Pietrobon Pathophys Migraine

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Review in Advance first posted online on November 26, 2012. (Changes may still occur before final publication online and in print.)
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Pathophysiology of Migraine
Daniela Pietrobon1, 2 and Michael A. Moskowitz3
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Department of Biomedical Sciences, University of Padova and 2 CNR Institute of Neuroscience, 35121 Padova, Italy; email: daniela.pietrobon@unipd.it
Annu. Rev. Physiol. 2013.75. Downloaded from www.annualreviews.org by INSERM-multi-site account on 01/25/13. For personal use only.
Neuroscience Center, Departments of Radiology and Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02129; email: moskowitz@helix.mgh.harvard.edu
Annu. Rev. Physiol. 2013. 75:23.123.27 The Annual Review of Physiology is online at http://physiol.annualreviews.org This articles doi: 10.1146/annurev-physiol-030212-183717 Copyright c 2013 by Annual Reviews. All rights reserved
Keywords
spreading depression, trigeminovascular system, neurogenic inammation, excitatory/inhibitory balance
Abstract
Migraine is a collection of perplexing neurological conditions in which the brain and its associated tissues have been implicated as major players during an attack. Once considered exclusively a disorder of blood vessels, compelling evidence has led to the realization that migraine represents a highly choreographed interaction between major inputs from both the peripheral and central nervous systems, with the trigeminovascular system and the cerebral cortex among the main players. Advances in in vivo and in vitro technologies have informed us about the signicance to migraine of events such as cortical spreading depression and activation of the trigeminovascular system and its constituent neuropeptides, as well as about the importance of neuronal and glial ion channels and transporters that contribute to the putative cortical excitatory/inhibitory imbalance that renders migraineurs susceptible to an attack. This review focuses on emerging concepts that drive the science of migraine in both a mechanistic direction and a therapeutic direction.
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INTRODUCTION
Aura: transient (2030-min) focal neurological event causing visual and/or sensory or speech disturbance Event-related potentials: stereotypical electrophysiological brain responses to a motor, cognitive, or sensory stimulus
CSD: cortical spreading depression Familial hemiplegic migraine (FHM): autosomal dominant headache syndrome accompanied by paroxysmal attacks that include typical migraine auras plus hemiplegic aura
Migraine is a common episodic neurological disorder with complex pathophysiology that manifests as recurrent attacks of typically throbbing and unilateral, often severe headache with certain associated features such as nausea, phonophobia, and photophobia. In one-third of patients the headache is preceded by transient neurological symptoms that are most frequently visual but may involve other senses and speech [migraine with aura (MA)] (1). Migraine is remarkably common [e.g., it affects 17% of females and 8% of males in the European population (2)], very costly [$18.5 billion Euros per year in Europe (3)], and disabling [one of the 20 most disabling diseases according to the World Health Organization (4)]. It is therefore a public health problem of great impact on both the individual and society. Most migraine attacks start in the brain, as suggested by (a) the premonitory symptoms (e.g., difculty with speech and reading, increased emotionality, sensory hypersensitivity) that in many patients are highly predictive of the attack, although such symptoms occur up to 12 h before the attack (5), and by (b) the nature of some typical migraine triggers such as stress, sleep deprivation, oversleeping, hunger, and prolonged sensory stimulation (6). 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 (7, 8). It is generally believed that migraine headache depends on the activation and sensitization of the trigeminovascular pain pathway (912) and that cortical spreading depression (CSD) is the neurophysiological correlate of migraine aura (10, 1315). CSD can be induced in animals by focal stimulation of the cerebral cortex and consists of a slowly propagating (26 mm min1 ) wave of strong neuronal and glial depolarization; the mechanisms of initiation and propagation of CSD remain unclear (16, 17). The 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 the major open issue in the neurobiology of migraine. Other important open questions concern the mechanisms of initiation, continuation, and termination of migraine pain. Migraine is a complex genetic disorder with heritability estimates as high as 50% and with a likely polygenic multifactorial inheritance (17, 18, 19). The complexity of the disease, which depends upon the interplay of multiple genes and gene-environment interactions, has hampered the identication of common susceptibility variants; the lack of consensus on most of the identied susceptibility loci probably reects clinical and genetic heterogeneity (17, 18, 19). Recent genome-wide association studies have identied a few risk factors for both MA and migraine without aura (MO) that map within or near transcribed regions of potentially interesting genes (2022). However, most of our present molecular understanding of migraine comes from studies of familial hemiplegic migraine (FHM), a rare, monogenic, autosomal dominant form of MA (18, 19, 23). Three FHM causative genes, all encoding ion channels or transporters, have been identied (2426). Additional FHM genes certainly exist and remain to be identied (27). Here, we review recent advances regarding the mechanisms of migraine pain and the mechanisms of the primary brain dysfunction(s) leading to the onset of a migraine attack and to episodic activation of the trigeminovascular pain pathway. We also discuss the insights into those mechanisms obtained from the functional analysis of FHM mouse models.
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MECHANISMS OF MIGRAINE PAIN Trigeminovascular Pain Pathways

A large body of indirect evidence indicates 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 (1012, 28). As discussed by Olesen et al. (11), whether nociception originates from pial, dural, or extracranial periarterial sensory afferents remains unclear; all three might be involved, possibly to different extents in different subtypes of migraine. In the rat these cranial perivascular bers have similar central projections terminating in the so-called trigeminocervical complex (TCC) comprising the C1 and C2 dorsal horns of the cervical spinal cord and the caudal division of the spinal trigeminal nucleus (TNC); the C-ber terminals are located mainly in supercial layers and the A- ber terminals in deep layers (2931). The TCC makes direct ascending connections with different areas in the brain stem and with higher structures, including several hypothalamic and thalamic nuclei, which in turn make ascending connections with the cortex (2931 and references therein) (Figure 1a). Congruently, stimulation of the dural afferents in experimental animals results in activation of second-order trigeminovascular neurons (mainly in laminae I, II, and V) in the TCC, as well as in activation of neurons in several brain stem [e.g., superior salivatory nucleus, ventrolateral periaqueductal gray (vlPAG), rostral ventromedial medulla (RVM)], hypothalamic, and thalamic [in particular, the ventroposteriomedial (VPM) and posterior (Po)] nuclei receiving connections from the TCC (3236; cf. References 10 and 30 for review and older references) (Figure 1a). Dura-sensitive VPM thalamic neurons project mainly in the trigeminal primary and secondary somatosensory (S1 and S2) cortices and the insular (Ins) cortex (components of the so-called pain matrix) and are thus likely to play a role in the perception of headache. Trigeminovascular Po thalamic neurons project beyond the pain matrix into nontrigeminal S1 cortex, as well as into auditory, visual, retrosplenial, ectorhinal, and parietal association cortices, and are thus likely to contribute to other aspects of the migraine experience, which includes disturbances in neurological functions involved in vision, audition, memory, motor function, limbic function, and cognitive performance (31, 36). The trigeminovascular projections to specic hypothalamic and brain stem nuclei likely contribute to other aspects of the complex migraine symptomatology, such as loss of appetite, uid retention, sleepiness, irritability, stress, pursuit of solitude, and autonomic symptoms (30). A large fraction of migraineurs experience exacerbation of headache by light (photophobia). Investigators recently uncovered a neural mechanism for migraine photophobia (36). Dura-sensitive thalamic neurons in the rat posterior thalamus receive monosynaptic input from retinal ganglion cells (mainly intrinsically photosensitive cells involved in non-image-forming functions), and light enhances the activity of dura-sensitive thalamic neurons located in the same area. The idea that a non-image-forming retinal pathway is involved in migraine photophobia is supported by the nding that exacerbation of headache by light was preserved in blind migraineurs who could sense light in the face of severe degeneration of rod and cone photoreceptors (36). The TCC receives descending projections from brain stem and hypothalamic nociceptive modulatory nuclei that may mediate descending modulation of trigeminovascular nociceptive trafc (30) (Figure 1b). Indeed, electrical stimulation of the vlPAG or the nucleus raphae magnus in the RVM results in inhibition of the response of trigeminovascular TCC neurons to dural stimulation (37, 38). Moreover, modulation of the response of trigeminovascular TCC neurons to dural stimulation occurred after injection of orexin A or B or a somatostatin antagonist in the posterior hypothalamus (39, 40) and after electrical stimulation of the A11 dopaminergic
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Afferent pathways
Dura mater Pia mater Cerebral cortex
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V1/V2 M1/M2 Ins ns Au PtA tA RSA
Cerebral cortex Midbrain vlPAG NCF Cerebellum
S1
S2
Corpus callosum
Hippocampus ippocampus
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Pons Hypothalamus SSN Medulla
1, C2 TCC
Efferent modulatory pathways

Ins Cerebral cortex Corpus callosum Midbrain
S1
Hippocampus ippocampus Cerebellum vlPAG Thalamus RVM A11 Hypothalamus PH Pons Medulla NCF
TNC, C
1, C2 TCC
Figure 1 Main neuronal structures and connections in the trigeminovascular pathways involved in migraine pain: (a) afferent pathways and (b) efferent modulatory pathways. This schematic of the pathways within a rodent brain shows only the nuclei and connections mentioned in the text. The arrows indicate the direction of the information ow. Abbreviations: A11, dopaminergic hypothalamic nucleus; Au, auditory cortex; Ins, insular cortex; M1/M2, motor cortices; NCF, nucleus cuneiformis; PH, posterior hypothalamus; Po, posterior thalamic nuclear group; PtA, parietal association cortex; RSA, retrosplenial cortex; RVM, rostral ventromedial medulla; S1 and S2, primary and secondary somatosensory cortices; SSN, superior salivatory nucleus; TCC, trigeminocervical complex (comprising the C1 and C2 dorsal horns of the cervical spinal cord and the caudal division of the spinal trigeminal nucleus); TG, trigeminal ganglion; TNC, trigeminal nucleus caudalis; vlPAG, ventrolateral periaqueductal gray; VPM, ventroposteriomedial thalamic nucleus; V1/V2, visual cortices.
hypothalamic nucleus, a modulation that was reversed by a D2 receptor antagonist (41). Lesioning of the A11 nucleus resulted in facilitation of dura-evoked ring, suggesting that the A11 nucleus provides descending tonic inhibitory modulation of trigeminovascular nociceptive trafc (41). The TCC also receives descending cortical projections from layer 5 pyramidal cells of the contralateral S1 cortex (innervating mainly neurons in deep laminae IIIV) and caudal Ins cortex
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(innervating exclusively laminae I and II, strictly contralaterally) (35) (Figure 1b). The direct corticotrigeminal outow mediated by these cortex-TCC connections may mediate specic top-down modulation of meningeal nociception; reduction of cortical activity in S1 and insular cortical areas (following K+ injection that produced CSD) resulted in reduced and enhanced responses, respectively, of TCC neurons to noxious electrical stimulation of the dura (35). Interestingly, the response to innocuous mechanical stimulation of periorbital skin was not affected by reduction of cortical activity in insula, suggesting selective modulation of nociceptive primary afferent input (35).
Meningeal Nociceptors
Whereas little is known about the response properties of pial trigeminal afferents, the dural afferents exhibit properties, including chemosensitivity and sensitization, characteristic of nociceptors in other tissues (12, 4247). In vivo recordings have shown that most C-type and slow A-delta-type rat dural afferents are activated and sensitized by an inammatory soup (IF) applied to the dura (46), and most mechanosensitive C-type guinea pig dural afferents are polymodal nociceptors activated by topical application of capsaicin (47). Similarly, most trigeminal ganglion (TG) neurons retrogradely labeled from rodent dura were sensitized by IF (43) and expressed acid-sensing ion channels (44), and most small-diameter neurons were capsaicin sensitive (45). Immunolabeling experiments have revealed a dense network of dural nerve bers immunoreactive for calcitonin generelated peptide (CGRP) and substance P (SP) (48) and extensive colocalization of TRPV1 receptors and CGRP in small-diameter rat dural bers (49). CGRP and SP immunoreactivities in the dura and around pial vessels were almost completely eliminated by intravenous capsaicin in guinea pig (50), supporting the idea that most peptidergic meningeal nociceptors are capsaicin sensitive. Congruently, topical application of capsaicin to the rat dura causes vasodilation mediated by CGRP (51). Nearly all dural afferents that can be activated in vivo by IF are mechanosensitive, and IF enhances their mechanosensitivity (46). The sensitization of mechanosensitive meningeal afferents provides a mechanism that may explain the throbbing nature of the migraine headache (typically attributed to vascular pulsation) as well as the exacerbation of the headache during events (e.g., coughing or sudden head movements) that increase intracranial pressure (42). However, the mechanisms that lead to episodic activation of the perivascular meningeal nociceptors (see next section) as well as the mechanism(s) that underlie their sustained activation and sensitization and the ensuing throbbing headache during a migraine attack remain incompletely understood and controversial.
Inammatory soup (IF): an acidic mixture of potassium, prostaglandins, serotonin, bradykinin, and histamine that stimulates and sensitizes nociceptors, causing hyperalgesia CGRP: calcitonin generelated peptide SP: substance P Transient receptor potential cation channel V1 (TRPV1) receptor: receptor implicated in transducing pain and scalding heat; also known as the capsaicin or vanilloid receptor
Vasodilation
Several experimental and clinical observations show that vasodilation of meningeal and/or extracranial arteries is neither necessary nor sufcient to cause migraine pain; therefore, the original vascular theory of migraine is untenable for most patients (52 and references therein). In migraineurs, on the one hand, neither extracranial nor intracranial arteries were dilated in sildenal- and nitric oxideinduced migraine attacks (53, 54), and on the other hand, arterial vasodilation produced by vasoactive intestinal polypeptide infusion did not provoke a migraine headache (55). Recently, a 912% dilation of extracranial and intracranial arteries was measured in CGRP-induced migraine headache; this modest vasodilation is likely insufcient to activate the perivascular afferents but might affect sensitized nociceptors (56). Furthermore, the modest amount of dilation in these studies and in other imaging studies was probably mediated by parasympathetic activation via a monosynaptic reex accompanying trigeminovascular activation (57).
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Meningeal Inammation and Peripheral Sensitization

MC: mast cell Neurogenic inammation (NI): a physiological mechanism causing dilation, edema (due to extravasation of plasma proteins), and other manifestations of inammation mediated by released neuropeptides from the peripheral ends of small-caliber primary afferent bers Peripheral sensitization: increased sensitivity to noxious or nonnoxious sensory stimulation caused by hyperresponsiveness within primary afferent bers Transient receptor potential cation channel A1 (TRPA1) receptor: receptor that detects noxious stimuli, cold, and stretch
On the basis of a large body of indirect evidence from both clinical and animal studies, a sterile meningeal inammation is considered one key mechanism that may underlie the sustained activation and sensitization of perivascular meningeal afferents during migraine attacks (12, 58, 59). Indirect clinical evidence is provided by the increased level of various inammatory mediators in the cephalic venous outow during spontaneous migraine attacks and by the efcacy of nonsteroidal anti-inammatory drugs in the acute treatment of migraine in many patients (12, 58, 59 and references therein). In experimental animals, activation of meningeal nociceptors in vivo leads to release of vasoactive proinammatory peptides such as CGRP and SP from their peripheral nerve endings; these peptides produce vasodilation of meningeal blood vessels (due mainly to CGRP), plasma extravasation, and local activation of dural mast cells (MCs), with ensuing release of cytokines and other inammatory mediators [i.e., neurogenic inammation (NI)] (12, 58, 59). Dural MC degranulation can produce a long-lasting activation and sensitization of rat dural nociceptors (60) as well as cephalic tactile hypersensitivity (61). Chemical inammation of the dura in awake animals induces facial and hind paw cutaneous allodynia (32) with a time course of development that is consistent with that seen in migraine patients (62). Also, the pharmacology of the IF-induced allodynia in animals shows important parallels with the clinical pharmacology of migraine pain (32). Glycerotrinitrate infusion, which may induce in migraineurs (but not in healthy subjects) a delayed migraine attack indistinguishable from the spontaneous attacks (63), produces a delayed inammation within rat dura (64). However, the endogenous processes that promote meningeal inammation and peripheral sensitization during spontaneous migraine attacks remain incompletely understood. Many investigators consider the NI produced by release of vasoactive proinammatory neuropeptides following activation of peptidergic meningeal nociceptors (by CSD or other different primary mechanisms; see next section) to be the endogenous inammatory process that sustains the activation and causes the sensitization of meningeal nociceptors in many migraine attacks. Indeed, measurements of CGRP levels in the external and internal jugular venous blood have provided evidence that CGRP is released during migraine attacks (6567). Also consistent with the NI hypothesis is the recent evidence that the headache-triggering substances ethanol and umbellulone (the major volatile constituent of the Californian headache tree) activate peptidergic meningeal trigeminal afferents (via different receptors: TRPV1 and TRPA1), causing CGRP release and neurogenic dura inammatory responses in experimental animals (68, 69). However, direct evidence that the release of inammatory molecules associated with NI sensitizes meningeal nociceptors is lacking. In certain types of migraine, endogenous processes different from NI and not requiring initial activation of meningeal nociceptors might promote meningeal inammation and cause sensitization and ensuing long-lasting activation of meningeal nociceptors. These processes may include direct activation of dural MCs by a number of exogenous and endogenous migraine triggers, as was shown to occur in vitro (12, 59, 70), as well as release of inammatory mediators from brain parenchyma (e.g., as a consequence of CSD) and/or from meningeal blood vessels or immune cells that may directly sensitize meningeal nociceptors.
Central Sensitization
After headache onset, approximately two-thirds of migraine patients develop cutaneous allodynia (i.e., perception of pain in response to normally innocuous stimuli) in the periorbital region that may spread to extracephalic regions (71, 72). After brief local application of IF to the dura in anesthetized animals, second-order trigeminovascular neurons in the TCC showed long-lasting increased responses to innocuous mechanical or thermal facial skin stimulation (73), whereas
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third-order trigeminovascular neurons in the posterior thalamus showed long-lasting increased responses to both cephalic and extracephalic skin stimuli (33). Interestingly, functional magnetic resonance imaging (fMRI) scans in migraine patients showed larger thalamic blood oxygen level dependent (BOLD) signals induced by brush and innocuous heat stimulation of the hand during migraine attacks with extracephalic allodynia than during migraine-free periods (33). These data suggest that facial allodynia reects sensitization of trigeminovascular neurons in the TCC receiving convergent input from the meningeal nociceptors and facial skin and that extracephalic allodynia reects sensitization of trigeminovascular thalamic neurons that process converging sensory information from the cranial meninges and extracephalic skin. The gradual spatial and temporal spread of allodynia and its expression are consistent with the idea that initiation of central sensitization depends on the afferent input from sensitized meningeal nociceptors (10, 71). The fact that the anesthetic block of the primary dural afferents after chemical stimulation of the rat dura did not inhibit the long-lasting hypersensitivity to cutaneous stimulation of TCC neurons suggests that, once established, central sensitization becomes independent of afferent input (10, 73). A recent animal study points to the activation of the descending facilitatory pathway arising from the RVM (Figure 1) as a key central mechanism involved in central sensitization of trigeminovascular neurons (32). Chemical inammation of the dura produces a (slowly developing) prolonged activation of RVM on cells, a cell class that facilitates nociceptive processes at the level of the dorsal horn, and only a transient inhibition of RVM off cells, the cells that inhibit nociceptive signals. IF-induced facial allodynia was almost abolished (and hind paw allodynia was reduced) after selective lesion of putative RVM pain-facilitating neurons; moreover, bilateral microinjection of bupivacaine into the RVM 30 min after dural IF prevented facial allodynia and delayed the onset of hind paw allodynia (32). fMRI studies in human subjects indicate that the PAG and nucleus cuneiformis (NCF), the major sources of input to the RVM (Figure 1), are involved in the maintenance of central sensitization in humans (74). Interestingly, positron emission tomography studies revealed activation of similar areas in the dorsal rostral brain stem during migraine attacks (75). A possible involvement of these areas in central sensitization during migraine has been proposed on the basis of fMRI ndings that show a lower activation of the NCF in migraine patients than in controls in response to noxious thermal stimulation of the hand during the interictal period (76).
Blood oxygen leveldependent functional magnetic resonance imaging (BOLD fMRI): a magnetic resonance method, often termed fMRI, that generates a BOLD signal that measures oxy- and deoxyhemoglobin levels in tissues and approximates relative blood ow changes in brain tissue Central sensitization: increased sensitivity to noxious or nonnoxious sensory stimulation caused by hyperresponsiveness of central neurons within the trigeminocervical complex or thalamus Interictal period: the period of time between migraine attacks
Calcitonin GeneRelated Peptide

Several ndings support a pivotal role of CGRP in migraine, including (a) the effectiveness of CGRP receptor antagonists in migraine treatment (77, 78) and (b) the induction of a delayed migraine-like headache by intravenous CGRP administration in a large fraction of migraine patients but not in controls (79), suggesting that most migraineurs are hypersensitive to CGRPmediated modulation of nociceptive pathways. The mechanisms underlying this hypersensitivity, the mechanisms of action of CGRP during a migraine attack, and the exact sites of action of CGRP receptor antagonists remain unclear and controversial (6567). The localization of CGRP receptors in the trigeminovascular system (TVS) points to multiple possible mechanisms at both peripheral and central sites (80). In the periphery, CGRP receptors are expressed in blood vessels, Schwann cells, and dural MCs at the meninges and in glial satellite cells and a subpopulation of TG neurons in the trigeminal ganglion (80, 81). A relevant role of CGRP-induced dural vasodilation in migraine is unlikely in view of the evidence that topical or systemic CGRP does not activate or sensitize rat dural afferents (82) and that vasodilation is neither necessary nor sufcient to trigger migraine (52). CGRP-induced dural MC degranulation may help maintain an inammatory cycle at the dura.
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Consistent with this idea are animal studies showing that dural MC degranulation (as well as topical application of some individual MC mediators to the dura) preferentially activates and sensitizes mechanosensitive C units, most of which express CGRP (60, 83), and increase CGRP release from capsaicin-sensitive dural afferents (84). It has been suggested that CGRP-mediated intraganglionic cross talk between neurons and between neurons and satellite glial cells may promote and maintain a neuron-glia inammatory cycle that could contribute to persistent peripheral trigeminal sensitization (65, 67). This suggestion is based mainly on the evidence that prolonged application of CGRP to cultures of TG neurons and/or satellite glial cells leads to increased gene expression and/or membrane targeting of specic receptors (e.g., P2X3 ) in neurons and to increased expression of inammatory genes and release of inammatory mediators from satellite glial cells; these inammatory mediators can sensitize TG neurons and act back on glial cells, further activating them (8590). It remains unclear whether similar phenomena occur within the TG upon prolonged activation of meningeal nociceptors in vivo. In the central TVS, CGRP receptors are expressed in the TNC (laminae I and II) (80) and in some neuronal cell bodies in the VPM thalamic nucleus (34). In the TNC, CGRP receptors are localized in a ber network forming irregular glomeruli-like structures partially colocalized with granular CGRP-immunoreactive structures, but not on second-order neurons, suggesting the possibility of CGRP-mediated signaling between central terminals of primary afferents as preand postsynaptic elements (80). Functional studies indicate that activation of TNC presynaptic CGRP receptors may lead to potentiation of excitatory neurotransmission. In fact, capsaicinevoked CGRP release, as well as bath application of CGRP, increased the excitability of TNC neurons in brain stem slices (91), and iontophoresis of a CGRP receptor antagonist reduced ring evoked by dural stimulation in vivo (92). The possibility of central mechanisms of CGRP action during a migraine attack is indirectly supported by animal studies showing that systemic CGRP does not activate or sensitize dural afferents (82) and that high doses of systemic CGRP receptor antagonists reduce the activity of TNC neurons (93) and VPM thalamic neurons (34) evoked by stimulation of dural afferents, as well as the number of Fos-positive neurons in the TNC (laminae I and II) after intravenous infusion of capsaicin (94). However, given the very poor permeability of the blood-brain barrier to CGRP (95, 96), it seems difcult to explain, on the basis of published data, how CGRP infusion can cause a migraine attack if one excludes a peripheral role for CGRP.
Dysfunctional Central Control of Pain

The large body of indirect evidence reviewed above supports the prevailing view that the headache phase of migraine begins with the activation and sensitization of trigeminovascular meningeal nociceptors, which lead to sequential activation (and, in most patients, to sensitization) of secondand third-order trigeminovascular neurons. In this formulation, such activation and sensitization in turn activate different areas of the brain stem and forebrain, resulting in pain and other accompanying migrainous symptoms. The bidirectional signaling between many of these structures contributes to the complexity of the symptoms. However, direct evidence in the clinical setting for increased trigeminal sensory trafcking during migraine is lacking, and a consistent cephalic pathology has not been detected. Therefore, some investigators propose the alternative view that migraine headache arises from dysfunction within subcortical brain stem and diencephalic nuclei that modulate trigeminal nociceptive inputs; dysfunction in these nuclei (in particular in the PAGRVM circuitry) would lead to abnormal central interpretation of normal sensory input in the TVS, causing normal sensory trafc from the meninges to be perceived as migraine pain (30). As in other tissues, high-threshold C- and A-delta bers are electrophysiologically silent, so the origins of this
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normal meningeal sensory input remain unclear. Nonetheless, functional imaging studies showing increased cerebral blood ow in the dorsal rostral brain stem and in the hypothalamus during migraine attacks that persisted even after sumatriptan had induced relief from headache (75, 97) are considered to provide indirect support for this view (30). In particular, the reported specicity of activation of brain stem areas such as the PAG and rostral pons in migraine (10) promoted the view that abnormal activity in the PAG-RVM circuitry could serve as the migraine headache generator. However, in light of more recent data, the specicity of activation of different brain stem areas depending on different head pains does not appear to hold (97 and references therein; 98). Moreover, a recent fMRI study showed activation of dorsal rostral brain stem areas only during the migraine attack and not during the preictal phase (99). Thus, it appears more likely that these brain stem areas function as modulators, rather than as generators, of migraine headache. Dysfunction in brain stem nuclei involved in central control of pain and central sensitization (76, 100) may facilitate and promote hyperexcitability of central trigeminovascular pathways. Recent reviews discuss evidence from clinical and animal studies that questions the notion that abnormalities in the PAG-RVM circuitry (or other descending mechanisms of pain inhibition) can generate migraine headache in the absence of peripheral sensory input (11, 12). For example, the brain stem generator hypothesis does not explain why abnormal descending modulation specically generates migraine pain (and not other pains in spinal or trigeminal tissues), given that the descending modulatory pathway projects onto multiple segments of the spinal cord. Moreover, abnormal descending modulation implies that disinhibition of second-order neurons (receiving convergent input from meninges and skin) would promote cephalic allodynia during the onset of the headache phase, but this is almost never the case, as allodynia takes one hour or longer to develop and is absent in approximately 30% of migraine patients.
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 likely exist.
Cortical Spreading Depression

Increasing evidence from animal studies supports the idea that CSD, the underlying mechanism of aura, can activate trigeminal nociception and thus trigger headache mechanisms. A direct nociceptive effect of CSD was demonstrated by the nding that a single CSD can lead to a long-lasting increase in ongoing activity of dural nociceptors and central trigeminovascular neurons in supercial and deep laminae of the TCC (101, 102). In most neurons activation occurred with a delay consistent with that between the onset of visual aura and the onset of headache; the delay as well as the magnitude and duration of neuronal activation were similar in peripheral and central neurons, suggesting that CSD-evoked activity of meningeal nociceptors is sufcient to activate the central neurons. Immediate neuronal activation by CSD was observed in a fraction of neurons, mainly C nociceptors and exclusively laminae I and II TCC neurons, suggesting that such activation may be mediated by peptidergic nociceptors with axon collaterals extending to the pia, where immediate activation may be mediated by increased K+ or other noxious mediators released in the wake of the CSD wave (57) (Figure 2). This hypothesis is supported by the demonstration that CSDinduced CGRP release from perivascular trigeminal bers contributes to the transient dilation of pial vessels measured during CSD (103). A possible explanation for the long-lasting activation
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of the dural afferents is that release of proinammatory neuropeptides in the dura promotes NI that sustains the activation of meningeal nociceptors and leads to their sensitization (12, 57, 101, 102). This idea is supported by the nding of CSD-induced plasma protein extravasation from dural blood vessels, which was abolished by trigeminal nerve section (57; but cf. 61, 104). Alternatively, it has been suggested that mediators released by the CSD wave may lead to sensitization and ensuing sustained activation of meningeal nociceptors (61). The mechanism of the delayed long-lasting neuronal activation remains unknown. A recent review discusses different potential mechanisms (61), including upregulation of matrix metalloproteinases (105) and the passage of normally sequestered and potentially noxious molecules (e.g., K+ , H+ , 5-hydroxytryptamine) into the extracellular space, reaching the pial and dural surfaces by bulk diffusion to access trigeminovascular afferents (Figure 2). In addition to the prolonged activation of TCC neurons, there are other signicant CSDdriven central effects, including gene upregulation in the TCC (57, 106) and dilation and increase in blood ow within the middle meningeal artery mediated by trigeminally evoked brain stem reexes (57) (Figure 2). These observations speak to the importance of noxious inputs from the TVS sufcient to drive cells and tissues within the pain matrix following CSD. Nevertheless, CSD may not be sufcient on the basis of the observation that freely moving rats do not seem to experience CSD as aversive, as they do not show pain behavior (107, 108) or cutaneous allodynia (109) after a CSD. However, whether these behavioral studies are suitable to detect a relatively mild head pain remains uncertain (110); moreover, only 6070% of migraine attacks lead to allodynia, and the propensity to develop allodynia increases with the number of attacks (110). Whether activation of the TVS induced by a CSD is sufcient to elicit the perception of headache in patients is unclear, although the evidence is clear that intense electrophysiological activity in, for example, the temporal lobe (e.g., in focal temporal lobe epilepsy) can activate overlying meningeal nociceptors and generate ipsilateral headache (111). If CSD does cause hemicranial pain due to activation of overlying meningeal nociceptors, the expectation is that the initial headache should develop contralateral to the unilateral aura symptoms (e.g., left visual aura caused by CSD in the right hemisphere is accompanied by right hemicranial pain), which seems to be the case in the majority of patients. The idea that CSD is noxious and may trigger headache is indirectly supported by the nding that the electrical stimulation threshold for induction of CSD in the rat cortex increases after
Figure 2 From cortical spreading depression (CSD) to trigeminovascular nociception. (a) It is believed that CSD is ignited by local elevations of extracellular [K+ ] above a critical level as a consequence of hyperactive neuronal circuits in the cerebral cortex. (b) CSD is a slowly propagating wave of strong neuronal and glial depolarization [cf. direct-current (DC) cortical potential trace] accompanied by depression of spontaneous and evoked electroencephalography (EEG) activity and by a large increase in extracellular [K+ ]. (c) Other noxious mediators (open circles), such as H+ , nitric oxide (NO), arachidonic acid (AA), and serotonin (5-hydroxytryptamine), besides glutamate and other neurotransmitters are released during CSD. It is hypothesized that these substances may activate trigeminal nociceptors innervating pial blood vessels and, via axon collaterals, dural trigeminal afferents and/or may slowly access the meningeal afferents after disruption of the blood-brain barrier (BBB) (e.g., as a consequence of upregulation of matrix metalloproteinases), leading to activation of central trigeminovascular neurons in the trigeminocervical complex (TCC; blue pathway). Activation of the meningeal afferents leads to release of proinammatory vasoactive neuropeptides, including calcitonin generelated peptide (CGRP), substance P (SP), and neurokinin A (NKA), that may promote neurogenic inammation in the dura and possibly sustain the activation of the trigeminovascular afferents and lead to their sensitization. Alternatively, mediators released by the CSD wave may lead to sensitization and ensuing activation of meningeal nociceptors. Also shown is a parasympathetic reex involving activation of the superior salivatory nucleus (SSN) and the sphenopalatine ganglion (SPG) leading to release of vasoactive intestinal peptide (VIP), NO, and acetylcholine (ACh) from the meningeal parasympathetic efferents. Other abbreviations: MMP9, matrix metalloproteinase 9; TG, trigeminal ganglion.
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chronic treatment with ve different migraine prophylactic drugs that are equally effective in reducing the frequency of MA and MO attacks (112); in contrast, two drugs ineffective in migraine prophylaxis do not affect susceptibility to experimental CSD (112, 113). This good correlation between inhibition of CSD and effectiveness in migraine prophylaxis depends upon an adequate clinical trial design that addresses whether there is a signicant change in frequency of aura as well as decrease in the following headache. In this respect, the design of clinical trials for two drugs (tonabersat and lamotrigine), reportedly effective in reducing the frequency of experimental CSDs
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produced by prolonged epidural application of KCl (114, 115), appears problematic. On the one hand, when tonabersat and lamotrigine were tested in relatively small populations of MA patients, the treatment did reduce the number of MA attacks (116, 117), supporting this notion. On the other hand, when relatively small populations of mainly MO patients were treated with tonabersat in low doses for three months or with lamotrigine, the treatment did not signicantly affect the mean number of headache days (118) or frequency of migraine (119), respectively. Further studies that are sufciently powered, including dose-ranging studies and measurements of the electrical threshold for experimental CSD induction after chronic treatment of animals with tonabersat and lamotrigine, will be required to solve these apparent discrepancies. The analysis of experimental CSD in FHM knockin mouse models has provided further support to the view of CSD as a key migraine trigger by demonstrating that both FHM1 knockin mice and FHM2 knockin mice show a lower electrical stimulation threshold for CSD induction and a higher velocity of CSD propagation (see next section) (120123). Although FHM3 mouse models are not available, investigators reported that FHM3 in two unrelated families cosegregates with a new eye phenotype with clinical features similar to those of experimental spreading depression in the retina (124), suggesting that the ability to facilitate CSD is likely also shared by FHM3 mutations. Moreover, a lower electrical threshold for CSD induction and for increased velocity of CSD propagation was measured in a mouse model of cerebral autosomal dominant arteriopathy, a systemic vasculopathy associated with a vefold-higher incidence of MA (125). Despite the strong support provided by animal studies, the idea that CSD may initiate the headache mechanisms in migraine is not generally accepted (10, 15). In fact, most migraineurs do not experience aura, and even MA patients experience attacks without aura; moreover, therapeutic intervention may abolish aura but not headache in some patients or may help with headache without affecting aura in others. Present evidence neither proves nor disproves the possibility that silent CSDs (i.e., CSDs involving areas of the brain that would not generate a perceived aura) may initiate the headache mechanisms in MO (10, 14, 126). Nevertheless, a well-documented imaging study in a young female with silent aura and CSD followed by headache (e.g., MO) leaves doubt about how well migraine patients access and report ongoing or newly initiated brain events (127). These apparent shortcomings speak to the urgent need to develop novel imaging and other biomarkers to classify the subtypes of migraine. Another argument that has been used against the idea that CSD may initiate the headache mechanisms is based on the fact that in some patients migraine premonitory symptoms may occur up to 1224 h before the onset of the aura and headache. One implication of these welldocumented premonitory symptoms is that different brain regions (including hypothalamic and other subcortical regions) are activated well before the onset of CSD (5). In this context, it is interesting that the interictal neurophysiological abnormalities in sensory information processing, typical of MO and MA patients, are not constant but change in intensity in temporal relation to the migraine attack (7, 8, 10 and references therein). In most instances, these perturbations are most intense 1224 h before the attack, i.e., during the interval when the premonitory symptoms appear, and then normalize a few hours before and/or during the attack, except for decits in pain processing (7, 8, 10, 99, 128, 129). Also, the neurophysiological reactivity to stress, one of the most common migraine triggers, increases in the period between attacks and is maximal (and signicantly higher than in healthy subjects) 13 days before an attack (128). These data suggest that in the brains of migraineurs some intrinsic mechanisms during the pain-free interval progressively increase the dysfunction in central information processing, the susceptibility to migraine triggers, and the neurophysiological readiness to generate a migraine attack. One can speculate that these mechanisms both may lead to the premonitory symptoms and, above a certain threshold of cortical dysfunction and/or in response to migraine triggers, may
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create the conditions for ignition of CSD (e.g., as a result of cortical hyperactivity in the brains attempt to normalize excessive cortical activation due to the decit in habituation).
Dysfunctional Regulation of Cortical Excitability

To understand the primary mechanisms of migraine attacks, it seems essential to understand the mechanisms underlying the interictal abnormal processing of sensory information, how they are affected by migraine triggers, and the nature of the relationship between these mechanisms and susceptibility to CSD. The analysis of interictal cortical excitability using psychophysics, electrophysiology, transcranial magnetic stimulation (TMS), and fMRI has produced contradictory ndings and interpretations regarding the mechanisms underlying the abnormal processing of sensory information (including trigeminal nociception) in migraineurs. It is beyond the scope of the present review to discuss in detail this very large and controversial literature (cf. References 7, 8, 10 for reviews and see, e.g., References 130134 for some recent studies). Depending on the study, the cortex of migraineurs is hyperexcitable as a consequence of either enhanced excitation or reduced inhibition or is hypoexcitable and/or has a lower preactivation level possibly due to serotonin hypoactivity and/or inefcient thalamocortical drive. Interestingly, recent TMS studies in MA patients point to decient regulatory mechanisms of cortical excitability and consequent reduced ability to dynamically maintain the cortical excitatory/inhibitory (E/I) balance and to prevent excessive increases in cortical excitation, rather than merely hypo- or hyperexcitability, as the mechanisms underlying abnormal sensory processing (135137). Decient cortical regulatory mechanisms likely underlie the much higher variability in visual cortex excitability (as measured by phosphene threshold) in MA and MO patients, particularly in the day before the attack (138; but cf. 129). The molecular and cellular mechanisms underlying the abnormal regulation of cortical function and its periodicity remain largely unknown. Possible hypothetical mechanisms include (a) alterations in the cortical circuits that dynamically maintain the E/I balance and are essential for correctly processing sensory information and for preventing overexcitation (139, 140) and (b) alterations of cortical neuromodulation by serotonergic, noradrenergic, or cholinergic inputs from the brain stem. The extent to which some of the cortical and/or subcortical alterations are affected by disease duration (e.g., repetitive CSDs) is unclear. Equally unclear is the extent to which the abnormal processing of trigeminal nociceptive input reects a primary dysregulation of central sensory processing or central sensitization persisting outside the attack (e.g., 100, 141). The functional analysis of FHM knockin mouse models supports the view of migraine as a disorder of brain excitability characterized by decient regulation of the cortical E/I balance. Such analysis gives insights into the possible underlying molecular and cellular mechanisms and their relationship to CSD susceptibility.
Transcranial magnetic stimulation (TMS): a noninvasive technique that induces weak electric currents in brain to cause neuronal depolarization or hyperpolarization
INSIGHTS FROM FAMILIAL HEMIPLEGIC MIGRAINE MOUSE MODELS

FHM is characterized by obligatory motor aura symptoms consisting of motor weakness or paralysis (often, but not always, unilateral) together with at least one of the MA aura symptoms. Apart from the motor aura and the possible longer duration of the aura, typical FHM attacks resemble MA attacks (1), and both types of attacks may alternate in patients and co-occur within families. Thus, FHM and MA may be part of the same spectrum and may share some pathogenetic mechanisms, despite clinical observations that the response to infusion of CGRP and glyceryl trinitrate seems to differ (142, 143). Some FHM patients can also have atypical severe attacks (with signs
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of diffuse encephalopathy, confusion or coma, prolonged hemiplegia, and in a few cases seizures) and/or permanent cerebellar symptoms (18, 19). FHM is genetically heterogeneous. Missense mutations in CACNA1A and SCNA1A, the genes encoding the pore-forming subunits of the neuronal voltage-gated Ca2+ channel CaV 2.1 (also known as the P/Q-type Ca2+ channel) and the Na+ channel NaV 1.1, cause FHM type 1 (FHM1) (24) and type 3 (FHM3) (26), respectively. Mutations in ATP1A2, the gene encoding the Na+ ,K+ ATPase 2 subunit, cause FHM type 2 (FHM2) (25). CaV 2.1 channels are widely expressed in the nervous system, including all structures implicated in the pathogenesis of migraine, and play a dominant role in controlling neurotransmitter release, particularly at central synapses; their somatodendritic localization points to additional postsynaptic roles, e.g., in neural excitability (144, 145). NaV 1.1 channels are expressed primarily in the central nervous system in late postnatal stages and show high expression in certain inhibitory interneurons, in which they play an important role in sustaining high-frequency ring (146). In the nervous system, the 2 Na+ ,K+ -ATPase isoform is expressed primarily in neurons during embryonic development and at birth, but almost exclusively in astrocytes in the adult; its colocalization with the Na+ /Ca2+ exchanger in microdomains that overlie subplasmalemmal endoplasmic reticulum and with glutamate transporters in astrocytic processes surrounding glutamatergic synapses suggests specic roles in the regulation of intracellular Ca2+ and glutamate clearance (23 and references therein). Whereas most genetic studies indicate that the FHM genes (except perhaps for ATP1A2) are not involved in common migraines (18, 23), some homozygous mutations in SLC4A4, the gene encoding the electrogenic Na+ ,HCO3 cotransporter NBCe1, are associated with hemiplegic migraine, MA, or MO, depending on the mutation (147). The transport activity of NBCe1 in astrocytes is thought to modulate neuronal excitability by regulating local pH (147). Only mutations producing near-total loss of function of the transporter expressed in glioma cells are associated with migraine, supporting a causative role and the view that hemiplegic migraine and common migraine represent a phenotypic spectrum that may share at least some genetic basis (147). The different FHM mutations and their functional consequences on recombinant mutant proteins in heterologous expression systems (and, for some mutations, in transfected neurons) were recently reviewed (18, 23, 145) and are not discussed in detail here. Rather, we discuss functional studies in FHM mouse models and the consequences of the mutations on the native proteins and on neurophysiological processes that are thought to be involved in the pathophysiology of migraine. Three different FHM mouse models were generated by introducing the human FHM1 R192Q or S218L and FHM2 W887R mutations into the orthologous genes (120122). Whereas in humans the R192Q and W887R mutations cause typical FHM attacks (24, 25), the S218L mutation causes a particularly dramatic clinical syndrome that may consist ofin addition to attacks of hemiplegic migraineslowly progressive cerebellar ataxia and atrophy; epileptic seizures; coma or profound stupor; and severe, sometimes fatal cerebral edema that can be triggered by trivial head trauma (148). Whereas homozygous R192Q, heterozygous S218L, and W887R knockin mice do not exhibit an overt phenotype, homozygous S218L mice model the main features of the severe S218L clinical syndrome (120122). Homozygous W887R knockin mice die at birth because of lack of spontaneous respiratory activity (122). The 2 Na+ ,K+ -ATPase protein was barely detectable in the brains of homozygous FHM2 knockin mice and was strongly reduced in the brains of heterozygous mutants (122). Previous studies of the effect of several FHM2 mutations on recombinant Na+ ,K+ -ATPases invariably showed complete or partial loss of function of the mutant pumps (23, 122, 149, 150). Analysis of the P/Q-type calcium current in different neurons (including cortical and TG neurons) of FHM1 knockin mice revealed gain of function of the CaV 2.1 current in a wide range
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of relatively mild depolarizations, reecting shifted activation of mutant CaV 2.1 channels to more negative voltages (45, 120, 121, 151, 152) (Figure 3). The shift to lower voltages of CaV 2.1 channel activation and the gain of function of the neuronal CaV 2.1 current were approximately twice as large in homozygous knockin mice than in heterozygous mice, revealing an allele dosage effect consistent with dominance of the mutation in FHM1 patients (121). The gain-of-function effect of the FHM1 mutations on native neuronal mouse CaV 2.1 channels is in agreement with the increased open probability of recombinant human CaV 2.1 channels carrying eight different FHM1 mutations (including R192Q and S218L) that was revealed by single-channel recordings (153155). Interestingly, FHM1 mutations may not affect the gating properties of native CaV 2.1 channels in specic neurons (45), possibly as a consequence of expression of specic CaV 2.11 splice variants and/or CaV 2.1 subunits (156, 157). In fact, in R192Q knockin mice the P/Q-type Ca2+ current is increased in a subtype of TG neuron that does not innervate the dura, but is unaltered in capsaicinsensitive TG neurons that innervate the dura (45) (Figure 3). Congruently, although P/Q-type calcium channels contribute to control of CGRP release from capsaicin-sensitive perivascular meningeal sensory bers (158, 159), the FHM1 mutation does not alter depolarization-evoked CGRP release from the dura (45) (Figure 3). This nding argues against the idea that facilitation of CGRP-dependent dural vasodilation and CGRP-dependent dural MC degranulation contributes to the generation of migraine pain in FHM1. However, the FHM1 mutation increases CGRP release from intact trigeminal ganglia (45) (Figure 3) and from cultured TG neurons (90) of R192Q knockin mice, suggesting alternative roles. If CGRP-mediated intraganglionic cross talk promotes and maintains a neuron-glia inammatory cycle that contributes to peripheral trigeminal sensitization (65, 67) (see above), then FHM1 mutations may facilitate these phenomena. Indeed, there is some evidence suggesting facilitation of CGRP-mediated neuron-to-glia cross talk following exposure to proinammatory stimuli in cultured TG neurons from R192Q knockin mice (90). The analysis of cortical synaptic transmission in FHM1 knockin mice revealed a very interesting differential effect of FHM1 mutations at excitatory and inhibitory synapses (151) (Figure 3). Excitatory synaptic transmission is enhanced as a consequence of increased action potential (AP)evoked Ca2+ inux and increased probability of glutamate release at cortical pyramidal cell synapses of R192Q knockin mice; congruently, short-term synaptic depression during trains of APs is enhanced (151). AP-evoked Ca2+ transients in individual synaptic terminals of cerebellar granule cells are enhanced and short-term facilitation is reduced at parallel berPurkinje cell synapses of S218L knockin mice (160). In striking contrast, inhibitory neurotransmission at cortical FS interneuron synapses is not altered in FHM1 knockin mice, despite being initiated by P/Q-type calcium channels (151; D. Vecchia & D. Pietrobon, unpublished observations). The demonstration that FHM1 mutations may differently affect synaptic transmission and short-term plasticity at excitatory and inhibitory cortical synapses (151) implies that the neuronal circuits that dynamically adjust the E/I balance during cortical activity are probably altered in FHM1. Functional alterations in these circuits are expected to lead to abnormal processing of sensory information (139, 140). The investigation of experimental CSD, elicited either by electrical stimulation of the cortex in vivo or by focal application of high KCl in cortical slices, revealed a lower threshold for CSD initiation and an increased velocity of CSD propagation in both FHM1 and FHM2 knockin mice (120122, 151) (Figure 3). In FHM1 knockin mice carrying the mild R192Q mutation or the severe S218L mutation, the strength of CSD facilitation as well as the severity of the post-CSD neurological motor decits and the propensity of CSD to propagate into subcortical structures were in good correlation with the strength of the gain of function of the CaV 2.1 channel and the severity of the clinical phenotype produced by the two FHM1 mutations (120, 121, 123, 148, 154, 161). The much higher propensity of CSD to propagate to the striatum in FHM1
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mutants compared with wild-type (WT) mice (S218L > R192Q) may explain their motor decits and the hemiplegia typical of FHM1 aura (161), whereas the propagation to the hippocampus and thalamus and the recurrent CSDs observed only in S218L mutants may explain the severe attacks with seizures, coma, and cerebral edema typical of patients with the S218L mutation (121, 161). The velocity of propagation and the frequency of CSDs, elicited by continuous epidural high-KCl application, were larger in female than in male FHM1 mouse mutants, in agreement with the higher female prevalence of migraine; the sex difference was abrogated by ovariectomy and enhanced by orchiectomy, suggesting that female and male gonadal hormones exert reciprocal effects (123, 162). However, no gender differences in the electrical threshold for CSD induction and the velocity of CSD propagation were found in FHM2 knockin mice (122). The gain of function of glutamate release at synapses onto cortical pyramidal cells can explain the facilitation of experimental CSD in FHM1 knockin mice (151). In fact, the facilitation of CSD in acute cortical slices of R192Q knockin mice was completely eliminated (both CSD threshold and velocity became similar to those in WT slices) when glutamate release at pyramidal cell synapses was brought back to WT values by partially inhibiting P/Q channels (151). The data are consistent with and support a model of CSD initiation in which CaV 2.1-dependent release of glutamate from cortical pyramidal cell synapses and activation of NMDA receptors (and possibly postsynaptic CaV 2.1 channels) play a key role in the positive feedback cycle that ignites CSD (151, 163165). It has been suggested that excessive NMDA receptormediated glutamatergic transmission consequent to impaired clearance of glutamate by astrocytic processes surrounding glutamatergic synapses [where the 2 Na+ ,K+ -ATPase is colocalized and functionally coupled with glutamate transporters (166168)] may underlie the facilitation of experimental CSD in the
Figure 3 Functional consequences of a familial hemiplegic migraine type 1 (FHM1) mutation on neuronal CaV 2.1 channels and neurophysiological processes involved in the pathophysiology of migraine. (a) Functional alterations in the cerebral cortex of an FHM1 knockin mouse model. (i ) The CaV 2.1 calcium current in cortical pyramidal cells (PC) is increased as a consequence of activation of mutant CaV 2.1 channels at lower voltages than in wild-type channels. (ii ) Action potential (AP)-evoked glutamate release and excitatory synaptic transmission at PC synapses are increased. In striking contrast, AP-evoked gamma-aminobutyric acid (GABA) release and inhibitory synaptic transmission at fast spiking (FS) interneuron synapses are unaltered, despite being initiated by CaV 2.1 channels. The gain of function of glutamate release at the recurrent synapses between PC is predicted to increase network excitation. In contrast, the gain of function of glutamate release at the synapses onto FS interneurons (PC-FS synapses) is predicted to lead to enhanced recruitment of interneurons and to enhanced inhibition. However, during high-frequency repetitive activity, the enhanced recruitment of FS interneurons is expected to cease rapidly because the PC-FS synapses depress strongly during AP trains (much more than do the recurrent PC-PC synapses), and short-term depression is even stronger in FHM1 knockin mice, particularly at PC-FS synapses. This analysis, although restricted to a specic subcircuit, shows that the differential effect of FHM1 mutations on excitatory and inhibitory neurotransmission may produce overexcitation in certain brain conditions but may leave the excitatory/inhibitory (E/I) balance within physiological limits in others, which is consistent with the episodic nature of the disease. (iii ) Experimental cortical spreading depression (CSD) is facilitated, as revealed by a decreased threshold for CSD induction, an increased rate of CSD propagation, and an increased propensity to propagate into subcortical structures. (b) Functional alterations in trigeminal neurons of an FHM1 knockin mouse model. (i ) CaV 2.1 current is unaltered in small-size, capsaicin-sensitive (CS) trigeminal ganglion (TG) neurons that innervate the dura but is increased in small-size, capsaicin-insensitive TG neurons expressing a T-type calcium current (CI-T neurons) that do not innervate the dura. (ii ) Depolarization-evoked calcitonin generelated peptide (CGRP) release in intact dura mater is unaltered. (iii ) Depolarization-evoked CGRP release in intact trigeminal ganglia is increased. Other abbreviations: AA, arachidonic acid; DC, direct current; EEG, electroencephalography; NKA, neurokinin A; NO, nitric oxide; SP, substance P.
NMDA: N-methyl-D-aspartic acid
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FHM2 mouse model (122). The contribution of impaired K+ clearance has been considered less important because the duration of the CSD is not prolonged in mutant mice (122). In migraineurs CSD is not induced by experimental depolarizing stimuli but arises spontaneously in response to specic triggers that somehow create conditions in the cortex for initiation of the positive feedback cycle that overwhelms the regulatory mechanisms controlling cortical extracellular [K+ ] and ignites CSD. Insights into how this might occur were provided by the differential effects of FHM1 mutations on cortical excitatory and inhibitory synaptic transmission (151), suggesting altered regulation of the cortical E/I balance in FHM1. It has been hypothesized that this dysregulation may in certain conditions (e.g., in response to migraine triggers such as intense, prolonged sensory stimulation) lead to disruption of the E/I balance and hyperactivity of cortical circuits (due mainly to excessive recurrent excitation) that may create the conditions for the initiation of spontaneous CSDs (e.g., by increasing the extracellular [K+ ] to above a critical value) (151, 169). Similar mechanisms might underlie the susceptibility to CSD in FHM2 (122). The functional studies in FHM mouse models suggest that impairment of the cortical circuits that dynamically adjust the E/I balance during cortical activity, due to excessive recurrent glutamatergic neurotransmission, may underlie both the abnormal regulation of cortical function and the susceptibility to CSD in FHM. FHM mutations may produce parallel dysfunctions in subcortical areas that may also contribute to the altered regulation of cortical function and to the disease in general in a way that remains to be established (e.g., by altering cortical neuromodulation by monoaminergic projections and/or by favoring hyperexcitability of central trigeminovascular pathways). In this context, CSD may represent just one manifestation of fundamental alterations (e.g., impairment of E/I balance) produced by FHM mutations in different brain areas. Similar mechanisms may underlie the abnormal regulation of cortical (and possibly subcortical) function in some common migraine subtypes; supporting this possibility is indirect evidence consistent with enhanced cortical glutamatergic neurotransmission (137, 170) and enhanced cortico-cortical or recurrent excitatory neurotransmission (130, 131, 133, 136) in MA and/or MO. Some of the susceptibility loci for MA and MO recently identied in genome-wide association studies also appear to be consistent with the idea of migraine as a disorder of glutamatergic neurotransmission and/or dysregulated brain E/I balance (2022). Given the wide clinical and genetic heterogeneity of migraine, different molecular and cellular mechanisms that remain largely unknown may well underlie the impaired regulation of brain function and the susceptibility to CSD in different migraineurs. Finally, recent advances in migraine pathophysiology have underscored the need for more efcacious and specic prophylactic migraine medications (171). These needs may one day be met by a greater understanding of cortical dysfunction at the synaptic and cellular levels and by therapeutic strategies that consider cortical E/I dysregulation and CSD as key targets for preventive migraine treatments. Consistent with these ideas, glutamatergic synaptic transmission is a major target to effectively counteract excessive excitatory activity caused by dysfunction of ion channels, transporters, and pumps in FHM and in some migraine variants. Particularly efcacious would be the development of drugs that increase CSD threshold independently of the specic cortical dysfunctions underlying susceptibility to CSD in different migraineurs. SUMMARY POINTS 1. Migraine is a common disabling brain disorder whose key manifestations are recurrent attacks of unilateral headache (that may be preceded by transient neurological aura symptoms in one-third of patients) and interictal hypersensitivity to sensory stimuli.
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2. A large body of indirect evidence supports the prevailing view that the headache phase of migraine depends on the activation and sensitization of trigeminal nociceptors that innervate the large blood vessels in the meninges. These processes then lead to sequential activation (and, in most patients, sensitization) of second- and third-order central trigeminovascular neurons, which in turn activate different areas of the brain stem and forebrain, resulting in pain and other migrainous symptoms. 3. Vasodilation of meningeal and/or extracranial arteries is neither necessary nor sufcient to cause migraine pain. A sterile meningeal inammation is one key mechanism that may underlie the sustained activation and sensitization of perivascular meningeal nociceptors, but the endogenous processes promoting the inammation during migraine attacks remain unclear. 4. Several ndings support a pivotal role of calcitonin generelated peptide (CGRP) in migraine, but the mechanisms of action of CGRP during a migraine attack and the mechanisms underlying the hypersensitivity of migraineurs to CGRP-mediated modulation of nociceptive pathways remain unclear. 5. Increasing evidence from animal studies supports the idea that cortical spreading depression (the mechanism underlying migraine aura) can cause sustained activation of meningeal nociceptors and central trigeminovascular neurons and can thus initiate the headache mechanisms. 6. In the period between attacks, migraineurs show abnormal processing of sensory information due to dysfunctional regulation of cortical excitability. 7. Migraine is a complex genetic disorder with likely polygenic multifactorial inheritance. Most of our present molecular understanding comes from familial hemiplegic migraine (FHM), a rare monogenic form for which three causative genes have been identied. These genes encode a neuronal voltage-gated calcium channel that controls neurotransmitter release at most central synapses, a neuronal voltage-gated sodium channel, and a glial Na+ ,K+ -ATPase. 8. Functional analysis of FHM knockin mouse models supports the view of migraine as a disorder of brain excitability characterized by decient regulation of the cortical excitatory/inhibitory balance as well as the view of CSD as a key migraine trigger. In fact, the FHM mouse models show enhanced cortical excitatory synaptic transmission with unaltered inhibitory synaptic transmission and facilitation of induction and propagation of CSD due to enhanced glutamatergic neurotransmission.
DISCLOSURE STATEMENT
The authors are not aware of any afliations, memberships, funding, or nancial holdings that might be perceived as affecting the objectivity of this review.
ACKNOWLEDGMENTS
D.P. is supported by grants from the University of Padova (Strategic Project: Physiopathology of Signaling in Neuronal Tissue) and from the Fondazione Cariparo (Excellence Project: Calcium
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Signaling in Health and Disease) and acknowledges support from Telethon-Italy (GGP06234). We gratefully thank Drs. Angelita Tottene and Dania Vecchia for preparing the gures. LITERATURE CITED
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Pietrobon Pathophys Migraine

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Pietrobon Pathophys Migraine

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MECHANISMS OF MIGRAINE PAIN Trigeminovascular Pain Pathways

Dura mater Pia mater Cerebral cortex

V1/V2 M1/M2 Ins ns Au PtA tA RSA

Cerebral cortex Midbrain vlPAG NCF Cerebellum

Efferent modulatory pathways

Meningeal Inammation and Peripheral Sensitization

Calcitonin GeneRelated Peptide

Dysfunctional Central Control of Pain

PRIMARY BRAIN DYSFUNCTIONS IN MIGRAINE

Cortical Spreading Depression

CGRP SP NKA MMP9 BBB leakage

Dysfunctional Regulation of Cortical Excitability

INSIGHTS FROM FAMILIAL HEMIPLEGIC MIGRAINE MOUSE MODELS

Cav2.1 current in cortical pyramidal cells increased

Cortical synaptic transmission:

DC potential po tial [K+] FS interneu interneuron erneuron on + + + + EEG

CGRP release at the dura unaltered

Cav2.1 current in TG neurons

CGRP release at the TG increased

NMDA: N-methyl-D-aspartic acid

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