Neurobiological Basis of Migraine

About the EditorsTurgay Dalkara, MD, PhD is Professor of 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 senior neuroscientist in the Departments of Radiology and Neurology at the Massachusetts General Hospital, Boston.

• List of Contributors xvForeword xxiPart I Anatomy and physiology 11 Functional anatomy of trigeminovascular pain 3Karl Messlinger and Mária Dux1.1 Anatomy of the trigeminovascular system 31.2 Trigeminal ganglion 91.3 Trigeminal brainstem nuclear complex 122 Physiology of the meningeal sensory pathway 31Andrew Strassman and Agustin Melo-Carrillo2.1 Anatomy of the trigeminovascular system 312.2 Nociceptive response properties of peripheral and central neurons in the meningeal sensory pathway 322.3 Activity of neurons in the meningeal sensory pathway under conditions associated with headache: CSD and nitroglycerin 362.4 Role of blood vessels in activation of the meningeal sensory pathway 382.5 Unique neuronal properties of the meningeal sensory pathway 392.6 Intracranial vs extracranial mechanisms of migraine: new findings 40References 413 Meningeal afferent ion channels and their role in migraine 49Gregory Dussor PhD3.1 Meningeal afferents and migraine pain 493.2 Transient receptor potential (TRP) channels and headache 493.3 Acid-sensing ion channels 543.4 Glutamate-gated channels 553.5 ATP-gated channels 553.6 K+ channels 563.7 Other ion channels that may contribute to dural afferent signaling 573.8 Conclusions 573.9 Acknowledgements 58References 584 Functional architecture of central pain pathways: focus on the trigeminovascular system 69Rodrigo Noseda and Luis Villanueva4.1 Introduction 694.2 Ascending trigeminal nociceptive pathways 694.3 Trigeminovascular pain is subject to descending control 774.4 Conclusions 82References 83Part II Special features of migraine pain 915 Visceral pain 93Michael S. Gold and G.F. Gebhart5.1 Organization of innervation 935.2 Common features of visceral pain and headache 965.3 Summary and conclusions 1015.4 Acknowledgement 101References 1026 Meningeal neurogenic inflammation and dural mast cells in migraine pain 107Dan Levy PhD6.1 Introduction 1076.2 The neurogenic inflammation hypothesis of migraine 1086.3 Meningeal neurogenic plasma protein extravasation and migraine 1086.4 Meningeal neurogenic vasodilatation and migraine 1106.5 Neurogenic mast cell activation in migraine 1116.6 Endogenous events that could promote meningeal NI in migraine 1136.7 Anti-migraine drugs and meningeal NI 1136.8 Is meningeal NI a pro-nociceptive event in migraine? 1146.9 Conclusions 115References 1167 Sensitization and photophobia in migraine 125Aaron Schain and Rami Burstein7.1 Introduction 1257.2 Experimental activation of trigeminovascular pathways 1257.3 Peripheral sensitization 1277.4 Central sensitization: medullary dorsal horn 1277.5 Central sensitization: thalamus 1297.6 Temporal aspects of sensitization and their implications to triptan therapy 1297.7 Modulation of central sensitization 1317.8 Neural substrate of migraine-type photophobia 133References 1358 Central circuits promoting chronification of migraine 139Christopher W. Atcherley, Kelsey Nation, Milena De Felice, Jennifer Y. Xie, Michael H. Ossipov, David W. Dodick and Frank Porreca8.1 Introduction 1398.2 Pharmacotherapy of migraine 1408.3 Medication overuse headache (MOH) and migraine chronification 1418.4 Central circuits modulating pain 1438.5 Evaluation of descending modulation: diffuse noxious inhibitory controls and conditioned pain modulation 1458.6 Conclusions 148References 1499 Triptans to calcitonin gene-related peptide modulators – small molecules to antibodies – the evolution of a new migraine drug class 157Richard J Hargreaves9.1 Introduction 1579.2 Trigeminovascular system – migraine physiology and pharmacology 1579.3 Small molecule CGRP receptor antagonists 1599.4 Current status of small molecule CGRP receptor antagonist programs 1619.5 Unraveling the site of action of small molecule CGRP receptor antagonists using clinical pharmacology and brain imaging 1629.6 Biologic approaches to CGRP modulation 1639.7 Summary and conclusion 167References 16810 Lessons learned from CGRP mutant mice 175Levi P. Sowers, Annie E. Tye and Andrew F. Russo10.1 Introduction 17510.2 Modeling migraine 17510.3 Calcitonin gene-related peptide (CGRP) in migraine 17610.4 What has CGRP manipulation in mice taught us about migraine? 17710.5 Conclusions 183References 183Part III Clinical characteristics of migraine 18911 The clinical characteristics of migraine 191F. Michael Cutrer MD, Ryan Smith MD and David W. Dodick MD11.1 Overview of migraine 19111.2 Migraine prodrome 19111.3 The migraine headache is the centerpiece of the syndrome 19211.4 Migraine aura 19411.5 Proposed aura types 19711.6 Postdrome 19811.7 Status migrainosus 199Summary 199References 19912 The premonitory phase of migraine 201Michele Viana and Peter J. Goadsby12.1 What is the premonitory phase? Towards a definition 20112.2 How common are premonitory symptoms? 20212.3 Do premonitory symptoms reliably predict a migraine attack? 20212.4 Premonitory symptoms in individuals 20312.5 Intra-patient variability of the premonitory phase 20312.6 Difference between patients with and without premonitory symptoms 20412.7 Premonitory symptoms in children 20412.8 Premonitory symptoms and migraine triggers 20412.9 Premonitory symptoms and pathophysiological studies 20512.10 Treatment during the premonitory phase 20612.11 Conclusion 206References 207Part IV Migraine genetics and CSD 20913 The genetic borderland of migraine and epilepsy 211Isamu Aiba and Jeffrey Noebels13.1 Introduction 21113.2 Gene-linked comorbidity 21113.3 The challenge of dissecting seizure and aura excitability defects 21213.4 Clinical overlap of migraine with aura and epilepsy phenotypes 21413.5 Acquired and genetic etiologies of migraine with aura and epilepsies 21613.6 Migraine aura is linked to specific genes with locus and allelic heterogeneity 21813.7 Correspondence of regional brain susceptibility for migraine in genetic epilepsy syndromes 21913.8 Are SD thresholds progressive? 22013.9 Spreading depolarization in cardiorespiratory brainstem regions, a candidate mechanism of SUDEP 22113.10 Brainstem SD is a “second hit” leading to SUDEP 22213.11 Tau ablation prevents seizures, SUDEP and brainstem SD threshold in models of SUDEP 22313.12 Conclusion 22313.13 Acknowledgements 223References 22314 Genetics of monogenic and complex migraine 233Else A. Tolner, Else Eising, Gisela M. Terwindt, Michel D. Ferrari and Arn M.J.M. van den Maagdenberg14.1 Migraine is a genetic disease 23314.2 How to identify genes for migraine? 23414.3 Gene identification in monogenic Familial Hemiplegic Migraine 23414.4 Functional studies of gene mutations in monogenic familial hemiplegic migraine 23614.5 Genetic studies in monogenic disorders in which migraine is a prominent part of the clinical phenotype 23914.6 Genome-wide association studies in common polygenic migraine 24014.7 Future directions in genetic migraine research 241References 24315 Lessons from familial hemiplegic migraine and cortical spreading depression 251Daniela Pietrobon15.1 Introduction 25115.2 FHM genes and functional consequences of FHM mutations 25215.3 Insights into the mechanisms underlying susceptibility to cortical spreading depression and initiation of migraine attacks from the functional analysis of FHM mouse models 25515.4 Acknowledgements 260References 26016 From cortical spreading depression to trigeminovascular activation in migraine 267Turgay Dalkara and Michael A. Moskowitz16.1 CSD causes the visual aura 26716.2 SD may underlie transient neurological dysfunctions preceding attacks 26916.3 Does SD cause headache? 27016.4 Human data supporting the parenchymal inflammatory signaling 27416.5 Meningeal neurogenic inflammation amplifies the parenchymal signal 27516.6 Understanding human CSD and migraine without aura 27616.7 Potential of CSD models to understand migraine and drug development 278References 278Part V Modeling and imaging in migraine 28517 Mathematical modeling of human cortical spreading depression 287Markus A. Dahlem17.1 Introduction 28717.2 Microscopic models: cellular and cytoarchitectonic detail 28817.3 Computational models 29117.4 Macroscopic models: large scale spatiotemporal phenomenology 292References 30118 Tools for high-resolution in vivo imaging of cellular and molecular mechanisms in cortical spreading depression and spreading depolarization 307K;;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 30718.2 Large-scale imaging of vascular dynamics with microscopic resolution 30818.3 Combining measurements of single-vessel diameter with imaging and quantification of intracellular Ca2+ in neurons and astrocytes 30918.4 NADH autofluorescence: an endogenous marker of energy metabolism 31118.5 Direct imaging of molecular O2 in blood and tissue 31218.6 Employing optogenetics to study inter-cellular communication 31418.7 Conclusions and outlook 314References 31519 Animal models of migraine aura 321Shih-Pin Chen, Jeremy Theriot, Cenk Ayata and KC Brennan19.1 Introduction: spreading depression and migraine 32119.2 In vivo and in vitro models of SD susceptibility 32219.3 Experimental preparations 32419.4 Methods to trigger SD 32719.5 Methods to detect CSD 32919.6 SD susceptibility attributes 33119.7 Recommended quality measures for experimental models of migraine aura 33319.8 Future directions 334References 33520 Human models of migraine 347Jakob Møller Hansen MD, PhD and Messoud Ashina MD, PhD, DMSc20.1 Introduction 34720.2 The first steps: GTN and the NO-hypothesis 34720.3 Calcitonin gene-related peptide (CGRP) 35120.4 Vasoactive intestinal peptide (VIP) and pituitary adenylate cyclase activating polypeptide (PACAP) 35320.5 Can we gain from the use of experimental models to study functional consequences of migraine mutations? 35420.6 Conclusion 355References 35521 Imaging pain and headache 363Duncan J. Hodkinson, Sophie L. Wilcox and David Borsook21.1 Introduction 36321.2 Functional brain changes in migraine 36321.3 Structural brain changes in migraine 36721.4 Insights from orofacial pain 37021.5 Conclusions 371References 372Index 377