HEADACHE PATHOPHYSIOLOGY Issues with Studies of Ray in addition to Wolff, Penfield Headache Can Be Evoked by Stimulation of Specific Brain Regions Alternative Mechanisms of “ Vascular” Drugs CHANGING CONCEPTS OF MIGRAINE PATHOGENESIS

HEADACHE PATHOPHYSIOLOGY Issues with Studies of Ray in addition to Wolff, Penfield Headache Can Be Evoked by Stimulation of Specific Brain Regions Alternative Mechanisms of “ Vascular” Drugs CHANGING CONCEPTS OF MIGRAINE PATHOGENESIS www.phwiki.com

HEADACHE PATHOPHYSIOLOGY Issues with Studies of Ray in addition to Wolff, Penfield Headache Can Be Evoked by Stimulation of Specific Brain Regions Alternative Mechanisms of “ Vascular” Drugs CHANGING CONCEPTS OF MIGRAINE PATHOGENESIS

Ott, Tanya, News Director has reference to this Academic Journal, PHwiki organized this Journal HEADACHE PATHOPHYSIOLOGY Andrew Charles, M.D. Professor Director, Headache Research in addition to Treatment Program David Geffen School of Medicine at UCLA MIGRAINE – A MULTISYMPTOM COMPLEX PATHOPHYSIOLOGICAL MECHANISMS 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 in addition to their significance in headache. Arch Surg. 1940;41:813-856.

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Issues with Studies of Ray in addition to Wolff, Penfield Stimulation of vessels was focal external stimulation or mechanical dilation There is no evidence that physiological relaxation of smooth muscle in addition to resultant dilation can cause pain 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. Vasoactive Drugs Cause Migraine After Significant Delay (hours), Not Correlated with Vasodilation Nitric oxide donors PDE inhibitors Histamine CGRP Vasoactive Intestinal Peptide – No migraine Schoonman, et al. 3T MRI-measured diameter changes of meningeal in addition to 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.

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 in addition to thalamus CHANGING CONCEPTS OF MIGRAINE PATHOGENESIS MIGRAINE IS A DISORDER OF BRAIN EXCITABILITY 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 Olesen, et al. 1981 Hadjikhani et al., 2001 Cao et al., 1999 CORTICAL “WAVES” IN MIGRAINE WITH AURA Bereczki et al., 2008

PET STUDY SHOWS SPREADING OLIGEMIA IN MIGRAINE PATIENT WITHOUT AURA Woods et al., 1994 Chalaupka, 2008 AND MIGRAINE WITHOUT AURA Afridi, S. K. et al. Brain 2005 128:932-939; Activation of the ipsilateral pons in patients with right-sided attacks (n = 8, A) in addition to left-sided attacks (n = 8, B)

Hypothalamic Activation in Migraine (Denuelle et al., Headache, 2007) MIGRAINE – A MULTISYMPTOM COMPLEX Cortical Activation Brainstem Activation Hypothalamic Activation 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

OPTICAL IMAGING OF CORTICAL SPREADING DEPRESSION Allows visualization of parenchymal in addition to vascular signals over large area with local electrophysiological recording Induction thresholds can be reliably established CSD evoked by KCl pulse — rat cortex. 5 minute recording OPTICAL IMAGING OF CORTICAL SPREADING DEPRESSION – K.C. Brennan Allows visualization of parenchymal in addition to vascular signals over large area with local electrophysiological recording Induction thresholds can be reliably established CSD evoked by KCl pulse — rat cortex. 5 minute recording

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 ISSUES WITH CLASSICAL CORTICAL SPREADING DEPRESSION IN MIGRAINE 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 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 VASCULAR EVENTS IN CORTICAL ARTERIOLES WITH CSD IN MOUSE INITIAL DILATION Conducted With Intrinsic Velocity Ahead of CSD SUBSEQUENT CONSTRICTION EVENTUAL DILATION

INTRINSIC VASCULAR CONDUCTION WITH CSD Brennan et al., J. Neurophys, In Press, 2007 CSD evoked by KCl pulse — mouse cortex. 5 minute recording ARTERIOLAR DILATION PROPAGATES AHEAD OF PARENCHYMAL CHANGES OF CSD COULD VASCULAR SIGNALING PLAY AN ACTIVE RATHER THAN MERELY PASSIVE ROLE IN CSD VASCULAR CELLS RELEASE DIFFUSIBLE MESSENGERS THAT MAY INFLUENCE ACTIVITY OF NEIGHBORING NEURONS AND GLIAL CELLS

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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 ASTROCYTE CALCIUM WAVES SLOWLY PROPAGATED WAVES EVOKED BY WIDE VARIETY OF STIMULI ASSOCIATED WITH ACTIVE RELEASE OF: ATP GLUTAMATE K+ LACTATE PROSTANOIDS INTERLEUKINS CAPABLE OF ACTIVE MODULATION OF NEURONAL AND VASCULAR ACTIVITY Multifocal Astrocyte Calcium Waves in Cortical Slice Multifocal CSD Evoked by KCl Crystal In Vivo CORTICAL WAVES MAY BE REPETITIVE, MULTIFOCAL EVENTS

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 HUMAN ASTROCYTE WITH BLOOD VESSEL AND NEURONS Maiken Nedergaard Neurons

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

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