migraine; an anatomic and physiological basis...1 migraine; an anatomic and physiological basis...
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Migraine; An Anatomic and Physiological Basis
Sheena K. Aurora, MDSwedish Headache Center
Swedish Pain CenterSeattle
MIGRAINE PATHOPHYSIOLOGY
Genetic basis
The sensitive brain
Triggering migraine
The migraine aura
Migraine pain and the features of the acute attack
THE P/Q GENE PRODUCT
Ophoff RA et al. Cell. 1996.
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THE GENETIC BASISFHM1
P/ Q channelPresynaptic
Voltage gatedOccipital Cortex
Trigeminal nucleus Caudalis
FHM2Linkage to Chromosome 1
Na-K ATP
FHM3Na Channel
Moskowitz Deciphering migraine mechanisms: clues from familial hemiplegic migraine genotypes.Ann Neurol. 2004 Feb;55(2):276-80.
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Interictal
• Channelopathy/ Genetics
• Brain/occipital cortex hyperexcitability
• Mitochondrial defect
• Magnesium deficiency
DWI at 8 Hours Perfusion at 8 Hours
T2-WI at 3 MonthsDWI at 3 Days
PWIKey
PWI: Persistent Visual Aura
Sanchez del Rio M, Bakker D, Wu O, Agosti R, Mitsikostas DD, Ostergaard L, Wells WA, Rosen BR, Sorensen G, Moskowitz MA, Cutrer M. Perfusion weighted imaging during migraine spontaneous visual aura
and headache.
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fMRI During Spontaneous MwA
Hadjikhani N, et al Mechanisms of migraine aura revealed by functional MRI in human visual cortex.
Proc Natl Acad Sci U S A. 2001 Apr 10;98(8):4687-92.
THE NEUROVASCULAR THEORY
Referred pain from dura mater and blood vessels
Peripheral neural processingnNeurogenic plasma protein extravasation (PPE)
nNeuropeptides
Central neural processing
Migraine is a neurovascular pain syndrome
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Brain Stem Involvement in Migraine
• Brain stem aminergic nuclei can modify trigeminal pain processing
• PET demonstrates brain stem activation in spontaneous migraine attacks
• Brain stem activation persists after successful headache treatment
• Brain stem: generator or modulator?
PET=positron emission tomography.Weiller C et al. Nat Med. 1995;1:658-660..
Which Structure is Involved?
PAG
Chronic Daily Headache; Denovo
Goadsby PJ. Neurovascular headache and a midbrain vascular malformation: evidence for a role of the brainstem in chronic migraine. Cephalalgia2002;22(2):107-111.
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T2 Image ISODATA Segmented Zones
Overlay of Segmented Zones
RN
SN
PAG
Automated Segmentation of Brain Tissue
y = 0.0016x + 5.6213r = 0.80, p < 0.006
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5.5
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6.5
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7.5
-10 190 390 590 790 990
Longevity of Migraine (Years * Frequency/year)
R2'
-PA
G (1
/ms)
Correlation of Iron in PAG with Longevity of Migraine
Bolay et al. Nat Med 2002
Laser Speckle contrast image
MMA
MMAcortex
3’
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Trigeminovascular Migraine Pain Activation
Bolay M et al. Intrinsic brain activity triggers trigeminal meningeal
afferents in a migraine model. Nature
Medicine 2002;8(2):136-142.
CSD produces Pain
Targeting Inflammation and Vasodilation
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The Trigeminovascular System
Adapted from Moskowitz & Cutrer. Ann Rev Med. 1993;44:145.
5-HT1 & migraine
Goadsby, 1997 Longmore et al., 1997
5-HT1B → constriction5-HT1D → PPE inhibition; TNC inhibition5-HT1F → PPE inhibition; TNC inhibition
iNos in Migraine
• Nitric Oxide (NO) = key physiological mediator in the body(neurotransmission & vasodilatation)
• L-arginine nitric oxide synthases (NOS) Nitric oxide (NO)• Three NOS isoforms:
eNOS (endothelial NOS) -CV systemnNOS (neuronal NOS) - neurotransmissioniNOS (inducible or inflammatory NOS) - promotes tissue pathology
* Readily induced upon inflammation or tissue injury* Triggers pathological vasodilation and edema* Sensitizes nerve terminals and causes hyperalgesia* Promotes cytokine production and induces COX1 & 2
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Peripheral sensitization in Migraine
Central Sensitization in Migraine
Burstein R, et al. Neurology. 2005;64:S16-S20.
SensitizedCentral neuron
(thalamus)
SensitizedPeripheral neuron
(trigeminal ganglion)
SensitizedCentral neuron
(dorsal horn of spinal cord)
Meningeal blood vessel
Cutaneous allodynia
Throbbing pain
Pain perception
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Pain modulation
Russo, 2001
Neurotransmitters that modulate nociceptive processing
• Ach• Norepinephrine• Serotonin• Dopamine• Glutamate• Anandamide/CB1• CCK
• GABA• Adenosine• Glycine• Endogenous opioids
Glutamate (Glu)
Excitatory pathwayInhibitory pathway
PKC PKA
Ca2+
Na+
Ca2+
Na+[Ca2+]i
Ca2+/CM
NOS NO
AC
ATP cAMP
•••
•• •
••
Glu•
••
Eγ β α
ERPIP2
NMDA Gly
PCP
Mg
Group II, III m
Glu
Group I mGlu
NMDAAMPA or KA
L-arg L-citDAG
IP3
Ramadan, 2003
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Glutamate in MigraineSupporting observations*
• Localization experiments• Support from functional studies
– activation of TNC cells by L-Glu– Glu release following TNC stimulation– activation/propagation of CSD by Glu– Increase nNOS activity by GluR activation– Release of SP following NMDA activation
*Ramadan, 2003
CNS Hyperexcitability
Unified Theory
Trigeminal Vascular SystemRole of Serotonin
NO Theory
Genetic Suscetibility
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