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Magnetoencephalographic analysis of cortical myoclonic jerks
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Electroencephalography and clinical Neurophysiology 99 (1996) 141-148
Magnetoe,ncephalographic analysis of cortical myoclonic jerks Yoshikazu Uesaka a, Yasuo Terao a, Yoshikazu Ugawa a,*, Masato Yumoto b, Ritsuko Hanajima a, Ichiro Kanazawa a aDepartment of Neurology, Institutefor Brain Research, School of Medicine, University of Tokyo, 7-3-1, Hongo, Bunkyo-ku, Tokyo 113, Japan bDepartment of Laboratory Medicine, School of Medicine, University of Tokyo, 7-3-1, Hongo, Bunkyo-ku, Tokyo 113, Japan Accepted for publication: 25 March 1996
Abstract
We studied the pre-myoclonus spike using magnetoencephalography in patients with cortical myoclonus (6 with cortical reflex myoclonus and one with epilepsia partialis continua). The spike was estimated as a single current dipole on the pre-central gyms in one patient with epilepsia partialis continua. In contrast, it was estimated as a single dipole on the post-central gyrus in 5 of 6 patients with cortical reflex myoclonus, and as two dipoles on the pre- and post-central gyrus in the remaining patient. We conclude that there are 3 physiological types of cortical myoclonus: (1) abnormal discharges in the motor cortex produce the myoclonus; (2) the source of the myoclonus is mainly the sensory cortex; (3) both the motor and sensory cortices play important roles in the production of myoclonus.
Keywords: Cortical myoclonus; Magnetoencephalography; Pre-myoclonus spike
1. Introduction Cortical myoclonus cc,nsists of lightning-like muscle jerk preceded by an electroencephalographic (EEG) spike over the opposite sensorimotor cortex. When it is large, the pre-myoclonus spike can be observed on routine polygraph recordings. If it is small or difficult to observe in background activity, the jerk-locked back averaging method is very useful for detecting it (Shibasaki and Kuroiwa, 1975, 1978; Chadwick et al., 1977). In jerklocked averaging, EEG activity is averaged with respect to the onset of myoclonus in the electromyographic (EMG) records. It enables us to detect EEG activities which are highly correlated with muscle jerks even though they are too small to be seen in polygraphic recordings. Recent topographic analysis of the premyoclonus spike in patients with cortical reflex myoclonus suggested that it is generated in the sensory rather than motor cortex (Shibasaki et al., 1991). In the present study we have taken advantage of the increased spatial resolution of magnetoencephalography (MEG) to localize the pre*myoclonus spike in patients * Corresponding author. Tel.: +81 3 38155411, ext. 3783; fax: +81 3 38132129.
with cortical reflex myoclonus and in one patient with epilepsia partialis continua (EPC). The results show that although sensory cortex is the most usual source of the pre-myoclonus spike, this is not always the case.
2. Subjects The subjects included 6 patients with cortical reflex myoclonus (Hallett et al., 1979; Kakigi and Shibasaki, 1987) and one with EPC as a sequel to Russian spring summer encephalitis. The 6 cortical reflex myoclonus patients consisted of 4 women with familial myoclonic epilepsy, one man with hypoxic encephalopathy with myoclonus (Lance-Adams syndrome), and one man with galactosialidosis. The diagnoses were made according to the clinical features and laboratory examinations. Marked low activity of fl-galactosidase and sialidase confirmed the diagnosis in the patient with galactosialidosis. Spontaneous jerks appeared in the left arm muscles 3 months after the episode of loss of consciousness in the patient with Russian spring summer encephalitis diagnosed by the serological tests (Takezawa et al., 1995). All the patients with cortical reflex myoclonus had giant somatosensory evoked potentials (SEPs) (according to the previously reported criteria (Uesaka et al., 1993)) and long
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latency reflexes (LLRs) without voluntary contraction. In the patient with EPC, the SEPs were normal in size and latency, and no LLRs were evoked. The jerk-locked back averaging method (see below) demonstrated a cortical EEG spike preceding the myoclonus in all the patients studied here. 3. Methods Magnetoencephalographic recordings were made in a dimly-lit, magnetically shielded room at the Tokyo University Hospital. The subjects were lying on the bed, and the heads and bodies were supported with a vacuum cast to prevent movements. Neuromagnetic fields were recorded using 37-channel first-order DC-SQUID (superconducting quantum interference device) gradiometer systems (Magnes, Bti Co. Ltd.). The pick-up coils, separated by 20.0 mm, are in a hexagonal array on a spherical surface (diameter 144 mm). The neuromagnetic field was recorded over a 144 mm diameter circular area above the parietal cortex contralateral to the studied muscle. Before recording the magnetic fields, the head shape of every subject was digitized 3-dimensionally using the sensor position indicator (SPI) system of Magnes to calculate the center of the local model sphere of the head in the measurement area. All the experiments were done while the subjects were completely relaxed. EMG activities were recorded from the muscles involved in the myoclonus using surface cup electrodes. For jerk-locked averaging, the EMG signals from the muscle in which myoclonic jerks occurred most frequently were rectified, and a trigger pulse was obtained by a pulse converter (Nihon Kohden) whenever the rectified EMG exceeded a pre-set level (conventional jerklocked averaging). Neuromagnetic fields and rectified EMG signals were averaged with respect to this EMG onset pulse. The total analysis time was 200 ms and the pre-trigger analysis time was 150 ms. The amplified signals of the SQUIDS were filtered with a bandwidth of 10-1200 Hz. The responses were digitized at 4166 Hz, and averaged on-line. EEG activities were recorded with scalp electrodes placed in accordance with the international 10-20 system using a time constant of 0.3 s and a high frequency cut off of 3000 Hz. The linked ear lobe was used as the reference. In the analysis of EEG activity preceding the myoclonus (jerk-locked averaged EEG), we used a special program. In this program, we determined the exact onset of myoclonic discharge in every single record, and EEGs and rectified EMGs were averaged with respect to this onset (Sakai et al., 1993) similarly to the method first reported by Barrett et al. (1985) for recording movement-related cortical potentials. With this method, we can reduce the amount of jitter between the actual onset of myoclonus and the trigger pulse used for averaging. The time relation between the cortical spike and myoclonus was slightly different with these two
methods (Sakai et al., 1993). The conventional method showed that the positive peak of pre-myoclonus spike preceded the onset of myoclonus by approximately the same interval as the known conduction time from cortex to muscle (Shibasaki and Kuroiwa, 1975; Chadwick et al., 1977; Shibasaki et al., 1978). However, precise analysis of latencies using the new method showed that the interval between the positive peak of pre-myoclonus spike and the onset of myoclonus was sometimes shorter than the cortical latency (Sakai et al., 1993). These results indicate that the cortical event for producing myoclonus begins to occur at the time between the onset and peak of premyoclonus spike (Sakai et al., 1993). We could use this method only for analyzing EEG activities because our MEG system has no program for off-line averaging. Somatosensory evoked magnetic fields (SEFs) following the median nerve stimulation were also recorded using the technique reported elsewhere (Uesaka et al., 1993). Isocontour field maps were calculated using a weighted least-squares approximation, and equivalent current dipoles were fitted with a least-squares method. To perform the dipole localization, a spherical volume conductor model (Sarvas, 1987) was used. We defined the recording area as a sphere which was fitted to the digitized headshape data below the sensors by a least squares method. The strength, position and orientation of one or two dipoles could be adjusted using a least-squares algorithm which optimized the extent to which the field of the theoretical sources accounted for the variance of the observed data, expressed as a correlation. In this study we adopted the localization of current dipoles as reliable only when their correlation exceeded 0.99. Magnetic resonance imaging (MRI) scans of the brain were obtained from all patients with the Siemens Magnetome machine (1.5 T). The thickness of each slice was 5 mm, with a distance of 7.5 mm between the centers of adjacent slices. Four reference points for the superimposition of MEG data on MRI were specified on the MRI scans by landmarks at two periauricular points, Cz point and the nasion. These landmarks defined the head-based coordinate system on the MRI scans, allowing the appropriate x, y and z locations obtained from the MEG data to be superimposed onto the MRI scans. Source locations were marked to the nearest slice. The method is detailed in a previous report (Yamamoto et al., 1988). According to the previous articles (Kido et al., 1980; Montemurro and Bruni, 1988), we detected the pre-, post-, and central sulci in the following way. On the MR images, the superior frontal and intraparietal sulci, both of which course antero-posteriorly, are clearly delineated. The former crosses the pre-central sulcus, the latter the post-central sulcus. The central sulcus is positioned between the preand post-central sulci. We defined the post-central gyrus as the gyrus between the central and post-central sulci. We estimated that the maximum spatial resolution of magnetoencephalogram was of the order of 3 mm (Yama-
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Fig. 1. Jerk-locked magnetic fields in a patient with familial myoclonic epilepsy (upper traces). The bottom trace is an average (n = 500) rectified EMG activity recorded from the right first dorsal interosseous muscle. The other 37 traces are average neuromagnetic activities. A biphasic magnetic field preceded the myoclonus. The interval between the first peak of pre-myoclonus magnetic field and the onset of myoclonus was 16.2 ms. The upward deflection of MEG recordings indicates an outward magnetic field. Waves forms for jerk-locked magnetic field are displayed on an array depicting the sensor detector coil geometry on the lower left. A1-A37 are the magnetometer pick-up coil locations, 20 mm apart. On every wave form, a vertical line indicates the EMG onset of myoclonus. Positive going peaks indicate magnetic fields emanating from the head, while negative peaks indicate those returning to the head. Biphasic pre-myoclonus activity was demonstrated. The center of the recording dewar, covering an area with a diameter of 144 mm, was positioned over the contralateral sensory-motor cortex (around C3 or C4 position of the international 10-20 system). An isocontour map at the first peak of pre-myoclonus magnetic field, indicated by the arrow in A23 and A7 traces (16.2 ms prior to the onset of myoclonus), is shown on the lower right. Each line represents a step of 10 fT. The shape of the contour map suggests a single current dipole positioned under the zeroline, pT, picotesla. moto et al., 1988). W e considered this resolution to be good e n o u g h for differentiating the positions of the sensory and motor cortices. Even though w e defined a part of brain (about one fourth of the cortex) as a spherical volu m e conductor instead o:f a real head shape model, our experiences that the N l n i and P l m c o m p o n e n t s of SEF were localized on the sensory cortex in all normal subjects (n = 50) also suggest that our M E G system has a good spatial resolution e n o u g h for the present investigation.
Informed consent was obtained from all the subjects. The procedures here described were approved by the Ethics Committee of the University of Tokyo. 4. Results In all the patients, jerk-locked averaging demonstrated that a biphasic magnetic field preceded the m y o c l o n u s in the hemisphere contralateral to the m u s c l e being studied. Average magnetic fields and E M G activity in a patient
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Fig. 2. Axial MRI of the brain in a patient with familial myoclonic epilepsy (case presented in Fig. 1). The estimated position of the center of the current dipole for the first peak of pre-myoclonus spike (red point) and N 1m component of giant SEF (yellow point) are superimposed on the MRI scan. They are positioned on the post-central gyrus. The MRI slice is 3.2 cm above the AC-PC line (anterior commissure-posterior commissure line) and parallel to it.
with familial myoclonic epilepsy are shown in Fig. 1 (upper). The first peak of pre-myoclonus magnetic field preceded the onset of myoclonic discharge in the first dorsal interosseous (FDI) muscle by 16.2 ms. The lower left traces of Fig. 1 show these magnetic activities displayed on an array depicting the sensor coil geometry. Dipole solutions were calculated at 0.24 ms intervals from the onset of pre-myoclonus spike to the onset of myoclonus. The correlation of the fitted dipoles exceeded 0.99 for the period of 19.4 ms and 12.2 ms prior to the onset of
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myoclonus. It was maximum at the first peak of premyoclonus spike (arrow). Positions of the estimated current dipoles did not move significantly (less than 3 mm) during this period. These results suggested that a single dipole in a single location could reasonably explain the pre-myoclonus spike during this period. An isocontour field map at the latency of the first peak of pre-myoclonus spike (lower right in Fig. 1) also suggested that the source of the first peak was well estimated as a single current dipole. The location of the single equivalent current di-
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Fig. 3. Waves of jerk-locked magnetic fields preceding the myoclonus of the forearm extensor muscle in the patient with galactosialidosis (left) reveal a biphasie pre-myoelonus activity, which has a small notch (arrow in the A24 trace) between the first and second peaks, lsocontour map (fight) for the peak of that small notch suggests the presence of two current dipoles. The dewar was placed over the sensory-motor cortex contralateral to the studied muscle similarly to Fig. 1. The upward deflection indicates an outward magnetic field.
Y. Uesaka et al. / Electroencephalography and clinical Neurophysiology 99 (1996) 141-148
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Fig. 4. The centers of the estimatJ~d two dipoles for the peak of the notch of pre-myoclonus spike are superimposed on the MRI of brain in the patient with galactosiaiidosis (two red points). One is positioned on the post-central gyms (the left slice), the other on the pre-central gyms (the right slice). Position of the current dipole fitted to the Nlm component of giant SEF after median nerve stimulation at the wrist is also superimposed (yellow point in the left slice). The generator of Nlm (corresponding to N20 component of giant SEP) was localized in the sensory cortex, which is consistent with the previous results (Uesaka et ai., 1993). The sensory cortex dipole for jerk-locked averaging was positioned medial to the dipole for Nlm component of SEF probably because the former corresponds to the forearm area in the sensory cortex, and the latter the hand area. The left slice is 4.2 em above the AC-PC line (anterior eommis.,;ure-posterior commissure line) and parallel to it. The right slice is 3.45 cm above the AC-PC line.
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pole was superimposed on the patient's MRI scan (red point in Fig. 2) and was located on the post-central gyms. In all the other patients with cortical reflex myoclonus, except the patient with galactosialidosis, the premyoclonus spike was similarly estimated as a single current dipole positioned on the post-central gyrus. In the patient with galactosialidosis, jerk-locked aver-
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Fig. 5. EEG activities averaged with respect to the onset of myoclonus in the left extensor carpi radials (ECR) muscle (n = 200) in the patient with EPC are shown in the upper figure. Monopolar EEG activities (reference: linked ear lobes) are presented. Myoclonus occurred in the left upper-limb muscles (first dorsal interosseous (FDI), ECR, and flexor carpi ulnaris (FCU) muscles), but not on the right. The premyoclonus EEG spike was localized on the hemisphere contralateral to the jerks. Its positive peak preceded the onset of myoclonus in the left ECR by 25.5 ms. Jerk-locked magnetic field (lower figure) also showed a biphasic pre-myoclonus field. The solid line indicates the onset of myocionus in ECR. The first peak of the magnetic field (upward arrow) preceded the onset of myoclonus by 31.6ms, and the second (downward arrow) by 15.8 ms, which was almost the same as the cortical latency of this muscle (16.6 ms) measured by magnetic cortical ~limnlation The dewar wag nlae,~a'lover the rie,ht ~en~orv-mntnr cortex
Fig. 6. The center of the current dipole for the first peak of premyoclonns spike and that for the second peak are superimposed on the MRI scan in the patient with EPC. That for the first peak is positioned on the pre-motor cortex (yellow point), and that for the second on the l~re-central gvrus (l~rimarv motor cortex) (red ~oint).
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aging demonstrated a biphasic pre-myoclonus spike (Fig. 3). A small notch (arrow in the left traces of Fig. 3) was present between the first and second peaks of the spike, suggesting that the spike consisted of more than one single dipole. In fact, single dipole fittings from the first peak to the second peak of pre-myoclonus spike showed no good correlation at any latencies. Double dipole solutions around the timing of the small notch had reliable correlations (>0.99). The isocontour field map at the latency of the peak of the notch (right traces of Fig. 3) also suggested that the pre-myoclonus spike consisted of two current dipoles. The positions of these two dipoles were superimposed on the MRI (Fig. 4). One source was estimated to be on the post-central gyms, and the other on the pre-central gyrus. In the patient with EPC, MEG studies showed that most of the spontaneous cortical spikes originated from the pre-central gyrus. Jerk-locked averaging showed a biphasic EEG spike preceding the myoclonus (upper traces of Fig. 5). The first peak of this spike preceded the onset of myoclonus in ECR by 25.5 ms, which was longer than the cortical latency of that muscle (16.6 ms). The second peak of the spike preceded the myoclonus by only 9.6 ms. The jerk-locked magnetic field also consisted of a biphasic spike (lower traces of Fig. 5). The first peak preceded the onset of myoclonus by 31.6 ms, and the second by 15.8 ms. The correlation of single dipole solution exceeded 0.99 during two periods around these two peaks (the first period, 37.4-26.1 ms prior to the onset of myoclonus; the second period, 21.3-11.2 ms prior to it), and it was at maximum at the time of the peak in both periods. The positions of dipoles did not show significant changes during each period, which indicates that these two peaks are reasonably estimated as a single fixed dipole at each position, respectively. The first peak was estimated to be produced by a current dipole positioned on the pre-motor cortex (yellow point in Fig. 6), and the second as one positioned on the primary motor cortex (red point in Fig. 6). In the jerk-locked averaged EEG wave forms (upper traces of Fig. 5), the initial negative peak of the premyoclonus spike at F4 was similar in size to its positive counterpart at P4 and it showed a phase-reversal at C4. These results indicate that this first peak is generated by a tangentially oriented dipole at around C4, which is consistent with the dipole localization for the first peak revealed by the MEG studies. In contrast, the negative peak of the second peak at P4 was much larger than its positive counterpart at F4. This suggests that the estimated dipole for the second peak is oriented not completely tangentially, but obliquely. In such a situation, although the second peak showed a phase reversal at front-central area, a real obliquely oriented dipole should be positioned more posteriorly. Actually, MEG studies analyzing only tangentially oriented components disclosed that the second peak is positioned more posteriorly than the first. These results of EEGs and MEGs are all consistent. There are
two possibilities to explain why the dipole for the second peak is oriented obliquely. One is that the primary motor cortex is oriented obliquely in this particular patient and a single dipole originated from it directed obliquely. The other is that a tangential dipole at the primary motor cortex is associated with another radial dipole at the latency of the second peak. Therefore, EEG studies showed a single obliquely oriented dipole summed up by these two dipoles, whereas MEG studies showed a single tangential dipole. Based on all the results obtained from EEG and MEG analyses, we conclude that activities in the premotor and primary motor cortices precede the myoclonus in this patient. In the 6 patients with cortical reflex myoclonus, the N l m and Plm components of giant SEF were localized on the post-central gyrus (shown in Fig. 2 in a patient with familial myoclonic epilepsy, and in Fig. 4 in the patient with galactosialidosis), which was consistent with the previous results (Uesaka et al., 1993). Those components of SEF were also estimated as dipoles positioned on the post-central gyrus in the patient with EPC. 5. Discussion
The present investigation showed 3 types of the premyoclonus spike in cortical myoclonus. (1) In the patient with EPC, activity over both pre-motor and motor cortices preceded the myoclonus. Premotor activity occurred at the first peak of pre-myoclonus spike and motor cortex activity at the second peak. These results suggest that abnormal discharges first occur in the pre-motor cortex at around the first peak of pre-myoclonus spike, then at around the second peak, activation of the primary motor cortex occurs. The finding that the second peak of the pre-myoclonus MEG spike revealed by the conventional jerk-locked averaging method preceded the myoclonus by 15.5 ms, which is almost the same as the cortical latency (16.6 ms), also supports our speculation that activation of the primary motor cortex occurs at around the second peak. This is consistent with the previous reports using the same method (Shibasaki and Kuroiwa, 1975; Chadwick et al., 1977; Shibasaki et al., 1978). The result that the interval between the second peak of pre-myoclonus spike and the onset of myoclonus (9.6 ms) was shorter than the cortical latency in the jerk-locked averaging with respect to the accurate onset of myoclonus is consistent with our previous report (Sakai et al., 1993) using the same off-line averaging method and also supports the above speculation. There are at least two possibilities to explain how these two activities produce the muscle jerks. One possibility is that the first activation of the premotor cortex induces late abnormal discharges in the primary motor cortex, which finally produce the muscle jerks. The other is that direct effects of the premotor and primary motor cortices onto the spinal motoneurons summate at the spinal level and activate the spinal motoneurons. No
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disinhibition of the sensory cortex was present in this patient (neither giant SEF nor abnormal SEP recovery (Ugawa et al., 1991)). Based on these results, we consider that abnormal discharges in the motor cortices cause the myoclonus in this patient, whatever the precise mechanisms are. Patients with EPC have several types of muscle jerks, such as very rapid irregular myoclonus (duration of EMG discharge is about 50 ms ) to clonic slow movement (duration of EMG discharge is 200-400 ms). Therefore, we do not intend to make a general conclusion from the results of a single case that all jerky movements in EPC originate from the motor cortices. However, we would like to conclude that myeclonus in this patient is produced by abnormal activation of the motor cortices. (2) In the patient with galactosialidosis, the pre-myoclonus spike was composed of two dipoles, each of which was positioned in the motor and sensory cortices. We conclude that both the motor and sensory cortices play important roles in producing the myoclonus in this patient. (3) In the other 5 patients with cortical reflex myoclonus, the pre-myoclonus spike was composed of one dipole in the sensory cortex. If there was abnormal discharge in the crown of the pre-central gyms, we could not detect such activity by MEG because only the tangentially oriented dipoles are recorded by MEG. Therefore, we cannot completely exclude some contribution of the motor cortex to the myoclonus in those patients. However, we would like to conclude that hypersynchronous discharges in the sensory cortex produce the myoclonus in these patients. There are two hypotheses to explain how the abnormally large discharges in the sensory cortex produce the myoclonus. One possibility is that direct projections from sensory cortex to spinal interneurons are activated by the spike discharge and moto, aeurons are activated by such interneurons. Alternatively, the sensory cortex may drive motor output via its connections with the precentral gyrus. In the latter case, the motor cortex would be activated by normally functioning connections, hence would not show the spike activity typical of an epileptic focus. Whatever the mechanisms, this third type is the most frequent variety of cortical reflex myoclonus (Shibasaki et al., 1991). There are several other reports about the generators of the pre-myoclonus spike, lln patients with EPC, the spike was found to originate from the motor cortex (Wieser et al., 1978; Celesia et al., 1994) or from both the motor and sensory cortices (Stiegfried and Bernoulli, 1976). In one patient with EPC who had also cortical reflex myoclonus, abnormal discharges in the post-central region produced the myoclonus (Cowan et al., 1986). We would speculate from the present results that the sensory cortex plays the most important role in producing muscle jerks in the majority of patients with cc,rtical reflex myoclonus. Such patients are also likely to have reflex muscle jerks and an enlarged SEP. However, patients who have muscle jerking in the absence of reflex involvement may be more
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likely to have spike activation in motor rather than sensory cortex. In conclusion, the spatial resolution of the MEG has shown that there are three types of cortical myoclonus: abnormal discharges responsible for the myoclonus originate from the motor cortex, the sensory cortex, or both of them. References
Barrett, G., Shibasaki, H. and Neshige, R. A computer-assisted method for averaging movement-related cortical potentials with respect to EMG onset. Electroenceph. clin. Neurophysiol., 1985, 60: 271281. Celesia, G.G., Parmeggiani, L. and Brigell, M. Dipole source localization in a case of epilepsia partialis continua without premyoclonic EEG spikes. Electroenceph. clin. Neurophysiol. 1994, 90: 316319. Chadwick, D., Hallett, M., Harris, R., Jennen, P., Raymond, E.H. and Marsden, C.D. Clinical biochemical and physiological features distinguishing myoclonus responsive to 5-hydroxytryptophan, tryptophan with a monoamine oxidase inhibition, and clonazepam. Brain, 1977, 100: 455--487. Cowan, J.M.A., Rothwell, J.C., Wise, R.J.S. and Marsden, C.D. Electrophysiological and positron emission studies in a patient with cortical myoclonus,epilepsia partialis continua and motor epilepsy. J. Neurol. Neurosurg. Psychiatry, 1986, 49: 796-807. Hallett, M., Chadwick, D. and Marsden, C.D. Cortical reflex myoclonus. Neurology 1979, 29:1107-1125. Kakigi, R. and Shibasaki, H. Generator mechanisms of giant somatosensory evoked potentials in cortical reflex myoclonus. Brain, 1987, 110: 1359-1373. Kido, D.K., LeMay, M., Levinson, A.W. and Benson, W.E. Computed tomographic localization of the precentral gyms. Radiology, 1980, 135: 373-377. Montemurro, D.G. and Bruni, J.E. Topography of the cerebral hemisphere. In: D.G. Montemurro and J.E. Bruni (Eds.), The Human Brain in Dissection. Oxford University Press, New York, 1988, 3447. Sakai, K., Ugawa, Y., Genba, K., Mannen, T. and Kanazawa, I. The interval between the positive peak of premyoclonus spike and the onset of myoclonus is shorter than the cortical latency in cortical myoclonus. Eur. Neurol. 1993, 33: 83-89. Sarvas, J. Basic mathematical and electromagnetic concepts of the biomagnetic inverse problem. Phys. Med. Biol. 1987, 32:1122.
Shibasaki, H. and Kuroiwa, Y. Electroencephalographic correlates of myoclonus. Eleetroenceph. clin. Neurophysioi., 1975, 39: 455463. Shibasaki, H., Yamashita, Y. and Kuroiwa, Y. Electroencephalographic studies of myoclonus: myoclonus-related cortical spikes and high amplitude somatosensoryevoked potentials. Brain, 1978, 101: 447460. Shibasaki, H., Kakigi, R. and Ikeda, A. Scalp topography of giant SEP and pre-myoclonus spike in cortical reflex myoclonus. Eleetroenceph. clin. Neurophysiol., 1991, 81: 31-37. Stiegfried, J. and Bernoulli, C. Stereo-electroencephalographicexploration and epilepsia partialis continua. Acta. Neurochir. 1976, 23 (suppl): 183-191. Takezawa, C., Sato, T., Mizutani, Y., Abe, S. and Morita, K. Russian spring-summer encephalitis: a case report. Neurol. Med. (Tokyo) 1995, 43: 251-255. Uesaka, Y., Ugawa, Y., Yumoto, M., Sakuta, M. and Kanazawa, I. Giant somatosensory magnetic field in patients with myoeionus epilepsy. Electroenceph. clin. Neurophysiol. 1993; 87: 300-305. Ugawa, Y., Genba, K., Shimpo, T. and Mannen, T. Somatosensory
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evoked potential recovery (SEP-R) in myoclonic patients. Eleclroenceph, clin. Neurophysiol. 1991, 80: 21-25. Wieser, HG., Graph, H.P., Bernoulli, C. and Siegfried, J. Quantitative analysis of intracerebral recordings in epilepsia partialis continua. Elech'oenceph. clin. Neurophysiol. 1978, 44: 14-22.
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Electroencephalography and clinical Neurophysiology 99 (1996) 141-148
Magnetoe,ncephalographic analysis of cortical myoclonic jerks Yoshikazu Uesaka a, Yasuo Terao a, Yoshikazu Ugawa a,*, Masato Yumoto b, Ritsuko Hanajima a, Ichiro Kanazawa a aDepartment of Neurology, Institutefor Brain Research, School of Medicine, University of Tokyo, 7-3-1, Hongo, Bunkyo-ku, Tokyo 113, Japan bDepartment of Laboratory Medicine, School of Medicine, University of Tokyo, 7-3-1, Hongo, Bunkyo-ku, Tokyo 113, Japan Accepted for publication: 25 March 1996
Abstract
We studied the pre-myoclonus spike using magnetoencephalography in patients with cortical myoclonus (6 with cortical reflex myoclonus and one with epilepsia partialis continua). The spike was estimated as a single current dipole on the pre-central gyms in one patient with epilepsia partialis continua. In contrast, it was estimated as a single dipole on the post-central gyrus in 5 of 6 patients with cortical reflex myoclonus, and as two dipoles on the pre- and post-central gyrus in the remaining patient. We conclude that there are 3 physiological types of cortical myoclonus: (1) abnormal discharges in the motor cortex produce the myoclonus; (2) the source of the myoclonus is mainly the sensory cortex; (3) both the motor and sensory cortices play important roles in the production of myoclonus.
Keywords: Cortical myoclonus; Magnetoencephalography; Pre-myoclonus spike
1. Introduction Cortical myoclonus cc,nsists of lightning-like muscle jerk preceded by an electroencephalographic (EEG) spike over the opposite sensorimotor cortex. When it is large, the pre-myoclonus spike can be observed on routine polygraph recordings. If it is small or difficult to observe in background activity, the jerk-locked back averaging method is very useful for detecting it (Shibasaki and Kuroiwa, 1975, 1978; Chadwick et al., 1977). In jerklocked averaging, EEG activity is averaged with respect to the onset of myoclonus in the electromyographic (EMG) records. It enables us to detect EEG activities which are highly correlated with muscle jerks even though they are too small to be seen in polygraphic recordings. Recent topographic analysis of the premyoclonus spike in patients with cortical reflex myoclonus suggested that it is generated in the sensory rather than motor cortex (Shibasaki et al., 1991). In the present study we have taken advantage of the increased spatial resolution of magnetoencephalography (MEG) to localize the pre*myoclonus spike in patients * Corresponding author. Tel.: +81 3 38155411, ext. 3783; fax: +81 3 38132129.
with cortical reflex myoclonus and in one patient with epilepsia partialis continua (EPC). The results show that although sensory cortex is the most usual source of the pre-myoclonus spike, this is not always the case.
2. Subjects The subjects included 6 patients with cortical reflex myoclonus (Hallett et al., 1979; Kakigi and Shibasaki, 1987) and one with EPC as a sequel to Russian spring summer encephalitis. The 6 cortical reflex myoclonus patients consisted of 4 women with familial myoclonic epilepsy, one man with hypoxic encephalopathy with myoclonus (Lance-Adams syndrome), and one man with galactosialidosis. The diagnoses were made according to the clinical features and laboratory examinations. Marked low activity of fl-galactosidase and sialidase confirmed the diagnosis in the patient with galactosialidosis. Spontaneous jerks appeared in the left arm muscles 3 months after the episode of loss of consciousness in the patient with Russian spring summer encephalitis diagnosed by the serological tests (Takezawa et al., 1995). All the patients with cortical reflex myoclonus had giant somatosensory evoked potentials (SEPs) (according to the previously reported criteria (Uesaka et al., 1993)) and long
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latency reflexes (LLRs) without voluntary contraction. In the patient with EPC, the SEPs were normal in size and latency, and no LLRs were evoked. The jerk-locked back averaging method (see below) demonstrated a cortical EEG spike preceding the myoclonus in all the patients studied here. 3. Methods Magnetoencephalographic recordings were made in a dimly-lit, magnetically shielded room at the Tokyo University Hospital. The subjects were lying on the bed, and the heads and bodies were supported with a vacuum cast to prevent movements. Neuromagnetic fields were recorded using 37-channel first-order DC-SQUID (superconducting quantum interference device) gradiometer systems (Magnes, Bti Co. Ltd.). The pick-up coils, separated by 20.0 mm, are in a hexagonal array on a spherical surface (diameter 144 mm). The neuromagnetic field was recorded over a 144 mm diameter circular area above the parietal cortex contralateral to the studied muscle. Before recording the magnetic fields, the head shape of every subject was digitized 3-dimensionally using the sensor position indicator (SPI) system of Magnes to calculate the center of the local model sphere of the head in the measurement area. All the experiments were done while the subjects were completely relaxed. EMG activities were recorded from the muscles involved in the myoclonus using surface cup electrodes. For jerk-locked averaging, the EMG signals from the muscle in which myoclonic jerks occurred most frequently were rectified, and a trigger pulse was obtained by a pulse converter (Nihon Kohden) whenever the rectified EMG exceeded a pre-set level (conventional jerklocked averaging). Neuromagnetic fields and rectified EMG signals were averaged with respect to this EMG onset pulse. The total analysis time was 200 ms and the pre-trigger analysis time was 150 ms. The amplified signals of the SQUIDS were filtered with a bandwidth of 10-1200 Hz. The responses were digitized at 4166 Hz, and averaged on-line. EEG activities were recorded with scalp electrodes placed in accordance with the international 10-20 system using a time constant of 0.3 s and a high frequency cut off of 3000 Hz. The linked ear lobe was used as the reference. In the analysis of EEG activity preceding the myoclonus (jerk-locked averaged EEG), we used a special program. In this program, we determined the exact onset of myoclonic discharge in every single record, and EEGs and rectified EMGs were averaged with respect to this onset (Sakai et al., 1993) similarly to the method first reported by Barrett et al. (1985) for recording movement-related cortical potentials. With this method, we can reduce the amount of jitter between the actual onset of myoclonus and the trigger pulse used for averaging. The time relation between the cortical spike and myoclonus was slightly different with these two
methods (Sakai et al., 1993). The conventional method showed that the positive peak of pre-myoclonus spike preceded the onset of myoclonus by approximately the same interval as the known conduction time from cortex to muscle (Shibasaki and Kuroiwa, 1975; Chadwick et al., 1977; Shibasaki et al., 1978). However, precise analysis of latencies using the new method showed that the interval between the positive peak of pre-myoclonus spike and the onset of myoclonus was sometimes shorter than the cortical latency (Sakai et al., 1993). These results indicate that the cortical event for producing myoclonus begins to occur at the time between the onset and peak of premyoclonus spike (Sakai et al., 1993). We could use this method only for analyzing EEG activities because our MEG system has no program for off-line averaging. Somatosensory evoked magnetic fields (SEFs) following the median nerve stimulation were also recorded using the technique reported elsewhere (Uesaka et al., 1993). Isocontour field maps were calculated using a weighted least-squares approximation, and equivalent current dipoles were fitted with a least-squares method. To perform the dipole localization, a spherical volume conductor model (Sarvas, 1987) was used. We defined the recording area as a sphere which was fitted to the digitized headshape data below the sensors by a least squares method. The strength, position and orientation of one or two dipoles could be adjusted using a least-squares algorithm which optimized the extent to which the field of the theoretical sources accounted for the variance of the observed data, expressed as a correlation. In this study we adopted the localization of current dipoles as reliable only when their correlation exceeded 0.99. Magnetic resonance imaging (MRI) scans of the brain were obtained from all patients with the Siemens Magnetome machine (1.5 T). The thickness of each slice was 5 mm, with a distance of 7.5 mm between the centers of adjacent slices. Four reference points for the superimposition of MEG data on MRI were specified on the MRI scans by landmarks at two periauricular points, Cz point and the nasion. These landmarks defined the head-based coordinate system on the MRI scans, allowing the appropriate x, y and z locations obtained from the MEG data to be superimposed onto the MRI scans. Source locations were marked to the nearest slice. The method is detailed in a previous report (Yamamoto et al., 1988). According to the previous articles (Kido et al., 1980; Montemurro and Bruni, 1988), we detected the pre-, post-, and central sulci in the following way. On the MR images, the superior frontal and intraparietal sulci, both of which course antero-posteriorly, are clearly delineated. The former crosses the pre-central sulcus, the latter the post-central sulcus. The central sulcus is positioned between the preand post-central sulci. We defined the post-central gyrus as the gyrus between the central and post-central sulci. We estimated that the maximum spatial resolution of magnetoencephalogram was of the order of 3 mm (Yama-
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Fig. 1. Jerk-locked magnetic fields in a patient with familial myoclonic epilepsy (upper traces). The bottom trace is an average (n = 500) rectified EMG activity recorded from the right first dorsal interosseous muscle. The other 37 traces are average neuromagnetic activities. A biphasic magnetic field preceded the myoclonus. The interval between the first peak of pre-myoclonus magnetic field and the onset of myoclonus was 16.2 ms. The upward deflection of MEG recordings indicates an outward magnetic field. Waves forms for jerk-locked magnetic field are displayed on an array depicting the sensor detector coil geometry on the lower left. A1-A37 are the magnetometer pick-up coil locations, 20 mm apart. On every wave form, a vertical line indicates the EMG onset of myoclonus. Positive going peaks indicate magnetic fields emanating from the head, while negative peaks indicate those returning to the head. Biphasic pre-myoclonus activity was demonstrated. The center of the recording dewar, covering an area with a diameter of 144 mm, was positioned over the contralateral sensory-motor cortex (around C3 or C4 position of the international 10-20 system). An isocontour map at the first peak of pre-myoclonus magnetic field, indicated by the arrow in A23 and A7 traces (16.2 ms prior to the onset of myoclonus), is shown on the lower right. Each line represents a step of 10 fT. The shape of the contour map suggests a single current dipole positioned under the zeroline, pT, picotesla. moto et al., 1988). W e considered this resolution to be good e n o u g h for differentiating the positions of the sensory and motor cortices. Even though w e defined a part of brain (about one fourth of the cortex) as a spherical volu m e conductor instead o:f a real head shape model, our experiences that the N l n i and P l m c o m p o n e n t s of SEF were localized on the sensory cortex in all normal subjects (n = 50) also suggest that our M E G system has a good spatial resolution e n o u g h for the present investigation.
Informed consent was obtained from all the subjects. The procedures here described were approved by the Ethics Committee of the University of Tokyo. 4. Results In all the patients, jerk-locked averaging demonstrated that a biphasic magnetic field preceded the m y o c l o n u s in the hemisphere contralateral to the m u s c l e being studied. Average magnetic fields and E M G activity in a patient
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Fig. 2. Axial MRI of the brain in a patient with familial myoclonic epilepsy (case presented in Fig. 1). The estimated position of the center of the current dipole for the first peak of pre-myoclonus spike (red point) and N 1m component of giant SEF (yellow point) are superimposed on the MRI scan. They are positioned on the post-central gyrus. The MRI slice is 3.2 cm above the AC-PC line (anterior commissure-posterior commissure line) and parallel to it.
with familial myoclonic epilepsy are shown in Fig. 1 (upper). The first peak of pre-myoclonus magnetic field preceded the onset of myoclonic discharge in the first dorsal interosseous (FDI) muscle by 16.2 ms. The lower left traces of Fig. 1 show these magnetic activities displayed on an array depicting the sensor coil geometry. Dipole solutions were calculated at 0.24 ms intervals from the onset of pre-myoclonus spike to the onset of myoclonus. The correlation of the fitted dipoles exceeded 0.99 for the period of 19.4 ms and 12.2 ms prior to the onset of
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myoclonus. It was maximum at the first peak of premyoclonus spike (arrow). Positions of the estimated current dipoles did not move significantly (less than 3 mm) during this period. These results suggested that a single dipole in a single location could reasonably explain the pre-myoclonus spike during this period. An isocontour field map at the latency of the first peak of pre-myoclonus spike (lower right in Fig. 1) also suggested that the source of the first peak was well estimated as a single current dipole. The location of the single equivalent current di-
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Fig. 3. Waves of jerk-locked magnetic fields preceding the myoclonus of the forearm extensor muscle in the patient with galactosialidosis (left) reveal a biphasie pre-myoelonus activity, which has a small notch (arrow in the A24 trace) between the first and second peaks, lsocontour map (fight) for the peak of that small notch suggests the presence of two current dipoles. The dewar was placed over the sensory-motor cortex contralateral to the studied muscle similarly to Fig. 1. The upward deflection indicates an outward magnetic field.
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Fig. 4. The centers of the estimatJ~d two dipoles for the peak of the notch of pre-myoclonus spike are superimposed on the MRI of brain in the patient with galactosiaiidosis (two red points). One is positioned on the post-central gyms (the left slice), the other on the pre-central gyms (the right slice). Position of the current dipole fitted to the Nlm component of giant SEF after median nerve stimulation at the wrist is also superimposed (yellow point in the left slice). The generator of Nlm (corresponding to N20 component of giant SEP) was localized in the sensory cortex, which is consistent with the previous results (Uesaka et ai., 1993). The sensory cortex dipole for jerk-locked averaging was positioned medial to the dipole for Nlm component of SEF probably because the former corresponds to the forearm area in the sensory cortex, and the latter the hand area. The left slice is 4.2 em above the AC-PC line (anterior eommis.,;ure-posterior commissure line) and parallel to it. The right slice is 3.45 cm above the AC-PC line.
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pole was superimposed on the patient's MRI scan (red point in Fig. 2) and was located on the post-central gyms. In all the other patients with cortical reflex myoclonus, except the patient with galactosialidosis, the premyoclonus spike was similarly estimated as a single current dipole positioned on the post-central gyrus. In the patient with galactosialidosis, jerk-locked aver-
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Fig. 5. EEG activities averaged with respect to the onset of myoclonus in the left extensor carpi radials (ECR) muscle (n = 200) in the patient with EPC are shown in the upper figure. Monopolar EEG activities (reference: linked ear lobes) are presented. Myoclonus occurred in the left upper-limb muscles (first dorsal interosseous (FDI), ECR, and flexor carpi ulnaris (FCU) muscles), but not on the right. The premyoclonus EEG spike was localized on the hemisphere contralateral to the jerks. Its positive peak preceded the onset of myoclonus in the left ECR by 25.5 ms. Jerk-locked magnetic field (lower figure) also showed a biphasic pre-myoclonus field. The solid line indicates the onset of myocionus in ECR. The first peak of the magnetic field (upward arrow) preceded the onset of myoclonus by 31.6ms, and the second (downward arrow) by 15.8 ms, which was almost the same as the cortical latency of this muscle (16.6 ms) measured by magnetic cortical ~limnlation The dewar wag nlae,~a'lover the rie,ht ~en~orv-mntnr cortex
Fig. 6. The center of the current dipole for the first peak of premyoclonns spike and that for the second peak are superimposed on the MRI scan in the patient with EPC. That for the first peak is positioned on the pre-motor cortex (yellow point), and that for the second on the l~re-central gvrus (l~rimarv motor cortex) (red ~oint).
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aging demonstrated a biphasic pre-myoclonus spike (Fig. 3). A small notch (arrow in the left traces of Fig. 3) was present between the first and second peaks of the spike, suggesting that the spike consisted of more than one single dipole. In fact, single dipole fittings from the first peak to the second peak of pre-myoclonus spike showed no good correlation at any latencies. Double dipole solutions around the timing of the small notch had reliable correlations (>0.99). The isocontour field map at the latency of the peak of the notch (right traces of Fig. 3) also suggested that the pre-myoclonus spike consisted of two current dipoles. The positions of these two dipoles were superimposed on the MRI (Fig. 4). One source was estimated to be on the post-central gyms, and the other on the pre-central gyrus. In the patient with EPC, MEG studies showed that most of the spontaneous cortical spikes originated from the pre-central gyrus. Jerk-locked averaging showed a biphasic EEG spike preceding the myoclonus (upper traces of Fig. 5). The first peak of this spike preceded the onset of myoclonus in ECR by 25.5 ms, which was longer than the cortical latency of that muscle (16.6 ms). The second peak of the spike preceded the myoclonus by only 9.6 ms. The jerk-locked magnetic field also consisted of a biphasic spike (lower traces of Fig. 5). The first peak preceded the onset of myoclonus by 31.6 ms, and the second by 15.8 ms. The correlation of single dipole solution exceeded 0.99 during two periods around these two peaks (the first period, 37.4-26.1 ms prior to the onset of myoclonus; the second period, 21.3-11.2 ms prior to it), and it was at maximum at the time of the peak in both periods. The positions of dipoles did not show significant changes during each period, which indicates that these two peaks are reasonably estimated as a single fixed dipole at each position, respectively. The first peak was estimated to be produced by a current dipole positioned on the pre-motor cortex (yellow point in Fig. 6), and the second as one positioned on the primary motor cortex (red point in Fig. 6). In the jerk-locked averaged EEG wave forms (upper traces of Fig. 5), the initial negative peak of the premyoclonus spike at F4 was similar in size to its positive counterpart at P4 and it showed a phase-reversal at C4. These results indicate that this first peak is generated by a tangentially oriented dipole at around C4, which is consistent with the dipole localization for the first peak revealed by the MEG studies. In contrast, the negative peak of the second peak at P4 was much larger than its positive counterpart at F4. This suggests that the estimated dipole for the second peak is oriented not completely tangentially, but obliquely. In such a situation, although the second peak showed a phase reversal at front-central area, a real obliquely oriented dipole should be positioned more posteriorly. Actually, MEG studies analyzing only tangentially oriented components disclosed that the second peak is positioned more posteriorly than the first. These results of EEGs and MEGs are all consistent. There are
two possibilities to explain why the dipole for the second peak is oriented obliquely. One is that the primary motor cortex is oriented obliquely in this particular patient and a single dipole originated from it directed obliquely. The other is that a tangential dipole at the primary motor cortex is associated with another radial dipole at the latency of the second peak. Therefore, EEG studies showed a single obliquely oriented dipole summed up by these two dipoles, whereas MEG studies showed a single tangential dipole. Based on all the results obtained from EEG and MEG analyses, we conclude that activities in the premotor and primary motor cortices precede the myoclonus in this patient. In the 6 patients with cortical reflex myoclonus, the N l m and Plm components of giant SEF were localized on the post-central gyrus (shown in Fig. 2 in a patient with familial myoclonic epilepsy, and in Fig. 4 in the patient with galactosialidosis), which was consistent with the previous results (Uesaka et al., 1993). Those components of SEF were also estimated as dipoles positioned on the post-central gyrus in the patient with EPC. 5. Discussion
The present investigation showed 3 types of the premyoclonus spike in cortical myoclonus. (1) In the patient with EPC, activity over both pre-motor and motor cortices preceded the myoclonus. Premotor activity occurred at the first peak of pre-myoclonus spike and motor cortex activity at the second peak. These results suggest that abnormal discharges first occur in the pre-motor cortex at around the first peak of pre-myoclonus spike, then at around the second peak, activation of the primary motor cortex occurs. The finding that the second peak of the pre-myoclonus MEG spike revealed by the conventional jerk-locked averaging method preceded the myoclonus by 15.5 ms, which is almost the same as the cortical latency (16.6 ms), also supports our speculation that activation of the primary motor cortex occurs at around the second peak. This is consistent with the previous reports using the same method (Shibasaki and Kuroiwa, 1975; Chadwick et al., 1977; Shibasaki et al., 1978). The result that the interval between the second peak of pre-myoclonus spike and the onset of myoclonus (9.6 ms) was shorter than the cortical latency in the jerk-locked averaging with respect to the accurate onset of myoclonus is consistent with our previous report (Sakai et al., 1993) using the same off-line averaging method and also supports the above speculation. There are at least two possibilities to explain how these two activities produce the muscle jerks. One possibility is that the first activation of the premotor cortex induces late abnormal discharges in the primary motor cortex, which finally produce the muscle jerks. The other is that direct effects of the premotor and primary motor cortices onto the spinal motoneurons summate at the spinal level and activate the spinal motoneurons. No
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disinhibition of the sensory cortex was present in this patient (neither giant SEF nor abnormal SEP recovery (Ugawa et al., 1991)). Based on these results, we consider that abnormal discharges in the motor cortices cause the myoclonus in this patient, whatever the precise mechanisms are. Patients with EPC have several types of muscle jerks, such as very rapid irregular myoclonus (duration of EMG discharge is about 50 ms ) to clonic slow movement (duration of EMG discharge is 200-400 ms). Therefore, we do not intend to make a general conclusion from the results of a single case that all jerky movements in EPC originate from the motor cortices. However, we would like to conclude that myeclonus in this patient is produced by abnormal activation of the motor cortices. (2) In the patient with galactosialidosis, the pre-myoclonus spike was composed of two dipoles, each of which was positioned in the motor and sensory cortices. We conclude that both the motor and sensory cortices play important roles in producing the myoclonus in this patient. (3) In the other 5 patients with cortical reflex myoclonus, the pre-myoclonus spike was composed of one dipole in the sensory cortex. If there was abnormal discharge in the crown of the pre-central gyms, we could not detect such activity by MEG because only the tangentially oriented dipoles are recorded by MEG. Therefore, we cannot completely exclude some contribution of the motor cortex to the myoclonus in those patients. However, we would like to conclude that hypersynchronous discharges in the sensory cortex produce the myoclonus in these patients. There are two hypotheses to explain how the abnormally large discharges in the sensory cortex produce the myoclonus. One possibility is that direct projections from sensory cortex to spinal interneurons are activated by the spike discharge and moto, aeurons are activated by such interneurons. Alternatively, the sensory cortex may drive motor output via its connections with the precentral gyrus. In the latter case, the motor cortex would be activated by normally functioning connections, hence would not show the spike activity typical of an epileptic focus. Whatever the mechanisms, this third type is the most frequent variety of cortical reflex myoclonus (Shibasaki et al., 1991). There are several other reports about the generators of the pre-myoclonus spike, lln patients with EPC, the spike was found to originate from the motor cortex (Wieser et al., 1978; Celesia et al., 1994) or from both the motor and sensory cortices (Stiegfried and Bernoulli, 1976). In one patient with EPC who had also cortical reflex myoclonus, abnormal discharges in the post-central region produced the myoclonus (Cowan et al., 1986). We would speculate from the present results that the sensory cortex plays the most important role in producing muscle jerks in the majority of patients with cc,rtical reflex myoclonus. Such patients are also likely to have reflex muscle jerks and an enlarged SEP. However, patients who have muscle jerking in the absence of reflex involvement may be more
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likely to have spike activation in motor rather than sensory cortex. In conclusion, the spatial resolution of the MEG has shown that there are three types of cortical myoclonus: abnormal discharges responsible for the myoclonus originate from the motor cortex, the sensory cortex, or both of them. References
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