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1 Sobell Department of Motor Neuroscience and Movement Disorders, Institute of Neurology, University College London, London WC1N 3BG, United Kingdom 2 University Paris-VII and Institut National de la Santé et de la Recherche Médicale U.483, Paris, France
Submitted 13 November 2002; accepted in final form 4 March 2003
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ABSTRACT |
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INTRODUCTION |
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;
Jeannerod et al. 1995;
Rizzolatti et al. 1998). There
are dense corticocortical projections to F5 from regions of posterior parietal
cortex that process visual inputs related to grasp
(Murata et al. 2000;
Sakata et al. 1995;
Taira et al. 1990). These
projections originate from parietal region AIP and terminate in the region of
F5 that lies in the bank of the inferior arcuate sulcus
(Luppino et al. 1999;
Rizzolatti et al. 1998;
Tanné-Gariépy et al.
2002). Single-unit activity within this same arcuate bank region
of F5 is related to grasp (Murata et al.
1997; Rizzolatti and Luppino
2001), and visually guided grasp of objects is temporarily
impaired after injection of the GABA agonist, muscimol, into this same region
(Fogassi et al. 2001).
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How then does area F5 influence movement of the hand and fingers? This
issue is of considerable importance in understanding how visuomotor activity
in F5 is transformed into motor commands that ultimately determine the
kinematics and dynamics of hand shaping that is appropriate for the object to
be grasped. It is known that intracortical microstimulation in area F5 evokes
discrete wrist and finger movements
(Gentilucci et al. 1988;
Godschalk et al. 1995;
Hepp-Reymond et al. 1994). The
most direct pathway that might mediate these effects is the corticospinal
projection (Dum and Strick
1991). A part of that projection does indeed arise from the F5
arcuate bank region, but it is rather weak in the macaque, and, critically, it
does not project to the motor nuclei in the cervical enlargement that
innervate the wrist and finger muscles. Thus He et al.
(1993) demonstrated that a
cluster of F5 corticospinal neurons that were labeled from the upper cervical
segments (C2–C4 segments) were not labeled when
the injection was made in the cervical enlargement
(C7–T1). This result was confirmed by Galea and
Darian-Smith (1994).
An alternative pathway through which F5 could influence hand movements
would be via the dense and numerous corticocortical connections from F5 to the
primary motor cortex (M1) (Ghosh et al.
1987; Godschalk et al.
1984; Jeannerod et al.
1995; Lu et al.
1994; Matelli et al.
1986; Muakassa and Strick 1979). Tokuno and Nambu
(2000) showed recently that
pyramidal tract neurons in M1 respond at short latency to stimulation in the
bank of the inferior arcuate sulcus. M1 gives rise to a very large number of
corticospinal projections to the cervical enlargement
(Dum and Strick 1991;
Galea and Darian Smith 1994;
He et al. 1993) including many
direct cortico-motoneuronal projections to motoneurons innervating wrist and
finger muscles (Armand et al.
1997; Fetz and Cheney
1980; Kuypers
1981; Lemon et al.
1986; Maier et al.
2002).
We investigated whether we could influence M1 outputs to intrinsic hand muscles through activation of the bank region of F5, and we report here robust, short-latency effects of conditioning stimulation of F5 on EMG responses evoked in hand muscles by single shocks to M1. Although other pathways may be involved, one possible mechanism to explain these results is a fast cortico-cortical pathway from F5 to M1 that facilitates the corticospinal outflow from M1 to hand motoneurons.
This work has been published previously in abstract form
(Cerri et al. 2002).
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METHODS |
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Identification of hand representations in F5 and M1
Two approaches were used to locate accurately these representations: magnetic resonance imaging (MRI) and repetitive intracortical microstimulation (rICMS).
MRI. This was used to determine the precise sulcal geometry of
the central and arcuate sulci to allow accurate placement of recording
chambers, microelectrode penetrations for ICMS mapping, and final placement of
intracortical microwire electrodes. Scans were carried out under deep general
anesthesia; for detailed, methods see Baker et al.
(1999).
rICMS MAPPING. After an initial injection of ketamine (10 mg/kg im), the monkey was intubated and anesthetized with isoflurane (2–2.5% in a 1:1 O2-N2O mixture). A craniotomy was made and a stainless steel chamber (18 mm ID) was mounted over the lateral surface of the precentral gyrus, giving access to the F5 and M1 hand areas. The orientation of the chamber was guided by the MRI scan and set to allow electrode penetrations in the depths of the central and inferior arcuate sulci. After the surgery, an antibiotic (terramycin LA 20 mg/kg, Pfizer, Sandwich, Kent, UK) and an analgesic (buprenorphine hydrochloride 5–10 µg/kg im; Vetergesic, Reckitt and Colman, York, UK) were administered.
Over periods ranging from 3 to 6 wk, rICMS was used to map the motor
representations of F5 and M1. For this, the monkey was lightly sedated with a
mixture of ketamine and medetomidine HCl (Dormitor, Pfizer). This preparation
allows investigation of the motor system under conditions in which the level
of motoneuronal excitability is reasonably stable, although cortical
stimulation thresholds may be somewhat elevated by the use of ketamine
(Olivier et al. 2002). The
doses used were 3.6 mg/kg ketamine and 0.044 mg/kg Dormitor, both given
intramuscularly. Small additional doses (1–2 mg/kg) of ketamine were
given every 15–30 min so as to provide a very low level of ongoing
muscle activity.
rICMS was delivered through a glass-insulated platinum-iridium
microelectrode with a low tip impedance (0.3–0.5 M
at 1 kHz).
Trains of 20 rICMS 0.2-ms biphasic constant current pulses at 300 Hz were
delivered at a rate of 0.5 Hz from a Neurolog NL800 stimulus isolator
(Digitimer) with a search intensity of 
40 µA. Biphasic pulses were used
to minimize electrode polarization. rICMS was tested every 250 µm along
each penetration to a depth of 7.5 mm from the point of electrode entry.
Mapping continued until a number of contiguous tracks within each area were
made from which digit movements could be evoked with low-threshold rICMS
(<10 µA for M1, <28 µA for F5; see
Fig. 1).
Chronic implant of cortical microwires
When rICMS mapping was complete, small arrays of fine low-impedance
(
20 k) elgiloy microwire electrodes were permanently implanted
intracortically at the center of these wrist and digit representations under
full anesthesia. Four to five electrodes were implanted in M1 and in F5.
Microwire electrodes were mounted in a single planar array of four to five
electrodes, with an inter-electrode distance of 1–1.3 mm. Their tips
were targeted at the inferior bank of the arcuate sulcus (F5) and rostral bank
of the central sulcus (M1) and were fixed 3–5 mm from the pial surface.
Electrodes were cemented to small bone screws and connected to a miniature
D-connector mounted on the skull. The impedance of the microwires remained
constant throughout the experimental period, and there were no continuity
leaks between connector and electrode tip.
PT electrodes
In one monkey (CS14), two fine varnish-insulated tungsten
electrodes were implanted in the medullary pyramid at stereotaxic coordinates
A3 and P2 (Olivier et al.
2001). Their location was confirmed during surgery by recording
the antidromic field potential from the surface of the motor cortex
(threshold: 60 µA).
Experimental protocol: recording and stimulation
The same sedative regime described in the preceding text was used to
investigate the effects evoked from the implanted microwire electrodes.
Experimental sessions were carried out twice per week. Initially, rICMS was
delivered through each of the microwires in turn, using the same stimulation
protocol described in the preceding text, and we documented the threshold and
nature of the movement evoked by rICMS through the microwire electrodes: in
both monkeys, the lowest threshold movements were observed in the thumb.
Accordingly, in subsequent sessions, EMG activity was recorded from intrinsic
thumb (thenar) muscles using either intramuscular wire or surface electrodes
and a Neurolog NL820/824 isolated amplifier system. Unrectified EMG and
stimulus trigger signals were acquired using a CED 1401plus interface (CED,
Cambridge, UK), with a sampling rate of 
8.8 kHz.
Interactions between stimuli delivered to F5 and M1 were investigated while there was evidence of low-level background EMG activity in the sampled muscles. Monophasic rather than biphasic current pulses were applied to pairs of microwires: this allowed us to define the motor effects due to cathodal versus anodal stimulation through a given electrode. Condition (C), test (T), and combined (C-T) stimuli were interleaved and delivered as follows. Conditioning stimuli were single or double shocks to F5 (duration: 0.2 ms, 70–200 µA); test stimuli were single shocks to M1 (duration: 0.2 ms, 70–200 µA). Condition-test intervals between 0 and 30 ms (F5 before m1) were tested, and the duty cycle was 0.5–1 Hz.
Histology
At the end of this study, both monkeys underwent a terminal experiment
under full anesthesia (Shimazu et al.
2002), at the end of which they were given an overdose of
pentobarbitone sodium (100 mg/kg) and perfused through the heart. Entry points
of microwire arrays were confirmed by photography of the fixed cortical tissue
(Fig. 1, B and
C). The tips of the microwire electrodes were localized
by passing DC current (20 µA for 20 s, tip positive) and the sites of
cortical (Suzuki and Azuma
1976) and PT stimulating electrodes were confirmed histologically.
Frozen parasaggital sections of the cortex (50 µm) were cut, mounted, and
Nissl stained. Each section was carefully inspected for electrode tracks and
sample sections photographed.
Analysis
EMG data for analysis were taken from sessions in which long periods of relatively stable EMG activity was present. EMG was rectified and averaged in relation to condition (C, T, or C-T), with 50 shocks per condition. Facilitation or suppression of EMG was identified by subtraction of the responses to condition and test stimuli, given alone, from the conditioned response. Peak amplitudes and response areas and latencies were measured from averaged data. For each C-T interval tested, the peak amplitudes of each of the 50 responses per condition were calculated; the 10% largest and smallest responses were then excluded. The average (F5+M1)/M1 ratio (± SE) was calculated for conditioned responses obtained at each C-T interval. A one-way ANOVA was then carried out to confirm a significant relationship between C-T interval and the level of facilitation. Subsequently a Wilcoxon signed-ranks test was carried out for pairs of test (M1 alone) versus conditioned (F5+M1) responses.
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RESULTS |
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Detailed rICMS mapping was carried out in both monkeys, CS13 and CS14, and results are shown in Fig. 1, B and C, respectively. In monkey CS13, there were 5 tracks in M1 and 13 in F5, and for CS14, 8 tracks in M1 and 5 in F5. Thresholds were considerably lower in M1 (8–10 µA) than in F5 (22–28 µA), and responses from M1 were more robust. In both monkeys, we found at least two to four tracks in each cortical area that yielded digit movements. The surface loci of these penetrations were used to target the intracortical implants, whose final positions are also shown in Fig. 1, B and C.
EFFECTS OF RICMS THROUGH MICROWIRES IN M1. We found that rICMS delivered through at least one pair of microwire electrodes implanted in M1 evoked digit movements; the rICMS protocol is given in METHODS. Thresholds from the fixed microwires were considerably higher than found in the mapping studies. In monkey CS13, the lowest-threshold effect (thumb flexion) was from microwires 2 as cathode (negative, –ve) and 1 as anode (positive, +ve); the threshold was 35 µA. The tips of both electrodes were in the deep cortical laminae (V, VI) in the anterior bank of the central sulcus (see legend to Fig. 1 for details). In monkey CS14, the lowest-threshold effects were evoked from electrode pair 4 (–ve) and 3 (+ve) and evoked thumb abduction (threshold: 50 µA); tips of both electrodes were located in lamina V in the anterior bank (see Fig. 1D). Other electrode combinations gave digit movements at higher thresholds.
EFFECTS OF RICMS THROUGH MICROWIRES IN F5. No motor effects were
observed from F5 electrode pairs in monkey CS13 with currents of
80 µA. In monkey CS14, rICMS between electrodes 10 (–ve)
and 7 (+ve) yielded thumb abduction/extension with a threshold of 60 µA.
The tip of electrode 10 was located in laminae V/VI in the bank of the
inferior limb of the arcuate sulcus (Fig.
1D), about 3 mm from the pial surface; electrode 7 was
located in the superficial layers (II and III) deep in the bank, 4.5 mm from
the surface (Fig. 1D).
All F5 electrodes in both monkeys were located in the inferior bank of the
arcuate sulcus.
From the histological analysis, it is unlikely that the cathodal effects in either cortical area resulted from activation of the underlying white matter. This was confirmed by terminal experiments in both monkeys, which single stimuli delivered to the implanted electrodes evoked relatively large indirect or I waves in the corticospinal tract, but only small direct or D waves, which would not be the case if there were significant current spread to the white matter (H. Shimazu, M. A. Maier, P. A. Kirkwood, G. Cerri, and R. N. Lemon, unpublished data).
Powerful conditioning of EMG responses from M1 by F5 stimulation
EMG recordings were taken from the thenar muscles in both monkeys because thumb movements had the lowest threshold responses for rICMS delivered through the intracortical microwires (see preceding text). A total of 21 recording sessions were carried out; typical results are shown in Fig. 2. Single 70-µA shocks applied to M1 evoked robust short-latency responses (Fig. 2B). In contrast, neither single nor double shocks delivered to F5 evoked any consistent EMG responses (see Fig. 2A). However, while F5 stimulation alone was ineffective in eliciting EMG responses, it had a striking facilitatory action when paired with M1 stimulation (Fig. 2C). The conditioned response was more than double the size of the test response. In this example, the separation between the second F5 and the M1 shock was 3 ms. The powerful conditioning effect is revealed by subtracting the test from the conditioned response (Fig. 2D). In all of the conditioning experiments, we selected an M1 test shock intensity that was clearly submaximal for the EMG response.
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Nature of responses in thenar muscles to single-pulse M1 stimulation
To clarify the mechanisms underlying the facilitation of M1 responses by F5 stimulation, we first wanted to establish the nature of the EMG responses evoked from M1. In both monkeys, application of single monophasic stimuli to M1 electrode pairs evoked clear EMG responses in thenar muscles; the thresholds were 50 µA in CS13 (electrode 2–ve, 1+ve) and 120 µA in CS14 (electrode 4–ve and 3+ve). Providing that there was some ongoing background EMG present, these responses were seen with high probability but with variable latency and amplitude. This can be seen in the superimposed unrectified EMG recordings (Fig. 2B) from monkey CS13. The mean latency in this case ranged from 7.3 to 9.5 ms (grand average: 8.6 ± 0.5 ms, n = 5 averages from 5 sessions).
In the other monkey (CS14), which was larger (body weight: 4.4
versus 3.1 kg for CS13), the mean latency of EMG responses to M1
stimulation in different sessions ranged from 9.7 to 14.0 ms (grand average:
12.5 ± 1.1 ms, n = 32 separate averages from 4 sessions).
Examples of averaged responses to single M1 stimuli in CS14 are shown
in Fig. 3A; note again
the variation in onset latency in different sessions. In this monkey, we were
able to compare the thenar EMG responses evoked from M1 with those obtained by
direct stimulation of the medullary pyramidal tract (PT). Single PT shocks
(250 µA) evoked short-latency EMG responses with little variation in
latency (cf. Olivier et al.
2001); the mean onset latency was 8.3 ms (4 sessions); this
latency is indicated by the vertical dashed line in
Fig. 3A.
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Because the M1-evoked responses had substantially longer latencies than
those evoked by direct corticospinal volley excited from the PT, it is
unlikely that the responses from M1 were due to a direct or D wave in the
corticospinal tract. A D wave from M1 would be expected to discharge the
target motoneurons at about the same latency as from the PT with a small
correction needed for the additional conduction time of 1.0 ms from
cortex to pyramid (Maier et al.
1997; Olivier et al.
2001). This delay is included in
Fig. 3A by placing the
PT stimulus delivery 1.0 ms later than the M1 stimulus (long arrow and
arrowhead, respectively). Thus the predicted latency for a D wave mediated
response from M1 would be 9.3 ms (8.3 + 1.0, dashed vertical arrow in
Fig. 3A),
substantially shorter than the observed mean value, 12.5 ms. Thus we can
conclude that the M1 evoked responses probably resulted from later descending
I waves (Lemon et al. 1987;
Maier et al. 2002;
Porter and Lemon 1993;
Shimazu et al. 2002). The
typical interval between D and successive I waves is 1.0–1.6 ms
(Edgley et al. 1997;
Lemon 2002). Thus the
corrected latency difference between the M1 and PT evoked responses (3.2
ms) suggests that thenar motoneurons were discharging after the arrival of the
I2 wave.
Paucity of thenar EMG responses to single- or double-shock stimulation of F5
Single F5 shocks of 100 µA (CS13) and 200 µA
(CS14) never produced any clear EMG effects
(Fig. 3B, gray line).
This was also true for double shocks separated by 3 ms (Figs.
2A and
3D), unless high
intensities were used. For example, in Fig.
3, double F5 shocks at 150 µA produced no response
(Fig. 3D), whereas at
180 and 200 µA, small responses were observed
(Fig. 3, E and
F). Responses from F5 were significantly later than from
M1 (paired t-test P = 0.007, n = 12 pairs of
averages from 2 sessions in CS14); measured from the second F5 shock,
the latency of responses to F5 was on average 1.5 ms ±1.0 ms longer
than those from M1.
Characteristics of facilitation from F5
SINGLE VERSUS DOUBLE SHOCKS. Figure 3, B and C, illustrates the facilitation produced by single and double F5 shocks, respectively; the condition-test interval was 6 ms. In both cases, the conditioned response was larger and earlier, but the effects were more pronounced with the double F5 shocks (intershock interval of 3 ms).
INTENSITY OF STIMULATION. Stronger F5 stimulation also greatly increased the facilitation of responses evoked from M1. In Fig. 3, D–F, the intensity of paired F5 shocks delivered 4.5 ms before the M1 shock was varied; the M1 shock intensity was kept constant at 175 µA. Figure 3D shows that the conditioned response (F5 + M1) was clearly facilitated by F5 stimulation (intensity 150 µA). Stronger F5 stimulation at 180 µA (Fig. 3E) and 200 µA (Fig. 3F) produced dramatic increases in the amplitude of the conditioned response. Delivered alone, these F5 stimuli evoked only small EMG responses.
LATENCY OF RESPONSES. It is noticeable that compared with the
test responses, the onset latency of the conditioned responses was clearly
shortened, and this occurred in an intensity-related manner. Thus the latency
shortening (conditiontest) was 0.5 ms at 150 µA
(Fig. 3D), 1.5 ms at
180 µA (Fig. 3E),
and 3.0 ms at 200 µA (Fig.
3F). These average values conceal considerable
sweep-by-sweep variation in latency, as noted in the preceding text. Detailed
examination of the latency of individual sweeps revealed a tendency for
latencies to cluster at particular values, separated by 1.0 ms. For
example, In Fig. 2C,
the superimposed sweeps show that the larger responses occurred at preferred
latencies just over 1 ms apart. Figure
4 shows the results of analysis for 104 conditioned responses
recorded in one session; in this case there are hints of clustering at
latencies of 10–12 ms. It is possible that this periodicity reflects the
discharge of thenar motoneurons in association with successive I waves
generated from M1 whose amplitude is modulated by conditioning shocks to F5
(see DISCUSSION).
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LOCATION OF EFFECTIVE ELECTRODES. Figure 5 demonstrates the specificity of the effects from F5. The most pronounced facilitation (Fig. 5A) was observed from one pair of F5 electrodes: electrode 10 as cathode (–) and 9 as anode (+; see inset in Fig. 5). A second pair (electrodes 8–6+,) was also effective, as shown in Fig. 5C, but no facilitation was obtained from three other combinations using electrodes 9, 7, and 6 as cathode (Figs. 5, B, D, and E, respectively). Both the effective cathodes (electrodes 8, 10) lay in the deep laminae (V or VI); all other electrodes were in the superficial layers (II or III; see Fig. 1D).
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Time course of F5-evoked facilitation
Figure 6 shows examples from CS13 and CS14 of facilitation of M1 responses by conditioning F5 shocks delivered at different condition-test (C-T) intervals. In the left hand series (Fig. 6, A–D), a single F5 shock was used; a double shock (separation 3 ms) was used in the series on the right (Fig. 6, E–H). Clear facilitation was observed with short C-T intervals (1.6 ms in Fig. 6A, 3.0 ms in Fig. 6E) and at longer intervals ranging from 6 to 10 ms.
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Figure 7 shows the full time
course of facilitation produced by double (A) or single (B)
shocks in monkey CS14. In each series, at each C-T interval, we
delivered 50 shocks per condition (F5 alone, M1 alone, and F5 + M1). The duty
cycle was 500 ms between each condition, and different C-T intervals were
tested in a block design. F5 stimulation alone produced no EMG responses. For
each sweep, we measured the peak voltage of the conditioned response (F5 + M1)
at the latency predicted by the average response (i.e., at 10–15 ms, see
Fig. 6, A–H).
This value was then normalized by dividing it by the peak voltage of the
response evoked by the test shock (M1 alone) that had just preceded it (i.e.,
delivered 500 ms earlier). The 
in
Fig. 7 are the means ±
SE of 40 such ratio measurements; the five largest and five smallest responses
were excluded. This procedure minimized the effect of slow changes in the
level of excitability during the course of experiment, largely caused by the
need to administer small additional doses of ketamine from time to time. These
changes are indicated by 
, which plot the mean amplitude (±SE) of
the responses to the test (M1 alone) shocks. Overall there was no significant
correlation between the amplitudes of the test and conditioned responses,
suggesting that these slow changes did not contribute to the ratio
measurements.
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DOUBLE SHOCKS. For the data shown in
Fig. 7A, the intensity
of the test stimulus was a single M1 shock (180 µA), and it was conditioned
by two shocks to F5 (each 80 µA). Separation between the F5 shocks was 3
ms, and C-T interval was measured from the second shock. A one-way ANOVA
confirmed that there was a significant relationship between C-T interval and
the amount of facilitation (df = 7, F = 8.6, P < 0.001).
A Wilcoxon signed-ranks test revealed that the first significant effect was at
3 ms (P < 0.001, ratio = 4.5). Although a large effect was also
present at C-T of 1.0 ms (ratio: 3.1), this did not reach significance because
of the large variance in response amplitude. Overall conditioning effects were
large, with the ratio of conditioned response to test response
(Fig. 7A, )
rising to >12 at C-T of 10 ms. No remaining conditioning effect was
observed at C-T of 30 ms. Similar results were obtained in the other monkey
(CS13), again with a consistent early facilitatory effect at C-T of
3.0 ms.
SINGLE SHOCK. In another session
(Fig. 7B), we tested
the effects of a single F5 shock (also 80 µA). The overall effect was
weaker than with double shocks (compare vertical axes in
Fig. 7, A and
B), but again the ANOVA showed that a C-T
interval-dependent facilitation was present (df = 7, F = 2.7,
P < 0.01). No significant effect was present for simultaneous
delivery of F5 and M1 (C-T = 0). The first significant point was at 1.0 ms
(P < 0.05). From 6 15 ms responses were all significantly
larger and returned to baseline at 30 ms.
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DISCUSSION |
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Nature of the responses to M1 stimulation.
Before considering the facilitatory effects of F5, we need to understand
the nature of the test responses evoked from M1. The tips of effective
electrodes were in the deep cortical layers in the anterior bank of the
central sulcus, located within the wrist/digit area of M1 (as defined by
previous mapping with rICMS). We used single bipolar stimuli with intensities
of 70–200 µA to activate a significant proportion of the cortical
output to the thenar muscles. The physical spread of the currents used should
be <1 mm and confined to the stimulated area
(Lemon 1984; Ranck 1975;
Tokuno and Nambu 2000).
Single-pulse stimulation gives least temporal and spatial facilitation and
provides the best means of documenting relatively direct connectivity, similar
to that demonstrated by single neuron cross-correlation techniques (see
Cheney and Fetz 1985;
Lemon et al. 1987;
Park et al. 2001).
Bipolar stimulation of M1 gives rise to a complex succession of small D and
I waves in the corticospinal tract (Maier
et al. 2002). The rather focal nature of the stimulation is
supported by the fact that the amplitude of these waves amount to only a few
percent of the fast volley evoked by supramaximal stimulation of the tract at
the level of the pyramidal tract (PT)
(Maier et al. 2002;
Shimazu et al. 2002). It is
likely that the EMG responses we observed resulted from the discharge of
motoneurons after temporal summation and facilitation of corticospinal inputs
associated with successive D and I waves
(Boniface et al. 1991;
Day et al. 1989;
Maier et al. 2002). In
contrast to the EMG responses evoked by direct stimulation of the PT, those
evoked from M1 showed rather late and variable onset latencies (Figs.
2,
3,
4), consistent with motoneurons
reaching threshold after arrival of later I waves (I2 or
I3).
Location of electrodes giving rise to facilitation from F5
The sites within F5 that were effective in facilitating outputs from M1 all
lay in the deep layers of the inferior bank of the arcuate sulcus, several
millimeters lateral to the spur (Fig.
1). This is in the distinctive subdivision of area F5 (F5ab of
Rizzolatti et al. 1998; PMvr
of Gabernet et al. 1999) from
which wrist and finger movements can be obtained by low-threshold rICMS
(Godschalk et al. 1995) and
which receives visual-related inputs from the parietal area AIP
(Rizzolatti et al. 1998;
Luppino et al. 1999;
Tanné-Gariépy et al.
2002). In this subdivision, recordings have been made from
so-called "canonical neurons," which have both
"visual" and "motor" properties: they respond to the
visual presentation of particular objects as well as discharging when the
monkey grasps the object (Rizzolatti and
Luppino 2001). Thus the facilitatory effects we have observed
could be of importance for F5-M1 interactions during visuomotor
transformations related to hand function. The results hint that such
interactions are organized in a rather focused fashion: only certain
combinations of electrodes within the F5 microwire array were effective
(Fig. 5), and this may reflect
the known somatotopical relationships between F5 and M1
(Gentilucci et al. 1988;
Kurata and Tanji 1986;
Rizzolatti et al. 1988).
Characteristic features of F5 facilitation
The facilitatory effects observed were of large amplitude with the test
response being increased several fold by F5 stimulation; double shocks
produced stronger effects than single. It is noteworthy that single F5 shocks
never produced any EMG responses when tested alone (Figs.
2,
3, and
6). This is consistent with the
general lack of short-latency excitatory postsynaptic potentials in hand
motoneurons after F5 stimulation (Shimazu
et al. 2002). Although it has been shown that there is a
concentration of corticospinal neurons in the same ventral premotor region
that we have stimulated (Dum and Strick
1991) and our most effective F5 electrodes had tips located in the
deeper cortical layers (V/VI), corticospinal projections from this subdivision
of F5 do not reach the lower cervical cord in the macaque
(Galea and Darian-Smith 1994;
He et al. 1993). The absence
of such projections makes it unlikely that the F5-M1 interaction we have
observed occurs at the level of the hand motoneurons themselves, but this
conclusion requires confirmation in the form of direct recordings from
motoneurons.
Indirect transmission via propriospinal neurons located within the upper
cervical segments (to which F5 corticospinal neurons do project, He et al.
1994) remains a possibility, although a number of our earlier studies have
suggested that such transmission is rather weak in the macaque monkey
(Maier et al. 1998;
Nakajima et al. 2000;
Olivier et al. 2001) and does
not target intrinsic hand motoneurons
(Pierrot-Deseilligny
1996).
Another possible site of interaction is within M1 itself. There are
numerous cortico-cortical projections from F5 to M1
(Ghosh et al. 1987;
Godschalk et al. 1984;
Jeannerod et al. 1995;
Lu et al. 1994;
Matelli et al. 1986; Muakassa
and Strick 1979). Pyramidal tract neurons in M1 can be excited from ventral
premotor cortex with latencies as short as 1–3 ms
(Ghosh and Porter 1988;
Tokuno and Nambu 2000). Such
short-latency excitatory effects are consistent with the latency of the first
significant evidence for facilitation from F5 (1–3 ms; see Figs.
6 and
7). Again, more direct evidence
will be needed to identify whether the interaction we have observed occurs at
cortical or subcortical sites or at both.
Excitation and inhibition
It is striking that all of the effects we observed were facilitatory: there
was no sign of inhibition in any of the interaction experiments, at any C-T
interval (Fig. 7). Yet Tokuno
and Nambu (2000) found that
most M1 PTNs were inhibited by ventral premotor cortex stimulation: of 33
PTNs, only 11 showed signs of early excitation, but in all of these, there
followed a long period of inhibition, lasting 100 ms; the remaining PTNs
showed only inhibitory responses. While these findings argue against M1 as the
site of interaction, it must be pointed out that the spinal targets of these
PTNs were not identified and so may have been different to those giving rise
to the EMG responses that we have studied. Again, further work is needed.
Facilitation and I waves
We observed several "jumps" in the latency of the conditioned
response when the intensity of the conditioning F5 shock was increased
(Fig. 3, D–F)
with a tendency for the conditioned responses to cluster at particular
latencies (Figs. 2C
and 4). These effects had a
periodicity of 1.0–1.5 ms. As discussed in the preceding text, this may
reflect the discharge of thenar motoneurons in response to successive I waves
generated in M1 at intervals of 1–1.6 ms (Edgley et al.
1990,
1997;
Kernell and Wu 1967;
Maier et al. 2002;
Patton and Amassian 1954;
Ziemann and Rothwell 2000).
Tokuno and Nambu (2000) also
found some evidence for periodicity in the responses of M1 PTNs and other
neurons in response to stimulation of nonprimary motor areas.
Thus we speculate that our results could be explained by conditioning
shocks to F5 modulating the amplitude of different corticospinal I waves.
Waxing and waning of motor evoked potentials in response to paired-pulse TMS
of human motor cortex has also been attributed to I-wave periodicity
(Ziemann et al. 1998). I waves
probably derive from synaptic activation of corticospinal neurons through
chains of cortical interneurons (Amassian
et al. 1987; Ziemann and
Rothwell 2000), and these interneurons could be sites for
convergence of synaptic inputs originating both within M1 and
beyond M1, that is, from other motor cortical areas with strong
projections to it, such as F5 (Ghosh et
al. 1987; Godschalk et al.
1984; Tokuno and Nambu
2000). We raise the possibility that such pathways are also
activated by rICMS and speculate that this is one of the mechanisms mediating
motor responses evoked from F5.
Conclusions
We demonstrate a robust facilitatory action of F5 stimulation on motor
outputs to the hand generated from M1. Such a pathway may be of importance for
F5-M1 interactions during visuomotor transformations related to hand function.
The sites of this interaction and the underlying mechanisms involved will
require further investigation (Shimazu et
al. 2002).
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ACKNOWLEDGMENTS |
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This work was supported in part by the Wellcome Trust, a European Union (EU) project (Quality of Research Training Grant-1999–00448; COSPIM) and an EU Marie-Curie Fellowship.
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FOOTNOTES |
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Address for reprint requests: R. Lemon, Sobell Department of Motor Neuroscience and Movement Disorders, Institute of Neurology, UCL, University College London, Queen Square, London WC1N 3BG. Tel +44 (0)20 7829 8785, Fax +44 (0)20 7419 7170, (E-mail rlemon{at}ion.ucl.ac.uk).
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