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Involvement of ipsilateral parieto-occipital cortex in the planning of reaching movements: Evidence by TMS
Neuroscience Letters 460 (2009) 112–116
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Neuroscience Letters journal homepage: www.elsevier.com/locate/neulet
Involvement of ipsilateral parieto-occipital cortex in the planning of reaching movements: Evidence by TMS Pierpaolo Busan a,∗ , Joanna Jarmolowska b , Mauro Semenic c , Fabrizio Monti c , Giovanna Pelamatti b , Gilberto Pizzolato c , Piero Paolo Battaglini a a b c
BRAIN Center, Department of Life Sciences, University of Trieste, Via Fleming, 22, 34127 Trieste, Italy Department of Psychology, University of Trieste, Trieste, Italy Department of Clinical and Experimental Medicine and Clinical and Experimental Neuroscience, University of Trieste, Trieste, Italy
a r t i c l e
i n f o
Article history: Received 13 November 2008 Received in revised form 19 April 2009 Accepted 12 May 2009 Keywords: Ipsilateral hemisphere Reaching Reaction time Transcranial magnetic stimulation
a b s t r a c t Involvement of the ipsilateral hemisphere during planning of reaching movements is still matter of debate. While it has been demonstrated that the contralateral hemisphere is dominant in visuo-motor integration, involvement of the ipsilateral hemisphere has also been proposed. Furthermore, a dominant role for left posterior parietal cortex has been shown in this process, independently of the hand and visual field involved. In this study, the possible involvement of ipsilateral parieto-occipital cortex in planning of reaching movements was investigated by transcranial magnetic stimulation (TMS). TMS was applied on four points of the parietal and occipital cortex at 50% (Time 1), 75% (Time 2) and 90% (Time 3) of reaction time from a go-signal to hand movement. The only effect observed was an increase in reaction time when a region around the parieto-occipital junction was stimulated at Time 2. These results provide further support to the hypothesis that, in the posterior parietal cortex, planning of reaching movements also relies on the ipsilateral hemisphere, in addition to the contralateral or dominant one. © 2009 Elsevier Ireland Ltd. All rights reserved.
The dorsal stream for processing of visual information plays a critical role in real-time control of action by transforming information about location of objects into the coordinate frames of effectors [20]. In this context, the posterior parietal cortex (PPC) plays a pivotal role. It comprises the parietal reach region (PRR), an area principally involved in transformation of spatial cues in motor programming [1,5,33]. The PRR is located in and around the intraparietal sulcus (IPS), close to the junction with the parieto-occipital sulcus (POS) [33]. In this region of the cortex, the left hemisphere plays a special role in organizing eye and limb movements during visually-guided reaching [13,19,28,31], but it is not completely clear whether reach representation in PPC is limb-dependent or not [9]. A number of studies have investigated the hemispheric distribution of visuo-motor transformations in the parietal cortex to better understand the specific involvement of the contraand ipsilateral hemisphere in planning and execution of reaching movements, although no definitive evidence has been found. A strong involvement of contralateral limb in PPC during planning of reaching movements has been demonstrated [14–16,18,35], as well as activation of both hemispheres [6,22,25]. Some neurons in the PPC were found to represent targets for movements of either limb,
∗ Corresponding author. Tel.: +39 0405587183; fax: +39 040567862. E-mail address: [email protected] (P. Busan). 0304-3940/$ – see front matter © 2009 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.neulet.2009.05.028
whereas other neurons represented only contralateral limb targets. More interestingly, a small number of cells also represented ipsilateral limb targets with representations that were not dependent on preferred directions [8]. In general, the ipsilateral hemisphere intervenes in information processing especially when considering motor and premotor cortices during planning and execution of movements [2,17,27]. This suggests that similar processes might also exist in other non-motor cortical regions. In the present study, we investigated the role of right parietooccipital cortex by assessing its involvement in planning of ipsilateral reaching movements. For this purpose, we applied single-pulse transcranial magnetic stimulation (TMS) over different points at various times of planning of reaching movements towards central, ipsi- and contralateral targets in space. TMS is a non-invasive technique that inhibits or facilitates information processing in stimulated brain areas during task execution [32]. TMS has already been used to study the relationship between PPC and different aspects of visuo-motor processing [3,10,21]. When TMS was applied over PPC during reaching movements, subjects were unable to correct the ongoing movement following a jump of the target [11]. A study on memory-delayed reaching movements showed that TMS on PPC interferes with spatial processing [34]. In spite of the relative abundance of information on this topic, data is still lacking about the exact involvement of the ipsilateral hemisphere in visuo-motor behaviour. In the present
P. Busan et al. / Neuroscience Letters 460 (2009) 112–116
study, evidence is reported on the involvement of ipsilateral parieto-occipital cortex in planning of visually-guided reaching movements, supporting the existence of specific ipsilateral cortical representations for planning of reaching movements in humans. Forty-four healthy volunteers (15 males, 29 females; age-range 20–42 years, mean age and standard deviation: m ± SD = 24.8 ± 4.2 years) participated in the study. All were right-handed according to the Oldfield test [24], and provided written informed consent after receiving information about TMS and its related risks, in accordance with the Declaration of Helsinki. Permission from the Local Ethic Committee was also obtained. Three experimental and two control sessions were carried out. The first and the second experiments involved 10 subjects (m ± SD = 25.3 ± 3.9 and 24.6 ± 2.5 years, respectively). The third experiment involved nine subjects (m ± SD = 23.9 ± 2.8 years). Eight (m ± SD = 27.2 ± 7.0 years) and seven subjects (m ± SD = 24.0 ± 3.1 years), respectively, participated in the control sessions. Each subject was comfortably seated in front of a table. Individuals placed their right hand on a light-detector on the table, located 5 cm from the chest. A cross, drawn at 35 cm from the subject along the midline, was used to maintain steady fixation. A small metal cylinder was placed on the fixation cross or at 40◦ from it, to the left or the right, and maintaining a constant distance between the light-detector and cylinder (35 cm). The cylinder was connected to an impedance-detector that allowed measurement of the time elapsed between the start of the movement (signalled by the lightdetector) and its completion (signalled by the touch of the cylinder). Arm and eye movements were continuously recorded with a digital video camera (Sony DCR-SR30E, sampling rate: 25 Hz) to discard incorrectly performed trials. At the beginning of each trial, subjects were asked to close their eyes. A tone from a loudspeaker signalled subjects to open their eyes and to reach and touch the target cylinder as soon as possible, while maintaining a steady fixation on the central cross. All experimental events were controlled by a PCMCIA acquisition board (NI-DAQ 6024E, National Instruments, Texas, USA) controlled by LABVIEW PC software that managed all experimental parameters, comprising both reaction (RT) and movement times (MT), measured as the time elapsed between the tone and hand movement and the duration of hand movement, respectively. Before TMS experiments, subjects performed a series of 21 reaching trials with targets randomly distributed in the centre, right and left to measure their mean reaction time (m-RT). This value was then used to calculate, subject by subject, the timing of TMS delivery. Mean-RT was determined independently of target positions to obtain a single reliable value for timing of TMS delivery, and reduce experimental variability. TMS pulses were applied at 50% (Time 1, Experiment 1), 75% (Time 2, Experiment 2) and 90% (Time 3, Experiment 3) of each subject’s m-RT. TMS at 50% of m-RT was delivered around eye-opening, while in all other stimulation times, the eyes were steadily opened. If execution of the task improved so as to reduce the m-RT more than 20%, a new m-RT was calculated from the 21 NO-TMS trials performed in the last point of stimulation on the scalp. The timing of TMS delivery was consequently modified. Mean-RT were longer than in usual psychometric experiments because a “double” reaction time paradigm was adopted. Indeed, the time elapsed from the acoustic signal to arm movement (reaction time) comprised the time required to open the eyes and plan the movement towards the target. Only one of the three TMS stimulation times was applied in each subject to minimize fatigue and avoid lengthy exposition to TMS. Subjects performed 42 randomized trials for each stimulated point: 21 trials with TMS and 21 without TMS (TMS and NO-TMS conditions, respectively). Of the 21 trials, 7 had the target on the right, 7 on the left and 7 in the centre. Each subject underwent 168 trials: 42 trials for 4 points (see below).
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Fig. 1. Points of stimulation and related effects of TMS obtained with stimulation delivered at 75% of m-RT. (A) Stimulated points on the scalp in the right parietooccipital cortex; (B) Reaction times with no distinction for target location. Mean data and standard deviations are reported. The asterisk indicates statistically significant differences.
A 7 cm figure-8 coil (Medtronic C-B60) oriented tangentially to the scalp with the handle perpendicular to the interhemispheric fissure and pointing leftward was used. The coil was positioned and secured in place by fixing it to a mechanical arm, and its position was continuously checked and readjusted as necessary. In each subject, the best cortical point activating the first dorsal interosseal muscle (FDI) was determined and the motor threshold was set as the stimulus intensity triggering at least 50 V responses on EMG recording in at least 50% of 10 consecutive stimulations. The intensity of the TMS pulse was then set at 120% of the FDI motor threshold. TMS pulses (duration: 280 s; Medtronic MagPro R30) were delivered at four different points on right parieto-occipital cortex. According to the 10–20 EEG coordinate system [26], these points of stimulation were localized on the superior occipital lobe (point a), around the parieto-occipital sulcus (points b and c) and on the posterior part of superior parietal lobule (point d) (Fig. 1A). The four points were always stimulated in a randomized order. TV recordings were analyzed off-line and all trials where the subject’s eyes did not remain still on the central fixation cross for the entire trial were excluded. To avoid the influence of inadequate attention, all trials with a RT longer than 1000 ms or shorter than 100 ms, and MT longer than 700 ms or shorter than 100 ms were also excluded. Moreover, trials were considered incorrectly performed when evident trajectory corrections were made or evident hesitation was present after the start of movements. Trajectory corrections were observed when the hand was initially moved toward a wrong position and then turned to the right one. Hesitations corresponded to the stopping of movement even if it was toward the correct target. RT and MT that dropped out the limit of two standard deviations from the mean of their condition were also discarded from analyses. Considering the above, about 10% of raw data was eliminated. Data was normally distributed (Shapiro-Wilk test), both in RT and MT, and thus no data transformation or correction was needed. Moreover, the homogeneity of variance was successfully checked within experiments. Parametrical analysis was conducted with repeated measures ANOVA considering the main effects and interactions between TMS conditions (yes/no), location of stimulation on the scalp (four positions) and target position in space (central, left and right). A p < 0.05
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was considered statistically significant. If interaction between main effects was statistically significant, post-hoc analyses were conducted. More specifically, if interaction between all main effects resulted significant, two-way ANOVAs between main factors were conducted (significance level set at p < 0.05, Bonferroni corrected). Finally, when interaction in a two-way ANOVA or between two main effects was significant, post-hoc analyses were conducted with Student’s t-test (significance level p < 0.05, Bonferroni corrected). The mean RT was different among subjects, ranging from 428 ± 24 ms in the fastest to 813 ± 26 ms in the slowest, with a mean value of 658 ± 98 ms in Experiment 1, 586 ± 114 ms in Experiment 2 and 593 ± 87 ms in Experiment 3. No significant differences were found between experiments (F2,26 = 1.573, p = 0.226). Standard deviations and, consequently, inter-individual variability, was very high, but the intra-subject variability was smaller, ranging from 18 ms to 65 ms in the TMS condition, and from 24 ms to 57 ms in the NO-TMS condition. Analysis of movement times did not yield statistically significant differences, and were thus not considered further. TMS applied at 50% of m-RT reduced RT in a unspecific manner (F1,9 = 12.589, p = 0.006). Significant results were obtained in main factor analysis for target location (F2,18 = 18.718, p < 0.001), indicating a slower RT toward the left (central vs. left: t = 4.352, p = 0.002; central vs. right: t = 1.471, p = 0.175; left vs. right: t = 5.232, p = 0.0005). The points of stimulation main factor was not significant (F3,27 = 1.294, p = 0.297). Likewise, no interactions were significant (target location vs. points of stimulation: F6,54 = 1.282, p = 0.281; target location vs. TMS: F2,18 = 2.324, p = 0.127; TMS vs. points of stimulation: F3,27 = 1.806, p = 0.170; target location vs. point of stimulation vs. TMS: F6,54 = 1.251, p = 0.295). The results are summarized in Table 1 (left). When TMS was applied at 75% of m-RT, significant results were obtained in main factor analysis for target location (F2,18 = 6.824, p = 0.006), indicating a slower RT towards the left (central vs. left: t = 2.832, p = 0.019; central vs. right: t = 0.638, p = 0.486; left vs. right: t = 2.987, p = 0.015). Points of stimulation and TMS main factors were not significant (F3,27 = 1.681, p = 0.194; F1,9 = 0.295, p = 0.600; respectively). Likewise, no interactions were significant (target location vs. points of stimulation: F6,54 = 0.835, p = 0.548; target location vs. TMS: F2,18 = 0.017, p = 0.983; target location vs. point of stimulation vs. TMS: F6,54 = 1.313, p = 0.267), except when considering the interaction between points of stimulation and TMS conditions (F3,27 = 4.493, p = 0.011). Post-hoc analysis revealed that the only point on the scalp that was influenced by TMS was point b (t = 3.302, p = 0.009; Fig. 1B). In particular, TMS caused a delay in RT for this point on the scalp and all target locations. The results are summarized in Table 1 (centre).
When TMS was applied at 90% of m-RT, significant results were obtained in main factor analysis for target location (F2,16 = 11.522, p = 0.001), indicating a slower RT towards the left (central vs. left: t = 2.579, p = 0.033; central vs. right: t = 0.727, p = 0.488; left vs. right: t = 3.643, p = 0.007). Points of stimulation and TMS main factors were not significant (F3,24 = 0.412, p = 0.746; F1,8 = 0.008 p = 0.929; respectively), and no significant interactions were found (target location vs. points of stimulation: F6,48 = 0.492, p = 0.811; target location vs. TMS: F2,18 = 0.017, p = 0.983; points of stimulation vs. TMS: F3,24 = 1.246, p = 0.315; target location vs. point of stimulation vs. TMS: F6,48 = 1.051, p = 0.405). The results are summarized in Table 1 (right). In control Experiment 1, subjects had to move their thumb, instead of their arm, away from the light-sensor when the target was in central position, and not when the target was on the left or the right. Thus, the reaching component was eliminated, maintaining visual detection, attention and motor planning. This allowed us to determine if the observed effects were related to planning of reaching movements. In fact, if significant results were confirmed, then the findings should be mainly related to unspecific visual, motor or attention effects. All subjects had to perform 24 trials for the point on the scalp (point b) and for the stimulation time that gave positive results in main experiments (Time 2): 12 with target in the centre, 6 in the left and 6 in the right. TMS was randomly delivered in half of trials. In control Experiment 2, the effective point on the scalp (point b) was investigated at effective stimulation time (Time 2), using the same procedure of main experiments, but asking subjects to use the left hand. This allowed controlling for possible pre-activation or facilitation in motor programming in the contralateral hand, so as to interfere with RT of ipsilateral hand by delaying it. In control Experiment 1, point b was stimulated with no significant differences (TMS: m ± SD = 702 ± 83 ms, NO-TMS: m ± SD = 702 ± 118 ms; t = 0.01, p = 0.99). In control Experiment 2, again, no significant differences were found when all target locations were considered altogether (TMS: m ± SD = 633 ± 108 ms, NO-TMS: m ± SD = 624 ± 110 ms; t = 1.01, p = 0.35). No effects for target location, TMS or interaction between them was found (TMS: m ± SD = central target 615 ± 104 ms, left target 625 ± 106 ms, right target 658 ± 133 ms; NO-TMS: m ± SD = central target 617 ± 105, left target 610 ± 126, right target 653 ± 123; target location main effect: F = 0.52, p = 0.59; TMS main effect: F = 0.02, p = 0.87; interaction: F = 0.02, p = 0.98) The present findings confirm the involvement of the ipsilateral parieto-occipital cortex in planning of reaching movements in a specific scalp location and in a specific time-window of stimulation during planning of movements. MT was unaffected by TMS when
Table 1 Mean reaction times and standard deviations (in ms) collected in the TMS and NO-TMS experiments. Data are reported for each of the three timing conditions, relatively to points of stimulation and target location. Bold characters indicate statistically significant comparisons. Points
Target position
TMS at 50% of m-RT
TMS at 75% of m-RT
TMS at 90% of m-RT
TMS
NO-TMS
TMS
NO-TMS
TMS
NO-TMS
A
Central Left Right
636 ± 105 664 ± 112 640 ± 123
672 ± 104 691 ± 114 624 ± 85
574 ± 124 582 ± 120 566 ± 111
574 ± 116 595 ± 131 576 ± 124
585 ± 80 612 ± 121 603 ± 102
578 ± 91 610 ± 72 569 ± 49
B
Central Left Right
626 ± 104 664 ± 114 646 ± 126
655 ± 103 715 ± 120 655 ± 111
596 ± 111 644 ± 156 595 ± 112
587 ± 120 614 ± 130 587 ± 114
584 ± 142 617 ± 106 568 ± 91
567 ± 87 624 ± 139 601 ± 124
C
Central Left Right
640 ± 131 671 ± 124 612 ± 125
636 ± 113 687 ± 101 627 ± 123
561 ± 118 580 ± 132 562 ± 123
569 ± 116 604 ± 132 564 ± 123
599 ± 105 619 ± 100 592 ± 77
577 ± 61 648 ± 97 587 ± 69
D
Central Left Right
608 ± 103 642 ± 89 593 ± 72
633 ± 91 680 ± 94 631 ± 94
582 ± 114 582 ± 120 579 ± 101
588 ± 124 595 ± 131 577 ± 94
586 ± 106 605 ± 86 568 ± 80
582 ± 97 617 ± 98 591 ± 104
P. Busan et al. / Neuroscience Letters 460 (2009) 112–116
stimulating during planning of actions, possibly because action execution was not directly influenced by the delivery of stimulation during action planning. This confirms the effectiveness of TMS during planning of movements, avoiding the possibility that TMS effect might be extended in a relatively long time, as would be the case if the findings in MT were highlighted. Before discussing results in more detail, three methodological issues must be addressed. (A) Location of stimulated points. Taking into account anatomical variability among subjects [29], and a range of ±8 mm when using 10–20 EEG system to individuate correspondences between electrodes and underlying cortex [23], we are confident that all stimulated points were on the medial parietooccipital cortex of right hemisphere. (B) Specificity of effects. Several effects were observed after TMS that were not specific for the stimulated cortical region. A general and non-localized facilitation of RT was obtained at 50% of m-RT for all stimulated points. This may be ascribed to inter-sensory facilitation [30], induced principally by noise and scalp sensation due to TMS, which could also cause a faster opening of eyes, considering that, in Experiment 1, stimulation was delivered around eye-opening. On the other hand, another explanation for facilitation of RT might be related to a specific effect on a targeted region, when stimulating slightly before its physiological activation, and, consequently, facilitating a cognitive response and related behaviour [7,32]. However, in the case of Experiment 1, inter-sensory facilitation is the more plausible explanation, considering that effects were not localized on a specific scalp region. A slower RT was observed when subjects reached targets in the left hemispace with the right hand. This effect is compatible with a “compatibility effect” phenomenon [12,26], usually indicated as facilitation in RT towards ipsilateral targets and slower RT towards contralateral ones. (C) Inter- and intra-variability of RT. Variability of the effect, namely differences between conditions for each subject, must be very small to result in a significant statistical difference. Consequently, with a large inter-variability, and therefore with a substantial standard deviation, as in the present experiment, it would be very difficult to highlight significant differences among various conditions. Nevertheless, the relatively small effect in point b in Experiment 2 was statistically significant, also considering that the tendency of significant data (slowing of RT with TMS) had an opposite trend with respect to the other data obtained, and that intra-subject variability was much smaller, resulting in a significant result. Thus, a more specific result (i.e. depending on the limb to be moved) was obtained when TMS was applied at 75% of m-RT in point b. It consisted in a delayed RT which was evident for all target positions considered. The result was specifically related to planning of reaching movements and not merely to visual detection, attention and/or motor planning. In fact, no delay of RT was observed in the first control experiment, when the requested movement was not a reaching one. As already mentioned, there is some degree of uncertainty in the literature about the exact role played by the ipsilateral hemisphere in planning of reaching movements. It has been already indicated that a strong representation of contralateral limb in PPC during planning of reaching movements exists [14–16,18,35], as well as activation of both hemispheres [6,22,25]. Moreover, data obtained from optic ataxia, where a lesion in the PPC is usually evident, normally show that the contralateral visual field and/or contralateral hand is affected by a spatial and/or a reaching deficit [4].
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Nonetheless, activation of cells in parietal regions that are exclusively modulated by ipsilateral reaching movements has been reported in monkeys [8]. Involvement of the ipsilateral hemisphere during information processing is well documented also in motor and premotor cortices during planning and execution of movements [2,17,27], suggesting that similar processes might behave in an analogous manner in other cortical regions, as suggested by the present data in the parieto-occipital cortex. Our findings suggest that specific processing of reaching movements for the ipsilateral limb is present in parieto-occipital cortex, independently from space. One possible explanation is that TMS pre-activated or facilitated motor programming in the contralateral hand, so as to interfere with RT of the ipsilateral hand by delaying it. However, the second control experiment showed that this is not the case. In fact, TMS delivered at the same time and position did not interfere with reaching movements when performed with contralateral hand. In conclusion, the present experiments support the existence of a more complex and wider ipsilateral network related to planning of reaching movements than previously suggested, adding information about the possibility of the existence of specific ipsilateral representations for planning of reaching movements in humans. Furthermore, even if planning of reaching movements might be primarily represented and controlled by the contralateral hemisphere, there is also the possibility that additional ipsilateral representations are involved that could be resumed in the case of brain damage. The finding might be of relevance not only for better knowledge of cortical functioning, but also for clinical and rehabilitation purposes. Acknowledgments Authors wish to thank Dr. Luigi Stebel for software and hardware assistance. This work was supported by grants from Ministero dell’Università e della Ricerca, Italy. References [1] A.P. Batista, C.A. Buneo, L.H. Snyder, R.A. Andersen, Reach plans in eye-centered coordinates, Science 285 (1999) 257–260. [2] N.M. Benwell, F.L. Mastaglia, G.W. Thickbroom, Changes in the functional MR signal in motor and non-motor areas during intermittent fatiguing hand exercise, Exp. Brain Res. 182 (2007) 93–97. [3] S. Bestmann, K.V. Thilo, D. Sauner, H.R. Siebner, J.C. Rothwell, Parietal magnetic stimulation delays visuomotor mental rotation at increased processing demands, Neuroimage. 17 (2002) 1512–1520. [4] A. Blangero, V. Gaveau, J. Luaute, G. Rode, R. Salemme, M. Guinard, D. Boisson, Y. Rossetti, L. Pisella, A hand and a field effect in on-line motor control in unilateral optic ataxia, Cortex 44 (2008) 560–568. [5] C.A. Buneo, M.R. Jarvis, A.P. Batista, R.A. Andersen, Direct visuomotor transformations for reaching, Nature. 416 (2002) 632–636. [6] J.L. Calton, A.R. Dickinson, L.H. Snyder, Non-spatial, motor-specific activation in posterior parietal cortex, Nat. Neurosci. 5 (2002) 580–588. [7] Z. Cattaneo, J. Silvanto, Time course of the state-dependent effect of transcranial magnetic stimulation in the TMS-adaptation paradigm, Neurosci. Lett. 443 (2008) 82–85. [8] S.W.C. Chang, A.R. Dickinson, L.H. Snyder, Limb-specific representation for reaching in the posterior parietal cortex, J. Neurosci. 28 (2008) 6128–6140. [9] C.L. Colby, R. Gattass, C.R. Olson, C.G. Gross, Topographical organization of cortical afferents to extrastriate visual area PO in the macaque: a dual tracer study, J. Comp. Neurol. 269 (1988) 392–413. [10] J.C. Culham, K.F. Valyer, Human parietal cortex in action, Curr. Opin. Neurobiol. 16 (2006) 1–8. [11] M. Desmurget, C.M. Epstein, R.S. Turner, C. Prablanc, G.E. Alexander, S.T. Grafton, Role of the posterior parietal cortex in updating reaching movements to a visual target, Nat. Neurosci. 2 (1999) 492–494. [12] P.M. Fitts, C.M. Seeger, S–R compatibility: spatial characteristics of stimulus and response codes, J. Exp. Psychol. 46 (1953) 199–210. [13] M.A. Goodale, Hemispheric differences in motor control, Behav. Brain Res. 30 (1988) 203–214. [14] S.T. Grafton, J.C. Mazziotta, R.P. Woods, M.E. Phelps, Human functional anatomy of visually guided finger movements, Brain 115 (1992) 565–587. [15] K.Y. Haaland, D.L. Harrington, Hemispheric control of the initial and corrective components of aiming movements, Neuropsychologia 27 (1989) 961–969.
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Neuroscience Letters journal homepage: www.elsevier.com/locate/neulet
Involvement of ipsilateral parieto-occipital cortex in the planning of reaching movements: Evidence by TMS Pierpaolo Busan a,∗ , Joanna Jarmolowska b , Mauro Semenic c , Fabrizio Monti c , Giovanna Pelamatti b , Gilberto Pizzolato c , Piero Paolo Battaglini a a b c
BRAIN Center, Department of Life Sciences, University of Trieste, Via Fleming, 22, 34127 Trieste, Italy Department of Psychology, University of Trieste, Trieste, Italy Department of Clinical and Experimental Medicine and Clinical and Experimental Neuroscience, University of Trieste, Trieste, Italy
a r t i c l e
i n f o
Article history: Received 13 November 2008 Received in revised form 19 April 2009 Accepted 12 May 2009 Keywords: Ipsilateral hemisphere Reaching Reaction time Transcranial magnetic stimulation
a b s t r a c t Involvement of the ipsilateral hemisphere during planning of reaching movements is still matter of debate. While it has been demonstrated that the contralateral hemisphere is dominant in visuo-motor integration, involvement of the ipsilateral hemisphere has also been proposed. Furthermore, a dominant role for left posterior parietal cortex has been shown in this process, independently of the hand and visual field involved. In this study, the possible involvement of ipsilateral parieto-occipital cortex in planning of reaching movements was investigated by transcranial magnetic stimulation (TMS). TMS was applied on four points of the parietal and occipital cortex at 50% (Time 1), 75% (Time 2) and 90% (Time 3) of reaction time from a go-signal to hand movement. The only effect observed was an increase in reaction time when a region around the parieto-occipital junction was stimulated at Time 2. These results provide further support to the hypothesis that, in the posterior parietal cortex, planning of reaching movements also relies on the ipsilateral hemisphere, in addition to the contralateral or dominant one. © 2009 Elsevier Ireland Ltd. All rights reserved.
The dorsal stream for processing of visual information plays a critical role in real-time control of action by transforming information about location of objects into the coordinate frames of effectors [20]. In this context, the posterior parietal cortex (PPC) plays a pivotal role. It comprises the parietal reach region (PRR), an area principally involved in transformation of spatial cues in motor programming [1,5,33]. The PRR is located in and around the intraparietal sulcus (IPS), close to the junction with the parieto-occipital sulcus (POS) [33]. In this region of the cortex, the left hemisphere plays a special role in organizing eye and limb movements during visually-guided reaching [13,19,28,31], but it is not completely clear whether reach representation in PPC is limb-dependent or not [9]. A number of studies have investigated the hemispheric distribution of visuo-motor transformations in the parietal cortex to better understand the specific involvement of the contraand ipsilateral hemisphere in planning and execution of reaching movements, although no definitive evidence has been found. A strong involvement of contralateral limb in PPC during planning of reaching movements has been demonstrated [14–16,18,35], as well as activation of both hemispheres [6,22,25]. Some neurons in the PPC were found to represent targets for movements of either limb,
∗ Corresponding author. Tel.: +39 0405587183; fax: +39 040567862. E-mail address: [email protected] (P. Busan). 0304-3940/$ – see front matter © 2009 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.neulet.2009.05.028
whereas other neurons represented only contralateral limb targets. More interestingly, a small number of cells also represented ipsilateral limb targets with representations that were not dependent on preferred directions [8]. In general, the ipsilateral hemisphere intervenes in information processing especially when considering motor and premotor cortices during planning and execution of movements [2,17,27]. This suggests that similar processes might also exist in other non-motor cortical regions. In the present study, we investigated the role of right parietooccipital cortex by assessing its involvement in planning of ipsilateral reaching movements. For this purpose, we applied single-pulse transcranial magnetic stimulation (TMS) over different points at various times of planning of reaching movements towards central, ipsi- and contralateral targets in space. TMS is a non-invasive technique that inhibits or facilitates information processing in stimulated brain areas during task execution [32]. TMS has already been used to study the relationship between PPC and different aspects of visuo-motor processing [3,10,21]. When TMS was applied over PPC during reaching movements, subjects were unable to correct the ongoing movement following a jump of the target [11]. A study on memory-delayed reaching movements showed that TMS on PPC interferes with spatial processing [34]. In spite of the relative abundance of information on this topic, data is still lacking about the exact involvement of the ipsilateral hemisphere in visuo-motor behaviour. In the present
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study, evidence is reported on the involvement of ipsilateral parieto-occipital cortex in planning of visually-guided reaching movements, supporting the existence of specific ipsilateral cortical representations for planning of reaching movements in humans. Forty-four healthy volunteers (15 males, 29 females; age-range 20–42 years, mean age and standard deviation: m ± SD = 24.8 ± 4.2 years) participated in the study. All were right-handed according to the Oldfield test [24], and provided written informed consent after receiving information about TMS and its related risks, in accordance with the Declaration of Helsinki. Permission from the Local Ethic Committee was also obtained. Three experimental and two control sessions were carried out. The first and the second experiments involved 10 subjects (m ± SD = 25.3 ± 3.9 and 24.6 ± 2.5 years, respectively). The third experiment involved nine subjects (m ± SD = 23.9 ± 2.8 years). Eight (m ± SD = 27.2 ± 7.0 years) and seven subjects (m ± SD = 24.0 ± 3.1 years), respectively, participated in the control sessions. Each subject was comfortably seated in front of a table. Individuals placed their right hand on a light-detector on the table, located 5 cm from the chest. A cross, drawn at 35 cm from the subject along the midline, was used to maintain steady fixation. A small metal cylinder was placed on the fixation cross or at 40◦ from it, to the left or the right, and maintaining a constant distance between the light-detector and cylinder (35 cm). The cylinder was connected to an impedance-detector that allowed measurement of the time elapsed between the start of the movement (signalled by the lightdetector) and its completion (signalled by the touch of the cylinder). Arm and eye movements were continuously recorded with a digital video camera (Sony DCR-SR30E, sampling rate: 25 Hz) to discard incorrectly performed trials. At the beginning of each trial, subjects were asked to close their eyes. A tone from a loudspeaker signalled subjects to open their eyes and to reach and touch the target cylinder as soon as possible, while maintaining a steady fixation on the central cross. All experimental events were controlled by a PCMCIA acquisition board (NI-DAQ 6024E, National Instruments, Texas, USA) controlled by LABVIEW PC software that managed all experimental parameters, comprising both reaction (RT) and movement times (MT), measured as the time elapsed between the tone and hand movement and the duration of hand movement, respectively. Before TMS experiments, subjects performed a series of 21 reaching trials with targets randomly distributed in the centre, right and left to measure their mean reaction time (m-RT). This value was then used to calculate, subject by subject, the timing of TMS delivery. Mean-RT was determined independently of target positions to obtain a single reliable value for timing of TMS delivery, and reduce experimental variability. TMS pulses were applied at 50% (Time 1, Experiment 1), 75% (Time 2, Experiment 2) and 90% (Time 3, Experiment 3) of each subject’s m-RT. TMS at 50% of m-RT was delivered around eye-opening, while in all other stimulation times, the eyes were steadily opened. If execution of the task improved so as to reduce the m-RT more than 20%, a new m-RT was calculated from the 21 NO-TMS trials performed in the last point of stimulation on the scalp. The timing of TMS delivery was consequently modified. Mean-RT were longer than in usual psychometric experiments because a “double” reaction time paradigm was adopted. Indeed, the time elapsed from the acoustic signal to arm movement (reaction time) comprised the time required to open the eyes and plan the movement towards the target. Only one of the three TMS stimulation times was applied in each subject to minimize fatigue and avoid lengthy exposition to TMS. Subjects performed 42 randomized trials for each stimulated point: 21 trials with TMS and 21 without TMS (TMS and NO-TMS conditions, respectively). Of the 21 trials, 7 had the target on the right, 7 on the left and 7 in the centre. Each subject underwent 168 trials: 42 trials for 4 points (see below).
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Fig. 1. Points of stimulation and related effects of TMS obtained with stimulation delivered at 75% of m-RT. (A) Stimulated points on the scalp in the right parietooccipital cortex; (B) Reaction times with no distinction for target location. Mean data and standard deviations are reported. The asterisk indicates statistically significant differences.
A 7 cm figure-8 coil (Medtronic C-B60) oriented tangentially to the scalp with the handle perpendicular to the interhemispheric fissure and pointing leftward was used. The coil was positioned and secured in place by fixing it to a mechanical arm, and its position was continuously checked and readjusted as necessary. In each subject, the best cortical point activating the first dorsal interosseal muscle (FDI) was determined and the motor threshold was set as the stimulus intensity triggering at least 50 V responses on EMG recording in at least 50% of 10 consecutive stimulations. The intensity of the TMS pulse was then set at 120% of the FDI motor threshold. TMS pulses (duration: 280 s; Medtronic MagPro R30) were delivered at four different points on right parieto-occipital cortex. According to the 10–20 EEG coordinate system [26], these points of stimulation were localized on the superior occipital lobe (point a), around the parieto-occipital sulcus (points b and c) and on the posterior part of superior parietal lobule (point d) (Fig. 1A). The four points were always stimulated in a randomized order. TV recordings were analyzed off-line and all trials where the subject’s eyes did not remain still on the central fixation cross for the entire trial were excluded. To avoid the influence of inadequate attention, all trials with a RT longer than 1000 ms or shorter than 100 ms, and MT longer than 700 ms or shorter than 100 ms were also excluded. Moreover, trials were considered incorrectly performed when evident trajectory corrections were made or evident hesitation was present after the start of movements. Trajectory corrections were observed when the hand was initially moved toward a wrong position and then turned to the right one. Hesitations corresponded to the stopping of movement even if it was toward the correct target. RT and MT that dropped out the limit of two standard deviations from the mean of their condition were also discarded from analyses. Considering the above, about 10% of raw data was eliminated. Data was normally distributed (Shapiro-Wilk test), both in RT and MT, and thus no data transformation or correction was needed. Moreover, the homogeneity of variance was successfully checked within experiments. Parametrical analysis was conducted with repeated measures ANOVA considering the main effects and interactions between TMS conditions (yes/no), location of stimulation on the scalp (four positions) and target position in space (central, left and right). A p < 0.05
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was considered statistically significant. If interaction between main effects was statistically significant, post-hoc analyses were conducted. More specifically, if interaction between all main effects resulted significant, two-way ANOVAs between main factors were conducted (significance level set at p < 0.05, Bonferroni corrected). Finally, when interaction in a two-way ANOVA or between two main effects was significant, post-hoc analyses were conducted with Student’s t-test (significance level p < 0.05, Bonferroni corrected). The mean RT was different among subjects, ranging from 428 ± 24 ms in the fastest to 813 ± 26 ms in the slowest, with a mean value of 658 ± 98 ms in Experiment 1, 586 ± 114 ms in Experiment 2 and 593 ± 87 ms in Experiment 3. No significant differences were found between experiments (F2,26 = 1.573, p = 0.226). Standard deviations and, consequently, inter-individual variability, was very high, but the intra-subject variability was smaller, ranging from 18 ms to 65 ms in the TMS condition, and from 24 ms to 57 ms in the NO-TMS condition. Analysis of movement times did not yield statistically significant differences, and were thus not considered further. TMS applied at 50% of m-RT reduced RT in a unspecific manner (F1,9 = 12.589, p = 0.006). Significant results were obtained in main factor analysis for target location (F2,18 = 18.718, p < 0.001), indicating a slower RT toward the left (central vs. left: t = 4.352, p = 0.002; central vs. right: t = 1.471, p = 0.175; left vs. right: t = 5.232, p = 0.0005). The points of stimulation main factor was not significant (F3,27 = 1.294, p = 0.297). Likewise, no interactions were significant (target location vs. points of stimulation: F6,54 = 1.282, p = 0.281; target location vs. TMS: F2,18 = 2.324, p = 0.127; TMS vs. points of stimulation: F3,27 = 1.806, p = 0.170; target location vs. point of stimulation vs. TMS: F6,54 = 1.251, p = 0.295). The results are summarized in Table 1 (left). When TMS was applied at 75% of m-RT, significant results were obtained in main factor analysis for target location (F2,18 = 6.824, p = 0.006), indicating a slower RT towards the left (central vs. left: t = 2.832, p = 0.019; central vs. right: t = 0.638, p = 0.486; left vs. right: t = 2.987, p = 0.015). Points of stimulation and TMS main factors were not significant (F3,27 = 1.681, p = 0.194; F1,9 = 0.295, p = 0.600; respectively). Likewise, no interactions were significant (target location vs. points of stimulation: F6,54 = 0.835, p = 0.548; target location vs. TMS: F2,18 = 0.017, p = 0.983; target location vs. point of stimulation vs. TMS: F6,54 = 1.313, p = 0.267), except when considering the interaction between points of stimulation and TMS conditions (F3,27 = 4.493, p = 0.011). Post-hoc analysis revealed that the only point on the scalp that was influenced by TMS was point b (t = 3.302, p = 0.009; Fig. 1B). In particular, TMS caused a delay in RT for this point on the scalp and all target locations. The results are summarized in Table 1 (centre).
When TMS was applied at 90% of m-RT, significant results were obtained in main factor analysis for target location (F2,16 = 11.522, p = 0.001), indicating a slower RT towards the left (central vs. left: t = 2.579, p = 0.033; central vs. right: t = 0.727, p = 0.488; left vs. right: t = 3.643, p = 0.007). Points of stimulation and TMS main factors were not significant (F3,24 = 0.412, p = 0.746; F1,8 = 0.008 p = 0.929; respectively), and no significant interactions were found (target location vs. points of stimulation: F6,48 = 0.492, p = 0.811; target location vs. TMS: F2,18 = 0.017, p = 0.983; points of stimulation vs. TMS: F3,24 = 1.246, p = 0.315; target location vs. point of stimulation vs. TMS: F6,48 = 1.051, p = 0.405). The results are summarized in Table 1 (right). In control Experiment 1, subjects had to move their thumb, instead of their arm, away from the light-sensor when the target was in central position, and not when the target was on the left or the right. Thus, the reaching component was eliminated, maintaining visual detection, attention and motor planning. This allowed us to determine if the observed effects were related to planning of reaching movements. In fact, if significant results were confirmed, then the findings should be mainly related to unspecific visual, motor or attention effects. All subjects had to perform 24 trials for the point on the scalp (point b) and for the stimulation time that gave positive results in main experiments (Time 2): 12 with target in the centre, 6 in the left and 6 in the right. TMS was randomly delivered in half of trials. In control Experiment 2, the effective point on the scalp (point b) was investigated at effective stimulation time (Time 2), using the same procedure of main experiments, but asking subjects to use the left hand. This allowed controlling for possible pre-activation or facilitation in motor programming in the contralateral hand, so as to interfere with RT of ipsilateral hand by delaying it. In control Experiment 1, point b was stimulated with no significant differences (TMS: m ± SD = 702 ± 83 ms, NO-TMS: m ± SD = 702 ± 118 ms; t = 0.01, p = 0.99). In control Experiment 2, again, no significant differences were found when all target locations were considered altogether (TMS: m ± SD = 633 ± 108 ms, NO-TMS: m ± SD = 624 ± 110 ms; t = 1.01, p = 0.35). No effects for target location, TMS or interaction between them was found (TMS: m ± SD = central target 615 ± 104 ms, left target 625 ± 106 ms, right target 658 ± 133 ms; NO-TMS: m ± SD = central target 617 ± 105, left target 610 ± 126, right target 653 ± 123; target location main effect: F = 0.52, p = 0.59; TMS main effect: F = 0.02, p = 0.87; interaction: F = 0.02, p = 0.98) The present findings confirm the involvement of the ipsilateral parieto-occipital cortex in planning of reaching movements in a specific scalp location and in a specific time-window of stimulation during planning of movements. MT was unaffected by TMS when
Table 1 Mean reaction times and standard deviations (in ms) collected in the TMS and NO-TMS experiments. Data are reported for each of the three timing conditions, relatively to points of stimulation and target location. Bold characters indicate statistically significant comparisons. Points
Target position
TMS at 50% of m-RT
TMS at 75% of m-RT
TMS at 90% of m-RT
TMS
NO-TMS
TMS
NO-TMS
TMS
NO-TMS
A
Central Left Right
636 ± 105 664 ± 112 640 ± 123
672 ± 104 691 ± 114 624 ± 85
574 ± 124 582 ± 120 566 ± 111
574 ± 116 595 ± 131 576 ± 124
585 ± 80 612 ± 121 603 ± 102
578 ± 91 610 ± 72 569 ± 49
B
Central Left Right
626 ± 104 664 ± 114 646 ± 126
655 ± 103 715 ± 120 655 ± 111
596 ± 111 644 ± 156 595 ± 112
587 ± 120 614 ± 130 587 ± 114
584 ± 142 617 ± 106 568 ± 91
567 ± 87 624 ± 139 601 ± 124
C
Central Left Right
640 ± 131 671 ± 124 612 ± 125
636 ± 113 687 ± 101 627 ± 123
561 ± 118 580 ± 132 562 ± 123
569 ± 116 604 ± 132 564 ± 123
599 ± 105 619 ± 100 592 ± 77
577 ± 61 648 ± 97 587 ± 69
D
Central Left Right
608 ± 103 642 ± 89 593 ± 72
633 ± 91 680 ± 94 631 ± 94
582 ± 114 582 ± 120 579 ± 101
588 ± 124 595 ± 131 577 ± 94
586 ± 106 605 ± 86 568 ± 80
582 ± 97 617 ± 98 591 ± 104
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stimulating during planning of actions, possibly because action execution was not directly influenced by the delivery of stimulation during action planning. This confirms the effectiveness of TMS during planning of movements, avoiding the possibility that TMS effect might be extended in a relatively long time, as would be the case if the findings in MT were highlighted. Before discussing results in more detail, three methodological issues must be addressed. (A) Location of stimulated points. Taking into account anatomical variability among subjects [29], and a range of ±8 mm when using 10–20 EEG system to individuate correspondences between electrodes and underlying cortex [23], we are confident that all stimulated points were on the medial parietooccipital cortex of right hemisphere. (B) Specificity of effects. Several effects were observed after TMS that were not specific for the stimulated cortical region. A general and non-localized facilitation of RT was obtained at 50% of m-RT for all stimulated points. This may be ascribed to inter-sensory facilitation [30], induced principally by noise and scalp sensation due to TMS, which could also cause a faster opening of eyes, considering that, in Experiment 1, stimulation was delivered around eye-opening. On the other hand, another explanation for facilitation of RT might be related to a specific effect on a targeted region, when stimulating slightly before its physiological activation, and, consequently, facilitating a cognitive response and related behaviour [7,32]. However, in the case of Experiment 1, inter-sensory facilitation is the more plausible explanation, considering that effects were not localized on a specific scalp region. A slower RT was observed when subjects reached targets in the left hemispace with the right hand. This effect is compatible with a “compatibility effect” phenomenon [12,26], usually indicated as facilitation in RT towards ipsilateral targets and slower RT towards contralateral ones. (C) Inter- and intra-variability of RT. Variability of the effect, namely differences between conditions for each subject, must be very small to result in a significant statistical difference. Consequently, with a large inter-variability, and therefore with a substantial standard deviation, as in the present experiment, it would be very difficult to highlight significant differences among various conditions. Nevertheless, the relatively small effect in point b in Experiment 2 was statistically significant, also considering that the tendency of significant data (slowing of RT with TMS) had an opposite trend with respect to the other data obtained, and that intra-subject variability was much smaller, resulting in a significant result. Thus, a more specific result (i.e. depending on the limb to be moved) was obtained when TMS was applied at 75% of m-RT in point b. It consisted in a delayed RT which was evident for all target positions considered. The result was specifically related to planning of reaching movements and not merely to visual detection, attention and/or motor planning. In fact, no delay of RT was observed in the first control experiment, when the requested movement was not a reaching one. As already mentioned, there is some degree of uncertainty in the literature about the exact role played by the ipsilateral hemisphere in planning of reaching movements. It has been already indicated that a strong representation of contralateral limb in PPC during planning of reaching movements exists [14–16,18,35], as well as activation of both hemispheres [6,22,25]. Moreover, data obtained from optic ataxia, where a lesion in the PPC is usually evident, normally show that the contralateral visual field and/or contralateral hand is affected by a spatial and/or a reaching deficit [4].
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Nonetheless, activation of cells in parietal regions that are exclusively modulated by ipsilateral reaching movements has been reported in monkeys [8]. Involvement of the ipsilateral hemisphere during information processing is well documented also in motor and premotor cortices during planning and execution of movements [2,17,27], suggesting that similar processes might behave in an analogous manner in other cortical regions, as suggested by the present data in the parieto-occipital cortex. Our findings suggest that specific processing of reaching movements for the ipsilateral limb is present in parieto-occipital cortex, independently from space. One possible explanation is that TMS pre-activated or facilitated motor programming in the contralateral hand, so as to interfere with RT of the ipsilateral hand by delaying it. However, the second control experiment showed that this is not the case. In fact, TMS delivered at the same time and position did not interfere with reaching movements when performed with contralateral hand. In conclusion, the present experiments support the existence of a more complex and wider ipsilateral network related to planning of reaching movements than previously suggested, adding information about the possibility of the existence of specific ipsilateral representations for planning of reaching movements in humans. Furthermore, even if planning of reaching movements might be primarily represented and controlled by the contralateral hemisphere, there is also the possibility that additional ipsilateral representations are involved that could be resumed in the case of brain damage. The finding might be of relevance not only for better knowledge of cortical functioning, but also for clinical and rehabilitation purposes. Acknowledgments Authors wish to thank Dr. Luigi Stebel for software and hardware assistance. This work was supported by grants from Ministero dell’Università e della Ricerca, Italy. References [1] A.P. Batista, C.A. Buneo, L.H. Snyder, R.A. Andersen, Reach plans in eye-centered coordinates, Science 285 (1999) 257–260. [2] N.M. Benwell, F.L. Mastaglia, G.W. Thickbroom, Changes in the functional MR signal in motor and non-motor areas during intermittent fatiguing hand exercise, Exp. Brain Res. 182 (2007) 93–97. [3] S. Bestmann, K.V. Thilo, D. Sauner, H.R. Siebner, J.C. Rothwell, Parietal magnetic stimulation delays visuomotor mental rotation at increased processing demands, Neuroimage. 17 (2002) 1512–1520. [4] A. Blangero, V. Gaveau, J. Luaute, G. Rode, R. Salemme, M. Guinard, D. Boisson, Y. Rossetti, L. Pisella, A hand and a field effect in on-line motor control in unilateral optic ataxia, Cortex 44 (2008) 560–568. [5] C.A. Buneo, M.R. Jarvis, A.P. Batista, R.A. Andersen, Direct visuomotor transformations for reaching, Nature. 416 (2002) 632–636. [6] J.L. Calton, A.R. Dickinson, L.H. Snyder, Non-spatial, motor-specific activation in posterior parietal cortex, Nat. Neurosci. 5 (2002) 580–588. [7] Z. Cattaneo, J. Silvanto, Time course of the state-dependent effect of transcranial magnetic stimulation in the TMS-adaptation paradigm, Neurosci. Lett. 443 (2008) 82–85. [8] S.W.C. Chang, A.R. Dickinson, L.H. Snyder, Limb-specific representation for reaching in the posterior parietal cortex, J. Neurosci. 28 (2008) 6128–6140. [9] C.L. Colby, R. Gattass, C.R. Olson, C.G. Gross, Topographical organization of cortical afferents to extrastriate visual area PO in the macaque: a dual tracer study, J. Comp. Neurol. 269 (1988) 392–413. [10] J.C. Culham, K.F. Valyer, Human parietal cortex in action, Curr. Opin. Neurobiol. 16 (2006) 1–8. [11] M. Desmurget, C.M. Epstein, R.S. Turner, C. Prablanc, G.E. Alexander, S.T. Grafton, Role of the posterior parietal cortex in updating reaching movements to a visual target, Nat. Neurosci. 2 (1999) 492–494. [12] P.M. Fitts, C.M. Seeger, S–R compatibility: spatial characteristics of stimulus and response codes, J. Exp. Psychol. 46 (1953) 199–210. [13] M.A. Goodale, Hemispheric differences in motor control, Behav. Brain Res. 30 (1988) 203–214. [14] S.T. Grafton, J.C. Mazziotta, R.P. Woods, M.E. Phelps, Human functional anatomy of visually guided finger movements, Brain 115 (1992) 565–587. [15] K.Y. Haaland, D.L. Harrington, Hemispheric control of the initial and corrective components of aiming movements, Neuropsychologia 27 (1989) 961–969.
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