J Neurophysiol 113: 1206 –1216, 2015. First published November 26, 2014; doi:10.1152/jn.00281.2014.

Online gain update for manual following response accompanied by gaze shift during arm reaching Naotoshi Abekawa1 and Hiroaki Gomi1,2 1

NTT Communication Science Laboratories, Nippon Telegraph and Telephone Corporation, Wakamiya, Morinosato, Atsugi, Kanagawa, Japan; and 2CREST, Japan Science and Technology Agency, Kawaguchi, Saitama, Japan Submitted 10 April 2014; accepted in final form 20 November 2014

Abekawa N, Gomi H. Online gain update for manual following response accompanied by gaze shift during arm reaching. J Neurophysiol 113: 1206 –1216, 2015. First published November 26, 2014; doi:10.1152/jn.00281.2014.—To capture objects by hand, online motor corrections are required to compensate for self-body movements. Recent studies have shown that background visual motion, usually caused by body movement, plays a significant role in such online corrections. Visual motion applied during a reaching movement induces a rapid and automatic manual following response (MFR) in the direction of the visual motion. Importantly, the MFR amplitude is modulated by the gaze direction relative to the reach target location (i.e., foveal or peripheral reaching). That is, the brain specifies the adequate visuomotor gain for an online controller based on gaze-reach coordination. However, the time or state point at which the brain specifies this visuomotor gain remains unclear. More specifically, does the gain change occur even during the execution of reaching? In the present study, we measured MFR amplitudes during a task in which the participant performed a saccadic eye movement that altered the gaze-reach coordination during reaching. The results indicate that the MFR amplitude immediately after the saccade termination changed according to the new gaze-reach coordination, suggesting a flexible online updating of the MFR gain during reaching. An additional experiment showed that this gain updating mostly started before the saccade terminated. Therefore, the MFR gain updating process would be triggered by an ocular command related to saccade planning or execution based on forthcoming changes in the gaze-reach coordination. Our findings suggest that the brain flexibly updates the visuomotor gain for an online controller even during reaching movements based on continuous monitoring of the gaze-reach coordination. visuomotor control; online reaching correction; eye-hand coordination

of a goal-directed reaching action, especially in dynamical environments, requires the online correction of arm movement (e.g., Elliott et al. 1999). Rapid and automatic online reach corrections are induced by a visual shift in the reach target or in the hand cursor (Day and Lyon 2000; Georgopoulos et al. 1981; Goodale et al. 1986; Prablanc and Martin 1992; Sarlegna et al. 2003; Saunders and Knill 2003, 2004). Additionally, background visual motion rapidly and unintentionally shifts an ongoing reach trajectory in the direction of the visual motion, called the manual following response (MFR) (Brenner and Smeets 1997; Gomi et al. 2006; Saijo et al. 2005; Whitney et al. 2003). The MFR is highly sensitive to the visual motion of a coarse pattern located in the visual periphery (Gomi et al. 2013), and the response can improve the reaching accuracy when participants are passively rotated in a

THE SUCCESSFUL PERFORMANCE

Address for reprint requests and other correspondence: N. Abekawa, NTT Communication Science Laboratories, Nippon Telegraph and Telephone Corporation, 3-1 Wakamiya, Morinosato, Atsugi, Kanagawa 243-0198, Japan (e-mail: [email protected]). 1206

chair (Whitney et al. 2003). These features suggested that the MFR is a functional way of adjusting arm movement against body motion that frequently causes retinal motion (Gomi 2008; Whitney et al. 2010). These rapid and unintentional visuomotor corrections are thought to be governed by a reflexive mechanism (Gaveau et al. 2014; Gomi 2008; Sarlegna and Mutha 2014). In addition, the visuomotor gains (i.e., the amplitude of the transient corrective response) are modulated based on task demands or conditions even when the identical visual stimulus is presented (Fig. 1A). For example, quick manual responses to a target shift are influenced by volitional intention (Day and Lyon 2000), the visibility of the participant’s own hand (Reichenbach et al. 2009), and visuomotor adaptation (Gritsenko and Kalaska 2010). Furthermore, corrective responses to a hand-cursor shift are modulated by accuracy demands (Knill et al. 2011) and by the task relevancy of visual perturbation (Franklin and Wolpert 2008). As regards background visual motion, the MFR is modulated depending on the spatial coordination of the gaze and reaching directions (Abekawa and Gomi 2010). A large spatial separation between the gaze and reaching directions reduces the effect of visual motion on arm movement. These task-dependent gain modulations imply the functional importance of reflexive visuomotor responses. Moreover, they are also a significant feature with respect to theoretical frameworks such as optimal feedback control. This theory postulates that the feedback gains in the sensorimotor control are adequately modulated and flexibly varied with time according to the motor task (for review see Scott 2004, 2012). However, the gain modulations observed in most previous visuomotor studies were restricted to block-by-block or trial-by-trial task changes, and there has been little investigation of flexible gain updating during the execution of a single reaching movement. Two possible hypotheses are considered, as shown conceptually in Fig. 1B. In this figure, gains A and B depict the visuomotor gain determined by tasks A and B, respectively. In the “preset” hypothesis, the gain is determined only in the reach planning stage (i.e., prior to the start of reach), and it was fixed during a reach. This means that gain A determined by task A is not updated even when the task change occurs during a reach (Fig. 1B). On the other hand, in the “updating” hypothesis, the gain is flexibly updated in real time during the course of the reaching movement when the task change occurs (gain A is updated to gain B according to the task change). This issue was addressed by a more recent study, which found that the gain of the manual response to a visual shift in the hand cursor (self-body state) was updated rapidly according to the change in distance to the target during a reach (Dimitriou

0022-3077/15 Copyright © 2015 the American Physiological Society

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UPDATING GAIN FOR ONLINE VISUOMOTOR CONTROL

A

Task demand

Task A or Task B

Task condition

visual information

visuomotor gain

online manual responses

Gain A or Gain B

B

Task change during reaching execution

task A

task B “preset” hypothesis

Gain A Gain B

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C Reaching planning

task A

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task B

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In the experiments, the MFR was estimated under four conditions (Fig. 1C). In the first two conditions (shown in Fig. 1C, top), the task was fixed during the reach where the gaze was directed toward or away from the reach target. In the remaining two conditions (shown in Fig. 1C, bottom), the task change occurred during the reach where the participants needed to make a saccadic eye movement, which changed the gaze-reach coordination. We showed that when the gaze-reach coordination changed during a reach the MFR amplitudes were regulated according to such changes, supporting the “updating” hypothesis. More interestingly, the gain updating was already initiated halfway even before the saccade terminated based on forthcoming changes in gaze-reach coordination. Our findings provide evidence that the brain flexibly updates the gain of online visuomotor corrections during a reach. Furthermore, continuous and predictive coding of gaze-reach coordination would be involved in such an updating process. MATERIALS AND METHODS

“updating” hypothesis

Reaching planning

1207

Time

Fig. 1. Schematic illustrations of gain modulation and possible hypotheses. A: task-specific gain modulation of the reflexive visuomotor responses. Gain A or gain B is determined according to task A or task B, respectively. B: the “preset” hypothesis predicts that the gain is determined before the start of reaching and is fixed during its execution. The “updating” hypothesis predicts that the gain is flexibly updated when the task change occurs during reaching. C: to distinguish the hypotheses, we measured the visuomotor response under 4 conditions. As in previous studies, the task was fixed during reaching (top) under 2 conditions. Under the remaining 2 conditions, the task was changed during reaching (bottom).

et al. 2013). Although this finding supports the “updating” hypothesis, it is not known whether this idea can be generalized to other types of gain modulation (specifically, gain modulation of the response to an environmental state) in online reflexive visuomotor responses. In the present study, we focused on the MFR modulation caused by the spatial coincidence of gaze and reach (Abekawa and Gomi 2010) and examined whether the MFR gain is updated during a reach. If the MFR gain is updated rapidly, we would also be able to provide evidence that 1) the gain of the response to an environmental state change (surrounding visual motion) is also updated during an ongoing movement and 2) the gain can be modulated not only by task demands (explicit states) but also by online eyehand coordination (implicit states).

Thirty-five people (16 men and 19 women, 19 – 40 yr old) including one of the authors participated in our experiments. Fourteen of the participants took part in several experiments. For a postsaccade experiment (see Experimental Paradigm), 14 and 11 people participated in the task of reaching toward the right and left sides, respectively. Sixteen people reaching to the right side and 15 reaching to the left side participated in a presaccade experiment (see Experimental Paradigm). Nine people participated in an attention experiment (see Experimental Paradigm). All the participants were right-handed. None of the participants had any known history of neurological, sensory, or motor disorders. All gave informed consent with regard to participation in the study, which was approved by the NTT Communication Science Laboratories Research Ethics Committee. Apparatus Each participant sat in a darkened room in front of a computer monitor (CV921PJ; Totoku Electric, Tokyo, Japan, size: 22 in., vertical refresh rate: 160 Hz, mean luminance: 22.4 cd/m2) as shown in Fig. 2. The participant’s head was stabilized by a chin rest on which a video-based eye tracking system (Eyelink2000; SR Research, KaMotion capture system

Eye tracking system

z x y Fig. 2. Experimental setup. Participants performed a reaching movement from the button switch on the desk to the monitor. Arrows labeled x, y, and z define the coordinate axes. Hand movements were visually occluded until the hand had passed the midpoint of the movement.

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UPDATING GAIN FOR ONLINE VISUOMOTOR CONTROL

Gaze factor Saccade No saccade R

L

M

MIS

MtoMIS MIStoM

MIS

M

MIStoM MtoMIS

Right side

A

Left side

nata, ON, Canada) was mounted. Monocular eye movement was recorded at a rate of 2,000 Hz. Visual stimuli were controlled by MATLAB (MathWorks, Natick, MA) and Cogent Graphics (University College London, London, UK) on a Microsoft (Seattle, WA) Windows operating system. Two photodiodes (S1223-1; Hamamatsu Photonics, Shizuoka, Japan) were attached to the top left and right corners of the monitor to detect the actual start time of the visual stimulus presentation. A button switch connected to the computer’s parallel port and located ⬃36 cm below the eye was used to detect the start of the arm movement. The signals from the photodiodes and the button switch were recorded at 2,000 Hz. An infrared marker was attached to the back of the hand around the base of the ring finger and tracked at 250 Hz with an OPTOTRAK system (OPTOTRAK3020; Northern Digital, Waterloo, ON, Canada). Each participant wore a simple cast to prevent his/her wrist from moving. The axis coordinates are shown in Fig. 2 (x: horizontal direction parallel to the monitor, y: perpendicular direction to the monitor, z: vertical direction). The eye-to-monitor distance was 50 cm.

Reaching factor

1208

RL

LR

B Post-saccade experiment

Experimental Paradigm

No saccade trial

Postsaccade experiment. The main purpose of this experiment was to determine whether the MFR gain is updated immediately after changes in the spatial relationship between the gaze and reach target. The participants performed a reaching movement under the four gaze conditions outlined in Fig. 3A. Under R and L conditions, the participants did not make a saccade but kept their gaze fixed on the right and left fixation points, respectively, on the monitor during reaching movement. Under these conditions, the task was fixed during reaching (i.e., the gaze-reach coordination was fixed) as shown in Fig. 1C, top. Under RL and LR conditions, the participant had to make a saccade from the right to left fixation points and from the left to right fixation points, respectively, during a reaching movement. Under these conditions, the task was changed during reaching as shown in Fig. 1C, bottom. There were two groups of participants: one group (n ⫽ 14) reached toward the right reach target on the monitor with their right hands (right-reaching session), and the other group (n ⫽ 11) reached toward the left reach target with their left hands (left-reaching session). In other words, with a right-reaching session, the gaze and reach target was matched for the R gaze condition and was mismatched for the L gaze condition. For RL and LR gaze conditions, the spatial relationship changed during the reaching movement from matching to mismatching and from mismatching to matching, respectively. With a left-reaching session, the gaze-reaching configurations were exactly opposite to those for right reaching, as shown in Fig. 3A. Figure 3B illustrates the time course of a single trial in the postsaccade experiment. At the beginning of each trial, the participants pressed a button located on the table, using their thumbs. This action was followed by the presentation of a reach target (blue-colored circle, 1-cm diameter), two cross markers (1 ⫻ 1 cm), and horizontal sine-wave gratings (width: 0.2 cm, height: 30 cm, 1 cycle: 4.5 cm, and contrast: 90%). The reach target was located at (x and z) of (14.5, ⫺5) cm from the center of the monitor in the right-reaching session and at (x and z) of (⫺14.5, ⫺5) cm from the center of the monitor in the left-reaching session. The two cross markers were located at (x and z) of (14, ⫺5) cm and (⫺14, ⫺5) cm, respectively from the monitor center. One was red (indicating the fixation marker), and the other was gray. Whether the right or left cross was colored red was randomly determined for each trial. Two gratings were located behind the two cross markers. After the participant had fixated the red cross marker for 700 ms, the reach target disappeared with a beep sound, cuing the participant to start the arm movement toward the remembered target location. The participant made a reaching movement at a relatively moderate speed toward the target location at the second beep (600 ms after the onset of arm movement). In the saccade trials, the color of the fixation

Visual motion Reaching start Reach target

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No sac. trial 132 192

Time [ms] Reach start Sac. Visual motion MFR cue onset estimation -200

-65

0

Fig. 3. Experimental paradigms for post- and presaccade experiments. A: each participant performed either a right-side or a left-side reaching movement. The experimental task consisted of 4 gaze conditions (R: fixated on the right side, L: fixated on the left side, RL: saccade from right to left side, LR: saccade from left to right side), which were randomly ordered. Abbreviations in the boxes indicate the spatial relationship between gaze and reach target. M and MIS denote match and mismatch, respectively. MtoMIS and MIStoM mean that the relationship changed from match to mismatch and from mismatch to match, respectively. B: time course of a single trial for the postsaccade experiment. Time 0 indicates the onset of the grating pattern motion (350 ms after the reaching start). In the saccade trials, a saccade cue was presented at the time of the reaching onset and eye movements were terminated before the onset of the grating motion. C: time course of a single trial for the presaccade experiment. A saccade cue and visual motion were presented 135 ms and 200 ms after the reaching onset, respectively. For details, see MATERIALS AND METHODS.

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Table 1. Saccade properties and relative timing for saccade and visual motion Saccade Latency from Saccade Cue

Postsaccade experiment Right-reaching Left-reaching Presaccade experiment Right-reaching Left-reaching

Saccade Initiation from Visual Motion Onset

Saccade Termination from Visual Motion Onset

RL

LR

RL

LR

RL

LR

214 ⫾ 9 198 ⫾ 17

199 ⫾ 12 219 ⫾ 14

⫺136 ⫾ 9 ⫺152 ⫾ 17

⫺151 ⫾ 12 ⫺131 ⫾ 14

⫺49 ⫾ 10 ⫺62 ⫾ 17

⫺59 ⫾ 12 ⫺50 ⫾ 15

223 ⫾ 11 210 ⫾ 12

215 ⫾ 13 229 ⫾ 10

158 ⫾ 11 145 ⫾ 12

150 ⫾ 13 164 ⫾ 10

246 ⫾ 13 234 ⫾ 12

245 ⫾ 16 246 ⫾ 12

Values (in ms) are means ⫾ SD.

modulation. The experiment was designed as a 2 ⫻ 2 factorial: two gaze directions (right and left) ⫻ two attention directions (right and left) for a total of four conditions as shown in Fig. 4A. For two conditions (gaze-right and attention-right and gaze-left and attentionleft), the gaze and attention positions were spatially matched. On the other hand, for the remaining two conditions (gaze-right and attentionleft and gaze-left and attention-right), the gaze and attention were spatially dissociated. The participant was instructed to make reaching movements toward the reach target on the right side of the monitor under those conditions. Figure 4B shows the time course of a single trial of the gaze-left and attention-right condition. The trial started with a button press, and then two horizontal sine-wave gratings, two potential targets for attention (white filled circles), a fixation point (black cross over one of the white filled circles), and a reach target (blue filled circle) were presented. After the participant had fixated on the fixation point for 700 ms, the color of one of the two potential targets for attention changed to red. The participant was instructed to direct his/her voluntary spatial attention to the red target while maintaining eye fixation. The reach target disappeared 700 ms after the appearance of the red attention cue, and then a beep cued the participant to start an arm movement of ⬃600-ms duration. In the visual motion trials (two-thirds of all trials), sine-wave gratings started to move either upward or downward 350 ms after the arm movement began. In the remaining one-third of the trials, the gratings were kept stationary (control trials). The properties of visual motion, such as size, speed, and duration, were the same as those in the saccade experiments (postand presaccade experiments). There were 12 possible combinations of gaze (right or left), attention (right or left), and visual motion (upward, downward, or stationary) directions. There were 48 trials under each condition, giving a total of 576 trials.

A

Fixation point Attention cue Reach target

Right

Gaze factor Left Right

B Visual motion 350 ms Reaching start "Go" beep 700 ms Attention cue (700 ms)

Left

Attention factor

marker changed from red to gray, and the gray marker on the opposite side changed to a red marker at the onset of the arm movement (saccade cue). The participant was asked to make a horizontal saccade to the new red-colored fixation marker (distance of 28 cm/31°) as quickly as possible while continuing the arm movement toward the original reach target location. In the no-saccade trials, the participant had to perform the arm movement without any eye movement. In two-thirds of the trials, the gratings started to move either upward or downward at a constant speed (50°/s, 300 ms) 350 ms after the onset of the arm movement. Both gratings (located on the right and left) always started to move simultaneously in the same direction. We refer to the motion of these gratings as visual motion and to the start timing of the visual motion as the visual motion onset. In the remaining one-third of trials, they remained stationary. The onset times of the saccade cue and the grating visual motion were chosen so that the visual motion was presented just after the termination of the saccade. Table 1 summarizes the actual saccade latencies from the saccade cue and the time of the saccade onset and termination from the visual motion onset obtained in this experiment (mean ⫾ SD values across participants); a minus value means that the saccade initiation and termination preceded the visual motion onset. Each participant performed 36 successful trials for each of 12 possible combinations of gaze conditions (R, L, RL, or LR) and visual motion directions (upward, downward, or stationary). The total number of trials was 432, and the trial order was randomized in each block of 24 trials. The success or failure of the trial was determined by the duration of the reaching movement and gaze behavior. The target movement duration was 600 ms, and the actual duration was given at the end of each trial. If the reaching duration was shorter than 530 ms, the trial was rejected and repeated later in the block. On the other hand, the end points of reaching movements were not used as trial rejection criteria. Participants were asked to make reaching movements toward the remembered location of a reach target regardless of whether visual motion was applied or not. As for the gaze behavior, the trial was rejected and repeated later when the saccade latency was shorter than 155 ms or longer than 275 ms. Presaccade experiment. The aim of this experiment was to examine whether the MFR gain change associated with a gaze shift is initiated before the end of the saccade. The experimental paradigm was almost the same as that for the postsaccade experiment except for the time course of a single trial. The saccade cue and the grating visual motion were presented 135 ms (corresponding to ⫺65 ms in Fig. 3C) and 200 ms (corresponding to 0 ms in Fig. 3C) after the onset of the reaching movements, respectively. These timings were selected so that the visual motion started before the saccade onset and the MFR was induced before saccade termination. The actual saccade latency and the interval between the visual motion onset and the saccade initiation/termination are shown in Table 1. There were 16 and 15 participants in the right-reaching and left-reaching sessions, respectively. The number of trials was the same as that in the postsaccade experiment (36 trials for each condition). Attention experiment. This experiment was conducted to compare the individual influences of gaze and spatial attention on the MFR

700 ms Fixation point Reach target

Fig. 4. Experimental paradigm for the attention experiment. A: the task consisted of 4 conditions (2 gaze locations ⫻ 2 attention locations). B: time course of a single trial. This is an example of a trial where the gaze is directed to the left side (cross marker) and attention is directed to the right side (red circle). Visual motion began 350 ms after the reaching onset.

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To confirm that voluntary attention was directed to the cued location, especially around the period when visual motion was presented, we measured the reaction time (RT) to a reaction stimulus, as frequently used in previous attention studies (e.g., Posner 1980). In all the control trials, the reaction stimulus (a 3-cm ⫻ 3-cm frame of thin lines) was presented for 56 ms at either the right or left potential target for attention during the reaching movement. The onset time of this stimulus was randomly determined in each trial between 250 and 450 ms after the reaching initiation. We determined this time range so that we could verify attentional allocation around the period of visual motion onset (350 ms after the reaching onset) in the visual motion trials. Note that the reaction stimulus was not presented in the visual motion trials, to avoid it interfering with the MFR. The participant was required to respond to the reaction stimulus as fast as possible by pressing the space bar of a computer keyboard with the left index finger while continuing to execute the right-hand reaching movement and to gaze at the fixation point. The keyboard was placed in front of the participant and near the button switch. We expected the RT to be shorter when the reaction stimulus was presented at the target for attention (valid trial) than when it was presented at another location (invalid trial). Because of the difference in visual sensitivity across the visual field, we presented the reaction stimulus with different luminance depending on whether it was presented at the gaze location or not: 24.6 cd/m2 for foveal vision and 29.1 cd/m2 for peripheral vision. Note that we compared RTs between the two conditions, which differed only in the cued location of attention (i.e., gaze locations and reaction stimulus locations were identical in each comparison). Data Analysis The recorded hand and eye positions were temporally aligned with respect to the photodiode trigger signal, which coincided temporally with the visual motion onset. These data were filtered (4th-order Butterworth low-pass filter with a cutoff of 30 Hz), and the velocity and acceleration patterns were calculated by three- and five-point numerical time differentiations of filtered data, respectively. We excluded trials in which the hand marker was not correctly detected or the movement was very different from the typical pattern under identical experimental conditions. These outliers were detected by employing a threshold of two times the squared sum values of the deviations from the median movement velocity pattern in the x-, y-, or z-axis. Trials were also removed in which multiple saccades were produced or the gaze shift was incorrect. As regards the attention experiment, we also excluded trials where the RT (measured by a key press) was more or less than three times the standard deviation from the median value. The ratio of trials available for analysis to the total number of trials (mean across participants) was 95% (410 trials), 95% (410 trials), and 94% (541 trials) in the postsaccade, presaccade, and attention experiments, respectively. To quantify the quick and transient manual response induced by the visual motion, we analyzed the velocity and acceleration pattern in the vertical direction (z-axis), since the direction of this manual response roughly coincides with that for the visual motion (Gomi et al. 2006; Saijo et al. 2005). The initiation of the manual response was defined as the onset time of significant differences in the successive t-test (P ⬍ 0.05) between the z-directional acceleration responses for the upward and downward stimuli, which continued over 20 ms. The beginning and end of the saccadic eye movements were detected by employing a velocity threshold (4.3°/s). To reduce the artifactual bias effect caused by movement fluctuations on the response estimation, we employed a control selection method, as described below. For every trial in which visual motion was applied, we selected five control (no visual motion) trials under identical experimental conditions, whose velocity pattern resembled that for each visual motion trial over a period of 0 –50 ms from the onset of visual motion. As demonstrated in our previous studies, visual motion does not affect manual movement during this period.

Then, the acceleration patterns of selected control trials were averaged, and the result was subtracted from the acceleration pattern for the corresponding visual motion trial. Finally, the mean acceleration deviation was calculated under each visual stimulus condition, and then the difference between the accelerations of the visual motion directions (upward ⫺ downward) was determined. The MFR amplitude was characterized by the temporal average of this pattern over a period of 132–192 ms after the onset of the visual motion. We chose this time range because it temporally matched the initial phase of the manual response observed in the present experiments. The detected actual mean latency across all the participants was 146 ⫾ 8 ms in the postsaccade experiment, which was slightly longer than that in our previous reports (Abekawa and Gomi 2010; Gomi et al. 2013; Saijo et al. 2005). This delay of latency is probably due to the difference in the size of the visual stimulus for driving the response: the stimulus used here was much smaller than that used in previous reports. We used a relatively small visual stimulus in the present experiments to reduce the image motion on the retina caused by saccadic eye movements, which could affect reaching movements. As described above, we estimated the initial 60-ms duration of the manual response (132–192 ms from the visual motion onset). In the postsaccade experiment, the visual motion started after the end of the saccade in every trial (the average interval across all participants was 55 ms; see Table 1). Thus the MFR amplitudes clearly reflect the visuomotor gain after saccade termination. In the presaccade experiment, the visual motion started before the saccade onset in every trial (the average preceding time was 154 ms; see Table 1) and the saccade was terminated after the time needed for estimating the MFR amplitudes (the average interval from visual motion onset to saccade end was 243 ms; see Table 1). Therefore, in this experiment, we quantified the visuomotor gain during or before a saccade. Statistical Analysis In the postsaccade and presaccade experiments, we used a two-way mixed-design ANOVA with spatial relationship factors between the gaze and the reach target as a repeated measure [match (M), mismatch (MIS), change from match to mismatch (MtoMIS), and change from mismatch to match (MIStoM)] and the reaching side as an independent measure (right or left) to test for significant differences in manual responses. In an attention experiment designed to test for significant differences in manual responses, we used two-way repeated-measures ANOVA with the relationship between gaze and reach target (match or mismatch) and the relationship between attention and reach target (match or mismatch) as factors. Throughout all experiments, Tukey’s honestly significant difference (HSD) was used for post hoc comparisons. RESULTS

Short-Latency Manual Following Response When the visual motion was suddenly presented during a reaching movement toward the location of the remembered target, the arm trajectory deviated in the direction of the visual motion (MFR). Since this kind of visually induced manual response is very rapid and transient, a velocity or acceleration profile is suitable for the analysis to avoid the inclusion of slow adjustments, as performed in previous studies (Abekawa and Gomi 2010; Day and Lyon 2000; Knill et al. 2011; Saijo et al. 2005). In the present study, the manual response was mainly induced in vertical directions, so we analyzed hand acceleration along the z-axis. Figure 5A shows example hand acceleration patterns for upward and downward visual motion directions under gazeright and right-reaching conditions obtained from a particular

J Neurophysiol • doi:10.1152/jn.00281.2014 • www.jn.org

UPDATING GAIN FOR ONLINE VISUOMOTOR CONTROL

0

100

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0.5 0 -0.5 0

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Fig. 5. Hand acceleration patterns from a particular participant in the postsaccade experiment (right-side reaching). A: mean hand acceleration patterns in the z-direction in upward and downward visual motion (right-side reaching with R gaze condition). Dashed curve denotes the acceleration without visual motion. Time 0 is the onset of the visual motion. Shaded area indicates the SD of the acceleration variability across all the trials. Filled triangle denotes the detected timing (136 ms) when the accelerations of the upward and downward visual motions deviated significantly. B: manual responses were calculated by taking the differences in the z-acceleration (upward minus downward visual motion) for each gaze condition. Green solid and dashed curves denote the manual responses when the gaze was fixated on the right (R) and left (L) side, respectively. Purple solid and dashed curves correspond to right-to-left (RL) and left-to-right (LR) saccades, respectively. Horizontal solid line indicates the time needed for estimating the amplitude of the manual response.

participant. Time 0 corresponds to the onset of the visual motion. Mean acceleration patterns (upward, downward, stationary) started to deviate significantly 136 ms (Fig. 5A) after the onset of the visual motion (see Data Analysis for details of latency detection). The latency of the manual responses (mean value across participants: 146 ms) was slightly slower than that described in previous studies (Abekawa and Gomi 2010; Gomi et al. 2013; Saijo et al. 2005), perhaps because of the small stimulus (see Data Analysis). Change in MFR Amplitudes After Saccade Termination Figure 5B shows MFR temporal patterns (difference between accelerations along the visual motion directions; see Data Analysis for details) for the same participant as in Fig. 5A under the four gaze conditions when reaching toward the right reach target (Fig. 3A). Under the no-saccade conditions (R and L), the peak of the response was greater when the participant fixated on the location of a reach target (R condition) than when he/she fixated away from the reach target (L condition). This indicates that the spatial coincidence between gaze and reach target modulates the MFR, as we previously reported (Abekawa and Gomi 2010). Under the saccade conditions (RL and LR), the visual motion was presented soon after saccade termination (Fig. 3B and Fig. 6A, top). The period from the saccade termination to the visual motion onset was ⬃40 – 80 ms (shown in Table 1), and the histograms of this period in all the trials are shown in Fig. 6A, bottom. If the MFR gain is updated even during the reaching movement, we would expect the MFRs under saccade conditions to depend on the saccade direction (toward or away from the reach target). As shown in Fig. 5B, the manual response for the RL condition (saccade away from the reach target) was smaller than that for the R condition. In contrast, for the LR condition (saccade toward the reach target), the response peak appeared to be slightly greater than that for the L condition. To quantify the response amplitudes, we took

A

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visual motion saccade termination

VM onset

Time

400

200

0 −50

0

50

100

150

Period from saccade termination to VM onset [ms]

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1.5

Reach target location Right side (N=14) Left side (N=11)

1.0

0.5

0

R

L

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LR

R

L

RL

LR

Gaze condition

C

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the temporal mean of the manual response for a period of 132–192 ms (Fig. 5B) and plotted the data averaged across all the participants in Fig. 6B. The tendency of the MFR modulation described for the particular participant above was also observed across all the participants (namely, R ⬎ L, R ⬎ RL, and L ⬍ LR) in the right-reaching session. To confirm that this MFR modulation cannot simply be attributed to the saccade direction itself or the visual field (right or left), we conducted a left-reaching session, where the spatial

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Gaze & Reach target Fig. 6. Manual following response (MFR) amplitudes for the 4 gaze conditions in a postsaccade experiment. A, top: time course of saccade termination and visual motion (VM) onset. Bottom: histogram of the period from the saccade termination to VM onset in all trials for all participants. B: mean amplitudes of the MFR across participants for right-side reaching (black bars) and left-side reaching (gray bars). Error bars denote SE. C: effect of spatial relationship between gaze and reach target on MFR amplitudes. Data for both reaching sessions were combined and replotted against 4 relationships between gaze and reach target. Statistical significance: **P ⬍ 0.01, ANOVA. Labels indicating the gaze conditions (R, L, RL, and LR) and the gaze-reach coordination (M, MIS, MtoMIS, and MIStoM) are the same as those in Fig. 3A.

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visual motion Time

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The above results of the postsaccade experiment indicate that the MFR gain was updated according to the change in the gaze-reach coordination after saccade termination during the execution of reaching. The next question here is whether the MFR gain is updated only after saccade termination. If the saccade and gain update process were executed sequentially, the MFR amplitude would not change before saccade termination. We attempted to answer this question by conducting a presaccade experiment, where the paradigm was almost the same as in the postsaccade experiment except for the time course of the presentation of the saccade cue and the visual motion (see MATERIALS AND METHODS and Fig. 3C). In this experiment, visual motion was presented before the saccade initiation (see Table 1 and Fig. 7A, top) and the period from the visual motion onset to saccade initiation is shown in Fig. 7A, bottom. Note that the saccade terminated after the MFR amplitude evaluation period (i.e., 192 ms from the visual motion onset) in 97% of all trials. Additionally, saccade initiation occurred during or after the evaluation period in 84% of all trials. Therefore, in this experiment, we estimated the MFR amplitudes during saccade execution or before saccade initiation rather than after saccade termination. The MFR amplitudes are shown in Fig. 7B with the same format as in Fig. 6B. In this presaccade experiment, we found that the MFR amplitudes varied with the four gaze conditions in a manner similar to that in the postsaccade experiment. For example, under no-saccade conditions (R and L) in the rightreaching session (Fig. 7B), the MFR amplitude was modulated according to whether or not the participant fixated on the reach target (namely, R ⬎ L). When the saccade was made away from the reach target (RL), the MFR appeared to decrease compared with that for the R condition. In contrast, when the

Eye movement

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relationships between the gaze and reach target for four gaze conditions were completely reversed from those in the rightreaching session (see Fig. 3A). As shown in Fig. 6B, we again observed a variation in the MFR amplitudes according to the spatial coincidence between the gaze and reach target (namely, R ⬍ L, R ⬍ RL, and L ⬎ LR). We then combined the data of the right-reaching and leftreaching sessions to quantify the MFR amplitudes under the four gaze-reaching conditions (M, MIS, MtoMIS, and MIStoM), irrespective of their actual location (i.e., right or left). As shown in Fig. 6C, the MFR was modulated by the gaze-reach coordination [1 of the main factors in ANOVA, F(3,69) ⫽ 39.2, P ⬍ 0.001]. In addition to the significant MFR difference between M and MIS (P ⬍ 0.001), we observed significant MFR differences between M and MtoMIS (P ⬍ 0.001) and between MIS and MIStoM (P ⫽ 0.009) (post hoc test using Tukey’s HSD). This clearly indicates that the MFR gain was updated after the gaze shift even if the shift occurred while the reaching movement was under way. We also found a significant difference between the MFRs for MIS and MtoMIS (P ⬍ 0.001), suggesting an excessive gain decrease in the postsaccadic period. In contrast, the difference was marginally significant (P ⫽ 0.08) between the MFRs for MIStoM and M, suggesting an insufficient increase in the “gain-up” condition (mismatch to match). These results suggest a downward bias in the updating of the MFR gain during a postsaccadic period.

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Gaze & Reach target Fig. 7. MFR amplitudes for the 4 gaze conditions in the presaccade experiment. Annotations and styles are the same as in Fig. 6. In this experiment, visual motion was presented before saccade initiation. Statistical significance: *P ⬍ 0.05, **P ⬍ 0.01.

saccade was made toward the reach target (LR), the MFR appeared to increase slightly compared with that for the L condition. This trend was also observed in the left-reaching session (Fig. 7B; R ⬍ L, R ⬍ RL, and L ⬎ LR). We plot the combined data of both reaching sessions in terms of the gaze-reaching relationship (i.e., match and mismatch) with statistical analyses (ANOVA and post hoc test with Tukey’s HSD) in Fig. 7C. The MFR was modulated by the gaze-reaching relationships [1 of the main factors in ANOVA, F(3,87) ⫽ 31.9, P ⬍ 0.001]. Under no-saccade conditions, the MFR differed significantly for M and MIS (P ⬍ 0.001). Importantly, under saccade conditions we also found a significant difference between M and MtoMIS (P ⬍ 0.01), suggesting that the MFR gain decreased when the saccade was made away from the reach target. In contrast, upregulation of the MFR (i.e., when the saccade was directed to the reach target) was not statistically significant but marginal (between MIS and MIStoM; P ⫽ 0.054). This difference between up-

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The aim of this experiment was to examine the possibility that attention shift rather than actual gaze shift affects MFR amplitudes as described in MATERIALS AND METHODS. The participants in the experiment were asked to keep their gaze and spatial attention directions separate. Figure 8A shows the MFR amplitudes (mean value across all participants) under the four conditions in which the instructed gaze and attention directions were varied (see MATERIALS AND METHODS for details). Larger MFRs were obtained when the participants fixated on the reach target (“gaze right” conditions) than when they fixated on another location (“gaze left” conditions). In contrast, the MFR did not vary with the direction of attention. We combined these data and replotted the MFR amplitudes against the spatial relationships between the gaze and reach target and between the attention and reach target in Fig. 8B. In this figure, “match” and “mismatch” denote conditions where each relationship is spatially matched and mismatched, respectively. We found that the gaze-reach relationship had a significant effect [main effect of 2-way ANOVA, F(1,8) ⫽ 9.37, P ⬍ 0.05] but the attention-reach relationship had no effect [F(1,8) ⫽ 0.013, P ⫽ 0.91] on the MFR amplitude. These results indicate that the MFR is not modulated by the spatial relationship between the attention and reach target but modulated by the relationship between gaze and reach target. To examine the attention effect on the MFR cautiously, we should verify whether spatial attention (voluntary attention) is actually directed to the cued location in this experimental task. To achieve this aim, we asked the participants to perform a RT task (see MATERIALS AND METHODS for details). If attention was appropriately allocated to the cued location, the RT should be shorter when the reaction stimulus appeared at the cued location (valid trial) than when it appeared at another location (invalid trial). This prediction was indeed confirmed, as shown in Fig. 8C, where the mean RTs of the valid and invalid trials were compared for each combination of attention cue and reaction stimulus location. Under the gaze-left condition (Fig. 8C, left), we found that the RTs for valid trials were significantly shorter than those for invalid trials when the reaction stimulus was presented on the right side [preplanned paired t-test: t(8) ⫽ 2.42, P ⬍ 0.05] and on the left side [t(8) ⫽ 2.40, P ⬍ 0.05]. This result holds under the gaze-right condition (Fig. 8C, right): a significant difference was observed when the reaction stimulus was presented on the right side [t(8) ⫽ 3.15, P ⬍ 0.05] and on the left side [t(8) ⫽ 2.84, P ⬍ 0.05]. Therefore, we conclude that the MFR was not modulated by the attention shift, although the participants correctly paid attention to the cued location in the attention experiment.

MFR Amp. [m/s2]

regulation and downregulation was perhaps similar to the downward bias observed in the postsaccade experiment. We also found significant differences between the MFR amplitudes of M and MIStoM (P ⬍ 0.001) and of MIS and MtoMIS (P ⬍ 0.001), suggesting that MFR updating was not completed. In summary, the results of the presaccade experiment suggest that gain updating was not completed but was mostly started during saccade execution or before saccade initiation according to the forthcoming relationship between gaze and reach target.

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Attention Cue & Reaction stimulus Fig. 8. Results of the attention experiment. A: mean MFR amplitudes across all participants for the combination of gaze and attention directions. Error bars denote SE. B: effect of spatial interaction between gaze and reach or between attention and reach target on the MFR amplitude. Filled and open bars, respectively, denote the spatial match and spatial mismatch of the corresponding factors. NS, not significant. C: reaction times (RTs) when pressing the button with the left hand in response to the presentation of the reaction stimulus when the gaze was directed to the left (left) and right (right) sides. RTs were plotted against the spatial relationship between the attention cue and reaction stimulus (valid or invalid). Each line corresponds to the location of the reaction stimulus (black line in right-side location and gray line in left-side location). Statistical significance: *P ⬍ 0.05, paired t-test. DISCUSSION

The aim of this study was to investigate whether the brain determines the gain of the reflexive visuomotor response only during the reaching preparation (“preset”) or could flexibly update the gain during the course of reaching execution (“updating”). We focused on the reflexive MFR induced by visual motion, since the amplitude of this response is known to be modulated by gaze-reach coordination. Our data showed that

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the MFR amplitudes were dynamically updated even during reaching movement according to the change in the gaze-reach coordination produced by the saccade, which supports the updating hypothesis. Furthermore, this gain updating would be already initiated by signals related to saccade planning or execution based on the forthcoming gaze-reach coordination. Updating MFR Gain During Reaching Movement In the postsaccade experiment, we found that the MFR was induced in a manner similar to that in the gaze-reach coordination soon after saccade termination (Fig. 6C), thus supporting the online gain-updating hypothesis. However, before drawing a final conclusion, we must consider several possible artifacts that could result from the introduction of eye movements. The first possibility is that the reaching behavior itself varied with the gaze conditions, which could affect the MFR. Indeed, several studies on eye-hand coupling have reported that eye position shifts affect reaching movements (Bock 1986; Henriques et al. 1998; Soechting et al. 2001; van Donkelaar 1997, 1998). However, we can rule out this possibility because we quantified the MFR amplitude by taking the difference between hand accelerations in different visual motion directions (i.e., upward-downward) for identical saccade directions. This subtraction method prevented any systematic bias in reaching trajectories caused by the eye position shift from the quantification of the MFR. Furthermore, to test the possibility that the MFR modulation is explained by the difference in reaching variability across gaze conditions, we analyzed the z-axis variability of the end-point hand positions in control trials. However, we found no significant difference in the variabilities of the four gaze conditions except for between M and MIS, and the trend of the change in variability according to the gaze conditions was different from that of MFR modulation. This result showed that reaching variability does not account for the MFR modulations obtained in the present experiment. These examinations therefore rule out the possibility that direct eyehand coupling explains the MFR modulations. The second possible artifact is that the motion sensitivity is enhanced immediately after saccades, which has been observed for reflexive ocular behavior induced by visual motion (Kawano and Miles 1986; Takemura and Kawano 2006). This postsaccadic enhancement could alter the MFR amplitude. However, this possibility is inconsistent with our data, where the MFR decreased significantly when the saccade was made away from the reach target (Fig. 6C). The third possible artifact is saccadic suppression, which reduces visual sensitivity in perception before, during, and after saccades (e.g., Ross et al. 2001). Although saccadic suppression can affect the MFR amplitude, it cannot fully explain our data because the MFR increased significantly when the saccade was directed toward the reach target (Fig. 6C). The final possible artifact is the shift in attention, which is tightly coupled with saccade planning and execution (e.g., Rizzolatti et al. 1987). However, the results of our attention experiment clearly argued against the possibility that top-down attention rather than gaze-reach coordination alters the MFR amplitude. The absence of an attention-related effect on the MFR is consistent with a recent study that showed that attention affected the visuomotor response to shifts in the reach

target but did not affect the response to shifts in the hand cursor (Reichenbach et al. 2014). Considering that the MFR would be a functional way of adjusting arm movement against own-body motion, these findings support the interpretation that implicit visuomotor responses related to the states of our body parts (shift in the hand location or whole body motion) are governed by the direct visuomotor binding mechanism that is independent of visual attention (Reichenbach et al. 2014). Taken together, our observed changes in MFR amplitudes are not based on saccade-related artifacts. MFR gain is updated according to the change in the gaze-reach coordination during an ongoing reaching movement. More interestingly, MFR gain updating was also observed in the presaccade experiment (Fig. 7C), in which the visual motion started before the saccade. Here we want to examine the time course of the saccade and the motor command producing the MFR. Considering the transmission delay of ⬃40 ms from the motor cortex to the motor response of the arm (Abbruzzese et al. 1994; Koike and Kawato 1995), the motor command of the MFR during the evaluation period (132–192 ms) would be sent by 152 ms (⫽ 192 ms ⫺ 40 ms) after the visual motion onset. This motor command of the MFR is probably sent before saccade termination since the earliest saccade termination was 164 ms after the visual motion onset in this experiment. Therefore, the MFR gain updating certainly started before or during the saccade rather than after saccade termination. Furthermore, to determine whether MFR gain updating started before or during the saccade, we reanalyzed the MFR amplitudes in the presaccade experiment using the partial data of the trials (57% for right reaching, 59% for left reaching) in which the saccade started ⬎152 ms (estimated end time of the MFR motor command for the evaluation period) after the visual motion onset. As a result, we found a significant decrease in MFR (P ⬍ 0.01) from the M to MtoMIS conditions and a marginal increase in MFR (P ⫽ 0.07) from the MIS to MIStoM conditions, as observed in our analysis of all the data (Fig. 7C). This may mean that MFR gain updating had already started before the saccadic eye movement and therefore suggests the involvement of planning information of hand-eye coordination in the MFR gain updating mechanisms. Temporal Aspects of Gain Modulation The temporal aspects of reflex modulation have long been a central issue in reflex studies mainly of the somatosensory reflex. There have been several lines of evidence showing reflex modulation during the foreperiod of task movements, suggesting preparatory gain settings (e.g., Ahmadi-Pajouh et al. 2012; Bonnet 1983; Evarts and Tanji 1974; Sullivan and Hayes 1987; reviewed in Bonnard et al. 2004). On the other hand, several recent studies have found that the amplitude of the stretch reflex built up gradually and was dynamically modified during the reaching movement (Kimura and Gomi 2009; Mutha et al. 2008). In contrast, with reflexive online visuomotor systems, the time course of the regulation is not fully understood. As mentioned in the introduction, many previous studies on visuomotor control have been limited to observing gain modulation based on block-by-block or trial-by-trial conditional changes (Abekawa and Gomi 2010; Day and Lyon 2000; Franklin and Wolpert 2008; Gritsenko and Kalaska 2010; Knill et al. 2011).

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UPDATING GAIN FOR ONLINE VISUOMOTOR CONTROL

The present result for the flexible gain updating of the MFR is consistent with a recent study that showed that the manual response to a shift in the hand cursor varied in gain during the reaching movement and this updating process occurred within 100 ms (Dimitriou et al. 2013). In the postsaccade experiment in the present study, gain updating of the MFR would occur less than ⬃300 ms after the saccade termination because the MFR amplitude was estimated between 132 and 192 ms after the visual motion onset, which was applied 40 – 60 ms after saccade termination. In addition, we also observed fast MFR updating before or during saccadic eye movements in the presaccade experiment. These findings obtained from different types of visuomotor responses strongly suggest that a reflexive online visuomotor system determines the adequate visuomotor gain and updates it rapidly and flexibly during a motor execution to respond effectively to unpredictable changes in the external world. Despite the fast updating process, the MFR amplitude for the saccade condition differed from that for the corresponding no-saccade condition. Our results in the postsaccade experiment showed an excessive gain decrease in the high-to-low direction (significant MIS ⬎ MtoMIS) and an insufficient gain increase in the low-to-high direction (marginally significant M ⬎ MIStoM). There are two potential explanations for this downward bias. First, the updating process is not completed just after the saccade. It is possible that the new gaze-reach coordination is not reliably computed in this epoch, so that the postsaccadic MFR amplitude is different from that for the corresponding no-saccade condition. This interpretation seems to be consistent with recent neurophysiological studies reporting that eye position signals coded in the dorsal visual system (Morris et al. 2012) and lateral intraparietal area (Xu et al. 2012) remain inaccurate and unreliable immediately after (⬃150 ms) a saccade. In addition, more recent behavioral research has suggested that the gain of the implicit visuomotor response decreased when the uncertainty in the state of the limb increased (Dimitriou et al. 2013). The downward bias in the present study could be ascribed to the increase in uncertainty about the representation of gaze direction and/or reach target location just after the eye movement. Second, even when the updating process itself is completed and the representation of gaze-reach coordination is reliable, the visuomotor gain decreases irrespective of saccade direction. This gain reduction is possibly caused by saccade suppression, which was observed in low-level motion perception and its effect continues just after the saccade (20 –50 ms) (Shioiri and Cavanagh 1989). Thus saccade-related gain loss in motion sensitivity could reduce the amplitude of a motioninduced MFR immediately after the saccade. For a further discussion of how and why downward bias was observed just after the saccade, an additional experimental paradigm should be introduced in a future study.

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Recent psychophysical, electrophysiological, and neuroimaging studies have reported that a reach target is stored in a gaze-centered frame of reference for reach planning, and the posterior parietal cortex is involved in constructing this representation (Cohen and Andersen 2002; Crawford et al. 2004; Medendorp et al. 2008; Snyder 2000; Thompson and Henriques 2011). In the gaze-centered target representation, the spatial relationship between gaze and reach target can be expressed explicitly. Thus it is possible that this gaze-centered target representation for reach planning is shared with the MFR modulation. The present experimental results showed that the gaze-reach coordination was rapidly updated and this updating was initiated before or during actual eye movement. This predictive updating would deny the possibility that gaze-reach coordination is recomputed sequentially after the termination of each saccade. One possible cortical mechanism for the rapid and predictive updating is spatial remapping, which is known to update the retinotopic representation of visual information across saccades (e.g., Duhamel et al. 1992). Spatial remapping is observed in the frontal, parietal, and occipital regions (Melcher and Colby 2008), and related changes in neural activity occur 250 ms or less before saccade execution (Kusunoki and Goldberg 2003). Additionally, psychophysical studies have shown that the remapping of attention (Mathôt and Theeuwes 2010; Rolfs et al. 2011) and of visual features (Melcher 2007) precedes (50 –150 ms) saccadic eye movements. The spatial remapping mechanism can predictively update the internal representation of the reach target in the gaze-centered coordinates, and thus the change in gaze-reach coordination is computed during or even before the eye movement. Therefore, it can be inferred that such a spatial remapping mechanism is involved in the MFR updating process. MFR modulation based on gaze-reach coordination might be associated with our natural behavior, namely, that we would usually direct our gaze toward the reach target when highly accurate reaching is required. From a functional viewpoint, our findings seem reasonable because the online visuomotor system is flexibly regulated in a dynamic fashion during the motor action in order to effectively respond to unpredictable changes in the external world. Additionally, our results predict the involvement of a sophisticated brain mechanism for the spatial coding of gaze and reach target. The computational and physiological mechanisms for the modulation and gain updating of online visuomotor systems should be addressed in more detail in future studies. ACKNOWLEDGMENTS We thank T. Inui for constructive discussions and E. Maeda and T. Yamada for support and encouragement. The experiments used Cogent Graphics, developed by J. Romaya at the Laboratory of Neurobiology at the Wellcome Department of Imaging Neuroscience, University College London. DISCLOSURES

Gaze-Centered Representation and Spatial Remapping of Reach Target The present results indicate that the spatial relationship between gaze and reach target is coded in the brain for MFR modulation and is updated across saccades in an online manner. What mechanism might underlie this process?

No conflicts of interest, financial or otherwise, are declared by the author(s). AUTHOR CONTRIBUTIONS Author contributions: N.A. and H.G. conception and design of research; N.A. and H.G. performed experiments; N.A. and H.G. analyzed data; N.A. and H.G. interpreted results of experiments; N.A. and H.G. prepared figures; N.A.

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UPDATING GAIN FOR ONLINE VISUOMOTOR CONTROL

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