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1Human Motor Control Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland; 2Department of Neurology, Medical University of Vienna, Austria; 3Research Unit of Exercise Science and Sports Medicine, Department of Human Biology, University of Cape Town, South Africa; and 4Biostatistics Branch, NINDS/NIH, Bethesda, Maryland
Submitted 30 March 2005; accepted in final form 19 April 2005
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMETHODSRESULTSDISCUSSIONGRANTSACKNOWLEDGMENTSREFERENCES |
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200 ms (long-latency afferent inhibition; LAI). Surround inhibition (SI) is the process that inhibits neighboring muscles not involved in a particular task. The neuronal mechanisms of SI are not known, and it is possible that LAI might contribute to it. Using transcranial magnetic stimulation (TMS) with and without movement of the index finger, the motor-evoked potentials (MEPs) were measured of two functionally distinct target muscles of the hand (abductor digiti minimi muscle = ADM, 1st dorsal interosseus muscle = FDI). Electrical stimulation was applied 180 ms before TMS to either the fifth finger or the index finger. Both homotopic and heterotopic finger stimulation resulted in LAI without movement. With index finger movement, motor output further decreased with homo- and heterotopic stimulation in the ADM. In the moving FDI, however, there was no change with either homo- or heterotopic stimulation. Additionally, in the unstimulated movement trials, LAI increased with the amount of unintentional co-activation that occurred despite attempts to maintain the ADM at rest. However, with finger stimulation added, there were almost no increased MEPs despite co-activation. These findings suggest that LAI increases during movement and can enhance SI. |
INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONGRANTSACKNOWLEDGMENTSREFERENCES |
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; Slobounov et al. 2002). Although it is generally assumed that fingers can move independently, it has been shown that humans rarely move one finger alone (Engel et al. 1997; Fish and Soechting 1992; Soechting and Flanders 1992). The second central phenomenon is surround inhibition (SI). In the motor system, SI is thought to produce a more precise movement just as SI in sensory systems produces more precise perceptions by creating an inhibitory zone around the central core of activation (Hallett 2003). Therefore the areas in the motor cortex (M1) not involved in the movement and surrounding the activated area of the moving muscle would be inhibited. Indeed, it was shown in two TMS studies that selective movement of one finger reduced the motor output to a resting hand muscle distant to the movement (Sohn and Hallett 2004a; Stinear and Byblow 2003). In both studies, MEP reduction depended on the amount of unintentional co-activation. Less co-activation during movement was associated with more effective SI. Furthermore, it has been shown recently that SI is disturbed in dystonia (Sohn and Hallett 2004b).
M1 excitability can be modulated by applying an electrical stimulus to a peripheral nerve as assessed by a test transcranial magnetic stimulation (TMS) pulse over the contralateral M1 at different interstimulus intervals (ISIs). Inhibition of the motor-evoked potential (MEP) by peripheral nerve stimulation seems to be most consistent with ISIs at 20 ms, called "short-latency afferent inhibition" (SAI) and at 200 ms called "long-latency afferent inhibition" (LAI) (Chen 2004; Chen et al. 1999; Classen et al. 2000; Kobayashi et al. 2003; Sailer et al. 2002; Tamburin et al. 2001; Tokimura et al. 2000). The effect also depends on the location of the peripheral stimulus (Classen et al. 2000; Kobayashi et al. 2003; Tamburin et al. 2001). At rest, stimulation applied to a digital nerve near the target muscle (homotopic stimulation) generally results in stronger inhibition than applied distant from it (heterotopic). To date, the effect of LAI during selective finger movement has not been examined.
In this study, we wanted to answer two questions. First, what is the effect of long-latency stimulation during selective finger movement, including possible differences in the effect between stimulating near or distant to the supposedly resting target muscle? Enhanced LAI on the muscle not involved in the task could help explain the genesis of SI. Second, does the effect of LAI depend on unintentional co-activation of the resting target muscle?
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METHODS |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONGRANTSACKNOWLEDGMENTSREFERENCES |
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Recording
Surface electromyographic (EMG) activity was recorded from the flexor digitorum superficialis muscle (FDS), the first dorsal interosseus (FDI), and the resting target muscle in the surround, the abductor digiti minimi (ADM) of the dominant hand, using silver-silver chloride surface EMG electrodes placed over the muscles in a belly-tendon montage. Recording of the extensor indicis proprius (EIP) muscles was added according to a previous study (Sohn and Hallett 2004a). EMG signals were amplified using a Nicolet Viking electromyograph (Skovlunde, Denmark) and band-pass filtered between 10 and 2,000 Hz. Signals were digitized at a frequency of 5 kHz and fed into a laboratory computer for further off-line analysis.
Stimulation
A figure-eight-shaped stimulation coil (7 cm in diameter for each half) connected to a Magstim 200 magnetic stimulator (Magstim, Whitland, Dyfed, UK) was positioned on the scalp over M1 at the optimal site for eliciting maximal amplitude MEPs in the ADM (hot spot). As measures of cortical excitability, resting motor threshold (RMT) and MEP amplitude were determined. Individual RMT was defined as the minimal stimulus intensity required to produce MEPs of >50 µV in the ADM in 
5 of 10 consecutive trials. MEP size at rest was determined by averaging peak-to-peak amplitudes over 25 single trials for each session. TMS over the ADM hot spot was used for simultaneous measurements of corticospinal output to the ADM and FDI (with and without movement of digit 2) based on the assumption that the RMT for the FDI is generally lower than for the ADM and the FDI hot spot is anatomically close to the ADM hot spot. TMS stimulus intensity was set at 140% of the individual RMT of the ADM.
Peripheral cutaneous stimulation was performed using ring electrodes around the interphalangeal joints of digits 2 and 5. The stimuli were applied at 200% of perception threshold (Classen et al. 2000) [stimulation strength: 7.3 ± 1.0 (SD) mA]. The ring electrodes were connected to a Nicolet Viking EMG machine (Skovlunde, Denmark). A stimulus was defined as being homotopic if it was applied to the finger related to the target muscle (digit 5 for ADM; digit 2 for FDI) and heterotopic if the peripheral stimulation was applied to the finger distant from the target muscle (digit 2 for ADM; digit 5 for FDI) regardless whether digit 2 was moved or not. Compound muscle action potentials (CMAPs) were determined in the ADM by stimulating the ulnar nerve at the wrist.
Experimental setting
The main experiment measuring the effect of peripheral stimulation on corticospinal output consisted of six trial blocks. Each block consisted of 25 MEPs. Ten subjects (4 men and 6 women, aged 22–50 yr) participated. The first three trial blocks were performed at rest in random order (unstimulated, stimulation digit 2, and stimulation digit 5). In the stimulated trials at rest, stimuli were applied 180 ms prior to the onset of TMS stimulation. This ISI was used because from a previous study LAI tended to be stronger with ISIs slightly shorter than 200 ms (Classen et al. 2000).
Before testing during active movement, the stimulator output was adjusted in each subject to produce the same MEP size in the ADM compared with MEP size at rest. After adjustment, the three movement trials were randomly performed (unstimulated, stimulation digit 2, and stimulation digit 5). A system of four timed sequential audible tones (1 tone each second) was used to obtain a stable movement onset time and to allow the subject to self-initiate the movement despite electrical stimulation occurring 160 ms prior to the onset of the go signal (i.e., the 4th tone). During movement, electrical stimulation was always delivered 160 ms prior to the fourth tone (onset of movement activity) so as to take place 180 ms prior to activation of TMS. The three events, electric stimulation, fourth tone and TMS, were set to occur in a fixed time pattern (Fig. 1, top). Before starting the test, all subjects were trained for 30 min for the three stimulation conditions to move their finger exactly at the fourth tone (±40 ms). By that time, all subjects had easily achieved an accuracy rate of >50%. During the test, onset of the FDS EMG signal was observed on-line by the investigator. Subjects had to perform continuously until they had completed 25 single trials matching the criterion. For analysis, the range of acceptable reaction times was set from –40 to +20 ms with respect to the fourth tone (see box in Fig. 1).
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The primary end point measure was the change in LAI with movement compared with rest. This was assessed by the size of TMS-evoked MEPs, accompanied by electrical stimulation of either the second or fifth fingers, in the ADM at rest and during volitional flexion of the second finger. To rule out that the same change in LAI also occurred on the moving muscle, we analyzed FDI MEP amplitudes obtained simultaneously in all conditions.
F-wave measurement
The effects of homo- and heterotopic stimulation on spinal excitability at rest and during tonic movement were tested by F-waves in five subjects (3 men and 2 women, aged 22–50 yr), one of whom also participated in MEP measurements. Surface EMG was recorded from the ADM muscle of the right hand. F-waves were elicited by supramaximal stimulation of the ulnar nerve at the wrist (constant current pulse, 0.2 ms). Six blocks were randomly tested: ulnar nerve stimulation alone or with preceding stimulation of digits 2 or 5 with ISI 180 ms (at rest and during movement 3 blocks each). For the movement trials, subjects were asked to contract the target muscle at 10–15% of maximal isometric voluntary force by flexing digit 2 against a force transducer wired for feedback into an oscilloscope. The trials were presented in random order, not faster than 0.2 Hz, with 24 trials for each condition.
Data analysis
Peak-to-peak amplitudes of the MEPs in the stimulated trials (rest and movement) were standardized in each subject to the mean MEP amplitude of the unstimulated trials (rest and movement) to adjust for individual variation. For comparisons between the effects of movement and stimulated finger on MEP, we used a three-factorial repeated-measure ANOVA (rmANOVA) with move as the movement condition, site as the location of the conditioning stimulus, and target as the muscle on which the MEP was measured. Results for MEPs were expressed as means ± SE. MEPs of the stimulated trials were tested against unstimulated MEP using paired t-test and Bonferroni correction. Unintentional co-activation was calculated as the percentage of the entire motor neuron pool (ADM background EMG amplitude divided by CMAP) to account for variation between subjects. As a secondary analysis, the effect of co-activation level on MEP in stimulated and unstimulated movement trials was calculated separately using analysis of covariance.
The effect of homo- and heterotopic stimulation on ADM F-waves at rest and during movement was analyzed using rmANOVA with move as the repeated measure and site of stimulation as the between-group variable.
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RESULTS |
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A three-factor rmANOVA (site of stimulation x target muscle x move) revealed a significant effect in site of stimulation (F = 9.1, P < 0.01), target muscle (F = 41.4, P < 0.01) and move (F = 4.0, P < 0.05). Move x target muscle interaction were highly significant (F = 41.5, P < 0.01; Fig. 2). No other interactions were significant.
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). With homo- and heterotopic stimulation during movement, a further reduction was found in the ADM only (P < 0.001; LAI with movement). MEPs in relation to unintentional co-activation during movement
Off-line analysis of EMG recordings in the period 40 ms before the TMS pulse showed that ADM was quiet at rest. During movement, EMG recordings indicated no or small and brief co-activation in the resting ADM. Figure 1 shows a typical example of co-activation in the resting ADM during movement of digit 2. Trials with a percentage <1% were found in 34% and <5% in 87%, mean 2.5%. As expected during movement of digit 2 without electric stimulation, co-activation of ADM significantly affected MEP size (F = 32.1, P < 0.01). However, in the stimulated trials with co-activation, there was no concurrent increase of MEP for homotopic and heterotopic stimulation (Fig. 3).
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONGRANTSACKNOWLEDGMENTSREFERENCES |
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; Classen et al. 2000; Kobayashi et al. 2003; Sailer et al. 2003). The new finding is that during movement, both homo- and heterotopic stimulation led to further decrease of LAI in the muscle not related to the movement while there was a decrease of LAI in the moving muscle. In view of possible interactions between LAI and SI during movement, two different explanations can be given for the further decrease of the motor output. The most feasible is that LAI has strengthened SI occurring during movement. The question has been raised which inhibitory central mechanisms during movement could contribute to SI (Hallett 2003). Although little is known of how they function in ordinary operations of the motor system, different types of inhibition have been revealed by TMS (Hallett 2003), such as short and long intracortical inhibition (SICI, LICI), interhemispheric inhibition, cerebellar inhibition, and inhibition mediated by a peripheral nerve stimulus (SAI and LAI). Two previous TMS studies on SI showed enhanced SICI during finger movement, suggesting that SICI contributes to SI (Sohn and Hallett 2004a; Stinear and Byblow 2003). In one study, however, SICI was only slightly increased. There was also decreased LICI that would appear to work against SI (Sohn and Hallett 2004a), but it was argued that LICI decreases SICI, so that decreased LICI may enhance SICI and possibly other inhibitory mechanisms. In our study, further inhibition of the MEP during movement may be explained by SI being enhanced by LAI. As LAI also decreases LICI (Sailer et al. 2002); this may also, in turn, further enhance SICI.
An alternative explanation for the additional decrease of the motor output in the surrounding muscle during movement is that SI might have enhanced LAI. However, the first proposed mechanism seems to be more likely because the reduced effect of SI due to unintentional co-activation becomes stronger again with long-latency afferent stimulation (Fig. 3). MEP amplitudes expectedly increased with the amount of (co)activation in the ADM during the unstimulated trials. On top of the biomechanical connections between digits or tendons, co-activation of noninstructed digits comes in part from distributed commands from the M1 hand representation (Hager-Ross and Schieber 2000; Slobounov et al. 2002). Even during single keystrokes of piano playing or typing, simultaneous motion of multiple digits occurs (Engel et al. 1997; Fish and Soechting 1992; Soechting and Flanders 1992). Stronger movements result in more co-activation (Hager-Ross and Schieber 2000; Slobounov et al. 2002). Therefore with stronger movements the effect of SI is less. Based on our results, long-latency afferent stimulation does not inhibit co-activation itself but may inhibit the effect of co-activation on motor output by strengthening SI.
In a previous study during movement, there was a slight decrease or no change in MEP amplitude in the nonrelated hand muscle with a corresponding increase in the movement-related muscles FDS, FDI, EIP (Sohn and Hallett 2004a). Here, we found increased ADM MEP during movement in 7 of 10 subjects during the adjustment of the test stimulus. The important point seems to be that MEP amplitude of ADM increased less than those that were found in the movement-related muscles FDS, FDI, and EIP. This indicates that SI may be a relative than rather an absolute phenomenon. Some of the increased MEP amplitude is due to a generalized increase in spinal excitability that masks what occurs cortically (Sohn and Hallett 2004a). Although we did not test for it, the training of 30 min in the experiments reported here and the change in level of attention with the four tones may also have enhanced M1 excitability in general.
A limitation of our study may be that we did not exclude a spinal contribution to the further inhibition during selective finger movement. Moreover, with long-latency afferent stimulation and ISIs around 200 ms, the further inhibition of the motor output during movement might be also generated by the sensory inputs that are processed through the thalamus, somatosensory cortex, and other structures. It has been shown that at rest LAI is a cortical phenomenon (Abbruzzese et al. 2001; Chen et al. 1999; Kobayashi et al. 2003). Although the studies were conducted with the target muscle at rest, they were based on the important finding that voluntary movement modulates the change in 20-Hz activity in magnetoencephalogram following 200 ms after median nerve stimulation (Salenius et al. 1997). Additionally, in studies on cutaneous reflexes (I1, I2, E1, E2, E3), it was doubtful that reflexes at an interval larger than 80 ms (E2, E3) are of spinal origin (Caccia et al. 1973; Farmer et al. 1990). We conducted F-wave amplitude measurements during tonic contraction. No effect was found with peripheral stimulation in addition to a trend toward excitation in the stimulated trials. Nevertheless, we cannot completely rule out the possibility that the enhancement of LAI during movement would be of both cortical and subcortical origin.
One functional implication based on our results could be that during movement the amount of SI is finely tuned by the sensory feedback of the periphery. During a selective movement with increasing strength, selectivity may be reduced by increased excitability in the surrounding cortex. However, depending on the afferent feedback, SI can be modulated, which further improves movement selectivity. This may be clinically relevant in movement disorders with loss of sensorimotor integration, particularly in dystonia in which SI is reduced (Sohn and Hallett 2004b). LAI at rest, for instance, is decreased in focal hand dystonia (Abbruzzese et al. 2001). Studying the effects of co-activation, SI and LAI on SI may be a useful way to further explore the pathophysiology of such conditions.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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Address for reprint requests and other correspondence: M. Hallett, Human Motor Control Section, NINDS/NIH, Bldg. 10/5N226, 10 Center Dr., Bethesda, MD 20892 (E-mail: hallettm{at}ninds.nih.gov)
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). All amplitudes are standardized to the mean MEP of the unstimulated trials (- - -). A clear interaction is shown between movement condition and target muscle (repeated-measure ANOVA, P < 0.01). At rest on both target muscles, there is long-latency afferent inhibition (LAI) with homo- and heterotopic stimulation compared with the unstimulated trials (P < 0.001). During movement, however, further inhibition is only shown in the ADM with homo- and heterotopic stimulation (P < 0.001).
) and digit 2 stimulation (
).