0306-4522/90 $3.00 + 0.00

Neurosc;ence Vol.35, No. 2, pp.217-226, 1990

PergamonPressplc 0 1990lBR0

Printed in Great Britain

COMMENTARY NEURONAL BASIS OF THE PARKINSONIAN RESTING TREMOR: A HYPOTHESIS AND ITS IMPLICATIONS FOR TREATMENT D. PARI?, R. CURRO’DOSSIand M. STERIADE Laboratoire de Neurophysiologie, Wpartement de Physiologic, FacultC de Medecine, Universite Lava&Quebec, Canada GIK 7P4 CONTENTS 1. INTRODUCTION RESTING TREMOR: PHENOMENOLOGY AND TREATME~ 2. PARKINSONIAN 3. BRIEF ANATOMICAL REVIEW OF THE VENTRAL NUCLEAR THALAMIC COMPLEX 3.1. Cell types 3.2. Nuclear systemati~tion ACTIVITIES OF VENTRAL LATERAL THALAMIC NEURONS 4. TREMOR-RELATED 4.1. Human studies 4.2. Primate models of the parkinsonian state 4.3. Discussion OF NEURONS OF THE INTERNAL SEGMENT OF THE GLOBUS 5. ACTIVITIES PALLIDUS IN NORMAL AND PARKINSONIAN MONKEYS 6. ELECTROPHYSIOLOGICAL PROPERTIES OF DORSAL THALAMIC NEURONS 7, ORIGIN OF THE PARKINSONIAN RESTING TREMOR A HY~THESIS 8. IMPLICATIONS FOR TREATMENT ACKNOWLEDGEMENTS REFERENCES

1. INTRODUCTION The last 10 years have witnessed radical changes in our conception of the neuron. Not so long ago, the dendritic tree was conceived as a leaky conductor which passively transmitted the synaptic influences to the cell body, while the soma was seen, electrophysiologically speaking, as a prolongation of the axon. A completely different picture has emerged from the in v&o and in vivo intra~liular studies performed in the last few years. It is now clear that both the soma and dendrites possess numerous chemo- and voltage-de~ndent conductances which are expressed differentially in the various types of

Abbreoiutiom:GPi, internal segment of the globus pallidus;

LTS, low-threshold calcium spike; MPTP, I-methyl-C phenyl-1,2,3,6_tetrahydropyridine; RE, reticular thalamic nucleus; VL, ventral lateral thalamic nucleus; VLa, anterior part of the ventral lateral nucleus; VLp, posterior part of the ventral lateral nucleus; VP, ventral posterior thalamic nucleus; VPL, lateral part of the ventral posterior thalamic nucleus; VPM, medial part of the ventral posterior thalamic nucleus.

217 218 218 218 219 219 219 220 220 220 220 222 223 223 223

neurons, thereby endowing them with unique electroresponsive capabilities. A central theme of the literature devoted to the electrophysiological properties of single neurons has been that these ionic conductances allow some type of cells to behave as resonators or oscillators which can sustain or generate rhythmic outputs.53~Y,79,82 The insertion of such elements in complex synaptic networks has functional implications which are only beginning to be understood. The rhythmic nature of some pathological manifestations like the tremors observed in various neurological conditions suggests that these electrophysiological properties could underlie some forms of involuntary movementss2 If so, the pharmacological sensitivity of the ionic conductances responsible for the resonating or oscillating capabi~ties could open new avenues in the treatment of these debilitating conditions. More than two decades ago, it was proposed, on the basis of single unit recordings performed in humans undergoing stereotaxic neurosurgery3r and in a primate model of Parkinson’s disease,47*ssthat the ventral lateral (VL) region of the thalamus is responsible for the resting tremor seen in the parkinsonian

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state. In those years, the basic electrophysiological properties of thalamic cells were unknown and the interpretation of tremor-related unit activities was therefore restricted to a synaptic analysis of the mechanisms involved. The purpose of this commentary is to re-interpret these and other data pertaining to the genesis of the parkinsonian resting tremor in light of the recent developments accomplished in electrophysiology. We will propose that the 34 Hz parkinsonian resting tremor is the consequence of a frequency transformation operated by VL thalamic neurons on the inhibitory input arising in the internal segment of the globus pallidus (GPi). The implications of this mechanistic hypothesis for the treatment of the resting tremor will be discussed.

2. PARKINSONIAN PHENOMENOLOGY

RESTING TRKMOI: AND TREATMENT

Together with the rigidity, postural instability and bradykinesia, the 34 Hz resting tremor constitutes the cardinal feature of Parkinson’s disease.’ This tremor results from alternating bursts of activity in antagonistic muscles and, as implied by its name, it ceases during purposeful movements.3’~so The parkinsonian resting tremor is quite variable. Although it is usually present during immobility, it can stop spontaneously and resume later. Moreover, it ceases during sleep. Usually the tremor predominates in the fingers, hands and forearms, and rarely affects the tongue, jaw, eyelids and arms. In many cases, one or more muscle groups beat at different frequencies. Dissociations between the two sides of the body as well as between lower and upper extremities have also been reported. On rare occasions, antagonistic muscles contracting at different frequencies have been observed. “Jo The origin of the resting tremor remains unknown. Although the parkinsonian state is believed to result from the degeneration of the nigrostriatal pathway and consequent reduction in striatal dopamine levels,)2 the main parkinsonian symptoms respond differentially to dopamine replacement therapy, thus underlining the fact that different neuronal mechanisms are involved. For instance, L-DGPA administration is effective in alleviating the rigidity and bradykinesia but was proved to be less efficient in controlling the resting tremor. Anticholiner~c agents such as atropine are the most commonly used drugs to treat the parkinsonian resting tremor. Unfortunately, the effectiveness of these drugs is limited and the long-term consequences of this practice are a source of concern.’ Some clinicians have relied on stereotaxic surgical procedures such as the electrocoagulation of the GPi or, more commonly, of a part of the VL thalamic complex to alleviate the parkinsonian resting tremor. The effectiveness of these procedures is well established and has been the topic of numerous follow-up

studies.30*33*73.85 For obscure reasons,85 these methods have been ignored since the introduction of the L-DOPA therapy. When pallidotomy and ~~amotomy are performed, the target structure is usually delimited by unit recordings guided by radiological coordinates. Many workers have reported that, in spite of the marked variations in the topographical anatomy of the thalamus, the limit between various nuclei of the ventral thalamic complex can easily be identified on the basis of the evoked and spontaneous activity of the recorded neurons.2*10,25.38 Nevertheless, the exact site of effective thalamotomy is still controversial. Post mortem histological controls are rare and complicated by the fact that the diameter of the lesion sites tends to increase with time.” Initially, the lesions were placed in the posterolater~orsal part of the VL nucleus2’ Thereafter, the most effective lesion sites were found to be located around the inferolateral limit of the VL thalamic region.8*62 Unfo~unately, the available histological controls do not allow us to be precise as to what part of the VL nuclear complex is critical to abolish the tremor. Therefore, the only way to gain further insight into the genesis of the resting tremor is to relate the behavior of the neurons recorded in and around the target structures during the surgical procedures to the connectivity of the various sectors of the ventral thalamic complex. 3. BRIEF ANATOMICAL REVIEW OF THE VENTRAL NUCLEAR THALAMIC COMPLEX

3.1. Cell types Briefly, two major cell types can be recognized in the ventral nuclear complex: local-circuit cells and relay neurons. 72 Local-circuit cells account for 2&30% of thalamic neurons.** They use GABA as a neurotransmitter6’.‘* and their soma is generally smaller than that of relay neurons: 200/.4mZ versus 350 pm2.71*78 Local-circuit cells are believed to constitute the substrate of the intranucle~ inhibitor processes underlying discriminative phenomena. In contrast with local-circuit cells whose axons are confined to the territory of their dendritic arbor, relay neurons have a bifurcating axon with a collateral toward the cerebral cortex and one reaching the reticular (RE) thalamic nucleus.” The RE nucleus is a thin sheet-like nucleus covering most of the dorsal thalamus. It contains only one cell type using GABA as a neurotransmitter34.~ and projecting back to dorsal thalamic nuclei.40~72~76~*3 The RE-thalamic connections are not only reciprocal but are also organized in such a way that particular districts of the RE nucleus are related to specific sectors of the dorsal thalamus.39g83In contrast with relay cells, RE neurons have intranuclear recurrent axonal collaterals.6’*go Moreover, at least in the cat, nei~boring RE neurons are synapti~lly coupied by dendrodendritic contacts. ‘*It has been proposed that

Parkinsonian tremor

through these tight intranuclear connections, the RE nucleus can synchronize the activities of large sectors of the dorsal thalamus.‘8y6’ 3.2. Nuclear systematization Neuroanatomical experiments carried out in a variety of primate and non-primate species have revealed that the ventraf nuclear compfex is composed of at least five interdigitated nuclei, each receiving largely distinct subcortical inputs. In the following account we will use the terminology of Jones@’ and, whenever possible, relate it to that of Schaltenbrand and Bailey7s which was often used by the investigators recording tremor-related unit activities. The ventral posterior (VP) nucleus is, as implied by its name, the most caudally-locate nucleus of the ventral complex. It is divided into medial (VPM) and lateral (VPL) sectors. The VPM receives trigeminal inputs concerning the head, face and oral cavity while the VPL is innervated by the medial lemniscus which conveys information concerning the contralateral trunk as well as the lower and upper lim6s.60~68 Most VP neurons display a topographic and modal specificity which allows them to respond to specific stimuli (such as pressure, tactile stimulation, stretching of the muscles or tendons) applied to a spatially restricted receptive field. 68*69Furthermore, neurons responsive to different submodalities are spatially segregated. The VP nucleus is composed of a large central region of neurons responsive to cutaneous stimuli surrounded by a thin layer of cells (300-500 pm) responding to the stimulation of deep tissues. This layer wraps much of the posterior, dorsal and anterior surface of the VP nucleus.4’,69 In primates, the VP nucleus projects to the first and second somatosensory cortices.14*42Using the terminology of Schaltenbrand and Bailey,” the VP nucleus is equivalent to the nucleus ventralis caudalis. The VL nucleus can be subdivided, on hodological grounds, into two subnuclei: a posterior (VLp) and an anterior @‘La) nucleus. The VLp covers the dorsal and anterior surface of the VP nucleus. Whereas the defining characteristic of the VLp resides in the massive projection it receives from the deep cerebellar nuclei,6 the subcortical input specific to the VLa is a GABAergic contingent45*66 originating in the GPi,20.“,46.65 The VLp and VLa can be further distinguished on the basis of the cortical projection fields to the motor5,43 and premotor cortices,44,86respectively. In the systematization of Schaltenbrand and Bailey,” the VLp is termed ventralis intermedius and ventrooralis posterior, while the VLa is termed ventro-oralis anterior. The last two parts of the ventral complex, the ventral medial and ventral anterior nuclei, have been explored rather seldomly in the course of stereotaxic neurosurgical inte~entions and will not be considered here.

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4. TREMOR-RELATED ACTWITIW OF VENTRAL LATERAL THALAMIC NEURONS 4.1.

Human studies

In the early 196Os, Guiot et al.28 discovered that a population of ventral thalamic units discharge rhythmically at the frequency of the resting tremor in parkinsonian patients. Thereafter, numerous studies confirmed and extended their findings in an attempt to delineate electrophysiologically the nuclei of the ventral thalamus and investigate their possible involvement in the genesis of the tremor. Although there are notable exceptions,37 the quality of most recordings was rather poor by today’s standards and in most cases the time base of the oscilloscopic traces does not permit an adequate assessment of the pattern of tremor-related discharges. For obvious reasons, no histological control ascertaining the localization of the recorded units was performed. In order to minimize the errors which could be introduced by individual variations in the topography of the human thalamus, some investigators standardized their stereotaxic measurements by dividing the distance between the anterior and posterior commissures in 10 equal parts and by expressing the results obtained in different patients in these terms.9,29,37 From the vantage point of resting tremor, three populations of ventral thalamic neurons have been distinguished in neurosurgical interventions: (a) units displaying no tremor-related activity; (b) tremorrelated units responsive to sensory stimuli or active during voluntary movements; and (c) unresponsive tremor-related cells. The first class of units encompass different types of thalamic cells: posteriorly-located cells responding to light touch,37.38cells discharging with various sensory or motor events located in front of the former type of cells,” and unresponsive neurons disseminated throughout the ventral thatamic compiex.‘~” The second class of neurons includes thalamic cells discharging in rhythmic trains related to the resting tremor5’ and responding to one of the following maneuvers: stimulation of the muscles or tendons, passive or active movements. The rhythmic activity of these ceI1s is usually disrupted during voluntary movements and when the tremor stops. The exact localization of these neurons is uncertain. According to the neuroanatomical and electrophysiological experiments performed in primates (see above), such neurons could be located in the shell portion of the VP nucleus or anywhere in the VLp nucleus. It has been claimed that they are located in the caudal portion of the VL complex (nucleus ventralis intermedius),63,70.87and that this locus coincides with the most effective lesion site to abolish tremor.25~37~63 It is interesting to note that the proponents of this view have stressed that the inferior border of the nucleus ventralis intermedius is the most effective site to abolish the tremor. This point will be discussed below.

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The neurons of the last class discharge ryhthmitally at the frequency of the resting tremor, are unresponsive to the sensory stimuli mentioned above, and are not affected by active and passive movements. Their rhythmic discharge persists even when the resting tremor ceases. These units are located rostrally and rostrodorsally to the neurons of the second class, in an area which seems to overlap with the VLa nucleus.87 According to Bertrand et al.” and Hardy ef a1.l’ the inferolateral limit of this region is one of the two optimal sites to abolish the resting tremor, the second being located just below the inferior limit of the caudai part of the VL complex. Moreover, they suggest that the effectiveness of these lesions would not result from the involvement of the thaiamus but from the destruction of paliidothalamic and pallidotegmental fibers, This interpretation is consistent with the effectiveness of GPi lesions to alleviate the resting tremor and can explain why lesion located at the inferior border of the VLp are more effective. As mentioned earlier, the low signal-to-noise ratio and the slow time base of the depicted oscilloscopic traces greatly complicate the assessment of the tremor-related unit activities. Most VLp neurons discharge short tremor-related bursts of 3-4 spikes at a frequency of 100-300 Hz.~~~”In contrast, VP neurons responsive to deep stimuli discharge tremorrelated spike trains lasting up to 200ms.‘* Finally, VLa neurons appear to discharge brief bursts of 448 spikes at a frequency 200-300 Hz.~‘.~’ The origin of these stereotyped high-frequency bursts will be discussed below. 4.2. Primate models C$ the parki~~~nian state In 30% of the monkeys prepared with electrolytic lesions of the ventromedial tegmentum, a 3-6 Hz tremor was observed. It shared many of the characteristics of the parkinsonian resting tremor.” In these animals, an important proportion of the thalamic neurons located rostrodorsally to the VP nucleus displayed rhythmic spike bursts appearing at a frequency of 3-6 Hz. This rhythmic activity resisted curari~tion49 and rhyzotomy.47 The tremor-related activity of these thalamic neurons occurred as short, high-frequency (300-400 Hz) bursts consisting of 4-6 spikes. 4.3. Discussion The mere fact that thalamic units discharge rhythmically with the tremor is by no means proof of their involvement in the genesis of the tr; nor. This is especially true of the VP neurons responsive to deep stimuli and of VLp neurons which, in intact experimental animals, discharge with the activation of some muscle groups anyway.57.84No more decisive is the effectiveness of VL lesions in abolishing the tremor since “large enough lesions anywhere, from globus pallidus through the anterior portion of the posterior limb of the internal capsule to ventrolateral

er al.

thalamus, will produce . . . some lessening of tremor” (Ref. 8, p. 446). Much more ‘significant is the discovery of VLa units unresponsive to sensory stimulation and unaffected by voluntary movements but rhythmically active at the frequency of the tremor. The persistence of this rhythmic activity when the tremor ceases definitely establishes that these unitary activities do not reflect a sensory feedback nor an efferent copy. In fact, these and other findings point to the VLa nucleus as a crucial link in the genesis of the parkinsonian resting tremor. Firstly, it projects to the premotor ~ortex~,‘~ and is thus in an excellent position to infiuence the activities of the motor cortex. Secondly, its main subcortical input originates in the GPi, whose lesion abolishes the parki~sonian resting tremor. Thirdly, Bertrand and co-workers have concluded. after an extensive review of their cases of thalamotomy, that the involvement of the pallidothalamic fibers explains the effectiveness of the lesions placed at the inferior border of the ventral complex in alleviating the tremor. ‘J’ The next logical step is therefore to ask what changes in pallidal activities underlie the rhythmic activities of VLa units. 5. ACTIVITIES OF NEURONS OF THE INTERNAL SEGMENT OF THE GLOBUS PALLIDUS IN NORMAL AND PARKINSONIAN MONKEYS

The recent primate studies have compared the activities of GPi neurons in the normal and parkinsonian state.24s59In these experiments, the parkinsonian syndrome was induced by the injection of the neurotoxin 1-methyl-4-phenyl-1,2,3,6_tetrahydropyridine (MPTP). It was found that both the discharge rate and pattern of GPi neurons were altered in the parkinsonian state. The firing rates of GPi neurons recorded in MPTP-treated monkeys were 5O%24 and 27%‘? higher than those of GPi neurons recorded in normal monkeys. Moreover, the tonic discharge characteristic of GPi neurons in intact animals was transformed after MPTP treatment into a burstsilence pattern occurring at a frequency of 12-I 5 Hz. No correlation with the tremor could be demonstrated. Similar results were obtained after Iesions of the ventromedial tegmentum.23 Electrical stimulation of the GPi evokes inhibitory postsynapti~ potentials in VLa neurons of cats and monkeys,Ba,89When approached with a strictly synaptic point of view, it is therefore difficult to understand how a 12-l 5 Hz inhibitory input could bring about the 3-6 Hz rhythmic activity of VLa neurons. However, new data pertaining to the intrinsic electrophysiological properties of thalamic cells could very well explain how such a transformation occurs. 6. ELECTROPHYSIOL~IC~ DORSAL THALAMIC

Dorsal thalamic neurons uniform ele~trophysiological

PROPERTIKS NEURONS

OF

display astonishingly properties.82 In every

Parkinsonian tremor nucleus studied so far, two firing modes have been recognized: a tonic, single-spike mode and a bursting mode. As illustrated in Fig. 1A, depending on the resting membrane potential, a depolarizing pulse of

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sufficient amplitude evokes a barrage of well-spaced action potentials lasting for the duration of the pulse, whereas the same depolarizing pulse triggers a brief (30 ms), high-frequency (250400 Hz) burst of 2-6

A 1

3,

3, li -L!z\ - -

4xLP -0.1 8

Fig. 1. Voltage and time dependence of low-threshold calcium conductance de-inactivation in dorsal thalamic neurons. (A) Effect of membrane potential on the response of a thalamic neuron to a depolarizing pulse of constant amplitude. At the resting potential, the depolarizing pulse induced tonic firing (Al). With membrane hyperpolarization, the response of the cell developed into a slow spike crowned by a few action potentials (A2, 3, 4). The tonic response recovered when the membrane potential was returned to rest (A4). Note the isolated slow spikes in A3 (arrows). (B), (C) Progessive de-inactiva~on of the low-threshold calcium conductance by decreasing the duration of the interval between two short-lasting hyperpolarizing pulses (B 1-4) and by the injection of repetitive su~th~shold h~~la~zing pulses (C). Current pulse intensities: 1.3 nA in (A); 2 nA in (B); 1nA in (C). The recordings illustrated in this and the following figure were performed in barbiturate-anesthetic cats. (A) Modified from Pare et QZ.~ (B), (C) Modified from Steriade et ~1.~

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action potentials when the potential is displaced in a hyperpolarizing direction to -65 mV and more. In vitro intracellular studies have shown that these stereotyped high-frequency bursts are generated by a slow, calcium-mediated depolarization deinactivated by sufficient membrane hyperpolarization and termed low-threshold calcium spike (LTS).3Ss36 Since recent reviews79.82have provided extensive discussion of the intrinsic properties of dorsd thalamic neurons, the remainder of this section will be devoted to the low-threshold calcium conductance which, as will be argued below, underlies the tremor-related rhythmic discharge of VLa neurons. The low-threshold calcium conductance is inactive at the resting potential, de-inactivated by membrane hyperpolarization, and activated at the break of the hy~~olarization or in response to a de~larization applied during the hyperpolarization. As initially described in the inferior olive, s5.56de-inactivation of the low-threshold calcium conductance in thalamic

neurons is not only voltage-dependent but also timedependent (Fig. 1A-C). Each LTS is followed by a relative refractory period lasting 170-200 ms.19*36 It has been hypothesized that the oscillatory properties of thalamic neurons may be implicated in the generation of tremor such as, for instance, that of Parkinson’s disease.52 It was further proposed that deafferentation (perhaps of the ~~~llothalamic inputs) could provide the means to trigger the oscillatory mode.S2 7. ORIGIN OF THE PARKINSONIAN RESTING

TREMOR:

A HYPOTHESIS

The properties of the calcium conductance underlying the LTS endow thalamic neurons with hysteretic capabiiities. For instance, when a train of short, repetitive hy~~ola~zing pulses is imposed to a thalamic neuron, the continuous train of hyperpolarizing pulses is temporally integrated and transformed into discrete LTSs*O(Fig. 2A, B). Although the fre-

A

20mV 2nA

IS

I

I

20mV

2nA

Fig. 2. Frequency transformation of rhythmic hyperpolarizations by dorsal thalamic neurons. (A) Polygraphic recording showing how the repetitive injection of sub-threshold hyperpolarizing ramps at a frequency of 12.5H.z is transformed in rhythmic bursting at 2.5Hz. The amplitude of fast spikes is truncated. The arrow points to an isolated slow spike. (B) Response of a VL neuron to a train of hyperpolarizing pulses delivered at a frequency of 12 Hz. Note the rhythmic occurrence of LTSs at 4 Hz. (A) Modified from Steriade et al.” (B) Unpublished data by D. Pare, R. Curro’Dossi and M. Steriade.

223

Parkinsonian tremor

quency transformation operated by thalamic cells has not yet been studied extensively, especially with respect to its dependence upon the resting potential and magnitude of the hyperpolarizations, it is worth mentio~ng that in the case of Fig. 2A, B, the hyperpolarizing current pulses were delivered at a frequency of IO-12SHz while the resulting LTSs occurred at a frequency of 2.5-4Hz. We propose that the hysteric capabilities conferred to dorsal thalamic neurons by the properties of the low-threshold calcium conductance underlie the rhythmic, tremor-related discharge of VLa neurons observed in Parkinson’s disease. By virtue of this property, VLa neurons transform the abnormal rhythmic 12-15 Hz inhibitory inputs originating in GPi neurons into a series of high-frequency bursts appearing rhythmi~lly at a frequency of 3-6 Hz. Of course, other intrinsic membrane conductances such as the persistent sodium conductance and transient potassium conductance would probably contribute to the genesis of the 6 Hz oscillation.** In our view, this rhythmic input would be transmitted by VLa axons to the premotor cortex and then, through corticocortical connections, to the motor cortex. However, it is unlikely that the precise timing required to produce alternating contractions among antagonistic muscles is brought about by alte~ating discharges in pools of VLa neurons linked to groups of antagonistic motor cortical neurons. Rather, we concur with Alberts,’ who proposed that the parkinsonian resting tremor represents an involuntary running of a program of motor behavior ordinarily used in the production of rapid voluntary alternating movements (Ref. 4, p. 363). This program could be stored anywhere from the motor or premotor cortices to the spinal cord and activated by the rhythmic VLa input. The persistence of VLa bursting discharges upon cessation of the tremor (during voluntary movements for instance) underscores this dependence of tremor genesis on the functional state of the structures sustaining this motor program. Numerous observations suggest that the synchronizing influence of the RE thalamic nucleus is not

critical to the genesis of the parkinsonian resting tremor. Firstly, phase and frequency dissociations between the tremor of different body parts are commonly observed. “*” Secondly, the tremor disappears during synchronized sleep, a behavior state during which RE neurons characteristically discharge highfrequency rhythmic (7-12 Hz) spike bursts as opposed to their tonic firing during waking.2’~81 Nevertheless, it is likely that the rhythmic input originating in VLa neurons will entrain RE neurons. It is therefore possible that the tremor-related activity of VLa cells is, through the tight intranuclear connectransmitted to other thalations linking RE cell~,‘~~~’ mic nuclei, such as the VLp. 8. IMPLICATIONS FOR TREATMENT If, as hypothesized above, rhythmic LTSs underlie the tremor-related discharge of VLa neurons, any pharmacological manipulations interfering with LTS genesis and GABAergic transmission would be effective in the treatment of the resting tremor. For instance, it has recently been shown that high molecular weight alcohols reversibly block the lowthreshold calcium conductance of dorsal thalamic neurons.26 The search for a related compound may lead to the disclosure of a potent tool to block the rhythmic recurrence of LTSs. Fortunately, drugs such as ethosuximide and dimethadione, which are already used for the treatment of petit-ma1 clinical seizures,74 have been shown to reversibly reduce the LTS of thalamic neurons in vitro I6 Moreover, ethosuximide is almost devoid of side effects.13 Its effectiveness in abolishing the tremor of MPTP-treated monkeys should threrefore be tested. Acknowledgements-This

work was supported by the Medical Research Council of Canada (MT-3689) and by a research fund from the Lava1 University. D. Pare is an MRC fellow. R. Curro’Dossi is a postdoctural fellow, on leave of absence from the Institute of Neurology, University of Padova, Italy. Our appreciation goes to D. Drolet and P. Giguere for their skillful technical assistance.

REFERENCES

Adams R. D. and Victor M. (1984) Principles of Neurology. McGraw-Hill, New York. :: Albe-Fessard D., Arfel G. and Guiot G. (1963) Activitts Sctriques ~act~~stiques de quelques structures c&&brales chez l’homme. Ann. Chir. 17, 1185-1214. 3. Albe-Fessard D., Guiot G., Lamarre Y. and Arfel G. (1966) Activation of thalamocortical projections related to tremorogenic processes. In Z%e~~u~~~ (eds Purpura D. P. and Yahr M. D.), pp. 237-249. Columbia University Press, New York. 4. Alberts W. W. (1972) A simple view of parkinsonian tremor. Electrical stimulation of cortex adjacent to the rolandic fissure in awake man. Brain Res. 44, 357-369. 5. Asanuma C., Thach W. T. and Jones E. G. (1983) Cytoarchitectonic delineation of the ventral lateral thalamic region in monkeys. Brain Res. Rev. 5, 219-235. 6. Asanuma C., Thach W. T. and Jones E. G. (1983) Distribution of cerebellar te~inations and their relation to other afferent terminations in the thalamic ventral lateral region of the monkey. Brain Res. Rev. 5, 237-265. 7. Bates J. A. V. (1969) The significance of tremor phasic units in the human thalamus. In Third Symposium on Parkinson’s Disease (eds Gillingham F. J. and Donaldson I. M. L.), pp. 118-124. Livingstone, Edinburgh. 8. Bertrand C. (1966) Localization of lesions. J. Neurosurg. 24, 446-448. 9. Bertrand C., Hardy J., Molina-Negro P. and Martinez S. N. (1969) Optimum physiological target for the arrest of tremor. In Third Symposium on Parkinson’s Disease (eds GiBingham F. J. and Donaldson I. M. L.), pp. 251-259. Livingstone, Edinburgh.

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Note added in proof-The

effects of monkey were tested by P. Bedard, J. Hbpital de l’Enfant-Jesus, Qu&ec). chronic administration of the drug.

ethos~imide on the resting tremor displayed by an MPTP-toted F. Latulipe and B. Gomez-Mancilla (Laboratoire de Neurobiologie, A 50% reduction (min/h) in the resting tremor was obtained with Dihydropyridines remained ineffective.