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Comparison of visual and auditory evoked cortical potentials in migraine patients between attacks
Clinical Neurophysiology 111 (2000) 1124±1129
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Comparison of visual and auditory evoked cortical potentials in migraine patients between attacks  fra a, A. Proietti Cecchini b, P.S. SaÂndor c, J. Schoenen c,* J. A a
Department of Neurology Semmelweis University of Medicine, Budapest, Hungary Department of Neurology University of Pavia ªC. Mondino Foundationº, Pavia, Italy c Department of Neurology University of LieÁge, CHR Citadelle, Boulevard Du 128 de Ligne, B-4000 LieÁge, Belgium b
Accepted 2 February 2000
Abstract Objective: As both habituation of pattern reversal visual evoked potentials (PR-VEP) (Schoenen J, Wang W, Albert A, Delwaide PJ. Potentiation instead of habituation characterizes visual evoked potentials in migraine patients between attacks. Eur J Neurol 1995;2:115± 122) and intensity dependence of auditory evoked cortical potentials (IDAP) (Wang W, Timsit-Berthier M, Schoenen J. Intensity dependence of auditory evoked potentials in migraine: an indication of cortical potentiation and low serotonergic neurotransmission? Neurology 1996;46:1404±1409) were found abnormal in migraine between attacks, we have searched for intraindividual correlations between both tests in 59 migraine patients (22 with aura [MA], 37 without aura [MO]) and in 23 healthy volunteers (HV). Methods: Amplitude change of the PR-VEP N1±P1 was measured between the 1st and 5th block of 50 sequential averagings during continuous stimulation at 3.1 Hz. IDAP was computed from N1±P2 amplitudes of 100 averagings during stimulations at 40, 50, 60 and 70 dB SL. Amplitude-stimulus intensity function (ASF) slopes and amplitude changes between 40 and 70 dB were calculated. MO and MA differed from HV in PR-VEP amplitude change (P 0:007) and IDAP slope (P 0:0004). Results: There was no signi®cant correlation between VEP amplitude changes and IDAP slopes, nor between the latter two and attack frequency or disease duration. A negative correlation was found between the amplitude of the ®rst block of averaged responses and potentiation of VEP in all subject groups (P 0:03) as well as between the amplitude of the auditory evoked potential, at 40 dB, and the percentage of amplitude increase between 40 and 70 dB in MO (P 0:004) and MA (P 0:007). ASF slopes and 40 dB amplitudes were signi®cantly correlated only in the MA group (P 0:002). These results con®rm the interictal de®cit of habituation in cortical processing of repetitive visual and auditory information in migraine. Since there is no intraindividual correlation between the cortical responses to these sensory modalities they are complementary tools for the study of migraine and may help to identify subgroups of patients with distinct pathlophysiological mechanisms. Conclusions: The strong negative correlation between the initial amplitude of evoked potentials and their amplitude increase during subsequent averaging con®rms that the response potentiation in migraine is likely to be due to a reduced preactivation level of sensory cortices. q 2000 Elsevier Science Ireland Ltd. All rights reserved. Keywords: Visual evoked potentials; Auditory evoked cortical potentials; Migraine; Pathophysiology; Cortical information processing
1. Introduction Migraine is a heterogenous disorder both from pathophysiologic (Schoenen, 1994) and genetic (Gardner and Hoffman, 1997) perspectives. Current knowledge about migraine pathogenesis is still incomplete. Neurophysiological studies performed between migraine attacks demonstrate a dysfunction in cortical information processing which may re¯ect abnormal excitability and play a role in pathogenesis. Hyperexcitability of the cerebral cortex has been suggested in migraineurs following studies showing hypersensitivity * Corresponding author. Tel.: 132-4-225-6391; fax: 132-4-225-6451. E-mail address: [email protected] (J. Schoenen).
to environmental light stimuli (Hay et al., 1994), higher prevalence of and lower thresholds for phosphenes produced by occipital transcranial magnetic stimulation (Aurora et al., 1998), more intense illusions to grating patterns (Wilkins et al., 1984; Marcus and Soso, 1989) or increased amplitudes of visual evoked potentials (Gawel et al., 1983; Diener et al., 1984). High amplitudes of averaged evoked potentials might however be a consequence of a de®cit in the physiological habituation of responses shown during repetitive stimulations for visual evoked potentials  fra et al., 1998a), auditory evoked (Schoenen et al., 1995; A cortical responses (Wang et al., 1996) as well as eventrelated potentials, such as auditory novelty P3 (Wang et
1388-2457/00/$ - see front matter q 2000 Elsevier Science Ireland Ltd. All rights reserved. PII: S13 88-2457(00)0027 1-6
CLINPH 99523
J. AÂfra et al. / Clinical Neurophysiology 111 (2000) 1124±1129
al., 1998), visual evoked oddball P3 (Evers et al., 1997) and contingent negative variation (Schoenen et al., 1984; Kropp and Gerber, 1993). Moreover, migraineurs are characterized between attacks by a strong intensity dependence of cortical auditory evoked potentials (Wang et al., 1996) which might be caused by a reduced central serotonergic transmission and hence a decreased cortical preactivation level (Hegerl and Juckel, 1993). In all previous studies only one method/test was used in different groups of migraine patients and healthy controls. Considering that abnormalities for various tests/modalities were found in migraine, the obvious question arises whether they coexist in the same patients and are correlated to each other. We have therefore performed a comprehensive study of visual and auditory evoked potentials in the same migraine patients and healthy volunteers. 2. Patients and methods 2.1. Subjects Eighty-two subjects were studied: 23 healthy volunteers (5 males and 18 females, age: 27 ^ 7 years: mean ^ SD) with no history of headache recruited from hospital and laboratory staffs and 59 outpatients with migraine recruited from a specialized headache clinic (13 males and 46 females, age: 36 ^ 11 years). According to the criteria of the International Headache Society (1988) 37 patients had exclusively migraine without aura (MO) (code 1.1; disease duration 15 ^ 11 years, attack frequency 4 ^ 3/month) and 22 migraine with typical aura (MA) (code 1.2.1; disease duration 14 ^ 8 years, attack frequency 2 ^ 0.5/month). With the exception of 3 patients in the MA group who had no aura in 20% of attacks, we included only subjects who suffered exclusively from one type of migraine. None of the patients received prophylactic anti-migraine therapy. They were studied at least 3 days after and before the last attack. Oral informed consent of patients was obtained and the study was approved by the local Ethics Committee. 2.2. Experimental design and recordings All patients were examined in a quiet room with dimmed light (30 Lux). To record visual evoked potentials (VEP) subjects were seated 1 m in front of a television monitor (mean luminance 260 cd/m 2, color temperature 95008Kelvin). Stimuli were presented as a checkerboard pattern of black and white squares (contrast 80%) subtending 1 deg., 8 min of arch at a reversal frequency of 3.1 Hz. With one eye patched, subjects were instructed to ®x a point in the middle of the screen. Needle electrodes were inserted into the scalp in the midline over the occipital region 2.5 cm above the inion (Oz: active electrode) and over the frontal region (Fz: reference). The ground electrode was placed on the forearm. During uninterrupted stimulation sequential blocks of 50 responses were averaged for a total duration
1125
of 2 min using a Cadwell 8400 apparatus (band pass 1±100 Hz, analysis time 300 ms). Auditory evoked cortical potentials (AEP) were elicited by 1000 Hz tones (50 ms total duration, 10 ms rise and fall times) delivered binaurally through earphones at a random repetition rate of 0.53±0.61 Hz at four intensities (40, 50, 60 and 70 dB) above sensation level (SL) in a randomized order. The EEG was recorded with a needle electrode at Cz and referenced to linked earlobes. The ampli®er system was the same Cadwell 8400 apparatus, ®lters were set at 1 Hz low- and 20 Hz high cut. For each stimulus intensity 100 artifact-free sweeps were averaged over a 400 ms epoch. All subjects underwent VEP and AEP recordings in one session in a randomized order. 2.3. Data analysis For VEPs 5 sequential blocks of 50 responses were analyzed in terms of peak latencies and peak-to-peak amplitudes of N1 and P1 determined by visual inspection. The N1 peak was de®ned as the most negative point between 60 and 90 ms post-stimulus, P1 as the most positive point following N1 between 80 and 120 ms post-stimulus. Habituation was expressed as the percentage change of amplitudes between the ®rst and the ®fth block of averagings. To calculate the intensity dependence of auditory evoked cortical potentials (IDAP) N1 (between 60 and 150 ms poststimulus) and P2 (between 120 and 200 ms post-stimulus) components were identi®ed for each averaged recording of 100 responses. Peak-to-peak amplitude of N1±P2 was measured for each stimulus intensity and the linear amplitude/stimulus intensity function (ASF) slope was expressed in mV/10 dB. Amplitude changes between stimulations at 40 and 70 dB (above SL) were calculated as well and expressed as percentages. Group differences in VEP habituation and IDAP slopes were analyzed by MANOVA and post-hoc Duncan's test; Pearson's product moment correlation test was used to search for correlations between VEP habituation and IDAP slopes, between initial amplitudes and VEP habituation and IDAP slopes or 40±70 dB amplitude changes in MO, MA and HV as well as between attack frequency/ disease duration and VEP habituation or IDAP slopes in MO and MA. 3. Results In all recordings N1 and P1 VEP components as well as N1 and P2 AEP components were clearly identi®ed. Their latencies were not signi®cantly different between groups. VEP amplitudes in the 1st block of averagings tended to be smaller in migraineurs than in healthy volunteers and the lowest mean amplitude was found in MA (Fig. 1). These differences were however not signi®cant (P 0:65). Mean amplitude changes in the ®fth block expressed as percentages of the ®rst block were -6.81 ^ 21.5% (SD) in HV,
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block amplitude in every subject group (r 20:46, P 0:03 in HV; r 20:36, P 0:03 in MO; r 20:51, P 0:04 in MA) (Fig. 4). A similar negative correlation was found between the AEP amplitude at 40 dB and the amplitude change at 70 dB in both groups of migraineurs (P 0:004 in MO; P 0:007 in MA) but not in HV (P 0:14). IDAP slopes and 40 dB amplitudes correlate signi®cantly only in the MA group (P 0:002) but in MO (P 0:881) or HV (P 0:482) (Fig. 5).
Fig. 1. VEP amplitude change. Amplitudes of pattern-reversal VEP during sequential averaging of 50 responses. First and ®fth block are shown. There is habituation of the VEP in healthy volunteers contrasting with potentiation in migraine patients with and without aura between attacks (for amplitude changes between 1st and 5th block: HV vs. MA: P 0:004, HV vs. MA: P 0:04).
4. Discussion
10.7 ^ 20.5 in MO and 11.2 ^ 25.5 in MA. The difference was signi®cant (P 0:007) between HV and MO (P 0:004) or HV and MA (P 0:04), but not between MO and MA (P 0:93). The IDAP slopes were 0.36 mV/10 dB ^ 0.64 (SD) in HV, 1.42 ^ 1.22 in MO and 0.93 ^ 0.68 in MA. The difference (P 0:0004) from HV tended to be more pronounced in MO (P 0:0007) than in MA (P 0:05) (Fig. 2). The AEP amplitude change at the 70 dB stimulation expressed as percentage of that at 40 dB was 15.65 ^ 21.0% (SD) in HV, 46.2 ^ 45.8 in MO and 32.9 ^ 40 in MA. The difference was signi®cant (P 0:015) between MO and HV (P 0:02), but not between MA and HV (P 0:14) or between MO and MA (P 0:21). No signi®cant correlation was found between VEP amplitude changes and IDAP slopes (Fig. 3), or VEP and AEP amplitude changes between 40 and 70 dB in any of the 3 subject groups. There was also no correlation between the electrophysiological measures and attack frequency or disease duration in the two migraine groups (Table 1). VEP habituation was negatively correlated with ®rst
This study combining visual and auditory evoked potentials in the same subjects con®rms our previous EP ®ndings  fra in migraine (Schoenen et al., 1995; Wang et al., 1996; A et al., 1998a). It shows indeed a lack of habituation of visual evoked potentials and a marked intensity dependence of auditory evoked cortical potentials in both migraineurs with or without aura between attacks. It discloses in addition two novel results. First, VEPs and AEPs are not correlated in the same individual in none of the patient groups, nor in healthy volunteers. Second, the amplitude change of evoked responses during repetition of the same stimulus (VEP) or after increase of stimulus intensity (AEP) tend to be negatively correlated to their initial amplitude, i.e. smaller initial amplitudes are associated with more pronounced amplitude increases and vice versa. While the latter is true for VEPs in all 3 subject groups, it does apply only to migraineurs for AEPs. The lack of correlation between VEPs and AEPs indicates that migraine patients do not necessarily present detectable cortical processing abnormalities for both sensory modalities. There may be several possible explanations for this heterogeneity. The mechanisms underlying habituation and augmentingreducing (i.e. intensity dependence) patterns of cortical response are complex and probably in part different. Subcortico-cortical monoaminergic pathways play a pivotal
Fig. 2. AEP amplitude change. Cortical AEP amplitudes during stimulation at intensities of 40 and 70 dB above threshold. Migraineurs show a tendency to stronger stimulus intensity dependence compared to healthy volunteers (HV). The amplitude change between 40 and 70 dB is signi®cantly larger in migraineurs without aura (P 0:02) compared with HV.
Fig. 3. Cortical information processing: correlation between visual and auditory system. Stimulus intensity dependence of auditory cortical evoked potentials (AEP ASF slope) are plotted against habituation of visual evoked potentials (VEP amplitude change). There was no signi®cant correlation in either group (all P . 0:05).
J. AÂfra et al. / Clinical Neurophysiology 111 (2000) 1124±1129
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Table 1 Detailed table of correlations between different electrophysiological measures and/or clinical characteristics of subjects a Correlation
Healthy volunteers (n 23)
Migraine without aura (n 37)
Migraine with aura (n 22)
VEP amplitude change ± IDAP slopes VEP amplitude change ± 40±70 dB change VEP amplitude change ± attack frequency VEP amplitude change ± disease duration IDAP slope ± attack frequency IDAP slope ± disease duration 40±70 dB change ± attack frequency 40±70 dB change ± disease duration
0.203 0.443
0.071 0.160 0.298 0.446 0.765 0.227 0.648 0.514
0.966 0.979 0.438 0.511 0.906 0.766 0.954 0.592
a
P values are shown.
role in controlling cortical excitability and signal to noise ratios. Because of their diffuse innervation of sensory cortices and their regular, `pacemaker'-like activity, serotonergic neurons in the raphe nuclei are particularly suited to modulate cortical information processing (Jacobs and Azmitia, 1992). There is indirect evidence that intensity dependence of AEPs is inversely correlated with central serotonergic transmission (Hegerl and Juckel, 1993). Considering the high AEP intensity dependence found on average in migraineurs we have therefore postulated that serotonergic raphe systems are hypofunctioning in migraine between attacks (Wang et al., 1996), which is in line with low peripheral serotonin levels (review by Ferrari, 1992). The lack of correlation between VEP and AEP patterns is not speci®c to migraine, suggesting that the physiological mechanisms that modulate these patterns differ for the two sensory modalities. The primary auditory cortex may have a richer 5-HT innervation than the visual cortex (Jacobs and Azmitia, 1992). Interestingly, the positive correlation between the AEP amplitude at 40 dB and the 40±70 dB amplitude increase was not found in healthy volunteers, suggesting that it might be a more direct consequence of migraine pathophysiology. Migraine is undoubtedly heterogenous from a pathophysiological point of view. It is most probably a polygenic disorder and the weight of the various genes might also differ between patients (Ferrari, 1998). For instance, at least three different genes are involved in familial
Fig. 4. VEP: cortical preactivation levels and habituation. Initial VEP amplitude is negatively correlated to amplitude change during repeated stimulation (for all groups: P , 0:05).
hemiplegic migraine, all of them probably coding for an ion channel (Gardner and Hoffman, 1997). The only gene that is hitherto identi®ed, codes for the alpha subunit of a P/Q calcium channel (CACNA1A) and may contain various missense mutations or deletions (Ophoff et al., 1996). Depending on the site of the mutation within the gene the functional consequence on the ion channel is either a loss or a gain of function (Kraus et al., 1998; Hans et al., 1999). As illustrated in Fig. 6, this could in theory result via increased intracellular calcium levels and increased afterhyperpolarization in a reduced ®ring rate of serotonergic raphe neurons and hence an increased intensity dependence of evoked cortical potentials or through the opposite mechanisms in an increased release of cortical serotonin which may reduce afterhyperpolarization of cortical neurons and thus habituation. EPs tend to normalize in migraineurs just before and during an attack re¯ecting attack-related changes in the activity of brain stem and cortical neurons (Kropp and  fra et al., 1999, abstract). Gerber, 1995; A It is unlikely that this is relevant for the lack of correlation between EP abnormalities, because EP changes occur within 48 h before or after the beginning of an attack and in our study only recordings made at a distance of at least 3 days from an attack were included. A low amplitude of evoked cortical potentials after a
Fig. 5. AEP: cortical preactivation levels and amplitude change. AEP amplitude at 40 dB is negatively correlated to amplitude change between 40 and 70 dB in migraine with and without aura (P , 0:01), but not in healthy volunteers.
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Fig. 6. Ca 21 channels: possible functional consequences depending on the site of gene mutations in the CACNA1A gene. Different mutations in the gene coding for the alpha subunit of the P/Q calcium channel (CACNA1A) lead to either a loss or a gain of function (Kraus et al., 1998; Hans et al., 1999). This could on the one hand result in reduced ®ring rate of serotonergic raphe neurons and increased intensity dependence of evoked cortical potentials or on the other hand in an increased release of cortical serotonin and reduced habituation (Lorenzon and Foehring, 1992).
small number of averagings or low intensity stimulations was found in migraine patients interictally in all our previous studies (Schoenen et al., 1995; Wang et al.,  fra et al., 1998a). This might be due to a low preac1996; A tivation level of sensory cortices (Grossberg and Gutowski, 1987) which can be caused by hypofunctioning state setting subcortico-cortical pathways (Hegerl and Juckel, 1993). That interictal cortical excitability is reduced in migraine is further suggested by a recent study using transcranial  fra et magnetic stimulation of motor and visual cortices (A al., 1998b). The negative correlation between initial VEP amplitude and its change during repeated stimulation is a preserved physiological pattern in migraine. By contrast, IDAP apparently is in¯uenced by initial AEP amplitudes at 40 dB only in migraineurs. Taken together, this suggests that cortical preactivation levels are pivotal for the pathophysiological abnormalities found in migraine. We found no signi®cant correlation between EP abnormalities in migraineurs and attack frequency or disease duration. This suggests that the EP abnormalities in migraine might re¯ect genetically determined rather than acquired changes of cortical excitability. Various EEG and EP patterns are known to have a genetic basis (Van Beijsterveldt and Boomsma, 1994). In a recent study of parent-child pairs both affected by migraine without aura we found indeed a strong signi®cant familial component to VEP and AEP characteristics (SaÂndor et al., 1999). References Aurora SK, Ahmad BK, Welch KMA, Bhardhwaj P, Ramadan NM. Transcranial magnetic stimulation con®rms hyperexcitability of occipital cortex in migraine. Neurology 1998;50:1111±1114.  fra J, Proietti Cecchini A, De Pasqua V, Albert A, Schoenen J. Visual A
evoked potentials during long-lasting pattern-reversal stimulations in migraine. Brain 1998a;121:233±241. Â fra J, Mascia A, GeÂrard P, Maertens de Noordhout A, Schoenen J. InterA ictal cortical excitability in migraine: a study using transcranial magnetic stimulation of motor and visual cortices. Ann eurol 1998b;44:209±215. Â fra J, SaÂndor P, Proietti-Cecchini A, Schoenen J. Abnormal visual and A auditory cortical evoked potentials tend to `normalize' just before and during migraine attacks. Acta Neurol Belg 1999;99(abstract):152. Diener HC, Ndosi NK, Koletzki E, Langohr HD. Visual evoked potentials in migraine. In: Pfaffenrath V, Lundberg PJ, Sjaastad O, editors. Updating in headache, Berlin: Springer Verlag, 1984. pp. 439±465. Evers S, Bauer B, Suhr B, Husstedt IW, Grotemeyer KH. Cognitive processing in primary headache: a study on event-related potentials. Neurology 1997;48:108±113. Ferrari MD. Biochemistry of migraine. [Review]. Path Biol 1992;40:284± 292. Ferrari MD. Migraine. Lancet 1998(April 4);351(9108):1043-1051. Gardner K, Hoffman EP. Current status of genetic discoveries in migraine:familial hemiplegic migraine and beyond. Curr Opin Neurol 1997;11:211±216. Gawel M, Connolly JF, Clifford Rose F. Migraine patients exhibit abnormalities in the visual evoked potential. Headache 1983;23:49±52. Grossberg S, Gutowski WE. Neural dynamics of decision making under risk: affective balance and cognitive-emotional interactions. Psychol Rev 1987;94:300±318. Hans M, Luvisetto S, Williams ME, Spagnolo M, Urrutia A, Tottene A, Brust PF, Johnson EC, Harpold MM, Stauderman KA, Pietrobon D. Functional consequences of mutations in the human alpha1A calcium channel subunit linked to familial hemiplegic migraine. J Neurosci 1999;19:1610±1619. Hay KM, Mortimer MJ, Barker DC, Debney LM, Good PA. 1044 Women with migraine: the effect of environmental stimuli. Headache 1994;34:166±168. Hegerl U, Juckel G. Intensity dependence of auditory evoked potentials as an indicator of central serotoninergic neurotransmission: a new hypothesis. Biol Psychiatr 1993;33:173±187. International Headache Society. Classi®cation and diagnostic criteria for headache disorders, cranial neuralgias and facial pain. Cephalalgia 1988;8(Suppl 7):1-96. Jacobs BL, Azmitia EC. Structure and function of the brain serotonin system. Physiol Rev 1992;72:165±229. Kraus RL, Sinnegger MJ, Glossmann H, Hering S, Striessnig J. Familial hemiplegic migraine mutations change alpha1A Ca 21 channel kinetics. J Biol Chem 1998;273:5586±5590. Kropp P, Gerber WD. Is increased amplitude of contingent negative variation in migraine due to cortical hyperactivity or to reduced habituation? Cephalalgia 1993;13:37±41. Kropp P, Gerber WD. Contingent negative variation during migraine attack and interval: evidence for normalization of slow cortical potentials during the attack. Cephalalgia 1995;15:123±128. Lorenzon NM, Foehring RC. Relationship between repetitive ®ring and afterhyperpolarizations in human neocortical neurons. J Neurophysiol 1992;67:350±363. Marcus DA, Soso MJ. Migraine and stripe induced visual discomfort. Arch Neurol 1989;46:1129±1132. Ophoff RA, Terwindt GM, Vergouwe MN, van Eijk R, Oefner PJ, Hoffman MG, Lamerdin JE, Mohrenweiser HW, Bulman DE, Ferrari M, Haan J, Lindhout D, van Ommen GJB, Hofker MH, Ferrari MD, Frants RR. Familial hemiplegic migraine and episodic ataxia type-2 are caused by mutations in the Ca 21 channel gene CACNL1A4. Cell 1996;87:543± 552. Â fra J, Proietti-Cecchini A, Albert A, Schoenen J. Familial SaÂndor PS, A in¯uences on cortical evoked potentials in migraine. NeuroReport 1999;10:1235±1238. Schoenen J. Pathogenesis of migraine: the biobehavioural and hypoxia theories reconciled. Acta Neurol Belg 1994;94:79±86.
J. AÂfra et al. / Clinical Neurophysiology 111 (2000) 1124±1129 Schoenen J, Maertens de Noordhout A, Timsit-Bertier M, Timsit M. Contingent negative variation (CNV) as a diagnostic and physiopathologic tool in headache patients. In: Clifford Rose F, editor. Migraine Proc 5th Int Migraine Symp, London, 1984, Basel: Karger, 1985. pp. 17±25. Schoenen J, Wang W, Albert A, Delwaide PJ. Potentiation instead of habituation characterizes visual evoked potentials in migraine patients between attacks. Eur J Neurol 1995;2:115±122. Van Beijsterveldt CE, Boomsma DI. Genetics of the human electroence-
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phalogram (EEG) and event-related brain potentials (ERPs): a review. Hum Genet 1994;94:319±330. Wang W, Schoenen J. Interictal potentiation of passive ``oddball'' auditory event-related potentials in migraine. Cephalalgia 1998;18:261±265. Wang W, Timsit-Berthier M, Schoenen J. Intensity dependence of auditory evoked potentials in migraine: an indication of cortical potentiation and low serotonergic neurotransmission? Neurology 1996;46:1404±1409. Wilkins AJ, Nimmo-Smith I, Tait A, McManus C, Della Sala S, Tilley A. A neurological basis for visual discomfort. Brain 1984;107:989±1017.
www.elsevier.com/locate/clinph
Comparison of visual and auditory evoked cortical potentials in migraine patients between attacks  fra a, A. Proietti Cecchini b, P.S. SaÂndor c, J. Schoenen c,* J. A a
Department of Neurology Semmelweis University of Medicine, Budapest, Hungary Department of Neurology University of Pavia ªC. Mondino Foundationº, Pavia, Italy c Department of Neurology University of LieÁge, CHR Citadelle, Boulevard Du 128 de Ligne, B-4000 LieÁge, Belgium b
Accepted 2 February 2000
Abstract Objective: As both habituation of pattern reversal visual evoked potentials (PR-VEP) (Schoenen J, Wang W, Albert A, Delwaide PJ. Potentiation instead of habituation characterizes visual evoked potentials in migraine patients between attacks. Eur J Neurol 1995;2:115± 122) and intensity dependence of auditory evoked cortical potentials (IDAP) (Wang W, Timsit-Berthier M, Schoenen J. Intensity dependence of auditory evoked potentials in migraine: an indication of cortical potentiation and low serotonergic neurotransmission? Neurology 1996;46:1404±1409) were found abnormal in migraine between attacks, we have searched for intraindividual correlations between both tests in 59 migraine patients (22 with aura [MA], 37 without aura [MO]) and in 23 healthy volunteers (HV). Methods: Amplitude change of the PR-VEP N1±P1 was measured between the 1st and 5th block of 50 sequential averagings during continuous stimulation at 3.1 Hz. IDAP was computed from N1±P2 amplitudes of 100 averagings during stimulations at 40, 50, 60 and 70 dB SL. Amplitude-stimulus intensity function (ASF) slopes and amplitude changes between 40 and 70 dB were calculated. MO and MA differed from HV in PR-VEP amplitude change (P 0:007) and IDAP slope (P 0:0004). Results: There was no signi®cant correlation between VEP amplitude changes and IDAP slopes, nor between the latter two and attack frequency or disease duration. A negative correlation was found between the amplitude of the ®rst block of averaged responses and potentiation of VEP in all subject groups (P 0:03) as well as between the amplitude of the auditory evoked potential, at 40 dB, and the percentage of amplitude increase between 40 and 70 dB in MO (P 0:004) and MA (P 0:007). ASF slopes and 40 dB amplitudes were signi®cantly correlated only in the MA group (P 0:002). These results con®rm the interictal de®cit of habituation in cortical processing of repetitive visual and auditory information in migraine. Since there is no intraindividual correlation between the cortical responses to these sensory modalities they are complementary tools for the study of migraine and may help to identify subgroups of patients with distinct pathlophysiological mechanisms. Conclusions: The strong negative correlation between the initial amplitude of evoked potentials and their amplitude increase during subsequent averaging con®rms that the response potentiation in migraine is likely to be due to a reduced preactivation level of sensory cortices. q 2000 Elsevier Science Ireland Ltd. All rights reserved. Keywords: Visual evoked potentials; Auditory evoked cortical potentials; Migraine; Pathophysiology; Cortical information processing
1. Introduction Migraine is a heterogenous disorder both from pathophysiologic (Schoenen, 1994) and genetic (Gardner and Hoffman, 1997) perspectives. Current knowledge about migraine pathogenesis is still incomplete. Neurophysiological studies performed between migraine attacks demonstrate a dysfunction in cortical information processing which may re¯ect abnormal excitability and play a role in pathogenesis. Hyperexcitability of the cerebral cortex has been suggested in migraineurs following studies showing hypersensitivity * Corresponding author. Tel.: 132-4-225-6391; fax: 132-4-225-6451. E-mail address: [email protected] (J. Schoenen).
to environmental light stimuli (Hay et al., 1994), higher prevalence of and lower thresholds for phosphenes produced by occipital transcranial magnetic stimulation (Aurora et al., 1998), more intense illusions to grating patterns (Wilkins et al., 1984; Marcus and Soso, 1989) or increased amplitudes of visual evoked potentials (Gawel et al., 1983; Diener et al., 1984). High amplitudes of averaged evoked potentials might however be a consequence of a de®cit in the physiological habituation of responses shown during repetitive stimulations for visual evoked potentials  fra et al., 1998a), auditory evoked (Schoenen et al., 1995; A cortical responses (Wang et al., 1996) as well as eventrelated potentials, such as auditory novelty P3 (Wang et
1388-2457/00/$ - see front matter q 2000 Elsevier Science Ireland Ltd. All rights reserved. PII: S13 88-2457(00)0027 1-6
CLINPH 99523
J. AÂfra et al. / Clinical Neurophysiology 111 (2000) 1124±1129
al., 1998), visual evoked oddball P3 (Evers et al., 1997) and contingent negative variation (Schoenen et al., 1984; Kropp and Gerber, 1993). Moreover, migraineurs are characterized between attacks by a strong intensity dependence of cortical auditory evoked potentials (Wang et al., 1996) which might be caused by a reduced central serotonergic transmission and hence a decreased cortical preactivation level (Hegerl and Juckel, 1993). In all previous studies only one method/test was used in different groups of migraine patients and healthy controls. Considering that abnormalities for various tests/modalities were found in migraine, the obvious question arises whether they coexist in the same patients and are correlated to each other. We have therefore performed a comprehensive study of visual and auditory evoked potentials in the same migraine patients and healthy volunteers. 2. Patients and methods 2.1. Subjects Eighty-two subjects were studied: 23 healthy volunteers (5 males and 18 females, age: 27 ^ 7 years: mean ^ SD) with no history of headache recruited from hospital and laboratory staffs and 59 outpatients with migraine recruited from a specialized headache clinic (13 males and 46 females, age: 36 ^ 11 years). According to the criteria of the International Headache Society (1988) 37 patients had exclusively migraine without aura (MO) (code 1.1; disease duration 15 ^ 11 years, attack frequency 4 ^ 3/month) and 22 migraine with typical aura (MA) (code 1.2.1; disease duration 14 ^ 8 years, attack frequency 2 ^ 0.5/month). With the exception of 3 patients in the MA group who had no aura in 20% of attacks, we included only subjects who suffered exclusively from one type of migraine. None of the patients received prophylactic anti-migraine therapy. They were studied at least 3 days after and before the last attack. Oral informed consent of patients was obtained and the study was approved by the local Ethics Committee. 2.2. Experimental design and recordings All patients were examined in a quiet room with dimmed light (30 Lux). To record visual evoked potentials (VEP) subjects were seated 1 m in front of a television monitor (mean luminance 260 cd/m 2, color temperature 95008Kelvin). Stimuli were presented as a checkerboard pattern of black and white squares (contrast 80%) subtending 1 deg., 8 min of arch at a reversal frequency of 3.1 Hz. With one eye patched, subjects were instructed to ®x a point in the middle of the screen. Needle electrodes were inserted into the scalp in the midline over the occipital region 2.5 cm above the inion (Oz: active electrode) and over the frontal region (Fz: reference). The ground electrode was placed on the forearm. During uninterrupted stimulation sequential blocks of 50 responses were averaged for a total duration
1125
of 2 min using a Cadwell 8400 apparatus (band pass 1±100 Hz, analysis time 300 ms). Auditory evoked cortical potentials (AEP) were elicited by 1000 Hz tones (50 ms total duration, 10 ms rise and fall times) delivered binaurally through earphones at a random repetition rate of 0.53±0.61 Hz at four intensities (40, 50, 60 and 70 dB) above sensation level (SL) in a randomized order. The EEG was recorded with a needle electrode at Cz and referenced to linked earlobes. The ampli®er system was the same Cadwell 8400 apparatus, ®lters were set at 1 Hz low- and 20 Hz high cut. For each stimulus intensity 100 artifact-free sweeps were averaged over a 400 ms epoch. All subjects underwent VEP and AEP recordings in one session in a randomized order. 2.3. Data analysis For VEPs 5 sequential blocks of 50 responses were analyzed in terms of peak latencies and peak-to-peak amplitudes of N1 and P1 determined by visual inspection. The N1 peak was de®ned as the most negative point between 60 and 90 ms post-stimulus, P1 as the most positive point following N1 between 80 and 120 ms post-stimulus. Habituation was expressed as the percentage change of amplitudes between the ®rst and the ®fth block of averagings. To calculate the intensity dependence of auditory evoked cortical potentials (IDAP) N1 (between 60 and 150 ms poststimulus) and P2 (between 120 and 200 ms post-stimulus) components were identi®ed for each averaged recording of 100 responses. Peak-to-peak amplitude of N1±P2 was measured for each stimulus intensity and the linear amplitude/stimulus intensity function (ASF) slope was expressed in mV/10 dB. Amplitude changes between stimulations at 40 and 70 dB (above SL) were calculated as well and expressed as percentages. Group differences in VEP habituation and IDAP slopes were analyzed by MANOVA and post-hoc Duncan's test; Pearson's product moment correlation test was used to search for correlations between VEP habituation and IDAP slopes, between initial amplitudes and VEP habituation and IDAP slopes or 40±70 dB amplitude changes in MO, MA and HV as well as between attack frequency/ disease duration and VEP habituation or IDAP slopes in MO and MA. 3. Results In all recordings N1 and P1 VEP components as well as N1 and P2 AEP components were clearly identi®ed. Their latencies were not signi®cantly different between groups. VEP amplitudes in the 1st block of averagings tended to be smaller in migraineurs than in healthy volunteers and the lowest mean amplitude was found in MA (Fig. 1). These differences were however not signi®cant (P 0:65). Mean amplitude changes in the ®fth block expressed as percentages of the ®rst block were -6.81 ^ 21.5% (SD) in HV,
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block amplitude in every subject group (r 20:46, P 0:03 in HV; r 20:36, P 0:03 in MO; r 20:51, P 0:04 in MA) (Fig. 4). A similar negative correlation was found between the AEP amplitude at 40 dB and the amplitude change at 70 dB in both groups of migraineurs (P 0:004 in MO; P 0:007 in MA) but not in HV (P 0:14). IDAP slopes and 40 dB amplitudes correlate signi®cantly only in the MA group (P 0:002) but in MO (P 0:881) or HV (P 0:482) (Fig. 5).
Fig. 1. VEP amplitude change. Amplitudes of pattern-reversal VEP during sequential averaging of 50 responses. First and ®fth block are shown. There is habituation of the VEP in healthy volunteers contrasting with potentiation in migraine patients with and without aura between attacks (for amplitude changes between 1st and 5th block: HV vs. MA: P 0:004, HV vs. MA: P 0:04).
4. Discussion
10.7 ^ 20.5 in MO and 11.2 ^ 25.5 in MA. The difference was signi®cant (P 0:007) between HV and MO (P 0:004) or HV and MA (P 0:04), but not between MO and MA (P 0:93). The IDAP slopes were 0.36 mV/10 dB ^ 0.64 (SD) in HV, 1.42 ^ 1.22 in MO and 0.93 ^ 0.68 in MA. The difference (P 0:0004) from HV tended to be more pronounced in MO (P 0:0007) than in MA (P 0:05) (Fig. 2). The AEP amplitude change at the 70 dB stimulation expressed as percentage of that at 40 dB was 15.65 ^ 21.0% (SD) in HV, 46.2 ^ 45.8 in MO and 32.9 ^ 40 in MA. The difference was signi®cant (P 0:015) between MO and HV (P 0:02), but not between MA and HV (P 0:14) or between MO and MA (P 0:21). No signi®cant correlation was found between VEP amplitude changes and IDAP slopes (Fig. 3), or VEP and AEP amplitude changes between 40 and 70 dB in any of the 3 subject groups. There was also no correlation between the electrophysiological measures and attack frequency or disease duration in the two migraine groups (Table 1). VEP habituation was negatively correlated with ®rst
This study combining visual and auditory evoked potentials in the same subjects con®rms our previous EP ®ndings  fra in migraine (Schoenen et al., 1995; Wang et al., 1996; A et al., 1998a). It shows indeed a lack of habituation of visual evoked potentials and a marked intensity dependence of auditory evoked cortical potentials in both migraineurs with or without aura between attacks. It discloses in addition two novel results. First, VEPs and AEPs are not correlated in the same individual in none of the patient groups, nor in healthy volunteers. Second, the amplitude change of evoked responses during repetition of the same stimulus (VEP) or after increase of stimulus intensity (AEP) tend to be negatively correlated to their initial amplitude, i.e. smaller initial amplitudes are associated with more pronounced amplitude increases and vice versa. While the latter is true for VEPs in all 3 subject groups, it does apply only to migraineurs for AEPs. The lack of correlation between VEPs and AEPs indicates that migraine patients do not necessarily present detectable cortical processing abnormalities for both sensory modalities. There may be several possible explanations for this heterogeneity. The mechanisms underlying habituation and augmentingreducing (i.e. intensity dependence) patterns of cortical response are complex and probably in part different. Subcortico-cortical monoaminergic pathways play a pivotal
Fig. 2. AEP amplitude change. Cortical AEP amplitudes during stimulation at intensities of 40 and 70 dB above threshold. Migraineurs show a tendency to stronger stimulus intensity dependence compared to healthy volunteers (HV). The amplitude change between 40 and 70 dB is signi®cantly larger in migraineurs without aura (P 0:02) compared with HV.
Fig. 3. Cortical information processing: correlation between visual and auditory system. Stimulus intensity dependence of auditory cortical evoked potentials (AEP ASF slope) are plotted against habituation of visual evoked potentials (VEP amplitude change). There was no signi®cant correlation in either group (all P . 0:05).
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Table 1 Detailed table of correlations between different electrophysiological measures and/or clinical characteristics of subjects a Correlation
Healthy volunteers (n 23)
Migraine without aura (n 37)
Migraine with aura (n 22)
VEP amplitude change ± IDAP slopes VEP amplitude change ± 40±70 dB change VEP amplitude change ± attack frequency VEP amplitude change ± disease duration IDAP slope ± attack frequency IDAP slope ± disease duration 40±70 dB change ± attack frequency 40±70 dB change ± disease duration
0.203 0.443
0.071 0.160 0.298 0.446 0.765 0.227 0.648 0.514
0.966 0.979 0.438 0.511 0.906 0.766 0.954 0.592
a
P values are shown.
role in controlling cortical excitability and signal to noise ratios. Because of their diffuse innervation of sensory cortices and their regular, `pacemaker'-like activity, serotonergic neurons in the raphe nuclei are particularly suited to modulate cortical information processing (Jacobs and Azmitia, 1992). There is indirect evidence that intensity dependence of AEPs is inversely correlated with central serotonergic transmission (Hegerl and Juckel, 1993). Considering the high AEP intensity dependence found on average in migraineurs we have therefore postulated that serotonergic raphe systems are hypofunctioning in migraine between attacks (Wang et al., 1996), which is in line with low peripheral serotonin levels (review by Ferrari, 1992). The lack of correlation between VEP and AEP patterns is not speci®c to migraine, suggesting that the physiological mechanisms that modulate these patterns differ for the two sensory modalities. The primary auditory cortex may have a richer 5-HT innervation than the visual cortex (Jacobs and Azmitia, 1992). Interestingly, the positive correlation between the AEP amplitude at 40 dB and the 40±70 dB amplitude increase was not found in healthy volunteers, suggesting that it might be a more direct consequence of migraine pathophysiology. Migraine is undoubtedly heterogenous from a pathophysiological point of view. It is most probably a polygenic disorder and the weight of the various genes might also differ between patients (Ferrari, 1998). For instance, at least three different genes are involved in familial
Fig. 4. VEP: cortical preactivation levels and habituation. Initial VEP amplitude is negatively correlated to amplitude change during repeated stimulation (for all groups: P , 0:05).
hemiplegic migraine, all of them probably coding for an ion channel (Gardner and Hoffman, 1997). The only gene that is hitherto identi®ed, codes for the alpha subunit of a P/Q calcium channel (CACNA1A) and may contain various missense mutations or deletions (Ophoff et al., 1996). Depending on the site of the mutation within the gene the functional consequence on the ion channel is either a loss or a gain of function (Kraus et al., 1998; Hans et al., 1999). As illustrated in Fig. 6, this could in theory result via increased intracellular calcium levels and increased afterhyperpolarization in a reduced ®ring rate of serotonergic raphe neurons and hence an increased intensity dependence of evoked cortical potentials or through the opposite mechanisms in an increased release of cortical serotonin which may reduce afterhyperpolarization of cortical neurons and thus habituation. EPs tend to normalize in migraineurs just before and during an attack re¯ecting attack-related changes in the activity of brain stem and cortical neurons (Kropp and  fra et al., 1999, abstract). Gerber, 1995; A It is unlikely that this is relevant for the lack of correlation between EP abnormalities, because EP changes occur within 48 h before or after the beginning of an attack and in our study only recordings made at a distance of at least 3 days from an attack were included. A low amplitude of evoked cortical potentials after a
Fig. 5. AEP: cortical preactivation levels and amplitude change. AEP amplitude at 40 dB is negatively correlated to amplitude change between 40 and 70 dB in migraine with and without aura (P , 0:01), but not in healthy volunteers.
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Fig. 6. Ca 21 channels: possible functional consequences depending on the site of gene mutations in the CACNA1A gene. Different mutations in the gene coding for the alpha subunit of the P/Q calcium channel (CACNA1A) lead to either a loss or a gain of function (Kraus et al., 1998; Hans et al., 1999). This could on the one hand result in reduced ®ring rate of serotonergic raphe neurons and increased intensity dependence of evoked cortical potentials or on the other hand in an increased release of cortical serotonin and reduced habituation (Lorenzon and Foehring, 1992).
small number of averagings or low intensity stimulations was found in migraine patients interictally in all our previous studies (Schoenen et al., 1995; Wang et al.,  fra et al., 1998a). This might be due to a low preac1996; A tivation level of sensory cortices (Grossberg and Gutowski, 1987) which can be caused by hypofunctioning state setting subcortico-cortical pathways (Hegerl and Juckel, 1993). That interictal cortical excitability is reduced in migraine is further suggested by a recent study using transcranial  fra et magnetic stimulation of motor and visual cortices (A al., 1998b). The negative correlation between initial VEP amplitude and its change during repeated stimulation is a preserved physiological pattern in migraine. By contrast, IDAP apparently is in¯uenced by initial AEP amplitudes at 40 dB only in migraineurs. Taken together, this suggests that cortical preactivation levels are pivotal for the pathophysiological abnormalities found in migraine. We found no signi®cant correlation between EP abnormalities in migraineurs and attack frequency or disease duration. This suggests that the EP abnormalities in migraine might re¯ect genetically determined rather than acquired changes of cortical excitability. Various EEG and EP patterns are known to have a genetic basis (Van Beijsterveldt and Boomsma, 1994). In a recent study of parent-child pairs both affected by migraine without aura we found indeed a strong signi®cant familial component to VEP and AEP characteristics (SaÂndor et al., 1999). References Aurora SK, Ahmad BK, Welch KMA, Bhardhwaj P, Ramadan NM. Transcranial magnetic stimulation con®rms hyperexcitability of occipital cortex in migraine. Neurology 1998;50:1111±1114.  fra J, Proietti Cecchini A, De Pasqua V, Albert A, Schoenen J. Visual A
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