Basal Gang, Centre National de la Recherche Scientifique Unité Mixte de Recherche 5543, Université Victor Segalen Bordeaux 2, 33076 Bordeaux Cedex, France
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ABSTRACT |
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Boraud, T., E. Bezard, B. Bioulac, and C. E. Gross. Ratio of Inhibited-to-Activated Pallidal Neurons Decreases Dramatically During Passive Limb Movement in the MPTP-Treated Monkey. J. Neurophysiol. 83: 1760-1763, 2000. Mink advanced the hypothesis in 1996 that the role of the basal ganglia (BG) is primarily one of focused selection; the encouragement of motor mechanisms inducing a desired movement and the inhibition of competing mechanisms. This would imply, in normal subjects, a ratio of inhibited-to-activated (I/A) movement-related globus pallidus pars internalis (GPi) neurons <1 and a drastic decrease of this ratio in the parkinsonian state. 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) intoxication should therefore decrease the specificity of the response of this neuronal population. To test this working hypothesis we studied the activity of GPi neurons in response to passive limb movement in the normal and the parkinsonian monkey. Extracellular unit recordings monitored any correlation between passive limb movements and eventual modifications of the neuronal activity of the GPi in two calm, awake, and drug naive monkeys (Macaca fascicularis) before and after MPTP intoxication. In the normal animal, arm- and leg-related neurons were located in clusters in the medial part of the GPi. The I/A ratio was 0.22. Most GPi cells were linked to a single joint. In the MPTP-treated monkey, the number of movement-related neurons increased, the I/A ratio dropped significantly to 0.03, and most responding cells were linked to several joints. These data, which cannot be explained by the classic "box" model, endorse Mink's hypothesis.
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INTRODUCTION |
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The term basal ganglia (BG) comprises a certain
number of nuclei in the forebrain, diencephalon, and midbrain thought
to play a significant role in the control of posture and movement
(Alexander and Crutcher 1990). It has been well
documented that subjects with degenerative diseases of the BG such as
Parkinson's disease (PD) can suffer from rigidity, abnormal posture,
and slowness in movement, and eventually present involuntary movements
induced by dopatherapy (Agid 1991
). Several aspects of
BG physiopathology can be explained by the "box" model of
organization proposed in the late 1980s (Albin et al.
1989
; Alexander and Crutcher 1990
) but the brain
mechanisms which actually underlie movement have not yet been
elucidated. Recent advances in our knowledge of these structures have
led Mink to postulate that the BG do not, in fact, instigate movement
(Mink 1996
). He suggests that when voluntary movement is
generated the role of the BG is to regulate the competing motor
mechanisms that come into action, inhibiting those that interfere with
the desired movement and disinhibiting those contributing to it. In
this way, the desired movement can proceed.
This hypothesis implies that the dopamine depletion observed in PD deprives the BG of the ability to disinhibit desired motor programs and completely inhibit competing motor programs; hence the appearance of major motor disorders, such as akinesia and rigidity. Mink has suggested that the validity of this theory could be tested by recording the extracellular unit activity of BG output neurons during movement in parkinsonian monkeys. This study has been designed to test the "Mink hypothesis" by comparing the influence of passive movement on neuronal activity in the globus pallidus pars internalis (GPi), the main BG output structure in primates, in both normal and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated monkeys.
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METHODS |
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Experiments were carried out on two cynomolgus monkeys
(Macaca fascicularis) weighing 3-4 kg. The recording
chamber was stereotactically installed under general anesthesia
(ketamine-hydrochloride 10-15 mg/kg im, Panpharma, France and xylazine
1.5-2.5 mg/kg im, Sigma) at an angle of 45° to the sagittal plane to
facilitate the positioning of the microelectrodes which were then
inserted parallel to the central axis of the chamber as previously
described (Boraud et al. 1996, 1998
). Monkeys were
rendered severely parkinsonian by bilateral intracarotidian injection
of an acute dose of MPTP (0.8 mg/kg each side) under arteriographic
control as previously described (Benazzouz et al. 1993
).
Their behavior was then clinically assessed on a monkey parkinsonian
rating scale (0-25) (see Bezard et al. 1997
).
Assessment showed that both monkeys developed a stable akineto-rigid
parkinsonian syndrome rated respectively 15.2/25 and 16.3/25 without
tremor. These ratings correspond approximately to stage IV on the Hoen
and Yahr scale (Bezard et al. 1997
).
Mean firing frequency and firing pattern were determined both in the
normal and the MPTP situation in the GPi. The
electrophysiological signal was displayed and stored in a computer
(PowerPc 6400, Apple) via the first channel of a MacLab interface
(MacLab/4S V1.0.6/1.7.2/0, AD Instruments) using Chart software (Chart
V3.5.6, AD Instruments), allowing both online and offline analysis. We
used mechanograms, obtained using a manipulandum connected to a
potentiometer (16S6-MCB, PK) and recorded via the second channel of the
MacLab interface to correlate changes in firing frequency to movements.
The manipulandum could be adapted to each joint to record the passive
movements we imposed. After carrying out a 10-s control recording of
basal neuronal activity, we initiated a sequence of 15 pseudosinusoidal flexion-extension (45°) movements for each joint. Each movement, followed by a short rest interval, was performed bilaterally at 0.2 Hz
(under visual control) at a regular rhythm imposed by a metronome.
Mechanograms obtained before and after MPTP treatment were compared
with the use of analysis of variance (ANOVA) and those which were
significantly different (P < 0.05) were rejected. The threshold of significance was defined as follows: a neuron was
considered to be joint related (Fig.
1A) if the mean activity provoked by 15 flexion-extensions was at least three times greater than the standard deviation from mean activity at rest as described elsewhere (Mushiake and Strick 1995).
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We analyzed the following parameters: effect on firing frequency
(activation or inhibition), side(s) linked (ipsilateral, contralateral,
or bilateral), and limb(s) and joint(s) linked. Distribution histograms
were built for each parameter and the normal and MPTP situations were
compared using the frequency of occurence method (2,
df =
1,
= number of categories for each parameter
studied, if
= 1, then P < 0.05 when
2 > 3.841 and if
= 2, then
P < 0.05 when
2 > 5.991).
Marking lesions were made by passing DC (30 µA for 10 s) through
the recording electrode at selected points. These were then used,
together with electrophysiological landmarks and the dark lines of
gliosis indicating recording tracks in the pallidal complex, to retrace
the anatomic path of electrode penetration (Fig. 1B shows an axonometric reconstruction). Tyrosine hydroxylase (TH) immunohistochemistry was used to assess the degree of midbrain dopaminergic cell loss (see Bezard et al. 1997 for
methods). This showed a dramatic reduction in TH-immunoreactive cell
body density in the substantia nigra of the two MPTP-treated monkeys;
83.7% and 77.2% neuronal loss compared with control values obtained in four normal animals.
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RESULTS |
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In GPi, both mean firing frequency and the number of bursting
neurons increased significantly after MPTP treatment. These results
agreed with previously published results obtained in the same
conditions (Boraud et al. 1996, 1998
).
In normal animals, passive movement modified the firing frequency of 82/168 GPi neurons (Fig. 2A). After MPTP-treatment this proportion increased, albeit nonsignificantly (97/171) (Fig. 2A). In the normal situation, mean firing frequency significantly decreased during passive movement in 18.3% (15/82) neurons and increased in 81.7% (67/82) (P < 0.05, Fig. 2A, left), giving an inhibited-to activated cells (I/A) ratio of 0.22. In the MPTP situation this ratio dropped to 0.03, with only 3.1% (3/97) neurons decreasing and 96.9% (94/97) increasing their frequency of discharge (P < 0.05, Fig. 2A).
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In the normal monkey, contralateral limb movement modified the firing frequency of 77/82 neurons, ipsilateral limb movement modified the firing frequency of 2/82 neurons, and either ipsi- or contralateral movement modified the firing frequency of 3/82 neurons (Fig. 2B, left). These proportions changed significantly in the MPTP-treated animal (P < 0.05, Fig. 1B, left). The number of neurons responding to either ipsi- or contralateral (13/97) and to ipsilateral movement (8/97) increased considerably, whereas only 78.4% (76/97) of neurons continued to respond to contralateral movement only.
MPTP intoxication also increased significantly the number of neurons responding to both superior and inferior limb movement (P < 0.05; normal, 1/82; MPTP, 21/97; Fig. 2B, middle), and the number of cells responding to multi-joint movement (P < 0.05; normal, 5/82; MPTP, 64/97; Fig. 2B, right). At the same time, the number of neurons responding to single joint movement decreased from 77/82 to 33/97.
Both before and after MPTP treatment, neurons were located in clusters with no obvious somatotopic organization (Fig. 1B).
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DISCUSSION |
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This study shows that after MPTP treatment the percentage of GPi neurons inhibited by passive movement decreases and the number of movement-related GPi neurons responding less specifically than in the normal situation to more than one joint, to both upper and lower limbs and bilaterally, increases.
Mink has advanced the postulate that, in the normal situation,
inhibition of GPi neurons disinhibits desired motor programs and
inhibits competing programs (Fig.
3A) (Mink
1996). This would imply that in the normal animal the I/A ratio
should be <1. Our results in normal monkeys show an I/A ratio of 0.22 which corroborates this hypothesis and is consistent with other studies
(Turner and Anderson 1997
). Mink has also suggested that
dopamine depletion impairs this selection process and brings the I/A
ratio down close to 0 (Fig. 3B) (Mink 1996
).
In our study MPTP treatment reduced the I/A ratio significantly to
0.03. This result also concords with Mink's model.
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A decrease in the specificity of neuronal response has already been
reported by Filion et al. (1988) but these results were based on subjective evaluation and the type of modification induced by
passive movement (inhibition or activation of the firing frequency) was
not investigated in this study. Bergman has suggested that dopamine
regulates the coupling between the different subcircuits of the BG
(Bergman et al. 1998
) and Mink has suggested that
dopamine depletion should therefore reduce and eventually lead to the
disappearance of this selective process (Mink 1996
). Our
results seem to concord with this hypothesis. However, we do not
resolve the debate as to whether this loss of specificity is the
primary mechanism for the genesis of rigidity in PD or a consequence of it.
The decrease in the I/A ratio and the sharp decrease in the specificity of the GPi neuronal response to passive limb movement that we observed supports Mink's hypothetical model of BG function, although his hypothesis refered to active movements. These results therefore need to be confirmed in a comparable study of the influence of active limb movement on GPi neuronal activity.
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ACKNOWLEDGMENTS |
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We thank C. Imbert and S. Dovero for technical assistance.
This study was supported by the Centre National de la Recherche Scientifique, the Institut Fédératif de Neurosciences (Institut National de la Santé et de la Recherche Médicale No. 8 and Centre National de la Recherche Scientifique No. 13), and the University Hospital of Bordeaux.
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FOOTNOTES |
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Address for reprint requests: T. Boraud, Basal Gang, CNRS UMR 5543, Université Victor Segalen Bordeaux 2, 146 rue Léo Saignat, 33076 Bordeaux Cedex, France.
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Received 16 August 1999; accepted in final form 29 November 1999.
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REFERENCES |
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