Physiopathology of the cerebellum in the monkey

491

Journal of the neurological Sciences, 1974, 22:491-509 ~' Elsevier Scientific Publishing Company, Amsterdam

Printed in The Netherlands

Physiopathology of the Cerebellum in the Monkey Part 2. Motor Disturbances associated with Partial and Complete Destruction of Cerebellar Structures L. J. POIRIER, J. LAFLEUR*, J. DE LEAN**, G. GUIOT*** L. LAROCHELLE**** AND R. BOUCHER Laboratoires de Neurobiologie et D~partement d'Anatomie, Facult~ de M~decine, Universit~ Laval, Quebec (Canada) (Received 16 January, 1974)

INTRODUCTION

In order to gain further information concerning the involvement of certain cerebellar mechanisms in the production of postural tremor (Larochelle, B6dard, Boucher and Poirier 1970) different lesions of the cerebellar structures including total cerebellectomy were produced in a series of monkeys. As certain of these animals, kept under observation for several weeks, concomitantly displayed various motor disturbances which evolved postoperatively in a different way it seemed worth reporting not only on postural tremor but also on the other motor disturbances. In this paper we therefore attempt to correlate the recorded motor disturbances with the different lesions and associated morphological changes. MATERIAL AND METHODS

Twenty-three monkeys (Macacamulatta) of both sexes and weighing from 2-5 kg, were used in this study. Lesions were produced either by surgery or with the help of stereotaxy under pentobarbital anesthaesia. Destruction of the cerebellar peduncles or nuclei was done stereotaxically using a high frequency current directed through a monopolar electrode. Complete or partial removal of the cerebellar structures was achieved by surgery as described elsewhere (Lafleur, De Lean, Boucher, Guiot, Larochelle and Poirier 1974). The superior cerebellar peduncle was unilaterally destroyed before its decussation Supported by Grants (MT-732 and DG-72) from the Medical Research Council of Canada. * Fellow of the Medical Research Council of Canada. ** Fellow of the Qu6bec Medical Research Council. *** Visiting scientist: The Canada Council. **** Scholar of the Medical Research Council of Canada.

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~. J. POIR1ER t'l a[.

at the level of the dorsolateral area of the upper pons in 3 monkeys ~SN2. SN 11 and SN37) which were allowed to survive 26, 7 and 11 weeks, respectively, after the operation. Partial destruction of the dentate (lateral) and interpositus cerebellar nuclei was stereotaxically done on one side in 2 monkeys ISN24 and SN36~ and on both sides in 2 other monkeys (SN20, SN49) which were allowed to survive 24, 70. 26 and 46 weeks after the operation, respectively. In another monkey ISN301 the 3 left cerebellar nuclei were damaged. This animal survived 30 weeks postoperatively. In 1 monkey (C11) the stereotaxic lesion destroyed the fastigial interposltus nuclei of both sides. In another monkey (SN63) nucleus interpositus and part of the fastigial and dentate nuclei were stereotaxically destroyed on both sides. The latter 2 animals were allowed to survive 7 weeks and 2~ years after the operation, respectively. The surgical lesions included total cerebellectomy in 3 monke5 s[C 1, ('4, C'9 ) which were allowed to survive 2, 14 and 48 weeks, respectively. Five monkew (C5. C6, C 10, SN54, SN55) had combined lesions of the cortex and nuclei of the cerebellum. In monkey C5 which survived 19 weeks postoperatively most of the hctmspherical cortex of the posterior lobe, the right flocculus and part of the anterior lobe on the right side were destroyed. In addition the right superior and middle cerebellar peduncles. the right dentate and interpositus nuclei and the left dentate nucleus were involved In monkey C6 which survived 4 weeks postoperatively most of the cerebellar cortex of the left hemisphere was removed and, in addition, the cerebellar nuclei and the middle and inferior cerebellar peduncles were involved on the corresponding side. In monkey CI0 which survived 3 weeks postoperatively the anterior lobe. lobulus simplex, the two superior cerebellar peduncles and the left fastigial nucleus were partially destroyed. In monkeys SN54 and SN55 which had survival periods of 22 and 19 weeks, respectively, most of the cortex of the left half of the posterior lobe of the cerebellum was removed. In addition the left middle cerebellar pc~tuncle and the left dentate nucleus were severely involved in SN54 and the left dentate nucleus was slightly damaged in SN55. Five other monkeys tC2. C3. C7. C8, C12t had lesions of the cortex of the cerebellum. In monkey C2 which survived 20 weeks postoperatively the neocerebellar division of the vermis and part of the culmen and nodulus were removed. In monkey C3 which survived 19 weeks postoperatively the cortex of the left half of the posterior lobe was removed, tn monkeys C7 and C8 which had survival periods of 36 and 35 weeks, respectively, a major part of the left hemispherical division of the posterior lobe (sparing the paravermial cortex) was destroyed. In monkey C t 2 the vermial lesion destroyed the caudal part of the central, the culmen, the clivus and the folium. This animal survived 2 weeks postoperatively Following the lesions the animals were frequently observed either in the cage, in a restraining chair or while moving freely in the animal room. The degree of tonicity was assessed by passive movement of the limbs. The motor disturbances and, more especially, postural tremor, were recorded with the help of cinematography. Postural tremor was also measured by electromyography (EMG). EMGs of the tremulous muscles were taken with copper wires introduced into the muscles through hypodermic needles. A Tektronik cathode ray oscilloscope (Model 565) and a Grass camera (Model C4) were used ['or recording the EMG activity. Except for monkey C1 all animals of this series were injected with harmaline (3 mg/kg, i.m.) one or

CEREBELLAR DISTURBANCES

493

several times. On completion of the experiments all animals were killed by an overdose of pentobarbital and their brains were perfused with 10~ neutral formalin and fixed in a solution of formalin. Schematic drawings of the cortical lesions were done. Serial sections of the brains were prepared and stained with basic fuchsin or cresyl violet and fast blue. RESULTS

Before describing the motor disturbances associated with different cerebellar lesions it appears appropriate to define the terminology used in this report. The main signs encountered in this series of animals include truncal ataxia, dysmetria, hypotonia and intention (acting) and postural (resting) tremor. The terminology used therefore rests to a great extent on the terminology proposed by Gordon Holmes (1922) and Walker and Botterell (1937). Truncal ataxia involves incoordination of the trunk characterized by oscillatory movements when the animal stands up, staggering with or without falling, causing the animal to broaden his base. Dysmetria is characterized by the inability to direct properly or limit the limb movements so that they may overshoot the desired point (hypermetria) or they do not reach the mark (hypometria). The animal with dysmetria decomposes the movement in such a way that "the various components of the act are no longer performed in their proper sequence" (Holmes 1922). Therefore the movements become jerky and awkward. Hypotonia is characterized by a significantly decreased resistance to passive mobilization of the limbs. In addition when "the proximal segment of the limb is shaken there is an abnormally increased excursion of the distal part of the limb as if there was an associated relaxation of the affected joint" (Walker and Botterell 1937). Intention or action tremor displayed during active movements is characterized by non-rhythmic oscillations of one part of the body around its axis. Postural or Parkinson-like tremor is characterized by alternating contractions of agonist and antagonist groups of muscles causing a rhythmic oscillation of one part of the body around its axis, usually at a frequency of approximately &-7/sec. Although the following description includes motor disturbances seen in the immediate postoperative days and partially associated with non-specific damage as a consequence of transient hypoxia and edema of the cerebellum and/or the brain stem, greater importance is given to the more sustained signs of motor impairment.

Efject o[" total cerebellectomy (monkeys CI, C4 and C9) Three monkeys with complete cerebellectomy (C1, C4 and C9) associated with bilateral and very severe to almost total cell loss in the whole olivary complex (except the "dorsal cap"), the pontine and reticulotegmental nuclei and the lateral reticular and lateral cuneate nuclei displayed a similar syndrome (Tables 1 and 2). It was characterized by truncal ataxia, dysmetria, intention tremor and hypotonia of the limbs and postural tremor. Spontaneous and/or drug-induced postoperative postural tremor, however, varied greatly from one animal to another. In all 3 animals the truncal ataxia, hypotonia and dysmetria were much more severe and associated with generalized weakness in the immediate postoperative days; these disturbances rapidly

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L

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Monkeys

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SUMMARY OF LESIONS OF CEREBELLAR STRUCTURES

TABLE

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495

CEREBELLAR DISTURBANCES

TABLE 2 MOTOR D I S T U R B A N C E S A N D EFFECT OF H A R M A L I N E IN M O N K E Y S W I T H ('EREBELLAR LESIONS

Truncal atavia

Monkeys

Cl C4 C9 C5 Cb CI0 SN54 SN55 C2 C3 C7 Cg C12 SN24 SN30 SN36 SN20 SN49 CI] SN63 SN2 SNII SN37

.~a 14 48 19 4 3 22 19 2O 19 36 35 2 24 30 70 26 46 7 142 2(+ 7 II

4h 4--,2 4-~2 3 2 3 0 0 3~1 0 0 0 0 0 0 0 0 0 3 3-+0 0 (I 0

D),smetr~!

H),potonia

L

R

L

R

4 4-+2 4-.2 1-+0 1 3 0 0 0 0 0 0 0 0 0 0 0 0 1--+0 1-+0 0 0 0

4 4-+2 4--+2 0 0 3 0 0 0 0 0 0 0 0 0 0 0 0 1-,0 1--+0 1--,0 0 0

4 4~2 4+2

4 4+2 4-,2 3 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 1 ~0 0 0

1 0 I 0 0 0 0 0 0 0 0 0 (I 0 0 0 0 0 0 I ~0

Lesions-induced postl.'al tremor L R

--+1 0 2 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0

1 0 2-+1 0 0 2 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0

Harmaline-induced postura[ tremor L R not 2 2 2 2 3 1 0 0 I 0 0 0 1 I 1 I 1 0 1 0 1 0

tested 1 3 0 0 3 0 0 0 0 0 0 0 0 0 0 1 I 0 1 1 0 I

P o s t o p e r a t i v e survival p e r i o d in w e e k s . b D e g r e e o f m o t o r disturbance+

improved for a period of 3-4 weeks following which they regressed more slowly. However they seriously impaired the motor performance of the animals until their death, as disclosed in monkeys C4 and C9 that survived 14 and 48 weeks, respectively. Intention tremor+ which was conspicuous during limb movements in the immediate postoperative period, could not be easily assessed after a period of a few weeks. All 3 monkeys displayed spontaneous postural tremor which, however, was present in the immediate postoperative period in 2 monkeys (C1, C9) and only after several days in the other animal (C4). It was more or less conspicuous in one or the other part of the body in the different animals. The administration of harmaline (3 mg/kg) either greatly exaggerated the lesion-induced postural tremor, or else it evoked postural tremor during a period of 3 4 hr in parts of the body which had displayed spontaneous postural tremor in the immediate postoperative period (Table 2).

EIl~,ct (?/'combined k'sions (?./'the cortex and nuclei of the cerebellum (monkeys C5. C6. C10, SN54 and SN55) In monkey C5 the hemispherical cortex of the posterior lobe of the cerebellum was destroyed except for the paraflocculus and part of the paramedian lobule on the left side and part of the paraflocculus on the right side. The caudal part of the

L . J . POIR|ER et al.

496

~C5 ~~

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~

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CEREBELLAR DISTURBANCES

497

anterior quadrangular lobule, the flocculus and the dentate and interpositus nuclei and the superior and middle cerebellar peduncles of the right side and the dentate nucleus of the left side were involved (Fig. 1 and Table 2). In addition this monkey displayed atrophy of the left cerebral peduncle and medullary pyramid, apparently related to the involvement of the corresponding sensori-motor cortex as a consequence of an unascertainable and older cause. These lesions result in almost total cell loss in the principal and medial accessory olives and the pontine nuclei of both sides and the left "dorsal cap" but they caused no detectable cell change in the two dorsal accessory olives and the left lateral cuneate nucleus and only a very slight cell loss in the right "dorsal cap", the right lateral cuneate nucleus and the two reticulotegmental nuclei. The lesions in monkey C5 were associated with severe truncal ataxia, dysmetria of the left limbs present only during the immediate postoperative period, slight and marked hypotonia of the left and right limbs, respectively, and postural tremor of the left limbs that was exaggerated by the administration of harmaline (Table 2). In monkey C6 the lesion involved a major part of the cortex of the left hemisphere sparing the ala centralis. In addition the vestibular area, the cerebellar nuclei and the inferior and middle cerebellar peduncles were damaged on the corresponding side (Figs. 1 and 2B, Table 1). These lesions were associated with almost total cell loss in the right "dorsal cap" and principal olive and with very severe cell loss in the right pontine nuclei. The left lateral reticular and lateral cuneate nuclei displayed very severe and moderate cell losses, respectively. The lesions in monkey C6 were associated with moderate truncal ataxia, slight dysmetria of the left limbs and a cervical dystonia with the chin deviated upwards and towards the left side. Postural tremor did not occur spontaneously in monkey C6 which, however, displayed postural tremor of the trunk and of the left upper limb in response to harmaline during the 4 week postoperative period (Table 2). In monkey C10 the destruction of the anterior lobe and of the lobulus simplex was associated with damage to both superior peduncles and to the left middle and inferior peduncles. In addition the destruction involved the dorsal part of the left fastigial nucleus (Fig. 1, Table l). These lesions caused very severe to almost total cell loss in the right principal and medial accessory olives, the left lateral reticular and lateral cuneate nuclei and in the two reticulotegmental nuclei. They also produced moderate cell loss in the right lateral reticular and lateral cuneate nuclei, the right dorsal accessory olive and the caudal part of right pontine nuclei. The lesions in monkey CI0 were associated during the 3 week postoperative period with severe truncal ataxia and severe dysmetria of the limbs of the two sides and a slight hypotonia of the left limbs. In addition this animal displayed postural tremor of the head, trunk and four limbs. The postural tremor was exaggerated by the administration of harmaline (Table 2). In monkeys SN54 and SN55 the destruction involved most of the cortex ol the left half of the posterior lobe of the cerebellum. In addition the left middle cerebellar peduncle and the left dentate nucleus were severely damaged in SN54 and the left dentate nucleus was slightly involved in SN55, respectively (Fig. 1, Table I). The lesions in these 2 monkeys caused very severe to almost total cell loss in the right

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Fig. 2. ,.I : section through the cerebellum ol mOl~kC5 ~,2 m which a major part of the vcrn,,~, ~as removed Basic fuchsin and fast blue: ~: 5. B: section through the Celebelhml of monkey ('¢~ to sho~ u subtotal lel'l hemicerebcilec*omy. Same stain: ×6. (': section through the cerebellum of monkey CIl to sho~ the bilateral lesions {t-I at ~hc level ol /he fastigial and interpositus nuclei. Same stain: < 5. D: section through the cerebellum of monkey SN20 to show parl of the bilateral lesinn, ~1 )at the Icxcl of the dentate and interpositus nuclei. Same stain: x 4. F,. F: transverse sections through upper pons and lower m~dbram respectivct~, oi molmkt_-x SN2 wha_h had a lesion (L) that cornpletely destroyed the right superior cerebellar peduncle (FI l:,,hnws *,he magnocellular division of the red nuclei (arrows). Note the pallor of the left red nucleus as a consequence of the degeneration of ascending cerebellofugal fibers. Same stare: * 6 and × 10. respectiveb. p r i n c i p a l o l i v e a n d p o n t i n e n u c l e i a n d in t h e r o s t r a l t h i r d o f t h e r i g h t m e d i a l a c c e s s o r y olive. T h e s e l e s i o n s a n d t h e a s s o c i a t e d m o r p h o l o g i c a l sustained and detectable motor

impairment.

c h a n g e s d i d n o t r e s u l t in

The administration

of harmalinc

:tu~

re-

d u c e d p o s t u r a l t r e m o r o f t h e left l i m b s in S N 5 4 b u t d i d n o t c a u s e a n y p e c u l i a r effect in S N 5 5 { T a b l e 21.

CEREBELLAR DISTURBANCES

499

Effect of lesions of the eerebellar cortex (monkeys C2, C3, C7, C8 and C12) In monkey C2 the destruction mainly involved the neocerebellar division of the vermis and impinged at both extremities on the culmen and the nodulus, respectively (Figs. 1 and 2A, Table 1). It was associated with very severe cell loss in the caudtil third of the two medial accessory olives (except the "dorsal cap") and with a slight cell loss in the pontine nuclei of both sides. This monkey displayed severe trunc~ll ataxia which gradually decreased during the 20 week postoperative period. Harmalinc did not induce postural tremor in this monkey (Table 2). In monkey C3 the lesion destroyed the cortex of the left half of the posterior lobe of the cerebellum (Fig. 1, Table 1). It was associated with almost total cell loss in the right principal olive (except the rostral part of the dorsal lamella) and in the rostral part of the right pontine nuclei. The rostral part of the right medial accessory olive also displayed very severe cell loss. The lesion did not produce any detectable motor impairment but the injection of harmaline repeatedly induced postural tremor of the trunk and of the left upper limb in monkey C3 (Table 2). In monkeys C7 and C8 the lesion destroyed a major part of the left hemispherical division of the posterior lobe, sparing the paravermial cortex (Fig. l, Table 1). It was associated with moderate to almost total cell loss in the right principal olive (except the rostral part of the dorsal lamella) and of the caudal part of the right pontine nuclei. No motor impairment was detectable and the administration of harmaline did not induce postural tremor in these 2 monkeys which survived 36 and 35 weeks after the operation, respectively (Table 2). In monkey C12 the vermal lesion involved the caudal part of the central, the culmen, the clivus and the folium (Fig. I, Table 1). No associated morphological changes were observed at the level of the lower brain stem and spinal cord in this animal which, however, was sacrificed within 2 weeks of the operation. The lesion was associated with misjudgement of distance without any other detectable motor impairment (Table 2).

E[]'ect o/lesions of the cerebellar nuclei (monkeys CI 1, SN20, SN24, SN30, SN36, SN49 and SN63) The cerebellar nuclei were more or less extensively destroyed in 7 monkeys (Table 1). In 3 monkeys (SN24, SN30, SN36) the left dentate and interpositus nuclei were partially involved and in addition the left fastigial nucleus was partially damaged in SN30 (Table 1). The lesions which also interrupt fibers surrounding those nuclei in the 3 animals and within the hilum of the dentate nucleus in SN30 and SN36 caused very severe cell loss in the rostral part (SN30, SN36) and over most of the extent (SN24) of the right principal and medial accessory olives. They were also associated with marked pallor of the fibers in approximately the dorsomedial third (SN30) and the ventromedial two-thirds (SN36) of the left superior cerebellar peduncle at the level of the dorsolateral area of the upper pons. In these 3 monkeys there was no sustained and detectable motor impairment but the injection of harmaline repeatedly induced postural tremor of the left upper limb in SN30 and SN36 and of the left limbs in SN24. In 2 other monkeys (SN20, SN49) the lesions partially destroyed the dentate and

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interpositus nuclei of both sides (Fig. 2D), the left and right lesions having been produced 16 and 3 weeks apart in SN20 and SN49. respectively [Fable 1}. In SN20 the lesions which interrupted fibers in the vicinity of these two nuclei were associated with very severe cell loss in approximately the rostral fourth of the teft principal olive and in approximately the rostral two-thirds of the right principal olive and the two medial accessory olives. There was also pallor of the fibers in the middle third of the two superior cerebellar peduncles in monkey SN20. In monkey SN49 the lesions of the cerebellar nuclei, located somewhat more medially than in monkey SN20, mainly interrupted fibers between the dentate and interpositus nuclei on both sides. The lesions were associated with moderate cell loss in the most rostral parts of the principal and medial accessory olives, the cell loss being somewhat more important on the right than on the left side. The lesions also resulted m marked pallor of the fibers in the middle third of the two superior cerebellar peduncles. The lesions did not produce any conspicuous motor .npairment in monkeys SN20 and SN49 but the injection of harmaline repeatedly produced postural tremor m the right upper and the left limbs of SN20 and in all four limbs of SN49 In the latter monkey, however, the harmaline-induced postural tremor of the two lower limbs was observed only in the postoperative period immediately followinu the second operation (Table 2). In monkey C11 the lesion destroyed on both sides the fastigial nucleus and extended laterally in nucleus interpositus: ventrally it destroyed the nodulus and interrupted fibers coursing in this area (Fig. 2C). In monkey SN63 a somewhat more laterally and caudally-located lesion destroyed on both sides nucleus interpositus and extended on each side in the fastigial and dentate nuclei, respectively. It also destroyed the uvula and fibers coursing on each side of this structure [Table 1 I. In the 2 monkeys the lesions caused very severe to almost total cell loss over all the extem [C111 and approximately the rostral two-thirds (SN63) of the dorsal and medial accessor> olives of both sides but not in the "dorsal caps" of the medial accessory olives, In addition the two lateral reticular nuclei displayed moderate cell toss in monkey SN63. in monkey Cll the lesions were associated with severe truncal ataxia, dvsmetria of the limbs of both sides and intention tremor which gradually became less conspicuous. The animal which stood up and walked on a broad base easily staggered and fell to one or the other side. There was no detectable hypotonia and the administration of harmaline did not induce postural tremor in monkey C I1 [Table 21. In monkey SN63 the bilateral lesions also resulted in truncal ataxia and dysmetria of the limbs which rapidly improved postoperatively. In this animal, however, the injection of harmaline repeatedly induced postural tremor of the two upper limbs over a period of 2½ years (Table 2).

Elfect of lesion of the superior cerehetlar peduncle (monkeys SN2, SNll and SN37} In 3 monkeys a unilateral lesion located in the dorsolateral part of the upper pons destroyed the superior cerebellar peduncle. In SN2 the right superior cerebellar peduncle was completely severed (Figs. 2E, 2F); in SNI1 the lesion destroyed the lateral half of the left superior cerebellar peduncle and in SN37 the lateral two-thirds of the right superior cerebeltar peduncle. In addition the ventral spino-cerebellar

CEREBELLAR DISTURBANCES

501

tract is interrupted in the 3 animals. SN2 displayed hypotonia and dysmetria associated with intention tremor in the right limbs and SN37 displayed hypotonia of the left limbs during the immediate postoperative period. All these signs, however, regressed and were undetectable after a few days. In all 3 monkeys the injection of harmaline (3 mg/kg) repeatedly induced postural tremor of the limbs ipsilaterally to the lesion, that is, the right limbs of SN2 and SN37 and the left upper limb of SN11 (Table 2). DISCUSSION

Several workers have reported truncal ataxia, dysmetria (of the limbs) and ataxic tremor following total (Luciani 1891; Munk 1906; Rademaker 1931; Aring and Fulton 1936)and subtotal (Ferrier and Turner 1894; Russell 1894; Lewandowski 1903) cerebellectomy in the monkey. Aring and Fulton (1936), however, were the first to point out the fact that the cerebellar signs regressed markedly, especially during the first 2 postoperative months. Nevertheless they neither mentioned simple or postural tremor nor described hypotonia following complete cerebellectomy. Truncal ataxia

Carrea and Mettler (1947) claimed that disturbances of equilibrium may be clinically distinguished from truncal ataxia in the monkey by the fact that animals with an impairment of equilibrium would be unable to escape or defend themselves, although they could display a type of incoordination similar to that in monkeys with truncal ataxia during locomotion. Disturbances of equilibrium in the monkey have been observed following section of the eighth nerve (Northington and Barrera 1934) destruction of the labyrinth (Northington and Barrera 1934; Dow 1938; Dow and Moruzzi 1958) or of the medial vestibular nucleus (Ferraro, Pacella and Barrera 1940). Similar disturbances have been reported following removal of the vermis in lower vertebrates (Russell 1894; Rothman 1913; Simonelli 1921)and in primates (Ferrier and Turner 1894; Botterell and Fulton 1938). Dow (1938), however, was the first to point out that such disturbances of equilibrium (or truncal ataxia) mainly involve lesions of the uvula and nodulus of the vermis. He also noted that truncal ataxia was unassociated with dysmetria, hypotonia and tremor of the limbs. Carrea and Mettler (1947), who confirmed the results of Dow, observed, in addition, that a bilateral destruction of the flocculus also resulted in a similar disturbance which, however, was not as severe and sustained as the truncal ataxia associated with the destruction of the uvula and nodulus. On the other hand, Carpenter (1959) also reported similar motor disturbances following bilateral destruction of the fastigial nuclei. He, however, mentioned that they rapidly (within 15 days) regressed unless the lesion simultaneously involved the fastigial nuclei and the nodulus. In this study truncal ataxia was present in monkeys following total cerebellectomy (CI, C4, C9), combined lesions of the cerebellar cortex and the cerebellar nuclei and/or the cerebellar inferior peduncle (C5, C6, C10), a lesion that involved the cortex of the neovermis and of the nodulus (C2) and bilateral lesions of the cerebellar nuclei (mainly the fastigial and interpositus nuclei) and of structures in the immediate vicinity including the nodulus or uvula and associated fiber fascicles (CI 1, SN63).

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~.. J. POIR1ER e l a[.

The latter motor disturbance, however, was not present in monkey CI2 lollowing removal of the culmen, clivus and folium and part of the centrum ; in the monkeys C3, SN54 and SN55 following removal of approximately the left half of the cortex of the posterior lobe associated with damage to the dentate nuclei in SN54 and SN55 ; and in monkeys SN20 and SN49 following bilateral lesions of the dentate and interpositus nuclei. These data which, in general, confirm the findings of Dow (I.938I) and those of other workers mentioned above, point to a close relationship between the involvement of the archicerebellum and its interconnections with the vestibular and fastigial nuclei and the appearance of truncal ataxia. It appears worth mentioning the fact that the medial accessory olive (especially its caudal part) and the dorsal accessory olive appear anatomically related to the flocculo-nodular lobe (and most likely to the uvula as well) and to the cerebellar nuclei (especially the fastigiai nucleus), respectively (this paper and Lafleur et al. 1974). Therefore the medial and dorsal accessory olives may represent important relay nuclei involved in the activity of the paleocerebellum, the uvula and the fastigial nuclei. D.vsmetria

Dysmetria (incoordination of the limbs) has been reported following lesions of the cerebellar hemisphere (Botterell and Fulton 1938 }, combined destruction of the hemispherical part of the anterior lobe and lobulus simplex (Carrea and Mettler 1947) or lesions of the cerebellar nuclei (Botterell and Fulton 1938: Carrea and Mettler 1947) following interruption of the superior cerebellar peduncle (Ferrier and Turner 1894; Ferraro and Barrera 1936: Walker and Botterell 1937: Carrea and Mettler 1955). It must, however, be mentioned that most lesions described above were not only not elective but, in addition, they more or less extensively destroyed neighbouring structures. For instance the lesions of the "deep cerebellar nuclei" described by Carrea and Mettter (1947) were associated with destruction of an area of the cerebellar cortex located at the junction between the paramedian lobule and crus It. In the present study (Table 2) bilateral dysmetria was severe only in 3 cerebellectomized monkeys (C1, C4, C9) and in another monkey (C10) which was allowed to survive 3 weeks following a combined lesion of the anterior lobe and tobulus simplex associated with extensive damage to both superior peduncles and to the left middle and inferior cerebellar peduncles as well as to the dorsal part of the left fastigial nucleus. On the one hand. moderate and transient dysmetria was observed in the limbs of both sides in animals with bilateral lesions of the fastigial and interpositus nuclei and the nodulus (C11 ) and with bilateral lesions involving mainly the uvula and nucleus interpositus but also parts of the dentate and fastigial nuclei (SN63). Moderate dysmetria of the left limbs was observed in 2 monkeys (C5, C6). In monkey C5 the bilateral lesions destroyed both hemispheric'a/divisions of the posterior lobe and involved the caudal part of the anterior lobe. the flocculus, the dentate and interpositus nuclei and the superior and middle cerebellar peduncles on the right side and the left dentate nucleus. In addition atrophy of the left medullary pyramid (unrelated to the lesions and of undetermined cause) possibly explained the absence of dysmetria in the right limbs in this particular monkey. In monkey C6 the lesion involved a major part of the cortex of the left hemisphere associated with damage

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to the cerebellar nuclei and the middle and inferior cerebellar peduncles on the corresponding side. In another monkey (SN2) transient and moderate dysmetria of the right limbs was associated with a lesion completely interrupting the fibers of the superior cerebellar peduncle and the ventral spinocerebellar tract at the level of the dorsolateral area of the upper pons. On the other hand more or less extensive destruction of the neocerebellar cortex of one side (C3, C7, C8) did not result in any detectable motor impairment as previously shown by Keller, Roy and Chase (1937) in monkeys with lesions of the posterior lobe that spared the deep cerebellar nuclei. It is also important to point out that several monkeys of this series with unilateral (SN24, SN30, SN36) or bilateral damage (SN20, SN49) to the dentate and interpositus nuclei showed no obvious motor disturbance. In the light of these data pointing out the absence or the marked compensation of dysmetria following different cerebellar lesions it appears that marked and sustained dysmetria{ associated with lesions which more especially include destruction of the anterior lobe and/or the inferior and superior cerebellar peduncles) is not dependent on the unilateral involvement of any particular structure of the cerebellum such as lesions confined to either the anterior or posterior lobe or combined lesions of the interpositus and fastigial nuclei or the interpositus and dentate nuclei. In this respect it is worth mentioning that both divisions (anterior and posterior lobes) of the cerebellum apparently receive information through branches of the same spinocerebellar axon (Armstrong, Harvey and Schild 1971: Cooke, Larson, Oscarsson and Sjolund 1971 ; Oscarsson 1973; see also review article by Massion 1973). Postural tremor

In this study postural tremor of the head, trunk and limbs was displayed by 3 cerebellectomized monkeys (C 1, C4, C9), and 2 other monkeys (C5, C 10) with bilateral and combined lesions of the cortex and of the cerebellar peduncles and nuclei. The tremor bursts, generally speaking, were less frequent and their amplitude less marked, especially in the limbs in the more remote postoperative period. The results may be compared with those of Carpenter and Stevens (1957) who reported postural or simple tremor in certain monkeys with surgically-induced lesions of the deep nuclei and the superior peduncle of the cerebellum. The present findings suggest that complete cerebellectomy, per se, would be sufficient to produce spontaneous, simple or postural tremor. Except for irregular attacks of postural tremor which were more obvious during the immediate postoperative period, the tremor bursts (4~7/sec) associated with complete cerebellectomy, however, were not as sustained and conspicuous as the type of tremor resulting from a unilateral lesion of the ventromedial tegmental area at midbrain level (Poirier 1960; Poirier, Sourkes, Bouvier, Boucher and Carabin 1966; Poirier, Bouvier, B6dard, Boucher, Larochelle, Olivier and Singh 1969). Unilateral and extensive destruction of the neocerebellar cortex on one side (monkeys C3, C7, C8)with slight (SN55)and severe damage (SN54)to the dentate nucleus or destruction of a major part of the cortex of an hemisphere associated with damage to the cerebellar nuclei on the same side (C6), however, did not result in any attack of spontaneously occurring postural tremor. Lesions of the cerebellar nuclei of one (SN24, SN30, SN36) or both sides (CI 1, SN20, SN49, SN63)

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or interruption of the superior cerebellar peduncle (SN2, SNI 1. SN37} did not cause any spontaneous spell of postural tremor in these monkeys. Therefore the attacks of postural tremor, transiently present in most instances, following extensive destruction of the cerebellum, could be related to disturbances involving not only cerebellar structures but also extracerebellar mechanisms. First. the associated major surgical trauma and the resulting edema may transiently disturb the normal functioning of different structures of the brain stem. Another consequence of the acute removal of the whole cerebellum is the bilateral suppression of numerous cerebellar efferent fibers normally reaching different levels of the brain stem. Therefore the acute suppression of many influences originating in the cerebellum and normally reaching the thalamus, the ponto-mesencephalic tegmentum including both divisions of the red nuclei, the medullary gigantocellular nuclei, etc. may also represent an ~mportant factor in the appearance of postural tremor especially in the immediate postoperative period. Complete cerebellectomy is also associated with the retrograde degeneration of numerous cell groups at the level of the brain stem and spinal cord (Brodal 1967. Lafleur et al. 1974; see also review article by Angaut 1973). These numerous neurons which project to the cerebellum could give rise to smaller ramifications ending in other structures of the brain stem and. therefore, their acute inactivation must also be taken into consideration in the appearance of postural tremor and other motor disturbances associated with extensive removal of the cerebellar structures. As described above with the exception of 5 monkeys with bilateral and extensive lesions of the cerebellar structures no spontaneously-occurring attacks of postural tremor were displayed by the other monkeys of this series following various unilateral and bilateral lesions of the cerebellum. As also reported previously (Larochelle et al. 1970) isolated lesions of the cerebellar nuclei, the superior cerebellar peduncle and the rubro-olivary fibers did not lead to the production ofpostural tremor in monkeys. In contradistinction the combined interruption of the rubro-olivary fibers and the corresponding nigrostriatal fibers represem an important neuropathological feature in the production of sustained and lesion-induced postural tremor (Poirier et al. 1969: Larochelle et al. 1970). Similarly the interruption of the rubro-olivo-cerebetlo-rubral loop at one point or another is associated with postural tremor only when harmaline (Larochelle et al. 1970) or another drug interfering with the metabolism of dopaminc. such as alpha-methyl-tyrosine (Bddard, Larochelle. Poirier and Sourkes 19701, haloperidol or reserpine (Larochelle, B6dard. Poirier and Sourkes 19711 is administered to the lesioned animal. Under such conditions the above-mentioned drugs apparently complete the lesion by causing a pharmacological interrupuon of the dopaminergic nigrostriatal pathway. In this study the administration of harmaline (3 mg/kg) either exaggerated the amplitude and increased the number of tremorigenic bursts {over a period of"approximately 3 hr) in groups of muscles that already displayed spontaneously-occurring post-lesional bursts associated with postural tremor, or else. harmaline induced tremor in parts of the body that had already displayed postural tremor in the immediate postoperative period in the same animals [monkeys CI, C4. C5, C9. C10J. In monkey C5, in which, however, there was concomitantly atrophy of the left cerebral peduncle (of undetermined cause} harmaline induced postural tremor oI

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the left but not of the right limbs. Moreover harmaline induced postural tremor in the ipsilateral limbs following unilateral damage to the dentate and interpositus nuclei (SN24, SN36) or to the cerebellar nuclei (SN30), or following destruction of the left half of the posterior lobe (C3) associated with severe damage to the left dentate nucleus (SN54) or almost total destruction of the cortex of one hemisphere associated with damage to the corresponding three cerebellar nuclei (C6) or partial or complete destruction of the superior cerebellar peduncle (SN2, SNI 1, SN37). Harmaline also caused postural tremor of the limbs of the 2 sides following bilateral damage to the dentate and interpositus nuclei (SN20, SN49) or destruction of the interpositus nuclei associated with damage to the dentate and fastigial nuclei (SN63) but not following bilateral lesions of the fastigial and interpositus nuclei (Cll). Harmaline did not produce any peculiar effect in monkeys with partial (C7, C8) or extensive (SN55) lesions of the neocortex of one side and in monkeys with lesions of approximately the anterior third of the vermis (C12) or of the whole neovermis and part of the culmen and nodulus (C2). In the light of the present and previous (Poirier et al. 1969; Larochelle et al. 1970] data it seems that the cerebellar structures whose damage represents an important factor in the appearance of postural tremor include an extensive area of the neocerebellar cortex, the corresponding cerebellopetal fibers from the principal olive and cerebellar corticofugal fibers ending in the corresponding dentate nucleus as well as cerebellofugal fibers originating in the latter structure and leaving the cerebellum by way of the superior cerebellar peduncle. In view of the fact that the dentate nucleus projects predominantly to the parvocellular division of the red nucleus and to the ventrolateral thalamic area (Mehler, Vernier and Nauta 1958; Flumerfelt, Otabe and Courville 1973) it is interesting to mention that two latter structures (parvocellular division of the red nucleus and ventrolateral thalamic area) have been shown to represent important targets in the production (Larochelle et al. 1970) and in the abolition of postural tremor, respectively. In summary, the disturbances of cerebellar activity contributing to the production of sustained postural tremor seem more specifically related to a series of interconnected nervous stru6tures. They include the rubro-olivary fibers originating in the parvocellular division of the red nucleus and ending in the neo-olivary part of the principal olive (Keller and Hare 1934; Poirier and Bouvier 1966), corresponding olivocerebellar fibers projecting to a wide area of the cerebellar neocortex as well as corticofugal fibers from the neocerebellar cortex to the dentate nucleus. This nervous circuitry also includes fibers from the latter nucleus to the parvocellular division of the red nucleus and to the ventrolateral thalamus by way of the superior cerebellar peduncle. Therefore it seems conceivable that a disruption of the above-mentioned series of interrelated nervous structures represents an important feature in the resulting disturbances of nervous activity taking place most likely at the level of the ventrolateral thalamus which represents the main target at which neurosurgeons aim to suppress tremor in Parkinsonian patients. Intention tremor and hypotonia

Generally speaking intention (acting) tremor was displayed by monkeys with extensive and bilateral lesions and more especially during the immediate postoperative

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period. Similarly hypotonia which was also more easily detectable in monkeys with extensive and bilateral lesions became less obvious m the late postoperative period (Table 2). The production of either intention [actingJ tremor and or hypotonia m monkeys have been attributed to lesions of the cerebellar hemispheres [Botterell and Fulton 1938) or to the interruption of the superior cerebellar peduncle l Walker and Botterell 1937; Carrea and Mettler [955 : Carpenter and Stevens 1957 : Poirier 1960). In the light of the data obtained ill this study and. more especially, m monkey> with long-standing lesions, it seems conceivable that these disturbances are. to ~l great extent, compensated by brain stem motor regulatory mechanisms which arc under the influence of numerous descending fibers from the cerebral cortcx tn addition to those from the cerebellar nuclei. The latter suggestion is supported by the t'acl that marked and sustained hypotonia may be observed in the contralateral limbs following lower midbrain ventromedial tegmental lesions which concomitantl~ interrupt ascending cerebellofugal fibers and the corresponding descending rubrotegrrlentospinal tract (Poirier et al. 1969).

SUMMARY

Profound truncal ataxia, dysmetria, posturat tremor of the head, trunk and limbs and hypotonia and intention (acting) tremor of the limbs were displayed by 3 monkeys with total cerebeltectomy and 2 monkeys with extensive damage to several structures of the cerebellum. Truncal ataxia, dysmetria, hypotonia and intention tremor gradually diminished during the immediate postoperative period whereas postural tremor became less conspicuous. The administration of harmaline, however, exaggerated or evoked postural tremor of the limbs and trunk for a period of 3-4 hr in these monkeys. On the one hand lesions of the vermis of the posterior lobe and of part of the nodulus in one animal or of the interpositus and fastigial nuclei of both sides and the nodulus in another animal or destruction of the uvula and the interpositus nuclei associated with partial involvement of dentate and fastigial nuclei of both sides in a third animal resulted in truncal ataxia and transient dysmetria. The latter animal repeatedly displayed postural tremor of the two upper limbs in response to harmaline. Harmaline, however, did not produce any peculiar effect in the 2 former animals. On the other hand unilateral or bilateral lesions of the dentate and interpositus nuclei or destruction of the left half of the posterior lobe (with or without involvement of the corresponding dentate nucleus) or interruption of the superior cerebellar peduncle did not result in any marked and/or sustained motor impairment. Nine out of l0 monkeys with such lesions, however, displayed postural tremor of the ipsilaterat limbs after the administration of harmaline. Truncal ataxia predominantly involves a disturbance of the uvula and nodulus and/or the fastigial nuclei and their interconnections with the vestibular nuclei and. most likely, with the dorsal and medial accessory olives. Dysmetria (or incoordination of the limbs) is apparently related to a combined impairment of structures of the anterior and posterior lobes of the cerebellum and their corresponding interconneclions with the cerebellar nuclei. Postural tremor is partly related to a disturbance

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at the level of a series of phylogenetically more recent structures including parts of the principal olive, neocerebellar cortex and dentate nucleus and the parvocellular division of the red nucleus as well as their nervous interconnections.

RESUME La c6r6bellectomie totale ou sub-totale s'accompagne d'ataxie tronculaire grave, de dysm6trie des membres, de tremblement postural de la t~te, du tronc et des membres ainsi que d'hypotonie et de tremblement d'action int6ressant surtout les membres sup6rieurs. L'ataxie tronculaire, la dysm6trie et l'hypotonie r6gressent durant la p6riode postop6ratoire tandis que le tremblement postural et le tremblement d'action deviennent presque imperceptibles, Par contre l'administration d'harmaline /lces animaux exag6re le tremblement postural d6j/~ existant ou le provoque. D'une part la destruction du vermis du lobe post6rieur et du nodule ou des deux noyaux interpos6s et fastigiaux ou l'atteinte bilat6rale et partielle des trois noyaux du cervelet s'accompagne d'ataxie tronculaire et de dysm6trie se manifestant transitoirement. Par contre l'harmaline administr6e /t 3 singes porteurs de 16sions des noyaux du cervelet n'induit du tremblement postural que chez Fun d'entre eux o4 la 16sion touche les noyaux dentel6s. D'autre part l'atteinte uni- ou bilat6rale des noyaux dentel6 et interpos6 ou la destruction de la moiti6 gauche du lobe post6rieur (avec ou sans atteinte du noyaux dent61e correspondant) ou, encore, l'interruption du p6doncule c6r6belleux supbrieur n'entraine aucun d6ficit moteur grave et/ou permanent. Cependant 9 des 10 singes porteurs de telles 16sions ont accus6 du tremblement postural des membres ipsilat6ral en r6ponse/i l'harmaline. L'ataxie tronculaire implique primordialement l'atteinte de l'uvule et du nodule et/ou des noyaux fastigiaux et de leurs interconnexions avec les noyaux vestibulaires et, selon toute 6vidence, avec les olives accessoires m6dianes et dorsales. La dysm6trie ou incoordination des membres semble reli6e /l l'atteinte de structures des lobes antbrieur et post6rieur du cervelet et de leurs interconnexions avec les noyaux du cervelet. Le tremblement postural (ou de repos) met en cause un ensemble de structures phylog6n6tiquement plus r6centes localis6es au niveau de l'olive principale, du n6ocortex du cervelet et du noyau dentel6 en plus du noyau rouge (division parvicellulaire) et leurs interconnexions nerveuses.

REFERENCES A NGAUT,P. (1973)Basesanatomo-fonctionnellesdes interrelations c6r6bello-c6r6brales,J. Physiol. (Par&).

67:53A-116A. ARING.C. D. ANDJ. F. FULTON(1936) Relation of the cerebrum to the cerebellum, Part 2 (Cerebellar tremor in the monkeyand its absence after removal of the principal excitable areas f the cerebral cortex {area 4 and 6a, upper part)), Part 3 (Accentuationof cerebellar tremor followinglesions of the premotor area (area 6a, upper part)), Arch. Neurol. Psychiat. (Chic.), 35: 439-466. ARMSTRONG,D. M., R. J. HARVEYANDR. F. SCHILD(1971) Distribution in the anterior lobe cerebellum of branches from climbing fibres to the paramedian lobule, Brain Res., 25: 203-206. BEDARD,P., L. LAROCHELLE,L. J. POIRIERANDT. L. SOURKES(1970) Reversible effect of L-DOPA on tremor and catatonia induced by alpha-methyl-paratyrosine, Canad. J. Physiol. Pharmacol., 48 : 82 84. BOTTERELL, E. H. ANDJ. F. FULTON(1938) Functional localization in the cerebellum of primates, Part I

508

l.. J. POIRIER et

al.

(Unilateral section of the peduncles), .I. comp. Neurol., 6q: 31 40. BRODAL, A. (1967) Anatomical studies of cerebellar fibre connections with special reference ~o problems of functional localisation. In: C. A. Fox AND R. S. SNn)rR {Eds.J. The Cerebellum (Progress in Brain Research, Vol. 25}, Elsevier, Amsterdam, pp. 135 173. CARPENTER, M, B. (1959) Lesions of the fastigial nuclei in the rhesus monkey, Amer. ,I..-t~t,~. t04:1 33. CARPENTER, M. B. AND G. H. STEW:NS (1957) Structural and functional relationships between the deep cerebellar nuclei and the brachium conjunctivum in the rhesus monkey, J. cornp. Neut,/., t(17:109 -163 CARREA, R. M. E. AND F. A. METTLER (19471 Physiologic consequences following extensive removals of the eerebellar cortex and deep cerebellar nuclei and effect of secondary cerebral ablations in the primate, J. eomp. Neurol., 87: 169-288. CARREA. R. M. E. AND F. A. METTLER (1955) Function of the primate brachium conjunctivmn and related structures, J. comp, Neuro/., 102:151 322. COOKE, J. D., B. LARSON, O. OSCARSSON ANI} B. SJ(HA'ND {1971 ) Origin and termination of ctmeocerebellar tract, L~p. Brain Res., 13:339 358. Dow, R. S. (1938) Effect of lesions in the vestibular part of cerebellum in primates, Arc4z. Nomad. PsvdH~t. (Chic. J, 40: 500-520. Dow, R. S. AND G. MORUZZI (19581 77/e Phvsialoy) and Pathology of the Cerebellunl. Umverslty of Minnesota Press, Minneapolis, Minn. FERRARO. A. ANI) S. E. BARRERA 11936~ The effects of lesions of the superior cerebellar peduncle in the Macacus rhesus monkey, Bull. neurol, lnst N.Y, 5 : 1 6 5 170. FERRARO, A., B, L, PA('ELLA AND S. E. BARRERA [19401 Effects of lesions of medial vestibular nucleus: anatomical and physiological study in ~lacacus rhesus monkeys..I, comp. Neurol.. 73: - Z6. FERRIER, D. AND W. A, TURNER [18941 A record of experiments illustrative of the symptomatology and degeneration following lesions of the cerebellum a n d its peduncles and related structures m monkeys, Phil. Trans. roy. Sot., London, Scr. B.. 185:719 778. FLt:MERFEt, I-, B. A.. S. OTARE AND J. COtJRVILI,E 119731 Distinct projections to the red nucleus IYom the dentate and interposed nuclei in the monkey, Brain Res., 50, 408-414. HOLMES. G. (19221 The Croonian lectures on the clinical symptoms of cerebellar disease and their interpretation, Lancet, 100 (1): 1177 1182, 1231- 1237: 100[2): 59 65, 111 115. KELLER. A. D. AND W. K. HARE [19341 Rubrospinal tracts in monkey. Effects of experimental secuon. Arch. Neurol. Psychiat. (Chic.. 32:1253 1272. KlZt LER, A. D., R. S. Roy AND W. P. CHASE 119371 Extirpations of the neocerebellar cortex without elicitmg so-called cerebellar signs. Amer. J. Phl'xioL. 118 720-733. LAEI,EUR. J.. J. DE L~AN AND L. J. POtRIER I1974/ Physiopathology of the cerebellum m tile monkey. Part I (Origin of cerebellar aflerem nervous fibers from the spinal cord and brain stem ~.J, m,urol. Sci.. 22: 47l 490, LAROCHEtLi~, L.. P. BI~DARD, R. BOt/CHIiR AND L. J. POIRIER 119701 The rubro-olivo-cerebello-rubral loop and postural tremor in the monkey, J. neuroL Sci., 11. 1. 53 64. LAROCHEt LE, L.. P. B~DARD, L. J PO1RW:RAND T. L. SOURKES [1971 I Correlative neuroanatomical and neuropharmacological study of tremor and catatonia in the monkey, Neuropharmacolooy, I 0. 3, 273-288. LEWANDOWSK1, M. (1903) Ueber die Verrichtungen des Kleinhirns. Arch. Anat, Phvxiol, ,,~hvsioL Abt.. -.27:129 191. L/'('IANI, L. (1891) II ('err'elletto." Nuori Studi di Fisioloaia Normah' e Patologtcu. Le Molmier. Firenze: G e r m a n translation. E. Besold, Leipzig. 1893. MASSION, J. (1973) Intervention des voles crrrbe Ilo-corticales et cortlcocOrrbelleuses dans l'organisation et la regulation du mouvement, ,1. Pht's-iol. (Pari,s~, 67: 117Axl70A. MEH1,ER, W. R., V. G. VERNIER AND W. J. H. NAUTA (1958} Efferent projections from dentate and interpositus nuclei in primates, Anal. Rec.. 130. 430. Mt:NK, H. [19061 Ueber die Funktionen des Kleinhirns, S.-B. Kon. preuss. Akad. Wis,~.. 2 2 : 4 4 3 480. NORTHINGTON, P. AND S. E. BARRF,RA [19341 Effects of unilateral and bilateral labyrinthectomy and intracranial section of eighth nerve: experiments on monkeys, Arch. NeuroL Psvchiat. Chic, , 32:51 7t. OSCARSSON, O. (19731 Functional orgamzation of spinocerebellar paths, In: A. I~;G~) {Ed.I. Handbook ~,f Sensory Physioloyy, Vol. 2 The Somatosensory System ), Springer, Berlin. pp. 339-380. P~)IRIER, L. J. {1960) Experimental and histological study of midbrain dyskinesias, J Neurophvsiol.. 23: 534-551. POIRIER, L. J. AND G. BOUWER 11966} The red nucleus and its efferent nervous pathways in the monkey, J. comp. Neurol., 128:222 244. POIRIER, L. J.. T. L. SOURKES. G. BOUV1ER. R. BOU('HI~ZRAND S. CARABIN 119661 Striatal amines, experimental tremor and the effect of harmaline in the monkey, Brain. 89: 37- 52. POIRIER, L. J., ~ . ~OUVIER, P. BEI)ARI). R BOUCHER, L. LAROCHELI.I', A. OLIVIER AND |). ,~INGII 11969

CEREBELLAR DISTURBANCES

509

Essai sur les circuits neuronaux impliqu6s dans le tremblement postural et l'hypokin6sie. Rev. neurol.. 120: 15-40. RADEMAr~ER, G. G. J. (1931) Das Stehen, Springer, Berlin. ROTHMAN, M. (1913) Zur Kleinhirnlokalisation, Berl. klin. Wschr., 50: 33f~339. Rt~sst~I,L, J. S. R. (1894) Experimental researches into the functions of the cerebellum, Phil. Trans. roy. Sot., London Set. B., 185:819 861. SIMOYEI H. G. (1921) Sulla funzione dei lobi medi del cervelletto, (II lobo posteriore (pyramis, uvula, nodulus, secondo ingvar)), Arch. ji'siol., 19:447 479. WALKER, A. E. AYD E. H. BO'rXERELI~(1937) The syndrome of the superior cerebellar peduncle in the monkey, BrahT, 60:329 353.