Transcranial Direct Current Stimulation of the Frontal Eye
Field to Modulate Eye Movements
Faculty of Social and Behavioural Sciences, Psychology Master Thesis Psychology, Brain and Cognition Name: Floris Jan Frederik Willem Roelofs Student Number: 10212434 Supervisor: Leon Reteig Date: 18/07/2017 Word count: 5119
Abstract The main focus of this study is to validate the results presented by Kanai et al. (2012). In their study they have found indicative data for a modulatory role of the Frontal Eye Fields (FEF) induced by transcranial direct current stimulation (tDCS) on saccade latencies. Because the data did not fully substantiate the hypothesised results and the effect sizes were mild, the aim of this study is to find more conclusive evidence on the modulatory role of the FEF and the influence of tDCS. By taking the design from Kanai et al. (2012) as reference, subjects received both anodal and cathodal stimulation during a prosaccade task over the course of two sessions in which saccade latency was measured. To estimate the effects of tDCS over time, baseline measurements were compared to subsequent stimulation and post stimulation blocks. A repeated measure ANOVA over 18 subjects revealed no significant effects of stimulation on saccade latency and accuracy. It seems like the data does not support the findings of Kanai et al. (2012) in which tDCS stimulation successfully reached and influenced the FEF. Implications for future research are discussed, as well as shortcomings and alternative theoretical interpretations of the current data.
Introduction With the rising interest and applicability of transcranial direct current stimulation (tDCS), much research arises on the effects of tDCS on different brain regions. Most of this research has been centered on the effects of stimulating the motor cortex and prefrontal cortex (PFC), both in experimental as well as clinical setting (Nitsche & Paulus, 2000, 2001; Boggio et al., 2006; Berryhill & Jones, 2012). tDCS applies electrical current at targeted areas of the brain through two sorts of electrodes, a positive anodal electrode and a negative cathodal electrode. The electrode that is not placed over a target area is called the reference electrode, usually placed on the opposite forehead in respect to the target area or the shoulder (Filmer, Dux & Mattingley, 2014). By stimulating the underlying cortex with the anodal electrode, the resting potential of the membrane can be depolarised, which lowers the firing threshold. In contrast, by inhibiting the underlying cortex with the cathodal electrode, the membrane will be brought in a hyperpolarising state, resulting in an increased firing threshold (Medeiros et al., 2012). Conceptually, one can think of the effects of depolarisation and hyperpolarisation caused by anodal and cathodal tDCS as modulations that make it more or less likely, respectively, that a stimulated neuron will produce an action potential (Filmer et al., 2014). After prolonged stimulation of the cortex, the effects can still be apparent after the stimulation (Nitsche et al., 2008; Zheng, Alsop & Schlaug, 2011; Brunoni et al., 2012) due to plasticity concepts of long-term potentiation (LTP) and long-term depression (LTD) caused by the alteration of synaptic transmission by tDCS.
In the present study we are interested if tDCS is able to reach and modulate the Frontal Eye Fields (FEF). The FEF is located in the dorsal prefrontal cortex and is involved with detecting stimuli within the visual field, controlling selective attention and initiating target orientated saccades (Robinson & Fuchs, 1969; Bruce & Goldberg, 1985; Paus, 1996; Moore, Armstrong & Fallah, 2003; Schall, 2009). A transcranial magnetic stimulation (TMS) study in 2006 showed that stimulation of the FEF (versus vertex) enhanced perceived contrast for peripheral relative to central visual stimuli (Ruff et al., 2006). Such an enhancement may play a functional role during saccade planning and execution and is in accordance with the perceived role of the FEF. In addition, the planning role of the FEF finds support by many fMRI studies in which FEF activity was shown prior to saccadic movements (Brown, Goltz, Vilis, Ford & Everling, 2006; Connolly, Goodale, Menon & Munoz, 2002; Sweeney, Luna, Keedy, McDowell & Clementz, 2007). Also, numerous studies on the effects of micro stimulation to the FEF have been published. For example, Moore and Fallah (2004) showed that electrical micro stimulation of the FEF resulted in an increased sensitivity to targets within the stimulation site, demonstrating that improvements in the deployment of covert spatial attention can be obtained by micro stimulation of FEF sites from which saccadic eye movements are also evoked. Given these results from previous studies, we can hypothesize what the effects of tDCS should be on saccadic eye movements. Because the FEF is mainly involved in the initiation of saccadic movement in a contralateral manner, anodal stimulation is expected to reduce the latency time of the saccades when moving contralateral with respect to the stimulation. Anodal stimulation will raise the
resting potential in the underlying cortex, which will reduce the firing threshold, causing the initiation of saccades with more ease and thereby shortening the latency time. In addition, under cathodal stimulation an increased latency time for saccadic movements is expected when moving contralateral in respect to the stimulation. This is because, under cathodal stimulation the underlying cortex will be hyperpolarised, which increases the fire threshold. This could result in an increased latency time. For saccadic movements ipsilateral in respect to the stimulation the opposite effects could be expected. Since the FEF initiates saccadic movements in a contralateral manner, anodal stimulation could potentially increase latency time for saccadic movements towards the stimulation site. Cathodal stimulation could in turn facilitate saccadic movements, thus decreasing latency time towards the stimulation site. One study that has investigated this relationship between tDCS stimulation of the FEF and latency of saccadic movements, is the study of Kanai, Muggleton and Walsh (2012). They used a pro- and antisaccade task in which, respectively, gaze-movement had to be directed towards or away from a peripheral horizontal stimulus. Two types of tDCS montages were used: Bilateral stimulation, with anodal stimulation over one FEF and the cathodal stimulation over the other FEF, and unilateral stimulation, in which half of the subjects had tDCS on the right side and the other half on the left. Under bilateral stimulation, the latency of saccades was influenced during a prosaccade task. The effect on latency was specific to saccades contralateral to the FEF stimulated by the anode, suggesting that anodal stimulation shortened saccade latency. No bilateral stimulation montage in combination with an
anti-saccade task was reported. During the prosaccade task with a unilateral montage, anodal stimulation shortened the latency of saccade contralateral to the stimulation site. However, unilateral cathodal stimulation over FEF did not have any effect on saccade latency. Conversely, cathodal tDCS had an effect in the antisaccade task but no effects of anodal tDCS were found under unilateral stimulation. Although these results reflect a modulatory role induced by tDCS, there are results missing from this study that should also confirm this hypothesis. First, importantly, cathodal stimulation should have lengthened the latency of contralateral prosaccades. Second, anodal tDCS should have shortened the latency of ipsilateral anti-saccades. As for the lack of these effects, it is possible that the effect size of this study was too small to detect with their experimental procedures. Apart from that, some differences in latency time were of such a size (~ 3 ms), that the eye-tracking device in the experiment could not distinguish accurately enough with the used sample rate of 250 Hz. The aim of this study is to find more conclusive evidence on the modulatory role of the FEF and the influence of tDCS on it by trying to validate the results presented by Kanai et al. (2012). Using their study as reference point for replication, a few important design choices are made to build on their study, hoping to solve the discrepancies found in their results. Because Kanai et al. (2012) reported only small effect sizes, this study is restricted only to prosaccades, using only a prosaccade task, focusing on this mechanism in more detail. Also, Duecker, Formisano and Sack (2013) have found a functional asymmetry between the FEF, where stimulation to the left FEF (lFEF) effected only the contralateral hemifield, but stimulation of the
right FEF (rFEF) effected both hemifields. Because of this hemispheric difference, only the rFEF will be stimulated in this study. To localise the rFEF, a subject-to-subject method is used with structural MRI scans, in comparison to Kanai et al. (2012) where standard MNI coordinates of the FEF were used. As for the tDCS montage, this study uses a unilateral instead of a bilateral montage, because anodal and cathodal stimulation in a bilateral montage could affect each other. By also changing the reference electrode from the shoulder to the left side of the forehead, the interelectrode distance will decrease, which might achieve a clearer online and offline effect from the stimulation, since it could enhance the focality of the stimulation (Moliadze, Antal & Paulus, 2010; Galletta et al., 2015). Also, by lengthening stimulation time from 10 to 15 minutes, the effects during and after stimulation might increase and prolong (Nitsche & Paulus, 2000). Instead of using an eye-tracker with a sample rate of 250 Hz, 1000Hz will be used to distinguish more accurately between latency times and finally, a within-subject is chosen, which typically have higher statistical power than between-subject designs (Guo, Logan, Glueck & Muller, 2013) as used by Kanai et al. (2012).
Methods Subjects Subjects were initially chosen if they had taken part in a previous MRI study at the University of Amsterdam (UvA). This way we could easily locate the exact location of the FEF per individual to place the tDCS electrodes. These students were approached with the question of whether they wanted to participate in our study. Prior to the experiment a screening took place to check if the subjects could participate in a study with tDCS without any problems. 19 questions were asked related to health and potential risk factors associated with the use of tDCS. After screening, 20 subjects participated in the experiment. All subjects were given information on the procedure during the experiment and the tDCS device. It was clearly stated that if subjects experienced discomfort, the tDCS session would come to a halt if askes and the experiment would be finished. After the subjects had read the information and was in agreement, an informed consent was signed. Task As in the experiment from Kanai et al. (2012) subjects carried out a prosaccade task with an eye-tracker set-up. Subjects were instructed to make an eye movement towards a target (black circle) in one of two designated positions (8.1 ̊ horizontally) away from the fixation point (Figure 1). The onset position of the target (left or right) had a displacement along the horizontal meridian of the screen and was randomised on each trial, with 50% left and 50% right trials, and delay (300– 3000 ms; mean: 500 ms) was randomized from an exponential distribution across
trials. After target onset, the fixation point would disappear from the centre of the screen. The size of all the stimuli was programmed to have width of 0.5 degrees of visual angle for the subject. Because saccades were being recorded, subjects were instructed to blink as little as possible during the task. Small breaks were programmed every 30 seconds for the subject in which they had the opportunity to blink as much as they liked and after pressing any key on the keyboard the task would resume. In this task we differentiated between two types of trials, fixation saccades (saccades directed towards the fixation stimulus) and target saccades (saccades directed towards target stimuli), as they would be analysed separately. In total, the subjects completed 120 trials per block. At the end of each block, subjects received a feedback message on their averaged reaction time in ms and accuracy of their endpoint in mm with an encouraging message to improve the score. Each block was completed within 5 minutes including calibration of the eye tracker at the beginning of each block.
Time Figure 1. Stimulus display for two trials. Subjects were asked to direct their gaze towards the stimulus as quick and accurate as possible. Time between stimulus onset and offset was randomised from an exponential distribution between 300-3000 ms with a mean of 500 ms from the truncated exponential distribution. Design The session began with a practice block in which the subjects could make themselves familiar with the prosaccade task. After the practice block the actual experimental sessions began. The first three blocks consisted out of a baseline-session in which no stimulation was given and to which subsequent performance would be compared. During the following tDCS-session the tDCS device was turned on and another three blocks had to be completed. The stimulation lasted for a total of 17 minutes, including a ramp-up and ramp-down time of 1 minute each. When the tDCS-session was over, the tDCS device was disconnected and the post-tDCS Fixation stimuli onset Fixation stimuli offset & target stimuli onset 1st trial Fixation stimuli onset 2nd trial
session began. In this session six blocks had to be completed for estimating offline tDCS effects. During the entire experiment, an experimenter walked in the room with the subject after three blocks were finished to have a small chat about the task to prevent the subject from losing motivation or interest. In total, all of the subjects had to complete these sessions twice with a minimum time interval of 48 hours and a maximum time interval of seven days, in which the tDCS-session would differ in the type of stimulation received by the subject (anodal and cathodal stimulation). The sequence of stimulation in the first and the second tDCS-session was counterbalanced between the subjects and was conducted double blind, so that neither the subject nor the researcher knew which stimulation was giving first during the experiment. The presentation of all the stimuli during the prosaccade task was carried out in Matlab (R2016a, The Math Works Inc., Natick, MA, 2000) by using Psych Toolbox (Brainard, 1997; Pelli, 1997; Kleiner et al, 2007) Eye-tracker Eye movements were recorded with the EyeLink1000 using a sampling rate of 1000 Hz using the EyeLink toolbox Matlab interface (Cornelissen, Peters & Palmer, 2002). Only the right eye was followed in this study. The head of the subjects was mounted in a headrest with a distance from the eyes to the centre of the screen set at 83 cm. For eye calibration nine reference points was used. To detect saccades, three thresholds are used: motion, velocity, and acceleration. The values of these are in degrees, degrees/sec, and degrees/sec² respectively. The saccadic motion threshold is used to delay the onset of a saccade until the eye has moved
significantly, set at 0.15 degrees in this study. The velocity threshold is the eye-movement velocity that must be exceeded for a saccade to be detected, here, set at 30 degrees/sec. Finally, the use of eye-movement acceleration is important for detection of small saccades, in this study the threshold was set at 8000 degrees/sec². Localization FEF Prior to the study, the location of the rFEF was determined with the structural MRI scan of the subject using the neuro-navigation program Visor2 (Advanced Neuro Technology, The Netherlands). According to multiple studies the FEF is located in the middle frontal gyrus at the junction of the pre-central sulcus and the superior frontal sulcus (Rosano et al., 2002; Grosbras & Paus, 2003; Amiez & Petrides, 2009; Vernet, Quentin, Chanes, Mitsumasu & Valero-Cabré, 2014). By using predetermined reference points (the nasion and the intersection between the helix and tragus in the ear on both sides) and the structural scan, the stimulation site could be found by using real-time 3D navigation. The stimulation electrode was placed five mm more posterior than the putative location of the rFEF to increase the likelihood the current would run frontally through it. tDCS The electrode placed over the rFEF had a surface of 3x3 cm, the reference electrode place on the forehead above the left eye had a surface of 5x7 cm. Both of these were placed using wax, consisting of a NaCl solution to improve conductivity. At the beginning of the experiment a short trial stimulation took place to allow the subject to experience how tDCS feels. The ramp-up and ramp-down time was 45
seconds towards a current of 1 mA that was maintained for 15 seconds. During the experimental session, the current was slowly built up and down with a ramp-up and ramp-down time of 60 seconds towards a current of 1 mA. The total stimulation time was 17 minutes including ramp-up and ramp-down time. If subjects experienced discomfort, the stimulation was turned off and the experiment would be finished. However, this did not occur during our experiment. Furthermore, no sham condition was included in this study. The stimulation was administered by the neuroConn DC-STIMULATOR PLUS. Analyses The data was analysed with a repeated measures ANOVA, with an alpha level of 0.05. Our independent variables were tDCS stimulation with two levels, cathodal and anodal stimulation and the direction of the saccades with two levels, left and right. The dependent variable was the saccadic latency, measured in millisecond (ms) over three time courses, the (i) baseline session, (ii) tDCS session and (iii) the post-tDCS session. Data has been analysed separately for trials towards the fixation stimulus and target stimulus because these trials were not comparable. In case there was an effect of stimulation on saccade latency, specific time points would be analysed with a paired t-test, also with an alpha level of 0.05, to determine differences in latencies from baseline for specific time courses, corrected for multiple comparisons using Bonferroni correction. When running the repeated measures ANOVA, the assumption of sphericity has been taken into account. If the data did not violate the assumption of sphericity, we did not need to modify the degrees of freedom. If the assumption was violated,
corrections had been applied to the degrees of freedom. If estimated epsilon (ε) was less than 0.75, the Greenhouse-Geisser correction has been used. However, if ε was greater than 0.75 the Huynd-Feldt correction has been used. For analysing the eye-tracking data, the same criteria have been applied as in the experiment of Kanai et al. (2012). We therefore rejected trials in which the eye position at the time of target onset deviated more than 1.8 degrees from the fixation point. Also, if saccade latency was shorter than 50 ms or longer then 400 ms, trials were excluded because this could be an indication that the subject did not attend the to the task properly. To analyse the eye-tracking data, median latency was determined for each subject per condition. The median was for latency since its distribution is typically skewed (Carpenter & Williams, 1995). Under the assumption of our research hypothesis, it was expected that, compared to the baseline, the latency time of the saccades were increased under cathodal stimulation when the gaze had to be moved in the contra-lateral direction of the stimulation. In addition, under anodal stimulation the latency time of the saccades should decrease when the gaze has to be moved in the contra-lateral direction of the stimulation. To estimate the effects of tDCS over time, we subtracted the baseline saccade latency, obtained before tDCS stimulation, from the data we obtained in subsequent tDCS and post-tDCS sessions. In order to determine if stimulation had any effect on eye accuracy, we exploratory analysed the precision of the saccades towards the stimuli, measured in perceived visual angle of deviation (θ) from the stimuli (White, Sparks & Stanford,
1994). A repeated measure ANOVA was used and baseline scores have been subtracted just like the main analyses. Results Before analysing the data, trials were rejected according to the aforementioned criteria. In total, two subjects were excluded from this study because not enough trials remained after the criteria selection for successful analyses. The final analyses were run with a total of 18 subjects. The main hypothesis of this study was that under anodal stimulation, saccades contralateral to the stimulation site would have a shorter latency time compared to baseline measurements in which no stimulation was given. In addition, under cathodal stimulation, saccades contralateral to the stimulation site would have a longer latency time compared to baseline. Median latency was determined for the subjects per condition (Figure 2A, B, C, D) and baseline measurements were compared to subsequent latencies during the tDCS and two post blocks by subtracting baseline latencies (Figure 3A, B, C, D). Shifts in latencies were analysed using a repeated measure ANOVA with stimulation (anodal and cathodal), eye direction (left and right) and time course (baseline, tDCS and post-tDCS sessions) as factors for both target saccades and fixation saccades. No main effect of stimulation was found F(1, 17) = .75, p = .40 for target saccades, indicating that stimulation had no effect. Also no interaction was found for eye direction (p-value > 0.5). There was a main effect on time course F(1.33, 22.55) = 5.29 , p = .02, indicating slower latency times as the task progressed which could be attributed to losing focus during the
task. As for fixation saccades, again, no main effect for stimulation was found F(1,17) = .15, p = .70 and no interaction was found for eye direction (p-value > 0.5). These results indicate that there was no significant difference between anodal and cathodal stimulation for saccades toward a target stimulus and saccades towards a fixation stimulus, thereby not confirming our main hypothesis.
Figure 2. Median latency (ms) for anodal and cathodal stimulation is plotted as a function of the time-points (Pre = baseline, tDCS = during stimulation, 0-15 and 15-30 = time after stimulation) for saccades towards (A) the left, directed at target stimuli. (B) The right, directed at target stimuli. (C) The left, directed at fixation stimuli. (D) The right, directed at fixation stimuli. The error bars correspondent to 1 standard error of the mean (SEM). 140 142 144 146 148 150 152 Pre tDCS 0-15 15-30 Sac cad e lat en cy (ms ) Time after tDCS (min) A Left, Target Anodal Cathodal 140 142 144 146 148 150 152 Pre tDCS 0-15 15-30 Sac cad e lat en cy (ms ) Time after tDCS (min) B Right, Target Anodal Cathodal 126 128 130 132 134 136 138 140 Pre tDCS 0-15 15-30 Sac cad e lat en cy (ms ) Time after tDCS (min) C Left, Fixation Anodal Cathodal 126 128 130 132 134 136 138 140 Pre tDCS 0-15 15-30 Sac cad e lat en cy (ms ) Time after tDCS (min) D Right, Fixation Anodal Cathodal
Figure 3. Median latency (ms) for anodal and cathodal stimulation after baseline subtraction is plotted as a function of the time-points (tDCS = during stimulation, 0-15 and 15-30 = time after stimulation) for saccades towards (A) the left, directed at target stimuli. (B) The right, directed at target stimuli. (C) The left, directed at fixation stimuli. (D) The right, directed at fixation stimuli. The error bars correspondent to 1 standard error of the mean (SEM). -3 -2 -1 0 1 2 3 4 tDCS 0-15 15-30 Sac cad e lat en cy (ms ) Time after tDCS (min) A Left, Target Anodal Cathodal -3 -2 -1 0 1 2 3 4 5 tDCS 0-15 15-30 Sac cad e lat en cy (ms ) Time after tDCS (min) B Right, Target Anodal Cathodal -5 -4 -3 -2 -10 1 2 3 tDCS 0-15 15-30 Sac cad e lat en cy (ms ) Time after tDCS (min) C Left, Fixation Anodal Cathodal -5 -4 -3 -2 -1 0 1 tDCS 0-15 15-30 Sac cad e lat en cy (ms ) Time after tDCS (min) D Right, Fixation Anodal Cathodal
For exploratory analyses we looked at the deviation subjects showed under different stimulations when guiding saccades towards target and fixation stimuli. Again, deviation was determined for the subjects per condition (Figure 4A, B, C, D) and baseline measurements were compared to subsequent deviations during the tDCS and two post blocks by subtracting baseline latencies (Figure 5A, B, C, D). However, no main effects or interactions have been found (All p-values > 0.05), indicating that stimulation did not affect saccade accuracy.
Figure 4. Mean deviation (perceived visual angle) from stimulus for anodal and cathodal stimulation is plotted as a function of the time-points (Pre = baseline, tDCS = during stimulation, 0-15 and 15-30 = time after stimulation) for saccades towards (A) the left, directed at target stimuli. (B) The right, directed at target stimuli. (C) The left, directed at fixation stimuli. (D) The right, directed at fixation stimuli. The error bars correspondent to 1 standard error of the mean (SEM). 0,77 0,78 0,790,8 0,81 0,82 0,83 0,84 0,85 pre tDCS 0-15 15-30 De vi at io n fr om st im ul us (θ ) Time after tDCS (min) A Left, Target Anodal Cathodal 0,690,7 0,71 0,72 0,73 0,74 0,75 0,76 0,77 0,78 pre tDCS 0-15 15-30 De vi at io n fr om st im ul us (θ ) Time after tDCS (min) B Right, Target Anodal Cathodal 0,8 0,82 0,84 0,86 0,88 0,9 0,92 0,94 0,96 pre tDCS 0-15 15-30 De vi at io n fo rm st im ul us (θ ) Time after tDCS (min) C Left, Fixation Anodal Cathodal 0,62 0,64 0,66 0,68 0,7 0,72 0,74 0,76 0,78 pre tDCS 0-15 15-30 De vi at io n fr om st im ul us (θ ) Time after tDCS (min) D Right, Fixation Anodal Cathodal
Figure 5. Figure 3. Mean deviation (perceived visual angle) from stimulus for anodal and cathodal stimulation after baseline subtraction is plotted as a function of the time-points (tDCS = during stimulation, 0-15 and 15-30 = time after stimulation) for saccades towards (A) the left, directed at target stimuli. (B) The right, directed at target stimuli. (C) The left, directed at fixation stimuli. (D) The right, directed at fixation stimuli. The error bars correspondent to 1 standard error of the mean (SEM). -0,07 -0,06 -0,05 -0,04 -0,03 -0,02 -0,01 0 0,01 0,02 pre tDCS 0-15 15-30 De vi at io n fr om st im ul us (θ ) Time after tDCS (min) A Left, Target Anodal Cathodal -0,03 -0,02 -0,01 0 0,01 0,02 0,03 0,04 0,05 pre tDCS 0-15 15-30 De vi at io n fr om st im ul us (θ ) Time after tDCS (min) B Right, Target Anodal Cathodal -0,14 -0,12 -0,1 -0,08 -0,06 -0,04 -0,02 0 0,02 0,04 pre tDCS 0-15 15-30 De vi at io n fr om st im ul us (θ ) Time after tDCS (min) C Left, Fixation Anodal Cathodal -0,06 -0,04 -0,02 0 0,02 0,04 0,06 0,08 pre tDCS 0-15 15-30 De vi at io n fr om st im ul us (θ ) Time after tDCS (min) D Right, Fixation Anodal Cathodal
Discussion The main aim of this research was to validate the results presented by Kanai et al. (2012) to see if anodal stimulation could shorten the latency of saccades to a contralateral visual cue and to see if tDCS was able to reach and modulate the FEF. The results of this study does not tend to support the findings Kanai et al. (2012) relating to these two questions. No main effect or interaction effect of stimulation on saccade latency time was found. Even after separate analyses for fixation and target stimuli, no significant effects have been discovered. It is thus unclear how tDCS modulates the function of the FEF and to what extend such a modulation can be measured with the present data. Although there is sufficient evidence that anodal stimulation from tDCS heightens potential firing of underlying neurons, this study has failed to produce a measurable effect for the FEF region. Our hypothesis that cathodal stimulation lowers the potential firing of underlying neurons, and thereby lengthening latency time for saccades to a contralateral visual cue, was also not confirmed. The FEF is responsible for initiating saccades in a contralateral manner, however anodal and cathodal stimulation did not shorten or lengthen, respectively, saccades in opposite direction of stimulation. The precision of saccadic movements was also not affected by either stimulation. Implications regarding these results are limited. That is, we did not found a behavioural effect of tDCS. This raises the possibility that tDCS stimulation over the FEF is ineffective. One tDCS study on the FEF from Ball, Lane, Smith and Ellison (2013) showed similar results, in which no effect of anodal and cathodal stimulation was evident at the FEF during a visual search task. Although a visual search task does
embody a wider range of integration of multiple cognitive processes (Treisman & Gelade, 1980), tDCS stimulation was not able to influence saccadic function, similarly to our results. Even though Kanai et al. (2012) had small effect sizes, our current study shows by replication that we should be cautious interpreting significant results. Although some changes have been made in tDCS montage, stimulation duration and design, a replication study is in a sense a check for reliability. Research must be repeated before a finding can be accepted as well established and findings obtained at one time might not hold true at another time with different researchers or different subjects. This process of double-checking is important to science because it may have a stimulating effect for future research, inspiring new studies to complement or (re-)interpret our current findings. The methodological changes that were made in respect to the study of Kanai et al. (2012) will be discussed here, as it is possible that these changes are what caused the discrepancy in the results. The main differences between the studies are tDCS montage, the duration of stimulation and the design. Kanai et al. (2012) have used both bilateral and unilateral montage of tDCS. Here, however, only a unilateral montage is used where only the right FEF has been stimulated. In addition, Kanai et al. (2012) had a 10-minute stimulation period, while this study used a 15-minute stimulation period. Finally, Kanai et al. (2012) used a between-subject design with 16 subjects. In this study, a within-subject design was used with 18 subjects. Because this study only looked at the right FEF, had a longer stimulation duration and more subjects were used within this condition, in combination with a
within-subject design which typically have higher statistical power than between-subject designs (Guo et al., 2013), we could as well, if not better, see if tDCS could reach and modulate the right FEF specifically. Considering previous publications from Kanai et al. (2012) and Ball et al. (2013) with different conclusions on accessibility and ability to modulate the FEF, this data seems to give more weight to the null findings reported by Ball et al. (2013). As for the effectiveness of the stimulation, we cannot be sure if the current of the tDCS actually reached the FEF in all of our subjects. By localising the FEF per subject as accurate as possible and placing the electrode appropriately, we have tried to maximise the change of the current running trough it. As for Kanai et al. (2012), they have used the standard MNI coordinates for targeting the FEF while acknowledging the exact location of the FEF can vary between subjects. Although they compensate for this by having sufficient subjects and relatively large electrodes and volume conduction of the current, a subject-to-subject localisation is more precise and favourable. Effectiveness of the stimulation is also dependent on the focality of the stimulation. Factors influencing this focality are the size of the electrodes and the distance between them (Nietsche et al., 2007). Since we have used the same size electrodes as Kanai et al. (2012) but decreased the interelectrode distance, focality should have improved. However, the exact distribution of current is dependant on many factors such as skull thickness or folding of the cortex (Miranda, Lomarev, & Hallett, 2006), thereby varying the current density among subjects, something that was not controlled for in this study. For future studies, focality and effectiveness of the stimulation could be improved by increasing the maximum
current density under the target electrode or reducing target electrode size but keeping current density constant (Nietsche et al., 2007). One related point on tDCS effectiveness, some articles have published on sub regions identified within the FEF (Leichnetz, 1982; Schnyder, Reisine, Hepp & Henn, 1985; Tian & Lynch, 1996). In contrast to not fully reaching the FEF, it is possible that these sub regions were simultaneously stimulated during the experiment. Distinct neurons have been identified for pre-saccadic and post-saccadic movements (Bruce & Goldberg, 1985), as well for suppressing saccade execution (Segraves & Goldberg, 1987). It could be that tDCS was not focal enough and could have hit multiple, counteracting cell types. If the saccade suppressing neurons were activated to the same extent as saccade execution neurons, it could have cancelled each other out. Kanai et al. (2012) also mentions this subset of neurons in their study, speculating that during a prosaccade task, saccade execution neurons would be more active since there is no task demand to suppress a reflexive saccade. Hereby explaining the effect of anodal stimulation on prosaccades. Since this study has not found any measurable effects, we cannot support their surmise. Lastly, saccades latencies could have been unaffected by stimulation because of the design of the prosaccade task. During the prosaccade task, subjects only had to make saccades to a fixed position either left or right from the fixation point. So in total, there where only 3 locations to which a saccade had to be made. During the practice block subjects already learned these places. It is possible that, because of the fixed places of the stimuli and the long duration of the prosaccade task, subjects were bored or performed the task in a more reflexive manner and thereby did not
require a lot of involvement from the FEF. A way to solve this problem is to integrate more target stimuli places in future designs. By randomising the height and distance of the target stimuli, saccade direction could be less predictable and harder to remember, thereby keeping the subject more focused and active during the task and potentially better involvement of the FEF by making the task less reflexive. In sum, no clear results have been found from replicating Kanai et al. (2012). After comparing the main differences between the experiments, it seems like our data supports the previous findings of Ball et al (2013) in which it was unsuccessful to reach and modulate the FEF. After focussing mainly on the rFEF, using a within-subject design, having a subject-to-subject localisation of the FEF and trying to increase the effectiveness of tDCS by prolonging stimulation time and improving the focality by decreasing the interelectrode distance we were unsuccessful to verify the results from Kanai et al (2012). For future studies, it is recommended to consider the possibility that a different tDCS montage could induce clearer effects, since the optimal electrode montage for FEF stimulation remains to be determined. Also, to keep subjects focused and improve the involvement of the FEF during a prosaccade task, more possible locations for target stimuli to occur should be integrated. By taking the results and shortcomings of this and previous studies in account, we can derive a more substantiated understanding of the modulatory role of tDCS on the FEF.
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