Abstract

Unimanual motor tasks, specifically movements that are complex or require high forces, activate not only the contralateral primary motor cortex (M1) but evoke also ipsilateral M1 activity. This involvement of ipsilateral M1 is asymmetric, such that the left M1 is more involved in motor control with the left hand than the right M1 in movements with the right hand. This suggests that the left hemisphere is specialized for movement control of either hand, although previous experiments tested mostly right-handed participants. In contrast, research on hemispheric asymmetries of ipsilateral M1 involvement in left-handed participants is relatively scarce. In the present study, left- and right-handed participants performed complex unimanual movements, whereas TMS was used to disrupt the activity of ipsilateral M1 in accordance with a “virtual lesion” approach. For right-handed participants, more disruptions were induced when TMS was applied over the dominant (left) M1. For left-handed participants, two subgroups could be distinguished, such that one group showed more disruptions when TMS was applied over the nondominant (left) M1, whereas the other subgroup showed more disruptions when the dominant (right) M1 was stimulated. This indicates that functional asymmetries of M1 involvement during ipsilateral movements are influenced by both hand dominance as well as left hemisphere specialization. We propose that the functional asymmetries in ipsilateral M1 involvement during unimanual movements are primarily attributable to asymmetries in the higher-order areas, although the contribution of transcallosal pathways and ipsilateral projections cannot be completely ruled out.

INTRODUCTION

The cortical motor system of each hemisphere controls primarily the contralateral body side via crossed corticospinal fibers. However, the primary motor cortex (M1) can also be involved in movements performed with the ipsilateral hand (Davare, Duque, Vandermeeren, Thonnard, & Olivier, 2007), specifically when actions are complex (Callaert et al., in press; Swinnen et al., 2010; Verstynen, Diedrichsen, Albert, Aparicio, & Ivry, 2005; Haaland, Elsinger, Mayer, Durgerian, & Rao, 2004; Singh, Higano, Takahashi, Abe, et al., 1998) or require high force (Perez & Cohen, 2008; Hortobagyi, Taylor, Petersen, Russell, & Gandevia, 2003; Muellbacher, Facchini, Boroojerdi, & Hallett, 2000; Hess, Mills, & Murray, 1986). In humans, ipsilateral control exhibits a functional asymmetry between hemispheres as shown by functional imaging, revealing that right-handed participants activate the left motor cortex during left-handed movements stronger than the right motor cortex during right-handed movements (Hayashi et al., 2008; Verstynen et al., 2005; Kobayashi, Hutchinson, Schlaug, & Pascual-Leone, 2003; Nirkko et al., 2001; Solodkin, Hlustik, Noll, & Small, 2001; Singh, Higano, Takahashi, Kurihara, et al., 1998; Li, Yetkin, Cox, & Haughton, 1996; Kim et al., 1993). These findings were corroborated by virtual lesion studies, using TMS to temporarily disrupt the activity of M1, although participants performed a complex finger sequence tapping task. TMS applied over M1 ipsilateral to the moving hand resulted in timing errors. Interestingly, more errors in motor behavior were seen when TMS was applied over the ipsilateral left M1 than over the ipsilateral right M1, suggesting that the left M1 is strongly involved in motor control of complex hand movements, irrespective of the hand being used (Chen, Gerloff, Hallett, & Cohen, 1997).

Here we aimed to answer two questions. First, as most studies tested only right-handed participants, the involvement of the ipsilateral M1 in unimanual movements in left-handed participants remains unclear. There are two possible hypotheses for the lateralization of the motor system, which can be disentangled by testing left-handed participants.

First, left-handed participants could exhibit the same hemispheric lateralization as right-handed participants, such that left M1 contributes to fine motor control of either hand. This “left hemispheric specialization” hypothesis has been supported by two fMRI studies of Kim et al. (1993) and Verstynen et al. (2005), reporting that in left-handed participants the left hemisphere is more activated during ipsilateral movements than the right hemisphere, although this hemispheric asymmetry is less pronounced than in right-handed participants.

Second, left-handed participants could exhibit a mirrored lateralization compared with right-handed participants, indicating that their motor-dominant (right) M1 is predominantly involved in ipsilateral control, suggesting that handedness determines which ipsilateral motor cortex is more involved. Kawashima, Inoue, Sato, and Fukuda (1997) demonstrated stronger activity in the dominant right hemisphere than in the nondominant left during ipsilateral movements using PET, supporting this “hand dominance hypothesis” in left-handed participants.

Our second research question was at which level of the nervous system these functional asymmetries might be manifested. Previous studies in animals have suggested that ipsilateral control can be exerted via uncrossed corticospinal fibers (Brus-Ramer, Carmel, & Martin, 2009). Similar to animals, humans also have these direct ipsilateral motor pathways; however, they are relatively scarce and represent only 10–25% of all the descending motor fibers (Nathan, Smith, & Deacon, 1990). Stimulating the motor cortex with high TMS intensities can evoke motor-evoked potentials (MEPs) in both hands (Kagerer, Summers, & Semjen, 2003). Latencies of the MEPs evoked in the hand ipsilateral to the stimulated hemisphere were somewhat longer than latencies found for the contralateral hand. However, this difference was relatively small (not more than 7 msec), implying that the ipsilateral MEPs were evoked via uncrossed corticospinal pathways rather than involving a transcallosal mechanism (Kagerer et al., 2003). Kagerer et al. (2003) revealed that TMS over the left M1 in right-handed participants evoked larger ipsilateral MEPs in the left hand than those induced in the right hand by TMS over the right M1, suggesting a strong influence from the left hemisphere to the left hand via the ipsilateral descending pathway. This also supported the idea that the ipsilateral projections innervated not only proximal muscles but also distal muscles. However, the specific functional role of the ipsilateral corticospinal pathways in unimanual movements remains relatively indefinite.

Alternatively to the uncrossed corticospinal pathway put forward by Kagerer et al. (2003), other studies have shown that one hemisphere can influence the other via transcallosal fibers. Accordingly, the hemisphere ipsilateral to the moving hand may indirectly interact with contralateral M1 via transcallosal pathways, often resulting in changes of corticomotor excitability at a subthreshold level, that is, without evoking MEPs. These interhemispheric M1–M1 interactions can be measured using a double-pulse TMS paradigm that tests predominantly inhibitory interhemispheric effects. Previous studies have suggested that interhemispheric inhibition (IHI) is asymmetric, such that stronger IHI was found from the dominant to the nondominant hemisphere than vice versa when measured in rest (Baumer et al., 2007; Netz, 1999; Netz, Ziemann, & Homberg, 1995). Moreover, when transcallosal interactions were determined during the preparation of a unimanual movement with either the dominant or nondominant hand, hemispheric asymmetries were only found when measured from the ipsilateral to the contralateral M1. More specifically, preparing a dominant (right) hand movement resulted in a disinhibition and even facilitation of the contralateral (left) hemisphere via transcallosal projections deriving from the ipsilateral (right) hemisphere. By contrast, no such strong modulations of IHI were observed when the nondominant hand performed a movement (Duque et al., 2007).

In the present study, we investigated the involvement of the ipsilateral M1 in unimanual movements in strongly right-handed participants as well as in strongly left-handed participants and thereby aimed to disentangle whether possible hemispheric asymmetries emerge in accordance with hand dominance or left hemispheric specialization. TMS was used to disrupt the ipsilateral M1 during the performance of a complex unimanual task in a “virtual lesion” approach. Additionally, we aimed to reveal further insights into which anatomical pathways mediate these asymmetries. Therefore, we applied TMS stimulation with intensities ranging from motor threshold to subthreshold intensities. Note that the latter were shown to depolarize intracortical and transcallosal interneurons without evoking a descending corticospinal volley (Di Lazzaro et al., 1998). Thus, a prominent role of the ipsilateral pathway would be ruled out if disruptions could be frequently induced by applying subthreshold TMS over the ipsilateral M1.

METHODS

Participants

Twelve strongly right-handed participants (6 men and 6 women, Oldfield range = 88/100, age = 22.7 ± 3.3 years) and 12 strongly left-handed participants (6 men and 6 women, Oldfield range = −70/−100, age = 23.4 ± 2.4 years) participated in this experiment (Oldfield, 1971). None had overt sensorimotor deficits, and all were naive with respect to the goals of the experiment. Informed written consent was obtained from all participants. The informed consent and the study were approved by the local Ethics Committee of Biomedical Research at K.U. Leuven in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki.

Tapping Task

We employed a complex finger coordination task that allowed us to match task difficulty across hands and participants and that was used previously to quantify the behavioral effect of disruptive TMS (van den Berg, Swinnen, & Wenderoth, 2010). This task required participants to perform a complex unimanual tapping pattern using their thumb (T), index (I), middle (M), and ring (R) finger of either hand. Participants were instructed to tap in time with a metronome, such that thumb (T) and middle (M) finger tapped alternately with index (I) and ring (R) finger (i.e., TM-IR-TM-IR; see Supplementary Movie). One week before the experiment, participants used an instruction movie to perform unsupervised practice of the metronome-guided unimanual tapping task with either hand (see Supplementary Movie). They could only participate in the experiment if they were able to perform the unimanual tapping task consistently for at least 11 sec at a minimum tapping frequency of 0.5 Hz. In the main experiment, participants closed their eyes while performing the unimanual tapping task at the rhythm imposed by a metronome. Before the main experiment, the so-called “spontaneous transition frequency” (STF) was determined for each participant and separately for the left hand (STFpreL) and right hand (STFpreR). STFpre was determined by increasing the frequency of the metronome every 2 sec by 0.125 Hz until the participant could not maintain the coordination pattern anymore, as indicated by a missed or incorrect finger tap, or a switch to another pattern. Active markers (infrared-emitting diodes) were placed on the nails of the fingers to register (at 100 Hz) the tapping movements by a three-dimensional tracking system (Optotrak 3020, NDI, Ontario, Canada).

Surface EMG was recorded from the right and left abductor pollicis brevis. Disposable Ag–AgCL surface electrodes (Blue sensor SP) were placed over the muscle belly. The EMG signal was amplified, sampled at 5000 Hz (CED Power 1401, Cambridge Electronic Design, Cambridge, United Kingdom), band-pass filtered (5–1500 Hz), and stored on a PC for on-line display and off-line analysis.

General TMS Procedure

A 70-mm figure-of-eight coil was connected to two Magstim 200 stimulators, which were coupled through a Bistim Module (Magstim, Whitland, Dyfed, United Kingdom). The coil was positioned over the hemisphere contralateral to the target muscle. The handle was pointed backward and 45° away from the midsaggital line, creating a posterior-to-anterior current. The hotspot of the abductor pollicis brevis, the thumb muscle strongly involved in the tapping movement, was determined as the optimal coil position for eliciting MEPs with maximal amplitude. The rest motor threshold (RMT) was determined for both hemispheres, defined as the minimum stimulus intensity to evoke MEPs of >50 μV in at least 5 of 10 consecutive trials.

Virtual Lesion Experiment

In the virtual lesion experiment, real or sham TMS stimulation was applied to M1 while participants performed ipsilateral unimanual movements to induce possible disruptions of motor behavior. A disruption was defined as a missed or incorrect finger tap or a switch to another pattern (Figure 1). Two pulses with the same stimulus intensity were applied with an ISI of 10 msec. Two pulses were chosen to create a virtual lesion, because pilot testing showed that a single pulse was not sufficient to disrupt behavior in a reliable way. This short interval was chosen to simulate an event-like disturbance similar to resetting experiments typically used to study coordination stability (de Poel, Peper, & Beek, 2007) and because a previous study (van den Berg et al., 2010), employing the same principle paradigm, indicated that this stimulation protocol is sufficient to disrupt behavior. The stimulus intensity of both pulses was varied, such that 85%, 90%, 95%, and 100% of the RMT were used. The relatively low stimulation intensities were chosen because a previous study revealed that stimulating the ipsilateral M1 at 110% RMT evoked nearly 100% disruptions of the tapping task, such that a lower intensity was used in the present experiment to avoid ceiling effects and to detect functional asymmetries with sufficient sensitivity (van den Berg et al., 2010; control condition of Experiment 2). Sham TMS, which does not result in cortical stimulation but maintains the ancillary aspects of TMS, was applied as a control condition. For sham TMS, the coil was rotated by 90° away from the head, such that the cortex was not stimulated, whereas unspecific effects such as the click when the coil discharged at an intensity of 100% RMT were still present (Lisanby, Gutman, Luber, Schroeder, & Sackeim, 2001).

Figure 1. 

Representative example of finger tapping with the left hand (left-handed participant). Taps of the fingers are represented by squares with different texture and shown relative to the beep of the metronome, as indicated by the thin vertical lines. Quasi-synchronous taps are connected by vertical lines. The thick black line indicates the TMS stimulation. Shortly after the TMS stimulation, a disruption is shown.

Figure 1. 

Representative example of finger tapping with the left hand (left-handed participant). Taps of the fingers are represented by squares with different texture and shown relative to the beep of the metronome, as indicated by the thin vertical lines. Quasi-synchronous taps are connected by vertical lines. The thick black line indicates the TMS stimulation. Shortly after the TMS stimulation, a disruption is shown.

Paced by a metronome, participants tapped at a constant frequency (STF-0.125 Hz) that allowed them to maintain performance for a whole trial (11 sec). Stimulation was randomly given between 5 and 10 sec following trial initiation. For the remainder of the manuscript, we will use the term “dominant hemisphere” or “dominant M1” (D-M1) for the hemisphere contralateral to the dominant hand (i.e., left for right-handed participants and right for left-handed participants) and “nondominant hemisphere” or “nondominant M1” (ND-M1) for the other hemisphere. D-M1 and ND-M1 were stimulated in alternating blocks (eight in total) applying two stimulations for each of the four stimulation intensities, as well as two additional sham stimulations. The order of stimulation intensity was randomized. In total, each hemisphere was stimulated for 40 times (eight trials per intensity + sham conditions). In half of the participants, TMS stimulation started in the left hemisphere, and in the other half, in the right hemisphere.

TMS induced MEPs in the contralateral, resting hand, and for these MEPs, the size was determined by the peak-to-peak amplitude. Moreover, TMS often resulted in an overt twitch of the resting thumb, which might have interfered with the tapping task either by distracting the subject from tapping or via sensory reafferences. Sensory reaffenrences can potentially influence the tapping hand via spinal pathways (Stubbs & Mrachacz-Kersting, 2009) or by evoking bilateral responses in the cortical somatosensory system (Iwamura, Iriki, & Tanaka, 1994) that can interact with M1 of either hemisphere (Swayne, Rothwell, & Rosenkranz, 2006). To control for these peripheral effects, we stimulated the median nerve of the resting hand at the level of the wrist evoking a similar thumb twitch as that elicited by TMS but without disrupting M1 activity. Electrical median nerve stimulation (S88 Dual Channel Stimulator, Grass, West Warwick, RI) was applied to the resting hand while the other hand performed the unimanual tapping task. Stimulation intensity was adjusted to elicit a consistent twitch of the thumb. For each hand, the tapping frequency was set at a constant frequency slightly below the participant's STF (STF = 0.125 Hz). Each hand was tested separately in a block of nine stimulations, and each block contained also three catch trials, in which no stimulation was given. Two blocks were performed per hand. Thus, the peripheral stimulation served as an additional control condition to verify that the tapping errors were caused by ipsilateral M1 stimulation rather than by sensory reafferences caused by the muscle twitch of the resting hand or because subjects were distracted from the task.

Interhemispheric Inhibition

In a separate session, IHI from the dominant to the ND-M1 and vice versa was measured during rest using a standard double-pulse paradigm (Ferbert et al., 1992). A test stimulus (TS) was delivered via the 70-mm coil with an intensity of 120% RMT as described above. In half of the trials, the TS was preceded by a conditioning stimulus (CS) delivered via a 50-mm figure of eight coil at the same intensities as used in the virtual lesion experiment (i.e., 85%, 90%, 95%, and 100% RMT) and with an ISI of 10 msec. To fit both coils on the subject's head, the CS coil was rotated such that the handle pointed 90° away from the nasion–inion line.

One block consisted of 5 single-pulse stimulations and 20 double-pulse stimulations (five for each CS intensity) in pseudorandomized order. The hemispheres were tested alternately for eight blocks in total. For each trial, the peak-to-peak amplitude of the MEP was determined. The individual MEP amplitudes were averaged for each hemisphere and condition. The percentage of IHI was calculated by %IHI = (nonconditioned MEP − conditioned MEP) / nonconditioned MEP × 100. Background EMG was determined as the root mean square error value of the EMG signal 50 msec before the TMS stimulation. Trials were excluded for further analysis if background EMG was too high (>5 μV) or on the rare occasion that one stimulator did not discharge. With this experimental protocol, we tested whether the stimulation intensities used in the virtual lesion experiment caused differential transcallosal effects as measured at rest.

Data Analysis

The percentage of induced disruptions were calculated as the ratio of the induced disruptions over the number of stimulations for each condition multiplied by 100%. Therefore, the EMG recordings and kinematics were analyzed to determine whether a disruption in the unimanual tapping pattern was induced by TMS or electrical stimulation. Disruption, that is, missing a tap, tapping with the wrong finger, or switching to another pattern, was defined as the time point when the tap of a finger (e.g., thumb) would be closer to the tap of the alternating (index/ring) finger than to the synchronized (middle) finger (Figure 1) as indicated by strong deviations from the metronome rhythm when the tapping frequency was analyzed separately for each finger (Supplementary Figure 1). If this disruption occurred within 1 sec after stimulation, it was defined as a TMS-induced disruption, otherwise it was defined as a spontaneous disruption. More specific analysis details are described in van den Berg et al. (2010).

A laterality quotient (LQ) was calculated for the STF, the percentage of induced disruptions by TMS, and the disruptions induced by peripheral stimulation to reveal the ratio between the left and right hand in the different handedness groups. The LQs were calculated by LQ = (XtappingRXtappingL)/(XtappingR + XtappingL), where X denotes STF, the percentage of disruptions induced by TMS, or the percentage of disruptions induced by peripheral stimulation, respectively. Thus, a positive LQ for the STF indicates that the tapping speed was higher for the right than for the left hand. A positive LQ for the percentage of TMS-induced disruptions (averaged across all stimulation frequencies) indicates that more disruptions were observed when the right hemisphere was stimulated while the right hand was tapping than when the left hemisphere was stimulated while the left hand was tapping. Finally, a positive LQ for disruptions induced by peripheral stimulation of the median nerve indicates that more disruptions were observed when the left hand was stimulated while the right hand was tapping than when the right hand was stimulated while the left hand was tapping.

Statistical Analysis

Differences in RMT were tested by an ANOVA for repeated measurements (repeated measures ANOVA) with the factors hemisphere (D-M1, ND-M1) and group (left-handed participants, right-handed participants). Differences in STF were tested by a repeated measures ANOVA with the factors hand (dominant hand [DH], nondominant hand [NDH]) and group (left-handed participants, right-handed participants). Differences between disruptions evoked by TMS over D-M1 versus ND-M1 (factor hemisphere) were tested with a repeated measures ANOVA, with the within-subject factors intensity (85%, 90%, 95%, 100% RMT) and the between-subject factor group (left-handed participants, right-handed participants). Planned comparisons were used to analyze the differences in induced disruptions between sham TMS, realTMS (100% RMT), and peripheral stimulation in left and right handers. IHI was analyzed by a repeated measures ANOVA with the factors hemisphere (D-M1, ND-M1), intensity (85%, 90%, 95%, 100% RMT), and group (left-handed participants, right-handed participants).

The level of significance was set to α = 0.05, and Fisher's least significant difference was used for further post hoc testing. Group results are reported by means and standard deviations.

RESULTS

Stimulation Intensities and Tapping Frequencies

No significant differences were found in RMT between the nondominant (47.9% ± 8.4%) and dominant (46.9% ± 8.6%) hemisphere (F(1, 22) = 1.94, p = .17) or between the left-handed (47.6% ± 7.7%) and right-handed participants (47.2% ± 9.2%, F(1, 22) = 0.01, p = .91). The ANOVA for STF showed a significantly higher STF for the dominant hand (1.3 ± 0.35 Hz) compared with the nondominant hand (1.2 ± 0.35 Hz, F(1, 22) = 33.0, p < .01). Additionally, the LQ calculated for the STF differed significantly between right handers (positive LQSTF) and left handers (negative LQSTF; Table 1).

Table 1. 

Overview of the Data (Mean ± SD) for the Right-handed and Left-handed Participants


Right Handed
Left Handed Left (Nondominant) Hemisphere Group
Left Handed Right (Dominant) Hemisphere Group
Left Handed (Pooled across Subgroups)
Age (years) 22 ± 3 24 ± 3 23 ± 2 23.4 ± 2.4 
Sex (male/female) 6/6 3/3 3/3 6/6 
Oldfield 92 ± 10** −86 ± 13 −97 ± 7 −91.5 ± 11.5 
STF (Hz) 
 LQ 0.035 ± 0.023** −0.04 ± 0.02 −0.05 ± 0.05 −0.04 ± 0.04 
 Tapping R 1.2 ± 0.3 1.2 ± 0.35 1.3 ± 0.35 1.35 ± 0.35 
 Tapping L 1.1 ± 0.3 1.5 ± 0.35 1.45 ± 0.41 1.45 ± 0.35 
RMT (% maximum stimulator output) 
 L hemisphere 46.8 ± 9.8 52.2 ± 9 44.2 ± 5 48.2 ± 8.1 
 R hemisphere 47.7 ± 9 49.5 ± 8.5 44.7 ± 6.8 47.1 ± 7.7 
Disruption TMS (%) 
 LQ −0.4 ± 0.3 −0.4 ± 0.3 0.3 ± 0.2** 0.05 ± 0.4 
 Tapping R 8.6 ± 3.8 10.9 ± 7 25.5 ± 8.9 18.2 ± 19.1 
 Tapping L 20.6 ± 9.8 21.8 ± 9.6 12.5 ± 2.8 17.7 ± 17.5 
Disruption medial nerve (%) 
 LQ −0.11 ± 0.33 −0.24 ± 0.47 0.2 ± 0.29* −0.02 ± 0.4 
 tapping R 18.2 ± 11.1 19.8 ± 15.5 26 ± 10 22.9 ± 12.9 
 tapping L 20.3 ± 9.3 28.1 ± 18 16.7 ± 7 22.4 ± 14.2 
Familial sinistrality – 33% 66% 50% 

Right Handed
Left Handed Left (Nondominant) Hemisphere Group
Left Handed Right (Dominant) Hemisphere Group
Left Handed (Pooled across Subgroups)
Age (years) 22 ± 3 24 ± 3 23 ± 2 23.4 ± 2.4 
Sex (male/female) 6/6 3/3 3/3 6/6 
Oldfield 92 ± 10** −86 ± 13 −97 ± 7 −91.5 ± 11.5 
STF (Hz) 
 LQ 0.035 ± 0.023** −0.04 ± 0.02 −0.05 ± 0.05 −0.04 ± 0.04 
 Tapping R 1.2 ± 0.3 1.2 ± 0.35 1.3 ± 0.35 1.35 ± 0.35 
 Tapping L 1.1 ± 0.3 1.5 ± 0.35 1.45 ± 0.41 1.45 ± 0.35 
RMT (% maximum stimulator output) 
 L hemisphere 46.8 ± 9.8 52.2 ± 9 44.2 ± 5 48.2 ± 8.1 
 R hemisphere 47.7 ± 9 49.5 ± 8.5 44.7 ± 6.8 47.1 ± 7.7 
Disruption TMS (%) 
 LQ −0.4 ± 0.3 −0.4 ± 0.3 0.3 ± 0.2** 0.05 ± 0.4 
 Tapping R 8.6 ± 3.8 10.9 ± 7 25.5 ± 8.9 18.2 ± 19.1 
 Tapping L 20.6 ± 9.8 21.8 ± 9.6 12.5 ± 2.8 17.7 ± 17.5 
Disruption medial nerve (%) 
 LQ −0.11 ± 0.33 −0.24 ± 0.47 0.2 ± 0.29* −0.02 ± 0.4 
 tapping R 18.2 ± 11.1 19.8 ± 15.5 26 ± 10 22.9 ± 12.9 
 tapping L 20.3 ± 9.3 28.1 ± 18 16.7 ± 7 22.4 ± 14.2 
Familial sinistrality – 33% 66% 50% 

Parameters that were significantly different in one group when compared with the others are indicated by **p < .05 or *p ≤ .08, t ≥ 1.94.

TMS-Induced Disruptions

TMS induced significantly more disruptions in ipsilateral unimanual movements when applied over the dominant motor cortex (19.4 ± 19.4%) than over the nondominant motor cortex (13.2 ± 15%, F(1, 22) = 5.2, p < .05). Moreover, this effect was specifically seen in right handers, as indicated by a Hemisphere × Group interaction (F(1, 22) = 4.4, p < .05) and post hoc tests (p < .05), which confirmed that the percentage of disruptions was significantly higher when TMS was applied over the dominant motor cortex compared with nondominant motor cortex. By contrast, left handers showed no hemispheric differences (p = 1.00). A main effect was also found for Intensity (F(3, 66) = 25.5, p < .01), and post hoc tests revealed that significantly more disruptions were induced with an intensity of 100% RMT than with all other intensities. However, this effect was driven by the right-handed group, who were most strongly affected when TMS was applied over the dominant (left) hemisphere at 100% RMT (Figure 2). By contrast, no difference between hemispheres was observed in the left-handed participants, not even at the highest stimulation intensity. This was confirmed by the ANOVA revealing a three-way interaction of Hemisphere × Intensity × Group (F(3, 66) = 3.5, p < .05). Significantly, more disruptions were induced with TMS stimulation at an intensity of 100% RMT than if lower intensities were used (p < .001 post hoc test). In the left-handed participants, this intensity effect was comparable in both hemispheres (p < .05 for both hemispheres), whereas in right-handed participants, this increase was only observed when TMS was applied over their dominant (left) M1 (p < .01), but not when applied over the nondominant (right) M1 (p = 1.00, post hoc test). Importantly, only TMS at the highest intensities induced more disruptions than sham TMS (p < .05) or median nerve stimulation (p < .05). For right-handers, this effect was only found when TMS was applied over the D-M1 (Figure 2). Surprisingly, median nerve stimulation induced significantly more disruptions than sham TMS for all conditions (p < .05), indicating that sensory afferences have a relatively strong influence on the tapping task of the contralateral hand.

Figure 2. 

Mean percentage of induced disruptions by TMS applied over the D-M1 or ND-M1 during ipsilateral hand movement in left and right handers. TMS pulses were applied with intensities ranging from 85% to -100% of RMT, and significant differences across intensities are indicated by * (p < .05). In addition, mean percentage of induced disruptions for sham TMS and peripheral stimulation are shown. Significant differences when real TMS stimulation was compared with sham TMS and the peripheral stimulation control condition for each of the four Group × Hemisphere combinations are indicated by ▴ (post hoc test, p < .05). Significant differences between sham and peripheral conditions are indicated by •. Vertical lines represent standard deviations.

Figure 2. 

Mean percentage of induced disruptions by TMS applied over the D-M1 or ND-M1 during ipsilateral hand movement in left and right handers. TMS pulses were applied with intensities ranging from 85% to -100% of RMT, and significant differences across intensities are indicated by * (p < .05). In addition, mean percentage of induced disruptions for sham TMS and peripheral stimulation are shown. Significant differences when real TMS stimulation was compared with sham TMS and the peripheral stimulation control condition for each of the four Group × Hemisphere combinations are indicated by ▴ (post hoc test, p < .05). Significant differences between sham and peripheral conditions are indicated by •. Vertical lines represent standard deviations.

Additionally, we performed an analysis to correlate behavioral asymmetries, BA = (STFND − STFD)/(STFND + STFD), and hemispheric disruption asymmetries, HDA = (%DISRND-M1 − %DISRD-M1)/(%DISRND-M1 + %DISRD-M1), using the total percentage of disruptions (%DISR) for the dominant (D-M1) and nondominant hemisphere (ND-M1). The ratios were calculated the same way as described in Verstynen et al. (2005). However, there was no significant correlation between HDA and BA (overall: r = −0.1376, p = .5213; right-handers: r = −0.2883, p = .3635; left-handers: r = −0.0002, p = .9996), indicating that hemispheric asymmetries did not predict behavioral asymmetries.

Two Subgroups in the Left-handed Participants

Closer inspection of the individual results of the left-handed participants (Supplementary Table 1) revealed that there were two subgroups, such that one group (6 participants; left (nondominant) hemisphere group) was more easily disrupted when stimulating the nondominant, left M1, whereas the other group (6 participants; right (dominant) hemisphere group) exhibited more disruptions when stimulating the dominant, right M1. We performed an extra ANOVA comparing the two subgroups of the left-handed participants (left (nondominant) hemisphere group, right (dominant) hemisphere group). A significant Hemisphere × Subgroup interaction (F(1, 9) = 26.1, p < .01; Figure 3) was found, indicating that in the right (dominant) hemisphere group (D group) significantly more disruptions were induced when the dominant than when the ND-M1 was stimulated whereas in the left (nondominant) hemisphere group (ND group) the reverse relationship was seen (post hoc; p < .05). This was further confirmed by significantly different LQ values calculated for TMS-induced disruptions (Table 1), which were positive for the right (dominant) hemisphere group (i.e., more disruptions when the right hemisphere was stimulated) and negative for the left (nondominant) hemisphere group (i.e., more disruptions when the left hemisphere was stimulated; p < .05). The same tendency was seen for the LQ calculated for disruptions induced by peripheral stimulation; however, this trend did not reach significance (p ≤ .08, t ≥ 1.94). Other parameters, however, such as the Oldfield score, the STF of the left versus right hand, or the RMT did not differ significantly between the two subgroups (Table 1).

Figure 3. 

Mean percentage of induced disruptions by TMS applied over the D-M1 and ND-M1 in the left-handed subgroups. Significant differences are indicated by * (post hoc test, p < .05). Vertical lines represent standard deviations.

Figure 3. 

Mean percentage of induced disruptions by TMS applied over the D-M1 and ND-M1 in the left-handed subgroups. Significant differences are indicated by * (post hoc test, p < .05). Vertical lines represent standard deviations.

In summary, our data indicated that disruptions of ipsilateral movements were induced most frequently when TMS was applied over the dominant (left) hemisphere in right handers. Half of our left handers exhibited the same hemispheric asymmetry, whereas the other half was a “mirror image” of the right handers such that more disruptions were induced by stimulating their dominant right hemisphere while performing the movement task with the right hand. Importantly, TMS-induced disruptions differed only from sham TMS and medial nerve stimulation when an intensity of 100% RMT was applied, but not for subthreshold intensities.

Interhemispheric Inhibition

Next, we tested whether transcallosal effects were induced when TMS was applied at subthreshold intensities while subjects were at rest. Note that IHI measured at rest seems to reflect the general transcallosal organization between the primary motor cortices (Wahl et al., 2007). When data were pooled across hemispheres and groups, significant IHI was found for each CS intensity (p < .05, single-sample t test). However, this overall effect was mainly driven by the left-handed participants, which had a significantly higher IHI (23.6% ± 22.1%) than right handers (9.4% ± 26.3%; group effect [F(1, 22) = 5.2, p < .05] averaged across all intensities). Additionally, IHI was largest when the CS was applied at 100% RMT, which differed significantly from all other subthreshold CS intensities (main effect of intensity [F(3, 66) = 6.3, p < .01] and post hoc tests, p < .05; Figure 4). Surprisingly, statistics revealed no significant differences in IHI when the CS was applied to the dominant hemisphere as compared with the nondominant hemisphere (no significant main effect or interactions including the factor hemisphere; F(1, 22) = 0.5, p = .47).

Figure 4. 

Mean percentage of IHI for the left and right handers. CS intensities ranged from 85% to 100% RMT. Significant differences are indicated by * (post hoc test, p < .05). Vertical lines represent standard deviations.

Figure 4. 

Mean percentage of IHI for the left and right handers. CS intensities ranged from 85% to 100% RMT. Significant differences are indicated by * (post hoc test, p < .05). Vertical lines represent standard deviations.

However, when we performed a separate analysis to compare the two subgroups of the left handers only, ANOVA revealed for the right (dominant) hemisphere group that IHI from the nondominant left M1 to the dominant right M1 was larger than vice versa, when high CS intensities (95% and 100% RMT) were used (Hemisphere × Intensity × Group interaction; F(3, 27) = 3.5, p < .05; Figure 5). No such differences were observed for the left (nondominant) hemisphere group.

Figure 5. 

Mean percentage of IHI for the left-handed subgroups. Significant differences are indicated by * (post hoc test, p < .05). Vertical lines represent standard deviations.

Figure 5. 

Mean percentage of IHI for the left-handed subgroups. Significant differences are indicated by * (post hoc test, p < .05). Vertical lines represent standard deviations.

Descending Volley of the Corticospinal Pathways

Finally, we investigated whether disruptions were more frequent when the TMS stimulation evoked a corticospinal volley. There was no evidence that TMS-induced MEPs in the ipsilateral, tapping hand. However, TMS induced frequently MEPs in the contralateral, resting hand. In an additional analysis, we pooled all data (but excluding sham TMS trials) across stimulation intensities and hemisphere within each participant. For all trials in which TMS induced a disruption in the ipsilateral hand, the median MEP amplitude was determined and compared with the median MEP amplitude calculated across all trials. A group analysis (dependent t test across all participants irrespective of their handedness) revealed that median MEP amplitudes in the nonmoving contralateral hand were significantly larger for ipsilateral disruption trials than when all trials were pooled (Figure 6). Moreover, data were pooled across participants, and a logistic regression revealed that the MEP amplitude measured in the contralateral, resting hand predicted ipsilateral TMS induced disruptions to a significant amount (χ2 = 21, p < .00001). Next, we tested whether the probability of inducing disruptions in the ipsilateral, tapping hand depended on the MEP size evoked in the contralateral, resting hand. MEPs were categorized based on their peak-to-peak amplitudes into small (<0.1 mV), medium (between 0.1 and 0.75 mV) or large (>0.75 mV), whereby the latter is likely to induce a perceivable switch in the resting hand. We calculated the percentage of induced disruptions separately for each MEP size category and each subject and subjected these data to a repeated measures ANOVA. We found that the percentage of induced disruptions increased with the MEP amplitude (Figure 6B; F(2, 38) = 7.47, p < .01), and Bonferroni post hoc tests revealed that significantly more disruptions occurred when large than when small MEPs were evoked (p < .001).

Figure 6. 

(A) Mean median MEP amplitude for the disruption trials as compared with all TMS stimulation trials (except sham). * indicates a significant difference (dependent t test, p < .05). (B) Mean percentage of induced disruptions for the MEP size categories small, medium, and large. ** indicates a significant difference (post hoc test, p < .001).

Figure 6. 

(A) Mean median MEP amplitude for the disruption trials as compared with all TMS stimulation trials (except sham). * indicates a significant difference (dependent t test, p < .05). (B) Mean percentage of induced disruptions for the MEP size categories small, medium, and large. ** indicates a significant difference (post hoc test, p < .001).

In summary, our analyses indicate that a disruption of the ipsilateral, tapping hand was more likely to occur when pyramidal neurons of the crossed corticospinal tract were strongly activated by TMS.

DISCUSSION

In the present study, we used disruptive TMS to evaluate hemispheric asymmetries concerning the involvement of the ipsilateral M1 in complex unimanual control. We tested left-handed participants to investigate whether these asymmetries would support the “left hemispheric specialization” hypothesis, that is, that specifically the left hemisphere exerts ipsilateral control during finger movements of both hands or the “hand dominance hypothesis” such that mainly the motor dominant hemisphere contributes to ipsilateral control. The present study shows that TMS stimulation applied over the dominant left M1 induced more disruptions in complex ipsilateral unimanual movements than TMS over the nondominant right M1, in all right-handed participants. The novel finding is that this hemispheric asymmetry was much more variable in left-handed participants who were categorized according to two subgroups: One group showed more disruptions when TMS was applied over the nondominant, left M1, whereas the other group showed more disruptions when TMS was applied over the dominant, right M1, suggesting that handedness as well as left hemispheric specialization contribute to the involvement of the ipsilateral M1 in unimanual movements.

These hemispheric asymmetries did not result from sensory reafferences deriving from the muscle twitch induced in the resting hand, because peripheral stimulation of the median nerve induced significantly less disruptions than TMS over M1. Also IHI as measured at rest exhibited no plausible relation with the observed hemispheric asymmetries, suggesting that the disruptive effect of stimulating ipsilateral M1 does not result from transcallosal spread of the induced brain activity. However, disruptions of ipsilateral movements were more likely to occur when TMS was strong enough to activate the crossing corticospinal tracts such that an MEP was elicited in the resting hand.

Hemispheric Asymmetries in Right and Left Handers

Previous studies concerning ipsilateral activation in right-handed participants (Hayashi et al., 2008; Verstynen et al., 2005; Kobayashi et al., 2003; Nirkko et al., 2001; Solodkin et al., 2001; Singh, Higano, Takahashi, Kurihara, et al., 1998; Chen et al., 1997; Kim et al., 1993) are in line with our result that the dominant left M1 is more involved in controlling complex, ipsilateral hand movements than the nondominant right M1. This view is also consistent with TMS studies showing that corticomotor excitability of the ipsilateral M1 is more strongly increased in the left than in the right hemisphere when measured in right-handed participants that perform a complex but not a simple finger sequence task (Ziemann & Hallett, 2001). By contrast, in left-handed participants, studies are inconsistent about the role of the primary motor cortex in ipsilateral hand movements, and results are less consistent than the results for right-handed participants. Kawashima et al. (1997) showed ipsilateral activation of the dominant hemisphere during movements of the nondominant right hand in left-handed participants; thus, compared with right-handed participants, they showed a mirrored hemispheric asymmetry. In contrast, Verstynen et al. (2005) and Kim et al. (1993) tested right-handed as well as left-handed subjects and reported that the left hemisphere was considerably more activated than the right hemisphere during movements with the ipsilateral hand, suggesting that the left hemisphere has a substantial role in unimanual motor control irrespective of hand dominance. However, both above studies and the experiment of Solodkin et al. (2001) reported that left-handed participants show less lateralization than right-handed participants during complex movements. Interestingly, Singh, Higano, Takahashi, Kurihara, et al. (1998) revealed that left handers exhibited bilateral activation during a unimanual task irrespective of which hand was used. By inspecting the individual data of Singh, Higano, Takahashi, Kurihara, et al. (1998), it can be seen that half of the left-handed participants showed a trend to more ipsilateral activation during the right hand task, whereas two other left-handed participants revealed more ipsilateral activation during the left hand task. Our results correspond with this subdivision of the left-handed participants, suggesting that the hemispheric asymmetry of the motor system is influenced by both a potential specialization of the left hemisphere for motor control and hand dominance. Moreover, the present results extend previous imaging work because our disruptive TMS approach revealed a causal link between M1 activity and the control of finger movements executed with the ipsilateral hand indicating that asymmetries of the motor system are functionally relevant. Currently, little is known about which factors determine hemispheric asymmetries in left-handed participants. Previous research found similar subgroups when left-handed participants performed a visually guided grasping task and suggested that hand preference is related to language lateralization (Gonzalez & Goodale, 2009). In right handers and most left handers, language is lateralized to the left hemisphere. However, in 10–27% of the left-handed population, this asymmetry is reversed and it was shown that language related activity of the right hemisphere increases with the degree of left handedness (Knecht et al., 2000; Pujol, Deus, Losilla, & Capdevila, 1999).

Our left-handed participants could be divided into two subgroups, such that in half of the participants complex finger tapping with the ipsilateral hand was more easily disrupted when the left than when the right hemisphere was stimulated, whereas the opposite asymmetry was found in the other half of the subjects. Other parameters like gender, age, and RMT did not differ between the subgroups. More importantly, STF, a parameter reflecting the tapping performance for each hand, as well as the LQ between hands did not differ significantly between the subgroups (Table 1). However, left handers that were more disruptable over their dominant, right M1 had a larger percentage of familial sinistrality (although this difference did not reach significance), suggesting that genetics might have some influence. Moreover, only for the left-handed subgroup that was more disruptable when the right (dominant) hemisphere was stimulated, IHI exhibited an asymmetry between hemispheres, such that more IHI was found from the nondominant to the dominant hemisphere than vice versa when measured with a CS of 95% and 100%. By contrast, in the other subgroup of the left-handed participants and in the right-handed participants, there were no substantial asymmetries between hemispheres (see below).

Potential Mechanisms Underlying Hemispheric Asymmetries of the Ipsilateral M1 in Unimanual Movements

Previous research suggested that hemispheric asymmetries might emerge at different levels of the nervous system (which are not necessarily mutually exclusive).

First, areas upstream from M1 and most notably parietal and premotor areas have been shown to exhibit functional asymmetries in humans. In right handers, it has been frequently reported that the superior parietal cortex and the dorsal premotor cortex of the left but not of the right hemisphere are strongly activated even when complex motor tasks are executed with the ipsilateral hand (Callaert et al., in press; Swinnen et al., 2010; Verstynen et al., 2005; Haaland et al., 2004; Singh, Higano, Takahashi, Abe, et al., 1998). Moreover, work in patients experiencing left hemispheric lesions has suggested that the left hemisphere contains general movement formulas or praxicons for unimanual movements of either hand (Haaland, 2006; Rushworth, Nixon, Wade, Renowden, & Passingham, 1998). Particularly, the premotor areas might regulate the involvement of ipsilateral M1 because they have dense connections to the M1 of either hemisphere and also to the spinal cord. Only a few studies have investigated hemispheric lateralization in left-handed participants using functional imaging (Solodkin et al., 2001; Dassonville, Zhu, Uurbil, Kim, & Ashe, 1997), but to our best knowledge, there are currently no data available about hemispheric asymmetries of higher-order motor areas in left-handed participants.

Second, the M1s of both hemispheres are connected via transcallosal fibers, and it is very likely that this is the major pathway mediating the contribution of ipsilateral M1 in movement control. However, it is also possible that the strength of these interhemispheric connections is asymmetric and, thus, constitutes the anatomical substrate underlying hemispheric asymmetries as described in our study. Several studies investigated whether IHI exhibits hemispheric asymmetries, that is, whether IHI differs when measured from the dominant to the nondominant hemisphere and vice versa. However, when IHI was measured at rest, these studies revealed inconsistent results. Some reported for right-handed participants that the dominant motor cortex exerts a greater inhibitory effect on the nondominant motor cortex than vice versa (Baumer et al., 2007; Netz, 1999; Netz et al., 1995), whereas others found no significant hemispheric differences (De Gennaro et al., 2004; Salerno & Georgesco, 1996). This suggests that potential interhemispheric asymmetries at rest are rather small, exhibit relatively large interindividual variability, and/or depend strongly on the used methodology (e.g., the intensity of the conditioning and the TS). Also our study revealed no significant hemispheric asymmetries of IHI except for one subgroup of six left-handed participants who exhibited more inhibition from the nondominant left M1 to the dominant right M1 than vice versa. However, these results need to be interpreted with care, because it is only based on six participants and difficult to reconcile with the disruption results, which would have predicted the opposite asymmetry. Most importantly, IHI measured at rest seems to reflect the general transcallosal organization between the primary motor cortices (Wahl et al., 2007) but might not be representative of the dynamic modulations of interhemispheric communication occurring during a motor task. Others have measured IHI during isometric contractions (i.e., a simple form of motor activity) but found no hemispheric asymmetries (Nelson, Hoque, Gunraj, Ni, & Chen, 2009). Finally, Duque et al. (2007) investigated the dynamic modulation of IHI during the preparation of unimanual motor responses in right handers. They showed that inhibition from the active motor cortex to the nonactive (ipsilateral) motor cortex increases at the beginning of a unimanual movement, independent of which hand prepares the movement. By contrast, inhibition exerted from the nonactive motor cortex to the active motor cortex decreased shortly before movement onset and even turned into facilitation, but only when the dominant hand was used (Duque et al., 2007). The authors argued that this contribution of the nondominant hemisphere might increase dexterity of the dominant hand. This view is inconsistent with our results, because we found that the dominant hemisphere played a prominent role in ipsilateral control in most of our participants. However, IHI during motor preparation might reflect other principles than during the control of ongoing movement, for example, because proprioceptive input is only processed in the latter situation. In summary, it is possible that hemispheric asymmetries of ipsilateral M1 involvement result from asymmetries in IHI, but currently this idea receives little experimental support, partly because it is a methodological challenge to measure IHI reliably against the background of a complex motor task.

Third, ipsilateral control could be exerted via uncrossed descending cortico-spinal fibers that project from the primary motor cortex directly to the ipsilateral hand, because it was shown that connection strength is stronger for one hemisphere than the other. Strutton et al. (2004) and Kagerer et al. (2003) quantified ipsilateral MEPs that were evoked when participants were at rest. Interestingly, these authors reported a hemispheric difference, such that larger ipsilateral MEPs were elicited when TMS was applied over the dominant than over the nondominant hemisphere of right-handed participants. Thereby, the uncrossed ipsilateral projections seem to exhibit hemispheric asymmetries, although it is not clear whether these pathways play a relevant role in movement control (Carson, 2005). In summary, all three levels of the nervous system might have contributed to the hemispheric differences observed in our study. However, the currently available evidence from mostly right-handed participants suggests that the functional asymmetries with respect to ipsilateral M1 involvement in motor control derive from higher-order areas and most from premotor cortex. Future studies might resolve this issue by testing left-handed participants.

In our study, we tried to disentangle the contribution of uncrossed, ipsilateral projections versus trancallosal pathways in mediating the influence of ipsilateral M1. Therefore, we applied TMS at subthreshold intensities following the rational that transcallosal interneurons have a lower stimulation threshold than pyramidal neurons of the corticospinal tract (Di Lazzaro et al., 1998). We hypothesized that the involvement of an uncrossed corticospinal pathway would be ruled out if even low-intensity TMS would induce more disruptions than the control conditions. Our data did not support this hypothesis because only TMS at the highest intensity (100% RMT) induced significantly more disruptions than sham control and medial nerve stimulation. There was no indication that TMS at 100% RMT induced ipsilateral MEPs, but this was not completely unexpected because MEPs are difficult to distinguish from the continuously changing EMG bursts of the tapping hand. However, disruptions of the ipsilateral hand were more likely to occur when a MEP was evoked in the resting contralateral hand, that is, when the TMS pulse was strong enough to result in a depolarization of (at least) crossed pyramidal neurons. This result does not allow us to decide whether the disruptive effect was mediated via ipsilateral or transcallosal pathways. However, it suggests that ipsilateral control is exerted by interneurons with strong facilitating synapses to pyramidal neurons or by pyramidal neurons themselves as opposed to inhibitory intracortical circuits that are believed to be also activated by subthreshold intensities.

Conclusions

The present study showed that for right-handed participants the dominant (left) M1 was strongly involved in controlling ipsilateral, complex unimanual movements. Interestingly, for left-handed participants the results were more divergent, as two subgroups could be distinguished: one showing a stronger involvement of the (nondominant) left M1 and the other showing a stronger involvement of the dominant (right) M1. Accordingly, we can conclude that the functional asymmetries found for M1 involvement in controlling ipsilateral movements are influenced by both hand dominance and a left hemisphere specialization for unimanual movement control.

Acknowledgments

This article was supported by research grant G.0577.06 and G.0758.10 from the fund for Scientific Research-Flanders (FWO-Flanders) and the K.U. Leuven Research Council (CREA/07/037).

Reprint requests should be sent to Nicole Wenderoth, Motor Control Laboratory, Research Center for Movement Control and Neuroplasticity, Department of Biomedical Kinesiology, Group Biomedical Sciences, K.U. Leuven, Tervuursevest 101, B-3001 Leuven, Belgium, or via e-mail: Nici.Wenderoth@faber.kuleuven.be.

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