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Lack of visual evoked potentials amplitude decrement during prolonged reversal and motion stimulation in migraineurs
Clinical Neurophysiology 125 (2014) 1223–1230
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Lack of visual evoked potentials amplitude decrement during prolonged reversal and motion stimulation in migraineurs Michal Bednárˇ a, Zuzana Kubová b, Jan Kremlácˇek b,⇑ a b
Department of Rehabilitation, Charles University in Prague, Faculty of Medicine in Hradec Králové and University Hospital, Hradec Králové, Czech Republic Department of Pathological Physiology, Charles University in Prague, Faculty of Medicine in Hradec Králové, Hradec Králové 500 38, Czech Republic
a r t i c l e
i n f o
Article history: Accepted 30 October 2013 Available online 19 November 2013 Keywords: Migraine Visual evoked potentials Habituation Visual processing Visual motion
h i g h l i g h t s Blinded assessment of VEPs amplitude decay during 2.5 min examination supported the theory of
repeated response decrement deficit in migraineurs. The repeated response decrement deficit was also observed during visual motion processing in the
extrastriatal regions of the visual cortex. Pattern-reversal VEPs to low contrast stimuli did not show a significant repeated response decrement
likely because of their high variability.
a b s t r a c t Objective: We evaluated response decrement during a short time repetitive low and high contrast reversal and low contrast motion stimulation in controls and migraineurs. Methods: A total of 39 migraine patients (out of which 19 were in the interictal period and without prophylactic treatment) and 36 healthy volunteers were examined using pattern-reversal (PR-VEP) and motion-onset (M-VEP) visual evoked potentials. Binocular stimulation lasted 2.5 min and the decrement assessment was blinded. Results: Evidence of significant decrement was observed in healthy volunteers for high contrast PR-VEP amplitude of P100-N75 ratios between the fifth and first blocks (0.9; p = 0.001) with a linear decline ( 0.7 lV/min, p = 0.001) and in the P100-N145 amplitude with linear decline ( 0.5 lV/min, p = 0.004). Significant decrement was also observed for the ratio between the fifth and first block P1-N2 amplitudes in M-VEP (0.9, p = 0.006). No significant decrement was noted in the low contrast PR-VEP or among migraineurs. Conclusions: We confirm differences in decrease of VEPs amplitude during short term examination between controls and migraineurs. We showed the decrement deficit also in the extrastriatal regions of the migraineurs’ visual cortex. Significance: Low contrast and motion-onset stimuli in short time decrement assessment did not increase the test sensitivity. Ó 2013 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.
1. Introduction Migraine is currently understood as a paroxysmal neurological disease with no underlying structural correlation. In essence, it is the dysfunction of neural cortical excitability. Neurophysiological methods appear to allow at least partially an insight into the neural mechanisms at the level of the central nervous system in migraine. Based on results of various neurophysiological studies a deficit of reduction in response to any repeated sensory stimulus is ⇑ Corresponding author. Tel.: +420 495 816 332. E-mail address: [email protected] (J. Kremlácˇek).
presently considered to be the main biomarker specific to migraine during the interictal period and thus it is assumed to play an important role in the pathophysiology of migraines. Schoenen et al. as the first in 1995, have described lack of decrement of pattern-reversal visual evoked potentials (PR-VEP) amplitude during repetitive stimulation compared with the expected decrement in healthy individuals (Schoenen et al., 1995). They equated the physiological decrement of PR-VEP amplitude with the term ‘‘habituation’’ and abnormal (insufficient) reactions in migraineurs with the term ‘‘habituation deficit’’. This terminology has been adopted by other authors who described ‘‘habituation deficit’’ in PR-VEP (e.g. Afra et al., 1998; Wang et al., 1999;
1388-2457/$36.00 Ó 2013 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved. http://dx.doi.org/10.1016/j.clinph.2013.10.050
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Bohotin et al., 2002; Ozkul and Bozlar, 2002; Di Clemente et al., 2005; Fumal et al., 2006). From the physiological point of view the habituation covers various mechanisms on different levels of neural processing and it should be distinguished from a refractoriness, fatigue or manipulation of subject’s attention, which can also lead to VEP amplitude decrement during prolonged stimulation. It is also uncertain whether the lack of VEP amplitude decrement usually observed in migraine patients involves just habituation deficit or if it includes some other processes as an increase of a sensitization (Groves and Thompson, 1970). For these reasons we will use the term amplitude decrement in following text. However, because most of former studies expressed their results in sense of habituation, even that they did not test the habituation utterly; we will discuss them as a habituation/decrement phenomenon in following. Lack of habituation/decrement of visual evoked potentials amplitude in migraine during the interictal period has been reported in a number of research studies (see studies above and for review Coppola et al., 2009); the VEP habituation/decrement normalizes before and during an attack (Judit et al., 2000). Despite the overwhelming number of studies which reported habituation/decrement deficit, some other studies opposed these findings (Oelkers et al., 1999; Oelkers-Ax et al., 2005; Sand et al., 2008, 2009). A recent study on this topic (Omland et al., 2013) used blinded assessment of PR-VEPs and also failed to confirm amplitude decrement deficit in migraineurs during the interictal period. An earlier article, published by the same authors (Omland et al., 2011), proposed the possibility of evaluating habituation using PRVEP induced by reversal of a small square checkerboard over a short interval of 3 min. Such a short-time examination of the response decrement was affirmed by our pilot study on a group of healthy volunteers (Bednar et al., 2013). This pilot study also used motion-onset VEP (M-VEP) evoked by abrupt onset of visual motion. The amplitude of response to this stimulation, generated in extrastriatal structures of the visual cortex (Schellart et al., 2004; Pitzalis et al., 2012), habituated very rapidly, even in cases where direct adaptation, resulting in ‘‘motion after-effect’’, was avoided (Kremlacek et al., 2007). The main negative component of M-VEP proved to be a promising candidate for the measurement of habituation. Beside the habituation/decrement dysfunction associated with migraine recent studies revealed also impairment of visual motion processing. The reports agree mainly on impaired detection of global motion (McKendrick and Badcock, 2004; McKendrick et al., 2006; Webster et al., 2011) on the level of V5, which corresponds to a lower phosphene threshold in this area (Battelli et al., 2002), higher BOLD response (Antal et al., 2011) or to anatomical findings of increased thickness in area V5 as well as in another motion processing area – the V3a (Granziera et al., 2006). These findings might also support the use of M-VEPs to evaluate repetition response suppression in migraine. Another approach for the effective assessment of habituation may be reduction of the contrast of the checkerboard pattern, as has been previously postulated – the ‘‘weaker’’ the stimulus the more pronounced the habituation (Thompson, 2009). When evaluating the sample population, on the basis of an inspiring article (Omland et al., 2013), we changed the strategy of evaluation to blind assessment. Great emphasis was placed on verifying the fulfillment of the diagnostic criteria for migraine, segregating migraine sufferers into three groups (no prophylactic treatment, in interictal and ictal phase of migraine and with prophylactic treatment) and defining the clinical phenotypes of migraineurs. Further attention was also given to information relating to hormonal changes in women within the group (menopause, menstruation cycle, etc.).
2. Study cohort The study cohort was composed of two groups. The first (control) group included 36 healthy volunteers (doctors, nurses, porters, administrative staff and their relatives or friends) (27 women and 9 men, with a mean age of 37 ± 12.7 in the range 18–62 years), the other group comprised of 39 patients with the diagnosis of migraine (20 women and 9 men, with a mean age of 41 ± 11.3 in the range of 18–62 years) (treated at the University hospital in Hradec Kralove). The group of migraine sufferers was further divided into three subgroups – 19 migraineurs in the interictal period (IntM) (13 women and 6 men, with a mean age of 37 ± 10.9 in the range 18–60 years), 10 migraineurs in the ictal period (IctM) (9 women and 1 man, with a mean age of 42 ± 11.6 in the range 19–62 years) and 10 migraineurs with chronic prophylactic treatment with anticonvulsant or anti depressive medication (MwT) (8 women and 2 men, with a mean age of 47 ± 8.4 years, range 25–57 years). All the following clinical and demographic data were recorded by a questionnaire that each subject filled prior to his/her examination on the day of investigation. The healthy volunteers were included in the study under the condition that the questionnaire confirmed that, besides the absence of headaches in their history, they did not suffer from any disease of the central nervous system (neurological or psychiatric) and were not taking any medication that could influence brain function. In the group of migraineurs (patients with a clinical diagnosis of migraine), the questionnaire corresponded to the diagnostic criteria for migraine according to ICDH-II (The International Classification of Headache Disorders: 2nd edition, 2004). We excluded patients with chronic migraine. The distribution of migraine patients into their individual groups was based on the questionnaires and telephone contact 72 h after the examination. The migraineurs were included into the group of IntM when no headache was present 72 h before and 72 h after the examination. Patients who reported a headache during this period were included in the group of IctM. Furthermore, both groups also had to meet the condition of being on no chronic medication. Migraineurs whose questionnaires revealed that they were on chronic prophylactic anticonvulsant medication or antidepressant medication were included in the group of MwT. The group of MwT patients included 4 topiramate (three at a dose of 50 mg daily, one at 75 mg), 2 valproate (one at a dose of 500 mg daily and one at 800 mg daily) and 1 lamotrigine (100 mg daily), 3 SSRIs (Selective Serotonin Reuptake Inhibitors) respectively, 2 escitalopram (10 mg) and 1 citalopram (40 mg daily). The proportion of migraine patients receiving magnesium medication in any group was not high (three in IntM, one in IctM and three in MwT). The group of 39 migraineurs consisted of 23 patients with the diagnosis of migraine without aura and 16 patients had migraines with aura (predominantly visual). The ratios of migraines without aura (MO) and with aura (MA) were 11:8, 7:3 and 5:5 in the IntM, IctM and the MwT groups respectively. The data from literature do not specifically differentiate MO and MA groups evaluation as no findings related to the general theme of the work showed any significant differences in the results (Omland et al., 2013). In the group of migraine patients, the mean duration of migraines was 21 ± 12.7 in the range of 2–50 years (15 ± 9.8 in IntM, 24 ± 14.8 in IctM and 28 ± 10.4 in MwT). The average frequency of migraine attacks per month (over the last 6 months) in the group of migraineurs was 4 ± 2.7 in the range of 1–13 (4 ± 3.6 in IntM, 3 ± 2.3 in IctM and 3 ± 1.5 at MwT). Average duration of attacks in migraineurs was 24 ± 21.2 (26 ± 21.5 for IntM, 23 ± 21.2 for IctM and 21 ± 20.2 for MwT) in the range of 4–72 h in all groups. In women the questionnaire also collected data related to the menstrual cycle and hormonal contraceptive use, taking into consideration the presumption of hormonal influence on VEP
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(Yilmaz et al., 1998, 2000; Avitabile et al., 2007). In the group of healthy volunteers, 6 women confirmed menopause, 10 women were in ovulatory phase (15 days after the menstrual cycle), 7 in proliferative phase (5–14 day) and 4 in menstrual phase. In the group of migraineurs, menopause was confirmed in 7 women (1 IntM, 2 IctM and 4 MwT), 11 women in the ovulatory phase (6 IntM, 5 IctM), 10 in proliferative phase (5 IntM, 2 IctM and 3 MwT) and 2 in menstrual phase (1 IntM and 1 MwT). The hormonal contraception contribution (all combined products of oestrogens and progestogens) was relatively low – 5 in the group of healthy volunteers and 4 in the group of migraineurs (3 IntM, 1 IctM). Prior to the actual electrophysiological examination, a visual acuity test was performed using Landolt C circles displayed on the monitor using the FrACT (Freiburg Visual Acuity and Contrast Test) test (Bach, 2007). In healthy volunteers, the mean visual acuity of the left eye was 1.04 ± 0.27 ranging from 0.57 to 1.57, the right eye was 0.99 ± 0.29 ranging from 0.45 to 1.57. In migraine patients, the mean visual acuity of the left eye was 0.95 ± 0.33 ranging from 0.45 to 1.57 (1.05 ± 0.35 ranging from 0.45 to 1.47 in IntM, 0.81 ± 0.26 ranging from 0.53 to 1.44 in IctM and 0.90 ± 0.31 ranging from 0.59 to 1.47 for MwT). The average visual acuity of the right eye in migraineurs was 0.85 ± 0.27 ranging from 0.36 to 1.43 (or 0.93 ± 0.27 ranging from 0.43 to 1.43 in IntM, 0.83 ± 0.23 ranging from 0.54 to 1.16 in IctM and 0.75 ± 0.27 ranging from 0.36 to 1.20 in MwT). 3. Method 3.1. Stimuli All subjects in the study were examined using three types of VEP according to the characteristics of the stimulus: 1. High contrast PR-VEP evoked by the reversal of dark and light fields of a checkerboard (check size of 13’), with 85% Michelson’s contrast and a reversal frequency of 2 Hz. The small checks were chosen to conform with literature data (Omland et al., 2011) that discussed the advantage of smaller checks evoking habituation in healthy individuals. 2. Low contrast PR-VEP – the same as previous but with contrast of 14%. 3. M-VEP induced by the onset of radial movement (expansion and contraction) of a sinusoidally modulated circular pattern with 14% contrast. The ratio of motion to stationary period was 100–400 ms.
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VEP was achieved using leads OZ, O1, O2 and PZ and the FZ reference was used for PR-VEP and the A2 (right earlobe) for the M-VEP. In order to minimize the influence of potential acoustic noise from the surroundings of the electrophysiology laboratory, the subjects used earplugs (attenuation 28 dB) during the VEP examination. The degree of cooperation was monitored using a camera system that was part of the evoked potentials laboratory equipment. All subjects underwent VEP examinations during the normal daily 8-h work period (7 am to 3 pm). All examinations abided with the Declaration of Helsinki (World Medical Association, 2004) and were approved by the Ethical Committee of the University Hospital in Hradec Králové and every participant signed a written informed consent after explanation of the experimental procedure. 3.3. Peaks/amplitudes evaluation In order to ensure a blind approach for the VEP assessments, all data from Synergy were exported, processed and analyzed in MATLAB rel.12b (Mathworks, USA). The pattern-reversal VEPs from all blocks were overlapped and outlined in the same color. Three peaks (N75, P100 and N145) were marked by experienced electrophysiologists (MB and JK). Subsequently, the peaks were automatically identified as a local extreme within an interval, defined as ±6 ms for PR-VEP and ±9 ms for M-VEP, from the location the markers were placed (see Fig. 1). For motion-onset VEPs the markers (P1, N2 and P3) were determined in a similar way, however, for this type of VEPs, an optimal derivation was also selected from O1, OZ, O2 and PZ as the localization of the response with the largest N2 peak can vary among subjects (Kuba et al., 2007). The derivation with the largest N2 and least VEP shape variability among blocks was selected. During the identification of the peaks, the VEPs were presented in a random order and without any description thereby ensuring that the neurophysiologists were blind to the diagnosis as well as to block order. 3.4. Statistics
All the subjects underwent investigations in the Electrophysiology Laboratory of the Department of Neurology, University Hospital in Hradec Králové over the period of December 2011 to July 2012. Visual stimulation was presented on a 17 in. computer monitor ViewSonic E70fSB at a vertical refresh rate of 60 Hz. The viewing distance was set to 125 cm. The stimulation area subtended an area of 11 by 14°. The examination was binocular, in a dark room, with the fixation point placed in the center of the screen. The average brightness of the stimuli was 40 cd/m2.
The drop in amplitudes over time was evaluated by (1) applying the linear regression to all 5 data points and for each subject using the linear function slope – decrement slope [lV/min]; (2) evaluating the ratio between the last and first block of amplitudes – 5:1 block ratio [-]. The acquired and calculated parameters did not show a normal distribution (Lilliefors test) even after logarithmic, square root or reciprocal transformations. Consequently, the less sensitive non-parametric tests were used. For intra-group statistics the two-sided sign test was applied to slopes across groups to test for statistically significant habituation within the results, the results were corrected for multiple comparisons (Benjamini and Yekutieli, 2001). The Kruskall-Wallis non-parametric test (a nonparametric variant of ANOVA) was used for inter-group comparisons. The statistical significance is reported at a threshold of p = 0.05.
3.2. Recording
4. Results
With the aid of an A–D converter (16 bit ADC), each of the three types of VEP was recorded in 5 blocks of 60 responses which were averaged. The amount of rejected responses (those with higher amplitude than 50 lV) was within 5% in the individual blocks. The duration of each epoch, recorded at a sampling frequency of 20 kHz and resampled to 3.3 kHz, was 300 ms with the filter settings in the range of 0.2–100 Hz. Recording of the
The VEPs from one control subject (see Fig. 1) demonstrate particular peaks used to evaluate the amplitude decrement. Fig. 2 presents distributions of those inter-peak amplitudes for all acquired VEPs in separate groups. The numerical values are listed for the first and fifth block in Table 1. The absolute amplitudes clearly show superiority of high contrast stimulation but for assessment of individual decrement we depicted intra-individual changes of
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High Contrast Pattern-reversal VEPs
Low Contrast Pattern-reversal VEPs
P100 N75
Low Contrast Motion-onset VEPs
P100 N145
N75
P1
N145
N2
P3 diagnose/block blind latency marking
OZ–FZ
OZ–FZ
5th block 4th block 3rd block 2nd block 1st block
O1–A2 O2–A2 OZ–A2 PZ–A2 automatic amplitude evaluation - maximal amplitude within the gray interval +
10 µV -
100 ms
Fig. 1. Sample responses of a control subject. The figure demonstrates the approach adopted for blind assessment of the VEPs: in the 1st step the latencies of expected peaks were marked on overlapped curves without known diagnosis and then amplitudes were determined as a local extreme (marked by white intersection) in an interval depicted by grey bars. For motion-onset VEPs the derivation for evaluation was selected from four based on visual inspection and preferred was correspondence of VEPs shape within group of five blocks and dominant N2 peak amplitude.
Fig. 2. Dynamics of inter-peak amplitudes among groups in time (across blocks). The figure shows distribution of inter-peak amplitudes for high contrast PR-VEP in the left part, low contrast PR-VEP in the middle and motion-onset M-VEPs in right part of the figure. Columns plot interpeak amplitudes of left respective right local extreme related to the dominant P100 or N2 VEP peak (see Fig. 1). The rows represent examined groups: controls, migraineurs in the interictal period, migraineurs in the ictal period and migraineurs with chronic prophylactic treatment. A distribution of amplitudes within plot for one block consists of median (circle with a dot), 25–75 percentile interval (black box), whiskers extend to the most extreme data points (solid line) and outliers (circles).
amplitudes with respect to the first block (see Fig. 3). Dynamics of the intra-individual changes corresponds to the tests of decrement on slope and 5:1 ratio, which are listed in Table 1. On the intragroup level significant decrements were observed in 9 out of 12
parameters in the control group. However, after the correction for multiple comparisons, the only significant changes formed the decrement slopes and 5:1 block ratio for P100-N75 to high contrast pattern-reversal, the slope of the P100-N145 to high contrast
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Table 1 Median with interquartile interval are listed for amplitude parameters and the decrement descriptors. Underlined probabilities reached significance, but only those in bold print overcome the multiple comparison correction. Amplitude
Controls
block 1 [lV] 17.6 [10.2; 20.3] n = 36 block 5 [lV] 14.4 [10.0; 20.4] [ ] 5/1 0.9 [0.9; 1.0] p = 0.001 ratio Slope [lV/min] 0.7 [ 1.4; 0.2] p = 0.001 12.1 [9.2; 21.1] n = 36 P100-N145 block 1 [lV] block 5 [lV] 12.3 [8.1; 19.3] 5/1 [ ] 0.9 [0.8; 1.0] p = 0.029 ratio Slope [lV/min] 0.5 [ 1.2; 0.0] p = 0.004
High contrast P100-N75 pattern-reversal
Low contrast P100-N75 pattern-reversal
block block 5/1 ratio Slope P100-N145 block block 5/1 ratio Slope
Low contrast motion-onset
P1-N2
P3-N2
1 [lV] 5 [lV] [ ]
10.4 [5.1; 13.0] n = 36 9.0 [6.0; 13.5] 0.9 [0.8; 1.1] p = 0.132
0.3 [ 1.1; 0.4] p = 0.243 [lV/min] 1 [lV] 11.0 [7.7; 19.0] n = 36 5 [lV] 9.7 [6.4; 16.0] [ ] 0.9 [0.7; 1.1] p = 0.065
[lV/min] 0.4 [ 1.4; 0.3] p = 0.029 5.8 [4.3; 9.0] n = 35 block 1 [lV] block 5 [lV] 4.9 [3.1; 7.5] 5/1 [ ] 0.9 [0.7; 1.0] p = 0.006 ratio Slope [lV/min] 0.5 [ 1.0; 0.0] p = 0.017 block 1 [lV] 9.4 [7.7; 11.8] n = 35 block 5 [lV] 8.4 [6.1; 12.0] 5/1 [ ] 0.9 [0.8; 1.0] p = 0.041 ratio Slope [lV/min] 0.5 [ 1.1; 0.1] p = 0.090
pattern-reversal and P1-N2 5:1 block ratio to motion-onset. Among migraineurs no significant decrement parameter was observed. The Kruskall–Wallis non-parametric test showed significant effect of groups on decrement slope for both amplitudes (P100N75: H(3, 71) = 14.30, p = 0.003; P100-N145: H(3, 71) = 12.67, p = 0.005;) in VEPs to high contrast pattern-reversal stimulation and for P1-N2 amplitude of motion-onset (H(3, 67) = 8.83, p = 0.032). The group effect on 5:1 block ratio was only in case of P100-N75 amplitude (H(3, 71) = 9.85, p = 0.020) recorded to high contrast pattern-reversal stimulation. Applying Tukey’s least significant difference procedure for multiple comparisons indicated that ranks of decrement slope of amplitudes to high contrast pattern-reversal stimulation differed among groups. The interpretation of the ranks is not straightforward, however, from the descriptive parameters it is clear that the decrement was more pronounced for controls (P100-N75 median [25 75 percentiles]: 0.7 [ 1.4 0.2] lV/min; P100-N145: 0.5 [ 1.2 0.0] lV/min) compared to interictal migraineurs (P100-N75: 0.7 [ 0.5 1.5] lV/ min; P100-N145: 0.5 [ 0.5 1.3] lV/min) and also to migraineurs with treatment (P100-N75: 0.0 [ 0.5 0.9] lV/min). Post-hoc tests showed also difference between P1-N2 decrement of M-VEPs in controls ( 0.5 [ 1.0 0.0] lV/min) and ictal migraineurs (0.5 [0.0 1.1] lV/min). No significant differences were registered for VEPs recorded in response to low contrast pattern-reversal stimulation. The same procedure showed that the group of controls had lower 5:1 block ratios in the P100-N75 amplitude of high contrast PRVEP (0.9 [0.9 1.0]) than the interictal migraineurs (1.1 [0.9 1.2]) and in P1-N2 amplitude ratio of M-VEPs between controls (0.9 [0.7 1.0]) and ictal migraineurs (1.1 [0.9 1.2]). We did not see statistically significant differences among the three groups of migraineurs.
Interictal migraine
Ictal migraine
Migraine with treatment
14.5 [11.3; 16.8] n = 19 17.4 [10.7; 19.5] 1.1 [0.9; 1.2] p = 0.167
17.0 [10.6; 23.2] n = 10 15.7 [11.2; 22.1] 1.0 [0.9; 1.1] p = 1.000
13.8 [11.9; 18.9] n = 10 13.5 [10.4; 17.3] 1.0 [0.9; 1.1] p = 1.000
0.7 [ 0.5; 1.5] p = 0.167
0.1 [ 0.4; 0.4] p = 1.000
0.0 [ 0.5; 0.9] p = 1.000
15.4 [10.9; 18.0] n = 19 16.5 [9.6; 17.7] 1.0 [0.9; 1.2] p = 1.000
17.8 [11.0; 26.5] n = 10 15.2 [12.1; 23.3] 0.9 [0.8; 1.0] p = 0.754
15.3 [13.4; 18.0] n = 10 15.5 [12.9; 19.4] 1.0 [1.0; 1.1] p = 1.000
0.5 [ 0.5; 1.3] p = 1.000 10.3 [8.2; 10.6] n = 18 9.1 [6.2; 11.6] 0.9 [0.7; 1.1] p = 0.815
0.4 [ 1.9; 0.2] p = 0.754 0.2 [ 0.4; 0.6] p = 0.754 8.7 [7.5; 12.2] n = 8 8.8 [6.3; 12.3] 1.0 [0.8; 1.1] p = 1.000
0.3 [ 1.9; 0.6] p = 0.481 0.0 [ 0.5; 0.4] p = 1.000 12.1 [7.5; 13.6] n = 18 12.9 [9.4; 17.5] n = 8 10.6 [7.0; 13.8] 13.5 [7.2; 18.5] 1.0 [0.8; 1.2] p = 1.000 1.0 [1.0; 1.1] p = 1.000
6.3 [5.1; 7.7] n = 10 6.2 [5.4; 9.6] 1.2 [0.7; 1.7] p = 0.754 0.3 [ 0.5; 1.5] p = 0.344 10.9 [8.8; 12.1] n = 10 8.3 [7.1; 13.9] 1.0 [0.8; 1.3] p = 1.000
0.2 [ 1.1; 1.1] p = 0.815
0.0 [ 0.2; 0.7] p = 1.000
0.4 [ 1.1; 0.8] p = 0.754
6.5 [4.2; 8.0] n = 18 5.3 [3.7; 8.4] 0.9 [0.6; 1.3] p = 0.481
5.3 [4.3; 11.0] n = 8 5.7 [4.6; 11.1] 1.1 [0.9; 1.2] p = 0.727
6.1 [5.4; 10.7] n = 10 4.8 [3.8; 7.3] 0.8 [0.8; 1.0] p = 0.344
0.5 [ 0.8; 0.7] p = 0.815 0.5 [0.0; 1.1] p = 0.289 10.0 [7.3; 13.1] n = 18 8.4 [6.4; 12.3] 0.9 [0.7; 1.1] p = 0.815 0.3 [ 1.0; 0.7] p = 0.238
12.1 [8.0; 16.7] n = 8 10.1 [7.4; 14.9] 0.9 [0.7; 1.0] p = 0.070 0.5 [ 0.8; 0.0] p = 0.289
0.3 [ 0.7; 0.0] p = 0.344 12.8 [8.8; 17.1] n = 10 8.5 [5.1; 15.6] 0.9 [0.8; 1.0] p = 0.344 0.8 [ 0.9; 0.0] p = 0.344
5. Discussion The fact that none of the group of migraineurs (IntM, IctM and MwT) showed any significant decrement to any of the followed parameters in all three types of VEP, whereas in healthy volunteers at least in some parameters two types of significant VEP decrement were found, can be considered to support the argument that decrement deficit is an electrophysiological characteristic of migraine. Statistical comparisons between individual groups showed greater decline in the amplitudes N75-P100 and P100-N145 for high contrast PR-VEP in healthy volunteers when compared with migraineurs in the interictal phase. We also observed a significant difference between controls and ictal migraineurs in M-VEPs N1-P1 amplitude decrement, which is not in agreement with hypothesis of the decrement/habituation normalization during the ictal phase (Judit et al., 2000). This lack of amplitude decrement was observed in a small group of 10 subjects probably due to range chosen for the inclusion criteria, i.e. 3 days before and after the beginning of an attack, that is larger than in some previous articles (Judit et al., 2000; Coppola et al., 2013). However, our primary concern was for sure to demarcate the interictal period, therefore we used such a range, which was also performed in many other studies (Afra et al., 2000; Ozkul and Bozlar, 2002; Siniatchkin et al., 2003; Fumal et al., 2006; Coppola et al., 2010). The actual definition of the interictal period does not reflect the reality of cyclical neurogenic changes in individual cases of migraine and might also contribute to the missing differentiation among groups of migraineurs. In future studies this should be eliminated and the ictal/interictal period should be determined relatively to individual attacks frequency. The low contrast pattern-reversal stimulation, as a less salient stimulus, should produce higher habituation (Thompson, 2009).
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Fig. 3. Dynamics of changes of the inter-peak amplitudes among groups in time (across blocks). The figure shows distribution of subject related changes of inter-peak amplitudes with respect to the first block. The described statistical significances of decrement slope or 5:1 block amplitude ratio, marked by bold outline around some boxes, are more pronounced in this figure where interindividual variability was removed. Detailed description of all dependences is listed in Table 1.
Despite our expectations, no significant decrement was seen in low contrast PR-VEP, even in healthy volunteers. This can be explained by the lower amplitude and greater variability in the shape of low contrast PR-VEP. Since the decrement effect during short 2.5 min paradigm was about the same relative size for high and low contrast stimulation in the control group (5:1 ratio was 0.9) and if we assume an equal absolute level of a spontaneous intra-individual variability across all tasks, then lower amplitudes of low contrast PR-VEP brought worse signal to noise ratio, which may have interfered with the measured decrement. In our contribution we also tested decrement using motion-onset stimuli beside the pattern-reversal ones. Both types of VEP have different cortical origins and while early and dominant peaks of the pattern-reversal VEP are generated in the primary visual area (Di Russo et al., 2005), the motion specific dominant negative peak originates in extrastriate areas of the dorsal stream like V3A (Pitzalis et al., 2012). The significant decrement of this motion specific peak has been already demonstrated during long (25 min) as well as short time interval (20 s) (Kremlacek et al., 2005, 2012) and, compared to pattern-reversal VEP, the motion related decrement was more expressed (Bednar et al., 2013). Results of the current study, however, have shown less significant decrement compared to high contrast reversal VEP that is very likely caused by even smaller amplitudes of the M-VEPs than those of the low contrast PR-VEP. In the situation when we found significant decrement of P1-N2 amplitude of M-VEP in controls and amplitude was 5.8 [4.3; 9.0] lV compared to P100-N75 17.6 [10.2; 20.3] lV of high contrast PR-VEP it might be of interest to increase the structure contrast, which, beside of increase may also stabilize
the M-VEPs amplitude (Kubova et al., 1995). This may, on the other side, go against expected effect as ‘‘intense stimuli may yield no significant observable response decrement’’ (Rankin et al., 2009). Within Introduction we mentioned studies agreeing on impairment of visual motion processing in extrastriate areas like V5 or V3a of migraineurs (McKendrick and Badcock, 2004; Granziera et al., 2006; McKendrick et al., 2006; Webster et al., 2011). Our study uses M-VEP, which dominant peak N2 originates just in areas MT+, V3a and in lateral occipital region (Pitzalis et al., 2012) and therefore the lack of the N2 peak response reduction in prolonged stimulation also supports the hypothesis of the dysfunction of motion processing in migraine. However, because we observed at the same time also a deficit in the decrement for PR-VEP amplitude, we cannot say that the observed deficit is specific for motion processing. Interestingly a recent study (Shepherd et al., 2012) of motion processing in migraineurs concluded that it is not motion processing per se but contrast sensitivity that is impaired in migraine. In our study we used both low and high contrast stimuli and because we found deficit in response decrement for high and low contrast stimuli we cannot confirm selective contrast sensitivity involvement. We should underline that the aforementioned conclusions were derived from a specific characteristic of the VEPs – their decrease during repetitive stimulation. We also compared mean VEP amplitudes across all blocks using the same statistical procedures as in decrement evaluation and we did not find any significant difference among groups for both amplitudes in all used VEPs. In comparison with a recent study (Omland et al., 2013), that contradicts our findings (i.e. they did not reported decrement/
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habituation deficit in migraineurs), our set of migraineurs in the interictal phase has a higher proportion of men, a higher average age, worse vision and significantly more severe course of migraines (having migraines for longer period, higher number of attacks and longer duration of attacks). Concurrently, we used a different definition of the interictal period (absence of headaches 72 h before and after the examination) as was used in the above study (48 h). In our study we attempted to limit sensory, directionally specific motion adaptation using stimuli with randomly alternating motion directions, however, to differentiate clearly habituation from other factors affecting measured response reduction is more complicated and several other characteristics, like dishabituation, should be fulfilled (Rankin et al., 2009). Therefore we used term ‘‘amplitude decrement’’ in description of our results. We, however, cannot exclude possibility, that measured response suppression is actually the habituation. Clinical monitoring of decrement with the aid of a highly sensitive tool that often assesses VEP amplitude changes over time in the order of tenths of microvolts can seem challenging. The very high sensitivity of the method at low specificity becomes a major limitation. We have to realize that an innumerable amount of undefinable factors comes to play, having a combined effect on the investigation of the subject in different ways. In our opinion, these factors contributed to the discrepant results more than the technical parameters of the various types of VEP investigations. Among these factors, which are expected to have effects at the level of activity or excitability of the central nervous system in healthy subjects or in migraineurs, data from literature support only a few, that include the following: fatigue (Kremlacek et al., 2007), level of alertness or attention (Torriente et al., 1999), metabolic characteristics (Sannita, 2006), age (Kuba et al., 2012), etc. As for migraineurs, the clinical and genetic phenotype can certainly also be considered a determinant of the electrophysiological characteristics. The one of the most pronounced effects, the attention modulation, can be controlled in various ways like using a continuous performance test.
6. Conclusion Our results support the existence of decrement deficit during the interictal phase of patients suffering from migraines as opposed to the ictal phase. We observed decrement deficit in response to high contrast checkerboard reversal and onset of motion in the visual field. This fact demonstrated that decrement deficit occurred in visual regions outside the primary sensory area. When using low-contrast stimulation we failed to produce any decrement deficit. We present a simple algorithm, which can be used for the blind evaluation in a single subject. For further studies, we suggest controlling of attention fluctuations during decrement examination and we support the inclusion of blinded assessment of VEPs as the changes in habituation are very small and the influence of subjective factors cannot be avoided in an unblinded evaluation. Acknowledgements This study was supported by Grant Agency of the Czech Republic 309/09/0869 and by the P37/07 (PRVOUK) program. References Afra J, Cecchini AP, De Pasqua V, Albert A, Schoenen J. Visual evoked potentials during long periods of pattern-reversal stimulation in migraine. Brain 1998;121:233–41.
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Visual evoked potentials in interictal migraine: no confirmation of abnormal habituation. Headache 2013;53:1071–86. Ozkul Y, Bozlar S. Effects of fluoxetine on habituation of pattern reversal visually evoked potentials in migraine prophylaxis. Headache 2002;42:582–7. Pitzalis S, Strappini F, De Gasperis M, Bultrini A, Di Russo F. Spatio-temporal brain mapping of motion-onset VEPs combined with fMRI and retinotopic maps. PLoS One 2012;7:e35771. Rankin CH, Abrams T, Barry RJ, Bhatnagar S, Clayton DF, Colombo J, et al. Habituation revisited: an updated and revised description of the behavioral characteristics of habituation. Neurobiol Learn Mem 2009;92:135–8.
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Clinical Neurophysiology journal homepage: www.elsevier.com/locate/clinph
Lack of visual evoked potentials amplitude decrement during prolonged reversal and motion stimulation in migraineurs Michal Bednárˇ a, Zuzana Kubová b, Jan Kremlácˇek b,⇑ a b
Department of Rehabilitation, Charles University in Prague, Faculty of Medicine in Hradec Králové and University Hospital, Hradec Králové, Czech Republic Department of Pathological Physiology, Charles University in Prague, Faculty of Medicine in Hradec Králové, Hradec Králové 500 38, Czech Republic
a r t i c l e
i n f o
Article history: Accepted 30 October 2013 Available online 19 November 2013 Keywords: Migraine Visual evoked potentials Habituation Visual processing Visual motion
h i g h l i g h t s Blinded assessment of VEPs amplitude decay during 2.5 min examination supported the theory of
repeated response decrement deficit in migraineurs. The repeated response decrement deficit was also observed during visual motion processing in the
extrastriatal regions of the visual cortex. Pattern-reversal VEPs to low contrast stimuli did not show a significant repeated response decrement
likely because of their high variability.
a b s t r a c t Objective: We evaluated response decrement during a short time repetitive low and high contrast reversal and low contrast motion stimulation in controls and migraineurs. Methods: A total of 39 migraine patients (out of which 19 were in the interictal period and without prophylactic treatment) and 36 healthy volunteers were examined using pattern-reversal (PR-VEP) and motion-onset (M-VEP) visual evoked potentials. Binocular stimulation lasted 2.5 min and the decrement assessment was blinded. Results: Evidence of significant decrement was observed in healthy volunteers for high contrast PR-VEP amplitude of P100-N75 ratios between the fifth and first blocks (0.9; p = 0.001) with a linear decline ( 0.7 lV/min, p = 0.001) and in the P100-N145 amplitude with linear decline ( 0.5 lV/min, p = 0.004). Significant decrement was also observed for the ratio between the fifth and first block P1-N2 amplitudes in M-VEP (0.9, p = 0.006). No significant decrement was noted in the low contrast PR-VEP or among migraineurs. Conclusions: We confirm differences in decrease of VEPs amplitude during short term examination between controls and migraineurs. We showed the decrement deficit also in the extrastriatal regions of the migraineurs’ visual cortex. Significance: Low contrast and motion-onset stimuli in short time decrement assessment did not increase the test sensitivity. Ó 2013 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.
1. Introduction Migraine is currently understood as a paroxysmal neurological disease with no underlying structural correlation. In essence, it is the dysfunction of neural cortical excitability. Neurophysiological methods appear to allow at least partially an insight into the neural mechanisms at the level of the central nervous system in migraine. Based on results of various neurophysiological studies a deficit of reduction in response to any repeated sensory stimulus is ⇑ Corresponding author. Tel.: +420 495 816 332. E-mail address: [email protected] (J. Kremlácˇek).
presently considered to be the main biomarker specific to migraine during the interictal period and thus it is assumed to play an important role in the pathophysiology of migraines. Schoenen et al. as the first in 1995, have described lack of decrement of pattern-reversal visual evoked potentials (PR-VEP) amplitude during repetitive stimulation compared with the expected decrement in healthy individuals (Schoenen et al., 1995). They equated the physiological decrement of PR-VEP amplitude with the term ‘‘habituation’’ and abnormal (insufficient) reactions in migraineurs with the term ‘‘habituation deficit’’. This terminology has been adopted by other authors who described ‘‘habituation deficit’’ in PR-VEP (e.g. Afra et al., 1998; Wang et al., 1999;
1388-2457/$36.00 Ó 2013 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved. http://dx.doi.org/10.1016/j.clinph.2013.10.050
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Bohotin et al., 2002; Ozkul and Bozlar, 2002; Di Clemente et al., 2005; Fumal et al., 2006). From the physiological point of view the habituation covers various mechanisms on different levels of neural processing and it should be distinguished from a refractoriness, fatigue or manipulation of subject’s attention, which can also lead to VEP amplitude decrement during prolonged stimulation. It is also uncertain whether the lack of VEP amplitude decrement usually observed in migraine patients involves just habituation deficit or if it includes some other processes as an increase of a sensitization (Groves and Thompson, 1970). For these reasons we will use the term amplitude decrement in following text. However, because most of former studies expressed their results in sense of habituation, even that they did not test the habituation utterly; we will discuss them as a habituation/decrement phenomenon in following. Lack of habituation/decrement of visual evoked potentials amplitude in migraine during the interictal period has been reported in a number of research studies (see studies above and for review Coppola et al., 2009); the VEP habituation/decrement normalizes before and during an attack (Judit et al., 2000). Despite the overwhelming number of studies which reported habituation/decrement deficit, some other studies opposed these findings (Oelkers et al., 1999; Oelkers-Ax et al., 2005; Sand et al., 2008, 2009). A recent study on this topic (Omland et al., 2013) used blinded assessment of PR-VEPs and also failed to confirm amplitude decrement deficit in migraineurs during the interictal period. An earlier article, published by the same authors (Omland et al., 2011), proposed the possibility of evaluating habituation using PRVEP induced by reversal of a small square checkerboard over a short interval of 3 min. Such a short-time examination of the response decrement was affirmed by our pilot study on a group of healthy volunteers (Bednar et al., 2013). This pilot study also used motion-onset VEP (M-VEP) evoked by abrupt onset of visual motion. The amplitude of response to this stimulation, generated in extrastriatal structures of the visual cortex (Schellart et al., 2004; Pitzalis et al., 2012), habituated very rapidly, even in cases where direct adaptation, resulting in ‘‘motion after-effect’’, was avoided (Kremlacek et al., 2007). The main negative component of M-VEP proved to be a promising candidate for the measurement of habituation. Beside the habituation/decrement dysfunction associated with migraine recent studies revealed also impairment of visual motion processing. The reports agree mainly on impaired detection of global motion (McKendrick and Badcock, 2004; McKendrick et al., 2006; Webster et al., 2011) on the level of V5, which corresponds to a lower phosphene threshold in this area (Battelli et al., 2002), higher BOLD response (Antal et al., 2011) or to anatomical findings of increased thickness in area V5 as well as in another motion processing area – the V3a (Granziera et al., 2006). These findings might also support the use of M-VEPs to evaluate repetition response suppression in migraine. Another approach for the effective assessment of habituation may be reduction of the contrast of the checkerboard pattern, as has been previously postulated – the ‘‘weaker’’ the stimulus the more pronounced the habituation (Thompson, 2009). When evaluating the sample population, on the basis of an inspiring article (Omland et al., 2013), we changed the strategy of evaluation to blind assessment. Great emphasis was placed on verifying the fulfillment of the diagnostic criteria for migraine, segregating migraine sufferers into three groups (no prophylactic treatment, in interictal and ictal phase of migraine and with prophylactic treatment) and defining the clinical phenotypes of migraineurs. Further attention was also given to information relating to hormonal changes in women within the group (menopause, menstruation cycle, etc.).
2. Study cohort The study cohort was composed of two groups. The first (control) group included 36 healthy volunteers (doctors, nurses, porters, administrative staff and their relatives or friends) (27 women and 9 men, with a mean age of 37 ± 12.7 in the range 18–62 years), the other group comprised of 39 patients with the diagnosis of migraine (20 women and 9 men, with a mean age of 41 ± 11.3 in the range of 18–62 years) (treated at the University hospital in Hradec Kralove). The group of migraine sufferers was further divided into three subgroups – 19 migraineurs in the interictal period (IntM) (13 women and 6 men, with a mean age of 37 ± 10.9 in the range 18–60 years), 10 migraineurs in the ictal period (IctM) (9 women and 1 man, with a mean age of 42 ± 11.6 in the range 19–62 years) and 10 migraineurs with chronic prophylactic treatment with anticonvulsant or anti depressive medication (MwT) (8 women and 2 men, with a mean age of 47 ± 8.4 years, range 25–57 years). All the following clinical and demographic data were recorded by a questionnaire that each subject filled prior to his/her examination on the day of investigation. The healthy volunteers were included in the study under the condition that the questionnaire confirmed that, besides the absence of headaches in their history, they did not suffer from any disease of the central nervous system (neurological or psychiatric) and were not taking any medication that could influence brain function. In the group of migraineurs (patients with a clinical diagnosis of migraine), the questionnaire corresponded to the diagnostic criteria for migraine according to ICDH-II (The International Classification of Headache Disorders: 2nd edition, 2004). We excluded patients with chronic migraine. The distribution of migraine patients into their individual groups was based on the questionnaires and telephone contact 72 h after the examination. The migraineurs were included into the group of IntM when no headache was present 72 h before and 72 h after the examination. Patients who reported a headache during this period were included in the group of IctM. Furthermore, both groups also had to meet the condition of being on no chronic medication. Migraineurs whose questionnaires revealed that they were on chronic prophylactic anticonvulsant medication or antidepressant medication were included in the group of MwT. The group of MwT patients included 4 topiramate (three at a dose of 50 mg daily, one at 75 mg), 2 valproate (one at a dose of 500 mg daily and one at 800 mg daily) and 1 lamotrigine (100 mg daily), 3 SSRIs (Selective Serotonin Reuptake Inhibitors) respectively, 2 escitalopram (10 mg) and 1 citalopram (40 mg daily). The proportion of migraine patients receiving magnesium medication in any group was not high (three in IntM, one in IctM and three in MwT). The group of 39 migraineurs consisted of 23 patients with the diagnosis of migraine without aura and 16 patients had migraines with aura (predominantly visual). The ratios of migraines without aura (MO) and with aura (MA) were 11:8, 7:3 and 5:5 in the IntM, IctM and the MwT groups respectively. The data from literature do not specifically differentiate MO and MA groups evaluation as no findings related to the general theme of the work showed any significant differences in the results (Omland et al., 2013). In the group of migraine patients, the mean duration of migraines was 21 ± 12.7 in the range of 2–50 years (15 ± 9.8 in IntM, 24 ± 14.8 in IctM and 28 ± 10.4 in MwT). The average frequency of migraine attacks per month (over the last 6 months) in the group of migraineurs was 4 ± 2.7 in the range of 1–13 (4 ± 3.6 in IntM, 3 ± 2.3 in IctM and 3 ± 1.5 at MwT). Average duration of attacks in migraineurs was 24 ± 21.2 (26 ± 21.5 for IntM, 23 ± 21.2 for IctM and 21 ± 20.2 for MwT) in the range of 4–72 h in all groups. In women the questionnaire also collected data related to the menstrual cycle and hormonal contraceptive use, taking into consideration the presumption of hormonal influence on VEP
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(Yilmaz et al., 1998, 2000; Avitabile et al., 2007). In the group of healthy volunteers, 6 women confirmed menopause, 10 women were in ovulatory phase (15 days after the menstrual cycle), 7 in proliferative phase (5–14 day) and 4 in menstrual phase. In the group of migraineurs, menopause was confirmed in 7 women (1 IntM, 2 IctM and 4 MwT), 11 women in the ovulatory phase (6 IntM, 5 IctM), 10 in proliferative phase (5 IntM, 2 IctM and 3 MwT) and 2 in menstrual phase (1 IntM and 1 MwT). The hormonal contraception contribution (all combined products of oestrogens and progestogens) was relatively low – 5 in the group of healthy volunteers and 4 in the group of migraineurs (3 IntM, 1 IctM). Prior to the actual electrophysiological examination, a visual acuity test was performed using Landolt C circles displayed on the monitor using the FrACT (Freiburg Visual Acuity and Contrast Test) test (Bach, 2007). In healthy volunteers, the mean visual acuity of the left eye was 1.04 ± 0.27 ranging from 0.57 to 1.57, the right eye was 0.99 ± 0.29 ranging from 0.45 to 1.57. In migraine patients, the mean visual acuity of the left eye was 0.95 ± 0.33 ranging from 0.45 to 1.57 (1.05 ± 0.35 ranging from 0.45 to 1.47 in IntM, 0.81 ± 0.26 ranging from 0.53 to 1.44 in IctM and 0.90 ± 0.31 ranging from 0.59 to 1.47 for MwT). The average visual acuity of the right eye in migraineurs was 0.85 ± 0.27 ranging from 0.36 to 1.43 (or 0.93 ± 0.27 ranging from 0.43 to 1.43 in IntM, 0.83 ± 0.23 ranging from 0.54 to 1.16 in IctM and 0.75 ± 0.27 ranging from 0.36 to 1.20 in MwT). 3. Method 3.1. Stimuli All subjects in the study were examined using three types of VEP according to the characteristics of the stimulus: 1. High contrast PR-VEP evoked by the reversal of dark and light fields of a checkerboard (check size of 13’), with 85% Michelson’s contrast and a reversal frequency of 2 Hz. The small checks were chosen to conform with literature data (Omland et al., 2011) that discussed the advantage of smaller checks evoking habituation in healthy individuals. 2. Low contrast PR-VEP – the same as previous but with contrast of 14%. 3. M-VEP induced by the onset of radial movement (expansion and contraction) of a sinusoidally modulated circular pattern with 14% contrast. The ratio of motion to stationary period was 100–400 ms.
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VEP was achieved using leads OZ, O1, O2 and PZ and the FZ reference was used for PR-VEP and the A2 (right earlobe) for the M-VEP. In order to minimize the influence of potential acoustic noise from the surroundings of the electrophysiology laboratory, the subjects used earplugs (attenuation 28 dB) during the VEP examination. The degree of cooperation was monitored using a camera system that was part of the evoked potentials laboratory equipment. All subjects underwent VEP examinations during the normal daily 8-h work period (7 am to 3 pm). All examinations abided with the Declaration of Helsinki (World Medical Association, 2004) and were approved by the Ethical Committee of the University Hospital in Hradec Králové and every participant signed a written informed consent after explanation of the experimental procedure. 3.3. Peaks/amplitudes evaluation In order to ensure a blind approach for the VEP assessments, all data from Synergy were exported, processed and analyzed in MATLAB rel.12b (Mathworks, USA). The pattern-reversal VEPs from all blocks were overlapped and outlined in the same color. Three peaks (N75, P100 and N145) were marked by experienced electrophysiologists (MB and JK). Subsequently, the peaks were automatically identified as a local extreme within an interval, defined as ±6 ms for PR-VEP and ±9 ms for M-VEP, from the location the markers were placed (see Fig. 1). For motion-onset VEPs the markers (P1, N2 and P3) were determined in a similar way, however, for this type of VEPs, an optimal derivation was also selected from O1, OZ, O2 and PZ as the localization of the response with the largest N2 peak can vary among subjects (Kuba et al., 2007). The derivation with the largest N2 and least VEP shape variability among blocks was selected. During the identification of the peaks, the VEPs were presented in a random order and without any description thereby ensuring that the neurophysiologists were blind to the diagnosis as well as to block order. 3.4. Statistics
All the subjects underwent investigations in the Electrophysiology Laboratory of the Department of Neurology, University Hospital in Hradec Králové over the period of December 2011 to July 2012. Visual stimulation was presented on a 17 in. computer monitor ViewSonic E70fSB at a vertical refresh rate of 60 Hz. The viewing distance was set to 125 cm. The stimulation area subtended an area of 11 by 14°. The examination was binocular, in a dark room, with the fixation point placed in the center of the screen. The average brightness of the stimuli was 40 cd/m2.
The drop in amplitudes over time was evaluated by (1) applying the linear regression to all 5 data points and for each subject using the linear function slope – decrement slope [lV/min]; (2) evaluating the ratio between the last and first block of amplitudes – 5:1 block ratio [-]. The acquired and calculated parameters did not show a normal distribution (Lilliefors test) even after logarithmic, square root or reciprocal transformations. Consequently, the less sensitive non-parametric tests were used. For intra-group statistics the two-sided sign test was applied to slopes across groups to test for statistically significant habituation within the results, the results were corrected for multiple comparisons (Benjamini and Yekutieli, 2001). The Kruskall-Wallis non-parametric test (a nonparametric variant of ANOVA) was used for inter-group comparisons. The statistical significance is reported at a threshold of p = 0.05.
3.2. Recording
4. Results
With the aid of an A–D converter (16 bit ADC), each of the three types of VEP was recorded in 5 blocks of 60 responses which were averaged. The amount of rejected responses (those with higher amplitude than 50 lV) was within 5% in the individual blocks. The duration of each epoch, recorded at a sampling frequency of 20 kHz and resampled to 3.3 kHz, was 300 ms with the filter settings in the range of 0.2–100 Hz. Recording of the
The VEPs from one control subject (see Fig. 1) demonstrate particular peaks used to evaluate the amplitude decrement. Fig. 2 presents distributions of those inter-peak amplitudes for all acquired VEPs in separate groups. The numerical values are listed for the first and fifth block in Table 1. The absolute amplitudes clearly show superiority of high contrast stimulation but for assessment of individual decrement we depicted intra-individual changes of
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High Contrast Pattern-reversal VEPs
Low Contrast Pattern-reversal VEPs
P100 N75
Low Contrast Motion-onset VEPs
P100 N145
N75
P1
N145
N2
P3 diagnose/block blind latency marking
OZ–FZ
OZ–FZ
5th block 4th block 3rd block 2nd block 1st block
O1–A2 O2–A2 OZ–A2 PZ–A2 automatic amplitude evaluation - maximal amplitude within the gray interval +
10 µV -
100 ms
Fig. 1. Sample responses of a control subject. The figure demonstrates the approach adopted for blind assessment of the VEPs: in the 1st step the latencies of expected peaks were marked on overlapped curves without known diagnosis and then amplitudes were determined as a local extreme (marked by white intersection) in an interval depicted by grey bars. For motion-onset VEPs the derivation for evaluation was selected from four based on visual inspection and preferred was correspondence of VEPs shape within group of five blocks and dominant N2 peak amplitude.
Fig. 2. Dynamics of inter-peak amplitudes among groups in time (across blocks). The figure shows distribution of inter-peak amplitudes for high contrast PR-VEP in the left part, low contrast PR-VEP in the middle and motion-onset M-VEPs in right part of the figure. Columns plot interpeak amplitudes of left respective right local extreme related to the dominant P100 or N2 VEP peak (see Fig. 1). The rows represent examined groups: controls, migraineurs in the interictal period, migraineurs in the ictal period and migraineurs with chronic prophylactic treatment. A distribution of amplitudes within plot for one block consists of median (circle with a dot), 25–75 percentile interval (black box), whiskers extend to the most extreme data points (solid line) and outliers (circles).
amplitudes with respect to the first block (see Fig. 3). Dynamics of the intra-individual changes corresponds to the tests of decrement on slope and 5:1 ratio, which are listed in Table 1. On the intragroup level significant decrements were observed in 9 out of 12
parameters in the control group. However, after the correction for multiple comparisons, the only significant changes formed the decrement slopes and 5:1 block ratio for P100-N75 to high contrast pattern-reversal, the slope of the P100-N145 to high contrast
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Table 1 Median with interquartile interval are listed for amplitude parameters and the decrement descriptors. Underlined probabilities reached significance, but only those in bold print overcome the multiple comparison correction. Amplitude
Controls
block 1 [lV] 17.6 [10.2; 20.3] n = 36 block 5 [lV] 14.4 [10.0; 20.4] [ ] 5/1 0.9 [0.9; 1.0] p = 0.001 ratio Slope [lV/min] 0.7 [ 1.4; 0.2] p = 0.001 12.1 [9.2; 21.1] n = 36 P100-N145 block 1 [lV] block 5 [lV] 12.3 [8.1; 19.3] 5/1 [ ] 0.9 [0.8; 1.0] p = 0.029 ratio Slope [lV/min] 0.5 [ 1.2; 0.0] p = 0.004
High contrast P100-N75 pattern-reversal
Low contrast P100-N75 pattern-reversal
block block 5/1 ratio Slope P100-N145 block block 5/1 ratio Slope
Low contrast motion-onset
P1-N2
P3-N2
1 [lV] 5 [lV] [ ]
10.4 [5.1; 13.0] n = 36 9.0 [6.0; 13.5] 0.9 [0.8; 1.1] p = 0.132
0.3 [ 1.1; 0.4] p = 0.243 [lV/min] 1 [lV] 11.0 [7.7; 19.0] n = 36 5 [lV] 9.7 [6.4; 16.0] [ ] 0.9 [0.7; 1.1] p = 0.065
[lV/min] 0.4 [ 1.4; 0.3] p = 0.029 5.8 [4.3; 9.0] n = 35 block 1 [lV] block 5 [lV] 4.9 [3.1; 7.5] 5/1 [ ] 0.9 [0.7; 1.0] p = 0.006 ratio Slope [lV/min] 0.5 [ 1.0; 0.0] p = 0.017 block 1 [lV] 9.4 [7.7; 11.8] n = 35 block 5 [lV] 8.4 [6.1; 12.0] 5/1 [ ] 0.9 [0.8; 1.0] p = 0.041 ratio Slope [lV/min] 0.5 [ 1.1; 0.1] p = 0.090
pattern-reversal and P1-N2 5:1 block ratio to motion-onset. Among migraineurs no significant decrement parameter was observed. The Kruskall–Wallis non-parametric test showed significant effect of groups on decrement slope for both amplitudes (P100N75: H(3, 71) = 14.30, p = 0.003; P100-N145: H(3, 71) = 12.67, p = 0.005;) in VEPs to high contrast pattern-reversal stimulation and for P1-N2 amplitude of motion-onset (H(3, 67) = 8.83, p = 0.032). The group effect on 5:1 block ratio was only in case of P100-N75 amplitude (H(3, 71) = 9.85, p = 0.020) recorded to high contrast pattern-reversal stimulation. Applying Tukey’s least significant difference procedure for multiple comparisons indicated that ranks of decrement slope of amplitudes to high contrast pattern-reversal stimulation differed among groups. The interpretation of the ranks is not straightforward, however, from the descriptive parameters it is clear that the decrement was more pronounced for controls (P100-N75 median [25 75 percentiles]: 0.7 [ 1.4 0.2] lV/min; P100-N145: 0.5 [ 1.2 0.0] lV/min) compared to interictal migraineurs (P100-N75: 0.7 [ 0.5 1.5] lV/ min; P100-N145: 0.5 [ 0.5 1.3] lV/min) and also to migraineurs with treatment (P100-N75: 0.0 [ 0.5 0.9] lV/min). Post-hoc tests showed also difference between P1-N2 decrement of M-VEPs in controls ( 0.5 [ 1.0 0.0] lV/min) and ictal migraineurs (0.5 [0.0 1.1] lV/min). No significant differences were registered for VEPs recorded in response to low contrast pattern-reversal stimulation. The same procedure showed that the group of controls had lower 5:1 block ratios in the P100-N75 amplitude of high contrast PRVEP (0.9 [0.9 1.0]) than the interictal migraineurs (1.1 [0.9 1.2]) and in P1-N2 amplitude ratio of M-VEPs between controls (0.9 [0.7 1.0]) and ictal migraineurs (1.1 [0.9 1.2]). We did not see statistically significant differences among the three groups of migraineurs.
Interictal migraine
Ictal migraine
Migraine with treatment
14.5 [11.3; 16.8] n = 19 17.4 [10.7; 19.5] 1.1 [0.9; 1.2] p = 0.167
17.0 [10.6; 23.2] n = 10 15.7 [11.2; 22.1] 1.0 [0.9; 1.1] p = 1.000
13.8 [11.9; 18.9] n = 10 13.5 [10.4; 17.3] 1.0 [0.9; 1.1] p = 1.000
0.7 [ 0.5; 1.5] p = 0.167
0.1 [ 0.4; 0.4] p = 1.000
0.0 [ 0.5; 0.9] p = 1.000
15.4 [10.9; 18.0] n = 19 16.5 [9.6; 17.7] 1.0 [0.9; 1.2] p = 1.000
17.8 [11.0; 26.5] n = 10 15.2 [12.1; 23.3] 0.9 [0.8; 1.0] p = 0.754
15.3 [13.4; 18.0] n = 10 15.5 [12.9; 19.4] 1.0 [1.0; 1.1] p = 1.000
0.5 [ 0.5; 1.3] p = 1.000 10.3 [8.2; 10.6] n = 18 9.1 [6.2; 11.6] 0.9 [0.7; 1.1] p = 0.815
0.4 [ 1.9; 0.2] p = 0.754 0.2 [ 0.4; 0.6] p = 0.754 8.7 [7.5; 12.2] n = 8 8.8 [6.3; 12.3] 1.0 [0.8; 1.1] p = 1.000
0.3 [ 1.9; 0.6] p = 0.481 0.0 [ 0.5; 0.4] p = 1.000 12.1 [7.5; 13.6] n = 18 12.9 [9.4; 17.5] n = 8 10.6 [7.0; 13.8] 13.5 [7.2; 18.5] 1.0 [0.8; 1.2] p = 1.000 1.0 [1.0; 1.1] p = 1.000
6.3 [5.1; 7.7] n = 10 6.2 [5.4; 9.6] 1.2 [0.7; 1.7] p = 0.754 0.3 [ 0.5; 1.5] p = 0.344 10.9 [8.8; 12.1] n = 10 8.3 [7.1; 13.9] 1.0 [0.8; 1.3] p = 1.000
0.2 [ 1.1; 1.1] p = 0.815
0.0 [ 0.2; 0.7] p = 1.000
0.4 [ 1.1; 0.8] p = 0.754
6.5 [4.2; 8.0] n = 18 5.3 [3.7; 8.4] 0.9 [0.6; 1.3] p = 0.481
5.3 [4.3; 11.0] n = 8 5.7 [4.6; 11.1] 1.1 [0.9; 1.2] p = 0.727
6.1 [5.4; 10.7] n = 10 4.8 [3.8; 7.3] 0.8 [0.8; 1.0] p = 0.344
0.5 [ 0.8; 0.7] p = 0.815 0.5 [0.0; 1.1] p = 0.289 10.0 [7.3; 13.1] n = 18 8.4 [6.4; 12.3] 0.9 [0.7; 1.1] p = 0.815 0.3 [ 1.0; 0.7] p = 0.238
12.1 [8.0; 16.7] n = 8 10.1 [7.4; 14.9] 0.9 [0.7; 1.0] p = 0.070 0.5 [ 0.8; 0.0] p = 0.289
0.3 [ 0.7; 0.0] p = 0.344 12.8 [8.8; 17.1] n = 10 8.5 [5.1; 15.6] 0.9 [0.8; 1.0] p = 0.344 0.8 [ 0.9; 0.0] p = 0.344
5. Discussion The fact that none of the group of migraineurs (IntM, IctM and MwT) showed any significant decrement to any of the followed parameters in all three types of VEP, whereas in healthy volunteers at least in some parameters two types of significant VEP decrement were found, can be considered to support the argument that decrement deficit is an electrophysiological characteristic of migraine. Statistical comparisons between individual groups showed greater decline in the amplitudes N75-P100 and P100-N145 for high contrast PR-VEP in healthy volunteers when compared with migraineurs in the interictal phase. We also observed a significant difference between controls and ictal migraineurs in M-VEPs N1-P1 amplitude decrement, which is not in agreement with hypothesis of the decrement/habituation normalization during the ictal phase (Judit et al., 2000). This lack of amplitude decrement was observed in a small group of 10 subjects probably due to range chosen for the inclusion criteria, i.e. 3 days before and after the beginning of an attack, that is larger than in some previous articles (Judit et al., 2000; Coppola et al., 2013). However, our primary concern was for sure to demarcate the interictal period, therefore we used such a range, which was also performed in many other studies (Afra et al., 2000; Ozkul and Bozlar, 2002; Siniatchkin et al., 2003; Fumal et al., 2006; Coppola et al., 2010). The actual definition of the interictal period does not reflect the reality of cyclical neurogenic changes in individual cases of migraine and might also contribute to the missing differentiation among groups of migraineurs. In future studies this should be eliminated and the ictal/interictal period should be determined relatively to individual attacks frequency. The low contrast pattern-reversal stimulation, as a less salient stimulus, should produce higher habituation (Thompson, 2009).
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Fig. 3. Dynamics of changes of the inter-peak amplitudes among groups in time (across blocks). The figure shows distribution of subject related changes of inter-peak amplitudes with respect to the first block. The described statistical significances of decrement slope or 5:1 block amplitude ratio, marked by bold outline around some boxes, are more pronounced in this figure where interindividual variability was removed. Detailed description of all dependences is listed in Table 1.
Despite our expectations, no significant decrement was seen in low contrast PR-VEP, even in healthy volunteers. This can be explained by the lower amplitude and greater variability in the shape of low contrast PR-VEP. Since the decrement effect during short 2.5 min paradigm was about the same relative size for high and low contrast stimulation in the control group (5:1 ratio was 0.9) and if we assume an equal absolute level of a spontaneous intra-individual variability across all tasks, then lower amplitudes of low contrast PR-VEP brought worse signal to noise ratio, which may have interfered with the measured decrement. In our contribution we also tested decrement using motion-onset stimuli beside the pattern-reversal ones. Both types of VEP have different cortical origins and while early and dominant peaks of the pattern-reversal VEP are generated in the primary visual area (Di Russo et al., 2005), the motion specific dominant negative peak originates in extrastriate areas of the dorsal stream like V3A (Pitzalis et al., 2012). The significant decrement of this motion specific peak has been already demonstrated during long (25 min) as well as short time interval (20 s) (Kremlacek et al., 2005, 2012) and, compared to pattern-reversal VEP, the motion related decrement was more expressed (Bednar et al., 2013). Results of the current study, however, have shown less significant decrement compared to high contrast reversal VEP that is very likely caused by even smaller amplitudes of the M-VEPs than those of the low contrast PR-VEP. In the situation when we found significant decrement of P1-N2 amplitude of M-VEP in controls and amplitude was 5.8 [4.3; 9.0] lV compared to P100-N75 17.6 [10.2; 20.3] lV of high contrast PR-VEP it might be of interest to increase the structure contrast, which, beside of increase may also stabilize
the M-VEPs amplitude (Kubova et al., 1995). This may, on the other side, go against expected effect as ‘‘intense stimuli may yield no significant observable response decrement’’ (Rankin et al., 2009). Within Introduction we mentioned studies agreeing on impairment of visual motion processing in extrastriate areas like V5 or V3a of migraineurs (McKendrick and Badcock, 2004; Granziera et al., 2006; McKendrick et al., 2006; Webster et al., 2011). Our study uses M-VEP, which dominant peak N2 originates just in areas MT+, V3a and in lateral occipital region (Pitzalis et al., 2012) and therefore the lack of the N2 peak response reduction in prolonged stimulation also supports the hypothesis of the dysfunction of motion processing in migraine. However, because we observed at the same time also a deficit in the decrement for PR-VEP amplitude, we cannot say that the observed deficit is specific for motion processing. Interestingly a recent study (Shepherd et al., 2012) of motion processing in migraineurs concluded that it is not motion processing per se but contrast sensitivity that is impaired in migraine. In our study we used both low and high contrast stimuli and because we found deficit in response decrement for high and low contrast stimuli we cannot confirm selective contrast sensitivity involvement. We should underline that the aforementioned conclusions were derived from a specific characteristic of the VEPs – their decrease during repetitive stimulation. We also compared mean VEP amplitudes across all blocks using the same statistical procedures as in decrement evaluation and we did not find any significant difference among groups for both amplitudes in all used VEPs. In comparison with a recent study (Omland et al., 2013), that contradicts our findings (i.e. they did not reported decrement/
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habituation deficit in migraineurs), our set of migraineurs in the interictal phase has a higher proportion of men, a higher average age, worse vision and significantly more severe course of migraines (having migraines for longer period, higher number of attacks and longer duration of attacks). Concurrently, we used a different definition of the interictal period (absence of headaches 72 h before and after the examination) as was used in the above study (48 h). In our study we attempted to limit sensory, directionally specific motion adaptation using stimuli with randomly alternating motion directions, however, to differentiate clearly habituation from other factors affecting measured response reduction is more complicated and several other characteristics, like dishabituation, should be fulfilled (Rankin et al., 2009). Therefore we used term ‘‘amplitude decrement’’ in description of our results. We, however, cannot exclude possibility, that measured response suppression is actually the habituation. Clinical monitoring of decrement with the aid of a highly sensitive tool that often assesses VEP amplitude changes over time in the order of tenths of microvolts can seem challenging. The very high sensitivity of the method at low specificity becomes a major limitation. We have to realize that an innumerable amount of undefinable factors comes to play, having a combined effect on the investigation of the subject in different ways. In our opinion, these factors contributed to the discrepant results more than the technical parameters of the various types of VEP investigations. Among these factors, which are expected to have effects at the level of activity or excitability of the central nervous system in healthy subjects or in migraineurs, data from literature support only a few, that include the following: fatigue (Kremlacek et al., 2007), level of alertness or attention (Torriente et al., 1999), metabolic characteristics (Sannita, 2006), age (Kuba et al., 2012), etc. As for migraineurs, the clinical and genetic phenotype can certainly also be considered a determinant of the electrophysiological characteristics. The one of the most pronounced effects, the attention modulation, can be controlled in various ways like using a continuous performance test.
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