Download Dexterous Finger Movements in Primate Without Monosynaptic

J Neurophysiol 92: 3142–3147, 2004.
First published June 2, 2004; 10.1152/jn.00342.2004.
Report
Dexterous Finger Movements in Primate Without Monosynaptic
Corticomotoneuronal Excitation
Shigeto Sasaki,1,* Tadashi Isa,2,* Lars-Gunnar Pettersson,3,* Bror Alstermark,4,*
Kimisato Naito,1 Kazuya Yoshimura,1 Kazuhiko Seki,2 and Yukari Ohki5
1
Tokyo Metropolitan Institute for Neuroscience, Tokyo 183-8526, Japan; 2Department of Developmental Physiology, National Institute
for Physiological Sciences, Okazaki 444-8585, Japan; 3Institute of Physiology and Pharmacology, Department of Physiology, Göteborg
University, 405 30 Göteborg, Sweden; 4Department of Integrative Medical Biology, Section of Physiology, Umeå University, 901 87
Umeå, Sweden; and 5Department of Integrative Physiology, Kyorin University School of Medicine, Shinkawa, Tokyo 181-8611, Japan
Submitted 2 April 2004; accepted in final form 25 May 2005
Kuypers showed that pyramidotomy caused near permanent
loss of the precision grip and of independent finger movements
(IFMs) of the hand (Lawrence and Kuypers 1968a,b). Transection of the rubrospinal tract (RST) after pyramidotomy
aggravated the symptoms, suggesting a role also for the RST.
It has later been shown that after pyramidotomy, some recovery may occur after ⬃1 yr (for references, see Porter and
Lemon 1993). To test the role of the direct and indirect CM
pathways, we have now made lesions of the CST in the lateral
funicle at the border of the C4–C5 segments (C4/C5), which is
just rostral to the forelimb MNs.
METHODS
Behavioral test
Three female monkeys (Macaca fuscata), body weight 5.35, 4.75,
and 4.5 kg, were trained to retrieve a morsel of food from a horizontal
tube positioned in the mid-sagittal plane, at shoulder level and at a
sagittal distance of 15 cm. Each experiment (30 min) consisted of
⬃100 trials. In each trial, the animal retrieved, with the precision grip,
a morsel of food positioned on a pin that was inserted through the
bottom of the tube. The movements were filmed with standard video
cameras (33 Hz) positioned above, below, and on the side of the
performing limb.
Surgery
INTRODUCTION
Much of the motor cortical research in primates is devoted to
the monosynaptic excitatory connection from the corticospinal
tract (CST) to motoneurons (MNs) that appears weakly in
primates such as the squirrel monkey and becomes gradually
stronger in the macaque and cebus monkeys, chimpanzee, and
orangutan to reach a peak in man (Kuypers 1981; Phillips and
Porter 1971; Porter and Lemon 1993; Shapovalov 1975).
Because the ability to perform skilled finger movements with
the hand has likewise increased during development, it was
suggested that the monosynaptic corticomotoneuronal (CM;
henceforth referred to as direct CM) connection might play a
decisive role in this control (Bernhard and Bohm 1954). In
behavioral experiments in the macaque monkey, Lawrence and
* These authors contributed equally to this work
Address for reprint requests and other correspondence: B. Alstermark, Dept.
of Integrative Medical Biology, Section of Physiology, Umeå University,
S-901 87 Umeå, Sweden (E-mail: [email protected]).
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The animals were first anesthetized with ketamine (0.3 ml) and
Xylazine (0.6 ml) and then with pentobarbital sodium (Nembutal, 60
mg/kg). The border between the C4 and C5 segments was exposed by
a laminectomy, and a transverse opening was made in the dura. The
CST lesion was made under a surgical microscope, in three steps.1) A
small opening in the pia mater was made at the lateral convexity of the
spinal cord. A horizontal strip in mediolateral direction of the lateral
funicle was then made by inserting a minute hook into the opening.
The hook was prepared from a 0.4 mm (OD) cannula. The tip (0.5
mm) was first bent (with fine pliers) at a right angle to assume the
shape of a hook. To provide stability during insertion into the spinal
cord, the cannula was bent a second time, at a right angle 5 mm from
the tip. In other words, the cannula assumed an L-shape with a small
hook at the tip. In this way, the proximal part of the cannula could be
held firmly by a small surgical clamp during insertion of the tip into
the spinal cord. In addition, bending the cannula a second time assured
that the hook could not be inserted ⬎5 mm deep, which corresponds
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Sasaki, Sigeto, Tadashi Isa, Lars-Gunnar Pettersson, Bror Alstermark, Kimisato Naito, Kazuya Yoshimura, Kazuhiko Seki, and
Yukari Ohki. Dexterous finger movements in primate without
monosynaptic corticomotoneuronal excitation. J Neurophysiol 92:
3142–3147, 2004. First published June 2, 2004; 10.1152/jn.00342.2004.
It is generally accepted that the precision grip and independent finger
movements (IFMs) in monkey and man are controlled by the direct
(monosynaptic) corticomotoneuronal (CM) pathway. This view is
based on previous observations that pyramidotomy causes near permanent deficits of IFMs. However, in addition to the direct CM
pathway, pyramidotomy interrupts several corticofugal connections to
the brain stem and upper cervical segments. Indirect (oligosynaptic)
CM pathways, which are phylogenetically older, have been considered to be of little or no importance in prehension. In three adult
macaque monkeys, complete transection of the direct CM pathway
was made in C4/C5, which is rostral to the forelimb segments (C6–
Th1). Electrophysiological recordings revealed lack of the direct
lateral corticospinal tract (LCST) volley, monosynaptic extracellular
field potentials in the motor nuclei, and monosynaptic CM excitation.
However, a disynaptic volley, disynaptic field potentials and disynaptic CM excitation mediated via C3–C4 propriospinal neurons remained after the lesion. Thus the lesion interrupted the monosynaptic
CM pathway and oligosynaptic LCST pathways mediated by interneurons in the forelimb segments. Precision grip and IFMs were
observed already after 1–28 days postoperatively. Weakness in force
and deficits in preshaping remained for an observation period of 3 mo.
Indirect CM pathways may be important for neuro-rehabilitation.
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DEXTEROUS FINGER MOVEMENTS WITHOUT MONOSYNAPTIC CORTICOMOTONEURONAL EXCITATION
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to the distance from the lateral convexity of the spinal cord to the
midline. 2) The dorsal part of the lateral funicle was transected, with
watch maker’s forceps, from the dorsal root entry zone ventrally to the
level of the horizontal strip lesioned in step 1. 3) The lesion was
extended ventrally, with watch maker’s forceps, at the most lateral
part of the lateral funiculus.
During surgery, the direct descending corticospinal volley, evoked
by transcranial magnetic stimulation, was recorded from the dorsal
part of the lateral funiculus in C5 before and after the lesion (in
monkeys I and G, not illustrated).
The opening of the dura mater was closed by a substitute (Preclude,
Gore and Associates). The skin and back muscles were sutured with
nylon or silk thread.
Electrophysiological experiments
RESULTS
Figure 1A illustrates the maximal extent of C4/C5 lesions
(black area) in three monkeys (Y, I, and G). The lesions
covered the area of normal distribution (Kuypers 1981; Porter
and Lemon 1993) of CS fibers (Y) or were larger than this area
(I and G). To assess the C4/C5 lesions, electrophysiological
recordings were made caudally. Figure 1B shows recordings
from the spinal half at mid thoracic level on the intact and
lesioned sides. On the intact side, electrical stimulation of the
contralateral pyramid (co Pyr) evoked a direct CS volley
followed, with a delay of ⬃1.2 ms, by a synaptic volley. The
latter volley is presumably caused by monosynaptic Pyr actiJ Neurophysiol • VOL
FIG. 1. Control of corticospinal tract (CST) lesion in C4–C5. A: histological
reconstruction of the spinal cord lesions in 3 different monkeys (Y, I, G). B: the
effect of stimulating the contralateral pyramid (Pyr) electrically (200 ␮A) and
recording from dissected spinal halves at thoracic level on the intact side (top)
and on the lesioned side (bottom). Solid vertical line, the onset of the direct
CST volley (lacking on the lesioned side); dashed line, the onset of the synaptic
CST volley (present on both sides). C: recordings of extracellular synaptic field
potentials (top) in the motor nuclei and the cord dorsum potentials (bottom)
evoked by electrical stimulation of the contralateral Pyr. Filled arrow, the
direct CST volley on the intact side. Open arrow, the monosynaptic pyramidal
field in the motor nuclei on the intact side. Arrowheads, the disynaptic field
potential in the motor nuclei on either side.
vation of neurons with long descending axons. In contrast, on
the lesioned side, the direct CS volley was completely abolished (solid line), while the synaptic volley (interrupted line)
remained (mediated by descending axons in an intact funicle).
Extracellular recordings of field potentials were made in the
lateral motor nuclei in C6–C8 (a train of 3 stimuli were applied
to the pyramid) as illustrated for the intact and lesioned sides
(Fig. 1C). After a delay of 0.3 ms from the direct CS volley
(filled arrow), a negative field potential (open arrow and solid
line) was recorded (top) on the intact side. This potential is due
to extracellular currents, which generate monosynaptic CM
excitatory postsynaptic potentials (EPSPs) in forelimb MNs.
On the lesioned side (Fig. 1C bottom), this field was lacking.
However, already the first Pyr stimulus evoked a later (1.2 ms)
small synaptic field (arrow head), which most likely is due to
disynaptic CM excitation evoked in forelimb MNs. On the
lesioned side this field was slightly facilitated by the second
and third Pyr volleys. On the intact side (Fig. 1C), a similar
field potential was recorded (arrow head), which was markedly
facilitated by the second and third Pyr volleys.
The latency to the onset of the disynaptic field was similar
on the intact and lesioned sides (interrupted line). Similar
electrophysiological results were obtained in the three monkeys.
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The animals were first anesthetized with ketamine (0.3 ml) and
Xylazine (0.6 ml) and after the tracheotomy, isofluorane was used
throughout the surgery. After surgery, anesthesia was changed to
␣-chloralose 75–100 mg/kg. Blood pressure was maintained around
100 mmHg and pCO2 at 4.0%. A drip of Ringer-glucose was given
during the entire experiment, and the urinary bladder was emptied
regularly. Atropin (0.5 mg), decadrone (4 mg), gentacine (1 ml) were
given just after anesthesia. Atropin was given at intervals of 4 –5 h.
The animals were paralyzed with pancuronium bromide (Myoblock 1
ml, 0.2 mg/ml) given at 30-min interval and artificially ventilated with
a pump. A pneumothorax was made just prior to intracellular recording.
A craniotomy was made that exposed the posterior part of cerebellum and the caudal brain stem to place the pyramidal electrode. It was
calibrated at the obex (angle 65° from the vertical line) and placed
⬃2.5 mm rostrally and 1.25 mm laterally and at depth of 5.0 mm from
the bottom of IVth ventricle. The threshold for eliciting the descending pyramidal volley was usually ⬃5 ␮A. Monopolar cathodal pulses
(0.1-ms duration) were applied by using tungsten electrodes with an
impedance ⬃50 –100 k⍀ and a tip diameter of 10 ␮m. A laminectomy
was made of the C2–Th1 and of the Th6–Th10 segments. The DR nerve
was dissected and mounted in a cuff with bipolar silver electrodes.
Other forelimb nerves were stimulated with inserted needle electrodes
through the skin.
Bipolar recordings of the descending volleys were made from
dissected spinal halves in the Th6–Th10 segments as described before
(Alstermark et al. 1981). Intracellular recordings were made from
antidromically identified forelimb MNs (and unidentified MNs) in the
lateral motor nuclei of the C6–Th1 segments. Glass capillary electrodes (tip diameter: ⬃1.0 ␮m, impedance: ⬃3–5 M⍀) filled with 2 M
potassium citrate were used. The cord dorsum potential was monitored with a silver ball electrode.
The experiments were subjected to prior ethical reviews by the
ethical committee of the Okazaki Organization of National Institutes
and were performed in accordance with the National Institutes of
Health guideline for the Care and Use of Laboratory Animals.
Report
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SASAKI ET AL.
is shown in Fig. 3A. In monkey Y, the precision grip was
present already the first postoperative day (Fig. 3B). The
preshaping prior to contact with the morsel was reduced. The
aperture between the finger tips was smaller than the thickness
of the morsel, and it was common that the thumb hit the
posterior part of the morsel. Then the monkey widened the
aperture, and the thumb was positioned on the side of the
morsel allowing a precision grip by flexion of the proximal
interphalangeal joint of the index finger and opposing movement of the thumb (Fig. 4A). Compared with the preoperative
movement, it was common that the digits slipped during
removal presumably due to low grip force so that more than
one attempt was required. Another difference from the preoperative state was that the duration of the movement was
substantially increased as is evident from the time-lines in Fig.
3, A–C (postoperative day 7). These defects became gradually
less pronounced but remained to the end of the observation
period (3 mo). A decreased force and slowing of the movement
was also found after pyramidotomy and after cervical hemisection of the spinal cord (Galea and Darian-Smith 1997).
Prehension improved markedly during the first postoperative
week. On the 7th postoperative day (Fig. 3C), the placement of
the index finger and thumb on the morsel closely resembled the
preoperative one.
Postoperatively, it was evident in some trials already in the
first experiments in monkey Y, that the thumb during preshaping could be moved without concomitant movements of digits
3–5. During the two first postoperative weeks, the ability to
perform independent finger movements improved, and in several trials, the extension of the index finger during preshaping
was not accompanied by parallel extension of the other digits.
Figure 4D shows superimposed stick figures of the index
finger (D2) and of digit 5 (D5) viewed from the lateral side at
the time of contact with the morsel. When the index finger was
flexed during removal of the morsel, there was always parallel
flexion of digit 5. This was the case throughout a postoperative
observation period of 3 mo in the three monkeys.
FIG. 2. Pyramidal effects in forelimb motoneurons (MNs). A–C: the effect of coPyr stimulation in
a deep radial (DR) MN recorded intracellularly (top)
on the intact side monkey G. Bottom: traces were
recorded from the cord dorsum in the same segment
as the motoneurone and show the direct CST volley
followed by a synaptic volley. D–F: the effect of
coPyr stimulation in another DR MN recorded intracellularly (top) on the lesioned side monkey G.
The cord dorsum recording showed the absence of
the direct CST volley, but the presence of the synaptic volley. The onset of a disynaptic excitatory
postsynaptic potential (EPSP) is indicated in D (1).
In F, 2 shows the onset of a presumed trisynaptic
inhibitory postsynaptic potential (IPSP), which starts
at the peak of the disynaptic EPSP. G: averaged
traces from the records shown in A and D, respectively. The stimulus artifacts have been removed
from the traces. Interrupted line, the onset of the
disynaptic IPSP in A and the disynaptic EPSP in
D.1, the latency difference between the mono- and
disynaptic EPSP recorded from the intact and lesioned sides, respectively. H: latency histogram of
coPyr EPSPs (from the 3rd volley) in forelimb MNs
recorded in the C6–C8 segments. Latency measurements are made from the incoming direct CST volley on the intact side.
J Neurophysiol • VOL
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Intracellular recording was made from a total of 59 forelimb
MNs in C6–C8 in the three animals on the intact (n ⫽ 22) and
lesioned (n ⫽ 37) sides. Pyr stimulation evoked EPSPs in all
MNs on the intact side (IPSP were recorded in 4 cells) and in
18 MNs on the lesioned side (IPSPs were seen in 9 cells).
Measurements of the latency from the arrival of the descending
CS volley to the onset of the EPSPs (Fig. 2H) showed a
monosynaptic range (from 0.4 to 1.0 ms) on the intact side
(white area), but a disynaptic range (1.0 –1.8 ms) in 15 cells on
the lesioned side (black area) and possibly a trisynaptic range
(from 1.8 to 2.0 ms) in 3 cells. Figure 2, A–C, shows intracellular recordings from a deep radial motoneuron on the intact
side. A single Pyr stimulus (A) evoked a monosynaptic EPSP,
which was cut by a disynaptic IPSP (see G,2). On the lesioned
side (Fig. 2, D–F), recordings from another deep radial motoneuron show that Pyr stimulation failed to evoke a monosynaptic EPSP.
However, even a single pyramidal stimulation evoked a
disynaptic EPSP (D,1). After the second and third Pyr volleys, the EPSP was slightly facilitated and was followed by an
IPSP (F, 2), which started at the peak of the EPSP. Figure 2G
shows a comparison of the averaged traces of the EPSPs
evoked by a single stimulus on the intact (A) and lesioned (D)
sides. The EPSP evoked in the motoneuron on the lesioned side
starts 0.9 ms later than the EPSP in the motoneuron on the
intact side, corresponding to one intercalated neuron. Note that
the onset of the IPSP (G, 2; intact side) was similar as for the
EPSP of the lesioned side, with a disynaptic linkage in both
cases. Based on these electrophysiological results, in addition
to the histological controls (Fig. 1), we conclude that the CST
lesions in the three monkeys were complete but that disynaptic
Pyr excitation could still be evoked in forelimb MNs on the
lesioned side.
The ability to take a morsel of food with a precision grip was
tested as shown in Fig. 3 (A–C, view from above and D from
below) with video frames and in Fig. 4 (A–C, top view) with
stick figures of the index finger and thumb. A preoperative trial
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DEXTEROUS FINGER MOVEMENTS WITHOUT MONOSYNAPTIC CORTICOMOTONEURONAL EXCITATION
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Independent finger movements were present regularly on the
9th postoperative day in monkey Y (smallest lesion), on the
25th day in monkey I, and on the 28th day in monkey G.
DISCUSSION
The fast and surprisingly good recovery observed in all three
monkeys of this study is in clear contrast to previous investigations (Galea and Darian-Smith 1997; Lawrence and Kuypers
1968a,b). After complete pyramidotomy, independent finger
movements were abolished for the whole observation period of
ⱕ11 mo (Lawrence and Kuypers 1968a).
In contrast, although all our monkeys showed deficits in
preshaping and force between the index finger and thumb, they
could grasp the morsel of food by using independent finger
movements after 1–28 days postoperatively. Because the
present lesions abolished both monosynaptic CM excitation as
well as excitation mediated via segmental interneurons (below
C5), we conclude that these pathways are not solely responsible
for fine finger control as has been taken for granted during
several decades especially for the monosynaptic excitatory CM
connection. However, deficits in force and preshaping of the
index finger and thumb prior to grasping were clearly evident
after the lesions and are most likely dependent on the monosynaptic CM pathway.
J Neurophysiol • VOL
It is indeed remarkable that the command for precision grip
and independent digit movements can be mediated via nonmonosynaptic CM pathways. A comparison with the location
of the RST (Holstege et al. 1988) suggests an incomplete RST
lesion in monkey Y but not in monkeys I and G. One possibility
is that the modest effect of the lesion in monkey Y on the
precision grip is due to a RST takeover. It is noteworthy that
60% of the RS neurons are activated during grasping of food
from small holes in the Klüver test (Miller et al. 1993). A
reorganization of the RS output to forearm muscles was found
after pyramidotomy, such that the normally predominant extensor excitation and flexor suppression was diminished (Belhaj-Saif and Cheney 2000).
As an alternative to an RST takeover, the possible role of
propriospinal neurons (PNs) should be considered. It was
recently shown that disynaptic CM EPSPs in the macaque
monkey can be mediated via PNs in the C3–C4 segments
(Alstermark et al. 1999). This system was first described in the
cat (Illert et al. 1977), which lacks monosynaptic CM connections. In the macaque monkey, the C3–C4 PNs are under strong
inhibitory control, and disynaptic EPSPs were found regularly
only after intravenous injection of strychnine (Alstermark et al.
1999). In the present study, disynaptic CM EPSPs could be
induced even without strychnine in half of the forelimb MNs
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FIG. 3. Prehension movements in monkey Y, preoperatively (A) and at postoperative day 1 (B) and 7 (C and D). A–C: the view
from above and D the view from below. The time intervals (ms) relative to the leftmost image are indicated in the top right corner
of the digitized video images.
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SASAKI ET AL.
after the CS lesion in C4/C5, occasionally even by a single
stimulus (Fig. 2D). It is postulated that the strength of inhibition has decreased so that C3–C4 PNs mediating disynaptic
EPSPs are more readily activated after a chronic CST lesion.
Enhanced propriospinal excitation of upper limb MNs was
found in stroke patients (Mazevet et al. 2003).
In monkeys I and G (Fig. 1A), the lesions extended more
ventrally than in monkey Y and probably completely transected
the RST. However, it is unlikely that these lesions have
transected a significant part of the axons of the C3–C4 PNs
because intracellular recording from forelimb MNs confirmed
that disynaptic Pyr EPSPs could be evoked in all three monkeys, and threshold mapping of the axons of C3-C4 PNs has
shown that they surround the ventral horn and extend ventromedially to the base (Alstermark and Isa, unpublished data).
Furthermore, in monkey G, we added an acute transection of
the CST in C2 (not illustrated), where after disynaptic CM
EPSPs were abolished in six of six tested MNs, which shows
that disynaptic Pyr EPSPs indeed could be mediated via C3–C4
PNs despite the larger lesion.
In the cat, C3–C4 PNs mediate the command for forelimb
target reaching, while the command for grasping with the
forepaw is mediated by interneurons in the forelimb segments
(Alstermark et al. 1981). However, recently Blagovechtchenski
et al. (2000) found that after combined spinal cord lesions
(CST⫹RuST in C5 and ventral quadrant lesion in C2) the
C3–C4 PNs can mediate the command for some components of
grasping like flexion in the proximal interphalangeal joints, but
not supination and flexion in the metacarpophalangeal joints by
J Neurophysiol • VOL
which intact cats bring the morsel of food to the mouth. It may
be hypothesized that evolution has given the C3–C4 PN system
a new or additional role in primates to command the precision
grip in relation to reaching. This may explain why the precision
grip and independent digit movements remain after transection
of the CST. There is some evidence from cortical lesions which
may support a C3–C4 PN takeover. Some CS fibers originate in
the premotor (PM) area and terminate in the C2–C4 segments
(Martino and Strick 1987). The recovery of manual dexterity
after lesion of the hand area in MI was abolished by reversible
inactivation of PM (Liu and Rouiller 1999). The recovery after
the MI lesion was very slow and incomplete. Structural reorganization in PM has been observed after M1 lesion (Frost et
al. 2003).
Our findings suggest that the role of CM pathways in
commanding the precision grip and independent digit movements must be broadened and include not only the direct
connection but also indirect ones. Transmission is apparently
so effective that the precision grip and independent finger
movements can be made within a day (monkey Y) even if the
monosynaptic CM connection (and to segmental interneurons)
is broken.
The fact that interneuronal networks exist may be important
for neuro-rehabilitation. Physiotherapy must aim at mobilizing
these networks, and such a mobilization may explain the
recovery of the precision grip and independent digit movements that may be observed in humans after complete interruption of the CM pathways in the brain stem (Bach-y-Rita
1981).
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FIG. 4. Stick figure representation of prehension movements preoperatively and at the postoperative days indicated in monkey
Y. A: the moment of 1st tactile contact between the index finger and the morsel. B: the moment of entry of the thumb into the tube.
C: precision grip of the morsel between the thumb and the index finger. The last frame before onset of removal of the morsel from
the pin. Blue lines represent the index finger and red lines the thumb. The following positions are indicated for the index finger:
the metacarpophalangeal joint (MCP), the proximal interphalangeal joint (PIP), the distal interphalangeal joint (DIP) and the finger
tip. For the thumb: MCP, DIP and the finger tip. D: stick figure of prehension movements from the 7th postoperative day. The
positions of the MCP, PIP, and DIP joints are indicated as well as the tips of the digits. The index finger (D2 in blue) and digit
5 (D5 in red) are superimposed. The digits have been aligned at the position of the PIP joint.
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DEXTEROUS FINGER MOVEMENTS WITHOUT MONOSYNAPTIC CORTICOMOTONEURONAL EXCITATION
ACKNOWLEDGMENTS
We thank A. Lundberg for stimulating discussions about the manuscript, S.
Kumagai, M. Mori, and Y. Morichika for taking care of the monkeys, and M.
Seo for histology.
GRANTS
This work was funded by a grant from the Human Frontier Science
Program.
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