Sobell Department of Neurophysiology, Institute of Neurology, University College London, London WC1N 3BG, United Kingdom
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ABSTRACT |
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Nakajima, K., M. A. Maier, P. A. Kirkwood, and R. N. Lemon. Striking Differences in Transmission of Corticospinal Excitation to Upper Limb Motoneurons in Two Primate Species. J. Neurophysiol. 84: 698-709, 2000. There is considerable debate as to the relative importance, for cortical control of upper limb movements, of direct cortico-motoneuronal (CM) versus indirect, propriospinal transmission of corticospinal excitation to cervical motoneurons. In the cat, which has no CM connections, a significant proportion of corticospinal excitation reaches forelimb motoneurons via a system of C3-C4 propriospinal neurons (PN). In contrast, in the macaque monkey most motoneurons receive direct CM connections, and, under the same experimental conditions as in the cat, there is little evidence for PN transmission. We have investigated corticospinal transmission in the New World squirrel monkey (Saimiri sciureus) because its CM projections are weaker than in the macaque. Intracellular recordings were made from motoneurons identified from the ulnar, median, and deep radial (DR) nerves in four adult squirrel monkeys under chloralose anesthesia and neuromuscular paralysis. Responses to stimulation of the contralateral medullary pyramid were recorded before and after a lesion to the dorsolateral funiculus (DLF) at C5, designed to interrupt direct corticospinal inputs to the lower cervical segments and unmask PN-mediated effects. This lesion greatly reduced the proportion of motoneurons showing either CM EPSPs or disynaptic IPSPs, but the proportion showing late EPSPs with segmental latencies beyond the monosynaptic range, evoked by repetitive but not single PT stimuli, was unaffected: 23 of 29 motoneurons (79%) before and 32 of 37 (86%) after the lesion; 41% of these late EPSPs had strictly disynaptic latencies after the lesion, only 14% before. These results are in striking contrast to the macaque (late EPSPs in only 18% of motoneurons before a C5 lesion, 19% after it). Transmission of the late EPSPs via C3-C4 PNs in the squirrel monkey was indicated by their absence after an additional C2 DLF lesion. Nearly all tested motoneurons also responded with short latency EPSPs to stimulation in the ipsilateral lateral reticular nucleus. By analogy with the cat, these EPSPs probably reflect antidromic activation of ascending collaterals of C3-C4 PNs with monosynaptic connections to motoneurons; the EPSPs were significantly smaller than in the cat but larger than in the macaque. These results suggest that the positive correlation across species between more advanced hand function and the strength of the CM system is accompanied by a negative correlation between hand function and the strength of the PN system. We hypothesize that in primates with more advanced hand function, the CM system effectively replaces PN-mediated control. This would include a contribution to the control of reaching movements, which are said to be specifically under the control of the PN system in the cat, and we speculate that these differences may be related to the degree of dexterity exhibited by the different species. This interpretation of the results predicts that in man, where the CM system is highly developed, the PN system is unlikely to be responsible for significant transmission of cortical commands to upper limb motoneurons.
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INTRODUCTION |
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Cortical commands associated with
voluntary movements can be transmitted to alpha motoneurons over a
number of different parallel pathways. The largest descending pathway
from the motor areas of the cerebral cortex is the corticospinal tract.
This tract exists in all mammals, but there are important species
differences in its areas of origin, patterns of termination, and
functions (Bortoff and Strick 1993; Kuypers
1981
; Nudo and Masterton 1990a
,b
; Porter
and Lemon 1993
). In primates, some corticospinal fibers make
direct corticomotoneuronal (CM) connections to spinal motoneurons, and
this CM system is particularly well-developed in Old World monkeys,
apes and humans (Heffner and Masterton 1975
, 1983
;
Kuypers 1981
; Palmer and Ashby 1992
). A
large amount of evidence suggests that the normal development and
integrity of the CM system is essential for the capacity to perform
skilled hand and finger movements (Armand et al. 1997
;
Galea and Darian-Smith 1995
; Lawrence and Hopkins
1976
; Olivier et al. 1997
).
The particular importance of direct corticospinal projections to
motoneurons is not self-evident from anatomical studies which show that
the primate corticospinal tract makes widespread terminations throughout the spinal gray matter, not just in the motor nuclei (Bortoff and Strick 1993; Kuypers 1981
;
Ralston and Ralston 1985
). For example, recent studies
of the corticospinal projections from the macaque primary and other
motor cortical areas have shown particularly dense terminations in
Rexed laminae V-VII in the cervical spinal cord; these projections are
generally stronger than those to the motor nuclei in lamina IX
(Armand et al. 1997
; Dum and Strick
1996
).
What is the function of indirect, non-monosynaptic projections from the
cortex? One possibility is indicated by studies on the cat
(Alstermark and Lundberg 1992; Illert et al.
1977
, 1978
). In this species, which completely lacks CM
projections (Illert et al. 1977
; Kuypers
1981
), an important pathway for cortical control of the
forelimb is a system of upper cervical propriospinal neurons (PN; Fig.
1) that transmits corticospinal
excitation onward to forelimb motoneurons (MN; Fig. 1). In addition to
descending monosynaptic connections to forelimb motoneurons, the
C3-C4 PNs also project
ascending axon collaterals to the lateral reticular nucleus (LRN; Fig.
1). In the cat, the C3-C4
system provides an important integrative system for motor commands
originating in the cortex, superior colliculus, red nucleus, and
reticular formation (Alstermark and Lundberg 1992
;
Baldissera et al. 1981
).
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It is of considerable importance to establish whether, in primates, a
PN system similar to that in the cat coexists with the CM system or
whether the CM system takes the place of PN transmission for cortical
excitation of upper limb motoneurons. Although there is evidence from
human experiments for the existence of oligosynaptic transmission (see
review by Pierrot-Deseilligny 1996), the identification of this pathway as one homologous to the PN system of the cat is only
indirect. Moreover, a recent study in the Old World macaque monkey, the
best available animal model for the human cortical control system,
failed to find direct electrophysiological evidence for significant
transmission of corticospinal excitation via a C3-C4 PN pathway
(Maier et al. 1998
).
This study, carried out in the New World squirrel monkey (Saimiri
sciureus), provides crucial new evidence in the debate about the
roles of the CM and PN systems. It is known that direct CM connections
to hand muscle motoneurons are significantly weaker in the squirrel
monkey than in other monkeys, including the macaque (Bortoff and
Strick 1993; Maier et al. 1997
). Here we
demonstrate that in the squirrel monkey, in parallel with the weak CM
input to upper limb motoneurons, there is also clear evidence for
corticospinal excitation of these motoneurons via a
C3-C4 PN pathway, similar to that in the cat. We suggest that if PN transmission is strong in the
cat, with no CM system, and moderately strong in the squirrel monkey,
with a weak CM system, then in other species in which the CM system is
well-developed, such as great apes and humans, the PN pathway is likely
to play only a minor role in transmitting cortical excitation to upper
limb motoneurons. We speculate therefore that these differences may be
related to the different degrees of dexterity exhibited by the
different species. This has important consequences for our
understanding of cortical control of human upper limb function.
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METHODS |
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Four purpose-bred male adult Saimiri sciureus monkeys
(0.65-0.77 kg) were used. Animal care and use were in accordance with the U. K. Animals (Scientific Procedures) Act. The methods used were identical to those described previously (Maier et al.
1998). Anesthesia was induced with 15 mg · kg
1 ketamine
intramuscularly and maintained with 1.5-2.5% isoflurane in 1:1
O2:N2O. A tracheal cannula
was inserted and one femoral artery and both femoral veins cannulated.
Nerve cuff stimulating electrodes were mounted on the left median and
ulnar nerves at the axilla and on the left deep radial (DR) nerve at
the elbow. An occipital craniotomy and a
C2-Th1 laminectomy were
performed. When surgery was complete, the isoflurane was discontinued
and anesthesia was maintained with
-chloralose (50 mg · kg
1 iv). The animal was paralyzed with
pancuronium bromide (Pavulon, Oregon-Technika, Cambridge, UK; 0.3 mg · kg
1 · hr
1
iv) and artificially ventilated at a rate of 45 cycles · min
1. The
adequacy of anesthesia was continuously assessed by reference to blood
pressure, heart rate, and pupillary reflexes. Body temperature and
general physiological condition were carefully maintained throughout
the experiment, including a mean blood pressure >80 mmHg.
The right medullary PT and left LRN were stimulated with
varnish-insulated tungsten electrodes. The optimal location of the PT
electrode was based on the threshold and amplitude of the corticospinal volleys evoked from it and recorded from the surface of the
dorsolateral funiculus (DLF) at a rostral site (usually
C4) and at a caudal site close to the region from
which motoneuron recordings were made
(C6-Th1) (see
Alstermark et al. 1981a; Maier et al.
1998
). The LRN electrode was positioned so as to produce a
large field potential (Maier et al. 1998
) when recording
from within upper limb motor nuclei on the ipsilateral (left) side. A
number of tracks were made in the region 2.1-2.5 mm lateral from obex
and from 0.6 mm rostral to 0.5 mm caudal from obex. The final electrode position was one which gave a field potential with a threshold of <30
µA (see Fig. 7).
Intracellular recordings were made from motoneurons in the
C6, C7,
C8, and Th1 segments with
glass microelectrodes filled with 3 M potassium acetate and having a DC
resistance of 4-10 M. A small pressure foot was used in most
experiments to reduce movement of the spinal cord. All motoneurons were
identified antidromically from the limb nerves. Stimuli to the PT and
LRN (1-3 shocks usually at 333 Hz) were delivered at 3 Hz; stimulus
duration was 0.1 ms. Intracellular and surface recordings were
digitized directly at 10 kHz using a 1401plus interface (CED,
Cambridge, UK). Membrane potential was monitored throughout the
recording, and only data from stable periods of recording used for
analysis (membrane potential <
50 mV). All latency, rise time
and amplitude measurements were derived from sets of measurements made
from a number of single traces. Population measurements are given as
means ± SD. Possible postsynaptic potentials smaller than 200 µV were not measured or counted.
In all four monkeys lesions of the left DLF in the C5 segment were made with fine watchmakers forceps. While the lesion was being made the corticospinal volleys recorded both above and below the lesion site were monitored. An additional lesion of the left DLF in the C2 segment was made in two of the monkeys. Small electrolytic lesions were placed at the PT and LRN stimulation sites at the end of the experiment, and the animal was killed with an intravenous overdose of barbiturate and perfused through the heart. DLF lesions were reconstructed postmortem from paraffin embedded blocks of spinal cord, and the sites of stimulating electrodes confirmed histologically.
Data from the macaque monkey referred to here consist either of
unpublished measurements or results published by Maier et al.
(1998) that have been reanalysed. For responses to the PT stimuli, segmental latencies were measured from the positive peak of
the corticospinal volley recorded at the same segment as the motoneuron
or after the C5 lesion from the equivalent time
measured from such a volley recorded before the lesion. For responses
to the LRN stimuli, absolute latencies were measured from
the stimulus artifact.
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RESULTS |
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We searched for evidence of propriospinal transmission of
corticospinal excitation, generated by stimulation of the contralateral pyramidal tract (PT; Fig. 1). The characteristic signs of such transmission have been established in the cat. They are as follows: 1) the EPSPs evoked from the corticospinal tract have a
disynaptic latency (Illert et al. 1976, 1977
);
2) the indirect nature of the PN linkage means that
repetitive stimulation of the PT is needed to evoke these EPSPs; they
are not obtained in response to single stimuli (Baldissera et
al. 1981
; Illert et al. 1976
, 1977
);
3) the location of the descending axons of
C3-C4 PNs in the ventral
part of the lateral funiculus (Fig. 1, inset) means that
these effects survive a lesion of the DLF at the
C5 level, cutting the fibers of the lateral
corticospinal tract projecting to the lower cervical segments
(C6-Th1) containing the
forelimb motor nuclei (Alstermark and Lundberg 1992
;
Illert et al. 1977
); 4) the EPSPs are,
however, abolished by a DLF lesion at the C2 level, since this interrupts the corticospinal input to the
C3-C4 PNs (Fig. 1)
(Illert et al. 1977
).
Responses of motoneurons before a lesion to the corticospinal tract at C5
From monkeys with intact spinal cords, we analyzed the recordings
from 29 spinal motoneurons, identified from the median (18), ulnar (9),
or DR (2) nerves. In most of these motoneurons (79%), single PT shocks
evoked early EPSPs (see median motoneuron in Fig.
2B) or an early EPSP followed
by an IPSP (ulnar motoneuron in Fig. 2F). These EPSPs were
identified as monosynaptic by the short segmental delay between the
arrival of the descending corticospinal volley at the recorded spinal
segment and the onset of the EPSP (0.7 ms in Fig. 2, B and
F). The mean segmental delay of monosynaptic EPSPs was
0.9 ± 0.1 (SD) ms (n = 23); the distribution is
plotted in Fig. 5A (hatched columns). These CM EPSPs were
generally small (0.6 ± 0.3 mV, n = 23; Fig.
9A) and relatively slow rising (cf. Maier et al.
1997).
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A striking finding in most (79%) motoneurons was that repetitive PT
stimulation (3 shocks at 333 Hz) evoked a late EPSP (Fig. 2D) not seen with a single shock (Fig. 2B). In
Fig. 2D, the segmental delay was 1.8 ms; in other
motoneurons, these late EPSPs had delays ranging from 1.4 to 3.3 ms
(2.5 ± 0.5 ms; Fig. 5A, filled columns). Based on
earlier studies, effects with delays in the range of 1.3-1.9 ms are
probably mediated by a disynaptic pathway (Eccles et al.
1956; Illert et al. 1976
; Jankowska et
al. 1976
; Maier et al. 1998
). These late EPSPs
were generally larger than the CM EPSPs; the mean amplitude of the late
EPSP evoked by the third PT shock was 1.7 ± 0.8 mV
(n = 21). Late EPSPs were never seen with single PT shocks.
IPSPs were observed in 76% of motoneurons in response to a single PT
shock; in most cases they began immediately after the early EPSP (Fig.
2F). "Pure" IPSPs, not preceded by a CM EPSP, were seen
in four motoneurons (14%). IPSPs had segmental delays ranging from 1.4 to 1.9 ms (1.6 ± 0.2 ms, n = 22). This is again within the disynaptic range and is similar to results in the macaque (Maier et al. 1998). IPSPs often showed powerful
facilitation with repetitive PT stimulation (cf. Fig. 2, F
and H).
Responses of motoneurons after a lesion to the corticospinal tract at C5
After these initial recordings, a lesion was made in the DLF at the C5 spinal level; reconstructed lesions from two of the experiments are shown in Fig. 3. These lesions abolished most of the negativity in the PT-evoked volley recorded caudal to the lesion. Similar lesions and volleys were recorded in the other experiments.
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Subsequently, recordings were made in all four animals from a further 37 motoneurons (median, 26; ulnar, 8; DR, 3). A typical set of records is shown in Fig. 4, A-D. In this median motoneuron, there was no response, either EPSP or IPSP, to a single PT shock after the lesion (Fig. 4B). Only 3 of 37 (8%) motoneurons sampled after the lesion showed an early CM EPSP. The response to repetitive PT stimulation was quite different: two or three PT shocks evoked a large, late EPSP (e.g., Fig. 4, C and D) with a segmental delay of 1.8 ms (Fig. 4D). Responses of this type were seen in the great majority of tested motoneurons (32 of 37, 86%). A further example, this time from a DR motoneuron, is given in Fig. 4, E-H, which shows a typical late EPSP to PTx3 (Fig. 4H; segmental delay 1.5 ms), but which was unresponsive to PTx1 (Fig. 4F). With single PT shocks, only one motoneuron showed an IPSP; even with repetitive stimulation only 6 of 37 (16%) showed an IPSP.
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The segmental latencies of all responses recorded before and after the C5 lesion are plotted in Fig. 5. The occurrence of monosynaptic CM EPSPs with short segmental delays (0.7-1.1 ms) was dramatically reduced by the C5 lesion (cf. Fig. 5, A and C), and this was also true of the IPSPs (Fig. 5, B and D), all of which fell within the disynaptic range (1.3-1.9 ms). Late EPSPs evoked by PTx3 were common both before and after the lesion, although in the intact cord they had a wider spread of latencies (1.4-3.0 ms), with relatively few in the disynaptic range. IPSPs were evoked in the majority of the motoneurons before the C5 lesion and this made the precise onset of late EPSPs difficult to identify. This may have lead to an overestimation of the segmental latency, and this is also suggested by the finding that after the lesion, the late EPSPs were much less broadly distributed and of 15 of 37 tested motoneurons (41%), almost one-half of those showing late EPSPs responded within the disynaptic range. The mean segmental delay for all late EPSPs after the lesion was 2.0 ± 0.3 ms.
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Abolition of late EPSPs by a C2 lesion
The latency of the late EPSPs, their dependence on repetitive
stimulation of the PT, and their persistence after the
C5 DLF lesion are all consistent with their
production via PNs in the upper cervical segments. Further confirmation
of this conclusion was obtained by demonstrating that, in four
motoneurons (2 monkeys), an additional DLF lesion at the
C2 level abolished the late EPSPs, as explained
in Fig. 1. The lesion and corticospinal volleys from one experiment are
shown in Fig. 6, A and
B; the median motoneuron in Fig. 6, C-F, was
unresponsive to either single or repetitive PT stimuli (Fig. 6,
D and E), although it still responded to
activation of other inputs, such as from peripheral nerves and from the
LRN (Fig. 6F; see next section). This result
indicates that the late EPSPs evoked from the PT were not mediated by a
supraspinal, brainstem pathway receiving corticospinal collaterals (cf.
Illert et al. 1977).
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Responses to stimulation of the lateral reticular nucleus
In further tests to identify the source of the late EPSPs we
stimulated the brainstem lateral reticular nucleus (LRN) ipsilateral to
the recorded motoneurons. In the cat, this nucleus receives ascending
collaterals of the C3-C4
PN neurons (Fig. 1) and therefore LRN stimulation evokes monosynaptic
EPSPs in forelimb motoneurons (Alstermark et al. 1981a;
Illert and Lundberg 1978
). At the beginning of each
experiment the region of the LRN was explored with a stimulating microelectrode while recording field potentials in motor nuclei in
C6 or C7. The electrode tip
was located at the optimal position (Fig.
7A) for evoking the
characteristic field potential shown in Fig. 7B, with a slow
negativity beginning at ~1.5 ms after the stimulus, reaching a
maximum at 3.0 ms and lasting for ~10-15 ms. The timing and form of
this field potential response is identical to that evoked by LRN
stimulation in the cat (Alstermark et al. 1981a
) and
macaque monkey (Maier et al. 1998
). The potential in Fig. 7B had a threshold of 20 µA; its amplitude increased
steadily with intensities up to 200 µA, but it showed little further
increase with stronger shocks (Fig. 7B). Stimulation in the
LRN evoked short latency EPSPs in all 18 motoneurons tested before the
C5 lesion and in most (34 of 36) after it. Figure
7, C and D, shows typical EPSPs evoked from the
LRN in a DR and in a median motoneuron, respectively. The mean
amplitude of the EPSP evoked by a 200 µA stimulus was 1.7 ± 0.9 mV (n = 18) before and 1.7 ± 0.8 mV
(n = 34) after the C5 lesion.
Figure 7E shows the amplitudes of the EPSPs in Fig.
7C plotted against stimulus strength, together with a
similar curve from another motoneuron. These curves are typical and
very similar in form to the equivalent measurements in the cat by
Alstermark and Sasaki (1986a)
.
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The latencies and rise times of the EPSPs evoked from the LRN are plotted in Fig. 8. It was not possible to estimate the segmental latency of the postsynaptic responses evoked by LRN stimulation, because no clear volley responsible for the effects could be discerned in the surface recording; therefore only the absolute latency, measured from the time of the stimulus, is plotted for the LRN responses. The monosynaptic nature of many of these EPSPs was indicated by their short and consistent absolute latencies, and the lack of facilitation or latency shortening with repetitive LRN stimulation (Fig. 7D). The distributions of EPSP latencies are plotted before (Fig. 8C) and after (Fig. 8D) the C5 lesion; the mean postlesion latency was 1.8 ± 0.3 ms (n = 34).
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As in the cat (Alstermark and Sasaki 1986a), there was a
clear positive correlation between the amplitude and rise time of the
EPSPs evoked from the LRN, measured as indicated by the dotted lines in
Fig. 8, A and B. This correlation was significant
both before the C5 lesion (Fig. 8E,
P = 0.002) and after it (Fig. 8F; P = 0.0046). Figure 8, G and H,
shows a similar relation between amplitude and rise time for
motoneurons of the macaque monkey (G, P = 0.0062 before lesion; H, P = 0.0035 after lesion).
Comparison of responses to stimulation of PT and LRN before and after the C5 lesion in squirrel and macaque monkeys
Many of the results reported here are strikingly different from
those in our previous study of the macaque monkey (Maier et al.
1998). With respect to the amplitude of the responses to PT and
LRN, Fig. 9, A and
B, shows that for the ulnar, median, and DR motoneurons
sampled in the two studies, the CM EPSPs (recorded before the
C5 lesion) were significantly smaller in the
squirrel monkey (0.6 ± 0.3 mV, n = 23; Fig.
9A) than in the macaque (1.9 ± 1.0 mV,
n = 62; Fig. 9B; Mann-Whitney U
test, P < 0.0001) (cf. Maier et al.
1997
). In contrast, the late EPSPs, on the third PT shock and
recorded after the C5 lesion (Fig. 9,
C and D), were generally, but not significantly,
larger in the squirrel monkey (1.2 ± 0.6 mV, n = 32) than in the macaque (0.9 ± 0.5 mV, n = 16, P = 0.063). EPSPs evoked from the LRN (Fig. 9,
E and F) were significantly larger in the
squirrel monkey (P < 0.0003).
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The occurrence of late EPSPs was also markedly different. This is shown in Fig. 10 which summarizes all the responses to PT and LRN in the two studies. Whereas in the squirrel monkey late EPSPs were common both before and after the C5 DLF lesion (79 and 86%, respectively), far fewer macaque motoneurons responded in this way (18 and 19%, respectively). Although the C5 lesion had little effect on the frequency of occurrence of late EPSPs in either species, it did affect the distribution of the segmental latencies (see Fig. 5, A and D). In the squirrel monkey the proportion of responses within disynaptic range increased from 14 to 41% after the lesion and in the macaque from 3 to 14%. This shift probably resulted from the general absence of contaminating IPSPs after the lesion (16% with PTx3; see above). IPSPs evoked by single PT shocks were common before the lesion in both species, but were found in only 3% of motoneurons after the lesion in the squirrel monkey and in only 24% in the macaque. The C5 lesion produced a striking reduction in both CM EPSPs and IPSPs in both studies, although the change was more marked in the squirrel monkey. Whereas in the macaque, with relatively large compound CM EPSPs, the corticospinal axons surviving the lesion could be expected to evoke effects in some motoneurons (36% of which still gave EPSPs, but nearly all with amplitudes <1.0 mV), the small amplitude of CM EPSPs in the intact squirrel monkey (Fig. 9A) may well mean that postlesional effects were too small to detect. The C5 DLF lesion had no effect on the occurrence of EPSPs from the LRN in either species.
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Correlation of responses in single motoneurons to LRN and PT stimulation
In the cat, Alstermark and Sasaki (1986a) have
demonstrated that across a population of forelimb motoneurons there is
a positive correlation between the amplitudes of the LRN-evoked EPSP
and the disynaptic EPSP evoked by PTx3 in the same motoneuron. Their data, recorded from motoneurons supplying muscles acting at the shoulder and elbow, has been replotted in Fig.
11A (
, dashed regression line, r = 0.54, P < 0.002). Figure
11A also shows that in both the squirrel monkey (
) and
macaque (
), a similar positive correlation exists (squirrel monkey,
thick regression line, r = 0.38, P = 0.035; macaque, thin regression line, r = 0.62, P = 0.015). All three regression lines fall below the
line of identity (dotted line). The distribution of data points with
small amplitudes is replotted for clarity in Fig. 11B.
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The arrowheads on the abscissa in Fig. 11A show important
species differences in the size of the LRN evoked effects; after the
C5 lesion, the mean amplitude of EPSPs evoked
from the LRN in the squirrel monkey (1.7 ± 0.8 mV,
n = 34) was larger than in the macaque
monkey (open arrowhead; 1.2 ± 0.7 mV, n = 67) and smaller than that found in the cat (open double arrowhead;
5.2 ± 2.1 mV, n = 23) motoneurons tested after a
C5 lesion (Alstermark and Sasaki
1986a). These differences among the three populations were
significantly different (Kruskal-Wallis rank test, P < 0.001). It should be noted that the cat data were measured at stimulus strengths of 500 µA as compared with 200 µA for the two monkey series. However, this makes little difference to the present
comparison. In the data of Alstermark and Sasaki (1986a)
the amplitudes of LRN EPSPs at 200 µA were reduced from the values at
500 µA by an average of 33% for the seven examples illustrated. If
the amplitudes of the LRN EPSPs in the cat data of Fig. 11A
are reduced by this same factor, the species differences remain clear
and still significant (Kruskal-Wallis rank test, P < 0.001).
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DISCUSSION |
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The major finding reported here is that in a primate species with
a rather weak CM system we have found significant transmission of
corticospinal excitation to arm and hand motoneurons by a
C3-C4 propriospinal
pathway. This is in distinct contrast to the findings of our previous
study, under identical experimental conditions, of the macaque monkey,
in which CM effects are stronger but where there is little evidence for
PN transmission (Maier et al. 1998).
There are four pieces of evidence that the late EPSPs evoked from the
PT in squirrel monkey motoneurons were mediated by a C3-C4 propriospinal
pathway: 1) most EPSPs had a segmental latency in the di- or
trisynaptic range; 2) all EPSPs were seen with repetitive but not single PT stimuli, indicating an indirect pathway;
3) the EPSPs persisted after a C5
lesion was made that abolished most of the corticospinal input to the
lower cervical segments where the target motoneurons are located. PNs
with axons running in the ventral parts of the lateral funiculus, as in
the cat (Illert et al. 1977, 1978
) (Fig. 1,
inset), are likely candidates for mediating these effects
(Maier et al. 1998
); and 4) the effects were
abolished by a second lesion to the DLF at C2,
which interrupted corticospinal input to the
C3-C4 segments
(Illert et al. 1977
).
Comparison of motoneuron responses in cat, squirrel monkey, macaque monkey, and human
It is particularly interesting to compare the results obtained in
studies of corticospinal excitation in three different species: cat,
squirrel monkey, and macaque (Fig. 12),
and to explore the significance of this comparison for the human motor
system. A similar anesthetic regime and experimental approach has been
employed in all the animal studies. In motoneurons recorded after the
C5 lesion, late EPSPs from the PT were common in
the squirrel monkey (86% of sampled motoneurons; Fig. 12A),
which is slightly less than in the cat, where all motoneurons show such
effects (Alstermark and Lundberg 1992; B. Alstermark,
personal communication). The proportion in the squirrel monkey is in
striking contrast to the macaque, in which only 18% of 88 tested upper
limb motoneurons showed evidence of di- or oligosynaptic EPSPs evoked
by repetitive PT stimulation after a C5 lesion
(Maier et al. 1998
). Both the latency and the amplitude
of the late EPSPs in monkeys tend to suggest that
C3-C4 transmission of
corticospinal excitation is weaker than in the cat. Thus in the
squirrel monkey, as in the macaque, some of the effects we have
observed were beyond the presumed disynaptic range (Fig. 5). However,
the distribution is not bimodal, as might be expected if the longer
latency effects were trisynaptic. If there is a relatively weak
convergence of PN neurons onto individual motoneurons in monkeys, then
EPSPs derived only from slowly conducting PN fibers, become more likely and disynaptic EPSPs would be expected at latencies longer than those
in this limited range; there is evidence in the cat for such slowly
conducting fibers (Alstermark and Sasaki 1986a
;
Alstermark et al. 1981a
). In any case, even if
only those late EPSPs that were strictly within the presumed
disynaptic range are compared, the same species differences are
observed (after C5 lesion: cat, 100%; squirrel
monkey, 41%; and macaque, 14%; see Fig. 10). These results suggest
that, under the experimental conditions used, PN neurons transmit a
significantly higher proportion of corticospinal excitation in the cat
than in the squirrel monkey, which in turn is higher than in the
macaque.
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The decline in the contribution of PN-transmitted corticospinal excitation from cat, to squirrel and macaque monkey is accompanied by a clear increase in the influence of the CM system. CM connections are absent in the cat (Fig. 12B, *), present but relatively weak in the squirrel monkey, and well developed in the macaque. In the squirrel monkey, the mean amplitude of the CM-EPSP in motoneurons supplying hand and forearm muscles was 0.6 ± 0.3 mV (n = 23) compared with 1.9 ± 1.0 mV (n = 62) in the macaque.
It is significant that the human CM system is the most highly developed
among primates (Heffner and Masterton 1975, 1983
; Kuypers 1981
). The estimated value given for CM-EPSPs in
Fig. 12B is 4.2 mV, substantially larger than in either
monkey species. This estimate is based on responses of single motor
units in hand and forearm muscles to transcranial electrical
stimulation of the motor cortex (de Noordhout et al.
1999
); similar estimates have been found in other human studies
(Day et al. 1989
; Palmer and Ashby 1992
).
Factors that might explain species differences in transmission of corticospinal excitation
There are a number of possible explanations for the species
differences in PN transmission. The first possibility is that the
corticospinal excitatory projection to the
C3-C4 PNs is much weaker
in the macaque than squirrel monkey or cat. This can only be
established by direct recording from these PNs. A second possibility, already referred to above, is that the projection of the macaque PNs to
upper limb motoneurons is relatively weak. Some insights into this
second explanation can be gained from the properties of the responses
to LRN stimulation. The field potentials (Fig. 7B) and EPSPs
(Fig. 7, C and D and Fig. 8, A and
B) evoked from the LRN were very similar to those reported
in great detail in the cat (Alstermark et al. 1981a) and
the macaque monkey (Maier et al. 1998
). Further, the
relationship between EPSP rise time and amplitude is remarkably similar
in both monkey species (Fig. 8, E-H) as compared with that
seen in the cat (Alstermark and Sasaki 1986a
). These
features all suggest that the EPSPs are likely to be due, at least in
part, to antidromic activation of ascending axons of PNs to the LRN
(see Discussion in Maier et al. 1998
). The amplitude of
EPSPs evoked in upper limb motoneurons from the LRN appear to be
largest in the cat, smaller in the squirrel monkey and smallest in the
macaque (see arrowheads in Fig. 11). Note that because proximal upper
limb muscles were represented in the macaque and not in the squirrel
monkey study (Maier et al. 1998
), any bias in motoneuron
selection between the two primate studies should have resulted in the
macaque EPSPs being larger than those in the squirrel monkey and more
like those in the cat. Figure 11 shows that this was not the case.
Also, the squirrel monkey EPSP amplitudes are clearly generally closer
to the origin in Fig. 11 than the EPSPs from even the fast motoneurons
in the cat population (Alstermark and Sasaki 1986a
).
We recognize the dangers of making these comparisons both between laboratories and between species, especially because motoneurons were not type-identified in either of the primate studies and nor were the muscles as precisely identified as in the cat studies. Nevertheless, these results tend to support the idea that some of the species differences in PN-mediated excitation from the PT are due to variations in the strength of the C3-C4 PN projection to upper limb motoneurons. In Fig. 12 this is indicated by the thickness of the line linking the C3-C4 PNs to MNs.
Inhibition of C3-C4 transmission
A complicating factor in estimating the strength of PN
transmission of corticospinal excitation is that stimulation of the corticospinal tract gives rise to feedforward inhibition of PN neurons
(Alstermark et al. 1984a,b
). Alstermark
and Sasaki (1986a)
considered that this feedforward inhibition
was one of the reasons why, for a given motoneuron, the size of the
EPSP from the LRN was always larger than that evoked from the PT. The
regression line relating the amplitudes of these two effects always lay
below the line of identity (Fig 11, fine dotted line), and the slope of
the regression line was taken to represent the degree of feedforward inhibition (Alstermark and Sasaki 1986a
). It is
interesting that in all three species investigated, there is a
significant relationship between the LRN EPSP and late EPSP from the PT
and that the regression lines have similar slopes. Although there is
considerable scatter in Fig. 11, this data provides no support for a
different degree of feedforward inhibition across the three species.
A recent report from Alstermark et al. (1999) challenges
the interpretation we are presenting here. In these experiments
disynaptic EPSPs were sought in upper limb motoneurons of the macaque
money from PT stimulation following a C5
dorsolateral lesion, but were not found, exactly as in Maier et
al. (1998)
. However, when strychnine was systemically
administered to this preparation, nearly all motoneurons showed
disynaptic excitation, which was abolished by a dorsolateral
C2 lesion. The authors conclude inter
alia that "the inhibitory control of the
C3-C4 PNs is stronger than
in the cat" and "it now seems that the need for re-evaluation [of
human studies interpreted via PN studies in the cat] is not so urgent."
Although the results from Alstermark et al. (1999) are
important and lead to a number of new questions, we believe that these results are open to more than one interpretation and that they therefore do not invalidate our conclusions. First, the claim that the
inhibitory control is stronger in the macaque monkey than in the cat
must remain a hypothesis until further detailed experiments with
strychnine are performed in the cat. Second, it is important that the
issue of the definition of the
"C3-C4 propriospinal
system" is carefully considered. The results of Alstermark et
al. (1999)
suggest that a significant number of C3-C4 PNs which project
via the ventral portion of the lateral funiculus to upper limb
motoneurons are under inhibitory control. The authors' interpretation
implies that when released from this inhibition the PN system in the
macaque is comparable in strength to that in the cat. However, an
important element in investigating this system in many of the
publications from Alstermark and his colleagues has been the
observation that "the vast majority" of PNs (86% of those
terminating above T9) (Alstermark et al.
1981a
) have an ascending collateral to the LRN, and many
properties of the system have been investigated on this basis, as
described above. Thus if the macaque has a PN system comparable to that in the cat, the EPSPs from the LRN should also have similar amplitudes to those in the cat. This prediction is in conflict with our data, which shows that these EPSPs are in fact substantially smaller than in
the cat (Fig. 11); note that these EPSPs, if they reflect antidromic
activation of C3-C4 PNs,
should not be affected by inhibition of these neurons. We contend that
it is a much more prudent assumption that if other interneurons are
released from inhibition by strychnine, then they should be taken as a
previously unknown category, which may not have the same properties and
connections as the well-known
C3-C4 interneurons
investigated in the cat in the absence of strychnine.
The function of feedforward or other sorts of inhibition of
C3-C4 PNs is still
unknown; it may be concerned with focusing the excitation transmitted
through this system during particular motor acts (Alstermark et
al. 1999; Pierrot-Desilligny 1996
), but this has
yet to be demonstrated.
The primary importance of the analogy between responses in man
(Pierrot-Deseilligny 1996) and the well-known system in
the cat is the ability to use some of the properties of the cat system to help evaluate the human measurements. If it is likely, as we suggest
above, that the system now revealed in the experiments of
Alstermark et al. (1999)
is substantially different from
that well-known in the cat, then the analogy is not a safe one for these purposes, and it remains the case that "deductions ... based on data from the cat should be regarded with great caution"
(Maier et al. 1998
). We suggest that, at the very least,
new experiments are needed to investigate whether or not the properties
of the connections revealed by strychnine (in either monkey or cat)
correspond to those of the well-known
C3-C4 system, before
extrapolation from cat to man is considered to be safe.
The relative contribution of the CM and PN systems to upper limb control in different species: a hypothesis
There are, of course, many differences between the motor behaviors
of the four species considered here. One is the striking variation in
dexterity (Figure 12D) (Heffner and Masterton 1975, 1983
). In the cat, with an index of dexterity of 2, there is a very restricted capacity for independent digit movements
(Boczek-Funcke et al. 1998
). Although the squirrel
monkey (index = 5) has much more advanced hand function than the
cat, independent finger movements are limited and there is no precision
grip or capacity to manipulate objects within the hand (Costello
and Fragaszy 1988
; Fragaszy 1983
). The macaque
monkey (index = 6) has both the capacity for true tip-to-tip
opposition of thumb and index in the precision grip and employs tactile
exploration and manipulation of objects (Heffner and Masterton
1975
, 1983
; Lawrence and Hopkins 1976
), and
these functions are further refined in the human hand (index = 7)
(Napier 1980
; Wiesendanger 1999
). Thus it
has been concluded that the relative development of the CM system in
the four species is important for the degree of dexterity which they
exhibit. One could therefore speculate that the apparently converse
relationship with the influence of the PN system is similarly related
to the degree of dexterity.
However, in attempting to assess the relative contribution of CM and PN
transmission of cortical commands, it is important to point out that in
the cat the C3-C4 PN
system has been implicated in the control of reaching movements but not
grasping (taking food with the paw) (Alstermark and Lundberg
1992; Alstermark et al. 1981b
). In keeping with
this function, it has been observed that motoneurons supplying proximal
upper limb muscles receive a strong PN input in this species
(Alstermark and Sasaki 1986b
). In contrast, the
observations of Maier et al. (1998)
suggest that this
input to motoneurons supplying this same group of muscles is generally
absent in the macaque monkey. This prompts us to suggest that the PN
system is of less importance in the control of reaching in primates
than in the cat.
Thus we hypothesize that in addition to the already well-established
function of the CM system in the control of the most distal upper limb
muscles, there is also a CM contribution to the control of reaching
that effectively takes the role of that mediated by the
C3-C4 system in the cat.
There is evidence that in primates, upper limb motoneurons supplying
muscles involved in reaching receive CM connections. In humans,
short-latency motor evoked potentials are evoked in muscles
acting at the shoulder and elbow by non-invasive cortical stimulation
(de Noordhout et al. 1999; Palmer and Ashby
1992
). In macaque monkey, CM EPSPs have been recorded in
motoneurons supplying proximal arm muscles (Maier et al.
1998
; Porter and Lemon 1993
). A recent study
reported CM cells showing postspike facilitation of muscles such as
deltoid, latissimus dorsi, biceps, and brachialis during reaching
movements (McKiernan et al. 1998
). Indeed, one can argue
that the highly coordinated acts of reach and skilled grasp in primates
(Jeannerod 1988
) requires the elaboration of the CM
system to involve not only selective control of the most distal
extremity but also that of more proximal upper limb muscles. This
latter control is essential for stabilizing and orienting the hand
(Humphrey and Reed 1983
; McKiernan et al.
1998
; Porter and Lemon 1993
).
Thus there is evidence for the existence of some appropriate projections, as well as teleological justification, for our proposal that the CM system in primates (in particular in the human) could fulfill the functional role that has been assigned to the PN system in the cat.
Other factors
SEGMENTAL INHIBITION.
In both the macaque and squirrel monkey most motoneurons showed
disynaptic inhibition from the PT. This inhibition was facilitated by
repetitive stimulation and was greatly reduced by the
C5 DLF lesion. This suggests that an important
part of the corticospinal projection to the lower cervical segments may
be to segmental inhibitory interneurons in accordance with anatomical
findings (Armand et al. 1997; Dum and Strick
1996
; Kuypers 1981
) and consistent with the
effects presumed to be mediated in
C3-C4 segments under strychnine (Alstermark et al. 1999
). Recordings of
spinal interneurons in the awake monkey (Perlmutter et al.
1998
) showed that many of these exerted postspike suppression
of upper limb EMG activity. Inhibition of unwanted muscle activity is
an important component of skilled arm and hand control (Schieber
1995
), and can be used to sculpt the final motor output by
changes during both preparation and execution of movement (Prut
and Fetz 1999
). In the squirrel monkey with an intact cord,
these inhibitory effects could have masked at least some of the late
EPSPs from the PT, especially those strictly within the disynaptic
range (cf. Fig. 5, A and C). However, in the
macaque monkey with a C5 lesion, such masking was
definitely not a significant factor since Maier et al.
(1998)
reported that only 34% of motoneurons tested after the
lesion with repetitive PT shocks showed IPSPs and these were small.
Moreover, 26% of motoneurons were found with neither a monosynaptic
EPSP nor a disynaptic IPSP that could have masked any later effects: none of these motoneurons showed late EPSPs.
ANESTHESIA.
The investigations of the
C3-C4 PN system in
different animal species have all been carried out under chloralose
anesthesia. Although there are good arguments for refuting a
species-specific anesthetic depression of
C3-C4 transmission (see
Maier et al. 1998), the results of these studies can
only strictly apply to the particular experimental conditions that have
been tested, which were the ones used in the original definition of the
C3-C4 PN system
(Illert et al. 1977
, 1978
). As we discussed above with regard to the recent experiments of Alstermark et al.
(1999)
, this can be regarded in many ways as a virtue, rather
than as a limitation. However, it is clear that more information is
needed about the transmission of corticospinal excitation under other pharmacological regimes and in the unanaesthetized state.
Conclusion
These findings suggest that the positive correlation across species between more advanced hand function and the strength of the CM system is accompanied by a negative correlation between this function and the strength of the PN system. The results indicate that in primates with more advanced hand function the CM system may have replaced PN-mediated control and also predicts that in man, where the CM system is more highly developed than in any other species, the C3-C4 PN system, as described in the cat, is unlikely to be responsible for significant transmission of cortical commands to upper limb motoneurons.
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ACKNOWLEDGMENTS |
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We acknowledge the expert advice and help of T. Morris and K. Thompson in carrying out these experiments. We thank N. Philbin, C. Seers, K. Sunner, H.-W. Yang, and R. Spinks for technical assistance, and L. Williams and staff at the University of South Alabama. We received useful comments on an earlier version of this mansuscript from M. Illert and J. Nielsen.
This study was funded by the Wellcome Trust and International Spinal Research Trust.
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FOOTNOTES |
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Address for reprint requests: R. N. Lemon, Sobell Department of Neurophysiology, Institute of Neurology, University College London, Queen Square, London WC1N 3BG, UK (E-mail: rlemon{at}ion.ucl.ac.uk).
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 8 December 1999; accepted in final form 12 April 2000.
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REFERENCES |
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