1. MIGRAINE AURA NEW INSIGHTS AND PERSISTENT QUESTIONS Andrew Charles, M.D. Professor Director, Headache Research and Treatment Program David Geffen School of Medicine at UCLA

2. MIGRAINE – A MULTISYMPTOM COMPLEX PATHOPHYSIOLOGICALMECHANISMS AURA LANGUAGE SYMPTOMS MOTORDYSFUNCTION YAWNING,POLYURIA

3. ICHD Classification of Migraine With Aura A. At least 2 attacks fulfilling criteria B–D B. Aura consisting of at least one of the following, but no motor weakness: 1. fully reversible visual symptoms including positive features (eg, flickering lights, spots or lines) and/or negative features (ie, loss of vision) 1. fully reversible visual symptoms including positive features (eg, flickering lights, spots or lines) and/or negative features (ie, loss of vision) 2. fully reversible sensory symptoms including positive features (ie, pins and needles) and/or negative features (ie, numbness) 2. fully reversible sensory symptoms including positive features (ie, pins and needles) and/or negative features (ie, numbness) 3. fully reversible dysphasic speech disturbance 3. fully reversible dysphasic speech disturbance C. At least two of the following: 1. homonymous visual symptoms and/or unilateral sensory symptoms 1. homonymous visual symptoms and/or unilateral sensory symptoms 2. at least one aura symptom develops gradually over ≥5 minutes and/or different aura symptoms occur in succession over ≥5 minutes 2. at least one aura symptom develops gradually over ≥5 minutes and/or different aura symptoms occur in succession over ≥5 minutes 3. each symptom lasts ≥5 and <60 minutes 3. each symptom lasts ≥5 and <60 minutes D. Headache fulfilling criteria B–D for 1.1 Migraine without aura begins during the aura or follows aura within 60 minutes E. Not attributed to another disorder

4. DIFFERENT CLINCIAL FEATURES OF MIGRAINE WITH VS. WITHOUT AURA Different patterns of inheritance Different patterns of inheritance Different occurrence relative to menstrual cycle Different occurrence relative to menstrual cycle Higher incidence of allodynia in patients with aura Higher incidence of allodynia in patients with aura Vibeke et al., Evidence of a genetic factor in migraine with aura: A population-based Danish twin study. Annals of Neurology. 1999;45:242-6. Vibeke et al., Evidence of a genetic factor in migraine with aura: A population-based Danish twin study. Annals of Neurology. 1999;45:242-6. MacGregor E. Oestrogen and attacks of migraine with and without aura. The Lancet Neurology. 2004;3:354-61. MacGregor E. Oestrogen and attacks of migraine with and without aura. The Lancet Neurology. 2004;3:354-61. Lipton RB, Bigal ME, Ashina S, Burstein R, Silberstein S, Reed ML, et al. Cutaneous allodynia in the migraine population. Ann Neurol. 2008;63:148-58. Lipton RB, Bigal ME, Ashina S, Burstein R, Silberstein S, Reed ML, et al. Cutaneous allodynia in the migraine population. Ann Neurol. 2008;63:148-58.

5. MIGRAINE WITH AURA HAS GREATER ASSOCIATION WITH: STROKE STROKE PATENT FORAMEN OVALE PATENT FORAMEN OVALE CARDIOVASCULAR DISEASE IN WOMEN CARDIOVASCULAR DISEASE IN WOMEN DEPRESSION DEPRESSION ANXIETY, PANIC, PHOBIAS, SUICIDAL IDEATION ANXIETY, PANIC, PHOBIAS, SUICIDAL IDEATION Schwedt TJ, Demaerschalk BM, Dodick DW. Cephalalgia. 2008;28:531-40. Kurth T, Gaziano JM, Cook NR, Logroscino G, Diener HC, Buring JE. Jama. 2006;296:283-91. Kurth T, Slomke MA, Kase CS, Cook NR, Lee IM, Gaziano JM, et al. Neurology. 2005;64:1020-6. Samaan Z, Farmer A, Craddock N, Jones L, Korszun A, Owen M, McGuffin P. The British Journal of Psychiatry. 2009;194:350-4.

6. HOWEVER…. VERY FEW MA PATIENTS HAVE AURA WITH 100% OF THEIR ATTACKS VERY FEW MA PATIENTS HAVE AURA WITH 100% OF THEIR ATTACKS MANY PATIENTS CLASSIFIED AS HAVING MIGRAINE WITHOUT AURA HAVE HAD 1 or 2 EPISODES WITH TYPICAL AURA MANY PATIENTS CLASSIFIED AS HAVING MIGRAINE WITHOUT AURA HAVE HAD 1 or 2 EPISODES WITH TYPICAL AURA CLINICAL SYMPTOMS MAY NOT MEET DEFINITION OF AURA (e.g. cognitive symptoms, timing relative to headache,) CLINICAL SYMPTOMS MAY NOT MEET DEFINITION OF AURA (e.g. cognitive symptoms, timing relative to headache,)

7. Olesen, et al. 1981 Hadjikhani et al., 2001 Cao et al., 1999 CORTICAL “WAVES” IN MIGRAINE WITH AURA Bereczki et al., 2008

8. PET STUDY SHOWS SPREADING OLIGEMIA IN MIGRAINE PATIENT WITHOUT AURA Woods RP, Iacoboni M, Mazziotta JC.. N Engl J Med. 1994;331:1689-92.

9. Woods et al., 1994 Chalaupka, 2008 Denuelle et al., 2008 Before sumatriptan 2 to 4 h after the attack onset After sumatriptan 4 to 6 h after the attack onset …AND MIGRAINE WITHOUT AURA

10. UNDERLYING PATHOPHYSIOLOGICAL MECHANISMS OF AURA MAY BE CLINICALLY SILENT UNDERLYING PATHOPHYSIOLOGICAL MECHANISMS OF AURA MAY BE CLINICALLY SILENT ABSENCE OF AURA SYMPTOMS, PARTICULARLY THOSE STRICTLY DEFINED BY ICHD CRITERIA, DOES NOT MEAN THAT CORTICAL PHENOMENA ARE NOT OCCURRING ABSENCE OF AURA SYMPTOMS, PARTICULARLY THOSE STRICTLY DEFINED BY ICHD CRITERIA, DOES NOT MEAN THAT CORTICAL PHENOMENA ARE NOT OCCURRING

11. Afridi, S. K. et al. Brain 2005 128:932-939; Activation of the ipsilateral pons in patients with right-sided attacks (n = 8, A) and left-sided attacks (n = 8, B)

12. Hypothalamic Activation in Migraine (Denuelle et al., Headache, 2007)

13. MIGRAINE – A MULTISYMPTOM COMPLEX AURA LANGUAGE SYMPTOMS MOTORDYSFUNCTION YAWNING,POLYURIA CorticalActivation BrainstemActivation HypothalamicActivation

15. OPTICAL IMAGING OF CORTICAL SPREADING DEPRESSION Allows visualization of parenchymal and vascular signals Allows visualization of parenchymal and vascular signals over large area with local electrophysiological recording over large area with local electrophysiological recording Induction thresholds can be reliably established Induction thresholds can be reliably established CSD evoked by KCl pulse --- rat cortex. 5 minute recording

16. OPTICAL IMAGING OF CORTICAL SPREADING DEPRESSION -- DIGITAL SUBTRACTION IMAGE K.C. Brennan CSD evoked by KCl pulse --- mouse cortex. 5 minute recording

17. Fabricius, M. et al. Brain 2006 129:778-790;. Recording of CSD in the injured human cortex over a period of 40 min SPREADING DEPRESSION IN HUMANS WITH BRAIN INJURY PLAYS A ROLE IN PROGRESSION OF INJURY

18. ISSUES WITH CLASSICAL CORTICAL SPREADING DEPRESSION IN MIGRAINE CLASSIC EEG FINDINGS OF CORTICAL SPREADING HAVE NOT BEEN OBSERVED IN MIGRAINE PATIENTS CLASSIC EEG FINDINGS OF CORTICAL SPREADING HAVE NOT BEEN OBSERVED IN MIGRAINE PATIENTS MOST PATIENTS DO NOT HAVE THE PROFOUND NEUROLOGICAL IMPAIRMENT ONE WOULD EXPECT WITH CLASSICAL CSD MOST PATIENTS DO NOT HAVE THE PROFOUND NEUROLOGICAL IMPAIRMENT ONE WOULD EXPECT WITH CLASSICAL CSD MIGRAINE MAY INVOLVE CORTICAL WAVES THAT ARE RELATED TO, BUT NOT IDENTICAL TO CSD OBSERVED IN ANIMAL MODELS MIGRAINE MAY INVOLVE CORTICAL WAVES THAT ARE RELATED TO, BUT NOT IDENTICAL TO CSD OBSERVED IN ANIMAL MODELS DIFFERENT TYPES OF CORTICAL WAVES MAY INVOLVE DISTINCT CELLULAR MECHANISMS DIFFERENT TYPES OF CORTICAL WAVES MAY INVOLVE DISTINCT CELLULAR MECHANISMS

19. VASCULAR EVENTS IN CORTICAL ARTERIOLES WITH CSD VASCULAR EVENTS IN CORTICAL ARTERIOLES WITH CSD – INITIAL DILATION Conducted With Intrinsic Velocity Ahead of CSD Conducted With Intrinsic Velocity Ahead of CSD – SUBSEQUENT CONSTRICTION – EVENTUAL DILATION OR SUSTAINED CONSTRICTION – MAY DEPEND ON METABOLIC STATE

20. INTRINSIC VASCULAR CONDUCTION WITH CSD Brennan et al., J. Neurophys, 2007 CSD evoked by KCl pulse --- mouse cortex. 5 minute recording

21. VASCULAR CELLS RELEASE DIFFUSIBLE MESSENGERS THAT MAY INFLUENCE ACTIVITY OF NEIGHBORING NEURONS AND GLIAL CELLS

22. K.C. Brennan Spontaneous CSD in setting of hypoxia – profound vasoconstriction

23. ARTERIOLAR DILATION PROPAGATES AHEAD OF PARENCHYMAL CHANGES OF CSD COULD VASCULAR SIGNALING PLAY AN ACTIVE ROLE IN CORTICAL WAVES? “It seems well to consider, therefore, that, however brought about, vascular changes may precede and condition the cortical depression”. Leao, J. Neurophys, 1945

24. HUMAN ASTROCYTE WITH BLOOD VESSEL AND NEURONS Maiken Nedergaard

25. Calcium wave evoked by mechanical stimulation in glial culture. Real Time Astrocytes are capable of widespread intercellular signaling via propagated waves of increased intracellular calcium

26. ASTROCYTE CALCIUM WAVES SLOWLY PROPAGATED WAVES EVOKED BY WIDE VARIETY OF STIMULI SLOWLY PROPAGATED WAVES EVOKED BY WIDE VARIETY OF STIMULI ASSOCIATED WITH ACTIVE RELEASE OF: ASSOCIATED WITH ACTIVE RELEASE OF: – ATP – GLUTAMATE – K+ – LACTATE – PROSTANOIDS – INTERLEUKINS CAPABLE OF ACTIVE MODULATION OF NEURONAL AND VASCULAR ACTIVITY CAPABLE OF ACTIVE MODULATION OF NEURONAL AND VASCULAR ACTIVITY

27. Multifocal Astrocyte Calcium Waves in Cortical Slice Multifocal CSD Evoked by KCl Crystal In Vivo CORTICAL WAVES MAY BE REPETITIVE, MULTIFOCAL EVENTS

28. Na+/K+ ATPase P/Q Ca 2+ Channel Nav1 Na+ Channel FHM Mutations Neurons Astrocytes Vascular cells ATP Adenosine GLUTAMATE Eicosanoids K+ ATP Adenosine Nitric Oxide Endothelin CGRP

29. PROPENSITY FOR CSD IS INCREASED BY: PROPENSITY FOR CSD IS INCREASED BY: GENES -- Transgenic mice expressing FHM1 genes show increased propensity for CSD GENES -- Transgenic mice expressing FHM1 genes show increased propensity for CSD GENDER – Female mice have a reduced threshold for CSD GENDER – Female mice have a reduced threshold for CSD HORMONES – Ovarian hormones reduce the threshold for CSD HORMONES – Ovarian hormones reduce the threshold for CSD van den Maagdenberg AMJM, Pietrobon D, Pizzorusso T, Kaja S, Broos LAM, Cesetti T, et al. Neuron. 2004;41:701-10.van den Maagdenberg AMJM, Pietrobon D, Pizzorusso T, Kaja S, Broos LAM, Cesetti T, et al. Neuron. 2004;41:701-10. Brennan KC, Romero-Reyes M, López Valdés HE, Arnold AP, Charles AC. Annals of Neurology. 2007;61:603-6.Brennan KC, Romero-Reyes M, López Valdés HE, Arnold AP, Charles AC. Annals of Neurology. 2007;61:603-6. Eikermann-Haerter K, Dileköz E, Kudo C, Savitz SI, Waeber C, Baum MJ, et al. J Clin Invest. 2009;119:99-109.Eikermann-Haerter K, Dileköz E, Kudo C, Savitz SI, Waeber C, Baum MJ, et al. J Clin Invest. 2009;119:99-109.

30. MEDICATIONS THAT INHIBIT CORTICAL EXCITABILITY PREVENT MIGRAINE WITH AND WITHOUT AURA Ayata et al., Annals of Neurology 2006. Ayata et al., Annals of Neurology 2006. – Diverse pharmacological agents that are effective for migraine prevention suppress cortical spreading depression in rat. Memantine for migraine prevention?? Memantine for migraine prevention?? – Identified as an inhibitor of CSD – Initial clinical results encouraging (Charles, et al, Journal of Headache and Pain, 2007). Specific neuronal, astrocytic, and vascular cortical mechanisms may represent individual distinct targets for new acute and preventive therapies Specific neuronal, astrocytic, and vascular cortical mechanisms may represent individual distinct targets for new acute and preventive therapies

31. MIGRAINE – A MULTISYMPTOM COMPLEX AURA LANGUAGE SYMPTOMS MOTORDYSFUNCTION YAWNING,POLYURIA CorticalActivation BrainstemActivation HypothalamicActivation

32. Acknowledgements UCLA Headache Research and Treatment Program UCLA Headache Research and Treatment Program – K.C. Brennan – Marcelo Romero Reyes – Hector Lopez-Valdes Feldman Lab Feldman Lab – Mike Baca UCSF/HHMI UCSF/HHMI – – Louis Ptáček – Ying-Hui Fu – Ying Xu – Archana Shenoy University of Vermont University of Vermont – Robert E. Shapiro Department of Neurology/Brain Mapping Center Department of Neurology/Brain Mapping Center – John Mazziotta – Arthur Toga