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Abstract

Background

Primary headaches are functional neurological diseases characterized by a dynamic cyclic pattern over time (ictal/pre-/interictal). Electrophysiological recordings can non-invasively assess the activity of an underlying nervous structure or measure its response to various stimuli, and are therefore particularly appropriate for the study of primary headaches. Their interest, however, is chiefly pathophysiological, as interindividual, and to some extent intraindividual, variations preclude their use as diagnostic tools.

Aim of the work

This article will review the most important findings of electrophysiological studies in primary headache pathophysiology, especially migraine on which numerous studies have been published.

Results

In migraine, the most reproducible hallmark is the interictal lack of neuronal habituation to the repetition of various types of sensory stimulations. The mechanism subtending this phenomenon remains uncertain, but it could be the consequence of a thalamocortical dysrythmia that results in a reduced cortical preactivation level. In tension-type headache as well as in cluster headache, there seems to be an impairment of central pain-controlling mechanisms but the studies are scarce and their outcomes are contradictory. The discrepancies between studies might be as a result of methodological differences as well as patients’ dissimilarities, which are also discussed.

Conclusions and perspectives

Electrophysiology is complementary to functional neuroimaging and will undoubtedly remain an important tool in headache research. One of its upcoming applications is to help select neurostimulation techniques and protocols that correct best the functional abnormalities detectable in certain headache disorders.

Keywords

Headache migraine evoked potentials blink reflex nociception neurostimulation electrophysiology

Introduction

Primary headaches are neurological syndromes that evolve in the absence of any underlying structural lesion, as defined by the 2nd edition of the International Classification of Headache Disorders (1). They are characterized by functional disturbances of the central nervous system at several levels, by a dynamic pattern over time (ictal/interictal) and by complex gene–environment interactions. There is no validated paraclinical diagnostic test, and the evaluation of these diseases in a pathophysiological perspective is difficult and tricky.

Electrophysiological surface recordings are an easy way to assess the spontaneous activity of the nervous system, or to evaluate its response to a stimulus. Basically, the different components of the nervous system (central nervous system or CNS, nerves, muscles) generate an electrical signal which is the result of summation of several action potentials. This signal can be recorded, most of the time with surface electrodes, and thereafter processed (amplification, filtering) in order to assess the global function of the underlying nervous structure.

In 1947, Dow and Whitty used electroencephalography (EEG) to detect interictal abnormalities in the brain function of their migrainous patients (2). Ever since, the usefulness of EEG in routine headache diagnosis has been controversial and is now only recommended in patients with atypical symptoms suggesting an underlying pathological process (such as thrombophlebitis, encephalitis, tumour) and especially epileptic phenomena. Evoked and event-related potential studies started in the late 1960s and have also demonstrated several abnormalities in headache patients, but because of high inter- and intraindividual variability, they do not have any usefulness in primary headache diagnosis. Nonetheless, like EEG, they can be helpful to exclude mimics in selected cases.

On the other hand, electrophysiological studies have widely contributed to a better understanding of headache pathophysiology, especially migraine. Electrophysiology continues to be part of the headache research armamentarium, and is complementary of more recent techniques like functional neuroimaging. In this article, we will review the main ‘pearls’ of the electrophysiological findings in headache, and afterwards describe their limitations. The last part of the review will discuss open questions and give suggestions for future studies.

Pearls

Electrophysiology is particularly suitable for the study of primary headaches that are functional disorders of the CNS. These techniques are non-invasive and the existence of portable devices can provide a high flexibility in patient recordings, for example in a recent study familial hemiplegic migraine patients were recorded at home throughout Denmark (3). Moreover, electrophysiological recordings are often technically simple to obtain for a trained physician, are harmless and can be repeated at many time points. The latter aspect is of high importance in diseases with such a dynamic pattern as headaches. Indeed, primary headaches are cyclic diseases characterized by the repetition of attacks that notably differ by their frequency, length and intensity. The biological mechanisms subtending this pattern are unknown, but thanks to the advantages mentioned above (flexibility etc.), electrophysiology appears particularly suitable to investigate the dynamics of primary headaches.

The majority of the following text will discuss electrophysiological findings in migraine, which is the best-studied headache type. We will not describe the different techniques reported here from a methodological point of view, as this had been the aim of a previous review article (see (4**) for more information).

Migraine

The most important electrophysiological studies performed in migraine demonstrate three functional characteristics of the disease, which are interrelated: 1. habituation modifications, 2. cortical dysexcitability and 3. abnormal functional connexions and circuits within the CNS.

Habituation modifications

Habituation is defined as a behavioural response decrement that results from repeated stimulations and does not involve sensory adaptation or fatigue, that is a decrease in peripheral receptor activity (5). The average habituation deficit to repetitive stimuli is probably the most reproducible and redundant hallmark of episodic migraine recordings in the interictal period, whatever the modality of stimulation, that is the neuronal population that is stimulated (see Figures 1 and 2). It is, however, not specific to migraine as it has been found in other diseases such as photosensitive epilepsy or tinnitus (6,7), and some psychiatric conditions. This interictal habituation deficit, sometimes resulting in potentiation, has been mainly demonstrated for visual evoked responses (VEP, Figure 1) (8**–10), but also for auditory (AEP) (11), somatosensory (SSEP, Figure 2) (12,13) pain (laser, LEP) (14,15) and event-related (contingent negative variation, CNV) responses (16,17). Moreover, it was also retrieved for the nociception-specific blink reflex (nsBR, Figure 1), a subcortical brainstem electromyographic (EMG) response that reflects trigeminal activity and is mediated by bulbopontine excitatory interneurons (18**). Besides this habituation deficit, migraineurs exhibit an increased intensity dependence of auditory evoked potentials (IDAP), which was found to be correlated to the lack of habituation and perhaps to be the consequence of it (19**). The habituation phenomenon has been extensively studied in migraineurs, and some characteristics have been drawn.

Figure 1.

The upper part of the figure represents visual evoked potential (VEP) recordings in a healthy volunteer (HV, (a)) and a migraineur in the interictal period (b). The deep blue triangles highlight the mean VEP amplitude at the beginning of the recording (a block corresponds to the averaging of 100 individual sweeps) and the light blue triangles show mean VEP amplitude at the end of the recording (sixth or last block). There is an amplitude decrease with time in the HV, that is habituation (a), whereas this habituation lacks in the migraine patient, in whom the first block amplitude is also smaller than in HV, suggesting a reduced cortical preactivation level (b). Part (c) represents the evolution of VEP amplitudes (numerical data, mean ± standard deviations) with time in a healthy volunteer (HV), migraineurs with (MA) and without (MO) aura in the interictal period, and in a migraineur in the ictal period. Note that both reduced initial VEP amplitude and the lack of habituation found in MO and MA normalize during the attack. The lower part of the figure represents nociception-specific blink reflex (nsBR) recordings in a HV (a1) and a migraineur (b1) interictally. Note the lack of habituation and the reduced initial amplitude in the migraine patient. Part (c1) of the figure is the average nsBR area under the curve (AUC) evolution with time in a HV, a migraineur without aura (MO) and a migraineur recorded in the ictal period.

Figure 2.

The upper part of the figure represents somatosensory evoked potentials (SSEPs) of the median nerve in a healthy volunteer (HV, (a, c)) and in migraineurs without (MO) and with aura (MA) (b, c). The typical electrophysiological abnormalities as mentioned previously are also retrieved and normalized in the ictal period (see Figure 1). The lower part of the figure represents the high frequency oscillations bursts (HFOs) extracted from broad-band SSEPs. Note that the early HFO burst is reduced interictally in the migraine patient (b1) compared with the HV (a1), reflecting reduced thalamocortical activity, whereas the late HFO burst remains normal at any time, suggesting a normal activity of cortical inhibitory interneurons.

– First, the habituation deficit is not constant in migrainous patients. The studies showing a lack of habituation are based on the averaging of numerous patient recordings, compared with healthy volunteers. Therefore, the habituation deficit cannot be considered as a diagnostic criterion of migraine. In addition, it was shown that the degree of habituation depended on the stimulus properties, for example the temporal or spatial frequencies of a visual pattern, which may explain why some authors did not retrieve any habituation deficit in migrainous patients (20).

– Second, habituation is a dynamic parameter that provides interesting data about the current CNS information processing. In migraine, important peri-ictal changes were found in habituation. During the days preceding the attack, the habituation deficit (CNV, P300) becomes maximal (21,22). It increases with stress which is a known migraine-provoking factor (23), or in the pre-menstrual period (LEP, (24)). Interestingly, most of the sensory modalities showing an interictal lack of habituation then normalize 12–24 hours before and during the migraine attack (13,17,18**,21,22,25). It takes 24–48 hours to get back to the abnormal habituation pattern seen in the headache-free interval (25). These sequential recordings have thus demonstrated that the cortical dysfunction level varied with the migraine cycle. Along the same line, recent data revealed that patients suffering from chronic migraine and evolving to episodic migraine after successful prophylactic treatment exhibited a switch of visual responses from normal habituation to potentiation (26**), as if chronic migraine corresponded to a ‘never ending attack’ (27) and the treatment restored the interictal habituation deficit found in the episodic form. This is not the case in medication-overuse headache (MOH) where habituation of SSEP remains impaired, whereas the initial response amplitude is increased, suggesting a sensitization of somatosensory cortices in MOH patients (13). However, this phenomenon was dependent on the drug of overuse, as it is maximal in patients overusing NSAIDs and almost non-existent in those who overuse only triptans (25).

– Third, genetics appears to be a determinant factor of the interictal dysfunction leading to deficient habituation in migraine. Hence, Sàndor et al. studied VEP and AEP in migrainous pairs (parents and their children), and found that habituation was abnormal in both parents and children, with a stronger relationship between related pairs (28**). A lack of habituation was also demonstrated in healthy volunteers with a familial history of migraine in first-degree relatives (29,30). It could thus be an endophenotypic marker of a genetic predisposition to migraine, even if these conclusions cannot be applied to individuals. Finally, Di Clemente et al. found that VEP and nsBR habituation deficits were correlated in migraineurs, which argues in favour of a common underlying pathological mechanism (31). However, VEP habituation and IDAP slope are not correlated (32).

– Fourth, the habituation can be modulated by external interventions, especially drugs known to provoke or alleviate migraine attacks, or transcranial magnetic stimulation (see below). Hence, various studies demonstrated a normalization of the interictal habituation deficit with several established preventive drugs like beta-blockers (33) or topiramate (34). This habituation deficit reversal has also been shown in children treated with behavioural therapy (35). The relationship between the normalization of habituation and the clinical improvement is probably more complex, as for example fluoxetine, a selective serotonin reuptake inhibitor (SSRI), is not an effective antimigraine drug but corrects the lack of habituation of VEP in patients (36), whereas riboflavin, which acts on mitochondrial metabolism, does not modify habituation (33). Moreover, the migraine-provoking agent nitroglycerin is able to induce nsBR and VEP changes similar to those found before and during a migraine attack when it is administered to healthy volunteers without any familial history of migraine (37).

Cortical dysexcitability

Assessment of cortical excitability by neurophysiological techniques has provided contradictory results that have long been debated. Interictal cortical dysexcitability has been indirectly suggested by two main neurophysiological variables: the cortical sensitivity to transcranial magnetic stimulation (TMS) and the reduced initial evoked potential (EP) amplitude, which is correlated to the lack of habituation described above.

– TMS is an easy and non-invasive way to study the excitability of the underlying cortical area. The main studies performed on migraine used single-pulse TMS (sTMS) to assess the visual or motor cortex activation thresholds, or repetitive TMS (rTMS) to inhibit (low frequencies, 1 Hz) or activate (high frequencies, 10 Hz) the underlying cortex. In sTMS, the motor threshold was found to be normal or increased (38 –41), but the latter is less relevant than the magnetophosphene threshold (PT) to visual cortex TMS, as an abnormal excitability of the occipital cortex has been suspected in migraine for a long time, especially with aura. The numerous trials on PT in migraine between attacks gave conflicting results, that is either increased PT suggesting cortical hypoexcitability (40 –42), or decreased PT in favour of a hyperexcitable state (43 –45). These discrepancies between various studies might be because of methodological differences (subject recruitment, proximity with a migraine attack, individual perception and description of phosphenes, etc.) (46). In a study with repetitive stimulations, Bohotin et al. revealed that 10 Hz (excitatory) rTMS was able to normalize the interictal deficient habituation, whereas 1 Hz (inhibitory) rTMS had no effect on VEP in migraineurs (47**). In apparent contradiction to these findings, Brighina et al. found that inhibitory rTMS increased subjective PT in healthy volunteers but surprisingly decreased it in migraine with aura (MA) patients (42). The authors suggest that the migrainous brain probably has a ‘non-physiological’ and paradoxical response to rTMS, which could be attributed to abnormal cortical processing. However, this paradoxical effect of modulating rTMS was also observed after stimulation of the motor cortex and not only by means of inhibitory (48,49), but also with the excitability enhancer rTMS. Short trains of 5 Hz (excitatory) rTMS delivered at 130% of resting motor threshold determined a significant depression of MEP size in MA patients rather than MEP facilitation as in controls (49). These paradoxical behaviours in response to rTMS point to altered synaptic plastic mechanisms that prevent the immediate and longer-lasting cortical changes reflecting adaptation to repeated stimulations. Further evidence comes from a long-term study showing that rTMS is able to induce VEP changes lasting up to several weeks in about 50% of healthy volunteers, whereas the effect lasts only several hours in most migraineurs (50).

– The initial amplitude of the evoked CNS responses to various sensory modalities is (or tends to be) lower in migraineurs recorded in the interictal period, that is VEP (8**,9,32,36,47**), AEP (19**,32), SSEP (12) and even the subcortical nsBR (29,31). In VEP and AEP, the initial amplitude is negatively respectively correlated with the potentiation and the IDAP (32), which suggests that a reduced cortical preactivation level might be responsible for the lack of habituation found in migraineurs (see next section: ‘Abnormal functional connexions and circuits: the ‘unifying’ thalamic hypothesis’).

Abnormal functional connexions and circuits: the ‘unifying’ thalamic hypothesis

The habituation modifications and cortical dysexcitability found in migraine were thus probably interrelated, but the origin of these phenomena per se remained obscure. Recent works have pointed out possible thalamocortical dysfunctional connexions that could provide an explanation for both abnormalities.

There are two main hypotheses subtending the lack of habituation found interictally in episodic migraine, a reduced intracortical inhibition or an increased cortical excitability, but neither has proved satisfactory as yet (51**).

– Light deprivation is supposed to decrease both excitatory and inhibitory processes within the cortex; however, it did not modify the habituation deficit found in migraineurs in a recent study, which argues against the reduced intracortical inhibition hypothesis (52).

– As for the hyperexcitability hypothesis, the results with TMS appear too contradictory from which to draw any conclusions (see above). Red glasses are known to increase the excitability of the human visual cortex. However, Afra et al. did not observe any significant modification of the VEP in MA patients wearing red glasses, whereas healthy volunteers had an increase of VEP amplitude (53). This result also disfavours the hyperexcitability hypothesis.

A third possibility arose from one of the more reproducible neurophysiological parameters, that is the finding of a recurrent reduced initial response of various sensory cortices. As stated previously, the correlation between this reduced initial response and the degree of habituation suggests that a reduced cortical preactivation level is responsible for the lack of habituation found in migraine.

Recent neurophysiological works have shed a new light on the possible pathophysiological mechanisms of this decreased cortical preactivation. Coppola et al. applied a specific filter to broad-band SSEP recordings in order to extract the high-frequency oscillations or HFOs (Figure 2). HFOs are thought to reflect thalamocortical cholinergic fibre activity (early component) and cortical inhibitory GABAergic interneuron activity (late component) (51**). Interictally, the early component of the HFO was significantly smaller in migraineurs than in healthy subjects, but became comparable between the two populations during the attack (Figure 2). The late component did not differ between the two groups at any time. Moreover, reduced early HFOs were associated with worsening of the clinical evolution of migraine (54). In a recent study, 10 Hz repetitive transcranial magnetic stimulation (rTMS)-induced activation of the sensorimotor cortex increased thalamocortical drive in migraineurs, because it was low at the baseline, and induced habituation of the broad-band SSEP. This was not possible in healthy subjects probably because their thalamocortical activity and habituation were already maximal before the rTMS (55). Thus, the deficit of habituation found in migraineurs could be because of impaired thalamocortical activity, namely reduced cortical preactivation, and not because of decreased intracortical inhibition (51**). That the thalamus abnormally controls the cortex in migraine between attacks is further evident by the analysis of the high-frequency oscillatory components embedded in the visual EPs (gamma-band oscillations, GBO) (56). Investigators observed a significant habituation deficit of the late GBO components, supposed to be of cortical origin, in migraineurs relative to healthy controls, which was interpreted as indicative of a dysfunction in cortical oscillatory networks that could be because of an abnormal thalamic rhythmic activity, namely a ‘thalamocortical dysrhythmia’ (56). Coppola et al. stressed that this thalamocortical dysrythmia could result from a functional (or anatomical?) thalamic disconnection from its modulating afferences, for example the brainstem serotoninergic pathways (56). This explanation may reconcile the controversy between increased cortical excitability and deficient inhibition, as an insufficient thalamocortical drive, namely a low level of cortical preactivation, results in a dysfunction of both inhibitory and excitatory cortical neurons. Lower inhibition and cortical preactivation may thus not be mutually exclusive, as the latter can promote the former through a reduction of lateral inhibition. The final common pathway of both dysfunctions is a heightened cortical response to repeated stimuli, that is hyperresponsivity.

Tension-type headache

Electrophysiological data on tension-type headache (TTH) are scarce compared with those on migraine. Early neurophysiological studies analysed electromyography, as pain caused by TTH was believed to be the result of an abnormal myofascial activity. More recent works now suggest that this is true for episodic TTH (ETTH) but not chronic TTH (CTTH), in which central dysnociception mechanisms are more likely involved (57).

Electromyographic responses

More than 20 surface EMG activity studies on TTH are available (58), but results are contradictory, therefore EMG has no diagnostic indication in TTH. The most common finding between positive studies was a slightly increased EMG activity, but this was not correlated to the intensity of the headache.

The so-called exteroceptive suppression of temporalis muscle activity corresponds to the suppression of voluntary EMG of the temporalis muscle in response to a painful stimulus in the trigeminal area. Two successive silence periods (ES1 and ES2) can be identified. The duration of the late component ES2 is decreased in CTTH but not ETTH, migraine or cluster headache patients (59). Modulation of ES2 by various parameters (drugs, pain, TMS) has led to the hypothesis that ES2 reflects the excitability of interneurons in the pontomedullary reticular formation (57). In CTTH, the excitability of these interneurons would be impaired because of inadequate control by the descending control from the limbic system through the serotoninergic raphe magnus nuclei (59). Several studies have been published on ES2 duration in TTH, with some discrepancies as ES2 was either shorter (60**–65) or normal (66 –68). Again, these discordant results might be attributed to methodological differences or to patient-related factors such as age, comorbidities and headache severity (57).

The blink reflex (BR) was mentioned above in the migraine section. In TTH, most studies involved the ‘standard’ BR, that is evoked in response to stimulation of large Aß myelinated fibre activation in the supraorbital nerve area, contrary to the nociception-specific BR or nsBR which is elicited by Aδ nociceptive afferents and has been mainly studied in migraine (58). The BR was normal in all forms of TTH (see (58) for a more detailed review), this was also the case of the sole nsBR study in CTTH (69). A single trial demonstrated a decrease of the R2 recovery cycle after double supraorbital stimulation in both ETTH and CTTH, suggesting a reduced excitability of brainstem interneurons (70).

The biceps femori flexion reflex (BFR) is a complex reflex mediated at both spinal and supraspinal levels in response to a nociceptive stimulus. In CTTH, studies found a lower RIII flexion reflex threshold which might suggest central sensitization of nociceptive circuits (71 –73) and/or be because of impaired supraspinal descending inhibitory control (72).

Cortical responses

Few studies are available on electroencephalography in TTH and those few provide inconsistent results (58). In contrast to migraine, most evoked potential studies (VEP, LEP, CNV) performed in TTH did not demonstrate any recurrent abnormalities like reduced preactivation or lack of habituation (14,16,74,75). The only abnormality was found in LEP by de Tommaso et al., who demonstrated increased N2-P2 amplitude in CTTH after pericranial skin stimulation (76,77). This higher amplitude was correlated with the total pericranial tenderness and with anxiety scores (the latter was interpreted as a hypervigilance to painful stimuli), and decreased after treatment with amitriptyline (78). An interesting but unique study recorded SSEP in response to intramuscular trapezius electrical stimulation using high-density EEG mapping, and found a significant reduction in magnitude of the dipolar source during and after induced tonic muscle pain in healthy volunteers but not in CTTH patients (79). They concluded that this lack of magnitude reduction might be because of impaired inhibition of the nociceptive input in CTTH patients, suggesting an abnormal supraspinal response to muscular pain (79).

Cluster headache

Electrophysiology could seem of modest importance to the understanding of cluster headache (CH) pathophysiology regarding other techniques like functional neuroimaging. However, it remains of high interest to study nociceptive spinal and supraspinal mechanisms, and to understand the mode of action of recent neuromodulation methods.

Subcortical electromyographic responses

A study of ‘standard’ BR found that the amplitude of the contralateral R2 response on the symptomatic side was lower than on the healthy side in the active cluster period (80). A further trial did not confirm these findings, but showed a decrease of R2 inhibition after supraorbital and peripheral conditioning stimuli in CH, the latter being partially reversed by naloxone IV (81). Another study demonstrated an R2 habituation deficit in untreated episodic CH patients during the cluster period, which was even more pronounced than in migraine patients (82). A more recent study with nsBR did not confirm these findings in a population of episodic and chronic CH patients on prophylactic medication, both during and outwith a bout (83). Finally, a study of nsBR found a decrease of latency ratio (cluster side vs. healthy side), as well as an increase of R2 area ratio in episodic CH patients during a bout (84). Overall, these findings suggest an impaired nociceptive processing at brainstem level in the CH period.

This impairment of pain control systems was also confirmed by the study of BFR, which exhibited a lower threshold in CH patients during (85) and outwith the bout period (86). Interestingly, the modifications of BFR have a circadian rhythm in ECH patients but not in CCH patients (86).

Evoked potentials

As in TTH, studies of evoked potentials are scarce in the CH population. Various abnormalities have been highlighted in sensory evoked potentials, but these are not as ‘homogenous’ as in migraine (84,87 –93). The intensity dependence of auditory evoked potentials (IDAP, see before) is also increased in CH patients, during and outwith the bout, which might suggest a decreased serotoninergic activity in the raphe-hypothalamic pathways (94).

Neuromodulation in cluster headache: mechanism of action

Posterior hypothalamic deep brain stimulation (hDBS) and occipital nerve stimulation (ONS) have shown their efficacy in the symptomatic treatment of drug-resistant CCH (95 –98). Electrophysiological measurements were performed in order to understand their mechanisms of action. The nsBR was not significantly modified after hDBS, but the latter decreased peripheral pain thresholds (95) and increased trigeminal cold detection and pain thresholds (99), suggesting subtle pain-modulating processes. In ONS, nsBR was paradoxically increased after treatment (97), which mirrors a more centrally located mode of action. That brief low frequency ONS does not modify nsBR in healthy volunteers, could also argue in favour of this suprasegmental mechanism (100). The latter was also proposed to explain occipital nerve steroid injection efficacy, after which CH patients have an R2 decrease, but that is not especially correlated to clinical improvement (101).

Pearls of headache electrophysiology: summary

The contribution of electrophysiology to the understanding of primary headache pathophysiology can be summarized as follows.

– In episodic migraine, there is an interictal lack of habituation of the brain to various sensory modalities, which is associated with a reduced cortical (and even subcortical) preactivation level suggesting an abnormal underlying cortical excitability. A recent hypothesis pointed out that the thalamus could play a key role in these phenomena: a thalamocortical dysrythmia (possibly because of a functional disconnection of the thalamus from the brainstem) would reduce the cortical preactivation level and thus impair the normal habituation process.

– In tension-type headache, available studies suggest that the chronic form would be associated with dysfunctioning supraspinal descending antinociceptive pathways coming from the limbic system through the serotoninergic raphe magnus nuclei to the interneurons of the pontomedullary reticular formation. This is not the case in the episodic form where an abnormal myofascial activity was retrieved but there were no signs of abnormal central antinociceptive control.

– Finally, in cluster headache, electrophysiological studies are scarce and their results are conflicting. Overall, impaired sensory and nociceptive processing can be suspected but no consistent underlying pathophysiological hypothesis has been proposed unlike in migraine.

Neuroimaging correlates of the lack of habituation

In order to better understand the underlying mechanisms of the interictal abnormalities found during the electrophysiological recordings in migraine patients, several studies recently focused on their neuroimaging correlates, especially on habituation which was often indirectly evaluated. Only a few studies are available and differ by their methodology (neuroimaging type: functional magnetic resonance imaging (fMRI) or positron emission tomography (PET), stimulation paradigms, etc.), leading to results discrepancies (102 –105). With ³H MR spectroscopy searching for occipital lactate changes during visual stimulation, Sándor et al. (106) reported increased baseline lactate levels in patients suffering from migraine with pure visual auras, whereas patients with complex neurological auras had normal baseline levels, but lactate increases, mimicking lack of habituation, during visual stimulation. In an fMRI study, an initial weaker blood-oxygen-level dependent (BOLD) signal was found during visual stimulation in 10 migraine patients (with and without aura). By contrast, a progressive increase of cortical occipital BOLD was found during sustained visual stimulation in migraineurs, a pattern resembling the VEP habituation deficit, whereas there was a habituation in healthy volunteers (107). More recently, Boulloche et al. (103) and Martin et al. (105) studied the visual cortex response in H₂¹⁵O PET (103) and fMRI-BOLD (105), using different stimulation paradigms in episodic migraineurs. Although the first authors indirectly found a lack of habituation (or a cortical hyperexcitability) to light, the second authors failed to demonstrate any lack of habituation to repetitive light stimuli in migraineurs. Aderjan et al. used a painful olfactive stimulation to study habituation over several days, unlike electrophysiological studies where the latter is often evaluated within minutes (102). The pain perception did not differ with time between healthy volunteers and migraine patients but the BOLD signal activity level of some antinociceptive structures (such as the prefrontal cortex, rostral cingulate cortex, red nucleus) decreased in migraineurs and increased in healthy volunteers, suggesting existing alterations of pain inhibitory circuits. Finally, another fMRI-BOLD trial designed with paired face stimuli speculated that the absence of haemodynamic refractory effects in migraineurs was the neurovascular correlate of the lack of habituation found in electrophysiology (104). However, habituation in face perception areas has never been studied in electrophysiological trials as it would require intracranial recordings (104). However, even recognizing that these interictal fMRI studies did not use completely comparable stimulus parameters to those typically used to demonstrate habituation with EPs, they confirm that cortical responsivity to repeated stimuli is abnormal in migraineurs.

Pitfalls

Methodological considerations

Methodological problems were extensively reviewed in a previous article (4**). Electrophysiological recordings can be easily contaminated by artefacts of various origins (external: alternative current etc., or internal/organic: ECG, EMG, drugs). There are also several recommendations in terms of signal sampling frequency and filtering, as well as stimulation frequencies for evoked responses. The latter have been pointed out as a possible explanation for discrepancies found in evoked potential studies, especially in migraine (46). Hence, there is a need for a better standardization, and some proposals for methodological optimization of recordings have been suggested before (4**).

Unfortunately, only part of the nervous system is accessible to non-invasive electrophysiological recordings. Deep structures are not easily reached (hypothalamus etc.), but indirect neurophysiological assessment methods can be found for some of them, for example analysis of HFOs as representing thalamocortical activity (51**,55). Moreover, not all structures provide a clear ‘witness’ of activation (for example the cerebellum, orbito-frontal cortex, hypothalamus) and knowing if they are being stimulated could be difficult.

Patient phenotypes

Differences between populations included in electrophysiological studies can also explain the variability of results and the lack of interindividual reproducibility. It is well known that evoked potential modifications can occur with age and coexisting comorbidities such as depression and anxiety. Between EP studies, inconsistencies can also be because of concomitant acute or preventive drugs, or even caffeine intake (82,83,108 –110).

Intrinsic recording discrepancies may also happen. In women, the menstrual cycle affects pain perception and should be considered when recordings are performed (24). The dynamic electrophysiological pattern of migraine can be used to situate a patient in his/her migraine ‘cycle’ at the time of the recording (see before, proximity to the last/next attack), using headache diaries and phone calls. It is important to emphasize again here that even in the interictal period not all migraineurs exhibit a habituation deficit or reduced initial response amplitudes, and that these electrophysiological traits were statistically demonstrated on averaged measures of several patients compared with healthy volunteers.

Heterogeneity of the disease

Headaches are heterogeneous polygenic diseases, and ICHD-II classification of primary headaches (1) is probably not accurate enough to classify patients into homogenous subgroups for electrophysiological studies. For example in migraine, the severity of the disease is an essential factor: studying a migraineur with high attack frequency in interictal period is a real challenge, and this patient cannot be reasonably considered as similar to another migraineur with one attack every other month. The extremity of this clinical spectrum is chronic migraine, now considered a ‘never ending attack’ (27), as patients exhibit similar electrophysiological patterns to those during the ictal state (111). In many older studies the chronic migraine subgroups included patients with and without various kinds of acute medication overuse; however, the electrophysiological profile of both patient types appears different, suggesting diverse mechanisms leading to headache chronification (13). Further subclassifications of headache patients, especially migraineurs, have been proposed according to associated symptoms like photophobia or vertigo. This method has already been employed in genetics (latent class analysis) but results were disappointing.

Conclusions: open questions and recommendations for future studies

Overall, the contribution of electrophysiology to the understanding of primary headache pathophysiology is more significant for migraine than for other primary headaches, where studies are comparatively rarer and often disclose a high variability of results for similar methods.

The reduced preactivation level of sensory cortices and the lack of habituation to sensory stimuli found in migraine could be the consequence of a thalamocortical dysrythmia as suggested by recent works (51**,55,56). A thalamic involvement in migraine pathophysiology is also suspected by other studies using different research methods (112 –114). The activity of the thalamus itself is modulated by several afferences, among them inputs from the aminergic nuclei of the dorsal rostral pons.

– Future electrophysiological works must understand the role of each structure in the dynamic mechanisms that lead to the migraine cycle, from one attack to the next, and from episodic to chronic migraine.

Given the heterogeneity of the disease, patients should be carefully selected as mentioned before, and perhaps classified according to their electrophysiological profile, which might subtend different underlying mechanisms.

– Moreover, further studies should focus on the connections between the cortex, the thalamus and the brainstem (trigeminal structures), and especially their modulations by excitatory and/or inhibitory stimuli.

– One of the upcoming applications of electrophysiology would be to help select neurostimulation techniques and protocols that would be able to correct the functional abnormalities detectable in certain headache disorders such as the lack of habituation in migraine (see example in Figure 3, (115)). Hence, previous results provided by electrophysiological measurements lead to therapeutic neurostimulation trials that gave encouraging results (115), these translational research protocols should be highly promoted in future.

– Conversely, electrophysiology remains a simple method to appreciate the mode of action of various pharmacological and non-pharmacological treatments.

Figure 3.

This figure presents two non-invasive neurostimulation techniques that are able to modify visual evoked potential (VEP) recordings in healthy volunteers (HV). VEP traces (six blocks of recordings) are represented before (a, a1) and after (b, b1) the application of intermittent theta burst stimulation (i-TBS, upper part of the figure) or inhibitory quadripulse (QPI, lower part) in one HV. Part (c, c1) shows average baseline N1P1 and P1N2 VEP amplitudes in 13 HV, and their evolution 3 hours after stimulation with i-TBS (upper part) or QPI (lower part). Part (d, d1) shows VEP habituation slopes values before and 3 hours after stimulation with i-TBS (upper part) or QPI (lower part). The degree of habituation is expressed as a negative slope, that is the more negative value, the higher the habituation.

Pearls, pitfalls and perspectives

Pearls

Electrophysiology is a non-invasive and easy way to access the activity of the nervous system, and is therefore particularly suitable for the study of primary headaches which are CNS functional disorders characterized by a dynamic pattern (ictal/interictal).

The most reproducible electrophysiological abnormality is the lack of habituation to repetitive stimuli found in migraine patients in the interictal period, whatever is the sensory modality. This lack of habituation could be the consequence of a thalamocortical dysrythmia resulting in a reduced preactivation level of sensory cortices.

Pitfalls

As a result of high inter- and intraindividual variability, electrophysiological measurements cannot be used for diagnosis of primary headaches but can be helpful to rule out mimics in some cases (secondary headaches, epileptic syndromes).

The discrepancies between electrophysiological studies might be because of methodological differences as well as patients’ dissimilarities.

Perspectives

Electrophysiology will remain an important tool in the headache research armamentarium. One of the upcoming applications of electrophysiology would be to help select neurostimulation techniques and protocols able to correct the functional abnormalities detectable in certain headache disorders such as the lack of habituation in migraine.

Footnotes

Funding

This work was supported by funding from the Walloon Region, DG06, Direction Générale Opérationnelle de l'Économie, de l'Emploi et de la Recherche. JS is supported by research convention 3.4.650.09 from the National Fund for Scientific Research (FNRS), Belgium and by research grants from the Faculty of Medicine-University of Liège.

Conflict of interest

None declared.

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Pearls and pitfalls: Electrophysiology for primary headaches

Abstract

Background

Aim of the work

Results

Conclusions and perspectives

Keywords

Introduction

Pearls

Migraine

Habituation modifications

Cortical dysexcitability

Abnormal functional connexions and circuits: the ‘unifying’ thalamic hypothesis

Tension-type headache

Electromyographic responses

Cortical responses

Cluster headache

Subcortical electromyographic responses

Evoked potentials

Neuromodulation in cluster headache: mechanism of action

Pearls of headache electrophysiology: summary

Neuroimaging correlates of the lack of habituation

Pitfalls

Methodological considerations

Patient phenotypes

Heterogeneity of the disease

Conclusions: open questions and recommendations for future studies

Pearls, pitfalls and perspectives

Pearls

Pitfalls

Perspectives

Footnotes

Funding

Conflict of interest

References