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Feature Review
Migraine: a disorder of brainexcitatoryinhibitory balance?Dania Vecchia 1 and Daniela Pietrobon 1 , 2
1 Department of Biomedical Sciences, University of Padova, 35121 Padova, Italy2 CNR Institute of Neuroscience, 35121 Padova, Italy
Migraine is a common disabling brain disorder whosekey manifestations are recurrent attacks of unilateralheadache and interictal hypersensitivity to sensory sti-muli. Migraine arises from a primary brain dysfunctionthat leads to episodic activation and sensitization of thetrigeminovascular pain pathway and as a consequence
to
headache.
Major
open
issues
concern
the
molecularand cellular mechanisms of the primary brain dysfunc-tion(s) and of migraine pain. We review here our currentunderstanding of these mechanisms, focusing on recentadvances regarding migraine genetics, headache mech-anisms, and the primary brain dysfunction(s) underlyingmigraine onset and susceptibility to cortical spreadingdepression, the neurophysiological correlate of migraineaura. We also discuss insights obtained from the func-tional analysis of familial hemiplegic migraine mousemodels.
IntroductionMigraine is a common episodic neurological disorder withcomplex pathophysiology that manifests itself as recurrentattacks of typically throbbing and unilateral, often severe,headache with associated features such as nausea, phono-phobia and/or photophobia; in a third of patients the head-ache is preceded by transient neurological symptoms thatare most frequently visual but may involve other senses(migraine with aura: MA) [1] (Table 1 ). Migraine is a publichealth problem of great impact upon boththe individual andsociety. It is one of the 20 most disabling diseases (according to World Health Organization ranking [2]). Furthermore, itis remarkably common (e.g., it affects 17% of femalesand 8%of males in the European population [3]) and very costly (EUR 18.5 billion/year in Europe [4]).
It
is
generally
believed
that
migraine
headache
dependson the activation and sensitization of the trigeminovascu-lar pain pathway [57] (Figure 1 ), and that cortical spread-ing depression (CSD)-like events underlie migraine aura[5,8,9] . CSD can be induced in animals by focal stimulationof the cerebral cortex and consists of a slowly propagating (26 mm/min) wave of strong neuronal and glial depolari-zation whose mechanisms of initiation and propagationremain unclear [10,11] . It is also generally recognized thatmost migraine attacks start in the brain. This is suggestedby the premonitory symptoms (such as difculty with
speech and reading, increased emotionality, sensory hypersensitivity) which in many patients are highly predictive of the attack although occurring up to 12 hbefore it [12] as well as by the nature of some typicalmigraine triggers (e.g., stress, sleep deprivation, oversleep-ing, hunger and/or prolonged sensory stimulation) [13] .
Psychophysical
and
neurophysiological
studies
have
pro- vided clear evidence that in the period between attacksmigraineurs show hypersensitivity to sensory stimuli andabnormal processing of sensory information, characterizedby increased amplitudes and reduced habituation of evoked and event-related potentials [14,15] .
The nature and mechanisms of the primary brain dys-function(s) leading to the onset of a migraine attack, toCSD susceptibility, and to episodic activation of the trige-minovascular pain pathway remain largely unknown andare major outstanding issues to be addressed in furthering our understanding of the neurobiology of migraine. Otherimportant open questions concern the mechanisms of mi-graine pain.
Here, we review recent advances regarding (i) the ge-netics of migraine; (ii) the mechanisms of migraine head-ache, focusing on the roles of meningeal inammation,calcitonin gene-related peptide (CGRP), central sensitiza-tion, and dysfunctional central control of pain; and (iii) themechanisms of the primary brain dysfunction(s) leading toepisodic activation of the trigeminovascular pain pathway.We also discuss insights into these mechanisms obtainedfrom the functional analysis of mouse models of familialhemiplegic migraine (FHM), a rare monogenic autosomaldominant form of MA.
Genetics of migraine
Migraine
is
a
complex
genetic
disorder,
with
heritability estimates as high as 50% and probable polygenic multifac-torial inheritance [16,17] . The complexity of the diseasehas hampered the identication of common susceptibility variants; the lack of consensus on most of the identiedsusceptibility loci probably reects clinical and geneticheterogeneity [16,17] .
Most of our current understanding of genetic factorsunderlying migraine comes from studies of FHM. Threecausative genes, all encoding ion channels or transporters,have been identied [16,1821] . Additional FHM genescertainly exist and remain to be identied [22] . Apart fromthe motor weakness or hemiparesis during aura, typicalFHM attacks resemble MA attacks (Table 1 ) and both
Review
Corresponding author: Pietrobon, D. ( [email protected] ). Keywords: migraine; trigeminovascular pain; spreading depression; excitatoryinhibitory balance; channelopathy..
0166-2236/$ see front matter 2012 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.tins.2012.04.007 Trends in Neurosciences, August 2012, Vol. 35, No. 8 507
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types of attacks may alternate in patients and co-occurwithin families, suggesting that FHM and MA may be partof the same spectrum and may share some pathogeneticmechanisms. Some FHM patients can also have atypicalsevere attacks and/or permanent cerebellar symptoms[16,21] .
FHM1 is caused by missense mutations in CACNA1A ,the gene encoding the pore-forming subunit of neuronalCa V 2.1 (P/Q-type) voltage-gated calcium channels [18,23] .These calcium channels are widely expressed in the ner- vous system, including all brain regions implicated in thepathogenesis of migraine. Ca V 2.1 channels play a domi-nant role in controlling neurotransmitter release, particu-larly at central synapses. Their somatodendriticlocalization points to additional postsynaptic roles, suchas in neural excitability [23,24] .
Analysis of the single channel properties of mutant re-combinant human Ca V 2.1 channels and of the P/Q-typecalcium current in different neurons [including corticaland trigeminal ganglion (TG) neurons] of knockin mice
carrying FHM1 mutations revealed that the mutationsproduce gain-of-function of Ca V 2.1 channels, mainly dueto increased channel open probability and channel activa-tion at lower voltages [23,2531] . However, the gain-of-function effect may be dependent on the specic Ca V 2.1splice variant and/or auxiliary subunit [32,33] . In TG neu-rons of FHM1 knockin mice the P/Q-type calcium currentwas increased in a subtype of neuron (that does not inner- vate the dura) but was unaltered in capsaicin-sensitiveneurons innervating the dura; congruently, the FHM1 mu-tation did not alter depolarization-evoked CGRP releasefrom the dura, but increased CGRP release from trigeminalganglia [31] . In the cerebral cortex of FHM1 knockin mice,excitatory synaptic transmission was enhanced as a conse-quence of increased action potential-evoked glutamaterelease at pyramidal cell synapses; in striking contrast,inhibitory neurotransmission at fast-spiking (FS) interneu-ron synapses was unaltered (despite being initiated by P/Q-type calcium channels) [26] (Figure 2a). Neuron sub-type- and synapse-specic effects may help to explain why a
(a) (b) Efferent modulatory pathways
TG
TCC
RVM
vlPAGNCF
A11PH
S1 Ins
TNCC1,C2
Afferent pathways
Dura mater
Cerebralcortex
Pia mater
TCC
RVM
vlPAGNCF
S1 S2 Ins
TNCC1,C2
SSN
VPMPo
Hypothalamus
Thalamus
TG
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Figure 1 . Schematic illustration of important neuronalstructures and connections in the trigeminovascular pathways involvedin migraineheadache. (a) Afferent pathways.The central projections of the trigeminal ganglion (TG) neurons that innervate the meninges terminate in the so-called trigeminocervical complex (TCC) comprising the C1C2 dorsalhorns of thecervical spinalcord and thecaudal division of thespinal trigeminal nucleus (TNC) (C-fibersmainly in superficial layers; A- d fibersin deep layers). TheTCC makes direct ascending connections with different areas in the brainstem (including the superior salivatory nucleus, SSN, the ventrolateral periacqueductal grey,vlPAG, the nucleus cuneiformis, NCF) and with higher structures including several hypothalamic and thalamic nuclei, which in turn make ascending connections with thecortex [99,144,145] . 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 neurons in several bra instem (e.g ., SSN, vlPAG, rostral ventromedial medul la, RVM), hypo thalamic and tha lamic ( in part icu lar theventroposteriomedial, VPM and posterior, Po) nuclei receiving connections from the TCC [60,73,92,105,111] ([5,99] for review and older references ). Dura-sensitive VPMthalamic neurons project mainlyin thetrigeminal primary andsecondary somatosensory (S1, S2)and theinsular (Ins) cortex(in theso-called pain matrix areas), andthusarelikely to play a role in the perception of the headache; whereas trigeminovascularPo thalamic neurons project well beyond the pain matrix into non-trigeminal S1,aswell as auditory, visual, retrosplenial, ectorhinal, and parietal association cortices, and thus are likely to contribute to other aspects of the migraine experience whichinclude disturbances in neurological functions involved in vision, auditory, memory, motor, and cognitive performance [105,145] . The trigeminovascular projections to
specific hypothalamic and brainstem nuclei are likely to contribute to other aspects of the complex migraine symptomatology such as loss of appetite, sleepiness,irritability, stress, pursuit of solitude, and autonomic symptoms [99] . (b) Efferent modulatory pathways. The TCC receives descending projections from brainstem andhypothalamic nociceptive modulatory nuclei that may mediate descending modulation of trigeminovascular nociceptive traffic [99] . Experimental evidence of modulationof TCC response to dural stimulation has been obtained for vlPAG, the nucleus raphae magnus in the RVM, the posterior hypothalamus (PH) and the A11 dopaminergichypothalamic nucleus (reviewed in [99] ). The TCC also receives descending cortical projections from layer 5 pyramidal cells of the contralateral S1 (innervating mainlyneurons in deeplaminaeIIIV) and caudal Ins cortex (innervating exclusively laminae I and II) [111] . It shouldbe noted that there areother afferent and efferent connections:this diagram only illustrates those mentioned in the text.
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calcium channel that is widely expressed in the nervoussystem produces the specic dysfunctions that cause FHM(the implications for specic migraine mechanisms are dis-cussed in the sections following).
FHM2 is caused by (mainly missense) mutations in ATP1A2 , the gene encoding the a 2 subunit of the Na + /K +
ATPase [16,19] . In the brain, this isoform is expressedprimarily in neurons during embryonic development andat time of birth but almost exclusively in astrocytes in theadult; its colocalization and functional coupling with glialglutamate transporters in astrocytic processes surround-ing glutamatergic synapses suggests a specic role inglutamate clearance [3436] (Figure 2a), whereas its colo-calization with the Na + /Ca 2+ exchanger in microdomains
that
overlie
subplasmalemmal
endoplasmic
reticulum
sug-gests a specic role in the regulation of intracellular Ca 2+
[21] . FHM2 mutations cause complete or partial loss-of-function of recombinant Na + /K + ATPases due to loss orreduction of catalytic activity (and/or more subtle function-al impairments) or impairment of plasma membrane de-livery [21,3739] . The a 2 Na + /K + ATPase protein wasbarely detectable in the brain of homozygous FHM2knockin mice and strongly reduced in the brain of hetero-zygous mutants [39] .
FHM3 is caused by missense mutations in SCNA1A , thegene encoding the pore-forming subunit of neuronalNa V 1.1 voltage-gated sodium channels [16,20] ; these chan-nels are highly expressed in particular inhibitory inter-neurons where they play an important role in sustaining high-frequency ring [40] (Figure 2 a). Conicting ndingswere obtained from the analysis of mutant recombinanthuman Na V 1.1 channels expressed in non-neuronal cells,pointing to either gain- or loss-of-function effects of FHM3mutations [41,42] . Given the evidence that an epilepsy-causing mutation produced opposite effects on recombi-nant Na V 1.1 channels and native Na V 1.1 channels inneurons of mouse models [40] , functional analysis inFHM3 mouse models appears necessary to shed lighton FHM3 mechanisms.
Whereas most genetic studies indicate that the FHMgenes (except perhaps for ATP1A2 ) are not involved in
common migraines [16,21] , some homozygous mutations in SLC4A4 (the gene encoding the electrogenic Na + /HCO 3cotransporter NBCe1) were recently found to be associatedwith either hemiplegic migraine, MA, or migraine withoutaura (MO), depending on the mutation [43] . Only muta-tions producing near total loss-of-function of the transport-er expressed in glioma cells were associated with migraine,supporting a causative role and the view that hemiplegicand common migraine represent a phenotypic spectrumthat may share at least some genetic basis [43] (Figure 2 a).
A loss-of-function frameshift mutation in KCNK18 [thegene encoding the weakly inward rectifying K + channel(TWIK)-related spinal cord potassium channel (TRESK)],cosegregated perfectly with typical MA in a large multi-
generational
family
[44] . TRESK
channels
are
two-pore-domain K + channels that are broadly expressed in thenervous system, with particularly high expression in TG,where they probably play an important role in control of neuronal excitability [44] . However, a mutation leading tocomplete loss-of-function of the TRESK channel was re-cently found in both migraine and control cohorts, indicat-ing that non-functional TRESK channels are not sufcientto cause typical migraine alone [45] .
Recent genome-wide association studies have identieda few risk factors for both MA and MO that map within ornear transcribed regions of interesting genes. These in-clude metadherin ( MTDH ), a gene that regulates the ex-pression of GLT-1 [46] , an astrocyte glutamate transporterthat plays a major role in removal of glutamate at gluta-matergic synapses [47] , and TRPM8 [48] , a gene thatencodes a cation channel expressed primarily in sensory neurons and that is involved in cold-sensing [49] .
Taken together, genetic ndings suggest that migraineis a nervous system disorder characterized by alteredsynaptic (in particular glutamatergic) transmission and/ or altered neuronal excitability.
Mechanisms of migraine headacheBased on a large body of indirect evidence, it is believedthat the development of migraine headache depends on theactivation and sensitization of trigeminal sensory afferents
Table 1. Main features of migraine without aura (MO), migraine with aura (MA), and familial hemiplegic migraine (FHM)Type Headache symptoms Aura symptomsMO Headache attacks (472 h in duration)
with at least two of:Unilateral locationThrobbingModerate or severe pain intensityAggravation by physical activity
And at least one of:Nausea and/or vomitingPhotophobia and phonophobia
None
MA Headache as in MO begins duringthe aura or follows aura (within 1 h)
At least one of:Fully reversible visual symptoms (e.g., ickering lights, spots, lines and/or loss of vision)Fully reversible sensory symptoms (i.e., pins and needles and/or numbness)Fully reversible dysphasic speech disturbance
Each aura symptom lasts 5 and 60 minFHM Headache as in MA Fully reversible motor weakness and at least one of the MA aura symptoms
Each aura symptom lasts 5 min and < 24 h
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that innervate cranial tissues, in particular the meningesand their large blood vessels [57] (Figure 1 a). The sensi-tization of mechanosensitive meningeal afferents providesa mechanism that may explain the throbbing nature of themigraine headache (typically attributed to arterial pulsa-tion) as well as the exacerbation of the headache during events that increase intracranial pressure [50] . The pri-mary mechanism(s) leading to activation and sensitizationof the perivascular trigeminal nociceptors remain incom-pletely understood and controversial, particularly in thecase of MO.
Vasodilation Infusion of vasodilator substances such as CGRP or glyceriltrinitrate (GTN) induce in migraineurs (but not in healthy subjects) a delayed migraine attack indistinguishable fromthe spontaneous attacks [51] . However, there is growing evidence that vasodilation of meningeal and/or extracrani-al arteries is neither necessary nor sufcient to causemigraine pain in most patients [52] . In contrast to aprevious study showing lack of signicant dilatation of extracranial and intracranial arteries during GTN-induced migraine [53] , a 912% dilatation of extracranial
(a)
(b)
N a +
HCO3
-
Astrocyte
Na V1.1?
H
Na
GABA AR
Ca V2.1
Inhibitory FS interneuron synapseExcitatory PC synapse
GluR NMDAR
Ca V2.1
FHM1
FHM3
Astrocyte
Na +G L U N a + , H +
K +
K +
Na +
H C O3
-
2 Na+,K+
ATPaseFHM2
FHM4 ? Na+, HCO 3
-
cotransporter
FHM1
FS interneuron
PC PC
FS interneuron
++
++
++
++
+ +
+ +
TRENDS in Neurosciences
Figure 2 . Differential alteration of cortical excitatory and inhibitory synaptic transmission in FHM. (a) In FHM1, gain-of-function of presynaptic Ca V 2.1 channels leads toenhanced action potential-evoked glutamate release and enhanced excitatory synaptic transmission at cortical pyramidal cell (PC) synapses (left panel); inhibitory synaptictransmission at FS interneuron synapses is unaltered, despite being initiated by Ca V 2.1 channels (right panel) [26] . In FHM2, given the specific colocalization and functionalcoupling of a 2 Na + /K+ pumps with glial glutamate transporters in astrocyte processes surrounding excitatory, but not inhibitory, synapses, loss-of-function of the pumpmight impair glutamate clearance and lead to specific gain-of-function of excitatory transmission, particularly NMDA receptor (NMDAR)-mediated transmission duringhigh-frequency action potential (AP) trains [39] . A decreased capacity of astrocytes to buffer activity-dependent extracellular alkalosis as a consequence of loss-of-functionof the Na + /HCO3 cotransporter NBCe1 has been proposed to also lead to enhanced NMDAR-mediated excitatory synaptic transmission [43] . The consequences of FHM3mutations on Na V 1.1 channels in FS interneurons, where they are highly expressed, remain unknown. (b) Schematic representationof theeffect of FHM1 mutations on thespecific cortical subcircuit involving recurrent excitatory synapses between PCs and reciprocal excitatory and inhibitory synapses between PCs and FS interneurons.Synaptic transmission is enhanced at excitatory synapses (as indicated by the thicker connection in the right panel compared to the left panel) but is unaltered at theinhibitory synapsesin FHM1 mouse models [26] . One predicts that the gain-of-function of glutamate release at the recurrent synapsesbetweenPCs would certainlyincreasenetwork excitation. By contrast, the gain-of-function of glutamate release at the synapses onto FS interneurons (PCFS synapses) would lead to enhanced recruitment of interneuronsand enhancedinhibition.However, during high-frequency repetitive activity the enhancedrecruitment of FS interneuronsis expectedto ceaserapidlybecausethePCFS synapses have been shown to depress stronglyduring AP trains(muchmore than therecurrent PCPC synapses), and short-term depression waseven strongerin FHM1 knockin mice, particularly at PCFS synapses (whereas short-term plasticity at the inhibitory FSPC synapses was unaltered) [26] . This analysis, despite beingrestricted to a specific subcircuit, makes the important point that the differential effects of FHM1 mutations on excitatory and inhibitory neurotransmission may produce
overexcitation in certain brain conditions, but may leave the E/I balance within physiological limits in others, which is consistent with the episodic nature of the disease.
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and intracranial arteries was recently measured in CGRP-induced migraine; this modest vasodilation is probably insufcient to activate the perivascular afferents but mightaffect sensitized nociceptors [54] .
Meningeal inammation Based on a large body of indirect evidence from both
clinical
and
animal
studies,
sterile
meningeal
inamma-tion is considered to be a key mechanism that may activateand sensitize perivascular meningeal afferents and lead tomigraine pain [7,55,56] . Indirect clinical evidence is pro- vided by the increased level of various inammatory med-iators in the cephalic venous outow during spontaneousmigraine attacks and by the efcacy of nonsteroidal anti-inammatory drugs in the acute treatment of migraine inmany patients [7,55,56] . In experimental animals, activa-tion of meningeal nociceptors in vivo leads to release of vasoactive proinammatory peptides (such as CGRP andsubstance P) from their peripheral nerve endings. Thesepeptides result in vasodilation of meningeal blood vessels(mainly due to CGRP), plasma extravasation, and localactivation of dural mast cells (MCs), with ensuing releaseof cytokines and other inammatory mediators (resulting in neurogenic inammation, NI) [5,7] . The dural trigemi-nal afferents exhibit properties characteristic of nocicep-tors in other tissues, including chemosensitivity andsensitization [7,31,50,57,58] . In vivo , most dural afferentswere activated and sensitized by an inammatory soup(IF) applied to the dura; nearly all IF-sensitive duralafferents were mechanosensitive and their mechanosensi-tivity was enhanced by IF [59] . Chemical inammation of the dura produced facial and hind-paw cutaneous allody-nia in awake behaving animals [60] , with a time-course of development that is consistent with that seen in migraine
patients [61] . The pharmacology of the IF-induced allody-nia in animals shows important parallels with the clinicalpharmacology of migraine pain [60] . Further support to theinammation hypothesis is provided by the evidence thatdural MC degranulation per se can produce a long-lasting activation and sensitization of rat dural nociceptors [62] , aswell as cephalic tactile hypersensitivity [63] .
However, the endogenous processes that promote men-ingeal inammation and peripheral sensitization during migraine attacks remain incompletely understood. Many investigators consider the NI produced by release of vaso-active proinammatory neuropeptides following activationof peptidergic meningeal nociceptors (by CSD or otherdifferent primary mechanisms; next section) as the endog-enous inammatory process that sustains the activationand causes the long-lasting sensitization of meningealnociceptors in many migraine attacks. Indeed, measure-ments of CGRP levels in the external and internal jugular venous blood have provided evidence that CGRP isreleased during migraine attacks [6466] . Consistent withthe NI hypothesis is also the recent evidence that theheadache-triggering substances ethanol and umbellolone(the major volatile constituent of the Californian headachetree) both activate peptidergic meningeal trigeminalafferents, causing CGRP release and neurogenic durainammatory responses in experimental animals [67,68] .However, direct evidence that the release of inammatory
molecules associated with NI is able to sensitize meningealnociceptors is lacking.
In certain types of migraine, endogenous processesdifferent from NI, and not requiring initial activation of meningeal nociceptors, might promote meningeal inam-mation and cause sensitization, ensuing long-lasting acti- vation of meningeal nociceptors. These processes may
include
direct
activation
of
dural
MCs
by
several
exoge-nous and endogenous migraine triggers, as was shown tooccur in vitro [7,56,69] . They may also include the release of inammatory mediators from brain parenchyma (e.g., as aconsequence of CSD) and/or from meningeal blood vesselsor immune cells, which might directly sensitize meningealnociceptors.
Central sensitization After headache onset, about two-thirds of migrainepatients develop cutaneous allodynia in the periorbitalregion that may spread to extracephalic regions [70,71] .Clinical observations and animal studies support the ideathat facial allodynia reects sensitization of trigeminovas-cular neurons in the trigeminocervical complex (TCC)which receive convergent input from the meningeal noci-ceptors and facial skin [5,70,72] . Extracephalic allodyniareects sensitization of trigeminovascular thalamic neu-rons that process converging sensory information from thecranial meninges and extracephalic skin [5,70,73] . More-over, these studies are consistent with the idea that initia-tion, but not maintenance, of central sensitization dependson the afferent input from sensitized meningeal nocicep-tors [5,61,70,72] . A recent study in rats points to theactivation of the descending facilitatory pathway arising from the rostral ventromedial medulla (RVM) (Figure 1 b)as a key central mechanism involved in IF-induced central
sensitization of trigeminovascular neurons [60] . Function-al magnetic resonance imaging (fMRI) studies in humansubjects indicate that the periacqueductal grey (PAG) andnucleus cuneiformis (NCF), the major sources of input tothe RVM (Figure 1 b), are involved in central sensitizationin humans [74] and that the NCF is hypofunctional inmigraine patients [75] . Interestingly, positron emissiontomography (PET) studies revealed activation of similarareas in the dorsal rostral brainstem during migraineattacks [76] .
CGRP Several ndings support a pivotal role of CGRP inmigraine, including (i) the effectiveness of CGRP receptorantagonists in migraine treatment [77,78] and (ii ) theinduction of a delayed migraine-like headache by intra- venous CGRP administrat ion in a large fraction of mi-graine patients but not in controls [79] , suggesting thatmost migraineurs are hypersensitive to CGRP-mediatedmodulation of nociceptive pathways. However, the mech-anisms underlying this hypersensitivity, the mechanismsof action of CGRP during a migraine attack, and the exactsites of action of CGRP receptor antagonists remainunclear and controversial [6466] . The localization of CGRP receptors in the trigeminovascular system pointsto multiple possible mechanisms at both peripheral andcentral sites [80] .
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In the periphery, CGRP receptors are expressed in blood vessels, Schwann cells and dural MCs at the meninges andin glial satellite cells and a subpopulation of TG neurons inthe TG [80,81] . A relevant role of CGRP-induced dural vasodilation in migraine is unlikely in view of the evidencethat topical or systemic CGRP does not activate or sensi-tize rat dural afferents [82] and the evidence that vasodi-
lation
is
neither
necessary
nor
sufcient
to
triggermigraine [52] . CGRP-induced dural MC degranulationmight contribute to maintaining an inammatory cycleat the dura. Consistent with this idea are animal studiesshowing that dural MC degranulation (as well as topicalapplication of some individual MC mediators to the dura)preferentially activate and sensitize mechanosensitive Cunits, most of which express CGRP [62,83] , and increaseCGRP release from capsaicin-sensitive dural afferents[84] . The facilitation of CGRP-induced dural vasodilationand/or MC degranulation does not seem to contribute toheadache generation in FHM1 because depolarization-evoked CGRP release from the dura was unaltered inFHM1 knockin mice [31] .
It has been suggested that CGRP-mediated intragan-glionic crosstalk between neurons and satellite glial cells,may promote and maintain a neuron-glia inammatory cycle, that may contribute to persistent peripheral trigem-inal sensitization [64,66] . This suggestion is mainly basedon the evidence that prolonged application of CGRP tocultures of TG neurons and/or satellite glial cells leads toincreased gene expression and/or membrane targeting of specic receptors (e.g., P2X 3 ) in neurons and to increasedexpression of inammatory genes and release of inam-matory mediators from satellite glial cells; these inam-matory mediators can sensitize TG neurons and act back on glial cells further activating them [8590] . It remains
unclear whether similar phenomena indeed occur withinthe TG upon prolonged activation of meningeal nociceptorsin vivo . If they do, they might be facilitated in FHM1, assuggested by ndings in TG neurons of FHM1 knockinmice, that show enhanced P2X 3 receptor activity [91] andenhanced CGRP release from intact trigeminal gangliaand/or cultured neurons [31,90] . Moreover, there is someevidence that facilitation of CGRP-mediated neuron to gliacrosstalk may occur in cultured TG neurons from FHM1knockin mice following exposure to proinammatory sti-muli [90] .
Within the central trigeminovascular system, expres-sion of CGRP receptors has been shown in the trigeminalnucleus caudalis (TNC, laminae III, in a ber network forming irregular glomeruli-like structures but not in sec-ond-order neurons) [80] , and in some neuronal cell bodiesin the ventroposteromedial (VPM) nucleus of the thalamus[92] (Figure 1a). Functional studies indicate that activa-tion of TNC presynaptic CGRP receptors may lead topotentiation of excitatory neurotransmission [93,94] . Thepossibility of central mechanisms of CGRP action during amigraine attack is indirectly supported by animal studiesshowing that systemic CGRP does not activate or sensitizedural afferents [82] . Furthermore, high doses of systemicCGRP receptor antagonists reduce the activity of TNCneurons [95] and VPM thalamic neurons [92] evoked by stimulation of dural afferents, as well as the number of
Fos-positive neurons in TNC (laminae III) after intrave-nous infusion of capsaicin [96] . However, given the very poor permeability of the bloodbrain barrier to CGRP[97,98] , it seems difcult to explain how CGRP infusioncan cause a migraine attack if one excludes a peripheralrole of CGRP.
Dysfunctional
central
control
of
pain Direct evidence in the clinical setting for increased activity of trigeminal neurons during migraine is lacking and aconsistent cephalic pathology has not been detected.Therefore, some investigators propose the alternative viewthat migraine headache arises from dysfunction withinsubcortical brainstem and diencephalic nuclei that modu-late trigeminal nociceptive inputs (Figure 1 b). Dysfunctionin these nuclei (in particular in the PAGRVM circuitry)would lead to abnormal central interpretation of normalsensory input in the trigeminovascular system, causing normal sensory trafc from the meninges to be perceived asmigraine pain [99,100] . Functional imaging studies show-ing increased cerebral blood ow in the dorsal rostralbrainstem and in the hypothalamus during migraineattacks [76,101] are considered to provide indirect supportfor this view [99] . However, it appears more likely thatthese brainstem areas function as migraine headachemodulators rather than generators because their activa-tion does not seem specic for migraine pain [101,102] .Moreover, a recent fMRI study showed activation of dorsalrostral brainstem areas only during the migraine attack and not during the preictal phase [103] . Dysfunction inbrainstem nuclei involved in central control of pain andcentral sensitization [75,104] may lead to hyperexcitability of central trigeminovascular pathways and contribute tothe development of migraine headache. Evidence from
clinical and animal studies that questions the notion thatabnormalities in the PAGRVM circuitry (or other des-cending mechanisms of pain inhibition) can generate mi-graine headache in the absence of peripheral sensory inputhas been discussed in recent reviews [6,7] .
Photophobia A large fraction of migraineurs experience exacerbation of headache by light (i.e., photophobia). A neural mechanismfor migraine photophobia has been recently uncovered[105] . It has been shown that dura-sensitive thalamicneurons in the rat posterior thalamus receive monosynap-tic input from retinal ganglion cells (mainly intrinsically photosensitive cells involved in non-image-forming func-tions) and that light enhances the activity of dura-sensitivethalamic neurons located in the same area (Figure 3). Theidea that a non-image-forming retinal pathway is involvedin migraine photophobia is supported by the nding thatexacerbation of headache by light was preserved in blindmigraineurs who could sense light in the face of severedegeneration of rod and cone photoreceptors [105] .
Primary brain dysfunctions in migraineThe nature and mechanisms of the primary brain dysfunc-tion(s) leading to episodic activation of the trigeminovas-cular pain pathway remain incompletely understoodand controversial. Given the wide genetic and clinical
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heterogeneity of the disorder, different primary mecha-nisms of migraine onset probably exist.
CSD Increasing evidence from animal studies support the ideathat CSD, the underlying mechanism of aura, can activatetrigeminal nociception and thus trigger the headachemechanisms. A direct nociceptive effect of CSD has beendemonstrated by the nding that a single CSD can lead to a
long-lasting
increase
in
ongoing
activity
of
dural
nocicep-tors and central trigeminovascular neurons in supercialand deep laminae of the TCC [106,107] . In most neurons,activation occurred with a delay consistent with that be-tween the onset of visual aura and the onset of headache;the delay as well as the magnitude and duration of neuro-nal activation were similar in peripheral and central neu-rons, suggesting that CSD-evoked activity of meningealnociceptors is sufcient to activate the central neurons.Immediate neuronal activation by CSD was observed in afraction of neurons, mainly C nociceptors and exclusively laminae I, II TCC neurons. This suggests that it might bemediated by peptidergic nociceptors with axon collateralsextending to the pia, where immediate activation could bemediated by increased K + or other noxious mediatorsreleased in the wake of the CSD wave. This hypothesisis supported by the demonstration that CSD-inducedCGRP release from perivascular trigeminal bers contrib-utes to the transient dilation of pial vessels measuredduring CSD [108] . The mechanism of the long-lasting and, in most neurons, delayed neuronal activation remainsunknown. One possibility is that release of proinamma-tory neuropeptides in the dura promotes NI that sustainsthe activation of meningeal nociceptors and leads to theirsensitization [7,106,107,109] . This idea is supported by thending of CSD-induced plasma protein extravasation fromdural blood vessels, which was abolished by trigeminal
nerve section [109] (but see [63,110] ). Different mecha-nisms that may potentially explain the delayed activationof dural afferents are discussed in [63] . The CSD-inducedactivation of central TCC neurons might be further modu-lated via direct cortexTCC connections, because it hasbeen shown that the reduction of cortical activity in pri-mary somatosensory and insular cortical areas following CSD results in reduced and enhanced responses of TCCneurons to noxious electrical stimulation of the dura,
respectively
[111] . Possibly,
this
top-down
modulation
of meningeal nociception may help to explain why somepeople experience migraine aura without headache.
In general, it remains unclear whether the activation of the trigeminovascular system induced by a CSD is sufcientto elicit the perception of headache in patients. It has beensuggested that it may not be sufcient on the basis of theobservation that freely moving rats do not seem to experi-ence CSD as being aversive because they do not show painbehavior [112,113] or cutaneous allodynia [114] aftera CSD(but see [115] ). The idea that CSD may trigger the headachemechanisms is indirectly supported by the nding that theelectrical stimulation threshold for induction of CSD in therat cortex increases after chronic treatment with ve differ-ent migraine prophylactic drugs thatareequally effective inreducing the frequency of MA and MO attacks [116] . More-over, two drugs ineffective in migraine prophylaxis did notaffect susceptibility to experimental CSD [116,117] . Howev-er, this correlation between inhibition of CSD and effective-ness in migraine prophylaxis does not appear to hold for twoother drugs (although larger clinical trials appear necessary for a denite conclusion) [118,119] .
The analysis of experimental CSD in FHM knockinmouse models has strengthened the view of CSD as akey migraine trigger by demonstrating that both FHM1and FHM2 knockin mice show a lower electrical stimula-tion threshold for CSD induction and a higher velocity of
Dura sensitive ( n = 20)
(a) (b)
3.60 4.16 4.52
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Figure 3 . A neural mechanism for exacerbation of migraine headache by light. (a) Extracellular single-unit electrophysiological recordings in deeply anesthetized ratsrevealed 20 neurons in the posterior thalamus that responded to stimulation of the dura, 14 of which were also photosensitive [105] . On average, dura-sensitive neuronsincreased their mean firing rate about twofold in responseto ambient fluorescence light (500 lux) and fourfold in response to bright light (50000 lux), By contrast, thalamicneurons unresponsive to stimulation of the dura were also unresponsive to light. (b) Histological analysis of the recording sites indicated that most dura/light-sensitive
neurons were localized at or above the dorsal border of the posterior thalamic nuclear group. Adapted, with permission, from [105] . LDVL, laterodorsal thalamic nucleus,ventrolateral; LPMR, LPLR, LPMC and LPLC, lateral posterior thalamic nuclei, mediorostral, laterorostral, mediocaudal and laterocaudal respectively; Po, posterior thalamicnuclear group; VPM, ventral posteromedial thalamic nucleus; VPL, ventral posterolateral thalamic nucleus; PLi,posterior limitans thalamicnucleus; PoT, posterior thalamicnuclear group, triangular; APT, anterior pretectal nucleus.
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CSD propagation [27,28,39] (Figure 4a). In FHM1 knockinmice carrying the mild R192Q or the severe S218L muta-tion, the strength of CSD facilitation as well as the severity of the post-CSD neurological motor decits and the pro-pensity of CSD to propagate into subcortical structureswere all in good correlation with the strength of the gain-of-function of the Ca V 2.1 channel and the severity of theclinical phenotype produced by the two FHM1 mutations[27,28,120122] . The velocity of propagation and the fre-quency of CSDs, elicited by continuous epidural high KClapplication, were larger in female than in male FHM1mouse mutants, in agreement with the higher femaleprevalence of migraine; the sex difference was abrogatedby ovariectomy and enhanced by orchidectomy, suggesting that female and male gonadal hormones exert reciprocaleffects [121,123] . However, no gender differences in the
electrical threshold for CSD induction and the velocity of CSD propagation were found in FHM2 knockin mice [39] . Although FHM3 mouse models are not available, thereport that FHM3 in two unrelated families cosegregateswith a new eye phenotype with clinical features similar toexperimental spreading depression in retina [124] sug-gests that, probably, the ability to facilitate CSD is alsoshared by FHM3 mutations. Moreover, a lower electricalthreshold for CSD induction and increased velocity of CSDpropagation were measured in a mouse model of cerebralautosomal dominant arteriopathy, a systemic vasculopa-thy associated with 5-fold increased incidence of MA [125] .
Despite the strong support provided by animal studies,the idea that CSD may initiate the headache mechanismsin migraine (particularly in MO) is not generally accepted,mainly because it seems unable to explain some clinical
(a)
(b)
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t y ( m m . m
i n - 1 )
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h o l d ( m i c r o
C )
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l o c i
t y ( m m
/ m i n )
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Figure4 . FHM mutations facilitate theinduction and the propagation of CSD. (a) Theanalysis of the thresholdfor initiation and therate of propagation of CSD, induced inanesthetizedmice by electrical stimulation of the visual cortex through a bipolar electrode, revealeda lower electrical stimulation threshold and a higher rateof propagationin both FHM1 and FHM2 knockin mice compared with wild-type (WT) mice [27,28,39] . Panel (i) shows the location of the stimulating and recording electrodes andrepresentative CSD recordings at sites 1 and 2 in WT and homozygous FHM1 knockin (KI) mice carrying the R192Q mutation; stimulation current pulses of increasingintensitywereapplied at 5 mininterval until a CSDwas observed (the chargedeliveredwith thefirststimulation elicitinga CSDwas taken as theCSD threshold). (ii) A lowerCSD threshold and a higher rate of CSD propagation were measured in KI mice carrying two different human FHM1 mutations (R192Q, causing typical FHM attacks, or
S218L,causing a severe hemiplegic migraine syndrome that is associated with ataxia, seizures, coma andsevere brain edemaoften triggeredby only a
mild head trauma)[27,28] . S218L KI mice showedbotha lowerthreshold forCSD inductionand a fasterrateof CSDpropagation compared with R192QKI mice.The facilitation of CSDwas alsodemonstratedto be dosage-dependent, with moresignificantdifferences observedin micehomozygous for the S218L KI comparedwith heterozygotes. (iii) Similar findingswere observed in KI mice carryingthe humanFHM2 mutationW887R [39] . Adapted, with permission, from [27] (i), [28] (ii) and [39] (iii). (b) The facilitation of induction andpropagation of CSD in acuteslices of somatosensory cortex of R192Q KI micewas completely eliminated whenglutamate release at pyramidal cellsynapseswas reduced toWT values using a subsaturating concentration of thespecific P/Qchannel blocker v -AgaIVA (Aga) [26] . (i) Pressure-ejection pulses of high KCl of increasing duration wereapplied at 8 mininterval through a glass micropipette on layer 2/3of acute slices of somatosensory cortexuntila CSD wasrecorded in a pyramidal cell at 600 mm from thepressure-ejection pipette; the duration of the first pulse eliciting a CSD was taken as the CSD threshold, and the rate of horizontal spread of the change in intrinsic opticalsignal as the velocity of CSD propagation. Similarly to observations made in vivo , the CSD threshold was lower (ii) and the CSD rate of propagation was higher (iii) inKIcompared to WT mice. After perfusion of slices from KI mice with 40nM Aga [a concentration that reduced the evoked EPSC recorded from KI pyramidal cells inmicroculture to the average value recorded from WT pyramidal cells, as shown by the representative traces in (iv) ], the CSD threshold increased (ii) and the CSD velocitydecreased (iii) to values strikingly similar to those measured in WT slices. Adapted, with permission, from [26].
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observations, in particular the lack of a xed relationshipbetween aura and headache [5,9] . The possibility thatsilent CSDs (i.e., CSDs involving areas of the brain thatwould not generate a perceived aura) may initiate theheadache mechanisms in MO is neither proven nor dis-proven by current evidence [5,8,126] . Another argumentthat has been used against the idea that CSD may initiate
the
headache
mechanisms
is
based
on
the
fact
that
in somepatients migraine premonitory symptoms may occur up to1224 h before the onset of the headache and aura, indi-cating that different brain regions are activated well beforethe onset of CSD [12] .
In this context, it is interesting that the interictalneurophysiological abnormalities in sensory informationprocessing, typical of MO and MA patients, are not con-stant but change in intensity in temporal relation to themigraine attack. In most instances, the intensity of the decit reaches the maximal value in the 1224 h beforethe attack (i.e., the same time when the premonitory symptoms appear) and then normalize a few hours beforeand/or during the attack (with the exception of decits inpain processing) [5,14,15,103,127,128] . Neurophysiologicalreactivity to stress, one of the most common migrainetriggers, increases in the period between attacks and ismaximal (and signicantly higher than in healthy sub- jects) 13 d before an attack [127] . These data suggest thatin the brain of migraineurs some intrinsic mechanisms areat work during the pain-free interval that progressively increase the dysfunction in central information processing and increase the susceptibility to migraine triggers and theneurophysiological readiness to generate a migraine at-tack. It seems possible that these mechanisms may lead toboth the premonitory symptoms and, above a certainthreshold of cortical dysfunction and/or in response to
migraine triggers, create the conditions for ignition of CSD (see below).
Dysfunctional regulation of cortical excitationinhibition (E/I) balance and sensory information processing The analysis of interictal cortical excitability using psy-chophysical, electrophysiological, transcranial magneticstimulation (TMS) and fMRI has produced contradictory ndings and interpretations regarding the mechanismsunderlying the abnormal processing of sensory information(including trigeminal nociception) in migraineurs. It isbeyond the scope of the present review to discuss in detailthis very large and controversial literature ([5,14,15] forreviews, and e.g., [129133] for some recent studies).Depending on the study, it has been concluded that eitherthe cortex of migraineurs is hyperexcitable as a conse-quence of either enhanced excitation or reduced inhibition,or that it is hypoexcitable and/or has a lower preactivationlevel possibly due to serotonin hypoactivity and/or inef-cient thalamo-cortical drive. Methodological problems, het-erogeneity of the subjects and/or the time period relative tothe last and next migraine attack, and a lack of detailedunderstanding of the underlying mechanisms involved incentral information processing, probably account for thecontradictory ndings and interpretations.
Interestingly, recent TMS studies in MA patients pointto decient regulatory mechanisms of cortical excitability
and ensuing reduced ability to dynamically maintain thecortical E/I balance and to prevent excessive increases incortical excitation rather than merely hypo- or hyperex-citability as the mechanisms that underlie abnormalsensory processing [134136] . The molecular and cellularmechanisms underlying the abnormal regulation of corti-cal function and its periodicity remain largely unknown.
The
extent
to
which
some
of
the
cortical
and/or
subcorticalalterations are affected by disease duration (e.g., repetitiveCSDs) is also unclear. Equally unclear is the extent towhich the abnormal processing of trigeminal nociceptiveinput reects a primary dysregulation of central sensory processing or central sensitization persisting outside theattack (e.g., [104,137] ).
The functional analysis of FHM knockin mouse mod-els supports the view of migraine as a disorder of brainexcitability characterized by decient regulation of thecortical E/I balance, and gives insights into the possibleunderlying molecular and cellular mechanisms and theirrelationship to CSD susceptibility. It has been shownthat the gain-of-function of glutamate release at synap-ses onto cortical pyramidal cells can explain the facilita-tion of experimental CSD in FHM1 knockin mice [26](Figure 4 b). The data are consistent with, and support amodel of, CSD init iat ion in which Ca V 2.1-dependentrelease of glutamate from cortical pyramidal cell synap-ses and activation of NMDA receptors (and possibly postsynaptic Ca V 2.1 channels) play a key role in thepositive feedback cycle that ignites CSD [26,138,139] .The demonstration that FHM1 mutations may different-ly affect synaptic transmission and short-term plasticity at cortical excitatory and inhibitory synapses (noting thelack of effect at FS interneuron synapses) [26] impliesthat, very probably, the FHM1 mutations alter the neu-
ronal circuits that dynamically adjust the E/I balanceduring cortical activity [140,141] (Figure 2 b). It seemsplausible to hypothesize that these alterations may incertain conditions lead to disruption of the E/I balance,overexcitation (due to excessive recurrent excitatory ac-tivity) and neuronal hyperactivity, that may create con-ditions for the initiation of spontaneous CSDs (e.g., by increasing the extracellular [K + ] above a critical value).Similar mechanisms might underlie the susceptibility to CSD in FHM2, given that loss-of-function of the a 2Na + /K + ATPase might impair glutamate clearance andmainly affect excitatory synaptic transmission [39](Figure 2 a).
Thus, ndings from FHM mouse models suggest thatimpairment of the cortical circuits that dynamically adjustthe E/I balance during cortical activity, due to excessiverecurrent glutamatergic neurotransmission, may underlieboth the abnormal regulation of cortical function and thesusceptibility to CSD in FHM (Figure 5). It is certainly possible that FHM mutations produce parallel dysfunc-tions in subcortical areas that might also contribute tothe altered regulation of cortical function and in generalto the disease in a way that remains to be established (e.g.,by altering cortical neuromodulation by monoaminergicprojections and/or by favoring hyperexcitability of centraltrigeminovascular pathways). In this context, CSDmight represent only one manifestation of fundamental
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alterations
(e.g.,
impairment
of
E/I
balance)
produced
by FHM mutations in different brain areas (Figure 5 ).
Similar mechanisms may underlie the abnormalregulation of cortical (and possibly subcortical) functionin some common migraine subtypes, for which thereis indirect evidence consistent with enhanced corticalglutamatergic neurotransmission [46,136,142] and en-hanced cortico-cortical or recurrent excitatory neuro-transmission [129,130,132,135] . Given the wide clinicaland genetic heterogeneity of migraine, different molecu-lar and cellular mechanisms may well underlie the im-paired regulation of brain function and the susceptibility to CSD in different migraineurs (parallel arrows inFigure 5 ).
Despite recent drug developments, there is a great needfor more efcacious and specic prophylactic migrainemedications [143] . The recent advances in our understand-ing of migraine primary brain dysfunctions support noveltherapeutic strategies that consider cortical E/I dysregula-tion and CSD as key targets of preventive migraine treat-ment. In particular, cortical glutamatergic synapsesappear as key therapeutic targets for novel drugs aimedat counteracting excessive glutamatergic synaptic trans-mission in FHM and some migraine subtypes. Particularly efcacious would be drugs that increase CSD thresholdindependently of the specic cortical dysfunctions under-lying susceptibility to CSD in different migraineurs.
Concluding
remarksTaken together, currently available evidence suggests thatmigraine is a disorder of brain excitability characterized by decient regulation of the E/I balance during corticalactivity. The mechanisms underlying the decient regula-tion of the cortical E/I balance might lead to both (i) thetypical interictal dysfunction in sensory (including trigem-inal nociceptive) information processing, that progressive-ly increases in the period between attacks, and (ii) inparticular conditions, ignition of CSD and activation of the trigeminovascular pain pathway. To verify this hypoth-esis, future studies should investigate the molecular andcellular mechanisms underlying cortical E/I balance dys-regulation and the susceptibility to CSD in migraine, inaddition to how migraine triggers modulate these mecha-nisms. Future research should also elucidate how thecortical and/or subcortical dyfunctions lead to activationand sensitization of the trigeminovascular pain pathway (Box 1 ).
Functional studies in genetic mouse models have begunto unravel the molecular and cellular mechanisms under-lying the dysfunctional regulation of the cortical E/I bal-ance and the susceptibility to CSD in FHM. Thesemechanisms remain largely unknown for the commonforms of migraine, for which the discovery of causativegenes is a key aspect of future research efforts (Box 1 ).Better knowledge of the mechanisms of initiation and
Dysfunctionalsensory
processing
Headache
Aura Activation, sensitizationof the trigeminovascular
pain pathway
Cortical E/I unbalance
Hyperactive cortical circuits
CSD
Migrainetriggers
?
Subcortical areas
?
FHMMigraine
FHM1FHM2
Migraine ?
Glutamatergic synapses
Recurrent excitation
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?
Cortex
Migraine
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Figure5 . Proposed pathophysiological mechanisms in the generation of migraine. It is proposed that migraine is a disorder of brain excitability characterized by deficientregulation of the E/I balance during cortical (and possibly subcortical) activity. In FHM(1,2) and possibly some other migraine subtypes (large blue arrow pathways),excessive recurrent glutamatergic neurotransmission in the cortex (pink boxes) is proposed to lead to alterations in the cortical circuits that dynamically adjust the corticalE/I balance. This results in dysfunctional sensory processing and, under certain conditions (e.g., migraine triggers), in disruption of the E/I balance and neuronalhyperactivity, which creates conditions for ignition of CSD and consequent generation of auraand activation of the trigeminovascular painpathway. Given the wide clinicaland genetic heterogeneity of migraine, different molecular and cellular mechanisms that remain to be elucidated may underlie the impaired regulation of cortical functionandthe susceptibility to CSD in differentmigraine subtypes (asindicated by theparallel thin blue arrow pathways). Theproposed schemealso includesthe possibility that,in both FHMand commonmigraine, dysfunctions in subcortical areas (greenbox) mightcontribute to thealtered regulation of cortical function andto the developmentof migraine headache (e.g., by leading to hyperexcitability of central trigeminovascular pathways).
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propagation of CSD and of CSD facilitation in mousegenetic models will help the development of novel prophy-lactic migraine medications. The understanding of themolecular and cellular mechanisms underlying corticalE/I balance dysregulation in different migraine forms willbe essential for the development of novel prophylacticmedications tailored to distinct therapeutic targets indifferent patients.
Note added in proof As this review went to press, Freilinger et al. [146] pub-lished the ndings of the rst genome-wide associationstudy of migraine without aura (MO). One of the suscepti-bility loci for MO identied in this study appears particu-larly interesting, since it is within the MEF2D gene thatencodes a transcription factor that mediates neuronalactivity-dependent transcription in neurons and plays akey role in many aspects of synapse and neural circuitdevelopment and function [147] .
AcknowledgmentsWe would like to apologize to the many investigators whose work we wereunable to cite due to space limitations. D.P. is supported by grants from
University of Padova (Strategic Project: Physiopathology of Signaling inNeuronal Tissue) and Fondazione Cariparo (Excellence Project: CalciumSignaling in Health and Disease) and acknowledges the support fromTelethon-Italy (GGP06234).
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Box 1. Outstanding questions
Genetics: which genes are involved in common migraine(s) andhow do they cooperate in causing the disease? What are theidentities of the FHM genes that remain to be identified?
Primary brain dysfunctions: although it is clear that most migraineattacks start in the brain, a major general outstanding questionconcerns the nature and mechanisms of the primary brain dysfunc-
tions that cause episodic activation of the trigeminovascular painpathway. To understand the primary brain mechanisms of migraine itseems essential that future studies address the following specificquestions:
( i) How are the cortical circuits that dynamically adjust the E/Ibalance specifically altered in FHM mouse models, and in whichconditions may these alterations lead to disruption of the E/Ibalance in a way that allows CSD ignition?
(ii) What are the molecular and cellular mechanisms underlying thedysfunctional regulation of the cortical E/I balance and theabnormal processing of sensory information, and its periodi-city, in migraineurs? How are they affected by migraine triggersand by repeated attacks?
( iii) Do silent CSDs occur in MO and what are the underlyingmolecular and cellular mechanisms?
Mechanisms of activation and sensitization of the trigeminovascularpain pathway: it is generally recognized that the throbbing migraineheadache is due to long-lasting sensitization of meningeal trigemi-novascular nociceptors (peripheral sensitization) together with, inmost patients, central sensitization of the trigeminovascular painpathway. A major general outstanding question is how the migraineprimary brain dysfunctions lead to activation and sensitization of thetrigeminovascular pathway. Specic questions to address are:(i) What are the mechanisms of the sustained, and in most cases,
delayed activation of dural trigeminal afferents induced by CSDin animal studies? Is NI involved? More generally, is NI theendogenous process underlying peripheral sensitization of meningeal nociceptors? Is a neuronglia inflammatory cycle atthe TG level involved? If other mechanisms are involved, what istheir nature?
(ii) Are subcortical and/or cortical structures that are involved inthe central control of pain dysfunctional in migraine? Whatare the molecular and cellular mechanisms of their specificdysfunctions?
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