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