A defective control of small-amplitude movements in monkeys with globus pallidus lesions: an experimental study on one component of pallidal bradykinesia

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E L S E V I E R Behavioural Brain Research 72 (1996) 57-62

BEHAVIOURAL BRAIN RESEARCH

R e s e a r c h r e p o r t

A defective control of small-amplitude movements in monkeys with globus pallidus lesions: an experimental study on one component of

pallidal bradykinesia

M e r y e m A l a m y ", J e a n - C l a u d e P o n s a, D a n i e l l e G a m b a r e l l i b, E l i s a b e t h T r o u c h e a , a CNRS, UPR 9013, 31 chemin Joseph Aiguier, 13402 Marseille Cedex 20, France

b Laboratoire d'Anatomh, Pathologique et de Neuropathologie, FacultO de Mddecine, 27 boulevard Jean Moulin, 13385 Marseille, France

Received 25 May 1994; revised 28 February 1995; accepted 28 February 1995

Abstract

The effects of globus pallidus (GP) lesion were examined in two monkeys trained to perform a visually guided pointing movement in simple and choice reaction time tasks involving small and large amplitude movements. The reaction time (RT) and the movement time (MT) were measured. The Y-axis error (EY) was also analyzed in order to assess the movement accuracy.

Unilateral GP lesion was made by locally injecting an excitatory amino acid, quisqualic acid. GP lesion led to little change in the RTs (simple and choice RTs) and in the EY, whereas a large increase in the MT occurred. The MT impairments seem to have been correlated with the movement amplitude, since they were larger in the case of small-amplitude than large-amplitude movements. These results suggest that the GP may be involved in the control of small-amplitude rather than large-amplitude movements. As various studies have shown that proprioceptive cues are more strongly involved in the control of discrete than large-amplitude movement,;, the MT deficit, i.e., the bradykinesia observed here, may reflect a defective integration of proprioceptive information occurring afte:r GP lesion.

Keywords: Globus pallidus; Reaction time task; Accuracy constraint; Movement amplitude; Movement time; Quisqualic acid lesion; Monkey

1. Introduction

The movement deficits resulting from impairment of the basal ganglia can be, either hyperkinetic in the case of involontary movements or hypokinetic, as in the case of the lengthening of movement initiation (akinesia) and decrease in the amplitude and velocity of volontary movements (bradykinesia). These findings are consistent with the idea that the basal ganglia may be involved in the control of both movement initiation and execution.

Studies involving experiraental lesion of the basal ganglia outputs at the level of the globus pallidus (GP) have shown the existence of an impaired movement latency which seemed to depend on the task [ 2 ] and on the availability of visual cues [1,2]. An increase in the movement time was ahvays observed after G P lesion [5,14,19] The decrease observed in the amplitude of the

* Corresponding author. Fax: (33) 91 77 50 83.

initial agonist E M G burst occurring after pallidal lesion [12] may be partly responsible for the lengthening of the m o t o r execution time recorded. The bradykinesia resulting from lesion of the substantia nigra (SN) [4,9,28,31,33], the other basal ganglia output structure, as well as that observed in patients with Parkinson's disease involved an increase in the movement time and in the movement variability [29]. Both in Parkinson's disease [ 10] as well as in animals with experimental SN lesions [ 3 ] , the akinesia was correlated with the movement amplitude and was more marked in movements with large amplitudes. This suggests that the subjects had difficulty in controlling the movement amplitude after lesion of the basal ganglia. The aim of our study was to analyze the akinesia and bradykinesia resulting from pallidal lesions, particularly as regards the control of the movement amplitude. We therefore investigated the effects of G P lesion on monkeys' movement performances in two reaction time tasks involving large and small-amplitude movements.

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58 Meryem Alamy et aL/Behavioural Brain Research 72 (1996) 57-62 2. Materials and methods

2.1. Behavioral task

Two Papio papio monkeys were used in these experiments. The subjects were trained to perform pointing tasks, the one consisting of a simple reaction time task (only subject R was tested in this paradigm) and the other consisting of a choice reaction time task involving a choice of amplitude. The subjects were placed in a working cage facing a vertical pointing board fitted with a handle on the lower part, on which they had to place their hand. After a variable preparatory period (500, 1000, 1500 or 2000 ms), they had to release the handle at the onset of a luminous signal, and point at the signal as accurately as possible with the index finger. The experimental paradigm used here has been described previously [30]. In the simple reaction time task (SRT), only the time of the target onset was unpredictable. In the choice reaction time task (CRT), the location of the target was also unpredictable (Fig. 1), and induced two kinds of movement in the same direction: movements with a large amplitude (target 29 cm from the handle) and those with a smaller amplitude (target 14 cm from the handle). The variables recorded (Fig. 1) were the reaction time (RT), defined as the time elapsing between the onset of the luminous signal and the handle release, the movement time (MT), taken to be the time elapsing between the handle release and the first contact of the finger and the pointing board, and the Y-axis error (EY). The EY were used to assess the movement accuracy, which was taken to be the mean distance between

Handle

---y.-

Stimulus

Contact

PP RT MT

M_

$RT CRT

Fig. 1. Experimental procedure: The subject placed its hand on the handle, thus triggering the onset of a luminous signal (Stimulus) after a variable preparatory period (PP). The reaction time (RT) was the time elapsing between the onset of the luminous signal and the handle release; the movement time ( M T ) was the time between handle release and the first contact made by the monkey's finger on the board. The subjects were trained to perform two reaction time tasks; a simple reaction time task (SRT) and choice reaction time task (CRT) involving large and small-amplitude movements.

the Y-axis coordinate of the target and the contact point, in millimeters. The monkeys received a juice reward whenever the movements were performed correctly, i.e., when 100<RT<600 ms, 100<MT<600 ms and - 20 mm < EY < + 20 mm. The RT and MT limits chose here correspond to a fairly wide range. This is because they had to give the subjects enough time both before and after the GP lesion, to perform the movements as accurately as possible. This accuracy constraint therefore meant that there had to be a trade-off during the performance of the tasks between the speed and the accuracy of the movement.

2.2. Lesion

The two subjects were anesthetized with pentobarbital (Nembutal, 35 mg/kg, i.v.). Their head was fixed in a stereotaxic apparatus adapted for use with radiological methods. The lesion methods used have been previously described [2]. Briefly, lesions were performed by injecting an analog of the excitotoxic amino acid, quisqualic acid (Quis) unilaterally into the GP at 0.18 M. The injections were performed using a Hamilton syringe implanted obliquely at an angle of 70 ° to the horizontal to avoid damaging the internal capsule. Four injections (0.6 gl) were administered in the frontal planes A16 (H3, L12), A17 (H6, L10), A18 (H4, L8) and A19 (H5, L7) into the GP, based on stereotaxic coordinates from the atlas by Davis and Huffman [7]. These coordinates were corrected using a ventriculographic technique and by performing electrophysiological recordings along the needle trajectory to record the spontaneous activity of the structures encountered along an oblique trajectory (Putamen, external segment of the globus pallidus, internal segment of the globus pallidus) at an angle of 70 ° to the horizontal.

2.3. Statistical analysis

After the initial training period, the mean values of the movement variables were recorded during the preoperative period at 10 sessions of 50 trials in each of the two situations. After the GP lesion, these variables were measured for two months and compared with the preoperative values using Student's t-test with a probability threshold of P < 0.05.

2.4. Histology

At the end of the experiments, the monkeys' brains were perfused with formalin, extracted and cut serially into 50 gm thick frontal sections. The slices were double- labelled with luxol blue and cresyl violet to assess the extent of the lesion by performing bilateral comparisons on the cell density and to check whether the passing

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Meryem Alamy et aL /Behavioural Brain Research 72 (1996) 57-62 59

fibers were still intact by analysing the staining on the side of the lesion and on the contralateral side.

3. Results

3.1. Behavioral observations

During the first few postoperative days, the subjects showed a transient tendency to flex their wrist and elbow and to extend the fingers of the hand contralateral to the lesion. These subjects tended to preferentially use the limb ipsilateral to the GP lesion, but they were able to perform the pointing movement with their contralateral limb. No postural impairments were observed in either the head or the posterior limbs.

The effects of GP lesion on the mean RT, MT and EY can be seen from Table 1 in the case of the simple RT (subject R only) anti from Table 2 in that of the

Table 1

Effects o f G P lesion during postoperative period (Postop) on reaction times (RT), movement times ( M T ) and Y axis errors ( E Y ) with small and large-amplitude movements in subject R when performing a simple reaction time task

Amplitude Variables Preop Postop

Small RT (ms) 282 ___ 30 341 ___ 45 a

MT (ms) 132 _ 16 217 _ 41 ~ EY (mm) 9 + 16 - 5 ___ 15 ~

Large R T (ms) 286 + 29 327 _ 43 ~

MT (ms) 184+ 18 252-t-29 ~

EY (mm) 13___6 -16__33

aSignificant difference from preoperative values (Preop) at P < 0 . 0 5 (Student's t-test).

Table 2

Effects o f G P lesion during postoperative period (Postop) on reaction times (RT), movement times ( M T ) and Y axis errors ( E Y ) with small and large-amplitude movements in subject R and E when performing a choice reaction time task

Subject Amplitude Variables Preop Postop

R Small RT (ms) 288 + 36 343 + 54 a

MT (ms) 126+13 241+59 a EY (mm) 7 + 7 5 + 1 2 Large RT (ms) 290 + 32 333 + 40"

MT (ms) 177+14 245+33 ~ EY (mm) 4 + 6 - 2 + 17

E Small

Large

RT (ms) 273 + 16 291 + 2 2 a 1V[T (ms) 163+16 276+45 a EY (mm) 14+2 17+2"

RT (ms) 282+ 19 291 _ 24 MT (ms) 186+ 14 249___ 20 a EY (mm) 13-1-5 15___4 aSignificant difference from preoperative values (Preop) at P < 0 . 0 5 (Student's t-test).

choice RT task (subjects E and R). In the simple RT task, we observed with subject R a significant increase in the RT in both the small-amplitude (20%, t=4.0, P < 0.05) and the large-amplitude movements (15%, t = 2.8, P < 0.05). In the choice RT task, a significant increase in the RT was observed in subjects R and E in the case of small-amplitude movements (19%, t=3.1, P<0.05 and 7%, t=2.3, P<0.05, respectively). The change in RT observed after GP lesion with large-amplitude movements amounted to 15% (t=3.2, P<0.05) with subject R and 3% (t= 1.0, P>0.05) with E. After GP lesion, the increase in RT observed with small-amplitude movements did not differ significantly from the increase in RT measured with large-amplitude movements in either subject R (t=0.1, P>0.05) or E (t=0.9, P>0.05).

In the simple RT task performed by subject R, a significant increase in the MT occurred with both the small-amplitude movements (65%, t=6.9, P<0.05) and the large-amplitude movements (38%, t=6.8, P<0.05).

In the choice RT task, unilateral GP lesion resulted in a significant increase in the MT in the case of small- amplitude movements with both subjects R (88%, t = 14, P<0.05) and E (69%, t = 9 , P<0.05). Similar effects were also observed on the large-amplitude movements with both R (41%, t = 8 , P<0.05) and E (34%, t=8.9, P<0.05). Comparisons of the increase in the MT between small-amplitude and large-amplitude movements showed that the deficit was greater in the case of small-amplitude than large-amplitude movements (t=2.5, P<0.05 with R and t=5.1, P<0.05 with E).

In the simple RT task, a significant increase in the EY was observed after GP lesion in the case of small- amplitude movements (t=2.0, P<0.05) with subject R but not in that of large-amplitude movements (t= 1.6, P>0.05). In the choice RT task, no significant change in EY was observed after GP lesion in the case of small- amplitude movements with subject R (t = 0.3, P > 0.05), but a significant change was observed with E (t=4.1, P<0.05). In the case of large-amplitude movements, there was no significant increase in EY with either small or large-amplitude movements in either subject R (t = 0.8, P>0.05) or E (t=0.9, P>0.05). Comparisons on the effects of GP lesion on EY with small and large- amplitude movements showed that the change in EY was not statistically significant in either subject (t = 0.4;

P > 0.05 with R and t = 1.2, P > 0.05 with E).

3.2. Histology

Histological tests in which bilateral comparisons were carried out on the cell density between the side of the lesion and the contralateral side showed the existence of spared passing fibers and the occurrence of pallidal cell loss accompanied by gliosis. In the two subjects, the lesion was restricted to the two segments of the GP. The extent of the lesion in subjects E and R is given in Fig. 2.

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60 Meryem Alamy et al./Behavioural Brain Research 72 (1996) 57-62 A

B

) ~n

Fig. 2. Histological reconstruction in four frontal planes of the effect of unilateral quisqualic acid injection into the globus pallidus (GP) in subject E (A) and R (B). Shading indicates areas of cell body loss as defined under microscopy in four frontal sections A13, A15, A17, A19. Scale bar: 3 mm. CI, capsula interna; GL, nucleus geniculati lateralis; GPe, external segment of globus pallidus; GPi, internal segment of globus pallidus; Put, putamen; SN, substantia nigra; St, nucleus subthalamicus; III, ventriculus tertius.

In subject E, the damage was observed in the dorso- median part of the G P e and the G P i and extended from A17 to A15 in the anteroposterior plane. In subject R, the lesion extended from A20 to A13 encompassing both the external and internal segments of the GP.

4. Discussion

The results of the present study show that unilateral G P lesion induced small but significant changes in the RT, whereas a large increase in the M T was observed in the simple RT task as well as in the choice RT task.

Little change in EY was observed after G P lesion. These data show that the G P plays an important part in the control of m o t o r execution. In our experimental para-

digm, the m o t o r execution deficit was found to be correlated with the movement amplitude, since the small- amplitude movements were more severely affected by G P lesion than the large-amplitude movements.

After the G P lesion, the RTs showed small but statistically significant changes in both the simple and choice RT tasks. In our experimental paradigm, the G P seems to play a role in m o t o r initiation. These results are not in agreement with those described by other authors who used a similar reaching task [14] or a tracking task [ 15,19]. These authors observed only a non statistically significant change in the RT after G P lesion. This discrepancy may be due to differences between the tasks, involving a different use of visual cues during the movement initiation phase [ 1,2] and/or to differences between the lesion techniques used.

In our study, comparisons between the effects of G P lesion on the simple RT and choice RT task performances of subject R showed that the change in the RT did not depend on the movement amplitude. These data suggest that in our experimental paradigm, the G P was not involved in programming the movement amplitude.

The m o t o r execution deficits observed in our study therefore, do not seem to have been due to any impairment of the amplitude programming. This result is in line with findings by Beaubaton et al. [ 5 ] which showed that the G P does not play a critical role in movement amplitude encoding. Moreover, electrophysiological data have shown that no consistent relationship exists between pallidal activity and movement parameters such as the direction, amplitude and velocity [6,18].

The task used in our study involved an accuracy constraint: no changes in the accuracy of the subjects' performances were observed after G P lesion. The accuracy may have been maintained by the subjects either by moving more slowly after G P lesion, since the M T increased in the present study, and/or by means of a compensatory visual guidance strategy [ 1 ]. The increase in the M T may mean that an increase in the visual control of the movement occurred, since the visual cues became available for a longer time. This control may be more efficient during the terminal adjustment phase, during which the accuracy can be improved [29].

Experimental studies have already shown that visual cues contribute to improving m o t o r performances after G P cooling [5,15] and after SN lesion [31,32].

The lengthening of the movement time observed in our study after G P lesion has also been reported to occur by other authors [5,14,15,19] H o r a k and Anderson [14] have reported that a decrease in the amplitude of the initial agonist E M G burst may be responsible for the lengthening of the movement time after G P lesion. Moreover, the authors of an electrophysiological study have reported that a change in the pattern of cellular activity occurred in the G P which was correlated with the amplitude of the arm movements in 50%

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Meryem Alamy et al./Behavioural Brain Research 72 (1996) 57-62 61

of the GPe cells and in :53% of the GPi neurons tested in monkeys trained to perform a tracking task during the premovement and motor execution phases [ 11 ].

In our experiments, the MT deficit was dependent on the movement amplitude, and was larger in the case of small-amplitude than large-amplitude movements.

Proprioceptive cues are known to be more strongly involved in the control of discrete movements than in those with larger amplitudes [24]. The performances of deafferented patients with proprioceptive disturbances were affected only in the case of small-amplitude movements [24,25]. Moreover, deafferented patients with sensory neuropathy exhibited an impaired effort sense only with small loads, whereas a similar ability to discriminate between larger loads was found to exist in both normal subjects and deafferented patients [24].

The results of several studies have shown that the basal ganglia are involved in the integration of the various kinds of somato-sensory information required to adapt a motor act to the environmental conditions [17,26]. Electrophysiological data have shown that a modulation of the GP activity occurs in response to proprioceptive stimulation [8,13,20,27]. The authors of electrophysiological studies have described the occurrence of short latency, direction specific neuronal responses in response to load perturbation or to passive joint rotation, which confirmed the existence of a proprioceptive drive [8,13,20]. The GP has been thought moreover to influence movement indirectly by modulat- ing the access to the motor system of afferent information most directly relevant to the generating of movement [17]. In the light of all these data, it seems possible that the GP may be involved in the integration of propriocep- tives cues, which would explain why the effects of GP lesion were more obvious in the case of small-amplitude movements, which require the integration of this particular type of information, than in the case of large-amplitude movements.

On the other hand, it has emerged from several studies that the control of movement in reaching tasks depends on visual and propriocepfive cues [16]. Proprioceptive cues were the more effective during motor execution [21] and may intervene specifically in the terminal phase of the trajectory [23], whereas visual cues were the more effective for triggering the movement [22] and during the terminal adjustment phase [16,21]. The effects of a defective proprioceptive integration are prob- ably most obvious during the motor execution phase, as shown by the increase in the movement time recorded in our study.

In conclusion, the extent of pallidal bradykinesia seems to be correlated with the movement amplitude and was found here to be most pronounced with the movements of the more discrete type involved in a reaching task. This bradykinesia may partly reflect a

defective integration of proprioceptive information after GP lesion.

Acknowledgment

The authors wish to thank Mr Georges. Povrda for his help in training the monkeys, Mme M. Auphan for histology and Dr Jessica Blanc for revising the English manuscript. This study was supported by grant MRT 88.C.0578 and Fondation pour la Recherche Mrdicale (FRM, France).

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