HEADACHE
PATHOPHYSIOLOGY
Andrew Charles, M.D.
Professor
Director, Headache Research and 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: Painsensitive structures of the head and their significance in headache.
Arch Surg. 1940;41:813-856.
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
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 and cerebral blood vessels during
nitroglycerin provoked migraine attack. Poster presented at Migraine Trust 2006. Cephalalgia. 2006 26:138889.
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
and 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
CORTICAL “WAVES” IN MIGRAINE WITH AURA
Olesen, et al. 1981
Hadjikhani et al., 2001
Bereczki et al., 2008
Cao et al., 1999
PET STUDY SHOWS SPREADING OLIGEMIA IN
MIGRAINE PATIENT WITHOUT AURA
…AND MIGRAINE WITHOUT AURA
Woods et al., 1994
Before sumatriptan
2 to 4 h after the attack onset
After sumatriptan
4 to 6 h after the attack onset
Chalaupka, 2008
Denuelle et al., 2008
Activation of the ipsilateral pons in patients with right-sided attacks (n = 8, A) and left-sided
attacks (n = 8, B)
Afridi, S. K. et al. Brain 2005 128:932-939;
Hypothalamic Activation in Migraine
(Denuelle et al., Headache, 2007)
MIGRAINE – A MULTISYMPTOM COMPLEX
Cortical
Activation
Hypothalamic
Activation
Brainstem
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
CSD evoked by KCl pulse --- rat cortex. 5 minute recording
OPTICAL IMAGING OF CORTICAL SPREADING DEPRESSION
• Allows visualization of parenchymal and 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 and vascular signals
over large area with local electrophysiological recording
• Induction thresholds can be reliably established
Recording of CSD in the injured human cortex over a period of 40 min
Fabricius, M. et al. Brain 2006 129:778-790;.
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
CSD evoked by KCl pulse --- mouse cortex. 5 minute recording
INTRINSIC VASCULAR CONDUCTION WITH CSD
Brennan et al., J. Neurophys, In Press, 2007
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
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
FHM Mutations
Neurons
Na+/K+ ATPase
P/Q Ca2+
Channel
K+
GLUTAMATE
Nav1 Na+ Channel
Adenosine
ATP
CGRP
Astrocytes
Nitric Oxide
Endothelin
Eicosanoids
ATP
Adenosine
Vascular cells
K+
MIGRAINE MECHANISMS
SPREADING DEPRESSION
Release of nociceptive and
inflammatory mediators
•ATP
•Glutamate
•Interleukins
Vasoconstriction
CGRP Release
ASTROCYTE CALCIUM WAVES
Blood Brain Barrier
Opening
Migraine pain begins during
hypoperfusion phase
Hyperperfusion
may outlast pain
Headache is not
temporally correlated
with either hypoor hyperperfusion
Olesen J, et al. Ann Neurol. 1990;28:791-798.
Chronic division of trigeminal nerve prolongs recovery from vasoconstriction
“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.”
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 generelated peptide receptor, compared with zolmitriptan for acute migraine: a randomised, placebo-controlled, paralleltreatment trial. Lancet. 2009;372:2115-2123
Adrenomedullin
Calcitonin Gene Related Peptide
Receptor Activity Modifying Protein
CGRP RECEPTOR STRUCTURE
Lennerz et al, J. Comp. Neurol., 2008
Dural Mast cells
Dural Arterioles
Trigeminal Schwann Cells
Trigeminal Ganglion
Neurons and Satellite Cells
Afferent fibers in TNC
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
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.
REDUCED THRESHOLD FOR ACTIVATION OF
CSD IN FEMALE VS. MALE MICE
Brennan et al., Annals of Neurology 2007
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
• Multiple migraine preventive
medications inhibit CSD
• CSD is altered by gender
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
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
DIFFERENCES IN BRAIN STRUCTURE IN
PATIENTS WITH MIGRAINE?
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
CORTICAL SPREADING DEPRESSION MAY BE ASSOCIATED
WITH BREAKDOWN OF THE BLOOD BRAIN BARRIER
White Matter Lesions in Migraine
Etiology ? Functional Significance?
CORTICAL WAVES
Spreading
depression
Astrocyte waves
Vascular waves
MODULATING
FACTORS
Genes
Gender/Hormones
Ionic/Metabolic
Drugs
Environment
DYSREGULATION
OF CORTICAL
BRAINSTEM,
HYPOTHALAMIC
EXCITABILITY
BBB Permeability
AURA
Visual
Sensory
Cognitive
NOCICEPTIVE ACTIVATION
Release of nociceptive messengers
Vasoconstriction
Vascular/metabolic uncoupling
BRAINSTEM /HYPOTHALAMIC
ACTIVATION
Trigeminal nucleus caudalis
Periaqueductal gray
Central sensitization
PAIN
SENSORY SENSITIVITY
Photo/phonophobia
Cutaneous allodynia
NAUSEA
VERTIGO
FATIGUE
MOOD CHANGE
POTENTIAL NEW THERAPIES FOR MIGRAINE
INHIBITORS OF CORTICAL SPREADING DEPRESSION
Memantine, Tonabersat, Transcranial Magnestic Stimulation
INHIBITORS OF CGRP RECEPTOR
Telcagepant
CIRCULATORY TRIGGERS
TO BRAIN EXCITABILITY?
PFO Closure
MODULATORS OF CERVICAL
INPUT TO HEADACHE
Occipital Nerve Stimulation
Adapted from Jones HR. Netter’s Neurology, St. Louis, MO; Saunders; 2005.
Acknowledgements
• UCLA Headache Research and Treatment Program
– K.C. Brennan
– Marcelo Romero Reyes
– Hector Lopez-Valdes
• Feldman Lab
– Mike Baca
• UCSF/HHMI
–
–
–
–
Louis Ptáček
Ying-Hui Fu
Ying Xu
Archana Shenoy
• University of Vermont
– Robert E. Shapiro
• Department of Neurology/Brain Mapping Center
– John Mazziotta
– Arthur Toga