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Reduced gating of middle-latency auditory evoked potentials (P50) in migraine patients: another indication of abnormal sensory processing?
Neuroscience Letters 306 (2001) 132±134
www.elsevier.com/locate/neulet
Reduced gating of middle-latency auditory evoked potentials (P50) in migraine patients: another indication of abnormal sensory processing? Anna Ambrosini a, Victor De Pasqua b, Judit AÂfra c, Peter S. Sandor d, Jean Schoenen b,* a Headache Clinics - IRCCS Neuromed via Atinense, 18, I-86077 Pozzilli (Isernia), Italy University Department of Neurology, CHR Citadelle, Boulevard XIIeÁme de Ligne, 1, B-4000 LieÁge, Belgium c National Institute of Neurosurgery, H-1145 Budapest Amerikai ut 57, Budapest, Hungary d Headache & Pain Unit , Neurology Department, University Hospitals Zurich, CH-8091 Zurich, Switzerland
b
Received 3 April 2001; received in revised form 27 April 2001; accepted 27 April 2001
Abstract Habituation of cortical evoked responses to repetitive stimuli is reduced in migraine between attacks. To explore another aspect of information processing, we measured auditory sensory gating. The amplitude of the P50 response to the second of two homologous stimuli was signi®cantly less reduced in migraineurs than in healthy volunteers. This lack of auditory sensory gating may be due to a hypofunction of monoaminergic subcortico-cortical pathways, which is also supposed to cause the interictal de®cit of cortical habituation to repetitive stimuli. q 2001 Elsevier Science Ireland Ltd. All rights reserved. Keywords: Migraine; Evoked potentials; Auditory P50; Sensory gating; Cortical processing; Habituation
Migraine patients are characterized interictally by a de®cient habituation of evoked cortical responses to repetitive visual stimuli [12], and by an increased intensity dependence of auditory evoked cortical potentials [13]. Both abnormalities in information processing could be due to a hypofunction of serotonergic brainstem projections to sensory cortices [6]. `Gating of sensory input' is another central phenomenon, which has a crucial role in the processing of incoming information. It allows the central nervous system to modulate its responses to external inputs in order to save resources for relevant stimuli. A typical expression of this phenomenon is the suppression of the cortical response to a test stimulus delivered after an identical conditioning stimulus. The middle-latency P50 component of the auditory evoked cortical potential is very sensitive to auditory sensory gating and thus a classical electrophysiological tool for its assessment [4]. Interestingly, gating of P13, the rat equivalent of human P50, is in¯uenced by serotonin [9]. The objective of the present study was to explore whether * Corresponding author. Tel./Fax: 132-4-2256451. E-mail address: [email protected] (J. Schoenen).
migraineurs between attacks have an impaired gating of auditory P50 as another expression of abnormal information processing. We recorded 27 migraineurs among whom seven were excluded from the ®nal analysis because they presented an attack within 3 days after the recording and it is established that cortical excitability changes dramatically the day before and during a migraine attack [8]. The 20 patients used for the analysis (migraineurs (MIG); median age 32.5 years, range 21±62; 6 men, 14 women; mean attack frequency 2.96 ^ 2.61/month) were all affected by migraine without aura (IHS code: 1.1) [5]. None of them suffered from any other kind of interictal headache. Patients were compared to a group of 14 healthy volunteers (HV); (median age 25.5 years, range 22±54; 6 men, 8 women). None of controls or MIG had any other medical condition detectable by history and clinical examination; none was taking drugs on a regular basis, nor had taken any drug within 3 days before the recordings. MIG were recorded at least 3 days after and before an attack. Occurrence of an attack was checked by a telephone call 4 days after the recording. The study was conducted after
0304-3940/01/$ - see front matter q 2001 Elsevier Science Ireland Ltd. All rights reserved. PII: S0 30 4- 39 40 ( 01) 0 18 71- 7
A. Ambrosini et al. / Neuroscience Letters 306 (2001) 132±134
approval of our institution's ethics committee and with the understanding and oral consent of each involved subject. Electrophysiological recordings were performed in an electrically shielded, dim-lighted room. Subjects were conformably seated in a reclining chair and asked to ®x a target in front of them in order to limit the occurrence of ocular artifacts. One hundred pairs of acoustic stimuli (a conditioning stimulus, S1, separated by 500 ms from a test stimulus, S2) were delivered at randomized intervals between 8.5 and 11.5 s. Stimuli consisted of clicks of 0.05 ms duration and 90 dB intensity above sensation level. If they elicited a startle reaction, their intensity was decreased by 5 dB. The Electroencephalogram (EEG) was recorded using an active electrode placed at Cz and linked mastoids as reference. EEG signals were ampli®ed by CED TM 1902 pre-ampli®ers and recorded by a CED TM (Cambridge, UK) 1401 device (sampling frequency 8000 Hz, passband ®lters 0.001±1000 Hz). Off-line analysis (software package: Signal TM, version 1.88, CED, Cambridge, UK) of the single trials was performed on unlabelled ®les, in order to keep the operator unaware of the diagnosis. On average 46.4 artifact-free trials per subject were selected (45.9 in HV, and 46.8 in MIG). P50s were identi®ed as the greatest positive waves in a latency range of 40±65 ms from stimulus onset, and their amplitudes were measured peak-to-peak with respect to the immediately preceding negative peaks. Latencies were measured with respect to stimulus onset. Gating of the auditory EP was expressed as the ratio between P50 amplitudes after S2 (P50-S2) and S1 (P50-S1). A low ratio is found for normal auditory gating while a high ratio indicates weak gating. Results were expressed as median values and ranges for quantitative variables. Intergroup differences of P50 amplitudes, latencies and ratios were tested by the Mann±Whitney U test. Wilcoxon Matched Pairs test was used to assess
Fig. 1. Auditory Evoked Potentials from a healthy volunteer and a migraine patient. S1 and S2 indicate the ®rst and the second auditory stimuli, respectively. P50 components are indicated by arrows.
133
intragroup differences of P50-S1 and P50-S2 amplitudes. Signi®cance level was P # 0:05. HV and MIG had a similar gender and age distribution. Inter-group differences of the amplitudes of P50-S1 (HV 1.01 mV, range 0.53±3.28; MIG 0.82 mV, range 0.16±2.93) and P50-S2 (HV 0.54 mV, range 0.19±2.02; MIG 0.79 mV, range 0.18±2.80) were not signi®cant. Latencies of P50-S1 and P50-S2 were not signi®cantly different between groups (P50-S1: HV 50.24 ms, range 46.83±55.98, MIG 49.67 ms, range 42.16±56.63; P50-S2: HV 49.89 ms, range 45.58±55.09, MIG 50.57 ms, range 42.66±62.9) (Fig. 1). Auditory sensory gating manifested itself in healthy volunteers as a marked reduction of P50-S2 amplitude compared to P50-S1, and thus a low P50-S2/P50-S1 ratio (P 0:001). Reduction of P50-S2 was also present in MIG (P 0:028), but it was much less pronounced than in healthy subjects (Fig. 2). The difference between HV and MIG was obvious when P50-S2/P50-S1 ratios were compared. The ratio was clearly higher in MIG (0.93, range 0.37±1.3) than in healthy controls (0.52, range 0.35±0.78) (P 0:0002) (Fig. 3). This study shows that gating of auditory responses is reduced in migraine patients between attacks. It is re¯ected by the markedly lower inhibition of the P50 cortical response to the second of two homologous auditory stimuli in MIG compared to healthy volunteers. Although some studies indicated the hippocampal C3 area as the possible generator of the auditory P50 wave [3], more recently it has been shown that this component might be due, at least in part, to the activity of the pedunculopontine nucleus, i.e. the cholinergic component of the ascending reticular system [11]. There is some evidence that its amplitude is modulated by monoaminergic subcortico-cortical pathways [9,10]. Increased P50 ratios are well documented in schizophrenics and thought to re¯ect decreased sensory gating [1]. This could, however, be due to a low amplitude of the ®rst P50
Fig. 2. Individual P50 amplitude values in healthy volunteers (HV) and migraineurs (MIG) following the ®rst (P50-S1) and the second stimulus (P50-S2).
134
A. Ambrosini et al. / Neuroscience Letters 306 (2001) 132±134
Fig. 3. Mean P50-S2/P50-S1 ratios in healthy volunteers (HV) and migraineurs (MIG).
(P50-S1) rather than to a lack of amplitude decrease of the second response (P50-S2) [7], contrary to migraineurs who have a normal P50-S1 amplitude. We suggest therefore that migraine is accompanied by a genuine impairment of auditory sensory gating, but schizophrenia by a global perceptual defect, expressing itself continuously during input processing. In migraine, sensory gating impairment and lack of habituation to repetitive stimulations are likely a consequence of the same dysfunction in the control of incoming information. Their common denominator could be an interictal hypofunction of raphe nuclei (and possibly locus coeruleus); interestingly, in positron emission tomography studies, activation in brainstem regions comprising these nuclei was found during migraine attacks [14,2]. Both these nuclei project to sensory cortices to control excitability and habituation, but also to the pedunculopontine nucleus involved in P50 gating [11]. Another argument in favor of this hypothesis could be the recent ®nding that serotonin receptor agonists injected into the rat pedunculopontine nucleus are able to reduce the amplitude of P13, the rat equivalent of human P50 [9]. This study was supported by Grants No. 3.4523.00 and 3.4566.96 of the National Fund for Medical Research ± Brussels (Belgium) and by Grant No. 125 of the Migraine Trust ± London (UK).
[1] Adler, L.E., Patchman, E., Franks, R.D., Pecevich, M., Waldo, M.C. and Freedman, R., Neurophysiological gating in schizophrenia, Biol. Psychiatry, 17 (1982) 639±654. [2] Bahra, A., Matharu, M.S., Buchel, C., Frackowiak, R.S.J. and Goadsby, P.J., Brainstem activation speci®c to migraine headache, Lancet, 357 (2001) 1016±1017. [3] Bickford-Wimer, P.C., Nagamoto, H., Johnson, R., Adler, L.E., Egan, M., Rose, G.M. and Freedman, R., Auditory sensory gating in hippocampal neurons: a model system in the rat, Biol. Psychiatry, 27 (1990) 183±192. [4] Boutros, N.N., Torello, M.W., Barker, B.A., Tueting, P.A., Wu, S.C. and Nasrallah, H.A., The P50 evoked potential component and mismatch detection in normal volunteers: implications for the study of sensory gating, Psychiatry Res, 57 (1995) 83±88. [5] Headache Classi®cation Committee of the International Headache Society, Classi®cation and diagnostic criteria for the headache disorders, cranial neuralgias and facial pain, Cephalalgia, 8(S7) (1988) 1±96. [6] Hegerl, U. and Juckel, G., Intensity depedence of auditory evoked potentials as an indicator of central serotonergic neurotransmission: a new hypothesis, Biol. Psychiatry, 33 (1993) 173±187. [7] Jin, Y., Potkin, S.G., Patterson, J.V., Sandman, C.A., Hetrick, W.P. and Bunney Jr, W.E., Effects of P50 temporal variability on sensory gating in schizophrenia, Psychiatry Res, 70 (1997) 71±81. [8] Judit, A., Sandor, P. and Schoenen, J., Habituation of visual and intensity dependence of auditory evoked cortical potentials tends to normalize just before and during the migraine attack, Cephalalgia, 20 (2000) 714±719. [9] Miyazato, H., Skinner, R.D., Crews, T., Williams, K. and Garcia-Rill, E., Serotonergic modulation of the P13 midlatency auditory evoked potential in the rat, Brain Res Bull., 51 (2000) 387±391. [10] Miyazato, H., Skinner, R.D. and Garcia-Rill, E., Neurochemical modulation of the P13 midlatency auditory evoked potential in the rat, Neuroscience, 92 (1999) 911±920. [11] Reese, N.B., Garcia-Rill, E. and Skinner, R.D., Auditory input to the pedunculopontine nucleus: I. Evoked potentials, Brain Res. Bull., 37 (1995) 257±264. [12] Schoenen, J., Wang, W., Albert, A. and Delwaide, P.J., Potentiation instead of habituation characterizes visual evoked potentials in migraine patients between attacks, Eur. J. Neurol., 2 (1995) 115±122. [13] Wang, W., Timsit-Berthier, M. and Schoenen, J., Intensity dependence of auditory evoked potentials is pronounced in migraine: an indication of cortical potentiation and low serotonergic neurotransmission? Neurology, 46 (1996) 1404±1409. [14] Weiller, C., May, A., Limmroth, V., Juptner, M., Kaube, H., Schayck, R.V., Coenen, H.H. and Diener, H.C., Brain stem activation in spontaneous human migraine attacks, Nat. Med., 1 (1995) 658±660.
www.elsevier.com/locate/neulet
Reduced gating of middle-latency auditory evoked potentials (P50) in migraine patients: another indication of abnormal sensory processing? Anna Ambrosini a, Victor De Pasqua b, Judit AÂfra c, Peter S. Sandor d, Jean Schoenen b,* a Headache Clinics - IRCCS Neuromed via Atinense, 18, I-86077 Pozzilli (Isernia), Italy University Department of Neurology, CHR Citadelle, Boulevard XIIeÁme de Ligne, 1, B-4000 LieÁge, Belgium c National Institute of Neurosurgery, H-1145 Budapest Amerikai ut 57, Budapest, Hungary d Headache & Pain Unit , Neurology Department, University Hospitals Zurich, CH-8091 Zurich, Switzerland
b
Received 3 April 2001; received in revised form 27 April 2001; accepted 27 April 2001
Abstract Habituation of cortical evoked responses to repetitive stimuli is reduced in migraine between attacks. To explore another aspect of information processing, we measured auditory sensory gating. The amplitude of the P50 response to the second of two homologous stimuli was signi®cantly less reduced in migraineurs than in healthy volunteers. This lack of auditory sensory gating may be due to a hypofunction of monoaminergic subcortico-cortical pathways, which is also supposed to cause the interictal de®cit of cortical habituation to repetitive stimuli. q 2001 Elsevier Science Ireland Ltd. All rights reserved. Keywords: Migraine; Evoked potentials; Auditory P50; Sensory gating; Cortical processing; Habituation
Migraine patients are characterized interictally by a de®cient habituation of evoked cortical responses to repetitive visual stimuli [12], and by an increased intensity dependence of auditory evoked cortical potentials [13]. Both abnormalities in information processing could be due to a hypofunction of serotonergic brainstem projections to sensory cortices [6]. `Gating of sensory input' is another central phenomenon, which has a crucial role in the processing of incoming information. It allows the central nervous system to modulate its responses to external inputs in order to save resources for relevant stimuli. A typical expression of this phenomenon is the suppression of the cortical response to a test stimulus delivered after an identical conditioning stimulus. The middle-latency P50 component of the auditory evoked cortical potential is very sensitive to auditory sensory gating and thus a classical electrophysiological tool for its assessment [4]. Interestingly, gating of P13, the rat equivalent of human P50, is in¯uenced by serotonin [9]. The objective of the present study was to explore whether * Corresponding author. Tel./Fax: 132-4-2256451. E-mail address: [email protected] (J. Schoenen).
migraineurs between attacks have an impaired gating of auditory P50 as another expression of abnormal information processing. We recorded 27 migraineurs among whom seven were excluded from the ®nal analysis because they presented an attack within 3 days after the recording and it is established that cortical excitability changes dramatically the day before and during a migraine attack [8]. The 20 patients used for the analysis (migraineurs (MIG); median age 32.5 years, range 21±62; 6 men, 14 women; mean attack frequency 2.96 ^ 2.61/month) were all affected by migraine without aura (IHS code: 1.1) [5]. None of them suffered from any other kind of interictal headache. Patients were compared to a group of 14 healthy volunteers (HV); (median age 25.5 years, range 22±54; 6 men, 8 women). None of controls or MIG had any other medical condition detectable by history and clinical examination; none was taking drugs on a regular basis, nor had taken any drug within 3 days before the recordings. MIG were recorded at least 3 days after and before an attack. Occurrence of an attack was checked by a telephone call 4 days after the recording. The study was conducted after
0304-3940/01/$ - see front matter q 2001 Elsevier Science Ireland Ltd. All rights reserved. PII: S0 30 4- 39 40 ( 01) 0 18 71- 7
A. Ambrosini et al. / Neuroscience Letters 306 (2001) 132±134
approval of our institution's ethics committee and with the understanding and oral consent of each involved subject. Electrophysiological recordings were performed in an electrically shielded, dim-lighted room. Subjects were conformably seated in a reclining chair and asked to ®x a target in front of them in order to limit the occurrence of ocular artifacts. One hundred pairs of acoustic stimuli (a conditioning stimulus, S1, separated by 500 ms from a test stimulus, S2) were delivered at randomized intervals between 8.5 and 11.5 s. Stimuli consisted of clicks of 0.05 ms duration and 90 dB intensity above sensation level. If they elicited a startle reaction, their intensity was decreased by 5 dB. The Electroencephalogram (EEG) was recorded using an active electrode placed at Cz and linked mastoids as reference. EEG signals were ampli®ed by CED TM 1902 pre-ampli®ers and recorded by a CED TM (Cambridge, UK) 1401 device (sampling frequency 8000 Hz, passband ®lters 0.001±1000 Hz). Off-line analysis (software package: Signal TM, version 1.88, CED, Cambridge, UK) of the single trials was performed on unlabelled ®les, in order to keep the operator unaware of the diagnosis. On average 46.4 artifact-free trials per subject were selected (45.9 in HV, and 46.8 in MIG). P50s were identi®ed as the greatest positive waves in a latency range of 40±65 ms from stimulus onset, and their amplitudes were measured peak-to-peak with respect to the immediately preceding negative peaks. Latencies were measured with respect to stimulus onset. Gating of the auditory EP was expressed as the ratio between P50 amplitudes after S2 (P50-S2) and S1 (P50-S1). A low ratio is found for normal auditory gating while a high ratio indicates weak gating. Results were expressed as median values and ranges for quantitative variables. Intergroup differences of P50 amplitudes, latencies and ratios were tested by the Mann±Whitney U test. Wilcoxon Matched Pairs test was used to assess
Fig. 1. Auditory Evoked Potentials from a healthy volunteer and a migraine patient. S1 and S2 indicate the ®rst and the second auditory stimuli, respectively. P50 components are indicated by arrows.
133
intragroup differences of P50-S1 and P50-S2 amplitudes. Signi®cance level was P # 0:05. HV and MIG had a similar gender and age distribution. Inter-group differences of the amplitudes of P50-S1 (HV 1.01 mV, range 0.53±3.28; MIG 0.82 mV, range 0.16±2.93) and P50-S2 (HV 0.54 mV, range 0.19±2.02; MIG 0.79 mV, range 0.18±2.80) were not signi®cant. Latencies of P50-S1 and P50-S2 were not signi®cantly different between groups (P50-S1: HV 50.24 ms, range 46.83±55.98, MIG 49.67 ms, range 42.16±56.63; P50-S2: HV 49.89 ms, range 45.58±55.09, MIG 50.57 ms, range 42.66±62.9) (Fig. 1). Auditory sensory gating manifested itself in healthy volunteers as a marked reduction of P50-S2 amplitude compared to P50-S1, and thus a low P50-S2/P50-S1 ratio (P 0:001). Reduction of P50-S2 was also present in MIG (P 0:028), but it was much less pronounced than in healthy subjects (Fig. 2). The difference between HV and MIG was obvious when P50-S2/P50-S1 ratios were compared. The ratio was clearly higher in MIG (0.93, range 0.37±1.3) than in healthy controls (0.52, range 0.35±0.78) (P 0:0002) (Fig. 3). This study shows that gating of auditory responses is reduced in migraine patients between attacks. It is re¯ected by the markedly lower inhibition of the P50 cortical response to the second of two homologous auditory stimuli in MIG compared to healthy volunteers. Although some studies indicated the hippocampal C3 area as the possible generator of the auditory P50 wave [3], more recently it has been shown that this component might be due, at least in part, to the activity of the pedunculopontine nucleus, i.e. the cholinergic component of the ascending reticular system [11]. There is some evidence that its amplitude is modulated by monoaminergic subcortico-cortical pathways [9,10]. Increased P50 ratios are well documented in schizophrenics and thought to re¯ect decreased sensory gating [1]. This could, however, be due to a low amplitude of the ®rst P50
Fig. 2. Individual P50 amplitude values in healthy volunteers (HV) and migraineurs (MIG) following the ®rst (P50-S1) and the second stimulus (P50-S2).
134
A. Ambrosini et al. / Neuroscience Letters 306 (2001) 132±134
Fig. 3. Mean P50-S2/P50-S1 ratios in healthy volunteers (HV) and migraineurs (MIG).
(P50-S1) rather than to a lack of amplitude decrease of the second response (P50-S2) [7], contrary to migraineurs who have a normal P50-S1 amplitude. We suggest therefore that migraine is accompanied by a genuine impairment of auditory sensory gating, but schizophrenia by a global perceptual defect, expressing itself continuously during input processing. In migraine, sensory gating impairment and lack of habituation to repetitive stimulations are likely a consequence of the same dysfunction in the control of incoming information. Their common denominator could be an interictal hypofunction of raphe nuclei (and possibly locus coeruleus); interestingly, in positron emission tomography studies, activation in brainstem regions comprising these nuclei was found during migraine attacks [14,2]. Both these nuclei project to sensory cortices to control excitability and habituation, but also to the pedunculopontine nucleus involved in P50 gating [11]. Another argument in favor of this hypothesis could be the recent ®nding that serotonin receptor agonists injected into the rat pedunculopontine nucleus are able to reduce the amplitude of P13, the rat equivalent of human P50 [9]. This study was supported by Grants No. 3.4523.00 and 3.4566.96 of the National Fund for Medical Research ± Brussels (Belgium) and by Grant No. 125 of the Migraine Trust ± London (UK).
[1] Adler, L.E., Patchman, E., Franks, R.D., Pecevich, M., Waldo, M.C. and Freedman, R., Neurophysiological gating in schizophrenia, Biol. Psychiatry, 17 (1982) 639±654. [2] Bahra, A., Matharu, M.S., Buchel, C., Frackowiak, R.S.J. and Goadsby, P.J., Brainstem activation speci®c to migraine headache, Lancet, 357 (2001) 1016±1017. [3] Bickford-Wimer, P.C., Nagamoto, H., Johnson, R., Adler, L.E., Egan, M., Rose, G.M. and Freedman, R., Auditory sensory gating in hippocampal neurons: a model system in the rat, Biol. Psychiatry, 27 (1990) 183±192. [4] Boutros, N.N., Torello, M.W., Barker, B.A., Tueting, P.A., Wu, S.C. and Nasrallah, H.A., The P50 evoked potential component and mismatch detection in normal volunteers: implications for the study of sensory gating, Psychiatry Res, 57 (1995) 83±88. [5] Headache Classi®cation Committee of the International Headache Society, Classi®cation and diagnostic criteria for the headache disorders, cranial neuralgias and facial pain, Cephalalgia, 8(S7) (1988) 1±96. [6] Hegerl, U. and Juckel, G., Intensity depedence of auditory evoked potentials as an indicator of central serotonergic neurotransmission: a new hypothesis, Biol. Psychiatry, 33 (1993) 173±187. [7] Jin, Y., Potkin, S.G., Patterson, J.V., Sandman, C.A., Hetrick, W.P. and Bunney Jr, W.E., Effects of P50 temporal variability on sensory gating in schizophrenia, Psychiatry Res, 70 (1997) 71±81. [8] Judit, A., Sandor, P. and Schoenen, J., Habituation of visual and intensity dependence of auditory evoked cortical potentials tends to normalize just before and during the migraine attack, Cephalalgia, 20 (2000) 714±719. [9] Miyazato, H., Skinner, R.D., Crews, T., Williams, K. and Garcia-Rill, E., Serotonergic modulation of the P13 midlatency auditory evoked potential in the rat, Brain Res Bull., 51 (2000) 387±391. [10] Miyazato, H., Skinner, R.D. and Garcia-Rill, E., Neurochemical modulation of the P13 midlatency auditory evoked potential in the rat, Neuroscience, 92 (1999) 911±920. [11] Reese, N.B., Garcia-Rill, E. and Skinner, R.D., Auditory input to the pedunculopontine nucleus: I. Evoked potentials, Brain Res. Bull., 37 (1995) 257±264. [12] Schoenen, J., Wang, W., Albert, A. and Delwaide, P.J., Potentiation instead of habituation characterizes visual evoked potentials in migraine patients between attacks, Eur. J. Neurol., 2 (1995) 115±122. [13] Wang, W., Timsit-Berthier, M. and Schoenen, J., Intensity dependence of auditory evoked potentials is pronounced in migraine: an indication of cortical potentiation and low serotonergic neurotransmission? Neurology, 46 (1996) 1404±1409. [14] Weiller, C., May, A., Limmroth, V., Juptner, M., Kaube, H., Schayck, R.V., Coenen, H.H. and Diener, H.C., Brain stem activation in spontaneous human migraine attacks, Nat. Med., 1 (1995) 658±660.