Menstrual Migraine Without Aura: Cortical Excitability to Magnetic Stimulation
D. Bettucci, R. Cantello, M. Gianelli, P. Naldi, R. Mutani
Headache Unit, Department of Neurology, University School of Medicine of Novara, Italy. Reprint requests to: Diego Bettucci, M.D,, Clinica Neurologica Ospedale Maggiore di Novara, CorsoMazzini, 18. 28100 Novera, Italia Accepted for Publication: May 5, 1992 SYNOPSIS
The purpose of the present study was the evaluation of the excitability threshold and the central motor conduction time (CCT) studied by means of electromagnetic cortical stimulation in tan subjects affected by menstrual migraine without aura, both in the ictal end the interictal period. The patients were chosen from among a group of 254 outpatients affected by migraine, diagnosed according to the International Headache Society criteria.1 The control group consisted of ten healthy female subjects. As far as CCTs were concerned no differences emerged between patients and controls. However In the patient group we found a significant increase in the excitability threshold values, both in the ictal and the interictal period, and in both hemispheres. If confirmed, the Increased excitability threshold may be a useful neurophysiological correlate of migraine without aura. Key Words: Menstrual migraine. Central motor conduction time. Excitability threshold. Abbreviations: CCT central motor conduction time, TES transcranial electromagnetic stimulation, FDI first dorsal interosseus muscle. MEP Motor evoked potential. (Headache 1992; 32:345-347) INTRODUCTION
Transcranial electromagnetic stimulation (TES) is a neurophysiological way of studying the threshold value of the cortical motor excitability and the central conduction time (CCT)2 in the motor system, both in healthy subjects3,4 and in patients with movement disorders.5-7 TES has been recently used to study headaches,8 together with EEG, EMG, evoked potentials, contingent negative variation and magnetoencephalography.9-18 TES is not expected to provide a differential diagnosis of headaches, but it may be useful for a better understanding of their pathogenesis.19 In subjects affected by migraine with sensimotor aura, the threshold to TES has been found to be increased during the interictal period in the hemisphere responsible for the aura symptoms. No changes have been found in migraineurs without aura. These results were explained by a recurrent ischemic mechanism which can alter the cerebral bio-electric function of the hemisphere in which aura-related phenomena occur.8 Migraine with aura differs from migraine without aura, in that the former is associated with cerebral oligemia.20-23 This has been found to correspond to the "aura" stage.24 Even if migraine without aura does not show an oligemic mechanism, we thought that TES studies might provide information as to the possible underlying cortical dysfunction. Thus, we evaluated the threshold to TES and CCT in subjects affected by migraine without aura, both in the ictal and interictal period. PATIENTS AND METHODS Ten patients affected by menstrual migraine without aura and selected from a group of 254 migrainous outpatients underwent the study, together with ten healthy control females. The diagnosis was made on the basis of the International Headache Society, Headache Classification Committee1 criteria. Menstrual migraine was chosen for both its predictability and the easier management of the investigation in outpatients. The average age was 32.7 years (range 26-46 years) for the patients and 30.6 years (range 25-42 years) for the control group. All neurological histories, neurological examinations, CT scans of the head and EEGs were normal. Both groups were comprised of right-handed subjects. The side of headaches was mostly on the right in three patients, mostly on the left in one patient, in the remaining six patients no preferential side was reported. Subjects suffered from headache from five to eight days per month, and the average disease duration was 6 years (range 3-9 years). Both patients and controls had regular menses. The patients did not take any kind of drug except nonsteroidal anti-inflammatory drugs which were withdrawn 2 days prior the onset of the menses. The patients underwent the first TES on the 2nd or 3rd day of menstruation, when the migraine ictal phase regularly occurred. A second TES was delivered interictally on the 14th day from the onset of the period. Controls were also examined on the 2nd-3rd and 14th day. This double series of stimulations also enabled us to check the intra- and inter-individual reproducibility of the test parameters. We used a Dantec stimulator with a maximum field strength of 1.9 Tesla, delivering a monophasic current pulse. It had a large coil, with fifteen turns of copper wire. In order to stimulate the left hemisphere (and evoke the motor potential of the right arm) the coil was positioned tangentially over the vertex
of the skull, so that the direction of current flow in the coil appeared anticlockwise. Turning the coil 180 allowed preferential stimulation of the right hemisphere. Motor evoked potentials (MEPs) were recorded from the first dorsal interosseus muscle (FDI) bilaterally, using surface electrodes. The threshold of TES was the minimum stimulus intensity that evoked a discernible MEP in more than 50% of sixteen consecutive stimulations, while the FDI was relaxed and with a signal of 100 µV/div. Intensity was progressively increased by steps of 0.047 T of the maximum stimulator output (1.9 T), until the threshold value was determined. The CCTs were measured according to the formula given by Rossini et al.25 The statistical evaluation was carried out by means of the Student test (comparison between the threshold values and CCTs in the patients and the control group) and by the t-test for paired data (intrasubject comparison between the values mentioned above). Both groups consisted of subjects who had given their informed consent. RESULTS
Threshold to TES (% of the maximum stimulus intensity): A - Stimulation during the ictal phase: the threshold values of the right and left hemisphere were respectively 60.75 (sd +6.98) and 52.50 (sd ±5.06) for the patient group, and 49.25 (sd ± 5.14) and 44.50 (sd ± 3.07) respectively for the control group. (Figure 1). B - Stimulation during the interictal phase: the threshold values of the right and left hemisphere were respectively 58.25 (sd ± 4.57) and 50.00 (sd ±3.54) for the patient group, and 48.24 (sd ±7.46) and 43.75 (sd ±3.77) respectively for the control group. (Figure 2).
CCT (milliseconds): A - CCT values during the ictal phase: 6.02 (sd ± 0.43) and 5.25 (sd ± 0.21) recording from the left and right FDI respectively in the patient group, and 5.5 (sd ± 1.05) and 5.12 (sd ± 1.48) from the left and the right FDI in the control group. B - CCT values during the interictal phase: 5.77 (sd ± 0.33) and 4.95 (sd ± 0.33) respectively from the left and right FDI in the patient group, and 5.74 (sd ±1.38) and 5.26 (sd ±1.56) in the control group. DISCUSSION
We found that the migraneurs did not show any significant difference in threshold or CCT values between the ictal and the interictal phase. Similarly, there was no significant difference between the two determinations in the control group. As far as the comparison between the two hemispheres is concerned, all patients and controls showed a significantly lower threshold to TES for the hemisphere contralateral to the dominant hand. This finding is in accordance with recent observations.26 On average, threshold values were significantly higher in migraine patients than in controls, even when considering both hemispheres. If confirmed by further studies, this observation appears at variance with previous findings,8according to which no changes should exist in the motor cortical threshold in patients affected by migraine without aura, at least in the interictal phase. High
threshold values, in both ictal and the interictal phase, cannot be related to underlying cerebral blood flow (CBF) alterations, which have not been found in this kind of migraine. This statement is supported by studies23,27-31 disclosing that there is no reduction in the CBF and/or in the regional CBF in migraine without aura. Therefore if a vascular cause can not explain high TES-threshold values in both the ictal and the interictal period, other pathophysiologic explanations must be found. We hypothesize that there is a dysfunction of the cerebral mechanisms regulating the motor cortical threshold; a dysfunction which could arise from alterations of the neurochemical mechanisms underlying the migrainous phenomenon.32,33 The changes noted appear to be persistent, since high threshold values proved consistently steady during test and retest. If confirmed, the increased TES-threshold may be a potentially useful neurophysiological correlate of migraine without aura. REFERENCES
1.
Headache Classification Committee of the International Headache Society. Cephalalgia 1988; 8, suppl.7:1-96.
2.
Barker AT, Freeston IL, Jalinour R: Magnetic stimulation of the human brain and peripheral nervous system: An introduction and the results of an initial evaluation, Neurosurgery 1987; 20:100-109.
3.
Rothwell JC, Thompson PD, Day BL, Dick JPR, Kachi T, Cowan JMA, Marsden CD: Motor cortical stimulation in intact man. I. General characteristics of EMG responses in different muscle. Brain 1987; 110:1173-1190.
4.
Day BL, Rothwell JC, Thompson PD, Dick JPR, Cowan J, Berardelli A, Marsden CD: Motor cortical stimulation in intact man.11, Multiple descending volley. Brain 1987; 110:1191-1210.
5.
Cantello R, Gianelli M, Bettucci D, Civardi C, De Angelis S, Mutani R: Parkinson's disease rigidity: magnetic motor evoked potentials in a small hand muscle. Neurology 1991; 41:1449-1461.
6.
Eisen AA, Shtybel W: Clinical experience with magnetic stimulation. Muscle and Nerve 1990; 13:995-1011.
7.
Rossini PM, Di Stefano E, Stanzione P: Nerve impulse propagation along central and peripheral fast conducting motor and sensory patways in man. ElectroencephaIogr Clin Neurophysiol 1985; 60:320-334.
8.
Maertens De Noordhout A, Shoenen J, Pepin JL, Delwaide PJ: Magnetic cortical stimulation in migraine. Cephalalgia 1989; 9 (suppl.10): 208-209.
9.
Hockaday JM, Debney LM: The EEG in migraine. In: J. Olesen and L. Edvinsson, Eds. Basic mechanisms of headache. Amsterdam: Elsevier 1988: 365-368.
10.
Clifford T, Lauritzen M, Bakke M, Olesen J, Moller E: Electromyography of pericranial muscles during treatments of spontaneus common migraine attacks. Pain 1982; 14:137-147.
11.
McLean C, Appenzeller O, Cordaro JY, Rhodes J: Flash evoked potentials in migraine. Headache 1975; 14:193-198.
12.
Lehtonen J, Hyyppa MT, Kaihola H-L, Kangasniemi P, Lang AM: Visual evoked potentials in menstrual migraine. Headache 1979; 19:63-70.
13.
Benna P, Bianco C, Costa P, Piazza D, Bergamasco B: Visual evoked potentials and brainstem auditory evoked potentials in migraine and transient ischemic attacks. Cephalalgia 1985; 5 (suppl.2):53-58.
14.
Bussone G, Sinatra MG, Boiardi A, LaMantia L, Frediani F, Cocchini F: Brainstem auditory evoked potentials in migraine patients in basal conditions and after chronic flunarizine treatment. Cephalalgia 1985; 5 (suppl.2):177-180.
15.
Timsit-Berthier M: Variation contingente negative composantes endogenes du potentiel evoque. Rev.EEG Neurophysiol. 1984; 14:77-96.
16.
Shoenan J, Timsit-Berthier M, Timsit M: Correlation between contingent negative variation and plasma levels of cathecolamines in headache patients. Cephalalgia 1985; 5:480.
17.
Maertens DeNoordhout A, Timsit M, Timsit-Berthier M, Shoenen J: Contingent negative variation in headache. Ann Neurol 1986; 19:78-80.
18.
Tepley N, Barkley J, Welch KMA., NageI-Leiby S, Moran JE, Simkins RT: Magnetoencephalographic studies in migraine. The migraine trust. 8th Migraine Trust International Symposium. 1990.
19.
Shoenen J: Clinical neurophysiology of migraine. Cuming lecture. 8th Migraine Trust International Symposium. 1990.
20.
Skinhoj E, Paulson OB: Regional cerebral blood flow in internal carotid distribution during migraine attack. Br Med J 1969; 3:569-570.
21.
Skinhoj E: Hemodynamic studies within the brain during migraine. Arch Neurol 1973; 29:95-98.
22.
Lauritzen M, Olesen J: Regional cerebral blood flow during migraine attacks by Xenon-133 inhalation and emission tomography. Brain 1984; 107:447-461.
23.
Skyhoj Olsen T, Olesen J: Regional cerebral blood flow in migraine and cluster headache. In: J Olesen and L Edvinsson, Eds. Basic mechanisms of headache. Amsterdam: Elsevier, 1988: 377-391.
24.
Olesen J, Larsen B, Lauritzen M: Focal hyperemia followed by spreading oligemia and impaired activation of rCBF in classic migraine. Ann Neurol 1981; 9:344-352.
25.
Caramia MD, Pardal AM, Zarola F, Rossini PM. Electric versus magnetic transcranial stimulation of the brain in healthy humans a comparative study of central motor tracts "conductivity" and "excitability". Brain Res 1989; 479:98-104.
26.
Cantello R, Gianelli M, Bettucci D, Tribolo A, Mutani R. Threshold to magnetic stimulation of hand motor cortex: effects of handedness. Clin Neurophysiol 1990; 20, (Suppl.ls): 87.
27.
Pearce JMS, Foster JB: An investigation of complicated migraine. Neurology 1965; 15:323-340.
28,
Boisen E: Strokes in migraine: report on seven strokes associated with severe migraine attacks. Dan Med Bull 1975; 22:100-106.
29.
Lauritzen M, Skyhoj Olsen T, Lassen NA, Paulson OB. The changes of regional cerebral blood flow during the course of classical migraine attacks. Ann Neurol 1983; 13:633-641.
30.
Skyhoj Olsen T, Friberg L, Lassen NA.: Ischemia may be the primary cause of neurological deficits in classic migraine. Arch Neurol 1987; 44:156-161.
31.
Olesen J, Friberg L, Olsen TS, Iversen HR, Lassen NA, Andersen AR, Karle A: Timing and topography of cerebral blood flow, aura and headache during migraine attacks. Migraine Trust. 8th Migraine Trust International Symposium, 1990.
32.
Sicuteri F: Migraine, a central biochemical dysnociception. Headache 1976; 16:145.
33.
Lance JW: Mechanism and management of headache. 4th Ed. Butterworth. London, 1982.
D. Bettucci, R. Cantello, M. Gianelli, P. Naldi, R. Mutani
Headache Unit, Department of Neurology, University School of Medicine of Novara, Italy. Reprint requests to: Diego Bettucci, M.D,, Clinica Neurologica Ospedale Maggiore di Novara, CorsoMazzini, 18. 28100 Novera, Italia Accepted for Publication: May 5, 1992 SYNOPSIS
The purpose of the present study was the evaluation of the excitability threshold and the central motor conduction time (CCT) studied by means of electromagnetic cortical stimulation in tan subjects affected by menstrual migraine without aura, both in the ictal end the interictal period. The patients were chosen from among a group of 254 outpatients affected by migraine, diagnosed according to the International Headache Society criteria.1 The control group consisted of ten healthy female subjects. As far as CCTs were concerned no differences emerged between patients and controls. However In the patient group we found a significant increase in the excitability threshold values, both in the ictal and the interictal period, and in both hemispheres. If confirmed, the Increased excitability threshold may be a useful neurophysiological correlate of migraine without aura. Key Words: Menstrual migraine. Central motor conduction time. Excitability threshold. Abbreviations: CCT central motor conduction time, TES transcranial electromagnetic stimulation, FDI first dorsal interosseus muscle. MEP Motor evoked potential. (Headache 1992; 32:345-347) INTRODUCTION
Transcranial electromagnetic stimulation (TES) is a neurophysiological way of studying the threshold value of the cortical motor excitability and the central conduction time (CCT)2 in the motor system, both in healthy subjects3,4 and in patients with movement disorders.5-7 TES has been recently used to study headaches,8 together with EEG, EMG, evoked potentials, contingent negative variation and magnetoencephalography.9-18 TES is not expected to provide a differential diagnosis of headaches, but it may be useful for a better understanding of their pathogenesis.19 In subjects affected by migraine with sensimotor aura, the threshold to TES has been found to be increased during the interictal period in the hemisphere responsible for the aura symptoms. No changes have been found in migraineurs without aura. These results were explained by a recurrent ischemic mechanism which can alter the cerebral bio-electric function of the hemisphere in which aura-related phenomena occur.8 Migraine with aura differs from migraine without aura, in that the former is associated with cerebral oligemia.20-23 This has been found to correspond to the "aura" stage.24 Even if migraine without aura does not show an oligemic mechanism, we thought that TES studies might provide information as to the possible underlying cortical dysfunction. Thus, we evaluated the threshold to TES and CCT in subjects affected by migraine without aura, both in the ictal and interictal period. PATIENTS AND METHODS Ten patients affected by menstrual migraine without aura and selected from a group of 254 migrainous outpatients underwent the study, together with ten healthy control females. The diagnosis was made on the basis of the International Headache Society, Headache Classification Committee1 criteria. Menstrual migraine was chosen for both its predictability and the easier management of the investigation in outpatients. The average age was 32.7 years (range 26-46 years) for the patients and 30.6 years (range 25-42 years) for the control group. All neurological histories, neurological examinations, CT scans of the head and EEGs were normal. Both groups were comprised of right-handed subjects. The side of headaches was mostly on the right in three patients, mostly on the left in one patient, in the remaining six patients no preferential side was reported. Subjects suffered from headache from five to eight days per month, and the average disease duration was 6 years (range 3-9 years). Both patients and controls had regular menses. The patients did not take any kind of drug except nonsteroidal anti-inflammatory drugs which were withdrawn 2 days prior the onset of the menses. The patients underwent the first TES on the 2nd or 3rd day of menstruation, when the migraine ictal phase regularly occurred. A second TES was delivered interictally on the 14th day from the onset of the period. Controls were also examined on the 2nd-3rd and 14th day. This double series of stimulations also enabled us to check the intra- and inter-individual reproducibility of the test parameters. We used a Dantec stimulator with a maximum field strength of 1.9 Tesla, delivering a monophasic current pulse. It had a large coil, with fifteen turns of copper wire. In order to stimulate the left hemisphere (and evoke the motor potential of the right arm) the coil was positioned tangentially over the vertex
of the skull, so that the direction of current flow in the coil appeared anticlockwise. Turning the coil 180 allowed preferential stimulation of the right hemisphere. Motor evoked potentials (MEPs) were recorded from the first dorsal interosseus muscle (FDI) bilaterally, using surface electrodes. The threshold of TES was the minimum stimulus intensity that evoked a discernible MEP in more than 50% of sixteen consecutive stimulations, while the FDI was relaxed and with a signal of 100 µV/div. Intensity was progressively increased by steps of 0.047 T of the maximum stimulator output (1.9 T), until the threshold value was determined. The CCTs were measured according to the formula given by Rossini et al.25 The statistical evaluation was carried out by means of the Student test (comparison between the threshold values and CCTs in the patients and the control group) and by the t-test for paired data (intrasubject comparison between the values mentioned above). Both groups consisted of subjects who had given their informed consent. RESULTS
Threshold to TES (% of the maximum stimulus intensity): A - Stimulation during the ictal phase: the threshold values of the right and left hemisphere were respectively 60.75 (sd +6.98) and 52.50 (sd ±5.06) for the patient group, and 49.25 (sd ± 5.14) and 44.50 (sd ± 3.07) respectively for the control group. (Figure 1). B - Stimulation during the interictal phase: the threshold values of the right and left hemisphere were respectively 58.25 (sd ± 4.57) and 50.00 (sd ±3.54) for the patient group, and 48.24 (sd ±7.46) and 43.75 (sd ±3.77) respectively for the control group. (Figure 2).
CCT (milliseconds): A - CCT values during the ictal phase: 6.02 (sd ± 0.43) and 5.25 (sd ± 0.21) recording from the left and right FDI respectively in the patient group, and 5.5 (sd ± 1.05) and 5.12 (sd ± 1.48) from the left and the right FDI in the control group. B - CCT values during the interictal phase: 5.77 (sd ± 0.33) and 4.95 (sd ± 0.33) respectively from the left and right FDI in the patient group, and 5.74 (sd ±1.38) and 5.26 (sd ±1.56) in the control group. DISCUSSION
We found that the migraneurs did not show any significant difference in threshold or CCT values between the ictal and the interictal phase. Similarly, there was no significant difference between the two determinations in the control group. As far as the comparison between the two hemispheres is concerned, all patients and controls showed a significantly lower threshold to TES for the hemisphere contralateral to the dominant hand. This finding is in accordance with recent observations.26 On average, threshold values were significantly higher in migraine patients than in controls, even when considering both hemispheres. If confirmed by further studies, this observation appears at variance with previous findings,8according to which no changes should exist in the motor cortical threshold in patients affected by migraine without aura, at least in the interictal phase. High
threshold values, in both ictal and the interictal phase, cannot be related to underlying cerebral blood flow (CBF) alterations, which have not been found in this kind of migraine. This statement is supported by studies23,27-31 disclosing that there is no reduction in the CBF and/or in the regional CBF in migraine without aura. Therefore if a vascular cause can not explain high TES-threshold values in both the ictal and the interictal period, other pathophysiologic explanations must be found. We hypothesize that there is a dysfunction of the cerebral mechanisms regulating the motor cortical threshold; a dysfunction which could arise from alterations of the neurochemical mechanisms underlying the migrainous phenomenon.32,33 The changes noted appear to be persistent, since high threshold values proved consistently steady during test and retest. If confirmed, the increased TES-threshold may be a potentially useful neurophysiological correlate of migraine without aura. REFERENCES
1.
Headache Classification Committee of the International Headache Society. Cephalalgia 1988; 8, suppl.7:1-96.
2.
Barker AT, Freeston IL, Jalinour R: Magnetic stimulation of the human brain and peripheral nervous system: An introduction and the results of an initial evaluation, Neurosurgery 1987; 20:100-109.
3.
Rothwell JC, Thompson PD, Day BL, Dick JPR, Kachi T, Cowan JMA, Marsden CD: Motor cortical stimulation in intact man. I. General characteristics of EMG responses in different muscle. Brain 1987; 110:1173-1190.
4.
Day BL, Rothwell JC, Thompson PD, Dick JPR, Cowan J, Berardelli A, Marsden CD: Motor cortical stimulation in intact man.11, Multiple descending volley. Brain 1987; 110:1191-1210.
5.
Cantello R, Gianelli M, Bettucci D, Civardi C, De Angelis S, Mutani R: Parkinson's disease rigidity: magnetic motor evoked potentials in a small hand muscle. Neurology 1991; 41:1449-1461.
6.
Eisen AA, Shtybel W: Clinical experience with magnetic stimulation. Muscle and Nerve 1990; 13:995-1011.
7.
Rossini PM, Di Stefano E, Stanzione P: Nerve impulse propagation along central and peripheral fast conducting motor and sensory patways in man. ElectroencephaIogr Clin Neurophysiol 1985; 60:320-334.
8.
Maertens De Noordhout A, Shoenen J, Pepin JL, Delwaide PJ: Magnetic cortical stimulation in migraine. Cephalalgia 1989; 9 (suppl.10): 208-209.
9.
Hockaday JM, Debney LM: The EEG in migraine. In: J. Olesen and L. Edvinsson, Eds. Basic mechanisms of headache. Amsterdam: Elsevier 1988: 365-368.
10.
Clifford T, Lauritzen M, Bakke M, Olesen J, Moller E: Electromyography of pericranial muscles during treatments of spontaneus common migraine attacks. Pain 1982; 14:137-147.
11.
McLean C, Appenzeller O, Cordaro JY, Rhodes J: Flash evoked potentials in migraine. Headache 1975; 14:193-198.
12.
Lehtonen J, Hyyppa MT, Kaihola H-L, Kangasniemi P, Lang AM: Visual evoked potentials in menstrual migraine. Headache 1979; 19:63-70.
13.
Benna P, Bianco C, Costa P, Piazza D, Bergamasco B: Visual evoked potentials and brainstem auditory evoked potentials in migraine and transient ischemic attacks. Cephalalgia 1985; 5 (suppl.2):53-58.
14.
Bussone G, Sinatra MG, Boiardi A, LaMantia L, Frediani F, Cocchini F: Brainstem auditory evoked potentials in migraine patients in basal conditions and after chronic flunarizine treatment. Cephalalgia 1985; 5 (suppl.2):177-180.
15.
Timsit-Berthier M: Variation contingente negative composantes endogenes du potentiel evoque. Rev.EEG Neurophysiol. 1984; 14:77-96.
16.
Shoenan J, Timsit-Berthier M, Timsit M: Correlation between contingent negative variation and plasma levels of cathecolamines in headache patients. Cephalalgia 1985; 5:480.
17.
Maertens DeNoordhout A, Timsit M, Timsit-Berthier M, Shoenen J: Contingent negative variation in headache. Ann Neurol 1986; 19:78-80.
18.
Tepley N, Barkley J, Welch KMA., NageI-Leiby S, Moran JE, Simkins RT: Magnetoencephalographic studies in migraine. The migraine trust. 8th Migraine Trust International Symposium. 1990.
19.
Shoenen J: Clinical neurophysiology of migraine. Cuming lecture. 8th Migraine Trust International Symposium. 1990.
20.
Skinhoj E, Paulson OB: Regional cerebral blood flow in internal carotid distribution during migraine attack. Br Med J 1969; 3:569-570.
21.
Skinhoj E: Hemodynamic studies within the brain during migraine. Arch Neurol 1973; 29:95-98.
22.
Lauritzen M, Olesen J: Regional cerebral blood flow during migraine attacks by Xenon-133 inhalation and emission tomography. Brain 1984; 107:447-461.
23.
Skyhoj Olsen T, Olesen J: Regional cerebral blood flow in migraine and cluster headache. In: J Olesen and L Edvinsson, Eds. Basic mechanisms of headache. Amsterdam: Elsevier, 1988: 377-391.
24.
Olesen J, Larsen B, Lauritzen M: Focal hyperemia followed by spreading oligemia and impaired activation of rCBF in classic migraine. Ann Neurol 1981; 9:344-352.
25.
Caramia MD, Pardal AM, Zarola F, Rossini PM. Electric versus magnetic transcranial stimulation of the brain in healthy humans a comparative study of central motor tracts "conductivity" and "excitability". Brain Res 1989; 479:98-104.
26.
Cantello R, Gianelli M, Bettucci D, Tribolo A, Mutani R. Threshold to magnetic stimulation of hand motor cortex: effects of handedness. Clin Neurophysiol 1990; 20, (Suppl.ls): 87.
27.
Pearce JMS, Foster JB: An investigation of complicated migraine. Neurology 1965; 15:323-340.
28,
Boisen E: Strokes in migraine: report on seven strokes associated with severe migraine attacks. Dan Med Bull 1975; 22:100-106.
29.
Lauritzen M, Skyhoj Olsen T, Lassen NA, Paulson OB. The changes of regional cerebral blood flow during the course of classical migraine attacks. Ann Neurol 1983; 13:633-641.
30.
Skyhoj Olsen T, Friberg L, Lassen NA.: Ischemia may be the primary cause of neurological deficits in classic migraine. Arch Neurol 1987; 44:156-161.
31.
Olesen J, Friberg L, Olsen TS, Iversen HR, Lassen NA, Andersen AR, Karle A: Timing and topography of cerebral blood flow, aura and headache during migraine attacks. Migraine Trust. 8th Migraine Trust International Symposium, 1990.
32.
Sicuteri F: Migraine, a central biochemical dysnociception. Headache 1976; 16:145.
33.
Lance JW: Mechanism and management of headache. 4th Ed. Butterworth. London, 1982.
