Electroencephalography (EEG)
Several decades passed since the pioneering electroencephalographic studies emphasizing abnormal electrocortical activities in migraine [
12]. During the last 60 years of publication, the most frequently described electrocortical phenomena in migraine patients were the so-called H response to flicker stimulation – also known as enhanced photic driving (PD) –, and the abnormal resting-state EEG rhythmic activity.
Enhanced PD of EEG during intermittent photic stimulation using fast Fourier transform analysis on steady-state visual evoked potentials (SS-VEPs), the so-called H response, was more prevalent in migraine patients than in healthy controls. Researchers observed that the fundamental components of the EEG spectra were increased equally in both MA and MO [
13,
14], predominantly in the temporo-parietal regions, with reduced interhemispheric coherence in fronto-temporo-parietal areas [
13]. The same phenomenon tends to be present also in juvenile MA patients [
14]. H-response showed a sensitivity of 86.4% and a specificity of 97.5% in MA and MO patients, but not in patients affected from basilar migraine [
15]. De Tommaso and coworkers [
16] observed that, although in both MO and MA groups PD was significantly enhanced with respect to controls, those patients experiencing aura showed more pronounced decreased phase synchronization between beta rhythms and higher Granger causality values – measuring the flow of connections and information across different brain areas – during light stimulation compared to MO patients. Response to photic stimulation was less represented in MA than in MO patients in two studies [
17,
18].
During the interictal period of MA patients, quantitative analysis of
spontaneous electroencephalographic activity showed alpha rhythm and peak frequency asymmetries over the posterior regions, increased power of alpha rhythm [
19], and widespread increase in delta [
14] and theta [
14,
19] total power in comparison with healthy controls. Reduction of alpha rhythm [
20] or unilateral reduction of alpha and theta activity was detected in MA patients with a pure visual aura [
21], mostly contralateral to the neurological signs [
21]. MA patients had greater alpha peak power interhemispheric asymmetry, chiefly in the posterior regions, and unrelated to the headache side, than MO [
14,
22]. In a resting state effective neural connectivity EEG study, MA patients showed higher flow of information transfer in beta band compared to MO patients and controls [
23]. When using a checkerboard pattern for visual stimulation, MA patients showed increased transfer entropy with high density of information flow in the frontal regions in all the bands of rhythmic activity as compared to MO patients [
23]. Using magnetoencephalography (MEG), researchers found that MA patients had significantly increased functional connectivity in the theta (4–8 Hz) band in the occipital area as compared with patients not experiencing aura [
24]. It is interesting to note that functional connectivity anomalies at the level of the frontal and occipital networks were detected also with the method of resting-state functional MRI [
25‐
27].
In summary, resting electric and magnetic activity may help to better differentiate MA from MO patients than PD.
Evoked potentials
With the help of cortical evoked potentials, higher cortical response amplitudes, an increased interhemispheric response asymmetry, and a deficit of response amplitude decrement were demonstrated by using different types of sensory stimuli and techniques in most of the MA patients.
Grand-average EP amplitude
Because in most cases the aura is visual, most of the published studies investigated visual evoked potentials (VEPs) to search for cerebral signatures associated with migraine aura. By analysing the evoked responses in a classical way of averaging a large quantity of trials, mainly increased amplitudes of steady-state (SS) or transient VEPs have been discovered in MA patients during attack-free intervals.
In some reports the grand-average of VEP N75-P100 and/or P100-N145 amplitudes has been found greater in MA patients than in controls [
28‐
33] and/or in MO patients [
28,
34,
35]. The amplitude of SS-VEP harmonics was also higher in MA than in MO or controls [
36]. In other studies, on the contrary, VEP amplitudes were found reduced in MA [
37], even when compared to MO [
38]. Most often, VEP amplitudes in MA were reported to be in the normal range [
39‐
45].
Decreased amplitude of the prerolandic component (N20) of somatosensory evoked potentials (SSEPs) in both MO and MA patients has been found in one study [
46], but amplitudes were within the normal range in others [
47‐
49].
Most of the researchers who recorded short-latency brainstem auditory evoked potentials (BAEP) were not able to find any interictal abnormalities in migraine, probably because they pooled patients with different migraine phenotypes (MO and MA or different MA subtypes) in different proportions in a single group (see Table 5 in [
50]). Higher P300 event-related potentials (ERPs) is a common finding in MA compared with other types of primary headaches [
51,
52]. In comparison with controls, basic P300 amplitude tended to be greater in a mixed group of MO and MA patients. Moreover, P300 amplitude was significantly reduced during mind wandering relative to on-task periods in migraineurs, contrasting to what happened in healthy controls. Authors argued that a more consistent propensity towards engaging in response attenuation during mind wandering states may provide migraineurs with an alternative compensatory strategy for reducing stimulus overload in cortex [
53].
To sum up, using EPs and ERPs, researchers found that the frequently reported increase in grand-average neural response to any kind of sensory stimuli in MA group is conceivably due to deficient short-term and long-term adaptive processes to external stimuli.
Interhemispheric asymmetry
Asymmetric neural activities in steady-state VEP amplitude, transient VEP P100 amplitude distribution and in N70 components were detected by some, both related [
29,
54,
55] or not [
56‐
58] with side of visual aura. A significant interhemispheric asymmetry of the N30 component amplitude has been observed in the MA group in comparison with control subjects [
46].
Similar to the results of VEP and SSEP studies, in one study mean interhemispheric asymmetries of all BAEP peak latencies (except peak IV and VI) were significantly increased in MO and MA patients as compared to those of the control group, despite the fact that the MA group included hemiplegic, and brainstem migraine [
59]. This datum was not confirmed in a more recent study [
60].
Response habituation
Analysing discrete blocks of small amounts of traces, authors found that during repetitive and stereotyped stimulus presentation, VEP amplitudes augmented progressively instead of diminishing (i.e. they lacked habituation) equally in MO and, sometimes even more so, in MA patients between attacks [
39‐
42,
44,
45,
61‐
63]. Some studies failed to confirm deficit of amplitude habituation in migraineurs during the interictal period [
30,
43,
64,
65]. Deficient lateral inhibitory mechanisms within the visual cortex might be one of the culprits for this abnormal information processing in migraine as clearly showed with SS-VEPs elicited by a windmill-dartboard pattern [
41]. Defective inhibitory mechanisms within the visual cortex in MA, but not in MO, were further confirmed in a paired-pulse flash-VEPs study [
66].
Since in MA patients, different aura phenotypes may be underpinned by different pathophysiological mechanisms, we studied VEP amplitude and habituation in a subgroup of MA with exclusively visual auras and another with visual aura followed by somatosensory and/or dysphasic complex neurological auras [
67]. We found a significant sustained increase of VEP amplitude in MA with complex aura – interpreted as a genuine increase in cortical excitability –, while it was within the normal range in migraine with pure visual aura. In both subgroups VEP habituation was equally deficient as compared with healthy controls, yet in those patients with complex aura the more pronounced the VEP habituation deficit the longer the distance from the last migraine attack [
67], as previously observed in another study from the same research group, but in a mixed group of MO and MA [
41]. In a study where VEPs were co-recorded with MRI spectroscopy, MA patients showed greater VEP amplitude and lack of habituation as compared with healthy controls [
68]. More interestingly, both cortical excitability enhancing and inhibiting transcranial direct current stimulation procedures were unable to induce significant changes in VEP amplitudes in MA, while they significantly potentiated and diminished N1-P1 VEP amplitude in healthy controls keeping a correlation with glutamate signals [
68].
In accordance with VEP studies, a significant habituation deficit has been detected interictally in MA recording SSEPs [
69] and auditory evoked potentials (AEPs) [
70]. Lack of response habituation is also responsible for the strong interictal dependence of AEPs on stimulus intensity, that, in turn, is known to be inversely related to cerebral serotonergic transmission [
44,
70]. There is also evidence for a loss of habituation during cognitive potentials as assessed by recording P300 amplitude in MA [
51,
52].
Techniques of neuromodulation
Studies with single-pulse and repetitive transcranial magnetic stimulation (TMS) have reported abnormal cortical responsivity revealed as greater motor evoked potential (MEP) amplitude, lower threshold for phosphenes production, and paradoxical effects in response to both depressing or enhancing repetitive TMS (rTMS) methodologies, predominantly in migraine with aura. Magneto-phosphenes measurements of MA patients were significantly lower - revealing higher excitability levels - than healthy controls measurements in most of [
71‐
77], but not in all [
78‐
82], the studies. Naeije et al. [
83] successfully used TMS in discriminating transient ischemic attacks of vascular origin from migraine aura without headache. Greater motor-evoked potential amplitude in response to increasing intensity of stimuli in MA patients compared to controls, with its normalization after levetiracetam preventive treatment, was revealed in one study [
84]. A group of authors observed that inhibitory trains of rTMS delivered over the motor cortex of MA significantly activates rather than inhibiting intracortical facilitatory circuits, which might depend on glutamatergic synaptic mechanisms [
85]. A datum further confirmed delivering inhibitory rTMS over V1 and assessing phosphene threshold which was normally enhanced in controls, but reduced in MA [
80], and raised again after prophylactic treatment with valproate [
86]. Nonetheless, other studies provided evidence for the same paradoxical effects over M1 since facilitatory rTMS recruited the excitatory circuits in mechanisms of glutamate-dependent short-term synaptic potentiation more easily in MA patients than in those without and healthy controls [
87,
88]. On the other hand, excitatory 5 Hz-rTMS at 130% of the resting motor threshold over M1 determines a significant depression in MEP size in MA rather than a clear MEP facilitation as in healthy subjects [
87].
In sum, both the paradoxical rTMS response and habituation deficit point to altered synaptic plasticity mechanisms, which prevent the immediate and longer-lasting cortical changes that reflect adaptation to repeated stimulations, i.e. learning and memory. Further studies are needed to verify whether these aberrant ways of responding of the cortex to neuromodulation are related to abnormal thalamic control [
89] or to a failure of the hypothalamic functional connectivity as recently described in a single MA patient with resting-state MRI [
90].
Electromyographic techniques
Even though brainstem trigeminal nuclei are well knowingly deeply involved in the pathophysiology of migraine without aura, the studies of the trigeminal system in MA are still sparse.
Perrotta et al. [
91] studied a group of MA patients between attacks by measuring the bilateral polysynaptic R2 component of the nociceptive blink reflex (nBR). They found comparable normal baseline activation to noxious supraorbital stimulation with delayed response lack of habituation in both MO and MA as compared with controls. However, they noted that despite the habituation deficit was equally present in both migraine groups, that of MA tended to be less pronounced than that observed in MO. Moreover, in the MA group the higher the frequency of the migraine attacks the more pronounced the habituation of the nBR R2 component [
91]. The same correlation was previously observed also in a group of MO patients [
92], and might be explained by the fact that patients with high attack frequency are more likely to be recorded in a closer temporal relationship to an attack, when nBR habituation tends to normalize [
93].
With the scope to correlate interictal neurophysiological abnormalities of migraine, especially with aura, with a specific genotype, researchers recorded single-fibre electromyography (SFEMG) to explore neuromuscular transmission, as a surrogate biomarker of presynaptic P/Q Ca2+ channels function, in a wide range of migraine aura subtypes. Abnormal finding on SFEMG reflecting subclinical disfunctions of neuromuscular transmission have been detected in patients suffering from MA in between attacks. Patients with unilateral sensorimotor symptoms and/or visual scotoma, other aura symptoms such as sensory/motor disturbances, and/or aphasia, and/or vertigo had noticeable abnormal SFEMG [
94,
95]. These findings were confirmed in a larger group of MA patients where subclinical abnormalities of neuromuscular transmission were progressively more noticeable starting from patients with mixed MO and MA to migraine with prolonged aura, with migraine with typical aura falling in between the two [
96,
97].
In one pilot study, the mild single endplate abnormalities detected by SFEMG in 3 MA patients disappeared during acetazolamide treatment in parallel with clinical improvement [
98].