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Abstract

Migraine is a very common disorder occurring in 20% of women and 6% of men. Central neuronal hyperexcitability is proposed to be the putative basis for the physiological disturbances in migraine. Since there are no consistent structural disturbances in migraine, physiological and psychophysical studies have provided insight into the underlying mechanisms. This is a review of the neurophysiological studies which have provided an insight to migraine pathogenesis supporting the theory of hyperexcitability.

Keywords

Migraine hyperexcitability neurophysiology psychophysics

INTRODUCTION

The exact pathogenesis of migraine remains to be determined. Migraine is an episodic disorder involving head pain and cortical phenomena without structural abnormalities. Therefore, only investigations aimed at studying the function of the brain provide an insight into migraine pathophysiology. Some studies which have been reviewed in the literature support the concept of central neuronal hyperexcitability as a pivotal physiological disturbance predisposing to migraine (1). The reasons for increased neuronal excitability may be multifactorial. Through genetic studies abnormality of calcium channels has been introduced as a potential mechanism of interictal neuronal excitability (2). Mutant voltage-gated P/Q type calcium channel genes probably influence presynaptic neurotransmitter release, possibly of excitatory amino-acid systems. Other genetic studies have demonstrated dysfunction in the ATP1A2 gene, which encodes an ion pump (3, 4). Recently, data in episodic ataxia and hemiplegic migraine patients with no mutation in either CACNA1A or ATP1A2 have demonstrated that a heterozygous mutation in EAAT1 can lead to decreased glutamate uptake, which can contribute to neuronal hyperexcitability to cause seizures, hemiplegia and episodic ataxia (5). It could therefore be hypothesized that genetic abnormalities result in a lowered threshold of response to trigger factors, since migraine is an episodic disorder involving head pain and cortical phenomena without structural abnormalities (6).

This paper will provide an overview the neurophysiological and psychophysical studies in migraine.

ELECTROENCEPHALOGRAM

Electroencephalography (EEG) was one of the first techniques which was undertaken to discern physiological differences between migraine and controls. A review suggests that EEG is not valuable as a diagnostic tool for primary headache disorders (7). In contrast, the technique has provided some useful information to be used in the research setting. This subject has been detailed elsewhere (8, 9) and only highlights will be presented here. Researchers have utilized four paradigms to study the EEG in migraine, namely background rhythm, photic or ‘H-response’, mapping techniques using spectral analysis, and magnetoencephalography (MEG). Slowing of background rhythm, both generalized (10, 11) and focal (9, 12–14), is described in children and adults during a migraine, but these findings are not universally reported (15–17). In a study where migraine was diet-induced, EEG was abnormal in 32% of patients on day 1or 2 (18). In another study of patients with nitroglycerin-induced migraine, the abnormal EEG rhythm disappeared after treatment with sumatriptan (19). Non-specific abnormalities on EEG were also modified by flunarizine in one study (18). It has been suggested that the enigmatic epileptic–epileptoid characteristics of EEG in migraineurs could be an expression of the electrically hyperactive ‘quasi epileptic foci’ located mainly within the brainstem and generated by the insufficient opioid inhibition of peptidergic neurons (20). The enhanced photic drive response on the EEG ‘H-response’ was thought to be characteristic of migraine (21), as recently confirmed by spectral analysis (22, 23). The specificity of the ‘H-response’, however, has been questioned, since it may occur with other primary headache disorders (7).

Recently, brain mapping using quantitative-topographical EEG (qEEG) (24) has been applied to study migraine. Briefly, unilateral reduction of alpha activity was demonstrable in migraine with visual aura in adults (25) and in children (26). This disturbance of alpha asymmetry was chiefly observed within 3 days of an attack. Some studies have showed an increase in alpha1 power (24, 27, 28), but a study in children has not documented a difference from controls (29). Finally, non-specific abnormalities on EEG have been modified with flunarizine in one study (30).

Magnetoencephalogramic studies have revealed large amplitude waves and DC shifts in migraine (31). These electromagnetic phenomena are reminiscent of those described with experimental cortical spreading depression (CSD) (32). Using the visual trigger modelled by Cao et al., Bowyer et al. have now been able to detect DC shifts when headache or aura are precipitated. These studies were performed using whole-head MEG, which permits precise localization of signals. In this study, headache was triggered in five of eight migraine patients and none of six controls. DC MEG shifts were observed in migraine subjects during visually triggered aura and in a patient studied during the first few minutes of spontaneous aura. No DC MEG shifts were seen in control subjects. This is additional evidence supporting the primary neural basis of migraine and confirms MEG-recorded DC shifts typical of those found during SCD, reported previously in migraine attacks. DC MEG waveforms arising during migraine aura were used to determine the effectiveness of prophylactic medication therapy with valproate on neuronal hyperexcitability. Using visual stimulation, widespread regions of hyperexcitability were detected throughout the occipital cortex in migraine patients, explaining the susceptibility for triggering spreading cortical depression and migraine aura. After 30 days of prophylactic treatment, reduced DC MEG shifts in the occipital cortex and reduced incidence of migraine attacks were observed. This study has confirmed that MEG can non-invasively determine the status of neuronal excitability before and after therapy (33). Similar findings have been found with topiramate (unpublished HFH MEG lab).

EVOKED POTENTIALS

Visual evoked potentials (VEP)

Various paradigms have been used to study migraine. Abnormal steady-state response evoked by a sine-wave visual stimulus (SVEP) was seen in migraineurs, and improved after administration of propranolol (34–36). A study using topographic analysis has confirmed these abnormal SVEP findings (37). Using flash or checkerboard pattern stimulation, studies have demonstrated differences in the amplitude of the visual evoked responses in migraineurs compared with controls (38–41); the increase in amplitude of VEP was demonstrated immediately after a migraine attack in two patients with migraine with aura (MA). One study has also demonstrated reduction of P100 amplitude after treatment with β-blockers (38). A multichannel VEP study has shown that migraineurs with visual hemianopia aura exhibited asymmetries in the VEP amplitude distribution (42).

Difference in latencies of the VEP have been reported in some migraine studies (43, 44), but not in others (45, 46). Finally, following a repetitive pattern-reversal stimulation, migraineurs, but not controls, displayed potentiation of VEP amplitude which reached its maximum in the second to fourth blocks (47). Similar results have been seen using prolonged stimulation (48).

Auditory evoked potentials

Drake has reported normal brainstem auditory evoked potentials (AEPs) in migraineurs (49). More recently, however, and in agreement with VEP studies, strong interictal dependence of the AEPs on stimulus intensity has been demonstrated in migraine (50). Furthermore, the response was modulated by Zolmitriptan (51).

Somatosensory evoked potentials

Attenuation of amplitude of somatosensory evoked potentials (SSEP) has been demonstrated in migraine patients during migraine with sensory aura (52). A similar finding has been demonstrated in the interictal phase of migraine (53) whereas another has shown no difference from controls (54).

Event-related potentials

Auditory event-related potentials have been studied in migraine. An increase in P300 latency was demonstrated in some studies (55, 56), but not in others (57). With repeated stimuli, contingent negative variations (CNV) amplitude was increased in migraineurs and defective habituation was demonstrated. CNV amplitude normalized after treatment with β-blockers (58, 59). Finally, CNV readings pre- and postsumatriptan were similar during migraine attacks (60).

ELECTROMYOGRAPHY AND EXTEROCEPTIVE SILENT PERIOD ES2

A large electromyographic (EMG) study of pericranial muscles has indicated higher amplitude of resting temporal muscle activity in chronic headache sufferers compared with migraineurs (61). The differential diagnostic value of EMG was questioned, however. Ictally, one study has reported higher muscle activity in temporalis and sternocleidomastoid muscles migraineurs (62), whereas another has reported lower occipital activity compared with tension-type headache (63). Finally, neuromuscular hyperexcitability has been demonstrated in a migraine ischaemic exercise test; the positive EMG test correlated with a low concentration of red blood cell magnesium (64).

Early and late suppression of ongoing EMG activity is obtained on slight stimulation of the trigeminal nerve (ES1 and ES2). Some studies have demonstrated shortened temporalis silent period tension-type headache (65–67). Others, using slightly different paradigms, have shown contradictory results (68, 69). Modulation of ES2 by pharmacological agents has also been studied; the duration of ES2 was increased by 5-HT antagonists decreased by 5-HT uptake blockers (70) interictally, and significantly increased following ictal administration of sumatriptan (71).

TRANSCRANIAL MAGNETIC STIMULATION

Transcranial magnetic stimulation (TMS) has been developed to study cortical physiology non-invasively (72, 73), and migraineurs have been studied with magnetic stimulation. Both the motor and occipital cortices have been investigated. Studies performed on motor cortex will first be reviewed.

TMS of motor cortex in migraine

Several studies have investigated the motor cortex of migraineurs using TMS. Three studies have been performed on the motor cortex, two of which reported an increase in excitability threshold in migraineurs and suggested that this neurophysiological correlate may be useful in the study of migraine mechanisms (74, 75). The first study, comparing subjects with migraine with and without aura with controls, demonstrated an increased motor threshold in classic migraine (74). The motor threshold was increased on the side corresponding to the aura. The threshold difference could not be attributed to attack frequency. The second study was performed on menstrual migraineurs during the cycle compared with controls (75). An increased threshold was demonstrated similar to the first study, but in this study the patients had migraine without aura (MoA). There were no differences found between the ictal and interictal phases. The last two studies were done by the same investigators. In the first, there was a difference in amplitude of motor evoked potentials (MEPs) in MA compared with controls, but no differences were found in the motor threshold (76). The differences in this study compared with previous reports of increased threshold were explained on the basis of attack frequency, which was higher in their group of patients.

In a second study performed on familial hemiplegic migraine (FHM), the threshold of motor cortex was higher on the side corresponding to the aura (77). The amplitudes were also lower with prolonged central motor conduction time. Although the differences in the above studies pertaining to MT in migraine were attributed to attack frequency, there were also some important technical differences (78).

Using paired pulses, a recent study has demonstrated reduced motor cortical excitability after administration of zolmitriptan, a centrally acting 5HT_1B/D used in the treatment of migraine (79). Again, this study, using paired impulses, demonstrated increased excitability. This technique thus provides a new window of opportunity to study cortical physiology and the effects of drugs in migraine.

Cortical silent period in migraine

Two studies have examined the cortical silent period (CSP), both reporting no differences in CSP at high levels of stimulus intensity (80, 81). One study found a shorter CSP in MA compared with controls at low stimulus intensity (81). Since the CSP, in part, is a measure of central inhibition of motor pathways, the shortened CSP that was measured in MA patients may suggest reduced central inhibition, thus inferring increased excitability. However, these results must be viewed as preliminary, since the investigator was not blinded to these results.

TMS of occipital cortex in migraine

Perhaps more relevant to migraine is to study TMS of the occipital cortex, since enhanced excitability of occipital cortex is possibly the basis for either spontaneous or triggered migraine aura (1). Occipital cortex excitability in migraine has been evaluated by the generation of phosphenes by TMS of occipital cortex. The very first study using this technique reported a low threshold for generation of phosphenes was found in MA, inferring hyperexcitability of the occipital cortex in migraine (82). Since this early study, there have been two more studies performed on the occipital cortex using TMS and measuring phosphenes, both confirming the initial reports of hyperexcitability (83–86). In one of the studies the threshold of phosphenes correlated with visually triggered headache. In the study by Young et al. (85), phosphenes were measured repeatedly in the same subjects and no relationship was found in threshold and timing of migraine attack or menstrual period. Battelli and colleagues have investigated the extrastriate visual area V5, which is important for the perception of motion. Both MA and MoA groups required significantly lower magnetic field strength for the induction of moving phosphenes compared with the control group; this difference was significant for V5 in both left and right hemispheres. In addition, the phosphenes were better defined and had clearer presentation in migraine groups, whereas in controls they tended to be more transient and ill-defined. Hyperexcitability of the visual cortex has also been demonstrated using repetitive TMS (rTMS) (87). In a study using 1-Hz rTMS, phosphene threshold was assessed before and after 15 min of rTMS. In normal controls there was increased phosphene threshold (PT) after rTMS; conversely, in migraine there was a reduction in PT, suggesting visual cortex excitability. Most studies with TMS have utilized the subjective sensation of phosphenes as a measure of excitability. Although these studies have shown important differences in migraine, the lack of objectivity makes data interpretation difficult. We have therefore developed objective physiological measures to assess differences in cortical excitability (88). To assess inhibitory function of the occipital cortex, a visual suppression method was utilized [magnetic suppression of visual accuracy (MSPA)]. Timed TMS impulses, usually 10% above phosphene threshold or where suppression was noted, were delivered to the visual cortex. Subjects were asked to report letters projected at a fixed luminance on the screen. Visual suppression was calculated based on the number of errors the subjects made. Using automated analysis, our results have confirmed that migraineurs had reduced errors, demonstrating a reduction in visual suppression (89). We have recently completed a study demonstrating a spectrum of illness in chronic migraine (90). A cohort of these subjects demonstrated decreased metabolism in cerebral metabolism, thus correlating with the MSPA studies. Using this objective model, we have data on topiramate demonstrating dynamic changes in episodic and chronic migraine in two subjects. Topiramate seemed to balance the dysfunction in cortical inhibition seen in chronic migraine.

Functional imaging in migraine demonstrating hyperexcitability

A link between CSD and migraine pathogenesis has been hypothesized for >40 years (91), and recent evidence has strengthened the concept that the neurological symptoms that can precede or accompany an attack (e.g. aura) arise from CSD, whereas migraine headache results, in part, from the ensuing trigeminal-induced meningeal inflammation and central activation (92). Using functional magnetic resonance imaging (fMRI) during spontaneous migraine auras, Hadjikhani et al. (93) have discovered at least eight neurovascular events in human occipital cortex that resembled CSD observed in experimental animals, expanding a previous fMRI study of visually triggered migraine that showed suppression of blood oxygen level-dependent (BOLD) response propagating into contiguous occipital cortical areas at a rate of 3–6 mm/min (94). These studies have demonstrated indirect evidence for CSD in migraine. In animals, the CSD's band of hyperexcited neurons travels into sulci or fissures eliciting signals that can be detected on a MEG (95, 96). Using the seven-channel MEG, Barkley et al. have reported DC shifts in spontaneous migraine (97). A further study of a larger number of patients has not been possible because of the unpredictable nature of migraine and time of capture of these spontaneous events. Using the visual trigger modelled by Cao et al. (98), Bowyer et al. have now been able to detect DC shifts when headache or aura were precipitated. These studies were performed using a whole-head MEG (148 channels), which permits precise localization of signals. In this study, headache was triggered in five of eight migraine patients and none of six controls. DC MEG shifts were observed in migraine subjects during visually triggered aura and in a patient studied during the first few minutes of spontaneous aura. No DC MEG shifts were seen in control subjects. This is additional evidence supporting the primary neural basis of migraine and confirms MEG recorded DC shifts typical of those found during CSD, reported previously in migraine attacks. DC MEG waveforms arising during migraine aura were used to determine the effectiveness of prophylactic medication therapy valproate on neuronal hyperexcitability. Using visual stimulation, widespread regions of hyperexcitability were detected throughout the occipital cortex in migraine patients, explaining the susceptibility for triggering CSD and migraine aura. After 30 days of prophylactic treatment, reduced DC MEG shifts in the occipital cortex and reduced incidence of migraine attacks were observed. This study has confirmed that MEG can non-invasively determine the status of neuronal excitability before and after therapy (33). Similar findings have been found with topiramate.

The somatosensory cortex has also been tested in migraineurs, using MEG (99). The study concluded that the population of neurons in the primary somatosensory cortex underlying the N20m were hyperexcitable, and that this hyperexcitability was linked to the frequency of migraine attacks.

A recent study has evaluated structural abnormalities in the motion processing network in migraineurs and compared it with age-matched controls (100). High-resolution cortical thickness was measured by diffusion tensor imaging (DTI). The authors concluded that a structural abnormality in the network of motion-processing areas could account for, or be the result of, the cortical hyperexcitability observed in migraineurs. The authors have also proposed that the finding in patients with both MA and MoA of thickness abnormalities in area V3A, previously described as a source in spreading changes involved in visual aura, raises the question as to whether ‘silent’ CSD develops also in MoA.

CONCLUSION

To summarize, no one single neurophysiological technique can be ascribed to best define differences in migraineurs versus non-migraineurs. Furthermore, even when the same technique is used, uniform results have not been demonstrated in migraine. These differences may be due to technical factors as outlined, but another important factor is that migraine has shifts of physiology and is therefore difficult to ascertain. However, some physiological studies, where increased excitability was inferred in migraine, are in keeping with the genetic studies in FHM, which also lend support to central neuronal excitability. Other studies, which support this hypothesis of a disorder of mitochondrial energy metabolism (101, 102), deficiency of systemic and brain Mg²⁺ (103) and abnormalities of glutamate metabolism (104), have been identified. As well as contributing to excitability of neurons, these same factors may be involved in sustaining the propagation of spreading depression (105). It should now be possible to investigate how closely these abnormalities correlate with direct measurements of brain excitability provided by the TMS technique. Independent of mechanism, these results add to the increasingly substantial body of evidence that enhanced excitability of brain cortex may be important in the overall pathogenesis of migraine.

PSYCHOPHYSICS

Overview

Behaviourally, individuals with migraine are clearly hypersensitive to many forms of sensory input, particularly visual. This suggests underlying neural hyperexcitability, which could arise either subcortically, cortically, or both. In summarizing the psychophysical findings, we will concentrate on psychophysical measures for which a cortical basis can be argued. In visual terms, that generally means using tests based on visual properties known to be extracted at the cortical level and not earlier in the pathway: contrast gain control, orientation selectivity, motion direction selectivity, binocular interactions, and global form and motion analysis.

In seeking behavioural evidence of cortical hyperexcitability, one must consider that hyperexcitability may arise in several ways, including alterations to either excitatory or inhibitory mechanisms, and through changes in synaptic efficacy or through changes in intrinsic neuronal properties. Moreover, such alterations could be very widespread within the neocortex, or they might be specific to particular cortical regions (defined by cytoarchitectural boundaries) or to particular neural pathways through cortex, and thus may be revealed only by psychophysical tasks that depend on that circuitry.

Visual discomfort

Most psychophysical investigations in migraine have involved the visual system, largely because visual symptoms are so prominent both interictally and during migraine episodes. The auras which precede headache in some migraineurs are most likely to be visual (106), and photophobia during episodes is a defining symptom of migraine (107). However, even interictally, many individuals with migraine are bothered by bright lights, glare, and by spatially or temporally repetitive patterns (visual discomfort) (108–110). This suggests a heightened gain in the visual pathway such that a stimulus that appears only moderately intense to a person without migraine elicits a response close to saturation in the individual with migraine. While visual discomfort induced by bright lights or glare is likely to arise early in the visual pathway, the particular sensitivity to spatially repetitive patterns such as square wave gratings points very strongly to a cortical origin, because orientation tuning arises first at this level. In the earliest description of visual discomfort using a very informal test, headache-prone individuals were noted to turn away from high-contrast striped patterns, particularly those of approximately 3 cycles/deg (108). This spatial frequency is the range in which humans are most sensitive normally, so it is not surprising that if the gain of responses to repetitive oriented patterns is increased, the effect would be largest in this range. More recent, more carefully controlled examinations have confirmed that a larger subset of migraineurs than of healthy headache-free controls experience hypersensitivity to high-contrast gratings, although by no means all migraineurs experience this phenomenon (110–113). This is manifest not only as an aversion to these patterns; the stimuli also elicit visual illusions. The illusions take the form of induced colour, motion and flicker, and shape distortions. The observation that the strength of visual discomfort is usually related to line length ((109), e.g. checkerboards do not induce as much discomfort as continuous lines) suggests a role for abnormally strong excitatory interactions between oriented cells with collinear receptive fields, perhaps with attendant abnormal inhibition among different orientation columns in the visual cortex. A recent fMRI study has reported both behavioural evidence of visual illusions and discomfort and elevated fMRI activation for square wave gratings with maximum effect at 1.2 cycles/deg in MA subjects relative to controls (MoA subjects were not tested) (114). Chronicle and colleagues (115) have demonstrated that the threshold luminance required to detect letter targets superimposed on square wave gratings is significantly elevated in MA subjects compared with controls, which they proposed might be due to weakened inhibition. A weak trend in the same direction was apparent in the MoA group. Shepherd has recently reported an association between heightened pattern sensitivity, the visual triggering of migraine episodes and the abnormal prolongation of the motion after-effect in migraine (116). However, this association was not related to aura condition.

Although stripes are one powerful inducer of visual discomfort, even stronger effects are generated by flickering patterns, especially those around 10 Hz, which is near the temporal peak of the spatio-temporal contrast sensitivity function (112, 113, 117). Full field or low spatial frequency flicker elicit reports of discomfort at significantly lower contrast levels in migraineurs (both MA and MoA) than in controls across a wide range of temporal frequencies (113). Although excessive sensitivity to high-contrast flicker does not necessarily indicate a cortical locus, it is suggestive of abnormality within the magnocellular visual processing stream.

Measurements at threshold

Visual discomfort is elicited by intense stimulation. It is important to ask whether individuals with migraine also show different sensitivity to very weak stimuli. The answer is mixed, but what is clear is that there is no evidence that migraineurs are more sensitive than normal at the bottom of the stimulus range. The measure for which the most information exists is contrast sensitivity, where the minimum detectable contrast (difference between bright and dark parts of an image) is measured, ideally across a range of spatial frequencies and temporal frequencies or flicker rates. Several reports indicate that migraineurs with or without aura are not different from controls in terms of contrast threshold (118–120); others have reported elevated thresholds ((111, 121) MA only). However, most of these studies have examined only a limited range of spatial or temporal frequencies. In a comprehensive recent study of MoA subjects (122), the entire spatial frequency range was examined under both static and dynamic (4 Hz) test conditions at photopic and scotopic illumination levels. Elevated thresholds were reported for low spatial frequency static and dynamic patterns both in scotopic and photopic vision, strongly suggesting a magnocellular abnormality. Thresholds are also elevated on contrast pedestal tasks designed to separate magnocellular from parvocellular function (123); on this measure both magno- and parvocellular tasks were affected in both MA and MoA groups. Finally, the flicker fusion limit (highest detectable flicker rate) is reduced in MoA and MA (124, 125), although for the MA groups this finding reached statistical significance only in the latter study.

Elevated contrast thresholds might indicate neurons with abnormally high activation thresholds. This could be taken as an indication of a hypoactive visual system, a conclusion at odds with the hypersensitivity at high contrast. Another scenario which might give rise to elevated contrast thresholds would be high levels of intrinsic noise within the visual pathway. This would necessitate stronger firing in response to an external stimulus in order to detect the input over the intrinsic noise.

Signal-to-noise considerations higher in the magnocellular pathway

One of the most consistent indicators of visual abnormality in migraine comes from measures of global motion perception, again suggesting a deficiency in the magnocellular pathway. Global motion refers to the overall average direction of motion of a field of moving dots. Direction of global motion can be detected very accurately by human observers even in the presence of considerable variation in the direction of motion of individual dots (126). The motion coherence threshold is the minimum percentage of dots that must be moving in the dominant direction, out of a field of dots moving in random directions, for that dominant direction to be accurately identified. Motion coherence thresholds has been reported to be abnormal in both MA and MoA for large dot arrays covering several degrees of visual field (119, 127, 128) and when tested more locally in perimetry paradigms (129, 130). In the motion perimetry studies, patches of reduced motion sensitivity are revealed in visual fields that appear normal by static perimetry. This inability to ascertain the direction of global motion is seen despite normal thresholds for the detection and discrimination of motion direction in low contrast Gabor patches (131). The latter finding suggests that the early stages of cortical direction processing are intact, but that the global combination of motion signals is abnormal higher in the motion pathway, most likely in area V3a or MT (areas implicated structurally in migraine (132) and functionally in aura (133)). It has been suggested that this deficit is best viewed as a signal-to-noise problem, and Antal and colleagues have recently provided direct evidence in support of this explanation (134). In their study, two tasks employing moving dot arrays were tested in the same participants. In one, the measure was coherence threshold and thus included direction ‘noise’, and the other involved 100% coherence across dots, but very short exposure times to take performance down to below ceiling levels. On the task involving noise, subjects with migraine (MA and MoA) showed significantly higher coherence thresholds than controls. In contrast, on the 100% coherence task, migraineurs performed more accurately than controls (significant for MA only) and with equivalent reaction times.

The signal-to-noise interpretation receives support from another study by the same research group using transcranial direct current stimulation (tDCS) of visual cortical area MT (V5) in healthy control subjects (135). In tDCS, direction of current flow (anodal or cathodal) determines whether the effect on neurons will be depolarizing and hence excitatory (anodal) or hyperpolarizing (cathodal). Performance on the ‘noisy’ motion coherence task was improved by cathodal stimulation, but unchanged by the anodal current, suggesting that hyperpolarizing may have reduced weak signals from individual noise dots to below threshold. On the other hand, on the 100% coherence task where there is no noise, added excitation would be expected to enhance the strength of the signal, which is weak due to its duration, not to its noise, whereas hyperpolarization would be expected to reduce the strength of this already weak signal, reducing performance accordingly. Precisely this outcome was observed.

While the signal-from-noise hypothesis of migraine dysfunction could be restricted to the projections of the magnocellular pathway, there is some suggestion that the problem is more ubiquitous than this in extrastriate visual areas. McKendrick and Badcock have recently reported two studies (127, 128) using variants of the Glass pattern paradigm (136), in which global form is extracted from correlations within static dot arrays (analogous in space to global motion in time). Both MA and MoA groups showed elevated coherence thresholds for extracting global form as well as for global motion, although the correlation between tasks in individual subjects was low. The pooling underlying Glass pattern detection is thought to occur at higher levels of the ventral visual pathway, most likely V4 (137).

Underlying mechanisms of hyperexcitability

One neuronal change that could underlie hyperexcitability would be weakened intracortical GABAergic inhibition. Chronicle and Mulleners were first to propose the impaired inhibition model, and specifically predicted that this might arise as a consequence of hypoxia induced by aura (138). If so, abnormalities indicative of impaired inhibition would be expected to be restricted to this migraine subgroup, and would also be expected to be correlated in severity with years with migraine and episode frequency (i.e. cumulative lifetime auras), a very difficult thing to estimate retrospectively. Several studies from these investigators and from other groups have been specifically designed to test the impaired GABAergic inhibition hypothesis, with mixed results.

Chronicle, Mulleners and colleagues have tested their hypothesis using metacontrast (139). In metacontrast, the task is to make a judgement about a briefly presented visual stimulus (e.g. identify a letter, detect a missing corner), which is followed at different intervals ranging from simultaneous to several hundred ms by a surround annulus. Performance accuracy typically shows a U-shaped function with a marked reduction when the mask follows the target by a short interval (in this task about 40 ms). Palmer et al. have reported that the MA group showed better performance overall than the MoA or control group, with a shallower suppressive dip. Furthermore, a small group of three MA patients on valproate (a GABA blocker) performed similarly to controls, whereas another small group on other prophylactics was not so affected. Lastly, as predicted, the MA group showed a significant correlation between migraine frequency and performance. The parallels between weak backward masking reported in this study in MA subjects and the single-pulse TMS results with letter naming noted earlier are very strong (140); in both cases, MA subjects showed less performance interference than controls, which would be consistent with impaired inhibition.

However, other data on masking and on other visual tasks in which inhibition may be implicated do not provide clear support for the GABA hypothesis. Huang et al. (114) have used a similar, although not identical visual task in an fMRI study to examine masking in MA and control subjects, and found no differences between controls and migraineurs in the strength of masking, as measured either behaviourally or in the fMRI cortical activation signal. In a different masking paradigm designed to evaluate the strength of feedback inhibition, simultaneous masking of a weak target by a higher contrast grating was stronger in both MA and MoA groups than in controls, but the proportionate reduction in masking when a delay allowing inhibitory feedback was introduced was equivalent in migraine and controls (118). This result is consistent with enhanced excitatory drive, but not weakened feedback inhibition. In a very recent study of binocular rivalry, dominance periods were slightly lengthened in both MA and MoA, consistent with enhanced recurrent excitation (141). Weakened reciprocal inhibition between left and right eye inputs to V1 would predict the opposite outcome—more rapid alternation and shorter dominance periods. Taking another approach, Shepherd has demonstrated that both the motion and tilt after-effects (116, 142) and the simultaneous tilt effect (143) are exaggerated in duration (motion) or amplitude (tilt); Shepherd argues that weakened inhibition would have predicted the opposite outcome in each case (142–144). Finally, several groups have examined orientation discrimination thresholds as a measure of inhibitory strength. Based on pharmacological manipulations of the GABAergic system, intracortical inhibition has been shown to make a major contribution to the sharpness of orientation tuning of visual cortical neurons (145) Weakened inhibition would therefore be expected to reduce the ability of migraineurs to make fine discriminations about the orientation of line patterns. In general, studies using either bars or gratings of moderately high spatial frequency have produced no evidence of impairment in either MA or MoA subjects, tested in either the fovea or the peripheral visual field using discriminations around the cardinal axes (120, 131, 146). However, two of these studies identified conditions under which orientation discrimination appeared impaired: for low spatial frequency (0.5 cycles/deg) foveal targets (147), and for discriminations around the oblique axes, despite comparable contrast sensitivity for these oblique stimuli (148). The first of these findings has been suggested to reflect a processing deficit limited to the magnocellular pathway; however, the oblique effect cannot be explained in this fashion, as the patterns (4 cycles/deg) would be expected to be excellent stimuli for the parvocellular (form and colour) pathway. One possible explanation raised by the authors is that the oblique impairment may reflect abnormality at a higher level in the extrastriate visual areas, since the effect was seen for both real and virtual orientated stimuli. In any case, overall the findings on orientation thresholds do not provide strong support for a global reduction in cortical GABAergic inhibition in migraine. Furthermore, the fact that the differences that are seen affect MoA and MA equally and are not related to cumulative lifetime auras (or migraine episodes) argues against the strong form of the Chronicle and Mullener hypothesis that auras play a causative role in impaired inhibition.

Adaptation level and cortical tone

Overall, behavioural studies performed with high-contrast noisy or spatiotemporally periodic stimuli show consistent evidence of hyperexcitability in migraine. These behavioural findings are consistent with findings of potentiation rather than habituation of the VEP in migraine ((149, 150) for review). However, it seems unlikely that this is due to the loss or permanent impairment of a class of neurons, such as GABAergic cells, because, although some of the abnormalities seen in migraine could arise from impaired inhibition, no impairments are found on other measures for which inhibition is known to be involved. Furthermore, there is strong evidence that some measures suggestive of hyperexcitability change over the course of the interictal and ictal periods, either systematically (151, 152) or less predictably (153). Thus the more likely candidates would be mechanisms that vary dynamically in the brain, such as those governing adaptation in neurons and/or neural networks. This would include hyperpolarizing membrane currents, which are modulated by brainstem neurotransmitter systems such as serotonin and noradrenalin (154). It would also include plastic synaptic processes such as long-term potentiation (LTP) and depression (LTD) and shorter term synaptic effects. A recent slice study of visual cortex in young guinea pigs (155) has found that identical stimulus conditions can produce LTP, LTD or no plastic change in different cortical pyramidal neurons, and that the only differentiating properties among these neurons were the dendritic calcium transients peak amplitudes and cumulative somatic calcium changes over the induction period. Since calcium channel abnormalities have been documented in FHM, and the mouse model of this channelopathy displays cortical hyperexcitability and a lower then normal threshold for CSD, the possibility of slight shifts in Ca²⁺ mechanisms seems plausible, making the difference between potentiation and depression of neural circuits of migraineurs and controls under similar visual stimulation conditions. Furthermore, recent evidence has shown dynamic changes in the direction of synaptic plasticity in adult rat visual cortex linked to the light–dark cycle, indicating that ‘cortical tone’ is a dynamic phenomenon even in normal individuals (156). Such an interpretation is supported by the rTMS findings in V1 and extrastriate cortex: whereas phosphene thresholds (V1) and reaction time to perform an illusory contour task (extrastriate) are elevated in controls, the same stimulation produces lowered phosphene thresholds and shorter reaction times in MA (MoA not tested) (157, 158). Similarly in motor cortex, rTMS decreased intracortical facilitation in controls but increased it in MA. Such a result is unlikely to arise if inhibition is simply weaker than normal; however, it would be expected if a stimulus which gradually depresses excitable synapses in one group potentiated the same neural networks in the other group. It would be helpful in this literature if different terms could be used to signify a general depression in responsiveness, when the actual mechanism is unknown, and inhibition, in the traditional sense of synaptic inputs which hyperpolarize, rather than depolarizing the postsynaptic cell membrane, most commonly involving the neurotransmitter GABA.

In summary, the behavioural data support the conclusions of the electrophysiological and imaging data in showing that the visual system at the cortical level is hyperexcitable in the sense of responding more strongly to intense, repetitive or long-lasting stimulation. In general, this conclusion applies to both MA and MoA when both have been examined, although far too frequently only MA patients have been studied. Among the issues which urgently need further investigation are the following: (i) what is the pattern of intrasubject variability over time on these measures; in particular, which effects are normalized by migraine episodes, and how consistent are measurements over the interictal period. There are scarcely any behavioural studies which have attempted what is clearly a formidable study; (ii) are there subgroups within migraine that are orthogonal to the aura/no aura dimension? A very common finding in behavioural studies of migraine is considerable variability in performance in both migraine groups, often introducing enough variance to obscure what may be real effects in subgroups of migraineurs. The pattern sensitivity indicator of Shepherd may be one useful diagnostic for re-sorting migraineurs; (iii) finally, examining the role of intrinsic noise introduced at various levels of the visual pathway may cast light on the value of signal-to-noise detection as a framework for understanding sensory abnormalities in migraine.

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The Brain is Hyperexcitable in Migraine

Abstract

Keywords

INTRODUCTION

ELECTROENCEPHALOGRAM

EVOKED POTENTIALS

Visual evoked potentials (VEP)

Auditory evoked potentials

Somatosensory evoked potentials

Event-related potentials

ELECTROMYOGRAPHY AND EXTEROCEPTIVE SILENT PERIOD ES2

TRANSCRANIAL MAGNETIC STIMULATION

TMS of motor cortex in migraine

Cortical silent period in migraine

TMS of occipital cortex in migraine

Functional imaging in migraine demonstrating hyperexcitability

CONCLUSION

PSYCHOPHYSICS

Overview

Visual discomfort

Measurements at threshold

Signal-to-noise considerations higher in the magnocellular pathway

Underlying mechanisms of hyperexcitability

Adaptation level and cortical tone

References