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Abstract

Although migraineurs appear in general to be hypersensitive to external stimuli, they maybe also have increased daytime sleepiness and complain of fatigue. Neurophisiological studies between attacks have shown that for a number of different sensory modalities the migrainous brain is characterised by a lack of habituation of evoked responses. Whether this is due to increased cortical hyperexcitability, possibly due to decreased inhibition, or to an abnormal responsivity of the cortex due a decreased preactivation level remains disputed. Studies using transcranial magnetic stimulation in particular have yielded contradictory results. We will review here the available data on cortical excitability obtained with different methodological approaches in patients over the migraine cycle. We will show that these data congruently indicate that the sensory cortices of migraineurs react excessively to repetitive, but not to single, stimuli and that the controversy above hyper- versus hypo-excitability is merely a semantic misunderstanding. Describing the migrainous brain as ‘hyperresponsive’ would fit most of the available data. Deciphering the precise cellular and molecular underpinnings of this hyperresponsivity remains a challenge for future research. We propose, as a working hypothesis, that a thalamo-cortical dysrhythmia might be the culprit.

Keywords

Migraine hyperresponsivity evoked potentials transcranial magnetic stimulation habituation pathophysiology thalamocortical dysrhythmia

INTRODUCTION

Despite great advances in knowledge about its pathophysiological facets, the exact pathogenesis of migraine is still not entirely understood.

Among the various neuronal structures that seem involved in migraine pathophysiology, the cerebral cortex has long been of interest, because the aura of the migraine attack clearly has a cortical origin and because in between attacks there are indications of global hypersensitivity to external stimuli in migraine patients during, and perhaps more interestingly, between attacks. Unfortunately, contradictory results have been obtained with neurophysiological methods used to assess excitability of the cerebral cortex, in particular with transcranial magnetic stimulation (TMS), which have led to controversy about the presence or not of interictal cortical hyperexcitability in migraine. Beyond the published results using TMS, we will review here the available clinical and neurophysiological data providing information about the response properties of the cortex to a stimulus in migraineurs. We will show that these data congruently indicate the sensory cortices of migraineurs react excessively to repetitive stimuli, and that the controversy is chiefly generated by a semantic misunderstanding.

The semantic controversy

In its strict physiological definition of a stimulus–response curve, the cortex would be hyperexcitable if it produces a response to a subliminal stimulus and/or if its response to a supraliminal stimulus is increased in amplitude. The cerebral cortex, however, is a complex neuronal network in which other response characteristics, such as change in discharge frequency, anatomical extent of the response or response modulation with persistent stimulation, may reflect different sensitivities to stimulations. All non-invasive neurophysiological methods used to study the responsiveness of the human brain to a stimulus are based on the recordings of the response of a complex population of neurons, not of single cells, which usually therefore integrate a number, if not all, of these response parameters. This largely explains why in the literature abnormal spread of evoked activity in the visual cortex of migraineurs (1) is considered as reflecting ‘hyperexcitability’, and why this interpretation is challenged (2) because the amplitude of visual evoked potentials (VEPs) is not increased in migraine, but rather decreased for low numbers of stimuli. To avoid further controversy, it would thus be preferable to abandon the term ‘hyperexcitability’ in favour of ‘hyperreactivity’ or ‘hyperresponsivity’ to characterize the response pattern of the migrainous brain to repeated stimulations. As we will see, what matters in terms of metabolic and/or functional consequences is the global output of cortical neurons to external stimuli. As a matter of fact, although the sensory cortex of a migraineur may respond normally or subnormally to a series of stimuli, in case of a deficit in habituation, its global response pattern over time, and thus its energy demands, can be exaggerated when stimuli persist or are repeated.

The migraine-related bias

Another peculiarity in migraine which may add to contradictory results between studies is the fact that the cortical response pattern undergoes dramatic changes during the attack. These changes appear up to 24 h before the beginning of the attack and may outlast it for at least 24 h, and may thus remain unrecognized if the timing of neurophysiological recordings in relation to the last/next attack is not precisely determined.

The objective

This article provides an overview of the studies on ‘cortical responsivity’ in migraine with different methodological approaches, with emphasis on the more recent data.

CORTICAL RESPONSIVITY AS JUDGED BY CLINICAL FEATURES

Interictal hypersensitivity to external stimuli

Migraine patients seem to be very susceptible to any kind of sensory overload.

For example, migraine patients are more sensitive to environmental light stimuli (3–5), which are even able to trigger an attack, in particular in migraine with aura (MA). Optical stimulation with grating patterns produces more visual discomfort and more intense illusions in migraineurs between attacks than in normal subjects (6–9). Migraine patients also have a lower auditory discomfort threshold compared with healthy subjects (8). Decreased auditory and visual discomfort thresholds seem to be migraine markers (10, 11) and they decrease even more so during the attack (8).

Behavioural response: reaction times

Several studies have investigated the involvement of executive functions by means of event-related potentials, with different paradigms, and by neuropsychological tests. Studies reporting reaction times (RTs) and error data (omissions to targets and responses to standards) recorded during a cognitive paradigm have documented either no significant differences between pain-free patients and controls in mean RTs (12–17), or longer (18, 19) or faster RTs (20). In several studies, migraineurs have been found to make more errors than controls (17). Neurophysiological tests have also found either normal (21–25), slower (26) or faster RTs (27).

Interestingly, RTs increase just before (28), during (12, 21) and for some time after the migraine attack (28).

Although the studies on reaction times do not allow any definitive conclusions about cortical responsivity, the contrasting results could be explained by the inverted U-shape relation between performance and level of arousal (reviewed in Hebb (29)).

Sleep and migraine

A relation seems to emerge between rapid eye movement (REM) sleep and the initiation of night-time headache (30), and between morning arousals with migraine and larger amounts of stage III–IV and REM sleep during the preceding night (31). Göder et al. (32) have performed sleep recordings during the nights preceding a migraine attack in two migraine without aura (MoA) patients. They found a significant decrease in the number of arousals, a decrease in REM sleep density, a significant decrease in beta power in the slow wave sleep, and a decrease of alpha power during the first REM period, and interpreted these data as a decrease in cortical activation during sleep preceding migraine attacks. Moreover, loss of dimensional complexity in the second sleep cycle was observed examining non-linear EEG measures during the development of a spontaneous migraine attack (33). Reduction in nocturnal motor activity close to the attack was observed by means of actigraphy and self-report diaries in children with MoA (34).

The study by Della Marca et al. (35) is the only full-night polysomnographic study in a group of MoA patients during pain-free nights. It shows a reduction in the cyclic alternating pattern and a lower index of high-frequency EEG arousals during REM sleep, which was interpreted by the authors as reflecting a general hypoactivity of the arousal systems in migraine during sleep.

One-quarter of migraine patients complain of sleepiness during various phases of an attack, including the pain and postdromal phases (36). Moreover, sleep disorders, such as parasomnias (somnambulism and nightmares), are more frequent in migraine patients than in controls (37, 38). In an uncontrolled study (39) and in a case–control study (40) excessive daytime sleepiness (EDS) has been found in migraineurs.

These results of electrophysiological and clinical studies tend to indicate a reduction of cortical arousal in migraine between attacks and reduced cortical activation during sleep, especially during the nights preceding an attack.

CORTICAL RESPONSIVITY AS JUDGED BY NEUROPHYSIOLOGICAL TESTS

Standard evoked potentials

During the last 30 years, evoked and event-related cortical responses have been extensively studied in migraine. Almost every stimulus modality has been used, but particularly visual and auditory stimulations. Various interictal abnormalities have been reported by analysing the evoked responses in a classical way of averaging a large number of single responses, mainly increased amplitudes (see Ambrosini et al. for a review (41)). When habituation of the evoked potential is assessed by averaging successive blocks of responses, the most consistent abnormality found in migraineurs between attacks is a deficit of habituation, or potentiation. This has been reported for visual (42), auditory (43, 44), somatosensory (45), cognitive (28, 46–50) and painful stimuli (51, 52).

The habituation deficit may have a familial character and was proposed as an endophenotypic marker for migraine (53, 54), as it can be found in asymptomatic subjects belonging to migraine families and thus at risk of developing the disorder (54, 55).

Short-term habituation or adaptation is defined as ‘a response decrement as a result of repeated stimulation’, and usually exhibits an exponential course (56). This behavioural phenomenon has been observed in neuronal circuits of any level of complexity. Habituation is a common feature of cortical responses to visual, auditory, olfactory and somatosensory stimuli, because it helps to limit the response range of neurons to encode sensory signals with much larger dynamic ranges. Although neural adaptation occurs at multiple stages of each sensory pathway, it is often stronger and more stimulus specific at cortical rather than subcortical stages, suggesting that additional cortical mechanisms contribute to habituation (57): it protects the cortex against the overflow of inward information and, at the same time, prepares the stimulated neuronal networks for the appearance of subsequent stimuli. Habituation is also a seminal phenomenon in learning processes (56, 58).

In theory, the habituation deficit in migraine could be due to hyperexcitability (secondary to hyperexcitable excitatory neurons) (59) or hypoexcitable inhibitory interneurons (60). The data showing that, besides the lack of habituation, evoked potentials are characterized in migraine by a low amplitude of the first block of averagings ((18, 42, 45, 61); review by Ambrosini et al. (41)) do not fit with the hyperexcitability hypothesis, which predicts the opposite, i.e. an increased amplitude. Interestingly, VEP habituation is inversely related to first block amplitude in migraineurs, but not in healthy volunteers, suggesting that in the former the habituation deficit may be a consequence of an initial hypoactivation of the visual cortex (62). We have therefore hypothesized that migraine patients have interictally a reduced preactivation level of sensory cortices, possibly due to insufficient activation by aminergic projections from the upper brainstem (2). Further support in favour of this hypothesis comes from studies of high-frequency oscillations embedded in standard evoked cortical potentials and from those using repetitive TMS to modify cortical excitability and evoked potentials (see below).

High-frequency oscillations

Appropriate filter settings allow the detection of high-frequency oscillations (HFOs) that are embedded within the classical broadband components of standard evoked potentials. They are thought to reflect spike activity in thalamo-cortical cholinergic fibres (early HFOs) and in cortical inhibitory GABA-ergic interneurons (late HFOs). In a study of somatosensory evoked potentials, we found that early HFOs were decreased in migraine, whereas late HFOs were normal (63), which suggests that activity in thalamo-cortical afferents is reduced, but activity in cortical inhibitory interneurons normal. We have also analysed the oscillations of lower frequency embedded in VEPs, gamma-band oscillations (GBOs), thought to reflect subcortical (early components) and cortical activity (late components) (64). The amplitude of early GBOs was increased in MA patients, which could be the electrophysiological correlate of visual discomfort (65, 66), a frequent interictal complaint in migraineurs. Moreover, there was a significant habituation deficit of the late GBO components in migraineurs relative to healthy controls. Taken together, these results indicate, on the one hand, that habituation of evoked potentials, and thus the dishabituation found in migraine, are predominantly cortical phenomena. On the other hand, they suggest that the dysfunction in cortical oscillatory networks could be due to abnormal thalamic control. High-frequency oscillations in thalamo-cortical neurons depend strongly on dendritic and astrocytic calcium conductances mediated by T-type Ca²⁺ channels (67–69). A change in thalamo-cortical activity due, for example, to an anatomical or functional disconnection of the thalamus from its controlling inputs (e.g. aminergic brain stem nuclei) can favour low-frequency activity, which at the cortical level will reduce lateral inhibition and enhance high-frequency phase-locked discharges in cortical networks of inhibitory interneurons. This is postulated to underlie the so-called ‘thalamo-cortical dysrhythmia syndromes’ (69, 70). Applied to migraine, this model would imply that a serotonergic disconnection of the thalamus, for example, can enhance low-frequency and gamma-frequency activity leading, respectively, to a deficit in habituation of broadband VEP and visual-evoked gamma-band oscillations (64).

In conclusion, the electrophysiological data discussed above favour a decrease of thalamo-cortical activity in migraine between attacks, which might explain the initial low cortical reactivity (low first block amplitude in evoked potential studies) and, possibly via reduced lateral inhibition, subsequent lack of habituation which allows, after a number of stimuli, the building up of a globally exaggerated response, i.e. hyperresponsivity.

Transcranial magnetic stimulation

TMS is an interesting tool, as it can non-invasively explore the excitability of certain cortical areas and, via repetitive stimulation (rTMS), durably modify it.

Magnetophosphenes

TMS of the visual cortex can produce phosphenes (magnetophosphenes), prevalence and threshold studies of which have provided conflicting results in migraineurs. Decreased (59, 60, 71–77), increased (78) and normal phosphene thresholds (PT) have indeed been reported (79–82). Device- and/or patient-related methodological differences may account for some of the discrepancies, but in particular the lack of reliability and reproducibility of subjective reports of phosphenes. When PTs were determined at five different time periods, variability was much greater in migraineurs than in healthy volunteers (83).

Another interesting finding shedding light on the contradictory magnetophosphene data comes from a study by Lo et al. (84), who compared the clinical characteristics of MoA patients who did perceive phosphenes (66%) with those who did not (34%). The latter had significantly higher attack frequency and pain scores, suggesting that patients with more severe migraine symptoms have a lower excitability of the visual cortex.

Motor evoked potentials

TMS studies of motor cortex have the advantage of relying on an objective measure, the motor evoked potential (MEP) recorded in peripheral muscles. Globally, thresholds for MEP are normal (77, 78, 80, 85) or increased in migraine (79, 86, 87), except in familial hemiplegic migraine, where decreased thresholds have been reported by one group (88, 89). Using paired TMS pulses, intracortical facilitation was found in one study (90), but not in another (79). The silent period (SP), which interrupts voluntary muscle activity after a single TMS pulse over the motor cortex and reflects both cortical and spinal mechanisms, was normal (85) or reduced (71). We have recently found in MA and MoA patients a reduction in the cortical SP recorded from facial muscles, which could reflect reduced intracortical inhibition (91).

Repetitive transcranial magnetic stimulation

VEPs can be used as objective indices of cortical excitability changes after rTMS. Bohotin et al. (92) found that in migraineurs 10-Hz rTMS, which facilitates the underlying cortex, increased moderately amplitude in the first block of 100 VEP averagings and normalized habituation over six successive blocks, whereas 1-Hz rTMS, which inhibits the underlying cortex, had no significant effect on habituation. By contrast, in healthy subjects 1-Hz rTMS reduced first block amplitude as well as habituation, whereas 10-Hz rTMS had no effect.

The above-mentioned rTMS-induced VEP changes had on average an after effect of 30 min. In a subsequent study searching for cumulative effects of repeated rTMS applications, we have shown that five consecutive daily sessions of rTMS over the occipital scalp induced VEP changes lasting up to several weeks in 50% of healthy subjects tested, but only several hours in most migraineurs, except in two patients in whom a change, i.e. an improved habituation by 10-Hz rTMS, persisted for 2 and 7 days (93).

TMS modulation of psycho-physical visual tests

It is well known that adequately timed TMS pulses are able to interfere with cortical functions. In migraine the inhibitory effect of TMS on visual processing has been studied in particular. MA patients were thus found less susceptible to TMS suppression of perceptual accuracy than both MoA and healthy subjects (60, 76, 94), which is in line with another evaluation of perceptual suppression of a single target using metacontrast masking (95). These findings suggest that inhibitory mechanisms are impaired in the visual cortex of MA patients, but the potential confounding role of habituation or attention-guided visual selection were not taken into account.

Transcranial direct current stimulation

Transcranial direct current stimulation (tDCS) is another atraumatic method able to modify the excitability of the underlying cortex: cathodal tDCS is inhibitory, anodal tDCS excitatory. Chadaide et al. (82) have studied the effect of tDCS on TMS-elicited PTs. Although baseline PTs and the anodal tDCS-induced PT decrease were similar between migraine patients and normal subjects, cathodal stimulation, which increased PT in healthy subjects, had no significant effect in the patient groups. This was found by the authors to strengthen the notion of deficient inhibitory processes in the visual cortex of migraineurs.

Magnetoencephalography

Since magnetoencephalography (MEG) records activity mainly from tangentially oriented cortical dipoles, it was thought to be the most suitable atraumatic method in migraine to detect cortical equivalents of the cortical spreading depression (CSD) phenomenon. In the first studies, indeed, various combinations of large-amplitude waves, suppression of spontaneous cortical activity and slow potential shifts were recorded during attacks chiefly in MA (96). In a later study (97), the same group confirmed during spontaneous and visually induced migraine aura the occurrence of slow potential shifts very similar to those found during CSD in animals and abnormal spread of visual-evoked activity, but the large-amplitude waves were found to be ocular artefacts (98).

In a patient having a migrainous scintillating scotoma in the right hemifield, a recent MEG study has shown alpha-band desynchronization in the opposite extra-striate and temporal cortex for the duration of the visual disturbance, and gamma-band desynchronization peaking 10 min following the aura (99).

Taken together, the MEG findings are favour of the occurrence of a cortical phenomenon similar to CSD during the migraine aura. They provide no evidence, however, favouring cortical hyperexcitability per se in migraine between attacks.

Effect of antimigraine drugs on neurophysiological tests

There is common agreement on effective preventive drug treatments in migraine, although their prioritization remains controversial. Prophylactic antimigraine drugs, such as β-blockers (e.g. propranolol), anticonvulsants (e.g. topiramate and valproate), tricyclic antidepressants (e.g. amitriptyline), antiserotonergic drugs (e.g. methysergide) and metabolic enhancers (e.g. riboflavine, coenzyme Q10) belong to very different pharmacological classes, which a priori suggests that they act on different pathophysiological aspects. The effect on neurophysiological tests of these drugs has been explored in migraine patients.

Mulleners et al. (100) have examined the effect of sodium valproate on the threshold for magnetophosphenes. They found that treatment with the drug was associated with an increase of thresholds in MA patients (in whom pretreatment thresholds were low), but not in MoA patients (in whom pretreatment thresholds were higher). Their conclusion was that the 30-day treatment with valproate had increased the inhibitory GABAergic tone in the cerebral cortex, a hypothesis which may be correct but does not take into account other effects of valproate such as that on cerebral serotonin content. Aurora et al. (76) have reported normalization of increased cortical excitability assessed with magnetic suppression of visual accuracy (see above) after 1 month's treatment with 100 mg topiramate. In contradistinction, topiramate was not able to normalize the abnormal pattern of EEG hypersynchronization during sustained flash stimulation, whereas levetiracetam was able to do so in another study (101), in which both drugs were reported to be clinically effective.

Beta-blockers effective in migraine prophylaxis, such as propranolol or metoprolol, decrease amplitude and increase habituation of contingent negative variation (CNV), an event-related slow cerebral potential (50, 102–104), and of visual evoked responses (105–107). Interestingly the post-treatment clinical improvement correlates positively with the amplitude decrease of the steady-state visual response (107), and a positive correlation has been found between the pretreatment CNV amplitude and the clinical efficacy of β-blockers (102, 103). After treatment with β-blockers, the increased intensity dependence of auditory evoked cortical potentials (IDAP) also tends to normalize, a decrease that is significantly correlated with clinical improvement (108). By contrast, in the same study riboflavin, which is thought to act in migraine by improving mitochondrial energy metabolism, had no effect on the IDAP.

Interestingly, selective serotonin reuptake inhibitors, which have not been found consistently effective in migraine, are also able to decrease amplitude of the steady-state VEP (femoxetine) (107) or the first block of the pattern-reversal VEP (fluoxetine) (109).

The recent study by Ayata et al. (110) showing that chronic administration of a number of different antimigraine prophylactics (topiramate, valproate, propranolol, amitriptyline or methysergide) reduces the occurrence and threshold of CSD in rats has raised great interest, since it tends to suggest that CSD inhibition is the master-key in migraine prevention (111). At the present time, however, there is no proof that CSD occurs in MoA, and drugs such as lamotrigine, effective in MA but not in MoA, or riboflavin, which has a priori no effect on neuronal excitability (108, 112), were not tested. That preventive antimigraine drugs do not act on a unique pivotal aspect of migraine pathophysiology is further underlined by their incomplete (therapeutic gain <50%) and variable efficiency.

CORTICAL RESPONSIVITY AS JUDGED BY FUNCTIONAL NEUROIMAGING

Blood flow and oxygen consumption are useful surrogate markers to detect synaptic activity in the brain, but do not allow to determine whether the underlying physiological event is excitatory or inhibitory, or another energy-consuming process. Positron emission tomography (PET) and functional magnetic resonance imaging (fMRI) methods have been used in migraine. We will not review here in detail the results obtained during attacks: activation in the dorsal part of the upper brain stem first reported by Weiller et al. (113) and activation in the pain neuromatrix as well as in auditory and visual cortices, the latter being attributed to the ictal sono- and photophobia; spreading parieto-occipital oligemia preceded by a brief hyperoxia which occurs during the visual aura and is compatible with CSD (114, 115). We will mainly concentrate on the few studies performed during the interictal state.

Positron emission tomography

In migraine patients who developed medication overuse headache, 18-fluoro-deoxy-glucose-PET has shown hypometabolism in several areas belonging to the pain network, such as insula, thalamus and anterior cingulate cortex (116). These hypometabolic areas tended to normalize after drug withdrawal, with the exception of the medial orbitofrontal cortex, where the hypometabolism worsened after withdrawal.

In an interictal PET study of the distribution of 5-HT1A receptors, increased binding of [18F]MPPF was found in the parieto-occipital cortex of MoA patients, suggesting reduced serotonergic innervation of these cortical areas (117). This is in line with the finding by Chugani et al. (118) of an increased whole brain 5-HT synthesis capacity in migraineurs with α-(11C) methyl-L-tryptophan PET.

Functional magnetic resonance imaging

With a visual incongruent line stimulation protocol, activation has been shown with fMRI in the contralateral visual cortex of four out of five MA patients, but only one of four controls; the remaining controls had, however, activation in the frontal cortex (119). This study confirms that cortical responsivity may have region-specific differences between migraineurs and healthy subjects.

In another interictal study using square wave gratings as visual stimulus (120), MA patients, in addition to reporting visual distortions and illusions, had an increased BOLD signal in the visual cortex, indicating an exaggerated response to the repeated stimuli.

The same authors (121) used a visual masking test to explore visual cortex inhibitory function with fMRI. The reduction in cortical activation associated with reduced target visibility or its invisibility was not different between MA patients and age- and sex-matched non-headache controls, suggesting that visual cortical inhibitory function was not impaired in migraine under the experimental conditions. This tends to be confirmed by another fMRI study (122), in which a weaker BOLD signal was found during stringent visual stimulation in 10 migraine patients (with and without aura), and this hypoactivation was proportional to the frequency and severity of migraine attacks. By contrast, when visual stimulation is prolonged, a progressive increase of cortical occipital activation was found in migraineurs (with and without aura), a pattern resembling the potentiation of VEP (see above), whereas there was habituation of the BOLD signal in healthy volunteers (123).

Finally, with 3H-MR spectroscopy searching for occipital lactate changes during visual stimulation, Sándor et al. (124) have reported increased baseline lactate levels in patients suffering from migraine with strictly visual auras, whereas patients with complex neurological auras had normal baseline levels, but lactate increases during visual stimulation.

The interictal fMRI studies confirm therefore that cortical responsivity to visual stimuli is abnormal in migraineurs. Exaggerated responses and lack of habituation to certain visual stimulation patterns have been reported, but stringent stimuli might induce subnormal activation. Whether the changes observed in occipital lactate levels reflect anaerobic metabolism or a disturbance in the astrocyte–neuron lactate shuttle remains to be determined.

Near-infrared spectroscopy and transcranial Doppler sonography

Near-infrared spectroscopy (NIRS) allows the evaluation of cerebral haemodynamic changes associated with functional brain activity by optical spectroscopic measures of oxyhaemoglobin and deoxyhaemoglobin concentrations. Using this method, two independent research groups have found in migraine patients a reduced vasodilatory response and oxyhaemoglobin increase induced by hypercapnia during breath holding (125, 126).

Zaletel et al. (127) have recorded simultaneously VEPs and cerebral blood flow velocity responses in the posterior cerebral artery and found significantly higher flow velocity increases in migraineurs (in proportion to the contrast of the checkerboard stimulation pattern) compared with healthy subjects, whereas VEP amplitudes did not differ between the two groups. They concluded that neurovascular coupling is increased interictally in migraine.

These studies suggest that the vascular and metabolic response may be proportionally greater than the neuronal response in migraineurs compared with healthy controls.

PERI-ICTAL CHANGES IN CORTICAL RESPONSIVITY

Prominent changes in evoked cortical potentials, and thus cortical responsivity, occur during and immediately before the migraine attack.

Sequential recordings have shown that during the days preceding the attack CNV amplitude and habituation deficit (128, 129) as well as the P300 habituation deficit (12) become maximal. During this time period migraineurs also show an exaggerated CNV amplitude increase and habituation decrease to stressful events (28).

Within the 12–24 h that immediately precede the attack, i.e. at a time point when so-called premonitory symptoms may occur, the pattern of evoked potentials surprisingly normalizes. This has been shown for intensity dependence of auditory evoked potentials (130) and habituation of CNV (41, 128, 129), VEP amplitude (130) and visual P300 latency (12), but nociceptive evoked potentials may behave differently (131). The normalization of electrocortical patterns is most pronounced during the attack itself and it takes 1 or 2 days after the attack before evoked potentials again become abnormal (130).

CONCLUSIONS

To summarize (Fig. 1), clinical, neurophysiological, as well as neuroimaging studies have disclosed abnormalities of cortical responsivity to external stimuli in both types of migraine between attacks.

Figure 1

Schematic view of the connexions between subcortical nuclei controlling thalamic and cortical excitability (on the left) and the changes at each anatomical level (on the right) leading interictally to increase, preictally to further increase and ictally to normalization of cortical habituation and responsivity.

The most reproducible abnormality in evoked potential studies is a deficit of habituation during stimulus repetition, of which the metabolic correlate has recently been demonstrated in functional neuroimaging studies. The underlying causes are not fully understood, but neuronal hyperexcitability is an oversimplified and misleading explanation. On the one hand, some studies suggest that insufficient cortical inhibitory processes might be responsible for the lack of habituation. There is, on the other hand, converging evidence from clinical and electrophysiological data that the preactivation level of sensory cortices is reduced because of inefficient thalamo-cortical drive. As a matter of fact, deficient inhibition and low preactivation may coexist, since the latter can promote the former via reduction of lateral inhibition. The final consequence on the functional properties of the cerebral cortex is a heightened response to repeated stimuli, i.e. hyperresponsivity, which results in an exaggerated energy demand and possibly in subtle cognitive dysfunction (17).

There is some indirect evidence that the thalamo-cortical dysrhythmia and ensuing decreased preactivation level of sensory cortices might be due to hypoactivity of the so-called state setting, chemically addressed subcortico-cortical projections (132). Among the latter, the serotonergic pathway seems to be the most relevant, but interactions between amines are well known (133–140).

It is well established that cortical responsivity fluctuates over time in relation to the migraine attack. It grows and leads to increased energy demands during the days immediately preceding the attack when habituation of evoked potentials reaches its minimum and amplitude its maximum. By contrast, just before the attack, at a time point when premonitory symptoms may occur, and during the attack habituation increases and normalizes, accompanied by increased thalamo-cortical drive (63). We postulate that these electrophysiological changes are due to further preictal decrease of serotonergic neurotransmission and cortical preactivation level, which flip to increased serotonergic transmission and preactivation levels during the attack. Interestingly, increased serotonin disposition (12, 134) and activation in the area of the raphe serotonergic neurons (113, 141), which contains state-setting aminergic nuclei projecting to thalamus and cortex, was observed during the migraine attack.

Finally, as hypothesized previously (2), cerebral metabolic homeostasis may be disrupted by the increased energy demands due to the ictal and, even more so, preictal cortical hyperresponsivity, because the neuronal energy reserve seems to be decreased in migraineurs (142–144). This may lead to ignition of the major alarm-signalling system of the brain, the trigeminovascular system, and thus to the migraine attack. During the latter, activation of the endogenous pain control systems would lead to increased central serotonergic transmission and normalization of cortical responsiveness, ‘by which this condition is dispersed and the equilibrium for the time restored’ (Edward Living 1873).

ACKNOWLEDGEMENTS

J.S.’s research activities are supported by research grant 3.4.563.04 of the National Fund for Scientific Research (Belgium), EU STREP EUROHEAD (LSHMCT-2004–5044837) and special research funds of the Faculty of Medicine-Liège University-Belgium.

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Is The Cerebral Cortex Hyperexcitable or Hyperresponsive in Migraine?

Abstract

Keywords

INTRODUCTION

The semantic controversy

The migraine-related bias

The objective

CORTICAL RESPONSIVITY AS JUDGED BY CLINICAL FEATURES

Interictal hypersensitivity to external stimuli

Behavioural response: reaction times

Sleep and migraine

CORTICAL RESPONSIVITY AS JUDGED BY NEUROPHYSIOLOGICAL TESTS

Standard evoked potentials

High-frequency oscillations

Transcranial magnetic stimulation

Magnetophosphenes

Motor evoked potentials

Repetitive transcranial magnetic stimulation

TMS modulation of psycho-physical visual tests

Transcranial direct current stimulation

Magnetoencephalography

Effect of antimigraine drugs on neurophysiological tests

CORTICAL RESPONSIVITY AS JUDGED BY FUNCTIONAL NEUROIMAGING

Positron emission tomography

Functional magnetic resonance imaging

Near-infrared spectroscopy and transcranial Doppler sonography

PERI-ICTAL CHANGES IN CORTICAL RESPONSIVITY

CONCLUSIONS

ACKNOWLEDGEMENTS

References