Insights into Visual Cortex Dysfunction as a Biomarker for Migraine with Aura
    https://www.mdpi.com/2035-8377/17/2/15
    These mutations enhance the excitability of CaV2.1 channels by reducing their activation threshold, thereby increasing calcium influx into presynaptic terminals. […] The resultant elevation in calcium influx promotes excessive glutamate release, precipitating CSD, a fundamental mechanism underlying the transient visual disturbances characteristic of migraine aura. […] CSD also initiates mechanisms of peripheral and central sensitisation that contribute to the manifestation of migraine headaches. […] A key factor in the pathogenesis of migraine aura is neurovascular coupling, the physiological mechanism that combines cerebral blood flow with neuronal activity. […] The onset of aura symptoms is correlated with the onset of an initial period of regional hyperaemia, which is followed by a prolonged oligemia.
  • #1 Migraine aura pathophysiology: the role of blood vessels and microembolisation
    https://pmc.ncbi.nlm.nih.gov/articles/PMC2921876/
    Recent experimental data in mice indicate that cerebral microembolism triggers cortical spreading depression (CSD), a biological substrate for migraine aura, without causing requisite tissue injury. […] If this possibility is true in human beings, blood vessel and blood flow disorders would then be acknowledged as a migraine trigger, and vascular causes and risk factors for migraine with aura would be more aggressively sought. […] CSD has a fundamental role in the genesis of migraine aura. Susceptibility to CSD is conferred by genes and modulated by hormones (ovarian and testicular) as well as by drugs that suppress CSD and prevent migraine attacks. Recently identified vascular triggers initiate CSD by causing transient, mild, and focal hypoperfusion, as determined experimentally. […] Thrombosis and microembolisation could thereby create a transient hypoxic-ischaemic focus to induce CSD followed by a migraine attack, whereas more prolonged occlusion of larger vessels might cause transient ischaemic attack or stroke.
  • #1 Migraine aura pathophysiology: the role of blood vessels and microembolisation
    https://pmc.ncbi.nlm.nih.gov/articles/PMC2921876/
    These pathophysiological considerations take on greater importance in light of recent experimental studies indicating that microembolism can serve as a trigger for CSD. […] We believe that these findings are relevant to human beings because the terminal vascular beds of the mouse and human brain are not too dissimilar. […] We propose that in patients with patent foramen ovale, brief periods of local and mild hypoperfusion develop as a consequence of microemboli arising from the venous circulation, or might develop in other conditions in response to injury to the vessel wall, local release of vasoactive substances, increased blood viscosity, circulating immune complexes, endothelial dysfunction, enhanced platelet-endothelial interaction, or platelet-leucocyte interaction among other mechanisms.
  • #1 Aura and the Mechanism of Migraine: The Next Treatment Target?
    https://www.neurologylive.com/view/aura-and-the-mechanism-of-migraine-the-next-treatment-target/1000
    The early brainstem/diencephalon activation likely mediates premonitory symptomatology, including abnormal sensory processing and vulnerability to various risk factors, and can lead to both activation of trigemino-vascular nociception and triggering [of ] aura/CSD. […] The findings highlight the potential role of the brainstem as a driver of CSD susceptibility and involvement of ascending pathways from the brainstem to the cortex in the initiation of CSD/aura, Vinogradova indicated. […] As CGRP has proved to be a viable target for therapeutic interventions in migraine, investigators have increasingly considered its possible role in CSD and migraine aura. […] Despite the success [with CGRP-blocking antibodies], where and how CGRP is causing migraine remain mostly unknown, Russo told NeurologyLive.
  • #1 Clinical neurophysiology of migraine with aura | The Journal of Headache and Pain | Full Text
    https://thejournalofheadacheandpain.biomedcentral.com/articles/10.1186/s10194-019-0997-9
    Abnormalities in alpha rhythm power and symmetry, the presence of slowing, and increased information flow in a wide range of frequency bands often characterize the spontaneous EEG activity of MA. […] Since most of the electrophysiological abnormalities mentioned above were more frequently present and had a greater amplitude in migraine with aura than in migraine without aura, neurophysiological techniques have been shown to be of great help in the search for the pathophysiological basis of migraine aura. […] The electrocortical phenomenon of cortical spreading depression (CSD) has been implicated in the genesis of migraine aura: it is a wave of neuronal hyperactivity followed by a wave of hypoactivity which often spreads postero-anteriorly and can reach the parietal and/or temporal lobes travelling at a speed of approx. 3mm/min.
  • #1 Clinical neurophysiology of migraine with aura | The Journal of Headache and Pain | Full Text
    https://thejournalofheadacheandpain.biomedcentral.com/articles/10.1186/s10194-019-0997-9
    Although in animal models CSD is able to ignite the trigeminovascular system, which is the condition for a headache to start, less is known about the possible biomarkers of CSD during the interictal migraine that might predispose to the aura and, perhaps, to the attack itself. […] The involvement of such a wide variety of brain structures in MA has already been witnessed many times and long before by the neurophysiological studies reviewed here. […] We hypothesized that the neurophysiological pattern which characterizes MA patients of an abnormal cortical rhythmic activity, an increased cortical responsivity, and deficient lateral inhibition may be ascribed to a thalamo-cortical dysrhythmia (TCD). […] In support of this theoretical explanation, some authors found a tendency to a reduction or a full reduction of the amplitude of the pre-synaptic burst of high-frequency oscillatory activity embedded in the common SSEPs reflecting thalamocortical activity in MA patients between attacks. […] In summary, there are few neurophysiological features peculiar to the brain of patients with migraine with aura, such as frequent detection of an increase in amplitude to evoked potentials and peculiar abnormalities of functional connectivity at the EEG during resting-state.
  • #1 Study Directly Links Mechanism of Aura to Migraine Pain | MDedge
    https://medauth2.mdedge.com/content/study-directly-links-mechanism-aura-migraine-pain
    Frustration has long plagued researchers who have sought to link the visual auras experienced by some migraineurs with the later onset of headache pain. But now, direct evidence from a new study in rats suggests that auras presumed to be caused by waves of depression of spontaneous electrical activity that propagate slowly through the occipital lobe of the cortex can trigger the activation of meningeal nociceptors. […] The relationship between CSD and migraine aura has a pathophysiological overlap that has led to the widely accepted theory that CSD is the electrophysiological substrate underlying the migraine aura. The question as to whether CSD is the brain mechanism causing the migraine headache is more controversial. Although circumstantial evidence and indirect data, including neuroimaging studies, provide strong evidence that CSD does occur in migraine, there is still no definitive demonstration in a migraine patient that CSD causes the proposed activation of nociceptors in the cranial pain-sensitive structures, specifically the meninges, large blood vessels, and large venous sinuses.
  • #1 Study Directly Links Mechanism of Aura to Migraine Pain | MDedge
    https://medauth2.mdedge.com/content/study-directly-links-mechanism-aura-migraine-pain
    The delayed neuronal activation observed in those 21 trials may be relevant to the typical delay between the onset of aura and the onset of migraine headache, though the underlying mechanisms remain unknown, wrote Dr. Zhang and coauthors. They noted that this observation may be the most clinically promising because intervention during the aura phase with drugs that would block the delayed induction of neuronal activation could potentially preempt the onset of migraine headache. […] The investigators proposed that the sustained activation of meningeal nociceptors could be the result of either a short-lasting release of algesic molecules during CSD that promotes an acute activation of the nociceptor and gives rise to an ongoing sensitization that typically outlasts the stimulus by 30-60 minutes, or an ongoing release of algesic molecules for up to 1 hour during CSD.
  • #1 Study Directly Links Mechanism of Aura to Migraine Pain | MDedge
    https://medauth2.mdedge.com/content/study-directly-links-mechanism-aura-migraine-pain
    However, because this period of sustained activation of the meningeal nociceptors may not be sufficient in and of itself to explain the 4- to 72-hour duration of the headache phase of migraine, Dr. Zhang and associates proposed that the duration of nociceptor activation may be sufficient to promote ongoing activity of central trigeminovascular neurons that eventually becomes independent of incoming signals from the nociceptors and can last many hours.
  • #1 Migraine with Aura: An Overview – Migraine Canada
    https://migrainecanada.org/posts/the-migraine-tree/roots/migraine-categories/migraine-with-aura-an-overview/
    The mechanism of the aura is an electrical wave called cortical spreading depression. The mechanism of the migraine is the inflammation around sensory nerves and the activation of different centres inside the brain. Following the Ping Pong Theory, it may be that a migraine could also trigger an aura, maybe because the migraine inflammation triggers the electrical wave. […] Yes. People with migraine with aura have an increased risk of stroke (3 to 4-times more than the general population). But this risk applies mostly to people below fifty, whose baseline stroke risk is very low.
  • #1 Migraine and risk of stroke | Journal of Neurology, Neurosurgery & Psychiatry
    https://jnnp.bmj.com/content/91/6/593
    Migraine and stroke are two common and heterogeneous neurovascular disorders responsible for a significant burden for those affected and a great economic cost for the society. There is growing evidence that migraine increases the overall risk of cerebrovascular diseases. […] The mechanism behind the migraine-stroke association is unknown. In light of the higher risk of stroke in people with migraine with aura, it is important to identify and modify any vascular risk factor. […] Numerous studies, including five meta-analyses, have linked migraine, particularly migraine with aura (MA), with increased risk of ischaemic stroke. The relative risk of ischaemic stroke is doubled in people with MA compared with migraine-free individuals. […] The association between migraine and ischaemic stroke is stronger for women, women younger than 45 years, women who use oral contraceptives and women who smoke.
  • #1 Migraine and risk of stroke | Journal of Neurology, Neurosurgery & Psychiatry
    https://jnnp.bmj.com/content/91/6/593
    The association between migraine and haemorrhagic stroke is more uncertain. […] The precise mechanisms by which migraine is linked to stroke are unknown and possibly multifactorial. […] Cortical spreading depression, the electrophysiological mechanism believed to underlie migraine aura, is an intense depolarising wave of neuronal and glial membranes that spreads slowly across the cerebral cortex. […] MA is associated with a lower triggering threshold for cortical spreading depression, making the migraine-susceptible brain more vulnerable to cerebral ischaemia.
  • #1 Modern understanding of the pathophysiology of migraine | CnsBytes US
    https://www.cnsbytes.us/migraine/modern-understanding-of-the-pathophysiology-of-migraine/
    With a better understanding of migraine pathophysiology, the focus of research has shifted to target-based approaches. In this context, the CGRP pathway has emerged as one of the primary mediators of migraine. In recent years, several monoclonal antibodies targeting the CGRP pathway have been studied and approved in select global regions for preventive treatment of episodic and chronic migraine.
  • #1 Aura and the Mechanism of Migraine: The Next Treatment Target?
    https://www.neurologylive.com/view/aura-and-the-mechanism-of-migraine-the-next-treatment-target/1000
    Other neurophysiologic targets being evaluated for potential intervention into CSD include 2 ion channel gating sites, the acid-sensing ion channels (ASICs) and the transient receptor potential ankyrin type 1 (TRPA1) channels. […] The data strongly suggest that deactivation of TRPA1 channels and blockade of CGRP would have therapeutic benefits in preventing migraine with aura.
  • #1 May lamotrigine be an alternative to topiramate in the prevention of migraine with aura? Results of a retrospective study | BMJ Neurology Open
    https://neurologyopen.bmj.com/content/2/2/e000059
    Latest evidence suggests that CSD can also determine meningeal nociceptor firing, thus leading to the activation of the trigemino-vascular system which has been linked to the development of migraine headache. However, the relationship between CSD and migraine headache is not fully understood yet. […] Lamotrigine is an antiepileptic, sodium channel blocking drug able to induce an indirect inhibition of neuronal glutamate release thus blocking CSD propagation throughout the cerebral cortex as shown by experimental model of CSD. The role of lamotrigine for the preventive treatment of migraine has been previously investigated. A double-blind, randomised, controlled, crossover study involving suffering from migraine with and without aura, concluded that lamotrigine was ineffective in reducing migraine frequency and intensity compared with topiramate, another antiepileptic drug approved as first-line agent for migraine prophylaxis, although efficacy outcomes of patients solely affected by migraine with aura were not reported at the end of the abovementioned study. On the other hand, evidence suggests that lamotrigine could be effective within the migraine aura clinical setting.
  • #1 Researchers identify unknown signalling pathway in the brain responsible for migraine with aura – University of Copenhagen
    https://healthsciences.ku.dk/newsfaculty-news/2024/07/researchers-identify-unknown-signalling-pathway-in-the-brain-responsible-for-migraine-with-aura
    A previously unknown mechanism by which proteins from the brain are carried to a particular group of sensory nerves causes migraine attacks, a new study shows. […] We have discovered that these proteins activate a group of sensory nerve cell bodies at the base of the skull, the so-called trigeminal ganglion, which can be described as a gateway to the peripheral sensory nervous system of the skull, says Postdoc Martin Kaag Rasmussen from the Center for Translational Neuromedicine at the University of Copenhagen, who is first author of the study. […] Our results suggest that we have identified the primary channel of communication between the brain and the peripheral sensory nervous system. It is a previously unknown signalling pathway important for the development of migraine headache, and it might be associated with other headache diseases too, says Professor Maiken Nedergaard, who is senior author of the study.
  • #1 Researchers identify unknown signalling pathway in the brain responsible for migraine with aura – University of Copenhagen
    https://healthsciences.ku.dk/newsfaculty-news/2024/07/researchers-identify-unknown-signalling-pathway-in-the-brain-responsible-for-migraine-with-aura/
    A previously unknown mechanism by which proteins from the brain are carried to a particular group of sensory nerves causes migraine attacks, a new study shows. […] We have discovered that these proteins activate a group of sensory nerve cell bodies at the base of the skull, the so-called trigeminal ganglion, which can be described as a gateway to the peripheral sensory nervous system of the skull, says Postdoc Martin Kaag Rasmussen from the Center for Translational Neuromedicine at the University of Copenhagen, who is first author of the study. […] At the root of the trigeminal ganglion, the barrier that usually prevents substances from entering the peripheral nerves is missing, and this enables substances in the cerebrospinal fluid to enter and activate pain-signalling sensory nerves, resulting in headaches.
  • #1 Researchers identify unknown signalling pathway in the brain responsible for migraine with aura – University of Copenhagen
    https://healthsciences.ku.dk/newsfaculty-news/2024/07/researchers-identify-unknown-signalling-pathway-in-the-brain-responsible-for-migraine-with-aura
    Most patients experience one-sided headaches, and this signalling pathway can help explain why. Our study of how proteins from the brain are transported shows that the substances are not carried to the entire intracranial space, but primarily to the sensory system in the same side, which is what causes one-sided headaches, says Martin Kaag Rasmussen. […] This means that when the proteins are released, they are carried to the trigeminal ganglion via the said signalling pathways, where they bind to a receptor of a pain-signalling sensory nerve, activating the nerve and triggering the migraine attack succeeding the aura symptoms. […] It is a previously unknown signalling pathway important for the development of migraine headache, and it might be associated with other headache diseases too.
  • #1 Migraine | Nature Reviews Disease Primers
    https://www.nature.com/articles/s41572-021-00328-4
    Migraine is a common, chronic, disorder that is typically characterized by recurrent disabling attacks of headache and accompanying symptoms, including aura. […] Spreading depolarization probably causes aura and possibly also triggers trigeminal sensory activation, the underlying mechanism for the headache. […] Despite earlier beliefs, vasodilation is only a secondary phenomenon and vasoconstriction is not essential for antimigraine efficacy. […] Goadsby, P. J. et al. Pathophysiology of migraine: a disorder of sensory processing. […] Burstein, R., Noseda, R. Borsook, D. Migraine: multiple processes, complex pathophysiology. […] Charles, A. C. Baca, S. M. Cortical spreading depression and migraine. […] Ayata, C. Lauritzen, M. Spreading depression, spreading depolarizations, and the cerebral vasculature. […] Schain, A. J., Melo-Carrillo, A., Strassman, A. M. Burstein, R. Cortical spreading depression closes paravascular space and impairs glymphatic flow: implications for migraine headache. […] Karatas, H. et al. Spreading depression triggers headache by activating neuronal Panx1 channels.
  • #2 Migraine aura pathophysiology: the role of blood vessels and microembolisation
    https://pmc.ncbi.nlm.nih.gov/articles/PMC2921876/
    Migraine attacks with auras are sometimes associated with underlying hereditary or acquired cerebrovascular disorders. A unifying pathophysiological explanation linking migraine to these conditions has been difficult to identify. On the basis of genetic and epidemiological evidence, we suggest that changes in blood vessels, hypoperfusion disorders, and microembolisation can cause neurovascular dysfunction and evoke cortical spreading depression, an event that is widely thought to underlie aura symptoms. […] Although migraine with aura has many causes (eg, neuronal network excitability), it seems that migraine and stroke might both be triggered by hypoperfusion and could therefore exist on a continuum of vascular complications in a subset of patients who have these hereditary or acquired comorbid vascular conditions.
  • #2 Migraine With Nonvisual Aura
    https://practicalneurology.com/articles/2022-may/migraine-with-nonvisual-aura
    Migraine is a neurobiologic disease in which a genetic predisposition combined with environmental influences leads to neurologic dysfunction, of which headache is the most common symptom. Migraine is associated with an aura in about 30% of people with the disease, and is the onset of fully reversible symptoms that progress slowly before or during the headache. Aura is considered 1 of the 4 phases of a migraine attack. […] The aura phase of a migraine attack is thought to be due to cortical spreading depression (CSD), which is a slowly propagating wave of depolarization followed by cortical inhibition for up to 30 minutes and then depression of or decrease in electrical activity. The wave of CSD causes physiologic changes of hyperemia followed by a prolonged phase of oligemia. These changes are due to electrolyte and neurotransmitter fluctuations that propagate from the nerve to adjacent cells. Thus, blood vessel changes result from CSD and not the direct cause of aura. Because these changes are due to electrophysiologic changes rather than decreased blood flow, aura symptoms are reversible. CSD also explains why aura symptoms occur progressively with slow spread before resolving, whereas vascular symptoms are immediate and sometimes irreversible.
  • #2 fMRI Insights into Visual Cortex Dysfunction as a Biomarker for Migraine with Aura
    https://www.mdpi.com/2035-8377/17/2/15
    A key component of this process is CSD, a wave of neuronal and glial depolarisation, which is triggered by ion channel dysfunction, elevated Ca2+ levels, and excessive glutamate release. […] Contemporary evidence implicates a complex interplay between cortical hyperexcitability, vascular dysregulation, and aberrant neuronal signalling, which collectively underpin both the visual disturbances characteristic of aura and the subsequent headache phase. […] CSD is recognised as the primary mechanism underlying migraine aura and may also trigger trigeminal sensory activation, which contributes to the headache phase. […] The pathophysiology of migraine aura is intrinsically connected to genetic factors, particularly mutations in the CACNA1A gene, which encodes the alpha-1 subunit of the CaV2.1 calcium channel.
  • #2 Migraine Headache: Practice Essentials, Background, Pathophysiology
    https://emedicine.medscape.com/article/1142556-overview
    Activation of the trigeminovascular system by CSD stimulates nociceptive neurons on dural blood vessels to release plasma proteins and pain-generating substances such as calcitonin gene-related peptide, substance P, vasoactive intestinal peptide, and neurokinin A. […] The initial cortical hyperperfusion in CSD is partly mediated by the release of trigeminal and parasympathetic neurotransmitters from perivascular nerve fibers, whereas delayed meningeal blood flow increase is mediated by a trigeminal-parasympathetic brainstem connection. […] In addition, through a variety of molecular mechanisms, CSD upregulates genes, such as those encoding for cyclo-oxygenase 2 (COX-2), tumor necrosis factor alpha (TNF-alpha), interleukin-1beta, galanin, and metalloproteinases. […] The serotonin receptor (5-hydroxytryptamine [5-HT]) is believed to be the most important receptor in the headache pathway.
  • #2 Migraine: Advances in the Pathogenesis and Treatment
    https://www.mdpi.com/2035-8377/15/3/67
    CGRP plays a key role in transmitting pain signals and promoting inflammation. Its release is stimulated by the activation of the trigeminovascular system (TGVS) and severe migraine episodes. Infusion of CGRP has been observed to provoke migraine-like attacks in patients with migraine with aura (MA). […] Elevated serum Hcy concentration has been linked to migraine with aura (MA), and some studies have noted a relationship between increased Hcy levels and higher frequency and severity of migraine; however, these findings are not supported by all research. Hyperhomocysteinemia (elevated Hcy) is hypothesized to initiate migraine with aura attacks through changes in pain threshold. […] CGRP’s role extends to the pathogenesis of migraine, which is an intricate neurovascular disorder. This is typically characterized by a throbbing or pounding headache, which affects one side of the head. It is often accompanied by other symptoms, such as photophobia (light sensitivity), phonophobia (sound sensitivity), nausea, vomiting, and even disability. […] Researchers have found that CGRP triggers the release of vasoactive neuropeptides in trigeminal neurons, leading to vasodilation of the cerebral vasculature, thereby contributing to the emergence of a migraine.
  • #2 Migraine: Advances in the Pathogenesis and Treatment
    https://www.mdpi.com/2035-8377/15/3/67
    Migraine, a prevalent neurological disorder characterized by chronic headaches, is influenced by various pathophysiological mechanisms. By examining molecular markers and leveraging imaging techniques, the research identifies key mechanisms and triggers in migraine pathology, thereby improving our understanding of its pathophysiology. Special emphasis is given to the role of calcitonin gene-related peptide (CGRP) in migraine development. CGRP not only contributes to symptoms but also represents a promising therapeutic target, with inhibitors showing effectiveness in migraine management. […] The markers of inflammation and oxidative stress have been associated with migraine in several studies. Proinflammatory cytokines, such as interleukin-1 (IL-1) and interleukin-6 (IL-6), have been implicated in this condition. It has been found that the level of IL-1α is elevated in the blood of children suffering from migraine with aura (MA). Similarly, adults with MA have been found to exhibit higher plasma levels of IL-1β during headache-free periods and early stages of attacks as compared to those suffering from migraine without aura (MO).
  • #2 Unexpected Discovery Leads to Better Understanding of Migraine | University of Utah Health
    https://healthcare.utah.edu/press-releases/2020/12/unexpected-discovery-leads-better-understanding-of-migraine
    Massive plumes of glutamate, a key neurotransmitter, surging in the brain could help explain the onset of migraine with aura and potentially a broad swath of neurologic disease, including stroke and traumatic brain injury according to an international study led by University of Utah Health scientists. […] Glutamate plumes are a completely new mechanism of migraine, and it’s a good bet that they are players in other diseases of the nervous system. […] The common denominator is an imbalance between release and reuptake and an excess of glutamate in the extra-cellular space, Brennan says. […] Parker and colleagues found that plumes predicted the onset of spreading depolarizations, and that preventing plumes inhibited them. […] This shows that plumes don’t just coincide with spreading depolarizations, Parker says. They are involved in their generation.
  • #2 Genetics of migraine aura: an update | The Journal of Headache and Pain | Full Text
    https://thejournalofheadacheandpain.biomedcentral.com/articles/10.1186/s10194-020-01125-2
    Migraine is a common brain disorder with a large genetic component. Of the two main migraine types, migraine with aura and migraine without aura, the genetic underpinning in the former is least understood. Given the evidence from epidemiological studies in cohorts and families that the genetic contribution is highest in migraine with aura, this seems paradoxical. […] The likely underlying mechanism of the aura is cortical spreading depolarisation (CSD), a brief wave of neuronal and glial depolarization that slowly self-propagates across the cerebral cortex, originating in the occipital cortex, that is followed by long-lasting suppression of brain activity. […] A possible explanation for why GWAS appears more successful in migraine without aura might be that both migraine types are distinct disorders with a different genetic architecture.
  • #2 Vestibular Migraine With Brainstem Auras: A Review of Pathogenesis, Clinical Varieties, Abortive and Prophylactic Treatment | Zhang | Journal of Neurology Research
    https://www.neurores.org/index.php/neurores/article/view/651/668
    The mutated FHM genes code for ion transport protein that have associated with disturbed ion homeostasis, which is triggered by environment, causing episodes of headache with neurological deficits. […] The CACNA1A (FHM1) gene encodes the 1 subunit of Cav2.1 (P-Q-type) Ca2+ channels that modulate neurotransmitter release. […] The FHM2/SHM2 ATP1A2 gene on chromosome 1q23 encodes the 2-subunit of a Na+/K+-ATPase, which exchanges Na+ ions for K+ ions, creating a steep sodium gradient that facilitates removal of K+ and glutamate from the synaptic cleft into glial cells. […] Glutamate is the major excitatory neurotransmitter in the central nervous system; and altered brain excitability caused by disturbed glutamate homeostasis plays a role in various paroxysmal neurological disorders. […] Migraine with or without aura will experience long lasting hypoperfusion.
  • #2 Migraine with aura and persistent foramen ovale | Eye
    https://www.nature.com/articles/eye2017269
    The association between migraine with aura and persistent foramen ovale (PFO), as well as other right-to-left shunts, is described. A hypothesis that might explain this association is discussed. […] People with migraine with aura have an increased prevalence of PFO than controls, but people with migraine without aura do not have an increased prevalence of PFO. […] Overall, the data suggest that prevalence of migraine with aura increases with the size of right-to-left shunts, whatever their cause. This resulted in the hypothesis that substances that circumvent the pulmonary filter by crossing the shunt may be responsible for precipitating attacks of migraine with aura. […] People with migraine with aura have high incidences of shunt related events. […] The majority of episodes of neurological, cardiovascular and cutaneous decompression illness are the result of paradoxical gas embolismvenous bubbles that form during decompression circumventing the lung filter by crossing a PFO or other right-to-left shunt.
  • #2 Migraine and risk of stroke | Journal of Neurology, Neurosurgery & Psychiatry
    https://jnnp.bmj.com/content/91/6/593
    Migraine and stroke are two common and heterogeneous neurovascular disorders responsible for a significant burden for those affected and a great economic cost for the society. There is growing evidence that migraine increases the overall risk of cerebrovascular diseases. […] The mechanism behind the migraine-stroke association is unknown. In light of the higher risk of stroke in people with migraine with aura, it is important to identify and modify any vascular risk factor. […] Numerous studies, including five meta-analyses, have linked migraine, particularly migraine with aura (MA), with increased risk of ischaemic stroke. The relative risk of ischaemic stroke is doubled in people with MA compared with migraine-free individuals. […] The association between migraine and ischaemic stroke is stronger for women, women younger than 45 years, women who use oral contraceptives and women who smoke.
  • #2 Migraine and risk of stroke | Journal of Neurology, Neurosurgery & Psychiatry
    https://jnnp.bmj.com/content/91/6/593
    The risk is greater for those with active migraine (ie, migraine attack the last 12 months) and higher frequency of attacks; however, there is no conclusive evidence that the severity of migraine attacks influence the risk of ischaemic stroke. […] The classification of migraine and specifically MA in population-based studies is challenging. However, the consistent findings of the association between MA and ischaemic stroke across various study designs and classification schemes make a systematic bias unlikely. […] MA in women younger than age of 45 years and late onset of MA increase the risk of ischaemic stroke. Active migraine and increased attack frequency increase the risk of ischaemic stroke. […] The association between migraine and stroke is complicated by the fact that almost any cerebrovascular event (ie, ischaemic stroke, haemorrhagic stroke, subarachnoid haemorrhage, venous thrombosis) can trigger a migraine-like attack (with or without aura), which may lead to misinterpretation of the stroke event as complicated migraine.
  • #2 Aura and the Mechanism of Migraine: The Next Treatment Target?
    https://www.neurologylive.com/view/aura-and-the-mechanism-of-migraine-the-next-treatment-target/1000
    We have speculated that there could be a connection between CGRP and CSD, [and] I think its possible that the vascular actions of CGRP could contribute to CSD, Russo added. […] The case for a primary role of glutamate in CSD was presented by Andrew Charles, MD, of the department of neurology at the David Geffen School of Medicine at the University of California, Los Angeles, and colleague Jan Hoffman, MD, PhD, of Kings College London. […] They described the release of glutamate in CSD as a regenerative process, with the subsequent activation of presynaptic NMDA receptors eliciting further release of glutamate. […] Akerman and colleagues noted that the cortical hyperemia and oligemia in CSD are accompanied with NO changes and that these are significantly attenuated with NOS inhibition.
  • #2 Study Directly Links Mechanism of Aura to Migraine Pain | MDedge
    https://medauth2.mdedge.com/content/study-directly-links-mechanism-aura-migraine-pain
    The delayed neuronal activation observed in those 21 trials may be relevant to the typical delay between the onset of aura and the onset of migraine headache, though the underlying mechanisms remain unknown, wrote Dr. Zhang and coauthors. They noted that this observation may be the most clinically promising because intervention during the aura phase with drugs that would block the delayed induction of neuronal activation could potentially preempt the onset of migraine headache. […] The investigators proposed that the sustained activation of meningeal nociceptors could be the result of either a short-lasting release of algesic molecules during CSD that promotes an acute activation of the nociceptor and gives rise to an ongoing sensitization that typically outlasts the stimulus by 30-60 minutes, or an ongoing release of algesic molecules for up to 1 hour during CSD.
  • #2 May lamotrigine be an alternative to topiramate in the prevention of migraine with aura? Results of a retrospective study | BMJ Neurology Open
    https://neurologyopen.bmj.com/content/2/2/e000059
    Our study is the first to compare the efficacy of lamotrigine and topiramate in solely patients suffering from migraine with aura. Both treatments showed to equally reduce monthly frequency of migraine attacks at 6 months of follow-up. Consequently, our results suggest a similar efficacy of both treatments within the clinical setting of migraine with aura. Interestingly, the majority of lamotrigine-treated patients included in our study had been previously treated with at least another migraine prophylactic agent, suggesting that the therapeutic effect of lamotrigine was certainly not obtained in a population of less resistant patients. […] Regarding the effects on aura frequency and duration, our results showed a trend towards a better efficacy of lamotrigine compared with topiramate. Responder rates for monthly aura frequency were similar between the two treatment groups. However, approximately half of the lamotrigine-treated patients reported a complete disappearance of aura at 6-month follow-up. Additionally, lamotrigine determined a reduction of aura duration per episode of approximately 15min. In line with previous findings, lamotrigine should then be considered in clinical practice for the treatment of prolonged or disturbing migraine with aura.
  • #2 Researchers identify unknown signalling pathway in the brain responsible for migraine with aura – University of Copenhagen
    https://healthsciences.ku.dk/newsfaculty-news/2024/07/researchers-identify-unknown-signalling-pathway-in-the-brain-responsible-for-migraine-with-aura/
    Our results suggest that we have identified the primary channel of communication between the brain and the peripheral sensory nervous system. It is a previously unknown signalling pathway important for the development of migraine headache, and it might be associated with other headache diseases too, says Professor Maiken Nedergaard, who is senior author of the study. […] Most patients experience one-sided headaches, and this signalling pathway can help explain why. Our study of how proteins from the brain are transported shows that the substances are not carried to the entire intracranial space, but primarily to the sensory system in the same side, which is what causes one-sided headaches, says Martin Kaag Rasmussen. […] This means that when the proteins are released, they are carried to the trigeminal ganglion via the said signalling pathways, where they bind to a receptor of a pain-signalling sensory nerve, activating the nerve and triggering the migraine attack succeeding the aura symptoms. […] It is a previously unknown signalling pathway important for the development of migraine headache, and it might be associated with other headache diseases too.
  • #3 Pathophysiology, clinical manifestations, and diagnosis of migraine in adults – UpToDate
    https://www.uptodate.com/contents/pathophysiology-clinical-manifestations-and-diagnosis-of-migraine-in-adults
    The pathophysiology, clinical manifestations, diagnosis, and complications of migraine will be reviewed here. Other aspects of migraine are discussed separately. […] The current state of knowledge suggests that a primary neuronal dysfunction leads to a sequence of changes intracranially and extracranially that account for migraine, including the four phases of premonitory symptoms, aura, headache, and postdrome. […] Cortical spreading depression — A causal association between migraine aura and headache is supported by evidence that both are linked to the phenomenon known as cortical spreading depression of Leão. Cortical spreading depression is a self-propagating wave of neuronal and glial depolarization that spreads across the cerebral cortex.
  • #3 1.2 Migraine with aura – ICHD-3
    https://ichd-3.org/1-migraine/1-2-migraine-with-aura/
    Recurrent attacks, lasting minutes, of unilateral fully-reversible visual, sensory or other central nervous system symptoms that usually develop gradually and are usually followed by headache and associated migraine symptoms. […] The aura is the complex of neurological symptoms that occurs usually before the headache of 1.2 Migraine with aura, but it may begin after the headache phase has commenced, or continue into the headache phase. […] Before or simultaneously with the onset of aura symptoms, regional cerebral blood flow is decreased in the cortex corresponding to the clinically affected area and often over a wider area. Blood flow reduction usually starts posteriorly and spreads anteriorly, and is usually above the ischaemic threshold. After one to several hours, gradual transition into hyperaemia occurs in the same region. Cortical spreading depression of Leão is the likely underlying mechanism.
  • #3 May lamotrigine be an alternative to topiramate in the prevention of migraine with aura? Results of a retrospective study | BMJ Neurology Open
    https://neurologyopen.bmj.com/content/2/2/e000059
    Migraine is a common disabling neurological disorder, characterised by unilateral, pulsating, severe headache attacks, frequently associated with autonomic symptoms such as nausea, vomiting, photophobia and phonophobia. In approximately 30% of cases, migraine is preceded by or associated with transient, reversible, focal neurological symptoms called aura, which develops gradually over 520min and usually lasts for less than an hour. The most common aura symptoms are visual and sensory ones, followed by language, motor and brainstem disturbances. […] Pathophysiology of migraine aura has been linked to cortical spreading depression (CSD), which consists in a self-propagating wave of depolarization, followed by a more slowly-propagating wave of neuronal inhibition usually developing within the occipital cortex and then spreading throughout more anterior cortical areas at a speed of 36mm/min. According to experimental models, CSD is characterised by changes in extracellular potassium concentrations and neuronal glutamate release, which determine the propagation of the depolarization wave. Perfusion weighted and functional MRI studies showed a causal relationship between CSD and aura within human visual cortex highlighting CSD causative role in determining the aura phenomenon.
  • #3 fMRI Insights into Visual Cortex Dysfunction as a Biomarker for Migraine with Aura
    https://www.mdpi.com/2035-8377/17/2/15
    These mutations enhance the excitability of CaV2.1 channels by reducing their activation threshold, thereby increasing calcium influx into presynaptic terminals. […] The resultant elevation in calcium influx promotes excessive glutamate release, precipitating CSD, a fundamental mechanism underlying the transient visual disturbances characteristic of migraine aura. […] CSD also initiates mechanisms of peripheral and central sensitisation that contribute to the manifestation of migraine headaches. […] A key factor in the pathogenesis of migraine aura is neurovascular coupling, the physiological mechanism that combines cerebral blood flow with neuronal activity. […] The onset of aura symptoms is correlated with the onset of an initial period of regional hyperaemia, which is followed by a prolonged oligemia.
  • #3 May lamotrigine be an alternative to topiramate in the prevention of migraine with aura? Results of a retrospective study | BMJ Neurology Open
    https://neurologyopen.bmj.com/content/2/2/e000059
    Lamotrigine is equally effective as topiramate for the preventive treatment of migraine with aura and exhibits a better tolerability profile. Lamotrigine should be considered in clinical practice especially for patients reporting prolonged aura and who do not respond, have contraindications or discontinue topiramate treatment due to side effects.
  • #4 Migraine Headache: Practice Essentials, Background, Pathophysiology
    https://emedicine.medscape.com/article/1142556-overview
    Migraine was previously considered to be a vascular phenomenon that resulted from intracranial vasoconstriction followed by rebound vasodilation. Currently, however, the neurovascular theory describes migraine as primarily a neurogenic process with secondary changes in cerebral perfusion associated with a sterile neurogenic inflammation (see Pathophysiology). […] The neurovascular theory holds that a complex series of neural and vascular events initiates migraine. According to this theory, migraine is primarily a neurogenic process with secondary changes in cerebral perfusion. […] In 1944, Leao proposed the theory of cortical spreading depression (CSD) to explain the mechanism of migraine with aura. CSD is a well-defined wave of neuronal excitation in the cortical gray matter that spreads from its site of origin at the rate of 2-6 mm/min.

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zapalenie neurogenne gen SCN1A syntaza tlenku azotu zwój trójdzielny mikroembolizacja kanał wapniowy nerw trójdzielny receptor serotoninowy tlenek azotu czynnik martwicy nowotworów alfa interleukina-1 cyklooksygenaza-2 topiramat przetrwały otwór owalny glutaminian migrena hemiplegiczna wazodilatator receptor NMDA homeostaza jonowa przepływ krwi mózgowej lamotrigina cytokiny prozapalne peptyd związany z genem kalcytoniny mutacje genetyczne gen CACNA1A migrena z aurą aura migrenowa