Afferent mechanism of cortical myoclonus studied by proprioception-related SEPs

Electroencephalography and clinical Neurophysiology 104 (1997) 51–59

Afferent mechanism of cortical myoclonus studied by proprioception-related SEPs Tatsuya Mima a, Kiyohito Terada a, Akio Ikeda a, Hidenao Fukuyama a, Tomoko Takigawa c, Jun Kimura b, Hiroshi Shibasaki a ,* a

Department of Brain Pathophysiology, Kyoto University School of Medicine, Shogoin, Sakyo-ku, Kyoto, 606-01, Japan b Department of Neurology, Kyoto University School of Medicine, Shogoin, Sakyo-ku, Kyoto, 606-01, Japan c Department of Neurology, Utano National Hospital, Kyoto, Japan Accepted for publication: 1 September 1996

Abstract Proprioception-related somatosensory evoked potentials (SEPs) to passive flexion movement of the middle finger at proximal interphalangeal joint were recorded in 7 patients with myoclonus of cortical origin who demonstrated enlarged electrical SEPs (giant SEPs). In 3 out of the 7 patients, the proprioception-related SEPs were also enlarged. The remaining 4 patients showed giant electrical SEPs without enhancement of proprioception-related SEPs. Long loop electromyographic response was recorded during the resting condition in all of the 3 patients with enlarged proprioception-related SEPs. We have previously reported that proprioceptionrelated SEPs are mainly generated by muscle afferent inputs, though electrical SEPs are thought to reflect mostly cutaneous inputs with some contribution from muscle afferents. Therefore, it is concluded that hyperexcitability of the sensorimotor cortex in cortical myoclonus is modality-specific. Cortical excitability is exaggerated to both cutaneous and deep receptor inputs in some patients, but only to cutaneous input in others.  1997 Elsevier Science Ireland Ltd. All rights reserved Keywords: Proprioception-related SEPs; Muscle afferent; Cortical myoclonus; Pathogenesis of giant SEPs; Hyperexcitability of sensorimotor cortex

1. Introduction It has been well known that cortical components of somatosensory evoked potentials (SEPs) to the median nerve electrical stimulation are extremely enlarged in some patients with myoclonus (Dawson, 1947; Halliday, 1967; Sutton and Mayer, 1974). These patients often show an enhanced long-loop electromyographic (EMG) reflex in response to electrical stimulation of the peripheral nerve (C reflex) (Sutton and Mayer, 1974). In addition, in most of them a pre-myoclonic cortical activity can be demonstrated by using the jerk-locked back averaging method (Shibasaki and Kuroiwa, 1975). Based on these electrophysiological findings, myoclonus of this kind is thought to be of cortical origin (cortical myoclonus) (Hallett et al.,

* Corresponding author. Tel.: +81 75 7513601; fax: +81 75 7513202.

0168-5597/97/$17.00  1997 Elsevier Science Ireland Ltd. All rights reserved PII S0921-884X(96)9608 9-0

1979; Obeso et al., 1985). In patients with cortical myoclonus, the enlarged electrical SEPs (giant SEPs) are thought to represent hyperexcitability of the sensorimotor cortex which might underlie the generation of those myoclonic jerks (Shibasaki et al., 1978; Shibasaki et al., 1985b; Shibasaki et al., 1986; Shibasaki et al., 1986; Kelly et al., 1981; Rothwell et al., 1984; Obeso et al., 1985; Obeso et al., 1986). Cortical myoclonus is elicited by various kinds of somatosensory stimuli. In some cases, cutaneous stimuli are most effective in evoking jerky involuntary movements (Sutton and Mayer, 1974; Sutton, 1975), while in others muscle stretch is an adequate stimulus to elicit the myoclonus (Dawson, 1946; Dawson, 1947; Rose´n et al., 1977). For further analysis of the modality-specificity of the cortical reflex myoclonus, cerebral evoked potentials to the so-called natural stimuli have been applied to the patients with cortical myoclonus. In the earlier pioneering studies,

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cortical responses to brisk muscle stretch or tendon tapping were reported to be enlarged in some patients with cortical myoclonus (Dawson, 1947; Rose´n et al., 1977; Hallett et al., 1979; Obeso et al., 1985). It was also reported that SEPs to mechanical (touch) stimulation were enhanced as were electrical SEPs (Kakigi and Shibasaki, 1987), but SEPs to CO2 laser stimulation (painrelated SEPs) were not enlarged at all (Kakigi et al., 1990). As is well known, primate sensorimotor cortex is so organized as to process the cutaneous and deep receptor inputs in parallel (Kaas, 1983; Mountcastle, 1984; Kaas and Pons, 1988). For better understanding of the pathogenesis of cortical myoclonus, therefore, it would be valuable to evaluate modality-specific cortical excitability. Recently, we have developed a standardized method to acquire SEPs to the brisk passive movements of the finger, which can selectively activate proprioception (proprioception-related SEPs) (Mima et al., 1996). In the present study, we applied this method to investigate the cortical excitability in patients with cortical myoclonus.

patients were accompanied by generalized convulsions and were clinically diagnosed as progressive myoclonus epilepsy (PME). Patient 1 was diagnosed as myoclonus epilepsy with ragged red fibers (MERRF) which was confirmed by mitochondrial gene analysis. The diagnosis of Lafora disease in Patient 2 was made by skin biopsy. The etiology was undetermined in the remaining 3 patients with PME. The main features of Patients 6 and 7 were non-progressive tremulous myoclonus beginning at old age without or with rare generalized seizures, which has previously been referred to as ‘cortical tremor’ (Ikeda et al., 1990; Toro et al., 1993). All patients showed postural and action myoclonus, and Patient 7 showed reflex myoclonus to the tendon tap. Some of the electrophysiological findings in Patients 1 to 3 have been reported elsewhere for other purposes (Shibasaki et al., 1994; Ikeda et al., 1995). All subjects gave informed consent for the experiments following the procedure approved by Kyoto University Ethical Committee. 2.2. Electrical SEPS

2. Materials and methods The mixed median nerve was electrically stimulated by a pair of electrodes placed 3 cm apart at the wrist with the cathode proximal to the anode. Electric square wave pulse of 0.2 ms duration was used, and the stimulus intensity was adjusted to produce weak twitching of the abductor pollicis brevis muscle. Stimulus frequency was kept constant at 1.1 Hz. Evoked responses were recorded from the scalp with 9 cup electrodes secured with collodion at 7 positions (Fz, F3, F4, C3, C4, P3 and P4) according to the International 10-20 System and two other positions (CP3 and CP4) according to the American EEG Society (Electrode Position Nomenclature Committee, 1994). The electrode impedance was kept below 5 kQ. Earlobe electrode ipsilateral to the stimuli served as the reference. Brain activ-

2.1. Subjects Subjects in the present study were 7 patients with cortical myoclonus of various etiology (Table 1). Myoclonus was judged to have possible cortical origin (cortical myoclonus) when it fulfilled at least one of the following three electrophyiological criteria; presence of enlarged cortical SEPs, enhanced long-loop reflex at rest (C-reflex), and cortical activity preceding myoclonic jerk demonstrated by jerk-locked back averaging method. In fact, all of the 7 patients showed giant SEPs to the median nerve electrical stimulation. Criteria for giant SEPs were the same as those used for the previous report (Ikeda et al., 1995). Five Table 1 Clinical profiles of 7 patients with cortical myoclonus Patient Diagnosis

Sex

Age

Onset age

Family history

Convulsions

Other symptoms

Anti-epileptic drugs (per day)

1

PME (MERRF) PME (Lafora disease) PME (Unknown)

F

28

14

Positive

Generalized

M

20

16

Positive

Generalized

Myopathy, dementia, cerebellar ataxia Dementia

M

35

12

None

Generalized

Myopathy, cerebellar ataxia

F

21

3

None

Generalized

None

M

45

15

None

Generalized

Cerebellar ataxia

6

PME (Unknown) PME (Unknown) CT

VPA; 1200 mg, CZP; 5 mg, DZP; 10 mg VPA; 1000 mg, CZP; 3 mg VPA; 3200 mg, CZP; 12 mg, DZP; 5 mg, CBZ; 200 mg, piracetam; 18g CZP; 5 mg, piracetam; 15g

F

58

50

None

None

None

7

CT

M

68

48

Positive

None

None

2 3

4 5

PB; 120 mg, VPA; 1400 mg, CZP; 4.5 mg, piracetam; 15g VPA; 3000 mg, ZSM; 400 mg, CZP; 4 mg None

*Abbreviations: F, female; M, male; PME, progressive myoclonus epilepsy; MERRF, myoclonus epilepsy with ragged red fibers; CT, cortical tremor; VPA, valproic acid; CBZ, carbamazepine; DZP, diazepam; CZP, clonazepam; PB, phenobarbital; ZSM, zonisamide.

T. Mima et al. / Electroencephalography and clinical Neurophysiology 104 (1997) 51–59

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Fig. 1. Electrical SEPs and proprioception-related SEPs in Patient 6. For the latter, the joint displacement is demonstrated as a horizontal thick bar in this and all other figures. All EEG records are in reference to the earlobe electrode ipsilateral to the stimulus, and upward deflection indicates relative negativity in grid 1 with respect to grid 2 in this and all other figures. P25, P30, N30, and N35 components of electrical SEPs are enlarged. P1, N1 and P2 components of proprioception-related SEPs are enlarged. Both SEPs are accompanied by long latency reflex in the left extensor carpi radialis (ECR) muscle. Two vertical dotted lines in both SEPs indicate the initial positive peak of cortical response and the onset of the reflex EMG activities, respectively.

ities were amplified and filtered by the bandpass of 1.6– 1500 Hz. The sampling rate was 5800 Hz for each channel. EEG signals were averaged with respect to the stimulus onset by an on-line system (Pathfinder II MEGA, Nicolet, Japan). The time window for the analysis was set from 9 ms before to 81 ms after the stimulus. Responses exceeding 180 mV in any channel were automatically rejected as including artifacts. The experiment was composed of two sessions, each consisting of 200 stimuli. 2.3. Proprioception-related SEPS Proprioception-related SEPs to the passive finger movement were recorded following the electrical SEP recording under the same condition. In order to exclude the possible effect of habituation to the somatosensory stimulus, the actual recording started after about 30 min rest. The upper limb which demonstrated larger electrical SEPs for each patient was selected for the recording. A specially devised equipment utilizing a servo motor system was used in the present study (MySystems Inc., Yamaguchi, Japan). The methods to activate pure proprioception have been described in detail elsewhere (Mima et al., 1996). The stimulus was a brisk passive flexion movement (4° in 25 ms) of the proximal interphalangeal (PIP) joint of the middle finger occurring every 860 ms. To minimize the effect of additional mechanical stimuli other than proprioception, the middle and distal phalanges of the middle

finger were tightly held in an individually molded plastic cap. The hand was immobilized by a strap with the forearm slightly supinated. The subjects were instructed to relax the hand and forearm completely during the recording. The subject kept the eyes open, while the movable part of the machine was placed out of sight to avoid the visual stimulus. The placement of the recording electrodes and the online averaging system were the same as those used for the electrical SEPs. EEG signals were filtered by the bandpass of 0.5–500 Hz, and the sampling rate was 2500 Hz for each channel. Analysis window was 100 ms including the pretrigger time of 9 ms. In each experiment, at least two sessions of 600–1200 stimuli each were separately averaged. 2.4. Long loop reflex The long loop EMG reflex was recorded simultaneously with the recording of both the electrical and proprioception-related SEPs while the hand was kept at rest. The surface EMG signals were bipolarly recorded by a pair of cup electrodes placed 3 cm apart over each of the forearm extensor and flexor muscles (extensor carpi radialis and flexor carpi radialis) bilaterally, and were filtered with the bandpass of 20–1500 Hz and rectified. Subjects were instructed to totally relax the forearm and hand muscles during the recording, which was confirmed by the surface EMG.

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Fig. 2. Electrical SEPs and proprioception-related SEPs in Patient 7. P25, P30, N30 and N35 components of electrical SEPs are enlarged. In proprioception-related SEPs, an additional negative potential between P1 and P2 was recognized at C3 (indicated by the asterisk), and P2 component of proprioception-related SEPs is enlarged. Both SEPs are accompanied by long latency reflex in the right extensor carpi radialis (ECR) muscle. Two vertical dotted lines in both SEPs indicate the initial positive peak of cortical response and the onset of the reflex EMG activities, respectively.

2.5. Data analysis The latency and amplitude of each recognizable peak as judged by visual inspection were measured by a computer cursor. In the electrical SEPs, the amplitude was measured from the preceding peak of opposite polarity. Terminology for the peaks of the electrical SEPs was according to the previous studies (Allison et al., 1989; Allison et al., 1991; Ikeda et al., 1995). N20 and P30 were measured at the contralateral parietal area (P3 or P4), P25 and N35 at the contralateral central area (C3 or C4), and P20 and N30 at the contralateral frontal area (F3 or F4). The upper limits of the normal range for the amplitude of electrical SEPs were set to the logarithmic mean value ± 3 S.D. obtained from normal subjects in our laboratory by using exactly the same method. The upper limits were 7.6 mV for N20, 5.9 mV for P20, 6.3 mV for P25, 9.5 mV for P30, 8.8 mV for N30 and 9.8 mV for N35 (Ikeda et al., 1995). Table 2 Relationship between SEPs and long loop EMG reflex in 5 patients with cortical myoclonus in whom the long loop reflex was recorded Patient Electrical stimulus

Passive movement

P25 (ms)

LLR (ms)

P25-LLR (ms)

P1 (ms)

LLR (ms)

P1-LLR (ms)

1 2

21.6 23.9

32.4 —

10.8 —

31.2 39.6

3 6 7

24.0 22.5 24.3

35.6 33.7 35.6

11.6 11.2 11.3

42.8 31.2 32.8

— (29.2) 47.6 — 40.8 41.6

— — 8.0 — 9.6 8.8

In the proprioception-related SEPs, the amplitude was calculated from the baseline which was determined by averaging the 9 ms segment of the analysis time window just before the stimulus onset. Terminology for the peaks of proprioception-related SEPs followed the one used in our studies of normal subjects reported elsewhere (Mima et al., 1996). P1 was identified at the contralateral central area (C3 or C4), N1 at the midfrontal area (Fz), P2 at the contralateral centroparietal area (CP3 or CP4) and N2 at the contralateral central area (C3 or C4). The upper limits of the amplitude of proprioception-related SEPs were the mean value ± 3 S.D. obtained from the normal subjects (Mima et al., 1996). The upper limits were 1.4 mV for P1, −2.0 mV for N1, and 2.8 mV for P2. 3. Results 3.1. Electrical stimulation In all of the 7 patients, 4 early cortical components of electrical SEPs were identified (N20-P20, P25, P30-N30 and N35—mean peak latencies: N20: 20.3 ms; P20: 21.0 ms; P25: 23.6 ms; P30: 28.0 ms; N30: 29.6 ms; N35: 38.4 ms). The amplitude of N20 and P20 was within normal range in all subjects (N20: 1.4–6.7 mV, mean: 3.2 mV; P20: 1.8–5.8 mV; mean: 3.3 mV). Amplitude of P25 was enlarged in 4 patients (Patients 3, 5, 6 and 7 (Fig. 1, Fig. 2)) (2.9–22.7 mV, mean: 9.8 mV). Amplitude of P30 was enlarged in 3 patients (Patients 1, 6 and 7 (Fig. 1, Fig. 2, Fig. 3)), and that of N30 in 4 patients (Patients 2, 4, 6 and 7 (Fig. 1, Fig. 2, Fig. 4)) (P30: 5.9–28.3 mV, mean: 12.2 mV; and N30: 6.1–24.7 mV, mean: 11.0 mV). Amplitude of N35

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Fig. 3. Electrical SEPs and proprioception-related SEPs in Patient 1. P30 and N35 components of the electrical SEPs are enlarged, but the proprioceptionrelated SEPs are not enlarged.

was enhanced in 4 patients (Patients 1, 2, 6 and 7 (Figs. 1– 4) (6.0–50.5 mV, mean: 19.7 mV). Enhanced long loop EMG reflex was observed from the forearm muscles (extensor carpi radialis and/or flexor carpi radialis) on the stimulated side in 4 patients (Fig. 1, Fig. 2; Patients 1, 3, 6 and 7). The onset latency of the rectified EMG response was 32.4–35.6 ms (mean: 34.3 ms) (Table 2). 3.2. Proprioceptive stimulation In all of the 7 patients, waveforms of the cortical responses to passive movements of the middle finger were similar to those seen in normal subjects, though some patients demonstrated slightly different waveform. Three patients showed significantly enlarged evoked

potentials to the passive movements (Patients 2, 6 and 7). The amplitude and latency of the components of proprioception-related SEPs are summarized in Table 3. The initial cortical component of the proprioceptionrelated SEPs was a positive peak at the contralateral central area, which was defined as P1. P1 was clearly identified in 5 patients with the mean peak latency of 35.5 ms (31.2–42.8 ms). Only one patient with cortical tremor (Patient 6) showed a significantly enlarged P1 (Fig. 1). A negative deflexion maximally seen at the midfrontal region (N1) was identified in all 7 patients with the mean peak latency of 46.4 ms (34.4–62.8 ms). In Patients 2 and 6, the amplitude of N1 was significantly enlarged (Fig. 1, Fig. 4). In one patient with cortical tremor (Patient 7), an additional negative peak at the contralateral central area was demonstrated (latency; 48 ms, amplitude; −3.7 mV),

Table 3 Amplitude and latency of proprioception-related SEPs in 7 patients with cortical myoclonus Patient (side)

1 (R) 2 (L) 3 (R) 4 (L) 5 (R) 6 (L) 7 (R) Normal upper limit (n = 10)b

Amplitudea (mV)

Latency (ms)

P1

N1

P2

P1

N1

P2

0.27 0.22 1.1 — — 5.4 1.3 1.4

−0.93 −3.7 −0.62 −0.74 −0.11 −3.1 −0.18 −2.0

1.1 1.5 1.1 1.7 1.3 4.1 3.5 2.8

31.2 39.6 42.8 — — 31.2 32.8 —

34.4 45.6 62.8 48.0 50.0 49.6 34.4 —

38.8 46.4 56.8 33.2 58.8 47.6 61.6 —

Amplitudes in italic show mean + 3 S.D. of normal values or larger. Measured from the baseline. Mima et al. (1996).

a

b

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Fig. 4. Electrical SEPs and proprioception-related SEPs in Patient 2. N30 and N35 components of electrical SEPs are enlarged. N1 of proprioceptionrelated SEPs is enlarged, which is accompanied by double-peaked long latency reflex in the left extensor carpi radialis (ECR) muscle. Two vertical dotted lines indicate the initial positive peak (P1) of cortical response and the onset of the second peak of the reflex EMG activities, respectively.

which has never been observed in normal subjects (Fig. 2). Its peak latency was longer than that of N1. A positive peak (P2) at the contralateral centroparietal region was identified in all subjects with the mean peak latency of 49.0 ms (33.2–61.2 ms). P2 was significantly enlarged in Patients 6 and 7 (Fig. 1, Fig. 2). In Patient 7, P2 was identified as a small notch at the contralateral centroparietal region, which was followed by a larger positive deflexion which has never been observed in the record of normal subjects (Fig. 2). In Patients 1, 2 and 7, a negative peak at the contralateral central area following the peak of P2 was identified (Patient 1 — peak latency: 46.4 ms, amplitude: −1.6 mV; Patient 2 — 61.6 ms, −6.2 mV; Patient 7 — 78.0 ms, −7.4 mV) (Fig. 2, Fig. 3 Fig. 4). As this negative activity (N2) was observed only in one third of normal subjects (Mima et al., 1996), further statistical evaluation of that peak was not performed. However, the amplitude of N2 in these patients is probably enlarged as compared with the mean amplitude of −0.20 mV in normal subjects. Reflex EMG activities to the passive movement of the middle finger were recorded from the forearm on the stimulated side muscles in 3 patients who showed enhanced proprioception-related SEPs (Patients 2, 6 and 7) (Figs. 1,2,4, Table 2). This long latency EMG response was not observed in any of the remaining patients whose proprioception-related SEPs were within the normal range in amplitude. The onset latency of the EMG response was 40.8 ms in Patient 6 (Fig. 1) and 41.6 ms in Patient 7 (Fig. 2). In Patient 2, two-peaked reflex EMG response was observed with the onset latency of the first and the second

component being 29.2 ms and 47.6 ms, respectively (Fig. 4). 4. Discussion General features of giant SEPs in the present patients with cortical myoclonus are consistent with those reported in our previous study (Ikeda et al., 1995). All of those 4 components (N20-P20, P25, N30-P30, and N35) of electrical SEPs were clearly identified in the present patients, and at least one of those components was significantly enlarged in each patient. In 3 patients of the present series, at least one of the components of the proprioception-related SEPs to the passive flexion of the middle finger (P1, N1 and/or P2) was significantly enhanced (Table 3). In Patient 7, there was an additional negativity at the contralateral central area immediately following N1 (Fig. 2). If one supposes that the cortical generator mechanism of evoked responses in cortical myoclonus is similar to that of normal subjects, the present findings suggest that N1 might reflect the compound response of the multiple cortical generators, one of which was pathologically enlarged in Patient 7. In addition, only the N2 peak was enlarged in Patient 1. However, since the amplitude of N2 was so variable in normal subjects (Mima et al., 1996), it was difficult to determine the significance of N2 enhancement. Pathogenesis of the giant electrical SEPs is thought to be related to the dysfunction of a cortical inhibitory mechanism (Shibasaki et al., 1978; Shibasaki et al., 1985a; Shibasaki et al., 1985b; Shibasaki et al., 1986;

T. Mima et al. / Electroencephalography and clinical Neurophysiology 104 (1997) 51–59

Shibasaki, 1988; Hallett et al., 1979; Rothwell et al., 1984; Obeso et al., 1985). Thus, it is reasonable to also note the enlarged proprioception-related SEPs in patients with giant electrical SEPs. However, the fact that the proprioception-related SEPs were not enlarged in 4 patients who showed giant electrical SEPs suggests that the pathological dysfunction in patients with cortical myoclonus may be modality-specific. Afferent mechanisms of the electrical SEPs and the proprioception-related SEPs are different. It is generally accepted that the most of the electrical SEPs is transmitted through the cutaneous nerves, though the muscle afferent input also contributes to the generation of SEPs to some extent (Burke et al., 1981; Burke et al., 1982; Gandevia et al., 1982; Gandevia et al., 1984; Burke and Gandevia, 1988; Gandevia and Burke, 1988; Halonen et al., 1988; Macefield et al., 1989; Gandevia and Burke, 1990; Allison et al., 1991; Peterson et al., 1995). In contrast, as we have demonstrated, the main part of the proprioception-related SEPs is caused by the muscle afferent input. The proprioception-related SEPs actually persisted in spite of the abolition of the tactile and joint afferents caused by ischemic anesthesia of the middle finger (Mima et al., 1996). Anatomical studies have demonstrated different cortical representations of the cutaneous receptors and the deep receptors (Kaas, 1983; Mountcastle, 1984; Kaas and Pons, 1988). Areas 3b and 1 mainly receive input from the former, whereas areas 3a and 2 from the latter. It is suggested that cortical disinhibition might occur selectively to each part of the primary somatosensory area and that the patients with cortical myoclonus can be divided into two subgroups according to the results of the present study. Namely, the responses to both the cutaneous and muscle afferent input are enlarged in some patients, while in others only the evoked potentials to the cutaneous stimuli are enhanced. The concern is whether the existence of enlarged proprioception-related SEPs is directly related to the pathogenesis of cortical myoclonus or not. All three patients who showed giant proprioception-related SEPs demonstrated exaggerated EMG responses to the passive movement at rest, which was not observed in other patients who had the proprioception-related SEPs of normal amplitude. Among those 3 patients, two patients with cortical tremor demonstrated the enhanced long latency reflex (LLR) to the passive finger movement (Fig. 1, Fig. 2). In these two patients, LLR (M2) was recorded at rest without any preceding short latency reflex (M1). In Patient 2 (Lafora disease), EMG responses to the passive movement were twopeaked: the first peak starting at 29.2 ms, which is consistent with the short latency monosynaptic spinal reflex (Fig. 4). The onset of the second peak of the rectified EMG was 47.6 ms, which corresponds to LLR (M2) observed during voluntary contraction of the muscle in normal subjects (Marsden et al., 1972; Marsden et al., 1976; Lee and Tatton, 1975; Lee and Tatton, 1978; Tatton et al., 1975; Marsden et al., 1977; Stanley, 1978). Enhanced LLR to

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electrical pulse seen in patients with cortical myoclonus is thought to be mediated by the sensorimotor cortex (C reflex), because the latency difference between the initial positive peak (P25) of electric SEPs and the LLR onset is similar to the conduction time of the impulse from the cortex to the forearm muscles (Sutton and Mayer, 1974; Sutton, 1975; Shibasaki et al., 1978; Shibasaki et al., 1985b; Hallett et al., 1979). However, studies using transcranial magnetic stimulation demonstrated that the central conduction time is slightly longer than the P25-LLR time interval (Sakai et al., 1993). It has not yet been clarified whether LLR (M2) is entirely a transcortical reflex or not (Marsden et al., 1973; Tatton et al., 1975; Wiesendanger and Miles, 1982). Concerning the LLR to the passive movements, the latency difference between the initial positive peak (P1) of the SEPs and the onset of LLR is similar to, but slightly shorter than, the corresponding latency difference in response to the electrical pulse (Table 2). One of the possible explanations for the shorter latency difference for the passive movement is a longer duration of the stimulus (25 ms). Thus, the peak of P1 may not exactly reflect the arrival time of the afferent impulse at the cortex, though we can assume that the onset of LLR corresponds to the responses to the earliest part of the flexion stimulus. Therefore, it is possible that LLR to the passive movement in the present study is also the transcortical reflex just like that to the electrical stimulus. In the present study reflex myoclonus to tendon tap was clinically observed in Patient 7, but other patients did not show prominent reflex myoclonus, possibly due to the effect of successful medical treatment. It is feasible that the enhanced LLR to the passive flexion movement corresponds to the reflex myoclonus itself. Therefore, it is concluded that the enlargement of the cortical responses to the passive movements with enhanced LLR is strongly related to the generator mechanisms of cortical myoclonus. Acknowledgements This study was partly supported by Grants-in-Aid for Scientific Research 06404031, Priority Scientific Research 06260225 and International Scientific Research 07044258 from the Japan Ministry of Education, Science and Culture to H.S. The authors wish to thank Dr. Kyoko Saida, Utano National Hospital for referring her patient to us. References Allison, T., McCarthy, G., Wood, C.C., Darcey, T.M., Spencer, D.D. and Williamson, P.D. Human cortical potentials evoked by stimulation of the median nerve. I. Cytoarchitectonic areas generating short-latency activity. J. Neurophysiol., 1989, 62: 694–710. Allison, T., McCarthy, G., Wood, C.C. and Jones, S.J. Potentials evoked in human and monkey cerebral cortex by stimulation of the median nerve. Brain, 1991, 114: 2465–2503. Burke, D. and Gandevia, S.C. Interfering cutaneous stimulation and the muscle afferent contribution to cortical potentials. Electroenceph. clin. Neurophysiol., 1988, 70: 118–125.

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