Trends in Neurosciences
ReviewFeature ReviewMigraine: a disorder of brain excitatory–inhibitory balance?
Introduction
Migraine is a common episodic neurological disorder with complex pathophysiology that manifests itself as recurrent attacks of typically throbbing and unilateral, often severe, headache with associated features such as nausea, phonophobia and/or photophobia; in a third of patients the headache is preceded by transient neurological symptoms that are most frequently visual but may involve other senses (migraine with aura: MA) [1] (Table 1). Migraine is a public health problem of great impact upon both the individual and society. It is one of the 20 most disabling diseases (according to World Health Organization ranking [2]). Furthermore, it is remarkably common (e.g., it affects 17% of females and 8% of males in the European population [3]) and very costly (EUR 18.5 billion/year in Europe [4]).
It is generally believed that migraine headache depends on the activation and sensitization of the trigeminovascular pain pathway 5, 6, 7 (Figure 1), and that cortical spreading depression (CSD)-like events underlie migraine aura 5, 8, 9. CSD can be induced in animals by focal stimulation of the cerebral cortex and consists of a slowly propagating (2–6 mm/min) wave of strong neuronal and glial depolarization whose mechanisms of initiation and propagation remain unclear 10, 11. It is also generally recognized that most migraine attacks start in the brain. This is suggested by the premonitory symptoms (such as difficulty with speech and reading, increased emotionality, sensory hypersensitivity) – which in many patients are highly predictive of the attack although occurring up to 12 h before it [12] – as well as by the nature of some typical migraine triggers (e.g., stress, sleep deprivation, oversleeping, hunger and/or prolonged sensory stimulation) [13]. Psychophysical and neurophysiological studies have provided clear evidence that in the period between attacks migraineurs show hypersensitivity to sensory stimuli and abnormal processing of sensory information, characterized by increased amplitudes and reduced habituation of evoked and event-related potentials 14, 15.
The nature and mechanisms of the primary brain dysfunction(s) leading to the onset of a migraine attack, to CSD susceptibility, and to episodic activation of the trigeminovascular pain pathway remain largely unknown and are major outstanding issues to be addressed in furthering our understanding of the neurobiology of migraine. Other important open questions concern the mechanisms of migraine pain.
Here, we review recent advances regarding (i) the genetics of migraine; (ii) the mechanisms of migraine headache, focusing on the roles of meningeal inflammation, calcitonin gene-related peptide (CGRP), central sensitization, and dysfunctional central control of pain; and (iii) the mechanisms of the primary brain dysfunction(s) leading to episodic activation of the trigeminovascular pain pathway. We also discuss insights into these mechanisms obtained from the functional analysis of mouse models of familial hemiplegic migraine (FHM), a rare monogenic autosomal dominant form of MA.
Section snippets
Genetics of migraine
Migraine is a complex genetic disorder, with heritability estimates as high as 50% and probable polygenic multifactorial inheritance 16, 17. The complexity of the disease has hampered the identification of common susceptibility variants; the lack of consensus on most of the identified susceptibility loci probably reflects clinical and genetic heterogeneity 16, 17.
Most of our current understanding of genetic factors underlying migraine comes from studies of FHM. Three causative genes, all
Mechanisms of migraine headache
Based on a large body of indirect evidence, it is believed that the development of migraine headache depends on the activation and sensitization of trigeminal sensory afferents that innervate cranial tissues, in particular the meninges and their large blood vessels 5, 6, 7 (Figure 1a). The sensitization of mechanosensitive meningeal afferents provides a mechanism that may explain the throbbing nature of the migraine headache (typically attributed to arterial pulsation) as well as the
Primary brain dysfunctions in migraine
The nature and mechanisms of the primary brain dysfunction(s) leading to episodic activation of the trigeminovascular pain pathway remain incompletely understood and controversial. Given the wide genetic and clinical heterogeneity of the disorder, different primary mechanisms of migraine onset probably exist.
Concluding remarks
Taken together, currently available evidence suggests that migraine is a disorder of brain excitability characterized by deficient regulation of the E/I balance during cortical activity. The mechanisms underlying the deficient regulation of the cortical E/I balance might lead to both (i) the typical interictal dysfunction in sensory (including trigeminal nociceptive) information processing, that progressively increases in the period between attacks, and (ii) in particular conditions, ignition
Note added in proof
As this review went to press, Freilinger et al. [146] published the findings of the first genome-wide association study of migraine without aura (MO). One of the susceptibility loci for MO identified in this study appears particularly interesting, since it is within the MEF2D gene that encodes a transcription factor that mediates neuronal activity-dependent transcription in neurons and plays a key role in many aspects of synapse and neural circuit development and function [147].
Acknowledgments
We would like to apologize to the many investigators whose work we were unable to cite due to space limitations. D.P. is supported by grants from University of Padova (Strategic Project: Physiopathology of Signaling in Neuronal Tissue) and Fondazione Cariparo (Excellence Project: Calcium Signaling in Health and Disease) and acknowledges the support from Telethon-Italy (GGP06234).
References (147)
Origin of pain in migraine: evidence for peripheral sensitisation
Lancet Neurol.
(2009)- et al.
Sporadic and familial hemiplegic migraine: pathophysiological mechanisms, clinical characteristics, diagnosis, and management
Lancet Neurol.
(2011) Familial hemiplegic migraine and episodic ataxia type-2 are caused by mutations in the Ca2+ channel gene CACNL1A4
Cell
(1996)Mutation in the neuronal voltage-gated sodium channel SCN1A in familial hemiplegic migraine
Lancet
(2005)Familial hemiplegic migraine
Neurotherapeutics
(2007)Function and dysfunction of synaptic calcium channels: insights from mouse models
Curr. Opin. Neurobiol.
(2005)Enhanced excitatory transmission at cortical synapses as the basis for facilitated spreading depression in CaV2.1 knockin migraine mice
Neuron
(2009)A Cacna1a knockin migraine mouse model with increased susceptibility to cortical spreading depression
Neuron
(2004)Familial hemiplegic migraine type 1 mutations K1336E, W1684R, and V1696I alter CaV2.1 Ca2+ channel gating: evidence for β-subunit isoform-specific effects
J. Biol. Chem.
(2004)Diverse functional consequences of mutations in the Na+/K+-ATPase α2-subunit causing familial hemiplegic migraine type 2
J. Biol. Chem.
(2008)
Dural afferents express acid-sensing ion channels: a role for decreased meningeal pH in migraine headache
Pain
Mast cell degranulation activates a pain pathway underlying migraine headache
Pain
The role of CGRP in the pathophysiology of migraine and efficacy of CGRP receptor antagonists as acute antimigraine drugs
Pharmacol. Ther.
Efficacy and tolerability of MK-0974 (telcagepant), a new oral antagonist of calcitonin gene-related peptide receptor, compared with zolmitriptan for acute migraine: a randomised, placebo-controlled, parallel-treatment trial
Lancet
Differential distribution of calcitonin gene-related peptide and its receptor components in the human trigeminal ganglion
Neuroscience
Involvement of capsaicin-sensitive afferent nerves in the proteinase-activated receptor 2-mediated vasodilatation in the rat dura mater
Neuroscience
Calcitonin gene-related peptide stimulation of nitric oxide synthesis and release from trigeminal ganglion glial cells
Brain Res.
Calcitonin gene-related peptide differentially regulates gene and protein expression in trigeminal glia cells: findings from array analysis
Neurosci. Lett.
Classification of primary headaches
Neurology
The global burden of migraine: measuring disability in headache disorders with WHO's Classification of Functioning, Disability and Health (ICF)
J. Headache Pain
Prevalence, burden, and cost of headache disorders
Curr. Opin. Neurol.
The economic cost of brain disorders in Europe
Eur. J. Neurol.
Neurobiology of migraine
Nat. Rev. Neurosci.
Migraine pain and nociceptor activation – where do we stand?
Headache
Cortical spreading depression triggers migraine attack: pro
Headache
Does cortical spreading depression initiate a migraine attack? Maybe not
Headache
Cortical spreading depression – new insights and persistent questions
Cephalalgia
Mechanisms of spreading depression and hypoxic spreading depression-like depolarization
Physiol. Rev.
Premonitory symptoms in migraine: an electronic diary study
Neurology
Characterization of consistent triggers of migraine with aura
Cephalalgia
Is the cerebral cortex hyperexcitable or hyperresponsive in migraine?
Cephalalgia
The brain is hyperexcitable in migraine
Cephalalgia
Molecular genetics of migraine
Hum. Genet.
Haploinsufficiency of ATP1A2 encoding the Na+/K+ pump α2 subunit associated with familial hemiplegic migraine type 2
Nat. Genet.
The genetic spectrum of a population-based sample of familial hemiplegic migraine
Brain
CaV2.1 channelopathies
Pflugers Arch.
Familial hemiplegic migraine mutations increase Ca2+ influx through single human CaV2.1 channels and decrease maximal CaV2.1 current density in neurons
Proc. Natl. Acad. Sci. U.S.A.
High cortical spreading depression susceptibility and migraine-associated symptoms in CaV2.1 S218L mice
Ann. Neurol.
Gain of function in FHM-1 CaV2.1 knock-in mice is related to the shape of the action potential
J. Neurophysiol.
Contribution of calcium-dependent facilitation to synaptic plasticity revealed by migraine mutations in the P/Q-type calcium channel
Proc. Natl. Acad. Sci. U.S.A.
Trigeminal ganglion neuron subtype-specific alterations of CaV2.1 calcium current and excitability in a Cacna1a mouse model of migraine
J. Physiol.
CaV2.1 P/Q-type calcium channel alternative splicing affects the functional impact of familial hemiplegic migraine mutations: implications for calcium channelopathies
Channels (Austin)
Similar perisynaptic glial localization for the Na+,K+-ATPase α2 subunit and the glutamate transporters GLAST and GLT-1 in the rat somatosensory cortex
Cereb. Cortex
Glutamate uptake stimulates Na+,K+-ATPase activity in astrocytes via activation of a distinct subunit highly sensitive to ouabain
J. Neurochem.
Glutamate transporter coupling to Na,K-ATPase
J. Neurosci.
Impaired plasma membrane targeting or protein stability by certain ATP1A2 mutations identified in sporadic or familial hemiplegic migraine
Channels (Austin)
Increased susceptibility to cortical spreading depression in the mouse model of familial hemiplegic migraine type 2
PLoS Genet.
NaV1.1 channels and epilepsy
J. Physiol.
Self-limited hyperexcitability: functional effect of a familial hemiplegic migraine mutation of the NaV1.1 (SCN1A) Na+ channel
J. Neurosci.
Divergent sodium channel defects in familial hemiplegic migraine
Proc. Nat. Acad. Sci. U.S.A.
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