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Effect of electrical stimulation of the thalamic Vim nucleus on hand tremor during stereotactic thalamotomy
Electroencephalography and clinical Neurophysiology 109 (1998) 376–384
Effect of electrical stimulation of the thalamic Vim nucleus on hand tremor during stereotactic thalamotomy A. Takahashi*, K. Watanabe, K. Satake, M. Hirato, C. Ohye Department of Neurosurgery, Gunma University School of Medicine, 3-39-22 Showa-Machi, Maebashi, Gunma, 371, Japan Accepted for publication: 15 May 1998
Abstract Objective: The aim of this study was to analyze the correlation between neuronal responses in the thalamic ventralis intermedius (Vim) nucleus to peripheral, natural stimulation and the modulation of tremor by electrical stimulation during stereotactic thalamotomy. Design and methods: The authors studied 36 patients with hand tremor using a microelectrode. The responses of tremor to electrical stimulation were analysed electromyographically. Sixty stimulation sites were divided into three groups. Results: Group A (20 sites) where responses to stretching of the contralateral forearm muscles were recorded. Group B (26 sites) where responses to stretching of the other muscles of the upper extremity were recorded. Electrical stimulation at sites in groups A and B temporarily suppressed the contralateral tremor, but the minimum current intensity to suppress tremor at sites in group A was less than that in group B. Electrical stimulation in group C (14 sites), where kinesthetic responses of contralateral lower extremity were recorded, resulted in increased amplitude of hand tremor. Selective coagulation including the area of tremor suppression resulted in abolition of the tremor in all patients. Conclusions: These results suggest that the most effective site for thalamotomy may also be suitable for chronic stimulation in the Vim nucleus. 1998 Elsevier Science Ireland Ltd. All rights reserved Keywords: Stereotactic surgery; Acute electrical stimulation; Intractable tremor; Microrecording
1. Introduction Correlation of extracellular recordings and electrical stimulation in the thalamic ventralis intermedius (Vim) nucleus and its surrounding structures using microelectrode techniques during the course of stereotactic thalamotomy for parkinsonian and non-parkinsonian tremor have revealed the presence of numerous, highly organized kinesthetic neurons in the lateral part of the Vim nucleus (Ohye and Narabayashi, 1979; Ohye, 1982, 1988; Raeva, 1986; Ohye et al., 1989). Selective coagulation including this area can achieve stable and constant arrest of tremor. Therefore, the lateral part of the thalamic Vim nucleus is considered to be the best therapeutic target for various types of intractable tremor. Acute electrical stimulation of the thalamic Vim nucleus also suppresses tremor transiently during stereotactic thala* Corresponding author. Tel.: +81 27 2207111; fax: +81 27 2336300.
0924-980X/98/$19.00 1998 Elsevier Science Ireland Ltd. All rights reserved PII S0924-980X (98)0003 4-4
motomy (Ohye and Narabayashi, 1979; Ohye, 1988; Benabid et al., 1993). Recently, chronic Vim stimulation using an implanted electrode for intractable tremor has become an alternative to Vim thalamotomy (Benabid et al., 1991, 1993, 1996; Nguyen and Degos, 1993; Deiber et al., 199). Site of implantation is usually determined by the results of acute electrical stimulation and recording (Benabid et al., 1993, 1996). However, acute stimulation of the thalamus may increase tremor amplitude depending on the stimulated site and parameters (Ohye et al., 1964; Alberts et al., 1966; Ohye and Narabayashi, 1979; Benabid et al., 1993). The most effective site for electrical stimulation to achieve the suppression of tremor and its mechanisms is still unclear (Lenz et al., 1988; Benabid et al., 1996). Therefore. the most effective site in the Vim nucleus for electrical stimulation may be different to that for Vim thalamotomy. The present study analyzed the correlation between responses in the Vim nucleus to peripheral, natural stimulation and the modulation of tremor by electrical stimulation
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Fig. 1. Diagram showing the profile of the trajectory in a case of a 60-yearold parkinsonian female (T.S. 60F PA). The profile of the trajectory was made by reference to the posterior commissure (PC) and the intercommissural line (horizontal line) on the corresponding plate from the standard atlas (16 mm lateral from the midline). Arrows indicate points where microrecording and electrical stimulation were performed. Electrically integrated values (arbitrary units) of the background activity at several points along trajectory are plotted and drawn on the bar and line graph.
of the same Vim point using electromyography (EMG) recordings.
2. Subjects and methods Thirty-six patients with drug-resistant hand tremor, 29 with Parkinson"s disease and 7 with essential tremor, were treated surgically after giving informed consent. EMG confirmed the presence of abnormal grouped discharges in the forearm flexor muscles and extensor muscles before the operation. Patients underwent surgery in the supine position under local anesthesia. A Leksell stereotactic frame was fixed and a burr hole was opened over the frontal region, the precise location of which was predetermined by our method of stereotactic magnetic resonance (MR) imaging (Kawashima et al., 1992). The anterior and posterior commissures were determined by ventriculography. To guide the recording
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electrode to the Vim nucleus, the tentative zero point was set on the level of the intercommissural line, 5 mm anterior to the posterior commissure and 16–17 mm lateral to the midline. For operative purpose, this trajectory toward zero point was used for orientation of the posterior recording electrode set with 3 mm interval as shown in Fig. 1 (also in Figs. 5 and 7A) (Ohye et al., 1989, 1990, 1993). Kinesthetic neurons are usually concentrated 1–2 mm medial to the internal capsule, so preoperative determination of the lateral border of the thalamus on stereotactic MR images is essential. Criteria for the identification of the Vim nucleus were as described previously (Ohye et al., 1989). In brief, the Vim nucleus was identified by high background activity with large spike discharge and an irregular oscillation in the thalamic ventral lateral region, and the presence of kinesthetic neurons or tremor-time locked rhythmic discharge. Tactile units which usually appear at the end of trajectory were excluded. The recording electrode was bipolar concentric type (steel-steel) with an outer diameter of 0.3 mm, interpolar distance of 0.3–0.5 mm and electrical resistance of about 100 kQ. This electrode could also be used for bipolar electrical stimulation simply by changing the line from the amplifier to the stimulator. Therefore, electrical stimulation was performed at exactly the same point where single-unit or clearly distinguishable multi-unit responses to a passive or active movement of a contralateral joint were obtained in the thalamic Vim nucleus. Stimuli were square pulses of 1 ms, 0.01–1 mA, at 100 Hz for 1 s. Electrical thalamic stimulation was performed at 86 sites where kinesthetic responses to peripheral natural stimulation were recorded extracellularly using the microelectrode technique. Among them, the 60 sites where electrical stimulation induced change in tremor were analyzed to investigate the correlation between responses to peripheral natural stimulation and effects on hand tremor by electrical stimulation. Responses to electrical stimulation were analyzed by visual inspection and by changes of tremor detected by EMG in the contralateral upper extremity. Minimum current intensity to modulate tremor was determined at each stimulated site. We also asked the patient what was felt during stimulation. Stimulated sites in this study were divided into three groups according to the somatotopic representation of the Vim nucleus (Table 1). Group A consisted of 20 sites where responses to stretching of the contralateral forearm flexor or extensor were recorded from 19 patients. Group B consisted of 26 sites where responses to stretching of the
Table 1 Classification of thalamic sites where electrical stimulation was performed and their electrophysiological properties
Group A Group B Group C
No. of sites
Kinesthetic response
Threshold to suppress tremor (mA, mean ± SD)
Distance from tentative target point (mm, mean ± SD)
20 26 14
Flexor/extensor Upper limb muscles except flexor and extensor Lower limb muscles
0.098 ± 0.064 0.165 ± 0.118 –
2442.11 ± 1636 3942.31 ± 1849.58 6346.15 ± 3049.76
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Fig. 2. Neuronal responses at 4500 mm from tentative target point shown in Fig. 1. Emissions of spikes are visible on the thalamic recording (upper trace) and on the lower trace where the impulses represent spikes of greater amplitude which responded to passive abduction of the contralateral shoulder joint as indicated by arrows. This thalamic site was classified as group B.
other muscles of the upper extremity were recorded from 23 patients. Group C consisted of 14 sites where kinesthetic responses of the contralateral lower extremity were recorded from 11 patients. In each group, the effects of electrical stimulation were reviewed in detail. Furthermore, to evaluate the influence of continuous electrical stimulation on voluntary action, continuous electrical stimulation (10–20 s) at the site where electrical stimulation for 1 s suppressed tremor was performed in 7 patients in group A during voluntary flexion-extension or grasping of the contralateral upper extremities.
3. Results Figs. 1–4 show typical examples of group A and group B observed at two different thalamic depths respectively in a 60-year-old patient with parkinsonian tremor. Fig. 1 shows two thalamic sites where kinesthetic neurons were recorded and then stimulated in presumed Vim nucleus, characterised by high background activity. Kinesthetic responses recorded at 4500 mm and 1000 mm from tentative target point are shown in Fig. 2 (group B) and Fig. 3 (group A), respectively. Fig. 4 shows the suppressive
Fig. 3. On-off responses of kinesthetic neurons to stretch forearm extensor muscle (arrows) recorded at 1000 mm from the tentative target point shown in Fig. 1. This thalamic site was classified as group A.
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Fig. 4. Electromyograms (EMGs) from the upper extremities recorded during electrical stimulation at two different thalamic depths in the same patient as in Fig. 1. The bar under each electromyographic trace indicates the time of electrical stimulation. Numbers beneath the bar show the current intensity of electrical stimulation. (A) EMGs recorded during electrical stimulation at 4500 mm from the tentative target point. Note the transient increase followed by decrease of the tremor amplitude and frequency. (B) EMGs recorded during electrical stimulation at 1000 mm from the tentative target point. Latency from the onset of stimulation to decreased tremor amplitude in the forearm extensor muscles was shorter than that in the antagonistic muscles. flex., forearm flexor muscles; ext., forearm extensor muscles.
effect on hand tremor by electrical stimulation at each thalamic sites. Electrical stimulation suppressed hand tremor most effectively in group A (N = 20). The minimum current intensity to suppress tremor was 0.098 ± 0.064 mA (mean ± SD). Transient tremor suppression was observed by visual inspection with stimulus currents as low as 0.1 mA. EMG showed the latency from the onset of stimulation to decreased tremor amplitude was shorter in the corresponding muscle (forearm flexor or extensor) eliciting kinesthetic responses at the thalamic site than that of other muscles and grouped discharges were decreased immediately (Fig. 4B). Transient increase of amplitude and frequency followed by decreased amplitude was usually seen in the antagonistic muscles. Decrease of grouped discharges in both agonistic and antagonistic muscles occurred temporarily at higher current intensity but tremor reappeared at once. No patient felt any sensory response (paresthesia or electric-like sensa-
tion around the contralateral receptive field) at threshold current intensities that suppressed tremor. Electrical stimulation was less effective in suppressing hand tremor in group B (N = 26) than in group A, although tremor was suppressed to some extent. Electrical stimulation with currents of around 0.1 mA could not induce marked decrease on EMG. The EMG patterns were similar to those of antagonistic muscles in group A. The frequency of grouped discharges during stimulation became higher than before stimulation. The amplitude showed a transient increase at the onset of stimulation (Fig. 4A). Complete arrest of tremor could be obtained at higher currents than those required in group A, but patients often complained of paresthesia in the peripheral receptive field and jerky movements of the extremity. These phenomena could be interpreted as the result of current spreading to the surrounding structures. Threshold current to suppress hand tremor in group B (0.165 ± 0.118
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Fig. 5. Diagram showing the profile of the trajectory in the case of a 48year-old female with essential tremor (F.Y. 48F Ess. T). The arrow indicates the point where microrecording and electrical stimulation were performed.
mA, mean ± SD) was significantly higher than that in group A (P , 0.05, z test). Electrical stimulation could not suppress hand tremor in group C (N = 14). Increased frequency and/or amplitude were often observed by both EMG and visual inspection. Fig. 5 shows the trajectory and a stimulated site in a patient with essential tremor. Fig. 6 shows responses of kinesthetic neurons to ankle joint movement and the tremor-driving effect by electrical stimulation in the same patient as Fig. 5. This effect on EMG continued during and after stimulation. The threshold current to increase tremor was higher than that of tremor suppression (0.33 ± 0.08 mA). In one patient who also had foot tremor, suppression of tremor amplitude was observed in the corresponding lower extremity muscle as in groups A and B. Continuous electrical stimulation was performed in 7 patients at sites in group A, at which transient electrical stimulation had suppressed hand tremor. Fig. 7A shows the trajectory and an stimulated site in a patient with parkinsonian tremor. In this site, kinesthetic neurons responded to stretch forearm flexor muscles were recorded (Fig. 7B). Fig. 8A shows transient suppression of hand tremor on EMG in the same patient as Fig. 7. Fig. 8B–E shows EMGs under continuous electrical stimulation (about 20 s) at the same site as Fig. 8A. The duration required to maintain suppression of hand tremor depended on the current intensity of electrical stimulation. Higher currents were needed to achieve complete arrest of tremor for 10–20 s (0.12 ± 0.06 mA, N = 11). Continuous stimulation (20 s) of the minimum current intensity to obtain complete suppression of tremor had no influence on voluntary movement of the contralateral arm in all patients. In fact patients often
considered that voluntary movement of the contralateral extremities was smoother than before stimulation. The EMG pattern of voluntary grasping did not change before and after continuous stimulation (Fig. 8E). Only one patient described transient paresthesia in the peripheral receptive field, which disappeared within a few seconds, at the onset of stimulation. In the same patient as shown in Figs. 7 and 8, rhythmic grouped discharges time-locked with the spontaneous tremor in the contralateral hand were observed at the deeper site (400 mm from tentative target point). As kinesthetic neurons responded to stretch forearm flexors had been recorded in the same thalamic depth, this site was classified as group A. In this occasion, simultaneous EMG and Vim recording showed that thalamic rhythmic grouped discharges of kinesthetic neurons followed the EMG activity to stretch the corresponding muscle, which was indicated by the contraction phase of the antagonistic muscles on EMG (Fig. 9A). Electrical stimulation at this site suppressed tremor effectively (Fig. 9B). Fig. 10 illustrates all stimulated sites referred to the posterior commissure and the intercommissural line on the sagittal plane. Tremor-suppression sites (group A and
Fig. 6. Neuronal recording and EMGs recorded from the same patient as in Fig. 5. (A) Responses to passive dorsiflexion of the ankle joint (arrows) recorded at 6000 mm from the tentative target point. This thalamic site was classified as group C. (B) EMGs from the upper extremities recorded during electrical stimulation performed at 6000 mm from the tentative target point. Electrical stimulation increased tremor amplitude in this case. The bar under the electromyographic trace indicates the time of electrical stimulation. Number beneath the bar shows the current intensity of electrical stimulation.
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1988, 1993). A recent study of chronic electrical stimulation of the Vim nucleus also included little coverage of this area (Benabid et al., 1996). Therefore, this is the first study of the correlation between microrecording of the kinesthetic neurons and the effects of electrical stimulation on tremor. The current intensity of electrical stimulation required to modulate hand tremor (around 0.1 mA) was low, so that the area involved by the electrical stimulation was restricted to the Vim nucleus. Especially in the hand area, the Vc nucleus was not involved judging from the threshold current to elicit sensory motor response. Electrical stimulation of about 0.1 mA is the suprathreshold level of the Vc nucleus to elicit sensory response (Lenz et al., 1988), so involvement of the Vc nucleus may produce strong paresthesia in the peripheral
Fig. 7. (A) Diagram showing the profile of the trajectory in a case of 57year-old parkinsonian female (K.S. 57F PA). The arrow indicates the point where microrecording and electrical stimulation were performed at 2400 mm from the tentative target point. (B) Neuronal recording at 2400 mm from the tentative target point in the same patient. Emissions of spikes are visible on the recording and the trace where the impulses represent spikes of greater amplitude which discharged at the end stage of stretching of the contralateral forearm flexor indicated by mechanical movement of the electromyographic trace. This thalamic site was classified as group A.
group B) were distributed in a relatively wide area of the Vim nucleus. The distances from the tentative zero point to sites in group C along the trajectory were longer than those in group A and group B. The trajectory of the electrode was inclined laterally 2–10 degrees from the midsagittal plane, so tremor-driving sites (group C) were located dorsolaterally to tremor-suppressing sites. After electrophysiological exploration, selective coagulation including the thalamic points where electrical stimulation suppressed tremor and kinesthetic neurons related to tremor were recorded resulted in complete abolition of the tremor in all patients.
4. Discussion Few studies have investigated the correlation between extracellular recordings and electrical stimulation in the thalamic Vim nucleus, compared to the numerous studies of the thalamic ventralis caudalis (Vc) nucleus (Lenz et al.,
Fig. 8. EMGs from the upper extremities recorded during electrical stimulation at 2400 mm from the tentative target point in the same patient as shown in Fig. 7. The bar under the electromyographic trace indicates the time of electrical stimulation. (A) EMGs during electrical stimulation for 1s. Current intensity of electrical stimulation is 0.08 mA. Note that a very low current intensity suppressed tremor, and the latency from the onset of stimulation to decreased tremor amplitude in the forearm flexor muscles was shorter than that in the extensor muscles. (B) EMGs during continuous electrical stimulation of 0.08 mA for about 20 s (threshold stimulation). Only the initial part was demonstrated. (C) Continuous electrical stimulation of 0.10 mA for about 20 s. Only the initial part was demonstrated. (D) Continuous electrical stimulation of 0.15 mA for about 20 s. Only the initial part was demonstrated. (E) Voluntary repetitive flexion and extension movements of the wrist joint during continuous electrical stimulation (about 20 s). Note that there was no difference on electromyograms before and after electrical stimulation.
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Fig. 9. (A) Simultaneous Vim recording and EMG in the same patient as Figs. 7 and 8 (K.S. 57F PA). Upper: rhythmic grouped discharges of kinesthetic neurons time locked with spontaneous tremor in the contralateral hand, which were responded to stretch forearm flexor, recorded at 1000 mm from the tentative target point. Lower: EMG activity of forearm flexor and extensor. Note that rhythmic grouped discharges of kinesthetic neurons follows EMG activity elicited by contraction of forearm extensor muscles. (B) EMGs during electrical stimulation performed at the same thalamic site.
receptive field. Patients in our series did not complain of paresthesia or other sensory responses if the current intensity was the threshold value to suppress hand tremor. Our results of acute stimulation were essentially the same as those of chronic thalamic Vim stimulation, but the current intensity could be reduced less than that of reported one (Benabid et al., 1996) to achieve complete suppression of tremor if the chronic electrode was implanted at the most lateral part of the Vim nucleus. Our correlation study between microrecordings and microstimulation achieved similar results to those in a recent experimental study in monkeys. Microstimulation of the primate motor thalamus evoked movements in the contralateral limbs, trunk or face, especially in the nucleus ventralis posterior lateralis pars oralis (VPLo) (Vitek et al., 1996). These evoked motor responses had a somatotopic organisation similar to that for neuronal responses to sensorimotor examination and were generally maximal about a
single joint. Although the possibility of a monkey equivalent of the human Vim nucleus is still controversial, VPLo has much the same physiological properties as the human Vim (Ohye et al., 1990; Macchi and Jones, 1997). The mechanism of tremor arrest by electrical Vim stimulation remains unclear (Benabid et al., 1993, 1996; Nguyen and Degos, 1993; Deiber et al., 1993). Tremor arrest may be due to the attenuation of a transcortical reflex loop passing through the Vim nucleus rather than an excitatory effect of electrical stimulation (Benabid et al., 1996). They claimed that frequency intensity relationship of Vim stimulation threshold for tremor suppression effect suggests that Vim stimulation mainly involves passing fibers rather than the cell bodies of Vim neurons. There is controversy about which elements of the central nervous system are involved in electrical stimulation (Ranck, 1975). The present study does not provide any direct information about this problem. Nevertheless, we found that the latency of tremor suppression from the onset of electrical stimulation is shorter in the corresponding muscle to elicit kinesthetic response than that in the other muscles. Moreover, simultaneous EMG and Vim recording often showed that rhythmic grouped discharges of kinesthetic neurons time-locked with spontaneous tremor in the contralateral hand follow the EMG activity (Fig. 9). These results suggest that kinesthetic neurons in the most lateral part of the Vim nucleus may not be tremorogenic but key station in the conduction of tremor rhythm from the contralateral corresponding muscles. Highfrequency electrical stimulation may induce temporary conduction block, while Vim-thalamotomy permanently cuts the tremor circuit. In this sense both procedures are equivalent in the blocking of signal transmission from the corre-
Fig. 10. Graph showing points of electrical stimulation and distance from the posterior commissure (PC) and the intercommissural line in all patients. Thalamic sites were classified into group A (open circle). group B (closed circle) and group C (asterisk).
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sponding muscle at the level of the cell body and/or the passing of fibers in the Vim nucleus. The main corticospinal motor pathway may not be involved directly in the tremor-conducting pathway because continuous electrical stimulation arrested the tremor but did not impair the voluntary action. These results are consistent with our previous experimental data from the tremor monkey showing that tremor-producing rhythmic burst discharges descend via the reticulospinal tract ipsilateral to the peripheral tremor, but not necessarily via the corticospinal tract (Ohye et al., 1984). Some patients complain of transient weakness or uncertainty of the treated limbs after Vim thalamotomy, but clinical and physiological examination reveals no deficits in voluntary action as long as the therapeutic lesion is confined to the most lateral part of the Vim nucleus (Nagaseki et al., 1986). The present study revealed that the site where electrical stimulation induced an increase of hand tremor amplitude was located dorsolaterally to the tremor-suppressing site in the Vim nucleus. Low frequency stimulation may be ineffective or even increase tremor amplitude (Benabid et al., 1993). Our results indicated that the tremor-driving effect of electrical stimulation was related to the stimulated site. We often observed a transient increase of tremor amplitude and frequency at the onset of electrical stimulation followed by decrease of amplitude in group A, especially in the corresponding antagonistic muscles eliciting a kinesthetic response. This transient tremor-driving effect seemed to be enhanced in group B compared with group A. Electrical stimulation induced only exaggeration of tremor with higher current intensity in group C. Somatotopographic representation of the kinesthetic zone of the Vim nucleus shows that the lower limb (group C) is represented in the dorsolateral part of the nucleus, and the upper limb (groups A and B) in the ventromedial part. Kinesthetic neurons directly related to hand tremor are located in the ventromedial part. Our results suggest that suppressive and driving effects on tremor are both results of electrical stimulation depending on the distance from kinesthetic neurons. Usually, the tremordriving effect became more marked than the tremor suppressive effect at stimulus sites further away from kinesthetic neurons directly related to the tremor (for hand tremor, these neurons respond to stretch forearm flexor/extensor) in the dorsolateral direction. However, a question naturally raises whether the same correlation between stimulated sites and electromyographic changes exists in foot tremor. As kinesthetic neurons directly related to foot tremor are located in the dorsolateral part of the Vim nucleus according to somatotopographic representation of the kinesthetic zone, it is presumed that the tremor-driving effect becomes more marked than the tremor suppressive effect at stimulated sites further away from the dorsolateral part in the ventromedial direction as to foot tremor. It is also possible that the tremor-driving effect is due to the alteration of muscle tone by electrical stimulation. Increase of muscle tone is one of the important factors in
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tremor generation. Electrical stimulation of the thalamic ventralis oralis nucleus (60 Hz, square pulse of 1 ms duration, 10–20 V, for 5–20 s) produced a non-reciprocal, concomitant increase in antagonistic muscle tone of contralateral extremities (Ohye et al., 1964). Current spread to the thalamic ventralis oralis nucleus and consequent increase of the tremor-related muscle may result in tremor driving considering that tremor-driving sites are located in the dorsal area of the Vim. Further studies are required to elucidate the mechanism of the different effects of Vim stimulation on tremor.
Acknowledgements This study was supported by Grant-in-Aid for encouragement of Young Scientists (A) 09771030 from the Ministry of Education, Science and Culture, Japan, 1997.
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Effect of electrical stimulation of the thalamic Vim nucleus on hand tremor during stereotactic thalamotomy A. Takahashi*, K. Watanabe, K. Satake, M. Hirato, C. Ohye Department of Neurosurgery, Gunma University School of Medicine, 3-39-22 Showa-Machi, Maebashi, Gunma, 371, Japan Accepted for publication: 15 May 1998
Abstract Objective: The aim of this study was to analyze the correlation between neuronal responses in the thalamic ventralis intermedius (Vim) nucleus to peripheral, natural stimulation and the modulation of tremor by electrical stimulation during stereotactic thalamotomy. Design and methods: The authors studied 36 patients with hand tremor using a microelectrode. The responses of tremor to electrical stimulation were analysed electromyographically. Sixty stimulation sites were divided into three groups. Results: Group A (20 sites) where responses to stretching of the contralateral forearm muscles were recorded. Group B (26 sites) where responses to stretching of the other muscles of the upper extremity were recorded. Electrical stimulation at sites in groups A and B temporarily suppressed the contralateral tremor, but the minimum current intensity to suppress tremor at sites in group A was less than that in group B. Electrical stimulation in group C (14 sites), where kinesthetic responses of contralateral lower extremity were recorded, resulted in increased amplitude of hand tremor. Selective coagulation including the area of tremor suppression resulted in abolition of the tremor in all patients. Conclusions: These results suggest that the most effective site for thalamotomy may also be suitable for chronic stimulation in the Vim nucleus. 1998 Elsevier Science Ireland Ltd. All rights reserved Keywords: Stereotactic surgery; Acute electrical stimulation; Intractable tremor; Microrecording
1. Introduction Correlation of extracellular recordings and electrical stimulation in the thalamic ventralis intermedius (Vim) nucleus and its surrounding structures using microelectrode techniques during the course of stereotactic thalamotomy for parkinsonian and non-parkinsonian tremor have revealed the presence of numerous, highly organized kinesthetic neurons in the lateral part of the Vim nucleus (Ohye and Narabayashi, 1979; Ohye, 1982, 1988; Raeva, 1986; Ohye et al., 1989). Selective coagulation including this area can achieve stable and constant arrest of tremor. Therefore, the lateral part of the thalamic Vim nucleus is considered to be the best therapeutic target for various types of intractable tremor. Acute electrical stimulation of the thalamic Vim nucleus also suppresses tremor transiently during stereotactic thala* Corresponding author. Tel.: +81 27 2207111; fax: +81 27 2336300.
0924-980X/98/$19.00 1998 Elsevier Science Ireland Ltd. All rights reserved PII S0924-980X (98)0003 4-4
motomy (Ohye and Narabayashi, 1979; Ohye, 1988; Benabid et al., 1993). Recently, chronic Vim stimulation using an implanted electrode for intractable tremor has become an alternative to Vim thalamotomy (Benabid et al., 1991, 1993, 1996; Nguyen and Degos, 1993; Deiber et al., 199). Site of implantation is usually determined by the results of acute electrical stimulation and recording (Benabid et al., 1993, 1996). However, acute stimulation of the thalamus may increase tremor amplitude depending on the stimulated site and parameters (Ohye et al., 1964; Alberts et al., 1966; Ohye and Narabayashi, 1979; Benabid et al., 1993). The most effective site for electrical stimulation to achieve the suppression of tremor and its mechanisms is still unclear (Lenz et al., 1988; Benabid et al., 1996). Therefore. the most effective site in the Vim nucleus for electrical stimulation may be different to that for Vim thalamotomy. The present study analyzed the correlation between responses in the Vim nucleus to peripheral, natural stimulation and the modulation of tremor by electrical stimulation
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Fig. 1. Diagram showing the profile of the trajectory in a case of a 60-yearold parkinsonian female (T.S. 60F PA). The profile of the trajectory was made by reference to the posterior commissure (PC) and the intercommissural line (horizontal line) on the corresponding plate from the standard atlas (16 mm lateral from the midline). Arrows indicate points where microrecording and electrical stimulation were performed. Electrically integrated values (arbitrary units) of the background activity at several points along trajectory are plotted and drawn on the bar and line graph.
of the same Vim point using electromyography (EMG) recordings.
2. Subjects and methods Thirty-six patients with drug-resistant hand tremor, 29 with Parkinson"s disease and 7 with essential tremor, were treated surgically after giving informed consent. EMG confirmed the presence of abnormal grouped discharges in the forearm flexor muscles and extensor muscles before the operation. Patients underwent surgery in the supine position under local anesthesia. A Leksell stereotactic frame was fixed and a burr hole was opened over the frontal region, the precise location of which was predetermined by our method of stereotactic magnetic resonance (MR) imaging (Kawashima et al., 1992). The anterior and posterior commissures were determined by ventriculography. To guide the recording
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electrode to the Vim nucleus, the tentative zero point was set on the level of the intercommissural line, 5 mm anterior to the posterior commissure and 16–17 mm lateral to the midline. For operative purpose, this trajectory toward zero point was used for orientation of the posterior recording electrode set with 3 mm interval as shown in Fig. 1 (also in Figs. 5 and 7A) (Ohye et al., 1989, 1990, 1993). Kinesthetic neurons are usually concentrated 1–2 mm medial to the internal capsule, so preoperative determination of the lateral border of the thalamus on stereotactic MR images is essential. Criteria for the identification of the Vim nucleus were as described previously (Ohye et al., 1989). In brief, the Vim nucleus was identified by high background activity with large spike discharge and an irregular oscillation in the thalamic ventral lateral region, and the presence of kinesthetic neurons or tremor-time locked rhythmic discharge. Tactile units which usually appear at the end of trajectory were excluded. The recording electrode was bipolar concentric type (steel-steel) with an outer diameter of 0.3 mm, interpolar distance of 0.3–0.5 mm and electrical resistance of about 100 kQ. This electrode could also be used for bipolar electrical stimulation simply by changing the line from the amplifier to the stimulator. Therefore, electrical stimulation was performed at exactly the same point where single-unit or clearly distinguishable multi-unit responses to a passive or active movement of a contralateral joint were obtained in the thalamic Vim nucleus. Stimuli were square pulses of 1 ms, 0.01–1 mA, at 100 Hz for 1 s. Electrical thalamic stimulation was performed at 86 sites where kinesthetic responses to peripheral natural stimulation were recorded extracellularly using the microelectrode technique. Among them, the 60 sites where electrical stimulation induced change in tremor were analyzed to investigate the correlation between responses to peripheral natural stimulation and effects on hand tremor by electrical stimulation. Responses to electrical stimulation were analyzed by visual inspection and by changes of tremor detected by EMG in the contralateral upper extremity. Minimum current intensity to modulate tremor was determined at each stimulated site. We also asked the patient what was felt during stimulation. Stimulated sites in this study were divided into three groups according to the somatotopic representation of the Vim nucleus (Table 1). Group A consisted of 20 sites where responses to stretching of the contralateral forearm flexor or extensor were recorded from 19 patients. Group B consisted of 26 sites where responses to stretching of the
Table 1 Classification of thalamic sites where electrical stimulation was performed and their electrophysiological properties
Group A Group B Group C
No. of sites
Kinesthetic response
Threshold to suppress tremor (mA, mean ± SD)
Distance from tentative target point (mm, mean ± SD)
20 26 14
Flexor/extensor Upper limb muscles except flexor and extensor Lower limb muscles
0.098 ± 0.064 0.165 ± 0.118 –
2442.11 ± 1636 3942.31 ± 1849.58 6346.15 ± 3049.76
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Fig. 2. Neuronal responses at 4500 mm from tentative target point shown in Fig. 1. Emissions of spikes are visible on the thalamic recording (upper trace) and on the lower trace where the impulses represent spikes of greater amplitude which responded to passive abduction of the contralateral shoulder joint as indicated by arrows. This thalamic site was classified as group B.
other muscles of the upper extremity were recorded from 23 patients. Group C consisted of 14 sites where kinesthetic responses of the contralateral lower extremity were recorded from 11 patients. In each group, the effects of electrical stimulation were reviewed in detail. Furthermore, to evaluate the influence of continuous electrical stimulation on voluntary action, continuous electrical stimulation (10–20 s) at the site where electrical stimulation for 1 s suppressed tremor was performed in 7 patients in group A during voluntary flexion-extension or grasping of the contralateral upper extremities.
3. Results Figs. 1–4 show typical examples of group A and group B observed at two different thalamic depths respectively in a 60-year-old patient with parkinsonian tremor. Fig. 1 shows two thalamic sites where kinesthetic neurons were recorded and then stimulated in presumed Vim nucleus, characterised by high background activity. Kinesthetic responses recorded at 4500 mm and 1000 mm from tentative target point are shown in Fig. 2 (group B) and Fig. 3 (group A), respectively. Fig. 4 shows the suppressive
Fig. 3. On-off responses of kinesthetic neurons to stretch forearm extensor muscle (arrows) recorded at 1000 mm from the tentative target point shown in Fig. 1. This thalamic site was classified as group A.
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Fig. 4. Electromyograms (EMGs) from the upper extremities recorded during electrical stimulation at two different thalamic depths in the same patient as in Fig. 1. The bar under each electromyographic trace indicates the time of electrical stimulation. Numbers beneath the bar show the current intensity of electrical stimulation. (A) EMGs recorded during electrical stimulation at 4500 mm from the tentative target point. Note the transient increase followed by decrease of the tremor amplitude and frequency. (B) EMGs recorded during electrical stimulation at 1000 mm from the tentative target point. Latency from the onset of stimulation to decreased tremor amplitude in the forearm extensor muscles was shorter than that in the antagonistic muscles. flex., forearm flexor muscles; ext., forearm extensor muscles.
effect on hand tremor by electrical stimulation at each thalamic sites. Electrical stimulation suppressed hand tremor most effectively in group A (N = 20). The minimum current intensity to suppress tremor was 0.098 ± 0.064 mA (mean ± SD). Transient tremor suppression was observed by visual inspection with stimulus currents as low as 0.1 mA. EMG showed the latency from the onset of stimulation to decreased tremor amplitude was shorter in the corresponding muscle (forearm flexor or extensor) eliciting kinesthetic responses at the thalamic site than that of other muscles and grouped discharges were decreased immediately (Fig. 4B). Transient increase of amplitude and frequency followed by decreased amplitude was usually seen in the antagonistic muscles. Decrease of grouped discharges in both agonistic and antagonistic muscles occurred temporarily at higher current intensity but tremor reappeared at once. No patient felt any sensory response (paresthesia or electric-like sensa-
tion around the contralateral receptive field) at threshold current intensities that suppressed tremor. Electrical stimulation was less effective in suppressing hand tremor in group B (N = 26) than in group A, although tremor was suppressed to some extent. Electrical stimulation with currents of around 0.1 mA could not induce marked decrease on EMG. The EMG patterns were similar to those of antagonistic muscles in group A. The frequency of grouped discharges during stimulation became higher than before stimulation. The amplitude showed a transient increase at the onset of stimulation (Fig. 4A). Complete arrest of tremor could be obtained at higher currents than those required in group A, but patients often complained of paresthesia in the peripheral receptive field and jerky movements of the extremity. These phenomena could be interpreted as the result of current spreading to the surrounding structures. Threshold current to suppress hand tremor in group B (0.165 ± 0.118
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Fig. 5. Diagram showing the profile of the trajectory in the case of a 48year-old female with essential tremor (F.Y. 48F Ess. T). The arrow indicates the point where microrecording and electrical stimulation were performed.
mA, mean ± SD) was significantly higher than that in group A (P , 0.05, z test). Electrical stimulation could not suppress hand tremor in group C (N = 14). Increased frequency and/or amplitude were often observed by both EMG and visual inspection. Fig. 5 shows the trajectory and a stimulated site in a patient with essential tremor. Fig. 6 shows responses of kinesthetic neurons to ankle joint movement and the tremor-driving effect by electrical stimulation in the same patient as Fig. 5. This effect on EMG continued during and after stimulation. The threshold current to increase tremor was higher than that of tremor suppression (0.33 ± 0.08 mA). In one patient who also had foot tremor, suppression of tremor amplitude was observed in the corresponding lower extremity muscle as in groups A and B. Continuous electrical stimulation was performed in 7 patients at sites in group A, at which transient electrical stimulation had suppressed hand tremor. Fig. 7A shows the trajectory and an stimulated site in a patient with parkinsonian tremor. In this site, kinesthetic neurons responded to stretch forearm flexor muscles were recorded (Fig. 7B). Fig. 8A shows transient suppression of hand tremor on EMG in the same patient as Fig. 7. Fig. 8B–E shows EMGs under continuous electrical stimulation (about 20 s) at the same site as Fig. 8A. The duration required to maintain suppression of hand tremor depended on the current intensity of electrical stimulation. Higher currents were needed to achieve complete arrest of tremor for 10–20 s (0.12 ± 0.06 mA, N = 11). Continuous stimulation (20 s) of the minimum current intensity to obtain complete suppression of tremor had no influence on voluntary movement of the contralateral arm in all patients. In fact patients often
considered that voluntary movement of the contralateral extremities was smoother than before stimulation. The EMG pattern of voluntary grasping did not change before and after continuous stimulation (Fig. 8E). Only one patient described transient paresthesia in the peripheral receptive field, which disappeared within a few seconds, at the onset of stimulation. In the same patient as shown in Figs. 7 and 8, rhythmic grouped discharges time-locked with the spontaneous tremor in the contralateral hand were observed at the deeper site (400 mm from tentative target point). As kinesthetic neurons responded to stretch forearm flexors had been recorded in the same thalamic depth, this site was classified as group A. In this occasion, simultaneous EMG and Vim recording showed that thalamic rhythmic grouped discharges of kinesthetic neurons followed the EMG activity to stretch the corresponding muscle, which was indicated by the contraction phase of the antagonistic muscles on EMG (Fig. 9A). Electrical stimulation at this site suppressed tremor effectively (Fig. 9B). Fig. 10 illustrates all stimulated sites referred to the posterior commissure and the intercommissural line on the sagittal plane. Tremor-suppression sites (group A and
Fig. 6. Neuronal recording and EMGs recorded from the same patient as in Fig. 5. (A) Responses to passive dorsiflexion of the ankle joint (arrows) recorded at 6000 mm from the tentative target point. This thalamic site was classified as group C. (B) EMGs from the upper extremities recorded during electrical stimulation performed at 6000 mm from the tentative target point. Electrical stimulation increased tremor amplitude in this case. The bar under the electromyographic trace indicates the time of electrical stimulation. Number beneath the bar shows the current intensity of electrical stimulation.
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1988, 1993). A recent study of chronic electrical stimulation of the Vim nucleus also included little coverage of this area (Benabid et al., 1996). Therefore, this is the first study of the correlation between microrecording of the kinesthetic neurons and the effects of electrical stimulation on tremor. The current intensity of electrical stimulation required to modulate hand tremor (around 0.1 mA) was low, so that the area involved by the electrical stimulation was restricted to the Vim nucleus. Especially in the hand area, the Vc nucleus was not involved judging from the threshold current to elicit sensory motor response. Electrical stimulation of about 0.1 mA is the suprathreshold level of the Vc nucleus to elicit sensory response (Lenz et al., 1988), so involvement of the Vc nucleus may produce strong paresthesia in the peripheral
Fig. 7. (A) Diagram showing the profile of the trajectory in a case of 57year-old parkinsonian female (K.S. 57F PA). The arrow indicates the point where microrecording and electrical stimulation were performed at 2400 mm from the tentative target point. (B) Neuronal recording at 2400 mm from the tentative target point in the same patient. Emissions of spikes are visible on the recording and the trace where the impulses represent spikes of greater amplitude which discharged at the end stage of stretching of the contralateral forearm flexor indicated by mechanical movement of the electromyographic trace. This thalamic site was classified as group A.
group B) were distributed in a relatively wide area of the Vim nucleus. The distances from the tentative zero point to sites in group C along the trajectory were longer than those in group A and group B. The trajectory of the electrode was inclined laterally 2–10 degrees from the midsagittal plane, so tremor-driving sites (group C) were located dorsolaterally to tremor-suppressing sites. After electrophysiological exploration, selective coagulation including the thalamic points where electrical stimulation suppressed tremor and kinesthetic neurons related to tremor were recorded resulted in complete abolition of the tremor in all patients.
4. Discussion Few studies have investigated the correlation between extracellular recordings and electrical stimulation in the thalamic Vim nucleus, compared to the numerous studies of the thalamic ventralis caudalis (Vc) nucleus (Lenz et al.,
Fig. 8. EMGs from the upper extremities recorded during electrical stimulation at 2400 mm from the tentative target point in the same patient as shown in Fig. 7. The bar under the electromyographic trace indicates the time of electrical stimulation. (A) EMGs during electrical stimulation for 1s. Current intensity of electrical stimulation is 0.08 mA. Note that a very low current intensity suppressed tremor, and the latency from the onset of stimulation to decreased tremor amplitude in the forearm flexor muscles was shorter than that in the extensor muscles. (B) EMGs during continuous electrical stimulation of 0.08 mA for about 20 s (threshold stimulation). Only the initial part was demonstrated. (C) Continuous electrical stimulation of 0.10 mA for about 20 s. Only the initial part was demonstrated. (D) Continuous electrical stimulation of 0.15 mA for about 20 s. Only the initial part was demonstrated. (E) Voluntary repetitive flexion and extension movements of the wrist joint during continuous electrical stimulation (about 20 s). Note that there was no difference on electromyograms before and after electrical stimulation.
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Fig. 9. (A) Simultaneous Vim recording and EMG in the same patient as Figs. 7 and 8 (K.S. 57F PA). Upper: rhythmic grouped discharges of kinesthetic neurons time locked with spontaneous tremor in the contralateral hand, which were responded to stretch forearm flexor, recorded at 1000 mm from the tentative target point. Lower: EMG activity of forearm flexor and extensor. Note that rhythmic grouped discharges of kinesthetic neurons follows EMG activity elicited by contraction of forearm extensor muscles. (B) EMGs during electrical stimulation performed at the same thalamic site.
receptive field. Patients in our series did not complain of paresthesia or other sensory responses if the current intensity was the threshold value to suppress hand tremor. Our results of acute stimulation were essentially the same as those of chronic thalamic Vim stimulation, but the current intensity could be reduced less than that of reported one (Benabid et al., 1996) to achieve complete suppression of tremor if the chronic electrode was implanted at the most lateral part of the Vim nucleus. Our correlation study between microrecordings and microstimulation achieved similar results to those in a recent experimental study in monkeys. Microstimulation of the primate motor thalamus evoked movements in the contralateral limbs, trunk or face, especially in the nucleus ventralis posterior lateralis pars oralis (VPLo) (Vitek et al., 1996). These evoked motor responses had a somatotopic organisation similar to that for neuronal responses to sensorimotor examination and were generally maximal about a
single joint. Although the possibility of a monkey equivalent of the human Vim nucleus is still controversial, VPLo has much the same physiological properties as the human Vim (Ohye et al., 1990; Macchi and Jones, 1997). The mechanism of tremor arrest by electrical Vim stimulation remains unclear (Benabid et al., 1993, 1996; Nguyen and Degos, 1993; Deiber et al., 1993). Tremor arrest may be due to the attenuation of a transcortical reflex loop passing through the Vim nucleus rather than an excitatory effect of electrical stimulation (Benabid et al., 1996). They claimed that frequency intensity relationship of Vim stimulation threshold for tremor suppression effect suggests that Vim stimulation mainly involves passing fibers rather than the cell bodies of Vim neurons. There is controversy about which elements of the central nervous system are involved in electrical stimulation (Ranck, 1975). The present study does not provide any direct information about this problem. Nevertheless, we found that the latency of tremor suppression from the onset of electrical stimulation is shorter in the corresponding muscle to elicit kinesthetic response than that in the other muscles. Moreover, simultaneous EMG and Vim recording often showed that rhythmic grouped discharges of kinesthetic neurons time-locked with spontaneous tremor in the contralateral hand follow the EMG activity (Fig. 9). These results suggest that kinesthetic neurons in the most lateral part of the Vim nucleus may not be tremorogenic but key station in the conduction of tremor rhythm from the contralateral corresponding muscles. Highfrequency electrical stimulation may induce temporary conduction block, while Vim-thalamotomy permanently cuts the tremor circuit. In this sense both procedures are equivalent in the blocking of signal transmission from the corre-
Fig. 10. Graph showing points of electrical stimulation and distance from the posterior commissure (PC) and the intercommissural line in all patients. Thalamic sites were classified into group A (open circle). group B (closed circle) and group C (asterisk).
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sponding muscle at the level of the cell body and/or the passing of fibers in the Vim nucleus. The main corticospinal motor pathway may not be involved directly in the tremor-conducting pathway because continuous electrical stimulation arrested the tremor but did not impair the voluntary action. These results are consistent with our previous experimental data from the tremor monkey showing that tremor-producing rhythmic burst discharges descend via the reticulospinal tract ipsilateral to the peripheral tremor, but not necessarily via the corticospinal tract (Ohye et al., 1984). Some patients complain of transient weakness or uncertainty of the treated limbs after Vim thalamotomy, but clinical and physiological examination reveals no deficits in voluntary action as long as the therapeutic lesion is confined to the most lateral part of the Vim nucleus (Nagaseki et al., 1986). The present study revealed that the site where electrical stimulation induced an increase of hand tremor amplitude was located dorsolaterally to the tremor-suppressing site in the Vim nucleus. Low frequency stimulation may be ineffective or even increase tremor amplitude (Benabid et al., 1993). Our results indicated that the tremor-driving effect of electrical stimulation was related to the stimulated site. We often observed a transient increase of tremor amplitude and frequency at the onset of electrical stimulation followed by decrease of amplitude in group A, especially in the corresponding antagonistic muscles eliciting a kinesthetic response. This transient tremor-driving effect seemed to be enhanced in group B compared with group A. Electrical stimulation induced only exaggeration of tremor with higher current intensity in group C. Somatotopographic representation of the kinesthetic zone of the Vim nucleus shows that the lower limb (group C) is represented in the dorsolateral part of the nucleus, and the upper limb (groups A and B) in the ventromedial part. Kinesthetic neurons directly related to hand tremor are located in the ventromedial part. Our results suggest that suppressive and driving effects on tremor are both results of electrical stimulation depending on the distance from kinesthetic neurons. Usually, the tremordriving effect became more marked than the tremor suppressive effect at stimulus sites further away from kinesthetic neurons directly related to the tremor (for hand tremor, these neurons respond to stretch forearm flexor/extensor) in the dorsolateral direction. However, a question naturally raises whether the same correlation between stimulated sites and electromyographic changes exists in foot tremor. As kinesthetic neurons directly related to foot tremor are located in the dorsolateral part of the Vim nucleus according to somatotopographic representation of the kinesthetic zone, it is presumed that the tremor-driving effect becomes more marked than the tremor suppressive effect at stimulated sites further away from the dorsolateral part in the ventromedial direction as to foot tremor. It is also possible that the tremor-driving effect is due to the alteration of muscle tone by electrical stimulation. Increase of muscle tone is one of the important factors in
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tremor generation. Electrical stimulation of the thalamic ventralis oralis nucleus (60 Hz, square pulse of 1 ms duration, 10–20 V, for 5–20 s) produced a non-reciprocal, concomitant increase in antagonistic muscle tone of contralateral extremities (Ohye et al., 1964). Current spread to the thalamic ventralis oralis nucleus and consequent increase of the tremor-related muscle may result in tremor driving considering that tremor-driving sites are located in the dorsal area of the Vim. Further studies are required to elucidate the mechanism of the different effects of Vim stimulation on tremor.
Acknowledgements This study was supported by Grant-in-Aid for encouragement of Young Scientists (A) 09771030 from the Ministry of Education, Science and Culture, Japan, 1997.
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