Highlights of Headache Research2013-2015

Highlights of Headache Research2013-2015

Morris Maizels MDMorris Maizels MD

Carolina Headache InstituteCarolina Headache Institute

Chapel Hill NC Chapel Hill NC

Overview of HighlightsOverview of Highlights

Promising therapiesPromising therapies• CGRP receptor monoclonal AbsCGRP receptor monoclonal Abs• SPG blocksSPG blocks

Onabotulinum toxinOnabotulinum toxin• Burstein: mechanism of actionBurstein: mechanism of action• Finkel: use in PTHFinkel: use in PTH

Clinical studies:Clinical studies:• Candesartan = propranololCandesartan = propranolol• IV diphenhydramine/metoclopramide > IV ketorolacIV diphenhydramine/metoclopramide > IV ketorolac• placebo studies in headacheplacebo studies in headache

AHS AbstractsAHS Abstracts Functional imaging Functional imaging

Calcitonin gene-related peptideCalcitonin gene-related peptide

neurotransmitter distributed throughout the neurotransmitter distributed throughout the trigeminovascular system and central brain regions trigeminovascular system and central brain regions involved in migraine pathogenesisinvolved in migraine pathogenesis

potent arterial and venous vasodilatorpotent arterial and venous vasodilator Evidence for involvement in migraineEvidence for involvement in migraine

• elevated jugular venous level during attackelevated jugular venous level during attack• IV CGRP IV CGRP migraine-like attack – only in migraine-like attack – only in

migraineurs - p 2-4 hoursmigraineurs - p 2-4 hours• raised serum CGRP levels reversed with triptans, raised serum CGRP levels reversed with triptans,

coinciding with migraine resolutioncoinciding with migraine resolution

Possible MOAs of CGRPPossible MOAs of CGRP

vasodilator, but blocking vasodilation does not vasodilator, but blocking vasodilation does not prevent the attackprevent the attack

released during cortical spreading depression released during cortical spreading depression (rats)(rats)

light sensitization (mice)light sensitization (mice) receptors on TNC primary afferents may receptors on TNC primary afferents may

facilitate nociceptive transmissionfacilitate nociceptive transmissionmodulates second-order TNC neurons modulates second-order TNC neurons

central sensitizationcentral sensitization

Dodick DW1, Goadsby PJ2, Spierings EL3, Scherer JC4, Sweeney SP5, Grayzel DS5.Safety and efficacy of LY2951742, a monoclonal antibody to calcitonin gene-related peptide, for the prevention of migraine: a phase 2, randomised, double-blind, placebo-controlled study.Lancet Neurol. 2014 Sep;13(9):885-92.

CGRP LY2951742CGRP LY2951742

fully humanized monoclonal antibody to CGRP Pharmacokinetics:Pharmacokinetics:

• peak concentrations in 7-13 dayspeak concentrations in 7-13 days• elimination half-life 28 dayselimination half-life 28 days

Dodick et alDodick et al• RDBPCTRDBPCT• EM: 4-14 migraine headache days/monthEM: 4-14 migraine headache days/month• LY2951742 150mg vs placeboLY2951742 150mg vs placebo

sq, q o wk x 12 weekssq, q o wk x 12 weeks

LY2514792 - ResultsLY2514792 - Results

ALD483 – presented at AHS 2014ALD483 – presented at AHS 2014

Endpoint ALD403 (%) Placebo (%) P Value

50% reduction 60 33 <.001

75% reduction 32 9 <.001

100% reduction 16 0 <.001

RDBPCT of AMG 334. Sun et al. AHS 2015 Scientific Assembly

RDBPCT of AMG 334. Sun et al. AHS 2015 Scientific Assembly

483 randomized483 randomized70 mg dose > placebo70 mg dose > placebo

• mean monthly migraine days -3.4 cf -2.3 mean monthly migraine days -3.4 cf -2.3 (p = .021)(p = .021)

• 50% responder rate 46.5% cf 30% (p =.011)50% responder rate 46.5% cf 30% (p =.011)

• change in monthly migraine attacks not change in monthly migraine attacks not statistically differentstatistically different

TEV-48125 4TEV-48125 4thth entry in the field – entry in the field –

• no published data available for reviewno published data available for review

Concerns re CGRP antagonismConcerns re CGRP antagonism

Is there a potential for cardiovascular risk in Is there a potential for cardiovascular risk in blocking vasodilation?blocking vasodilation?

Prior CGRP antagonists demonstrated Prior CGRP antagonists demonstrated hepatotoxicityhepatotoxicity

Sphenopalatine ganglion blocksSphenopalatine ganglion blocks

3 catheters marketed3 catheters marketedprevious techniques:previous techniques:

• cotton plegetscotton plegets

• lidocaine drip with head hyperextended/ lidocaine drip with head hyperextended/ laterally rotatedlaterally rotated

Anatomy of sphenopalatine fossaAnatomy of sphenopalatine fossa

SPG cathetersSPG catheters

A Double-Blind, Placebo-Controlled Study of RepetitiveTransnasal Sphenopalatine Ganglion Blockade With Tx360® as Acute Treatment for Chronic MigraineCady, Saper, et al. Headache 2015.

A Double-Blind, Placebo-Controlled Study of RepetitiveTransnasal Sphenopalatine Ganglion Blockade With Tx360® as Acute Treatment for Chronic MigraineCady, Saper, et al. Headache 2015.

RDBPCT, 2:1 randomizationRDBPCT, 2:1 randomizationSPG blockade w 0.3cc bupivicaine 0.5% or SPG blockade w 0.3cc bupivicaine 0.5% or

saline, twice/wk x 6 weekssaline, twice/wk x 6 weeks

Figure 3. Treatment with bupivacaine delivered with the Tx360® device reduced average pooled NRS scores compared to those treated with saline. Average NRS scores from all treatments pooled are shown. Between group p values: Before Treatment p = .010*; 15

Numeric rating scale scores for pooled Numeric rating scale scores for pooled treatments 1-12treatments 1-12

Baseline 30m 24 hrBaseline 30m 24 hr

Bupivicaine 3.18 Bupivicaine 3.18 2.41 2.41 2.85 2.85

Saline 3.78 Saline 3.78 3.45 3.45 4.20 4.20

Long-Term Efficacy of a Double-Blind, Placebo-Controlled,Randomized Study for Repetitive Sphenopalatine BlockadeWith Bupivacaine vs Saline With the Tx360® Device forTreatment of Chronic Migraine. Headache 2015

Long-Term Efficacy of a Double-Blind, Placebo-Controlled,Randomized Study for Repetitive Sphenopalatine BlockadeWith Bupivacaine vs Saline With the Tx360® Device forTreatment of Chronic Migraine. Headache 2015

Secondary outcomes not clinically Secondary outcomes not clinically significant, but trendssignificant, but trends

• # headache days/month: -5.7 cf -1.9# headache days/month: -5.7 cf -1.9

• QOL outcomes: HIT-6: QOL outcomes: HIT-6: -5.1 cf -2.1 at 1 month; -5.1 cf -2.1 at 1 month; -4.8 cf -1.6 at 6 months-4.8 cf -1.6 at 6 months

Noninvasive sphenopalatine ganglion block for acute headache in the emergency department: a randomized placebo-controlled trial. Schaffer JT1, et al. Ann Emerg Med. 2015

Noninvasive sphenopalatine ganglion block for acute headache in the emergency department: a randomized placebo-controlled trial. Schaffer JT1, et al. Ann Emerg Med. 2015

Primary end-point: 50% reduction in pain at 15 Primary end-point: 50% reduction in pain at 15 minutes:minutes:• 49% (20/41) bupivacaine group (20/41

patients) vs 41% (19/46) saline groupSecondary endpoints, at 24 hours:

• headache free (25% difference; 95% CI 2.6% to 43.6%)

• nausea free (17% difference; 95% CI 0.8% to 32.5%).

SPG (INL) BackgroundSPG (INL) Background

IN cocaine – cluster headache. Barre 1982IN cocaine – cluster headache. Barre 1982 IN lidocaine – cluster headache. Kittrelle 1985IN lidocaine – cluster headache. Kittrelle 1985 Maizels et al. JAMA 1996Maizels et al. JAMA 1996

• Urgent Care patient populationUrgent Care patient population

• 50% relief: 29/53 (55%) cf 6/28 (21%) (P=.004).

• Relapse 10/24 (42 %) cf 5/6 (83 %) (usually within the first hour after treatment).

AHS Acute Treatment Guidelines (Headache 2015) –Level C (insufficient evidence)

Intranasal lidocaine to prevent headache following migraine aura.Maizels M. Headache. 1999

Intranasal lidocaine to prevent headache following migraine aura.Maizels M. Headache. 1999

15 y/o male, 100% of migraine attacks preceded by 15 y/o male, 100% of migraine attacks preceded by aura, and 100% of auras followed by migraineaura, and 100% of auras followed by migraine

Headache always contralateral to auraHeadache always contralateral to aura INL administered contralateral to auraINL administered contralateral to aura  Over 75 episodes (1 ½ years), INL prevented

migraine following aura on all but two occasions There was no effect on the duration of the aura

itself.

Clinical impressions of SPG blocks (SHS Listserv/IHS Abstracts)

Clinical impressions of SPG blocks (SHS Listserv/IHS Abstracts)

efficacy for acute therapy > preventiveefficacy for acute therapy > preventivepreventive efficacy for CM <25 - ~50%preventive efficacy for CM <25 - ~50%

• many of us see occasional dramatic responsemany of us see occasional dramatic responsemay have greater efficacy for various facial may have greater efficacy for various facial

pain syndromespain syndromesAHS 2015 - case reports with NDPH, IIHAHS 2015 - case reports with NDPH, IIH fluoroscopy not necessarily betterfluoroscopy not necessarily betterpatient self-administration may be considered patient self-administration may be considered

after successful office administrationafter successful office administration

Positioning for self-administration of Intranasal Lidocaine

Positioning for self-administration of Intranasal Lidocaine

Questions re SPG blocksQuestions re SPG blocks

Will we ever have data to answer q of efficacy?Will we ever have data to answer q of efficacy? Which headache conditions are most responsive?Which headache conditions are most responsive? Which headache phenotypes are most responsive?Which headache phenotypes are most responsive?

• frontal pain?frontal pain?• unilateral vs bilateral?unilateral vs bilateral?

How many treatments needed to determine efficacy?How many treatments needed to determine efficacy? Does increase in temperature predict efficacy?Does increase in temperature predict efficacy? Is one catheter superior to another?Is one catheter superior to another? Is any catheter superior to non-catheter techniques?Is any catheter superior to non-catheter techniques?

Effectiveness of SPG Stimulation for Cluster Headache. Jensen et al. AHS Scientific Assembly 2015

Effectiveness of SPG Stimulation for Cluster Headache. Jensen et al. AHS Scientific Assembly 2015

33 patients - 5956 treated attacks33 patients - 5956 treated attacks20/33 (61%) responders20/33 (61%) responders

• 5 both acute and frequency5 both acute and frequency

• 10 acute10 acute

• 5 frequency5 frequency

• frequency responders – mean 82% dec in frequency responders – mean 82% dec in attack frequencyattack frequency

Selective inhibition of meningeal nociceptors by botulinum neurotoxin type A. Burstein R et al. Cephalalgia 2014. (IHS Best Ms. Award 2015)

Selective inhibition of meningeal nociceptors by botulinum neurotoxin type A. Burstein R et al. Cephalalgia 2014. (IHS Best Ms. Award 2015)

studied spontaneous and evoked firing of C- studied spontaneous and evoked firing of C- and A-delta meningeal nociceptors in rats, to and A-delta meningeal nociceptors in rats, to intracranial dura and extracranial suture-intracranial dura and extracranial suture-receptive fields, before and after BoNT-A receptive fields, before and after BoNT-A administrationadministration

inhibited C- but not A-delta fibersinhibited C- but not A-delta fibersbefore sensitization: prevented mechanical before sensitization: prevented mechanical

hypersensitivityhypersensitivityafter sensitization: reversed mechanical after sensitization: reversed mechanical hypersensitivityhypersensitivity

 (b) Possible scenario of extracranial origin of intracranial pain. (c) Possible scenario of intracranial origin of extracranial pain.

Burstein R et al. Cephalalgia 2014;34:853-869

Copyright © by International Headache Society

Figure 1. Peripheral innervation of intracranial and extracranial structures relevant to migraine.

Copyright © by International Headache Society

Figure 9.Selective inhibition of mechanosensitivity of suture branches of C- but not Aδ-units.

Onabotulinum Toxin A for the Treatment of Headache in Service Members With a History of Mild Traumatic Brain Injury. Yerry, Kuehn, Finkel. Headache 2015.

Onabotulinum Toxin A for the Treatment of Headache in Service Members With a History of Mild Traumatic Brain Injury. Yerry, Kuehn, Finkel. Headache 2015.

64 subjects (63 male)64 subjects (63 male)• mean age of 31.3 + 7.5 (range 20-59) yearsmean age of 31.3 + 7.5 (range 20-59) years

Most patients (36; 56.3%) described more than 1 headache typeMost patients (36; 56.3%) described more than 1 headache type• 48 (75%) had continuous pain. 48 (75%) had continuous pain. • The most prevalent treating diagnosis was mixed continuous The most prevalent treating diagnosis was mixed continuous

headache with migraine features on more than 15 days per headache with migraine features on more than 15 days per month (n = 26; 40.6%). month (n = 26; 40.6%).

The mean time from injury to the first injections was 10.8 + 21.9 The mean time from injury to the first injections was 10.8 + 21.9 (1-96) months. (1-96) months.

Forty (62.5%) patients received the FDA chronic migraine Forty (62.5%) patients received the FDA chronic migraine protocol. protocol.

Forty-one (64%) patients reported being better. Forty-one (64%) patients reported being better. Two patients discontinued for side effects. Two patients discontinued for side effects. Twenty-seven (41%) remained on active duty.Twenty-seven (41%) remained on active duty.

Other Therapies on the HorizonOther Therapies on the Horizon

AVP-825AVP-825

AVP-825 – Breath-Powered bi-directional AVP-825 – Breath-Powered bi-directional intranasal delivery of low-dose sumatriptan intranasal delivery of low-dose sumatriptan powderpowder

compared to sumatriptan 100 mg:compared to sumatriptan 100 mg:

• faster improvement at 10-30 minutesfaster improvement at 10-30 minutes

• = suma po at 2 hours and 24 hours= suma po at 2 hours and 24 hoursclaim of lower systemic exposure to claim of lower systemic exposure to

sumatriptansumatriptan

Non-invasive VNS for Acute Treatment of high-frequency and chronic migraine. Barbanti et al. AHS 2015

Non-invasive VNS for Acute Treatment of high-frequency and chronic migraine. Barbanti et al. AHS 2015

48 migraineurs treated 130 attacks48 migraineurs treated 130 attacksResponse rate 46% - 1 hr, 60% 2 hrResponse rate 46% - 1 hr, 60% 2 hrPain-free: 23% 1 hr, 33% 2 hrPain-free: 23% 1 hr, 33% 2 hr““When considering all attacks, pain relief When considering all attacks, pain relief

was 22% and 35%, and pain-free 18% and was 22% and 35%, and pain-free 18% and 23%23%

Topical anti-inflammatory therapy in the treatment of acute migraine:role of trigeminal nerve peripheral fibers. Bauer et al. AHS 2015

Topical anti-inflammatory therapy in the treatment of acute migraine:role of trigeminal nerve peripheral fibers. Bauer et al. AHS 2015

5% topical ketoprofen gel applied bilaterally 5% topical ketoprofen gel applied bilaterally over 3 branches of TGNover 3 branches of TGN

pain relief defined as 1-point reduction on 4-pain relief defined as 1-point reduction on 4-point scalepoint scale

22 subjects – 49 severe headaches (data for 22 subjects – 49 severe headaches (data for moderate headaches not reported)moderate headaches not reported)

• 77% vs 60% pain-relief (no time point)77% vs 60% pain-relief (no time point)

• 24-hr pain-free 50% cf 26%24-hr pain-free 50% cf 26%

Altered placebo and drug labeling changes the outcome of  episodic migraine attacks. Kam-Hansen1, et al et Burstein R.Sci Transl Med. 2014 Jan.

Altered placebo and drug labeling changes the outcome of  episodic migraine attacks. Kam-Hansen1, et al et Burstein R.Sci Transl Med. 2014 Jan.

66 subjects with episodic migraine66 subjects with episodic migraine each received 3 packets of Rx, each with 1 rizatriptan and1 each received 3 packets of Rx, each with 1 rizatriptan and1

placebo tabletplacebo tablet packets were labeled:packets were labeled:

• MaxaltMaxalt• PlaceboPlacebo• Maxalt or placeboMaxalt or placebo

Results:Results:• Whether active or placebo, efficacy greatest for belief of Whether active or placebo, efficacy greatest for belief of

active Rxactive Rx• Placebo labeled as Maxalt p= Maxalt labeled as placebo.Placebo labeled as Maxalt p= Maxalt labeled as placebo.• Label of “uncertain” = “Maxalt”Label of “uncertain” = “Maxalt”

Differential Effectiveness of Placebo Treatments: A Systematic Review of Migraine Prophylaxis. Meissner, et al. JAMA Intern Med. 2013;173:1941-1951.

Differential Effectiveness of Placebo Treatments: A Systematic Review of Migraine Prophylaxis. Meissner, et al. JAMA Intern Med. 2013;173:1941-1951.

% responders[95% CI]

Sham surgery 0.58 [0.37-0.77]

Sham acupuncture 0.38 [0.30-0.47]

Oral agents 0.22 [0.17-0.28]

A quantification of the placebo response in migraine prophylaxis. van der Kuy PH, Lohman JJ.Cephalalgia. 2002;22:265-70.

A quantification of the placebo response in migraine prophylaxis. van der Kuy PH, Lohman JJ.Cephalalgia. 2002;22:265-70.

mean 50% responder rate:mean 50% responder rate:placebo 23.5% cf active 45%placebo 23.5% cf active 45%

mean decrease of migraine attacks mean decrease of migraine attacks placebo 16.8% cf active 42%placebo 16.8% cf active 42%

Queries re placebo responseQueries re placebo response

How much does physician optimism How much does physician optimism influence treatment outcome?influence treatment outcome?

If an individual responds to a drug that has If an individual responds to a drug that has been found to be equivalent to placebo in been found to be equivalent to placebo in well-designed trials, is that individual’s well-designed trials, is that individual’s response necessarily a placebo response?response necessarily a placebo response?

http://www.tylervigen.com/spurious-correlationshttp://www.tylervigen.com/spurious-correlations

Stovner LJ1, Linde M2, Gravdahl GB2, et al.

A comparative study of candesartan versus propranolol for migraine prophylaxis: A randomised, triple-blind, placebo-controlled, double cross-over study.

Cephalalgia. 2013 Dec 11;34(7):523-532.

Tronvik E1, et al. Prophylactic treatment of migraine with an angiotensin II receptor blocker: a randomized controlled trial. JAMA. 2003;289(1):65-9.

Tronvik E1, et al. Prophylactic treatment of migraine with an angiotensin II receptor blocker: a randomized controlled trial. JAMA. 2003;289(1):65-9.

60 adults, 2-6 migraine attacks/month60 adults, 2-6 migraine attacks/month Placebo run-in of 4 weeksPlacebo run-in of 4 weeks

12 week periods of Rx or placebo with 4 week 12 week periods of Rx or placebo with 4 week placebo washoutplacebo washout

In 12 weeks:In 12 weeks:mean # ha days: 18.5 vs 13.6 (p=.001)mean # ha days: 18.5 vs 13.6 (p=.001)days w migraine: 12.6 vs 9.0 (p<.001)days w migraine: 12.6 vs 9.0 (p<.001)hours w migraine: 92.2 vs 59.4 (p<.001)hours w migraine: 92.2 vs 59.4 (p<.001)

Responders Responders No significant difference in HRQOLNo significant difference in HRQOL

Candesartan RDBPCTCandesartan RDBPCT

50% responder rate: n(%)50% responder rate: n(%)

CandesartanCandesartan PlaceboPlacebo ppHA daysHA days 16 (32%) 16 (32%) 1 (1.6%)1 (1.6%) .001.001

Migraine daysMigraine days 23 (40%) 23 (40%) 2 (3.5%) <.0012 (3.5%) <.001

HA severity index 23 (40%)HA severity index 23 (40%) 2 (3.5%) <.0012 (3.5%) <.001

Comments:Comments:

Overall low efficacy, with very low placebo response.Overall low efficacy, with very low placebo response.

Candesartan vs propranololCandesartan vs propranolol

72 adults with EM or CM72 adults with EM or CM 3 12-week periods3 12-week periods Candesartan 16 mg, Propranolol SR 160 mgCandesartan 16 mg, Propranolol SR 160 mg Primary outcome measure: days w headache Primary outcome measure: days w headache

• candesartan 2.95 vs propranolol 2.91 vs placebo 3.53 (p=0.02 for candesartan 2.95 vs propranolol 2.91 vs placebo 3.53 (p=0.02 for both)both)

Reduction of headache days on active medication compared to placebo: Reduction of headache days on active medication compared to placebo: 0.6/28 days0.6/28 days

Responder rate: Responder rate: Candesartan 43%Candesartan 43%Propranolol 40%Propranolol 40%Placebo 23% (p = 0.025 and <0.05 respectively)Placebo 23% (p = 0.025 and <0.05 respectively)

Author’s conclusion: “It is confirmed that candesartan 16 mg is effective Author’s conclusion: “It is confirmed that candesartan 16 mg is effective for migraine prevention, with an effect size similar to propranolol 160mg).for migraine prevention, with an effect size similar to propranolol 160mg).

Possible MOA of candesartanPossible MOA of candesartan

Angiotensin IIAngiotensin II vasoconstriction vasoconstriction increased sympathetic discharge increased sympathetic discharge adrenal medullary catecholamine release adrenal medullary catecholamine release

Brain actions of Angiotensin:Brain actions of Angiotensin:• modulates cerebrovascular flow via AT1 receptor modulates cerebrovascular flow via AT1 receptor • increased levels of dopamine and 5HIAA increased levels of dopamine and 5HIAA

(primary serotonin metabolite)(primary serotonin metabolite)• influences pineal melatonin synthesisinfluences pineal melatonin synthesis

A Randomized Trial of Intravenous Ketorolac Versus Intravenous Metoclopramide Plus Diphenhydramine for Tension-Type and All Nonmigraine, Noncluster Recurrent Headaches. Benjamin W. Friedman, et al.Ann Emerg Med. 2013.

A Randomized Trial of Intravenous Ketorolac Versus Intravenous Metoclopramide Plus Diphenhydramine for Tension-Type and All Nonmigraine, Noncluster Recurrent Headaches. Benjamin W. Friedman, et al.Ann Emerg Med. 2013.

120 patients who meet criteria for TTH in ED120 patients who meet criteria for TTH in EDketorolac 30mg IV vs ketorolac 30mg IV vs

diphenhydramine 25mg + metoclopramide diphenhydramine 25mg + metoclopramide 20mg IV20mg IV

Ketorolac(%) Ketorolac(%) Dip/Met(%)Dip/Met(%) HA-free in ED 16/60 (27)HA-free in ED 16/60 (27) 27/60(45)27/60(45)Req’d rescue 27/60 (45)Req’d rescue 27/60 (45) 8/60 (13)8/60 (13)24hr HA-free 5/60 (8)24hr HA-free 5/60 (8) 16/60(27)16/60(27)

A randomized trial of IV Diphenhydramine adjuvant therapy for acute migraine. Friedman et al. AHS 2015 Scientific Assembly

A randomized trial of IV Diphenhydramine adjuvant therapy for acute migraine. Friedman et al. AHS 2015 Scientific Assembly

did not improve migraine outcomesdid not improve migraine outcomes

Basic Science HighlightsBasic Science Highlights

Migraine is a Migraine is a whole brain disorderwhole brain disorderThe migraine brain displays The migraine brain displays altered altered

interictal pain processing dynamicsinterictal pain processing dynamicsMigraine changes the brain Migraine changes the brain

((neuroplasticityneuroplasticity))

What can a dead salmon teach us about functional imaging?What can a dead salmon teach us about functional imaging?

fMRI Evidence of Consciousness in a Dead Salmon

fMRI Evidence of Consciousness in a Dead Salmon

Bennett et al. “Neural Correlates of Interspecies Perspective Taking in the Post-Mortem Atlantic Salmon: An Argument For Proper Multiple Comparisons Correction” Journal of Serendipitous and Unexpected Results, 2010. IgNobel Award in Neuroscience 2012

Guidance from a neuroimagerGuidance from a neuroimager

I can tell you that the data are (have to be) manipulated so much to get those pretty maps, that you really can't evaluate the work after the fact.  I just try to look for consistency across studies, figuring any dodgy stats or biases ought to even out.

The missing link: Enhanced functional connectivity between amygdala and visceroceptive cortex in migraine. Hadjikhanai et al.Cephalalgia 2013. 33; 1264–1268

The missing link: Enhanced functional connectivity between amygdala and visceroceptive cortex in migraine. Hadjikhanai et al.Cephalalgia 2013. 33; 1264–1268

Methods:Methods:• 22 migraineurs22 migraineurs

• 11 MA, 11 MwoA11 MA, 11 MwoA• 2.5-4 attacks/month2.5-4 attacks/month• disease duration ~15 yearsdisease duration ~15 years

• 11 CTS11 CTS• 9 TGN9 TGN• 20 healthy controls20 healthy controls

Results: Increased connectivity between the amygdala Results: Increased connectivity between the amygdala and anterior insula, thalamus, and somatosensory cortexand anterior insula, thalamus, and somatosensory cortex

Statistical maps of connectivity between the amygdala and the rest of the brain (p<0.005,uncorrected), in MWA, MWoA, TGN and CTS.

Statistical maps of connectivity between the amygdala and the rest of the brain (p<0.005,uncorrected), in MWA, MWoA, TGN and CTS.

The missing link: Enhanced functional connectivity between amygdala and visceroceptive cortex in migraine. Hadjikhanai et al.Cephalalgia 2013. 33; 1264–1268

The missing link: Enhanced functional connectivity between amygdala and visceroceptive cortex in migraine. Hadjikhanai et al.Cephalalgia 2013. 33; 1264–1268

Amygdala may be involved in both ascending and Amygdala may be involved in both ascending and descending nociceptive pathwaysdescending nociceptive pathways

Sensitization of amygdala demonstrated during a Sensitization of amygdala demonstrated during a migraine attackmigraine attack

Single episode of CSD (unlikely to elicit pain) induced Single episode of CSD (unlikely to elicit pain) induced c-fos expression in amygdala (rat)c-fos expression in amygdala (rat)

CSD-like phenomena may underlie MwoA as well as CSD-like phenomena may underlie MwoA as well as MA (“silent aura”)MA (“silent aura”)• Common migraine preventives suppress CSD Common migraine preventives suppress CSD

(in rats)(in rats)• longer treatment duration longer treatment duration greater suppression greater suppression

The insular cortexThe insular cortex

component of limbic systemcomponent of limbic system input from thalamus, efferent to cingulate and pre-input from thalamus, efferent to cingulate and pre-

frontal cortexfrontal cortex functions include perception of pain through integration functions include perception of pain through integration

from somatosensory and visceral sensory modalitiesfrom somatosensory and visceral sensory modalities Penfield – direct electrical stimulation Penfield – direct electrical stimulation abdominal abdominal

pain, nausea, alterations in gastric motility, and pain, nausea, alterations in gastric motility, and tingling/numbness in face, hand, arms, and tonguetingling/numbness in face, hand, arms, and tongue

activated during migraine attacksactivated during migraine attacks increased inter-ictal levels of glutamate in migraineurs increased inter-ictal levels of glutamate in migraineurs

Might lateralization of migraine have clinical significance?Might lateralization of migraine have clinical significance?

Patients with:• right-sided pain activate the right dorsolateral pons• left-sided pain activate the left dorsolateral pons• bilateral pain activate the left side of the dorsolateral pons

predominantly, but there are bilateral activations present. Activation persists after pain control (sumatriptan) The data suggest that unilateral pain, one of the hallmark

features of migraine, results from an asymmetrical brainstem dysfunction.

A PET study exploring the laterality of brainstem activation in A PET study exploring the laterality of brainstem activation in migraine using glyceryl trinitrate. Afridi, et al. Brain 2005.migraine using glyceryl trinitrate. Afridi, et al. Brain 2005.

Laterality and gender differences of amygdala functionsLaterality and gender differences of amygdala functions

Inflammation-induced ERK activation in the CeA only occurs in the right, but not the left hemisphere

Stimulation of:Stimulation of:• right amygdala right amygdala negative emotions (fear, sadness) negative emotions (fear, sadness)• left amygdala left amygdala happiness or fear/anxiety/sadness happiness or fear/anxiety/sadness

Memory of a horror movie:Memory of a horror movie:• enhanced with activity of left amygdala in women, right enhanced with activity of left amygdala in women, right

amygdala in menamygdala in men Right amygdala linked to taking action Right amygdala linked to taking action

• males respond to emotional stimuli physicallymales respond to emotional stimuli physically Left amygdala Left amygdala more thought than action in response to more thought than action in response to

emotionally stressful stimuliemotionally stressful stimuli

Altered structure and resting-state functional connectivity of the basal ganglia in migraine patients without aura.Yuan et al. J Pain 2013.

Altered structure and resting-state functional connectivity of the basal ganglia in migraine patients without aura.Yuan et al. J Pain 2013.

Reduced volume in Lt caudate and Rt nucleus Reduced volume in Lt caudate and Rt nucleus accumbens (NAc) in migraine cf controlsaccumbens (NAc) in migraine cf controls

Increased connectivity between BG and brain regions Increased connectivity between BG and brain regions with nociceptive and somatosensory processingwith nociceptive and somatosensory processing

Correlations between:Correlations between:• disease duration and:disease duration and:

• volume of bilateral caudate and Rt NAcvolume of bilateral caudate and Rt NAc• connectivity Rt NAc <–> bilateral ACCconnectivity Rt NAc <–> bilateral ACC

• frequency of migraine attacks and increased frequency of migraine attacks and increased connectivity bilateral caudate <–> Lt insulaconnectivity bilateral caudate <–> Lt insula

Disrupted default mode network connectivity in migraine without aura. Tessitore et al. The Journal of Headache and Pain 2013, 14:89

Disrupted default mode network connectivity in migraine without aura. Tessitore et al. The Journal of Headache and Pain 2013, 14:89

The default mode network – an anatomically defined brain system that preferentially activates when individuals engage in internal tasks such as  daydreaming, envisioning the future, retrieving memories, and gauging others' perspectives.

DMN activity - related to individual stressful DMN activity - related to individual stressful experiences and coping strategies to promote experiences and coping strategies to promote adaptation (allostasis)adaptation (allostasis)

reduced functional connectivity within the reduced functional connectivity within the prefrontal and temporal cortices of the DMN in prefrontal and temporal cortices of the DMN in patients with MwoA during the interictal periodpatients with MwoA during the interictal period

Effects of Long-Term Acupuncture Treatment on Resting-State Brain Activity in Migraine Patients: A RandomizedControlled Trial on Active Acupoints and Inactive Acupoints. Zhao et al.

Effects of Long-Term Acupuncture Treatment on Resting-State Brain Activity in Migraine Patients: A RandomizedControlled Trial on Active Acupoints and Inactive Acupoints. Zhao et al.

long-term active acupoint therapy long-term active acupoint therapy more extensive and more extensive and remarkable cerebral response compared with remarkable cerebral response compared with acupuncture at inactive acupoints. acupuncture at inactive acupoints.

most of the regions were involved in the pain matrix, most of the regions were involved in the pain matrix, default mode network, and cognitive components of default mode network, and cognitive components of pain processingpain processing

decrease in VAS was significantly related to:decrease in VAS was significantly related to:• increased average Regional homogeneity (ReHo) increased average Regional homogeneity (ReHo)

values in the anterior cingulate cortex in both groupsvalues in the anterior cingulate cortex in both groups• increased average ReHo values in the insula, only in increased average ReHo values in the insula, only in

the active acupoint group.the active acupoint group.

Beyond Neurovascular: Migraine as a Dysfunctional Neurolimbic Pain Network. Maizels, Aurora, Heinricher. Headache Oct 2012.

Beyond Neurovascular: Migraine as a Dysfunctional Neurolimbic Pain Network. Maizels, Aurora, Heinricher. Headache Oct 2012.

Summary of recent functional imaging studies in migraineSummary of recent functional imaging studies in migraine

Diffuse changes in volume and connectivity are Diffuse changes in volume and connectivity are consistently found interictally, as well as during an acute consistently found interictally, as well as during an acute migraine attack.migraine attack.

Interpretation of significance of findings must await Interpretation of significance of findings must await confirmation of reported findingsconfirmation of reported findings

It is unclear if migraine alters brain function (especially It is unclear if migraine alters brain function (especially neurolimbic centers) diffusely, or if alterations of neurolimbic centers) diffusely, or if alterations of neurolimbic centers are a response to migraine neurolimbic centers are a response to migraine progressionprogression

Laterality of brainstem center activation is seen in Laterality of brainstem center activation is seen in several structures relevant to migraineseveral structures relevant to migraine

Facing depression with botulinum toxin: A randomized controlled trial. Wollmer, de Boer, Kalak, et al. Journal of Psychiatric Research 46 (2012) 574-581

Facing depression with botulinum toxin: A randomized controlled trial. Wollmer, de Boer, Kalak, et al. Journal of Psychiatric Research 46 (2012) 574-581

RDBPCT 30 patients 1:1RDBPCT 30 patients 1:1 29u(f)/39u(m) to 5 regions in glabella region29u(f)/39u(m) to 5 regions in glabella region Ham-D scores at 6 weeks:Ham-D scores at 6 weeks:

•  47.1% cf 9.2% ( p = 0.002)• larger effect size at 16 weeks

90% correctly guessed their treatment group, but results not associated with satisfaction with cosmetic result

MOA - ?sustained and persistent relaxation response

Facing depression with botulinum toxin: A randomized controlled trial. Wollmer, de Boer, Kalak, et al. Journal of Psychiatric Research 46 (2012) 574-581

Facing depression with botulinum toxin: A randomized controlled trial. Wollmer, de Boer, Kalak, et al. Journal of Psychiatric Research 46 (2012) 574-581

Facial feedback hypothesisFacial feedback hypothesis• mutual interaction between emotions and facial mutual interaction between emotions and facial

muscle activity (Darwin, 1872; James, 1890)muscle activity (Darwin, 1872; James, 1890)• ““Refuse to express a passion, and it dies” Refuse to express a passion, and it dies”

(William James (1890) (William James (1890) Negative emotions, like anger, fear, and sadness, that are Negative emotions, like anger, fear, and sadness, that are

prevalent in depression are associated with activation of prevalent in depression are associated with activation of the corrugator and procerus muscles in the glabellar the corrugator and procerus muscles in the glabellar region of the face.region of the face.

In patients with depressive disorders, facial EMG In patients with depressive disorders, facial EMG reveals a relative overactivity of the corrugator muscles reveals a relative overactivity of the corrugator muscles during different affective imagery paradigms.during different affective imagery paradigms.

Facial feedback hypothesis and human mirror neuron networkFacial feedback hypothesis and human mirror neuron network

hypothesis that muscles of emotional expression hypothesis that muscles of emotional expression may converselymay conversely influence emotional experience

mirror neuron - a neuron that fires both when an animal acts and when the animal observes the same action performed by another• confirmation in primates and birds• indirect evidence in humans

human mirror neuron system may underlie empathy deficits may explain features of autism ?basis for N170 changes in migraineurs

What I’ve learned 2014/2015What I’ve learned 2014/2015

Help and hope are on the way!Help and hope are on the way!Our toolbox is expanding.Our toolbox is expanding.

Migraine is a whole brain disorderMigraine is a whole brain disorder Some of the personality changes of the “difficult” Some of the personality changes of the “difficult”

migraineur may be due to alterations of functional migraineur may be due to alterations of functional connectivity in the neurolimbic pain matrix.connectivity in the neurolimbic pain matrix.

Being a headache doc is the most rewarding thing I can Being a headache doc is the most rewarding thing I can do. At its best, I am a healer, but each day, I may be do. At its best, I am a healer, but each day, I may be counselor, educator, priest, and even shaman. I am counselor, educator, priest, and even shaman. I am privileged to hear the stories of my patients, and to privileged to hear the stories of my patients, and to become part of their story. And to be part of the become part of their story. And to be part of the community of headache docs.community of headache docs.

AppendixAppendix

Wolff Award 2015Wolff Award 2015

Schwedt et al. Accurate classification of Schwedt et al. Accurate classification of chronic migraine via brain magnetic chronic migraine via brain magnetic resonance imagingresonance imaging

Non-hormonally mediated menstrual headache:end-menstrual migraine. Calhoun, Pruitt. Abstract AHS 2015

Non-hormonally mediated menstrual headache:end-menstrual migraine. Calhoun, Pruitt. Abstract AHS 2015

30/119 women in a hormonal headache 30/119 women in a hormonal headache clinic had end-menstrual migraineclinic had end-menstrual migraine

28/30 had ferritin levels <5028/30 had ferritin levels <50anecdotal observation from author that iron anecdotal observation from author that iron

replacement leads to improvementreplacement leads to improvement

KetamineKetamine

IV ketamine for the subacute treatment of IV ketamine for the subacute treatment of refractory chronic migraine. Mazuera, refractory chronic migraine. Mazuera, Ashina, Lipton.Ashina, Lipton.

Ketamine infusions as treatment for Ketamine infusions as treatment for headache. (Jefferson Center)headache. (Jefferson Center)

SHS Listserv discussions re use of SHS Listserv discussions re use of intranasal ketamineintranasal ketamine

Headache 2014: Most AccessedHeadache 2014: Most Accessed

The Relation Between Migraine, Typical Migraine Aura and ‘Visual Snow’Volume 54, Issue 6 

Orofacial Pain: A Guide for the Headache PhysicianVolume 54, Issue 1 

Wine and HeadacheVolume 54, Issue 6 

Clinical Aspects of Medication Overuse HeadachesVolume 54, Issue 1 

CAM in the Real World: You May Practice Evidence-Based Medicine, But Your Patients Don'tVolume 54, Issue 6

Headache 2014: Most SharedHeadache 2014: Most Shared

Choosing Wisely in Headache Medicine: The American Headache Society's List of Five Things Physicians and Patients Should QuestionVolume 54, Issue 10 

Meditation for Migraines: A Pilot Randomized Controlled TrialVolume 54, Issue 9 

The Relation Between Migraine, Typical Migraine Aura and ‘Visual Snow’Volume 54, Issue 6

Trigger Point Injections for Headache Disorders: Expert Consensus Methodology and Narrative ReviewVolume 54, Issue 9

So Many Migraines, So Few Subspecialists: Analysis of the Geographic Location of United Council for Neurologic Subspecialties (UCNS) Certified Headache Subspecialists Compared to United States Headache DemographicsVolume 54, Issue 8

Headache 2014: Most CitedHeadache 2014: Most Cited

Obesity and Headache: Part I - A Systematic Review of the Epidemiology of Obesity and HeadacheVolume 54, Issue 2 

A Critical Evaluation of Migraine Trigger Site Deactivation SurgeryVolume 54, Issue 1

The Prevalence of Migraine in Restless Legs SyndromeVolume 54, Issue 5 

Pseudotumor Cerebri PathophysiologyVolume 54, Issue 3

High-Pressure Headaches, Low-Pressure Syndromes, and CSF Leaks: Diagnosis and ManagementVolume 54, Issue 2