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Disruption of the proprioceptive mapping in the medial wall of parkinsonian monkeys.

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Disruption of the Proprioceptive Mapping in
the Medial Wall of Parkinsonian Monkeys
Ludovic Escola, PhD, Thomas Michelet, MS, Gaelle Douillard, MS, Dominique Guehl, MD, PhD,
Bernard Bioulac, MD, PhD, and Pierre Burbaud, MD/PhD
Parkinsonian patients present an impairment of proprioceptor-guided movement that could imply abnormal processing
in the frontal mesial cortex. To test this hypothesis, we compared neuronal response to joint displacement in the supplementary and presupplementary motor areas of two monkeys, before and after the progressive establishment of an
1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)–induced parkinsonian syndrome. After MPTP administration,
neurons were activated by the passive movement of numerous joints in various directions and no longer simply by one
or two joints in one direction. This impairment of the focused selection of proprioceptive inputs, imputable to dopamine
depletion, could impede motor planning and thus contribute to akinesia.
Ann Neurol 2002;52:581–587
Akinesia cannot be regarded as a simple motor disorder. This major and most disabling symptom of Parkinson’s disease (PD) involves fundamental aspects of
motor planning such as initiation, motivation, and sensorimotor integration. Evidence would now suggest
that the processing of proprioceptive inputs is impaired
in the parkinsonian situation,1 and several reports have
shown that patients have difficulty executing motor
tasks requiring this type of control.2–5 Several studies
have shown a decrease in the activity of the frontal
component of somatosensory evoked potential, which
is thought to reflect neuronal activity in the functional
loops involving the basal ganglia and the frontal cortex.6 –9 It also has been reported that regional cerebral
blood flow is depressed in the frontal motor areas of
parkinsonian patients during tactile discrimination
tasks or the sensory processing of vibratory stimulations.10,11 Elucidation of the mechanisms underlying
the disturbances in sensorimotor integration exhibited
by parkinsonian patients could well provide a clue to
the genesis of akinesia.
It is now generally accepted that the supplementary
motor area (SMA), a region particularly well connected
with the basal ganglia,12–14 plays a major role in motor
planning.15,16 We still know little, however, about the
precise role played by this area in the pathophysiology
of PD. The SMA is made up of two distinct areas: the
rostral, that is, the pre-SMA (or F6), and the caudal,
the SMA proper (SMAp or F3).17,18 Both these areas
are influenced by the dopaminergic system, either directly through the mesocortical network19,20 or indirectly via the corticosubcortical loops.21–23 It is
thought that the pre-SMA is involved in the selection
and updating of motor programs24 and the learning
and control of sequential behaviors.25–27 The SMAp,
on the other hand, which receives somatosensory inputs15,16 and is somatotopically organized,17 could be
more particularly involved in the sensorimotor integration necessary for movement planning.
The electrophysiological activity of the frontal cortex
neurons in the parkinsonian situation has not yet been
investigated, and we know little about the role played
by the SMA in the analysis of proprioceptive information. A few studies have analyzed the sensory receptive
fields of the SMA in the physiological situation,18,28 –30
but the literature is scarce on this question. To test the
hypothesis that the sensorimotor disorders observed in
patients suffering from PD may be linked to a dysfunction in the cortical processing of sensory information,
we therefore conducted an electrophysiological investigation of proprioceptive mapping in the SMA of monkeys rendered parkinsonian by 1-methyl-4-phenyl1,2,3,6-tetrahydropyridine (MPTP) treatment.
From the Laboratoire de Neurophysiologie, Unité Mixte de Recherche Centre National de Recherche Scientifique, Université Victor
Segalen, Bordeaux, France.
Address correspondence to Dr Burbaud, Laboratoire de Neurophysiologie, Unité Mixte de Recherche Centre National de Recherche
Scientifique, 5543, Université Victor Segalen, 146, rue Léo Saignat,
33076 Bordeaux, France.
Received Jan 8, 2002, and in revised form June 18. Accepted for
publication June 21, 2002.
Published online Sep 25, 2002, in Wiley InterScience
( DOI: 10.1002/ana.10337
© 2002 Wiley-Liss, Inc.
Materials and Methods
MPTP Intoxication and Clinical Assessment
Recordings were conducted for two female monkeys (Macaca
mulatta), weighing 5 and 6kg. Animals were housed in individual primate cages. Their care was supervised by veterinarians skilled in the health care and maintenance of nonhuman
primates, in strict accordance with the European Community Council Directive for experimental procedures in animals.
Surgery and Electrophysiological Recordings
A stainless steel recording chamber (diameter, 19mm) was
implanted in the skull of each monkey under general anesthesia (ketamine, 10mg/kg; xylazine, 2mg/kg; diazepam,
0.5mg/kg; atropine sulfate, 0.2mg/kg). Supplemental doses
of ketamine were given every hour to maintain a state of
deep anesthesia. The central axis of the cylinder was stereotactically positioned at A24 and L0 in both monkeys. A
head holder was embedded with dental cement around the
chamber for immobilization during neuronal recording. Antibiotic (ampicillin, 100mg/kg) and analgesic (paracetamol,
30mg/kg) treatments were given for 1 week after surgery.
Extracellular single-unit activity was recorded using tungsten
microelectrodes insulated with epoxy (impedance, 0.5–
1.0Mohms at 1kHz). Neuronal activity was amplified (10 –
20K), filtered (300 –3KHz), and displayed on an oscilloscope. A window discriminator was used to select spikes
from background activity. These then were processed
through an analogic-digital interface and stored on-line in a
Somatosensory Receptor Fields
We chose to limit our investigation to the arm regions of the
pre-SMA and SMAp. To map precisely proprioceptive inputs
to these regions, we systematically explored the neuronal response to passive movement in the three situations, before
MPTP treatment, presymptomatic and symptomatic. Monkeys were trained to remain quiet during this procedure and
often were rewarded with fruit juice. The four joints of the
contralateral upper (shoulder, elbow, wrist, fingers) and
lower limb (hip, knee, ankle, toes) were gently displaced in
the following directions: shoulder (antepulsion, retropulsion,
abduction, adduction, rotation), elbow (flexion, extension,
pronation, supination), wrist (flexion, extension, cubital inclination, radial inclination), fingers (extension, flexion), hip
(extension, flexion, abduction, adduction), knee (extension,
flexion), ankle (extension, flexion), and toes (extension,
Intracortical Microstimulation
Intracortical microstimulation (ICMS) was performed after
each neuronal recording. Characterization of the motor response induced by ICMS in the pre-SMA and the SMAp
allowed us to localize the arm region in each area. A train of
cathodal pulses (width, 0.2 milliseconds; train duration, 50 –
150 milliseconds at 300Hz; intensity, ⬍80␮A) was applied
through a constant-current stimulator, and the same electrode was used for extracellular recording. Movements were
recorded only if they were evoked repeatedly and were clearly
identified by both investigators.
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Once recordings were completed in the naive monkey, the
same animals were intoxicated with MPTP to induce a parkinsonian syndrome. To mimic the slow evolution of human
PD, we used a very gradual schedule of intoxication that allowed us to define a presymptomatic as well as a symptomatic situation. Monkeys were treated three times a week with
injections of MPTP hydrochloride (0.1mg/kg IV; Sigma, St.
Louis, MO) in saline. Injections were performed in the
evening after the recording session (after 18:00 hours) under
light sedation with ketamine (10mg/kg) to limit the invasive
nature of the procedure. Clinical assessment was performed
at 09:00 hours every morning by two independent examiners
who evaluated monkeys’ behavior in their cages during spontaneous activity and as they reached for appetizing fruit. Performance was scored on a parkinsonian monkey rating
scale.31 The ratings of the two examiners were averaged and
the concordance of their observations checked using Kendall’s correlation coefficient. The following symptoms were
assessed: tremor (0 –3), general level of activity (0 –3), body
posture (flexion of spine; 0 –3), vocalization (0 –2), freezing
(0 –2), rigidity of each arm (0 –3 for each upper limb), and
arm movements (reaching for food with each arm; 0 –3 for
each upper limb). The scores for each item were totalized to
give the total daily (TD) score. Maximum TD score was 25.
After each assessment, monkeys were classified as presymptomatic if TD less than or equal to 3, or symptomatic if TD
was greater than 3. Neither of the monkeys required tube
feeding at any stage, and no dopaminergic medication was
given during the protocol.
Once experiments were completed, electrolytic lesions were
made by applying an anodal direct current (20␮A, 20 seconds) through the recording microelectrode. One week later,
monkeys were deeply anesthetized (Nembutal, 100mg/kg)
and perfused through the ascending aorta with 500ml of
0.9% saline, followed by 2 L of 4% paraformaldehyde in
phosphate buffer (pH 7.4) as fixative. After the position of
the recording chamber was marked on the surface of the
brain, the brain was removed from the skull and sliced into
5mm frontal sections for the mesencephalon and 20mm
frontal sections for the mesial frontal cortex. Mesencephalon
sections were postfixed for 12 hours at 4°C in 20% sucrose
in Tris-buffered saline (pH 7.4) and frozen in isopentane
cooled on dry ice. Frontal lobe sections then were cut into
30␮m frontal sections with a cryostat. Dopamine depletion
was measured using tyrosine hydroxylase (TH) immunohistochemistry (IR). Sections were incubated overnight at 4°C
in serum containing TH antibody (anti-TH; BioRad, Ivry/
Seine, France) diluted 1 to 5,000 in phosphate-buffered saline (PBS) with Triton X-100 and 1.5% bovine serum albumin, rinsed in PBS and incubated 1 hour at room
temperature in goat anti–mouse IgG serum (Biosys, Compiègne, France) diluted 1:200 in PBS with Triton X-100 and
1.5% bovine serum albumin. They then were rerinsed as
above and incubated in avidin–peroxydase complex (Elite
ABC; Biosys) diluted 1 to 1,000 for 1 hour. This was followed by thorough rinsing and treatment with 3,3diaminobenzidine tetrahydrochloride (DAB; Sigma, St.
Quentin Fallavier, France) diluted in PBS and H202. All
slices then were rinsed in PBS, mounted on gelatine-coated
slides, dried, dehydrated in gradual concentrations of ethanol, cleared in xylene, and coverslipped in Neoantelan (Polylabo, Strasbourg, France). The level of dopamine depletion
was evaluated by counting the number of substantia nigra
pars compacta (SNc) and ventral tegmental area (VTA) neurons identified by tyroxyne hydroxylase labeling. Control sections from a drug-naive monkey processed according to the
same protocol were used as reference sections. Serial coronal
sections (50␮m) were stained with hemalun-chrome (Sigma,
St. Quentin Fallavier, France). The coordinates of each recorded cell, coupled with marker lesions and electrode tracks,
allowed us to situate precisely each recording site. The border between the pre-SMA and the SMAp was determined
using microstimulation data, sulcal landmarks, and cytoarchitectonic criteria. Neurons located outside the medial wall
(supplementary motor eye field, cingulate cortex) were not
used for data analysis.
The percentage of neurons responding to passive limb movement in each situation was analyzed with a ␹2 test. For the
analysis of the number of joints whose mobilization modified
neuronal activity, we used a two-way analysis of variance,
with the two areas (pre-SMA, SMAp) and three situations
(control, presymptomatic, symptomatic) as factors. For the
analysis of dopamine depletion, the two factors used for the
two-way analysis of variance were the histological area (SNc,
VTA) and the clinical situation (control monkey, lesioned
monkeys). The dependant variable was the number of TH
immunoreactive neurons on histological sections. A Kendall’s
correlation coefficient was used to study the correlation between the number of joints whose mobilization modified
neuronal activity and the clinical score for certain symptoms,
that is, limb rigidity and general level of activity.
We recorded a total of 502 neurons in the mesial frontal wall. Of these, 299 were recorded in the pre-SMA
(113 in the control situation, 78 in the presymptomatic situation, and 108 in the symptomatic situation)
and 203 in the SMAp (89 in the control situation, 32
in the presymptomatic situation, and 82 in the symptomatic situation). Because no statistical difference was
found between results for both monkeys, data were
pooled for further analysis. The number of neurons of
each area that we were able to hold for complete somatosensory examination in each of the three situations is given in the Table.
The neuronal response of the SMA to passive limb
movement was studied during passive contralateral
limb movement. The motor response evoked at each
recording site by ICMS was used to delimit the boundaries of the pre-SMA and the SMAp and chart the somatotopic organization within each structure. We voluntarily limited our study to the arm region of each
Before MPTP intoxication, the pre-SMA was characterized by the fact that motor response to ICMS was
rare and at a high threshold (⬎50␮A). There were few
somatosensory proprioceptive fields in this area (Fig 1).
SMAp neurons, on the other hand, were easily excitable (⬍50␮A), and response to sensory stimulation was
frequent. In general, SMAp neurons responded to the
mobilization of one or two joints in a specific direction; for example, a neuron would respond to passive
flexion of the elbow but not to extension. As expected,
in this situation, passive contralateral limb movement
activated a higher percentage of neurons in the SMAp
than in the pre-SMA (␹2 ⫽ 61.4; df ⫽ 1; p ⬍ 0.001).
The mean number of joint movements that activated
SMAp neurons was 1.4 ⫾ 0.8.
Presymptomatic MPTP monkeys had a normal clinical score (TD ⫽ 0.49 ⫾ 0.70), normal behavior, and
no clinically observable rigidity. Symptomatic MPTP
monkeys had an abnormal clinical score (TD ⫽
Table. Number of Neurons Responding to the Displacement of a Particular Joint in the Arm Regions of the pre-SMA and SMAp
(n ⫽ 78)
(n ⫽ 61)
(n ⫽ 83)
(n ⫽ 74)
(n ⫽ 26)
(n ⫽ 67)
These regions were defined by intracortical microstimulation before 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine intoxication. N ⫽ total
number of neurons for which we were able to perform complete somatosensory mapping in each area and each situation.
SMA ⫽ supplementary motor area; SMAp ⫽ SMA proper.
Escola et al: SMA Mapping in Parkinsonian Monkeys
Fig 1. Mapping of response to passive limb movement in the
mesial frontal cortex. Top view of the mesial frontal cortex
area recorded in this study. (dotted lines) Location of the
recording chamber; (rectangle) recording area ( [dotted zone]
presupplementary motor area (pre-SMA); (striped zone) supplementary motor area proper (SMAp). PS ⫽ principal sulcus;
ARC ⫽ arcuate sulcus; CS ⫽ central sulcus; ML ⫽ medial
line. On the right, an enlarged schema of this part of the cortex indicates the number of neurons within the arm regions of
these areas to passive contralateral limb movement in the control and the symptomatic situation. (filled circles) Somatosensory response to joint displacement (n ⫽ 12); (open circles)
no somatosensory response to joint displacement (n ⫽ 12). The
size of each circle is proportional to the number of recorded
neurons (n) responding or not to proprioceptive stimulation.
7.89 ⫾ 1.90), a moderate increase in muscular tone, a
decrease in spontaneous locomotor activity with obvious akinesia, and frequent postural tremor.
For the SMAp, virtually no difference was observed
in the percentage of neurons activated by the passive
mobilization of a contralateral joint (see Fig 1) between
the normal, presymptomatic (␹2 ⫽ 0.001, not significant), and symptomatic situation (␹2 ⫽ 0.06, not significant). For the pre-SMA, however, the percentage
was significantly higher in the symptomatic (60.5%;
␹2 ⫽ 49.3; p ⬍ 0.001) and even the presymptomatic
situation (28.3%; ␹2⫽ 5.37; p ⬍ 0.05) than it was in
the pre-MPTP situation (7.5%). In the symptomatic
animal, the percentage of responding neurons was eight
times that observed in the pre-MPTP situation.
The number of joint movements activating a particular neuron increased drastically in the symptomatic
situation. Neurons frequently were activated not only
by the passive displacement of one contralateral joint
Annals of Neurology
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but also by that of other joints of the same upper limb
and even of the lower limb. Figure 2 provides an illustration of this spreading of somatosensory receptor
fields. The specific characteristics of the neuronal response to joint displacement are given in the Table.
This shows that (1) in the symptomatic, and even in
the presymptomatic situation, neurons of the arm regions of each area began to respond to the displacement of lower limb joints, (2) neurons responded to
the displacement of proximal joints (shoulder, elbow,
hip, ␹2 on the whole, the mean number of joints modifying the activity of each neuron increased both in the
pre-SMA and the SMAp (F[5,178] ⫽ 13.9; p ⬍
0.0001; Fig 3A).
Whereas, before MPTP intoxication, neurons responded to the displacement of a specific joint in a
specific direction, in the lesioned monkey, neurons
tended to respond to displacement of the same joint in
several directions. The mean number of joint movements modifying neuronal activity increased in symptomatic monkeys for both the pre-SMA and the SMAp
(see Fig 3B). This abnormal scenario, which we had
never seen in the normal monkey, was observed in the
symptomatic situation in 67.4% of SMAp and 47.8%
of pre-SMA neurons. Because the limb rigidity inherent to the parkinsonian syndrome potentially can augment the volume of proprioceptive inputs to cortical
neurons, we tested limb rigidity in each monkey daily
before neuronal recording. The mean number of joints
whose mobilization modified neuronal activity was calculated for all neurons recorded during a given experimental session. Statistical analysis showed, however,
no correlation between this parameter and limb rigidity, either in the pre-SMA (r2 ⫽ 0.09, not significant)
or the SMAp (r2 ⫽ 0.36, not significant). Because the
general level of activity can serve as an index of akinesia, we also analyzed the relation between monkeys’
clinical scores for general activity and the mean number of joints whose mobilization modified neuronal activity. No linear correlation was found for this symptom either (r2⫽ 0.19, not significant in the SMAp and
r2 ⫽ 0.25, not significant in the pre-SMA).
The number of TH⫹ immunoreactive neurons was
compared postmortem on mesencephalic slices between
areas (SNc, VTA) and situations (control monkey, lesioned monkeys; F[5, 12] ⫽ 218.2 ⫽ p ⬍ 0.0001).
There was a drastic loss of dopaminergic neurons in
the mesencephalon of the parkinsonian monkeys. In
comparison with results obtained in the control monkey, the number of TH⫹ neurons had decreased by
93% ( p ⬍ 0.001) in the SNc and by 69% ( p ⬍
0.001) in the VTA.
These data show a considerable loss of selectivity in the
processing of proprioceptive information in the SMA
Fig 2. Somatosensory receptive fields of the arm regions of the presupplementary motor area (SMA) and the SMA proper (SMAp).
Control versus symptomatic situation. Examples of data obtained from recordings performed after preliminary delimitation of the
pre-SMA and the SMAp by intracortical microstimulation (M1 ⫽ primary motor area; CgS ⫽ cingulate sulcus). (center) Medial
view of a Macaca mulatta cortex. (top left quadrant) Data collected during neuronal recordings in both situations in the pre-SMA
of monkey 1. (bottom left) Data collected during neuronal recordings in both situations in the pre-SMA of monkey 2. (top right)
Data collected during neuronal recordings in both situations in the SMAp of monkey 1. (bottom right) Data collected during neuronal recordings in both situations in the SMAp of monkey 2. In each quadrant, the dotted line drawn on the frontal section on
the left represents the track down which the electrode was lowered, first in the control, then in the symptomatic situation, using the
same stereotactic coordinates. The data collected in each situation are presented in graphic form on the right. The vertical line represents the recording track. On each side of the line, circles indicate the position of the neurons encountered; empty circles correspond
to neurons unresponsive to joint displacement; filled circles correspond to neurons activated by one or several joint displacements.
This neuronal response is illustrated with pictures of monkeys; for each situation, darkened areas show the joints whose passive displacement elicited a neuronal response.
in the parkinsonian situation. Before MPTP, most
neurons located in the arm region of the SMAp were
activated by the passive mobilization of one joint, more
rarely of two, in one specific direction. In contrast, in
the symptomatic parkinsonian monkey, and even in
the presymptomatic animal, we observed a spreading
and blurring of these proprioceptive receptive fields.
We also observed a surprising increase in the frequency
of response to passive movement in the pre-SMA of
the MPTP-treated monkey. Whereas only a few preSMA neurons responded to passive limb movement in
the untreated animal, the proportion of responding
neurons rose dramatically in the MPTP-treated mon-
key. In the symptomatic situation, both SMAp and
pre-SMA neurons responded to the movement of several joints, often in different directions. These modifications would appear to be the result of neither limb
rigidity nor akinesia. Although it is true that both
symptoms remained moderate, even in the symptomatic situation, no linear correlation was observed between clinical scores for either of these symptoms and
the number of passive movements that influenced neuronal activity.
Two major hypotheses can be put forward to explain
this loss of selectivity. Reduced dopaminergic innervation of the cortex may directly impair the processing
Escola et al: SMA Mapping in Parkinsonian Monkeys
normal connections within the subcortical structures or
in the frontal cortex.
Several recent reports have shown that parkinsonian
patients have difficulty executing motor tasks requiring
sensorimotor control.1–5 Our results show a dysfunction in the treatment of proprioceptive information by
the neurons of the SMA in the parkinsonian situation,
which apparently are linked more to a surfeit of inappropriate information than to a decrease in the quantity of information received. Cortical neurons may receive inputs of a misleading complexity or themselves
may be incapable of efficiently treating the information
they receive. Whatever the case, it is likely that the resulting avalanche of unnecessary information distorts
the elaboration of the command message and thus impairs the initiation of appropriate motor programs.
We thank S. Dovero and M. Goillandeau for their technical support, S. Pease for correcting the manuscript, and C. Hammond and
F. Tison for their useful comments.
Fig 3. Quantitative analysis of response to joint mobilization.
(A) Mean number of mobilized joints modifying neuronal
activity in the arm region in each area; (B) mean number of
joint movements modifying neuronal activity in the arm region
in each area. *p ⬍ 0.01; **p ⬍ 0.0001.
capacity of this structure. The mesocortical tract emanates from the ventral tegmental area19,20 and then
widely innervates the frontal cortex, particularly the
pre-SMA and SMAp.22 The number of dopaminergic
neurons in the ventral tegmental area decreased by
69% after MPTP treatment. The abnormal response of
cortical neurons to proprioceptive information therefore could be caused, in part at least, by a decrease in
the activity of the mesocortical pathway. A second hypothesis postulates a possible dysfunction of the striatopallidothalamocortical loop. The reduction in dopamine release in the nigrostriatal pathway modifies the
characteristics of the corticostriatal inputs received by
medium spiny neurons.23 This modification could
have a domino effect on the other structures in the
loop, impairing the selection process throughout the
loop. Note that an increased neuronal response to passive movement and a loss of selectivity also have been
reported in the internal pallidum of MPTP-treated
monkeys.31 Thus, apparently whatever its mechanism
of action, dopamine depletion impairs the focused selection of somatosensory information processing within
the frontal mesial cortex, presumably through the disturbance of lateral inhibition.32 There remains, of
course, the possibility that the gradual schedule of intoxication used in this study to mimic the slow evolution of PD may have favored the development of ab-
Annals of Neurology
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