Clinical Neurophysiology 122 (2011) 153162

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Clinical Neurophysiology
journal homepage: www.elsevier.com/locate/clinph

Plasticity of motor cortex induced by coordination and training

*, A. Boyadjian F. Tyc
Laboratoire Plasticit et Physio-Pathologie de la Motricit, UMR 6196, CNRS, 31 Chemin J. Aiguier, 13402 Marseille Cedex 20, France

a r t i c l e

i n f o

a b s t r a c t
Objective: To study the modications induced by training of a coordinated movement on the primary motor cortex (M1) maps of one proximal muscle and one distal muscle activated alone and during their co-contraction. Methods: Six healthy female sport students performed a 6-week training program during which they were trained in darts 34 times a week. At the end each subject had made more than 1200 throws. Transcranial magnetic stimulation (TMS) was used to map the proximal medial deltoid (MD) and the distal brachio-radialis (BR) muscle representations on M1. Motor evoked potentials (MEPs) amplitude and excitability curves were used to test corticomotor excitability. Results: The cortical representation areas of each muscle separately increased after training. The cortical representation and the excitability curve of the BR muscle increased during co-activation with the MD. Combining co-contraction and training produced a further enlargement of the M1 representation of the BR muscle. Conclusions: The enlargement of the BR representation in M1 suggests the development of overlapping zones specifying functional synergies between distal and proximal muscles. Signicance: Our ndings support the idea that training of a coordinated movement involving several muscles and joints requires an activity-dependent coupling of cortical networks. 2010 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.

Article history: Accepted 24 May 2010 Available online 17 June 2010 Keywords: TMS Motor cortex Training Coordination Plasticity Mapping

1. Introduction In healthy humans, the ability to learn novel motor skills through practice is accompanied by functional reorganization of the motor system including the primary motor cortex (M1) (Pascual-Leone et al., 1994; Karni et al., 1995; Nudo et al., 1996; Classen et al., 1998). Motor practice induces changes in cortical motor representation that can be measured with transcranial magnetic stimulation (TMS). The changes are principally an enlargement of the cortical representation of the muscle used in the task and a facilitation of the motor evoked potentials (MEPs), indicating an increase in cortical excitability. In short-term motor learning studies, cortical changes can be observed for a few minutes (Garry et al., 2004), whereas learning a piano sequence produces more pronounced changes (Pascual-Leone et al., 1994, 1995). Classen et al. (1998) used TMS to evoke isolated and directional thumb movements and showed that training modied the thumb cortical networks, which encoded movement kinetics. This suggests a short-term memory for movement that is the rst step in skill acquisition (Classen et al., 1998; Karni et al., 1995). Most of the cited studies were focused on distal hand muscles known to have larger cortical
* Corresponding author. Tel./fax: +33 3 20 74 85 66. ). E-mail address: tycfr@free.fr (F. Tyc

representations and explored the effects of short-term plasticity on their cortical representations. TMS has been used to map cortical representations of different muscles at rest (Wassermann et al., 1992) and during low level activity (Wilson et al., 1995). Motor cortex representations in humans have shown discrete amplitude peaks included within a diffuse representation. Maps of different upper extremity muscles overlapped on the motor cortex in spite of a lateral shift (Peneld and Rasmussen, 1950). The threshold for the activation of proximal muscles by transcranial electrical stimulation (TES, Rothwell et al., 1987) or TMS (Wassermann et al., 1992) was higher than for distal muscles. A low level voluntary contraction permitted the observation of MEPs at a lower rate of stimulation (Wilson et al., 1995), especially for proximal muscles of the upper extremities that were difcult to map at rest (Levy et al., 1991; see Amassian et al., 1995). Since Peneld and Boldrey (1937) and Peneld (1950), the large representation of distal muscles has been generally associated with a ne level of control. Cortical maps revealed some size differences depending on handedness and the muscle location (proximal versus distal). Wassermann et al. (1992) showed that distal muscle representations were larger than proximal ones, and that they were larger for the dominant side, contrary to proximal muscles. A few studies have investigated the changes of proximal muscle and Boyadjian, representation induced by motor practice (see Tyc

1388-2457/$36.00 2010 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.clinph.2010.05.022

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2006). Liepert et al. (1999) have shown that short-term training of synchronous thumb and foot movements modied motor output maps due to interactions between hand and foot representation areas in M1. This result indicated a shift of the thumb motor output map towards the leg map. Changes in hand muscle corticomotor excitability in relation to static shoulder positions have been interpreted as a proximaldistal synergism operating through reaching movements (Ginanneschi et al., 2005). More recently, comparison of the effects of short-term training at proximal and distal upper limb joints, revealed a greater effect on the pathways controlling the index nger and a smaller effect on pathways controlling more proximal joints (Krutky and Perreault, 2007). These ndings suggested a difference in the motor cortical contributions to shortterm motor plasticity in the pathways controlling proximal and distal joints in the upper limb. Ackerley et al. (2007) used TMS to explore whether training in different coordination patterns affects the development of motor plasticity. A simple repetitive thumb movement made in synchrony, or in syncopation, with respect to an auditory metronome, shifted both synchronized and syncopated motor practice modied thumb movements in the trained direction. These studies have raised questions about the role of the motor cortex in coordinating multi-joint movements and the impact of training. To date, it has not been established whether long-term training of a complex coordinated movement affects the cortical representation of muscles during their co-activation. In a previous study, we examined the effect of highly-skilled behaviour on motor cortex representations of upper extremity muscles in volleyball players. We showed an expansion of proximal muscle representation in the contralateral M1 with an increase in overlap between proximal and distal muscle representations (Tyc et al., 2005). This overlap was suggested to play a role in muscle control during coordinated multi-joint movements. It was consistent with other ndings that generated the hypothesis that M1 could control the different limb segments as a whole rather than individually (Scott 2000). For example, shoulder, elbow and wrist muscle activation during pointing movements appeared to involve common motor cortical circuits (Devanne et al., 2002). As Schieber (2001) has suggested, an organization of the motor cortex with larger representations of the proximal muscles overlapping those of the distal muscles might facilitate coordination and motor learning. The purpose of the present study was to use TMS to further analyze the changes in cortical representations of a shoulder muscle and of a forearm muscle used to execute a complex coordinated movement. The key parameters in our protocol were the learning of a coordinated complex movement, the co-contraction of a proximal and a distal muscle, and long-term motor training. We chose the traditional game of darts, in which all joints in an upper limb are involved in a specic coordination pattern and timing of proximal and distal muscles (Temprado et al., 1997). We report the changes in the cortical representations of the proximal medial deltoid (MD) and the distal brachio-radialis (BR) muscles following a six-week training period together with an enlargement of the scalp-evoked motor maps when the two muscles are co-contracted. and Part of this work has been presented in abstract form (Tyc Boyadjian, 2008).

written consent for the study. All subjects were right-handed according to the Edinburgh Handedness Inventory (Oldeld, 1971). 2.2. Training protocol The subjects participated in a six-week training program during which they trained at throwing darts 34 times a week. Each subject received a complete dart game set including a dartboard and three darts. The dartboard was used on the side showing 10 concentric circles worth one point for the external circle and 10 points for the centre. The throwing distance was indicated by a black line on the oor set at 2.4 m from the dartboard. The subject had her right hip facing the target, with her right foot on the black line and threw the dart with her right arm. In this specic position MD and BR muscles are co-contracted as shown by EMG recordings (Fig. 1). During each training session the subject had to maintain the same position at the same distance from the dartboard and place darts as close as possible to the centre of the target in order to obtain a maximum number of points. Each session lasted 15 20 min and consisted of 6080 throws. At the end of the six weeks, each subject had made more than 1200 throws. Before starting the six-week training program and at the end of the six-week training program, each subject performed a test with 15 throws. The mean point obtained per dart was calculated by summing the number of points of the 15 throws and then dividing by 15. Comparison of the two scores provided an evaluation of the effect of training. 2.3. Electromyographic recordings (EMG) The skin was prepared for EMG recordings obtained from paired surface electrodes placed over the belly of the MD and BR muscles of the right arm (see Fig. 1). A large reference electrode was placed around the wrist. EMGs were recorded over a 250 ms time window including 50 ms prior to the stimulus. EMG signals were amplied (1000) with high pass ltering at 10 Hz and low pass ltering at 1 kHz before being sampled at 2 kHz by an A/D converter and stored on a computer for off-line analysis. 2.4. Transcranial magnetic stimulation A snugly tting cap was positioned over the subjects head and a grid was drawn with stimulus sites spaced 1.5 cm from the vertex using the nasion-inion line and the inter-aural line as references. TMS was delivered using a gure-of-eight coil with external loop diameter of 9 cm connected to a MagStim 200 electromagnetic stimulator (maximum output intensity 2.0 T, Magstim, Dyfed, UK). The coil was held tangentially to the skull positioned at 45 in relation to the nasion-inion line with the handle to the rear so that the induced monophasic current ow was in a posterior to anterior direction. This is the most favorable orientation for activating the corticospinal tract transynaptically (Kaneko et al., 1996). The junction of the coil was placed over the site to be stimulated on the left hemisphere that elicited MEPs in the right contralateral target muscles. 2.5. Experimental protocol Two sessions of identical measurements were carried out. The rst one was carried out before the training period (control) and the second one at the end of the training period (six weeks later). To record EMG activity, subjects were comfortably seated and adopted a static position in order to produce constant low level activity in each muscle. EMG activity was displayed on line on a computer screen to allow the subject to maintain a constant and stable low EMG activity set at 5% of the maximal EMG activity. Two sets of 2 s recordings were made to measure EMG activity,

2. Methods 2.1. Subjects Studies conforming to the standards set by the declaration of Helsinki were carried out on six healthy female sport students (mean age 21 0.26) who did not regularly participate in a sport involving specic arm activity. All subjects gave their free informed

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Fig. 1. Photo showing the position of the throwing arm and the place of the electrodes on MD and BR muscles. Right, rectied EMG obtained during the three phases of throwing. Note the co-activation of MD and BR muscles during throwing.

the rst during low level activity produced during mapping and the second during maximum voluntary contraction. The value of the rectied EMG during low activity was divided by the values obtained during maximal EMG activity to quantify the activity during mapping. The mean values of the rectied EMG during low level activity were stable at 5% of the maximal EMG activity in both sessions. For MD recordings, the subject placed their arm in a stable position aiming at a target to throw a dart. For BR, recordings were obtained under two conditions. (1) Alone condition: the subject maintained the 5% low activity in the BR muscle in a static position with the forearm on an arm-rest. Particular care was taken to ensure that only the BR muscle was contracted and no EMG activity could be recorded in the MD muscle as veried online at high magnication on the screen. Mapping only started when the MD muscle was silent. (2) Co-active condition: the subject maintained 5% low EMG activity in both muscles (BR and MD). 2.6. Motor output mapping Prior to mapping, the hot spot and the active motor threshold (aMT) were determined for each muscle. The hot spot was the site at which the largest MEP could be induced with suprathreshold single stimuli applied with TMS. The aMT was dened as the lowest stimulation intensity that induced a peak-to-peak MEP amplitude of more than 200 lV in 5 out of 10 trials in the target muscle. The TMS intensity was then adjusted to 1.2 times the aMT of each muscle for mapping. Three TMS response maps were established on the left hemisphere: one for MD muscle and two for BR muscle (Alone and Co-active condition). Four stimuli were delivered at each grid site with intervals randomly ranging between 3 and 5 s. The four recordings were averaged and stored on a computer for further off-line analysis. 2.7. Excitability curves Excitability curves (Ridding and Rothwell, 1997) were obtained by stimulating the BR hot spot with ten increasing TMS intensities (from 1.2 to 1.65 aMT) under two conditions. Alone condition, with only the BR muscle contracted and Co-active condition with the two muscles (BR and MD) contracted. At each intensity, three stimuli were applied and MEPs stored for further analysis. 2.8. Data analysis To determine the cortical representation of each muscle the four non-rectied EMG recordings were averaged for each stimulation site. The peak-to-peak amplitude of the MEPs was measured and plotted on medio-lateral and antero-posterior coordinates. For each subject and for each muscle, a contour plot was drawn with its external borderline corresponding to the amplitude of

the minimal MEP (2D representation). The area of the contour plot, i.e. the muscle map representation on the scalp in cm2 was then calculated. For 3D representation, the Lorentzian 3D function was used to t data by the LevenbergMarquard nonlinear least-mean-square et al., 2005; Devanne et al., algorithm (Press et al., 1986; Tyc 2006). This algorithm determines the function parameters that minimize the sum of the squared differences between the observed and the predicted values of the dependent variable using a gradient descent-based optimization procedure. Before tting, the baseline was adjusted to the mean rectied EMG activity recorded during the 2 s low level activity. The Lorentzian equation relating the peak-to-peak amplitude of the MEP and the antero-posterior (y) and medio-lateral (x) coordinates was given by the following equation:

Z max Z  2    2  xx0 yy0 1 1 a b

Zmax is the estimated amplitude of the maximal MEP that is located at coordinates x0 and y0. The parameters a and b reect the straightness of the peak in the medio-lateral and antero-posterior directions, respectively. It has been shown that the estimated coordinates of the theoretical hot spot (x0 and y0) of each muscles representation were within the area from which MEPs were evoked and very close to the site at which the largest response was obtained experimentally (Devanne et al. 2006). For excitability curve tting, we used the Boltzmann sigmoidal function where MEPmax represents the plateau level, S50 the stimulus intensity required to obtain the 50% plateau value, and k reects the slope of the curve:

MEP

MEPmax 1 ess50 =k

For statistics a two-way ANOVA for repeated measurements was calculated. Muscle representation variables (2D and 3D) and the excitability curves were compared between sessions for both muscles and between both conditions for BR muscle (Alone and Co-active) using a paired t-test as appropriate. To test the effect of independent variables on excitability curves, we used a t-test based on the standard error of estimate associated with each best-t parameter in each subject. The level of signicance was set at 5%. 3. Results The six-week training period induced an increase in the performance in the throwing test for each subject. Before training, the 15 throws test resulted in a score between 47 and 89 points

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Fig. 2. Mean of 4 MEPs produced by TMS in MD and BR muscles at each scalp position in one subject before and after the 6 weeks training session. The location of the MEP traces on the grid corresponds to the scalp sites from where they were evoked. V, vertex position.

with a mean of 70 points for the six subjects (4.7 points per dart). The score after training was 77 to 112 points with a mean of 94 points (6.3 points per dart). The aMT were stable and no statistical difference was observed throughout the training session for each subject and for both muscles. The aMT of the BR muscle expressed as a percentage of the maximal stimulator output were 34.8 1.72% (mean SEM) before the training program and 34 2.08% after training. For the MD

muscle the aMT were 37.7 2.69% and 37 2.21% before and after the training program. By stimulating M1 and recording the MEPs from the target muscles, an estimate of the representation of each muscle was obtained on the scalp. Fig. 2 is an example of the MEPs obtained for the MD and BR muscle representations before and after six-weeks training in one subject. The location of MEP traces on the grid corresponds to the scalp position from which they were evoked. The same

 , A. Boyadjian / Clinical Neurophysiology 122 (2011) 153162 F. Tyc Table 1 Map areas and number of MEPs for MD muscle for six subjects before and after the 6 weeks training. Means are shown SEM. MD map area (cm2) Before 1 2 3 4 5 6 Mean 37.1 21.2 32.3 22.4 22.6 27.4 27 2.6 After 47 34.9 35.9 26.4 30.7 32.1 35 2.9 % 127 165 111 118 136 117 129 8.0 Number of MEP Before 15 12 17 11 12 13 13 0.9 After 22 16 17 14 16 17 17 1.1 % 147 133 100 127 133 131 128 6.3

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cant interaction was found (F = 0.0546, P = 0.824). The BR muscle representation was determined before and after training, as was the representation of the MD muscle (Fig. 2). Training induced similar increases in the number of MEPs and map area for the BR muscle as was observed for the MD muscle representation (Fig. 3B). The size of the surface area of the cortical representation of the BR after training was signicantly different from before training (p < 0.02). The results are given in Table 2 for the six subjects (BR alone). 3.1. The effects of co-contraction Mapping was performed to evaluate the effect of co-contraction on the representation of the BR muscle (Fig. 2, BR Co-active). The surface area of the BR representation increased during co-contraction as shown in Fig. 3C. Table 2 provides the results for the six subjects (BR Co-active). The mean number of cortical sites from which a MEP could be obtained on the BR muscle in the Co-active condition was 19 compared to 16 in the Alone condition. The mean BR muscle representation area was 39 cm2 in the Co-Active Condition and was signicantly larger (p < 0.02) than the 31 cm2 when the BR muscle was tested alone. 3.2. Dual effects of co-contraction and training The effect of co-contraction of both muscles was measured on the BR muscle representation before and after the training session.

protocol was applied to each subject. The data obtained for the six subjects before and after training on MD muscle are provided in Table 1. The mean number of sites from which a MEP could be induced in the MD muscle increased from 13 to 17. The mean surface area of the MD muscle representation containing the sites increased signicantly (p < 0.006) from 27 to 35 cm2 after training. This modication is illustrated by the contour plots obtained in one subject in Fig. 3A. After the training session the mean motor area for the MD muscle represented 129% of the mean motor area obtained before training. For the BR muscle cortical map area, the interaction between session (before and after training) and condition (Alone and Co-active) was tested with two way repeated ANOVA. No statistically signi-

Fig. 3. Cortical representations obtained in one subject for MD (A) and BR (B) muscles before (straight line) and after (dotted line) training. C and D, cortical representations of BR muscle obtained in the Alone (arrows) and the Co-Active (dashed line) Conditions before training (C) and after training (D).

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Table 2 Map areas and number of MEPs for BR muscles of six subjects before and after the 6 weeks training in the two conditions: Alone (only BR muscle contracted) and Co-Active (BR and MD muscles co-contracted). Means are shown SEM. BR Alone Before Map area (cm2) 1 38.4 2 31.7 3 39.1 4 28.6 5 24.8 6 25.3 Mean 31 2.6 Number of MEP 1 17 2 17 3 19 4 16 5 13 6 14 Mean 16 0.9 After 58.8 39.3 42.8 40.3 29.8 32.6 41 4.2 25 20 20 19 15 18 20 1.3 % 153 124 110 141 120 129 129 6.3 147 118 105 119 115 129 122 5.8 BR Co-Active Before 54.5 34.5 41.2 39.9 31.3 34.1 39 3.4 22 17 20 19 15 18 19 1.0 After 60.1 42.6 50.3 54.5 34.6 44.9 48 3.7 26 23 21 24 18 20 22 1.2 % 110 123 122 137 111 132 122 4.4 118 135 105 126 120 111 119 4.4 % Co-Active/Alone Before 142 109 105 140 126 135 126 6.4 129 100 105 119 115 129 116 4.9 After 102 109 118 135 116 138 120 5.8 104 115 105 126 120 111 113 3.5

One example obtained in one subject is shown in Fig. 3C and D where an increase in the surface area of the BR muscle was observed. Data for the six subjects are given in Table 2, conrming the effect of co-contraction and the effect of training on the mean surface area of BR muscle representation. The mean number of cortical sites from which a MEP could be obtained on the BR in the CoActive Condition was 19 before training against 22 after training. The 48 cm2 of the mean surface area of the BR muscle reached after training must be compared to the 39 cm2 measured before training. The increase was signicant (p < 0.02) and represented 122% of the map area before training. 3.3. 3D representation of the MD and BR muscles To estimate the coordinates (x0, y0) of the theoretical hot spots, a 3D representation of the muscles was calculated in order to follow the modication of the location of the hot spots in the three experimental situations. Fig. 4A illustrates the modication obtained on 3D representations after training for both muscles. It indicates an increase in the cortical excitability associated with an increase of the cortical surface from which the muscle could be activated. The mean R2 values were between 0.71 and 0.84 for the six subjects. The distances between the theoretical hot spots of the MD and the BR (Table 3) were signicantly different (p < 0.03) in the Alone Condition but not in the Co-Active Condition (p < 0.06). For one subject g. 4B (left) shows that the co-contraction induced a reduction of the inter-spot distance from 18 to 7.5 mm before training. After training, the inter-spot distance was 4.1 mm for the BR alone while the location of the hot-spots nearly coincided (0.5 mm) in the Co-Active Condition. The histograms in Fig. 4B (right) show the differences in inter-spot distances between before and after training. In the Alone Condition a reduction of the inter-spot distances was observed in ve out of six subjects and in all subjects in the Co-Active Condition. The reduction emphasizes the dual effect of training and co-contraction. 3.4. Excitability curves The excitability curves measured on the BR muscle showed an increased MEP area when the stimulation intensity was increased before and after the training session under the Alone and Co-Active Condition (Fig. 5, left). During co-activation, the plateau levels of the curves reached higher values in each subject and for each

session compared to the levels reached when the BR muscle was activated alone. The histograms of Fig. 5 (right) conrm that the values of the plateau levels obtained from the excitability curves before and after training for the six subjects were systematically and signicantly higher during co-contraction (142% and 159% before and after training). The increase in cortical excitability resulted from the combined effects of training and co-contraction. 4. Discussion The principal nding of the present study is that co-activation of the proximal MD muscle with the distal BR muscle enlarges the cortical representation of the BR muscle and that a six-weeks training period produces an enlargement of the cortical motor representations of the co-contracted muscle. 4.1. Condition of recordings At rest, proximal muscles are difcult to map (Levy et al., 1991; Amassian et al., 1995). Stimulus intensity can reach 80% of the maximal intensity of the stimulator that is approximately twice the and Boyadjian, 2006). intensity used during low level activity (Tyc In contrast, when a muscle is slightly activated, the MEP threshold is decreased and TMS mapping is facilitated (Wilson et al., 1995). Our experimental protocol relies on these observations. 4.2. Location of training-dependent plasticity The increase of MEP size induced by co-activation and training reects a modication of the excitability of the cortico-spinal system as a whole without providing evidence that plasticity occurs at cortical levels. However, it can be argued that the observed effects on corticomotor excitability cannot exclusively operate at the spinal level even though the spinal neuronal circuitry has been shown to exhibit adaptive plasticity in experimental animals (Wolpaw and Carp, 1993) and in humans (Baylor and Benjuya, 1989). Because TES produces a greater proportion of direct activation of corticospinal neurons than TMS (Day et al., 1987a, b; Rothwell, 1997) and because training induces an increase in MEPs evoked by TMS but not by TES brain stem or cervical stimulation (Classen et al., 1998; Muellbacher et al., 2001; Perez et al., 2004; Garry et al., 2004), this form of plasticity is more likely to occur at the level of the cortical networks than at subcortical levels.

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Fig. 4. (A) Three-dimensional reconstructions of MD and BR muscles based on MEP recordings before and after training. The total variance accounted for by tting the Lorentzian function to the data points is given by the R2 value. (B) Left, the diagrams illustrate the measure of the distance between MD and BR hot spots in one subject chosen to illustrate the maximal reduction of the inter-spot distances. Right, the histograms represent the differences between inter-spot distances before and after training in the two conditions for the six subjects.

4.3. Reproducibility of cortical M1 maps Although there can be no doubt that the brain displays plasticity, stability of cortical networks is also needed, as discussed in a recent review by Wandell and Smirnakis (2009). That motor cortical map representations are reproducible in subjects over a long period of time is well documented. The

TMS-mapped representations of two intrinsic hand muscles were found to be very reproducible when mapping was repeated after intervals of up to 181 days (Wilson et al., 1993). A method for mapping the motor cortex by TMS was tested statistically for its reproducibility and found to be reliable for mapping the human motor cortex (Mortifee et al., 1994). Maeda et al. (2002) investigated the reproducibility of mapping techniques on six normal

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Table 3 Distances (mm) between estimated hot spot of MD and BR muscles before and after training in the two conditions (Alone and Co-active) for the six subjects. These data were used to measure the differences between inter-spot distances represented in Fig. 4B right. Distance between MD and BR hot spot Alone Condition Before 1 2 3 4 5 6 Mean 20.0 18.0 10.4 15.3 15.5 15.3 15.7 After 18.1 4.1 11.5 9.8 7.2 13 10.6 Co-Active Condition Before 22.7 7.5 11.7 14.2 15.3 13.2 14.1 After 14.2 0.5 11.3 11.3 10.4 8.8 9.4

4.4. A cortical representation of coordination? The capacity of M1 to undergo plastic reorganization following skill acquisition and training is well established in humans and animals (Pascual-Leone et al., 1994, 1995; Classen et al., 1998; Karni et al., 1998; Kleim et al., 1998; Liepert et al., 2000; Plautz et al., and 2000; Yahagi and Kasai, 1998; Muellbacher et al., 2001; Tyc Boyadjian, 2006.). Many studies have investigated the effect of short-term training on the cortical representation of distal muscles and Boyexecuting repetitive sequences of nger movements (Tyc adjian, 2006). For example, in normal human subjects instructed to practice a repetitive sequence of nger movements, the amplitude and extent of nger muscle representation assessed by TMS increased in M1 contralateral to the performing hand as the speed of performance increased over a single day of training (PascualLeone et al., 1994). In contrast, we focus our experiments on the effects of a six-week training period on the cortical representation of a complex coordinated movement namely the movement executed by a subject playing darts, in which all the joints in an upper limb are involved in a specic coordination pattern and timing of proximal and distal muscles (Temprado et al., 1997; Scott, 2000). Motor patterns at each joint must be carefully coordinated to smoothly move the joints and the hand through space. Many studies have described the trajectories of hand and arm movements under normal conditions as straight hand paths called stereotyped movements (Bernstein, 1967; Flash and Hogan, 1985; Wolpert et al., 1995). These were dened as simple basic motor elements (primitives). The notion that skilled movements might reect a process for the concatenation of consecutive movement elements into complex movements was suggested by Sosnik et al. (2004). On this assumption, a new primitive movement could be generated by training which would be different from the sum of the elements that comprised the sequence of initial movements (Engel et al., 1997). By studying the acquisition of skilled motor performance, Karni et al. (1995, 1998) showed that performance was paralleled by the emergence of a more extensive representation of a trained sequence of movements in M1. It has been suggested that a specic representation of the sequence might be implemented at the M1 level as a new functional unit, differentially from the component movements (Karni et al., 1998). In monkeys, practice-dependent changes in the functional topography of M1 were reported by Nudo

volunteers, each studied on two occasions several weeks apart (ranging from 21 to 132 days) and showed a low degree of variability of repetitive TMS (rTMS) effects in the human brain. The areas of the scalp from which responses were evoked from corticospinal cells projecting to three intrinsic hand muscles were systematically mapped using TMS on eight normal subjects at different intervals (24 h, one week and two weeks). The area, volume, and centre of gravity of these maps did not change signicantly over that period. It was concluded that TMS mapping is suitable for studies that aim to examine the effect of various interventions on the cortical representation of individual muscles in human subjects (Miranda et al., 1997; Uy et al., 2002.; Pitcher et al., 2003; Monls et al., 2005). Variation in the response to TMS in the general population allowed Wassermann (2002) to state with condence that the MEP to single and paired TMS is a sensitive measurement of the corticospinal function. Taken together, and even though some differences in aMT and cortical excitability exist between subjects, these ndings demonstrate that cortical maps are reproducible in a given subject over long periods of time and are similar in both hemispheres, and are similar in left- and right-handed subjects. The stability of aMT observed in our experiments between the two sessions validates our choice to consider the rst session of measurements before training as the control condition, as well as our use of map parameters for investigation of long-term effects of training.

Fig. 5. (A) Excitability curves obtained on the BR muscle hot spot for one subject before and after training in the two conditions Alone (straight line) and Co-Active (dotted line). (B) Histograms representing the values of the plateau obtained on the excitability curves before and after training in the two conditions for the six subjects. Note the different scale for subject number 3 on the right (ordinates). * indicates a signicant difference (p < 0.05) in the plateaus reached in the Alone and Co-Active conditions; ** indicate a signicant difference (p < 0.05) in the plateaus reached before training and after training.

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et al. (1996, 2001). After a few weeks of training on a task that required skilled manipulation, a new movement representation was observed in M1 that was not found in untrained brains. These ndings support the idea of a cortical representation of the learned motor sequence in M1 and underpinned our experimental protocol. Our nding that the co-activation of the proximal and the distal muscles enhanced the TMS-evoked motor output in the distal BR muscle showed that some functional networks were triggered during coordinated movements. We interpreted the enlargement of the motor cortical output maps to the muscles involved in the task and their overlap indicative of a functional link between the two target muscles carrying out the coordination. Our observation that the proximal muscle modied the excitability curves of the distal muscle conrmed that the sharing of networks is necessary for coordination, as observed in other studies (Devanne et al., 2002; Ginnaneschi et al., 2006). TMS studies have shown that the cortical representations of different muscles overlap on M1 (Wilson et al., 1993; Wassermann et al., 2005; Devanne et al., et al., 1993; Liepert et al., 1999; Tyc 2006). In animals, studies involving the superposition of M1 topographical maps obtained by micro-stimulation, have shown that motor cortical zones controlling different forelimb segments are interconnected by intrinsic horizontal collaterals (Capaday et al., 1998; Huntley and Jones, 1991; Keller, 1993; Rioult-Pedotti and Donoghue, 2003; Tokuno and Tanji, 1993). In Rhesus monkeys, Park et al. (2001) found regions combining both distal and proximal muscles following electrical stimulation of the cortical surface. In the cat, simultaneous stimulations of two cortical points were additive and resulted in a new movement that was a combination of the movements elicited by stimulation of each point on its own (Ethier et al., 2006). Brain imaging or TMS have shown that arm or hand movements were triggered by large areas of the motor cortex (Amassian et al., 1995; Devanne et al., 2002; Hallet, 2000; Kobayashi and Pascual-Leone, 2003; Sanes et al., 1995; Schieber and Hibbard, 1993; Walsh and Cowey, 2000 Schieber, 2001). These ndings suggest that widely distributed motor cortical territories are functionally linked during coordinated movements. Whether the expansion of the muscle representations in M1 observed in the darts players can be related to the development of a functional unit remains a matter of speculation. However, the highly distributed organization of M1, convergence, divergence and horizontal connections with wide overlapping territories of different muscles, makes the hypothesis of a cortical representation of movement coordination plausible. Acknowledgements We thank our students for giving their time to participate in this study. We thank Professor A.R. Lieberman for editing our manuscript and correcting the English language. We are grateful to Professor John C. Rothwell for his advice. References
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