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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

6

6.5

7

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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