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Abstract

Neurophysiological testing has become a valuable tool for investigating brain excitability and nociceptive systems in headache disorders. Previous reviews have suggested that most neurophysiological tests have limited value for headache diagnosis, but a vast potential for exploring the pathophysiology of headaches, the central effects of certain pharmacological treatments and phenotype-genotype correlations. Many protocols, however, lack standardization. This meta-analytical review of neurophysiological methods in migraine was initiated by a task force within the EUROHEAD project (EU Strep LSHM-CT-2004-5044837-Workpackage 9). Most of the neurophysiological approaches that have been used in headache patients are reviewed, i.e. evoked potentials, nociception-specific blink reflex, single-fibre electromyography, neuroimaging methods (functional MRI, PET, and voxel-based morphometry) and the nitroglycerin attack-provoking test. For each of them, we summarize the results, analyse the methodological limitations and propose recommendations for improved methodology and standardization of research protocols. The first part is devoted to electrophysiological methods, the second to neuroimaging techniques and the NTG test.

Keywords

Electrophysiology methodology migraine neurophysiology

Introduction

Neurophysiological testing has become a valuable tool for investigating, atraumatically in humans, CNS functions, including those related to pain processing. Previous studies in headache disorders have suggested that most neurophysiological tests have limited value for diagnosis, but a vast potential for studying pathophysiology and the effects of pharmacological treatment (1). They also may contribute to improve phenotype-genotype correlations.

Considering the great number and variety of neurophysiological tests that have been used up to now in headache patients, sometimes with differing results, there seems to be a timely need for the standardization of methods. In this article we will critically review the available data published for neurophysiological tests in headache and propose some recommendations for optimized research protocols. We will focus on those tests that have been used in migraine (2) and have provided the most relevant and novel information for the understanding of migraine pathophysiology. Electrophysiological tests such as evoked potentials, single fibre electromyography and the nociceptive blink reflex, will be described in this first part of the article. The imaging techniques, such as functional magnetic resonance imaging (fMRI), positron emission tomography (PET) and voxel-based magnetic resonance imaging morphometry (VBM), as well as the attack-provoking nitroglycerin test, will be discussed in the second companion paper.

Electrophysiological tests

In migraine, interictal abnormalities of cerebral information processing were first detected by studying an event-related potential, contingent negative variation (CNV). Thereafter, similar changes were also found for the more simple modality-specific evoked potentials, which are less dependent on attention and motivation. The somatosensory modality has been less frequently studied than the visual and auditory modalities; the results have been summarized elsewhere (2). More recently, it has been shown that in migraineurs between attacks laser-evoked cortical nociceptive potentials have the same abnormality as the other evoked potentials, i.e. a deficit of habituation (3). In the present review, we will focus on visual and auditory evoked potentials, which are most frequently examined in migraine.

We will also review the data and lessons coming from studies of single fibre EMG and the nociceptive blink reflex in migraine patients, as these two methods have yielded interesting results in recent years.

The vast literature on transcranial magnetic stimulation and the controversial information it provides on cortical excitability in migraine have been discussed in detail elsewhere (4).

Visual evoked potentials (VEP) D Magis & J Schoenen

Definition

Visual evoked potentials are electrical potential differences recorded from the scalp in response to visual stimuli. They represent a mass response of cortical and possibly subcortical visual areas. Visual evoked potentials to stimuli repeated at low rates are defined as transient visual evoked potentials (usually abbreviated as VEPs). VEPs can be elicited by either patterned or unpatterned stimuli. The most commonly used are pattern-reversal, pattern onset-offset and flash stimuli. Steady-state visual evoked potentials (abbreviated as SVEPs) are responses to visual stimuli at relatively high frequencies (above 3.5/s).

Published data

The available published data on VEP studies in migraine are presented in Table 1, including the methods used in each study (5–44). The table illustrates the great variability of methods. It also shows that VEP abnormalities have been found in most studies, although the type of abnormality varies.

Table 1

Available VEP studies in migraine

First Author	Year	Material			Methods								Main findings in migraineurs
First Author	Year	Nb patients & CTRL	Mean age (SD/Range)	Timing of recordings	Spatial frequency	Stimulation rate	Luminance	Contrast	Reference Active electrodes	Number of trials	Frequency Filter	Measured components	Main findings in migraineurs
Kennard	1978	28 MA 30 CTRL	39 (?)	? Days after attack	34′	2 Hz	?	?	Fz MO, LO, RO	256	?	N1, P1, N2	Increased amplitude and latency of P1
Benna	1985	10 MO No CTRL	36 (25–46)	8 days after attack	?	?	?	?	?	?	?	N1, P1	Aspecific amplitude and latencies assymetries
Brinciotti	1986	24 MO 19 MA ? CTRL	11.4 (7–16)	7 days after attack	50′	1.6 Hz	?	?	?	100 × 2	?	P2	No difference with CTRL
Polich	1986	20 MA 20 CTRL	32.8 (23–44)	Headache free at test	?	3.9 Hz	?	?	Cz Oz, O2, O1	200 × 2	?	N1, P1, N2	Reduced P1 amplitude
Mariani	1988	22 MO 20 CTRL	39.4 (17–60)	2 days after attack	38′	1 Hz	?	?	Fz MO, LO, RO	128 × 2	?	P1	No difference with CTRL
Raudino	1988	34 MO 6 MA 20 CTRL	34.8 (14–78)	Headache free at test	?	1.5 Hz	?	?	Fz Cz	?	?	P1	Increased P1 amplitude and latencies close to the attack
Diener	1989	54 MO 4 MA 87 CTRL	42.3 (?)	Baseline (? /attack), after 4 months treatment and 3 months after washout period	small?	1.56 Hz	?	?	A1 Oz	64	?	P1	At baseline, significantly increased latencies and higher amplitudes
Lai	1989	13 MO 25 MA No CTRL	29 (17–38)	During attacks precipitated by food and fasting	27.6′	?	?	?	Fpz MO, LO, RO	128	?	N1, P1	Latencies and amplitudes within normal limits.
Drake	1990	50 MO 37 CTRL	? (16–67)	?	56′	1.88 Hz	?	?	Fz Oz, O1, O2	200 × 2	BP 1–250 Hz	N1, P1, N2	No difference with CTRL
Mariani	1990	20 MA 20 CTRL	34.2 (19–55)	2 days after attack	38′	1 Hz	?	?	Fz Oz, O1, O2	128 × 2	?	N1, P1	Increased latencies of P1
Tsounis	1993	22 MO 20 MA 37 CTRL	36.5 (15–56)	2 weeks after attack	49′	1 Hz	?	?	Fz Oz, O1, O2, T5, T6	128 × 2	?	P1	P1 latencies shorter on the symptomatic side (hemifield stimulation)
Schoenen	1995	27 MO 9 MA 16 CTRL	32 (?)	At least 1 week after attack	1°8′	3.1 Hz	?	?	Fz Oz	50 × 5	?	N1, P1, N2	No difference in amplitude or latencies. Potentiation of N1-P1 and P1-N2 amplitudes in migraineurs; habituation in CTRL.
Tagliati	1995	8 MO 7 MA 15 CTRL	31.7 (17–56)	7 days after attack	Large	1 Hz	?	?	Fz 9 active	240	?	N1, P1	Reduced amplitudes ipsilateral to visual aura around Oz
Rossi	1996	71 MO, MA & TTH 19 CTRL	? Children	2 days after attack	15′ 30′	1.7 Hz	?	75%	?	100 × 2	BP 1–250 Hz	P1	No difference with CTRL
Aloisi	1997	16 MO 4 MA ? CTRL	10.1 (6–13)	7 days after attack	30′	1.1 Hz	112 cd/m²	98%	C2 Fpz	256 × 2	BP 0.3–300 Hz	P1, N2	Inverse correlation between P1 amplitude and serum magnesium levels
Lahat	1997	44 MO ? CTRL	? (3–17)	?	34′ × 24′	2 Hz			?	?	?	P1, N2	Increased P1-N2 amplitude
Sener	1997	23 MO16 MA17 CTRL	33.4 (7.2)	1 week after attack	52′	2 Hz	?	90%	Fz Oz	200 × 2	BP 1Hz-1 kHz	N1, P1	No difference with CTRL
Shibata	1997a	14 MO19 MA43 CTRL	41.3 (20–70)	2–20 days after attack	30′	2 Hz	400 cd/m²	?	Fz Oz	100 × 2	BP 1–100 Hz	N1, P1, N2	Increased P1 amplitude
Shibata	1997b	14 MO15 MA23 CTRL	42.9 (22–65)	5 days after attack	30′	2 Hz	800 cd/m²	80%	Fz Oz, MO, LO, RO	100 × 2	BP 1–100 Hz	N1, P1	Increased P1 amplitude in MA, higher on the contralateral side of visual aura
Afra	1998	25 MO15 MA25 CTRL	36 (?)	5 days after attack	1°8′	3.1 Hz	240 cd/m²	80%	Fz Oz	100 × 15	BP 1–100 Hz	N1, P1, N2	Trend to lower 1st block N1-P1 amplitudeLack of habituation during long lasting visual stimulation
Shibata	1998	20 MA19 ME34 CTRL	41, 48	1–30 days after attack	30′	2 Hz	800 cd/m²	80%	Fz Oz, MO, LO, RO	100 × 2	BP 1–100 Hz	N1, P1	Increased N1-P1 amplitude soon after the attack. Amplitude asymmetry correlated to disease duration.
Lahat	1999	53 ‘headache’No CTRL	Under 5 years	?	?	?	?	?	?	?	?	N1, P1, N2	P1-N2 amplitude significantly larger
Oelkers	1999	13 MO13 MA28 CTRL	29.1 (5.9)	At least 3 days before and after attack	11′21′42′85′	1 Hz	?	>99%	A1 + A2 Oz	50 × 5	BP 0.01–30Hz	N1, P1, N2	Prolonged N2 latency in MA when small checks presented
Sandor	1999	40 MO (20 parents and their children) No CTRL	44.4 (7.5)17 (6.1)	At least 3 days before and after attack	1°8′	3.1 Hz	?	?	?	50 × 5	?	N1, P1	Similar lack of habituation patterns in related migrainous pairs
Wang	1999	22 MO13 ETTH20 CTTH26 CTRL	35.3 (9.6)27.1 (10.9)27.8 (8.4)	At least 1 week after attack	1°8′	3 Hz	?	80%	Fz Oz	50 × 5	BP 0.1–100 Hz	N1, P1, N2	Elongated N2 latency in MA interictally Reduced habituation in migraine but not CTTH or ETTH
Khalil	2000	37 MO47 MA8 MO + MA62 CTRL	40.2 (12)	Headache free at test	37.8′	2 Hz	54.2 cd/m²	95%	Fz Cz	240	?	P1	P1 amplitude increased in migraineurs but decreased in MA with long disease duration
Sand	2000	15 MO6 MA22 CTRL	39.3 (9.2)	3 days after attack, 24h within test or interictal	8′33′	2 Hz	?	97%	Fz, Oz O1, O2	100 × 2	BP 2–200 Hz	N1, P1, N2	Significant habituation to small checks in CTRL but not in migraineurs (except preattack subgroup)Potentiation in CTRL for medium sized checks
Yucesan	2000	22 MO < 2y dis27 MO > 10y dis17 CTRL	29 (8.1)37 (6.9)35.6 (8.5)	At least 1 week after attack	Large	2 Hz	?	90%	Fpz Oz	250 × 2	BP 1Hz–1 kHz	N1, P1	No correlation between amplitude of VEPs and duration of the disease.
Afra	2000a	12 MA10 CTRL	34 (16)	At least 3 days before and after an attack	1°8′	3.1 Hz	260 cd/m² 100 cd/m²	?	Fz Oz	50 × 5	BP 1–100 Hz	N1, P1, N2	Increased amplitude and potentiation with red light in HV and not in MA
Afra	2000b	37 MO22 MA23 CTRL	36 (11)	At least 3 days before and after an attack	1°8′	3.1 Hz	260 cd/m²	80%	Fz Oz	50 × 5	BP 1–100Hz	N1, P1, N2	Negative correlation between 1st block amplitude and potentiation of VEP in all subject groups
Judit	2000	69 MO4 MA4 MO + MANo CTRL	?	At least 3 days before and after, just before, during, 1 day or 2 day after	1°8′	3.1 Hz	260 cd/m²	80%	Fz Oz	100 × 5	BP 1–100Hz	N1, P1	Normalization of EP habituation just before and during the attack.
Logi	2001	40 MO19 MA30 CTRL	35.8 (13.7)38.3 (9.6)	Interictal (>10 days)	14,3′	1 Hz	75 cd/m²	50%	Fpz’ Oz, LO, RO	Min 100 × 2 or 3	BP 1–60 Hz	N1, P1	Asymmetry in right-left amplitude
Marrelli	2001	20 MO14 MA14 TTH10 CTRL	11.9 (1.8)11.5 (2.3)	Attack free for at least one week	30′	1.1 Hz8.1 Hz (SS)	112 cd/m²	90%	Fpz Oz	256 at 1.1 Hz100 at 8.1 Hz	BP 0.3–300 Hz	P1	No difference with CTRL
Yilmaz	2001	16 MO29 MA22 CTRL	31.5 (11–64)33.5 (15–60)	During and between attacks	?	2 Hz	?	?	Fz Oz	200	?	N1, P1, N2	Elongated N2 latency in MA interictally
Kochar	2002	25 ‘migraine’No CTRL	?	During and 7 days after attack	?	?	?	?	?	?	?	P1	Prolonged P1 latency at the time of acute attack
Ozkul	2002	44 MO35 MA40 CTRL	33 (8)	At least 3 days before and after the attack	1°8′	3.1 Hz	260 cd/m²	80%	Fz Oz	50 × 5	BP 1–100 Hz	N1, P1	Significant lack of habituation in migraineurs corrected after fluoxetine prophylaxis
Coutin-Churchman	2003	23 MA50 CTRL	? (18–53)? (18–47)	Interictal period	30′	2 Hz	50 cd/m²	95%	Fpz Oz, T3, T4	100 × 2	BP 0.5–100 Hz	P1, theta angle (vectors)	No difference in latency or amplitudeSignificant alteration in vector orientation, laterality of deviation correlated with laterality of symptoms
Oelkers-Ax	2004	67 MO32 MA24 TTH82 CTRL	? (6–18)	Headache free at test	60′30′15′7.5′	1 Hz	87.6 cd/m² 0.6 cd/m²	>99%	Cz Oz	?	LP 30 Hz	N1, P1, N2	Decline of N2 latency with increasing age shifted to lower spatial frequencies in headache patients
Spreafico	2004	53 ‘migraine’20 CTRL	?	During migraine prophylactic treatment, or without prophylaxis	?	?	?	?	?	?	?	P1	Lower P1 latencies
Oelkers-Ax	2005	123 ‘headache’82 CTRL	? (6–18)	At least 72h before and after an attack	7.5′	1 Hz	?	30%	Cz Oz	50 × 5	LP 30 Hz	N1, P1, N2	Lack of N2 latency reduction with ageNo difference in habituation

Legend: MO = migraine without aura, MA = migraine with aura, TTH = tension-type headache, ME = migraine equivalent (aura without headache), CTRL = healthy controls. BP = bandpass, LP = low pass, HP = high pass.

Interests

The majority of VEP studies demonstrate interictally increased amplitude of grand averages or lack of habituation in sequential blocks of averaging. The habituation pattern may have a familial character (29). As electroretinograms are normal (25), this indicates that information processing in the visual cortex is abnormal in migraineurs between attacks and that it could represent an endophenotypic marker for the disorder.

The advantage of evoked potential studies is that the method is non-invasive and that it can be repeated in the same individual at different time points, e.g. during an attack (35) or after pharmacotherapy (11).

Moreover, evoked potential studies can be performed with portable recording devices, which is of interest for field studies of population isolates and of genotype-phenotype correlations.

Limitations

There is no published information on the intra- and interindividual reproducibility of VEP habituation. For diagnostic and research purposes, the International Federation of Clinical Neurophysiology recommends replicating any electrophysiological test at least once. Regarding habituation, it is not known at which time delay such replication can be performed without interfering with the habituation phenomenon itself. Variability may be greater for averaging of smaller numbers of responses, as used to evaluate habituation.

Visual impairment interferes with morphology, amplitude and latency of VEPs. Patients with known visual disturbances (e.g. visual loss due to previous optic neuritis) should be excluded or analysed separately. Modified sensitivity to perception of contrast or patterns should be a criterion for exclusion, as it is frequently found interictally in migraineurs. In the case of optic deficits, the recordings should be made with correcting glasses.

There is a need for a better standardization between different studies/centres.

Recommendations for improved methodology

To standardize methods and allow comparisons between laboratories, the Guidelines recommended by the International Federation of Clinical Neurophysiology for the general use of VEP in clinical neurology should be followed (45).

The following information should be included in the ‘methods’ section of published studies.

Stimulus characteristics

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Type of pattern: checkerboard, square-wave gratings, sine-wave gratings. Orientation of gratings: horizontal, vertical … It should be achromatic black and white, unless a specific effect of various wave lengths is explored.

•

Size of pattern elements: defined by the visual angle that they subtend in the subject's visual field. Checks are traditionally expressed in minutes of arc, whereas gratings are reported in cycle per degree (cpd). To calculate the visual angle of the pattern elements, the following equation is used: a = arctan (W/2D) × 120 where a is the visual angle in minutes of arc, W is the width of the check in millimetres and D is the distance of the pattern from the corneal surface in millimetres. The visual angle can be converted to cycles per degree (cpd) by the equation: cpd = 30/a for bars and cpd = 42.3/a for checks. The measure in cpd defines the spatial frequency.

•

Total field size: expressed in degrees of visual angle. The location of the central fixation point in the field should also be noted.

•

Rate of presentation/alternation of the pattern: refers to the number of stimulus events per unit of time (temporal frequency). Stimulus frequency is expressed in Hertz (Hz) and represents the number of full cycles of stimulus presentation per second.

•

Stimulus luminance: measured by a photometer and expressed in candela per square meter (cd/m²). It should be uniform and vary by less than 20% between the centre and the periphery of the field. The mean luminance should be measured at the centre of the field and can be expressed for spatially mirror symmetric stimuli by the equation: Mean luminance = (Lmax + Lmin)/2 where Lmax and Lmin are the maximum and minimum luminance values across the stimulus field. It is important to notice that the response amplitude and peak latency will vary with the stimulus luminance.

•

Background luminance: should be kept constant throughout the recording and remain the same for each given protocol.

•

Contrast: i.e. the difference in luminance between the bright and the dark portion of the pattern. It is expressed by the equation C = [(Lmax − Lmin)/(Lmax + Lmin)] × 100%.

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Type of stimulator: patterned stimuli may be displayed in various ways (TV, oscilloscope, projector screen …). There is no perfect stimulator. Comparable results among laboratories will be possible only if the physical characteristics of the stimuli are matched.

Recordings

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Electrodes: type and position.

•

Recording equipment: type and bandwidth of the amplifiers and preamplifiers.

•

Number of repeats.

For clinical purposes, the IFCN committee recommends the following parameters to obtain reliable and reproducible VEPs.

Black and white pattern-reversal checkerboard or vertical gratings for stimulation.

Pattern elements: 14–16′, 28–32′, 56–64′ (ideally all of them in clinical practice). The smaller size of 14–16′ is optimal to stimulate the fovea but is easily affected by visual acuity changes. The wider size patterns may also stimulate the parafoveal region and may elicit normal responses in cases of foveal dysfunction.

Full field size greater than 8°.

Frequency of presentation of the pattern: 1Hz is preferred for transient VEPs; suggested frequency for SVEPs is 4 or 8 Hz.

Mean luminance of at least 50 cd/m² of the centre field.

Background luminance matched as closely as possible to the mean luminance of the stimulus.

Contrast between 60 and 95%.

System bandpass filtering of 1.0 to 250–300 Hz.

Montage: two recording electrodes are sufficient, as VEPs are widely distributed over the scalp from the vertex to the inion. The montages suggested for a reproducible VEP are: Oz-Fpz or Oz-A1-A2 (linked ears) with a ground electrode placed at Cz.

Analysis time of 250 ms for transient VEP, 2 s for SVEP.

Number of repeats: averaging of at least 100 individual trials.

There are no guidelines as far as habituation is concerned, as it is not routinely assessed in clinical practice. Nonetheless, the following parameters are considered important for the study of habituation.

•

Luminance: a change in luminance interferes with peak amplitudes and latencies.

•

Band pass filtering: it should ideally be minimal in habituation studies.

•

Spatial frequency 1°8′ is recommended

•

Stimulation frequency: this is important as higher stimulation rates induce faster habituation; 3.1 Hz can be recommended.

•

Number of blocks of averaging: the optimal number of blocks has to be defined; usually five or six blocks of 50–100 averaging are used. We recommend recording evoked potentials continuously and averaging off-line, which allows measurement of habituation on blocks of a variable number of responses without stimulus interruption.

•

The time interval between the recording session and the last/next attack is crucial as habituation markedly changes in the peri-attack interval (33); an interval of at least 72 h is recommended, which indicates that patients with high attack frequencies have to be studied separately.

Studies needed

Studies are needed to assess the reproducibility of VEP habituation in healthy volunteers and in migraineurs. Several physiological models indicate that habituation is positively related to the amplitude of the initial response. Thus, the relation between the amplitude of the first block of averaging and the degree of habituation should be assessed in all studies.

Auditory evoked cortical potentials (AEP) D Magis & J Schoenen

Definition

Auditory stimuli elicit in the CNS small electrical potentials, which, depending on their generators in the auditory pathways, can be separated into short (brain stem), middle and long latency auditory evoked potentials. Middle latency AEP originate in the auditory cortex. In migraine between attacks (46) they were found to steeply increase in amplitude with increasing stimulus intensity reflecting a pronounced intensity-dependence of auditory evoked potentials (IDAP), which is likely to reflect reduced central serotonin neurotransmission.

Literature data

The available published data on AEP studies in migraine are presented in Table 2, including the methods used in each study (32, 34, 46–54). There are only three published studies exploring habituation of cortical auditory evoked potentials. The first (46) reported potentiation at high but not at low intensities. This was confirmed by a second study (54) measuring simultaneously intensity dependence and habituation for each stimulation intensity, but not in another study using a somewhat different methodology (32). The majority of IDAP studies show that the intensity-dependence is more pronounced in migraine with some evidence for a genetic influence (51; 53).

Table 2

Available AEP studies in migraine

First Author	Year	Material			Methods						Main findings in migraineurs
First Author	Year	Nb patients & CTRL	Mean age (SD/Range)	Timing of recordings	Stimulus intensities	Stimulation rate	Reference Active electrodes	Number of trials	Frequency Filter	Measured components	Main findings in migraineurs
Wang	1996	25 MO10 MA25 CTRL	?	Between attacks	40, 50, 60, 70 dB (random)	?	?	40 × 3		N1-P2ASF slope	Higher IDAPAt 70 dB, significant potentiation
Proietti-Cecchini	1997	16 ‘migraine’27 CTRL	35.8 (13.5)26.8 (6)	At least 7 days from last attack	40, 50, 60, 70 dB	0.53–0.61 Hz (random)	Linked earlobes (A1 + A2) Cz	100 × 4	BP 1–20 Hz	ASF slope	Evidence for IDAP as a surrogate marker for central serotoninergic transmission
Sandor	1999	No migraineurs22 CTRL	24 (3)22 (3)	/	40, 50, 60, 70 dB	0.53–0.61 Hz (random)	Linked mastoïds Cz	100 × 4	BP 1–30 HzBP 1–100 Hz	ASF slope	Variability too large to compare individuals.
Roon	1999	No migraineurs38 CTRL	23 (2)24 (3)	/	40, 50, 60, 70 dB	?	Right mastoid Cz	100 × 4	BP 1–100 Hz	ASF slope	Poor repeatability, big samples needed
Afra	2000	37 MO22 MA23 CTRL	36 (11)	At least 3 days before and after an attack	40, 50, 60, 70 dB (random)	0.53–0.61 Hz (random)	Linked earlobes (A1 + A2) Cz	100 × 4	BP 1–20 Hz	N1-P2ASF slopeChange in amplitude	Correlations:— Amplitude at 40 dB and percentage of amplitude increase between 40 and 70 dB in MO— ASF slopes and 40 dB amplitude in MA
Sandor	2000a	24 MO2 MANo CTRL	30.9 (14.4)	At least 3 days before and after an attack	40, 50, 60, 70 dB	0.53–0.61 Hz (random)	Linked earlobes (A1 + A2) Cz	100 × 4	BP 1–20 Hz	ASF slope	Decrease of IDAP with Bbloquers and not B2, correlated with clinical improvement: B2 and Bbloquers act differently
Sandor	2000b	40 MO (20 parents and their children)No CTRL	44.4 (7.5)17 (6.1)	At least 3 days before and after attack	40, 50, 60, 70 dB	0.53–0.61 Hz (random)	Linked earlobes (A1 + A2) Cz	100 × 4	BP 1–20 Hz	ASF slope	Similar EP patterns in related migrainous pairs.Evidence for genetic influence on IDAP in migraineurs
Sand	2000	15 MO6 MA22 CTRL	39.3 (9.2)	At least 3 days after an attackPre-attack group = 24h within testInterictal group = no headache after test	40, 55 and 70 dB	0.6 Hz	Linked earlobes (A1 + A2) Cz	160 × 3	BP 1–200 Hz	N1-P2ASF slope	No significant difference with CTRL
Siniatchkin	2000	46 MIG & CTRL from MIG families46 CTRL	(7–52)(7–56)	At least 5 days from the last attack	70, 80, 90, 100 dB	0.45–0.55 Hz (random)	Linked mastoïds Cz	80 × 4	BP 0.5–250 Hz	ASF slope	High IDAP may also be found in CTRLEvidence for genetic influence
Ambrosini	2001	20 MO14 CTRL	32.5 (21–62)25.5 (22–54)	At least 3 days before and after an attack	90 dB2 following stimuli(S1-S2)	0.08–0.12 Hz (random)	Linked mastoïds Cz	100 × 2	BP 0.001–1000 Hz	Gating of AEP = ratio between amplitude P50-S2 and P50-S1	Amplitude of P50 to the second of 2 homologous stimuli less reduced in migraineurs.
Ambrosini	2003	14 MO14 CTRL	31.2 (12.9)35.2 (14.7)	At least 3 days before and after an attack	50, 60, 70, 80 dB	0.474 Hz	Linked mastoïds Cz	30 × 4	BP 0.001–1000 Hz	N1-P2ASF slope	IDAP is higher in migraineursAEP potentiation at all stimulus intensities.Negative correlation between IDAP and habituation.

Legend: MO = migraine without aura, MA = migraine with aura, CTRL = healthy controls. BP = bandpass. IDAP = intensity-dependence of auditory evoked potentials.

Interests

Intensity-dependence could be a marker of central serotoninergic neurotransmission, as it can be modulated by drugs increasing or decreasing serotoninergic activity (48). Therefore, it could be a useful and non-invasive surrogate for detecting an action of pharmacological agents on central serotonin transmission (46).

As for VEPs, the advantage of cortical auditory evoked potential is that the method is non-invasive and that it can be replicated in the same individual at different time points, e.g. during an attack (55) or after pharmacotherapy (52). Moreover, AEPs can be recorded with portable devices, which is of interest for field studies of population isolates and genotype-phenotype correlations.

Limitations of the method

Their sensitivity to cognitive factors makes the AEP vulnerable to general changes in attention and vigilance. Their low voltage combined with relatively high background electrical noise requires the use of highly sensitive amplifiers and computer averaging equipment.

Two studies showed poor IDAP repeatability for pathophysiology (50) and pharmacological studies (49). It was concluded that variability was too large to compare individuals, and that therefore IDAP could not be used for diagnosis, but that it could be used for intraindividual comparisons.

Hearing impairment may interfere with amplitude and latencies of AEP, but there is no information on its possible influence on habituation or amplitude-stimulus function. It is likely, however, that mild hearing loss is not a major confounding factor as long as the stimulus sensation level (SL) is determined at the beginning of the recording.

Recommendations for improved methodology

As for VEPs, the first step to optimize cortical AEP methodology and to allow more reliable comparisons between centres is to comply with the Guidelines recommended by the International Federation of Clinical Neurophysiology.

To obtain reliable and reproducible cortical AEP in clinical practice, the committee recommends the following method.

•

For clinical research studies, a set of five recording channels is recommended, including electrodes Fz, Cz, F3 and F4 of the international 10/20 system referenced to the linked mastoid processes, but this is rarely possible in clinical practice, as many evoked potential recording devices offer no more than two recording channels.

•

For recordings with minimal distortion, bandpass settings should be 0.1 (0.3) to 30 (100) Hz.

•

Averaging should be performed after artefact rejection and include at least 200 responses per condition.

•

Recordings should be repeated at least once to evaluate consistency.

There are no guidelines for habituation and IDAP studies, as the latter are not commonly used in clinical practice. The following parameters are of importance.

•

The intensity of the stimulus is a crucial variable for habituation study of AEP. Patients with an otologic disease should be detected by audiometric testing. We propose excluding the patients showing an average tone loss above 20 dB (compared with normal hearing level dB nHL) (International Bureau for Audiophonology recommendations). Adjusting stimulus intensity to sensation level, which is used in most studies, may be harmful and painful in patients with end organ hearing loss and auditory recruitment. The following intensities should be recorded: 40-50-60-70 dB above sensation level (dB SL) if absence of significant hearing loss has been ascertained, or above the normal hearing threshold (dB nHL), at which an average normal subject can perceive the stimulus 50% of the time, if the otologic status is uncertain (see Table 2). Which of SL or nHL has been used to set the intensity should be clearly announced in the methods.

•

Different stimulus intensities should be administered in a randomized or pseudorandomized sequence, ideally the first intensity should not be the lowest or the highest one (sequence example: 60-70-50-40 dB and not 40-50-60-70 dB).

•

As for the stimulus rate, most of the studies in migraine used a randomized interstimulus interval (ISI) of 1.6 to 2.2 s (0.61–0.45 Hz). The average ISI should be approximately 1500 ms (45).

•

The optimal number of blocks of averaging for each intensity has to be defined; four to five blocks of 30 averaged responses can be used; as for the other evoked potentials, we recommend recording evoked potentials continuously and averaging off-line, which allows measurement of habituation on blocks of a variable number of responses without stimulus interruption.

•

The interval between the recording and the last/next attack is crucial; an interval of at least 72 h is recommended, which indicates that patients with high attack frequencies have to be studied separately.

Studies needed

Simultaneous recordings of AEP and cochlear responses could be of interest to exclude a subclinical dysfunction of cochlear processing in migraineurs. Recently, we have analysed, between attacks in migraineurs without a history of vertigo, the vestibulo-collic reflex (VCR) (or vestibular evoked myogenic potential-VEMP), an inhibitory brain stem reflex that explores an oligosynaptic pathway most probably including the saccular macula, the inferior vestibular nerve, the lateral (Deiter's) vestibular nucleus, the vestibulospinal tract and the neck motor neurones innervating the ipsilateral sternocleidomastoid muscle. We found that amplitude and habituation of the VCR are reduced (56), an abnormality very similar to that found for cortical evoked potentials.

Single-fibre electromyography A Ambrosini & M Ertas

Definition and literature data

Single-fibre electromyography (SFEMG) is the best and safest neurophysiological method to assess the neuromuscular junction performances in vivo in human subjects. Although there is a priori no clinical reason suggesting an abnormality of neuromuscular transmission in migraine patients, most (57–61), but not all (62), recent studies found such mild subclinical abnormalities in some subgroups of migraineurs. The working hypothesis for these findings was that some migraineurs might share genetic abnormalities on the CACNA1A gene similar to those found in familial hemiplegic migraine type 1 (FHM1) patients, as suggested by some linkage and sib-pair analysis studies (63–65). Normalization of the abnormal SFEMG values was obtained in two migraine patients by a treatment with acetazolamide, which is also used in FHM1 and EA-2 patients (66).

Limitations of the method

Recordings

There are two methods to obtain SFEMG recordings (67). The most commonly used is voluntary muscular contraction, where the mean MCD values are calculated from the intervals between two consecutive discharges of a single muscle fibre potential. This method requires good cooperation of the subject, who has to adequately dose his muscle contraction. SFEMG may also be performed during electrical stimulation of intramuscular motor axons (Stimulation-SFEMG); in this case mean MCD is calculated from the interval between the stimulus artefact and the single muscle fibre potential. Stimulation-SFEMG is easy to perform and does not require any patient collaboration except for relaxation. It suffers, however, from the risk of insufficient stimuli and consequent miscalculations.

SFEMG may be performed in different muscles; the muscles most commonly explored are extensor digitorum communis (EDC), frontalis and orbicularis oculi muscles. While the orbicularis oculi muscle is probably the best to reveal neuromuscular transmission abnormalities in ocular type myasthenia gravis (68), the EDC muscle is commonly used in generalized neuromuscular transmission defects such as generalized type myasthenia gravis. In their studies Ambrosini et al. (57–59, 66) used stimulation SFEMG of EDC, Domitrz et al. (61), Ertas and Baslo (69) and Coban (60) used voluntary EDC contraction SFEMG and Terwindt et al. (62) used stimulation SFEMG of frontalis muscle. These studies are thus heterogeneous, and the results obtained from them cannot be appropriately compared.

Reference values

Migraine is a very common disease, affecting 10–15% of the general population, and often undiagnosed or misdiagnosed. Moreover, it can occur at any age before 40–50 years and is characterized by a strong genetic component, which may explain why neurophysiological abnormalities can be found in asymptomatic relatives of migraine patients (29, 53). Consequently, most normative SFEMG values reported in the literature cannot be applied in migraine studies without reservation because pre-symptomatic, or even symptomatic, migraineurs may have been included in the ‘normal’ control group. It is thus necessary to establish normal control values for SFEMG in healthy subjects without a personal migraine history, but also without a family history of migraine. Only some investigators (57–60) took into account this important potential bias.

One of the most critical points in assessing the presence of SFEMG abnormalities in migraine patients is to define the electrophysiological parameters to be measured and their normative values. In many studies (57–59, 62, 66, A. Ambrosini et al., unpublished data) average mean MCD values (indices of the mean jitter of all the examined fibres) were used to compare migraineurs with healthy controls; in some of them (57, 58, 61, 66; A. Ambrosini et al., unpublished data) neuromuscular transmission abnormalities were also evaluated by the percentage of single fibres with abnormal mean MCD values in each recording.

The upper normal limits commonly accepted for stimulation-SFEMG recordings are 25 µs for the mean of MCD values and l0% or less fibres with a MCD value higher than 40 µs. However, these values were obtained in groups of control subjects that have probably included migraineurs and subjects at genetic risk for migraine. Normal values should thus be assessed on more strictly selected healthy volunteers. In their studies Ambrosini et al. found that in 16 healthy controls no one had single fibre jitter values exceeding 40 µs, and any abnormally high jitter value in migraineurs was considered as a neuromuscular transmission abnormality. Ambrosini et al. (57–59, 66), and Terwindt et al. (62) considered an SFEMG abnormal if the mean of MCD values exceeded that of control subjects by two standard deviations. Domitrz et al. (61), who used SFEMG during voluntary contraction, reported as cut-offs 33.8 µs for the mean of MCD values and 55 μs for single fibre jitter value on the basis of their own reference values. They did not take into account the percentage of abnormal fibres. Ertas and Baslo (69) and Coban (60), who also studied SFEMG during voluntary contraction, considered the test as abnormal if 15% or more MCD values exceeded 55 µs and borderline if 10% of MCD values were above this threshold.

In conclusion, the concept of SFEMG abnormality may vary between studies and needs to be clearly defined with regard to the parameter measured and to the control population that was recorded to define normal values.

Blinding

Terwindt et al. (62) stress that insufficient blindness may influence recordings and analyses of SFEMG tests. In their study the SFEMG performers were reported to be unaware of the diagnoses. It seems difficult, however, to maintain blinding in such a selected small group of patients who generally also undergo various other investigations. Ambrosini et al. (57–59) and Domitrz et al. (61) were blinded to the clinical aura features of the examined patients, but were informed about the general diagnosis. Although bias due to the incomplete blinding cannot be excluded in these studies, it probably had no major role, as significant differences were found only between subgroups of migraine with aura patients and not between the three groups of subjects taken together.

Recommendations for improved methodology

Recordings

The two different methods for obtaining SFEMG recordings both have advantages and disadvantages. The most sensitive one is stimulation-SFEMG of orbicularis oculi muscle (for ocular type myasthenia gravis), the most reproducible one stimulation-SFEMG of extensor digitorum communis muscle and the most reliable one SFEMG during voluntary EDC contraction. There is thus at present no evidence-based reason to favour one method over the other

Control reference values

Each investigator should select an appropriate control group in order to assess in his laboratory setting the upper normal limit for mean MCD values and percentage of abnormally high single fibre jitter values and/or blocking.

SFEMG measures

From a statistical point of view, the best upper cut-off is the mean of MCD values of control subjects +3 s.d. and the percentage of abnormal MCD values.

Blinding

Complete blinding to the clinical diagnosis is recommended, but may be difficult to obtain. Partial blinding to certain phenotypic features may, however, suffice, especially in studies of migraine subgroups.

Nociception-specific blink reflex D Magis, H Kaube & J Schoenen

Definition

The nociception-specific blink reflex (nsBR) is an oligosynaptic reflex of brain stem origin. It can be obtained by a newly developed concentric surface electrode first described by Kaube et al. (70). Low intensity stimuli delivered supraorbitally by this electrode are concentrated on a small cutaneous area and result in a high current density that is able to stimulate preferentially Aδ fibres and therefore to produce a nociception-specific R2 response without inducing the R1 response recorded in routine blink reflex studies. The nociception-specificity is supported by the fact that local anaesthesia and analgesics reduce dramatically the R2 amplitude (70).

Literature data

Up to now, five studies were performed with the nsBR electrode in migraine (71–75) (Table 3). In two of them (71, 72), the R2 amplitude was found increased and its latency decreased during a migraine attack, which was considered to reflect sensitization of trigeminal nociception, predominantly on the headache side. These abnormalities were not found in sinusitis pain (71), and disappeared with acute antimigraine treatment (72). A significant interictal lack of habituation of the nsBR response in migraineurs was demonstrated in three studies (73–75). A correlation was found in migraine between the habituation patterns of nsBR and visual evoked potentials, suggesting a common underlying mechanism (74). Finally, the nsBR habituation deficit could be a trait marker of the disease, as it was also present in healthy subjects with first-degree migrainous relatives (75).

Table 3

Available studies of NSBR in migraine

First Author	Year	Material			Methods									Main findings in migraineurs
First Author	Year	Nb patients & CTRL	Mean age (SD/Range)	Timing of recordings	Electrode type	Area of stimulation	Intensity	Stimulus duration	ISI	Number of stimuli / block	Number of blocks	Analysis	Measured components	Main findings in migraineurs
Katsarava	2002	14 MO14 CTRL with sinusitis	35.5	During attack & pain free	Concentric electrode	Left and right supraorbital areas	1.5 × PT	0.3 ms	15–17 s	6	1	Rectified EMG1st sweep of each block excluded	R2 amplitudeR2 latency	Decreased R2 latency during attackIncreased R2 amplitude on headache side during attack
Kaube	2002	17 MO		Interictally, during attack and after treatment with zolmitriptan & lysine acetylsalicylate	Standard electrode, concentric electrode	Left and right supraorbital areas	1.5 × PT	0.3 ms	15–17 s	6	1	Rectified EMG1st sweep of each block excluded	R1 R2 amplitudeR1 R2 latencies	No differences detected between subjects with standard electrodeDecreased R2 latencies during attack with concentric electrodeIncreased R2 amplitude during attack (mostly on headache side)Treatment reduced R2 amplitude and increased latency
Katsarava	2003	17 MO15 CTRL	40 (24–56)35 (27–47)	Interictally, during attack and after treatment with zolmitriptan & lysine acetylsalicylate	Concentric electrode	Left and right supraorbital areas	1.5 × PT	0.3 ms	15–17 s	6	2	Rectified EMG1st sweep of each block excluded	R2 AUCR2 habituationR2 latency	Habituation deficit interictallyDifference of habituation between and during attacksIncreased R2 amplitude interictallyNo difference between headache and non headache sides
Di Clemente	2004	13 MO13 CTRLwithout FH13 CTRLwith FH	2924	Interictally	Concentric electrode	Right supraorbital area	1.5 × PT	0.3 ms	15–17 s	6	10	Rectified EMG1st sweep of each block excluded	R2 AUCR2 habituationR2 latency	Habituation deficit interictallyAsymptomatic CTRL with 1st degree migrainous relatives have the same NSBR abnormalities as patients with full-blown migraine attacks.AUC of 1st block responses is smaller in migraineurs.
Di Clemente	2005	15 MO15 CTRL	28 (10.8)23.9 (3.4)	Interictally	Concentric electrode	Right supraorbital area	1.5 × PT	0.3 ms	15–17 s	6	10	Rectified EMG1st sweep of each block excluded	R2 AUCR2 habituationR2 latencyVEP correlation	Habituation deficit in migraine patientsHabituations of PR-VEP and NSBR correlated

Legend: MO = migraine without aura, MA = migraine with aura, CTRL = healthy controls. PT = pain threshold. NSBR = nociception-specific blink reflex.

Interests of the method

The nociception-specific blink reflex is a simple way to explore the nociceptive trigeminal system at the level of the brain stem. Because of the selective depolarization of superficial Aδ fibres, the method could be a more practical, cheaper and safer alternative to laser stimulation, but the latter more specifically activates nociceptive afferents including C fibres. Up to now all available studies of nsBR have used the same stimulation parameters: electrical pulses delivered at 1.5 times the individual pain threshold, having a 0.3 ms duration and separated by pseudorandomized ISI from 15 to 17 s.

Limitations of the method

In their studies, Katsarava et al. (73) and Di Clemente et al. (74, 75), did not use the same method to define habituation. Both excluded the first sweep of each block to avoid contamination with the R3 component (70). In Katsarava's study, habituation was calculated as the regression coefficient of the five remaining successive R2 responses of a six-sweep block. The average habituation value was averaged on two blocks (mean regression coefficient). In Di Clemente et al.'s studies, 10 blocks of six sweeps each were recorded. Habituation was defined as the percentage change between the R2 areas under the curve (AUC) in the tenth and first blocks. The latter analysis was used to avoid variability due to inter-individual differences in R2 AUC (76), and also to permit comparison with the habituation pattern of PR-VEP (74).

Recently, it was suggested in a methodological trial that trains of three stimuli could be more reliable than single shocks to elicit the nsBR, because it induces R2 response of greater amplitude (77). However, this stimulation modality is rather painful and has not yet been applied to migraine patients.

Recommendations for improved methodology

As mentioned above, the nsBR studies published hitherto in headache patients are based on a similar methodology, except as far as calculation of habituation is concerned. As in spite of this both studies in which habituation was assessed found a similar interictal habituation deficit in migraineurs, one may assume that the difference in methodology did not play an important role. However, using mean values of habituation determined on several averaged recordings could limit variability between subjects (76). Another methodological bias with nsBR recordings could be caused by the stimulation electrode. As a matter of fact, electrodes used up to now are custom-built and not commercially available. Slight differences inevitably exist between electrodes in different laboratories and might contribute to discrepancies in results. For future studies, it seems necessary that the various research groups with an interest in nsBR come to an agreement on one and the same stimulation electrode.

The number of blocks to be averaged is an important variable with regard to the patients' comfort. We have shown in one study of 10 blocks of averaging (74) that the lack of habituation in migraineurs was significant already in the fifth block. To study habituation the procedure could thus be limited to five blocks, i.e. 50 stimuli.

The side of stimulation does not appear to be important when recordings are made interictally, as no migraine study disclosed any significant side difference (73, 74). However, interictal studies in patients with side-locked hemicrania remain to be performed. Ictal recordings should be performed on both forehead sides, as the R2 area significantly increases on the headache side during an attack (71, 72).

Finally, it remains to be decided whether the triple stimulus could increase stability and reproducibility of nsBR recordings. Studies are underway and results are expected soon.

Studies needed

There is a lack of studies on the reproducibility of nsBR data, as for most electrophysiological studies in migraine. Moreover, all available studies used a stimulus intensity set at 1.5 times the individual pain threshold. Although no significant differences in pain thresholds were found in nsBR studies between migraineurs and healthy subjects, pain perception clearly has a subjective component. In future studies it would be of interest to compare results obtained with the individually adjusted stimulus intensity and with a fixed intensity.

Acknowledgements

The leading authors, D. Magis and J. Schoenen, are grateful to Mrs P. Gerard for help with literature search and referencing. This work is supported by the EU STREP EUROHEAD (LSHM-CT-2004–5044837) (Workpackage 9).

References

Sandrini

Friberg

Janig

Jensen

Russell

Sanchez del Rio

Neurophysiological tests and neuroimaging procedures in non-acute headache: guidelines and recommendations. Eur J Neurol 2004; 11:217–24.

Ambrosini

Maertens de Noordhout

Sandor

Schoenen

Electrophysiological studies in migraine: a comprehensive review of their interest and limitations. Cephalalgia 2003; 23 (Suppl. 1):13–31.

Valeriani

de Tommaso

Restuccia

Le Pera

Guido

Iannelti

Reduced habituation to experimental pain in migraine patients: a CO(2) laser evoked potential study. Pain, 2003; 105:57–64.

Maertens de Noordhout

Ambrosini

Sandor

Schoenen

Transcranial magnetic stimulation in migraine. In: Hallett

Chokroverty

eds. Magnetic stimulation in clinical neurophysiology, 2nd edn. Philadelphia: Elsevier 2005:411–8.

Kennard

Gawel

Rudoloph

Rose

Visual evoked potentials in migraine subjects. Res Clin Stud Headache 1978; 6:73–80.

Benna

Bianco

Costa

Piazza

Bergamasco

Visual evoked potentials and brainstem auditory evoked potentials in migraine and transient ischemic attacks. Cephalalgia 1985; 5 (Suppl. 2):53–8.

Brinciotti

Guidetti

Matricardi

Cortesi

Responsiveness of the visual system in childhood migraine studied by means of VEPs. Cephalalgia 1986; 6:183–5.

Polich

Ehlers

Dalessio

DJ.

Pattern-shift visual evoked responses and EEG in migraine. Headache 1986; 26:451–6.

Mariani

Moschini

Pastorino

Rizzi

Severgnini

Tiengo

Pattern-reversal visual evoked potentials and EEG correlations in common migraine patients. Headache, 1988; 28:269–71.

10.

Raudino

Visual evoked potential in patients with migraine. Headache, 1988; 28:531–3.

11.

Diener

Scholz

Dichgans

Gerber

Jack

Bille

Central effects of drugs used in migraine prophylaxis evaluated by visual evoked potentials. Ann Neurol 1989; 25:125–30.

12.

Lai

Dean

Ziegler

Hassanein

RS.

Clinical and electrophysiological responses to dietary challenge in migraineurs. Headache 1989; 29:180–6.

13.

Drake

Pakalnis

Hietter

Padamadan

Visual and auditory evoked potentials in migraine. Electromyogr Clin Neurophysiol 1990; 30:77–81.

14.

Mariani

Moschini

Pastorino

Rizzi

Severgnini

Tiengo

Pattern reversal visual evoked potentials (VEP-PR) in migraine subjects with visual aura. Headache 1990; 30:435–8.

15.

Tsounis

Milonas

Gilliam

Hemi-field pattern reversal visual evoked potentials in migraine. Cephalalgia 1993; 13:267–71.

16.

Schoenen

Wang

Albert

Delwaide

PJ.

Potentiation instead of habituation characterizes visual evoked potentials in migraine between attacks. Eur J Neurol 1995; 2:115–22.

17.

Tagliati

Sabbadini

Bernardi

Silvestrini

Multichannel visual evoked potentials in migraine. Electroencephalogr Clin Neurophysiol 1995; 96:1–5.

18.

Rossi

Pastorino

Bellettini

Chiodi

Mariani

Cortinovis

Pattern reversal visual evoked potentials in children with migraine or tension-type headache. Cephalalgia 1996; 16:104–6.

19.

Aloisi

Marrelli

Porto

Tozzi

Cerone

Visual evoked potentials and serum magnesium levels in juvenile migraine patients. Headache 1997; 37:383–5.

20.

Evers

Bauer

Suhr

Husstedt

Grotemeyer

KH.

Cognitive processing in primary headache: a study on event-related potentials. Neurology 1997; 48:108–13.

21.

Lahat

Nadir

Barr

Eshel

Aladjem

Bistritze

Visual evoked potentials: a diagnostic test for migraine headache in children. Dev Med Child Neurol 1997; 39:85–7.

22.

Sener

Haktanir

Demirci

Pattern-reversal visual evoked potentials in migraineurs with or without visual aura. Headache 1997; 37:449–51.

23.

Shibata

Osawa

Iwata

Pattern reversal visual evoked potentials in classic and common migraine.J Neurol Sci 1997; 145:177–81.

24.

Shibata

Osawa

Iwata

Simultaneous recording of pattern reversal electroretinograms and visual evoked potentials in migraine. Cephalalgia 1997; 17:742–7.

25.

Afra

Cecchini

De Pasqua

Albert

Schoenen

Visual evoked potentials during long periods of pattern-reversal stimulation in migraine. Brain 1998; 121:233–41.

26.

Shibata

Osawa

Iwata

Pattern reversal visual evoked potentials in migraine with aura and migraine aura without headache. Cephalalgia 1998; 18:319–23.

27.

Lahat

Baar

Barzilai

Cohen

Berkovitch

Visual evoked potentials in the diagnosis of headache before 5 years of age. Eur J Pediatr 1999; 158:892–5.

28.

Oelkers

Grosser

Lang

Geisslinger

Kobal

Brune

Visual evoked potentials in migraine patients: alterations depend on pattern spatial frequency. Brain 1999; 122:1147–55.

29.

Sandor

Afra

Proietti-Cecchini

Albert

Schoenen

Familial influences on cortical evoked potentials in migraine. Neuroreport 1999; 10:1235–8.

30.

Wang

Ding

Wang

YH.

Personality and response to repeated visual stimulation in migraine and tension-type headaches. Cephalalgia 1999; 19:718–24.

31.

Khalil

Legg

Anderson

DJ.

Long term decline of P100 amplitude in migraine with aura. J Neurol Neurosurg Psychiatry 2000; 69:507–11.

32.

Sand

Vingen

JV.

Visual, long-latency auditory and brainstem auditory evoked potentials in migraine: relation to pattern size, stimulus intensity, sound and light discomfort thresholds and pre-attack state. Cephalalgia 2000; 20:804–20.

33.

Yucesan

Sener

Mutluer

Influence of disease duration on visual evoked potentials in migraineurs. Headache 2000; 40:384–8.

34.

Afra

Cecchini

Sandor

Schoenen

Comparison of visual and auditory evoked cortical potentials in migraine patients between attacks. Clin Neurophysiol 2000; 111:1124–9.

35.

Judit

Sandor

Schoenen

Habituation of visual and intensity dependence of auditory evoked cortical potentials tends to normalize just before and during the migraine attack. Cephalalgia 2000; 20:714–9.

36.

Logi

Bonfiglio

Orlandi

Bonanni

Iudice

Sartucci

Asymmetric scalp distribution of pattern visual evoked potentials during interictal phases in migraine. Acta Neurol Scand 2001; 104:301–7.

37.

Marrelli

Tozzi

Porto

Cimini

Aloisi

Valenti

Spectral analysis of visual potentials evoked by pattern-reversal checkerboard in juvenile patients with headache. Headache 2001; 41:792–7.

38.

Yilmaz

Bayazit

Erbagci

Pence

Visual evoked potential changes in migraine: influence of migraine attack and aura. J Neurol Sci 2001; 184:139–41.

39.

Kochar

Srivastava

Maurya

Jain

Aggarwal

Visual evoked potential and brainstem auditory evoked potentials in acute attack and after the attack of migraine. Electromyogr Clin Neurophysiol 2002; 42:175–9.

40.

Ozkul

Bozlar

Effects of fluoxetine on habituation of pattern reversal visually evoked potentials in migraine prophylaxis. Headache 2002; 42:582–7.

41.

Coutin-Churchman

Padron dF. Vector analysis of visual evoked potentials in migraineurs with visual aura. Clin Neurophysiol 2003; 114:2132–7.

42.

Oelkers-Ax

Bender

Just

Pfuller

Parzer

Resch

Pattern-reversal visual-evoked potentials in children with migraine and other primary headache: evidence for maturation disorder?

Pain 2004; 108:267–75.

43.

Spreafico

Frigerio

Santoro

Ferrarese

Agostoni

Visual evoked potentials in migraine. Neurol Sci 2004; 25 (Suppl. 3):S288–S290.

44.

Oelkers-Ax

Parzer

Resch

Weisbrod

Maturation of early visual processing investigated by a pattern-reversal habituation paradigm is altered in migraine. Cephalalgia 2005; 25:280–9.

45.

45 International Federation of Clinical Neurophysiology. Recommendations for the Practice of Clinical Neurophysiology. Guidelines of the International Federation of Clinical Neurophysiology. Electroencephalogr Clin Neurophysiol Supplement 1999; 52:1–304.

46.

Wang

Timsit-Berthier

Schoenen

Intensity dependence of auditory evoked potentials is pronounced in migraine: an indication of cortical potentiation and low serotonergic neurotransmission?

Neurology 1996; 46:1404–9.

47.

Ambrosini

De Pasqua

Afra

Sandor

Schoenen

Reduced gating of middle-latency auditory evoked potentials (P50) in migraine patients: another indication of abnormal sensory processing?

Neurosci Lett 2001; 306:132–4.

48.

Proietti-Cecchini

Afra

Schoenen

Intensity dependence of the cortical auditory evoked potentials as a surrogate marker of central nervous system serotonin transmission in man: demonstration of a central effect for the 5HT1B/1D agonist zolmitriptan (311C90, Zomig). Cephalalgia 1997; 17:849–54, discussion 799.

49.

Roon

Sandor

Schoonman

Lamers

Schoenen

Ferrari

Auditory evoked potentials in the assessment of central nervous system effects of antimigraine drugs. Cephalalgia 1999; 19:880–5.

50.

Sandor

Roon

Ferrari

van Dijk

Schoenen

Repeatability of the intensity dependence of cortical auditory evoked potentials in the assessment of cortical information processing. Cephalalgia 1999; 19:873–9.

51.

Sandor

Afra

Proietti Cecchini

Albert

Schoenen

From neurophysiology to genetics: cortical information processing in migraine underlies familial influences – a novel approach. Funct Neurol 2000; 15 (Suppl. 3):68–72.

52.

Sandor

Afra

Ambrosini

Schoenen

Prophylactic treatment of migraine with beta-blockers and riboflavin: differential effects on the intensity dependence of auditory evoked cortical potentials. Headache 2000; 40:30–5.

53.

Siniatchkin

Kropp

Neumann

Gerber

Stephani

Intensity dependence of auditory evoked cortical potentials in migraine families. Pain 2000; 85:247–54.

54.

Ambrosini

Rossi

De Pasqua

Pierelli

Schoenen

Lack of habituation causes high intensity dependence of auditory evoked cortical potentials in migraine. Brain 2003; 126:2009–15.

55.

Judit

Sandor

Schoenen

Habituation of visual and intensity dependence of auditory evoked cortical potentials tends to normalize just before and during the migraine attack. Cephalalgia 2000; 20:714–9.

56.

Allena

Magis

Mariano da Silva

De Pasqua

Bisdorff

Schoenen

The vestibulo-collic reflex is smaller and lacks habituation in migraine patients between attacks. Cephalalgia 2005; 25:863–1020.

57.

Ambrosini

de Noordhout

Alagona

Dalpozzo

Schoenen

Impairment of neuromuscular transmission in a subgroup of migraine patients. Neurosci Lett 1999; 276:201–3.

58.

Ambrosini

de Noordhout

Schoenen

Neuromuscular transmission in migraine: a single-fiber EMG study in clinical subgroups. Neurology 2001; 56:1038–43.

59.

Ambrosini

de Noordhout

Schoenen

Neuromuscular transmission in migraine patients with prolonged aura. Acta Neurol Belg 2001; 101:166–70.

60.

Coban

Examination of probable neuromuscular transmission abnormalitity in migraine, cluster headache and related primary headache disorders by using single fiber electromyography. Doctoral thesis; Istanbul Faculty of Medicine, 2004.

61.

Domitrz

Kostera-Pruszczyk

Kwiecinski

A single-fibre EMG study of neuromuscular transmission in migraine patients. Cephalalgia 2005; 25:817–21.

62.

Terwindt

Kors

Vein

Ferrari

van Dijk

JG.

Single-fiber EMG in familial hemiplegic migraine. Neurology 2004; 63:1942–3.

63.

May

Ophoff

Terwindt

Urban

van Eijk

Haan

Familial hemiplegic migraine locus on 19p13 is involved in the common forms of migraine with and without aura. Human Genet 1995; 96:604–8.

64.

Nyholt

Lea

Goadsby

Brimage

Griffiths

LR.

Familial typical migraine: linkage to chromosome 19p13 and evidence for genetic heterogeneity. Neurology 1998; 50:1428–32.

65.

Terwindt

Ophoff

van Eijk

Vergouwe

Haan

Frants

Involvement of the CACNA1A gene containing region on 19p13 in migraine with and without aura. Neurology 2001; 56:1028–32.

66.

Ambrosini

Pierelli

Schoenen

Acetazolamide acts on neuromuscular transmission abnormalities found in some migraineurs. Cephalalgia 2003; 23:75–8.

67.

Sanders

Stålberg

EV.

AAEM minimonograph #25: single-fiber electromyography. Muscle Nerve 1996; 19:1069–83.

68.

Valls-Canals

Povedano

Montero

Pradas

Stimulated single-fiber EMG of the frontalis and orbicularis oculi muscles in ocular myasthenia gravis. Muscle Nerve 2003; 28:501–3.

69.

Ertas

Baslo

MB.

Abnormal neuromuscular transmission in cluster headache. Headache 2003; 43:616–20.

70.

Kaube

Katsarava

Kaufer

Diener

Ellrich

Diener

HC.

A new method to increase nociception specificity of the human blink reflex. Clin Neurophysiol 2000; 111:413–6.

71.

Katsarava

Lehnerdt

Duda

Ellrich

Diener

Kaube

Sensitization of trigeminal nociception specific for migraine but not pain of sinusitis. Neurology 2002; 59:1450–3.

72.

Kaube

Katsarava

Przywara

Drepper

Ellrich

Diener

HC.

Acute migraine headache: possible sensitization of neurons in the spinal trigeminal nucleus?

Neurology 2002; 58:1234–8.

73.

Katsarava

Giffin

Diener

Kaube

Abnormal habituation of ‘nociceptive’ blink reflex in migraine – evidence for increased excitability of trigeminal nociception. Cephalalgia 2003; 23:814–9.

74.

Di Clemente

Coppola

Magis

Fumal

De Pasqua

Schoenen

Nociceptive blink reflex and visual evoked potential habituations are correlated in migraine. Headache 2005; 45:1388–93.

75.

Di Clemente

Coppola

Magis

Fumal

De Pasqua

Schoenen

Interictal habituation deficit of the nociceptive blink reflex: an endophenotypic marker for presymptomatic migraine?

Brain 2007; 130:765–70.

76.

Katsarava

Ellrich

Diener

Kaube

Optimized stimulation and recording parameters of human ‘nociception specific’ blink reflex recordings. Clin Neurophysiol 2002; 113:1932–6.

77.

Giffin

Katsarava

Pfundstein

Ellrich

Kaube

The effect of multiple stimuli on the modulation of the ‘nociceptive’ blink reflex. Pain 2004; 108:124–8.

Evaluation and Proposal for Optimalization of Neurophysiological Tests in Migraine: Part 1—Electrophysiological Tests

Abstract

Keywords

Introduction

Electrophysiological tests

Visual evoked potentials (VEP) D Magis & J Schoenen

Definition

Published data

Interests

Limitations

Recommendations for improved methodology

Studies needed

Auditory evoked cortical potentials (AEP) D Magis & J Schoenen

Definition

Literature data

Interests

Limitations of the method

Recommendations for improved methodology

Studies needed

Single-fibre electromyography A Ambrosini & M Ertas

Definition and literature data

Limitations of the method

Recordings

Reference values

Blinding

Recommendations for improved methodology

Recordings

Control reference values

SFEMG measures

Blinding

Nociception-specific blink reflex D Magis, H Kaube & J Schoenen

Definition

Literature data

Interests of the method

Limitations of the method

Recommendations for improved methodology

Studies needed

Acknowledgements

References