All About Migraine

PH75CH16-Pietrobon ARI 9 January 2013 11:25
ANNUAL
REVIEWS Further Pathophysiology of Migraine
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Annual Reviews content online,
including:
Daniela Pietrobon1,2 and Michael A. Moskowitz3
1
• Other articles in this volume Department of Biomedical Sciences, University of Padova and 2 CNR Institute of
• Top cited articles Neuroscience, 35121 Padova, Italy; email: daniela.pietrobon@unipd.it
• Top downloaded articles 3
• Our comprehensive search Neuroscience Center, Departments of Radiology and Neurology, Massachusetts General
Hospital, Harvard Medical School, Boston, Massachusetts 02129;
email: moskowitz@helix.mgh.harvard.edu
Annu. Rev. Physiol. 2013. 75:365–91 Keywords

First published online as a Review in Advance on spreading depression, trigeminovascular system, neurogenic inflammation,
November 26, 2012
excitatory/inhibitory balance
The Annual Review of Physiology is online at
http://physiol.annualreviews.org Abstract
This article’s doi: Migraine is a collection of perplexing neurological conditions in which the
10.1146/annurev-physiol-030212-183717
brain and its associated tissues have been implicated as major players during
Copyright c 2013 by Annual Reviews. an attack. Once considered exclusively a disorder of blood vessels, compelling
All rights reserved
evidence has led to the realization that migraine represents a highly chore-
ographed interaction between major inputs from both the peripheral and
central nervous systems, with the trigeminovascular system and the cerebral
cortex among the main players. Advances in in vivo and in vitro technologies
have informed us about the significance to migraine of events such as cortical
spreading depression and activation of the trigeminovascular system and its
constituent neuropeptides, as well as about the importance of neuronal and
glial ion channels and transporters that contribute to the putative cortical
excitatory/inhibitory imbalance that renders migraineurs susceptible to an
attack. This review focuses on emerging concepts that drive the science of
migraine in both a mechanistic direction and a therapeutic direction.
365
INTRODUCTION
Migraine is a common episodic neurological disorder with complex pathophysiology that manifests
Aura: transient as recurrent attacks of typically throbbing and unilateral, often severe headache with certain
(20–30-min) focal associated features such as nausea, phonophobia, and photophobia. In one-third of patients the
neurological event headache is preceded by transient neurological symptoms that are most frequently visual but may
causing visual and/or
involve other senses and speech [migraine with aura (MA)] (1). Migraine is remarkably common
sensory or speech
disturbance [e.g., it affects 17% of females and 8% of males in the European population (2)], very costly
[$18.5 billion Euros per year in Europe (3)], and disabling [one of the 20 most disabling diseases
Event-related
potentials: according to the World Health Organization (4)]. It is therefore a public health problem of great
stereotypical impact on both the individual and society.
electrophysiological Most migraine attacks start in the brain, as suggested by (a) the premonitory symptoms (e.g.,
brain responses to a difficulty with speech and reading, increased emotionality, sensory hypersensitivity) that in many
motor, cognitive, or
patients are highly predictive of the attack, although such symptoms occur up to 12 h before the
sensory stimulus
attack (5), and by (b) the nature of some typical migraine triggers such as stress, sleep deprivation,
CSD: cortical
oversleeping, hunger, and prolonged sensory stimulation (6). Psychophysical and neurophysio-
spreading depression
logical studies have provided clear evidence that in the period between attacks migraineurs show
Familial hemiplegic
hypersensitivity to sensory stimuli and abnormal processing of sensory information, character-
migraine (FHM):
autosomal dominant ized by increased amplitudes and reduced habituation of evoked and event-related potentials
headache syndrome (7, 8).
accompanied by It is generally believed that migraine headache depends on the activation and sensitization of
paroxysmal attacks the trigeminovascular pain pathway (9–12) and that cortical spreading depression (CSD) is the
that include typical
neurophysiological correlate of migraine aura (10, 13–15). CSD can be induced in animals by focal
migraine auras plus
hemiplegic aura stimulation 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 CSD
remain unclear (16, 17).
The mechanisms of the primary brain dysfunction(s) leading to the onset of a migraine attack,
to CSD susceptibility, and to episodic activation of the trigeminovascular pain pathway remain
largely unknown and the major open issue in the neurobiology of migraine. Other important
open questions concern the mechanisms of initiation, continuation, and termination of migraine
pain.
Migraine is a complex genetic disorder with heritability estimates as high as 50% and with
a likely polygenic multifactorial inheritance (17, 18, 19). The complexity of the disease, which
depends upon the interplay of multiple genes and gene-environment interactions, has hampered
the identification of common susceptibility variants; the lack of consensus on most of the iden-
tified susceptibility loci probably reflects clinical and genetic heterogeneity (17, 18, 19). Re-
cent genome-wide association studies have identified a few risk factors for both MA and mi-
graine without aura (MO) that map within or near transcribed regions of potentially interesting
genes (20–22). However, most of our present molecular understanding of migraine comes from
studies of familial hemiplegic migraine (FHM), a rare, monogenic, autosomal dominant form
of MA (18, 19, 23). Three FHM causative genes, all encoding ion channels or transporters,
have been identified (24–26). Additional FHM genes certainly exist and remain to be identified
(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 episodic
activation of the trigeminovascular pain pathway. We also discuss the insights into those mecha-
nisms obtained from the functional analysis of FHM mouse models.
366 Pietrobon · Moskowitz

MECHANISMS OF MIGRAINE PAIN
Trigeminovascular Pain Pathways

A large body of indirect evidence indicates that the development of migraine headache depends
on the activation and sensitization of trigeminal sensory afferents that innervate cranial tissues, in
particular, the meninges and their large blood vessels (10–12, 28). As discussed by Olesen et al.
(11), whether nociception originates from pial, dural, or extracranial periarterial sensory afferents
remains unclear; all three might be involved, possibly to different extents in different subtypes of
migraine.
In the rat these cranial perivascular fibers have similar central projections terminating in the
so-called trigeminocervical complex (TCC) comprising the C1 and C2 dorsal horns of the cervical
spinal cord and the caudal division of the spinal trigeminal nucleus (TNC); the C-fiber terminals
are located mainly in superficial layers and the A-δ fiber terminals in deep layers (29–31). The
TCC makes direct ascending connections with different areas in the brain stem and with higher
structures, including several hypothalamic and thalamic nuclei, which in turn make ascending con-
nections with the cortex (29–31 and references therein) (Figure 1a). Congruently, stimulation of
the dural afferents in experimental animals results in activation of second-order trigeminovascular
neurons (mainly in laminae I, II, and V) in the TCC, as well as in activation of neurons in several
brain stem [e.g., superior salivatory nucleus, ventrolateral periaqueductal gray (vlPAG), rostral
ventromedial medulla (RVM)], hypothalamic, and thalamic [in particular, the ventroposteriome-
dial (VPM) and posterior (Po)] nuclei receiving connections from the TCC (32–36; cf. References
10 and 30 for review and older references) (Figure 1a).
Dura-sensitive VPM thalamic neurons project mainly in the trigeminal primary and secondary
somatosensory (S1 and S2) cortices and the insular (Ins) cortex (components of the so-called pain
matrix) and are thus likely to play a role in the perception of headache. Trigeminovascular Po thala-
mic neurons project beyond the pain matrix into non–trigeminal S1 cortex, as well as into auditory,
visual, retrosplenial, ectorhinal, and parietal association cortices, and are thus likely to contribute
to other aspects of the migraine experience, which includes disturbances in neurological functions
involved in vision, audition, memory, motor function, limbic function, and cognitive performance
(31, 36). The trigeminovascular projections to specific hypothalamic and brain stem nuclei likely
contribute to other aspects of the complex migraine symptomatology, such as loss of appetite,
fluid 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-sensitive
thalamic neurons in the rat posterior thalamus receive monosynaptic input from retinal ganglion
cells (mainly intrinsically photosensitive cells involved in non-image-forming functions), and light
enhances the activity of dura-sensitive thalamic neurons located in the same area. The idea that
a non-image-forming retinal pathway is involved in migraine photophobia is supported by the
finding that exacerbation of headache by light was preserved in blind migraineurs who could sense
light in the face of severe degeneration of rod and cone photoreceptors (36).
The TCC receives descending projections from brain stem and hypothalamic nociceptive
modulatory nuclei that may mediate descending modulation of trigeminovascular nociceptive
traffic (30) (Figure 1b). Indeed, electrical stimulation of the vlPAG or the nucleus raphae magnus
in the RVM results in inhibition of the response of trigeminovascular TCC neurons to dural
stimulation (37, 38). Moreover, modulation of the response of trigeminovascular TCC neurons
to dural stimulation occurred after injection of orexin A or B or a somatostatin antagonist in
the posterior hypothalamus (39, 40) and after electrical stimulation of the A11 dopaminergic
www.annualreviews.org • Migraine 367

a Afferent pathways Dura mater
Pia mater
TG
Cerebral cortex
V1/V2 Cerebral cortex

Au
tA RSA
PtA Corpus
M1/M2 S2 Ins
ns callosum Midbrain
S1
Hippocampus
ippocampus
vlPAG NCF Cerebellum
mus
Thala
Po
VPM
RVM
TNC, C
1, C2
Pons
Hypothalamus SSN TCC
Medulla
b Efferent modulatory pathways
Cerebral Corpus
Ins callosum Midbrain
S1 cortex
Hippocampus
ippocampus
Cerebellum
vlPAG NCF
Thalamus
RVM
TNC, C
A11 1, C2
TCC
Hypothalamus PH Pons
Medulla
Figure 1
Main neuronal structures and connections in the trigeminovascular pathways involved in migraine pain: (a) afferent pathways and
(b) efferent modulatory pathways. This schematic of the pathways within a rodent brain shows only the nuclei and connections
mentioned in the text. The arrows indicate the direction of the information flow. Abbreviations: A11, dopaminergic hypothalamic
nucleus; Au, auditory cortex; Ins, insular cortex; M1/M2, motor cortices; NCF, nucleus cuneiformis; PH, posterior hypothalamus; Po,
posterior thalamic nuclear group; PtA, parietal association cortex; RSA, retrosplenial cortex; RVM, rostral ventromedial medulla; S1
and S2, primary and secondary somatosensory cortices; SSN, superior salivatory nucleus; TCC, trigeminocervical complex (comprising
the C1 and C2 dorsal horns of the cervical spinal cord and the caudal division of the spinal trigeminal nucleus); TG, trigeminal
ganglion; TNC, trigeminal nucleus caudalis; vlPAG, ventrolateral periaqueductal gray; VPM, ventroposteriomedial thalamic nucleus;
V1/V2, visual cortices.
hypothalamic nucleus, a modulation that was reversed by a D2 receptor antagonist (41). Lesioning
of the A11 nucleus resulted in facilitation of dura-evoked firing, suggesting that the A11 nucleus
provides descending tonic inhibitory modulation of trigeminovascular nociceptive traffic (41).
The TCC also receives descending cortical projections from layer 5 pyramidal cells of the
contralateral S1 cortex (innervating mainly neurons in deep laminae III–V) and caudal Ins cortex

(innervating exclusively laminae I and II, strictly contralaterally) (35) (Figure 1b). The direct corti-
cotrigeminal outflow mediated by these cortex-TCC connections may mediate specific top-down
modulation of meningeal nociception; reduction of cortical activity in S1 and insular cortical areas
Inflammatory soup
(following K+ injection that produced CSD) resulted in reduced and enhanced responses, respec- (IF): an acidic mixture
tively, of TCC neurons to noxious electrical stimulation of the dura (35). Interestingly, the response of potassium,
to innocuous mechanical stimulation of periorbital skin was not affected by reduction of cortical prostaglandins,
activity in insula, suggesting selective modulation of nociceptive primary afferent input (35). serotonin, bradykinin,
and histamine that
stimulates and
sensitizes nociceptors,
Meningeal Nociceptors
causing hyperalgesia
Whereas little is known about the response properties of pial trigeminal afferents, the dural affer- CGRP: calcitonin
ents exhibit properties, including chemosensitivity and sensitization, characteristic of nociceptors gene–related peptide
in other tissues (12, 42–47). In vivo recordings have shown that most C-type and slow A-delta-type SP: substance P
rat dural afferents are activated and sensitized by an inflammatory soup (IF) applied to the dura
Transient receptor
(46), and most mechanosensitive C-type guinea pig dural afferents are polymodal nociceptors ac- potential cation
tivated by topical application of capsaicin (47). Similarly, most trigeminal ganglion (TG) neurons channel V1 (TRPV1)
retrogradely labeled from rodent dura were sensitized by IF (43) and expressed acid-sensing ion receptor:
channels (44), and most small-diameter neurons were capsaicin sensitive (45). Immunolabeling receptor implicated in
transducing pain and
experiments have revealed a dense network of dural nerve fibers immunoreactive for calcitonin
scalding heat; also
gene–related peptide (CGRP) and substance P (SP) (48) and extensive colocalization of TRPV1 known as the capsaicin
receptors and CGRP in small-diameter rat dural fibers (49). CGRP and SP immunoreactivities or vanilloid receptor
in the dura and around pial vessels were almost completely eliminated by intravenous capsaicin
in guinea pig (50), supporting the idea that most peptidergic meningeal nociceptors are capsaicin
sensitive. Congruently, topical application of capsaicin to the rat dura causes vasodilation mediated
by CGRP (51).
Nearly all dural afferents that can be activated in vivo by IF are mechanosensitive, and IF en-
hances their mechanosensitivity (46). The sensitization of mechanosensitive meningeal afferents
provides 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, the
mechanisms that lead to episodic activation of the perivascular meningeal nociceptors (see next
section) as well as the mechanism(s) that underlie their sustained activation and sensitization and
the ensuing throbbing headache during a migraine attack remain incompletely understood and
controversial.
Vasodilation
Several experimental and clinical observations show that vasodilation of meningeal and/or
extracranial arteries is neither necessary nor sufficient to cause migraine pain; therefore, the
original vascular theory of migraine is untenable for most patients (52 and references therein).
In migraineurs, on the one hand, neither extracranial nor intracranial arteries were dilated in
sildenafil- 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 migraine
headache (55). Recently, a 9–12% dilation of extracranial and intracranial arteries was measured
in CGRP-induced migraine headache; this modest vasodilation is likely insufficient to activate
the perivascular afferents but might affect sensitized nociceptors (56). Furthermore, the modest
amount of dilation in these studies and in other imaging studies was probably mediated by parasym-
pathetic activation via a monosynaptic reflex accompanying trigeminovascular activation (57).

Meningeal Inflammation and Peripheral Sensitization

On the basis of a large body of indirect evidence from both clinical and animal studies, a sterile
MC: mast cell meningeal inflammation is considered one key mechanism that may underlie the sustained acti-
Neurogenic vation and sensitization of perivascular meningeal afferents during migraine attacks (12, 58, 59).
inflammation (NI): Indirect clinical evidence is provided by the increased level of various inflammatory mediators
a physiological in the cephalic venous outflow during spontaneous migraine attacks and by the efficacy of non-
mechanism causing steroidal anti-inflammatory drugs in the acute treatment of migraine in many patients (12, 58,
dilation, edema (due to
59 and references therein). In experimental animals, activation of meningeal nociceptors in vivo
extravasation of plasma
proteins), and other leads to release of vasoactive proinflammatory peptides such as CGRP and SP from their periph-
manifestations of eral nerve endings; these peptides produce vasodilation of meningeal blood vessels (due mainly
inflammation to CGRP), plasma extravasation, and local activation of dural mast cells (MCs), with ensuing re-
mediated by released lease of cytokines and other inflammatory mediators [i.e., neurogenic inflammation (NI)] (12, 58,
neuropeptides from
59). Dural MC degranulation can produce a long-lasting activation and sensitization of rat dural
the peripheral ends of
small-caliber primary nociceptors (60) as well as cephalic tactile hypersensitivity (61). Chemical inflammation of the
afferent fibers dura in awake animals induces facial and hind paw cutaneous allodynia (32) with a time course of
Peripheral development that is consistent with that seen in migraine patients (62). Also, the pharmacology
sensitization: of the IF-induced allodynia in animals shows important parallels with the clinical pharmacology
increased sensitivity to of migraine pain (32). Glycerotrinitrate infusion, which may induce in migraineurs (but not in
noxious or nonnoxious healthy subjects) a delayed migraine attack indistinguishable from the spontaneous attacks (63),
sensory stimulation
produces a delayed inflammation within rat dura (64).
caused by
hyperresponsiveness However, the endogenous processes that promote meningeal inflammation and peripheral sen-
within primary sitization during spontaneous migraine attacks remain incompletely understood. Many investiga-
afferent fibers tors consider the NI produced by release of vasoactive proinflammatory neuropeptides following
Transient receptor activation of peptidergic meningeal nociceptors (by CSD or other different primary mechanisms;
potential cation see next section) to be the endogenous inflammatory process that sustains the activation and
channel A1 (TRPA1) causes the sensitization of meningeal nociceptors in many migraine attacks. Indeed, measure-
receptor: receptor
ments of CGRP levels in the external and internal jugular venous blood have provided evidence
that detects noxious
stimuli, cold, and that CGRP is released during migraine attacks (65–67). Also consistent with the NI hypothesis is
stretch the recent evidence that the headache-triggering substances ethanol and umbellulone (the major
volatile constituent of the Californian “headache tree”) activate peptidergic meningeal trigeminal
afferents (via different receptors: TRPV1 and TRPA1), causing CGRP release and neurogenic
dura inflammatory responses in experimental animals (68, 69). However, direct evidence that the
release of inflammatory molecules associated with NI sensitizes meningeal nociceptors is lacking.
In certain types of migraine, endogenous processes different from NI and not requiring initial
activation of meningeal nociceptors might promote meningeal inflammation and cause sensitiza-
tion and ensuing long-lasting activation of meningeal nociceptors. These processes may include
direct activation of dural MCs by a number of exogenous and endogenous migraine triggers, as
was shown to occur in vitro (12, 59, 70), as well as release of inflammatory mediators from brain
parenchyma (e.g., as a consequence of CSD) and/or from meningeal blood vessels or immune
cells that may directly sensitize meningeal nociceptors.
Central Sensitization
After headache onset, approximately two-thirds of migraine patients develop cutaneous allodynia
(i.e., perception of pain in response to normally innocuous stimuli) in the periorbital region that
may spread to extracephalic regions (71, 72). After brief local application of IF to the dura in
anesthetized animals, second-order trigeminovascular neurons in the TCC showed long-lasting
increased responses to innocuous mechanical or thermal facial skin stimulation (73), whereas

third-order trigeminovascular neurons in the posterior thalamus showed long-lasting increased

responses to both cephalic and extracephalic skin stimuli (33). Interestingly, functional magnetic
resonance imaging (fMRI) scans in migraine patients showed larger thalamic blood oxygen level–
Blood oxygen
dependent (BOLD) signals induced by brush and innocuous heat stimulation of the hand during level–dependent
migraine attacks with extracephalic allodynia than during migraine-free periods (33). These data functional magnetic
suggest that facial allodynia reflects sensitization of trigeminovascular neurons in the TCC receiv- resonance imaging
ing convergent input from the meningeal nociceptors and facial skin and that extracephalic allo- (BOLD fMRI):
a magnetic resonance
dynia reflects sensitization of trigeminovascular thalamic neurons that process converging sensory
method, often termed
information from the cranial meninges and extracephalic skin. The gradual spatial and temporal fMRI, that generates a
spread of allodynia and its expression are consistent with the idea that initiation of central sensiti- BOLD signal that
zation depends on the afferent input from sensitized meningeal nociceptors (10, 71). The fact that measures oxy- and
the anesthetic block of the primary dural afferents after chemical stimulation of the rat dura did deoxyhemoglobin
levels in tissues and
not inhibit the long-lasting hypersensitivity to cutaneous stimulation of TCC neurons suggests
approximates relative
that, once established, central sensitization becomes independent of afferent input (10, 73). blood flow changes in
A recent animal study points to the activation of the descending facilitatory pathway aris- brain tissue
ing from the RVM (Figure 1) as a key central mechanism involved in central sensitization of Central sensitization:
trigeminovascular neurons (32). Chemical inflammation of the dura produces a (slowly develop- increased sensitivity to
ing) prolonged activation of RVM “on” cells, a cell class that facilitates nociceptive processes at noxious or nonnoxious
the level of the dorsal horn, and only a transient inhibition of RVM “off” cells, the cells that in- sensory stimulation
caused by
hibit nociceptive signals. IF-induced facial allodynia was almost abolished (and hind paw allodynia
hyperresponsiveness of
was reduced) after selective lesion of putative RVM pain-facilitating neurons; moreover, bilateral central neurons within
microinjection of bupivacaine into the RVM 30 min after dural IF prevented facial allodynia and the trigeminocervical
delayed the onset of hind paw allodynia (32). complex or thalamus
fMRI studies in human subjects indicate that the PAG and nucleus cuneiformis (NCF), the Interictal period: the
major sources of input to the RVM (Figure 1), are involved in the maintenance of central sensiti- period of time between
zation in humans (74). Interestingly, positron emission tomography studies revealed activation of migraine attacks
similar areas in the dorsal rostral brain stem during migraine attacks (75). A possible involvement
of these areas in central sensitization during migraine has been proposed on the basis of fMRI
findings 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 Peptide

Several findings support a pivotal role of CGRP in migraine, including (a) the effectiveness of
CGRP receptor antagonists in migraine treatment (77, 78) and (b) the induction of a delayed
migraine-like headache by intravenous CGRP administration in a large fraction of migraine 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 CGRP
receptors in the trigeminovascular system (TVS) points to multiple possible mechanisms at both
peripheral and central sites (80).
In the periphery, CGRP receptors are expressed in blood vessels, Schwann cells, and dural MCs
at the meninges and in glial satellite cells and a subpopulation of TG neurons in the trigeminal
ganglion (80, 81). A relevant role of CGRP-induced dural vasodilation in migraine is unlikely
in view of the evidence that topical or systemic CGRP does not activate or sensitize rat dural
afferents (82) and that vasodilation is neither necessary nor sufficient to trigger migraine (52).
CGRP-induced dural MC degranulation may help maintain an inflammatory cycle at the dura.

Consistent with this idea are animal studies showing that dural MC degranulation (as well as topical
application of some individual MC mediators to the dura) preferentially activates and sensitizes
mechanosensitive C units, most of which express CGRP (60, 83), and increase CGRP release from
capsaicin-sensitive dural afferents (84).
It has been suggested that CGRP-mediated intraganglionic cross talk between neurons and be-
tween neurons and satellite glial cells may promote and maintain a neuron-glia inflammatory cycle
that could contribute to persistent peripheral trigeminal sensitization (65, 67). This suggestion
is based mainly on the evidence that prolonged application of CGRP to cultures of TG neurons
and/or satellite glial cells leads to increased gene expression and/or membrane targeting of specific
receptors (e.g., P2X3 ) in neurons and to increased expression of inflammatory genes and release of
inflammatory mediators from satellite glial cells; these inflammatory mediators can sensitize TG
neurons and act back on glial cells, further activating them (85–90). It remains unclear whether sim-
ilar phenomena occur within the TG upon prolonged activation of meningeal nociceptors in vivo.
In the central TVS, CGRP receptors are expressed in the TNC (laminae I and II) (80) and
in some neuronal cell bodies in the VPM thalamic nucleus (34). In the TNC, CGRP receptors
are localized in a fiber network forming irregular glomeruli-like structures partially colocalized
with granular CGRP-immunoreactive structures, but not on second-order neurons, suggesting
the possibility of CGRP-mediated signaling between central terminals of primary afferents as pre-
and postsynaptic elements (80). Functional studies indicate that activation of TNC presynaptic
CGRP receptors may lead to potentiation of excitatory neurotransmission. In fact, capsaicin-
evoked CGRP release, as well as bath application of CGRP, increased the excitability of TNC
neurons in brain stem slices (91), and iontophoresis of a CGRP receptor antagonist reduced firing
evoked by dural stimulation in vivo (92).
The possibility of central mechanisms of CGRP action during a migraine attack is indirectly
supported by animal studies showing that systemic CGRP does not activate or sensitize dural
afferents (82) and that high doses of systemic CGRP receptor antagonists reduce the activity of
TNC neurons (93) and VPM thalamic neurons (34) evoked by stimulation of dural afferents,
as well as the number of Fos-positive neurons in the TNC (laminae I and II) after intravenous
infusion of capsaicin (94). However, given the very poor permeability of the blood-brain barrier
to CGRP (95, 96), it seems difficult to explain, on the basis of published data, how CGRP infusion
can cause a migraine attack if one excludes a peripheral role for CGRP.
Dysfunctional Central Control of Pain

The large body of indirect evidence reviewed above supports the prevailing view that the headache
phase of migraine begins with the activation and sensitization of trigeminovascular meningeal no-
ciceptors, which lead to sequential activation (and, in most patients, to sensitization) of second-
and third-order trigeminovascular neurons. In this formulation, such activation and sensitization
in turn activate different areas of the brain stem and forebrain, resulting in pain and other ac-
companying migrainous symptoms. The bidirectional signaling between many of these structures
contributes to the complexity of the symptoms. However, direct evidence in the clinical setting
for increased trigeminal sensory trafficking during migraine is lacking, and a consistent cephalic
pathology has not been detected. Therefore, some investigators propose the alternative view that
migraine headache arises from dysfunction within subcortical brain stem and diencephalic nuclei
that modulate trigeminal nociceptive inputs; dysfunction in these nuclei (in particular in the PAG-
RVM circuitry) would lead to abnormal central interpretation of normal sensory input in the TVS,
causing normal sensory traffic from the meninges to be perceived as migraine pain (30). As in other
tissues, high-threshold C- and A-delta fibers are electrophysiologically silent, so the origins of this

normal meningeal sensory input remain unclear. Nonetheless, functional imaging studies show-
ing increased cerebral blood flow in the dorsal rostral brain stem and in the hypothalamus during
migraine attacks that persisted even after sumatriptan had induced relief from headache (75, 97)
are considered to provide indirect support for this view (30). In particular, the reported specificity
of activation of brain stem areas such as the PAG and rostral pons in migraine (10) promoted
the view that abnormal activity in the PAG-RVM circuitry could serve as the migraine headache
generator. However, in light of more recent data, the specificity of activation of different brain
stem areas depending on different head pains does not appear to hold (97 and references therein;
98). Moreover, a recent fMRI study showed activation of dorsal rostral brain stem areas only 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 the PAG-RVM circuitry (or other descending mechanisms of pain inhibition) can
generate migraine headache in the absence of peripheral sensory input (11, 12). For example, the
brain stem generator hypothesis does not explain why abnormal descending modulation specifi-
cally generates migraine pain (and not other pains in spinal or trigeminal tissues), given that the
descending modulatory pathway projects onto multiple segments of the spinal cord. Moreover,
abnormal descending modulation implies that disinhibition of second-order neurons (receiving
convergent input from meninges and skin) would promote cephalic allodynia during the onset
of the headache phase, but this is almost never the case, as allodynia takes one hour or longer to
develop and is absent in approximately 30% of migraine patients.
PRIMARY BRAIN DYSFUNCTIONS IN MIGRAINE

The nature and mechanisms of the primary brain dysfunction(s) leading to episodic activation of
the trigeminovascular pain pathway remain incompletely understood and controversial. Given the
wide genetic and clinical heterogeneity of the disorder, different primary mechanisms of migraine
onset likely exist.
Cortical Spreading Depression

Increasing evidence from animal studies supports the idea that CSD, the underlying mechanism
of aura, can activate trigeminal nociception and thus trigger headache mechanisms. A direct noci-
ceptive effect of CSD was demonstrated by the finding that a single CSD can lead to a long-lasting
increase in ongoing activity of dural nociceptors and central trigeminovascular neurons in super-
ficial and deep laminae of the TCC (101, 102). In most neurons activation occurred with a delay
consistent with that between the onset of visual aura and the onset of headache; the delay as well as
the magnitude and duration of neuronal activation were similar in peripheral and central neurons,
suggesting that CSD-evoked activity of meningeal nociceptors is sufficient to activate the central
neurons. Immediate neuronal activation by CSD was observed in a fraction of neurons, mainly C
nociceptors and exclusively laminae I and II TCC neurons, suggesting that such activation may be
mediated by peptidergic nociceptors with axon collaterals extending to the pia, where immediate
activation may be mediated by increased K+ or other noxious mediators released in the wake of
the CSD wave (57) (Figure 2). This hypothesis is supported by the demonstration that CSD-
induced CGRP release from perivascular trigeminal fibers contributes to the transient dilation
of pial vessels measured during CSD (103). A possible explanation for the long-lasting activation

of the dural afferents is that release of proinflammatory neuropeptides in the dura promotes NI
that sustains the activation of meningeal nociceptors and leads to their sensitization (12, 57, 101,
102). This idea is supported by the finding of CSD-induced plasma protein extravasation from
dural 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 sensitization
and ensuing sustained activation of meningeal nociceptors (61). The mechanism of the delayed
long-lasting neuronal activation remains unknown. A recent review discusses different potential
mechanisms (61), including upregulation of matrix metalloproteinases (105) and the passage of
normally sequestered and potentially noxious molecules (e.g., K+ , H+ , 5-hydroxytryptamine) into
the extracellular space, reaching the pial and dural surfaces by bulk diffusion to access trigemino-
vascular afferents (Figure 2).
In addition to the prolonged activation of TCC neurons, there are other significant CSD-
driven central effects, including gene upregulation in the TCC (57, 106) and dilation and increase
in blood flow within the middle meningeal artery mediated by trigeminally evoked brain stem
reflexes (57) (Figure 2). These observations speak to the importance of noxious inputs from the
TVS sufficient to drive cells and tissues within the pain matrix following CSD. Nevertheless,
CSD may not be sufficient on the basis of the observation that freely moving rats do not seem to
experience CSD as aversive, as they do not show pain behavior (107, 108) or cutaneous allodynia
(109) after a CSD. However, whether these behavioral studies are suitable to detect a relatively mild
head pain remains uncertain (110); moreover, only 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 sufficient to elicit the perception of
headache in patients is unclear, although the evidence is clear that intense electrophysiological ac-
tivity in, for example, the temporal lobe (e.g., in focal temporal lobe epilepsy) can activate overlying
meningeal nociceptors and generate ipsilateral headache (111). If CSD does cause hemicranial pain
due to activation of overlying meningeal nociceptors, the expectation is that the initial headache
should develop contralateral to the unilateral aura symptoms (e.g., left visual aura caused by CSD
in the right hemisphere is accompanied by right hemicranial pain), which seems to be the case in
the majority of patients.
The idea that CSD is noxious and may trigger headache is indirectly supported by the finding
that the electrical stimulation threshold for induction of CSD in the rat cortex increases after
−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−→
Figure 2
From cortical spreading depression (CSD) to trigeminovascular nociception. (a) It is believed that CSD is ignited by local elevations of
extracellular [K+ ] above a critical level as a consequence of hyperactive neuronal circuits in the cerebral cortex. (b) CSD is a slowly
propagating wave of strong neuronal and glial depolarization [cf. direct-current (DC) cortical potential trace] accompanied by
depression of spontaneous and evoked electroencephalography (EEG) activity and by a large increase in extracellular [K+ ]. (c) Other
noxious mediators (open circles), such as H+ , nitric oxide (NO), arachidonic acid (AA), and serotonin (5-hydroxytryptamine), besides
glutamate and other neurotransmitters are released during CSD. It is hypothesized that these substances may activate trigeminal
nociceptors innervating pial blood vessels and, via axon collaterals, dural trigeminal afferents and/or may slowly access the meningeal
afferents after disruption of the blood-brain barrier (BBB) (e.g., as a consequence of upregulation of matrix metalloproteinases), leading
to activation of central trigeminovascular neurons in the trigeminocervical complex (TCC; blue pathway). Activation of the meningeal
afferents leads to release of proinflammatory vasoactive neuropeptides, including calcitonin gene–related peptide (CGRP), substance P
(SP), and neurokinin A (NKA), that may promote neurogenic inflammation in the dura and possibly sustain the activation of the
trigeminovascular afferents and lead to their sensitization. Alternatively, mediators released by the CSD wave may lead to sensitization
and ensuing activation of meningeal nociceptors. Also shown is a parasympathetic reflex involving activation of the superior salivatory
nucleus (SSN) and the sphenopalatine ganglion (SPG) leading to release of vasoactive intestinal peptide (VIP), NO, and acetylcholine
(ACh) from the meningeal parasympathetic efferents. Other abbreviations: MMP9, matrix metalloproteinase 9; TG, trigeminal
ganglion.

chronic treatment with five different migraine prophylactic drugs that are equally effective in
reducing the frequency of MA and MO attacks (112); in contrast, two drugs ineffective in migraine
prophylaxis do not affect susceptibility to experimental CSD (112, 113). This good correlation
between inhibition of CSD and effectiveness in migraine prophylaxis depends upon an adequate
clinical trial design that addresses whether there is a significant change in frequency of aura as well
as decrease in the following headache. In this respect, the design of clinical trials for two drugs
(tonabersat and lamotrigine), reportedly effective in reducing the frequency of experimental CSDs
b
CSD
wavef
efrront
wavefront
(Neurogenic)
inflammation
DC
potential
c VIP CGRP
NO SP
[K+] ACh NKA
MMP9
BBB leakage
Dura
EEG
Pia
Cerebral cortex
1 min
CSD
SPG
K+ H+ NO AA
Cerebral cortex
a SSN
CSD
K+
TCC
TG
TCC

produced by prolonged epidural application of KCl (114, 115), appears problematic. On the one
hand, when tonabersat and lamotrigine were tested in relatively small populations of MA patients,
the treatment did reduce the number of MA attacks (116, 117), supporting this notion. On the
other hand, when relatively small populations of mainly MO patients were treated with tonabersat
in low doses for three months or with lamotrigine, the treatment did not significantly affect the
mean number of headache days (118) or frequency of migraine (119), respectively. Further studies
that are sufficiently powered, including dose-ranging studies and measurements of the electrical
threshold for experimental CSD induction after chronic treatment of animals with tonabersat and
lamotrigine, will be required to solve these apparent discrepancies.
The analysis of experimental CSD in FHM knockin mouse models has provided further support
to the view of CSD as a key migraine trigger by demonstrating that both FHM1 knockin mice
and FHM2 knockin mice show a lower electrical stimulation threshold for CSD induction and a
higher velocity of CSD propagation (see next section) (120–123). Although FHM3 mouse models
are not available, investigators reported that FHM3 in two unrelated families cosegregates with
a new eye phenotype with clinical features similar to those of experimental spreading depression
in the retina (124), suggesting that the ability to facilitate CSD is likely also shared by FHM3
mutations. Moreover, a lower electrical threshold for CSD induction and for increased velocity of
CSD propagation was measured in a mouse model of cerebral autosomal dominant arteriopathy,
a systemic vasculopathy associated with a fivefold-higher incidence of MA (125).
Despite the strong support provided by animal studies, the idea that CSD may initiate the
headache mechanisms in migraine is not generally accepted (10, 15). In fact, most migraineurs do
not experience aura, and even MA patients experience attacks without aura; moreover, therapeutic
intervention may abolish aura but not headache in some patients or may help with headache
without affecting aura in others. Present evidence neither proves nor disproves the possibility that
silent CSDs (i.e., CSDs involving areas of the brain that would not generate a perceived aura)
may initiate the headache mechanisms in MO (10, 14, 126). Nevertheless, a well-documented
imaging study in a young female with silent aura and CSD followed by headache (e.g., MO) leaves
doubt about how well migraine patients access and report ongoing or newly initiated brain events
(127). These apparent shortcomings speak to the urgent need to develop novel imaging and other
biomarkers to classify the subtypes of migraine.
Another argument that has been used against the idea that CSD may initiate the headache
mechanisms is based on the fact that in some patients migraine premonitory symptoms may
occur up to 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 and
other subcortical regions) are activated well before the onset of CSD (5).
In this context, it is interesting that the interictal neurophysiological abnormalities in sensory
information processing, typical of MO and MA patients, are not constant but change in intensity
in temporal relation to the migraine attack (7, 8, 10 and references therein). In most instances,
these perturbations are most intense 12–24 h before the attack, i.e., during the interval when
the premonitory symptoms appear, and then normalize a few hours before and/or during the
attack, except for deficits in pain processing (7, 8, 10, 99, 128, 129). Also, the neurophysiological
reactivity to stress, one of the most common migraine triggers, increases in the period between
attacks and is maximal (and significantly 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 the
pain-free interval progressively increase the dysfunction in central information processing, the
susceptibility to migraine triggers, and the neurophysiological readiness to generate a migraine
attack. One can speculate that these mechanisms both may lead to the premonitory symptoms
and, above a certain threshold of cortical dysfunction and/or in response to migraine triggers, may

create the conditions for ignition of CSD (e.g., as a result of cortical hyperactivity in the brain’s
attempt to normalize excessive cortical activation due to the deficit in habituation).
Transcranial
magnetic stimulation
Dysfunctional Regulation of Cortical Excitability
(TMS): a noninvasive
To understand the primary mechanisms of migraine attacks, it seems essential to understand the technique that induces
mechanisms underlying the interictal abnormal processing of sensory information, how they are weak electric currents
in brain to cause
affected by migraine triggers, and the nature of the relationship between these mechanisms and
neuronal
susceptibility to CSD. depolarization or
The analysis of interictal cortical excitability using psychophysics, electrophysiology, transcra- hyperpolarization
nial magnetic stimulation (TMS), and fMRI has produced contradictory findings 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 reviews
and see, e.g., References 130–134 for some recent studies). Depending on the study, the cortex of
migraineurs is hyperexcitable as a consequence of either enhanced excitation or reduced inhibition
or is hypoexcitable and/or has a lower preactivation level possibly due to serotonin hypoactivity
and/or inefficient thalamocortical drive. Interestingly, recent TMS studies in MA patients point to
deficient 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 in
cortical excitation, rather than merely hypo- or hyperexcitability, as the mechanisms underlying
abnormal sensory processing (135–137). Deficient cortical regulatory mechanisms likely underlie
the much higher variability in visual cortex excitability (as measured by phosphene threshold) in
MA and MO patients, particularly in the day before the attack (138; but cf. 129).
The molecular and cellular mechanisms underlying the abnormal regulation of cortical 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 are
affected by disease duration (e.g., repetitive CSDs) is unclear. Equally unclear is the extent to
which the abnormal processing of trigeminal nociceptive input reflects a primary dysregulation
of central sensory processing or central sensitization persisting outside the attack (e.g., 100, 141).
The functional analysis of FHM knockin mouse models supports the view of migraine as a
disorder of brain excitability characterized by deficient regulation of the cortical E/I balance.
Such analysis gives insights into the possible underlying molecular and cellular mechanisms and
their relationship to CSD susceptibility.
INSIGHTS FROM FAMILIAL HEMIPLEGIC MIGRAINE

MOUSE MODELS
FHM 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 trinitrate
seems 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 CACNA1A and SCNA1A, the genes
encoding the pore-forming subunits of the neuronal voltage-gated Ca2+ channel CaV 2.1 (also
known as the P/Q-type Ca2+ channel) and the Na+ channel NaV 1.1, cause FHM type 1 (FHM1)
(24) and type 3 (FHM3) (26), respectively. Mutations in ATP1A2, the gene encoding the Na+ ,K+ -
ATPase α2 subunit, cause FHM type 2 (FHM2) (25).
CaV 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 neurotransmitter
release, particularly at central synapses; their somatodendritic localization points to additional
postsynaptic roles, e.g., in neural excitability (144, 145). NaV 1.1 channels are expressed primarily
in the central nervous system in late postnatal stages and show high expression in certain
inhibitory interneurons, in which they play an important role in sustaining high-frequency firing
(146). In the nervous system, the α2 Na+ ,K+ -ATPase isoform is expressed primarily in neurons
during embryonic development and at birth, but almost exclusively in astrocytes in the adult;
its colocalization with the Na+ /Ca2+ exchanger in microdomains that overlie subplasmalemmal
endoplasmic reticulum and with glutamate transporters in astrocytic processes surrounding
glutamatergic synapses suggests specific roles in the regulation of intracellular Ca2+ and glutamate
clearance (23 and references therein).
Whereas most genetic studies indicate that the FHM genes (except perhaps for ATP1A2) are
not involved in common migraines (18, 23), some homozygous mutations in SLC4A4, the gene
encoding the electrogenic Na+ ,HCO3 − cotransporter NBCe1, are associated with hemiplegic
migraine, MA, or MO, depending on the mutation (147). The transport activity of NBCe1 in as-
trocytes is thought to modulate neuronal excitability by regulating local pH (147). Only mutations
producing near-total loss of function of the transporter expressed in glioma cells are associated
with migraine, supporting a causative role and the view that hemiplegic migraine and common
migraine represent a phenotypic spectrum that may share at least some genetic basis (147).
The different FHM mutations and their functional consequences on recombinant mutant
proteins in heterologous expression systems (and, for some mutations, in transfected neurons) were
recently reviewed (18, 23, 145) and are not discussed in detail here. Rather, we discuss functional
studies in FHM mouse models and the consequences of the mutations on the native proteins and on
neurophysiological processes that are thought to be involved in the pathophysiology of migraine.
Three different FHM mouse models were generated by introducing the human FHM1
R192Q or S218L and FHM2 W887R mutations into the orthologous genes (120–122). Whereas
in humans the R192Q and W887R mutations cause typical FHM attacks (24, 25), the S218L
mutation causes a particularly dramatic clinical syndrome that may consist of—in addition
to attacks of hemiplegic migraine—slowly progressive cerebellar ataxia and atrophy; epileptic
seizures; coma or profound stupor; and severe, sometimes fatal cerebral edema that can be
triggered by trivial head trauma (148). Whereas homozygous R192Q, heterozygous S218L, and
heterozygous W887R knockin mice do not exhibit an overt phenotype, homozygous S218L mice
model the main features of the severe S218L clinical syndrome (120–122). Homozygous W887R
knockin mice die at birth because of lack of spontaneous respiratory activity (122).
The α2 Na+ ,K+ -ATPase protein was barely detectable in the brains of homozygous FHM2
knockin mice and was strongly reduced in the brains of heterozygous mutants (122). Previous
studies of the effect of several FHM2 mutations on recombinant Na+ ,K+ -ATPases invariably
showed complete or partial loss of function of the mutant pumps (23, 122, 149, 150).
Analysis of the P/Q-type calcium current in different neurons (including cortical and TG
neurons) of FHM1 knockin mice revealed gain of function of the CaV 2.1 current in a wide range

of relatively mild depolarizations, reflecting shifted activation of mutant CaV 2.1 channels to more
negative voltages (45, 120, 121, 151, 152) (Figure 3). The shift to lower voltages of CaV 2.1
channel activation and the gain of function of the neuronal CaV 2.1 current were approximately
twice as large in homozygous knockin mice as in heterozygous mice, revealing an allele dosage
effect consistent with dominance of the mutation in FHM1 patients (121). The gain-of-function
effect of the FHM1 mutations on native neuronal mouse CaV 2.1 channels is in agreement with
the increased open probability of recombinant human CaV 2.1 channels carrying eight different
FHM1 mutations (including R192Q and S218L) that was revealed by single-channel recordings
(153–155).
Interestingly, FHM1 mutations may not affect the gating properties of native CaV 2.1 channels
in specific neurons (45), possibly as a consequence of expression of specific CaV 2.1α1 splice variants
and/or CaV 2.1β subunits (156, 157). In fact, in R192Q knockin mice the P/Q-type Ca2+ current is
increased in a subtype of TG neuron that does not innervate the dura, but is unaltered in capsaicin-
sensitive TG neurons that innervate the dura (45) (Figure 3). Congruently, although P/Q-type
calcium channels contribute to control of CGRP release from capsaicin-sensitive perivascular
meningeal sensory fibers (158, 159), the FHM1 mutation does not alter depolarization-evoked
CGRP release from the dura (45) (Figure 3). This finding argues against the idea that facilitation of
CGRP-dependent dural vasodilation and CGRP-dependent dural MC degranulation contributes
to the generation of migraine pain in FHM1. However, the FHM1 mutation increases CGRP re-
lease from intact trigeminal ganglia (45) (Figure 3) and from cultured TG neurons (90) of R192Q
knockin mice, suggesting alternative roles. If CGRP-mediated intraganglionic cross talk promotes
and maintains a neuron-glia inflammatory cycle that contributes to peripheral trigeminal sensiti-
zation (65, 67) (see above), then FHM1 mutations may facilitate these phenomena. Indeed, there
is some evidence suggesting facilitation of CGRP-mediated neuron-to-glia cross talk following
exposure to proinflammatory stimuli in cultured TG neurons from R192Q knockin mice (90).
The analysis of cortical synaptic transmission in FHM1 knockin mice revealed a very interesting
differential effect of FHM1 mutations at excitatory and inhibitory synapses (151) (Figure 3).
Excitatory synaptic transmission is enhanced as a consequence of increased action potential (AP)-
evoked Ca2+ influx and increased probability of glutamate release at cortical pyramidal cell synapses
of R192Q knockin mice; congruently, short-term synaptic depression during trains of APs is
enhanced (151). AP-evoked Ca2+ transients in individual synaptic terminals of cerebellar granule
cells are enhanced and short-term facilitation is reduced at parallel fiber–Purkinje cell synapses
of S218L knockin mice (160). In striking contrast, inhibitory neurotransmission at cortical FS
interneuron synapses is not altered in FHM1 knockin mice, despite being initiated by P/Q-type
calcium channels (151; D. Vecchia & D. Pietrobon, unpublished observations). The demonstration
that FHM1 mutations may differently affect synaptic transmission and short-term plasticity at
excitatory and inhibitory cortical synapses (151) implies that the neuronal circuits that dynamically
adjust the E/I balance during cortical activity are probably altered in FHM1. Functional alterations
in these circuits are expected to lead to abnormal processing of sensory information (139, 140).
The investigation of experimental CSD, elicited either by electrical stimulation of the cortex
in vivo or by focal application of high KCl in cortical slices, revealed a lower threshold for CSD
initiation and an increased velocity of CSD propagation in both FHM1 and FHM2 knockin mice
(120–122, 151) (Figure 3). In FHM1 knockin mice carrying the mild R192Q mutation or the
severe S218L mutation, the strength of CSD facilitation as well as the severity of the post-CSD
neurological motor deficits and the propensity of CSD to propagate into subcortical structures
were in good correlation with the strength of the gain of function of the CaV 2.1 channel and
the severity of the clinical phenotype produced by the two FHM1 mutations (120, 121, 123,
148, 154, 161). The much higher propensity of CSD to propagate to the striatum in FHM1

i Cav2.1 current in cortical ii Cortical synaptic transmission:

pyramidal cells increased • Increased glutamate release at pyramidal cell synapses
• Unaltered GABA release at FS interneuron synapses
Dysfunctional regulation of cortical E/I balance
a
DC iii CSD
++ Pyramidal potential
po tial • Lower threshold
++ cells • Increased velocity and
extent of propagation
[K+]
++ FS interneu
erneuron
on
interneuron
++
+ + EEG
+ +
CSD
wavefront
1 min
(Neurogenic)
b inflammation CGRP
NKA
SP
i CGRP release at the dura unaltered

Dura
Pia
K+ H+ NO AA
Cerebral cortex
ii Cav2.1 current in TG neurons

• Unaltered in CS dural afferents
• Increased in CI-T neurons not
innervating the dura
TG
iii CGRP release at the TG increased
TCC

mutants compared with wild-type (WT) mice (S218L > R192Q) may explain their motor deficits
and the hemiplegia typical of FHM1 aura (161), whereas the propagation to the hippocampus
and thalamus and the recurrent CSDs observed only in S218L mutants may explain the severe
NMDA:
attacks with seizures, coma, and cerebral edema typical of patients with the S218L mutation N-methyl-D-aspartic
(121, 161). The velocity of propagation and the frequency of CSDs, elicited by continuous acid
epidural high-KCl application, were larger in female than in male FHM1 mouse mutants, in
agreement with the higher female prevalence of migraine; the sex difference was abrogated by
ovariectomy and enhanced by orchiectomy, suggesting that female and male gonadal hormones
exert reciprocal effects (123, 162). However, no gender differences in the electrical threshold for
CSD induction and the velocity of CSD propagation were found in FHM2 knockin mice (122).
The gain of function of glutamate release at synapses onto cortical pyramidal cells can explain
the facilitation of experimental CSD in FHM1 knockin mice (151). In fact, the facilitation of CSD
in acute cortical slices of R192Q knockin mice was completely eliminated (both CSD threshold
and velocity became similar to those in WT slices) when glutamate release at pyramidal cell
synapses was brought back to WT values by partially inhibiting P/Q channels (151). The data
are consistent with and support a model of CSD initiation in which CaV 2.1-dependent release of
glutamate from cortical pyramidal cell synapses and activation of NMDA receptors (and possibly
postsynaptic CaV 2.1 channels) play a key role in the positive feedback cycle that ignites CSD
(151, 163–165). It has been suggested that excessive NMDA receptor–mediated glutamatergic
transmission consequent to impaired clearance of glutamate by astrocytic processes surrounding
glutamatergic synapses [where the α2 Na+ ,K+ -ATPase is colocalized and functionally coupled
with glutamate transporters (166–168)] may underlie the facilitation of experimental CSD in the
←−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−
Figure 3
Functional consequences of a familial hemiplegic migraine type 1 (FHM1) mutation on neuronal CaV 2.1
channels and neurophysiological processes involved in the pathophysiology of migraine. (a) Functional
alterations in the cerebral cortex of an FHM1 knockin mouse model. (i ) The CaV 2.1 calcium current in
cortical pyramidal cells (PC) is increased because mutant CaV 2.1 channels activate at lower voltages than do
wild-type channels. (ii ) Action potential (AP)-evoked glutamate release and excitatory synaptic transmission
at PC synapses are increased. In striking contrast, AP-evoked gamma-aminobutyric acid (GABA) release and
inhibitory synaptic transmission at fast spiking (FS) interneuron synapses are unaltered, despite being
initiated by CaV 2.1 channels. The gain of function of glutamate release at the recurrent synapses between
PC is predicted to increase network excitation. In contrast, the gain of function of glutamate release at the
synapses onto FS interneurons (PC-FS synapses) is predicted to lead to enhanced recruitment of
interneurons and to enhanced inhibition. However, during high-frequency repetitive activity, the enhanced
recruitment of FS interneurons is expected to cease rapidly because the PC-FS synapses depress strongly
during AP trains (much more than do the recurrent PC-PC synapses), and short-term depression is even
stronger in FHM1 knockin mice, particularly at PC-FS synapses. This analysis, although restricted to a
specific subcircuit, shows that the differential effect of FHM1 mutations on excitatory and inhibitory
neurotransmission may produce overexcitation in certain brain conditions but may leave the
excitatory/inhibitory (E/I) balance within physiological limits in others, which is consistent with the episodic
nature of the disease. (iii ) Experimental cortical spreading depression (CSD) is facilitated, as revealed by a
decreased threshold for CSD induction, an increased rate of CSD propagation, and an increased propensity
to propagate into subcortical structures. (b) Functional alterations in trigeminal neurons of an FHM1
knockin mouse model. (i ) CaV 2.1 current is unaltered in small-size, capsaicin-sensitive (CS) trigeminal
ganglion (TG) neurons that innervate the dura but is increased in small-size, capsaicin-insensitive TG
neurons expressing a T-type calcium current (CI-T neurons) that do not innervate the dura. (ii )
Depolarization-evoked calcitonin gene–related peptide (CGRP) release in intact dura mater is unaltered.
(iii ) Depolarization-evoked CGRP release in intact trigeminal ganglia is increased. Other abbreviations: AA,
arachidonic acid; DC, direct current; EEG, electroencephalography; NKA, neurokinin A; NO, nitric oxide;
SP, substance P.

FHM2 mouse model (122). The contribution of impaired K+ clearance has been considered less
important because the duration of the CSD is not prolonged in mutant mice (122).
In migraineurs CSD is not induced by experimental depolarizing stimuli but arises sponta-
neously in response to specific triggers that somehow create conditions in the cortex for initiation
of the positive feedback cycle that overwhelms the regulatory mechanisms controlling cortical
extracellular [K+ ] and ignites CSD. Insights into how this might occur were provided by the
differential effects of FHM1 mutations on cortical excitatory and inhibitory synaptic transmission
(151), suggesting altered regulation of the cortical E/I balance in FHM1. It has been hypothesized
that this dysregulation may in certain conditions (e.g., in response to migraine triggers such as
intense, prolonged sensory stimulation) lead to disruption of the E/I balance and hyperactivity of
cortical circuits (due mainly to excessive recurrent excitation) that may create the conditions for
the initiation of spontaneous CSDs (e.g., by increasing the extracellular [K+ ] to above a critical
value) (151, 169). Similar mechanisms might underlie the susceptibility to CSD in FHM2 (122).
The functional studies in FHM mouse models suggest that impairment of the cortical 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 in
subcortical areas that may also contribute to the altered regulation of cortical function and to the
disease in general in a way that remains to be established (e.g., by altering cortical neuromodulation
by monoaminergic projections and/or by favoring hyperexcitability of central trigeminovascular
pathways). In this context, CSD may represent just one manifestation of fundamental alterations
(e.g., impairment of E/I balance) produced by FHM mutations in different brain areas.
Similar mechanisms may underlie the abnormal regulation of cortical (and possibly subcortical)
function in some common migraine subtypes; supporting this possibility is indirect evidence
consistent with enhanced cortical glutamatergic neurotransmission (137, 170) and enhanced
cortico-cortical or recurrent excitatory neurotransmission (130, 131, 133, 136) in MA and/or MO.
Some of the susceptibility loci for MA and MO recently identified in genome-wide association
studies also appear to be consistent with the idea of migraine as a disorder of glutamatergic
neurotransmission and/or dysregulated brain E/I balance (20–22). Given the wide clinical and
genetic heterogeneity of migraine, different molecular and cellular mechanisms that remain
largely unknown may well underlie the impaired regulation of brain function and the susceptibility
to CSD in different migraineurs.
Finally, recent advances in migraine pathophysiology have underscored the need for more
efficacious and specific prophylactic migraine medications (171). These needs may one day be
met by a greater understanding of cortical dysfunction at the synaptic and cellular levels and by
therapeutic strategies that consider cortical E/I dysregulation and CSD as key targets for preventive
migraine treatments. Consistent with these ideas, glutamatergic synaptic transmission is a major
target to effectively counteract excessive excitatory activity caused by dysfunction of ion channels,
transporters, and pumps in FHM and in some migraine variants. Particularly efficacious would
be the development of drugs that increase CSD threshold independently of the specific cortical
dysfunctions underlying susceptibility to CSD in different migraineurs.
SUMMARY POINTS
1. Migraine is a common disabling brain disorder whose key manifestations are recurrent
attacks of unilateral headache (that may be preceded by transient neurological aura 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 phase
of migraine depends on the activation and sensitization of trigeminal nociceptors that
innervate the large blood vessels in the meninges. These processes then lead to sequen-
tial activation (and, in most patients, sensitization) of second- and third-order central
trigeminovascular neurons, which in turn activate different areas of the brain stem and
forebrain, resulting in pain and other migrainous symptoms.
3. Vasodilation of meningeal and/or extracranial arteries is neither necessary nor sufficient
to cause migraine pain. A sterile meningeal inflammation is one key mechanism that may
underlie the sustained activation and sensitization of perivascular meningeal nocicep-
tors, but the endogenous processes promoting the inflammation during migraine attacks
remain unclear.
4. Several findings 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 the
headache 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 identified.
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 deficient 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 with
unaltered inhibitory synaptic transmission and facilitation of induction and propagation
of CSD due to enhanced glutamatergic neurotransmission.
DISCLOSURE STATEMENT
The authors are not aware of any affiliations, memberships, funding, or financial holdings that
might be perceived as affecting the objectivity of this review.
ACKNOWLEDGMENTS
D.P. is supported by grants from the University of Padova (Strategic Project: Physiopathology of
Signaling in Neuronal Tissue) and from the Fondazione Cariparo (Excellence Project: Calcium

Signaling in Health and Disease) and acknowledges support from Telethon-Italy (GGP06234).
We gratefully thank Drs. Angelita Tottene and Dania Vecchia for preparing the figures.
LITERATURE CITED
1. Lipton RB, Bigal ME, Steiner TJ, Silberstein SD, Olesen J. 2004. Classification of primary headaches.
Neurology 63:427–35
2. Stovner LJ, Hagen K. 2006. Prevalence, burden, and cost of headache disorders. Curr. Opin. Neurol.
19:281–85
3. Olesen J, Gustavsson A, Svensson M, Wittchen HU, Jonsson B. 2012. The economic cost of brain
disorders in Europe. Eur. J. Neurol. 19:155–62
4. Leonardi M, Steiner TJ, Scher AT, Lipton RB. 2005. The global burden of migraine: measuring
disability in headache disorders with WHO’s Classification of Functioning, Disability and Health (ICF).
J. Headache Pain 6:429–40
5. Giffin NJ, Ruggiero L, Lipton RB, Silberstein SD, Tvedskov JF, et al. 2003. Premonitory symptoms in
Annu. Rev. Physiol. 2013.75:365-391. Downloaded from www.annualreviews.org
migraine: an electronic diary study. Neurology 60:935–40

6. Hauge AW, Kirchmann M, Olesen J. 2011. Characterization of consistent triggers of migraine with
aura. Cephalalgia 31:416–38
7. Coppola G, Pierelli F, Schoenen J. 2007. Is the cerebral cortex hyperexcitable or hyperresponsive in
by 132.183.15.120 on 02/15/13. For personal use only.
migraine? Cephalalgia 27:1427–39

8. Aurora SK, Wilkinson F. 2007. The brain is hyperexcitable in migraine. Cephalalgia 27:1442–53
9. Moskowitz MA. 1984. The neurobiology of vascular head pain. Ann. Neurol. 16:157–68
10. Pietrobon D, Striessnig J. 2003. Neurobiology of migraine. Nat. Rev. Neurosci. 4:386–98
11. Olesen J, Burstein R, Ashina M, Tfelt-Hansen P. 2009. Origin of pain in migraine: evidence for
peripheral sensitisation. Lancet Neurol. 8:679–90
12. Levy D. 2010. Migraine pain and nociceptor activation—where do we stand? Headache 50:909–16
13. Lauritzen M. 1994. Pathophysiology of the migraine aura. The spreading depression theory. Brain
117(Pt. 1):199–210
14. Ayata C. 2010. Cortical spreading depression triggers migraine attack: pro. Headache 50:725–30
15. Charles A. 2010. Does cortical spreading depression initiate a migraine attack? Maybe not. Headache
50:731–33
16. Somjen GG. 2001. Mechanisms of spreading depression and hypoxic spreading depression-like
depolarization. Physiol. Rev. 81:1065–96
17. Maher BH, Griffiths LR. 2011. Identification of molecular genetic factors that influence migraine. Mol.
Genet. Genomics 285:433–46
18. de Vries B, Frants RR, Ferrari MD, van den Maagdenberg AM. 2009. Molecular genetics of migraine.
Hum. Genet. 126:115–32
19. Russell MB, Ducros A. 2011. Sporadic and familial hemiplegic migraine: pathophysiological mechanisms,
clinical characteristics, diagnosis, and management. Lancet Neurol. 10:457–70
20. Anttila V, Stefansson H, Kallela M, Todt U, Terwindt GM, et al. 2010. Genome-wide association study
of migraine implicates a common susceptibility variant on 8q22.1. Nat. Genet. 42:869–73
21. Chasman DI, Schurks M, Anttila V, de Vries B, Schminke U, et al. 2011. Genome-wide association study
reveals three susceptibility loci for common migraine in the general population. Nat. Genet. 43:695–98
22. Freilinger T, Anttila V, de Vries B, Malik R, Kallela M, et al. 2012. Genome-wide association analysis
identifies susceptibility loci for migraine without aura. Nat. Genet. 44:777–82
23. Pietrobon D. 2007. Familial hemiplegic migraine. Neurotherapeutics 4:274–84
24. Ophoff RA, Terwindt GM, Vergouwe MN, van Eijk R, Oefner PJ, et al. 1996. Familial hemiplegic
migraine and episodic ataxia type-2 are caused by mutations in the Ca2+ channel gene CACNL1A4.
Cell 87:543–52
25. De Fusco M, Marconi R, Silvestri L, Atorino L, Rampoldi L, et al. 2003. Haploinsufficiency of ATP1A2
encoding the Na+ /K+ pump α2 subunit associated with familial hemiplegic migraine type 2. Nat. Genet.
33:192–96

26. Dichgans M, Freilinger T, Eckstein G, Babini E, Lorenz-Depiereux B, et al. 2005. Mutation in the
neuronal voltage-gated sodium channel SCN1A in familial hemiplegic migraine. Lancet 366:371–77
27. Thomsen LL, Kirchmann M, Bjornsson A, Stefansson H, Jensen RM, et al. 2007. The genetic spectrum
of a population-based sample of familial hemiplegic migraine. Brain 130:346–56
28. Mayberg M, Langer RS, Zervas NT, Moskowitz MA. 1981. Perivascular meningeal projections from
cat trigeminal ganglia: possible pathway for vascular headaches in man. Science 213:228–30
29. Edvinsson L. 2011. Tracing neural connections to pain pathways with relevance to primary headaches.
Cephalalgia 31:737–47
30. Akerman S, Holland PR, Goadsby PJ. 2011. Diencephalic and brainstem mechanisms in migraine. Nat.
Rev. Neurosci. 12:570–84
31. Noseda R, Jakubowski M, Kainz V, Borsook D, Burstein R. 2011. Cortical projections of functionally
identified thalamic trigeminovascular neurons: implications for migraine headache and its associated
symptoms. J. Neurosci. 31:14204–17
32. Edelmayer RM, Vanderah TW, Majuta L, Zhang ET, Fioravanti B, et al. 2009. Medullary pain
facilitating neurons mediate allodynia in headache-related pain. Ann. Neurol. 65:184–93
33. Burstein R, Jakubowski M, Garcia-Nicas E, Kainz V, Bajwa Z, et al. 2010. Thalamic sensitization
transforms localized pain into widespread allodynia. Ann. Neurol. 68:81–91
34. Summ O, Charbit AR, Andreou AP, Goadsby PJ. 2010. Modulation of nociceptive transmission with
calcitonin gene-related peptide receptor antagonists in the thalamus. Brain 133:2540–48
35. Noseda R, Constandil L, Bourgeais L, Chalus M, Villanueva L. 2010. Changes of meningeal excitability
mediated by corticotrigeminal networks: a link for the endogenous modulation of migraine pain.
J. Neurosci. 30:14420–29
36. Noseda R, Kainz V, Jakubowski M, Gooley JJ, Saper CB, et al. 2010. A neural mechanism for
exacerbation of headache by light. Nat. Neurosci. 13:239–45
37. Knight YE, Goadsby PJ. 2001. The periaqueductal grey matter modulates trigeminovascular input: a
role in migraine? Neuroscience 106:793–800
38. Lambert GA, Hoskin KL, Zagami AS. 2008. Cortico-NRM influences on trigeminal neuronal sensation.
39. Bartsch T, Levy MJ, Knight YE, Goadsby PJ. 2004. Differential modulation of nociceptive dural input
to [hypocretin] orexin A and B receptor activation in the posterior hypothalamic area. Pain 109:367–78
40. Bartsch T, Levy MJ, Knight YE, Goadsby PJ. 2005. Inhibition of nociceptive dural input in the trigeminal
nucleus caudalis by somatostatin receptor blockade in the posterior hypothalamus. Pain 117:30–39
41. Charbit AR, Akerman S, Holland PR, Goadsby PJ. 2009. Neurons of the dopaminergic/calcitonin
gene-related peptide A11 cell group modulate neuronal firing in the trigeminocervical complex: an
electrophysiological and immunohistochemical study. J. Neurosci. 29:12532–41
42. Strassman AM, Levy D. 2006. Response properties of dural nociceptors in relation to headache.
J. Neurophysiol. 95:1298–306
43. Vaughn AH, Gold MS. 2010. Ionic mechanisms underlying inflammatory mediator-induced sensitiza-
tion of dural afferents. J. Neurosci. 30:7878–88
44. Yan J, Edelmayer RM, Wei X, De Felice M, Porreca F, Dussor G. 2011. Dural afferents express
acid-sensing ion channels: a role for decreased meningeal pH in migraine headache. Pain 152:106–13
45. Fioretti B, Catacuzzeno L, Sforna L, Gerke-Duncan MB, van den Maagdenberg AM, et al. 2011.
Trigeminal ganglion neuron subtype-specific alterations of CaV 2.1 calcium current and excitability in
a Cacna1a mouse model of migraine. J. Physiol. 589:5879–95
46. Strassman AM, Raymond SA, Burstein R. 1996. Sensitization of meningeal sensory neurons and the
origin of headaches. Nature 384:560–64
47. Bove GM, Moskowitz MA. 1997. Primary afferent neurons innervating guinea pig dura. J. Neurophysiol.
77:299–308
48. Messlinger K, Hanesch U, Baumgartel M, Trost B, Schmidt RF. 1993. Innervation of the dura mater
encephali of cat and rat: ultrastructure and calcitonin gene-related peptide-like and substance P-like
immunoreactivity. Anat. Embryol. 188:219–37
49. Shimizu T, Toriumi H, Sato H, Shibata M, Nagata E, et al. 2007. Distribution and origin of TRPV1
receptor-containing nerve fibers in the dura mater of rat. Brain Res. 1173:84–91

50. Jansen I, Alafaci C, Uddman R, Edvinsson L. 1990. Evidence that calcitonin gene-related peptide
contributes to the capsaicin-induced relaxation of guinea pig cerebral arteries. Regul. Pept. 31:167–78
51. Dux M, Santha P, Jancso G. 2003. Capsaicin-sensitive neurogenic sensory vasodilatation in the dura
mater of the rat. J. Physiol. 552:859–67
52. Brennan KC, Charles A. 2010. An update on the blood vessel in migraine. Curr. Opin. Neurol. 23:266–74
53. Kruuse C, Thomsen LL, Birk S, Olesen J. 2003. Migraine can be induced by sildenafil without changes
in middle cerebral artery diameter. Brain 126:241–47
54. Schoonman GG, van der Grond J, Kortmann C, van der Geest RJ, Terwindt GM, Ferrari MD.
2008. Migraine headache is not associated with cerebral or meningeal vasodilatation—a 3T magnetic
resonance angiography study. Brain 131:2192–200
55. Rahmann A, Wienecke T, Hansen JM, Fahrenkrug J, Olesen J, Ashina M. 2008. Vasoactive intestinal
peptide causes marked cephalic vasodilation, but does not induce migraine. Cephalalgia 28:226–36
56. Asghar MS, Hansen AE, Amin FM, van der Geest RJ, Koning P, et al. 2011. Evidence for a vascular
factor in migraine. Ann. Neurol. 69:635–45
57. Bolay H, Reuter U, Dunn AK, Huang Z, Boas DA, Moskowitz MA. 2002. Intrinsic brain activity
triggers trigeminal meningeal afferents in a migraine model. Nat. Med. 8:136–42
58. Waeber C, Moskowitz MA. 2005. Migraine as an inflammatory disorder. Neurology 64:S9–15
59. Levy D. 2009. Migraine pain, meningeal inflammation, and mast cells. Curr. Pain Headache Rep.
13:237–40
60. Levy D, Burstein R, Kainz V, Jakubowski M, Strassman AM. 2007. Mast cell degranulation activates a
pain pathway underlying migraine headache. Pain 130:166–76
61. Levy D. 2012. Endogenous mechanisms underlying the activation and sensitization of meningeal
nociceptors: the role of immuno-vascular interactions and cortical spreading depression. Curr. Pain
Headache Rep. 16:270–77
62. Burstein R, Cutrer MF, Yarnitsky D. 2000. The development of cutaneous allodynia during a migraine
attack: clinical evidence for the sequential recruitment of spinal and supraspinal nociceptive neurons in
migraine. Brain 123(Pt. 8):1703–9
63. Schytz HW, Schoonman GG, Ashina M. 2010. What have we learnt from triggering migraine? Curr.
Opin. Neurol. 23:259–65
64. Reuter U, Bolay H, Jansen-Olesen I, Chiarugi A, Sanchez del Rio M, et al. 2001. Delayed inflammation
in rat meninges: implications for migraine pathophysiology. Brain 124:2490–502
65. Villalon CM, Olesen J. 2009. The role of CGRP in the pathophysiology of migraine and efficacy of
CGRP receptor antagonists as acute antimigraine drugs. Pharmacol. Ther. 124:309–23
66. Recober A, Russo AF. 2009. Calcitonin gene-related peptide: an update on the biology. Curr. Opin.
Neurol. 22:241–46
67. Ho TW, Edvinsson L, Goadsby PJ. 2010. CGRP and its receptors provide new insights into migraine
pathophysiology. Nat. Rev. Neurol. 6:573–82
68. Nicoletti P, Trevisani M, Manconi M, Gatti R, De Siena G, et al. 2008. Ethanol causes neurogenic
vasodilation by TRPV1 activation and CGRP release in the trigeminovascular system of the guinea pig.
69. Nassini R, Materazzi S, Vriens J, Prenen J, Benemei S, et al. 2012. The ‘headache tree’ via umbellulone
and TRPA1 activates the trigeminovascular system. Brain 135:376–90
70. Baun M, Pedersen MH, Olesen J, Jansen-Olesen I. 2012. Dural mast cell degranulation is a putative
mechanism for headache induced by PACAP-38. Cephalalgia 32:337–45
71. Burstein R, Yarnitsky D, Goor-Aryeh I, Ransil BJ, Bajwa ZH. 2000. An association between migraine
and cutaneous allodynia. Ann. Neurol. 47:614–24
72. Lipton RB, Bigal ME, Ashina S, Burstein R, Silberstein S, et al. 2008. Cutaneous allodynia in the
migraine population. Ann. Neurol. 63:148–58
73. Burstein R, Yamamura H, Malick A, Strassman AM. 1998. Chemical stimulation of the intracranial
dura induces enhanced responses to facial stimulation in brain stem trigeminal neurons. J. Neurophysiol.
79:964–82
74. Lee MC, Zambreanu L, Menon DK, Tracey I. 2008. Identifying brain activity specifically related to the
maintenance and perceptual consequence of central sensitization in humans. J. Neurosci. 28:11642–49

75. Weiller C, May A, Limmroth V, Juptner M, Kaube H, et al. 1995. Brain stem activation in spontaneous
human migraine attacks. Nat. Med. 1:658–60
76. Moulton EA, Burstein R, Tully S, Hargreaves R, Becerra L, Borsook D. 2008. Interictal dysfunction of
a brainstem descending modulatory center in migraine patients. PLoS ONE 3:e3799
77. Olesen J, Diener HC, Husstedt IW, Goadsby PJ, Hall D, et al. 2004. Calcitonin gene-related peptide
receptor antagonist BIBN 4096 BS for the acute treatment of migraine. N. Engl. J. Med. 350:1104–10
78. Ho TW, Ferrari MD, Dodick DW, Galet V, Kost J, et al. 2008. Efficacy and tolerability of MK-0974
(telcagepant), a new oral antagonist of calcitonin gene-related peptide receptor, compared with zolmitrip-
tan for acute migraine: a randomised, placebo-controlled, parallel-treatment trial. Lancet 372:2115–23
79. Lassen LH, Haderslev PA, Jacobsen VB, Iversen HK, Sperling B, Olesen J. 2002. CGRP may play a
causative role in migraine. Cephalalgia 22:54–61
80. Lennerz JK, Ruhle V, Ceppa EP, Neuhuber WL, Bunnett NW, et al. 2008. Calcitonin receptor-like
receptor (CLR), receptor activity-modifying protein 1 (RAMP1), and calcitonin gene-related peptide
(CGRP) immunoreactivity in the rat trigeminovascular system: differences between peripheral and
central CGRP receptor distribution. J. Comp. Neurol. 507:1277–99
81. Eftekhari S, Salvatore CA, Calamari A, Kane SA, Tajti J, Edvinsson L. 2010. Differential distribution
of calcitonin gene-related peptide and its receptor components in the human trigeminal ganglion.
Neuroscience 169:683–96
82. Levy D, Burstein R, Strassman AM. 2005. Calcitonin gene-related peptide does not excite or sensitize
meningeal nociceptors: implications for the pathophysiology of migraine. Ann. Neurol. 58:698–705
83. Zhang XC, Strassman AM, Burstein R, Levy D. 2007. Sensitization and activation of intracranial
meningeal nociceptors by mast cell mediators. J. Pharmacol. Exp. Ther. 322:806–12
84. Dux M, Rosta J, Santha P, Jancso G. 2009. Involvement of capsaicin-sensitive afferent nerves in the
proteinase-activated receptor 2-mediated vasodilatation in the rat dura mater. Neuroscience 161:887–94
85. Fabbretti E, D’Arco M, Fabbro A, Simonetti M, Nistri A, Giniatullin R. 2006. Delayed upregulation
of ATP P2X3 receptors of trigeminal sensory neurons by calcitonin gene-related peptide. J. Neurosci.
26:6163–71
86. Zhang Z, Winborn CS, Marquez de Prado B, Russo AF. 2007. Sensitization of calcitonin gene-related
peptide receptors by receptor activity-modifying protein-1 in the trigeminal ganglion. J. Neurosci.
27:2693–703
87. Li J, Vause CV, Durham PL. 2008. Calcitonin gene-related peptide stimulation of nitric oxide synthesis
and release from trigeminal ganglion glial cells. Brain Res. 1196:22–32
88. Vause CV, Durham PL. 2010. Calcitonin gene-related peptide differentially regulates gene and protein
expression in trigeminal glia cells: findings from array analysis. Neurosci. Lett. 473:163–67
89. Capuano A, De Corato A, Lisi L, Tringali G, Navarra P, Dello Russo C. 2009. Proinflammatory-activated
trigeminal satellite cells promote neuronal sensitization: relevance for migraine pathology. Mol. Pain 5:43
90. Ceruti S, Villa G, Fumagalli M, Colombo L, Magni G, et al. 2011. Calcitonin gene-related peptide-
mediated enhancement of purinergic neuron/glia communication by the algogenic factor bradykinin
in mouse trigeminal ganglia from wild-type and R192Q CaV 2.1 knock-in mice: implications for basic
mechanisms of migraine pain. J. Neurosci. 31:3638–49
91. Meng J, Ovsepian SV, Wang J, Pickering M, Sasse A, et al. 2009. Activation of TRPV1 mediates
calcitonin gene-related peptide release, which excites trigeminal sensory neurons and is attenuated by
a retargeted botulinum toxin with anti-nociceptive potential. J. Neurosci. 29:4981–92
92. Storer RJ, Akerman S, Goadsby PJ. 2004. Calcitonin gene-related peptide (CGRP) modulates
nociceptive trigeminovascular transmission in the cat. Br. J. Pharmacol. 142:1171–81
93. Fischer MJ, Koulchitsky S, Messlinger K. 2005. The nonpeptide calcitonin gene-related peptide
receptor antagonist BIBN4096BS lowers the activity of neurons with meningeal input in the rat spinal
trigeminal nucleus. J. Neurosci. 25:5877–83
94. Sixt ML, Messlinger K, Fischer MJ. 2009. Calcitonin gene-related peptide receptor antagonist
olcegepant acts in the spinal trigeminal nucleus. Brain 132:3134–41
95. Edvinsson L, Nilsson E, Jansen-Olesen I. 2007. Inhibitory effect of BIBN4096BS, CGRP(8–37),
a CGRP antibody and an RNA-Spiegelmer on CGRP induced vasodilatation in the perfused and
non-perfused rat middle cerebral artery. Br. J. Pharmacol. 150:633–40

96. Asghar MS, Hansen AE, Larsson HB, Olesen J, Ashina M. 2012. Effect of CGRP and sumatriptan on
the BOLD response in visual cortex. J. Headache Pain 13:159–66
97. Denuelle M, Fabre N, Payoux P, Chollet F, Geraud G. 2007. Hypothalamic activation in spontaneous
migraine attacks. Headache 47:1418–26
98. Mainero C, Zhang WT, Kumar A, Rosen BR, Sorensen AG. 2007. Mapping the spinal and supraspinal
pathways of dynamic mechanical allodynia in the human trigeminal system using cardiac-gated fMRI.
Neuroimage 35:1201–10
99. Stankewitz A, Aderjan D, Eippert F, May A. 2011. Trigeminal nociceptive transmission in migraineurs
predicts migraine attacks. J. Neurosci. 31:1937–43
100. Mainero C, Boshyan J, Hadjikhani N. 2011. Altered functional magnetic resonance imaging resting-state
connectivity in periaqueductal gray networks in migraine. Ann. Neurol. 70:838–45
101. Zhang X, Levy D, Noseda R, Kainz V, Jakubowski M, Burstein R. 2010. Activation of meningeal
nociceptors by cortical spreading depression: implications for migraine with aura. J. Neurosci. 30:8807–14
102. Zhang X, Levy D, Kainz V, Noseda R, Jakubowski M, Burstein R. 2011. Activation of central
trigeminovascular neurons by cortical spreading depression. Ann. Neurol. 69:855–65
103. Busija DW, Bari F, Domoki F, Horiguchi T, Shimizu K. 2008. Mechanisms involved in the
cerebrovascular dilator effects of cortical spreading depression. Prog. Neurobiol. 86:379–95
104. Ebersberger A, Schaible HG, Averbeck B, Richter F. 2001. Is there a correlation between spreading
depression, neurogenic inflammation, and nociception that might cause migraine headache? Ann.
Neurol. 49:7–13
105. Gursoy-Ozdemir Y, Qiu J, Matsuoka N, Bolay H, Bermpohl D, et al. 2004. Cortical spreading
depression activates and upregulates MMP-9. J. Clin. Investig. 113:1447–55
106. Moskowitz MA, Nozaki K, Kraig RP. 1993. Neocortical spreading depression provokes the expression
of c-fos protein-like immunoreactivity within trigeminal nucleus caudalis via trigeminovascular
mechanisms. J. Neurosci. 13:1167–77
107. Koroleva VI, Bures J. 1993. Rats do not experience cortical or hippocampal spreading depression as
aversive. Neurosci. Lett. 149:153–56
108. Akcali D, Sayin A, Sara Y, Bolay H. 2010. Does single cortical spreading depression elicit pain behaviour
in freely moving rats? Cephalalgia 30:1195–206
109. Fioravanti B, Kasasbeh A, Edelmayer R, Skinner DP Jr, Hartings JA, et al. 2010. Evaluation of cuta-
neous allodynia following induction of cortical spreading depression in freely moving rats. Cephalalgia
31:1090–100
110. Levy D, Moskowitz MA, Nuseda R, Burstein R. 2012. Activation of the migraine pain pathway by
cortical spreading depression: Do we need more evidence? Cephalalgia 32:581–82
111. Bernasconi A, Andermann F, Bernasconi N, Reutens DC, Dubeau F. 2001. Lateralizing value of
peri-ictal headache: a study of 100 patients with partial epilepsy. Neurology 56:130–32
112. Ayata C, Jin H, Kudo C, Dalkara T, Moskowitz MA. 2006. Suppression of cortical spreading depression
in migraine prophylaxis. Ann. Neurol. 59:652–61
113. Hoffmann U, Dilekoz E, Kudo C, Ayata C. 2011. Oxcarbazepine does not suppress cortical spreading
depression. Cephalalgia 31:537–42
114. Smith MI, Read SJ, Chan WN, Thompson M, Hunter AJ, et al. 2000. Repetitive cortical spreading de-
pression in a gyrencephalic feline brain: inhibition by the novel benzoylamino-benzopyran SB-220453.
115. Bogdanov VB, Multon S, Chauvel V, Bogdanova OV, Prodanov D, et al. 2011. Migraine preventive
drugs differentially affect cortical spreading depression in rat. Neurobiol. Dis. 41:430–35
116. Hauge AW, Asghar MS, Schytz HW, Christensen K, Olesen J. 2009. Effects of tonabersat on migraine
with aura: a randomised, double-blind, placebo-controlled crossover study. Lancet Neurol. 8:718–23
117. Lampl C, Katsarava Z, Diener HC, Limmroth V. 2005. Lamotrigine reduces migraine aura and
migraine attacks in patients with migraine with aura. J. Neurol. Neurosurg. Psychiatry 76:1730–32
118. Goadsby PJ, Ferrari MD, Csanyi A, Olesen J, Mills JG. 2009. Randomized, double-blind, placebo-
controlled, proof-of-concept study of the cortical spreading depression inhibiting agent tonabersat in
migraine prophylaxis. Cephalalgia 29:742–50

119. Steiner TJ, Findley LJ, Yuen AW. 1997. Lamotrigine versus placebo in the prophylaxis of migraine
with and without aura. Cephalalgia 17:109–12
120. van den Maagdenberg AM, Pietrobon D, Pizzorusso T, Kaja S, Broos LA, et al. 2004. A Cacna1a knockin
migraine mouse model with increased susceptibility to cortical spreading depression. Neuron 41:701–10
121. van den Maagdenberg AM, Pizzorusso T, Kaja S, Terpolilli N, Shapovalova M, et al. 2010. High
cortical spreading depression susceptibility and migraine-associated symptoms in CaV 2.1 S218L mice.
Ann. Neurol. 67:85–98
122. Leo L, Gherardini L, Barone V, De Fusco M, Pietrobon D, et al. 2011. Increased susceptibility to cortical
spreading depression in the mouse model of familial hemiplegic migraine type 2. PLoS Genet. 7:e1002129
123. Eikermann-Haerter K, Dilekoz E, Kudo C, Savitz SI, Waeber C, et al. 2009. Genetic and hormonal
factors modulate spreading depression and transient hemiparesis in mouse models of familial hemiplegic
migraine type 1. J. Clin. Investig. 119:99–109
124. Vahedi K, Depienne C, Le Fort D, Riant F, Chaine P, et al. 2009. Elicited repetitive daily blindness:
a new phenotype associated with hemiplegic migraine and SCN1A mutations. Neurology 72:1178–83
125. Eikermann-Haerter K, Yuzawa I, Dilekoz E, Joutel A, Moskowitz MA, Ayata C. 2011. Cerebral auto-
somal dominant arteriopathy with subcortical infarcts and leukoencephalopathy syndrome mutations
increase susceptibility to spreading depression. Ann. Neurol. 69:413–18
126. Denuelle M, Fabre N, Payoux P, Chollet F, Geraud G. 2008. Posterior cerebral hypoperfusion in
migraine without aura. Cephalalgia 28:856–62
127. Woods RP, Iacoboni M, Mazziotta JC. 1994. Brief report: bilateral spreading cerebral hypoperfusion
during spontaneous migraine headache. N. Engl. J. Med. 331:1689–92
128. Siniatchkin M, Averkina N, Andrasik F, Stephani U, Gerber WD. 2006. Neurophysiological reactivity
before a migraine attack. Neurosci. Lett. 400:121–24
129. Siniatchkin M, Reich AL, Shepherd AJ, van Baalen A, Siebner HR, Stephani U. 2009. Peri-ictal changes
of cortical excitability in children suffering from migraine without aura. Pain 147:132–40
130. Wilkinson F, Karanovic O, Wilson HR. 2008. Binocular rivalry in migraine. Cephalalgia 28:1327–38
131. Battista J, Badcock DR, McKendrick AM. 2011. Migraine increases centre-surround suppression for
drifting visual stimuli. PLoS ONE 6:e18211
132. McKendrick AM, Battista J, Snyder JS, Carter OL. 2011. Visual and auditory perceptual rivalry in
migraine. Cephalalgia 31:1158–69
133. Siniatchkin M, Kroner-Herwig B, Kocabiyik E, Rothenberger A. 2007. Intracortical inhibition and
facilitation in migraine—a transcranial magnetic stimulation study. Headache 47:364–70
134. Cosentino G, Fierro B, Vigneri S, Talamanca S, Palermo A, et al. 2011. Impaired glutamatergic
neurotransmission in migraine with aura? Evidence by an input-output curves transcranial magnetic
stimulation study. Headache 51:726–33
135. Antal A, Lang N, Boros K, Nitsche M, Siebner HR, Paulus W. 2008. Homeostatic metaplasticity of the
motor cortex is altered during headache-free intervals in migraine with aura. Cereb. Cortex 18:2701–5
136. Conte A, Barbanti P, Frasca V, Iacovelli E, Gabriele M, et al. 2010. Differences in short-term primary
motor cortex synaptic potentiation as assessed by repetitive transcranial magnetic stimulation in
migraine patients with and without aura. Pain 148:43–48
137. Siniatchkin M, Sendacki M, Moeller F, Wolff S, Jansen O, et al. 2011. Abnormal changes of synaptic
excitability in migraine with aura. Cereb. Cortex 22:2207–16
138. Antal A, Arlt S, Nitsche MA, Chadaide Z, Paulus W. 2006. Higher variability of phosphene thresholds
in migraineurs than in controls: a consecutive transcranial magnetic stimulation study. Cephalalgia
26:865–70
139. Shu Y, Hasenstaub A, McCormick DA. 2003. Turning on and off recurrent balanced cortical activity.
Nature 423:288–93
140. Monier C, Chavane F, Baudot P, Graham LJ, Fregnac Y. 2003. Orientation and direction selectivity
of synaptic inputs in visual cortical neurons: a diversity of combinations produces spike tuning. Neuron
37:663–80
141. Moulton EA, Becerra L, Maleki N, Pendse G, Tully S, et al. 2010. Painful heat reveals hyperexcitability
of the temporal pole in interictal and ictal migraine states. Cereb. Cortex 21:435–48

142. Hansen JM, Thomsen LL, Olesen J, Ashina M. 2008. Calcitonin gene-related peptide does not cause
the familial hemiplegic migraine phenotype. Neurology 71:841–47
143. Hansen JM, Thomsen LL, Olesen J, Ashina M. 2010. Coexisting typical migraine in familial hemiplegic
migraine. Neurology 74:594–600
144. Pietrobon D. 2005. Function and dysfunction of synaptic calcium channels: insights from mouse models.
Curr. Opin. Neurobiol. 15:257–65
145. Pietrobon D. 2010. CaV 2.1 channelopathies. Pflüg. Arch. 460:375–93
146. Catterall WA, Kalume F, Oakley JC. 2010. NaV 1.1 channels and epilepsy. J. Physiol. 588:1849–59
147. Suzuki M, Van Paesschen W, Stalmans I, Horita S, Yamada H, et al. 2010. Defective membrane
expression of the Na+ -HCO3 − cotransporter NBCe1 is associated with familial migraine. Proc. Natl.
Acad. Sci. USA 107:15963–68
148. Kors EE, Terwindt GM, Vermeulen FL, Fitzsimons RB, Jardine PE, et al. 2001. Delayed cerebral
edema and fatal coma after minor head trauma: role of the CACNA1A calcium channel subunit gene
and relationship with familial hemiplegic migraine. Ann. Neurol. 49:753–60
149. Tavraz NN, Friedrich T, Durr KL, Koenderink JB, Bamberg E, et al. 2008. Diverse functional
consequences of mutations in the Na+ /K+ -ATPase α2 -subunit causing familial hemiplegic migraine
type 2. J. Biol. Chem. 283:31097–106
150. Tavraz NN, Durr KL, Koenderink JB, Freilinger T, Bamberg E, et al. 2009. Impaired plasma membrane
targeting or protein stability by certain ATP1A2 mutations identified in sporadic or familial hemiplegic
migraine. Channels 3:82–87
151. Tottene A, Conti R, Fabbro A, Vecchia D, Shapovalova M, et l. 2009. Enhanced excitatory transmission
at cortical synapses as the basis for facilitated spreading depression in CaV 2.1 knockin migraine mice.
Neuron 61:762–73
152. Inchauspe CG, Urbano FJ, Di Guilmi MN, Forsythe ID, Ferrari MD, et al. 2010. Gain of function in
FHM-1 CaV 2.1 knock-in mice is related to the shape of the action potential. J. Neurophysiol. 104:291–99
153. Tottene A, Fellin T, Pagnutti S, Luvisetto S, Striessnig J, et al. 2002. Familial hemiplegic migraine
mutations increase Ca2+ influx through single human CaV 2.1 channels and decrease maximal CaV 2.1
current density in neurons. Proc. Natl. Acad. Sci. USA 99:13284–89
154. Tottene A, Pivotto F, Fellin T, Cesetti T, van den Maagdenberg AM, Pietrobon D. 2005. Specific kinetic
alterations of human CaV 2.1 calcium channels produced by mutation S218L causing familial hemiplegic
migraine and delayed cerebral edema and coma after minor head trauma. J. Biol. Chem. 280:17678–86
155. Catterall WA, Dib-Hajj S, Meisler MH, Pietrobon D. 2008. Inherited neuronal ion channelopathies:
new windows on complex neurological diseases. J. Neurosci. 28:11768–77
156. Mullner C, Broos LA, van den Maagdenberg AM, Striessnig J. 2004. Familial hemiplegic migraine type
1 mutations K1336E, W1684R, and V1696I alter CaV 2.1 Ca2+ channel gating: evidence for β-subunit
isoform-specific effects. J. Biol. Chem. 279:51844–50
157. Adams PJ, Garcia E, David LS, Mulatz KJ, Spacey SD, Snutch TP. 2009. CaV 2.1 P/Q-type calcium
channel alternative splicing affects the functional impact of familial hemiplegic migraine mutations:
implications for calcium channelopathies. Channels 3:110–21
158. Hong KW, Kim CD, Rhim BY, Lee WS. 1999. Effect of ω-conotoxin GVIA and ω-agatoxin IVA on
the capsaicin-sensitive calcitonin gene-related peptide release and autoregulatory vasodilation in rat pial
arteries. J. Cereb. Blood Flow Metab. 19:53–60
159. Akerman S, Williamson DJ, Goadsby PJ. 2003. Voltage-dependent calcium channels are involved
in neurogenic dural vasodilatation via a presynaptic transmitter release mechanism. Br. J. Pharmacol.
140:558–66
160. Adams PJ, Rungta RL, Garcia E, van den Maagdenberg AM, MacVicar BA, Snutch TP. 2010.
Contribution of calcium-dependent facilitation to synaptic plasticity revealed by migraine mutations in
the P/Q-type calcium channel. Proc. Natl. Acad. Sci. USA 107:18694–99
161. Eikermann-Haerter K, Yuzawa I, Qin T, Wang Y, Baek K, et al. 2011. Enhanced subcortical spreading
depression in familial hemiplegic migraine type 1 mutant mice. J. Neurosci. 31:5755–63
162. Eikermann-Haerter K, Baum MJ, Ferrari MD, van den Maagdenberg AM, Moskowitz MA, Ayata C.
2009. Androgenic suppression of spreading depression in familial hemiplegic migraine type 1 mutant
mice. Ann. Neurol. 66:564–68

163. Pietrobon D. 2005. Migraine: new molecular mechanisms. Neuroscientist 11:373–86

164. Tottene A, Urbani A, Pietrobon D. 2011. Role of different voltage-gated Ca2+ channels in cortical
spreading depression: specific requirement of P/Q-type Ca2+ channels. Channels 5:110–14
165. Ayata C, Shimizu-Sasamata M, Lo EH, Noebels JL, Moskowitz MA. 2000. Impaired neurotransmitter
release and elevated threshold for cortical spreading depression in mice with mutations in the α1A
subunit of P/Q type calcium channels. Neuroscience 95:639–45
166. Cholet N, Pellerin L, Magistretti PJ, Hamel E. 2002. Similar perisynaptic glial localization for
the Na+ ,K+ -ATPase α2 subunit and the glutamate transporters GLAST and GLT-1 in the rat
somatosensory cortex. Cereb. Cortex 12:515–25
167. Pellerin L, Magistretti PJ. 1997. Glutamate uptake stimulates Na+ ,K+ -ATPase activity in astrocytes
via activation of a distinct subunit highly sensitive to ouabain. J. Neurochem. 69:2132–37
168. Rose EM, Koo JC, Antflick JE, Ahmed SM, Angers S, Hampson DR. 2009. Glutamate transporter
coupling to Na,K-ATPase. J. Neurosci. 29:8143–55
169. Pietrobon D. 2010. Insights into migraine mechanisms and CaV 2.1 calcium channel function from
mouse models of familial hemiplegic migraine. J. Physiol. 588:1871–78
170. Prescot A, Becerra L, Pendse G, Tully S, Jensen E, et al. 2009. Excitatory neurotransmitters in brain
regions in interictal migraine patients. Mol. Pain 5:34
171. Olesen J, Ashina M. 2011. Emerging migraine treatments and drug targets. Trends Pharmacol. Sci.
32:352–59

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PH75CH16-Pietrobon ARI 9 January 2013 11:25

Annu. Rev. Physiol. 2013. 75:365–91 Keywords

366 Pietrobon · Moskowitz

MECHANISMS OF MIGRAINE PAIN

Trigeminovascular Pain Pathways

www.annualreviews.org • Migraine 367

a Afferent pathways Dura mater

V1/V2 Cerebral cortex

b Efferent modulatory pathways

368 Pietrobon · Moskowitz

www.annualreviews.org • Migraine 369

Meningeal Inflammation and Peripheral Sensitization

370 Pietrobon · Moskowitz

third-order trigeminovascular neurons in the posterior thalamus showed long-lasting increased

Calcitonin Gene–Related Peptide

www.annualreviews.org • Migraine 371

Dysfunctional Central Control of Pain

372 Pietrobon · Moskowitz

PRIMARY BRAIN DYSFUNCTIONS IN MIGRAINE

Cortical Spreading Depression

www.annualreviews.org • Migraine 373

374 Pietrobon · Moskowitz

www.annualreviews.org • Migraine 375

376 Pietrobon · Moskowitz

INSIGHTS FROM FAMILIAL HEMIPLEGIC MIGRAINE

www.annualreviews.org • Migraine 377

378 Pietrobon · Moskowitz

www.annualreviews.org • Migraine 379

i Cav2.1 current in cortical ii Cortical synaptic transmission:

i CGRP release at the dura unaltered

ii Cav2.1 current in TG neurons

380 Pietrobon · Moskowitz

www.annualreviews.org • Migraine 381

382 Pietrobon · Moskowitz

www.annualreviews.org • Migraine 383

migraine: an electronic diary study. Neurology 60:935–40

migraine? Cephalalgia 27:1427–39

384 Pietrobon · Moskowitz

www.annualreviews.org • Migraine 385

386 Pietrobon · Moskowitz

www.annualreviews.org • Migraine 387

388 Pietrobon · Moskowitz

www.annualreviews.org • Migraine 389

390 Pietrobon · Moskowitz

163. Pietrobon D. 2005. Migraine: new molecular mechanisms. Neuroscientist 11:373–86

www.annualreviews.org • Migraine 391

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