Edited by: Andre R. Brunoni, Universidade de São Paulo, Brazil
Reviewed by: Andrea Antal, University Medical Center Goettingen, Germany; Thiago Leiros Costa, Universidade de São Paulo, Brazil
*Correspondence: Ryota Kanai, Institute of Cognitive Neuroscience, University College London, 17 Queen Square, WC1N 3AR London, UK. e-mail:
This article was submitted to Frontiers in Neuropsychiatric Imaging and Stimulation, a specialty of Frontiers in Psychiatry.
This is an open-access article distributed under the terms of the
Transcranial direct current stimulation (tDCS) has been successfully applied to cortical areas such as the motor cortex and visual cortex. In the present study, we examined whether tDCS can reach and selectively modulate the excitability of the frontal eye field (FEF). In order to assess potential effects of tDCS, we measured saccade latency, landing point, and its variability in a simple prosaccade task and in an antisaccade task. In the prosaccade task, we found that anodal tDCS shortened the latency of saccades to a contralateral visual cue. However, cathodal tDCS did not show a significant modulation of saccade latency. In the antisaccade task, on the other hand, we found that the latency for ipisilateral antisaccades was prolonged during the stimulation, whereas anodal stimulation did not modulate the latency of antisaccades. In addition, anodal tDCS reduced the erroneous saccades toward the contralateral visual cue. These results in the antisaccade task suggest that tDCS modulates the function of FEF to suppress reflexive saccades to the contralateral visual cue. Both in the prosaccade and antisaccade tasks, we did not find any effect of tDCS on saccade landing point or its variability. Our present study is the first to show effects of tDCS over FEF and opens the possibility of applying tDCS for studying the functions of FEF in oculomotor and attentional performance.
Delivering direct current from scalp to cortex over several minutes has been shown to induce a long-lasting change in cortical excitability. This stimulation technique called transcranial direct current stimulation (tDCS) has been applied to many cortical areas, most notably the motor cortex (Priori et al.,
The goal of the present study was to examine whether tDCS can reach and modulate the excitability of the frontal eye fields (FEF), which is one of the key areas involved in controlling eye movements and selective attention (Robinson and Fuchs,
There are several lines of evidence that impairment or inactivation of the FEF prolongs saccade latency in the prosaccade task. Patients with lesions in the FEF show a prolonged latency for prosaccades toward the direction contralateral to the lesion in an overlap condition in which the initial fixation point remained displayed even after the saccade target appeared (Gaymard et al.,
In the second part of our study, we examined possible effects of tDCS over FEF in the antisaccade task (Hallet,
One important role of FEF in the antisaccade task is the generation of volitional saccades. Patients with a localized lesion in FEF show a normal percentage of errors in suppressing reflexive saccades, whereas the latency of correct antisaccades was increased bilaterally (Pierrot-Deseilligny et al.,
Sixteen subjects (6 males and 10 females) were recruited from the community of University College London. They were all right-handed and had normal or corrected-to-normal visual acuity. Informed written consent was obtained from each participant. During the experiment, they sat 57 cm away from a 17′′ CRT monitor running with a 100-Hz refresh rate. Their head was immobilized by a chin- and headrest on which an eyetracker (Eyelink, SMI, Berlin/Germany) was mounted. The experiment conformed to the Declaration of Helsinki and was approved by a local (University College London) ethical committee. Informed consent was obtained from all subjects.
Direct current was delivered by a constant current stimulator (Schneider Electronics, Gleichen, Germany) via a pair of anodal and cathodal electrodes placed over left and right FEF. The electrodes were covered with flat synthetic sponges soaked in 0.9% NaCl solution. The contact surface of the sponges was 3 cm × 3 cm for both electrodes. The maximum current density under the electrode was 0.11 mA/cm2. This is slightly higher than typical current density ranging 0.029 and 0.08 mA/cm2 (Nitsche et al.,
Structural MRI images of all participants were obtained prior to the experiment. The positions of left FEF and right FEF were determined for individual participants using FSL (FMRIB Software Library, Oxford, UK) in the following transformation steps; first we converted individual structural images to the standard MNI coordinates, and then the coordinates for left FEF and right FEF in MNI coordinates were transformed back to the real image space. The MNI coordinates for L-FEF and R-FEF were (−32.3, −4.4, 49.8) and (31.3, −4.5, 50.9). Those values are calculated from the Talairach coordinate given in Paus (
While it is known that the exact location of FEF can be variable between individuals, our approach of targeting FEF using the standard coordinate has proved to be sufficiently effective for interfering with functions of FEF (e.g., Muggleton et al.,
The task for the participants was to make an eye movement to a target (black square) in response to the onset of the target presented in one of two designated positions (8.1° away from the fixation horizontally), which were indicated by hollow square frames (Figure
The central fixation point remained on the screen even after the saccade target appeared. In a study of FEF patients, no impairment was found in a gap condition in which the initial fixation point was removed 200 ms before the onset of the saccade target (Pierrot-Deseilligny et al.,
First, each participant completed one practice block of 40 trials before starting the actual experimental session. After the practice, participants completed a session consisting of five pairs of blocks (10 blocks in total; see Figure
For half of the participants, the anodal electrode was placed over left FEF and cathodal over right FEF, and the polarity of the electrodes was reversed for the other half of the participants. Saccade data were analyzed according to whether saccade direction was contralateral to the anode or the cathode.
The gaze direction of the right eye was sampled at 250Hz using EyeLink system (SR Research Ltd, Ontario, Canada). We calculated saccade latency, landing position with respect to the target and variability of saccade amplitudes. To determine the onset and offset of a saccade, we used a velocity criterion. When eye velocity exceeded 26.8°/s, that time point was regarded as the onset of a saccade and when eye velocity went down again below 26.8 deg/s, the time point immediately after this sample was regarded as the termination of the saccade. Data points for saccade latencies, amplitudes, and landing positions were collapsed across two consecutive 5 min sessions (40 trials ×2) in order to increase the robustness of estimating these parameters.
Median rather than mean was used for saccade latency because the distribution of saccade latencies is typically skewed (e.g., Carpenter and Williams,
Trials were rejected from the analyses if eye position at the time of target onset deviated from the fixation more than 1.8°, if the first saccade after target onset was directed to the opposite side from the target, or if saccade latency was longer than 400 ms or shorter than 50 ms. Trials were sorted according to whether saccade direction was contralateral to anode position or cathode position.
Sixteen new subjects participated in the cathode only condition (5 males and 11 females), and yet another 16 subjects (8 males and 8 females) participated in the anode only condition. None of them had participated in the bilateral tDCS experiment. The experiment conformed to the Declaration of Helsinki and was approved by a local (University College London) ethical committee. Informed consent was obtained from all subjects.
The experiments were conducted in the same manner as the first experiment. Both for the anodal experiment and cathodal experiment, half of subjects in each experiment had tDCS on the right side and the other half on the left. Data were sorted according to whether saccade target appeared contralateral to the tDCS site.
The duration and intensity parameters were identical to the bilateral experiment. When stimulating the motor cortex with tDCS, reference electrodes are often placed on the contralateral forehead because other electrode montages were found to be ineffective (Nitsche and Paulus,
As in the prosaccade experiment with unilateral tDCS, 16 subjects participated in the cathode only condition, and another 16 subjects participated in the anode only condition. Three of participants who took part in the cathode condition took part also in the prosaccade experiment (two of them were in the anode condition and one of them was in the cathode condition). Three participants in the anode condition took part also in the prosaccade experiment (two of them were in the anode condition and one of them was in the cathode condition). However, these two experiments involved different tasks and were conducted at least 6 months apart and therefore carry-over and practice effects are expected to be negligible. The experiment conformed to the Declaration of Helsinki and was approved by a local (University College London) ethical committee. Informed consent was obtained from all subjects.
The stimuli were identical to the prosaccade experiments described above. The only difference was that the subjects were instructed to make a saccade to the box opposite to the black cue. Both for the anodal experiment and cathodal experiment, half of subjects in each experiment had tDCS on the right side and the other half on the left. Data were sorted according to whether the correct saccade direction was contralateral or ipsilateral to the tDCS site. The stimulation methods for tDCS were identical to the prosaccade experiment with unilateral tDCS described above. No sham condition was included in this study.
In the first experiment, we applied tDCS bilaterally with anode over one FEF and cathode over the other. Since anode and cathode often produce opposite effects, we expected this bilateral tDCS configuration would yield a large difference between leftward and rightward saccade properties if any effect was to be observed.
The time course of saccade latency is shown in Figure
In order to examine whether other metrics of saccades were altered by tDCS, we used two measures to estimate accuracy of saccades. One was the variability of the saccade landing point, which we calculated as the standard deviation of the horizontal position of the saccade landing point. The other measure was the mean landing position with respect to the target position. These two measures, variability and landing position, are indicative of the level of noise and systematic bias in saccade execution, respectively (e.g., White et al.,
There were no statistically significant effects of anodal or cathodal stimulation on accuracy or variability. For the landing point of saccades, a repeated measures ANOVA with tDCS and time course as factors did not show any significant effect on the landing point (tDCS,
These results together show that tDCS primarily influences saccade latency but has no effect on saccade amplitude or its variability. The effect on latency was specific to saccades contralateral to the FEF stimulated by the anode, suggesting that anodal stimulation shortened saccade latency. The latency difference produced by tDCS was 7.8 ms on average across the entire time course of the experiment. However, it is unclear whether the change in saccade latency was due to the anodal stimulation only, or alternatively was caused by a combination of anodal and cathodal effects, which shifted the balance between the left and right FEF.
In order to isolate effects of anodal and cathodal tDCS, we applied either anodal or cathodal tDCS over one FEF with the reference electrode over the ipisilateral shoulder (deltoid muscle).
The results of anodal tDCS are shown in Figure
The time course of saccade latency in the experiment with cathodal tDCS is shown in Figure
The results of the antisaccade experiment are shown in Figure
On the other hand, cathodal tDCS had an effect in the antisaccade task (Figures
In order to evaluate possible changes in the ability to suppress automatic saccades toward the peripheral cue, we calculated the percentage of trials in which the subjects erroneously made a saccade to the peripheral cue and examined possible changes in the inhibition error rates due to tDCS.
The percentages of inhibition errors are shown in Figure
In the present study, we have shown that tDCS over FEF can modulate saccade properties in prosaccade and antisaccade tasks. Our main findings are summarized as (1) anodal tDCS shortens the latency of contralateral prosaccades, (2) cathodal tDCS lengthens the latency of ipsilateral antisaccades, (3) anodal tDCS reduces automatic error saccade to the contralateral cue, and (4) saccade amplitudes and their variability are unaffected by tDCS. In this section, we elaborate on each of these points and provide comparisons with related TMS and lesion studies on FEF and saccade generation.
The only effect we observed by tDCS over FEF in the prosaccade experiment was shortening of saccade latency in the direction contralateral to anodal stimulation. The positive effect of anodal tDCS and no effect of cathodal tDCS support the idea that the effect we found in the bilateral tDCS experiment is primarily due to the shortening of saccade latency due to activation of FEF by anodal stimulation rather than lengthening of latency due to suppression of FEF by cathodal stimulation.
Anodal tDCS is believed to increase the spontaneous firing rate of the cortex under the stimulating electrode by depolarizing the membrane potential (Bindman et al.,
In the antisaccade task, cathodal tDCS delayed the generation of antisaccades toward the direction ipisilateral to the stimulation site. This is informative for understanding the functions of FEF and possibly the neighboring areas stimulated by tDCS in the antisaccade task. As we outlined in the introduction, FEF has been implicated in generation of volitional saccades and suppression of reflexive saccades. These two presumed functions of the FEF make distinct predictions as to the consequences of tDCS over FEF during the antisaccade task. If the generation of volitional saccades were to be suppressed by cathodal tDCS over FEF, the latency of contralateral saccades would have been prolonged. However, this is not clearly the case. Instead, the prolongation occurred only for ipisilateral saccades. This result may be regarded as somewhat puzzling, but can be understood if we assume that a successful antisaccade consists of a serial, rather than parallel, processes of suppression of an automatic reflexive saccade and programming and generation of a volitional saccade. In the ipisilateral antisaccade trials, the visual cue appeared on the side contralateral to the tDCS. If cathodal tDCS over FEF were to impair the suppression of reflexive saccade to the contralateral visual cue, it would take longer to suppress the reflexive saccade to the contralateral visual cue and thereby delay the programming of an ipisilateral saccade.
The finding of prolongation of ipisilateral antisaccade is consistent with previous TMS studies over FEF in the antisaccade task (Müri et al.,
A more direct way to test the idea that tDCS over FEF interferes with suppression of reflexive saccades is to examine the changes in the inhibition error rate after tDCS. If the cathodal tDCS over FEF impaired the ability to suppress reflexive saccades, the number of error saccades would be expected to increase. However, our results did not show a significant increase in the error rate (Figure
On the other hand, we did detect a small change in the inhibition error rate with the anodal tDCS, which produced a significant change. It reduced the errors of making saccades to the visual cue presented contralateral to the stimulation electrode. This is again consistent with the idea that tDCS over FEF modulates the suppression of reflexive saccades. That is, our results can be interpreted as anodal tDCS facilitated the FEF function to suppress erroneous reflexive saccades to contralateral visual cues.
Although anodal tDCS shortened the contralateral saccade latency, we did not find a change in accuracy as measured by the landing point and variability, which would be expected if one considered a potential trade-off between saccade latency and accuracy (Schall,
So far, we have explained the effects of tDCS on prosaccades and antisaccade invoking a different mechanism for each. To explain the effect of cathodal tDCS in the antisaccade task, we assumed that cathodal tDCS impairs the suppression of contralateral reflexive saccade, and for the facilitation of prosaccades by anodal tDCS, we explained that prosaccade latency was shortened by enhanced activity level of FEF. These two explanations may appear to conflict with each other. The interpretation of the FEF activity as the efficiency of suppressing contralateral saccade contradicts the results of the prosaccade experiment. Conversely, if we interpret the FEF activity as the speed of saccadic response as we did for explaining the results of the prosaccade experiment, the results of the antisaccade experiment cannot be explained. For instance, the suppression hypothesis predicts that cathodal tDCS would shorten contralateral prosaccades by reducing the suppression of saccade generation. However, our results showed no effect, or if anything an opposite effect.
These apparent conflicts can be reconciled if we consider (1) that the effect of tDCS is dependent on the activity level during the task and (2) that FEF consists of both saccade execution neurons and saccade suppression neurons. In support of the first point, an earlier study of tDCS showed that when tDCS was delivered over the motor cortex while subjects were engaged in a mental task, deactivating the motor cortex, subsequent effects of the tDCS on motor-evoked potentials were much reduced compared with delivery of tDCS during a passive condition (Antal et al.,
As for the second point, it is known that subset of FEF neurons with foveal receptive fields serve for suppressing saccade execution (Segraves and Goldberg,
However, there remain two predictions made by this framework that are not measured in the present data. First, cathodal tDCS should have lengthened contralateral prosaccades. Second, anodal tDCS should have shortened ipsilateral antisaccade. As for the lack of these effects, it is possible that the effect size was too small to detect with our experimental procedures. In the unilateral cathodal tDCS condition, the prosaccade latency was slightly (∼3 ms) longer for the contralateral than ipsilateral saccades (Figure
One of the weaknesses of our present study is the lack of a sham condition, which introduces ambiguity as to whether latency change over time comes from effects of tDCS or practice over trials. While the unilateral tDCS conditions were used as a way to introduce a no stimulation condition, we cannot rule out the possibility that the FEF on the unstimulated side was modulated by tDCS over the contralateral FEF via interhemispheric connectivity between homologous regions (e.g., Suppa et al.,
Hemispheric differences in the functions of human FEF have been reported in several aspects cognitive functions such as top-down attention to early visual areas (Silvanto et al.,
The effects of anodal tDCS on prosaccade latency both in the bilateral and unilateral stimulation and the effects of cathodal tDCS in the antisaccade task both suggest that the induced electric current reached the FEF as intended. Further, as we have discussed, the effects of cathodal tDCS were by and large consistent with previous offline TMS studies on FEF both in the antisaccade tasks (Müri et al.,
One disadvantage of tDCS is that compared to TMS, the stimulation spreads to larger cortical regions due to the volume conduction (see, Wagner et al.,
One of the advantages of tDCS over TMS for interfering with FEF functions is that tDCS does not produce uncomfortable twitches or eye blinks. Also, the auditory and tactile sensations produced by a TMS pulse briefly suppress the generation of microsaccades for a few hundred milliseconds (Kanai et al.,
In summary, our present study shows that tDCS can be used to modulate activity of FEF over a time course of up to 30 min. It opens the possibility of applying tDCS for studying functions of FEF and for enhancing oculomotor and attentional performance in the future.
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
BOLD, blood-oxygen-level dependent; FEF, frontal eye field; MEP, motor-evoked potential; rTMS, repetitive TMS; tDCS, transcranial direct current stimulation; TMS, transcranial magnetic stimulation.