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Pathophysiology and Imaging of Chronic Migraine and Medication Overuse
HeadacheHeadache
Catherine D. Chong, PhDTodd J Schwedt MD FAHSTodd J. Schwedt, MD, FAHS
DisclosuresTodd Schwedt
C lti All A A t i T h l i I A i D– Consulting: Allergan, Amgen, Autonomic Technologies Inc, Avanir, Dr. Reddy’s, GBS, Supernus, Teva
– Options: GBS, Second Opinion– Research Funding: NIH, DOD, PCORI, American Migraine Foundation,
Mayo Clinic, Arizona State University– Royalties: UpToDate, Cambridge University Pressy p , g y
Catherine Chong– None
Learning ObjectivesAt the conclusion of this lecture, participants will be better able to:
• Describe pathophysiologic mechanisms of chronic migraine
• Describe pathophysiologic mechanisms of medication overuse headache
• Discuss how brain imaging research has contributed to our understanding of chronic migraine and medication overuse headache pathophysiologyp p y gy
Case #1: Episodic to Chronic Migraine
• 38 yo woman with migraine x 25 yrs
• Slow progression in frequency from EM to CM
• CM pattern x 5 years• CM pattern x 5 years
• Always sensitive to lights, sounds, odors, touch of skin, but worse over last yearyear.
• Wants to know why she is having such frequent migraines and why she is so bothered by sensory stimuliso bothered by sensory stimuli.
Is CM pathophysiology different than EM pathophysiology?EM pathophysiology?
• Probably similar• Probably similar• Patients commonly move in and out of CM and EM patterns• Symptoms are similar, but more frequent and severe in CM
• Pathophysiologic mechanisms (and symptoms) that occur during migraine attacks in EM might be continuous in CMg g g
• Atypical functions associated with migraine are likely more i l i CM d EMatypical in CM compared to EM
What are these Pathophysiologic Mechanisms?Mechanisms?
• Atypical modulation and processing of nociceptive signals typ ca odu at o a d p ocess g o oc cept e s g a s(and other sensory modalities)– Reduced inhibition– Enhanced facilitation
C t l S iti ti• Central Sensitization
T i i l A ti ti• Trigeminal Activation
Atypical Modulation of Nociceptive Signals• Descending pain system –
mostly pain inhibiting– Nucleus cuneiformis– Nucleus cuneiformis– Periaqueductal gray– Rostral ventral medulla
• Atypical in migraine– Pain‐induced activation– Functional connectivity– Structure
Bingel U , Tracey I Physiology 2008;23:371-380
Atypical Brainstem Modulation of Nociceptive Traffic
Less activation of pain‐inhibiting brainstem regions in response to pain
• 12 migraineurs with ictal allodynia12 migraineurs with ictal allodynia– 7‐10 days after last attack
• 12 healthy controls
• Painful heat stimulation during fMRI• Painful heat stimulation during fMRI
• Controls ‐ greater activation in dorsolateral pons (nucleus cuneiformis)cuneiformis).
• Dysfunction of brainstem descending pain modulatory system.
Moulton EA et. al. PLoS ONE 2008;3:e3799.
Atypical Functional Connectivity of Pain Modulating Regionsg
Chronic migraineurs with allodynia have atypical functional connectivity of periaqueductal gray and nucleus cuneiformis to other brainstem and thalamic pain processing
Dorsal
PAG Seed
processing
Dorsal Pons
Ventral M d llMedulla
Thalamus
Correlations between functional connectivity strength and allodynia symptom severity.
Schwedt TJ, et. al. Pain Med 2014;15:154-65.
Pain Facilitation in MigraineIn migraineurs, brain regions that process pain have atypical:
– Functional activation in response to pain and visual stimuli– Functional connectivity– Structure
In many cases,migraineurs with more frequent headaches have more atypical brainIn many cases, migraineurs with more frequent headaches have more atypical brain function and structure.
Main Effect of HeatMain Effect of Heat Pain
Schwedt TJ, et. al. Cephalalgia 2014;34:947-958.
Brain regions that process pain are “hyperactive” in migraineurs
Migraineurs with higher frequency headaches have greater “hyperactivity”
Schwedt TJ, et. al. Cephalalgia 2014;34:947-958.
The Migraine Brain – Enhanced Facilitation and Reduced Inhibition of PainReduced Inhibition of Pain
Migraine vs. Healthy ControlsHealthy Controls
Schwedt TJ et. al., Lancet Neurology 2015;14:81-91.
The Migraine Brain is Hyperactive in Response to Visual StimuliVisual Stimuli
5 Hz square wave flickering checkerboard
Datta R, et. al. Cephalalgia 2013;33:365-374.
Schwedt TJ et. al., Lancet Neurology 2015;14:81-91.
Central Sensitization• Effects of nociceptive stimulus are sustained after end of stimulation
Longer lasting paing g p
• Amplified effects of nociceptive stimuli
More severe pain
• Very low level of nociceptive input required to sustain effects of nociceptive stimulus
Lower thresholds for pain maintenance
• Activation of nociceptors with typically non‐nociceptive inputp yp y p p
Non‐painful stimuli are perceived as painful
Cutaneous Allodynia• Clinical manifestation of central sensitization
k f f f• Risk factor for increasing migraine frequency– Web‐based survey of 2331 migraine patients
70% d ll d i b li– 70% reported allodynia at baseline assessment
– Follow‐up survey at least 6 months later (n=1992)
– Allodynia was a risk factor for increasing number of migraine days• Independent from age, baseline # migraine days, depression
Louter MA et. al. Brain 2013;136:3489-96.
Cutaneous Allodynia
• Cutaneous AllodyniaReduced pain induced activation of brainstem regions– Reduced pain‐induced activation of brainstem regions that inhibit pain
– Altered functional connectivity of pain inhibiting regions
Alt d b i t t t– Altered brainstem structure
Moulton EA et. al. PLoS ONE 2008;3:e3799. Schwedt TJ, et. al. Pain Med 2014;15:154-65. Chong CD, et. al. Unpublished data.
Trigeminal Activation
• Interictal serum levels of CGRP higher in CM (n = 103) vs.
EM ( 43)• EM (n= 43)• healthy controls (n= 31)
• Accurate in differentiating CMAccurate in differentiating CM• Concentration of 43.34 pg/mL• Correctly classified 90.4% of
CMs vs. healthy• Correctly classified 85.7% CM
vs. EM
Cernuda‐Morollon E, et. al. Neurology 2013;81:1191‐1196.
Case Conclusions• Chronic Migraine: Wants to know why she is having such frequent
migraines and why she is so bothered by sensory stimuli.
– Brain reacts abnormally to stimulation• even between migraine attackseven between migraine attacks• increases the perception of sensory stimuli
– Increased excitability of the trigeminal system • Further sensitizes the system• Lowers the threshold for full‐blown migraine attacks
Case #2 – Medication Overuse
• 38 yo woman with migraine x 25 yrs
• Slow progression in frequency from EM to CM
• CM pattern x 5 years; Daily headaches x 2 years
• Using oxycodone daily x 2 years to treat migraine
• You tell her that the oxycodone is likely making her migraine worse and that she• You tell her that the oxycodone is likely making her migraine worse and that she must d/c as part of her treatment plan.
• She wants to know how using oxycodone could make her migraines worse.She wants to know how using oxycodone could make her migraines worse.
Atypical Structure of Pain Processing Regions in MOHRegions in MOH
Lai TH, et. al. Cephalalgia 2016;0:1‐10
Gray Matter Changes Associated With MOH
Riederer F, et. al. World J Biol Psychiatry 2012;13:517‐25
Gray Matter Changes Associated With MOH
D f ti i i• Dysfunction in pain processing and modulating regions
• PAG volume correlates with anxietyanxiety
Riederer F, et. al. World J Biol Psychiatry 2012;13:517‐25
Functional Activation (fMRI) Changes in MOH
Chiapparini L, et. al. Neurol Sci 2009; 1:71‐4
Resting‐state functional connectivitydiscriminates MOH from non MOHdiscriminates MOH from non‐MOH
Brain Reward SystemBrain Reward System
Fc‐alterations with:• Nucleus accumbensNucleus accumbens• DRP
Torta DM, et. al. NeuroImage:Clinical, 2016;11:686‐693
SUMMARY:Brain Structural and Functional Findings in MOHg
• Alterations in Structure and Function in Regionsginvolved in:– Pain processingp g– Pain modulation– Affective and cognitive processing of painAffective and cognitive processing of pain– AddictionReward– Reward
Pain‐Processing in MOH after Withdrawal
Before ithdra alBefore withdrawal
After withdrawal
Ferraro S, et al. Pain Med 2012;13:255‐62
PET in Medication Overuse Headache
Hypometabolism in MOH:Hypometabolism in MOH:• thalamus • ant. Cingulate• insulainsula• OFC
After Withdrawal of MO:• Persistent hypometabolism in OFC
Fumal A, et al. Brain 2006; 129:543‐50
Predicting Response to Treatment
Treatment responders had more OFC volume than those who didn’t respondLai TH, et. al. Cephalalgia 2016;0:1‐10
Brain Patterns that might Predispose to MOH
Genetic component:• MOH is 3x higher in patients with family history of MOH• Allele of histone deacetylases 3 proteiny p• Low risk converters to MOH: polymorphism of CGRP • MOH linked to polymorphisms: angiotensin‐convertingMOH linked to polymorphisms: angiotensin converting
enzyme, brain‐derived neurotrophic factor, catechol‐O‐methyltransferase enzyme and serotonin transporter
Case Conclusions• Patient with MOH: wants to know how using oxycodone could make her
migraines worse.
– Frequent use of migraine abortive medications changes the function and even structure of the brain, including areas of the brain that are responsible for pain
– The good news: most of the brain changes are likely to be reversible once medication overuse is discontinued
MOH
Alterations in Pain‐Processing Regions:Normalize following withdrawal
Secondary to medication overuse
Alterations in OFC:Persist following withdrawal
Alterations in SN/VTA:Persist following withdrawal
Brain traitPredisposes to MO
Future Directions in MOH• Compare MOH to other pain disorders with MO
• Alterations in structure and function specific• Alterations in structure and function specific to different medications that are overused
• Relationship between history of MO and brain alterations?
Thank You!Thank You!