Altered processing of sensory stimuli in patients with migraine
Altered processing of sensory stimuli
in patients with migraine
Marina de Tommaso, Anna Ambrosini, Filippo Brighina, Gianluca Coppola, Armando Perrotta, Francesco Pierelli, Giorgio Sandrini, Massimiliano Valeriani, Daniele Marinazzo, Sebastiano Stramaglia and Jean Schoenen
Abstract Migraine is a cyclic disorder, in which functional and morphological brain changes fluctuate over time, culminating periodically in an attack. In the migrainous brain, temporal processing of external stimuli and sequential recruitment of neuronal networks are often dysfunctional. These changes reflect complex CNS dysfunction patterns. Assessment of multimodal evoked potentials and nociceptive reflex responses can reveal altered patterns of the brain's electrophysiological activity, thereby aiding our understanding of the pathophysiology of migraine. In this Review, we summarize the most important findings on temporal processing of evoked and reflex responses in migraine. Considering these data, we propose that thalamocortical dysrhythmia may be responsible for the altered synchronicity in migraine. To test this hypothesis in future research, electrophysiological recordings should be combined with neuroimaging studies so that the temporal patterns of sensory processing in patients with migraine can be correlated with the accompanying anatomical and functional changes.
de Tommaso, M.
et al. Nat. Rev. Neurol. 10, 144–155 (2014); published online 18 February 2014;
Introduction
Migraine is the most prevalent neurological disorder in
peripheral and central portions of the trigeminovascular
the general population, with a cumulative lifetime inci
system—the main painsignalling system of the brain.
dence of 43% in women and 18% in men.1 The episodic
The relative importance and exact sequence of activa
form of migraine is characterized by recurrent head
tion of these structures during a migraine attack might
ache attacks, which are often accompanied by nausea,
vary with the migraine type, and remains a topic for
vomiting photophobia or phonophobia.2 Some patients
develop chronic migraine (at least 15 days of head
The temporal precision and noninvasiveness of
ache per month, including at least 8 days with typical
electro physiological methods make them particu
migraine attacks).2 In about 20% of patients, migraine
larly wellsuited to study of the cyclic functional brain
attacks are preceded by or associated with an aura com
changes associated with migraine.5 Investigators using
posed of transient focal neurological symptoms, such as
these techniques have demonstrated that the migrainous
scintillating scotomata (blurred areas in the visual field),
brain has altered functioning between migraine attacks,
University of Bari, Italy
par aesthesias or language disturbances. As interictal
and that this brain dysfunction undergoes cyclic changes
(M.d.T., S.S.). University
symptoms and overt brain lesions are absent, migraine
up to initiation of the attack.6 Various electrophysiologi
of Palermo, Italy (F.B.).
is commonly considered to be a prototypic functional
cal parameters have been studied in migraine research,
G. B. Bietti Foundation, IRCCS, Italy (G.C.).
brain disorder.
including multimodal evoked potentials, steadystate
C. Mondino Institute of
The common migraine types, migraine with and
visual evoked responses, noxious evoked cortical
Neurology Foundation, IRCCS, Italy (G.S.).
without aura, are determined by complex inter
responses, and nociceptive reflexes. The results have
Ospedale Pediatrico
actions between multiple additive genetic, environ
provided three main sets of observations, which were
Bambino Gesù, IRCCS,
mental, hormonal and endogenous (cognitive and
consistent across most studies. First, between attacks, a
Italy (M.V.). University of Ghent, Belgium
emotional) factors.3 These factors modify dynamic
stimulusfrequencydependent increase occurs in photic
(D.M.). Liège University,
interactions between various brain areas and compo
driving and synchronization of EEG alpha (8–13 Hz) and
Belgium (J.S.). Headache Clinic,
nents that define the individual's level of susceptibil
beta (13–30 Hz) rhythms. Second, the interictal migrain
Istituto di Ricovero e
ity to migraine. The susceptibility level fluctuates and
ous brain is characterized by a habituation (or adapta
Cura a Carattere
at times becomes sufficiently intense to precipitate a
tion) deficit of cortical evoked responses to repetitive,
Scientifico (IRCCS) Neuromed,
migraine attack. The neural components involved in
nonnoxious sensory stimuli—this deficit normalizes
Via Atinense 18,
susceptibility to migraine include the cerebral cortex,
during an attack. Third, responses or reflexes evoked
Pozzilli, 86077 Isernia, Italy (A.A., A.P., F.P.).
brainstem, hypothalamus and thalamus, as well as
by noxious stimuli also fail to habituate interictally, but
this abnormality does not reverse during an attack. It
Correspondence to: A.A.
Competing interests
should, however, be noted that not all studies confirmed
The authors declare no competing interests.
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Key points
Another interesting aspect of visual y induced changes
■ Migraine is the most prevalent neurological disorder in the general population
in EEG recordings is that they might differ between
and exerts a considerable societal burden; in some patients, migraine becomes
migraine types. Some SSVEP studies found no differ
unremittingly chronic
ences between migraine with and without aura,13 but
■ Electrophysiological studies can characterize the abnormal functioning of the
one study showed that interhemispheric SSVEP asym
migrainous brain between, immediately before and during attacks, and aid
metry was increased in about half of patients affected
monitoring of the effects of therapeutic interventions
by migraine with aura, whereas in those with migraine
■ Most electrophysiological studies of migraine describe functional changes
without aura, the amplitude of the second harmonic was
between attacks, including hyperresponsivity to repeated sensory stimuli
increased.14 Another group found an increased ampli
with abnormal temporal processing, malfunctioning sequential recruitment of neuronal networks, and impaired habituation
tude of the second harmonic in both migraine groups,
■ The abnormalities of sensory processing vary over the migraine cycle: they
but an augmented amplitude of the fourth harmonic at
worsen preictally but tend to disappear during the attack; furthermore, the
high spatial frequency only in patients who had migraine
abnormalities differ between episodic and chronic migraine
with aura.15 The investigators interpreted their results as
■ Refined neurophysiological investigations suggest that the cyclic brain
reflecting increased responsivity of the primary visual
dysfunctions in migraine might be related to an abnormal cross-talk between
cortex in both types of migraine, albeit with extension
thalamus and cortex (thalamocortical dysrhythmia)
of this increased responsivity to include secondary
■ Understanding the dysfunction of temporal information processing in
visual areas in migraine with aura. This hypothesis is
migraine paves the way for novel acute and preventive therapies, including pathophysiology-based neuromodulatory techniques
being further tested in studies of EEG mapping during
intermittent visual stimulation, as described below.
In this Review, we describe the data on alterations of
neuronal processing in patients with migraine, affect
The role of neuronal networks in determining responsiv
ing habituation, potentiation, summation, sequential
ity of the brain to visual stimulation can be assessed com
dipolar source activation, and synchronization. We
prehensively by studying the synchronization and causal
provide an overview of these neurophysiological studies
connections of different brain areas using nonlinear
and describe the novel methods used to explore func
analysis methods. In healthy individuals, the oscillatory
tional brain connectivity in the migrainous brain. We
activity in the alpha range is suppressed during flicker
pay particular attention to the temporal dimension of
stimulation, possibly as a result of desynchronization.16
these abnormalities, which seems crucial to understand
By contrast, in patients who have migraine without aura,
ing the functional brain changes in migraine and their
the alpha rhythm remains highly synchronized across
different brain areas during visual stimulation.17 This
pattern does not depend on the alpha amplitude, but
EEG changes induced by visual stimuli
pertains to the synchrony of temporal activation and
Increased photic driving
dynamic interactions (such as functional connectiv
Many studies have focused on steadystate visual evoked
ity) between brain areas,18 and to their modification by
potentials (SSVEPs), which are the EEG response to
sensory stimuli. Some researchers have suggested that
repetitive visual stimulation. SSVEPs are not generated
functional connectivity is determined by both cortico
by amplitude modulation; instead, they primarily result
cortical and thalamocortical loops.19 The mechanisms
from phase alignment of the ongoing background EEG
underlying temporal synchrony of EEG rhythms are
activity7 with the changes in frequency of the repeti
not simply a result of the balance between excitatory
tive stimulus. This phenomenon, called photic driving,
and inhibitory inputs. Anticonvulsants, for instance,
reflects the tendency of cortical neurons to synchronize
modulate alpha rhythm synchronization differentially:
their firing with the frequency of the visual stimuli.
topiramate, an established migraine preventing drug, has
Although normal brain activity is entrained by repeti
no effect on alpha oscillations, whereas levetiracetam,
tive lowfrequency (±10 Hz) light stimuli, increased
which might also be effective in migraine prevention,
photic driving has been described in response to
reduces alpha synchronization.20 Lowfrequency repeti
mediumfrequency (±20 Hz) light stimuli in patients
tive transcranial magnetic stimulation (rTMS), which
with migraine, and is called the H response.8 SSVEPs to
has been studied as a preventive treatment in migraine
flash stimuli in the mediumfrequency range confirmed
and is thought to inhibit the underlying occipital cortex,
increased photic driving in individuals with migraine,
has no effect on alpha phase synchronization.21
without any relation to migraine severity or duration.9,10
Oscillatory properties of neuronal networks can be
This observation was interpreted as hyperresponsivity
accurately assessed by measuring the directed flow of
of the brain to visual stimuli. Further analysis showed
information between their components, using Granger
that in patients with migraine, SSVEP amplitude was
causality22,23 or dynamic causal modelling,24 both of
less stable over time than in controls.11 Fluctuation of
which measure effective connectivity. Granger causal
increased photic drive over the migraine cycle has also
ity detects connectivity only in linear data; however,
been reported.10,12 This instability, changes over the
a modified version, kernel Granger causality,23can
migraine cycle, and methodological differences prob
be used to infer direct dynamic influences from non
ably explain some of the contradictory results reported
linear signals such as EEG data. In a preliminary study,
in the literature.12
individuals who had migraine without aura showed
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properties and characteristics of habituation27 have been
revised and refined,28 but the underlying neural mecha
nisms are still not completely understood. Habituation
has multiple roles, ranging from pruning of irrelevant
information to protection of the cerebral cortex against
overstimulation. This phenomenon has been studied to
disentangle the neuronal substrates of behaviour, learn
ing processes, and processing of CNS information in
Migraine without aura (
n = 19)
health and disease.29–32
Migraine with aura (
n = 19)
Controls (
n = 11)
The majority of interictal evoked potential studies
in patients with migraine support the notion that the
migrainous brain is characterized by impaired habitu
ation to repetitive stimuli. The habituation deficit is
observed across several sensory modalities, and is usual y
accompanied by a normal to low amplitude of early
responses in averaged data. Lack of habituation is the
most prominent (and probably genetically determined)
consequence of the functional brain abnormality that
characterizes many migraine patients between attacks.33
Of note, the abnormal visual information processing
that occurs in migraine between attacks corresponds
neither to sensitization nor to dishabituation (that is,
restoration to the full strength of a response previously
weakened by habituation). It is accompanied by initially
decreased or normal amplitude of response after a small
number of stimuli, followed by a stable amplitude, or
even a transient amplitude increase (potentiation).34–43
Figure 1 Temporal evolution in effective connectivity, as
The first evidence for altered interictal habituation in
revealed by kernel Granger causality analysis of averaged
patients with migraine came from studies of contingent
EEG data. Recordings were taken from patients with
negative variation (CNV), a slow eventrelated corti
migraine and healthy controls during a 10 s flash
cal response representing higher mental functions.44–47
stimulation at a 21 Hz frequency.
a In the alpha band,
Subsequently, deficient habituation was demonstrated
causal/effective connections across scalp derivations are
for another eventrelated potential, P300, which is eli
weaker in individuals with migraine without aura than in
cited in the process of decisionmaking after visual48
those with migraine with aura or individuals with no
migraine (healthy controls).
b By contrast, individuals
or auditory49,50 stimulation. Deficient habitu ation was
with migraine with aura have increased causality across
also subsequently described for several other modality
cortical areas in the beta band. This phenomenon might be
specific evoked potentials: patternreversal visual
subtended by increased cortical activation in migraine with
evoked potentials (VEPs),33–42 visual evoked magneto
aura during visual stimulation. The figure is based on data
encephalographic (MEG) responses,43 auditory evoked
from a study by de Tommaso
et al.25
potentials (AEPs),51,52 and somatosensory evoked poten
tials (SSEPs).53–55 Several other studies, however, were
increased phase synchronization in the alpha band and
not able to reproduce these results and found no habitu
reduced connectivity during intermittent flash stimula
ation deficit in individuals with migraine, possibly
tion, whereas those who had migraine with aura dis
because of differences in the methods used or selection
played clear desynchro nization in the beta frequency
of patients.56–62
range and increased connectivity during visual stimula
The reasons for the discrepant results of habituation
tion (Figure 1).25 Given that brain activation is now
studies are not fully understood. Insufficient blinding of
described in terms of increased connectivity of different
the investigator has been suggested as a possible culprit;63
functional brain networks, visual stimulation seems to
however, since the same researchers have found the same
induce a more vigorous cortical activation and spread
result (that is, normal habituation) in individuals with
of information in migraine with aura than in migraine
migraine in both blinded and nonblinded studies,57 and
without aura (which is charac terized by weak interaction
lack of habituation has also been reported in a blinded
between cortical regions), possibly because of a prevalent
study, this factor is unlikely to be the sole cause.64 Factors
resonance of rhythmic activity generated at subcortical
directly related to the pathophysiology of migraine are
and thalamic levels.22
probably involved. For instance, the habituation deficit
does not remain constant in individuals with migraine.
Evoked responses to non-noxious stimuli
The deficit varies over the migraine cycle: it is profound
Impaired habituation
during the interictal state, normalizes briefly before
Habituation—a response decrement as a result of
and during the attack and increases again a few days
repeated stimulation26—is a multifactorial process. The
after the attack.65 Moreover, genetic variants can have an
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effect on habituation profiles.66,67 Finally, spontaneous
contrasts with the interictal habituation deficit observed
clinical worsening or improvement of attack frequency
in episodic migraine. Interestingly, the habituation
can influence the baseline level of thalamocortical activa
deficit reappears when patients evolve from chronic
tion68,69 and, hence, the degree of habituation in patients
to episodic migraine.83 Since the response pattern in
chronic migraine is indistinguishable from that observed
during migraine attacks,43,51–62,70–72 our research group has
Variation over the migraine cycle
suggested that patients with chronic migraine are locked
Episodic migraine
in an ictallike state.84
Episodic migraine is, by definition, a cyclic disorder.
The most prevalent factor associated with the tran
The attack itself is not an abrupt event, but the result
sition from episodic to chronic migraine is acute
of a sequential process that might start as the socalled
medication overuse. In medication overuse headache
prodromal or premonitory symptoms several hours
(MOH), the cortical response pattern suggests that the
before the aura or the headache. Moreover, attack fre
brain is locked in a preictal state, characterized by an
quency varies over the patient's lifetime. It is, therefore,
increased amplitude of responses to intermittent stimuli
of major pathophysiological interest to study the changes
(sensitization) and a consistent deficit of habituation to
in brain responsivity associated with various stages of
continuous or repetitive stimuli.54 This pattern might
the migraine cycle. During the days preceding an attack,
vary with the class of drug overused. In triptan over
CNV and P300 habituation is minimal, and the ampli
users, the initial SSEP amplitude is normal, whereas it is
tude of these responses is maximal.70,71 Within the
increased in overusers of NSAIDs and in those overusing
12–24 h immediately preceding an attack, and during
drugs from both classes.54,85 In both groups of overusers,
the attack, habituation of evoked potentials normalizes.
however, SSEP habituation was abnormal.
This pattern has been shown for CNV,36,70,71 VEP,57,72 and
SSEP61 amplitudes, and for visual P300 latency.73 The
Possible mechanisms of habituation
R2 component recorded during blink reflexes—evoked
Genetic predisposition is likely to influence the brain's
by an electrical stimulus delivered with a classic non
responsivity patterns, although its effects are variable
nociceptive surface electrode—showed a habituation
between patients and migraine types. In migrainous
deficit in patients before a migraine attack,76 although in
child–parent pairs, habituation of evoked potentials
another study only slight habituation abnormalities were
has a clear familial pattern.66,71 Moreover, in asympto
found interictally.77 In a longitudinal study of brainstem
matic individuals who have a firstdegree relative with
AEPs, habituation of wave IV–V amplitude was deficient
migraine, and are thus at risk of developing migraine
in patients with migraine, but did not change over the
during their lifetime, cortical evoked potentials79 and
migraine cycle.78
nociceptive blink reflexes86 (nBRs, discussed under
To our knowledge, no single satisfactory explanation
processing of noxious stimuli below) showed amplitude
exists for the cyclic nature of episodic migraine, except
and habituation abnormalities similar to those found
for the one related to the ovarian cycle and variations
interictally in people with migraine.
in sex hormone levels. Nonetheless, various experimen
The neural mechanisms underlying habituation and
tal data suggest some interesting avenues for further
its impairment in patients with migraine remain poorly
research. For instance, cortical responsivity is cyclic in
understood.87 In theory, habituation deficits could be due
individuals with migraine,71 and varies in parallel with
to increased excitatory mechanisms, decreased activity
changes in platelet serotonin content.73 The period
of inhibitory interneurons, or reduced baseline activa
icity of neurophysiological brain activity might also
tion of sensory cortices according to the ‘ceiling' theory.
be related to psychophysical, genetic66,79 or metabolic
This theory postulates that an individual's sensory cor
factors,80 or to the biorhythms of hypothalamic activity.81
tices have variable baseline activation levels, but their
Migraine periodicity might thus be the result of several
maximum activation level (the ceiling) remains constant.
inter acting biological cycles. Indeed, the migraine cycle
During repetitive stimulation, the maximum activation
is probably caused not by a single determining factor,
level is reached rapidly, and subsequently the response
but by a complex interplay between intrinsic cerebral,
amplitude decreases sharply (habituation) in individu
hormonal and environmental factors acting on a geneti
als with normal baseline activation, while habituation
cally predisposed nervous system. Disentanglement
is delayed or absent in individuals in whom baseline
of this interplay is a challenge for future research, and
activation is low.88 Both increased cortical excitability
will be a prerequisite for the development of effective
and decreased activity of inhibitory neurons would be
expected to give rise to a high initial response ampli
tude, indicating genuine hyperexcitability, and a linear
Chronic migraine
decrease on habituation. The ceiling theory can also
Cortical responsivity is different in episodic and chronic
account for the normal or decreased initial amplitude
migraine. For instance, the initial amplitude of visual
and the nonlinear and cyclic changes in habituation.
MEG responses (P100m) was greater in chronic migraine
Studies of highfrequency oscil ations (HFOs) embed
than in interictal episodic migraine.82 Moreover, these
ded in evoked cortical responses have contributed to our
responses show substantial habituation (comparable to
understanding of the abnormal information processing
that of healthy controls) to repetitive stimuli,82 which
in migraine. The amplitude of early HFOs embedded in
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Response habituation
Interictal lack of
Ictal normalization of
Normalization of interictal lack
in healthy controls
habituation in migraine
habituation in migraine
of habituation after HF-rTMS
Decreased Increased Increased
Figure 2 Cortical response patterns during the migraine cycle. This schematic overview shows amplitude changes in the
N20–P25 component of averaged EEG recordings in patients with migraine and healthy controls.
a HFOs and
b somatosensory evoked potentials. In healthy controls (panel 1), the N20–P25 component habituates, and early HFOs
(reflecting thalamocortical drive) are greater than late HFOs (generated by intrinsic cortical activation). In patients with
migraine between attacks (panel 2), habituation is absent and early HFOs are reduced, although late HFOs are normal. During
a migraine attack (panel 3), habituation and early HFOs normalize. After 10 Hz HF-rTMS is applied over the somatosensory
cortex in patients with episodic migraine (panel 4), the interictal lack of habituation reverses, and both early and late HFOs
increase. Abbreviations: HFO, high-frequency oscillation; HF-rTMS, high-frequency repetitive transcranial magnetic stimulation.
the common SSEPs, which is thought to reflect spiking
of P50 middlelatency AEPs92 and the significant habit
activity in thalamocortical cholinergic afferents, is
uation deficit in late visualevoked highfrequency
decreased interictally in patients with migraine and
activity (oscillations in the gamma range, 20–35 Hz),93
normalizes during attacks, whereas that of late HFOs,
in comparison with healthy controls. Taken together,
which probably reflect the activity of inhibitory cor
these studies indicate dysfunction of thalamocorti
tical interneurons, remains normal89 or decreases90
cal oscillatory networks, and patients with migraine
between attacks. Moreover, a reduction in amplitude
might, therefore, be considered to have thalamocortical
of early HFOs is associated with worsening of the clini
cal course of migraine.68 Contrasting with these results,
The thalamocortical dysrhythmia theory postulates
increased amplitudes of early and late HFOs has been
that when anatomical or functional disconnection of the
reported between attacks in patients with migraine.91
thalamus from subcortical areas is present, the rhythmic
These dis parate findings might be a result of differences
thalamocortical activity might change to favour low
in recording parameters and patient selection.
frequency activity (mainly 4–7 Hz theta waves). At the
In patients with migraine, activation of the sensori
cortical level, this change will result in reduced firing
motor cortex induced by 10 Hz rTMS increased the
rates of excitatory pyramidal cells at the beginning of
amplitude of early and late HFOs in SSEPs, and induced
stimulation, and of fastspiking inhibitory interneurons
habituation of the broadband SSEP.55 rTMS significantly
during stimulus repetition.94,95 Reduced firing of fast
increased the amplitude of late HFOs, but had no effect
spiking interneurons leads to disinhibition of adjacent
on either early HFOs or habituation of the broadband
cortical columns, which is reflected by a progressive rise
SSEP in nonmigrainous controls, probably because
in highfrequency gamma band oscillations—the so
their thalamocortical activity was already maximal at
called edge effect.95 This theory could explain both the
baseline.55 These observations support the hypothesis
reduced thalamic and thalamocortical activity observed
that the habituation deficit in patients with migraine is
with HFOs, and the rise in late visualevoked gamma
due to reduced thalamic activation and, hence, reduced
band oscillations.
baseline activation of sensory cortices. Concordant data
Several findings support the thalamocortical dysrhyth
indicate that the interictal habituation deficit and low
mia theory. Shortrange lateral inhibition in the visual
initial amplitude of VEPs in individuals with migraine
cortex is more pronounced in migraine patients than
normalizes after 10 Hz rTMS over the visual cortex.36
in healthy volunteers at the beginning of the stimulus
Further evidence that control of thalamocortical activ
session.65 Moreover, shortrange lateral inhibition in
ity is abnormal in people with migraine between attacks
the visual cortex increases over successive responses
is suggested by the marked reduction in sensory gating
in people with migraine, but remains unchanged in
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healthy controls.65 Several quantitative EEG studies in
Processing of noxious stimuli
individuals with migraine have shown a widespread
Another feature that is present in patients with
increase in slow (mostly theta) oscillatory activity,
migraine concerns the altered processing of nociceptive
chiefly over temporooccipital areas,96,97 which similarly
stimuli, which has been studied using nocicep
concords with the thalamocortical dysrhythmia theory.
tive trigeminal and biceps femoris reflexes, as well as
thermonociceptiveinduced cortical evoked responses.
Amplitude–stimulus intensity functionAnother timerelated modality of stimulus processing
The nociceptive flexion reflex
that seems to be altered in people with migraine is the
Pain disorders are commonly accompanied by central
progressive amplitude adaptation of cortical responses
sensitization, which amplifies the CNS response to
to repetitive stimuli of increasing intensity, which is
painful stimuli. This amplification also occurs during
referred to as the amplitude–stimulus intensity function.
migraine attacks108 and worsens with increasing attack
When stimuli are delivered at increasing intensity, the
frequency.109 One mechanism underlying central sensi
evoked cortical responses increase in certain individu
tization is the activitydependent change in excitability
als, but decrease in others.98 This socalled augmenting–
of central nociceptors, which results in abnormal ampli
reducing response has been widely studied, mainly in
fication of pain sensation in physiological nociception—
the context of auditory stimuli. The intensity depend
a phenomenon referred to as temporal summation of pain
ence of AEPs (IDAP) is expressed by the amplitude–
stimuli110 that is equivalent to ‘windup' phenomenon
stimulus intensity slope of the cortical N1–P2 wave,
(facilitation of widedynamicrange nociceptive neurons
where N1 is the greatest negative component 60–150 ms
located in the deep laminae of the spinal cord dorsal horn
post stimulus and P1 is the greatest positivity from
and the spinal trigeminal nucleus after constantintensity
120–200 ms. Interestingly, IDAP correlates inversely with
stimulation of C fibres) in animal experiments.111
central serotonergic transmission, as evaluated indirectly
The nociceptive flexion or withdrawal reflex (NWR) is
by biochemical and pharmacological methods.99
a reliable measure of spinal nociception, as demonstrated
Although the grand average of longlatency AEPs
by the fact that it requires Aδfibre activation, that the
has normal latency and amplitude in patients with
reflex threshold is related to the pain perception thresh
migraine,57,100 IDAP is significantly increased inter
old, and that the reflex magnitude correlates positively
ictally compared with healthy volunteers in most51,52,72—
with pain intensity ratings.112,113 Temporal summation
although not all57—studies. IDAP normalizes the day
of pain develops in paral el with tem poral summation of
before and during the migraine attack, similarly to VEP
the NWR of the lower limbs, reflected by a progres
habituation.72 In fact, the interictal increase in IDAP
sive increase in magnitude of the NWR after constant
in people with migraine can be attributed to a habitu
intensity electrical stimulation (which activates both
ation deficit of the cortical response to highintensity
Aδ and C fibres,113–115 and is inhibited by
Nmethyld
auditory stimuli.52 IDAP is also strongly influenced by
aspartate receptor antagonists).116 Interestingly, descend
sensory overload.101 Indeed, when IDAP is assessed
ing pain control systems modulate temporal summation
during intense flash stimulation, two subgroups of
of the NWR,117 and might be dysfunctional in a number of
patients with migraine can be identified—one reacts
chronic pain dis orders, including migraine. For example,
to the stimulus by a decrease in IDAP, as do controls,
studies of tem poral summation of the NWR in people
whereas the other reacts by an increase in IDAP. The
with migraine show facilitation of temporal pain pro
underlying neuro biological basis of this difference
cessing between attacks.118 Administration of a nitric
between clinical y similar patients is unknown, but might
oxide donor, such as glyceryl trinitrate, induces transi
be related to differences in genetic background and/or
tory facilitation of temporal summation of the NWR
within 120 min in patients who will go on to develop a
An increased IDAP (that is, an augmenting pattern)
glyceryl trinitratetriggered migraine attack several hours
suggests the presence of decreased central serotonergic
transmission.102,103 A high IDAP correlates positively with
In individuals with chronic headache, such as MOH
clinical symptoms of major depression104 that are thought
in the setting of episodic migraine, the threshold for
to be associated with decreased serotonergic signal
temporal summation of the NWR is markedly reduced
ling, and normalizes in depressed patients treated with
compared with that in controls or in patients with epi
selective serotonin reuptake inhibitors.105 IDAP abnor
sodic migraine, which indicates strong facilitation in
malities also correlate with personality traits thought
the temporal processing of pain.118 In patients with
to be associated with decreased serotonergic transmis
MOH, the painsuppressing effect of supraspinal diffuse
sion in individuals with migraine.106 Treatment with
noxious inhibitory control (pain inhibition by hetero
migrainepreventing drugs such as βblockers, which
topic painful stimulation) on temporal summation of
increase serotonergic transmission, normalizes the
the NWR is deficient.118 This effect, which in humans
increased interictal IDAP in patients with migraine.107
is termed conditioned pain modulation,120 can be tested
All things considered, the increased IDAP in migraine
by heterotopic application of a painful cold stimulus.119
could be secondary to reduced activity of raphe corti
The deficits in conditioned pain modulation or supra
cal mono aminergic pathways, which causes low baseline
spinal diffuse noxious inhibitory control and facilitation
activation levels of auditory cortices.
of temporal summation of the NWR normalize after
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neuropathic pain in healthy volunteers,127 and with
the caudal displacement of cortical evoked potentials
in the cingulate gyrus after intramuscular nociceptive
stimulation of the trapezius muscle in patients with
migraine.128 This difference with the data on LEPs can
be explained by the different methodologies used, which
involved stimulation of different nociceptive afferents.129
Similarly to the cortical evoked potentials elicited
by nonnoxious stimuli, LEPs75,130 and CHEPs131 show
habituation deficits in patients with migraine between
attacks. However, in contrast with nonnoxious cortical
evoked potentials, the lack of habituation of LEPs persists
during the attack, and is associated with an increased
Patients with migraine (GTN)
N2–P2 amplitude.132
Patients with migraine (placebo)
Nonlinear analysis of ongoing EEG changes reveals
Controls (placebo)
subtle changes in the cortical response to painful laser
stimuli in patients with migraine.133 For example, indi
viduals with episodic migraine have markedly reduced
predictability of their EEG rhythms after the laser stimu
Temporal summation threshold of the nociceptive withdra
lus compared with healthy individuals, although their
Figure 3 Facilitation of temporal pain processing between migraine attacks.
averaged LEPs seem normal; however, the averaging
Facilitation of the temporal summation threshold of the biceps femoris nociceptive
technique used to extract evoked potentials from the
withdrawal reflex is markedly more facilitated by glyceryl trinitrate administration
background EEG signals might neglect subtle changes
(versus placebo) in patients with migraine than in healthy controls. Abbreviation:
in the processing of pain by the brain. Future studies
GTN, glyceryl trinitrate. Permission obtained from John Wiley and Sons, West
using analysis of single (nonaveraged) nociceptive
Sussex (UK),
Eur. J. Pain 15, 482–490 (2011).
evoked potentials, refined neurophysiological techniques
and a combination of neurophysiological and imaging
drug withdrawal, which could be related to the reduc
methods will help to characterize the pathophysiologi
tion in activity of anandamide hydrolase (also known
cal features of central processing of pain in patients with
as fatty acid amide hydrolase) and, hence, slowing of the
migraine. In chronic migraine and MOH, painrelated
degradation of endocannabinoids.121
cortical potentials as a response to electrical forehead or
forearm stimulation were facilitated, but no change was
Nociceptive trigeminal evoked responses
observed in the nBR.134
The nBR is evoked in orbicularis oculi muscles by stim
ulating the supraorbital nerve via a concentric high
Thalamocortical dysrhythmia in migraine
density electrode, which mainly activates Aδ afferents.
Given the results of the abovedescribed neurophysio
This reflex is mediated via interneurons of the spinal
logical studies, the pathogenesis of migraine seems to be
trigeminal nucleus. Migraine is characterized by an
driven by complex dysfunction of thalamocortical con
interictal deficit of nBR habituation during both short74
nectivity and temporal activation of neuronal networks.
and long38 series of stimuli. nBR habituation normal
Thalamocortical dysrhythmia might also explain the
izes during migraine attacks,74 and individuals at risk
phenomena observed in patients with migraine who are
of developing migraine lack nBR habituation deficits,86
treated with transcranial neuromodulation techniques—
whereas habituation of nociceptive laserevoked poten
for instance, the increased variability of dynamic changes
tials (LEPs, discussed further below) remains deficient.75
in excitability135 or the paradoxical homeostatic cer
Patients with migraine also show temporal summation
ebral plasticity.136–138 In a proofofconcept study, the
plastic cortical changes induced by rTMS were found
Brief radiant heat pulses generated by CO laser stim
to be inversely related to thalamocortical activation.139
ulation or contact thermodedelivered stimuli excite
This observation suggests that the paradoxical effects
Aδ and C fibre thermonociceptors in superficial skin
observed after rTMS in patients with migraine might be
layers.123 In turn, the Aδ fibre input generates LEPs or
a consequence of abnormal thalamocortical drive, which
contactheat evoked potentials (CHEPs) in the cortex.
impairs shortterm and longterm changes in cortical
The N2–P2 component of LEPs and CHEPs is thought
synaptic effectiveness, and finally leads to maladaptive
to be generated in the posterior part of the anterior
responses. Taken together, the dysfunctions found in the
cingulate cortex and in the bilateral insula.124
migrainous brain suggest an impairment of thalamo
Compared with healthy controls and people with epi
cortical control of temporal activation of different
sodic migraine between attacks, the brain distribution of
LEP is shifted rostrally in patients with migraine during
Thalamocortical dysrythmia has also been pro
an attack125 and in patients with chronic migraine.126
posed to underlie other functional brain disorders.140,141
This anterior shift of activation contrasts with the pos
In patients with chronic neuropathic pain, over
terior shift of LEPs observed during capsaicininduced
activation in the theta and beta range—suggestive of
150 MARCH 2014 VOLUME 10
2014 Macmillan Publishers Limited. All rights reserved
trigeminovascular system and induce a migraine attack.
Mitochondrial ATP
Also, whether the abnormal temporal processing of noci
of sensory cortices
Deficient habituation
ceptive information predisposes to migraine attacks,
of evoked potentials
central sensitization and, possibly, chronic migraine is not
proven, but would intuitively seem probable. However,
and connectivity
the fact that the interictal cortical hyperrespons ivity to
Amygdala, hypothalamus
sensory stimuli in migraine can be alleviated by neuro
PAG, monoaminergic nuclei
stimulation techniques55 (see below) and by preventive
(familiar or sporadic
antimigraine drugs, both of which also decrease attack
hemiplegic migrane)
frequency,107 supports indirectly the hypothesis that the
Central sensitizing
brain dysfunction between attacks could predispose
of pain processing
patients to recurrent attacks. Considering that the cer
Potentials evoked by
Cortical spreading
ebral energy reserve (ATP content) between attacks is sig
Nociceptive blink reflex
nificantly lower in individuals with migraine compared
Temporal summation of
nociceptive withdrawal reflex
with healthy individuals,80 it is tempting to speculate that
the cortical hyperresponsivity might contribute to dis
ruption of the brain's metabolic homeostasis by increas
Amplifies and persists in
ing energy demand, thereby initiating the biochemical
cascade that leads to the migraine attack.6
Figure 4 A neurophysiological model of migraine pathogenesis. Activation of the
trigeminovascular system—the main pain-signalling system in the brain—triggers
Prospects for clinical research
migraine headache (1). The migraine aura is caused by CSD, which may or may not
The results of MRI studies suggest that migraine is
activate the trigeminovascular system. Genetic channelopathies (2) predispose to CSD in the rare familial and sporadic hemiplegic forms of migraine. Interictal
associ ated with altered interictal functional connectivity
thalamocortical dysrhythmia causes hyperresponsivity of sensory cortices (3) as
in subcortical and cortical areas that are devoted to cog
well as abnormal pain processing (4). The thalamocortical dysrhythmia itself may
nitive functions and pain processing.144,145 Connectivity
be induced by decreased control from brainstem monoaminergic nuclei (5).
was stronger between the periaqueductal grey and
Cortical hyperresponsivity combined with a decreased mitochondrial energy
several brain areas associated with pain processing, such
reserve favours metabolic strain (6). This process could trigger CSD in the cortex
as the prefrontal cortex, anterior cingulate and amygdala,
and, via subcortical chemosensitive structures, activate the trigeminovascular
areas that are very similar to brain regions implicated
system. The migraine attack is associated with sensitization of central nociceptive
in neurophysiological data on sequential cortical activa
pathways (7). Abnormalities of responses evoked by noxious stimuli amplify and persist in chronic migraine (8). Dashed lines indicate hypothetical connections, for
tion during painful stimuli.125,126,144,146 Diffusionweighted
which there is currently little or no experimental evidence. Abbreviations: CSD,
MRI studies showed that microstructural alterations of
cortical spreading depression; PAG, periaqueductal grey.
white matter, and thus of functional connectivity, are
present across the orbitofrontal cortex, insula, thala
thalamocortical dysrhythmia—was found in the corti
mus and dorsal midbrain.147 These alterations might
cal ‘pain matrix'. In six patients who were successfully
reflect maladaptive plastic changes driven by dysrupted
treated by central lateral thalamotomy, the overactivity
exo genous and endogeneous multimodal task process
attenuated along with the pain.142
ing.147 In another fMRI study, thalamic sensitization cor
Further assessment with modern neuroimaging
related with widespread mechanical al odynia during the
methods will be required to disentangle the anatom
migraine attack.148 Moreover, in a diffusion tensor MRI
ical correlates of thalamocortical dysrhythmia in
study, our research group found dynamic ictal and inter
migraine. A functional MRI (fMRI) study in people
ictal microstructural variations in the thalamus that were
with migraine revealed a lack of habituation of the
related to the time since the last migraine attack, and
blood oxygen leveldependent signal during repetitive
seemed to mimic the cyclic neurophysiological changes
trigeminal nociceptive stimulation in areas of the pain
described above.149
matrix (anterior insula and middle cingulate gyrus).143
Collectively, these observations suggest that a search
Interestingly, this difference between patients with
for optimal methods of influencing the cortical tem
migraine and healthy controls was not found for olfac
poral processing of exogenous stimuli that can trigger
tory stimuli, which the researchers attributed to the fact
a migraine attack, or methods for modulating endo
that olfaction is not relayed in the thalamus.
genous trigeminal noxious inputs that lead to central
Our research group has proposed that hypofunction
sensitization and eventually chronic headache, could
ing serotoninergic projections to the thalamus and cortex
result in novel interventions for migraine prevention. The
might cause functional disconnection of the thalamus,
modes of action of anticonvulsants or antidepressants, as
leading to thalamocortical dysrhythmia and reduced
well as of other pharmacological or nonpharmacologi
cortical habituation (Figure 4).40
cal interventions, such as neuromodula tion methods,
It has not yet been demonstrated whether the altered
should be reconsidered in terms of their ability to nor
synchronicity and deficient habituation of neuronal
malize the complex abnormalities of brain connectivity
responses to external stimuli in migraine has a role in
and hyperresponsivity found in patients with migraine.150
the cortical predisposition to spreading depression,
For example, noninvasive cortical neuromodulation
or in other phenomena that are able to activate the
techniques such as rTMS and transcranial direct current
NATURE REVIEWS NEUROLOGY
VOLUME 10 MARCH 2014
151
2014 Macmillan Publishers Limited. All rights reserved
Box 1 Neurophysiological findings associated with migraine
differs between patients with migraine and healthy con
trols (Box 1). The neuronal networks involved in sensory
Several abnormalities of sensory processing may be observed in patients with
processing are characterized by different modalities of
sequential recruitment under different environmental
Interictal light-induced EEG changes
or endogenous conditions. The patterns of temporal
■ Stimulus-frequency-dependent increase in photic drive
activation have been analysed over a range of neuronal
■ Alpha frequency synchronization and decrease in functional connectivity
(in migraine without aura)
activities, from progressive changes of neuronal recruit
■ Beta frequency desynchronization and increase in functional connectivity
ment in the habituation or intensity dependence phenom
(in migraine with aura)
ena, to facilitation of noxious stimuli summation, and
Interictal (and ictal) changes in non-noxious sensory evoked potentials
complex patterns of variability, phase synchronization
■ Trend towards lower amplitude of averaged responses to brief sequences
and causality that are adapted to describe the properties
of repeated stimuli
of a chaotic and nonlinear system. These intricate pro
■ Deficient habituation during prolonged stimulus repetition (normalizes
cesses not only differ between patients with migraine and
healthy individuals, but also vary according to the phases
■ Increased intensity-dependence of auditory evoked potentials (normalizes
of the migraine cycle in the same patient.
The mechanisms underpinning these complex changes
Interictal (and ictal) changes in noxious sensory evoked responses
are far from being understood, and how they fit into the
■ Deficient habituation of cortical evoked responses (persists during attack)
puzzle of migraine pathogenesis is still unclear. Owing
■ Deficient habituation of nociceptive blink reflexes (normalizes during attack)■ Facilitation of temporal summation of the biceps femoris flexion reflex
to their complexity, however, the brain dysfunctions are
unlikely to be explained simply by an imbalance between
Changes in chronic migraine■ Increased amplitude of averaged cortical responses to small numbers of
excitatory and inhibitory circuits.87 We propose that
repeated non-noxious and noxious stimuli
thalamocortical dysrhythmia could be the culprit for
■ Deficient habituation of sensory evoked responses to noxious stimuli despite
abnormal central processing of nonnoxious and noxious
normal habituation of sensory responses evoked by non-noxious stimuli
sensory stimuli in patients with migraine, and that the
thalamocortical dysrhythmia itself might be caused
by genetically determined inadequate control of the
stimulation (tDCS) have already been assessed in clini
thalamus and cortex by monoaminergic (serotonergic)
cal trials. Several studies have investigated the hypoth
projections originating in the brainstem (Figure 4). We
esis that the cortex in patients with migraine patients
further postulate that the cortical hyperresponsivity to
is hyperexcitable between attacks. However, inhibitory
sensory stimuli might contribute causally to migraine
lowfrequency rTMS over the vertex had no superior
attack repetition, because it favours excessive energy
therapeutic effect to sham stimulation,151 and cathodal
expenditure in a brain with a reduced energy reserve.
(inhibitory) tDCS over the occipital cortex had no signifi
To reduce discrepancies between studies, more atten
cant preventive effect on migraine attacks , although the
tion should be paid to blinding of investigators, so that
latter intervention did reduce attack intensity compared
accurate clinical data and headache diaries can be col
with placebo.152 By contrast, in a pilot trial designed to
lected before and during testing. In addition, prospec
assess an alternative hypothesis—that the visual cortex
tive studies should be conducted to monitor patients'
is not hyperexcitable
per se, but, rather, insufficiently
clinical fluctuations throughout the migraine cycle. It
activated at baseline (as described above87)—anodal
will also be of utmost importance to gather more data
(facilitatory) tDCS over the occipital cortex significantly
on the (neurophysiological) phenotype–genotype cor
decreased attack frequency and intensity when used as
relations in patients with the various migraine types.
preventive therapy in patients with migraine.150
Finally, improved insight into the nature of the inter
The challenge for future research, therefore, lies in
ictal dysfunction of temporal information processing in
identification of the precise anatomical structures and
individuals with migraine will, we hope, pave the way
functional networks involved in migraine, and determi
for novel therapeutic targets, and could herald improved
nation of which pharmacological and nonpharmacologi
cal interventions can optimal y modulate the function of
these areas and thereby improve temporal information
processing. Such investigations wil involve simultaneous
recordings of the abovereported phenomena via neuro
We initially searched the PubMed database to identify
physiological and functional neuroimaging techniques,
articles published up to June 2013. The search terms
along with the application of nonlinear algorithms to
used were "migraine", "electroencephalography",
model brain complexity.153 Novel therapeutic inter
"EEG", "evoked potentials", "habituation", "temporal summation", "nociceptive withdrawal reflex" and "blink
ventions can then be tested for their capacity to normal
reflex", alone and in combination. The literature search
ize the anatomical and functional changes associated
was updated using the additional keywords "migraine",
with migraine and its subtypes.
"habituation" and "evoked potentials" to identify full-text papers written in English and published in peer-reviewed
journals up to December 2013, using the PubMed and
Most of the data described here suggest that the cortical
Google Scholar databases. Reviews were considered only
processing of nonnoxious and noxious sensory stimuli
when they introduced new concepts or hypotheses.
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2014 Macmillan Publishers Limited. All rights reserved
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125. de Tommaso, M.
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and without hearing loss.
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All authors researched data for and participated in
analysis of laser-evoked potentials during
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writing of the article. In addition,M.d.T., A.A., G.C., F.P.
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Abnormal thalamocortical activity in patients
M.d.T., A.A. and J.S. contributed to reviewing and/or
processing of pain in chronic migraine.
with complex regional pain syndrome (CRPS)
editing of the manuscript before submission. M.d.T.
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type.
Pain 150, 41–51 (2010).
and A.A. contributed equally to this manuscript.
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Source: http://www.amicacard.it/data/convenzionanti/upload/63068/studio%20Nature_emicrania.pdf
Cloning of the nptII gene of Escherichia coli and construction of a recombinant strain harboring functional recA and nptII antibiotic resistance S. Ghanem Botany and Microbiology Department, Faculty of Science, Helwan University, Ain Helwan, Cairo, Egypt Corresponding author: S. Ghanem
Immunopharmacology and Immunotoxicology, 28:1–7, 2006Copyright © Informa HealthcareISSN: 0892-3973 print / 1532-2513 onlineDOI: 10.1080/08923970601067045 g , Vol. 28, No. 4, November 2006: pp. 1–14 A Pilot Study of an anti-MRSA Bio-Engineered Lacteal Complex (anti-MRSA BLC) in a Murine Septicemia Model Nix, and D.W. DeYoung