## Introduction

Learning new motor skills, or optimizing existing ones, require the ability to detect and correct movement errors. Enduring errors can be progressively corrected thanks to adaptation mechanisms. In laboratory conditions, motor errors eliciting sensorimotor adaptation are induced by perturbations of the movement, or its goal. For visuo-manual adaptation, the perceived trajectory or the actual trajectory of the limb is perturbed respectively through optical distortion, or force fields. Previous studies indicate that visuo-manual adaptation involves neural plasticity mechanisms in the cerebellum (Weiner et al. 1983; Martin et al. 1996; Pisella et al. 2005; Luaute et al. 2009; Taylor et al. 2010; Werner et al. 2010; Donchin et al. 2012) and in parieto-frontal areas of the cerebral cortex (Clower et al. 1996; Della-Maggiore et al. 2004; Pisella et al. 2004; Hadipour-Niktarash et al. 2007; Luaute et al. 2009). In contrast, only the brainstem–cerebellar centers have so far been shown to contribute to the adaptation of eye movements (smooth pursuit: Chou and Lisberger 2004, vestibulo-ocular-reflex: Anzai et al. 2010, vergence: Takagi et al. 2001, saccades: See reviews in Hopp and Fuchs 2004; Tian et al. 2009; Iwamoto and Kaku 2010; Pelisson et al. 2010).

The first aim of the present study was to assess the role of the pIPS in saccadic adaptation. We decided to target this area, which is thought to be the parietal eye fields (for review see: Muri 2006), because of the fMRI results reported by Gerardin et al. (2012). Further, we focussed on the pIPS of the right hemisphere because in the latter study, adaptation of leftward saccades was associated with activation in the contralateral (right), but not in the ipsilateral (left) hemisphere. The second aim of the study was to test whether the pIPS is similarly involved in the adaptation of VSs and RSs. To these aims, we used fMRI-guided single-pulse transcranial magnetic stimulation (spTMS) to interfere with the normal processing of the right pIPS during the adaptation of RSs and VSs.

## Materials and Methods

### Subjects

Eighteen healthy subjects participated in the study. Of these, 6 participated only in the first experiment (VS experiment); 6 participated only in the second experiment (RS experiment); and 6 participated in both experiments. Thus, each experiment involved 12 subjects. The 2 groups of 12 subjects were matched in age (VS experiment: 29 ± 9.5; RS experiment: 29 ± 9.6 years) and gender (6 females and 6 males in each group). Thirteen participants were naïve to the goals of the study. All subjects had normal or corrected-to-normal vision, and no history of neurological or psychological disorder. Subjects gave their informed written consent and were financially compensated for their participation. All procedures complied with the Ethical Principles of the World Medical Association (Declaration of Helsinki) and were approved by the local ethics committee (CCPPRB Lyon B).

### Experimental Design

Each experiment involved 2 steps. In the first step, fMRI was used to localize the oculomotor region of the posterior part of the right intraparietal sulcus (pIPS) in each subject (see for detailed procedures: Gerardin et al. 2012). In the second step, spTMS was used to assess the role of the pIPS in saccadic adaptation.

#### fMRI

fMRI was performed with a 1.5-T Siemens Sonata MRI scanner at CERMEP (Bron, France). Following a T1-weighted anatomical scan (1 × 1 × 1 mm), T2*-weighted functional scans (EPI, echo-planar imaging) were acquired from 29 axial slices covering the entire head (repetition time: 3000 ms, echo time: 50 ms, rotation angle: 80°, resolution: 3 × 3 × 3 mm). These anatomical and functional scans were performed using an 8-channel SENSE head coil.

The stimuli used during the functional scans were produced using light-emitting diodes (LEDs, 3 mm diameter) located at the rear of the magnet and visible through a mirror attached to the head coil. An infrared eye tracker (ISCAN, Woburn, MA, United States of America) located below the LEDs recorded, at a frequency of 240 Hz, the vertical and horizontal positions of the left eye via the same mirror. The eye tracker was calibrated by asking subjects to fixate a series of 9 LEDs covering the field used during scanning. The triggering of the scans, the monitoring of eye movements, and the control of the visual stimuli were controlled in real time by customary software.

Functional saccade localizer scans were obtained by alternating pro- and antisaccade blocks with central fixation blocks. During prosaccade blocks, a green fixation point indicated to the subjects that they had to make a saccade toward the target. During antisaccade blocks, a red fixation point indicated to the subjects that they had to make a saccade in the opposite direction, toward the mirror position of the target. Targets were presented for 1500 ms at a random location of 4°, 10°, 16°, or 20° in the left or right visual hemifield.

The fMRI data were analyzed with the Brain Voyager QX software (Brain Innovations, Maastricht, The Netherlands). Preprocessing of functional images involved correcting for slice scan time and head movements, temporal high-pass filtering (3 cycles), and linear trend removal. No spatial smoothing was used. The functional images were aligned with the anatomical data (transformed into Talairach space). For each subject, the oculomotor part of the right pIPS was identified by contrasting all blocks of saccades (pro- and anti-) with fixation blocks, and the locus of highest activity in the pIPS was used for the spTMS sessions.

#### fMRI-guided spTMS

spTMS sessions were run in a dark room. Subjects were sitting 57 cm away from a 140-Hz computer screen (30° × 40°), with their head stabilized by a chin rest, cheekbone rests, frontal support, and a band behind the head. The presentation of visual stimuli (6-mm diameter black circles on a gray background) on the screen was controlled by a Visual Stimuli Generation system (CRS, Cambridge, United Kingdom).

Binocular eye movements were recorded using an infrared tracker (Eyelink 1000; SR Research, Canada) with a frequency of 500 Hz and a spatial resolution of 0.05°. At the beginning of each session, the eye tracker was calibrated by presenting a sequence of 9 fixation points forming an array on the computer screen and asking subjects to fixate each point in turn. Laboratory-made software allowed online monitoring of eye movements, triggering of the visual stimulation, and triggering of the spTMS pulses relative to the timing of primary saccade detections. Eye-movement data were stored for offline analysis.

spTMS was delivered via a figure-of-eight coil (90 mm) coupled to a Magstim Rapid. Prior to each session, transcranial magnetic stimulation (TMS) was applied to the right motor cortex to determine the motor threshold, which was defined as the lowest stimulation intensity inducing a visible twitch in the resting contralateral hand in 5 of 10 trials (Schutter and van Honk 2006). The intensity of spTMS applied over the right pIPS and the vertex during the sessions was set to 120% of the motor threshold, corresponding to an average intensity of 67% (range: 52–84%) of the maximum output intensity (2T). The coil was precisely placed over the right pIPS by using a neuronavigation system (SofTaxicOptic, EMS s.r.l., Bologna, Italy), which was fed with the individual Talairach coordinates of fMRI identified pIPS. The coil was maintained in place with a hydrostatic arm (Manfrotto, Feltre, Italy) for the entire duration of the session.

#### Experimental Procedures of spTMS Sessions

Figure 1.

Schematics of an adaptation trial. Eye (black line) and target (gray bars) positions are represented as a function of time. When the saccade is detected (velocity threshold: 80–90°/s), the visual display jumped toward the fixation point and spTMS occurred at a certain timing (30, 60, or 90 ms) after saccade detection (these 3 spTMS timings were used in separate sessions). Target was switched off 50 ms after saccade completion.

Figure 1.

Schematics of an adaptation trial. Eye (black line) and target (gray bars) positions are represented as a function of time. When the saccade is detected (velocity threshold: 80–90°/s), the visual display jumped toward the fixation point and spTMS occurred at a certain timing (30, 60, or 90 ms) after saccade detection (these 3 spTMS timings were used in separate sessions). Target was switched off 50 ms after saccade completion.

Figure 2.

Schematic illustration of the experimental protocols used to induce VS (a) and RS (b) adaptation. The long horizontal arrows indicate primary saccades. The short horizontal arrows indicate corrective saccades. When a horizontal primary saccade was detected (velocity threshold: 80–90°/s), the target (for RSs), or the visual display (for VSs), jumped. spTMS occurred at 30, 60, or 90 ms after detection of the horizontal primary saccade. Fifty milliseconds after saccade termination, a blank screen replaced the visual display. Note that only trials involving rightward saccades are illustrated in this figure.

Figure 2.

Schematic illustration of the experimental protocols used to induce VS (a) and RS (b) adaptation. The long horizontal arrows indicate primary saccades. The short horizontal arrows indicate corrective saccades. When a horizontal primary saccade was detected (velocity threshold: 80–90°/s), the target (for RSs), or the visual display (for VSs), jumped. spTMS occurred at 30, 60, or 90 ms after detection of the horizontal primary saccade. Fifty milliseconds after saccade termination, a blank screen replaced the visual display. Note that only trials involving rightward saccades are illustrated in this figure.

Both preadaptation and postadaptation phases consisted of a block of 24 trials without spTMS and a block of 24 trials with spTMS; in the latter block, the same spTMS timing as in the corresponding adaptation phase was used. In the preadaptation phase, the no spTMS block was performed before the spTMS block, whereas in the postadaptation phase, the sequence was reversed. Each 24-trial block comprised 12 rightward saccade trials and 12 leftward saccade trials, in random order. The design of the pre- and postadaptation trials was the same as for the adaptation phase, except that the visual display was switched off as soon as the horizontal saccade was detected.

To keep subjects attentive during sessions, we required them to perform a discrimination task. After every trial, they had to indicate (by pressing a key) whether the letter “E” (not shown in Fig. 2), which was displayed on the fixation point (for reactive trials) or the central target (for voluntary trials), was complete or truncated.

To evaluate if our 2 protocols were triggering the 2 different types of saccades, a separate, complementary experiment, ran without spTMS, was conducted on age-matched neurologically healthy participants (N = 5). In this experiment, we assessed the proportion in which adaptation transferred from RSs to VSs and vice versa. Results revealed that the transfers of adaptation between saccades elicited in the 2 protocols were similar to those reported in previous studies both for RSs and for VSs, hence validating our protocols as eliciting these different saccade categories (Supplementary Fig. 1).

### TMS Data Analysis

The eye-movement data were analyzed using a custom program developed in Matlab v.7.1 (MathWorks Inc., Natick, MA, United States of America). Data from the left and right eyes were averaged, and all subsequent analyses were performed on the horizontal and vertical components of the cyclopean eye position. The start and end times of all saccades were identified based on a velocity threshold of 50°/s. Trials for which a primary saccade was not correctly detected online, or was contaminated by eye blinks, were eliminated; 4.8 ± 3.7% of all trials were eliminated in this way.

\eqalign{\hbox{Gain}\;\hbox{change}\;\hbox{of}\;\hbox{saccade}\;n\;(\hbox{spTMS)} \cr&=\displaystyle{{\hbox{Gain}\;\hbox{of}\;\hbox{saccade}\;n - \;\hbox{Mean}\;\hbox{gain}\;\hbox{of}\;\hbox{\,pre spTMS}\;\hbox{block}} \over {\hbox{Mean}\;\hbox{gain}\;\hbox{of}\;\hbox{\,pre spTMS}\;\hbox{block}}}}

Similarly, the gain change of each saccade of the no spTMS block of the postadaptation phase was calculated as follows:

$$\hbox{Gain}\;\hbox{change}\;\hbox{of}\;\hbox{saccade}\;n\;(\hbox{no}\;\hbox{spTMS}) = \displaystyle{{\hbox{Gain}\;\hbox{of}\;\hbox{saccade}\;n - \;\hbox{Mean}\;\hbox{gain}\;\hbox{of}\;\hbox{\,pre no}\;\hbox{spTMS}\;\hbox{block}} \over {\hbox{Mean}\;\hbox{gain}\;\hbox{of}\;\hbox{\,pre no}\;\hbox{spTMS}\;\hbox{block}}}$$

Negative (positive) values of gain changes corresponded to a decrease (increase) of saccade amplitude relative to preadaptation.

During the adaptation phase, secondary corrective saccades were identified as saccades directed toward the stepped target position and initiated within 500 ms after the offset of the primary saccade. The gain of these corrective saccades was calculated in the same way as for primary saccades. Their latency was computed as the duration of fixation since the preceding primary saccade. The proportion of corrective saccades (out of the total number of adaptive trials) was also measured.

Statistical analyses were performed with Statistica 9 (Statsoft Inc., Tulsa, OK, United States of America). The latency and the gain of saccades measured during the preadaptation phase were submitted to a 4-way ANOVA with 3 within-subject factors (TMS: on or off; saccade direction: leftward or rightward; and TMS type: pIPS 30 ms, pIPS 60 ms, pIPS 90 ms, or vertex) and 1 between-subject factor (experiment: VS or RS). Gain changes during the adaptation phase, which were computed relative to the gain measured during the preadaptation phase with TMS, were analyzed using a 4-way ANOVA with 3 within-subjects factors (block of trials: 1–4; saccade direction; and TMS type) and 1 between-subject factor (experiment). The same 4-way ANOVA was also used to analyze the latency, the proportion, and the gain of corrective saccades. Gain changes in postadaptation with and without TMS, which were computed relative to the gain measured during the preadaptation (with and without TMS, respectively), were submitted to a 4-way ANOVA with 3 within-subject factors (TMS, saccade direction, and TMS type) and 1 between-subject factor (experiment). ANOVAs yielding significant results were followed by post hoc Tukey's honestly significant difference (HSD) tests. The significance level was set at P < 0.05.

## Results

This study was aimed at evaluating the involvement of the parietal cortex in saccadic adaptation. First, the oculomotor region of the pIPS was localized by fMRI. Then, in 2 separate experiments, spTMS was applied in each trial of an adaptation paradigm, to assess the implication of pIPS in the adaptation of VSs (VS experiment) and of RSs (RS experiment).

### Localizer Scans

The fMRI saccade localizer scans revealed a cluster of activated voxels in the pIPS in each subject. A representative individual example is illustrated in Figure 3. Over all subjects, the average Talairach coordinates corresponding to the location of the peak of activity in pIPS were: x = 13 ± 5, y = −63 ± 6, and z = 52 ± 5.

Figure 3.

Representative example of fMRI localizer scan results showing the oculomotor area of the right pIPS in 1 subject (Talairach coordinates: x = 9; y = −63; z = 48). The parietal area activation measured in the fMRI saccade localizer scan was overlaid onto 2-dimensional anatomical slices. In the sagittal (SAG) slice (left panel), anterior (A) is shown on the left and posterior (P) is shown on the right. In the coronal (COR) and transversal (TRA) slices (middle and right panels), the right hemisphere (R) is shown on the left. Cortical activation of the pIPS is shown in white color.

Figure 3.

Representative example of fMRI localizer scan results showing the oculomotor area of the right pIPS in 1 subject (Talairach coordinates: x = 9; y = −63; z = 48). The parietal area activation measured in the fMRI saccade localizer scan was overlaid onto 2-dimensional anatomical slices. In the sagittal (SAG) slice (left panel), anterior (A) is shown on the left and posterior (P) is shown on the right. In the coronal (COR) and transversal (TRA) slices (middle and right panels), the right hemisphere (R) is shown on the left. Cortical activation of the pIPS is shown in white color.

In the following, we present the results of the 2 experiments. The results of the preadaptation phase will be presented first, followed by the results of the adaptation and postadaptation phases.

Figure 4.

Saccadic gain in the preadaptation phase of the VS experiment (a) and the RS experiment (b). The mean values of saccade gain are plotted as a function of the different spTMS sessions: pIPS at 30 ms (dark gray bars), pIPS at 60 ms (black bars), pIPS at 90 ms (light gray bars), and vertex (white bars). Error bars are standard error of the means (SEMs). The ANOVA with 3 within-subject factors (TMS presence, saccade direction, and TMS type) and 1 between-subject factor (experiment) did not reveal any significant effect (spTMS factor, F3,66 < 2.47, P > 0.07).

Figure 4.

Saccadic gain in the preadaptation phase of the VS experiment (a) and the RS experiment (b). The mean values of saccade gain are plotted as a function of the different spTMS sessions: pIPS at 30 ms (dark gray bars), pIPS at 60 ms (black bars), pIPS at 90 ms (light gray bars), and vertex (white bars). Error bars are standard error of the means (SEMs). The ANOVA with 3 within-subject factors (TMS presence, saccade direction, and TMS type) and 1 between-subject factor (experiment) did not reveal any significant effect (spTMS factor, F3,66 < 2.47, P > 0.07).

Figure 5.

Development of adaptation for the VS experiment (a) and the RS experiment (b) in the different spTMS sessions. Gain changes relative to the gain in preadaptation with spTMS are plotted separately for rightward and leftward saccades as a function of adaptation blocks (1–4). The gray shaded areas represent mean values ±1 SEM gain change measured during the vertex sessions. The dark gray, black and light gray lines correspond to gain changes for sessions during which spTMS was applied over the right pIPS with a delay of 30, 60, or 90 ms, respectively after saccade onset. The error bars show SEMs. The asterisks indicate significant differences in gain changes between the pIPS-TMS and vertex-TMS sessions, as follows: *P < 0.05; **P < 0.01; ***P < 0.001 (post hoc HSD Tukey's tests).

Figure 5.

Development of adaptation for the VS experiment (a) and the RS experiment (b) in the different spTMS sessions. Gain changes relative to the gain in preadaptation with spTMS are plotted separately for rightward and leftward saccades as a function of adaptation blocks (1–4). The gray shaded areas represent mean values ±1 SEM gain change measured during the vertex sessions. The dark gray, black and light gray lines correspond to gain changes for sessions during which spTMS was applied over the right pIPS with a delay of 30, 60, or 90 ms, respectively after saccade onset. The error bars show SEMs. The asterisks indicate significant differences in gain changes between the pIPS-TMS and vertex-TMS sessions, as follows: *P < 0.05; **P < 0.01; ***P < 0.001 (post hoc HSD Tukey's tests).

In sum, the application of spTMS over the right pIPS 60 ms after saccade detection resulted in less adaptation of VSs in both directions (VS experiment). In contrast, the application of spTMS over the right pIPS at 90 ms enhanced the gain change of rightward RSs at the end of the adaptation phase (RS experiment).

### No Effect of spTMS Over the Right pIPS on the Production of Corrective Saccades

Table 1

Latency, rate, and gain of corrective saccades measured during the adaptation phase.

TMS type pIPS (ms)

Vertex
30 60 90
Latency (ms) 282 ± 7.9 284 ± 7.8 295 ± 7.3 270 ± 7.6
Rate (%) 27.5 ± 2.0 29.3 ± 2.1 31.9 ± 2.2 32.9 ± 2.1
Gain 1.15 ± 0.06 1.38 ± 0.13 1.28 ± 0.09 1.17 ± 0.10
TMS type pIPS (ms)

Vertex
30 60 90
Latency (ms) 282 ± 7.9 284 ± 7.8 295 ± 7.3 270 ± 7.6
Rate (%) 27.5 ± 2.0 29.3 ± 2.1 31.9 ± 2.2 32.9 ± 2.1
Gain 1.15 ± 0.06 1.38 ± 0.13 1.28 ± 0.09 1.17 ± 0.10

Note: The mean parameter values (±SEMs) are depicted separately for the 4 TMS types. No significant effect of the TMS type factor was observed (4-way ANOVA, F3,526 < 1.8, P > 0.14).

Thus, the effects of spTMS over the right pIPS on saccadic gain changes reported in the previous section are not accompanied by spTMS effects on corrective saccades.

### Effect of spTMS Over the Right pIPS on Adaptation After-Effects

Figure 6.

Adaptation after-effects in the postadaptation blocks for the VS experiment (a) and the RS experiment (b). After-effects were calculated as gain changes in the postadaptation blocks relative to the mean gain measured during the preadaptation blocks, separately for the spTMS block (rightward panels) and for the no spTMS block (leftward panels). The mean after-effect values are plotted separately for the different spTMS sessions: pIPS at 30 ms (dark gray bars), pIPS at 60 ms (black bars), pIPS at 90 ms (light gray bars), and vertex (white bars). Error bars show SEMs. Significant differences in the adaptation after-effects between pIPS and vertex sessions are indicated by asterisks: *P < 0.05 and ***P < 0.001 (post hoc HSD Tukey's tests).

Figure 6.

Adaptation after-effects in the postadaptation blocks for the VS experiment (a) and the RS experiment (b). After-effects were calculated as gain changes in the postadaptation blocks relative to the mean gain measured during the preadaptation blocks, separately for the spTMS block (rightward panels) and for the no spTMS block (leftward panels). The mean after-effect values are plotted separately for the different spTMS sessions: pIPS at 30 ms (dark gray bars), pIPS at 60 ms (black bars), pIPS at 90 ms (light gray bars), and vertex (white bars). Error bars show SEMs. Significant differences in the adaptation after-effects between pIPS and vertex sessions are indicated by asterisks: *P < 0.05 and ***P < 0.001 (post hoc HSD Tukey's tests).

By contrast, for RSs, no significant effect of spTMS on after-effects was observed, whether measured in postadaptation with spTMS (Fig. 6b, left panel, post hoc Tukey's HSD tests, P > 0.91), or without spTMS (Fig. 6b, right panel, post hoc Tukey's HSD test, P > 0.67). Despite a trend for larger after-effects at this timing than for the vertex session, this negative outcome indicates that the facilitatory effect of pIPS-TMS with a 90-ms delay, which was observed during the adaptation phase, was not maintained in the postadaptation phase.

To summarize, for VSs, the adaptation after-effects were significantly smaller in the session with spTMS applied over the pIPS at 60 ms than in the vertex session (VS experiment). In contrast, for RSs, spTMS never affected the after-effect (RS experiment).

## Discussion

Single-pulse TMS applied over the right pIPS, 60 ms after the onset of leftward and rightward VSs, largely reduced the amount of adaptation and the size of the after-effect, when compared with the application of TMS over the vertex. A markedly different pattern of results was found for RSs: Right pIPS-TMS applied 90 ms after the onset of rightward saccades led to larger adaptation at the end of the adaptation phase, with no persistent change in the after-effect. Given the lack of specific modifications of baseline saccade parameters, this pattern of TMS effects clearly results from the modification of different adaptation or error processing mechanisms engaged by the RS and VS protocols.

The application of spTMS over the right pIPS modified the adaptation of VSs in both directions (left and right). Previous studies have shown that the right parietal cortex is dominant for both visual hemifields in visual, attentional, and/or motor processes (Corbetta et al. 1993; Mangun et al. 1994; van Koningsbruggen et al. 2009). The bilateral effect of spTMS on saccade adaptation could then be due to this dominance of the right parietal cortex. For the VSs, a significant impairment on the development and the retention of adaptation was found when the spTMS was applied 60 ms after saccade onset. In this case, the pulse occurred ∼20 ms after saccade completion (mean saccade duration: 40 ms). This indicates that the adaptation of VSs critically depends on functions taking place in the right pIPS almost immediately after saccade termination.

## Funding

This work was supported by Agence Nationale de la Recherche (ANR-06-NEURO-001) to DP and by Institut National de la Santé et de la Recherche Médicale (INSERM) U864.

## Notes

We thank all subjects for their participation. We also thank Prof. C. Tilikete for seeing all participants before their inclusion, Dr V. Gaveau for helpful comments and F. Volland for building the fMRI-compatible set-up. The staff of Centre d'Etude et de Recherche Multimodal et Pluridisciplinaire en Imagerie du vivant (CERMEP) is also acknowledged for the fMRI exams. Conflict of Interest: None declared.

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