pietrobon pathophys migraine

8/12/2019 Pietrobon Pathophys Migraine

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Pathophysiology of MigraineDaniela Pietrobon 1, 2 and Michael A. Moskowitz31Department of Biomedical Sciences, University of Padova and 2CNR Institute of Neuroscience, 35121 Padova, Italy; email: [email protected] 3Neuroscience Center, Departments of Radiology and Neurology, Massachusetts GeneralHospital, Harvard Medical School, Boston, Massachusetts 02129;email: [email protected]

Annu. Rev. Physiol. 2013. 75:23.1–23.27

The Annual Review of Physiology is online at http://physiol.annualreviews.org

This article’s 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 thebrain and its associated tissues have been implicated as major players duringan attack.Once consideredexclusivelya disorder of blood vessels, compellingevidence has led to the realization that migraine represents a highly chore-ographed interaction between major inputs from both the peripheral andcentral nervous systems, with the trigeminovascular system and the cerebralcortex among the main players. Advances in in vivo and in vitro technologieshave informed us about thesignicance to migraine of events such as corticalspreading depression and activation of the trigeminovascular system and its

constituent neuropeptides, as well as about the importance of neuronal andglial ion channels and transporters that contribute to the putative corticalexcitatory/inhibitory imbalance that renders migraineurs susceptible to anattack. 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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Aura: transient

(20–30-min) focalneurological event causing visual and/orsensory or speechdisturbance

Event-relatedpotentials:stereotypicalelectrophysiologicalbrain responses to amotor, cognitive, orsensory stimulus

CSD: corticalspreading depression

Familial hemiplegicmigraine (FHM):autosomal dominant headache syndromeaccompanied by paroxysmal attacksthat include typicalmigraine auras plushemiplegic aura

INTRODUCTION Migraine is a common episodic neurological disorder with complex pathophysiology that manifestsas 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 theheadache 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 diseasesaccording 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 theattack (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 neurophysio-logical studies have provided clear evidence that in the period between attacks migraineurs show

hypersensitivity to sensory stimuli and abnormal processing of sensory information, character-ized 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 (9–12) and that cortical spreading depression (CSD) is theneurophysiological correlateof migraine aura (10, 13–15). CSD can be induced in animalsby focalstimulation of the cerebral cortex and consists of a slowly propagating (2–6 mm min− 1) wave of strong neuronal and glial depolarization; the mechanisms of initiation and propagation of CSDremain 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 remainlargely unknown and the major open issue in the neurobiology of migraine. Other important open questions concern the mechanisms of initiation, continuation, and termination of migrainepain.

Migraine is a complex genetic disorder with heritability estimates as high as 50% and witha likely polygenic multifactorial inheritance (17, 18, 19). The complexity of the disease, whichdepends upon the interplay of multiple genes and gene-environment interactions, has hamperedthe identication of common susceptibility variants; the lack of consensus on most of the iden-tied susceptibility loci probably reects clinical and genetic heterogeneity (17, 18, 19). Re-cent genome-wide association studies have identied a few risk factors for both MA and mi-graine without aura (MO) that map within or near transcribed regions of potentially interestinggenes (20–22). However, most of our present molecular understanding of migraine comes fromstudies of familial hemiplegic migraine (FHM), a rare, monogenic, autosomal dominant formof MA (18, 19, 23). Three FHM causative genes, all encoding ion channels or transporters,have been identied (24–26). Additional FHM genes certainly exist and remain to be identied(27).

Here, we review recent advances regarding the mechanisms of migraine pain and the mecha-nisms of the primary brain dysfunction(s) leading to the onset of a migraine attack and to episodicactivation of the trigeminovascular pain pathway. We also discuss the insights into those mecha-nisms 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 dependson the activation and sensitization of trigeminal sensory afferents that innervate cranial tissues, inparticular, the meninges and their large blood vessels (10–12, 28). As discussed by Olesen et al.(11), whether nociception originates from pial, dural, or extracranial periarterial sensory afferentsremains 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 theso-called trigeminocervical complex (TCC) comprising theC1 and C2 dorsal horns of thecervicalspinal cord and the caudal division of the spinal trigeminal nucleus (TNC); the C-ber terminalsare located mainly in supercial layers and the A-δ ber terminals in deep layers (29–31). The TCC makes direct ascending connections with different areas in the brain stem and with higherstructures, including several hypothalamic andthalamic nuclei,which in turn make ascending con-nections with the cortex (29–31 and references therein) (Figure 1 a ). Congruently, stimulation of

the dural afferents in experimental animals results in activation of second-order trigeminovascularneurons (mainly in laminae I, II, and V) in the TCC, as well as in activation of neurons in severalbrain stem [e.g., superior salivatory nucleus, ventrolateral periaqueductal gray (vlPAG), rostral ventromedial medulla (RVM)], hypothalamic, and thalamic [in particular, the ventroposteriome-dial (VPM) and posterior (Po)] nuclei receiving connections from the TCC (32–36; cf. References10 and 30 for review and older references) (Figure 1 a ).

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 painmatrix)and arethus likelyto play a role in theperceptionofheadache.Trigeminovascular Po thala-mic neurons project beyondthe pain matrix into non–trigeminal S1 cortex, as well as into auditory, visual, retrosplenial, ectorhinal, and parietal association cortices, and are thus likely to contributeto other aspects of the migraine experience, which includes disturbances in neurological functionsinvolved 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). In- vestigators recently uncovered a neural mechanism for migraine photophobia (36). Dura-sensitivethalamic neurons in the rat posterior thalamus receive monosynaptic input from retinal ganglioncells (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 thending that exacerbation of headache by light was preserved in blind migraineurs whocould senselight in the face of severe degeneration of rod and cone photoreceptors (36).

The TCC receives descending projections from brain stem and hypothalamic nociceptivemodulatory nuclei that may mediate descending modulation of trigeminovascular nociceptivetrafc (30) (Figure 1 b ). Indeed, electrical stimulation of the vlPAG or the nucleus raphae magnusin the RVM results in inhibition of the response of trigeminovascular TCC neurons to duralstimulation (37, 38). Moreover, modulation of the response of trigeminovascular TCC neuronsto dural stimulation occurred after injection of orexin A or B or a somatostatin antagonist inthe posterior hypothalamus (39, 40) and after electrical stimulation of the A11 dopaminergic

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b Efferent modulatory pathways

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NCFCFvlPAGlP G NCFvlPAG

RVMVMRVM

PHHPHA11 A11

a Afferent pathways

Pons TCCCC TCC

TCCCC TCC

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Dura mater

Pia materTG

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T N C , C 1 , C 2

T N C , C 1 , C 2

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 connectionsmentioned in the text. The arrows indicate the direction of the information ow. Abbreviations: A11, dopaminergic hypothalamicnucleus; 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; S1and S2, primary and secondary somatosensory cortices; SSN, superior salivatory nucleus; TCC, trigeminocervical complex (comprisingthe C1 and C2 dorsal horns of the cervical spinal cord and the caudal division of the spinal trigeminal nucleus); TG, trigeminalganglion; 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). Lesioningof the A11 nucleus resulted in facilitation of dura-evoked ring, suggesting that the A11 nucleusprovides descending tonic inhibitory modulation of trigeminovascular nociceptive trafc (41).

The TCC also receives descending cortical projections from layer 5 pyramidal cells of thecontralateral S1 cortex (innervating mainly neurons in deep laminae III–V) and caudal Ins cortex





Inammatory soup

(IF): an acidic mixtureof potassium,prostaglandins,serotonin, bradykinin,and histamine that stimulates andsensitizes nociceptors,causing hyperalgesia

CGRP: calcitoningene–related peptide

SP: substance P

Transient receptor potential cation channel V1 (TRPV1)receptor:receptor implicated intransducing pain andscalding heat; alsoknown as the capsaicinor vanilloid receptor

(innervatingexclusively laminaeI andII, strictly contralaterally)(35) (Figure1 b ). Thedirect corti-cotrigeminal outow mediated by these cortex-TCC connections may mediate specic top-downmodulation 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, respec-tively, ofTCC neurons tonoxious electricalstimulationofthe dura (35). Interestingly, theresponseto innocuous mechanical stimulation of periorbital skin was not affected by reduction of corticalactivity 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 affer-ents exhibit properties, including chemosensitivity and sensitization, characteristic of nociceptorsin other tissues (12,42–47). In vivo recordingshave shown that most C-typeand slow A-delta-typerat 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 ac-tivated 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 ionchannels (44), and most small-diameter neurons were capsaicin sensitive (45). Immunolabelingexperiments have revealed a dense network of dural nerve bers immunoreactive for calcitoningene–related peptide (CGRP) and substance P (SP) (48) and extensive colocalization of TRPV1receptors and CGRP in small-diameter rat dural bers (49). CGRP and SP immunoreactivitiesin the dura and around pial vessels were almost completely eliminated by intravenous capsaicinin guinea pig (50), supporting the idea that most peptidergic meningeal nociceptors are capsaicinsensitive.Congruently, topicalapplication of capsaicin to therat dura causesvasodilationmediatedby CGRP (51).

Nearly all dural afferents that can be activated in vivo by IF are mechanosensitive, and IF en-hances their mechanosensitivity (46). The sensitization of mechanosensitive meningeal afferentsprovides a mechanism that may explain the throbbing nature of the migraine headache (typi-cally 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, themechanisms 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 andthe ensuing throbbing headache during a migraine attack remain incompletely understood andcontroversial.

Vasodilation Several experimental and clinical observations show that vasodilation of meningeal and/orextracranial arteries is neither necessary nor sufcient to cause migraine pain; therefore, theoriginal 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 insildenal- and nitric oxide–induced migraine attacks (53, 54), and on the other hand, arterial

vasodilation produced by vasoactive intestinal polypeptide infusion did not provoke a migraineheadache (55). Recently, a 9–12% dilation of extracranial and intracranial arteries was measuredin CGRP-induced migraine headache; this modest vasodilation is likely insufcient to activatethe perivascular afferents but might affect sensitized nociceptors (56). Furthermore, the modest amountof dilation in these studies andin other imagingstudies wasprobablymediatedby parasym-pathetic activation via a monosynaptic reex accompanying trigeminovascular activation (57).





MC: mast cell

Neurogenicinammation (NI):a physiologicalmechanism causingdilation, edema (due toextravasation of plasmaproteins), and othermanifestations of inammationmediated by releasedneuropeptides fromthe peripheral ends of small-caliber primary afferent bers

Peripheralsensitization:increased sensitivity tonoxious or nonnoxioussensory stimulationcaused by hyperresponsiveness within primary afferent bers

Transient receptor potential cation channel A1 (TRPA1)receptor: receptorthat detects noxiousstimuli, cold, andstretch

Meningeal Inammation and Peripheral Sensitization On the basis of a large body of indirect evidence from both clinical and animal studies, a sterilemeningeal inammation is considered one key mechanism that may underlie the sustained acti-

vation and sensitization of perivascular meningeal afferents during migraine attacks (12, 58, 59).Indirect clinical evidence is provided by the increased level of various inammatory mediatorsin the cephalic venous outow during spontaneous migraine attacks and by the efcacy of non-steroidal 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 vivoleads to release of vasoactive proinammatory peptides such as CGRP and SP from their periph-eral 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 re-lease 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 duralnociceptors (60) as well as cephalic tactile hypersensitivity (61). Chemical inammation of thedura 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 inhealthy 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 inammationand peripheralsen-sitization during spontaneous migraine attacks remain incompletely understood. Many investiga-tors consider the NI produced by release of vasoactive proinammatory neuropeptides followingactivation of peptidergic meningeal nociceptors (by CSD or other different primary mechanisms;see next section) to be the endogenous inammatory process that sustains the activation andcauses the sensitization of meningeal nociceptors in many migraine attacks. Indeed, measure-ments of CGRP levels in the external and internal jugular venous blood have provided evidencethat CGRP is released during migraine attacks (65–67). Also consistent with the NI hypothesis isthe recent evidence that the headache-triggering substances ethanol and umbellulone (the major volatile constituent of the Californian “headache tree”) activate peptidergic meningeal trigeminalafferents (via different receptors: TRPV1 and TRPA1), causing CGRP release and neurogenicdura inammatory responses in experimental animals (68, 69). However, direct evidence that therelease of inammatory molecules associated with NI sensitizes meningeal nociceptors is lacking.

In certain types of migraine, endogenous processes different from NI and not requiring initialactivation of meningeal nociceptors might promote meningeal inammation and cause sensitiza-tion and ensuing long-lasting activation of meningeal nociceptors. These processes may includedirect 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 brainparenchyma (e.g., as a consequence of CSD) and/or from meningeal blood vessels or immunecells 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 inanesthetized animals, second-order trigeminovascular neurons in the TCC showed long-lastingincreased responses to innocuous mechanical or thermal facial skin stimulation (73), whereas





Blood oxygen

level–dependent functional magneticresonance imaging (BOLD fMRI):a magnetic resonancemethod, often termedfMRI, that generates aBOLD signal that measures oxy- anddeoxyhemoglobinlevels in tissues andapproximates relativeblood ow changes inbrain tissue

Central sensitization:

increased sensitivity tonoxious or nonnoxioussensory stimulationcaused by hyperresponsiveness of central neurons withinthe trigeminocervicalcomplex or thalamus

Interictal period: theperiod of time betweenmigraine attacks

third-order trigeminovascular neurons in the posterior thalamus showed long-lasting increasedresponses to both cephalic and extracephalic skin stimuli (33). Interestingly, functional magneticresonance 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 duringmigraine attacks with extracephalic allodynia than during migraine-free periods (33). These datasuggest that facial allodynia reects sensitization of trigeminovascular neurons in the TCC receiv-ing convergent input from the meningeal nociceptors and facial skin and that extracephalic allo-dynia reects sensitization of trigeminovascular thalamic neurons that process convergingsensory information from the cranial meninges and extracephalic skin. The gradual spatial and temporalspread of allodynia and its expression are consistent with the idea that initiation of central sensiti-zation 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 didnot inhibit the long-lasting hypersensitivity to cutaneous stimulation of TCC neurons suggeststhat, once established, central sensitization becomes independent of afferent input (10, 73).

A recent animal study points to the activation of the descending facilitatory pathway aris-ing 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 develop-ing) 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 in-hibit nociceptive signals. IF-induced facial allodynia was almost abolished (and hind pawallodynia was reduced) after selective lesion of putative RVM pain-facilitating neurons; moreover, bilateralmicroinjection of bupivacaine into the RVM 30 min after dural IF prevented facial allodynia anddelayed the onset of hind paw allodynia (32).

fMRI studies in human subjects indicate that the PAG and nucleus cuneiformis (NCF), themajor sources of input to the RVM (Figure 1 ), are involved in the maintenance of central sensiti-zation 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 fMRIndings 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).

Calcitonin Gene–Related PeptideSeveral 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 delayedmigraine-like headache by intravenous CGRP administration in a large fraction of migraine pa-tients but not in controls (79), suggesting that most migraineurs are hypersensitive to CGRP-mediated 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 (65–67). The localization of CGRPreceptors in the trigeminovascular system (TVS) points to multiple possible mechanisms at bothperipheral and central sites (80).

In theperiphery, CGRP receptorsare expressedin blood vessels, Schwann cells, andduralMCsat the meninges and in glial satellite cells and a subpopulation of TG neurons in the trigeminalganglion (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 duralafferents (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.





normal meningeal sensory input remain unclear. Nonetheless, functional imaging studies show-ing increased cerebral blood ow in the dorsal rostral brain stem and in the hypothalamus duringmigraine 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) promotedthe view that abnormal activity in the PAG-RVM circuitry could serve as the migraine headachegenerator. However, in light of more recent data, the specicity of activation of different brainstem 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 dur-ing 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 thePAG-RVM circuitry (orother descending mechanisms of pain inhibition) cangenerate 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 speci-cally generates migraine pain (and not other pains in spinal or trigeminal tissues), given that thedescending modulatory pathway projects onto multiple segments of the spinal cord. Moreover,abnormal descending modulation implies that disinhibition of second-order neurons (receivingconvergent 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 todevelop 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 mechanismof aura, can activate trigeminal nociception and thus trigger headache mechanisms. A direct noci-ceptive effect of CSD was demonstrated by the nding that a singleCSD can lead to a long-lastingincrease in ongoing activity of dural nociceptors and central trigeminovascular neurons in super-cial 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 delayas well asthe 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 centralneurons. 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 bemediated by peptidergic nociceptors with axon collaterals extending to the pia, where immediateactivation 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 CSD-induced CGRP release from perivascular trigeminal bers contributes to the transient dilationof pial vessels measured during CSD (103). A possible explanation for the long-lasting activation





of the dural afferents is that release of proinammatory neuropeptides in the dura promotes NIthat 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 fromdural blood vessels, which was abolished by trigeminal nerve section (57; but cf. 61, 104). Alter-natively, it has been suggested that mediators released by the CSD wave may lead to sensitizationand ensuing sustained activation of meningeal nociceptors (61). The mechanism of the delayedlong-lasting neuronal activation remains unknown. A recent review discusses different potentialmechanisms (61), including upregulation of matrix metalloproteinases (105) and the passage of normally sequestered and potentially noxious molecules (e.g., K + , H + , 5-hydroxytryptamine) intothe 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 CSD-driven central effects, including gene upregulation in the TCC (57, 106) and dilation and increasein blood ow within the middle meningeal artery mediated by trigeminally evoked brain stemreexes (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 toexperience CSD as aversive, as they do not show pain behavior (107, 108) or cutaneous allodynia(109) aftera CSD. However, whether thesebehavioral studies aresuitable todetecta relativelymildhead pain remains uncertain (110); moreover, only 60–70% 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 ac-tivityin, forexample,the temporal lobe (e.g., in focal temporal lobe epilepsy)can activate overlyingmeningealnociceptors andgenerateipsilateral headache (111). If CSDdoes cause hemicranialpaindue to activation of overlying meningeal nociceptors, the expectation is that the initial headacheshould develop contralateral to the unilateral aura symptoms (e.g., left visual aura caused by CSDin the right hemisphere is accompanied by right hemicranial pain), which seems to be the case inthe majority of patients.

The idea that CSD is noxious and may trigger headache is indirectly supported by the ndingthat the electrical stimulation threshold for induction of CSD in the rat cortex increases after

−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−→

Figure 2From 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 ) Othernoxious mediators (open circles ), such as H+ , nitric oxide (NO), arachidonic acid (AA), and serotonin (5-hydroxytryptamine), besidesglutamate and other neurotransmitters are released during CSD. It is hypothesized that these substances may activate trigeminalnociceptors innervating pial blood vessels and, via axon collaterals, dural trigeminal afferents and/or may slowly access the meningealafferents after disruption of the blood-brain barrier (BBB) (e.g., as a consequence of upregulation of matrix metalloproteinases), leadingto 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 gene–related peptide (CGRP), substance P(SP), and neurokinin A (NKA), that may promote neurogenic inammation in the dura and possibly sustain the activation of thetrigeminovascular afferents and lead to their sensitization. Alternatively, mediators released by the CSD wave may lead to sensitizationand 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, trigeminalganglion.





chronic treatment with ve different migraine prophylactic drugs that are equally effective inreducing the frequency of MA and MO attacks (112); in contrast, twodrugs ineffective in migraineprophylaxis do not affect susceptibility to experimental CSD (112, 113). This good correlationbetween inhibition of CSD and effectiveness in migraine prophylaxis depends upon an adequateclinical trial design that addresses whether there is a signicant change in frequency of aura as wellas decrease in the following headache. In this respect, the design of clinical trials for two drugs(tonabersat and lamotrigine), reportedly effectivein reducing the frequencyof experimental CSDs

CSDSDCSD

K+

erebral cortex

EEG

[K +]

DCpotential

CSDSDw av ef f r o n t

CSDwavefr ont

CGRP

SPNKA

CSD

Cerebral c rtex

K + H+ NO AA

TCC

(Neurogenic)in ammation

SSN

TG

TCC

SPG

MMP9BBB leakage

1 min

a

b

c VIP

NOACh

Dura

Pia





produced by prolonged epidural application of KCl (114, 115), appears problematic. On the onehand, 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 theother 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 themean number of headache days (118) or frequency of migraine (119), respectively. Further studiesthat are sufciently powered, including dose-ranging studies and measurements of the electricalthreshold for experimental CSD induction after chronic treatment of animals with tonabersat andlamotrigine, will be required to solve these apparent discrepancies.

The analysis of experimental CSD in FHM knockin mouse models has providedfurther support to the view of CSD as a key migraine trigger by demonstrating that both FHM1 knockin miceand FHM2 knockin mice show a lower electrical stimulation threshold for CSD induction and ahigher velocity of CSD propagation (see next section) (120–123). Although FHM3 mouse modelsare not available, investigators reported that FHM3 in two unrelated families cosegregates witha new eye phenotype with clinical features similar to those of experimental spreading depressionin 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 theheadache mechanisms in migraine is not generally accepted (10, 15). In fact, most migraineurs donotexperience aura, and even MA patients experience attacks without aura; moreover, therapeuticintervention 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-documentedimaging study in a young female with silent aura and CSD followed by headache (e.g., MO) leavesdoubt 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 headachemechanisms is based on the fact that in some patients migraine premonitory symptoms may occur up to 12–24 h before the onset of the aura and headache. One implication of these well-documented premonitory symptoms is that different brain regions (including hypothalamic andother 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 12–24 h before the attack, i.e., during the interval whenthe premonitory symptoms appear, and then normalize a few hours before and/or during theattack, except for decits in pain processing (7, 8, 10, 99, 128, 129). Also, the neurophysiologicalreactivity 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) 1–3 days before an attack (128). These data suggest that in the brains of migraineurs some intrinsic mechanisms during thepain-free interval progressively increase the dysfunction in central information processing, thesusceptibility to migraine triggers, and the neurophysiological readiness to generate a migraineattack. One can speculate that these mechanisms both may lead to the premonitory symptomsand, above a certain thresholdof cortical dysfunction and/or in response to migraine triggers, may





Transcranial

magnetic stimulation (TMS): a noninvasivetechnique that induces weak electric currentsin brain to causeneuronaldepolarization orhyperpolarization

create the conditions for ignition of CSD (e.g., as a result of cortical hyperactivity in the brain’sattempt to normalize excessive cortical activation due to the decit in habituation).

Dysfunctional Regulation of Cortical Excitability To understand the primary mechanisms of migraine attacks, i t seems essential to understand themechanisms underlying the interictal abnormal processing of sensory information, how they areaffected by migraine triggers, and the nature of the relationship between these mechanisms andsusceptibility to CSD.

The analysis of interictal cortical excitability using psychophysics, electrophysiology, transcra-nial magnetic stimulation (TMS), and fMRI has produced contradictory ndings and interpre-tations 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 reviewsand see, e.g., References 130–134 for some recent studies). Depending on the study, the cortex of migraineurs is hyperexcitableas a consequence of eitherenhanced excitationor reduced inhibition

or is hypoexcitable and/or has a lower preactivation level possibly due to serotonin hypoactivity and/or inefcient thalamocortical drive.Interestingly, recentTMSstudies in MA patients point todecient regulatory mechanisms of cortical excitability and consequent reduced ability to dynami-cally maintain the cortical excitatory/inhibitory (E/I) balance and to prevent excessive increases incortical excitation, rather than merely hypo- or hyperexcitability, as the mechanisms underlyingabnormal sensory processing (135–137). Decient cortical regulatory mechanisms likely underliethe 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 func-tion 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 essen-tial 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 areaffected 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 dysregulationof 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 adisorder 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 andtheir relationship to CSD susceptibility.

INSIGHTS FROM FAMILIAL HEMIPLEGIC MIGRAINE MOUSE MODELSFHM is characterized by obligatory motor aura symptoms consisting of motor weakness or paral-

ysis (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 mecha-nisms, despite clinical observations that the response to infusion of CGRP and glyceryl trinitrateseems to differ (142, 143). Some FHM patients can also have atypical severe attacks (with signs





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 CACNA1Aand SCNA1A, the genesencoding the pore-forming subunits of the neuronal voltage-gated Ca2+ channel Ca V 2.1 (alsoknown as the P/Q-type Ca2+ channel) and the Na+ channel Na V 1.1, cause FHM type 1 (FHM1)(24) and type 3 (FHM3) (26), respectively. Mutations in ATP1A2 , the gene encoding the Na + ,K + - ATPase α 2 subunit, cause FHM type 2 (FHM2) (25).

Ca V 2.1 channels are widely expressed in the nervous system, including all structures impli-cated in the pathogenesis of migraine, and play a dominant role in controlling neurotransmitterrelease, particularly at central synapses; their somatodendritic localization points to additionalpostsynaptic roles, e.g., in neural excitability (144, 145). Na V 1.1 channels are expressed primarily in the central nervous system in late postnatal stages and show high expression in certaininhibitory interneurons, in which they play an important role in sustaining high-frequency ring(146). In the nervous system, the α 2 Na + ,K + -ATPase isoform is expressed primarily in neuronsduring 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 surroundingglutamatergic synapses suggests specic roles in theregulation of intracellular Ca2+ and glutamateclearance (23 and references therein).

Whereas most genetic studies indicate that the FHM genes (except perhaps for ATP1A2) arenot involved in common migraines (18, 23), some homozygous mutations in SLC4A4, the geneencoding the electrogenic Na+ ,HCO 3

− cotransporter NBCe1, are associated with hemiplegicmigraine, MA, or MO, depending on the mutation (147). The transport activity of NBCe1 in as-trocytes is thought to modulate neuronal excitability by regulating local pH (147). Only mutationsproducing 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 commonmigraine 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 expressionsystems (and,for somemutations, in transfectedneurons)were

recently reviewed (18, 23, 145) and are not discussed in detail here. Rather, we discuss functionalstudies in FHMmousemodels andthe consequencesof themutations on thenative proteins andonneurophysiological processes that are thought to be involved in the pathophysiology of migraine.

Three different FHM mouse models were generated by introducing the human FHM1R192Q or S218L and FHM2 W887R mutations into the orthologous genes (120–122). Whereasin humans the R192Q and W887R mutations cause typical FHM attacks (24, 25), the S218Lmutation causes a particularly dramatic clinical syndrome that may consist of—in additionto attacks of hemiplegic migraine—slowly progressive cerebellar ataxia and atrophy; epilepticseizures; coma or profound stupor; and severe, sometimes fatal cerebral edema that can betriggered by trivial head trauma (148). Whereas homozygous R192Q, heterozygous S218L, and W887R knockin mice do not exhibit an overt phenotype, homozygous S218L mice model themain features of the severe S218L clinical syndrome (120–122). Homozygous W887R knockinmice die at birth because of lack of spontaneous respiratory activity (122).

The α 2 Na+ ,K + -ATPase protein was barely detectable in the brains of homozygous FHM2knockin mice and was strongly reduced in the brains of heterozygous mutants (122). Previousstudies 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 Ca V 2.1 current in a wide range





of relatively mild depolarizations, reecting shifted activation of mutant Ca V 2.1 channels to morenegative voltages (45, 120, 121, 151, 152) (Figure 3 ). The shift to lower voltages of Ca V 2.1channel activation and the gain of function of the neuronal Ca V 2.1 current were approximately twice as large in homozygous knockin mice than in heterozygous mice, revealing an allele dosageeffect consistent with dominance of the mutation in FHM1 patients (121). The gain-of-functioneffect of the FHM1 mutations on native neuronal mouse Ca V 2.1 channels is in agreement withthe increased open probability of recombinant human Ca V 2.1 channels carrying eight different FHM1 mutations (including R192Q and S218L) that was revealed by single-channel recordings(153–155).

Interestingly, FHM1 mutations may not affect the gating properties of native Ca V 2.1 channelsin specicneurons (45), possibly as a consequence ofexpressionof specicCa V 2.1α 1 splicevariantsand/or Ca V 2.1β subunits (156,157). In fact,in R192Q knockinmice the P/Q-type Ca2+ current isincreased in a subtype of TG neuronthat does notinnervate thedura, butis unalteredin capsaicin-sensitive TG neurons that innervate the dura (45) (Figure 3 ). Congruently, although P/Q-typecalcium channels contribute to control of CGRP release from capsaicin-sensitive perivascularmeningeal sensory bers (158, 159), the FHM1 mutation does not alter depolarization-evoked

CGRP releasefromthe dura (45)( Figure3 ). This ndingargues againstthe idea that facilitation of CGRP-dependent dural vasodilation and CGRP-dependent dural MC degranulation contributesto the generation of migraine pain in FHM1. However, the FHM1 mutation increases CGRP re-lease from intact trigeminal ganglia (45) (Figure 3 ) and from cultured TG neurons (90) of R192Qknockin mice, suggesting alternative roles. If CGRP-mediated intraganglionic cross talk promotesand maintains a neuron-glia inammatory cycle that contributes to peripheral trigeminal sensiti-zation (65, 67) (see above), then FHM1 mutations may facilitate these phenomena. Indeed, thereis some evidence suggesting facilitation of CGRP-mediated neuron-to-glia cross talk followingexposure 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 interestingdifferential 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)-evokedCa2+ inuxand increasedprobabilityof glutamate release at cortical pyramidalcell synapses

of R192Q knockin mice; congruently, short-term synaptic depression during trains of APs isenhanced (151). AP-evoked Ca2+ transients in individual synaptic terminals of cerebellar granulecells are enhanced and short-term facilitation is reduced at parallel ber–Purkinje cell synapsesof S218L knockin mice (160). In striking contrast, inhibitory neurotransmission at cortical FSinterneuron synapses is not altered in FHM1 knockin mice, despite being initiated by P/Q-typecalciumchannels (151;D. Vecchia & D. Pietrobon,unpublished observations). Thedemonstrationthat FHM1 mutations may differently affect synaptic transmission and short-term plasticity at excitatoryandinhibitory cortical synapses (151) implies that theneuronal circuits that dynamically adjust theE/I balance duringcortical activity areprobablyaltered in FHM1. Functionalalterationsin 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 cortexin vivo or by focal application of high KCl in cortical slices, revealed a lower threshold for CSDinitiation and an increased velocity of CSD propagation in both FHM1 and FHM2 knockin mice

(120–122, 151) (Figure 3 ). In FHM1 knockin mice carrying the mild R192Q mutation or thesevere S218L mutation, the strength of CSD facilitation as well as the severity of the post-CSDneurological 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 Ca V 2.1 channel andthe 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





i Cav2.1 current in corticalpyramidal cells increased

ii Cortical synaptic transmission:• Increased glutamate release at pyramidal cell synapses• Unaltered GABA release at FS interneuron synapses Dysfunctional regulation of cortical E/I balance

iii CSD• Lower threshold• Increased velocity and

extent of propagation

i CGRP release at the dura unaltered

ii Cav2.1 current in TG neurons• Unaltered in CS dural afferents• Increased in CI-T neurons not

innervating the dura

iii CGRP release at the TG increased

CSDSD

wavefrontavefront

CSD

wavefront

1 min

Pyramidalyramidalcellsells

FSS interneurneuronn

Pyramidalcells

FS interneuron++

++

++

++

++

++

CGRPNKASP

TCC

(Neurogenic)in ammation

TG

b

a

Dura

Pia

EEGEGEEG

[K K ][K +]

DC pooten tialia l

DCpotential

r br l or ex

K + H+ NO AA





FHM2 mouse model (122). The contribution of impaired K + clearance has been considered lessimportant 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 sponta-neously in response to specic triggers that somehow create conditions in the cortex for initiationof the positive feedback cycle that overwhelms the regulatory mechanisms controlling corticalextracellular [K + ] and ignites CSD. Insights into how this might occur were provided by thedifferential effects of FHM1 mutations on cortical excitatory and inhibitory synaptic transmission(151), suggesting alteredregulation of the cortical E/I balance in FHM1. It has been hypothesizedthat this dysregulation may in certain conditions (e.g., in response to migraine triggers such asintense, 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 forthe 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 cir-cuits 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 insubcortical areas that may also contribute to the altered regulation of cortical function and to thedisease in general in a waythat remains tobe established (e.g.,byaltering cortical neuromodulationby monoaminergic projections and/or by favoring hyperexcitability of central trigeminovascularpathways). 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.

Similarmechanisms mayunderlie theabnormal regulationof cortical (and possibly subcortical)function in some common migraine subtypes; supporting this possibility is indirect evidenceconsistent with enhanced cortical glutamatergic neurotransmission (137, 170) and enhancedcortico-cortical or recurrentexcitatoryneurotransmission (130, 131,133,136) in MA and/or MO.Some of the susceptibility loci for MA and MO recently identied in genome-wide associationstudies also appear to be consistent with the idea of migraine as a disorder of glutamatergicneurotransmission and/or dysregulated brain E/I balance (20–22). Given the wide clinical and

genetic heterogeneity of migraine, different molecular and cellular mechanisms that remainlargely unknown may well underlie theimpaired regulation of brain function andthesusceptibility to CSD in different migraineurs.

Finally, recent advances in migraine pathophysiology have underscored the need for moreefcacious and specic prophylactic migraine medications (171). These needs may one day bemet by a greater understanding of cortical dysfunction at the synaptic and cellular levels and by therapeutic strategies thatconsidercortical E/I dysregulation andCSDas key targets forpreventivemigraine treatments. Consistent with these ideas, glutamatergic synaptic transmission is a majortarget to effectively counteract excessive excitatory activity caused by dysfunction of ion channels,transporters, and pumps in FHM and in some migraine variants. Particularly efcacious wouldbe the development of drugs that increase CSD threshold independently of the specic corticaldysfunctions underlying susceptibility to CSD in different migraineurs.

SUMMARY POINTS

1. Migraine is a common disabling brain disorder whose key manifestations are recurrent attacksof unilateral headache (that maybe preceded by transient neurological aura symp-toms in one-third of patients) and interictal hypersensitivity to sensory stimuli.





2. A large body of indirect evidence supports the prevailing view that the headache phaseof migraine depends on the activation and sensitization of trigeminal nociceptors that innervate the large blood vessels in the meninges. These processes then lead to sequen-tial activation (and, in most patients, sensitization) of second- and third-order centraltrigeminovascular neurons, which in turn activate different areas of the brain stem andforebrain, 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 nocicep-tors, but the endogenous processes promoting the inammation during migraine attacksremain unclear.

4. Several ndings support a pivotal role of calcitonin gene–related peptide (CGRP) in mi-graine, but the mechanisms of action of CGRP during a migraine attack and the mecha-nisms 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 de-pression (the mechanism underlying migraine aura) can cause sustained activation of meningeal nociceptors and central trigeminovascular neurons and can thus initiate theheadache mechanisms.

6. In the period between attacks, migraineurs show abnormal processing of sensory infor-mation 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 neurotrans-mitter 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 exci-tatory/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 withunaltered inhibitory synaptic transmission and facilitation of induction and propagationof 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.

ACKNOWLEDGMENTSD.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





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.

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