Hemispheric Differences in Motor Cortex Excitability During a Simple Index Finger Abduction Task in Humans

John G. Semmler and Michael A. Nordstrom

Department of Physiology, The University of Adelaide, Adelaide, South Australia 5005, Australia

    ABSTRACT
Abstract
Introduction
Methods
Results
Discussion
References

Semmler, John G. and Michael A. Nordstrom. Hemispheric differences in motor cortex excitability during a simple index finger abduction task in humans. J. Neurophysiol. 79: 1246-1254, 1998.Transcranial magnetic (TMS) and electrical (TES) stimulation was used to assess the contribution of the corticospinal pathway to activation of the first dorsal interosseous muscle (FDI) in each hand of 16 right-handed subjects. TMS was applied at relaxed threshold intensity while the subject performed isometric index finger abduction at seven force levels [0.5 N to 50% maximal voluntary contraction (MVC)]. In a separate session, TES of equivalent intensity was applied to each hemisphere in 5 of these subjects while they performed the same force-matching protocol. In the resting state, mean threshold intensity for a muscle-evoked potential (MEP) in FDI using TMS was similar for the hemispheres controlling the dominant and nondominant hands. The size of the threshold MEPs in resting FDI after TMS and TES were also similar in each hand. With TMS, contraction-induced facilitation of the MEP in FDI was significantly larger when the nondominant hand was used for index finger abduction. In the pooled data, the nondominant/dominant ratio of MEP areas (normalized to the maximum M wave) ranged from 1.7 in the weakest contraction (0.5 N) to 1.1 in the strongest (50% MVC). Eight subjects had significant differences between hands in favour of the nondominant hand, whereas in two subjects contraction-induced facilitation of MEPs was larger in the dominant hand. In five subjects for whom detailed motor unit data were available from a previous study, lateral differences in MEP facilitation were positively correlated with differences in FDI motor unit synchronization between hands. With TES, contraction-induced facilitation of the MEP was similar in each hand, suggesting that spinal excitability was equivalent on both sides. For the group of five subjects tested with both stimulation techniques, contraction-induced facilitation of the MEP was significantly larger after TMS than that obtained with TES when the contraction was performed with the nondominant hand, but not when the dominant hand was used to perform the task. We conclude that the extent of corticospinal neuron involvement in the command for simple index finger abduction in right-handed subjects is generally greater when the nondominant hand is used, compared with the same task performed with the dominant hand.

    INTRODUCTION
Abstract
Introduction
Methods
Results
Discussion
References

Transcranial stimulation of the motor cortex using magnetic (TMS) or electrical (TES) stimulators are powerful techniques for assessing the integrity and operation of the fast corticospinal pathway in humans (Rothwell et al. 1991). Several previous studies in man have reported that hand preference is associated with asymmetries in the ability to activate corticospinal neurons controlling small hand muscles with TMS under resting conditions. The hemisphere controlling the dominant hand was found to have a larger cortical representation for the target muscle (Wassermann et al. 1992) and a lower threshold for a muscle evoked potential (MEP) in passive muscle (Macdonell et al. 1991; Triggs et al. 1994). In these three studies, TMS was used to examine the excitability of the corticospinal pathway while the muscles were relaxed. Although these findings are of interest, it is of greater functional importance to establish the relative contribution of the corticospinal neurons in the two hemispheres during the voluntary activation of their target muscles. The pattern or extent of corticospinal neuron activity while the hand is actually being used might, for example, be related to differences in fine motor skill in preferred and nonpreferred hands.

In the present study we have used TMS and TES to assess hemispheric differences in excitability of corticospinal neurons during voluntary contraction of the first dorsal interosseous (FDI) muscle in dominant and nondominant hands of right-handed subjects. This was accomplished by between-hand comparisons of the extent of facilitation of the MEP produced by TMS and TES delivered at relaxed threshold intensity as index finger abduction was performed at various target forces. When a muscle is activated in a voluntary contraction the MEP after TMS and TES increases in size, because of increased excitability of corticospinal and alpha motoneurons involved in the task (Hess et al. 1987; Maertens de Noordhout et al. 1992; Ugawa et al. 1995). Because of differences in the site of activation of the corticospinal pathway with the two stimulation techniques (reviewed in Rothwell et al. 1991), corticospinal neuron excitability makes a greater contribution to contraction-induced facilitation of the MEP when TMS is used. If there are hemispheric differences in the activity of corticospinal neurons during task performance depending on which hand is used, we would expect to see an asymmetric pattern of contraction-induced facilitation of the MEP in FDI muscle of the two hands with TMS, but not TES.

This investigation was prompted by our earlier observation that when FDI muscle is activated during index finger abduction, motor unit short-term synchronization in FDI is significantly lower in the dominant hand of right-handed subjects than in the nondominant hand and in both hands of left-handed subjects (Semmler and Nordstrom 1995). Several lines of evidence implicate corticospinal neurons in the generation of motor unit short-term synchronization in man (Farmer et al. 1990; Farmer et al. 1993). One possible explanation for our finding of reduced motor unit synchronization in the dominant hand of right-handers is that the corticospinal neurons were less active during the task when it was performed with the dominant hand. The present experiments using TMS and TES were designed as a more direct test of this hypothesis.

Preliminary results of these experiments have been presented previously in abstract form (Nordstrom and Semmler 1996a,b).

    METHODS
Abstract
Introduction
Methods
Results
Discussion
References

TMS was used to study MEPs produced in right and left FDI in 16 healthy subjects (13 males), ranging in age from 18 to 50 yr. In five of these subjects (including the two authors), experiments were repeated by using TES. Experiments were performed with the informed consent of the subjects and with the approval of the Ethics Committee for Human Experimentation at the University of Adelaide. The hand used for writing was designated the dominant hand and in each subject this was the right hand. The degree of laterality was assessed by a questionnaire using the Edinburgh Handedness Inventory (Oldfield 1971). A laterality quotient (LQ) was calculated on the basis of answers to the questionnaire, with a value of 1 indicating strong right-handedness, a value of -1 indicating strong left-handedness and a value of zero indicating no consistent hand dominance. All 16 subjects were right-hand dominant with a mean LQ of 0.81 (range 0.4-1.0).

Experimental apparatus

Subjects were seated in a dental chair with a head rest and neck support that minimized head movement. The right or left arm and hand was secured in a manipulandum (Semmler and Nordstrom 1995). The distal interphalangeal joint of the index finger was aligned with a load cell, which measured the force of index-finger abduction and straps over the other fingers minimized the contribution from other muscles to the abduction force. The force signal (bandwidth 0-5 kHz) was recorded on FM tape (Vetter model 400D, 22 kHz/ch). The surface electromyogram (EMG) of the left and right FDI was recorded with bipolar Ag-AgCl electrodes placed 2-3 cm apart overlying the muscle. Surface EMG signals were amplified (×200-1000), filtered (5 Hz-1 kHz), digitized, averaged on-line (2-kHz sampling rate) on a personal computer, and recorded on tape. Surface electrodes placed over the ulnar nerve at the wrist were used to deliver supramaximal electrical stimulation of the ulnar nerve with a Digitimer D180 electrical stimulator to produce a maximal M-wave in FDI.

Protocol 1: contraction-induced facilitation of MEPs with TMS

Responses to TMS were recorded in left and right FDI muscles of all sixteen subjects in the same experimental session. The hand to be tested first in a session was chosen at random. The hand was secured in the manipulandum and the subject was provided with visual feedback of the index finger abduction force on an oscilloscope screen. The subject was asked to perform maximal index finger abduction, with care taken to minimize contribution from other muscles. The largest of three attempts was taken as the maximum voluntary contraction force (MVC) for index finger abduction. The maximal M-wave was then obtained in relaxed FDI by supramaximal electrical stimulation of the ulnar nerve (average of responses to five stimuli at <0.5 Hz, pulse duration 100 µs).

TMS was applied with a Magstim 200 magnetic stimulator through a 90-mm circular coil. An anticlockwise current (viewed from above) was used to activate the right side muscles (left motor cortex) and a clockwise current was used to activate the left side muscles (right motor cortex). Intensities were expressed as a percentage of the maximum output of the stimulator. The coil was initially placed at the vertex and the optimal scalp position for TMS was determined by moving the coil from this position and observing the site at which the largest MEP was produced in relaxed FDI using weak suprathreshold TMS. The optimal scalp position was marked and the stimulating coil was fixed at this location on the scalp using a clamp and external support. The threshold stimulus intensity for a MEP in relaxed FDI was then determined using 2% increments of stimulator output. Relaxed threshold was defined as the lowest intensity of TMS for which three out of five stimuli evoked a MEP of amplitude >50 µV in resting FDI. TMS at relaxed threshold intensity (20/trial, <0.2 Hz) were then applied with the FDI at rest and while the subject performed isometric index finger abduction at various static target forces (0.5, 1.0, 2.0, 3.5, and 5.0 N), as well as 25 and 50% of the subject's MVC for index finger abduction. Subjects were instructed to match the target force as closely as possible using visual feedback. The order of contractions was randomized for force levels of 0.5 to 5 N. To minimize the effects of fatigue, the contraction levels of 25 and 50% MVC were performed last and with an intermittent 50% duty cycle of activation. During these trials, the subject was given audio cues that indicated when to contract and relax the FDI muscle. TMS was given 2-s into the3-s contraction, with a 3-s rest between contractions. Once the averaged MEPs had been obtained for the series of target forces with one hand, the stimulating coil was reversed to change the direction of current flow, and the protocol was repeated for the opposite hand. The head and coil position was constantly monitored throughout the experiment by one investigator, and care was taken to ensure that the coil position did not stray from the optimal scalp location for trials at the different target forces.

Protocol 2: contraction induced facilitation of MEPs with TES

Five of the sixteen subjects (mean LQ = 0.83, range 0.5-1) were tested in a second session on a separate day by using TES and a similar protocol as in the experiments using TMS. Responses to TES were obtained in both hands in the same experimental session. TES was applied with a Digitimer D180 electrical stimulator. Stimuli were delivered via two 9-mm diameter surface electroencephalographic (EEG) electrodes filled with conducting gel and fixed on the scalp with collodion at the vertex (cathode) and ~7 cm laterally (anode).

Relaxed threshold intensity for TES was established in resting FDI in all but one subject using the criteria previously described. In the subject in whom MEPs could not be elicited in resting FDI using TES, the threshold stimulus intensity for a MEP at the 0.5 N contraction level was used instead for all TES trials at various contraction levels. Stimulus intensities for TES ranged from 25-95% of the maximum stimulator output of 750 V. Subjects contracted the FDI at the same force levels used for the TMS trials and TES (10/trial, < 0.5 Hz, 50-100 µs pulse duration) were applied to the contralateral hemisphere. The final procedure for each hand was supramaximal stimulation of the ulnar nerve to obtain a maximal M-wave in FDI (average of 5 trials). The protocol was then repeated for the other hand by using anodal stimulation of the opposite hemisphere.

Analysis

Averaged MEPs were obtained from FDI after TMS (n = 20) and TES (n = 10) at each target contraction level and also in resting muscle. The MEP areas were measured from the digitized records and normalized as a percentage of the area of the maximal FDI M-wave in that hand.

Data are presented as mean ± SD, unless otherwise stated. Paired t-tests were used for comparisons between dominant and nondominant hands for threshold stimulation intensity and normalized MEP area in the resting condition. Analysis of variance (ANOVA) was employed for comparisons between stimulation type (TMS, TES), hand dominance (dominant, nondominant) and contraction level (0.5 N to 50% MVC). For all statistical comparisons, significance was reported for P < 0.05.

    RESULTS
Abstract
Introduction
Methods
Results
Discussion
References

Mean MVC for index finger abduction was 39.9 ± 8.7 N with the nondominant hand and 38.8 ± 10.5 N with the dominant hand in the sixteen subjects. These values were not significantly different (paired t-test, P > 0.05). Mean maximal M-wave areas were not significantly different between nondominant (37.7 ± 20.3 mV·ms) and dominant (41.6 ± 14.4 mV·ms) hands in the 21 experimental sessions (paired t-test, P > 0.05; n = 21).

Threshold intensity for a MEP in resting FDI using TMS ranged from 26-58% of maximum stimulator output in the sixteen subjects. Mean relaxed threshold intensity with TMS was 40 ± 8% for FDI in the nondominant hand and 38 ± 5% in the dominant hand, a nonsignificant difference (paired t-test, P > 0.05, n = 16). There were no significant differences between hands in the size of normalized MEPs evoked in resting FDI by TMS at relaxed threshold intensity (nondominant vs. dominant; 1.2 ± 1.0% of maximal M-wave area vs. 0.8 ± 0.8%; paired t-test, P > 0.05) or relaxed threshold TES (nondominant vs. dominant; 0.6 ± 0.2% of maximal M-wave area vs. 0.8 ± 0.4%; paired t-test, P > 0.05, n = 4).

The mean latency of the MEP using relaxed threshold TMS was 23.4 ± 1.5 ms (n = 32) with the FDI relaxed and 21.9 ± 1.8 ms (n = 224) in active muscle (unpaired t-test, P < 0.001). With TES, mean MEP latency was 22.0 ± 1.6 ms (n = 8) in relaxed and 21.9 ± 1.2 ms (n = 56) in active muscles (unpaired t-test, P > 0.05). With TMS, there was no significant difference in MEP latencies between hands in relaxed FDI. However, with active muscles, the MEP latency was slightly shorter in the nondominant hand (21.7 ± 1.9 ms) compared with the dominant hand (22.1 ± 1.7 ms; paired t-test, P < 0.001, n = 112). There were no significant differences between hands in MEP latencies using TES in either relaxed or active conditions.

Averaged MEP responses in FDI of both hands after relaxed threshold TMS and TES under passive and active conditions are shown for one subject in Fig. 1. With both TMS (Fig. 1A) and TES (Fig. 1B), MEP size increased with increasing muscle activation. This was a universal finding in all subjects. In this subject, the normalized MEPs with TMS were consistently larger in the nondominant hand at each active contraction level (Fig. 1A), ranging from 15 times higher than the dominant hand in the weakest contraction (0.5 N) (normalized MEP area 17.8 vs. 1.2%) to 1.5 times higher (70.8 vs. 53.1%) in the strongest (50% MVC). There was no consistent difference in MEP area between hands in active FDI using TES in this subject (Fig. 1B) or any of the other four subjects in whom TES was used.


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FIG. 1. Contraction-induced facilitation of muscle-evoked potentials (MEPs) from first dorsal interosseous muscle (FDI) in dominant and nondominant hands of 1 subject after transcranial magnetic stimulation (TMS) and transcranial electrical stimulation (TES). A: TMS at relaxed threshold intensity. Averaged MEPs (n = 20) for dominant (left) and nondominant (right) hand are shown for passive condition (top) and 5 different levels of voluntary isometric index finger abduction (bottom), ranging from 0.5 to 50% MVC. Lowermost trace is maximal M-wave in FDI for that hand. TMS intensity was 36% of maximum stimulator output for both hemispheres. Dashed vertical lines, stimulus onset. B: TES at relaxed threshold intensity. Averaged MEPs (n = 10) for dominant (left) and nondominant (right) hand are shown for corresponding trials in same subject by using TES. Data arranged as in A. Intensity of TES was 85% of maximum stimulator output for right hemisphere and 68% for left hemisphere. Horizontal calibration bars = 10 ms. Vertical calibration bars = 1.25 mV for traces passive to 50% MVC and 5 mV for maximal M-wave. With TMS, MEP was consistently larger in nondominant hand compared with dominant hand, particularly at low force levels. No consistent difference between hands was observed with TES.

The data obtained by using TMS are summarized for the 16 subjects in Fig. 2. The mean normalized MEP area increased monotonically with muscle activation level in each hand. Contraction level had a significant effect on normalized MEP area in the two-way ANOVA (F[1,210] = 44.8, P < 0.0001). At each level of active contraction force the mean normalized MEP was larger in the nondominant hand. Two-way ANOVA (dominance, contraction level) revealed that the extent of facilitation of the MEP using TMS in active muscle was significantly different in dominant and nondominant hands (F[1,210] = 12.2, P < 0.001). The ratio of normalized MEP areas (nondominant/dominant) ranged from 1.7 (12.3 ± 2.1% of maximal M-wave vs. 7.5 ± 1.9%) in the weakest contraction (0.5 N) to 1.1 (64.2 ± 4.6% vs. 56.8 ± 4.6%) in the strongest (50% MVC). The effect of hand dominance on the extent of MEP facilitation was consistent across all activation levels with TMS (the interaction of dominance and contraction level was not significant in the two-way ANOVA; F[6,210] = 0.3, P > 0.05).


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FIG. 2. Contraction-induced facilitation of MEPs after TMS was larger in nondominant hand at each active force level in pooled data. Mean ± SE normalized MEP areas from dominant (open circle ) and nondominant (bullet ) hands of 16 right-handed subjects after relaxed threshold TMS at various levels of voluntary contraction. Horizontal axis: force of index finger abduction. Mean normalized MEP area increased monotonically with increasing contraction force and at each force level mean normalized MEP was larger in nondominant hand. Extent of contraction-induced facilitation of MEP using TMS was significantly different in dominant and nondominant hands [two-way analysis of variance (ANOVA), P < 0.001].

The effect of hand dominance on the extent of MEP facilitation was not consistent for all subjects, as the interaction (subject × hand dominance) was significant in the two-way ANOVA (F[15,192] = 2.1, P < 0.05). In eight subjects, the amount of MEP facilitation using TMS was consistently larger for the nondominant hand at the different levels of active contraction in FDI and a paired t-test on data from each subject (pooled for all active contraction levels) revealed significant differences in normalized MEP between hands (all P < 0.05). In two subjects, MEP facilitation was significantly larger for the dominant hand over all force levels (paired t-test, both P < 0.01). For the remaining six subjects the extent of MEP facilitation with TMS was similar in the two hands at each force level.

Differences in the pattern of contraction-induced MEP facilitation in the two hands revealed with TMS were related to the stated degree of hand preference. For each subject, we calculated a mean normalized MEP area for each hand by pooling TMS data over all active contraction levels. Linear regression (Fig. 3) revealed a significant positive relationship between the nondominant/dominant ratio of normalized MEP areas in each subject and their laterality quotient, obtained by questionnaire (R2 = 0.33, P < 0.02, n = 16).


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FIG. 3. Relationship between lateral differences in extent of contraction-induced facilitation of MEPs using TMS and laterality quotient. For each subject (n = 16), laterality quotient is plotted against ratio of mean normalized MEP areas after TMS (pooled for all active contraction levels) in nondominant and dominant hands (ND/D MEP ratio). Linear regression revealed a significant positive relationship between these variables (R2 = 0.33, P < 0.02, n = 16).

A comparison of contraction-induced facilitation of the MEP using TMS and TES (Fig. 4) confirmed that differences between hands were not due to differences in spinal motoneuron excitability. TES predominantly excites corticospinal axons directly and with TES there was no significant difference in the extent of MEP facilitation with muscle activation between the two hands (2-way ANOVA; F[1,56] = 0.03, P > 0.05). Responses to TMS are more strongly influenced by the excitability of corticospinal neurons in motor cortex, in addition to spinal alpha motoneuron excitability. The difference in the amount of facilitation of the MEP with TMS and TES in each hand when the muscle is activated is a measure of the increased size of the stimulus-evoked corticospinal output because of involvement of corticospinal neurons in the task. This comparison is shown in Fig. 4 for the five subjects who were tested with both TMS and TES. This was a representative subpopulation of the larger group tested with TMS, as it included two subjects in whom contraction-induced facilitation of the MEP was larger in the nondominant hand with TMS, one with the opposite result and two with no consistent differences between hands. For the nondominant hand (Fig. 4A), the normalized MEP area was usually larger with TMS than TES for active contractions and the differences between the two stimulation techniques were significant (2-way ANOVA; F[1, 56] = 5.1, P < 0.05). The largest relative difference was seen with the 2 N contraction, for which the ratio of normalized MEP areas with the two stimulation techniques (TMS/TES) was 2.6. For 25% MVC the ratio was 1.36 and it was 0.9 for 50% MVC. For the dominant hand (Fig. 4B), mean normalized MEP area was larger with TMS than TES at four of seven active contraction levels, but the differences were less marked than in the nondominant hand and were not significant overall (2-way ANOVA; F[1, 56] = 0.001, P > 0.05). These results suggest that the differences in MEP facilitation between hands that are observed after TMS, but not TES, are related to increased excitability of corticospinal neurons when the nondominant hand is used for the task.


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FIG. 4. Comparison of contraction-induced facilitation of MEPs in each hand with TMS and TES. A: mean (±SE) normalized MEP areas in FDI of nondominant hand in 5 right-handed subjects following TMS (bullet ) and TES (black-square) at various levels of voluntary contraction force. B: data from dominant hand in these subjects obtained with TMS (open circle ) and TES (square ). In nondominant hand normalized MEP was generally larger after TMS than TES and differences between 2 stimulation techniques were significant (2-way ANOVA, P < 0.001). For dominant hand there were no significant differences in normalized MEP amplitudes with TMS and TES (2-way ANOVA, P > 0.05).

In a recent study of six right-handed subjects we found that the mean strength of motor unit synchronization in FDI was significantly weaker in the dominant hand (Semmler and Nordstrom 1995). A total of 199 motor-unit pairs were used for that comparison. The mean (±SE) strength of FDI motor unit synchronization in the nondominant hand was 0.39 ± 0.03 (n = 111) extra synchronous discharges s- and in the dominant hand it was 0.23 ± 0.03 s- (n = 88). In that study, isometric index finger abduction was used to activate FDI motor units, with most contractions in the range between 0.5 and 3.5 N and none above 4 N. The difference in motor unit synchronization between hands may reflect differences in corticospinal neuron activity during the task and we were interested to examine whether or not a relationship existed between the extent of motor unit synchronization in FDI and the contraction-induced facilitation of the MEP with TMS. Five subjects in the present study were part of the earlier motor unit study. For comparison with their motor unit synchronization data, we calculated a mean normalized MEP area in each hand by pooling TMS data from the 0.5-3.5 N contractions (i.e., comparable to the forces used in the motor unit experiments). Linear regression revealed a positive relationship between the nondominant/dominant ratio of normalized MEP areas (pooled for the 0.5-3.5 N contractions) in each subject and the ratio of the strength of FDI motor unit synchronization in the two hands (R2 = 0.93, n = 5, P < 0.01).

    DISCUSSION
Abstract
Introduction
Methods
Results
Discussion
References

The main finding in the present study is that the contraction-induced facilitation of the MEP in FDI was significantly larger in this group of right-handed subjects when the nondominant hand was used for index finger abduction, but only with TMS and not TES. The similarity of the contraction-induced facilitation of the MEP in each hand using TES suggests that differences in spinal motoneuron excitability are not responsible for the differences seen using TMS. The differences between hands seen with TMS are likely to reflect greater corticospinal neuron activation during the task when it is performed with the nondominant hand. The pattern of contraction-induced facilitation of the MEP in the two hands was not uniform for all subjects and this was correlated with the stated degree of hand preference.

Activation of the corticospinal pathway with TMS and TES

It seems that both TMS and TES can activate corticospinal neurons either directly or transsynaptically, eliciting D- and I-wave volleys in the descending corticospinal axons (Burke et al. 1993; Day et al. 1989, Edgley et al. 1990, 1997; Rothwell et al. 1994). The response of a corticospinal neuron to transsynaptic activation is dependent on its background level of excitation. The propensity for indirect activation of corticospinal neurons (presumably transsynaptically via corticocortical and/or thalamocortical fiber systems) is greater for TMS than TES. Weak anodal TES in the conscious human does not appear to evoke I-waves in the corticospinal volley to FDI motoneurons, whereas weak TMS appears to produce only I-waves and no D-waves (Day et al. 1989). D-waves after TMS appear to be preferentially generated at a site near the soma (Edgley et al. 1990; Edgley et al. 1997) and are thus also influenced by the degree of background excitation of the corticospinal neuron. D-waves after TES may also be generated at the initial segment, or further along the axon at sites deeper within the brain (Edgley et al. 1997). In the latter case, activation is independent of corticospinal neuron excitability and it is thought that this mode of excitation is more important with TES. Because of these differences in preferred site of activation with the two techniques, the size of the corticospinal output after TMS is strongly dependent on corticospinal neuron excitability, while this factor is less important when TES is used. Baker et al. (1995) have recently recorded from the medullary pyramid of the monkey and shown task-related changes in size of the corticospinal output evoked by TMS, but not by electrical stimulation of the corticospinal fibers at the cerebral peduncle. Task-related differences in the size of MEPs have been demonstrated that are large with TMS and smaller (Flament et al. 1993; Schieppati et al. 1996) or nonexistent (Datta et al. 1989) with TES. Findings such as these are usually interpreted as evidence of task-related alteration in excitability of corticospinal neurons, which has a greater influence on the size of the corticospinal output evoked by TMS than TES.

Contraction-induced facilitation of MEPs with TMS and TES

Increasing levels of voluntary activation of the FDI muscle resulted in a large, monotonic increase in size of the MEP produced by both TMS and TES (Figs. 2 and 4), in agreement with previous findings (Hess et al. 1987; Maertens de Noordhout et al. 1992; Ugawa et al. 1995). In data pooled from all subjects, contraction-induced MEP facilitation with TMS was larger at all force levels when the nondominant hand was used (Fig. 2). A similar result was reported recently as an incidental finding in normal subjects in a study of cortical motor excitability in dystonia (Ikoma et al. 1996). In the present study, MEP latency was slightly shorter in the nondominant hand under active conditions with TMS, but not TES. This is probably because of recruitment of larger motor units with fast-conducting axons contributing to the larger MEPs elicited in nondominant FDI. A less likely explanation, which we cannot rule out, is that the relative size of D- and I-waves in the descending corticospinal volleys produced by TMS in the active state differed between sides.

MEP size is a function of the size or effectiveness of the corticospinal output evoked by the stimulus and the excitability of spinal motoneurons and interneurons. Although the earliest part of the MEP can be reasonably attributed to corticomotoneuronal projections, one cannot exclude corticospinal influences mediated via spinal interneurons from influencing later parts of the MEP (Nielsen et al. 1993). Could lateral differences in spinal excitability explain the larger contraction-induced facilitation of the MEP in the nondominant hand seen with TMS? There is some evidence for lateral differences in H-reflexes of wrist (Tan 1989a) and thumb (Tan 1989b) flexor muscles that are related to hand preference. Maximal amplitude of H reflexes, H-reflex recovery curves, and facilitation of the H reflex with voluntary activation were all reported to be larger in the preferred hand. This may reflect lateral differences in tonic presynaptic inhibition at the Ia-afferent synapse with motoneurons of the target muscle. Lateral differences in activity of the descending pathways, which are known to modulate levels of presynaptic inhibition in a number of reflex pathways (see Rudomin 1990), may contribute to these differences. Lateral differences in excitability of spinal circuits revealed by H-reflex testing are unlikely to be responsible for the present findings with TMS, as they are in the opposite direction (higher for the dominant arm).

In the present study, stimulus intensity was threshold for a response in FDI at rest for both TMS and TES. The size of threshold MEPs was similar with TMS and TES, from which we infer that the size of the evoked corticospinal output was similar on both sides with both techniques in the resting state. The similarity of the MEP facilitation on each side with TES (Fig. 4) with muscle activation suggests that the corticospinal output evoked by TES and the pattern of (mono- and oligosynaptic) compound EPSPs produced in FDI motoneurons, were similar on both sides at each force level. A less plausible alternative explanation for the results seen with TES is that with voluntary activation lateral differences in spinal excitability were counterbalanced by lateral differences in the size of the corticospinal output elicited by TES. The similarity of MEP facilitation on each side with TES (Fig. 4) therefore make it unlikely that the differences in MEP facilitation between hands with TMS (Figs. 2 and 4) were due to differences in excitability of FDI motoneurons or interneuronal circuits activated by the corticospinal volleys. For this to be the case, one would need to argue that the corticospinal output elicited by TMS activates motoneurons by a different means at a segmental level than that elicited by TES. Although it is conceivable that the two techniques do not necessarily activate the same population of corticospinal neurons (Edgley et al. 1997) to produce a MEP of equivalent size, there is no evidence to suggest that the corticospinal volleys elicited by the two techniques (with different balance of D- and I-waves) act differently in exciting motoneurons. Both techniques appear to activate motoneurons in the same order as the voluntary command (Bawa and Lemon 1993; Gandevia and Rothwell 1987), in accordance with the size principle.

Comparison of the size of the MEP evoked by TMS and TES of equivalent intensity (Fig. 4), provides an opportunity to identify the relative importance of changes in corticospinal neuron or spinal motoneuron excitability in the lateral differences in contraction-induced facilitation of the MEP with TMS. Although one cannot exclude the possibility that cortical excitability may make some contribution to the MEP after TES, it is generally accepted that cortical excitability has a greater influence on responses to TMS than TES in small hand muscles. Contraction-induced facilitation of the MEP was larger using TMS than TES in 10 of 14 comparisons in the grouped data (Fig. 4). Hess et al. (1987) found that contraction-induced facilitation of the MEP in abductor digiti minimi (ADM) of the right hand was about 40% larger with TMS than TES for contractions of 5-10% of MVC in their mostly right-handed subjects, but did not test the left hand. In the present study, contraction-induced facilitation of MEPs in FDI was significantly larger with TMS than TES when the nondominant hand was used for the task, but not when the dominant hand was used (Fig. 4). For FDI of the right hand, the differences in MEP facilitation with TMS and TES were small. The normalized MEP was 14% larger (Fig. 4B) with TMS for both the 2 and 3.5 N contractions (~5-10% MVC), a smaller difference than that reported by Hess et al. (1987) in ADM. We found a much greater difference, however, between TMS and TES for MEPs in FDI of the nondominant hand (Fig. 4A) at these forces (TMS/TES ratio 2.6 at 2 N and 2.3 at 3.5 N). The most likely explanation for the larger MEPs in the nondominant hand with TMS compared with TES of similar intensity is that under conditions of voluntary activation TMS evokes a larger corticospinal output because of increased excitability of corticospinal neurons activated during performance of the task. Corticospinal output does not increase to the same extent with TES, as responses to TES are less sensitive to corticospinal neuron excitability. Overall, the involvement of corticospinal neurons in the task appears to be much greater when index finger abduction is performed with the nondominant hand, because contraction-induced facilitation of the MEP in the dominant hand was similar with TMS and TES (Fig. 4) and the MEP in the nondominant hand was significantly larger than that in the dominant hand using TMS (Fig. 2).

Two previous studies have found little evidence for a role of corticospinal neuron excitability changes in the contraction-induced facilitation of the MEP (Maertens de Noordhout et al. 1992; Ugawa et al. 1995). Maertens de Noordhout et al. (1992) compared the contraction-induced facilitation of MEPs in tibialis anterior muscle using three techniques (TMS, TES, and cervical electrical stimulation). These authors found a comparable degree of facilitation with each technique, and concluded that increases in spinal excitability had the greatest effect on the facilitation of the MEP with voluntary activation. However, for activation of leg muscles, both TMS and TES appear to primarily activate corticospinal neurons directly (Priori et al. 1993) and this may be why facilitation of the MEP was similar with the two techniques. Apart from this methodological limitation, the conclusions of Maertens de Noordhout et al. (1992) are in keeping with anatomic (Kuypers 1981) and electrophysiological (Clough et al. 1968; Jankowska et al. 1975) evidence that suggests that the fast-conducting, direct corticospinal pathway is less effective in activating the lower leg muscles compared with the intrinsic hand muscles. Sustained tonic activation of tibialis anterior may well be achieved largely by activation of less direct pathways not amenable to study with TMS, such as the reticulospinal pathway. Ugawa et al. (1995) examined contraction-induced MEP facilitation by using the right FDI muscle in subjects whose hand preference was not stated and found a similar extent of facilitation for TMS and TES at 10 and 25% MVC and a larger MEP with TMS at 50% MVC. As the subjects were probably mostly right-handed, these findings for the dominant hand at low forces are in agreement with those of the present study. Ugawa et al. (1995) standardized stimulus intensities for TMS and TES under conditions of weak voluntary activation, whereas in the present study stimuli were standardized at relaxed threshold intensity. The latter approach allows the increase in corticospinal neuron excitability accompanying the transition from rest to the active state to contribute to contraction-induced MEP facilitation and should enhance the differences in responses to TMS and TES under active conditions. The finding of larger MEP facilitation with TMS at the 50% contraction level by Ugawa et al. (1995) was not observed in the present study and is difficult to reconcile with evidence that corticospinal neurons are less active in power tasks compared with precision tasks (Muir and Lemon 1983). Ugawa et al. (1995) normalized the MEPs with respect to the size of MEPs obtained with weak stimuli during minimal voluntary contraction. A normalization procedure using minimal MEPs, which are somewhat variable as well as very small, could lead to quite large effects on the magnitude of the normalized MEP and may have influenced their results.

Hemispheric differences in corticospinal excitability

We have recently shown that motor unit short-term synchronization in FDI is stronger in the nondominant hand of right-handed subjects than in the dominant hand (Semmler and Nordstrom 1995). Short-term synchronization (a tendency of neurons to discharge within a few milliseconds of each other that is slightly greater than expected by chance) is a prominent feature of the discharge of motor units in the hand muscles and is believed to arise by the simultaneous generation of excitatory postsynaptic potentials in the motoneurons by activity in shared branched-axon collaterals from single last-order neurons (Datta and Stephens 1990; Sears and Stagg 1976). The corticospinal pathway is important in the generation of motor unit short-term synchronization in man (Farmer et al. 1990, 1993), presumably via monosynaptic projections, which are known to project widely within the motoneuron pool from single corticomotoneuronal cells (Mantel and Lemon 1987). Task-related differences have been noted in motor-unit synchrony (Bremner et al. 1991), as well as MEP amplitude using TMS (Datta et al. 1989; Flament et al. 1993; Schieppati et al. 1996). Surprisingly however, TMS is not very effective at synchronizing the discharge of concurrently active motor units (Mills and Schubert 1995). In the present study, we have shown that lateral differences in contraction-induced facilitation of the MEP with TMS parallel lateral differences in motor unit synchronization in FDI. For the five subjects who contributed to both studies, there was a significant positive correlation between these two variables (R2 = 0.93). We conclude from these observations that hemispheric differences in corticospinal neuron activity contribute to differences in FDI motor unit synchrony between hands during index finger abduction.

In the resting state in man, the hemisphere controlling the dominant hand has the lower (between 2-6% of stimulator output) threshold for TMS activation of small hand muscles (Macdonell et al. 1991; Triggs et al. 1994) and the larger cortical representation of the target muscle (Wassermann et al. 1992). In the present study, relaxed threshold for TMS was about 2% lower on average for the hemisphere controlling the dominant hand, but the differences were not statistically significant, possibly because of the smaller sample size than previous studies (16 subjects compared with 19 and 60 in the previous studies). The differences between sides revealed with TMS in the resting state may be related to anatomic asymmetries in the number of corticospinal axons (Nathan et al. 1990) or motor cortical representation of hand muscles (Nudo et al. 1992) that seem to favour the right side. In contrast with the data obtained under resting conditions, our findings suggests that in most right-handed subjects voluntary activation of FDI for simple index finger abduction is accomplished with greater corticospinal activity when the nondominant hand is used. Other techniques have revealed evidence of asymmetry in hemispheric activity during voluntary finger movements in man. Tarkka and Hallett (1990) recorded EEG movement-related potentials preceding self-paced index finger abduction and reported that a component attributed to motor cortex activity was greater when the nondominant hand was used. Measurements of cerebral blood flow in right-handed humans reveal a greater increase in flow in the Rolandic region of the right hemisphere during finger movements of the left hand than vice versa (Halsey et al. 1979). By using magnetoencephalography however, Volkmann et al. (1996) have reported that in right-handed subjects a larger area of motor cortex was activated when fingers of the right hand were voluntarily moved. Unfortunately with these techniques the cortical neurons responsible for the increased activity cannot be identified, so it is not possible to directly relate these observations to the present conclusions regarding hemispheric asymmetry in corticospinal neuron activity.

The lateral differences in the extent of contraction-induced facilitation of the MEP with TMS, which we have argued indicates the extent of corticospinal neuron activation during task performance, were not uniform for all subjects. The overall tendency was for greater MEP facilitation when the nondominant hand was used. This pattern was clear in 50% of subjects, but the opposite pattern was seen in 2 of 16 subjects. The significant correlation between the differences in contraction-induced MEP facilitation with TMS in each hand and the laterality quotient (assessed by questionnaire) (Fig. 3) raises the possibility that these differences are related to the extent to which the right hand is preferentially used for everyday tasks. A larger sample than the present study, with a wider range of laterality quotient values, is needed before a definitive conclusion can be reached on this point. Nevertheless, this finding indicates the need to explore a relationship between corticospinal involvement in a task and laterality in future studies. As questionnaires are somewhat limited for this purpose, such studies should in addition use quantitative measures of digital dexterity to assess laterality.

It is well-established that the the corticospinal tract is the neuronal substrate for independent activation of muscles moving the digits (Kuypers 1981) and that this pathway is essential for the skilled use of the fingers in tasks such as writing, grasping objects between thumb and index finger, or fastening buttons. The details of the specific role of the corticospinal projections in skilled finger movements are still under investigation and it is not known how their activation patterns are altered as motor skill is honed by training, or as tasks become automated by practice. The CNS has the capacity to change the balance of the descending command between direct and indirect pathways depending on the requirements of the task and direct recording of neurons in motor cortex provides several examples of corticospinal neurons that are more active in tasks requiring precise voluntary control of muscle activation than power tasks (Cheney and Fetz 1980; Muir and Lemon 1983). It is of interest that the largest differences between hands in MEP facilitation with TMS in the present study were seen in the low-force contractions (Fig. 2), which is consistent with reduced involvement of corticospinal neurons in the command for power tasks (Cheney and Fetz 1980; Muir and Lemon 1983).

Simplistically, one might expect that the dominant hand would accomplish its more skilled performance in everyday tasks by a relatively stronger descending influence from corticospinal neurons. Apparently this is not the case for a simple tonic isometric contraction of first dorsal interosseous, as both the motor unit synchrony and TMS data suggest that this task is accomplished with less activity in corticospinal neurons when performed with the dominant hand than with the nondominant hand. The corollary is that indirect descending pathways contribute relatively more to this task when it is performed with the dominant hand. In right handers, it is usually possible to demonstrate clear lateral differences in hand skill (Provins and Magliaro 1993). Perhaps the reduced involvement of the corticospinal pathway in the voluntary command when a simple task such as index finger abduction is performed with the dominant hand is an adaptation accompanying skill-training of the hand. By dropping out of the neural network commanding the simple task (this being relegated to indirect brain stem descending pathways) corticospinal neurons may be freed to command more complex aspects of a task performed with a skilled hand, if the need arises. The index finger abduction task was very simple to perform and it would be interesting to investigate whether or not a more demanding task performed with dominant and nondominant hands might reveal a different pattern of corticospinal neuron activity in the two hemispheres and to determine the relationship (if any) between this pattern and task performance.

In summary, results obtained in the present study with TMS and our previous motor unit synchronization data (Semmler and Nordstrom 1995) point to a reduced involvement of corticospinal neurons in the descending command controlling FDI when the dominant hand is used to perform simple index finger abduction in right-handed subjects. It remains to be seen whether or not these differences in corticospinal function may be related to differences in the ability to use the hands that are associated with a lifetime of preferred use of the dominant hand for fine motor tasks.

    ACKNOWLEDGEMENTS

  The authors thank M. V. Sale for assistance with some of the experiments and Dr. M. C. Ridding for comments on the manuscript.

  This work formed part of the PhD studies of J. G. Semmler, who was supported by a University of Adelaide Postgraduate Research Scholarship. M. A. Nordstrom was an R. D. Wright fellow of the National Health and Medical Research Council of Australia.

    FOOTNOTES

   Present address for J. G. Semmler: Dept. of Kinesiology, University of Colorado, Boulder CO 80309.

  Address for reprint requests: M. A. Nordstrom, Dept. of Physiology, University of Adelaide, Adelaide SA 5005, Australia.

  Received 25 March 1997; accepted in final form 18 November 1997.

    REFERENCES
Abstract
Introduction
Methods
Results
Discussion
References

0022-3077/98 $5.00 Copyright ©1998 The American Physiological Society