Brain, Vol. 122, No. 7, 1327-1340,
July 1999
© 1999 Oxford University Press
Corticomotoneuronal synaptic connections in normal man
An electrophysiological study
University Department of Neurology, Hôpital de la Citadelle, Liège, Belgium
Correspondence to:
Alain Maertens de Noordhout, MD, University Department of Neurology, Hôpital de la Citadelle, Boulevard du XIIème de Ligne, 1, B-4000 Liège, Belgium E-mail: al.maertens{at}chu.ulg.ac.be
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In order to determine the mono- or oligosynaptic character of connections between pyramidal axons and individual spinal motor neurons, we constructed peri-stimulus time histograms (PSTHs) of the firing probability of voluntarily activated single motor units (SMUs) of various upper and lower limb muscles upon slightly suprathreshold transcranial anodal electrical stimulations of the motor cortex in normal subjects. Weak anodal cortical stimuli are known to activate preferentially fast-conducting pyramidal axons directly, bypassing cell bodies and cortical interneurons. A narrow bin width (0.1 ms) was chosen to measure precisely the duration of the PSTH excitatory peak, which corresponds to the rise time of the underlying compound excitatory post-synaptic potentials (EPSP). A short duration PSTH peak indicates sharp-rising EPSPs, most commonly encountered in the case of monosynaptic connections. In flexor carpi radialis and soleus SMUs, the PSTHs of built-in responses to anodal cortical stimuli were compared with those produced by 1A afferent stimulation able to elicit a Hoffmann reflex, which is known to be largely monosynaptic. In all upper and lower limb muscles, excitable SMUs responded to anodal cortical stimuli with a highly synchronized peak of increased firing probability. In flexor carpi radialis and soleus SMUs, the mean duration of this peak was significantly narrower than that evoked by 1A afferent stimulation, indicating that monosynaptic corticomotor neuronal transmission dominates low-threshold motor units, even in proximal arm and leg muscles. In the various muscles studied, and particularly in forearm SMUs, we did not observe broad PSTH peaks against the activation of non-monosynaptic corticomotor neuronal pathways, even with near-threshold stimuli. In some triceps and forearm flexor SMUs, subthreshold anodal pulses caused significant inhibition of their voluntary firing, with a latency consistent with activation of 1A inhibitory interneurons by the descending volleys. Measurements of the maximal number of counts in the excitatory PSTH peak upon anodal cortical stimuli provide comparisons of the strength of monosynaptic inputs to various muscles which seems to be maximal for hand and finger extensor muscles, and also for deltoid.
corticospinal tract; motor neurons; motor cortex stimulation
EPSP = excitatory post-synaptic potential; H-reflex = Hoffmann reflex; PSTH = peri-stimulus time histograms; PTN = pyramidal tract neurons; SMU = single motor unit; TCS = transcranial anodal electrical stimulations; TMS = transcranial magnetic stimulation
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Introduction |
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The anatomical development and functional role of the corticospinal tract increase with the ability of mammalian species to perform complex hand movements and culminate in human hand control (Kuypers, 1981
; Nathan et al., 1990). It is generally accepted that connections between pyramidal axons and spinal 
-motor neurons are largely monosynaptic in humans. However, this statement is poorly documented by direct anatomical and electrophysiological evidence (Iwatsubo et al., 1990), for obvious ethical reasons. In lower mammals, direct corticomotor neuronal connections are virtually absent, while in monkeys and apes, dense monosynaptic corticospinal projections have been demonstrated by extensive studies, not only for hand and forearm muscles, but also to some extent for more proximal muscles (for a review, see Porter and Lemon, 1993; Lemon, 1997).
Conversely, non-invasive electrophysiological studies (Gracies et al., 1991; Nielsen and Pierrot-Deseilligny, 1991; Burke et al., 1994; Pauvert et al., 1998) suggest that in man, part of the descending command to forearm muscles might be transmitted over non-monosynaptic pathways, via cervical interneurons somewhat comparable with propriospinal neurons described in the cat (Alstermark and Sasaki, 1985). Although such non-monosynaptic corticospinal pathways are well documented by direct recordings in lower mammals such as the cat (for a review, see Alstermark and Lundberg, 1992) and are probably present in some New World monkeys (Maier et al., 1997), they do not seem to play a significant role in Old World primates with more advanced motor functions. For example, in a recent study, Maier et al. found little evidence for propriospinally mediated excitatory post-synaptic potentials (EPSPs) from the medullary pyramid in intracellular recordings from upper limb motor neurons (Maier et al., 1998).
It is possible to activate non-invasively primary motor areas of the brain in conscious man, either with electrical (Merton and Morton, 1980) or magnetic (Barker et al., 1985) stimulators. Several studies conducted in man and animals have emphasized the different modes of activation of the motor cortex by electrical and magnetic stimulations (Day et al., 1989; Edgley et al., 1990, 1997; Burke et al., 1993). While the sites of cortical excitation with magnetic stimulation remain debated, there is general agreement that slightly suprathreshold anodal electrical stimuli essentially activate the axons of fast-conducting pyramidal tract neurons (PTNs), bypassing cell bodies and cortical interneurons (Day et al., 1987, 1989). We used this interesting property of weak anodal cortical stimuli to analyse the way in which PTNs recruit voluntarily activated single motor units (SMUs) of various upper and lower limb muscles. Peri-stimulus time histograms (PSTHs) of the SMUs' firing probability were constructed upon anodal cortical stimuli with a very narrow bin width (0.1 ms), in order to measure precisely the duration of the peaks of increased firing probability of the SMU to cortical stimuli. It was shown by Fetz and Gustafsson that the duration of a single PSTH excitatory peak corresponds to the rise time of the underlying compound EPSP, provided its amplitude exceeds 1 mV (Fetz and Gustafsson, 1983). A narrow peak indicates a short rise time, most commonly observed for monosynaptic EPSPs (Kirkwood, 1995). To validate this hypothesis, we compared durations of the PSTH peaks evoked in flexor carpi radialis and soleus SMUs by anodal cortical stimuli and by 1A afferent fibre stimulations evoking a Hoffmann reflex (H-reflex) in these muscles. Despite some caveats (Burke et al., 1984), it is generally accepted that the H-reflex is mediated mostly through monosynaptic pathways. It was assumed, therefore, that if the duration of an SMU PSTH peak to cortical anodal stimulation was shorter or equal to that evoked by electrical stimulation of 1A fibres, then the corticomotor neuronal connection was likely to be monosynaptic.
Moreover, using stronger stimuli, the present method also allows estimation of the strength of monosynaptic inputs to various muscles. Using the formula proposed by Ashby and Zilm (Ashby and Zilm, 1982), it is possible to estimate from the number of counts in a PSTH peak, the size of the underlying compound EPSP. Although this formula does not take into account the variation of SMU excitability at different firing rates (Jones and Bawa, 1995) and the depth of afterhyperpolarization (Burke, 1981), it allows some comparisons between different muscles and with previously published studies. Knowing the amplitude of a unitary monosynaptic EPSP, it is also possible to estimate grossly the number of PTN axons converging onto a single motor neuron.
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Subjects were volunteer staff members or visiting scientists (eight men and four women aged 25–49 years). They gave informed consent and the study was approved by the Ethical Committee of the University Hospital of Liège, Belgium.
The experimental setup used in these experiments was similar to that described by Day et al. (Day et al., 1987, 1989). Single motor unit potentials were recorded by thin (0.3 mm diameter) concentric EMG needles (Medelec DMC 37 and N53153) with a narrow recording field (0.019 mm2). Such thin needles offer optimal SMU potential discrimination from the background EMG noise, with the disadvantage that the shape of SMU potentials tends to change more easily with slight needle displacements. Subjects were instructed to activate voluntarily the selected SMUs at a relatively steady rate, which they found comfortable (6–12 Hz for hand and forearm extensor muscles, 4–9 Hz for forearm flexor, proximal arm and leg muscles) with visual and audio feedback. Individual SMU responses to cortical or nerve stimuli were filtered (0.5–10 kHz), amplified (100 µV/V), digitized (CED 1401plus, Cambridge Electronic Design) and stored for off-line analysis (SigAv program, Cambridge Electronic Design, Cambridge, UK). The relatively high value of 0.5 kHz was chosen for high-pass filters to offer a stable baseline and SMU potentials with a sharp rise time, allowing optimal latency discrimination to construct PSTHs with a narrow bin width. Simultaneously, SMU potentials were fed into a pulse discriminator, and transformed into 0.1 ms pulses for on-line construction of PSTHs (SigAv program, CED, and Microsoft Excel for illustrations). These generally were compiled from responses to 100 stimuli but, in some cases, 200 stimuli were used to increase the clarity of the PSTH peak. Transcranial electrical stimuli (TCS) were administered at random intervals (between 5 and 8 s) with a Digitimer D180 stimulator with a time constant of 100 µs. The stimulating anode was fixed on the scalp over the presumed target muscle's cortical representation area with collodion (6 cm lateral to the vertex and 1 cm frontal to the line between the vertex and the external auditory meatus for hand and forearm muscles, 3 cm lateral to the vertex, on the same line for proximal arm muscles, at the vertex for leg muscles). The reference cathode was located at the vertex for hand muscle activation, on the opposite hemisphere 6 cm apart from the anode for arm muscles and at Fpz (standard 10–20 EEG montage) for leg muscles. The intensity of cortical stimuli was adjusted to 1–30% of the maximal stimulator output above motor thresholds of individual units (30–60% of maximum for hand muscles, 35–70% of maximum for proximal arm muscles, 50–80% of maximum for leg muscles). For most SMUs, serial PSTHs were constructed with increasing stimulus intensities, until SMU potentials could no longer be discriminated from a more widespread response or until multiple PSTH peaks were evoked (see Day et al., 1987). For 13 units, responses to electrical stimulation were compared with those evoked by magnetic cortical stimuli (Magstim 200) with a 90 mm mean diameter coil centred at the vertex, with counterclockwise current flow in the coil to activate the left hemisphere. For H-reflex studies, median or posterior tibial nerves generally were stimulated at the elbow or the popliteal fossa with a constant current Grass S88 stimulator with 1 ms duration square pulses. For some units, several pulse durations (0.2, 0.5 and 1 ms) were used to investigate the effect of pulse duration on PSTH peak width. Stimulus intensities were adjusted to evoke an H-reflex in flexor carpi radialis or soleus muscles with a minimal direct motor response, concomitantly recorded with surface electrodes. The intensity of nerve stimulation was adjusted to evoke an H-reflex of 10–20% of the maximal response.
The following parameters of SMU responses were measured: (i) latency and duration of the first PSTH excitatory peak evoked by cortical or peripheral nerve stimulation and (ii) the maximal number of counts in the peak resulting from the strongest electrical cortical stimuli which produced a single PSTH peak. A PSTH peak of increased firing probability was defined as the number of bins whose counts exceeded the mean plus three SDs of the baseline firing probability. For example, a sequence of 100 stimuli and a unit fired voluntarily at 10 Hz corresponded to the presence of five or more counts in three adjacent bins. Under the same conditions, a period of significant suppression of SMU firing was defined as the absence of counts over a 5 ms (50 bins) period. If the unit was fired at a slower rate, values were modified accordingly.
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Anodal electrical stimulation of the motor cortex
Excitatory responses to near-threshold electrical anodal stimulation of the motor cortex were obtained in 113 of 140 tested SMUs of 12 normal subjects, located in 11 upper and two lower limb muscles (Table 1
). Single motor units studied were selected among those activated during a weak contraction of the target muscle, and chosen because they could be extracted easily from the background EMG activity and fired by the subject at relatively steady rates. In hand and finger extensors, deltoid, biceps or tibialis anterior, all units explored responded clearly to anodal cortical stimuli, while in triceps, flexor carpi radialis, trapezius or soleus, even strong (up to 80% of the maximal stimulator output in some instances) cortical stimuli failed to modify the spontaneous firing of some voluntarily activated SMUs. This held particularly true for wrist flexors, triceps and soleus, where up to one-third of the units tested showed no apparent response to anodal cortical stimuli with the setup used here (Table 1). However, due to massive muscle twitches evoked by such strong stimuli, it was often impossible to complete a full recording session without losing the selected unit.
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In all 113 SMUs responding to anodal cortical stimulation, slightly suprathreshold stimuli evoked a clear-cut, short-latency peak of increased firing probability on PSTHs compiled from responses to 100 stimuli (Figs 1 and 2
). In a given muscle, the onset latency of the SMU peak of increased firing probability to anodal cortical stimuli was 0.1–6 ms longer than that of surface-recorded responses of the corresponding muscle. This indicates that the first SMUs recruited during weak voluntary contraction were usually small, relatively slow conducting ones, in agreement with Henneman's size principle (Henneman et al., 1965). This was investigated in more detail for four clearly individualized motor units of extensor indicis of one subject: the first two voluntarily recruited SMUs showed a PSTH peak with latencies of 20 and 17.2 ms, while one large unit recruited only with strong voluntary activation had a PSTH peak latency of 14.6 ms, very close to the onset latency of the global muscle response recorded by surface electrodes (14.5 ms). The last SMU, recruited at a moderate contraction level showed an intermediate PSTH peak latency of 15.7 ms. In that subject, central motor conduction time was calculated to be 5.5 ms, including the synaptic delay. The distance from C7 to the muscle motor point was measured as 55 cm. Thus, if one assumes that conduction velocities are relatively homogeneous in fast-conducting PTN axons, conduction velocities within explored SMUs ranged from 38 m/s for small, early recruited ones to 60 m/s for the high threshold one, neglecting the possibility of intramuscular delays if the needle recorded SMU activity at some distance from the motor point. In this subgroup, small and slow-conducting units also showed the largest response and lowest activation threshold by anodal stimulations. These results are summarized in Table 2.
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In seven SMUs located in triceps and finger flexor muscles, the first detectable event in PSTHs collected at low stimulus intensities was some suppression of their ongoing voluntary discharge, with a latency slightly longer (2–10 ms) than that of the excitatory peak evoked with higher stimulus intensities and lasting for 5–15 ms. When the stimulus intensity was increased slightly, the excitatory peak appeared and became larger with stronger stimuli (Fig. 3
). We were unable to observe SMUs upon which anodal cortical stimuli exerted purely inhibitory effects, i.e. an early excitatory PSTH peak could always be evoked if the stimulus intensity was increased.
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In all upper and lower limb muscles tested, SMU excitatory responses to weak anodal cortical stimuli consisted of a highly synchronized single PSTH peak of increased firing probability, with a mean duration of 0.97 ± 0.29 ms (range 0.5–1.6 ms). Values obtained for the various muscles explored are quoted in Table 1
, and do not differ significantly from one muscle to another. Responses obtained in more distal SMUs showed no increased temporal dispersion when compared with more proximal ones. Upper and lower limb SMUs showed PSTH peaks of similar durations, indicating that there is little distance-dependent dispersion of the conduction within central and peripheral pathways. In 13 units, responses to anodal cortical stimuli were compared with those elicited by magnetic cortical stimuli. Even with slightly suprathreshold intensities, the latter evoked a broad (1.6–5.5 ms duration) peak of increasing SMU firing probability, often made up of multiple subpeaks. The latency of the single PSTH peak of increased firing probability evoked by anodal cortical stimuli was always shorter than that of the earliest peak produced by magnetic stimulation with the coil in the `standard' position (Figs 1 and 2). The mean difference ± SD was 1.4 ± 0.3 ms (range 0.7–1.8 ms).
Particular attention was paid to the behaviour of SMUs located in forearm muscles (33 units studied), as these are considered by Pierrot-Deseilligny and colleagues as the main target for non-monosynaptic corticomotor neuronal connections (see Pierrot-Deseilligny, 1996). Even at threshold and slightly above, all excitable units explored responded to anodal cortical stimuli with a narrow, short-latency excitatory PSTH peak. Its mean duration was not significantly longer for forearm SMUs than for those located in shoulder or hand muscles (see Table 1). Four triceps SMUs which could not be recuited by anodal stimuli showed early excitatory responses to magnetic cortical stimulations in the same way as other units, which seems to indicate that in some instances, anodal stimuli may be less efficient than magnetic pulses or perhaps that the localization of the stimulating anode was not optimal.
The size of the PSTH peak to anodal stimuli increased with stronger shocks, while its latency remained constant for all stimulus intensities used, which did not exceed 30% of maximum above the motor threshold (Fig. 1). However, in many units studied with increasing stimulus intensities, the number of counts in the peak tended to saturate for strong (20–30% of maximum above threshold) stimuli (Fig. 2). Anodal stimuli strong enough to evoke multiple PSTH peaks (see Day et al., 1987) were not used in this study. Under such conditions, the maximal number of counts in the PSTH peak of various upper and lower limb units is given in Table 1. The highest values were obtained for hand muscles and forearm extensors. Knowing the maximal number of counts in PSTH peaks for various muscles, it is possible, with the formula proposed by Ashby and Zilm (Ashby and Zilm, 1982), to obtain a gross estimate of the size of the underlying composite EPSPs: (total number of counts in the peak of increased SMU firing probability x mean interspike interval)/number of stimuli administered. If the maximal excursion of the hyperpolarization of the membrane potential of a tonically fired motor neuron is of the order of 10 mV (Ashby and Zilm, 1982), then a compound EPSP of 30 units calculated with the above equation would correspond to an amplitude of 3 mV. In the case of a unit fired rhythmically at 10 Hz, this also means that the stimulus is able to recruit it some 30 ms before its expected firing time. These statements have to be applied with some caution: indeed, when an SMU is fired at relatively low rates, it is more likely to respond to a stimulus of a given intensity than when activated at faster rates (Jones et al., 1996). Also, small units are known to have more pronounced afterhyperpolarization (Burke, 1981). Thus, EPSP sizes calculated with this formula could be underestimated in the case of small units fired rapidly and overestimated in the case of large units fired slowly (Awiszus and Feistner, 1994). Thus, as most recruited SMUs were small ones, and fired at relatively high rates, the values quoted below may be underestimated. The maximal amplitudes of compound EPSPs estimated with this equation for SMUs located in various muscles are given in Table 1. In the present study, amplitudes ranged from 1.7 mV in soleus motor neurons to 6.8 mV for first dorsal interosseous units. In general, calculated EPSPs were largest for distal hand muscles, finger extensors and deltoid, and were also larger for wrist and finger extensors than for flexors. In leg muscles, calculated compound EPSPs showed higher amplitudes in tibialis anterior than soleus.
H-reflex studies
In flexor carpi radialis muscle, responses elicited in eight SMUs by electrical stimulation of 1A fibres of the median nerve in an H-reflex paradigm were recorded with the same PSTH technique. For each SMU, the intensity of median nerve stimulation was adjusted to produce PSTH peaks of similar amplitude to those produced with anodal cortical stimuli. The mean duration of the PSTH peak corresponding to an SMU H-reflex (1.24 ± 0.39 ms, range 0.7–1.8 ms) was slightly, but significantly, longer than with anodal cortical stimuli (0.94 ± 0.27 ms, range 0.6–1.5 ms) (P < 0.03, Wilcoxon). Latencies of SMU responses to median nerve stimuli were slightly longer than those to cortical stimuli. An illustrative example is given in Fig. 4. Similar observations were made on nine soleus SMUs, which showed a slightly broader PSTH peak upon tibial nerve than anodal cortical stimuli (1.3 ± 0.32 ms versus 1.14 ± 0.25 ms, P < 0.03, Wilcoxon). Finally, median nerve stimuli of various durations (0.2, 0.5 and 1 ms) were used to elicit an H-reflex response in the same motor unit, in order to evaluate the effect of stimulus duration on the dispersion of the SMU response. As shown in Fig. 5, increasing the stimulus duration from 0.2 to 1 ms had no marked influence on PSTH peak durations.
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Arguments for the use of anodal electrical cortical stimulation
The first aim of the present study was to characterize synaptic connections between fast-conducting PTNs and spinal motor neurons supplying various distal and proximal muscles, and particularly forearm muscles. Similar studies have been conducted before (Palmer and Ashby, 1992
; Jones et al., 1996) with transcranial magnetic stimulation (TMS). However, even threshold TMS produces multiple descending impulses in PTN axons, which are probably, in part, the result of activation of excitatory cortical interneurons (Day et al., 1989; Edgley et al., 1990, 1997). The complex nature of the volley set up by TMS makes it difficult to interpret any later responses in PSTHs of single motor units. TCS stimulation of the motor cortex is uncomfortable, but offers a major advantage over TMS for such studies: it is known from animal and human studies that slightly suprathreshold anodal stimuli only evoke one descending volley in PTN axons (D wave; Patton and Amassian, 1954; Kernell and Wu, 1967; Boyd et al., 1986; Day et al., 1987). The timing of the D wave, and the observation that it is not markedly influenced by anaesthetics and remains intact after removal of cortical grey matter (Patton and Amassian, 1954; Burke et al., 1993), strongly suggests that it is the result of direct activation of PTN axons. D wave activation by weak anodal cortical stimuli thus provides the `simplest' model of cortical stimulation, avoiding the complication of trans-synaptic activation characterized by TMS. Anodal stimulation, in contrast to TMS, evokes a single PSTH peak of increased SMU firing probability, and this allows reliable estimation of the rise time of the underlying EPSP (Fetz and Gustafsson, 1983). In addition, provided that some important assumptions are made about the use of the Ashby and Zilm model (Ashby and Zilm, 1982) (see below), the size of the underlying compound EPSP can be estimated (see Results). One possible problem of anodal cortical stimuli is highlighted by the work of Burke and colleagues (Burke et al., 1993), which shows that increasing the stimulus intensity resulted in a D wave of shorter latency in pyramidal tract recordings, suggesting that PTN axons can be stimulated deeper in the white matter with stronger stimuli (see also Edgley et al., 1990, 1997). However, in this study, as illustrated by Figs 1 and 2, the latency of the PSTH peak remained stable with all intensities of stimulation used, indicating that the stimulation site was constant.
Characteristics of corticomotor neuronal synaptic connections
From the results obtained in 113 excitable SMUs of 13 different proximal and distal muscles, there are strong arguments suggesting that connections between PTNs and spinal motor neurons supplying the muscles tested are dominated by monosynaptic transmission. Most excitable SMUs of all muscles explored responded to weak anodal cortical stimulation with a single, short latency and narrow PSTH peak of increased firing probability. The duration of the early PSTH peak to anodal TCS was very similar for SMUs of proximal and distal muscles, indicating that dispersion within PTN axons and peripheral nerves is negligible. For the 113 SMUs with an early excitatory peak, the mean duration of this peak was 0.97 ms, slightly shorter than the mean PSTH peak durations (1.24 and 1.3 ms) obtained in flexor carpi radialis and soleus SMUs upon stimulation of 1A fibres in an H-reflex paradigm. The latter values are very close to those obtained by Jones et al. (Jones and Bawa, 1995; Jones et al., 1996) for flexor carpi radialis H-reflexes. On the other hand, the mean duration of the PSTH peak to anodal stimulation (0.97 ms) was shorter than that of the first PSTH subpeak of SMU responses to TMS in the Jones et al. study (1.33 ms) using a similar methodology (Jones et al., 1996). Fetz and Gustafsson have shown that, provided the amplitude of the underlying compound EPSP exceeds 1 mV, the duration of a single PSTH peak corresponds to the rise time of this EPSP (Fetz and Gustafsson, 1983). Thus, we can estimate that the mean rise time of compound EPSPs elicited in our SMUs by anodal stimuli is close to 1 ms. This compares well with the mean value (0.93 ms for upper limb motor neurons) recently quoted by Maier et al. for monosynaptic EPSPs recorded in macaque monkeys upon medullary pyramid stimulation (Maier et al., 1998).
In our study, EPSPs generated in -motor neurons by weak anodal cortical stimuli have a sharper rise than those induced by 1A fibre activation or by TMS. There are several possible explanations for this finding. First, the afferent volley in 1A fibres may not be as synchronous as the volley generated in pyramidal axons because of the intrinsic characteristics of the stimuli: the pulse generated by the cortical stimulator has a time constant of 100 µs while the nerve stimulator delivers 1 ms square pulses which could activate 1A fibres during the rise or decay phase. This explanation seems unlikely, as a reduction of the pulse duration from 1 to 0.5 and 0.2 ms had little effect on the duration of PSTH peaks (see Fig. 5). Moreover, the mean values of PSTH peak duration in the H-reflex paradigm that we obtained were very close to those of Jones et al. (Jones et al., 1996) who used a shorter stimulus (0.5 ms). One could also argue that as the latency of PSTH peaks to 1A stimulation is slightly longer than with TCS, more dispersion could therefore occur. This also seems very unlikely, as the duration of PSTH peaks to anodal TCS were very similar in proximal arm and in leg muscles. Secondly, as already pointed out (Burke et al., 1984), H-reflexes may not be purely monosynaptic, thus inducing some dispersion of the compound EPSP resulting from 1A afferent stimulation. The same could be true for low intensity TMS. While it has been shown by several authors (Edgley et al., 1990; Burke et al., 1993; Baker et al., 1995) that TMS is able to activate PTN axons directly, there are also strong arguments based on SMU response latencies (Day et al., 1989; see also Fig. 1) suggesting that a slightly suprathreshold TMS with the coil centred over the vertex as used here and by Jones et al. (Jones et al., 1996) produces little if any direct PTN axon activation in humans but instead activates cell bodies or cortical excitatory interneurons.
Thirdly, the duration of PSTH peaks upon anodal TCS could be shortened artificially by the occurrence of an IPSP (inhibitory post-synaptic potential) immediately after the early excitatory response, which could obliterate the end of the EPSP. In that case, one would expect to observe a shortening of the excitatory peak upon stimulations of increasing intensities, which was not the case here. Moreover, when slightly suprathreshold anodal stimuli were used, which did not induce suppression of SMU firing (see upper panels of Figs 1 and 2), the PSTH peak duration was not longer, in spite of the fact that threshold stimuli are more likely to induce a greater jitter of D wave in PTN axons (see Kernell and Wu, 1967). Finally, another possible explanation of the finding that PSTH peaks were significantly narrower with cortical anodal than with 1A afferent stimuli could be that synaptic connections between PTN axons and -motor neurons take place closer to the motor neuron cell bodies, thus reducing the temporal dispersion of the EPSP. However, there is to date no anatomical evidence to support this hypothesis (see Jones et al., 1996).
The short duration of the excitatory PSTH peak to anodal stimulation is evidence in favour of largely predominant monosynaptic corticomotor neuronal connections in humans. These seem to be the case, not only for hand and forearm motor neurons, but also for proximal muscles such as the trapezius, deltoid and pectoralis major, or for leg muscles, which have not been investigated extensively in monkeys (for a review, see Porter and Lemon, 1993). Large PSTH peaks were also obtained with anodal TCS in deltoid and pectoralis major (Colebatch et al., 1990). On the contrary, using magnetic stimulation, Palmer and Ashby found relatively weak excitatory projections to deltoid with a similar recording technique (Palmer and Ashby, 1992). We have no straightforward explanation for this discrepancy, but it could be related to the different modes of activation of PTNs by weak electrical anodal and magnetic stimuli. The latter acting largely trans-synaptically could be more dependent on the cortical inputs generated by conscious command and preparation of movement (Baker et al., 1995). These are obviously more important for hand than for proximal muscles.
Contrary to the findings of Pierrot-Deseilligny and his colleagues, we were unable with the present method to demonstrate activation by cortical stimulation of oligosynaptic corticomotor neuronal pathways to low-threshold forearm SMUs (Gracies et al., 1991; Burke et al., 1994; Pauvert et al., 1998). Even with near-threshold stimuli, PSTH peaks remained narrow, without significant latency or duration shortening when increasing stimulus intensities. Also, the range and mean PSTH peak duration (see Table 1) were not significantly different in forearm and more distal or proximal muscles. This does not imply that such non-monosynaptic connections do not exist, but that they do not seem to play a major role in the corticospinal activation of low-threshold, early recruited motor neurons by descending inputs. However, with the present method, most motor units recruited during moderate and strong contraction cannot be studied, so that definitive conclusions cannot be drawn. It could be that afterhyperpolarization following corticomotor neuronal responses or active inhibition prevent the occurrence of late oligosynaptic responses. Nevertheless, in all recordings, at least one series was collected at near-threshold stimulus intensities, without revealing any evidence of late excitation. Recently, Maier et al. also failed to find direct evidence for a significant role for such non-monosynaptic connections in the macaque monkey (Maier et al., 1998). Recent observations also suggest that in macaque, single motor units recorded in both hand and elbow muscles respond to single stimuli delivered direct to the pyramidal tract with a brief peak of increased discharge probability, with a duration very similar to that described here (E. Olivier, S. N. Baker and R. N. Lemon, personal communication). These authors could find no evidence for non-monosynaptic transmission. Interestingly, such oligosynaptic connections can be found in New World squirrel monkeys (Maier et al., 1997), in which direct corticomotor neuronal connections are much weaker.
In the present work, a substantial proportion (27/140) of SMUs explored showed no clear response to anodal stimuli, particularly in triceps, wrist flexor and soleus muscles. This could be partly related to suboptimal positioning of the stimulating cathode as some of the triceps SMUs unresponsive to anodal TCS showed a clear excitatory peak upon TMS. In that case, one should also expect to have missing responses in SMUs of biceps and forearm extensors for example, which was not observed. Absent responses from some motor units were also observed by Palmer and Ashby with magnetic stimulations, particularly in triceps (Palmer and Ashby, 1992). This could indicate that fast-conducting PTN axons preferentially activate arm flexors, finger extensors and foot dorsiflexors, as suggested by the preferential distribution of muscle weakness in lesions of the motor cortex. A tentative explanation for the differences between SMU responses to TMS and anodal TCS would be that magnetic stimuli, which activate PTN cell bodies and excitatory interneurons, might be more efficient in activating consciously recruited muscles while anodal TCS simply recruits naturally predominant pathways.
As previously reported (Calancie et al., 1987; Palmer and Ashby, 1992), some SMUs responded to stimuli that were subthreshold to evoke an early excitatory peak by some reduction of their spontaneous firing, with a latency slightly longer than that of the excitatory peak and lasting for 5–15 ms. Like others, we found motor units with such an inhibitory pattern mostly in triceps and sometimes in deltoid. In Maier's direct recordings of macaque motor neurons (Maier et al., 1998), IPSPs were also encountered most often in triceps. While this low-threshold inhibition could possibly originate from the cortex itself, its most likely origin seems to be a disynaptic projection of corticospinal fibres to spinal motor neurons through 1A inhibitory interneurons (Jankowska et al., 1976; Phillips and Porter, 1977). One interposed synapse could certainly account for the slightly longer latency of inhibitory than excitatory effects. Interestingly, in some units, such inhibitory pathways seem to have a lower threshold than the direct excitatory ones (Davey et al., 1994).
Conduction velocities, order of recruitment and size of SMU responses
As previously noted (Hess et al., 1987), the first voluntarily activated units also seemed to be those preferentially activated by TCS, as shown by threshold values given in Table 2. According to Henneman's size principle (Henneman et al., 1965), they were small units with relatively slow conduction velocities. Larger SMUs with faster conduction velocities showed higher activation thresholds and smaller PSTH peaks. Although our sample was rather small, early recruited units were also those which showed the largest responses to TCS. If one assumes that impulses travelling down the pyramidal axons show little dispersion, as suggested by recordings of a well-synchronized D wave in the pyramidal tract (Patton and Amassian, 1954; Burke et al., 1993), and that recorded SMU potentials were close to the muscle motor point, then conduction velocities within motor neurons can be estimated as in Table 2. Values ranged from 38 m/s for low-threshold units to 60 m/s in large, high-threshold ones.
Estimation of strength of corticospinal projection to different muscles
The maximal amplitude of early PSTH peaks gives an estimate of strength of corticospinal projections to different muscles, taking into account the mean voluntary firing rate of SMUs (Ashby and Zilm, 1982). Two important assumptions must be made here; the first is that the membrane potential during afterhyperpolarization is in the order of 10 mV, and the second that the amplitude and shape of the after-hyperpolarization are similar for different rates (Jones and Bawa, 1995; Jones et al., 1996). Despite having to make these assumptions, the values given in Table 1 provide a useful means of comparing corticomotor neuronal influence over different SMUs in different muscles. As explained in the Results, the size of compound EPSPs can be underestimated or overestimated depending on the SMU size and firing rate. In the present work, most SMUs studied were low-threshold, small ones. If anything, this would lead to underestimation of the EPSP size, as units were fired at relatively high rates. Despite this, the maximal values obtained were similar to those quoted by Nakajima et al. with magnetic stimulation, but somewhat higher than those quoted by Day et al. using anodal TCS, and by Palmer and Ashby and Awiszus and Feistner with magnetic stimuli (Day et al., 1987; Palmer and Ashby, 1992; Awiszus and Feistner; 1994; Nakajima et al., 1998). These gross estimates of compound EPSP values also reflect the convergence of fast-conducting PTN axons onto a single motor neuron. If such axons have similar conduction velocities, there should be little temporal dispersion of unitary EPSPs at the motor neuron which summate into a large compound EPSP. As the estimated amplitude of unitary motor neuronal EPSPs to motor cortex stimulation is 100–200 µV (see Porter and Lemon, 1993, p. 179–186), a maximal compound EPSP of > 6 mV in 1DI (see Table 1) should be the result of convergence of 30–60 PTN axons onto a single motor neuron. From the results summarized in Table 1, convergence of PTN axons onto single motor neurons is maximal for hand muscles and finger extensors, and more pronounced for finger extensors than flexors and for foot dorsiflexors than extensors. Again, the muscles in which we found maximal PTN convergence onto SMUs are also those showing most prominent weakness in the case of motor cortex damage.
In conclusion, the present study supports the idea that human corticospinal connections are essentially monosynaptic for the first voluntarily recruited -motor neurons, even in proximal arm and shoulder muscles. We found no evidence of oligosynaptic excitatory connections to forearm motor neurons. In some motor units, anodal cortical stimuli suppressed the spontaneous firing of SMUs with a lower intensity than required to produce excitatory effects, probably by activation of inhibitory 1A interneurons. Our results also confirm that the first voluntarily recruited motor units are also the ones most readily excitable by TCS and that they are relatively small and slow-conducting, in agreement with Henneman's size principle. This also indicates that cortical stimulation is a rather `physiological' stimulus as it seems to govern motor units in relatively the same way as voluntary command.
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We wish to thank Professor R. N. Lemon for kindly reading this manuscript and for his very helpful suggestions. This work was supported by a research grant of the Belgian `Fondation Charcot' against Multiple Sclerosis and by grant no. 3.3623.94F of the `Fonds National de la Recherche Scientifique'.
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Received February 12, 1999. Accepted March 1, 1999.
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