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NEUROSCIENCE |
1 Sobell Department of Motor Neuroscience and Movement Disorders, Institute of Neurology, UCL, Queen Square, London WC1N 3BG, UK
2 Dipartimento di Neuroscienze, Università degli Studi di Parma, Parma, Italy
3 Institute of Cognitive Neuroscience and Department of Psychology, UCL, Queen Square, London WC1N 3AR, UK
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(Received 23 October 2006;
accepted after revision 22 February 2007;
first published online 1 March 2007)
Corresponding author R. Lemon: Sobell Department of Motor Neuroscience and Movement Disorders, Institute of Neurology, UCL, Queen Square, London WC1N 3BG, UK. Email: rlemon{at}ion.ucl.ac.uk
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Introduction |
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Cortico-cortical interconnections between F5 and M1 (Dum & Strick, 2005) provide a means by which representations of objects and hand shapes needed to grasp them could be transformed into motor commands controlling hand and digit muscles. In the monkey, when a single stimulus delivered to F5 conditioned a test M1 stimulus, the late indirect (I) waves of the resulting corticospinal volley were selectively facilitated (Cerri et al. 2003; Shimazu et al. 2004). These late I2–I3 components are thought to result from excitatory afferent inputs to corticospinal neurones, including activity in cortico-cortical pathways from premotor areas (Amassian et al. 1987). If cortico-cortical F5–M1 interactions are mediated by neuronal circuits that produce the late I-waves, then facilitation of the I-waves would be expected in visually guided grasp.
In a recent study, paired-pulse TMS was used to probe I-wave interactions during preparation to grasp visible objects in human subjects (Cattaneo et al. 2005). The paired-pulse protocol used a suprathreshold (130% of resting motor threshold, RMT) followed shortly after by a subthreshold (90% of RMT) stimulus (Ziemann et al. 1998). The resulting I-wave interactions from paired-pulse TMS are thought to act exclusively at the cortical level, facilitating the interactions of the late I-waves (di Lazzaro et al. 1999; Hanajima et al. 2002). Cattaneo et al. (2005) found that motor-evoked potentials (MEPs) elicited several hundred milliseconds prior to movement onset had a pattern of facilitation that predicted subsequent muscle activity when grasping the same object. Thus there was greater facilitation in the first dorsal interosseous (1DI) when subjects were preparing to grasp a handle than a disc, and vice-versa for abductor digiti minimi (ADM). Control experiments involving equivalent hand and digit movements, but without a visible and graspable object, failed to produce MEP interactions. The results suggested that responses to paired-pulse TMS reflect the visuomotor transformations and action preparation that occur during natural grasping behaviour.
By contrast, single-pulse TMS with a posteriorly directed current preferentially facilitates the first I-wave (I1) (Sakai et al. 1997). MEPs from single-pulse TMS over M1 have been shown to be suppressed in the preparation period preceding the ‘go’ signal in pre-cued reaction time tasks (Hasbroucq et al. 1997, 1999; Touge et al. 1998).
In this study we used both single- and paired-pulse TMS protocols to investigate the time course of M1 excitability prior to self-paced object-orientated grasp. In the first experiment we investigate when visuomotor information reaches M1. In the second and third experiments we investigated whether object-specific modulation of M1 excitability occurs in a sustained fashion throughout the period of motor preparation or only just before motor execution. This question arises from recordings during delayed-response experiments in monkeys that have shown two distinct neuronal firing patterns in the dorsal and ventral premotor cortex that could modulate M1 excitability. Firstly, there is tonic set-related firing of neurones that is sustained or builds up from the instruction cue to the approaching ‘go’ signal (Wise & Mauritz, 1985; Murata et al. 1997; Crammond & Kalaska, 2000). Secondly neurones can show phasic activation, with excitation on object presentation and/or movement initiation (Weinrich & Wise, 1982; Rizzolatti & Luppino, 2001). Either of these excitation patterns could be present in M1 inputs prior to grasp.
To investigate when visuomotor information first reaches M1, TMS was delivered at different time points after presentation of either a handle or a disc. By using both single- and paired-pulse TMS protocols, we examined the contrasting pattern of suppression and facilitation of MEPs that occurred during movement preparation. We hypothesized that the object x muscle interaction should be absent when TMS was delivered very early after subjects were first presented with a visible object, since object-based visual information would not yet have been processed in the cortical circuits that control M1 excitability. We found that significant modulation was present only when TMS was delivered 150 ms or more after object presentation, and not at earlier latencies. The form of this modulation was differential, including single-pulse suppression and paired-pulse MEP facilitation, suggesting that the suppression during other types of tasks (Hasbroucq et al. 1997, 1999; Touge et al. 1998) is also present during visuomotor grasp.
In a second experiment we tested the hypothesis that object-related modulation of M1 processing occurs only immediately prior to the execution of grasp. When the cue to grasp was a tone 1200 ms after object presentation, and TMS was delivered at 150 or 800 ms after object presentation, the MEP interaction was abolished. In the third experiment, we tested whether predictability affected motor preparation. When TMS served as the ‘go’ signal, but occurred at unpredictable times after visual presentation of the object, the MEP interaction was also abolished.
Our findings suggest that visuomotor inputs to M1 become excitable only just before the command to grasp is generated, and do not show sustained modulation of M1 output during the delay period between observation and subsequent action. Our results show both suppression and facilitation of the MEP within the same experimental block, according to the components of the corticospinal volley that are influenced by TMS. This suggests that these components may have different functional roles in the control of visuomotor grasp.
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Methods |
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In total 46 naive right-handed healthy volunteers (19 males, mean age (± S.D.) 26.4 ± 5.68 years) participated in this study, with informed written consent. The study complied with institutional guidelines (The National Hospital and Institute of Neurology Joint Research Ethics Committee) and was approved by the local ethics committee. The experiments were carried out in accordance with the Declaration of Helsinki.
TMS
TMS pulses were delivered using the same protocol as Cattaneo et al. (2005) with single-pulse (130% RMT; Rossini et al. 1994) or paired-pulse (130 and 90% RMT for the first and second stimulus, respectively) stimulation at interstimulus intervals (ISIs) of 1.3, 2.5 and 4.1 ms. TMS pulses were delivered using two Magstim 200 stimulators (Magstim, Whitland, UK) through one figure-of-eight TMS coil (7 cm diameter). The coil handle was at 45 deg to the midline, pointing laterally and backwards with a posteriorly directed current. Stimuli were applied to the ‘hotspot’ on the scalp over the left primary motor cortex characterized as the point from which a low-threshold MEP could be evoked from both the 1DI and ADM of the right hand. EMG was recorded using bipolar (belly tendon) surface electrodes, sampled at 4 kHz and high-pass filtered (3 Hz).
Experimental protocols
Subjects were seated with their hands resting pronated on a table in front of two objects, a handle and a disc, that were individually presented (Fig. 1). Subjects wore occluding goggles (PLATO; Translucent Technologies, Toronto, Canada) operated under computer control to prevent vision during the intertrial interval. For all experiments trials began with goggles opening. Subjects were asked to either observe the object or, on grasp trials, to reach out and grasp the object and hold the object for 
0.5 s. Subjects were instructed to move in a self-paced manner, rather than as fast as possible. A touch-sensitive electronic circuit was used to determine the time of object contact. Objects were presented in random order and TMS condition, the order of which (single-paired-pulse) were also randomized. Experiments were designed to keep sessions brief; protocols are shown in Fig. 2.
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Experiment 1a. In 10 subjects, sham TMS, delivered in counterbalanced blocks at 50 and 800 ms, was the cue to grasp; single pulses were at 65% of stimulator output and delivered over the contralateral hand area, but with the coil tilted at 90 deg to the scalp and both wings touching the head so there was no cortical stimulation.
Experiment 2. In eight subjects, the cue to grasp was a tone 1200 ms after object presentation, while TMS occurred in 75% of these trials in blocks at 150 and 800 ms after object presentation. To encourage subjects to prepare the grasping movement following presentation of the object, and to remain prepared throughout the trial, the ‘go’ signal to grasp occurred at 250 or 2000 ms in 16% of trials (Fig. 2B).
Experiment 3. To test the effect of unpredictable TMS, eight subjects performed a task where objects and TMS conditions were presented in random order. Single- and paired-pulse (only ISI 2.5 ms) TMS served as the cue to grasp and occurred once per object at 90 ms intervals in a 150–780 ms window after object presentation, giving eight trials per object and per TMS condition. To increase the unpredictability of the imperative cue, in two of these trials there was no TMS (Fig. 2C).
EMG analysis
EMG activity from each grasp trial was high-pass filtered (40 Hz) and rectified. Integrated EMG activity was calculated for the hand preshaping phase, 300 ms preceding object contact. EMG activity for each trial was normalized to that subject's average EMG in that muscle across grasp of both objects. Normalizing relative to the pooled-object EMG in this way meant that EMG values for the handle were no longer independent from EMG values for the disc. Therefore, to test for specific involvement of each muscle in grasping each object, we performed paired t tests on each block comparing ADM (handle) and 1DI (handle). To test whether there was a differential effect of object within a muscle, paired t tests were performed between grasp of handle and disc for that muscle. When we performed several such tests we used Bonferroni correction and report the corrected probability values.
Object contact
The time taken to contact the grasped objects was recorded. For experiments 1, 1a and 2, a within-subject repeated-measures ANOVA was performed for the factors of object (handle versus disc) and TMS delivery time (50 versus 100 ms, 150 versus 800 ms, 50 versus 800 ms). In experiment 1, data from TMS delivery time was then divided into short (50 and 100 ms) and long (150 and 800 ms) intervals. A repeated-measures ANOVA was performed with the additional between-subject factor of interval (short versus long). For experiments 1 and 1a, a repeated-measures ANOVA was performed with the additional between-subject factor TMS (TMS versus sham TMS) for delivery at 50 and 800 ms after object presentation. Paired and independent t tests were performed, as necessary. Statistical analysis of object contact time and EMG data for TMS at 100 and 150 ms was restricted to nine subjects, because object contact time was not reliably recorded in two subjects for technical reasons.
Reaction time
For experiments 1 and 3, the timing of the first EMG activity after the ‘go’ signal was used as a measure of reaction time. In experiment 1, the mean reaction time using pooled data from TMS at 800 and 150 ms was calculated for each subject. A between-subjects one-way ANOVA was performed for the factor of TMS protocol (random versus blocked).
MEP analysis
Since we did not want MEP size to be influenced by any ongoing EMG activity, trials with EMG activity in the 150 ms preceding the TMS pulse were discarded (5% of trials overall). Statistical analysis was performed on a MEP facilitation ratio (paired-pulse MEP/single-pulse MEP). This was calculated within subjects and blocks for each muscle, object and paired-pulse (ISI 1.3, 2.5 and 4.1 ms) condition.
For experiment 1, a repeated-measures ANOVA was performed using within-subject factors of grasp (grasp versus observation), ISI (1.3 versus 2.5 versus 4.1 ms), object (handle versus disc) and muscle (ADM versus 1DI) for each TMS delivery condition (50, 100, 150 and 800 ms). Three follow-up ANOVAs were performed to identify the key object x muscle interactions in specific grasp, ISI and TMS delivery conditions. First, a within-subject ANOVA investigated observation and grasp conditions when TMS was delivered at 150 and 800 ms using the factors of ISI, object and muscle. A second ANOVA examined each ISI interval for TMS at 150 and 800 ms in the grasp condition using the within-subject factors of object and muscle. The differential effect of long (150 and 800 ms) and short (50 and 100 ms) TMS delivery times at ISI 2.5 ms was then compared in the third ANOVA, with factors of TMS delivery, object, muscle and the between-subjects factor of interval (long versus short). Lastly, the contribution of single- and paired-pulse (ISI 2.5 ms) TMS to the facilitation ratio in the grasping condition was examined. For each subject, muscle and TMS condition (single- and paired-pulse), the average MEP for the handle was divided by the sum of the average MEP for both objects, i.e. disc plus handle, and expressed as a percentage. Paired t tests were carried out on each muscle and TMS delivery time, comparing the percentage facilitation for the handle in single- and paired-pulse TMS conditions. As the percentage contribution for the disc was dependent on the percentage contribution for the handle, a significant effect on the t test for the handle was equivalent to an object x TMS condition interaction for that muscle.
In experiments 2 and 3, repeated-measures ANOVAs were performed on the MEP facilitation ratios for the factors of object and muscle. In experiment 3 (random TMS), data were first pooled according to TMS condition (single- or paired-pulse).
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Figure 3B illustrates the characteristic activation pattern produced when shaping the hand to grasp the two different objects. In the 300 ms before object contact, ADM, which abducts the little finger, was more strongly activated for grasping the disc, which required spreading the digits than for grasp of the handle. This differential activation was present for all delivery times, paired t test, P
0.05 (Bonferroni corrected). However, 1DI showed less clear and non-significant modulation. Overall, the crossed pattern of activation produced a significant object x muscle interaction in the 300 ms pre-contact period for all TMS delivery times (Fig. 3B, 50 ms: P < 0.05; 100, 150 and 800 ms: P < 0.01; Bonferroni corrected).
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M1 excitability was investigated during object observation alone and prior to grasp with single- and paired-pulse (ISI 1.3, 2.5 and 4.1 ms) TMS at different times from object presentation. A repeated-measures ANOVA was used to test whether manipulation of these factors resulted in an object x muscle interaction of the MEP facilitation ratio at the different TMS delivery times. At the earlier 50 and 100 ms intervals there was no significant object x muscle interaction for all combinations of grasp, ISI and object (all, P > 0.1). For later TMS delivery at 150 and 800 ms there was a significant grasp x object x muscle interaction (both, P < 0.05). How the pattern of MEP facilitation varied with these factors and relates to the muscle activity elicited during grasp will be discussed in turn.
Object observation versus preparation to grasp
Prior to the grasping task, subjects were instructed to just observe the object (see Methods, experiment 1). At the late intervals, prior to grasp there was a significant object x muscle interaction of the MEP facilitation ratio (P < 0.01) that was not present during object observation alone (P > 0.2) as illustrated in Fig. 3A and E for ISI 2.5 ms. The results suggest that the mechanism underpinning the interaction seen with TMS at 150 and 800 ms is preparation for grasp of a visible object. As already noted, the early intervals did not show a significant effect.
The effect of ISI
Prior to grasp, for TMS at 150 and 800 ms, a significant object x muscle interaction of the MEP facilitation ratio only occurred at ISI 2.5 ms (both, P < 0.05) not at ISI 1.3 or 4.1 ms (all, P > 0.05). Figure 4A illustrates the changes in excitability caused by paired-pulse TMS at different ISI intervals when TMS was delivered at 800 ms. At ISI 2.5 ms the modulation was more than double that of ISI 1.3 and 4.1 ms, which suggests a specific temporal interaction. This may reflect the selectivity of paired-pulse TMS at ISI 2.5 ms in enhancing the late I-waves of corticospinal activity (Shimazu et al. 2004; Cattaneo et al. 2005).
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MEPs elicited prior to grasp showed a pattern which reflected three factors. These were: first, the muscle activity subsequently used by the subject to grasp the object; second, the TMS condition (single- or paired-pulse); and finally, the time of TMS delivery from object presentation.
The MEPs elicited by paired-pulse TMS (ISI 2.5 ms) delivered 800 ms after object presentation will be described first. To isolate the effect of the paired-pulse MEP (ISI 2.5 ms) from that of the single-pulse, the percentage facilitation for the handle and disc was calculated separately for TMS conditions (see Methods). The paired-pulse MEP, elicited 260–657 ms before movement onset, showed clear facilitation of the muscle that was preferentially activated during subsequent grasp of the object. Thus the MEPs were larger in ADM for the disc than the handle (Fig. 3C, far right column). The single-pulse MEP showed the reverse pattern, indicating suppression of the muscle that was more highly activated during grasp of the object (Fig. 3C). A significant paired t test (P = 0.005) comparing the single- and paired-pulse MEPs represents an interaction of TMS condition x object for ADM. 1DI, which showed less differential EMG activity for grasp of the two objects, did not show a significant effect (P > 0.1) (Fig. 3D, 800 ms).
The timing of TMS delivery was important. There was a clear evolution of the object x TMS condition interaction in ADM in the period following object presentation. The interaction was absent at 50 and 100 ms (P > 0.2), reaching significance at 150 ms (P < 0.05) and still stronger significance at 800 ms (P < 0.01; see above). For 1DI, there was no clear modulation of MEPs evoked by either single- or paired-pulse TMS at any timing (Fig. 3D; all, P > 0.1). The contrasting effect of early and late TMS delivery on MEP modulation was confirmed by statistical analysis on the MEP facilitation ratio: there was a significant interval (800 and 150 ms versus 100 and 50 ms) x object x muscle interaction (P < 0.05), reflecting the suppression by single-pulse TMS and facilitation by paired-pulse TMS at late but not at early delivery after object presentation, in ADM but not 1DI.
Effect of TMS on timing of grasp and EMG activity
When subjects were preparing to grasp the object, delivery of single- and paired-pulse TMS immediately after visual presentation (50 and 100 ms) appeared to have a disruptive effect on their grasping behaviour. This was not seen at later timings of TMS delivery (150 and 800 ms). The effects were observed in two behavioural measures. First, while EMG activity in ADM and 1DI showed a reciprocal pattern for disc versus handle for later TMS delivery (see Fig. 3B, 150 and 800 ms), for TMS at 50 and 100 ms, both muscles showed greater activation for the disc (Fig. 3B, left columns).
Second, the time of grasp onset (the time between the ‘go’ signal (TMS delivery) and object contact) was longer for early versus late TMS (Fig. 4B, filled symbols). The EMG activity illustrating the TMS protocols (Fig. 2A) highlights the difference in object contact time in the four TMS delivery conditions when grasping the handle. This increase in object contact time with early TMS was even more marked when grasping the disc (Fig. 4B). The difference in object contact time for the handle and disc with early TMS was confirmed in a repeated-measures ANOVA with a significant main effect of object (P < 0.05). Subsequent paired t tests showed that this was significant at both 50 and 100 ms (P = 0.05 and P < 0.05, respectively). In contrast, for later TMS intervals (150 and 800 ms), there was no main effect of object (P > 0.5) nor an interaction of TMS time and object (P > 0.3). A repeated-measures ANOVA with the between-subject factor of interval (long (150 and 800 ms) versus short (50 and 100 ms)) showed a main effect of object (P < 0.05) but no main effect of or interaction with interval (P > 0.1).
As the changes in behaviour with early TMS could be related to the early timing of the ‘go’ signal rather than the delivery of TMS itself, we examined the effect of sham TMS on subjects' performance (see Methods, experiment 1a). Sham TMS was delivered at 50 or 800 ms after object presentation (Fig. 4B; open symbols). There was no significant main effect on object contact times of object or sham TMS delivery time (50 versus 800 ms), nor was there an object x sham TMS delivery time interaction (all, P > 0.3). Between-subjects analysis with data collected from experiment 1a revealed a significant object x TMS (TMS versus sham TMS) interaction at 50 ms (P < 0.05) but not at 800 ms (P > 0.8). Independent t tests isolated this effect to increased object contact time with the disc for real TMS compared with sham (mean ± S.D., 1.55 ± 0.28 s versus 1.32 ± 0.25 s, respectively, P < 0.05). The modulation of EMG according to the object grasped was significant for grasps after both real (Fig. 3B; P < 0.005) and sham TMS (P < 0.001), but only with real TMS at 50 ms was there increased EMG activity during grasp for the disc in both ADM and 1DI. These data all indicate that the disturbed pattern of EMG and object contact were due to TMS delivery rather than the requirement for subjects to reach and grasp almost immediately after object presentation.
Pattern of modulation of M1 inputs during the object presentation period
The second part of the study investigated whether modulation of inputs to M1 was sustained throughout the period after visual presentation until the ‘go’ signal was given, or whether modulation occurred for only a brief period just prior to grasp. To distinguish between these two possibilities, we dissociated the cue to grasp from the delivery of TMS (Fig. 2B, experiment 2, see Methods). An auditory cue was now given as the ‘go’ signal 1200 ms after object presentation, and TMS was delivered in blocks at either 150 or 800 ms after object presentation; that is either 150 or 400 ms before the auditory cue to grasp. For both timings, and in both ADM and 1DI, when TMS was dissociated from the cue to grasp, the object x muscle interaction of the MEP facilitation ratio evoked by paired-pulse TMS at ISI 2.5 ms was abolished (both, P > 0.2; experiment 2, Fig. 5A). This was also true for the other ISI intervals (all, P > 0.2; not shown in Fig. 5). EMG activity during grasp, as previously, showed a significant object x muscle interaction (Fig. 5B, 150 ms: P < 0.01; 800 ms: P < 0.01; Bonferroni corrected).
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We tested whether subjects performing the blocked trials (experiment 1) reached and grasped faster than those tested in the random condition (experiment 3), as would be expected with increased preparedness. Reaction time data for TMS (as the cue to grasp) at 150 and 800 ms in the blocked trials were compared with those from the random TMS experiment. The reaction times were indeed faster TMS at 150 and 800 ms in the blocked condition compared with the random condition (Fig. 5C, 460 and 470 ms versus 520 ms). However, this was not significant (one-way ANOVA, P > 0.3), perhaps because subjects were not instructed to perform under any particular time constraint, leading to considerable individual differences in reaction time.
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Facilitation and suppression of MEPs by TMS delivered during preparation for grasp
When TMS was delivered 800 ms after visual presentation of an object it evoked either suppression or facilitation of the MEP, depending on whether single- or paired-pulse TMS was used, respectively. Paired-pulse stimulation elicited a larger amplitude MEP in ADM when grasping the disc, whilst single-pulse TMS evoked suppression, and vice versa for the handle (Fig. 3C).
These MEPs were elicited 260–657 ms before movement onset yet clearly reflected the subsequent grasp-related muscle activity. In ADM, which was much more active during hand shaping for grasping the disc than for the handle (Fig. 3B) the MEPs also revealed a strong differential activation for the two objects (Fig. 3C). 1DI showed somewhat more activation for the handle than for the disc, but the differences were far less marked than for ADM (Fig. 3B). Notably, the differential 1DI activity for grasp of the two objects was not significant and the object-based modulation in the MEP from 1DI was attenuated (Fig. 3D). Thus the level of differential EMG activity elicited by the grasping task underlies the degree of modulation in the MEP, as shown previously (Cattaneo et al. 2005).
The direction of MEP modulation was determined by the TMS protocol employed: facilitation with paired-pulse TMS (ISI 2.5 ms) and suppression with single-pulse TMS. MEP suppression could reflect mechanisms operating at both cortical and subcortical levels. For example, the spinal H-reflex is reduced in the movement preparation period (Touge et al. 1998; Hasbroucq et al. 1999). Inhibition of motoneurones through spinal interneurones during delay periods has been directly demonstrated by Prut & Fetz (1999). At the cortical level, local inhibitory inputs to corticospinal neurons can be strongly activated by TMS (Ziemann, 1999), while cortico-cortical inputs from premotor areas can also exert inhibition of corticospinal neurons (Tokuno & Nambu, 2000) and suppression of movement (Wise & Kurata, 1989; Sawaguchi et al. 1996). These pathways may be susceptible to TMS in delay period tasks where subjects are withholding a response until a ‘go’ signal is given.
In contrast, the characteristic effects evoked by paired-pulse TMS protocol are thought to occur largely at the cortical level, through interactions between I-waves evoked by the first (suprathreshold) stimulus and the second (subthreshold) stimulus (Tokimura et al. 1996; Ziemann et al. 1998; di Lazzaro et al. 1999). Although both early and late I-waves are thought to arise from presynaptic inputs to corticospinal neurons, they show different characteristics. There is evidence that the later I-waves (I2 and I3) are particularly sensitive to interactions induced by paired-pulse TMS (Amassian et al. 1987; di Lazzaro et al. 1999; Hanajima et al. 2002; Shimazu et al. 2004), while the I1 is much less labile and probably represents a different class of input to the corticospinal neuron distinct from those evoking the later I-waves (Ziemann et al. 1998; Ilic et al. 2002).
Time course of excitation prior to visually guided grasp
The time course of the modulation of the MEP indicates that object-related information that can usefully influence hand shape reaches the motor cortex around 150 ms after object presentation. This is a physiologically plausible timescale. Visual cues for movement reach frontal areas at approximately 100 ms (Schluter et al. 1998; Terao et al. 1998), and therefore we would not expect to see any effect on MEPs congruent with the pattern of upcoming grasp for the earliest TMS delivery at 50 ms, and this was indeed the case. Up to 100 ms there was no interaction of either single- or paired-pulse MEPs (Fig. 3C, 50 and 100 ms). Subsequently there is a period, exemplified by the findings at 150 ms, where single-pulse TMS suppressed activity in the muscle being prepared for grasp (Fig. 3C, 150 ms). This suppression was also seen at 800 ms, and at this time point the MEP in this muscle showed significant facilitation with paired-pulse TMS at ISI 2.5 ms (Fig. 3C, 800 ms). We have previously reported a similar significant interaction for paired-pulse TMS delivered at 1200 ms (Cattaneo et al. 2005).
Disruptive effects of early paired-pulse TMS
The behavioural results showed disruption when TMS was delivered 50 and 100 ms after object presentation. Object contact time increased when TMS was delivered at very short intervals (Figs 2A and 4B). This suggests that early TMS acts as a virtual lesion, possibly impairing the subsequent transfer of object-related information to M1, thereby explaining the absence of an MEP interaction at these early intervals. Interestingly, a disruption of grasp by paired-pulse TMS over ventral premotor cortex was recently reported by Davare et al. (2006) when TMS was delivered 50 or 100 ms after the ‘go’ signal. We suggest that the disruption of grasp by paired-pulse TMS over M1 may reflect interference in premotor–M1 interactions and their reciprocal interconnections (Dum & Strick, 2005) at this key time point. TMS can have two distinct functions in studies of the motor system: as a probe of cortical excitability and as a virtual lesion (Merabet et al. 2003). In this study, we have primarily used TMS as a probe. Interestingly, however, TMS immediately after object presentation may additionally function as a virtual lesion.
In this light, we can ask whether the increased object contact time was due to TMS delivery per se or to the requirement for subjects to reach and grasp almost immediately after object presentation. Figure 4B demonstrates that there was no disruption of performance when sham TMS acted as an early ‘go’ signal at 50 ms. Therefore the explanation must lie in the disruptive effect of TMS itself. It seems likely that TMS at 50 and 100 ms may disrupt or prevent processing of the early visuomotor information required to select the appropriate reach-to-grasp movement. TMS delivery before visuomotor information has reached M1 may make it less able to respond to subsequent inputs thus delaying object contact.
Pattern of excitation during movement preparation
In principle the modulation of M1 outputs prior to grasp could reflect sustained facilitation from 150 to 800 ms after object presentation by grasp-related visuomotor inputs. However, several arguments suggest that increased excitability is restricted to the period just before grasp. Firstly, while some premotor cortex neurones can show tonic set-related activity in a delayed response reach-to-grasp task (Wise & Mauritz, 1985; Crammond & Kalaska, 2000), the majority of neurones in ventral premotor area F5 show a phasic peak of firing after object presentation and then again for initiation of grasp (Murata et al. 1997). A study of perceptual size illusion effects on human grasping concluded that the motor plan for grasping is formed just before movement execution (Westwood & Goodale, 2003). Finally, TMS has been shown to delay voluntary reactions, while leaving the form of the response unaffected (Day et al. 1989). Taken together, these results suggests that the specific parameters for grasp may be stored upstream of M1.
By dissociating TMS from the cue to grasp, and delivering it at intervals that have previously produced MEP modulation, we were able to investigate changes in the excitability of the cortico-cortical inputs to M1 in the period between visual presentation and cue to grasp. With the cue to grasp at 1200 ms, neither TMS at 150 ms nor TMS at 800 ms produced an interaction in the MEP (Fig. 5A, left), although the grasp-related EMG activity did show the usual interaction (Fig. 5B, left). This suggests that a peak of excitability occurs in the inputs to M1 at or just before the planned grasp, but not before. Although the effect was not present 400 ms prior to the ‘go’ signal, we know from our previous experiment (Cattaneo et al. 2005), which used a 10% jitter in TMS stimulation time, that this effect is present in a window of at least 100 ms around the time of the cue to grasp.
If transmission of the inputs conveying visuomotor information to M1 occurs just before movement onset, how can TMS, when it is given as the cue to move, evoke MEPs with such a significant modulation? We suggest that in the blocked trials of experiment 1, subjects anticipated the delivery of the TMS as the ‘go’ signal and that therefore TMS probed the system just as subjects were about to execute the grasping action. Thus TMS was delivered in the period when visuomotor inputs had their greatest anticipatory influence on M1. In experiment 3, random TMS was used to directly test this ‘predictability’ hypothesis. Randomized TMS abolished the interaction effects seen in the MEP (Fig. 5A, right). The subsequent grasp-related EMG activity was unaffected, showing the normal differential activation for the two objects (Fig. 5B, right). The results suggest that excitatory inputs to M1 are modulated only just before the moment of grasp execution, rather than being maintained in a steady state for long periods prior to grasp.
Conclusions
In a series of experiments we have shown that, during the movement preparation period of self-paced visuomotor grasp, there are object- and muscle-specific changes in the excitability of M1. Depending on whether single- or paired-pulse TMS was delivered, the MEP in the muscle most activated during later preshaping of the hand for grasp was either suppressed or facilitated. Thus TMS can be used to measure contrasting patterns of corticospinal excitability during movement preparation. Our study focused particularly on the time course of these modulations. TMS over M1 delivered early, at 50 or 100 ms after object presentation, caused disruption of the subsequent movement whilst TMS delivered later, at 150 or 800 ms, elicited task-related modulation of the MEP. The effect for later TMS was abolished when stimulation was 400 ms or earlier from the imperative cue or if the time of the ‘go’ signal was unpredictable. This strongly indicates that the visuomotor grasping circuit does not modulate M1 outputs throughout the period from object presentation until the moment of grasp execution. Rather, inputs to M1 that facilitate grasp show raised excitability in the period immediately before grasp is executed. We suggest that the parietal-premotor circuit may prepare and then maintain grasp motor programmes during the delay period, forwarding them to primary motor cortex only at the time they are finally needed for action. Depending on whether single- or paired-pulse TMS was delivered, the MEP in the muscle most activated during hand preshaping was either suppressed or facilitated. Thus TMS can be used to enhance contrasting patterns of corticospinal excitability during movement preparation.
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Binkofski F, Buccino G, Posse S, Seitz RJ, Rizzolatti G & Freund H (1999). A fronto-parietal circuit for object manipulation in man: evidence from an fMRI-study. Eur J Neurosci 11, 3276–3286.[CrossRef][Medline]
Cattaneo L, Voss M, Brochier T, Prabhu G, Wolpert DM & Lemon RN (2005). A cortico-cortical mechanism mediating object-driven grasp in humans. Proc Natl Acad Sci U S A 102, 898–903.
Cerri G, Shimazu H, Maier MA & Lemon RN (2003). Facilitation from ventral premotor cortex of primary motor cortex outputs to macaque hand muscles. J Neurophysiol 90, 832–842.
Crammond DJ & Kalaska JF (2000). Prior information in motor and premotor cortex: activity during the delay period and effect on pre-movement activity. J Neurophysiol 84, 986–1005.
Davare M, Andres M, Cosnard G, Thonnard J-L & Olivier E (2006). Dissociating the role of ventral and dorsal premotor cortex in precision grasping. J Neuroscience 26, 2260–2268.
Day BL, Rothwell JC, Thompson PD, Maertens de NA, Nakashima K, Shannon K & Marsden CD (1989). Delay in the execution of voluntary movement by electrical or magnetic brain stimulation in intact man. Evidence for the storage of motor programs in the brain. Brain 112, 649–663.
Dum RP & Strick PL (2005). Frontal lobe inputs to the digit representations of the motor areas on the lateral surface of the hemisphere. J Neurosci 25, 1375–1386.
Fogassi L, Gallese V, Buccino G, Craighero L, Fadiga L & Rizzolatti G (2001). Cortical mechanism for the visual guidance of hand grasping movements in the monkey: a reversible inactivation study. Brain 124, 571–586.
Gallese V, Murata A, Kaseda M, Niki N & Sakata H (1994). Deficit of hand preshaping after muscimol injection in monkey parietal cortex. Neuroreport 5, 1525–1529.[Medline]
Grezes J, Armony JL, Rowe J & Passingham RE (2003). Activations related to ‘mirror’ and ‘canonical’ neurones in the human brain: an fMRI study. Neuroimage 18, 928–937.[CrossRef][Medline]
Hanajima R, Ugawa Y, Terao Y, Enomoto H, Shiio Y, Mochizuki H, Furubayashi T, Uesugi H, Iwata NK & Kanazawa I (2002). Mechanisms of intracortical I-wave facilitation elicited with paired-pulse magnetic stimulation in humans. J Physiol 538, 253–261.
Hasbroucq T, Kaneko H, Akamatsu M & Possamai CA (1997). Preparatory inhibition of cortico-spinal excitability: a transcranial magnetic stimulation study in man. Brain Res Cogn Brain Res 5, 185–192.[CrossRef][Medline]
Hasbroucq T, Kaneko H, Akamatsu M & Possamai CA (1999). The time-course of preparatory spinal and cortico-spinal inhibition: an H-reflex and transcranial magnetic stimulation study in man. Exp Brain Res 124, 33–41.[CrossRef][Medline]
Ilic TV, Meintzschel F, Cleff U, Ruge D, Kessler KR & Ziemann U (2002). Short-interval paired-pulse inhibition and facilitation of human motor cortex: the dimension of stimulus intensity. J Physiol 545, 153–167.
Jeannerod M, Arbib MA, Rizzolatti G & Sakata H (1995). Grasping objects: the cortical mechanisms of visuomotor transformation. Trends Neurosci 18, 314–320.[CrossRef][Medline]
di Lazzaro V, Rothwell JC, Oliviero A, Profice P, Insola A, Mazzone P & Tonali P (1999). Intracortical origin of the short latency facilitation produced by pairs of threshold magnetic stimuli applied to human motor cortex. Exp Brain Res 129, 494–499.[CrossRef][Medline]
Merabet LB, Theoret H & Pascual-Leone A (2003). Transcranial magnetic stimulation as an investigative tool in the study of visual function. Optom Vis Sci 80, 356–368.[Medline]
Murata A, Fadiga L, Fogassi L, Gallese V, Raos V & Rizzolatti G (1997). Object representation in the ventral premotor cortex (area F5) of the monkey. J Neurophysiol 78, 2226–2230.
Murata A, Gallese V, Luppino G, Kaseda M & Sakata H (2000). Selectivity for the shape, size, and orientation of objects for grasping in neurons of monkey parietal area AIP. J Neurophysiol 83, 2580–2601.
Prut Y & Fetz EE (1999). Primate spinal interneurons show pre-movement instructed delay activity. Nature 401, 590–594.[CrossRef][Medline]
Rizzolatti G & Luppino G (2001). The cortical motor system. Neuron 31, 889–901.[CrossRef][Medline]
Rossini PM, Barker AT, Berardelli A, Caramia MD, Caruso G, Cracco RQ, Dimitrijevic MR, Hallett M, Katayama Y & Lucking CH & (1994). Non-invasive electrical and magnetic stimulation of the brain, spinal cord and roots: basic principles and procedures for routine clinical application. Report of an IFCN committee. Electroencephalogr Clin Neurophysiol 91, 79–92.[CrossRef][Medline]
Sakai K, Ugawa Y, Terao Y, Hanajima R, Furubayashi T & Kanazawa I (1997). Preferential activation of different I waves by transcranial magnetic stimulation with a figure-of-eight-shaped coil. Exp Brain Res 113, 24–32.[CrossRef][Medline]
Sawaguchi T, Yamane I & Kubota K (1996). Application of the GABA antagonist bicuculline to the premotor cortex reduces the ability to withhold reaching movements by well-trained monkeys in visually guided reaching task. J Neurophysiol 75, 2150–2156.
Schluter ND, Rushworth MF, Passingham RE & Mills KR (1998). Temporary interference in human lateral premotor cortex suggests dominance for the selection of movements. A study using transcranial magnetic stimulation. Brain 121, 785–799.
Shimazu H, Maier MA, Cerri G, Kirkwood PA & Lemon RN (2004). Macaque ventral premotor cortex exerts powerful facilitation of motor cortex outputs to upper limb motoneurons. J Neurosci 24, 1200–1211.
Terao Y, Fukuda H, Ugawa Y, Hikosaka O, Hanajima R, Furubayashi T, Sakai K, Miyauchi S, Sasaki Y & Kanazawa I (1998). Visualization of the information flow through human oculomotor cortical regions by transcranial magnetic stimulation. J Neurophysiol 80, 936–946.
Tokimura H, Ridding MC, Tokimura Y, Amassian VE & Rothwell JC (1996). Short latency facilitation between pairs of threshold magnetic stimuli applied to human motor cortex. Electroencephalogr Clin Neurophysiol 101, 263–272.[CrossRef][Medline]
Tokuno H & Nambu A (2000). Organization of nonprimary motor cortical inputs on pyramidal and nonpyramidal tract neurons of primary motor cortex: An electrophysiological study in the macaque monkey. Cereb Cortex 10, 58–68.
Touge T, Taylor JL & Rothwell JC (1998). Reduced excitability of the cortico-spinal system during the warning period of a reaction time task. Electroencephalogr Clin Neurophysiol 109, 489–495.[CrossRef][Medline]
Weinrich M & Wise SP (1982). The premotor cortex of the monkey. J Neurosci 2, 1329–1345.[Abstract]
Westwood DA & Goodale MA (2003). Perceptual illusion and the real-time control of action. Spat Vis 16, 243–254.[CrossRef][Medline]
Wise SP & Kurata K (1989). Set-related activity in the premotor cortex of rhesus monkeys: effect of triggering cues and relatively long delay intervals. Somatosens Mot Res 6, 455–476.[Medline]
Wise SP & Mauritz KH (1985). Set-related neuronal activity in the premotor cortex of rhesus monkeys: effects of changes in motor set. Proc R Soc Lond B Biol Sci 223, 331–354.[Medline]
Ziemann U (1999). Intracortical inhibition and facilitation in the conventional paired TMS paradigm. Electroencephalogr Clin Neurophysiol Suppl 51, 127–136.[Medline]
Ziemann U, Tergau F, Wassermann EM, Wischer S, Hildebrandt J & Paulus W (1998). Demonstration of facilitatory I wave interaction in the human motor cortex by paired transcranial magnetic stimulation. J Physiol 511, 181–190.
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  G. Prabhu, R. Lemon, and P. Haggard On-Line Control of Grasping Actions: Object-Specific Motor Facilitation Requires Sustained Visual Input J. Neurosci., November 14, 2007; 27(46): 12651 - 12654. [Abstract] [Full Text] [PDF]
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) were evoked first during object observation (two blocks) and then grasp (two blocks) with transcranial magnetic stimulation (TMS) delivery being the cue to grasp. TMS was delivered in two counterbalanced blocks of 50 and 100 ms (group A), and 150 and 800 ms (group B), after visual presentation of the object (OP). B, experiment 2, eight subjects in two counterbalanced blocks (TMS at 150 and 800 ms after object presentation) grasped the objects on hearing a 100 ms tone that occurred randomly at 1200 (83.3% of trials), 250 (8.3%) and 2000 ms (8.3%). For 25% of trials there was no TMS. C, in experiment 3 (eight subjects) TMS (as the cue to grasp) was delivered at random intervals 150–780 ms after object presentation. Trials without TMS occurred once per object. Note, as this was not a reaction time study there was considerable variation in object contact time.
