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.
Table of 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 SakadÂic 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
