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
Altered processing of sensory stimuli in patients with migraineAltered processing of sensory stimuli in patients with migraineMarina 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.
144 MARCH 2014 VOLUME 10
2014 Macmillan Publishers Limited. All rights reserved 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 NATURE REVIEWS NEUROLOGY VOLUME 10 MARCH 2014 145
2014 Macmillan Publishers Limited. All rights reserved 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 146 MARCH 2014 VOLUME 10
2014 Macmillan Publishers Limited. All rights reserved 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 NATURE REVIEWS NEUROLOGY VOLUME 10 MARCH 2014 147
2014 Macmillan Publishers Limited. All rights reserved 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 148 MARCH 2014 VOLUME 10
2014 Macmillan Publishers Limited. All rights reserved 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 NATURE REVIEWS NEUROLOGY VOLUME 10 MARCH 2014 149
2014 Macmillan Publishers Limited. All rights reserved 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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and A.A. contributed equally to this manuscript.
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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