Neurobiological Basis of Migraine

Published with the New York Academy of Sciences

A timely, broad-ranging exploration of the neurobiological basis and molecular mechanisms of migraines

Migraines impact the lives of a significant portion of the world's population, afflicting sufferers with severe pain, nausea, and often visual impairment. The WHO views migraines as an important public health issue, and ranks them in its top twenty most disabling illnesses. Neurobiological Basis of Migraine reviews the latest advances made in our understanding of the primary basic mechanisms of migraine headache and provides valuable insights into how these findings are being translated into novel treatment and prevention strategies around the world.

Written for researchers and clinicians alike, the book features edited contributions from distinguished experts in the field, taking a focused, yet wide-ranging approach to the subject. It begins by exploring the pathways and networks mediating migraine headaches, their underlying physiological mechanisms, characteristics of visceral pain, and the concept of dural neurogenic inflammation. From there the authors delve into the mechanisms sustaining the head pain and photophobia associated with migraines, and they review the pharmacology of newly discovered migraine treatments. These basic chapters are followed by clinical and genetic studies linking to key issues, including cortical spreading depression, ion channels, transporters, and epilepsy.

    Reviews of the latest advances in our understanding of the neurobiological basis of migraine
    Translates important research findings from around the globe into novel treatments strategies currently being investigated
    Provides researchers and clinicians with a deep understanding of the primary mechanisms of migraine from migraine modeling to clinical applications
    Includes contributions by many of the most respected researchers in the field, world-wide
    Discusses exciting recent developments in migraine mutations and their role in CSD, as well as the role of CSD in aura and trigeminal activation

Timely, comprehensive, and authoritative, Neurobiological Basis of Migraine is an indispensable working resource for clinicians and migraine, headache, and pain researchers, including neurobiologists, neuropharmacologists, neurologists, and vascular neurobiologists, as well as graduate students in those fields who are involved in researching migraine headaches.

Contents

List of Contributors xv

Foreword xxi

Part I Anatomy and physiology 1

1 Functional anatomy of trigeminovascular pain 3
Karl Messlinger and Mária Dux

1.1 Anatomy of the trigeminovascular system 3

1.2 Trigeminal ganglion 9

1.3 Trigeminal brainstem nuclear complex 12

2 Physiology of the meningeal sensory pathway 31
Andrew Strassman and Agustin Melo-Carrillo

2.1 Anatomy of the trigeminovascular system 31

2.2 Nociceptive response properties of peripheral and central neurons in the meningeal sensory pathway 32

2.3 Activity of neurons in the meningeal sensory pathway under conditions associated with headache: CSD and nitroglycerin 36

2.4 Role of blood vessels in activation of the meningeal sensory pathway 38

2.5 Unique neuronal properties of the meningeal sensory pathway 39

2.6 Intracranial vs extracranial mechanisms of migraine: new findings 40

References 41

3 Meningeal afferent ion channels and their role in migraine 49
Gregory Dussor PhD

3.1 Meningeal afferents and migraine pain 49

3.2 Transient receptor potential (TRP) channels and headache 49

3.3 Acid-sensing ion channels 54

3.4 Glutamate-gated channels 55

3.5 ATP-gated channels 55

3.6 K+ channels 56

3.7 Other ion channels that may contribute to dural afferent signaling 57

3.8 Conclusions 57

3.9 Acknowledgements 58

References 58

4 Functional architecture of central pain pathways: focus on the trigeminovascular system 69
Rodrigo Noseda and Luis Villanueva

4.1 Introduction 69

4.2 Ascending trigeminal nociceptive pathways 69

4.3 Trigeminovascular pain is subject to descending control 77

4.4 Conclusions 82

References 83

Part II Special features of migraine pain 91

5 Visceral pain 93
Michael S. Gold and G.F. Gebhart

5.1 Organization of innervation 93

5.2 Common features of visceral pain and headache 96

5.3 Summary and conclusions 101

5.4 Acknowledgement 101

References 102

6 Meningeal neurogenic inflammation and dural mast cells in migraine pain 107
Dan Levy PhD

6.1 Introduction 107

6.2 The neurogenic inflammation hypothesis of migraine 108

6.3 Meningeal neurogenic plasma protein extravasation and migraine 108

6.4 Meningeal neurogenic vasodilatation and migraine 110

6.5 Neurogenic mast cell activation in migraine 111

6.6 Endogenous events that could promote meningeal NI in migraine 113

6.7 Anti-migraine drugs and meningeal NI 113

6.8 Is meningeal NI a pro-nociceptive event in migraine? 114

6.9 Conclusions 115

References 116

7 Sensitization and photophobia in migraine 125
Aaron Schain and Rami Burstein

7.1 Introduction 125

7.2 Experimental activation of trigeminovascular pathways 125

7.3 Peripheral sensitization 127

7.4 Central sensitization: medullary dorsal horn 127

7.5 Central sensitization: thalamus 129

7.6 Temporal aspects of sensitization and their implications to triptan therapy 129

7.7 Modulation of central sensitization 131

7.8 Neural substrate of migraine-type photophobia 133

References 135

8 Central circuits promoting chronification of migraine 139
Christopher W. Atcherley, Kelsey Nation, Milena De Felice, Jennifer Y. Xie, Michael H. Ossipov, David W. Dodick and Frank Porreca

8.1 Introduction 139

8.2 Pharmacotherapy of migraine 140

8.3 Medication overuse headache (MOH) and migraine chronification 141

8.4 Central circuits modulating pain 143

8.5 Evaluation of descending modulation: diffuse noxious inhibitory controls and conditioned pain modulation 145

8.6 Conclusions 148

References 149

9 Triptans to calcitonin gene-related peptide modulators – small molecules to antibodies – the evolution of a new migraine drug class 157
Richard J Hargreaves

9.1 Introduction 157

9.2 Trigeminovascular system – migraine physiology and pharmacology 157

9.3 Small molecule CGRP receptor antagonists 159

9.4 Current status of small molecule CGRP receptor antagonist programs 161

9.5 Unraveling the site of action of small molecule CGRP receptor antagonists using clinical pharmacology and brain imaging 162

9.6 Biologic approaches to CGRP modulation 163

9.7 Summary and conclusion 167

References 168

10 Lessons learned from CGRP mutant mice 175
Levi P. Sowers, Annie E. Tye and Andrew F. Russo

10.1 Introduction 175

10.2 Modeling migraine 175

10.3 Calcitonin gene-related peptide (CGRP) in migraine 176

10.4 What has CGRP manipulation in mice taught us about migraine? 177

10.5 Conclusions 183

References 183

Part III Clinical characteristics of migraine 189

11 The clinical characteristics of migraine 191
F. Michael Cutrer MD, Ryan Smith MD and David W. Dodick MD

11.1 Overview of migraine 191

11.2 Migraine prodrome 191

11.3 The migraine headache is the centerpiece of the syndrome 192

11.4 Migraine aura 194

11.5 Proposed aura types 197

11.6 Postdrome 198

11.7 Status migrainosus 199

Summary 199

References 199

12 The premonitory phase of migraine 201
Michele Viana and Peter J. Goadsby

12.1 What is the premonitory phase? Towards a definition 201

12.2 How common are premonitory symptoms? 202

12.3 Do premonitory symptoms reliably predict a migraine attack? 202

12.4 Premonitory symptoms in individuals 203

12.5 Intra-patient variability of the premonitory phase 203

12.6 Difference between patients with and without premonitory symptoms 204

12.7 Premonitory symptoms in children 204

12.8 Premonitory symptoms and migraine triggers 204

12.9 Premonitory symptoms and pathophysiological studies 205

12.10 Treatment during the premonitory phase 206

12.11 Conclusion 206

References 207

Part IV Migraine genetics and CSD 209

13 The genetic borderland of migraine and epilepsy 211
Isamu Aiba and Jeffrey Noebels

13.1 Introduction 211

13.2 Gene-linked comorbidity 211

13.3 The challenge of dissecting seizure and aura excitability defects 212

13.4 Clinical overlap of migraine with aura and epilepsy phenotypes 214

13.5 Acquired and genetic etiologies of migraine with aura and epilepsies 216

13.6 Migraine aura is linked to specific genes with locus and allelic heterogeneity 218

13.7 Correspondence of regional brain susceptibility for migraine in genetic epilepsy syndromes 219

13.8 Are SD thresholds progressive? 220

13.9 Spreading depolarization in cardiorespiratory brainstem regions, a candidate mechanism of SUDEP 221

13.10 Brainstem SD is a “second hit” leading to SUDEP 222

13.11 Tau ablation prevents seizures, SUDEP and brainstem SD threshold in models of SUDEP 223

13.12 Conclusion 223

13.13 Acknowledgements 223

References 223

14 Genetics of monogenic and complex migraine 233
Else A. Tolner, Else Eising, Gisela M. Terwindt, Michel D. Ferrari and Arn M.J.M. van den Maagdenberg

14.1 Migraine is a genetic disease 233

14.2 How to identify genes for migraine? 234

14.3 Gene identification in monogenic Familial Hemiplegic Migraine 234

14.4 Functional studies of gene mutations in monogenic familial hemiplegic migraine 236

14.5 Genetic studies in monogenic disorders in which migraine is a prominent part of the clinical phenotype 239

14.6 Genome-wide association studies in common polygenic migraine 240

14.7 Future directions in genetic migraine research 241

References 243

15 Lessons from familial hemiplegic migraine and cortical spreading depression 251
Daniela Pietrobon

15.1 Introduction 251

15.2 FHM genes and functional consequences of FHM mutations 252

15.3 Insights into the mechanisms underlying susceptibility to cortical spreading depression and initiation of migraine attacks from the functional analysis of FHM mouse models 255

15.4 Acknowledgements 260

References 260

16 From cortical spreading depression to trigeminovascular activation in migraine 267
Turgay Dalkara and Michael A. Moskowitz

16.1 CSD causes the visual aura 267

16.2 SD may underlie transient neurological dysfunctions preceding attacks 269

16.3 Does SD cause headache? 270

16.4 Human data supporting the parenchymal inflammatory signaling 274

16.5 Meningeal neurogenic inflammation amplifies the parenchymal signal 275

16.6 Understanding human CSD and migraine without aura 276

16.7 Potential of CSD models to understand migraine and drug development 278

References 278

Part V Modeling and imaging in migraine 285

17 Mathematical modeling of human cortical spreading depression 287
Markus A. Dahlem

17.1 Introduction 287

17.2 Microscopic models: cellular and cytoarchitectonic detail 288

17.3 Computational models 291

17.4 Macroscopic models: large scale spatiotemporal phenomenology 292

References 301

18 Tools for high-resolution in vivo imaging of cellular and molecular mechanisms in cortical spreading depression and spreading depolarization 307
K��v��lc��m K��l��ç, Hana Uhlirova, Peifang Tian, Payam A. Saisan, Mohammad Abbas Yaseen, Jonghwan Lee, Sergei A. Vinogradov, David A. Boas, Sava Sakadžic and Anna Devor ´

18.1 Introduction 307

18.2 Large-scale imaging of vascular dynamics with microscopic resolution 308

18.3 Combining measurements of single-vessel diameter with imaging and quantification of intracellular Ca2+ in neurons and astrocytes 309

18.4 NADH autofluorescence: an endogenous marker of energy metabolism 311

18.5 Direct imaging of molecular O2 in blood and tissue 312

18.6 Employing optogenetics to study inter-cellular communication 314

18.7 Conclusions and outlook 314

References 315

19 Animal models of migraine aura 321
Shih-Pin Chen, Jeremy Theriot, Cenk Ayata and KC Brennan

19.1 Introduction: spreading depression and migraine 321

19.2 In vivo and in vitro models of SD susceptibility 322

19.3 Experimental preparations 324

19.4 Methods to trigger SD 327

19.5 Methods to detect CSD 329

19.6 SD susceptibility attributes 331

19.7 Recommended quality measures for experimental models of migraine aura 333

19.8 Future directions 334

References 335

20 Human models of migraine 347
Jakob Møller Hansen MD, PhD and Messoud Ashina MD, PhD, DMSc

20.1 Introduction 347

20.2 The first steps: GTN and the NO-hypothesis 347

20.3 Calcitonin gene-related peptide (CGRP) 351

20.4 Vasoactive intestinal peptide (VIP) and pituitary adenylate cyclase activating polypeptide (PACAP) 353

20.5 Can we gain from the use of experimental models to study functional consequences of migraine mutations? 354

20.6 Conclusion 355

References 355

21 Imaging pain and headache 363
Duncan J. Hodkinson, Sophie L. Wilcox and David Borsook

21.1 Introduction 363

21.2 Functional brain changes in migraine 363

21.3 Structural brain changes in migraine 367

21.4 Insights from orofacial pain 370

21.5 Conclusions 371

References 372

Index 377

Turgay Dalkara, MD, PhD is Professor Neurology and Chair of the Institute of Neurological Sciences and Psychiatry at Hacettepe University, Ankara, Turkey. He also holds a joint appointment at the department of Radiology at the Massachusetts General Hospital, Harvard University, Boston.

Michael A. Moskowitz, MD is Professor of Neurology at Harvard Medical School and a former Member of the Harvard-MIT Division of Health Science & Technology.  He is also a senior neuroscientist in the Departments of Radiology and Neurology at the Massachusetts General Hospital, Boston