Cerebral Cortex Advance Access originally published online on June 15, 2005
Cerebral Cortex 2006 16(3):425-436; doi:10.1093/cercor/bhi122
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Published by Oxford University Press 2005.
Dorsolateral Prefrontal Cortex Prevents Short-latency Saccade and Vergence: a TMS Study
Laboratoire de Physiologie de la Perception et de l'Action; UMR 7152 CNRS-Collège de France; 11, place Marcelin Berthelot; 75005 Paris; France
Address correspondence to Olivier A. Coubard, Laboratoire de Physiologie de la Perception et de l'Action, UMR 7152 CNRS-Collège de France, 11, place Marcelin Berthelot, 75005 Paris, France. Email: olivier.coubard{at}college-de-france.fr.
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Abstract |
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This study explores whether vergence eye movements along the median plane can be triggered with short latencies, and the role of the dorsolateral prefrontal cortex (DLPFC) in controlling such movements. We used a gap paradigm and applied transcranial magnetic stimulation (TMS) in 10 humans making saccades or vergence. TMS over the motor cortex had no effect on any eye movement parameter. TMS over DLPFC influenced eye movement initiation but not their metrics. TMS over the right DLPFC accelerated the triggering of saccades bilaterally but did not influence divergence. TMS over the left DLPFC speeded up the triggering of ipsilateral saccades and exacerbated the anticipatory mode of triggering of divergence. For convergence, TMS effects were mild: rightward TMS increased the proportion of short latencies but failed to shorten the group mean latency; leftward TMS influenced triggering in some individuals only. For saccades and convergence under TMS, some subjects showed an emerging population of short latencies in their latency distribution. Horizontal saccadic intrusions (80% of trials) and vertical saccades (recorded in one subject) intruding on vergence were unlikely to assist vergence triggering. We conclude that the prefrontal mechanisms underlying voluntary eye movement control are similar for saccades and vergence although some specificities exist.
Key Words: direction and depth eye movements • eye movement control • hemispheric asymmetry • human • inhibition • prefrontal cortex
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Introduction |
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The dorsolateral prefrontal cortex (DLPFC) corresponds in humans to area 46, encircled caudally by area 9 (Rajkowska and Goldman-Rakic, 1995
; Pandya and Yeterian, 1998). Through its various connections to other prefrontal areas, to post-Rolandic and subcortical regions, the DLPFC takes part of multiple networks carrying out specialized functions, and plays a major role in attention, working memory and response inhibition (Goldman-Rakic, 1998). In the rhesus monkey, Funahashi et al. (1993) showed that DLPFC neurons maintain information in working memory by coding the location of the stimulus and suppressing reflexive saccades during the memory delay. Using single-pulse transcranial magnetic stimulation (TMS) in humans, Müri et al. (1999) found that the stimulation over the right DLPFC increased the rate of express saccades contralaterally. The authors proposed that the magnetic pulse interfered transiently with the inhibitory control exerted by the DLPFC onto the superior colliculus and preventing unwanted express saccades.
The express triggering concerned eye movements elicited with short latencies and showing a distinct peak in distribution. Express saccades range between 80 and 120 ms in humans, and can be promoted by introducing a gap (that is, a time interval) between fixation offset and target onset (Saslow, 1967; Fischer and Ramsperger, 1984). The express triggering has been extensively studied for saccades (Fischer and Weber, 1993), less for vergence eye movements. Three studies (Tam and Ono, 1994; Takagi et al., 1995; Coubard et al., 2004) showed that the gap effect generalized vergence and/or combined saccade–vergence eye movements by shortening their latency, but a distinct short-latency vergence population was reported only when vergence was combined with a saccade (Coubard et al., 2004). A hitherto neglected question in oculomotor research is the role of the DLPFC in the triggering of vergence. Coubard et al. (2003) addressed this issue by extending Müri et al.'s experiment to convergence and combined saccade–convergence movements. They found that TMS over the right DLPFC did not influence pure convergence along the median plane, whereas it elicited short latencies bilaterally for both saccade and convergence components of combined saccade–convergence movements.
In these reports, evidence for short-latency vergence with or without TMS concerned only combined saccade–vergence in response to stimuli in both direction and depth (Coubard et al., 2003, 2004). A remaining question is whether short-latency vergence can be observed for stimuli requiring a pure vergence along the median plane, and whether the human DLPFC plays a role in preventing such putative short-latency vergence. The goal of the present study was to investigate further this issue by restricting the setup to stimuli in either direction or depth, but not both. A first question concerns the identification of conditions that promote naturally (without TMS) short-latency saccades and vergence. Prior findings have shown that saccade and vergence latencies depend upon the spatial arrangement of stimuli. Yang et al. (2002) and Bucci et al. (2004) showed shorter latencies for movements initiated from near (20 cm; saccades or divergence) than for movements initiated from far (150 cm; saccades or convergence). Shorter mean latencies at near might be due to higher rates of express latencies, but this was not investigated. Coubard and Kapoula (2005) showed that the ability to inhibit an eye movement towards a distracter presented at various locations in direction or in depth was poorer when the distracter was close to the observer (20 or 40 cm) than when it was farther. Based on these observations, the present study aimed (i) to create favourable conditions for the emergence of short latencies for both saccades and vergence; and (ii) to test under such conditions whether TMS over the DLPFC promotes further short-latency triggering. To achieve these goals, we used a gap paradigm as in the prior study, but this time a close fixation point (40 cm) was used for both saccades and vergence. As saccade latency (Fischer et al., 1997a) and vergence latency (Yang et al., 2002) both increase with age, we conducted the experiment on young adults. We expected our setup, together with the prefrontal TMS, to cause the emergence of express saccades, but also of short-latency vergence. The results showed that it is possible for some subjects to elicit short latencies for both saccades and vergence; TMS over the DLPFC does enhance short-latency triggering for the two types of eye movements.
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Materials and Methods |
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Subjects
The study conformed to the Declaration of Helsinki. Ten healthy volunteers (seven women and three men) gave their consent and were paid for the study. Subject age ranged 20–28 years. All were naive to the purpose of the experiment, and three of them (subjects 1, 3, 4) had previously participated in eye movement recordings. The handedness was right dominant: 89.2 ± 13.1% (range 66.7–100%, with 100% indicating absolute right-handedness) to the Edinburgh Handedness Inventory (Oldfield, 1971). Binocular vision was normal (for details see Supplementary Section 1).
Transcranial Magnetic Stimulation
We used a focal figure-of-eight coil connected to a MagStim module (model 200) with a maximum stimulator output of 2.2 T. Each wing of the coil measured 70 mm in diameter; the maximum focus was at the intersection of the two wings.
To define motor thresholds, the intersection of the wings was applied on the motor hand area (MHA; see the following section for localization) and the intensity of the stimulator was increased and decreased until it reached a value for which visible jerks of contralateral hand muscles occurred in 10 out of 20 trials. For the group of subjects, the motor threshold ranged from 32 to 50% for the left hemisphere and from 33 to 49% for the right hemisphere.
To stimulate the DLPFC, the intensity was set at 30% above motor threshold. In some subjects showing eye blinks in the recording of eye movements, the intensity could be reduced to up to 10% above motor threshold. We fixed such a value as the minimum intensity acceptable to include subjects in the study. The stimulation intensity ranged between 40 and 64% for the left DLPFC, and between 41 and 64% for the right DLPFC, corresponding respectively to 10–31% and 13–31% above motor threshold.
The single-pulse TMS had a rise time of 
200 µs and duration of 1 ms. A click occurred simultaneously with the pulse.
Coil Positioning
The MHA was defined by motor threshold stimulation as described in the prior section. The MHA was localized 35–45 mm lateral to the sagittal plane, depending upon the subjects (Fig. 1B). To stimulate the MHA, the coil was oriented such that the induced current orientation (ICO) was antero-medial, as used in prior studies (Sakai et al., 1997).
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To stimulate the DLPFC, the coil was placed 50 mm anteriorly to the MHA (Fig. 1B), as in previous studies (Müri et al., 1999
; Coubard et al., 2003), and the ICO was antero-lateral, as used by Hill et al. (2000). During the recordings, the experimenter held the handle of the coil. Head movements were minimized using a bite bar that was attached to the table of LEDs.
As the DLPFC lies close to the frontal eye field (FEF), one could argue that the magnetic pulse contaminated both areas. In humans, the FEF is located at the intersection between the superior frontal sulcus and the precentral sulcus, with some lateral extension in the precentral gyrus (Pierrot-Deseilligny et al., 2004). Ro et al. (2002) located the FEFs in 10 humans using TMS. They first localized the MHA (as in the present study) and then applied TMS on several sites around the putative FEF, i.e. 20 mm rostrally to the MHA. The final localization of FEF was the site where TMS induced significant delays in contralateral saccade latency, which is considered as a reliable functional marker of the FEF since Thickbroom et al. (1996). Ro et al. found active sites in seven out of their 10 subjects. The median location of FEF was 15 mm directly anterior to the MHA, and most important, the range of significant sites was 12.5–20 mm anteriorly to the MHA. Considering that a standard figure-of-eight coil stimulation covers a circular area of 30 mm at 20 mm below the coil — that is, in the region of the cortical surface (Walsh and Pascual-Leone, 2003), our criterion (50 mm rostrally to the MHA) excluded the possibility to stimulate concomitantly the FEF. Another important variable in the use of TMS is the orientation of the coil (Hill et al., 2000). The antero-lateral ICO used here also minimized the probability to stimulate the FEF lying caudally to the DLPFC.
Eye Movement Recording
An infrared-light eye movement device IRIS (Skalar Medical, The Netherlands) was used. As we aimed to study saccades and vergence in the horizontal plane, the sensors were clipped and fixed into the frame in the horizontal direction. Thus, we recorded only horizontal eye movements. The system measured linearly within 3% horizontal eye movements up to 25°. The optimal resolution was 2 min of arc. Data collection was done using REX software (Timothy C. Hain, Northwestern University Medical School, Chicago, IL); the sample frequency was 500 Hz. Horizontal eye position signals were stored on a disk for off-line analysis. Another computer was used to monitor the triggering of the diodes and the TMS in synchrony.
Stimuli
The subjects faced a horizontal table in which 2.9-mm-diameter red light-emitting diodes (LED) were embedded. In the following description, the amplitudes of vergence were calculated considering the mean interpupillar distance for the group of subjects (60 ± 2 mm).
Five LEDs were used (Fig. 1A). The fixation point was a diode located centrally at 40 cm from the subject's eyes. The mean angle of vergence for fixating this diode was 8.5°. Four targets could be turned on, one at a time: at 10° left or right (for saccades), in the center at 20 cm (for convergence) or in the center at 150 cm (for divergence). The required vergence amplitude was 8.2° (16.7–8.5°) for the convergence, and 6.2° (8.5–2.3°) for the divergence.
The experiment was performed in a dark room. The luminance of the background was 0 cd/m2 when all diodes were switched off. The luminance of each diode (1.6 mcd/m2) was well above perceptual threshold.
The present spatial arrangement contrasts those priorly used and aiming to study saccades and vergence either made alone or combined (Coubard et al., 2003, 2004). The present study investigated pure saccades and pure vergence only. Indeed, the two lateral diodes at 40 cm called for pure saccades as they were placed on an isovergence circle so that the vergence angle at any location on this curve was unchanged (8.5°). The central diodes at 20 or 150 cm called for a pure vergence along the median plane. However, the term pure is used here in the technical sense and does not imply that subjects performed effectively pure movements. Most of the time and despite methodological precautions, a transient vergence accompany saccades, and small saccades intrude vergence (Zee et al., 1992; Collewijn et al., 1995) (see Saccade and Vergence Detection).
Oculomotor Task
We used a gap paradigm (Fig. 1C) to elicit short-latency eye movements. For each trial, the central fixation diode was turned on for 2–2.5 s. The subject was instructed to fixate the LED as accurately as possible. Then a 200 ms gap was introduced before the appearance of the target, which stayed on for 1.5 s. The instruction was to move naturally towards the target without anticipating the movement. A 1 s pause was introduced before the next trial. The timing of LEDs was partially conditioned by the TMS, which was delivered at an average of every 4.95 s.
A single-pulse TMS was delivered either simultaneously with the appearance of the target (0 ms) or 20 or 40 ms later (Fig. 1C). When no TMS was delivered (25% of the trials), a fake click occurred, which was produced by a speaker located 50 cm above and behind the subject's head, randomly at 0, 20 or 40 ms after target onset.
Design
Each of the 10 subjects completed 32 experimental conditions: two stimulated cortical areas (left or right DLPFC) x 4 TMS conditions (no TMS, TMS at 0, 20 or 40 ms) x 4 target locations [left or right, in front of or behind the fixation point (FP)]. The number of trials per experimental conditions was 36. Each subject performed 18 blocks distributed in three sessions of six blocks; 6 days separated two sessions. A block was defined as a set of 64 experimental trials preceded and followed by calibration, and during which the eye movement recording was performed continuously. In a session, the TMS was delivered on the right DLPFC in three blocks and on the left DLPFC in three other blocks. The order of the stimulated DLPFC (left or right) was counterbalanced. Each block mixed all TMS conditions and target locations. The probability for delivering TMS was 0.75 (0.25 at 0 ms, 0.25 at 20 ms and 0.25 at 40 ms); such probability has been shown to induce minimal contextual influence on the latency of no-TMS trials (Kapoula et al., 2005a). The no-TMS trials (25%) were the baseline for the study of eye movement parameters. The probability of each target to appear was 0.25. The order of presentation of trials was random. The randomization of target presentation was obtained by building 180 distinct blocks (18 blocks x 10 subjects) using an automatic procedure that respected an equal number of trials per experimental condition within a block. Thus, none of the blocks was used twice either between or within subjects.
In addition to the main experiment, a control was done to check the area-specificity of TMS effects by stimulating the primary motor cortex (MC). TMS over MC had no effect on any eye movement parameter (see Supplementary Section 2).
Calibration
As we recorded only horizontal eye movements, we did a calibration only in the horizontal plane. We used six diodes in addition to the central diode, located at 40 cm on the isovergence circle at 5°, 10° and 15° on both sides of the central diode. Each of these diodes was lighted on one at a time during 1.5 s, at least twice, at the beginning and at the end of each block of 64 experimental trials. During each block, the recording of eye movements was continuous and binocular. A polynomial calibration was established using fixation periods lasting at least 200 ms with an error staying below 0.5°. The average fixation error remaining below 1° indicated a very reliable calibration.
Saccade and Vergence Detection
We calculated two signals (Fig. 2). A horizontal saccade or conjugate horizontal signal was the average of the calibrated left and right eye positions (Fig. 2A,B). A horizontal vergence or disconjugate signal was calculated by subtracting the right eye position from the left eye position, so that convergence resulted in a positive deviation (Fig. 2C) and divergence in a negative deviation (Fig. 2D). The horizontal conjugate signal was used for the analysis of saccade trials, the disconjugate signal for that of vergence trials. The eye velocity of either horizontal conjugate or disconjugate signal was computed using a symmetrical two-point differentiator after low-pass filtering with a Gaussian finite impulse response (FIR) filter (cut-off frequency 33 Hz).
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The detection of either saccades or vergence was done automatically, and carefully checked by the experimenter. For saccades, the onset and offset of the movement was decided at the point when the velocity of the horizontal conjugate signal went, respectively, beyond and below 15°/s. For vergence, the onset of the movement was determined at the point when the velocity of the disconjugate signal exceeded 5°/s; the offset of vergence was determined by visual inspection at the point when the disconjugate signal stabilized. These criteria are standard (Takagi et al., 1995
; Yang et al., 2002). For vergence onset, we excluded the possibility to mark a transient saccade-related (particularly, a putative not recorded vertical saccade-related) transient vergence by marking only disconjugate deviations whose time course and amplitude were related to movements aiming to reach the target. Thus, following these criteria, irrelevant transient vergence could not be marked. As the present study focused on the initiation of saccades and vergence and on prefrontal TMS effects on such triggering, it was of importance that the point when the movement onset was detected corresponded actually to the initiation of the movement and not to any alteration of the velocity signal due to artefacts. This was of particular importance for vergence that has lower velocity than saccade. A possible source of artefact may have been the TMS itself occurring simultaneously with target onset or a few milliseconds later. Nevertheless, recall that the intensity of the stimulator was set for each subject at a level for which no artefact occurred on the signal. Figure 2 shows typical eye movement trajectories under TMS (see also Figs S1 and S2 in Supplementary Material).
Another issue that needs discussion is that vergence movements are mostly accompanied by small saccades (Zee et al., 1992; Collewijn et al., 1995), and one could argue that saccadic intrusions (SI) may be responsible for faster triggering of vergence. In a specific study (O.A. Coubard and Z. Kapoula, submitted for publication), we examined SI in the horizontal plane by applying a 15°/s threshold detector on the conjugate signal during vergence trials. The analysis was centered on the first saccade intruding on vergence trials. Briefly, for no-TMS and TMS conditions, we found almost no saccade prior to vergence onset. SI were found only during the course of the vergence, some tens of milliseconds after vergence onset. For the no-TMS condition, SI occurred in 84.0 ± 8.6% (mean ± SD) of trials and their latency was 58 ± 21 ms after vergence onset. TMS over the DLPFC had no effect on SI either on their rate of occurrence or on their latency. Indeed, the rates of SI were 78.6 ± 15.7% under TMS over the right DLPFC and 79.6 ± 13.5% under TMS over the left DLPFC [Friedman analysis of variance (ANOVA), P > 0.05]. SI latencies were 57 ± 22 ms under TMS over the right DLPFC and 56 ± 27 ms under TMS over the left DLPFC (ANOVA, P > 0.05). The examination of the time course of horizontal SI relative to vergence onset, reported in the Supplementary Section 3, showed that SI onset was lagged behind vergence onset, and thus could not account for vergence initiation.
Vertical saccades are also known to accompany vergence along the median plane (Zee et al., 1992; Collewijn et al., 1995). We examined a putative contribution of vertical saccades to vergence initiation in one subject using an eye tracker allowing the recording of both horizontal and vertical eye movements (see Supplementary Section 4). Despite a careful adjustment of the table at eye level, convergence was systematically associated with a downward saccade, and divergence with an upward saccade. As for horizontal SI, vertical saccades were detected only some tens of milliseconds after vergence onset and thus could not account for the onset of vergence along the median plane.
Based on these observations, we decided not to distinguish vergence trials with SI from vergence trials without SI; the two types of trials were therefore pooled together in the analysis of vergence trials reported below.
Data Analysis
Eye movements following unstable fixation or contaminated by blinks (3.5% of trials; range 0.4–21.3%), anticipatory eye movements initiated before target onset (0.08%; 0–0.4%) or with latencies <80 ms (0.9%; 0.09–3.6%) were rejected. We discarded also eye movements with latencies >400 ms (0.2%; 0–0.6%), which is the upper latency limit in adults for slow regular saccades (Fischer et al., 1997b). In all, 4.8% of the trials (1.3–22.0%) were excluded from the analysis.
We analyzed the reaction time (RT) or latency, the frequency of latencies between 80 and 120 ms, the gain (amplitude of eye movement/amplitude of target) and the peak velocity (Fig. 2). For the gain of vergence, the movement amplitude was calculated within each subject considering his interpupillar distance. The median RTs and the averages of gain and of peak velocity were submitted to an ANOVA to evaluate the effects of TMS (four levels: 0, 20, 40 ms, no-TMS) and of the side of stimulation (two levels: left or right DLPFC). Post-hoc tests were calculated using the Newman–Keuls method. The rates of 80–120 ms latencies and of anticipatory latencies were submitted to Friedman ANOVA and Wilcoxon test for respectively group and two by two comparisons.
As the express triggering is idiosyncratic, we also analyzed individual rates of 80–120 ms latencies and distributions. For each subject, a 
2 test was done between no-TMS and TMS-0 conditions for the number of 80–120 ms latencies and of anticipatory latencies. This analysis is reported exhaustively in the Supplementary Section 5 for no-TMS and TMS-0 conditions.
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Saccade and Vergence Triggering without TMS
Group mean latencies were fast regular for saccades (150 ms) and vergence (160 ms, P > 0.05; Fig. 3A). The group mean rate of 80–120 ms latencies tended to be higher for saccades than for vergence: 20% for the former and 10% for the latter (P < 0.05 between rightward saccades and convergence). The group mean rate of anticipatory latencies (<80 ms) was not different from zero, except for divergence (2.4%, P < 0.05; Fig. 3B).
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Here we use the limits 80–120, 121–180 and 181–400 ms for express, fast regular and slow regular latencies, respectively. Although arbitrary and intended to saccades (Fischer and Ramsperger, 1984
; Fischer et al., 1997b), such limits help to describe latency distributions; the biological significance of express latencies particularly for vergence will be addressed in the Discussion. Using a gap paradigm without TMS, individual latency distributions tended towards unimodality (see Supplementary Section 5). For saccades, we observed in most cases a mode of fast regular latencies accompanied by 20% or more of 80–120 ms latencies. For both convergence and divergence, the most frequent distribution pattern was a population of fast-to-slow regular latencies with <10% of 80–120 ms latencies.
Effects of Prefrontal TMS on Saccade and Vergence Triggering
General Result
TMS over DLPFC influenced only the triggering of eye movements, not their metrics (see Supplementary Section 6). Three-way ANOVA on RTs (as factors eye movement type, TMS, and side of stimulation) showed a main effect of TMS [F(3,27) = 8.3, P < 0.001], but no main effect of eye movement type or of the side of stimulation (F < 1). The highest TMS effect was for stimulation delivered simultaneously with target onset (TMS-0 condition). TMS delivered 20 ms later had a lower effect, whereas TMS delivered 40 ms after target onset had no effect. Thus, we will present in the following sections only data between no-TMS and TMS-0 conditions. Further two-way ANOVAs performed within each type of eye movement (as factors TMS and side of stimulation) showed a main effect of the side of stimulation [F(1,9) = 6.1, P < 0.05] for rightward saccades, which enables us to present the results separately for TMS over right DLPFC and TMS over left DLPFC.
Effects of TMS over the Right DLPFC on Saccade and Vergence Latency
Prefrontal TMS over the right hemisphere yielded a significant increase in the mean rate of 80–120 ms latencies for leftward saccades [+12.7 points of percentage (pts %), P < 0.01], for rightward saccades (+13.8 pts %, P < 0.05) and for convergence (+13.4 pts %, P < 0.05), but not for divergence (Fig. 4A). The corresponding latencies were shorter for saccades, but not for convergence (P = 0.064) and divergence (Fig. 4B). Figure 4C shows the distributions pooling the data of all subjects. Notice that the rate of anticipatory latencies did not significantly increase for any type of eye movement (P > 0.05).
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At the individual level, TMS enhanced significantly the rate of 80–120 ms latencies (without significantly increasing the proportion of latencies <80 ms) in four out of 10 subjects for leftward saccades, in five subjects for rightward saccades and in four subjects for convergence. Examples of individual distributions are provided in Figure 4D,E. TMS rendered some of the latency distributions bimodal or trimodal with a higher proportion of short-latencies compared with the no-TMS condition. For saccades, a peak of 80–120 ms latencies was observable in subject 1 for leftward saccades and in subject 4 for saccades in both directions (Fig. 4D). The new observation is that, for convergence, a peak of 80–120 ms latencies also emerged under TMS for subjects 1 and 4, resulting in a bimodal distribution for the former and in a trimodal distribution for the latter (Fig. 5E).
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To summarize, TMS over the right DLPFC enhanced the proportion of short-latency saccades bilaterally, thus shortening their mean latency. The TMS effect on convergence was mild, as the higher proportion of short latencies was not accompanied by a significant decrease in latency. There was no TMS effect on divergence. For some subjects, TMS caused the emergence of a population of short latencies for both saccades and convergence.
Effects of TMS over the Left DLPFC on Saccade and Vergence Latency
TMS over the left DLPFC influenced saccade triggering ipsilaterally but not contralaterally. Indeed, the magnetic stimulation increased the rate of 80–120 ms latencies only for leftward saccades (+13.4 pts %, P < 0.01), decreasing its mean latency (Fig. 5A,B). Group distributions of saccades show a shift of the mode to the left on the time axis for leftward saccades but not for rightward saccades (Fig. 5C). At the individual level, TMS enhanced significantly the rate of 80–120 ms latencies (with no significant increase in the anticipation rate) in three out of 10 subjects. Some additional anticipatory movements occurred in subject 8 under TMS, but their proportion was not statistically significant (Fig. 5D).
TMS over the left DLPFC tended to influence convergence, but the group mean difference between no-TMS and TMS conditions failed to reach significance for both the rate of 80–120 ms latencies (P = 0.066) and the latency (P = 0.064; Fig. 5A,B). At the individual level, TMS caused the enhancement of the rate of 80–120 ms latencies in three subjects. Note that it was the same subjects who exhibited short-latency convergence with TMS over the right DLPFC, and that they again performed a null or negligible proportion of anticipatory latencies (Fig. 5E).
TMS over left DLPFC influenced the triggering of divergence. The rate of 80–120 ms latencies increased significantly (+10.7 pts %, P < 0.05), but failed to render the corresponding latency smaller (Fig. 5A,B). This effect was accompanied by a significant increase in the rate of anticipatory latencies (+5.6 pts %) as it can be seen from the group distribution (Fig. 5C). TMS effect on divergence concerned most subjects; the increasing rate of anticipations was significant in two subjects (Fig. 5E).
In summary, TMS over the left DLPFC increased the rate of short-latency saccades only ipsilaterally, thus shortening the mean latency of leftward saccades. TMS influence on convergence was weaker than that of rightward stimulation. For divergence, the proportion of short-latencies was significantly exacerbated under TMS and concerned both 80–120 ms and anticipatory latencies.
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Discussion |
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TMS over the right DLPFC accelerated the triggering of saccades bilaterally, while TMS over the left DLPFC speeded up the triggering of ipsilateral saccades. For convergence, TMS effects were mild: rightward TMS enhanced the proportion of short latencies (but not of anticipations) but failed to reduce significantly the corresponding group mean latency; TMS over the left DLPFC concerned only three subjects and failed to influence significantly both the rate of short latencies and the mean latency for the group of subjects. Finally, TMS over the left DLPFC promoted the anticipatory mode of initiation that was specific to divergence whereas TMS over the right DLPFC had no influence on this movement. Prefrontal TMS effects were area-specific as TMS over the motor cortex had no effect; time-specific as TMS delivered over the DLPFC after target onset had little or no effect; and triggering-specific as saccade and vergence metrics were unchanged under TMS. After methodological considerations, we discuss the results with reference to our prior report, then comment upon the new results concerning TMS over the left DLPFC. We end with a discussion on the neural pathways underlying short-latency saccades and vergence.
TMS effects did not concern all subjects. Our aim was to gather conditions favourable to reflexive triggering of saccades and vergence (gap paradigm, young adults, close fixation point), and prefrontal TMS was expected to enhance further the reflexive triggering. The absence of effects in the experimental condition may be simply due to a bottom effect or a physiological limit, some subjects already showing short-latency saccades or vergence in the baseline condition without TMS. On the other hand, some of the negative results may be due to the intrinsic limits of TMS technology. Due to brain anatomical differences or insufficient intensity discharge, TMS may have been inefficient in some subjects. However, we observed a general tendency of TMS over the DLPFC to decrease eye movement latency which is consistent with prior studies using TMS (Müri et al., 1999) or examining patients (Pierrot-Deseilligny et al., 2004). Another issue that needs discussion is the biological significance of short latencies for saccades and vergence. We used the limits 80–120 ms to identify express movements that are defined for saccades as short-latency saccades showing a distinct peak in latency distribution (Fischer and Ramsperger, 1984). Although the examination of latency distribution is not a definite method for identifying express saccades (Reuter-Lorenz et al., 1991; Kingstone and Klein, 1993; Krauzlis and Miles, 1996b), the existence of express saccades has received extensive support (Fischer and Weber, 1993) and neurophysiological studies confirmed that they involve a specific neural pathway, shorter than that subserving regular saccades (Isa and Kobayashi, 2004). Concerning eye movements other than saccades, the express nature of short latencies is still under debate and will be discussed below for vergence.
The results concerning the influence of TMS over the right DLPFC on bilateral saccades and convergence are partially consistent with our prior report (Coubard et al., 2003). In that study, we had found no influence of TMS over the right DLPFC either on ipsilateral saccades or on convergence along the median plane. Several factors could explain these apparent discrepancies with the present study. First, the new subjects showed a higher rate of 80–120 ms latencies than the previous ones even in the baseline condition (without TMS). The mean rate of 80–120 ms latencies for the group of subjects in the baseline condition was 17.7% for leftward saccades (against 3.6% in our prior report), 20.6% for rightward saccades (against 8.3%) and 9.2% for convergence along the median plane (against 0%). Consistently, the mean latency was 150 ms for saccades (against 170 ms in our prior report) and 160 ms for vergence (against 250 ms for convergence). Another important variable is the use of a different spatial arrangement. The initial fixation point was at a shorter viewing distance (40 versus 150 cm). In our prior report, the small angle of convergence at the fixation point (2.3°) may have solicited the saccadic system independently from the vergence system. The resulting observation (unilateral effect for saccade) might reflect the functioning of the saccadic system alone. In contrast in the present study, the higher convergence angle at 40 cm (8.5°) may have resulted in an early interaction between saccade and vergence components. Indeed, the present effects for saccades and convergence under TMS over the right DLPFC are consistent with our prior result for combined saccade–vergence movements: we had observed an increased rate of short latencies for both the saccadic and the convergence components bilaterally (Coubard et al., 2003).
A new finding is that TMS over the DLPFC influenced the triggering of convergence along the median plane. The effect was weaker than for saccades, and rightward TMS tended to have a greater influence than leftward TMS. For some subjects, the higher proportion of short latencies took the form of an emerging population resembling express latencies of saccades. Whether such short-latency convergence could be of express nature is unknown and needs to be investigated further. The fact that short-latency convergence had previously been found only for convergence combined with a saccade raised the question of the possible contribution of saccadic intrusions during vergence. Our analysis of horizontal saccades intruding on vergence showed that they occurred after the initial smooth vergence and thus could not be invoked to explain short-latency convergence. Vertical saccades are also known to intrude on and boost vergence. Our control examining vertical position of the eyes during vergence also showed that vertical saccades were also lagged behind the initial smooth vergence and thus unlikely to assist vergence triggering. Finally, one could also argue that a transient saccade-related (e.g. not recorded vertical saccade-related) vergence may have caused a vergence disturbance in the disconjugate signal, but a careful examination of markers also excluded the possibility to mark transient vergence. In all, we suggest that the short-latency triggering described to date for saccades can generalize symmetrical convergence (without the contribution of saccades) under particular conditions of spatial arrangement and prefrontal disinhibition. This assumption is supported by a recent study showing that unwanted short-latency convergence could occur when a convergence distracter has to be ignored (Coubard and Kapoula, 2005).
The effects of TMS over the left DLPFC on saccade and vergence latency were explored here for the first time. Despite the doubts concerning TMS technology and its sources of variability (stimulation intensity, orientation of the coil), they suggest a functional asymmetry between the two prefrontal areas. TMS over the left DLPFC influenced saccade express triggering only ipsilaterally. This result is compatible with the lesion study by Pierrot-Deseilligny et al. (2003) in which three DLPFC-damaged patients were investigated. In their study, as the lesion was either left (two patients) or right (one patient), data were pooled into contralateral and ipsilateral groups, and compared to a normal group. Even though the authors emphasized the impairment in antisaccades, memory-guided and predictive saccades, they also reported a striking result in the visually guided gap task: a significant higher rate of express latencies (using the 80–120 ms limits) was found for ipsilateral saccades (42%) compared with contralateral saccades (16%) and controls (8%). In our view, one explanation for such a result is that the two left-lesioned patients tended to perform a higher rate of express saccades to the left side (ipsilateral) than to the right side, which resulted in a higher error rate for the ipsilateral group. Pooling our mean express rate differences for saccades (in TMS-0 condition) into contralateral and ipsilateral groups would also provide a higher express rate for the latter (rightward saccades under right TMS + leftward saccades under left TMS = 13.8 + 13.4 = 27.2 points of percentage) than for the former (leftward saccades under right TMS + rightward saccades under left TMS = 12.7–2.7 = 10 points of percentage).
For divergence, whereas TMS over the right DLPFC had no effect, TMS over the left DLPFC caused so many anticipations that it is impossible to conclude about an express-like mode of triggering for this movement. TMS influence on divergence took the form of an exacerbated proportion of short latencies including anticipations. Anticipated divergence contrasted convergence that was little anticipated and could be explained by some passive relaxation of the eyes. Against this hypothesis is our recent observation in a distracter task: when normal subjects were asked to fixate a position on the median plane and ignore distracters presented in depth (either in front of or behind the fixation location), they almost never diverged spontaneously but, in contrast, were prone to produce convergence erratic movements or a convergent drift (Coubard and Kapoula, 2005). Thus, the anticipatory mode of triggering for divergence, also described in prior studies (Takagi et al., 1995; Coubard et al., 2004), would rather be a volitional behavior that may correspond to a phylogenetic survival of an oculomotor function aiming to rapidly detect a predator or a prey. The present study showed that the left DLPFC could play a crucial role in the anticipatory mode of triggering specific to divergence.
We now move to the neural substrate of prefrontal TMS effects. In neuropsychology, the prefrontal cortex has been commonly associated with executive control. Executive control involves several cognitive processes such as hypothesis generation, information maintenance and set shifting, all of which is probably being underlied by a single mechanism — inhibition (Roberts et al., 1998). Indeed, maintaining information requires to suppress responses to irrelevant stimuli occurring during the delay. Switching from one task to another requires to inhibit repetition of the prior routine. Patient and neuroimaging studies have shown that the right prefrontal cortex is a critical component of the neural basis of inhibition. Goel and Vartanian (2004) showed a dissociation between right inferior frontal cortex (IFC) (also named ventrolateral prefrontal cortex; Brodmann's areas 44, 45, 47/12) and right DLPFC in hypotheses generation and maintenance, respectively. In their review, Aron et al. (2004) suggested that the right IFC would subserve inhibitory processes common to response inhibition and set shifting tasks. A remaining question concerns how inhibitory processes are neurally implemented. We believe that neurophysiological oculomotor research can help to understand this issue. The present study showed that it was possible using TMS to interfere with the inhibitory prefrontal function exerted on automatic routines such as express-like short-latency eye movements. The physiological mechanisms responsible for express latencies are known for saccades. Prior to an express saccade, the visual and motor bursts of saccade-related neurons of the superior colliculus (SC) merge into a single visuomotor burst, thus shortening saccade latency (reviewed by Isa and Kobayashi, 2004). In the rhesus monkey, the unilateral lesion of SC abolishes all express saccades contralaterally, whereas that of FEF has little effect on express saccades and preserves the bimodal distribution (Schiller et al., 1987). Saccade-related neurons of the SC receive several sources of inhibition, including a direct projection from the DLPFC (Goldman and Nauta, 1976; Leichnetz et al., 1981). To explain the enhancement of contralateral saccades by TMS over the DLPFC, Müri et al. (1999) suggested that the magnetic pulse interferes with the functioning of this direct prefrontotectal tract, thus releasing the activity of saccade-related neurons of the ipsilateral SC. The time of target onset corresponding to 200 ms after fixation offset is the critical time window to interfere with the prefrontal inhibition. Indeed, stimulating the DLPFC later, as in our control conditions, or before, for example at the middle of the gap, as done by Müri et al. (1999), has less or no effect on saccade latency. The time of target onset in the 200 ms gap paradigm corresponds to the maximum imbalance in activity between saccade- and fixation-related neurons. Indeed, when the fixation point switches off in the gap paradigm, electrophysiological studies have shown that saccade-related neurons progressively increased their activity during the gap period prior to an express saccade. Such an activity was described in the SC (Edelman and Keller, 1996; Dorris et al., 1997) and in the FEF (Everling and Munoz, 2000). One hypothesis is that this activity may be due to the release of inhibition exerted by fixation-neurons which exhibit exactly the reverse pattern: after FP offset, they decrease progressively their activity during the gap period and prior to an express saccade in the FEF and prefrontal cortex (areas 8 and 46) (Tinsley and Everling, 2002) but not in the SC (Dorris et al., 1997; Everling et al., 1998).
Another interpretation for the release of express saccades by prefrontal TMS could be that the magnetic pulse interferes with other cortico-subcortical networks involving the DLPFC (Alexander et al., 1986). Indeed, saccade-related neurons of SC are also inhibited by the substantia nigra pars reticulata (SNpr) (Hikosaka and Wurtz, 1983; Deniau and Chevalier, 1985), which is itself controlled by the caudate nucleus (CN) (Hikosaka et al., 1993) and a neural network involving the subthalamic nucleus (Matsumura et al., 1992). This hypothesis was recently challenged by Condy et al. (2004), who examined the ability to suppress reflexive saccades in patients suffering from a focal lesion of different subcortical structures. They showed that patients with a basal ganglia lesion, a thalamic lesion or a lesion restricted to the posterior part of the posterior limb of the internal capsule performed normally. In contrast, patients with a focal lesion involving the prefrontotectal tract were impaired to suppress saccades, supporting the hypothesis of a direct inhibitory control exerted by the DLPFC onto the SC (see also Gaymard et al., 2003).
Our result for convergence suggests (i) the existence of mechanisms underlying a short-latency mode of triggering for convergence; and (ii) that the DLPFC could contribute to control these mechanisms. Whether this short-latency convergence would be of express nature is unknown. Short-latency disparity vergence has previously been described in monkeys (Busettini et al., 1996) and humans (Busettini et al., 2001), but those studies used small disparity steps applied to large textured patterns, and a prior saccade to boost response amplitude — a setup which is rather different from ours. Using a gap paradigm, Krauzlis and Miles showed a latency reduction for pursuit comparable to that of saccades by comparison with a no-gap condition in both monkeys (Krauzlis and Miles, 1996a) and humans (Krauzlis and Miles, 1996b). The authors extensively discussed the putative express nature of short-latency pursuit and concluded that their short-latency pursuit was not express, particularly because pursuit latency was not sensitive to target eccentricity, contrary to (express) saccades. For vergence, further behavioral and neurophysiological investigations are needed to conclude on an express mode of triggering. Nevertheless, we discuss here the possible pathways that could be involved in short-latency vergence. The vergence premotor circuitry receives projections from deep cerebellar nuclei (Gamlin et al., 1996; Gamlin, 1999), and from vergence-related neurons in the prearcuate cortex lying just anteriorly to the saccade-related region of the FEF (Gamlin and Yoon, 2000). The SC is also involved in the control of vergence eye movements, either pure or combined with a saccade (Chaturvedi and van Gisbergen, 1999, 2000). We suggest that the inhibitory control of DLPFC on short-latency vergence triggering could act through the direct inhibitory prefrontotectal tract as for saccades. Another hypothesis is that TMS acts through the glutamatergic frontal projection to the pons described by Gamlin and co-workers (Gamlin et al., 1996; Gamlin and Yoon, 2000; Gamlin, 2002). However, such a projection concerns the region of the FEF and our methodology rather aimed to stimulate the DLPFC. Furthermore, the FEF is almost a triggering area (Pierrot-Deseilligny et al., 2004) and TMS over FEF would have likely delayed responses rather than shortened latencies, as it can be observed for the posterior parietal cortex (PPC) (e.g. Kapoula et al., 2004). Finally, the fact that the effects of TMS over the DLPFC vary from one hemisphere to another could be due to a functional prefrontal asymmetry, which has to be further confirmed by lesion and brain imaging studies. Left–right prefrontal asymmetry could also be due indirectly to descending pathways from the PPC onto the SC (Paré and Wurtz, 2001), as the right and left PPCs are known to control differently saccade and vergence eye movements (Kapoula et al., 2005b).
The human dorsolateral prefrontal cortex exerts an inhibitory control on saccade and vergence triggering, preventing short-latency saccades and vergence. This control could act via its direct projections onto the superior colliculus. The right DLPFC is crucial to control saccades bilaterally and would be dominant for convergence triggering, whereas the left DLPFC is involved in the control of ipsilateral saccades and plays a critical role in the anticipatory mode of triggering that is specific to divergence.
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionSupplementary MaterialReferences |
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Supplementary Material can be found at: http://www.cercor.oxfordjournals.org.
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O.A.C. was funded by a fellowship of Neuro-Ophthalmology Berthe Fouassier, Fondation de France. Mechanics were completed by Michel Ehrette and Yves Dupraz (LPPA), electronics by Gintautas Daunys (Siauliai, Lithuania). Thomas Eggert (Munich, Germany) developped the software Analyse allowing the analysis of eye movements.
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