Edited by: Agnes Gruart, University Pablo de Olavide, Spain
Reviewed by: José M. Delgado-García, University Pablo de Olavide, Spain; Tjerk Peter Gutteling, Radboud University Nijmegen, Netherlands
*Correspondence: René M. Müri, Perception and Eye Movement Laboratory, Department of Neurology and Clinical Research, University Hospital Bern Inselspital, 3010 Bern, Switzerland e-mail:
This article was submitted to the journal Frontiers in Behavioral Neuroscience.
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This study investigated the roles of the right and left dorsolateral prefrontal (rDLPFC, lDLPFC) and the medial frontal cortex (MFC) in executive functioning using a theta burst transcranial magnetic stimulation (TMS) approach. Healthy subjects solved two visual search tasks: a number search task with low cognitive demands, and a number and letter search task with high cognitive demands. To observe how subjects solved the tasks, we assessed their behavior with and without TMS using eye movements when subjects were confronted with specific executive demands. To observe executive functions, we were particularly interested in TMS-induced changes in visual exploration strategies found to be associated with good or bad performance in a control condition without TMS stimulation. TMS left processing time unchanged in both tasks. Inhibition of the rDLPFC resulted in a decrease in anticipatory fixations in the number search task, i.e., a decrease in a good strategy in this low demand task. This was paired with a decrease in stimulus fixations. Together, these results point to a role of the rDLPFC in planning and response selection. Inhibition of the lDLPFC and the MFC resulted in an increase in anticipatory fixations in the number and letter search task, i.e., an increase in the application of a good strategy in this task. We interpret these results as a compensatory strategy to account for TMS-induced deficits in attentional switching when faced with high switching demands. After inhibition of the lDLPFC, an increase in regressive fixations was found in the number and letter search task. In the context of high working memory demands, this strategy appears to support TMS-induced working memory deficits. Combining an experimental TMS approach with the recording of eye movements proved sensitive to discrete decrements of executive functions and allows pinpointing the functional organization of the frontal lobes.
Cognitive processes are well known to influence eye movements (Kowler,
Because of these characteristics, eye movements can be particularly helpful in the observation of efficient and strategic exploration behavior, abilities commonly referred to as executive functions. These functions allow us to organize our thoughts and actions in a goal-directed way, create a plan, initiate and monitor its execution, while keeping track of the progress. They inhibit inappropriate thoughts and actions and adapt our behavior flexibly to a changing environment (e.g., Jurado and Rosselli,
When assessing executive functions, a fundamental problem is the low process-behavior correspondence: While an executive deficit may lead to a myriad of behavioral difficulties, a specific behavior can be generated by a variety of impaired executive (and non-executive) processes (Tranel et al.,
This study set out to investigate and compare the functional roles of the right and left dorsolateral prefrontal cortex (rDLPFC, lDLPFC) and the medial frontal cortex (MFC) in executive functions. Even though executive functions are known to have their neural basis in the frontal cortex (Alvarez and Emory,
We used two computerized visual search tasks based on parts A and B of the Trail Making Test (Reitan and Wolfson,
Here, we explore the functional roles of the rDLPFC, lDLPFC and the MFC in efficient and goal directed visual behavior. In our quest to observe executive functions “at work”, we were interested in how inhibitory TMS over the three frontal regions influence visual strategies associated with good (i.e., fast) performance as well as poor (i.e., slow) performance in control conditions of two tasks with low and high cognitive demands. As the rDLPFC, lDLPFC and the MFC have all been linked to executive functioning, we expected a functional inhibition of these areas to affect the use of efficient visual strategies. We expected TMS-induced changes in eye movement parameters previously described to reflect executive functioning. Specifically, we were interested in planning (i.e., anticipatory fixations, see Mennie et al.,
In this study, we used TMS-induced changes in efficient visual strategies during specific cognitive demands as a tool to pinpoint executive functions associated with the rDLPFC, lDLPFC and the MFC.
Each of the three TMS groups consisted of 18 naive, healthy subjects. Six males and 12 females, mean age 32.0 ± 11.2 (mean ±
In both tasks, subjects were instructed to search for and click on 16 stimuli on a computer screen in ascending order as fast as possible and without errors. This was done by moving a mouse cursor over a stimulus on the screen and pressing the mouse key. In the number search task, the stimuli were numbers 1–16. In the second task, the stimuli consisted of numbers and letters, which had to be processed in an alternating manner (1-A-2-B… until the letter H was reached). The numbers and letters appeared in white dots before a gray background (Figure
To minimize learning of the spatial positions of stimuli over experimental trials, four different spatial layouts of stimuli were used in consecutive order. To ensure the same search difficulty, the spatial distance between two consecutive stimuli at all positions in the sequence was held constant across the four different stimulus layouts.
Before the experiment, subjects performed two practice trials to gain familiarity with the tasks. Experimental trials started with the appearance of the visual search display that was preceded by a fixation cross in the middle of the screen and at the same location as the first stimulus. If a mouse key press occurred after the cursor was placed over the correct stimulus, a clicking noise was played automatically and all stimuli in the white dots briefly disappeared, leaving the white dots empty for 250 ms. If a mouse click was made at the wrong location, e.g., if stimuli were not clicked in the correct order, subjects heard a buzzer sound which indicated that the error had to be corrected. Errors were thus accounted for by processing time. Clicking on stimuli left them unmarked, which required participants to mentally keep track of the progress. An experimental trial ended when all 16 stimuli were clicked in the correct order.
The stimuli were presented on a 20-inch TFT display (41 × 31 cm), with a 1600 × 1200 pixel resolution, 32 bit color depth and a refreshing rate of 60 Hz. Subjects were positioned at a distance of 71.5 cm from the screen, resulting in a visual angle of 32 (width) × 24 (height) degrees. Screen displays consisted of 16 stimuli that were 1.7 cm in diameter, corresponding to 1.3° visual angle.
In each of the three TMS groups, subjects completed two experimental sessions: one session with TMS, and one control session without stimulation (TMS is a within subjects factor). The order of the TMS and control session was randomized. Each session consisted of six number search task trials and six number and letter search trials that were performed in alternating order (12 trials per experimental session, and a total of 24 trials in the two sessions of the experiment). To minimize learning effects, the time interval between the two sessions was at least 1 week.
Processing time (cumulative mouse reaction time) per trial was used to assess global performance. To assess visual behavior, we measured the number of stimulus fixations, the number of fixations on the next stimulus in the sequence (anticipatory fixations, e.g., fixations on stimulus “3” while searching for “2” in the number search task, or fixations on stimulus “5” while searching for “E” in the number and letter search task) as well as the fixation number on the previous stimulus in the sequence (regressive fixations, e.g., fixations on stimulus “1” while searching for “2” in the number search task, or fixations on “A” while searching for “2” in the number and letter search task) in relation to the total number of fixations (i.e., % stimulus-, % anticipatory-, and % regressive fixations) in experimental trials.
The experiment was designed to ensure that a sufficient amount of fixations for valid statistical analysis could be measured over the course of the six experimental trials per condition and subject.
A TMS stimulator (MagPro, Medtronic Functional Diagnostics, Skovlunde, Denmark) was used to generate repetitive biphasic magnetic pulses. Before experimental sessions, a continuous train of theta burst TMS (TBS) was applied (600 pulses in total; a burst of three pulses with 30-Hz was repeated at intervals of 100 ms; Nyffeler et al.,
The dorsolateral prefrontal cortex was located as previously described (Müri et al.,
The MFC stimulation site was located as described by Hadland et al. (
Data acquisition started typically 4 min after stimulation and was typically completed within 20 min after stimulation. Eye movements were assessed using a video based infrared eyetracking system (HiSpeed™, SensoMotoric Instruments GmbH, Teltow, Germany), at a sampling rate of 240 Hz and a spatial resolution of 0.5 – 1.0° (manufacturer's specification: <0.025°). To identify fixations, the minimum fixation duration was set at 80 ms and the dispersion threshold was 150 pixels. To avoid head movements subjects were made to position their chin on a rest. Before the experiment, a 13 point calibration session was performed. If necessary, this was repeated during the course of the experiment. To account for eccentric viewing and measuring inaccuracy, fixations within a 1.7 cm or 1.3° visual angle radius from the center of a stimulus (double the radius of the stimulus) were considered as fixations on this stimulus, avoiding overlapping stimulus fixation areas between stimuli. To allow for drift compensation, fixation data were manually recalibrated after the experiment for best possible stimulus fit. The stimuli presentation and recording of mouse clicks was performed with E-Prime software (Schneider et al.,
We calculated repeated measures analysis of variances (ANOVAs) in all TMS groups (rDLPFC, MFC, lDLPFC). To detect within-subjects differences between the control and TMS condition (TMS is a within subjects factor), processing time and eye movement parameters (% stimulus fixations, % anticipatory fixations, % regressive fixations) served as dependent variables.
To identify good and bad visual strategies, we calculated Pearsons correlations between eye movement parameters (% stimulus fixations, % anticipatory fixations, % regressive fixations) and processing time in control condition trials. The level of significance was set at 0.05.
To investigate a possible effect of stimulation on eye movement regions, we tested for TMS-induced changes in general eye movement parameters: TMS over the rDLPFC, lDLPFC, and over the MFC did not alter the number of fixations [right DLPFC:
Looking ahead was identified as a good visual strategy in both tasks. The percentage of anticipatory fixations was negatively correlated with processing time in control conditions of the number search task (
Table
Processing time per trial (sec) | 28.9±1.7 | 28.9±1.5 | 27.2±1.6 | 27.6±1.6 | 26.4±1.6 | 26.4±1.3 |
Number of fixations per trial | 88.6±4.9 | 88.4±4.3 | 86.3±5.2 | 90.7±5.5 | 85.4±4.6 | 88.2±4.5 |
Fixation duration (msec) | 307.6±9.4 | 304.4±9.7 | 306.5±9.6 | 298.3±8.3 | 290.8±10.6 | 295.0±8.5 |
% Stimulus fixations | 61.3±0.9 | 60.2±1.3 | 56.1±2.5 | 55.6±2.4 | ||
% Regressive fixations | 0.43±0.1 | 0.33±0.1 | 0.56±0.1 | 0.57±0.1 | 0.54±0.1 | 0.46±0.1 |
% Anticipatory fixations | 9.1±1.0 | 10.0±1.2 | 8.2±0.8 | 9.2±1.2 |
Irrespective of stimulation site, TMS had no effects on processing time in the number search task [right DLPFC:
TMS over the rDLPFC led to a highly significant decrease in anticipatory fixations [
After rDLPFC stimulation, a decrease in the number of fixations on stimuli and a concurrent increase in background fixations [
In sum, functional inhibition of the rDLPFC led to a decrease in anticipatory fixations, a good visual strategy in a task with low executive demands, without affecting performance itself. This was paired with a general decrease in fixations on task relevant stimuli and a concurrent increase in background fixations, where only the moving mouse cursor was visible.
Table
Processing time per trial (sec) | 34.8±2.4 | 36.2±2.8 | 34.2±2.3 | 32.1±1.6 | 34.0±2.0 | 33.0±1.8 |
Number of fixations per trial | 107.3±6.6 | 112.7±9.0 | 106.6±6.4 | 104.4±5.3 | 108.0±5.2 | 107.7±5.6 |
Fixation duration (msec) | 291.0±8.1 | 292.6±9.4 | 291.5±7.6 | 295.8±7.6 | 276.2±8.6 | 286.3±6.8 |
% Stimulus fixations | 57.0±1.4 | 55.4±2.0 | 59.4±1.1 | 61.0±1.2 | 54.5±2.8 | 56.7±2.1 |
% Regressive fixations | 0.99±0.2 | 0.98±0.2 | 0.82±0.2 | 1.12±0.1 | ||
% Anticipatory fixations | 3.9±0.5 | 3.8±0.6 |
TMS over the rDLPFC or lDLPFC, or over the MFC had no effects on processing time in the number and letter search task [right DLPFC:
Subjects showed an increase in anticipatory fixations after TMS over the MFC [
TMS over the lDLPFC led to a significant increase in the relative number of regressive fixations [
In sum, inhibition of both the lDLPFC and the MFC led to an increase in anticipatory fixations, considered to be a good visual strategy in this task. In the number and letter search task a TMS-induced increase in looking ahead reflects an increase in looking at a different stimulus category. This did not affect performance.
Inhibition of the left DLPFC led to an increase in regressive fixations. This increase in a
This study investigated and compared the functional roles of the rDLPFC, lDLPFC and the MFC in executive functions using a TBS approach.
We observed executive functions “at work” by measuring eye movements that showed how two visual search tasks were solved. In our quest to observe efficient, strategic and goal directed visual exploration behavior, we were particularly interested in TMS-induced changes in visual strategies associated with good and poor performance in two tasks with low and high cognitive demands. While performance was unchanged, the specific pattern of modulated eye movements when confronted with a specific cognitive demand shed light on what processes were impaired as a result of TMS over the three frontal areas.
In the number search task, functional inhibition of the rDLPFC resulted in a decrease of anticipatory fixations, which was found to be a good visual strategy in control conditions. This was paired with a rDLPFC TMS-induced decrease of stimulus fixations. These effects suggest that in conditions with low executive demands, functional inhibition of the rDLPFC interfered with the anticipation of future events as well as the attention to task relevant information.
In the more demanding number and letter search task, inhibition of the lDLPFC and the MFC led to an increase in anticipatory fixations. In this task, anticipatory fixations were found to be a good visual strategy and also reflect attention to a different stimulus category. In view of unchanged performance, these effects might represent a compensatory attempt to account for TMS-induced deficits in attentional switching from one aspect of information to another. In the number and letter search task, inhibition of the lDLPFC also led to an increase in regressive fixations, a
While all three frontal areas are known to be involved in executive functions, their specific functional specialization is still unclear. In part, this is due to most localization studies being either strictly descriptive or correlative. Here, we offer an experimental TMS approach that can prospectively induce temporally circumscribed functional decrements in healthy subjects. TMS-induced functional decrements are homogenous among subjects and rather focal neuroanatomically, despite possible remote effects (Knoch et al.,
Our first task was an easy and highly overlearned task. It required searching for and performing a mouse-click on numbers in sequential order. In the absence of attentional switching or working memory demands, this low demand task was considered a suitable tool to observe basic executive functions such as mental anticipation of future events and focusing on task relevant information. Looking at stimuli that will become relevant at a later point in time was described as a major contribution (Land,
In this task, TMS over the rDLPFC resulted in a decrease in anticipatory fixations, a visual strategy associated with fast performance. We interpret this as a deficit in anticipating future events, i.e., planning. These effects were paired with a rDLPFC TMS-induced deficit in paying attention to task relevant stimuli and suppress irrelevant information, an executive function also known as response selection.
In line with these results, a number of studies suggest that planning and response selection are linked. “Look-ahead fixations” were described as both a task dependent, goal-directed strategy (Pelz and Canosa,
It remains unclear why the TMS-induced decrease in a visual strategy associated with good performance in control conditions did not affect performance. We speculate that the rDLPFC TMS-induced deficit might not have been strong enough to affect performance. Given the low task demands, it seems plausible that subjects were able to maintain the same performance despite the decrease in anticipatory fixations.
A large body of lesion and imaging studies provides evidence that the prefrontal cortex plays a crucial role in planning (Koechlin et al.,
A selective involvement of the dorsolateral prefrontal cortex in inhibition and response selection was found in a clinical study (Gehring and Knight,
To conclude, we suggest that the rDLPFC plays an important role in planning, a task dependent, top-down process aimed at acquiring information for future use by looking ahead. Planning and response selection appear to be closely related, as the specific contribution of the rDLPFC seems to lie in the mental generation of action sequences, the suppression of irrelevant information and the attention to relevant information.
In contrast to the first task, the number and letter search task is more demanding. It requires switching attention from a number sequence to a sequence of letters. The task has been described as a valid measure of the ability to alternate between cognitive categories (Olivera-Souza et al.,
Stimulation over both the MFC and the lDLPFC resulted in a significant increase in anticipatory fixations in the number and letter search task. In this task, looking ahead means looking at a letter before clicking on the preceding number number and vice versa. Hence, anticipatory fixations in this task seem to be aimed at guiding attention toward a different stimulus dimension, which will become relevant next. This might facilitate attentional switching. It has been documented that during switch implementation, the relevant stimulus dimension is fixated more (Chevalier et al.,
At first glance, it seems that the increase in anticipatory fixations after inhibition of the lDLPFC and the MFC is contrary to the decrease in anticipatory fixations after inhibition of the rDLPFC (see above). This would raise the question whether these effects are due to possible remote effects of TMS on other parts of the frontal cortex. However, this interpretation does not take into account the different cognitive demands of the two tasks. Importantly, no opposing effects of TMS over the three stimulation sites were found on any visual strategy in the context of the same cognitive demands.
A crucial involvement of the MFC and the lDLPFC in attentional switching was found previously using variants of the Trail Making Test and other paradigms. A combined fMRI and TMS study showed that medial frontal regions, especially the pre—supplementary motor area is essential for task switching (Rushworth et al.,
After TBS over the lDLPFC, subjects displayed more regressive fixations in the number and letter search task. As mentioned above, this task makes high working memory demands. The lDLPFC TMS-induced increase in this
D'Esposito and Postle (
After inhibition of the lDLPFC, we found both an increase in anticipatory fixations as well as an increase in regressive fixations in the number and letter search task. As described, these are likely to reflect compensatory strategies to account for TMS-induced deficits in attentional switching and working memory, respectively. These compensatory strategies are very different: Anticipatory fixations imply a memory buffer to store information about future events. They enhance the working memory load, instead of lowering it. In contrast, attempts to deal with a high working memory load are more likely to result in a decrease in anticipatory fixations, paired with an increase in regressive fixations. This pattern was found in violin players in an attempt to reduce the information load in the memory buffer (Wurtz et al.,
To conclude, we suggest that the right DLPFC specifically contributes to executive functioning by two related mechanisms: First, it suppresses attention to irrelevant information and guides attention toward task relevant information. Second, it plays a crucial role in anticipating future events. In contrast, the left DLPFC together with the MFC seem to support the switching of attention from one aspect to another by guiding attention toward the relevant information during switch implementation. The specific contribution of the left DLPFC in executive functioning lies in keeping information active in a working memory buffer by re-accessing or rehearsing it.
Because of the explorative approach of this study, our data have to be interpreted carefully. To extend knowledge on executive functions and their functional specification, further studies should specifically address our hypotheses. The quest for the functional specification of frontal structures must include experimental approaches to expand previous knowledge from descriptive lesion studies and correlational imaging methods. Executive functions are likely to be mediated by dynamic and flexible networks instead of discrete foci (Elliott,
We believe that the use of qualitative behavior data might be beneficial both with respect to advancing theoretical concepts of executive functions as well as understanding their neural basis.
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.
The study was supported by Swiss National Foundation, Grant No: 108146