Abstract

The antisaccade (AS) task, which requires the ability to suppress unwanted reflexive glances, has proven to be a powerful tool for the analysis of executive control. Performing this task activates a large frontoparietal network, but which area is specifically responsible for reflexive saccade (RS) inhibition has not yet been demonstrated. We reversibly inactivated portions of the principal sulcus in 2 monkeys trained to perform AS and RS tasks. Here we show that inactivation of a circumscribed area in the ventral bank of the principal sulcus induced a strong impairment of RS inhibition without affecting RS triggering. Our results are compatible with a partitioning of the principal sulcus into functional subregions, in which a well-delineated area is critically involved in RS suppression.

Introduction

Intelligent behavior requires the ability to remain goal oriented in the face of distracting, but potentially important events. For example, a driver must focus on the road and at the same time monitor peripheral events such as traffic lights or pedestrians. This requires the ability to dissociate the focus of attention from the orientation of gaze. Such uncoupling may be experimentally investigated by an oculomotor paradigm called the antisaccade (AS) task (Munoz and Everling 2004). A subject is presented with an unpredictable peripheral target and is required to initiate an eye movement in the opposite direction. Although the target is not the saccadic goal, its location must be processed because it determines the parameters of the ensuing saccade. AS impairments are observed in a wide variety of neurological and psychiatric diseases and are a good hallmark of impaired voluntary control of attention (Munoz and Everling 2004). Functional imaging studies in humans and electrophysiological recordings in primates have revealed the activation of a large frontoparietal network in subjects performing the AS task, including the posterior parietal cortex (human: Matthews and others 2002; Matsuda and others 2004; monkey: Gottlieb and Goldberg 1999; Zhang and Barash 2004), the frontal eye field (FEF) (human: Cornelissen and others 2002; Matsuda and others 2004; monkey: Everling and Munoz 2000), the supplementary eye field (human: Sweeney and others 1996; monkey: Schlag-Rey and others 1997; Amador and others 2004), the anterior cingulate cortex (human: Milea and others 2003), and the dorsolateral prefrontal cortex (DLPFC) (human: McDowell and others 2002; Pierrot-Deseilligny and others 2003; monkey: Funahashi and others 1993). However, it has proven difficult to ascribe a specific role to each cortical area in a task that requires multiple processing such as target detection, inhibition of a reflexive saccade (RS), inversion of the saccade vector, and triggering of a nonvisually guided saccade (Munoz and Everling 2004). Anatomical and electrophysiological data are consistent with a role of the DLPFC in RS suppression. Although this area is monosynaptically connected to the caudal pole of the superior colliculus (Goldman and Nauta 1976; Leichnetz and others 1981), where saccade-related neurons are located (Everling and others 1999), electrical stimulation of the monkey DLPFC does not elicit saccades (Boch and Goldberg 1989). It is therefore likely that this connection exerts an inhibitory influence over saccade triggering. This hypothesis is supported by impaired RS inhibition in patients with prefrontal lesions (Guitton and others 1985; Pierrot-Deseilligny and others 1991), although damage to neighboring areas such as the FEF or the underlying white matter is rarely avoided. In primates, no lesions or inactivation studies have ever been performed in animals trained on the AS task, but a recent study has shown that bilateral and marked AS impairments result from systemic injection of a subanesthetic dose of ketamine (Condy and others 2005). Because this drug affects the metabolism of frontal areas including the DLPFC (Holcomb and others 2001), it is compatible with a role of this area in the inhibitory process required in the AS task. In order to test this hypothesis, we injected muscimol, a γ-aminobutyric acid (GABA) agonist, in the principal sulcus of monkeys trained on RS and AS tasks. We predicted that inactivation of this area, a region equivalent to the human DLPFC (Fig. 1a), should selectively impair an inhibitory mechanism and result in increased AS error rate without affecting RS triggering.

Figure 1

Regions of interest and behavioral tasks. (a) On each hemisphere, a chamber was implanted above the posterior half of the principal sulcus. (b) RS task: a white central fixation point instructed the monkey to trigger a saccade toward the subsequently appearing target. AS task: a gray fixation point was the instruction to trigger a saccade in the direction opposite to the subsequently appearing target. A 200-ms gap was used in both tasks, and 16° peripheral targets were presented at one of the 6 possible radial locations. (c) Effective sites (large dots) from both hemispheres of both monkeys have been collapsed on a single hemisphere, with reference to cortical sulci. Note that effective sites are not intermingled with noneffective sites (small dots), but gathered in the posterior third of the principal sulcus, mainly in the fundus. Circled dots indicate sites at which a similar volume of saline was injected, once (single circle) or twice (double circle). The numbers on injection sites are referred to in the text or in other figures. (d) Anatomical data confirmed that most of the effective sites were located along the ventral bank. A tracer was injected in site 2, at a depth at which muscimol induced a markedly increased AS error rate (dark area circled by white dots). PS, principal sulcus; vb, ventral bank.

Figure 1

Regions of interest and behavioral tasks. (a) On each hemisphere, a chamber was implanted above the posterior half of the principal sulcus. (b) RS task: a white central fixation point instructed the monkey to trigger a saccade toward the subsequently appearing target. AS task: a gray fixation point was the instruction to trigger a saccade in the direction opposite to the subsequently appearing target. A 200-ms gap was used in both tasks, and 16° peripheral targets were presented at one of the 6 possible radial locations. (c) Effective sites (large dots) from both hemispheres of both monkeys have been collapsed on a single hemisphere, with reference to cortical sulci. Note that effective sites are not intermingled with noneffective sites (small dots), but gathered in the posterior third of the principal sulcus, mainly in the fundus. Circled dots indicate sites at which a similar volume of saline was injected, once (single circle) or twice (double circle). The numbers on injection sites are referred to in the text or in other figures. (d) Anatomical data confirmed that most of the effective sites were located along the ventral bank. A tracer was injected in site 2, at a depth at which muscimol induced a markedly increased AS error rate (dark area circled by white dots). PS, principal sulcus; vb, ventral bank.

Materials and Methods

Monkeys

Two male green monkeys (Cercopitheca aethiops sabaeus), belonging to the same family as macaques, (i.e., Cercopithecinae), weighing 5 kg, were used for these experiments. Care and treatment of these monkeys were in strict accordance with National Institutes of Health guidelines (1996) and the recommendations of the European Economical Community (86/609) and the French National Committee (87/848).

Surgical Procedures

All surgical procedures were performed under general anesthesia and aseptic conditions. Anesthesia was induced by an intramuscular injection of ketamine (10 mg/kg) and atropine and maintained by halothane inhaled through an endotracheal tube. After surgery, antibiotics (Amoxicilline 30 mg/kg, Enrofloxacine 5 mg/kg) and analgesic (Tolfenamic acid 5 mg/kg) were given for 10 days. During a first surgical procedure, a scleral search coil on both eyes and a head-restraining device were implanted. The monkeys were then trained to perform saccade tasks. Once a stable and satisfactory level of performance was reached, a second surgical procedure was performed for the implantation of a stainless steel recording chamber (Crist Instruments, Hagerstown, MD) over the posterior half of the principal sulcus, one on each hemisphere.

Behavioral Tasks

Behavioral experiments took place in a dimly illuminated room with background luminance of 0.20 cd/m2. Monkeys were seated in a primate chair, 80 cm in front of a monitor on which visual stimuli were displayed. Visual paradigms and data acquisition were under the control of a computer running a real-time data acquisition system (REX). Eye position was digitized and sampled at 500 Hz and stored for off-line analysis.

RS Task

The RS task started with the presentation of a central 2° × 2° green fixation stimulus (luminance, 0.56 cd/m2). The trial was initiated once the monkey fixated in a 3° × 3° electronic window centered on the fixation stimulus. This stimulus was then switched off after 700–1200 ms and followed by a 200-ms blank screen (gap). A 16° eccentric green target (size, 2° × 2°; luminance, 0.56 cd/m2) was then presented during 1000 ms at one of the 6 possible radial locations (0°, 45°, 135°, 180°, 225°, or 315°) (Fig. 1b). An RS block of trials consisted of 24 trials, in a semirandom order. Failure to trigger a saccade toward the peripheral target within 2000 ms after target onset or the triggering of a contraversive saccade automatically terminated the trial. After each trial, the monkey received a drop of juice if the saccade endpoint fell within a 5° × 5° electronic window centered on the target.

AS Task

The same sequence of events occurred in the AS task (Fig. 1b), but the fixation stimulus was red (luminance, 0.50 cd/m2). The monkey was rewarded with a drop of juice if the primary saccade (i.e., the first saccade triggered after peripheral target presentation) was triggered toward and terminated in the hemifield opposite to the target. An AS block of trials consisted of 96 AS, each target location being presented 16 times. In this task, a correct response was a saccade initially triggered in the hemifield opposite to the target, but no amplitude criterion was imposed. Consequently, a saccade initially triggered toward the target automatically interrupted the trial and was scored as an error. Hereafter, the terms “ipsilateral” and “contralateral” refer to the side of the injection site. Thus, an ipsilateral RS refers to a saccade triggered toward an ipsilateral target, that is, in the hemifield ipsilateral to the injected hemisphere. A contralateral AS refers to a saccade triggered toward the hemifield contralateral to the injected hemisphere, that is, in response to an ipsilateral target.

Principal Sulcus Location and Intracerebral Microinjections

The principal sulcus was first located by visual inspection, immediately after the craniotomies performed during the second surgical procedure. A more accurate topography of the banks and the fundus of the sulcus were provided by electrophysiological recording sessions. Neuronal activity was recorded while the monkeys were at rest with tungsten microelectrodes (Frederick Haer and Co. [Brunswick, ME], 8–9 MΩ at 1 kHz). It was checked that currents up to 300 μA (80 ms of biphasic pulses at 350 Hz) could not elicit saccades from the most posterior effective sites (i.e., sites at which muscimol induced a significant increased AS error rate) in the principal sulcus. The sites and the depth of the injections were then chosen according to electrophysiological data, with a maximum of 2 injections in a week. Muscimol (Sigma Aldrich, Lyon, France), a GABA A agonist, was injected through a 30-gauge stainless steel tubing cannula lowered into the brain with a transdural guide tube. The guide tube was held by a grid (Crist and others 1988). Once the tip of the injection cannula was at the desired level, 4 μl of muscimol (5 μg/μl) were injected with a 10-μl Hamilton syringe in 0.2 μl steps, during 8 min (0.5 μl/min). In order to demonstrate that the effects observed with muscimol were not secondary to increased local pressure, 9 injections (Monkey 1, n = 6; Monkey 2, n = 3) of a comparable volume of saline (4 μl) were interleaved between muscimol experiments. They were performed under the same experimental conditions and at various sites, including sites at which muscimol induced deficits in the AS task (Fig. 1c).

The location of FEF (anterior bank of the arcuate sulcus) was also determined in both monkeys by visual inspection during the second surgical procedure. Electrical stimulation was then used to confirm that low-threshold currents (80 ms of biphasic pulses at 350 Hz, current <50 μA) could reliably evoke contraversive saccades from this area. Lastly, we checked that muscimol injected in the anterior bank of the arcuate sulcus (n = 6) induced marked impairments of RSs, as previously described (Dias and others 1995; Sommer and Tehovnik 1997).

Experimental Protocol

An experimental session began with preinjection trials (one RS and one AS block) during which it was checked that the monkey's performance corresponded to its pre-established baseline performance. Consistent with previous studies (Bell and others 2000), our monkeys' AS error rates in control experiments were low, being below 30% in monkey V and below 35% in monkey I. Muscimol or saline was then injected. Postinjection trials started 20 min after injection and lasted for 2.5 h. AS blocks of trials were performed 20, 30, 60, 90, 105, 120, and 150 min after injection, and RS blocks of trials were performed 20, 60, 105, and 150 min after injection.

In ketamine experiments (see Results), the postinjection schedule was different because the effect of ketamine on the AS task does not generally exceed 45 min (Condy and others 2005), and only 0° and 180° target locations were used. A subanesthetic dose of ketamine (0.6 or 0.8 mg/kg) was injected intramuscularly, either alone (K-only) or after intracortical muscimol injection (M + K), while the monkey remained seated in its chair. In K-only experiments, one RS and one AS block of trials were performed before injection. In M + K experiments, ketamine was injected once an increased AS error rate was observed for the ipsilateral horizontal target location. Series of AS blocks of 32 trials were then performed, 6, 10, 14, 18, 22, 26, 34, 38, 42, 46, 50, and 54 min, after ketamine injection. Only two RS blocks of trials were performed, 28 and 58 min after injection, because we chose to concentrate on AS data. Intramuscular injections of saline (S) were performed in similar conditions (n = 6 in each monkey).

Histological Procedure

After the completion of this study, the brain of both monkeys was analyzed in order to provide histological confirmation of the location of the effective sites.

Data Analysis and Statistics

In both RS and AS tasks, normal values were obtained from the saline experiments. Because our experiments were long lasting (150 min), normal values were calculated for each block of trials in order to account for a possible fluctuation of the monkey's performance during the recording session.

In the RS task, we analyzed saccade latency and saccade gain; the latter defined as the ratio of saccade amplitude to target eccentricity. Only saccades with a latency of 60–2000 ms were analyzed. For both parameters, we pooled, within each block of trials, values obtained for 45°, 0°, and 315° targets (rightward saccades) and for 135°, 180°, and 225° targets (leftward saccades) because they did not differ significantly. Postinjection data for each block were then compared with the corresponding block of saline experiments with a Student's t-test (saccade latency) and a Mann-Whitney test (saccade gain).

In the AS task, we analyzed correct AS latency and AS error rate, defined as the percentage of saccades initially directed toward the target within a given block of trials. Because high error rates could be observed in postinjection trials, it was necessary to pool AS latency for similar directions (45°, 0°, and 315°; 135°, 180°, and 225°) within each block of trials in order to obtain a sufficient number of data. Postinjection AS latencies were compared with the corresponding blocks of saline experiments using a Student's t-test. Data on the AS error rate were not pooled. We thus obtained a normal range for each direction and for each block of trials. Comparison of AS error rate between saline and muscimol experiments was performed within similar postinjection blocks, using a χ2-test. An effective site was defined as a site at which muscimol induced a significantly increased error rate compared with control experiments.

The methods used for the analysis of ketamine experiments have been presented in detail elsewhere (Condy and others 2005). RS and AS latencies and AS error rate were determined in S, K-only, and M + K experiments. Comparisons between M + K versus K-only and M + K versus S were performed within each block of trials using a χ2-test for AS error rate and a Student's t-test for AS and RS latencies.

Results

Muscimol induced a significantly increased error rate at 18 sites among the 53 injected sites (Monkey V, n = 13; Monkey I, n = 5) (Table 1). Normal error rates were obtained at all other sites despite repeated injections performed at different depths, and these sites will not be considered any further.

Table 1

AS error rate (range) in saline and muscimol experiments, before and 105 min after injection, at all effective sites

 Preinjection +105 min 
 Ipsi targets Contra targets Ipsi targets Contra targets 
Monkey V     
Saline (n = 6) 11 (3–19) 10 (3–20) 13 (9–22) 11 (5–21) 
Muscimol site     
    1 17 33*** 0§§§ 
    2 21 46*** 0§§§ 
    3 15 73*** 14 
    4 18 13 31** 0§§§ 
    5 23 85*** 0§§§ 
    6 16 11 43*** 0§§§ 
    7 14 16 64*** 0§§§ 
    8 22 14 57*** 0§§§ 
    9 22 23 62*** 
    10 15 46*** 0§§§ 
    12 21 42*** 
    13 21 19 46*** 0§§§ 
    15 19 18 36*** 
Monkey I     
Saline (n = 3) 9 (0–29) 13 (0–33) 14 (0–29) 10 (0–35) 
Muscimol site     
    11 24 14 75*** 0§§ 
    14 23 75*** 0§§ 
    16 23 33 71*** 0§§ 
    17 23 63*** 14 
    18 24 33 86*** 0§§ 
 Preinjection +105 min 
 Ipsi targets Contra targets Ipsi targets Contra targets 
Monkey V     
Saline (n = 6) 11 (3–19) 10 (3–20) 13 (9–22) 11 (5–21) 
Muscimol site     
    1 17 33*** 0§§§ 
    2 21 46*** 0§§§ 
    3 15 73*** 14 
    4 18 13 31** 0§§§ 
    5 23 85*** 0§§§ 
    6 16 11 43*** 0§§§ 
    7 14 16 64*** 0§§§ 
    8 22 14 57*** 0§§§ 
    9 22 23 62*** 
    10 15 46*** 0§§§ 
    12 21 42*** 
    13 21 19 46*** 0§§§ 
    15 19 18 36*** 
Monkey I     
Saline (n = 3) 9 (0–29) 13 (0–33) 14 (0–29) 10 (0–35) 
Muscimol site     
    11 24 14 75*** 0§§ 
    14 23 75*** 0§§ 
    16 23 33 71*** 0§§ 
    17 23 63*** 14 
    18 24 33 86*** 0§§ 

Note: A χ2-test was used for comparisons between muscimol (most affected direction) and saline experiments. Ipsi, ipsilateral; contra, contralateral. Asterisks denote increased error rates; **P < 0.01, ***P < 0.001. Sections denote decreased error rates; §§P < 0.01, §§§P < 0.01.

Anatomical Location of Effective Sites

Reconstruction on a lateral view of the frontal lobe, with reference to cortical sulci, revealed that effective sites were not scattered among ineffective sites but gathered in a well-defined area corresponding to the posterior third of the principal sulcus (Fig. 1c). Electrical stimulation and behavioral data confirmed that the most posterior sites of this area were rostral to the FEF. Based on the results of electrophysiological recordings, muscimol was usually delivered near the fundus of the principal sulcus (Fig. 1d). Subsequent anatomical data obtained in both monkeys confirmed that the critical area in which muscimol induced a significantly increased AS error rate corresponded mainly to the ventral bank of the posterior third of the principal sulcus. Although the spread of the injected drug precludes any precise determination of the depth of the critical sites within the principal sulcus, we occasionally observed that muscimol injected more superficially (1.5 mm closer to the dura) did not induce a significant impairment.

Effect of Muscimol Injection on the AS Task

Within these effective sites, the error rate usually started to increase 20–60 min after the injection and remained significantly increased in subsequent blocks of trials until the end of the recording session, that is, 2.5 h after the injection. A typical example of the effect of muscimol injection on the AS task is illustrated in Figure 2. In this case, muscimol was injected into the left principal sulcus, at a site located in the middle of our effective zone (Fig. 2, inset). The error rate started to increase soon after injection, for all left-sided (i.e., ipsilateral) targets, and remained significantly increased until the end of the experiment. By contrast, a tendency for decreased error rates was observed for contralateral targets. Among all effective sites, increased error rates were most often observed for 3 (72% of effective sites) or 2 (22%) target locations and rarely confined to only 1 (6%) target location. However, a constant feature in both monkeys was that increased error rates were exclusively observed for ipsilateral targets (Table 1). This is illustrated in Figure 3, which presents AS error rates for each target location at 4 effective sites (Fig. 3a). In order to better describe our monkeys' behavior in the AS task, we analyzed primary saccade endpoints. As shown in Figure 3b (muscimol injected in the left hemisphere), misdirected saccades, which, after the injection, were more frequent toward left-sided targets, were clearly RSs directed toward the target. These were either full amplitude RSs reaching the target or, more often, small amplitude RSs interrupted by a contraversive corrective saccade. Although high error rates were occasionally reached, 100% error rates were never observed simultaneously in all affected directions. The occurrence of correct ASs even at the peak of the effect demonstrates that muscimol did not affect our monkeys' ability to recall the stimulus-response rule. An analysis over time showed that errors did not occur more frequently at a certain period of a block of trials (e.g., at the end) but were interleaved with correct responses. Normal error rates were always confirmed on the day following the injection.

Figure 2

AS error rate after muscimol injection: temporal aspect. In this experiment, muscimol was injected in the ventral bank of the left principal sulcus (site 7, large dot, inset). The error rate increased shortly after muscimol injection for all left-sided targets and remained significantly increased until the end of the recording session (χ2: *P < 0.05, **P < 0.01, ***P < 0.001). Note the low error rate for right-sided targets, especially at 0° and 315° (χ2: §P < 0.05, §§§P < 0.001). Dotted lines represent performances after saline injection. PI, preinjection block.

Figure 2

AS error rate after muscimol injection: temporal aspect. In this experiment, muscimol was injected in the ventral bank of the left principal sulcus (site 7, large dot, inset). The error rate increased shortly after muscimol injection for all left-sided targets and remained significantly increased until the end of the recording session (χ2: *P < 0.05, **P < 0.01, ***P < 0.001). Note the low error rate for right-sided targets, especially at 0° and 315° (χ2: §P < 0.05, §§§P < 0.001). Dotted lines represent performances after saline injection. PI, preinjection block.

Figure 3

AS error rate after muscimol injection: spatial aspect. (a) At these 4 effective sites, as in all other effective sites, postinjection error rates (light gray area) were increased exclusively for ipsilateral targets. Note low error rates for contralateral targets, often below control error rates (dark gray area: highest error rate observed in saline experiments). The error rates from the most affected postinjection block of trials are presented. (b) AS endpoints. In this experiment, muscimol was injected in the left principal sulcus (site 5). In postinjection blocks, the monkey made more errors when the target (square) was on the left side. RSs were clearly directed toward the target. Note that the monkey was still able to trigger correct rightward ASs.

Figure 3

AS error rate after muscimol injection: spatial aspect. (a) At these 4 effective sites, as in all other effective sites, postinjection error rates (light gray area) were increased exclusively for ipsilateral targets. Note low error rates for contralateral targets, often below control error rates (dark gray area: highest error rate observed in saline experiments). The error rates from the most affected postinjection block of trials are presented. (b) AS endpoints. In this experiment, muscimol was injected in the left principal sulcus (site 5). In postinjection blocks, the monkey made more errors when the target (square) was on the left side. RSs were clearly directed toward the target. Note that the monkey was still able to trigger correct rightward ASs.

Muscimol also affected correct AS latency. At 17/18 sites, postinjection trials in muscimol experiments revealed significantly increased contralateral AS latency (AS triggered away from the injection site) and decreased ipsilateral AS latency (AS triggered toward the injected hemisphere) (Table 2). This effect, illustrated at 4 sites in Figure 4, was observed throughout the effective zone, that is, at posterior (site 4), middle (site 7), or anterior (sites 9 and 10) sites, and over successive blocks of trials. Interestingly, postdrug changes in AS latency and increased AS error rates appeared in similar blocks of trials (Fig. 4). The only site at which no significant change in AS latency was observed in postdrug trials was the most anterior site (site 15), at which only a slight increase AS error rate was detected.

Figure 4

Effect of muscimol injection on AS and RS latency. Contralateral AS (i.e., AS away from the injection site) latency significantly increased after muscimol injection, whereas significantly increased RS latency was rarely observed. The first blocks of trials in which a change in AS latency was observed coincided with the first blocks in which an increased error rate was observed (vertical dashed line). The location of the corresponding injection site is indicated by a black dot. Comparison between ipsilateral and contralateral saccade latency was done using a t-test: *P < 0.05, **P < 0.01, ***P < 0.001.

Figure 4

Effect of muscimol injection on AS and RS latency. Contralateral AS (i.e., AS away from the injection site) latency significantly increased after muscimol injection, whereas significantly increased RS latency was rarely observed. The first blocks of trials in which a change in AS latency was observed coincided with the first blocks in which an increased error rate was observed (vertical dashed line). The location of the corresponding injection site is indicated by a black dot. Comparison between ipsilateral and contralateral saccade latency was done using a t-test: *P < 0.05, **P < 0.01, ***P < 0.001.

Table 2

AS latency (ms, mean ± standard deviation) in saline and muscimol experiments, before and 105 min after injection, at all effective sites

 Preinjection +105 min 
 Ipsi targets Contra targets Ipsi targets Contra targets 
 Contra AS Ipsi AS Contra AS Ipsi AS 
Monkey V     
Saline (n = 6) 158 ± 36 160 ± 43 159 ± 38 161 ± 35 
Muscimol site     
    1 178 ± 34 170 ± 27 172 ± 33 158 ± 36 
    2 175 ± 39 171 ± 30 182 ± 26* 149 ± 28§§ 
    3 174 ± 44 170 ± 39 160 ± 53 126 ± 43§§§ 
    4 181 ± 48 166 ± 40 174 ± 24 158 ± 27 
    5 181 ± 54 178 ± 49 179 ± 51 136 ± 33§§§ 
    6 185 ± 64 174 ± 55 189 ± 44*** 145 ± 20 
    7 149 ± 36 144 ± 34 211 ± 38*** 154 ± 35 
    8 174 ± 85 156 ± 45 183 ± 51* 137 ± 43§§§ 
    9 172 ± 42 156 ± 52 155 ± 35 162 ± 40 
    10 180 ± 47 182 ± 66 180 ± 55** 143 ± 45§§ 
    12 166 ± 34 143 ± 35 180 ± 36** 152 ± 40 
    13 147 ± 45 182 ± 62 153 ± 36 144 ± 27§ 
    15 159 ± 37 162 ± 49 146 ± 42 149 ± 52 
Monkey I     
Saline (n = 3) 167 ± 52 173 ± 51 167 ± 47 163 ± 33 
Muscimol site     
    11 157 ± 56 170 ± 44 189 ± 51 178 ± 32 
    14 185 ± 44 129 ± 32 195 ± 73 172 ± 40 
    16 228 ± 20 208 ± 26 238 ± 82*** 160 ± 45 
    17 173 ± 42 150 ± 35 176 ± 52 149 ± 45§§ 
    18 179 ± 62 176 ± 41 241 ± 66*** 183 ± 41 
 Preinjection +105 min 
 Ipsi targets Contra targets Ipsi targets Contra targets 
 Contra AS Ipsi AS Contra AS Ipsi AS 
Monkey V     
Saline (n = 6) 158 ± 36 160 ± 43 159 ± 38 161 ± 35 
Muscimol site     
    1 178 ± 34 170 ± 27 172 ± 33 158 ± 36 
    2 175 ± 39 171 ± 30 182 ± 26* 149 ± 28§§ 
    3 174 ± 44 170 ± 39 160 ± 53 126 ± 43§§§ 
    4 181 ± 48 166 ± 40 174 ± 24 158 ± 27 
    5 181 ± 54 178 ± 49 179 ± 51 136 ± 33§§§ 
    6 185 ± 64 174 ± 55 189 ± 44*** 145 ± 20 
    7 149 ± 36 144 ± 34 211 ± 38*** 154 ± 35 
    8 174 ± 85 156 ± 45 183 ± 51* 137 ± 43§§§ 
    9 172 ± 42 156 ± 52 155 ± 35 162 ± 40 
    10 180 ± 47 182 ± 66 180 ± 55** 143 ± 45§§ 
    12 166 ± 34 143 ± 35 180 ± 36** 152 ± 40 
    13 147 ± 45 182 ± 62 153 ± 36 144 ± 27§ 
    15 159 ± 37 162 ± 49 146 ± 42 149 ± 52 
Monkey I     
Saline (n = 3) 167 ± 52 173 ± 51 167 ± 47 163 ± 33 
Muscimol site     
    11 157 ± 56 170 ± 44 189 ± 51 178 ± 32 
    14 185 ± 44 129 ± 32 195 ± 73 172 ± 40 
    16 228 ± 20 208 ± 26 238 ± 82*** 160 ± 45 
    17 173 ± 42 150 ± 35 176 ± 52 149 ± 45§§ 
    18 179 ± 62 176 ± 41 241 ± 66*** 183 ± 41 

Note: In postinjection trials, a t-test was used for comparisons between muscimol and saline experiments. Ipsi, ipsilateral; contra, contralateral. Asterisks denote increased latency; *P < 0.05, **P < 0.01, ***P < 0.001. Sections denote decreased latency; §P < 0.05, §§P < 0.01, §§§P < 0.001.

Improved Performances for Contralateral Targets

In the AS task, we observed that, in addition to increased error rates for ipsilateral targets, our monkeys frequently performed better for contralateral targets after muscimol injection (Table 1 and Fig. 2). However, statistical confirmation of this phenomenon was difficult because of the low error rates of our 2 monkeys during preinjection trials and saline experiments. In order to demonstrate that muscimol improves contralateral RS suppression, we combined local intracerebral muscimol microinjection with systemic injection of ketamine. We recently showed that systemic administration of ketamine, a noncompetitive N-methyl-D-aspartate receptor antagonist, at a subanesthetic dose (i.e., in the range of 0.4–1.0 mg/kg; humans: Ghoneim and others 1985; Taffe and others 2002; monkeys: Taffe and others 2002) elicits a reliable, marked, and bilaterally increased AS error rate in monkeys (Condy and others 2005). We therefore hypothesized that if muscimol does improve performances for contralateral targets in the AS task, muscimol injected prior to ketamine administration should prevent or at least minimize the ketamine-induced increased error rate for contralateral targets but should have an additional effect for ipsilateral targets, resulting in markedly asymmetrical performances. To address this issue, we performed 2 additional experiments at 2 effective sites, one in each hemisphere (left side, site 9; right side, site 6) in monkey V. Compared with K-only experiments, M + K experiments muscimol showed a significantly reduced AS error rate for contralateral targets from 6 to 22 min after ketamine injection at site 9 (Fig. 5a), and from 14 to 54 min after ketamine injection at site 6. In contrast, a higher error rate was observed for ipsilateral targets from 6 to 46 min (site 9) and at 6, 10, 38, 42, 46, and 50 min (site 6) after ketamine injection. A similar trend was observed for AS latency, which was significantly reduced for contralateral ASs and significantly increased for ipsilateral ASs (Fig. 5b).

Figure 5

Effect of prior muscimol injection on ketamine-induced increased error rate. The gray area corresponds to the preketamine block, the vertical arrow to ketamine injection. Contra, contralateral target; ipsi, ipsilateral target. K, ketamine; M, muscimol. (a) AS error rate (ketamine 0.8 mg/kg; muscimol site 9, left hemisphere). Compared with K-only experiments, prior muscimol injection resulted in a lower error rate for contralateral targets (large asterisks) and a higher error rate for ipsilateral targets (small asterisks). (b) AS latency (ketamine 0.6 mg/kg; muscimol site 6, right hemisphere). Decreased AS latency was observed for contralateral targets (large asterisks) and increased AS latency for ipsilateral targets (small asterisks). No ipsilateral data were available at 10 min postinjection of ketamine because of a 100% error rate. The comparisons between M + K and K-only experiments were done using a t-test for latencies and a χ2-test for error rates. *P < 0.05, **P < 0.01, ***P < 0.001.

Figure 5

Effect of prior muscimol injection on ketamine-induced increased error rate. The gray area corresponds to the preketamine block, the vertical arrow to ketamine injection. Contra, contralateral target; ipsi, ipsilateral target. K, ketamine; M, muscimol. (a) AS error rate (ketamine 0.8 mg/kg; muscimol site 9, left hemisphere). Compared with K-only experiments, prior muscimol injection resulted in a lower error rate for contralateral targets (large asterisks) and a higher error rate for ipsilateral targets (small asterisks). (b) AS latency (ketamine 0.6 mg/kg; muscimol site 6, right hemisphere). Decreased AS latency was observed for contralateral targets (large asterisks) and increased AS latency for ipsilateral targets (small asterisks). No ipsilateral data were available at 10 min postinjection of ketamine because of a 100% error rate. The comparisons between M + K and K-only experiments were done using a t-test for latencies and a χ2-test for error rates. *P < 0.05, **P < 0.01, ***P < 0.001.

Effect of Muscimol Injection on the RS Task

RS accuracy and latency were analyzed at each effective site. Compared with saline experiments, muscimol did not induce any significant changes in saccade gain at any of these sites. However, a significant although inconsistent effect on RS latency was found at 8/18 sites (Table 3). Significant differences in RS latencies were most often observed in isolated blocks of trials, with no clear tendency toward either increased or decreased saccade latency. As illustrated in Figure 4, the systematic bias found in AS latency (i.e., increased contralateral AS latency, decreased ipsilateral AS latency) was not observed for RSs. For example, 105 min postinjection (Table 3), contralateral RS latency was decreased at 2 sites (monkey V, sites 6 and 10) but increased at 2 sites (monkey I, sites 11 and 17).

Table 3

RS latency (ms, mean ± standard deviation) in saline and muscimol experiments, before and 105 min after muscimol or saline injection, at all effective sites

 Preinjection +105 min 
 Ipsi RS Contra RS Ipsi RS Contra RS 
Monkey V     
Saline (n = 6) 163 ± 48 143 ± 37 136 ± 39 163 ± 49 
Muscimol site     
    1 157 ± 58 134 ± 21 144 ± 38 199 ± 91 
    2 143 ± 38 153 ± 50 159 ± 27 142 ± 37 
    3 178 ± 47 181 ± 38 140 ± 26 148 ± 39 
    4 161 ± 31 192 ± 43 162 ± 52 140 ± 32 
    5 154 ± 27 235 ± 53 134 ± 42 169 ± 46 
    6 171 ± 42 174 ± 65 160 ± 38 120 ± 24§§ 
    7 211 ± 89 186 ± 57 131 ± 27 149 ± 19 
    8 161 ± 48 153 ± 34 162 ± 54 139 ± 22 
    9 178 ± 34 164 ± 33 143 ± 31 155 ± 41 
    10 170 ± 54 162 ± 34 146 ± 40 125 ± 34§§ 
    12 160 ± 50 136 ± 20 175 ± 45 144 ± 35 
    13 173 ± 42 179 ± 31 157 ± 27 138 ± 27 
    15 168 ± 41 177 ± 51 181 ± 36** 166 ± 61 
Monkey I     
Saline (n = 3) 146 ± 26 158 ± 50 175 ± 46 146 ± 32 
Muscimol site     
    11 136 ± 35 160 ± 54 158 ± 29 231 ± 53*** 
    14 146 ± 34 132 ± 38 188 ± 35 158 ± 20 
    16 178 ± 35 150 ± 15 176 ± 30 167 ± 40 
    17 125 ± 23 165 ± 20 141 ± 25§ 212 ± 44*** 
    18 147 ± 34 155 ± 17 172 ± 34 169 ± 29 
 Preinjection +105 min 
 Ipsi RS Contra RS Ipsi RS Contra RS 
Monkey V     
Saline (n = 6) 163 ± 48 143 ± 37 136 ± 39 163 ± 49 
Muscimol site     
    1 157 ± 58 134 ± 21 144 ± 38 199 ± 91 
    2 143 ± 38 153 ± 50 159 ± 27 142 ± 37 
    3 178 ± 47 181 ± 38 140 ± 26 148 ± 39 
    4 161 ± 31 192 ± 43 162 ± 52 140 ± 32 
    5 154 ± 27 235 ± 53 134 ± 42 169 ± 46 
    6 171 ± 42 174 ± 65 160 ± 38 120 ± 24§§ 
    7 211 ± 89 186 ± 57 131 ± 27 149 ± 19 
    8 161 ± 48 153 ± 34 162 ± 54 139 ± 22 
    9 178 ± 34 164 ± 33 143 ± 31 155 ± 41 
    10 170 ± 54 162 ± 34 146 ± 40 125 ± 34§§ 
    12 160 ± 50 136 ± 20 175 ± 45 144 ± 35 
    13 173 ± 42 179 ± 31 157 ± 27 138 ± 27 
    15 168 ± 41 177 ± 51 181 ± 36** 166 ± 61 
Monkey I     
Saline (n = 3) 146 ± 26 158 ± 50 175 ± 46 146 ± 32 
Muscimol site     
    11 136 ± 35 160 ± 54 158 ± 29 231 ± 53*** 
    14 146 ± 34 132 ± 38 188 ± 35 158 ± 20 
    16 178 ± 35 150 ± 15 176 ± 30 167 ± 40 
    17 125 ± 23 165 ± 20 141 ± 25§ 212 ± 44*** 
    18 147 ± 34 155 ± 17 172 ± 34 169 ± 29 

Note: In postinjection trials, a t-test was used for comparisons between muscimol and saline experiments. Ipsi, ipsilateral; contra, contralateral. Asterisks denote increased latency; **P < 0.01, ***P < 0.001. Sections denote decreased latency; §P < 0.05, §§P < 0.01.

Discussion

In the present study, we show that injection of muscimol into a circumscribed region of the monkey principal sulcus impaired RS inhibition without affecting RS triggering. An involvement of the FEF in the observed deficits, either directly or secondary to a spread of muscimol from the injected sites, could be ruled out for the following reasons. The most posterior effective sites were rostral to the FEF because no saccades could be elicited by electrical stimulation. A muscimol spread to the FEF would have resulted in increased contralateral RS latency (Dias and others 1995; Sommer and Tehovnik 1997), especially at the most posterior sites with increasing intensity in the latest blocks of trials. Such impairments were observed at 6 sites (monkey I, n = 3; monkey V, n = 3) located in the anterior bank of the arcuate sulcus, but not at the most posterior effective sites. At site 1, for example, in which muscimol was injected in the left hemisphere, rightward RS latency was not significantly different from saline injection at 150 min postinjection (t-test, t = 1.64, degree of freedom = 25, P = 0.113). At site 18, in which muscimol was injected in the right hemisphere, leftward RS latency remained normal up to and including the last block of trials, 150 min postinjection (t-test, t = 1.80, ddl = 21, P = 0.08). Moreover, higher error rates were observed at sites located at a more distant location from the FEF (e.g., sites 7, 11, 14) than at posterior sites (e.g., sites 1, 2) (Fig. 1c and Table 1).

It may therefore be assumed that the observed impairments resulted from principal sulcus inactivation. The contiguity of effective sites suggests a well-delineated area, located in the caudal third of the principal sulcus, mainly in its ventral bank. It overlaps with the caudal part of area 46v/9, which includes the depth of the dorsal bank, the fundus, and most of the ventral bank of the principal sulcus (Barbas and Pandya 1989; Petrides and Pandya 1999). Although the anatomy of the DLPFC suggests a partitioning of the principal sulcus into distinct subregions (Cavada and Goldman-Rakic 1989; Goldman-Rakic 1995), very few studies have been able to link a precise subregion of the principal sulcus to a specific behavior. Suzuki and Azuma (1977) have described in the ventral bank of the principal sulcus a population of fixation neurons, called “G-neurons,” that showed an increased activity when animals gazed at a small behaviorally relevant spot of light. Interestingly, anatomical connections of area 46v/9 are consistent with a role in high-order visuomotor tasks. It is more strongly connected with visual association areas than any other areas in the principal sulcus (Barbas and Mesulam 1985) and receives strong inputs from the lateral intraparietal area (LIP), a major oculomotor area (Cavada and Goldman-Rakic 1989). It is directly connected to the superior colliculus, a structure that links cerebral oculomotor areas with brainstem premotor structures (Wurtz and Optican 1994). Preliminary anatomical data from tracing experiments performed at effective sites suggest that the presently identified subregion is connected with LIP and the superior colliculus.

Normal RS gain and the absence of any clearly increased RS latency after injection suggest that sensory afferents and excitatory oculomotor commands were unaffected. Injection of muscimol in the region of the principal sulcus may have induced a short-term memory deficit (Sawaguchi and Iba 2001). However, because our monkeys were highly trained on the AS task and had been performing it for several months, the stimulus-response rule was probably no longer encoded in working memory but rather in a more long-term memory system (Goldman-Rakic 1995). This is supported by the triggering of correct ASs, even at the peak of the effect, and the consistently negligible error rate in the RS task. Therefore, the increased AS error rate observed at effective sites could reasonably be ascribed to impaired inhibition of ipsilateral RSs, which may also have been responsible for the relatively decreased ipsilateral AS latency.

The principal sulcus is directly connected to the superior colliculus, a major oculomotor structure involved in the generation of both replace by RS and AS (Everling and Munoz 2000). It contains fixation neurons in its rostral pole and saccade-related neurons in its caudal pole. The latter consist of burst neurons, which discharge immediately before saccade triggering, and buildup neurons whose activity reflects an attentional shift, not necessarily followed by an eye movement (Kustov and Robinson 1996; Ignashchenkova and others 2004). Neurons from both rostral and caudal poles inhibit each other. In a RS gap task, fixation neurons cease firing at fixation point offset whereas buildup neurons progressively increase their activity. At stimulus onset, the activity of buildup neurons further increases and burst neurons phasically discharge, resulting in saccade triggering. The probability of a RS being generated with a shorter latency increases with increasing buildup neurons' activity, becoming closer to a given threshold (Dorris and Munoz 1998). Thus, successful RS suppression requires decreased prestimulus activity in buildup neurons. Electrophysiological recordings in primates have shown that such inhibition is provided by fixation neurons and extracollicular structures (AS task: Everling and others 1999; countermanding task: Pare and Hanes 2003). Accordingly, increased AS error rate could result from decreased activity in fixation neurons or increased activity in saccade-related neurons. Recent electrophysiological studies have shown that the rostral superior colliculus exerts a bilateral inhibitory influence on saccade triggering, with stronger suppressive effects on ipsilateral saccade (Sugiuchi and others 2005). It could therefore be proposed that the presently identified DLPFC subregion would contain the so-called G-neurons and project toward the rostral superior colliculus. However, such hypothesis does not account for the unexpected decreased error rate observed for contralateral targets, confirmed by the combination of systemic ketamine administration and muscimol injection. Consequently, improved performances for contralateral targets could be the primary effect of muscimol injection, resulting from increased inhibition of the ipsilateral caudal superior colliculus. According to this hypothesis, muscimol would increase the activity of prefrontal efferent neurons, that is, exert a paradoxical effect (Grace and Bunney 1979; Waszczak and others 1980). We recently hypothesized (Gaymard and others 2003) that DLPFC inhibitory effects would be exerted on the superior colliculus via activation of collicular inhibitory interneurons (Munoz and Istvan 1998). Thus, increased prefrontal output would strengthen the inhibition of ipsilateral collicular saccade-related neurons and thus facilitate contralateral saccade suppression. Decreased performances for ipsilateral targets would therefore be secondary to an interhemispheric imbalance. It could be mediated via GABAergic callosal neurons that connect each subregion of the principal sulcus with its contralateral counterpart (Andersen and others 1985; Rao and others 2000). It could also take place at a lower level because reciprocal inhibition has been demonstrated between saccade-related neurons of both superior colliculi (Munoz and Istvan 1998; Takahashi and others 2005). Minimal effect observed on RS suggests that muscimol interacts mainly with a phasic inhibitory mechanism that is transiently required, for example, during the AS task.

Improved performances for contralateral targets in the muscimol–ketamine experiments further confirmed that GABAergic agents are able to reverse or prevent ketamine-induced effects (Farber and others 2003). Ketamine induces a blockade of NMDA receptors located on GABAergic neurons. Thus, the increased error rate observed after systemic ketamine administration probably resulted from decreased GABAergic inhibition in the DLPFC. This result strengthens the view of subanesthetic ketamine as a pharmacological model of schizophrenia because, in this disease, both prefrontal GABAergic interneuron impairments (Lewis and others 2004) and an increased AS error rate have been reported (Gooding and others 2004).

Comparison with previous studies is restricted because our study is the first to report impaired ASs in primates. Furthermore, previous muscimol inactivations performed in this area did not involve the banks of the principal sulcus (Sawaguchi and Iba 2001). Nevertheless, neuronal activity related to oculomotor inhibition has occasionally been reported in the principal sulcus, during a suppressed saccade task (Boch and Goldberg 1989) and a delayed AS task (Funahashi and others 1993). The location of the area delineated in the present study is also consistent with recent results obtained in humans. Brain activation during the AS task has been observed slightly anterior to the FEF (Connolly and others 2000). In a recent study (Ploner and others 2005), we tested patients with an acute focal lesion involving the prefrontal cortex and found a significantly increased AS error rate in patients with a lesion involving a prefrontal region, located slightly more ventrally than initially assumed (Pierrot-Deseilligny and others 1991). In monkeys, neurons in the dorsal bank of the principal sulcus are mainly activated by spatial stimuli, whereas ventral bank neurons are more responsive to stimuli related to object identification or processing (Wilson and others 1993). In our task, the spatial characteristic of the response was determined by the color of a central cue. The region we have identified, located between dorsal and ventral dorsolateral frontal areas, may therefore be well suited for the control of spatially oriented behavior in response to nonspatial cues.

In conclusion, we consider our results as unambiguous evidence for the involvement of the principal sulcus in RS inhibition. This physiologically identified area is in accordance with the hypothesis of a partitioning of the principal sulcus into well-defined functional subregions. The demonstration of a specific connectivity would provide further evidence that it is indeed a distinct region. A large series of clinical studies has shown that impaired inhibition in the AS task is a good behavioral index of increased distractibility (Hutton and others 2002; Munoz and Everling 2004), as it is encountered in various neurological and psychiatric disorders (Everling and Fischer 1998). The effect of chemical agents acting upon specific neurotransmitters in this area should improve our understanding of the pharmacological basis of distractibility and hopefully provide insights for new therapeutic strategies.

The authors are grateful to C. François, J. Féger, D. Tandé, and J. Yelnik for their help during surgical procedures and to D.P. Munoz and S. Boehnke for helpful comments on an earlier version of the manuscript. This work was supported by Institut de Recherche Servier. Conflict of Interest: None declared.

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