HEADACHE PATHOPHYSIOLOGY

Andrew Charles, M.D.

Professor

Director, UCLA Goldberg Migraine ProgramMeyer and Renee Luskin Chair in Migraine and Headache Studies

Director, Headache Research and Treatment Program

David Geffen School of Medicine at UCLA

Disclosures

Amgen – Consultant for educational material

Eli Lilly – Global scientific advisory board

eNeura – Medical Advisory Board

St. Jude Medical – Clinical trial steering committee

Takeda Pharmceuticals – Grant support for

laboratory research

50 year old woman

Episodic “attacks” for last 20 years, occurring twice per month

Her partner “knows attack is beginning” when she becomes

“negative about everything and irritable”

Patients reports that she feels tired and yawns, then develops mild

nausea and difficulty focusing vision.

Develops moderate neck pain eventually spreading to retro-orbital

region bilaterally

Has difficulty speaking and concentrating

Each episode lasts for hours, and she feels like she “has to go to

sleep”. Cognitive dysfunction and fatigue are most disabling

symptoms

Identifies bright light and strong smells as triggers

Audrey

What Is the Diagnosis?

Chronic fatigue syndrome

Chronic Lyme disease

Hypothyroidism

Migraine with aura

Premonitory Aura PostdromeHeadache

Yawning, Polyuria

Neck Pain, Fatigue, Mood change Light sensitivity, Sound sensitivity

Visual changesNumbness/tinglingLanguage dysfunctionCognitive dysfunctionBrainstem symptoms

Nausea

Headache

Cutaneous allodynia

Hypothalamus, Brainstem

Cortex

Cortex Brainstem Thalamus Hypothalamus Cortex Thalamus

Hypothalamus

Timeline of a Migraine Attack 4-72 hours

Predisposing

Factors

Genes

Hormones

Metabolism

Environment

Medications

Symptoms

Brain Activation

CGRP, PACAP ReleaseDopamine?

Hypothalamic peptides?Glutamate?Neurochemistry

Neurophysiology Thalamocortical circuit changes Pain/emotion network changes

• Patient scanned daily with fMRI

for 30 days

• 3 migraine attacks captured

• Interictal and ictal periods captured

Sensory Sensitization Before Headache

Ipsilateral Contralateral

Alterations in function and sensitization of

the thalamus play a role in migraine

Measuring Functional Connectivity

with MRI

Based on low frequency (.1 Hz) oscillations in blood

oxygen level dependent (BOLD) MRI signal

Synchronization of these oscillations in different

brain regions is interpreted as functional

connectivity between those regions.

“Resting states” refers to activity in brain regions

that occurs in the absence of external stimulation

DEFAULT MODE NETWORK

Abnormal Functional Connectivity in Migraine

Chronic migraine associated with altered

connectivity of anterior insula, amygdala, pulvinar,

mediodorsal thalamus, middle temporal cortex, and

periaqueductal gray

UPDATED FIGURES AND REFERENCES TO BE INSERTED

45 year old woman

– Constant neck “tightness”

– Daily moderate headache that is bilateral, constant,

sometimes associated with light sensitivity

– 8 attacks per month of markedly worse neck pain and

headache. Neck pain worsens before and after

headache. Some response of both to sumatriptan

– Normal neurological exam, diffuse cervical paraspinous

muscle tenderness

Clinical Case

What is the diagnosis?

A. Chronic migraine

B. Cervicogenic headache

C. Intracranial hypertension due to cervical stenosis

D. Vertebral artery dissection

Neck Pain and Migraine

Neck pain is a common symptom of migraine

May occur as part of premonitory phase or

postdrome in addition to attack phase

Neck related disability scores high in migraine

patients

Cervical nerves and headache

Advances in Migraine Genetics

Migraine Biomarkers?Elevated CSF levels of:

– Glutamate

– CGRP

– NGF

Elevated blood levels of

– Glutamate

– CGRP

Decreased CSF and blood levels of

– Beta-endorphin

van Dongen RM, et al. Migraine biomarkers in cerebrospinal fluid: A systematic

review and meta-analysis. Cephalalgia 2016.

Does blood brain barrier open in migraine? Likely not much….

CGRP (calcitonin gene-related peptide)

What is it?Peptide produced in neural cells throughout the body,

involved in:

– Pain transmission

– Vasodilation

– Inflammation

– Regeneration of motor neurons

CGRP Receptor

For review, see Kaiser EA, Russo AF. Neuropeptides 2013; 47:451-461.

CGRP in Migraine and Cluster Headache

CGRP is released into the circulation during a migraine or

cluster headache attack 1,2

CGRP infusion evokes migraine 3

Serum CGRP levels may be elevated in chronic migraine 4

CGRP receptor antagonists effectively abort migraine

attacks 5,6

1. Goadsby PJ, Edvinsson L, Ekman R. Vasoactive peptide release in the extracerebral circulation of humans during migraine headache. Ann Neurol 1990; 28:183-187.

2. 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

3. Hansen JM, Hauge AW, Olesen J, Ashina M. Calcitonin gene-related peptide triggers migraine-like attacks in patients with migraine with aura. Cephalalgia : 2010; 30(10): 1179-

86.

4. Cernuda-Morollon E, Larrosa D, Ramon C, Vega J, Martinez-Camblor P, Pascual J. Interictal increase of CGRP levels in peripheral blood as a biomarker for chronic migraine.

Neurology 2013; 81(14): 1191-6.

5. 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

6. 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

CGRP Release in Migraine Attacks

Goadsby PJ, Edvinsson L, Ekman R. Vasoactive peptide release in the extracerebral circulation of humans during migraine headache. Ann Neurol 1990; 28: 183-7.

Goadsby PJ, Edvinsson L. The trigeminovascular system and migraine: studies characterizing cerebrovascular and neuropeptide changes seen in humans and cats. Ann Neurol 1993; 33(1): 48-56.

• CGRP but not neuropeptide Y, VIP, or substance P

released in migraine with and without aura

• Elevated CGRP levels observed in jugular but not

antecubital venous blood on same side as pain

• Greater elevation in CGRP observed in migraine with

aura

• CGRP levels normalize upon treatment with sumatriptan

CGRP Release in Cluster Headache Attacks

CGRP levels elevated in jugular blood ipsilateral to side

of cluster headache

VIP levels also elevated but not neuropeptide Y or

substance P

Treatment with oxygen or sumatriptan normalized CGRP

levels, but opioid had no effect.

Goadsby PJ, Edvinsson L. Human in vivo evidence for trigeminovascular activation in cluster

headache. Neuropeptide changes and effects of acute attacks therapies. Brain 1994; 427-34.

Nesbitt A D , and Goadsby P J BMJ 2012;344:bmj.e2407

Constant

Fc

Variable

MONOCLONAL ANTIBODIES

Mouse

“-omab”

Chimeric

Variable region mouse

“-ximab”

Humanized

Antigen binding region mouse

“-zumab”

Antigen binding

region

Light Chain

Heavy Chain

Human

100% human

“-umab”

CGRP RECEPTORS

CGRP CGRPCGRP

CGRP

CGRP

CGRP

CGRP

CGRP

AMY1 RECEPTORS

CGRP RECEPTORS

CGRP

CGRPCGRP

CGRP

CGRP

CGRP CGRP

CGRP

CGRP

AMY1 RECEPTORS

Summary

• New therapeutic targets based on:

– Better understanding of migraine anatomy – targets for

neuromodulation approaches

– Study of mechanisms of migraine occurring before

headache

– Increased understanding of role of brain networks and

brain “rhythms”

– Better understanding of mechanisms of current migraine

medications

– New antibody approaches to specifically targeting

migraine mechanisms