headache pathophysiology andrew charles, m.d. professor director, headache research and treatment...
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HEADACHEHEADACHEPATHOPHYSIOLOGYPATHOPHYSIOLOGY
Andrew Charles, M.D.Andrew Charles, M.D.ProfessorProfessor
Director, Headache Research and Treatment ProgramDirector, Headache Research and Treatment ProgramDavid Geffen School of Medicine at UCLADavid Geffen School of Medicine at UCLA
MIGRAINE – A MULTISYMPTOM COMPLEXMIGRAINE – A MULTISYMPTOM COMPLEX
PATHOPHYSIOLOGICALMECHANISMS
Penfield W. A contribution to the mechanism of intracranial pain. Penfield W. A contribution to the mechanism of intracranial pain. Assoc Res Nerv Ment Dis. 1935;15:399-416.Assoc Res Nerv Ment Dis. 1935;15:399-416.
Ray BS, Wolff HG. Experimental studies in headache: Pain-Ray BS, Wolff HG. Experimental studies in headache: Pain-sensitive structures of the head and their significance in headache. sensitive structures of the head and their significance in headache. Arch Surg. 1940;41:813-856.Arch Surg. 1940;41:813-856.
Issues with Studies of Issues with Studies of Ray and Wolff, PenfieldRay and Wolff, Penfield
Stimulation of vessels was focal external Stimulation of vessels was focal external stimulation or mechanical dilationstimulation or mechanical dilation
There is no evidence that physiological There is no evidence that physiological relaxation of smooth muscle and resultant relaxation of smooth muscle and resultant dilation can cause paindilation can cause pain
Headache Headache CanCan Be Evoked by Be Evoked by Stimulation of Specific Brain Stimulation of Specific Brain
RegionsRegions
Headache can be evoked by lesions Headache can be evoked by lesions or electrodes in the periaqueductal or electrodes in the periaqueductal grey in the brainstem in the absence grey in the brainstem in the absence of vasodilationof vasodilation
Head pain can be evoked by stimulation of Head pain can be evoked by stimulation of insular cortex in the absence of vascular insular cortex in the absence of vascular changechange
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 Vasoactive Drugs Cause Migraine After Significant Delay (hours), Significant Delay (hours), NotNot Correlated Correlated
with Vasodilation with Vasodilation
Nitric oxide donorsNitric oxide donors
PDE inhibitorsPDE inhibitors
HistamineHistamine
CGRPCGRP
Vasoactive Intestinal Peptide – No Vasoactive Intestinal Peptide – No migraine 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.
Alternative Mechanisms ofAlternative Mechanisms of“ Vascular” Drugs “ Vascular” Drugs
-blockers-blockers– Inhibit neuronal adrenergic signalingInhibit neuronal adrenergic signaling
Calcium channel blockersCalcium channel blockers– Inhibit neuronal calcium channelsInhibit neuronal calcium channels
CaffeineCaffeine– Neuronal/glial adenosine receptor antagonistNeuronal/glial adenosine receptor antagonist
ErgotaminesErgotamines– Modulate central 5-HT receptorsModulate central 5-HT receptors
TriptansTriptans– Activate neuronal 5-HT1 receptors in brainstem Activate neuronal 5-HT1 receptors in brainstem
and thalamusand thalamus
CHANGING CONCEPTS OF CHANGING CONCEPTS OF MIGRAINE PATHOGENESISMIGRAINE PATHOGENESIS
MIGRAINE IS A DISORDER OF BRAIN MIGRAINE IS A DISORDER OF BRAIN EXCITABILITYEXCITABILITY
VASODILATION MAY OCCUR AS PART VASODILATION MAY OCCUR AS PART OF THE DISORDER, BUT IS NOT OF THE DISORDER, BUT IS NOT REQUIREDREQUIRED FOR MIGRAINE PAIN FOR MIGRAINE PAIN
VASOCONSTRICTION MAY BE MORE VASOCONSTRICTION MAY BE MORE IMPORTANT THAN VASODILATION AS IMPORTANT THAN VASODILATION AS AN INITIAL TRIGGER FOR MIGRAINE AN INITIAL TRIGGER FOR MIGRAINE SYMPTOMSSYMPTOMS
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 PET STUDY SHOWS SPREADING OLIGEMIA IN MIGRAINE PATIENT OLIGEMIA IN MIGRAINE PATIENT
WITHOUT AURAWITHOUT AURA
Woods et al., 1994
Chalaupka, 2008
Denuelle et al., 2008
Before sumatriptan2 to 4 h after the attack onset
After sumatriptan4 to 6 h after the attack onset
…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) and left-sided attacks (n = 8, B)
Hypothalamic Activation in Migraine (Denuelle et al., Headache, 2007)
MIGRAINE – A MULTISYMPTOM COMPLEXMIGRAINE – A MULTISYMPTOM COMPLEX
Cortical Cortical ActivationActivation
BrainstemBrainstemActivationActivation
HypothalamicHypothalamicActivationActivation
CORTICAL SPREADING CORTICAL SPREADING DEPRESSION (CSD)DEPRESSION (CSD)
WAVE OF ACTIVATION FOLLOWED BY WAVE OF ACTIVATION FOLLOWED BY REDUCED ACTIVITY THAT SPREADS REDUCED ACTIVITY THAT SPREADS ACROSS THE SURFACE OF THE BRAINACROSS THE SURFACE OF THE BRAIN
SPREADS WITH CHARACTERISTICS SPREADS WITH CHARACTERISTICS THAT ARE VERY SIMILAR TO THE THAT ARE VERY SIMILAR TO THE CLINICAL SYMPTOMS AND PET AND CLINICAL SYMPTOMS AND PET AND MRI CHANGES OF MIGRAINEMRI CHANGES OF MIGRAINE
OPTICAL IMAGING OF CORTICAL SPREADING DEPRESSIONOPTICAL IMAGING OF CORTICAL SPREADING DEPRESSION• Allows visualization of parenchymal and vascular signalsAllows visualization of parenchymal and vascular signals over large area with local electrophysiological recordingover 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
OPTICAL IMAGING OF CORTICAL SPREADING DEPRESSION -- OPTICAL IMAGING OF CORTICAL SPREADING DEPRESSION -- K.C. BrennanK.C. Brennan• Allows visualization of parenchymal and vascular signalsAllows visualization of parenchymal and vascular signals over large area with local electrophysiological recordingover 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
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 ISSUES WITH CLASSICAL CORTICAL SPREADING DEPRESSION IN MIGRAINESPREADING DEPRESSION IN MIGRAINE
• CLASSIC EEG FINDINGS OF CORTICAL CLASSIC EEG FINDINGS OF CORTICAL SPREADING DEPRESSION RARELY SEEN IN SPREADING DEPRESSION RARELY SEEN IN HUMANSHUMANS
• MOST PATIENTS DO NOT HAVE THE PROFOUND MOST PATIENTS DO NOT HAVE THE PROFOUND NEUROLOGICAL IMPAIRMENT ONE WOULD NEUROLOGICAL IMPAIRMENT ONE WOULD EXPECT WITH CLASSICAL CSDEXPECT WITH CLASSICAL CSD
MIGRAINE MAY INVOLVE CORTICAL WAVES THAT MIGRAINE MAY INVOLVE CORTICAL WAVES THAT ARE RELATED TO, BUT NOT IDENTICAL TO CSD ARE RELATED TO, BUT NOT IDENTICAL TO CSD OBSERVED IN ANIMAL MODELSOBSERVED IN ANIMAL MODELSDIFFERENT TYPES OF CORTICAL WAVES MAY BE DIFFERENT TYPES OF CORTICAL WAVES MAY BE PRODUCED BY DISTINCT CELLULAR MECHANISMSPRODUCED BY DISTINCT CELLULAR MECHANISMS
VASCULAR EVENTS IN VASCULAR EVENTS IN CORTICAL ARTERIOLES WITH CORTICAL ARTERIOLES WITH
CSD IN MOUSECSD IN MOUSE– INITIAL DILATIONINITIAL DILATION
• Conducted With Intrinsic Velocity Conducted With Intrinsic Velocity Ahead of CSDAhead of CSD
–SUBSEQUENT CONSTRICTIONSUBSEQUENT CONSTRICTION–EVENTUAL DILATIONEVENTUAL DILATION
INTRINSIC VASCULAR CONDUCTION WITH CSDINTRINSIC VASCULAR CONDUCTION WITH CSDBrennan et al., J. Neurophys, In Press, 2007Brennan et al., J. Neurophys, In Press, 2007
CSD evoked by KCl pulse --- mouse cortex. 5 minute recording
ARTERIOLAR DILATION PROPAGATES AHEADARTERIOLAR DILATION PROPAGATES AHEADOF PARENCHYMAL CHANGES OF CSDOF PARENCHYMAL CHANGES OF CSD
COULD VASCULAR SIGNALING PLAY AN ACTIVECOULD VASCULAR SIGNALING PLAY AN ACTIVERATHER THAN MERELY PASSIVE ROLE IN CSD?RATHER THAN MERELY PASSIVE ROLE IN CSD?
VASCULAR CELLS RELEASE DIFFUSIBLE MESSENGERSVASCULAR CELLS RELEASE DIFFUSIBLE MESSENGERSTHAT MAY INFLUENCE ACTIVITY OF NEIGHBORINGTHAT MAY INFLUENCE ACTIVITY OF NEIGHBORING
NEURONS AND GLIAL CELLSNEURONS AND GLIAL CELLS
Calcium wave evoked by mechanical stimulation in glial culture. Real TimeCalcium wave evoked by mechanical stimulation in glial culture. Real Time
Astrocytes are capable of widespread intercellular Astrocytes are capable of widespread intercellular signaling via propagated waves of increased signaling via propagated waves of increased
intracellular calciumintracellular calcium
ASTROCYTE CALCIUM ASTROCYTE CALCIUM WAVESWAVES
• SLOWLY PROPAGATED WAVES EVOKED BY SLOWLY PROPAGATED WAVES EVOKED BY WIDE VARIETY OF STIMULIWIDE VARIETY OF STIMULI
• ASSOCIATED WITH ASSOCIATED WITH ACTIVEACTIVE RELEASE OF: RELEASE OF:– ATPATP– GLUTAMATEGLUTAMATE– K+K+– LACTATELACTATE– PROSTANOIDSPROSTANOIDS– INTERLEUKINSINTERLEUKINS
• CAPABLE OF CAPABLE OF ACTIVEACTIVE MODULATION OF MODULATION OF NEURONAL AND VASCULAR ACTIVITYNEURONAL AND VASCULAR ACTIVITY
Multifocal Astrocyte Multifocal Astrocyte Calcium Waves in Cortical Calcium Waves in Cortical Slice Slice
Multifocal CSD Evoked by Multifocal CSD Evoked by KCl Crystal In Vivo KCl Crystal In Vivo
CORTICAL WAVES MAY BE REPETITIVE, CORTICAL WAVES MAY BE REPETITIVE, MULTIFOCAL EVENTS MULTIFOCAL EVENTS
A ROLE FOR ASTROCYTE WAVES IN MIGRAINE?A ROLE FOR ASTROCYTE WAVES IN MIGRAINE?
SIMILAR TEMPORAL AND SPATIAL CHARACTERISTICS AS SIMILAR TEMPORAL AND SPATIAL CHARACTERISTICS AS MIGRAINE EVENTSMIGRAINE EVENTSOCCUR IN PARALLEL WITH CSDOCCUR IN PARALLEL WITH CSDASSOCIATED RELEASE OF ATP, GLUTAMATE, AND ASSOCIATED RELEASE OF ATP, GLUTAMATE, AND OTHER NEURO- AND VASO-ACTIVE SUBSTANCESOTHER NEURO- AND VASO-ACTIVE SUBSTANCESASSOCIATED CHANGES IN EXTRACELLULAR IONIC ASSOCIATED CHANGES IN EXTRACELLULAR IONIC COMPOSITIONCOMPOSITIONINTIMATE SPATIAL RELATIONSHIPS WITH SYNAPSE AND INTIMATE SPATIAL RELATIONSHIPS WITH SYNAPSE AND VASCULATUREVASCULATURE
COULD EXPLAIN DRAMATIC PROPAGATION WITH COULD EXPLAIN DRAMATIC PROPAGATION WITH RELATIVELY MILD NEUROLOGICAL SYMPTOMS RELATIVELY MILD NEUROLOGICAL SYMPTOMS
HUMAN ASTROCYTE WITH BLOOD VESSEL AND NEURONSMaiken Nedergaard
Na+/K+ ATPase
P/Q Ca2+ Channel Nav1 Na+ ChannelFHM Mutations
Neurons
Astrocytes
Vascular cells
ATP
Adenosine
GLUTAMATE
Eicosanoids
K+
K+
ATP
Adenosine
Nitric OxideEndothelin
CGRP
Release of nociceptive and Release of nociceptive and inflammatory mediatorsinflammatory mediators•ATPATP•GlutamateGlutamate•InterleukinsInterleukins
VasoconstrictionVasoconstrictionCGRP ReleaseCGRP Release
SPREADING DEPRESSIONDEPRESSION
ASTROCYTEASTROCYTE CALCIUM WAVES
MIGRAINE MECHANISMSMIGRAINE MECHANISMS
Blood Brain Barrier Blood Brain Barrier OpeningOpening
Olesen J, et al. Ann Neurol. 1990;28:791-798.
Headache is not temporally correlated
with either hypo-or hyperperfusion
Migraine pain begins during Migraine pain begins during hypoperfusion phasehypoperfusion phase
Hyperperfusion may outlast pain
““The cerebrovascular trigeminal neuronal system, in which CGRP is theThe cerebrovascular trigeminal neuronal system, in which CGRP is themost potent vasoactive constituent, may participate in a reflex or local most potent vasoactive constituent, may participate in a reflex or local response to excessive cerebral vasoconstriction that restores normal response to excessive cerebral vasoconstriction that restores normal vascular diameter.”vascular diameter.”
Chronic division of trigeminal nerve prolongs recovery from vasoconstrictionChronic division of trigeminal nerve prolongs recovery from vasoconstriction
CGRP CGRP (Calcitonin Gene Related Peptide)(Calcitonin Gene Related Peptide) IN MIGRAINEIN MIGRAINE
CGRP IS RELEASED INTO JUGULAR VENOUS CGRP IS RELEASED INTO JUGULAR VENOUS SYSTEM DURING A MIGRAINE ATTACKSYSTEM DURING A MIGRAINE ATTACK
CGRP INFUSION EVOKES MIGRAINECGRP INFUSION EVOKES MIGRAINE
CGRP RECEPTOR ANTAGONISTS EFFECTIVELY CGRP RECEPTOR ANTAGONISTS EFFECTIVELY ABORT A MIGRAINE ATTACKABORT A MIGRAINE ATTACK
WHERE IS THE SITE OF ACTION?WHERE IS THE SITE OF ACTION?
Lassen L, Haderslev P, Jacobsen V et al. CGRP may play a causative role in migraine . Cephalalgia. 2002;22:54-61Lassen 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 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):427-434of 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 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;350:1104-1110Migraine. 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. 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;70:1304-1312Neurology. 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 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. peptide receptor, compared with zolmitriptan for acute migraine: a randomised, placebo-controlled, parallel-treatment trial. Lancet. 2009;372:2115-21232009;372:2115-2123
CGRP RECEPTOR STRUCTURE
Adrenomedullin Calcitonin Gene Related Peptide
Receptor Activity Modifying Protein
Lennerz et al, J. Comp. Neurol., 2008
Dural Mast cells
Dural Arterioles
Trigeminal GanglionNeurons and Satellite Cells
Trigeminal Schwann Cells
Afferent fibers in TNC
HEADACHE GENETICSHEADACHE GENETICSMULTIPLE POSSIBLE GENES FOR MIGRAINE – NONE MULTIPLE POSSIBLE GENES FOR MIGRAINE – NONE HAVE BEEN SHOWN YET FOR COMMON FORMS OF HAVE BEEN SHOWN YET FOR COMMON FORMS OF MIGRAINEMIGRAINE
GENES FOR FAMILIAL HEMIPLEGIC MIGRAINEGENES FOR FAMILIAL HEMIPLEGIC MIGRAINE– FHM1 - CACNA1AFHM1 - CACNA1A – NEURONAL P/Q CALCIUM – NEURONAL P/Q CALCIUM
CHANNEL – INCREASES NEUROTRANSMITTER CHANNEL – INCREASES NEUROTRANSMITTER RELEASERELEASE
– FHM2 - ATP1A2FHM2 - ATP1A2 – ASTROCYTE SODIUM PUMP – – ASTROCYTE SODIUM PUMP – DYSFUNCTION INCREASES EXTRACELLULAR KDYSFUNCTION INCREASES EXTRACELLULAR K++
– FHM3 - SCN1AFHM3 - SCN1A – NEURONAL SODIUM CHANNEL – – NEURONAL SODIUM CHANNEL – INCREASED ACTION POTENTIAL FIRINGINCREASED ACTION POTENTIAL FIRING
ROLE OF GENDER AND ROLE OF GENDER AND HORMONES IN CORTICAL HORMONES IN CORTICAL
EXCITABILITY AND MIGRAINEEXCITABILITY AND MIGRAINE
In children, migraine prevalence is In children, migraine prevalence is almost equal in boys and girls.almost equal in boys and girls.
During reproductive years, prevalence During reproductive years, prevalence of migraine is 3 X as high in women as of migraine is 3 X as high in women as men during reproductive years.men during reproductive years.
After menopause, migraine prevalence After menopause, migraine prevalence remains 2X as high in women as men.remains 2X as high in women as men.
REDUCED THRESHOLD FOR ACTIVATION REDUCED THRESHOLD FOR ACTIVATION OF CSD IN FEMALE VS. MALE MICEOF CSD IN FEMALE VS. MALE MICE
Brennan et al., Annals of Neurology 2007Brennan et al., Annals of Neurology 2007
GROWING EVIDENCE THAT CSD IN GROWING EVIDENCE THAT CSD IN RODENT MODELS IS A VALID RODENT MODELS IS A VALID
MODEL FOR MIGRAINEMODEL FOR MIGRAINE
• Genetic alterations associated with Genetic alterations associated with familial hemiplegic migraine, and familial hemiplegic migraine, and possibly migraine with aura, alter possibly migraine with aura, alter CSDCSD
• Multiple migraine preventive Multiple migraine preventive medications inhibit CSD medications inhibit CSD
• CSD is altered by genderCSD is altered by gender
MEMANTINE FOR MIGRAINE MEMANTINE FOR MIGRAINE PREVENTIONPREVENTION
Activity dependent blocker of NMDA Activity dependent blocker of NMDA receptorsreceptorsIdentified as a blocker of CSD in rodentsIdentified as a blocker of CSD in rodentsAppears to be effective as a migraine Appears to be effective as a migraine preventive therapy for significant percentage preventive therapy for significant percentage of patients with frequent migraine who had of patients with frequent migraine who had failed other preventive therapiesfailed other preventive therapiesIt is generally very well toleratedIt is generally very well toleratedWell designed studies are warrantedWell designed studies are warranted
Peeters et al., JPET, 2007Peeters et al., JPET, 2007Charles, et al., Journal of Headache and Pain, 2007Charles, et al., Journal of Headache and Pain, 2007Bigal et al., Headache, 2008Bigal et al., Headache, 2008
PFO and MIGRAINE?PFO and MIGRAINE?
HIGHER INCIDENCE OF BIG PFO’s IN HIGHER INCIDENCE OF BIG PFO’s IN PATIENTS WHO HAVE MIGRAINE WITH AURA.PATIENTS WHO HAVE MIGRAINE WITH AURA.
UNBLINDED, UNCONTROLLED STUDIES UNBLINDED, UNCONTROLLED STUDIES SHOW SIGNIFICANT REDUCTION IN SHOW SIGNIFICANT REDUCTION IN MIGRAINES FOLLOWING PFO CLOSUREMIGRAINES FOLLOWING PFO CLOSURE
BUT….BUT….
STRONG POSSIBLITY OF PLACEBO EFFECTSTRONG POSSIBLITY OF PLACEBO EFFECT
MEDICATIONS (PLAVIX) MAY HAVE ROLEMEDICATIONS (PLAVIX) MAY HAVE ROLE
BLINDED, CONTROLLED STUDIES ARE REQUIREDBLINDED, CONTROLLED STUDIES ARE REQUIRED
DIFFERENCES IN BRAIN DIFFERENCES IN BRAIN STRUCTURE IN PATIENTS WITH STRUCTURE IN PATIENTS WITH
MIGRAINE?MIGRAINE?
MIGRAINE AND THE BLOOD MIGRAINE AND THE BLOOD BRAIN BARRIERBRAIN BARRIER
Opening of BBB during a migraine Opening of BBB during a migraine attack has been speculated based on attack has been speculated based on efficacy of medications not expected to efficacy of medications not expected to cross intact BBBcross intact BBB
Opening of BBB could contribute to Opening of BBB could contribute to migraine via multiple mechanismsmigraine via multiple mechanisms
Could be a mechanism for white matter Could be a mechanism for white matter lesions in migraine lesions in migraine Young VG, Halliday GM, Kril JJ. Neuropathologic correlates of Young VG, Halliday GM, Kril JJ. Neuropathologic correlates of
white matter hyperintensities. Neurology. 2008;71:804-811white matter hyperintensities. Neurology. 2008;71:804-811
CORTICAL SPREADING DEPRESSION MAY BE ASSOCIATEDWITH BREAKDOWN OF THE BLOOD BRAIN BARRIER
White Matter Lesions in MigraineEtiology ? Functional Significance?
MODULATING FACTORSGenesGender/HormonesIonic/MetabolicDrugsEnvironment
DYSREGULATION OF CORTICAL BRAINSTEM, HYPOTHALAMICEXCITABILITY
CORTICAL WAVESSpreading depressionAstrocyte wavesVascular waves
BRAINSTEM /HYPOTHALAMICACTIVATIONTrigeminal nucleus caudalisPeriaqueductal grayCentral sensitization
AURAVisual SensoryCognitive
PAIN
SENSORY SENSITIVITYPhoto/phonophobiaCutaneous allodyniaNAUSEA VERTIGOFATIGUEMOOD CHANGE
NOCICEPTIVE ACTIVATIONRelease of nociceptive messengersVasoconstrictionVascular/metabolic uncoupling
BBB Permeability
MODULATORS OF CERVICAL INPUT TO HEADACHE
Occipital Nerve Stimulation
INHIBITORS OF CORTICAL SPREADING DEPRESSIONMemantine, Tonabersat, Transcranial Magnestic Stimulation
POTENTIAL NEW THERAPIES FOR MIGRAINE
Adapted from Jones HR. Netter’s Neurology, St. Louis, MO; Saunders; 2005.
INHIBITORS OF CGRP RECEPTORTelcagepant
CIRCULATORY TRIGGERS TO BRAIN EXCITABILITY?
PFO Closure
AcknowledgementsAcknowledgements• UCLA Headache Research and Treatment ProgramUCLA Headache Research and Treatment Program
– K.C. BrennanK.C. Brennan – Marcelo Romero ReyesMarcelo Romero Reyes– Hector Lopez-ValdesHector Lopez-Valdes
• Feldman LabFeldman Lab– Mike BacaMike Baca
• UCSF/HHMIUCSF/HHMI– Louis Ptáček– Ying-Hui FuYing-Hui Fu– Ying XuYing Xu– Archana ShenoyArchana Shenoy
• University of VermontUniversity of Vermont– Robert E. ShapiroRobert E. Shapiro
• Department of Neurology/Brain Mapping CenterDepartment of Neurology/Brain Mapping Center– John MazziottaJohn Mazziotta– Arthur TogaArthur Toga