Abstract

Using transcranial magnetic stimulation (TMS), we addressed the contribution of both hemispheres to the visuomotor control of each hand. The subjects had to press one of two buttons as quickly as possible after the go-signal. A precue preceding this conveyed full, partial or no advance information (hand and/or button), such that reaction time (RT) shortened with increasing amount of information. We gave TMS over each hemisphere at various time intervals (100–350 ms) after the go-signal and before the expected onset of response, and measured its effect on RT, movement time (MT) and error rate. At short intervals (100–200 ms), left hemisphere TMS delayed RT and prolonged MT of both hands, while right hemisphere TMS delayed RT only of the right hand, without affecting error rates. At long intervals (250–350 ms), TMS produced slightly more pronounced RT delays of the contralateral hand. RT was delayed more if the precues were less informative. The results suggest the importance of interhemispheric transmission of visuomotor information for motor implementation. The right hemisphere may play a role mainly in calculating target and effector information, determining RT, while the left hemisphere may play a role in elaborating the motor program and determining MT.

Introduction

The left and right cerebral hemispheres play different roles in motor control. Early studies showed that left hemispheric lesions are more likely to produce apraxia, pointing to the left hemispheric dominance for programming motor skills in right-handers (Liepmann, 1920, 1977[1900]; de Ajuriaguerra et al., 1960; Kimura and Archibald, 1974; De Renzi et al., 1982; Goodglass and Kaplan, 1983; Haaland and Harrington, 1996). Later clinical studies, however, indicated that praxis function might be distributed more over both hemispheres, at least compared with language (De Renzi, 1989; Foundas et al., 1995; Leiguarda and Marsden, 2000; Hanna-Pladdy et al., 2001; Lausberg et al., 2003), whereas psychological studies have suggested that each hemisphere may exert differential control over the left and right hands depending on the specific requirements of the motor task. For example, left hand responses are generally faster than the right in reaction time (RT) tasks emphasizing rapid initiation of responses (Goodman and Kelso, 1980; Carson, 1989; Haaland and Yeo, 1989; Bradshaw et al., 1990; Carson et al., 1990, 1993, 1995). This latter finding has been ascribed to the greater participation of right hemisphere in spatial processing (see Discussion).

Despite the voluntary–automatic dissociation in apraxia (Liepmann, 1977[1900] ), recent studies have attempted to investigate the ecological implication of apraxia by specifying aspects of action planning to which each hemisphere might contribute (Hanna-Pladdy et al., 2002, 2003). Such attempts are important since purposeful and efficient actions in daily life are selected and executed through continuous interaction with the outer environment; whereas some motor actions rely on advance information collected prior to the movement and stored in memory for some while, others may utilize visuospatial information collected online. Thus, different cortical processes may be invoked to realize the same motor action, involving the two hemispheres to different degrees contingent on the amount of advance information utilized for preparing the movement. One way to look into this problem is to evaluate the contribution of each hemisphere to the motor implementation of left and right hand responses that require processing of different amounts visuomotor information. By employing a precued variant of choice reaction time (PCRT) task (Rosenbaum, 1980; Goodman and Kelso, 1980), we addressed how the contribution of each hemisphere to motor actions executed by both hands varies according to the cognitive-motor demands of the task.

In this task, a precue conveying either no, partial or full information about the movement to be performed is given before the go-signal, with the result that RT to the go-signal shortens with increasing amount of advance information. To perform this task, information about both the effector (hand) and the target for movement has to be combined before the movement is made (Hoshi and Tanji, 2000). We applied TMS shortly after the go-signal and before the expected onset of response, to cause a transient disruption in cortical processing, and observed the resultant behavioral changes. If the task performance is delayed by TMS at a certain time, this should indicate that the focal cortical area just underneath the coil is then active and necessary for the task. By comparing the effect of TMS given at various time periods, we reasoned that we would be able to see how the physiological activities of those cortical regions evolve with time (Terao et al., 1998). In particular, we also investigated the contribution of the left and right hemispheres to motor control by measuring the difference in the effect of TMS on left and right hand responses when delivered over the left and right hemispheres.

Materials and Methods

Subjects

Ten normal subjects (9 male, 1 female, age 38.3 ± 2.2 years, range 30–51 years) were recruited for the present study. All were right-handed with an Edinburgh Handedness Score of 100 (Oldfield, 1971), with the exception of one male subject who scored −60 and primarily used the left hand in daily activities. Since we wanted to address motor control in right-handed subjects, we excluded this subject from the analysis. The experimental procedures were approved by the ethical committee of the University of Tokyo and performed according to the declaration of Helsinki. All subjects gave their written informed consent prior to participation.

Experimental Setup

A personal computer was used to control the visual stimulus presentation of the task and data acquisition in real-time, using Superlab Pro version 2 (Cedrus, San Pedro, USA). It could also trigger the magnetic stimulator at a programmed time after the visual stimulus. Visual stimuli (see below) were presented on a white background of a 15-inch monitor screen (Multiscan 17sf9, SONY, Tokyo, Japan) at a viewing distance of 50 cm. A response pad (RB-620, Cedrus, San Pedro, USA) was furnished with two home keys and two target buttons. The two home keys were positioned in the front row and two target buttons in the rear. An electronic switch connected to each home key recorded the time of release and that connected to each target button the time of button press with a resolution of 2 ms.

Task

We employed a variant of the precued choice reaction time (PCRT) task, originally developed by Goodman and Kelso (1980) and Rosenbaum (1980) and modified by Hoshi and Tanji (2002). The participants' task was to release the home key with the indicated hand (left or right) and to press the left or right target button of the response pad with that hand (Fig. 1A). The responses were fully specified by the go-signal. Before the onset of the go-signal, a precue was presented that conveyed full, partial or no information about the movement to be performed, i.e. the response hand or the button to press. In this paradigm, reaction time usually decreases with the amount of advance information, i.e. as the precue becomes more informative (Rosenbaum, 1980).

Figure 1.

Task procedure (A) and sites of TMS (B). Task procedure. A beep sound signaled the beginning of each trial. Two seconds after this, a precue was presented on the monitor screen for 500 ms, which provided the subjects either with no information about the button to be pressed (no information condition), partial information about either the button to be pressed (pb condition) or the hand to be used for pressing (ph condition), or information about both the button and hand (full information condition). After a random interval of 2–3 s, the go-signal prompted the subjects to release the home key with one of the hands, and to press the indicated target button (gray square) with the same hand. Reaction (RT) and movement times (MT) were measured respectively between the times of go-signal onset and button release, and between the times of home key release and target button press. Sites of TMS: 15 scalp positions centered on Cz were selected for TMS, either over the midline or over lines 5 cm to the left or right of it. Distances between these grid points were 2.5 cm in the antero-posterior direction. The lateral scalp positions were considered to represent the DLPFC, premotor, motor, APC and PPC regions.

Figure 1.

Task procedure (A) and sites of TMS (B). Task procedure. A beep sound signaled the beginning of each trial. Two seconds after this, a precue was presented on the monitor screen for 500 ms, which provided the subjects either with no information about the button to be pressed (no information condition), partial information about either the button to be pressed (pb condition) or the hand to be used for pressing (ph condition), or information about both the button and hand (full information condition). After a random interval of 2–3 s, the go-signal prompted the subjects to release the home key with one of the hands, and to press the indicated target button (gray square) with the same hand. Reaction (RT) and movement times (MT) were measured respectively between the times of go-signal onset and button release, and between the times of home key release and target button press. Sites of TMS: 15 scalp positions centered on Cz were selected for TMS, either over the midline or over lines 5 cm to the left or right of it. Distances between these grid points were 2.5 cm in the antero-posterior direction. The lateral scalp positions were considered to represent the DLPFC, premotor, motor, APC and PPC regions.

The go-signal dictated two movement variables, i.e. the hand (right or left) and the button to be pressed (right or left), in a spatially compatible manner; the square colored in gray of the upper two indicated the side of the button to be pressed. The photograph in the lower half showed the dorsal aspect of the hand and indicated the hand to be used for pressing the button.

There were four precue information conditions. In the full information condition, the precue was identical to the go-signal and specified both the button to be pressed and the hand to be used. In the partial hand (ph) condition, the precue specified the hand to be used but not the button. In this type of presentation, the upper two squares were left blank. In the partial button condition (pb), the precue provided information about the button to be pressed but not about the hand. In this type of precue, the lower photograph in the cue was left blank. In the no information condition, no advance information was provided. In this type of presentation, the upper two squares as well as the lower photograph were left blank. The precue was always valid, such that the information provided did not contradict that included in the go-signal. Both the go-signals and precues were presented over an area of 5.2 cm × 19.2 cm on the monitor screen, subtending a visual angle of ∼5.9° × 10.9°.

Transcranial Magnetic Stimulation (TMS)

TMS was delivered with a figure eight coil (inner diameter 8 cm, outer diameter 11.5 cm) connected to a magnetic stimulator (Magstim 200, Magstim, Welwyn Garden City, UK) to enable localized stimulation of the brain and to study the topography of effective regions with maximal spatial resolution (Wassermann et al., 1992; Wilson et al., 1993).

The coil was placed tangentially over the scalp, such that the induced current passed forward in the brain. First, we looked for the optimal scalp position (‘hand motor area’) over each hemisphere where the maximal motor evoked potential (MEP) could be elicited in contralateral first dorsal interossei (FDI) muscles. In most subjects, this point was usually located 5 cm to the left and right of the line connecting antitragi of both sides and running through Cz. We then determined the active motor threshold over the right hand motor area as the lowest stimulus intensity sufficient to elicit five MEPs of at least 50 μV over 10 consecutive trials while the subjects maintained 10% maximal voluntary contraction.

For the following experiments, we set the intensity of TMS 5–10% of maximal stimulus output of the stimulator above this threshold, which ranged from 35 to 65% (mean ± SEM = 48.3 ± 3.3%) in percentages of the maximal output. This intensity was selected to ensure physical stimulation of the cerebral structures and at the same time to minimize the intersensory facilitation accompanying TMS (see Terao et al., 1997, 1998, 2001).

TMS was delivered over the scalp at various time intervals between the go-signal and the expected onset of button release (termed the premovement period), i.e. 50, 100, 150, 200, 250, 300 and 350 ms after the go-signal. Employing the PCRT task, primate (Halsband and Passingham, 1982; Petrides, 1982; Murray and Wise, 1997; Riehle et al., 1997; Murray et al., 2000) and human neuroimaging studies with functional magnetic resonance imaging (fMRI) and positron emission tomography (PET; Deiber et al., 1991, 1996; Iacoboni et al., 1996; MacDonald et al., 2000; Passingham et al., 2000; Dasonville et al., 1997; Schumacher and D'Esposito, 2002; Adam et al., 2003) have delineated a network of cortical regions involved in motor preparation, including the parietal cortex, premotor cortex, primary motor cortex and prefrontal cortex of both hemispheres. On the other hand, midline cortical regions are engaged only minimally in the preparation and execution of visuomotor task, except for a small contribution of the supplementary motor cortex.

Based on these studies, 15 scalp positions were selected for stimulation (Fig. 1B). Over the midline, five points separated by 2.5 cm each were marked over the scalp centered on Cz. 5 corresponding grid points each were also marked over two lines 5 cm to the left and right of this. According to previous TMS and neuroimaging studies (Schluter et al., 1998, 2001), the lateral scalp regions were considered to cover the dorsolateral prefrontal cortex (DLPFC), premotor cortex, motor cortex, and anterior and posterior parietal cortices. The midline regions were considered to cover the presupplementary (preSMA) and supplementary motor areas (SMA) anteriorly and the midline parietal regions posteriorly, with Cz and a point 2.5 cm anterior to this corresponding to the approximate location of SMA.

In test trials, TMS was delivered over the lateral scalp regions of the left and right hemispheres at various time intervals. For control trials, we applied TMS over the midline region (midline TMS). Theoretically, RT in trials in which TMS was delivered off scalp could be used as the control RT. However, RT in off-scalp TMS trials was typically longer than that of test trials by about 50 ms, implying that it could not be used as control RT. This is probably because the additional scalp sensations evoked by TMS produce intersensory facilitation of reaction times (Terao et al., 1997). Having subjects perform the task while discharging TMS off scalp only controls for the click sound and not for intersensory facilitation induced by scalp sensations. Since midline cortical regions are presumably involved only minimally in motor preparation (see above), midline TMS trials were considered optimal for controlling intersensory facilitation; since this causes a similar sensation to lateral TMS with less effect on the cortical processes involved in the present task.

As an additional control for any cortical effects of midline TMS, we compared the effect of stimuli anterior or posterior to Cz. We reasoned that since anterior midline motor areas send some projections to the spinal cord (Dum and Strick, 1996), TMS over the midline frontal regions might affect RT more than TMS to posterior sites. In fact, the effect of TMS on RT, movement time (MT) and selection and response error rates was very similar across the five midline sites. This was comfirmed by a repeated measures ANOVA on RT, MT and selection and response error rates with three factors, time interval of TMS, site of stimulation (five levels), and response hand. Performance in midline TMS trials was not affected by the site of TMS [effect of site. RT: F(4,20) = 2.128, P = 0.0751; MT: F(4,20) = 1.194, P = 0.3162; selection error rate: F(4,20) = 1.234, P = 0.2940; response error rate: F(4,20) = 1.284, P = 0.2784], or its interaction with time interval [RT: F(20,100) = 1.298, P = 0.1698; MT: F(20,100) = 0.695, P = 0.8348; selection error rate: F(20,100) = 1.114, P = 0.3263; response error rate: F(20,100) = 0.503, P = 0.9665] or with hand [RT: F(4,20) = 0.322, P = 0.8634; MT: F(4,20) = 0.439, P = 0.7805; selection error rate: F(4,20) = 0.054, P = 0.9945; response error rate: F(4,20) = 0.061, P = 0.9932]. The interaction among these three factors also failed to reach significance [RT: F(20,100) = 0.388, P = 0.9973; MT: F(20,100) = 0.325, P = 0.9980; selection error rate: F(20,100) = 1.188, P = 0.2539; response error rate: F(20,100) = 1.138, P = 0.3023]. Selecting only three midline scalp locations, Cz and points 2.5 and 5 cm behind this, did not significantly change the results. Thus, midline TMS was considered not to affect the task performance and the data for the five midline locations were combined to give control performance (see Results).

Procedure

Before the test sessions, the subjects were given one or two practice sessions of 32 trials each (without TMS) until RT became stable. During this short practice, all subjects reached an overall performance level of >90% correct responses.

Each test trial started with a warning sound of 0.91 s duration. 2 s later, a precue was presented for 500 ms, followed by a delay period varying from 2 to 3 s to prevent anticipation. During these periods, the subjects were required to wait with their two index fingers resting on the home keys. The appearance of a go-signal prompted the subjects to release one of the hands from the corresponding home key and to press the indicated side of target button with the same hand. The subjects were asked to respond as quickly as possible making the best use of advance information, while avoiding error responses (see below). A quick response was also encouraged to exclude the confound of online movement correction (see Discussion). The go-signal was extinguished when a response was made or otherwise stayed on for 3 s. In either case, no feedback was given to the subjects and the next trial started with the warning sound 2 s after the extinction of go-signal when the screen turned blank. The non-indicated finger had to remain on the home key throughout each trial. The RT was measured between the onset of go-signal to the release of home key, and the MT was defined as the time from the release of the home key to the pressing of target button.

The following were considered error responses: responses with RT <100 ms or >900 ms, responses made before the go-signal was presented, responses made by the non-indicated hand and responses in which the wrong target button was pressed (the former three types were termed the time errors, and the latter two the selection and response errors). The frequency with which response errors occurred (error rate) was calculated by dividing the number of errors made by the total number of trials in the same block of session. We were interested in the selection and response error rates.

TMS was applied over one of 15 scalp positions and at one of the six time intervals, yielding a complete session comprising 90 blocks for each subject. Each block of test session consisted of 32 trials (4 information conditions × 4 response alternatives [2 hands × 2 target buttons] × 2 repetitions for each trial type) that lasted for 6–7 min. Thus, the trial number for each subject amounted to a total of 2880 (90 blocks × 32 trials). All variable parameters (precue conditions, interval of TMS, site of TMS) were counterbalanced across blocks of sessions as well as across subjects.

Data Analysis and Statistical Assessment

The main interest of the analysis was to study how TMS affected task performance in terms of RT, MT and error rates, in comparison with those of control trials.

All trials with errors (time, selection and response errors as defined above) were removed before the RT and MT analysis. Then, the mean RT and MT of trials in which TMS was delivered over the lateral scalp regions (test RT) were calculated for each task condition (2 hemispheres × 5 scalp positions × 4 information conditions × 2 response hands). Also, the mean RT and MT in control trials were calculated for the same TMS intervals. As described, control performance was defined as that when TMS was applied over the midline. The TMS effect, i.e. the delay of RT and prolongation of MT, was calculated by subtracting the control RT and MT from test RTs and MTs. The delay of RT and prolongation of MT was plotted against the site or the time interval of TMS, separately for the response hand or precue information, depending on the effect of interest.

The error analysis focused on whether TMS affected the selection and response error rates. We calculated the increase in error rate by subtracting the control error rates from the test error rates. Plots were also made as described above for the RT/MT analysis. Since the overall number of errors was small (up to 10% of the total trials), we combined the data separately for early (100–200 ms) and late (250–350 ms) TMS intervals where appropriate.

Data of six out of nine subjects who completed all the task conditions were used for statistical analysis. Three of subjects completed only those sessions in which the test TMS was delivered over the left hemisphere. The analysis addressed two aspects of TMS effect: first whether TMS significantly changed the performance relative to baseline (control trials), and second whether the performance differed among different combinations of stimulus condition (hemisphere, site and time of TMS), precue information, and the response hand. Repeated measures analysis of variance (ANOVA) was conducted with factors of hemisphere (left or right, or in some cases, left, right, or midline), site [DLPFC, premotor, motor, anterior parietal coertex (APC) and posterior parietal cortex (PPC) over both hemispheres) and time of TMS (100, 150, 200, 250, 300, 350 ms), response hand (left or right) and precue information condition (full, ph, pb, no). For each ANOVA, we selected two to three factors out of the five possible factors, which were considered appropriate for analysis. For all the behavioral analyses, the significance criterion was set at P < 0.05. Post-hoc analysis using Bonferroni/Dunn's correction for multiple comparisons was carried out to see what differences contributed to the significant differences detected by ANOVA.

Results

Performance in Control Trials

Selection Error Rate

The subjects released the wrong side of home key in 4.0 ± 1.1% (mean ± SEM) of the total trials. The error rate was significantly smaller for the full and ph than for the pb and no information conditions [Table 1A; F(3,15) = 9.829, P < 0.0001; no information, pb > ph, full information: P < 0.05 corrected for multiple comparisons]. Selection error rates of the left and right hands were similar [F(1,5) = 0.664, P = 0.5739].

Table 1

Baseline task performance (selection and response error rates in%)


 
no
 
pb
 
ph
 
Full
 
Total
 
(A) Selection error rate      
    Left hand 6.0 ± 1.3 6.4 ± 1.2 1.0 ± 0.5 1.4 ± 0.6 4.4 ± 1.2 
    Right hand 4.0 ± 0.9 5.4 ± 1.3 1.1 ± 0.5 1.9 ± 0.6 3.6 ± 1.0 
(B) Response error rate      
    Left hand 10.3 ± 1.2 10.1 ± 1.1 7.5 ± 1.1 8.6 ± 1.2 9.1 ± 1.2 
    Right hand
 
6.1 ± 0.9
 
8.7 ± 1.2
 
5.4 ± 0.8
 
6.0 ± 1.0
 
6.6 ± 1.0
 

 
no
 
pb
 
ph
 
Full
 
Total
 
(A) Selection error rate      
    Left hand 6.0 ± 1.3 6.4 ± 1.2 1.0 ± 0.5 1.4 ± 0.6 4.4 ± 1.2 
    Right hand 4.0 ± 0.9 5.4 ± 1.3 1.1 ± 0.5 1.9 ± 0.6 3.6 ± 1.0 
(B) Response error rate      
    Left hand 10.3 ± 1.2 10.1 ± 1.1 7.5 ± 1.1 8.6 ± 1.2 9.1 ± 1.2 
    Right hand
 
6.1 ± 0.9
 
8.7 ± 1.2
 
5.4 ± 0.8
 
6.0 ± 1.0
 
6.6 ± 1.0
 

(A) The frequency of error trials in which the subjects released the wrong side of home key are expressed as a percentage of the total trial number (selection error rate). The values give mean ± SEM (also in the following tables unless otherwise indicated). (B) The frequency of error trials in which the subjects pressed the wrong target button are expressed as a percentage of the total trial number (response error rate).

Response Error Rate

The subjects pressed the wrong target button in 7.8 ± 1.1% of the total trials. The error rate was slightly smaller in the ph and full information conditions than in the pb and no information conditions, but the difference did not reach significance (Table 1B). The error rate was significantly larger for left hand responses (9.1 ± 1.2%) than for right hand responses (6.6 ± 1.0%) [F(1,5) = 11.184, P = 0.0008].

Reaction Time

Consistent with the view that the participants made use of the precue information, RT decreased with increasing amount of precue information [F(3,15) = 260.311, P < 0.0001] (Table 2A).

Table 2

Baseline task performance (reaction and movement times in ms)


 
no
 
pb
 
ph
 
Full
 
Total
 
(A) Reaction time      
    Left hand 501.2 ± 13.5 500.0 ± 14.4 434.2 ± 12.8 391.1 ± 13.0 456.6 ± 13.4 
    Right hand 504.9 ± 19.7 493.0 ± 15.3 454.0 ± 18.1 411.1 ± 18.3 465.8 ± 17.8 
(B) Movement time      
    Left hand 186.0 ± 4.5 179.6 ± 3.8 184.3 ± 4.4 201.7 ± 9.4 187.9 ± 5.5 
    Right hand
 
174.7 ± 4.0
 
176.6 ± 4.5
 
176.9 ± 4.2
 
197.5 ± 11.6
 
181.4 ± 6.0
 

 
no
 
pb
 
ph
 
Full
 
Total
 
(A) Reaction time      
    Left hand 501.2 ± 13.5 500.0 ± 14.4 434.2 ± 12.8 391.1 ± 13.0 456.6 ± 13.4 
    Right hand 504.9 ± 19.7 493.0 ± 15.3 454.0 ± 18.1 411.1 ± 18.3 465.8 ± 17.8 
(B) Movement time      
    Left hand 186.0 ± 4.5 179.6 ± 3.8 184.3 ± 4.4 201.7 ± 9.4 187.9 ± 5.5 
    Right hand
 
174.7 ± 4.0
 
176.6 ± 4.5
 
176.9 ± 4.2
 
197.5 ± 11.6
 
181.4 ± 6.0
 

(A) Reaction times (RTs) are given under different precue conditions (no, pb, ph, and full information). (B) RTs in error trials were excluded from the analysis. Movement times (MTs) are given under different precue conditions. MTs in error trials were excluded from the analysis.

Overall, RT was slightly shorter for the left than for the right hand [F(1,5) = 8.103, P = 0.044]. More specifically, RT was slightly shorter for the left than the right hand in the more informative (full and ph precue) conditions but comparable for both hands in the less informative (pb and no precue) conditions [significant interaction between precue information and response hand; F(3,15) = 5.385, P < 0.0011].

Movement Time

The MT ranged approximately from 180 to 200 ms and was slightly but significantly longer in the full information condition [F(3,15) = 9.176, P < 0.0001] than in the other three precue conditions (Table 2B; P < 0.0001 with Bonferroni's correction). MT was similar for the left and right hands across all information conditions [main effect of hand: F(1,5) = 2.151, P = 0.1427].

TMS Effect on Error Rate

Selection and Response Error Rate

Overall, the selection and response error rates (left hand: 5.2 ± 0.1%, 9.7 ± 0.5%; right hand: 4.1 ± 0.1%, 6.4 ± 0.4%) were not significantly affected by TMS. The effect of TMS was similar across all the stimulus sites, time of TMS, or precue information. The error rates of the right and left hands were not significantly or differentially affected by TMS applied over the left or right hemisphere.

TMS Effect on Reaction Time

In contrast, TMS had a significant effect on RT and MT.

The Topography of the TMS Effect on RT

Figure 2A shows a typical result in one subject. Although the overall spatial effect of TMS was weak, at a short interval (100 ms), the effect of TMS on RT (i.e. delay of RT) was maximal over posterior locations (APC, PPC) of the left hemisphere. At 150 ms, it expanded also to anterior cortical regions (DLPFC) of both hemispheres. From 200 to 250 ms, the effect gradually subsided at all sites, and at 250 ms, there was no significant delay over any of the regions studied. At 300 ms, the induced delay was maximal over the motor cortex of the left hemisphere, but no local maxima of TMS effect was noted over the corresponding region of the right hemisphere. At 350 ms, TMS effect again was unremarkable at any site. Thus, a time dependent shift in effective regions was noted from posterior to anterior cortical regions, and finally to the left motor area. The same trend is also apparent in Figure 2B, where we pooled the data averaged for all precue conditions across all subjects since the time courses showed a similar trend for the four precue conditions [F(25,125) = 4.772, P < 0.0001]. Again, the effective site of TMS also shifted from posterior to anterior cortical regions with time when TMS was applied over the left and right hemispheres, with the latest effect over the motor cortex of the left hemisphere at 300–350 ms. Overall, however, the topographical effect of TMS was very small as compared to its temporal effect.

Figure 2.

Topographical effect of TMS on RT. In order to see how the topography of TMS effect changed with the time after the go-signal, data of both hands were pooled and the induced delay of RT was plotted as a function of stimulus location at different times of TMS in one subject (A) and for the data averaged across all subjects (B). TMS was applied over the left (left column) or right hemisphere (right column) at various time intervals (100–350 ms) after the go-signal presentation. In (A), data for the four precue conditions were plotted separately, whereas in (B) the four conditions were collapsed. Numbers on the abscissa denote: 1, dorsolateral prefrontal cortex; 2, premotor cortex; 3, motor cortex; and 4 and 5, the anterior and posterior parietal cortices. Asterisks indicate significant difference from baseline RT at P < 0.0001 corrected for multiple comparisons. Note that the TMS effect varied robustly with time but not much with the stimulus site.

Figure 2.

Topographical effect of TMS on RT. In order to see how the topography of TMS effect changed with the time after the go-signal, data of both hands were pooled and the induced delay of RT was plotted as a function of stimulus location at different times of TMS in one subject (A) and for the data averaged across all subjects (B). TMS was applied over the left (left column) or right hemisphere (right column) at various time intervals (100–350 ms) after the go-signal presentation. In (A), data for the four precue conditions were plotted separately, whereas in (B) the four conditions were collapsed. Numbers on the abscissa denote: 1, dorsolateral prefrontal cortex; 2, premotor cortex; 3, motor cortex; and 4 and 5, the anterior and posterior parietal cortices. Asterisks indicate significant difference from baseline RT at P < 0.0001 corrected for multiple comparisons. Note that the TMS effect varied robustly with time but not much with the stimulus site.

Time Course of the TMS Effect on RT

Since the effect of TMS did not vary greatly with the stimulus locations within each hemisphere, we collapsed the data for the five sites of each hemisphere and looked at the time course of the TMS effect in the two hemispheres. When TMS was applied over the left hemisphere (Fig. 3B), the overall delay of RT was most prominent 100–150 ms after the presentation of the go-signal, subsiding at 200–250 ms. A small effect appeared again at 300 ms [effect of time interval of TMS: F(5,25) = 27.802, P < 0.0001]. Similar phases could be seen when TMS was applied over the right hemisphere. In the following, we will term these two phases the early and late phases of the premovement period.

Figure 3.

Time course of TMS effect on RT. (A) Graphic illustration of the delay of RT induced in the left (left column) and right hand (right column) responses by TMS delivered at various times (100–350 ms from top to bottom figures). The circles at each stimulus location has a diameter proportional to the delay of RT induced by TMS, and are also color coded according to the delay. (For key, see the panel linked to the bottom right of this figure.) Note that during the early phase of premovement period, RT of the right hand is delayed by TMS over both hemispheres, whereas RT of the left hand is delayed by TMS over the left hemisphere only. (B) The RT delay induced by TMS was plotted as a function of the time of stimulation, separately for TMS over the left (black curve) and right hemispheres (gray curve). Data for all sites of stimulation (DLPFC, premotor, motor, APC and PPC) and for both hands were pooled. Asterisks indicate significant difference from baseline. Error bars indicate standard errors (also in the following). (C) RT delay induced in the left and right hand responses when TMS was applied over the left hemisphere. The black curve is for left hand responses, and the gray curve is for right hand responses. (D) A similar plot as (C) when TMS was applied over the right hemisphere.

Figure 3.

Time course of TMS effect on RT. (A) Graphic illustration of the delay of RT induced in the left (left column) and right hand (right column) responses by TMS delivered at various times (100–350 ms from top to bottom figures). The circles at each stimulus location has a diameter proportional to the delay of RT induced by TMS, and are also color coded according to the delay. (For key, see the panel linked to the bottom right of this figure.) Note that during the early phase of premovement period, RT of the right hand is delayed by TMS over both hemispheres, whereas RT of the left hand is delayed by TMS over the left hemisphere only. (B) The RT delay induced by TMS was plotted as a function of the time of stimulation, separately for TMS over the left (black curve) and right hemispheres (gray curve). Data for all sites of stimulation (DLPFC, premotor, motor, APC and PPC) and for both hands were pooled. Asterisks indicate significant difference from baseline. Error bars indicate standard errors (also in the following). (C) RT delay induced in the left and right hand responses when TMS was applied over the left hemisphere. The black curve is for left hand responses, and the gray curve is for right hand responses. (D) A similar plot as (C) when TMS was applied over the right hemisphere.

The overall time course of RT delay differed when TMS was applied over the left and right hemispheres [Fig. 3B, interaction between time of TMS and hemisphere: F(5,25) = 2.997, P = 0.0105]. This interaction indicated that the delay induced over the left hemisphere was slightly but significantly larger than that over the right hemisphere during the early phase (150 and 200 ms), whereas the delay was slightly larger for TMS over the right hemisphere during the late phase (300 ms).

The TMS Effect on RT of the Left and Right Hands

Pooling the data for the four precue conditions, we now looked at how TMS affected RT of the left and right hands when TMS was applied over various cortical regions of the left and right hemispheres at various time intervals. In Figure 3A, the colors and sizes of the circles over each cortical region depict the delay induced over each region. Again, the TMS effect varied more robustly with time than with the site of TMS (next section). Remarkably, the hemisphere over which TMS was effective differed for responses made by the left or right hand. At intervals of 100–200 ms, RT of the left hand was delayed by TMS applied over the left hemisphere but not over the right hemisphere. In contrast, right hand responses were delayed by TMS over either the left or right hemispheres during the same intervals. At 250 ms, the effect of TMS was minimal over all the stimulus locations. Finally, at 300 ms, we saw a small bilateral effect of TMS from both the left and right hemispheres.

ANOVA confirmed these observations. The effect of TMS on both hands differed when TMS was applied over the left and right hemispheres [interaction between time of TMS × response hand × hemisphere: F(1,5) = 17.649, P < 0.0001]. During the early phase, TMS over the right hemisphere significantly delayed the right hand responses relative to baseline (Fig. 3D; P < 0.0001 corrected for multiple comparisons at 100–200 ms), but not the left. In contrast, the delay induced in the two hands was largely comparable when TMS was given over the left hemisphere (Fig. 3C; P>0.05). During the late phase, the delay induced in both hands was comparable whether TMS was applied over the left or right hemisphere, but with a slight contralateral predominance (Fig. 3C,D; P > 0.05).

Precue Information and the TMS Effect on RT

The TMS effect on RT was also affected by the amount of precue information [effect of precue information: F(3,15) = 39.735, P < 0.0001]; the delay induced by TMS became progressively smaller as the precue was more informative (magnitude of delay induced: no > pb > ph > full, difference at P < 0.001 corrected for multiple comparisons). However, the overall time course of RT delay was similar for all precue conditions, with two peaks at 100–200 ms and 250–300 ms.

The hemispheric difference in TMS effect on RT of both hands also varied with the amount of precue information. Applied during the early phase, TMS over the left hemisphere delayed RTs of both the left and right hands to a similar degree, and the delay decreased with increasing amount of precue information. TMS over the right hemisphere, however, largely delayed RT of the right hand with little effect on the left hand in any of the precue conditions.

In the no and pb conditions, TMS applied during the late phase delayed RT mainly in the contralateral hand. Under the ph and full information conditions, RT delay was small for both hands.

TMS Effect on Movement Time

The Topography of the TMS Effect on MT

Figure 4A depicts how TMS affected MT in one subject. Figure 4B shows averaged data across all subjects collapsed for all precue conditions. TMS prolonged MT when applied over the left but not over the right hemisphere. Prolongation was most pronounced at intervals of 100–200 ms after the go-signal, but gradually subsided by 250 ms, with similar effect at 300–350 ms. The TMS effect could be seen after stimulation over a widespread scalp region covering the left hemisphere but not over the right hemisphere. The magnitude of TMS effect was similar for the four precue conditions.

Figure 4.

Topographical effect of TMS on MT. In order to see how the topography of TMS effect changed with the time after the go-signal, data of both hands were pooled and prolongation of MT induced by TMS applied over the left and right hemispheres was plotted as a function of stimulus location at different times of TMS in one subject (A) and for the data averaged across all subjects (B). Conventions as in Figure 2A,B. In (A), data for the four precue conditions were plotted separately, whereas these conditions were pooled in (B). At each interval, there were no focal maxima of TMS effect at any of the cortical regions studied, implying that the TMS effect varied more robustly with time than with the stimulus site.

Figure 4.

Topographical effect of TMS on MT. In order to see how the topography of TMS effect changed with the time after the go-signal, data of both hands were pooled and prolongation of MT induced by TMS applied over the left and right hemispheres was plotted as a function of stimulus location at different times of TMS in one subject (A) and for the data averaged across all subjects (B). Conventions as in Figure 2A,B. In (A), data for the four precue conditions were plotted separately, whereas these conditions were pooled in (B). At each interval, there were no focal maxima of TMS effect at any of the cortical regions studied, implying that the TMS effect varied more robustly with time than with the stimulus site.

Time Course of the TMS Effect on MT

As with the delay of RT, prolongation of MT was significantly affected by the time of TMS [F(5,25) = 14.462, P < 0.0001]. The overall time course of the effect differed when TMS was applied over the left and right hemispheres [Fig. 5B; main effect of hemisphere: F(1,5) = 197.197, P < 0.0001, interaction between time of TMS and hemisphere: F(5,25) = 0.485, P < 0.0001]. When TMS was applied over the left hemisphere, the overall MT prolongation was largest 100–200 ms after the presentation of the go-signal, subsiding after 250 ms. In contrast, TMS over the right hemisphere had no significant effect on MT at any TMS interval.

Figure 5.

Time course of TMS effect on MT. (A) Graphical illustration of the effect of TMS on MT of both hands (left hand responses: left column; right hand responses: right column). Conventions as in Figure 3A. (B) Prolongation of MT induced by TMS was plotted as a function of the time of stimulation, separately for TMS over the left and right hemispheres. Conventions as in Figure 3B. TMS at time intervals from 100–200 ms (early phase) induced a significant MT prolongation when applied over the left hemisphere but not over the right hemisphere. Asterisks indicate significant difference from baseline MT at each interval. (C) MT delay induced in the left and right hand responses when TMS was applied over the left hemisphere. Conventions as in Figure 3C. During the early phase, TMS prolonged MTs of both hands to a similar degree. (D) A similar plot as (C) when TMS was applied over the right hemisphere. No significant prolongation of MT was induced by TMS over the right hemisphere at any TMS interval.

Figure 5.

Time course of TMS effect on MT. (A) Graphical illustration of the effect of TMS on MT of both hands (left hand responses: left column; right hand responses: right column). Conventions as in Figure 3A. (B) Prolongation of MT induced by TMS was plotted as a function of the time of stimulation, separately for TMS over the left and right hemispheres. Conventions as in Figure 3B. TMS at time intervals from 100–200 ms (early phase) induced a significant MT prolongation when applied over the left hemisphere but not over the right hemisphere. Asterisks indicate significant difference from baseline MT at each interval. (C) MT delay induced in the left and right hand responses when TMS was applied over the left hemisphere. Conventions as in Figure 3C. During the early phase, TMS prolonged MTs of both hands to a similar degree. (D) A similar plot as (C) when TMS was applied over the right hemisphere. No significant prolongation of MT was induced by TMS over the right hemisphere at any TMS interval.

TMS Effect on MT of the Left and Right Hands

When MTs of the left and right hands were analyzed separately for data collapsed over the five stimulus locations of each hemisphere, left hemisphere TMS prolonged MT of the left and right hands by a similar amount at intervals of 100–200 ms [Fig. 5A,C, main effect of hand: F(1,5) = 0.003, P = 0.9578, interaction between time and hand: F(5,25) = 0.950, P = 0.4474]. In contrast, right hemisphere TMS did not affect MT of either hand at any time interval of TMS (Fig. 5D).

Precue Information and the TMS Effect on MT

The overall TMS effect on MT as well as its time course were similar for all precue information conditions [effect of precue information: F(3,15) = 0.637, P = 0.5913; interaction between time × precue information: F(15,75) = 0.872, P = 0.5966]; TMS over the left hemisphere but not over the right hemisphere prolonged MTs of both hands to a similar degree for all four precue information conditions.

Discussion

Topography and Temporal Variation of TMS Effects

In the present study, TMS was used with a PCRT paradigm to study the relative involvement of right and left motor cortices in the generation of right and left hand movements. Because the task required processing of visual information about both the effector (the left or right hand) and target (the left or right button), we expected to see an information flow from the posterior (visual cortical regions) to anterior cortical regions (motor regions), as in our previous study (Terao et al., 1998). However, the expected topographical effect of TMS was rather small; the TMS effect varied more robustly with the time than with the site of stimulation (Fig. 3). This suggested that anterior and posterior cortical regions were involved in a network-like fashion during the task, so that disruption of cortical processing at one site led to distributed effects in the whole network.

The novel finding of the present study was the marked difference in the effect of TMS on left and right hand responses when it was applied over each hemisphere. Applied during the early phase of premovement period, left hemisphere TMS delayed RT and prolonged MT of both hands (Figs 3 and 5), whereas right hemisphere TMS delayed RT only of the right hand. This points to the hemispheric asymmetry in cortical processing required for the task, although some caution should be exerted in inferring the topographic activity of cortical processing from the magnitude of TMS effect over each area (see next section).

There seemed to be two distinct phases of TMS effect in the premovement period, i.e. 100–200 ms and 250–350 ms after the go-signal. Since these phases resembled those observed for the cortical preparation of vocalization (Terao et al., 2001), the early phase was considered to represent sensory processing of the presented visual information and accumulation of motor buffer, i.e. programming of movement based on the visual information, whereas the late phase would correspond to the output process whereby the motor buffer is released to contralateral limb muscles. The fact that TMS induced significant MT changes at early to intermediate but not late intervals was also consistent with the view that the early phase of the premovement period was devoted to motor programming.

Possible Mechanism of TMS Inducing the Behavioral Effects

The cortical area activated directly by TMS is relatively focal. Indeed the focality of the stimulus has been successfully used to map the time-varying maxima of activities in the oculomotor cortical regions (Terao et al., 1998). Nevertheless, TMS can also modulate neural circuits in nearby or remote, connected brain regions, both within or between the two hemispheres (Ferbert et al., 1992; Fox et al., 1997; Paus et al., 1997, 1998; Siebner et al., 2000, 2001; Civardi et al., 2001; Gerschlager et al., 2001; Strafella and Paus, 2001; Burle et al., 2002; Münchau et al., 2002; Werhahn et al., 2002; Bäumer et al., 2003; Okabe et al., 2003; Schambra et al., 2003; Strafella et al., 2003; Murase et al., 2004).

It is likely that both focal and remote effects of TMS contributed to the TMS-induced behavioral changes in the present study. The widespread effect of TMS over each hemisphere can be explained if several cortical areas, including the motor cortex, premotor cortex, dorsolateral prefrontal cortex and parietal cortical areas, are active (Deiber et al., 1996) and presumably functionally interconnected (Gerloff et al., 1998; Civardi et al., 2001) during the performance of PCRT task. Interhemispheric interactions may also be at work during the task performance, with which TMS can also interfere. However, the apparent asymmetry of the TMS effect over the right and left hemispheres precludes a simple explanation of all the results on the basis of interhemispheric ‘spread’. On the other hand, it is also possible that subtle asymmetries in inhibitory tones could contribute to the interhemispheric difference of TMS effect (Ziemann and Hallett, 2001; Ilic et al., 2004), but these issues could not be addressed neurophysiologically using the double pulse technique or cortical silent period (Classen et al., 1997; Ziemann et al., 1997; Burle et al., 2002; Werhahn et al., 2002; Murase et al., 2004) because the regions that affected MT and RT included various cortical areas other than the motor cortex, over which TMS did not evoke any motor evoked potential or cortical silent period at the intensity used in the present study.

Hemispheric Asymmetry in the Cortical Processing of Left and Right Hand Responses

With these caveats in mind, the data are consistent with the notion of left hemispheric dominance in motor programming; TMS over the left hemisphere affected RT and MT of both hands when applied during the early phase. In contrast, during the late phase, TMS over the left and right hemispheres delayed RT of both hands to a similar degree, although the effect of TMS was slightly stronger on the contralateral hand (Fig. 3). This would also be understood if the late stage represents a process in which motor output is emitted from the motor cortex to the contralateral hand.

However, the delay of RT of the right hand when TMS was delivered over the right hemisphere during the early phase was unexpected from the conceptual framework of hemispheric dominance. In this context, differential hemispheric engagement for right and left hand movements has been reported in functional magnetic resonance imaging (fMRI) studies. Ipsilateral motor cortex activation during unilateral hand movements, especially of the left hand, has been ascribed to the interhemispheric modulation of the activity of contralateral motor cortex by the ipsilateral motor cortex (Chen et al., 1997; Kobayashi et al., 2003; Carbonnell et al., 2004). Thus, complex left finger tapping more or less engages both motor areas, whereas right finger tapping activates only the left hemisphere (Kim et al., 1993; Mattay et al., 1996; Singh et al., 1998). Additionally, right-sided movements were associated with a greater volume of activation in the contralateral motor cortex than left-sided movements (Dassonville et al., 1997). If greater hemodynamic responses are associated with greater TMS effect, these findings would predict that left hand responses would be delayed by TMS over both hemispheres, whereas a delay in right hand responses would result only with TMS over the left but not the right hemisphere. However, this was not the case.

Predominant Transfer of Visuomotor Information from the Right to Left Hemisphere

In order to explain the differential effect of TMS on left and right hand responses, therefore, one must postulate distinct roles for the left and right hemispheres that differ for the left and right hand responses in integrating body-part and target information, and subsequent interhemispheric transmission of visuomotor information. Left hand advantage is noted in tasks emphasizing rapid initiation of movements in response to a go-signal and where the time constraints require the movement to be fully programmed before its initiation (Carson et al., 1995). The right hemisphere appears to play a role in the integration of information about the position and orientation of an effector, which in some situations is succeeded by a left hemisphere mediated right hand advantage for the execution of movement (Carson, 1989; Carson et al., 1993; Boulinguez et al., 2001; Barthélémy and Boulinguez, 2002). Thus, the left-right difference in RT has been explained by engagement of the right hemisphere prior to the go-signal. If advance information is processed in the right hemisphere, then right hand responses require this information to be transmitted interhemispherically to the left hemisphere, whereas left hand responses can be computed within the right hemisphere itself (Fig. 6). Thus, the left hand advantage in RT can be explained by the crossed–uncrossed difference in transmission of relevant visuomotor information. We postulate that, in the present study, RT of the right hand was slower than the left hand under the more informative conditions because the amount of information transmitted may be greater in these conditions (Table 2A). Marzi et al. (1991) showed that interhemispheric transfer is faster from the right to left hemisphere than in the reverse direction. This asymmetry in information transmission provides an optimal setup for the proposed information flow.

Figure 6.

Schematic illustration of cortical processing taking place during motor implementation. Shadings of the cortical areas denote the level of cortical activities occurring in those areas; black areas indicate cortical areas with prominent activity, whereas gray areas represent those with less prominent activity. According to previous behavioral studies, advance processing of the precue information takes place primarily in the right hemisphere before the go-signal (top row). After the go-signal, cortical processing is largely taken over by the left hemisphere, whereas some processing also persists in the right hemisphere (middle row). For right hand responses (left column), information processed in the right hemisphere has to be sent to the left hemisphere, presumably via the corpus callosum, for motor output from the left hemisphere. TMS conceivably disrupts the inter-, but not intrahemispheric transfer of information from the right to left hemisphere (the arrows between two hemispheres represent interhemispheric transmission of information, and the gray arrow transmission disrupted by TMS). On the other hand, processing and transfer of information for the left hand responses (right column) may proceed within the right hemisphere with the help of information processed in the left hemisphere (hatched arrows represent persisting interhemispheric interaction from the left to right hemisphere). The former may have largely subsided, such that TMS over the right hemisphere does not significantly affect left hand responses.

Figure 6.

Schematic illustration of cortical processing taking place during motor implementation. Shadings of the cortical areas denote the level of cortical activities occurring in those areas; black areas indicate cortical areas with prominent activity, whereas gray areas represent those with less prominent activity. According to previous behavioral studies, advance processing of the precue information takes place primarily in the right hemisphere before the go-signal (top row). After the go-signal, cortical processing is largely taken over by the left hemisphere, whereas some processing also persists in the right hemisphere (middle row). For right hand responses (left column), information processed in the right hemisphere has to be sent to the left hemisphere, presumably via the corpus callosum, for motor output from the left hemisphere. TMS conceivably disrupts the inter-, but not intrahemispheric transfer of information from the right to left hemisphere (the arrows between two hemispheres represent interhemispheric transmission of information, and the gray arrow transmission disrupted by TMS). On the other hand, processing and transfer of information for the left hand responses (right column) may proceed within the right hemisphere with the help of information processed in the left hemisphere (hatched arrows represent persisting interhemispheric interaction from the left to right hemisphere). The former may have largely subsided, such that TMS over the right hemisphere does not significantly affect left hand responses.

TMS Effect on Interhemispheric Transmission of Visuomotor Information

Marzi et al. (1998) reported a larger effect of single-pulse TMS on inter- rather than intrahemispheric transfer of information at the occipital pole using a visuomotor paradigm. In the same way, the effect of right hemisphere TMS on right hand responses in the present study may be explained if TMS interfered only with transmission of processed information from the right to left hemisphere required to make right hand responses [note the gray arrow in Fig. 6 (left column) indicating TMS interference with interhemispheric transmission]. Interhemispheric transfer of information may be more complex than intrahemispheric processing of information and hence more susceptible to disruption by TMS (Marzi et al., 1998). Meanwhile, for left hand responses, although some processing may proceed within the right hemisphere, this would be carried out mostly intrahemispherically and may have been more resistant to the effect of TMS.

By the same token, left hemisphere TMS should delay RT of the left hand when applied over the ipsilateral left hemisphere because left hemisphere TMS would block interhemispheric transmission of information from the left to right hemisphere. Some part of the delay in left hand responses by left hemisphere TMS may actually be ascribed to the disruption of interhemispheric information. However, according to the above scheme, the information flow from the left to right hemisphere may be much smaller than that flowing in the opposite direction, and thus the effect of TMS on the former would be very small. Therefore, the effect of left hemisphere TMS on left hand RT may rather reflect disruption of motor programming occurring in the left hemisphere for both hand responses.

Based on the results, a dual system straddling both hemispheres may be proposed for movement implementation. Advance processing takes place in the right hemisphere, which is partly taken over by left hemisphere after the go-signal. In this process, the right hemisphere may play a role mainly in processing target and effector information and determining RT, while the left hemisphere may play a role in elaborating the motor program such as the pattern of EMG discharges and determining MT. Interhemispheric transmission of visuomotor information is important throughout this process, especially for making right hand responses, because information flow from the left to right hemisphere is then required.

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Author notes

1Department of Neurology, Division of Neuroscience, Graduate School of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, Japan 113-8655, 2Third Department of Internal Medicine, National Defense Medical College, Tokyo, Japan 113-8655, 3Department of Clinical Laboratory, Division of Neuroscience, Graduate School of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, Japan 113-8655 and 4Department of Psychosomatic Medicine, Division of Medical Science, Graduate School of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, Japan 113-8655