1. HEADACHE PATHOPHYSIOLOGY Andrew Charles, M.D. Professor Director, Headache Research and Treatment Program David Geffen School of Medicine at UCLA

2. MIGRAINE – A MULTISYMPTOM COMPLEX PATHOPHYSIOLOGICAL MECHANISMS

3.  Penfield W. A contribution to the mechanism of intracranial pain. Assoc Res Nerv Ment Dis. 1935;15:399-416.  Ray BS, Wolff HG. Experimental studies in headache: Pain- sensitive structures of the head and their significance in headache. Arch Surg. 1940;41:813-856.

4. Issues with Studies of Ray and Wolff, Penfield Stimulation of vessels was focal external stimulation or mechanical dilation There is no evidence that physiological relaxation of smooth muscle and resultant dilation can cause pain

5. Headache Can Be Evoked by Stimulation of Specific Brain Regions Headache can be evoked by lesions or electrodes in the periaqueductal grey in the brainstem in the absence of vasodilation Head pain can be evoked by stimulation of insular cortex in the absence of vascular change Raskin NH, et al. Headache. 1987;27:416-420. Haas DC, et al. Headache. 1993;33:452-455. Ostrowsky K, et al. Cereb Cortex. 2002;12:376-385.

6. Vasoactive Drugs Cause Migraine After Significant Delay (hours), Not Correlated with Vasodilation Nitric oxide donors PDE inhibitors HistamineCGRP Vasoactive Intestinal Peptide – No migraine Schoonman, et al. 3T MRI-measured diameter changes of meningeal and cerebral blood vessels during nitroglycerin provoked migraine attack. Poster presented at Migraine Trust 2006. Cephalalgia. 2006 26:1388- 89. Kruus, et al. Migraine can be induced by sildenafil without changes in middle cerebral artery diameter. Brain. 2003;26:241-247. Rahman et al., Vasoactive intestinal peptide causes marked cerebral vasodilation but does not induce migraine. Cephalalgia. 28, 226-236, 2008.

7. Alternative Mechanisms of “ Vascular” Drugs  -blockers –Inhibit neuronal adrenergic signaling Calcium channel blockers –Inhibit neuronal calcium channels Caffeine –Neuronal/glial adenosine receptor antagonist Ergotamines –Modulate central 5-HT receptors Triptans –Activate neuronal 5-HT1 receptors in brainstem and thalamus

8. CHANGING CONCEPTS OF MIGRAINE PATHOGENESIS MIGRAINE IS A DISORDER OF BRAIN EXCITABILITY MIGRAINE IS A DISORDER OF BRAIN EXCITABILITY VASODILATION MAY OCCUR AS PART OF THE DISORDER, BUT IS NOT REQUIRED FOR MIGRAINE PAIN VASODILATION MAY OCCUR AS PART OF THE DISORDER, BUT IS NOT REQUIRED FOR MIGRAINE PAIN VASOCONSTRICTION MAY BE MORE IMPORTANT THAN VASODILATION AS AN INITIAL TRIGGER FOR MIGRAINE SYMPTOMS

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

10. PET STUDY SHOWS SPREADING OLIGEMIA IN MIGRAINE PATIENT WITHOUT AURA

11. 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

12. 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)

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

14. MIGRAINE – A MULTISYMPTOM COMPLEX CorticalActivation BrainstemActivation HypothalamicActivation

15. CORTICAL SPREADING DEPRESSION (CSD) WAVE OF ACTIVATION FOLLOWED BY REDUCED ACTIVITY THAT SPREADS ACROSS THE SURFACE OF THE BRAIN SPREADS WITH CHARACTERISTICS THAT ARE VERY SIMILAR TO THE CLINICAL SYMPTOMS AND PET AND MRI CHANGES OF MIGRAINE

17. 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

18. OPTICAL IMAGING OF CORTICAL SPREADING DEPRESSION -- K.C. Brennan 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

19. 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

20. ISSUES WITH CLASSICAL CORTICAL SPREADING DEPRESSION IN MIGRAINE CLASSIC EEG FINDINGS OF CORTICAL SPREADING DEPRESSION RARELY SEEN IN HUMANS CLASSIC EEG FINDINGS OF CORTICAL SPREADING DEPRESSION RARELY SEEN IN HUMANS 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 DIFFERENT TYPES OF CORTICAL WAVES MAY BE PRODUCED BY DISTINCT CELLULAR MECHANISMS

21. VASCULAR EVENTS IN CORTICAL ARTERIOLES WITH CSD IN MOUSE VASCULAR EVENTS IN CORTICAL ARTERIOLES WITH CSD IN MOUSE – INITIAL DILATION Conducted With Intrinsic Velocity Ahead of CSD Conducted With Intrinsic Velocity Ahead of CSD – SUBSEQUENT CONSTRICTION – EVENTUAL DILATION

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

23. ARTERIOLAR DILATION PROPAGATES AHEAD OF PARENCHYMAL CHANGES OF CSD COULD VASCULAR SIGNALING PLAY AN ACTIVE RATHER THAN MERELY PASSIVE ROLE IN CSD?

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

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. A ROLE FOR ASTROCYTE WAVES IN MIGRAINE? SIMILAR TEMPORAL AND SPATIAL CHARACTERISTICS AS MIGRAINE EVENTS OCCUR IN PARALLEL WITH CSD ASSOCIATED RELEASE OF ATP, GLUTAMATE, AND OTHER NEURO- AND VASO-ACTIVE SUBSTANCES ASSOCIATED CHANGES IN EXTRACELLULAR IONIC COMPOSITION INTIMATE SPATIAL RELATIONSHIPS WITH SYNAPSE AND VASCULATURE COULD EXPLAIN DRAMATIC PROPAGATION WITH RELATIVELY MILD NEUROLOGICAL SYMPTOMS

29. HUMAN ASTROCYTE WITH BLOOD VESSEL AND NEURONS Maiken Nedergaard

30. 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

31. Release of nociceptive and inflammatory mediators ATPATP GlutamateGlutamate InterleukinsInterleukins Vasoconstriction CGRP Release DEPRESSION SPREADING DEPRESSION ASTROCYTE ASTROCYTE CALCIUM WAVES MIGRAINE MECHANISMS Blood Brain Barrier Opening

32. Olesen J, et al. Ann Neurol. 1990;28:791-798. Headache is not temporally correlated with either hypo- or hyperperfusion Migraine pain begins during hypoperfusion phase Hyperperfusion may outlast pain

33. “The cerebrovascular trigeminal neuronal system, in which CGRP is the most potent vasoactive constituent, may participate in a reflex or local response to excessive cerebral vasoconstriction that restores normal vascular diameter.” Chronic division of trigeminal nerve prolongs recovery from vasoconstriction

34. CGRP (Calcitonin Gene Related Peptide) IN MIGRAINE CGRP IS RELEASED INTO JUGULAR VENOUS SYSTEM DURING A MIGRAINE ATTACK CGRP INFUSION EVOKES MIGRAINE CGRP RECEPTOR ANTAGONISTS EFFECTIVELY ABORT A MIGRAINE ATTACK WHERE IS THE SITE OF ACTION? Lassen L, Haderslev P, Jacobsen V et al. CGRP may play a causative role in migraine. Cephalalgia. 2002;22:54-61 Goadsby PJ, Edvinsson L. Human in vivo evidence for trigeminovascular activation in cluster headache. Neuropeptide changes and effects of acute attacks therapies. Brain. 1994;117 ( Pt 3):427-434 Olesen J, Diener H-C, Husstedt IW et al. Calcitonin Gene-Related Peptide Receptor Antagonist BIBN 4096 BS for the Acute Treatment of Migraine. N Engl J Med. 2004;350:1104-1110 Ho TW, Mannix LK, Fan X et al. Randomized controlled trial of an oral CGRP receptor antagonist, MK-0974, in acute treatment of migraine. Neurology. 2008;70:1304-1312 Ho TW, Ferrari MD, Dodick DW et al. Efficacy and tolerability of MK-0974 (telcagepant), a new oral antagonist of calcitonin gene- related peptide receptor, compared with zolmitriptan for acute migraine: a randomised, placebo-controlled, parallel- treatment trial. Lancet. 2009;372:2115-2123

35. CGRP RECEPTOR STRUCTURE Adrenomedullin Calcitonin Gene Related Peptide Receptor Activity Modifying Protein Lennerz et al, J. Comp. Neurol., 2008

36. Dural Mast cells Dural Arterioles Trigeminal Ganglion Neurons and Satellite Cells Trigeminal Schwann Cells Afferent fibers in TNC

37. HEADACHE GENETICS MULTIPLE POSSIBLE GENES FOR MIGRAINE – NONE HAVE BEEN SHOWN YET FOR COMMON FORMS OF MIGRAINE GENES FOR FAMILIAL HEMIPLEGIC MIGRAINE – FHM1 - CACNA1A – NEURONAL P/Q CALCIUM CHANNEL – INCREASES NEUROTRANSMITTER RELEASE – FHM2 - ATP1A2 – ASTROCYTE SODIUM PUMP – DYSFUNCTION INCREASES EXTRACELLULAR K + – FHM3 - SCN1A – NEURONAL SODIUM CHANNEL – INCREASED ACTION POTENTIAL FIRING

38. ROLE OF GENDER AND HORMONES IN CORTICAL EXCITABILITY AND MIGRAINE In children, migraine prevalence is almost equal in boys and girls. During reproductive years, prevalence of migraine is 3 X as high in women as men during reproductive years. After menopause, migraine prevalence remains 2X as high in women as men.

39. REDUCED THRESHOLD FOR ACTIVATION OF CSD IN FEMALE VS. MALE MICE Brennan et al., Annals of Neurology 2007

40. GROWING EVIDENCE THAT CSD IN RODENT MODELS IS A VALID MODEL FOR MIGRAINE Genetic alterations associated with familial hemiplegic migraine, and possibly migraine with aura, alter CSD Genetic alterations associated with familial hemiplegic migraine, and possibly migraine with aura, alter CSD Multiple migraine preventive medications inhibit CSD Multiple migraine preventive medications inhibit CSD CSD is altered by gender CSD is altered by gender

41. MEMANTINE FOR MIGRAINE PREVENTION Activity dependent blocker of NMDA receptors Identified as a blocker of CSD in rodents Appears to be effective as a migraine preventive therapy for significant percentage of patients with frequent migraine who had failed other preventive therapies It is generally very well tolerated Well designed studies are warranted Peeters et al., JPET, 2007 Charles, et al., Journal of Headache and Pain, 2007 Bigal et al., Headache, 2008

42. PFO and MIGRAINE? HIGHER INCIDENCE OF BIG PFO’s IN PATIENTS WHO HAVE MIGRAINE WITH AURA. UNBLINDED, UNCONTROLLED STUDIES SHOW SIGNIFICANT REDUCTION IN MIGRAINES FOLLOWING PFO CLOSURE BUT…. STRONG POSSIBLITY OF PLACEBO EFFECT MEDICATIONS (PLAVIX) MAY HAVE ROLE BLINDED, CONTROLLED STUDIES ARE REQUIRED

43. DIFFERENCES IN BRAIN STRUCTURE IN PATIENTS WITH MIGRAINE?

44. MIGRAINE AND THE BLOOD BRAIN BARRIER Opening of BBB during a migraine attack has been speculated based on efficacy of medications not expected to cross intact BBB Opening of BBB could contribute to migraine via multiple mechanisms Could be a mechanism for white matter lesions in migraine Young VG, Halliday GM, Kril JJ. Neuropathologic correlates of white matter hyperintensities. Neurology. 2008;71:804-811

45. CORTICAL SPREADING DEPRESSION MAY BE ASSOCIATED WITH BREAKDOWN OF THE BLOOD BRAIN BARRIER

46. White Matter Lesions in Migraine Etiology ? Functional Significance?

47. MODULATING FACTORS Genes Gender/Hormones Ionic/Metabolic Drugs Environment MODULATING FACTORS Genes Gender/Hormones Ionic/Metabolic Drugs Environment DYSREGULATION OF CORTICAL BRAINSTEM, HYPOTHALAMIC EXCITABILITY DYSREGULATION OF CORTICAL BRAINSTEM, HYPOTHALAMIC EXCITABILITY CORTICAL WAVES Spreading depression Astrocyte waves Vascular waves CORTICAL WAVES Spreading depression Astrocyte waves Vascular waves BRAINSTEM /HYPOTHALAMIC ACTIVATION Trigeminal nucleus caudalis Periaqueductal gray Central sensitization AURA Visual Sensory Cognitive PAIN SENSORY SENSITIVITY Photo/phonophobia Cutaneous allodynia NAUSEA VERTIGO FATIGUE MOOD CHANGE SENSORY SENSITIVITY Photo/phonophobia Cutaneous allodynia NAUSEA VERTIGO FATIGUE MOOD CHANGE NOCICEPTIVE ACTIVATION Release of nociceptive messengers Vasoconstriction Vascular/metabolic uncoupling BBB Permeability

48. MODULATORS OF CERVICAL INPUT TO HEADACHE Occipital Nerve Stimulation INHIBITORS OF CORTICAL SPREADING DEPRESSION Memantine, Tonabersat, Transcranial Magnestic Stimulation POTENTIAL NEW THERAPIES FOR MIGRAINE Adapted from Jones HR. Netter’s Neurology, St. Louis, MO; Saunders; 2005. INHIBITORS OF CGRP RECEPTOR Telcagepant CIRCULATORY TRIGGERS TO BRAIN EXCITABILITY? PFO Closure

49. 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