Effects of unilateral deactivations of dorsolateral prefrontal cortex and anterior cingulate cortex on saccadic eye movements.

J Neurophysiol 111: 787– 803, 2014. First published November 27, 2013; doi:10.1152/jn.00626.2013.

Effects of unilateral deactivations of dorsolateral prefrontal cortex and anterior cingulate cortex on saccadic eye movements Michael J. Koval,1 R. Matthew Hutchison,2 Stephen G. Lomber,1,2,3 and Stefan Everling1,2,3 1 Graduate Program in Neuroscience, University of Western Ontario, London, Ontario, Canada; 2Robarts Research Institute, University of Western Ontario, London, Ontario, Canada; and 3Department of Physiology and Pharmacology, University of Western Ontario, London, Ontario, Canada

Submitted 3 September 2013; accepted in final form 20 November 2013

Koval MJ, Hutchison RM, Lomber SG, Everling S. Effects of unilateral deactivations of dorsolateral prefrontal cortex and anterior cingulate cortex on saccadic eye movements. J Neurophysiol 111: 787–803, 2014. First published November 27, 2013; doi:10.1152/jn.00626.2013.—The dorsolateral prefrontal cortex (dlPFC) and anterior cingulate cortex (ACC) have both been implicated in the cognitive control of saccadic eye movements by single neuron recording studies in nonhuman primates and functional imaging studies in humans, but their relative roles remain unclear. Here, we reversibly deactivated either dlPFC or ACC subregions in macaque monkeys while the animals performed randomly interleaved pro- and antisaccades. In addition, we explored the wholebrain functional connectivity of these two regions by applying a seed-based resting-state functional MRI analysis in a separate cohort of monkeys. We found that unilateral dlPFC deactivation had stronger behavioral effects on saccades than unilateral ACC deactivation, and that the dlPFC displayed stronger functional connectivity with frontoparietal areas than the ACC. We suggest that the dlPFC plays a more prominent role in the preparation of pro- and antisaccades than the ACC. saccades; monkeys; cortical cooling; functional connectivity

40 yr has demonstrated that a number of cortical areas participate in the generation of saccadic eye movements in primates. Of particular importance are the frontal eye field (FEF; Bruce et al. 1985), supplementary eye field (SEF; Schlag and Schlag-Rey 1987), and lateral intraparietal area (LIP; Shibutani et al. 1984), from which saccades can be directly evoked by electrical microstimulation. Two additional regions that are frequently activated in human functional neuroimaging studies lie in the dorsolateral prefrontal cortex (dlPFC), and the presupplementary motor area/anterior cingulate cortex (ACC). In monkeys, these areas correspond to the dlPFC in and around the principal sulcus (areas 46 and 9/46; Petrides and Pandya 1999), and the ACC in the rostral cingulate sulcus (area 24c; Picard and Strick 1996). Activations in the dlPFC and ACC are typically not seen in neuroimaging experiments when simple visually-guided saccades are compared with fixation (Luna et al. 1998; Sweeney et al. 1996), but instead when a more complex saccade task is compared with a simple saccade task (Brown et al. 2004; DeSouza et al. 2003; McDowell et al. 2008; Sweeney et al. 1996). A well-studied example is the comparison of the performance of antisaccades, which requires subjects to look away from a suddenly appearing stimulus (Hallett 1978; Munoz and Everling 2004), with the perfor-

RESEARCH OVER THE PAST

Address for reprint requests and other correspondence: M. J. Koval, Biomedical Engineering Dept., Duke Univ., 136 Hudson Hall, Box 90281, Durham, NC 27708-0281 (e-mail: [email protected]). www.jn.org

mance of prosaccades, which requires subjects simply to look toward the stimulus. Event-related functional magnetic resonance imaging (fMRI) studies using long instruction periods (DeSouza et al. 2003; Ford et al. 2005) or rapid designs with catch trials (Brown et al. 2007) have shown that the dlPFC and ACC are more active for anti- than prosaccades during the instruction, but not the response period. This suggests that both areas are involved in saccade preparation, but not the generation of the motor command, consistent with the finding that both areas contain neurons with task-selectivity for pro- or antisaccades during the preparatory period (Johnston et al. 2007). A more modulatory function of these areas also fits with the finding that electrical microstimulation of the dlPFC and ACC at physiologically-relevant current levels fails to elicit saccades (Boch and Goldberg 1989; Phillips et al. 2011; Wegener et al. 2008). The dlPFC and ACC are highly interconnected (Barbas and Pandya 1989; Bates and Goldman-Rakic 1993; Morecraft and Van Hoesen 1993; Paus et al. 2001), and both areas have anatomical connections with the FEF, SEF, LIP, and basal ganglia (Bates and Goldman-Rakic 1993; Cavada and Goldman-Rakic 1989; Huerta and Kaas 1990; Selemon and Goldman-Rakic 1988, 1985; Wang et al. 2004). The dlPFC has direct projections to the intermediate layers of the superior colliculus (SC), a midbrain structure directly implicated in saccade control (Goldman and Nauta 1976; Johnston and Everling 2006, 2009; Leichnetz et al. 1981), whereas the projections of the ACC appear to target mainly the periaqueductal gray, an area involved in pain and defensive behavior (Leichnetz et al. 1981). This suggests that the dlPFC may have stronger connections with areas involved in the control of saccades than the ACC. To test this hypothesis, we investigated the functional connectivity (FC) of these two regions by applying a seed-based analysis to an existing resting-state fMRI dataset. Our laboratory has previously found strong lateralized effects of unilateral dlPFC deactivation on the activity of SC saccade-related neurons: unilateral dlPFC cooling decreased activity in the SC ipsilateral to deactivation, and increased activity in the SC contralateral to deactivation (Johnston et al. 2013). These changes in SC saccade neuron activity were associated with a strong saccade bias toward the side of deactivation. Here we tested whether unilateral ACC deactivation has similar effects on the performance of pro- and antisaccades. To directly compare the effects of unilateral dlPFC and ACC deactivation in macaque monkeys, we implanted cryoloops (Lomber et al. 1999) in the posterior portion of the

0022-3077/14 Copyright © 2014 the American Physiological Society

787

Downloaded from www.physiology.org/journal/jn by ${individualUser.givenNames} ${individualUser.surname} (146.185.200.230) on January 12, 2019.

788

SACCADIC EFFECTS OF COOLING dlPFC AND ACC

principal sulcus to deactivate the dlPFC (parts of areas 9/46 and 46), and at the same anterior/posterior level in the cingulate sulcus to deactivate the ACC (parts of area 24c).

use of laboratory animals and were approved by the Animal Use Subcommittee of the University of Western Ontario Council on Animal Care.

MATERIAL AND METHODS

Surgical Procedures

All surgical and experimental procedures were carried out in accordance with the Canadian Council of Animal Care policy on the

Two male macaque monkeys (Macaca mulatta, 11–16 kg) were prepared for chronic deactivation studies by using a surgical protocol that has been previously described (DeSouza and Everling 2004). In the first surgery, a head restraint post was anchored to a dental acrylic implant, which allowed the animal to be trained on the behavioral task (described below). MRI provided an image of the neural anatomy in situ, from which the individual cryoloops were custom-designed to fit into the posterior principal sulcus or the anterior cingulate sulcus. The methods for cryoloop design, insertion, and implementation have previously been described (Lomber et al. 1999). In the second surgery, cryoloops were implanted in the posterior end of the principal sulcus to deactivate parts of areas 46 and 9/46 of the dlPFC, and thus the likely macaque homolog of the human middle frontal gyrus (Petrides and Pandya 1999). In addition, at the most caudal extent of the principal sulcus is what Petrides and Pandya (1999) have identified as the anterior part of area 8A. The effects of dlPFC cooling likely encroached on this area, although to a much lesser extent than the effects on areas 46 and 9/46. Cryoloops were also implanted in the anterior cingulate sulcus to deactivate parts of area 24c of the dorsal ACC. These cryoloop locations, and the cortical areas that were targeted for deactivation, are highlighted in Figs. 1A and 2, respectively. The cryoloop in the anterior cingulate sulcus was placed at the same position on the anterior-posterior axis as the cryoloop in the posterior end of the principal sulcus. This area of the dorsal ACC was the same at which our laboratory had previously found neurons that were rule-selective with an anti-/prosaccade task (Johnston et al. 2007). Animals received analgesics and antibiotics postoperatively and were closely monitored by a veterinarian for behavioral deficits. Cryoloop Method of Reversible Cryogenic Deactivation Cryoloops were constructed from 23-gauge hypodermic stainless steel tubing and designed to deactivate both the upper and lower banks of the sulcus in which they were implanted (Fig. 1A). Cryoloops implanted in the posterior principal sulcus and anterior cingulate sulcus were both 4 ⫻ 6 mm in dimension, with an estimated range of 1.5–2.0 mm and thus deactivated an estimated 72–96 mm3 of cortical tissue, which we assume was similar for both dlPFC and ACC cooling. Chilled methanol pumped through a cryoloop deactivates adjacent cortical tissue by disrupting synaptic activity therein (Lomber et al. 1999). Methanol pumped through Teflon tubing was

Fig. 1. Reversible cryogenic deactivation and the behavioral task. A: a cryoloop was implanted in the anterior cingulate sulcus to deactivate the anterior cingulate cortex (ACC), and the posterior principal sulcus to deactivate the dorsolateral prefrontal cortex (dlPFC). Room-temperature methanol (solid line) was pumped through Teflon tubing that passed through a methanol ice bath which was reduced to subzero temperatures by the addition of dry ice. Chilled methanol (dotted line) was pumped through the cryoloop, then back to the reservoir from whence it came. Cryoloop temperature was monitored with an attached thermocouple and maintained in the range of 1–3°C by adjusting the flow rate of the peristaltic pump. The vertical dashed line on the lateral and medial views indicates where the coronal section was taken from. B: in the overlap condition, the central fixation point (FP) remained visible for the duration of the trial, whereas, in the gap condition, the central FP was removed 200 ms prior to stimulus appearance. The task instruction was provided by the color of the central FP: either green for an antisaccade away from the stimulus, or red for a prosaccade toward the peripheral stimulus. Stimulus appearance was the signal to perform the instructed saccade. The arrow which indicates the correct saccade direction is shown only for the purposes of this figure and thus was not included as part of the task display. J Neurophysiol • doi:10.1152/jn.00626.2013 • www.jn.org Downloaded from www.physiology.org/journal/jn by ${individualUser.givenNames} ${individualUser.surname} (146.185.200.230) on January 12, 2019.


789

sessions (Johnston et al. 2013). Stimulus appearance was the signal for the monkey to perform the instructed saccade, and a correct response was followed immediately by a water reward. Behavioral Analysis

Fig. 2. Location of ACC (left) and dlPFC (right) regions of interest (ROIs) displayed on the coronal, sagittal, and horizontal views of the F99 template brain.

chilled when passed through a methanol ice bath that was reduced to subzero temperatures by the addition of dry ice. Each cooling session consisted of precool, cooling, and postcool periods that were between 10 and 15 min in duration. We chose this length of time to avoid frustrating an animal that was impaired on the task in the cooling period, while still allowing the animal enough time with which to perform a sufficient number of trials for analysis. A cooling session started with a precool period, after which the pump was turned on. Cryoloop temperature was monitored with an attached thermocouple and maintained in the desired range of 1–3°C by adjusting flow rate of the peristaltic pump. At the end of the cooling period, the pump was turned off, and cryoloop temperature rapidly returned to normal. This allowed us to observe normal behavior both before and almost immediately following deactivation. A postcool period could also serve as a control period for comparison to the cooling period that followed, and this cycle was continued for as long as the animal was willing to work. Behavioral Task Two monkeys were trained to perform a randomly-interleaved pro-/antisaccade task in which they were required to look either toward (prosaccade) or away from (antisaccade) a peripheral visual stimulus (Fig. 1B). Eye movements were monitored at 500 Hz with high-speed infrared video eye tracking (Eyelink, SR Research, Kanata, ON, Canada). The task instruction was provided on each trial by the color of a central fixation point, either red or green, against the black background of the monitor screen. The animal was required to maintain fixation on the central fixation point. In the overlap condition, the central fixation point remained visible for the duration of the trial, whereas in the gap condition, the central fixation point was removed 200 ms prior to stimulus appearance (Fig. 1B). The presence of a gap period facilitates rapid orienting of gaze toward a stimulus and thus manipulates the inhibitory demands of the task. It has previously been shown that saccadic reaction times (SRTs) are reduced, and the incidence of express saccades increased, on gap compared with overlap prosaccade trials (Bell et al. 2000; Fischer and Boch 1983; Fischer and Ramsperger 1984). The gap condition has also been shown to decrease SRTs, and increase direction errors, on antisaccade trials (Bell et al. 2000; Fischer and Weber 1992, 1997). This has been interpreted as reflecting an increase of “inhibitory load” for antisaccades in the gap condition (Curtis et al. 2001). When only the animal’s behavior was being recorded, the peripheral stimulus was presented at 8° to either the left or right of fixation. When the activity of a SC saccade neuron was also recorded, the stimulus appeared within a range of 4 –12° on the horizontal axis. This was because, in the cell recording sessions, the stimulus was presented either in the neuron’s response field, or at the mirror location in the opposite visual field. Our laboratory has previously published the neuronal effects of unilateral dlPFC deactivation from these single-neuron recording

Data analysis was performed using custom-designed software programmed in Matlab (Mathworks, Natick, MA). Saccade onset was identified as the time at which saccade velocity exceeded 30°/s following stimulus onset, while saccade end was identified as the time at which saccade velocity then fell back below 30°/s (Everling and DeSouza 2005). Each trial was visually inspected and excluded from analysis if the animal blinked at around the time of stimulus or saccade onset, and if saccade latencies were either below 80 ms (anticipations) or above 500 ms (no response). Also excluded from analysis were 1) trials within the first 3 min of the cooling and postcool periods, to allow cortical tissue sufficient time to reach the desired state of deactivation or reactivation (Horel 1991), and 2) sessions with fewer than five trials (correct and error combined) per condition in any of the precool, cooling, or postcool periods, for either the overlap or gap conditions. Task performance was identified as the percentage of correct trials per session, which was calculated as the number of correct trials divided by the number of correct and error trials combined. Skipped and broken fixation trials were calculated as percentages of the total number of correct, error, broken fixation, skipped, and no response trials combined. Skipped trials occurred when the animal did not initiate fixation within 2,000 ms of central fixation point appearance. Broken fixation trials were those in which the animal initiated fixation, but then looked away from the central fixation point prior to onset of the peripheral stimulus and thus the response period of the trial. No response trials occurred when the animal initiated and maintained fixation for the duration of the fixation period, but did not respond within 500 ms of peripheral stimulus appearance. The incidence of no response trials was found to be negligible both in this analysis and those reported previously (Johnston et al. 2013; Koval et al. 2011), and thus was not included here. Session means were calculated for the SRT, saccade velocity, duration, and gain of correct responses, and the SRT of errors. Figure 3 provides a schematic representation of

Fig. 3. Schematic representation of the FP, stimulus (S), and eye position (EP) trace. Saccadic reaction time (SRT) is the difference between stimulus onset (first vertical dashed line) and saccade onset (second vertical dashed line) for either a prosaccade (descending solid line; Pro-SRT) or an antisaccade (ascending dotted line; Anti-SRT). Saccade duration (SD) is the difference between the onset and end of a saccade (second and third vertical dashed lines). Eye velocity (EV) increases, peaks, and returns to zero within the duration of the saccade. Saccade gain (SG) is the difference between the endpoint and target of a saccade (horizontal dotted lines).

J Neurophysiol • doi:10.1152/jn.00626.2013 • www.jn.org Downloaded from www.physiology.org/journal/jn by ${individualUser.givenNames} ${individualUser.surname} (146.185.200.230) on January 12, 2019.

790


these measures. SRT was identified as the time between stimulus onset and saccade onset. Peak saccade velocity was identified as the maximal velocity between saccade onset and end. Saccade duration was identified as the time between saccade onset and saccade end. Saccade gain was identified as the accuracy of the endpoint of the primary saccade relative to the saccade target location, which on prosaccade trials was the peripheral stimulus, and on antisaccade trials was the mirror position in the opposite visual field. Saccade gain was calculated as the eye position on the horizontal axis at the end of the saccade, divided by the target location. All calculations were performed for 16 conditions. These consisted of dlPFC or ACC deactivation in the overlap and gap conditions, for prosaccades and antisaccades directed ipsiversive or contraversive to the side of deactivation. For each session, trials from the precool and postcool periods were combined into a single noncool period, for comparison with the trials from the cooling period. A mean value was calculated for each session, and then the populations of session means were compared between the noncool and cooling periods. Significance was assessed with a Wilcoxon signed rank test (P ⬍ 0.01). All analyses were performed for each monkey individually and both monkeys combined. To further evaluate the effects of dlPFC and ACC deactivation across sessions, the data were normalized by computing a cooling effect index (CEI). This analysis was performed for task performance, SRT, saccade velocity, and saccade duration in each of the 16 conditions. The CEI is analogous to a microstimulation effect index that has previously been described (Phillips et al. 2011). Here, the CEI was defined as the contrast ratio between trials in the noncool and cooling periods of each session, for both monkeys combined. For example, the CEI for SRT within one of the 16 conditions (cnd) was calculated as: CEI SRTcnd ⫽ 共cool SRTcnd ⫺ non SRTcnd兲 ⁄ 共cool SRTcnd ⫹ non SRTcnd兲 CEIs for task performance, saccade velocity, and saccade duration were calculated in a similar manner. This index provides values in the range of ⫺1 to ⫹1. Positive values indicate an increase with cooling compared with the noncool periods, while negative values indicate a decrease. A mean CEI (⫾SE) was calculated across all sessions and assessed with a Wilcoxon signed rank test for zero median (P ⬍ 0.01). FC of dlPFC and ACC Determined by Resting-state fMRI Subjects and data acquisition. Data were collected from 11 naive, isoflurane-anesthetized (1%) macaque monkeys (4 Macaca mulatta and 7 Macaca fascicularis) that were not used as part of the cooling experiments. These data have been published previously as two different datasets: set 1 (N ⫽ 6, repetition time ⫽ 2 s, echo-planar image resolution ⫽ 1.3 ⫻ 1.3 ⫻ 1.5 mm, 2 scans of 300 volumes) (Hutchison et al. 2011, 2012a, 2012b, 2013; Shen et al. 2012) and set 2 (N ⫽ 5, repetition time ⫽ 2 s, echo-planar image resolution ⫽ 1 mm3, 10 scans of 150 volumes) (Babapoor-Farrokhran et al. 2013). Animal preparation, imaging parameters, and preprocessing are described therein. One monkey from set 1 was scanned again with the increased spatial resolution and scan numbers of set 2, and the original scanning session from set 1 removed from the analysis. Statistical analysis. Four manually drawn regions of interest (ROIs) were selected using anatomical landmarks (Fig. 2). These were chosen to coincide with the locations of the implanted cryoloops in the other monkey group (Fig. 1A). Statistical analysis was carried out in the same manner as has been used in some of our laboratory’s previous reports and shown to reveal robust FC networks (Hutchison et al. 2012a, 2012b). Briefly, the mean time course for each ROI was extracted for every scan of each animal, and the extracted time courses were then used as predictors in a model for multiple regression at the individual scan level in which nuisance covariates for white matter,

cerebrospinal fluid, and six motion parameters were included. This was followed by a second level fixed-effects analysis to calculate the significantly connected voxels shared between the scans acquired for each monkey. The group-level analysis was conducted by implementing a third-level fixed-effects analysis. Corrections for multiple comparisons were implemented at the cluster level with Gaussian random field theory (z ⬎ 2.3; cluster significance: P ⬍ 0.05, corrected). The group-level analysis produced thresholded z-statistic maps showing brain regions significantly correlated with each seed region across all subjects. The group z-scores were projected from volume data to the F99 cortical surface with the CARET (http://www.nitrc.org/projects/ caret) enclosed-voxel method (Van Essen et al. 2001). RESULTS

Deactivation of dlPFC or ACC We performed 55 dlPFC deactivation sessions (22 with monkey A, 33 with monkey C), and 31 ACC deactivation sessions (20 with monkey A, 11 with monkey C). The results for both monkeys combined are provided for dlPFC deactivation (Table 1) and ACC deactivation (Table 2). To demonstrate that the deactivation effects were similar for both animals, results are also provided for monkey A with deactivation of the dlPFC (Table 3) or ACC (Table 4), and monkey C with deactivation of the dlPFC (Table 5) or ACC (Table 6). Examples from individual sessions of dlPFC deactivation effects on SRTs in the gap condition are shown in Figure 4. Also shown is the distribution of dlPFC deactivation effects on SRTs (Fig. 5), task performance (Fig. 6), saccade velocity (Fig. 7) and duration (Fig. 8) in the gap condition. Finally, all effects of dlPFC and ACC deactivation in the overlap and gap conditions are summarized in Fig. 9. dlPFC Deactivation Altered Ipsiversive and Contraversive SRTs SRT analysis revealed that dlPFC deactivation increased contraversive SRTs, decreased ipsiversive prosaccade SRTs, and increased ipsiversive antisaccade SRTs (Fig. 9A). There were no effects of ACC deactivation on SRT. With dlPFC deactivation there was an increase of contraversive SRT for prosaccades (CEI ⫽ 0.077 ⫾ 0.008, P ⬍ 0.001) and antisaccades (CEI ⫽ 0.043 ⫾ 0.008, P ⬍ 0.001) in the gap condition (Fig. 5). Examples of these effects within individual sessions are shown in Fig. 4. There was also an increase of contraversive SRT for prosaccades (CEI ⫽ 0.071 ⫾ 0.007, P ⬍ 0.001) and antisaccades (CEI ⫽ 0.034 ⫾ 0.009, P ⬍ 0.001) in the overlap condition. Also in the overlap condition, there was both a decrease of ipsiversive prosaccade SRT (CEI ⫽ ⫺0.019 ⫾ 0.005, P ⬍ 0.001) and an increase of ipsiversive antisaccade SRT (CEI ⫽ 0.021 ⫾ 0.007, P ⬍ 0.01), while in the gap condition there was only a decrease of ipsiversive prosaccade SRT (CEI ⫽ ⫺0.044 ⫾ 0.006, P ⬍ 0.001; Fig. 5). dlPFC Deactivation Increased the Incidence of Ipsiversive Saccades Analysis of task performance revealed that dlPFC deactivation increased the incidence of ipsiversive saccades. This was demonstrated by an increased rate of both correct ipsiversive prosaccades, and ipsiversive errors on contraversive saccade trials (Fig. 9B). More specifically, task performance was reduced on contraversive antisaccade trials in the overlap con-



791

Table 1. Effects of dlPFC deactivation on both monkeys combined Prosaccades

Antisaccades

Contraversive

Ipsiversive

dlPFC⫹

dlPFC⫺

dlPFC⫹

246.9 96.0 290.2 41.4 1.02 5.4 24.4

284.9† 94.7 281.0† 42.6* 1.01 4.3 24.9

231.5 96.3 302.2 40.5 1.05 5.1 23.1

Contraversive

dlPFC⫺

Ipsiversive

dlPFC⫹

dlPFC⫺

dlPFC⫹

dlPFC⫺

253.1 92.5 248.1 50.9 1.17 5.0 34.2

268.5† 84.0† 215.6† 58.3† 1.20 5.6 34.6

256.3 94.4 265.7 50.8 1.25 5.2 34.2

266.7* 96.3 274.6* 51.0 1.31† 5.2 30.9

222.5 73.7 250.6 49.6 1.10 5.0 37.2

242.9† 62.0† 222.7† 56.2† 1.11 4.7 42.1*

221.6 79.0 271.9 49.8 1.25 4.7 38.3

219.3 84.1* 277.6 50.5 1.32† 4.1 40.0

Overlap (n ⫽ 55) SRT, ms Correct, % Velocity, °/s Duration, ms Accuracy (gain) Skipped trials, % Broken fixation, %

223.2† 97.9* 304.4 40.1 1.05 4.6 24.9 Gap (n ⫽ 55)

SRT, ms Correct, % Velocity, °/s Duration, ms Accuracy (gain) Skipped trials, % Broken fixation, %

202.4 93.6 280.7 42.3 1.01 5.3 29.6

239.0† 85.6† 273.1* 43.2 1.01 4.2 30.5

189.0 94.7 291.3 41.4 1.02 4.8 29.9

173.1† 98.4† 296.1 40.9 1.03 4.9 34.5

n, No. of. deactivation sessions. SRT, saccadic reaction time; dlPFC, dorsolateral prefrontal cortex; dlPFC⫹, combined pre- and postcool period; dlPFC⫺, cool period. *P ⬍ 0.01, †P ⬍ 0.001, Wilcoxon signed-rank test.

dition (CEI ⫽ ⫺0.053 ⫾ 0.010, P ⬍ 0.001) and gap condition (CEI ⫽ ⫺0.120 ⫾ 0.027, P ⬍ 0.001; Fig. 6), and on contraversive prosaccade trials in the gap condition (CEI ⫽ ⫺0.058 ⫾ 0.018, P ⬍ 0.001; Fig. 6). Task performance also improved slightly on ipsiversive prosaccade trials in both the overlap condition (CEI ⫽ 0.008 ⫾ 0.003, P ⬍ 0.01) and gap condition (CEI ⫽ 0.019 ⫾ 0.003, P ⬍ 0.001; Fig. 6). Ipsiversive antisaccade task performance was unaffected by dlPFC deactivation, but was improved by ACC deactivation in the overlap condition (CEI ⫽ 0.028 ⫾ 0.009, P ⬍ 0.01). This was the only instance of an increased incidence of ipsiversive saccades with ACC deactivation.

dlPFC Deactivation Impaired Contraversive Saccades: Velocity and Duration Prefrontal lesion and deactivation studies tend to report effects on task performance and SRT, but not other saccade parameters. An exception is Fukushima and colleagues (1990) who reported decreased antisaccade velocity in human patients with schizophrenia, a psychiatric disorder which is thought to disrupt prefrontal function, and with lesions that included both the dlPFC and FEF (Fukushima et al. 1994). Here we found that dlPFC deactivation both decreased the velocity (Fig. 9C) and increased the duration (Fig. 9D) of contraversive saccades, whereas there were no effects of ACC deactivation on either

Table 2. Effects of ACC deactivation on both monkeys combined Prosaccades Contraversive

Antisaccades Ipsiversive

ACC⫹

ACC⫺

ACC⫹

216.7 95.9 291.1 38.7 1.00 4.4 19.7

220.7 96.8 296.3 38.6 1.01 3.8 23.1

209.2 96.1 289.7 39.3 1.00 4.6 18.8

ACC⫺

Contraversive

Ipsiversive

ACC⫹

ACC⫺

ACC⫹

ACC⫺

226.8 92.3 267.4 48.9 1.26 4.2 32.9

232.6 91.7 264.6 48.8 1.30 2.9 29.4

227.6 90.0 253.7 49.9 1.31 4.5 31.7

228.8 94.8* 259.3 49.5 1.34 2.9 27.1*

199.6 79.9 263.9 48.2 1.26 4.4 37.8

202.7 74.5 258.1 47.5 1.21 2.4 34.4

196.2 83.0 257.2 48.8 1.27 3.7 36.4

196.0 82.9 264.7 47.4 1.28 3.0 34.7


210.6 98.2 293.1 38.5 1.00 3.5 17.7 Gap (n ⫽ 31)


183.3 93.4 286.4 39.7 1.00 4.4 27.6

187.5 93.8 290.7 39.2 1.00 3.3 23.6

169.8 94.2 281.4 39.9 0.98 4.1 24.6

166.1 95.1 285.5 39.6 0.98 3.7 24.7

n, No. of. deactivation sessions. ACC, anterior cingulate cortex; ACC⫹, combined pre- and postcool period; ACC⫺, cool period. *P ⬍ 0.01, †P ⬍ 0.001, Wilcoxon signed-rank test. J Neurophysiol • doi:10.1152/jn.00626.2013 • www.jn.org Downloaded from www.physiology.org/journal/jn by ${individualUser.givenNames} ${individualUser.surname} (146.185.200.230) on January 12, 2019.

792


Table 3. Effects of dlPFC deactivation on monkey A Prosaccades Contraversive


dlPFC⫹

dlPFC⫺

dlPFC⫹

182.5 94.4 299.1 35.8 1.00 2.8 10.9

215.0† 93.8 290.0* 36.5 0.99 2.8 13.7

176.3 93.9 298.4 35.8 1.02 2.9 9.7

Contraversive

dlPFC⫺

Ipsiversive

dlPFC⫹

dlPFC⫺

dlPFC⫹

dlPFC⫺

183.5 93.0 263.0 48.7 1.38 2.5 24.8

209.6† 80.1† 222.0† 59.4† 1.50* 3.6 25.2

189.9 93.6 265.3 49.0 1.43 2.7 25.1

198.8 93.9 268.9 49.4 1.51 2.3 19.1

153.2 85.2 263.6 47.9 1.18 2.0 28.1

166.5† 76.2 225.6† 57.1† 1.22 2.9 37.5*

151.6 87.2 266.9 46.9 1.37 1.7 28.9

158.9 90.5 270.0 48.4 1.48 2.3 34.2


168.8* 96.9 296.8 35.9 1.01 3.2 17.2* Gap (n ⫽ 22)

SRT, ms Correct, % Velocity, °/s Duration, ms Accuracy, gain Skipped trials, % Broken fixation, %

144.7 94.4 299.4 36.0 0.98 3.0 12.9

170.1† 94.1 292.6* 36.4 0.98 1.9 14.5

140.8 94.7 297.3 35.9 0.99 2.6 13.6

132.9† 98.3* 295.1 35.9 1.00 1.9 22.8

n, No. of. deactivation sessions. *P ⬍ 0.01, †P ⬍ 0.001, Wilcoxon signed rank test.

saccade velocity or duration. With dlPFC deactivation there was a decrease of contraversive antisaccade velocity in the overlap condition (CEI ⫽ ⫺0.076 ⫾ 0.009, P ⬍ 0.001) and gap condition (CEI ⫽ ⫺0.064 ⫾ 0.009, P ⬍ 0.001; Fig. 7), and a corresponding increase of contraversive antisaccade duration in the overlap condition (CEI ⫽ 0.065 ⫾ 0.007, P ⬍ 0.001) and gap condition (CEI ⫽ 0.060 ⫾ 0.007, P ⬍ 0.001; Fig. 8). These effects were similarly found for contraversive prosaccades, although to a lesser extent. There was a small decrease of saccade velocity in both the overlap condition (CEI ⫽ ⫺0.018 ⫾ 0.004, P ⬍ 0.001) and gap condition (CEI ⫽ ⫺0.016 ⫾ 0.006, P ⬍ 0.01; Fig. 7), and a slight increase of saccade duration in the overlap condition (CEI ⫽ 0.013 ⫾ 0.004, P ⬍ 0.01). The only effect of dlPFC deactivation on the kinematics of ipsiversive saccades was a

small increase of ipsiversive antisaccade velocity in the overlap condition (CEI ⫽ 0.017 ⫾ 0.005, P ⬍ 0.01). Additional Effects of dlPFC and ACC Deactivation In addition to the effects on SRT, task performance, and saccade kinematics, there were also a few effects on antisaccade accuracy, the onset latency of errors, and the incidence of broken fixation trials. First, with dlPFC deactivation there was an increase of ipsiversive antisaccade gain, and thus reduced accuracy of ipsiversive antisaccades. This overshoot of the saccade target was found in both the overlap condition (CEI ⫽ 0.016 ⫾ 0.004, P ⬍ 0.001) and gap condition (CEI ⫽ 0.016 ⫾ 0.004, P ⬍ 0.001). Second, both dlPFC and ACC deactivation affected the latency of antisaccade errors: dlPFC deactivation increased the SRT of

Table 4. Effects of ACC deactivation on monkey A Prosaccades Contraversive ACC⫹


ACC⫺

ACC⫹

ACC⫺

Contraversive

Ipsiversive

ACC⫹

ACC⫺

ACC⫹

ACC⫺

183.2 95.1 287.3 46.4 1.38 1.5 26.9

195.3* 94.0 282.5 47.2 1.45 1.0 21.3

179.4 90.5 252.2 47.9 1.43 2.2 23.8

190.2 96.0* 255.5 47.6 1.46 1.3 17.2*

151.1 86.5 280.2 45.5 1.38 1.6 33.4

169.6† 82.6 265.7* 46.6 1.32 1.3 28.2

143.1 89.8 259.5 46.3 1.37 1.4 31.8

149.9* 89.9 266.9 45.6 1.40 1.1 28.4


169.7 95.3 301.5 34.5 0.98 1.8 12.3

178.0 97.4 302.4 34.8 0.99 1.1 16.9

171.4 95.8 288.3 35.3 0.98 2.4 11.0


141.1 95.0 301.5 34.8 0.99 2.1 19.2

145.9 95.8 298.9 34.8 0.98 1.9 14.4

133.7 96.1 287.8 35.4 0.96 2.0 16.6

180.4* 98.6 289.0 35.5 0.98 2.0 9.8 Gap (n ⫽ 20) 135.2 97.2 287.6 35.6 0.96 1.0 15.0

n, No. of. deactivation sessions. *P ⬍ 0.01, †P ⬍ 0.001, Wilcoxon signed-rank test. J Neurophysiol • doi:10.1152/jn.00626.2013 • www.jn.org Downloaded from www.physiology.org/journal/jn by ${individualUser.givenNames} ${individualUser.surname} (146.185.200.230) on January 12, 2019.


793

Table 5. Effects of dlPFC deactivation on monkey C Prosaccades

Antisaccades

Contraversive

Ipsiversive

dlPFC⫹

dlPFC⫺

dlPFC⫹

289.8 97.1 284.3 45.1 1.03 7.1 33.3

331.5† 95.2 274.9 46.7* 1.03 5.3 32.3

268.4 97.9 304.7 43.6 1.07 6.5 32.1

Contraversive

dlPFC⫺

Ipsiversive

dlPFC⫹

dlPFC⫺

dlPFC⫹

dlPFC⫺

299.5 92.1 238.1 52.4 1.03 6.7 40.5

307.8 86.6 211.3† 57.6† 1.00 6.9 40.9

300.6 94.9 265.9 52.0 1.13 6.8 40.2

312.0 98.0* 278.5* 52.1 1.18* 7.2 38.7

268.7 66.0 242.0 50.8 1.05 6.9 43.2

291.5* 52.5† 220.9† 55.7† 1.04 5.8 45.2

268.2 73.5 275.2 51.8 1.17 6.7 44.6

259.6 79.9 282.9 51.9 1.20* 5.3 43.9


259.5 98.6 309.4 42.9 1.07 5.5 30.0 Gap (n ⫽ 33)


240.9 93.1 268.3 46.5 1.02 6.8 40.8

285.0† 80.0† 260.2 47.8 1.03 5.8 41.2

222.2 94.6 287.3 45.0 1.04 6.3 40.8

199.9† 98.4† 296.8 44.3 1.06 6.9 42.2

n, No. of. deactivation sessions. *P ⬍ 0.01, †P ⬍ 0.001, Wilcoxon signed rank test.

contraversive errors on ipsiversive antisaccade trials in the gap condition (control ⫽ 200.5 ⫾ 7.9 ms, cool ⫽ 231.8 ⫾ 9.4 ms, CEI ⫽ 0.088 ⫾ 0.020, P ⬍ 0.001), while ACC deactivation decreased the SRT of ipsiversive errors on contraversive prosaccade trials in the gap condition (control ⫽ 225.7 ⫾ 15.7 ms, cool ⫽ 196.2 ⫾ 9.1 ms, CEI ⫽ ⫺0.131 ⫾ 0.026, P ⬍ 0.01). Third, dlPFC and ACC deactivation also had an effect on the incidence of broken fixation trials: the tendency to break fixation increased on contraversive antisaccade trials in the gap condition with dlPFC deactivation (CEI ⫽ 0.059 ⫾ 0.025, P ⬍ 0.001), and decreased on ipsiversive antisaccade trials in the overlap condition with ACC deactivation (CEI ⫽ ⫺0.140 ⫾ 0.046, P ⬍ 0.01).

Resting-state FC of dlPFC and ACC ROIs encompassing portions of the dlPFC and ACC were selected to approximate the locations of the cryoloops implanted in the other subset of monkeys used in the present study. Figure 10 displays the resting-state FC results of the ROIs selected in the right hemisphere with superimposed cytoarchitectonic areas (Van Essen et al. 2012). The ROIs show extensive connectivity with local and distributed brain areas that are specific for the respective ROI. The FC patterns in the contralateral hemisphere to the ROI are similar to those observed in the ipsilateral hemisphere, although the connectivity tends to be slightly weaker. Furthermore, the connectivity

Table 6. Effects of ACC deactivation on monkey C Prosaccades Contraversive ACC⫹


ACC⫺

ACC⫹

ACC⫺

Contraversive

Ipsiversive

ACC⫹

ACC⫺

ACC⫹

ACC⫺

306.1 87.2 231.2 53.4 1.03 8.9 43.7

300.4 87.5 232.1 51.5 1.02 6.4 44.2

315.3 89.1 256.4 53.6 1.09 8.6 46.1

298.9 92.6 266.3 52.8 1.11 5.9 44.9

287.9 68.7 234.3 53.2 1.05 9.4 45.9

262.9 59.6 244.4 49.2* 1.01 4.5 45.7

293.0 70.5 252.9 53.4 1.10 7.9 44.6

279.7 70.0 260.8 50.7 1.08 6.5 46.2


302.2 97.1 272.1 46.4 1.03 9.1 33.2

298.3 95.6 285.3 45.7 1.05 8.6 34.4

278.1 96.7 292.2 46.6 1.04 8.6 32.9


259.9 90.5 258.8 48.5 1.02 8.6 43.0

263.3 90.2 275.9 47.3 1.04 5.8 40.2

235.4 90.6 269.7 48.0 1.01 7.9 39.1

265.5 97.4 300.4 43.9 1.03 6.3 32.0 Gap (n ⫽ 11) 222.3 91.3 281.7 46.8 1.03 8.6 42.3

n, No. of. deactivation sessions. *P ⬍ 0.01, †P ⬍ 0.001, Wilcoxon signed rank test. J Neurophysiol • doi:10.1152/jn.00626.2013 • www.jn.org Downloaded from www.physiology.org/journal/jn by ${individualUser.givenNames} ${individualUser.surname} (146.185.200.230) on January 12, 2019.

794


Fig. 4. Individual session examples of dlPFC deactivation effects on SRTs. Two example sessions (top and bottom) are presented for contraversive prosaccades (on left) and contraversive antisaccades (on right) in the gap condition. SRTs are plotted sequentially for correct trials. On each plot, the vertical line on the left indicates the start of the cooling period, while the vertical line on the right indicated the end of the cooling period.

patterns are not dependent on the hemisphere in which the seeds are placed as the profiles are approximately mirrored when the ROIs are placed within the same region of the left hemisphere (Fig. 11). For the ACC ROI placed in the cingulate sulcus, all areas within the ACC extending into the subgenual area show strong correlations. Dorsal and ventral regions of the medial PFC are highly functionally connected to the cingulate ROI. Also apparent is strong positive connectivity with the hippocampus and regions along the hippocampal sulcus. On the lateral

surface, regions in the superior and inferior temporal sulci are functionally connected, as are the primary visual areas, extending within the lunate and inferior occipital sulci. There is also strong positive connectivity with areas immediately ventrolateral to the principal sulcus and rostrally in the PFC. Notably absent was significant FC with the posterior cingulate, parietal cortex, and only limited connectivity with areas in the arcuate sulcus corresponding to the FEF (Fig. 10A). In addition to positively correlated activity near the dlPFC ROI, significant FC was found to extend throughout the prin-

Fig. 5. Distribution of dlPFC deactivation effects on SRTs in the gap condition. SRTs for contraversive prosaccades, ipsiversive prosaccades, contraversive antisaccades, and ipsiversive antisaccades are plotted for the dlPFC⫹ period against the dlPFC⫺ period. Solid symbols indicate sessions with a significant difference between the dlPFC⫹ and dlPFC⫺ periods (Wilcoxon rank sum test, P ⬍ 0.01).



795

Fig. 6. Distribution of dlPFC deactivation effects on task performance in the gap condition. Task performance for contraversive prosaccades, ipsiversive prosaccades, contraversive antisaccades, and ipsiversive antisaccades is plotted for the dlPFC⫹ period against the dlPFC⫺ period.

cipal and arcuate sulcus encompassing the anterior bank of the arcuate sulcus that corresponds to the location of the FEF (Fig. 10B). Beyond these regions, and unlike the ACC ROI, strong connectivity is observed within the intraparietal sulcus, parieto-occipital sulcus, and posterior cingulate areas. Regions of the rostral ACC and dorsomedial PFC (SEF) are functionally connected to the dlPFC ROI. Moderate z-score values can also be observed on the superior and inferior temporal gyrus as well as with some early visual areas. DISCUSSION

Here we found that unilateral dlPFC cooling both facilitated ipsiversive saccades and impaired contraversive saccades, while there was a lack of unilateral ACC cooling effects. Ipsiversive saccade facilitation was demonstrated by an increased incidence of ipsiversive saccades and reduced SRTs, while the contraversive saccade impairments were increased SRTs, increased saccade duration, and reduced saccade velocities. In addition, a seed-based analysis of resting-state fMRI displayed stronger FC of cortical saccade areas with the dlPFC than the ACC. Together these findings suggest that the dlPFC plays a more prominent role in the preparation of pro- and antisaccades than the ACC. The deficits after unilateral dlPFC cooling (increased SRTs and reduced velocity of contraversive saccades) have similarly been found during unilateral muscimol deactivation of the dlPFC, FEF, and LIP (Condy et al. 2007; Li et al. 1999; Sommer and Tehovnik 1997). These cortical areas project

directly to the SC (Fries 1984; Goldman and Nauta 1976; Leichnetz et al. 1981; Lynch et al. 1985; Stanton et al. 1988). Saccade-related neurons in the SC have low-frequency prestimulus discharge that is inversely related to contraversive saccade latency in monkeys (Dorris and Munoz 1998; Dorris et al. 1997; Everling et al. 1999), and high-frequency perisaccadic discharge that is positively correlated with contraversive saccade velocity in monkeys (Rohrer et al. 1987; Stanford et al. 1996; Van Opstal et al. 1990) and cats (Berthoz et al. 1986; Munoz and Guitton 1986). Therefore the increased SRTs and reduced velocity of contraversive saccades after unilateral cortical deactivation (dlPFC, FEF, or LIP) suggest there was a decrease of saccade neuron activity in the SC ipsilateral to deactivation. Unilateral muscimol deactivation of the dlPFC, FEF, and LIP has also been shown to increase the incidence of ipsiversive saccades, i.e., saccades toward the side of deactivation (Condy et al. 2007; Dias et al. 1995; Wardak et al. 2002). In the present study, we found that unilateral dlPFC cooling increased the incidence of ipsiversive errors on contraversive antisaccade trials. Given that SC saccade neurons have a higher level of prestimulus activity for antisaccade errors than correct antisaccades in the gap task (Everling et al. 1998), the increased incidence of ipsiversive antisaccade errors suggests there was an increase of saccade neuron activity in the SC contralateral to deactivation. In an earlier report, our laboratory (Johnston et al. 2013) tested these hypotheses by simultaneously cooling the dlPFC


796


Fig. 7. Distribution of dlPFC deactivation effects on saccade velocity in the gap condition. Saccade velocity for contraversive prosaccades, ipsiversive prosaccades, contraversive antisaccades, and ipsiversive antisaccades is plotted for the dlPFC⫹ period against the dlPFC⫺ period. Solid symbols indicate sessions with a significant difference between the dlPFC⫹ and dlPFC⫺ periods (Wilcoxon rank sum test, P ⬍ 0.01).

and recording the activity of SC saccade neurons both ipsilateral and contralateral to the side of deactivation. We reported that unilateral dlPFC cooling increased the onset latency of saccade-related activity in the SC ipsilateral to deactivation (Johnston et al. 2013). Given that corticotectal projections are primarily ipsilateral (Leichnetz et al. 1981; Selemon and Goldman-Rakic 1988; Stanton et al. 1988), this reduction of activity at the ipsilateral SC suggests that the dlPFC has an excitatory influence on SC saccade neurons. We also found that unilateral dlPFC cooling increased the level of saccade neuron activity in the SC contralateral to deactivation (Johnston et al. 2013). Ipsilateral corticotectal projections imply that this effect of cortical deactivation on the contralateral SC may have been mediated indirectly by interhemispheric inhibition at the level of cortical areas (Palmer et al. 2012; Schlag et al. 1998) or collicular structures (Munoz and Istvan 1998; Takahashi et al. 2005). While this evidence supports a role of the dlPFC in the preparation of contraversive saccades, it must be taken into consideration that an overt shift of gaze is also preceded by a covert shift of attention (Deubel and Schneider 1996). The premotor theory of attention posits that an attention shift is functionally equivalent to saccade preparation (Rizzolatti et al. 1987). Schall and colleagues, on the other hand, have shown that covert attention can be modulated independent of saccade preparation (Juan et al. 2004), and furthermore that covert attention and saccade preparation are mediated by separate neuronal populations in the FEF (Juan et al. 2008; Pouget et al. 2009; Sato and Schall 2003; Thompson et al. 1997, 2005). The

dlPFC is also proposed to play a role in both covert attention (Lau et al. 2004; Manly et al. 2003; Owen et al. 1996; Petrides et al. 2002; Rowe and Passingham 2001; Rowe et al. 2000) and saccade preparation (Brown et al. 2007; DeSouza et al. 2003; Ford et al. 2005; Johnston et al. 2007, 2013; Koval et al. 2011), and thus it is difficult to dissociate the effects of dlPFC deactivation that we observed here. Consequently, the effects on contraversive saccades may have actually been caused by an effect on the allocation of spatial attention toward the contralateral visual field. Support for a role of the dlPFC in contralateral shifts of attention comes from single-neuron recording studies with monkeys in which the activity of dlPFC neurons increased when attending to a stimulus (Lebedev et al. 2004; Rainer et al. 1998), and when a stimulus appeared at an attended location (DeSouza and Everling 2004; di Pellegrino and Wise 1993; Everling et al. 2002). This modulation of neuronal activity by attention has been shown to correlate with task performance, which suggests that the dlPFC plays an important role in attentional filtering (Lennert and Martinez-Trujillo 2011). dlPFC neurons also show an increase of activity when a stimulus appears in their contralateral visual field (Everling et al. 2006; Funahashi et al. 1989, 1990), and this response is enhanced both when the monkey is attending to the contralateral location at which the stimulus appears (Everling et al. 2002), and for covert shifts of attention toward contralateral targets (Kaping et al. 2011). Similarly, human neuroimaging has shown that when covertly attending to a contralateral stimulus, there is an enhanced response at both the dlPFC and



797

Fig. 8. Distribution of dlPFC deactivation effects on SD in the gap condition. SD for contraversive prosaccades, ipsiversive prosaccades, contraversive antisaccades, and ipsiversive antisaccades is plotted for the dlPFC⫹ period against the dlPFC⫺ period. Solid symbols indicate sessions with a significant difference between the dlPFC⫹ and dlPFC⫺ periods (Wilcoxon rank sum test, P ⬍ 0.01).

posterior parietal cortex (Ikkai and Curtis 2011). Electrical microstimulation of the posterior parietal cortex, in addition to the FEF, SEF, and SC, has been shown by Crawford and colleagues to evoke contraversive shifts of both the eyes and head in head unrestrained monkeys (Constantin et al. 2009; Martinez-Trujillo et al. 2003a, 2003b; Monteon et al. 2010). Saccade kinematics were unimpaired by these perturbations, indicating that the proposed cortical saccade control network (Pierrot-Deseilligny et al. 2004) may actually send signals to the SC that encode gaze rather than saccades (Klier et al. 2003). Together these studies suggest that the dlPFC contributes to a spatial priority map which, as part of a dorsal frontoparietal network, guides contraversive shifts of both attention and gaze (Corbetta and Shulman 2011). These contributions are akin to the enhancement of task-relevant representations by which the dlPFC is proposed to support goaldirected behavior (Braver et al. 2007; Miller and Cohen 2001; Munakata et al. 2011). A Paucity of Unilateral ACC Cooling Effects Human neuroimaging studies have shown a greater instruction-related blood oxygen level-dependent signal in the dlPFC and ACC for antisaccades than prosaccades, and for correct antisaccades than error antisaccades (Brown et al. 2007; DeSouza et al. 2003; Ford et al. 2005). Therefore, it has been proposed that the dlPFC and ACC play a role in saccade preparation, which is consistent with the finding from monkey neurophysiology studies that both the dlPFC and ACC contain

neurons with task-selectivity for pro- or antisaccades during the preparatory period (Johnston et al. 2007). Evidence for a similar role of the dlPFC and ACC in cognitive saccade control has also come from neuroanatomical studies, which have shown that the dlPFC and ACC are highly interconnected (Barbas and Pandya 1989; Bates and Goldman-Rakic 1993; Morecraft and Van Hoesen 1993; Paus et al. 2001) and share similar connections with saccade-related brain areas such as the FEF, SEF, LIP, and basal ganglia (Bates and GoldmanRakic 1993; Cavada and Goldman-Rakic 1989; Huerta and Kaas 1990; Selemon and Goldman-Rakic 1988, 1985; Wang et al. 2004). However, whereas the dlPFC has direct corticotectal projections (Goldman and Nauta 1976; Johnston and Everling 2006; 2009; Leichnetz et al. 1981), the cortico-mesencephalic projections of the ACC appear to target the periaqueductal gray instead (Leichnetz et al. 1981). Given that the saccade commands sent from the SC to the brain stem saccade generator (Gandhi and Katnani 2011; Munoz et al. 2000; Scudder et al. 2002; Sparks 2002) appear to play a critical role in saccade initiation (Pierrot-Deseilligny et al. 1991; Wurtz and Goldberg 1972), the absence of ACC corticotectal projections suggests that the ACC does not play a prominent role in pro- and antisaccade preparation. Resting-state fMRI allows for an empirical characterization of the temporal relationship between brain regions in the absence of an explicit task (Biswal et al. 1995; Fox and Raichle 2007), which can be interpreted as a measure of FC (Friston and Buchel 2007; Friston 2011). Although the precise relation-


798


Fig. 9. Effects of dlPFC and ACC deactivation on prosaccades and antisaccades. Mean cooling effect indexes (CEIs) are displayed for SRT (A), task performance (B), saccade velocity (C), and SD (D). Each plot contains 16 conditions divided into four groups (left to right): contraversive prosaccades, ipsiversive prosaccades, contraversive antisaccades, and ipsiversive antisaccades. Each group is further divided into four conditions (left to right): dlPFC deactivation in the overlap condition (PFC-OVR), dlPFC deactivation in the gap condition (PFC-GAP), ACC deactivation in the overlap condition (ACC-OVR), and ACC deactivation in the gap condition (ACC-GAP). Conditions with a mean CEI significantly different than zero are indicated by a 99% confidence interval that is entirely either less than or greater than zero. *P ⬍ 0.01.

ship is still unclear, evidence has linked the spontaneous blood oxygen level-dependent activity (0.01– 0.1 Hz) and their synchronization to slow, ongoing fluctuations in neuronal activity (Leopold and Maier 2012; Shmuel and Leopold 2008). The technique has revealed robust and reproducible FC patterns across subjects (Beckmann et al. 2005; Damoiseaux et al. 2006) and within multiple species (Hutchison and Everling 2012; Vincent et al. 2007). These intrinsic connectivity networks can resemble task-evoked patterns (although see Mennes et al. 2013; Smith et al. 2009) and appear be to be constrained (though not fully determined) by the underlying anatomical connectivity (Damoiseaux and Greicius 2009; Honey et al. 2009; van den Heuvel et al. 2009). In the present study, by selecting comparable regions of the cryoloop locations, we were able identify the unique FC profiles of the

deactivated prefrontal and cingulate region and found that the dlPFC displayed stronger FC with frontopatietal areas than the ACC. FC analyses therefore suggest that the dlPFC, but not the ACC, is part of the network that is involved in spatial or attentional orienting (Chica et al. 2011; Corbetta et al. 1998, 2000; Curtis et al. 2005; Hon et al. 2006). This conclusion from the FC results is directly supported by our finding of an abundance of unilateral dlPFC cooling effects, and only very few effects with unilateral ACC cooling. However, it is difficult to interpret this negative result of ACC cooling, given the limited spread of deactivation. While a benefit of the cooling method is that it allowed us to limit our deactivation to one particular area, the absence of an effect leaves open the possibility that deactivating a different subregion of the ACC could have had an effect. The lack of

Fig. 10. Resting-state functional connectivity of right ACC (A) and dlPFC (B) ROIs. The group averaged (N ⫽ 11) and thresholded (z ⬎ 3.0; cluster significance: P ⬍ 0.05, corrected) positive z-score maps are shown on the flattened cortical surface of the ipsilateral hemisphere for the ROI indicated in red. Overlaid are the cytoarchitectonic areas by Van Essen et al. (2012), with the frontal eye field outlined in green.



799

Fig. 11. Resting-state functional connectivity of the left and right ACC (top) and dlPFC (bottom) ROIs. The group averaged (N ⫽ 11) and thresholded positive z-score maps, normalized to the space of the F99 template (Van Essen 2004), are shown on the lateral, medial, dorsal, ventral and flattened cortical surface of both hemispheres for each ROI indicated in red (z ⬍ 3.0; cluster significance: P ⬍ 0.05, corrected).

impairments that we observed could thus be attributed to the particular area of the ACC that we deactivated, and the behavioral task that we used to test the function that this area serves. Here we chose to deactivate the same area of the ACC in which we had previously found neurons that were selective for prosaccades or antisaccades (Johnston et al. 2007). Deactivation of this area had rather weak effects, although this may be explained by differences between the tasks. The randomlyinterleaved task used for this deactivation study provided a rule cue at the beginning of each trial, whereas the recording study used an uncued blocked task in which the relevant rule was determined based on either the delivery or omission of reward. Given that the ACC has been implicated in reinforcementguided behavior (Buckley et al. 2009; Kennerley et al. 2006), this may explain why the uncued task elicited a response from neurons in this area of the ACC, whereas performance of the cued task was not affected by deactivation of the same area. On the other hand, we may have deactivated an area of the ACC that has only a weak influence on the saccade system. The ACC is a heterogenous area that consists of rostral and dorsal subregions, of which the dorsal ACC extends from the genu of the corpus callosum to between the vertical planes of the anterior and posterior commissures (Paus 2001). Two

distinct cingulate eye fields (CEF) have been identified in the dorsal ACC: a rostral CEF and caudal CEF (Wang et al. 2004). Both the rostral CEF for one of their monkeys, and the cryoloop that we implanted in the cingulate sulcus of our monkeys, were aligned with the posterior end of the principal sulcus. This suggests that we may have deactivated the rostral CEF, in which case the rostral CEF may have only a weak influence on the oculomotor system. This is supported by the antisaccade impairments found by clinical neuropsychology studies of dorsal ACC lesions. Patients with the caudal set of lesions, centered on the vertical plane of the anterior commissure (VAC), had greater impairments than patients with the rostral set of lesions, which were located anterior to the VAC (Gaymard et al. 1998; Milea et al. 2003). Using the VAC as a landmark (Paus 2001), the location of these caudal and rostral lesions in human patients corresponds roughly with that of the caudal CEF and rostral CEF found in monkeys, respectively. Alternatively, the weak effect of ACC deactivation could also have been the result of cooling an area of the ACC that was neither the rostral nor caudal CEF. Wang and colleagues (2004) found that the location of the CEFs relative to the posterior principal sulcus was different between their two monkeys. In one monkey the rostral CEF was aligned with the


800


posterior end of the principal sulcus, while in the other monkey there appears to have been either an anterior shift of the CEF locations, or a posterior shift of the FEF location. Consequently, the posterior end of the principal sulcus, and thus our cryoloop in the anterior cingulate sulcus, may have been located between the rostral and caudal CEFs. Given that Wang and colleagues (2004) identified the CEFs as being particularly involved in saccade control, ACC deactivation in an area other than the rostral or caudal CEF would not be expected to have an effect on saccades. A more precise localization of the CEFs, however, is required to determine whether the posterior end of the principal sulcus is an appropriate landmark for identifying a saccade-related area in the dorsal ACC. We must also consider a role of the ACC in the monitoring of task performance, given that the ACC receives a dopaminergic training signal from the midbrain that is elicited by errors (Holroyd and Coles 2002). This has been demonstrated as a negative-polarity event-related potential (i.e., an errorrelated negativity), attributed to the ACC, that is time-locked to the onset of an incorrect response (Holroyd and Coles 2002). Errors have also been associated with an increased hemodynamic response at the ACC (Polli et al. 2005). In addition to errors, ACC neurons have been shown to encode serial order (Procyk and Joseph 2001; Procyk et al. 2000) and reward (Ito et al. 2003; Niki and Watanabe 1979). Alternatively, the ACC has been proposed to monitor task conditions for conflict (Carter and van Veen 2007). Together, these hypotheses suggest that the ACC may play a role in monitoring for conflict, errors, and reward. Detection of this task-related information could prepare the saccade network for task-switching (Johnston et al. 2007) and the generation of intentional saccades (Muri and Nyffeler 2008; Pierrot-Deseilligny et al. 2004). In conclusion, here we found stronger behavioral effects on saccades with unilateral dlPFC deactivation than unilateral ACC deactivation, and stronger FC with frontoparietal areas for the dlPFC than the ACC. Together these findings indicate that the dlPFC plays a more prominent role in saccade preparation than the ACC. ACKNOWLEDGMENTS We wish to thank J. S. Gati and R. S. Menon for help with acquisition of the resting-state fMRI data; S. Hughes and B. Soper for assistance with surgical procedures; J. Majewski, D. Pitre, and M. Rebuli for animal care and facility maintenance; and S. Vijayraghavan for comments on an earlier version of this manuscript. GRANTS This work was supported by operating grants from the Canadian Institutes of Health Research (CIHR) awarded to S. Everling and S. G. Lomber. M. J. Koval was supported by a CIHR Canada Graduate Scholarship. R. M. Hutchison was supported by a CIHR postdoctoral fellowship. DISCLOSURES No conflicts of interest, financial or otherwise, are declared by the author(s). AUTHOR CONTRIBUTIONS Author contributions: M.J.K., S.G.L., and S.E. performed experiments; M.J.K., R.M.H., and S.E. analyzed data; M.J.K., R.M.H., and S.E. interpreted results of experiments; M.J.K., R.M.H., and S.E. prepared figures; M.J.K. and S.E. drafted manuscript; M.J.K., R.M.H., and S.E. edited and revised manu-

script; M.J.K., R.M.H., S.G.L., and S.E. approved final version of manuscript; S.E. conception and design of research.

REFERENCES Babapoor-Farrokhran S, Hutchison RM, Gati JS, Menon RS, Everling S. Functional connectivity patterns of medial and lateral macaque frontal eye fields reveal distinct visuomotor networks. J Neurophysiol 109: 2560 –2570, 2013. Barbas H, Pandya DN. Architecture and intrinsic connections of the prefrontal cortex in the rhesus monkey. J Comp Neurol 286: 353–375, 1989. Bates JF, Goldman-Rakic PS. Prefrontal connections of medial motor areas in the rhesus monkey. J Comp Neurol 336: 211–228, 1993. Beckmann CF, DeLuca M, Devlin JT, Smith SM. Investigations into resting-state connectivity using independent component analysis. Philos Trans R Soc Lond B Biol Sci 360: 1001–1013, 2005. Bell AH, Everling S, Munoz DP. Influence of stimulus eccentricity and direction on characteristics of pro- and antisaccades in non-human primates. J Neurophysiol 84: 2595–2604, 2000. Berthoz A, Grantyn A, Droulez J. Some collicular efferent neurons code saccadic eye velocity. Neurosci Lett 72: 289 –294, 1986. Biswal B, Yetkin FZ, Haughton VM, Hyde JS. Functional connectivity in the motor cortex of resting human brain using echo-planar MRI. Magn Reson Med 34: 537–541, 1995. Boch RA, Goldberg ME. Participation of prefrontal neurons in the preparation of visually guided eye movements in the rhesus monkey. J Neurophysiol 61: 1064 –1084, 1989. Braver TS, Gray JR, Burgess GC. Explaining the many varieties of working memory variation: dual mechanisms of cognitive control. In: Variation In Working Memory, edited by Conway ARA, Jarrold C, Kane MJ, Miyake A, and Towse J. Oxford, UK: Oxford University Press, 2007, p. 76 –106. Brown MR, DeSouza JF, Goltz HC, Ford K, Menon RS, Goodale MA, Everling S. Comparison of memory- and visually guided saccades using event-related fMRI. J Neurophysiol 91: 873– 889, 2004. Brown MR, Vilis T, Everling S. Frontoparietal activation with preparation for antisaccades. J Neurophysiol 98: 1751–1762, 2007. Bruce CJ, Goldberg ME, Bushnell MC, Stanton GB. Primate frontal eye fields. II. Physiological and anatomical correlates of electrically evoked eye movements. J Neurophysiol 54: 714 –734, 1985. Buckley MJ, Mansouri FA, Hoda H, Mahboubi M, Browning PG, Kwok SC, Phillips A, Tanaka K. Dissociable components of rule-guided behavior depend on distinct medial and prefrontal regions. Science 325: 52–58, 2009. Carter CS, van Veen V. Anterior cingulate cortex and conflict detection: an update of theory and data. Cogn Affect Behav Neurosci 7: 367–379, 2007. Cavada C, Goldman-Rakic PS. Posterior parietal cortex in rhesus monkey. II. Evidence for segregated corticocortical networks linking sensory and limbic areas with the frontal lobe. J Comp Neurol 287: 422– 445, 1989. Chica AB, Bartolomeo P, Valero-Cabre A. Dorsal and ventral parietal contributions to spatial orienting in the human brain. J Neurosci 31: 8143– 8149, 2011. Condy C, Wattiez N, Rivaud-Pechoux S, Tremblay L, Gaymard B. Antisaccade deficit after inactivation of the principal sulcus in monkeys. Cereb Cortex 17: 221–229, 2007. Constantin AG, Wang H, Monteon JA, Martinez-Trujillo JC, Crawford JD. 3-Dimensional eye-head coordination in gaze shifts evoked during stimulation of the lateral intraparietal cortex. Neuroscience 164: 1284 –1302, 2009. Corbetta M, Akbudak E, Conturo TE, Snyder AZ, Ollinger JM, Drury HA, Linenweber MR, Petersen SE, Raichle ME, Van Essen DC, Shulman GL. A common network of functional areas for attention and eye movements. Neuron 21: 761–773, 1998. Corbetta M, Kincade JM, Ollinger JM, McAvoy MP, Shulman GL. Voluntary orienting is dissociated from target detection in human posterior parietal cortex. Nat Neurosci 3: 292–297, 2000. Corbetta M, Shulman GL. Spatial neglect and attention networks. Annu Rev Neurosci 34: 569 –599, 2011. Curtis CE, Calkins ME, Iacono WG. Saccadic disinhibition in schizophrenia patients and their first-degree biological relatives. A parametric study of the effects of increasing inhibitory load. Exp Brain Res 137: 228 –236, 2001. Curtis CE, Cole MW, Rao VY, D’Esposito M. Canceling planned action: an FMRI study of countermanding saccades. Cereb Cortex 15: 1281–1289, 2005.


SACCADIC EFFECTS OF COOLING dlPFC AND ACC Damoiseaux JS, Greicius MD. Greater than the sum of its parts: a review of studies combining structural connectivity and resting-state functional connectivity. Brain Struct Funct 213: 525–533, 2009. Damoiseaux JS, Rombouts SA, Barkhof F, Scheltens P, Stam CJ, Smith SM, Beckmann CF. Consistent resting-state networks across healthy subjects. Proc Natl Acad Sci U S A 103: 13848 –13853, 2006. DeSouza JF, Everling S. Focused attention modulates visual responses in the primate prefrontal cortex. J Neurophysiol 91: 855– 862, 2004. DeSouza JF, Menon RS, Everling S. Preparatory set associated with prosaccades and anti-saccades in humans investigated with event-related FMRI. J Neurophysiol 89: 1016 –1023, 2003. di Pellegrino G, Wise SP. Effects of attention on visuomotor activity in the premotor and prefrontal cortex of a primate. Somatosens Mot Res 10: 245–262, 1993. Dias EC, Kiesau M, Segraves MA. Acute activation and inactivation of macaque frontal eye field with GABA-related drugs. J Neurophysiol 74: 2744 –2748, 1995. Dorris MC, Munoz DP. Saccadic probability influences motor preparation signals and time to saccadic initiation. J Neurosci 18: 7015–7026, 1998. Dorris MC, Pare M, Munoz DP. Neuronal activity in monkey superior colliculus related to the initiation of saccadic eye movements. J Neurosci 17: 8566 – 8579, 1997. Everling S, DeSouza JF. Rule-dependent activity for prosaccades and antisaccades in the primate prefrontal cortex. J Cogn Neurosci 17: 1483–1496, 2005. Everling S, Dorris MC, Klein RM, Munoz DP. Role of primate superior colliculus in preparation and execution of anti-saccades and pro-saccades. J Neurosci 19: 2740 –2754, 1999. Everling S, Dorris MC, Munoz DP. Reflex suppression in the anti-saccade task is dependent on prestimulus neural processes. J Neurophysiol 80: 1584 –1589, 1998. Everling S, Tinsley CJ, Gaffan D, Duncan J. Filtering of neural signals by focused attention in the monkey prefrontal cortex. Nat Neurosci 5: 671– 676, 2002. Everling S, Tinsley CJ, Gaffan D, Duncan J. Selective representation of task-relevant objects and locations in the monkey prefrontal cortex. Eur J Neurosci 23: 2197–2214, 2006. Fischer B, Boch R. Saccadic eye movements after extremely short reaction times in the monkey. Brain Res 260: 21–26, 1983. Fischer B, Ramsperger E. Human express saccades: extremely short reaction times of goal directed eye movements. Exp Brain Res 57: 191–195, 1984. Fischer B, Weber H. Characteristics of “anti” saccades in man. Exp Brain Res 89: 415– 424, 1992. Fischer B, Weber H. Effects of stimulus conditions on the performance of antisaccades in man. Exp Brain Res 116: 191–200, 1997. Ford KA, Goltz HC, Brown MR, Everling S. Neural processes associated with antisaccade task performance investigated with event-related FMRI. J Neurophysiol 94: 429 – 440, 2005. Fox MD, Raichle ME. Spontaneous fluctuations in brain activity observed with functional magnetic resonance imaging. Nat Rev Neurosci 8: 700 –711, 2007. Fries W. Cortical projections to the superior colliculus in the macaque monkey: a retrograde study using horseradish peroxidase. J Comp Neurol 230: 55–76, 1984. Friston K, Buchel C. Functional connectivity: eigenimages and multivariate analyses. In: Statistical Parametric Mapping: The Analysis of Functional Brain Images, edited by Friston KJ, Ashburner JT, Kiebel SJ, Nichols TE, and Penny WD. Amsterdam: Elsevier, 2007, p. 492–507. Friston KJ. Functional and effective connectivity: a review. Brain Connect 1: 13–36, 2011. Fukushima J, Fukushima K, Miyasaka K, Yamashita I. Voluntary control of saccadic eye movement in patients with frontal cortical lesions and Parkinsonian patients compared with that in schizophrenics. Biol Psychiatry 36: 21–30, 1994. Fukushima J, Fukushima K, Morita N, Yamashita I. Further analysis of the control of voluntary saccadic eye movements in schizophrenic patients. Biol Psychiatry 28: 943–958, 1990. Funahashi S, Bruce CJ, Goldman-Rakic PS. Mnemonic coding of visual space in the monkey’s dorsolateral prefrontal cortex. J Neurophysiol 61: 331–349, 1989. Funahashi S, Bruce CJ, Goldman-Rakic PS. Visuospatial coding in primate prefrontal neurons revealed by oculomotor paradigms. J Neurophysiol 63: 814 – 831, 1990.

801

Gandhi NJ, Katnani HA. Motor functions of the superior colliculus. Annu Rev Neurosci 34: 205–231, 2011. Gaymard B, Rivaud S, Cassarini JF, Dubard T, Rancurel G, Agid Y, Pierrot-Deseilligny C. Effects of anterior cingulate cortex lesions on ocular saccades in humans. Exp Brain Res 120: 173–183, 1998. Goldman PS, Nauta WJ. Autoradiographic demonstration of a projection from prefrontal association cortex to the superior colliculus in the rhesus monkey. Brain Res 116: 145–149, 1976. Hallett PE. Primary and secondary saccades to goals defined by instructions. Vision Res 18: 1279 –1296, 1978. Holroyd CB, Coles MG. The neural basis of human error processing: reinforcement learning, dopamine, and the error-related negativity. Psychol Rev 109: 679 –709, 2002. Hon N, Epstein RA, Owen AM, Duncan J. Frontoparietal activity with minimal decision and control. J Neurosci 26: 9805–9809, 2006. Honey CJ, Sporns O, Cammoun L, Gigandet X, Thiran JP, Meuli R, Hagmann P. Predicting human resting-state functional connectivity from structural connectivity. Proc Natl Acad Sci U S A 106: 2035–2040, 2009. Horel JA. Use of cold to reversibly suppress local brain function in behaving animals. In: Methods in Neurosciences: Lesions and Transplantation, edited by Conn PM. New York: Academic, 1991, p. 97–110. Huerta MF, Kaas JH. Supplementary eye field as defined by intracortical microstimulation: connections in macaques. J Comp Neurol 293: 299 – 330, 1990. Hutchison RM, Everling S. Monkey in the middle: why non-human primates are needed to bridge the gap in resting-state investigations. Front Neuroanat 6: 29, 2012. Hutchison RM, Gallivan JP, Culham JC, Gati JS, Menon RS, Everling S. Functional connectivity of the frontal eye fields in humans and macaque monkeys investigated with resting-state fMRI. J Neurophysiol 107: 2463– 2474, 2012a. Hutchison RM, Leung LS, Mirsattari SM, Gati JS, Menon RS, Everling S. Resting-state networks in the macaque at 7 T. Neuroimage 56: 1546 –1555, 2011. Hutchison RM, Womelsdorf T, Gati JS, Everling S, Menon RS. Restingstate networks show dynamic functional connectivity in awake humans and anesthetized macaques. Hum Brain Mapp 34: 2154 –2177, 2013. Hutchison RM, Womelsdorf T, Gati JS, Leung LS, Menon RS, Everling S. Resting-state connectivity identifies distinct functional networks in macaque cingulate cortex. Cereb Cortex 22: 1294 –1308, 2012b. Ikkai A, Curtis CE. Common neural mechanisms supporting spatial working memory, attention and motor intention. Neuropsychologia 49: 1428 –1434, 2011. Ito S, Stuphorn V, Brown JW, Schall JD. Performance monitoring by the anterior cingulate cortex during saccade countermanding. Science 302: 120 –122, 2003. Johnston K, Everling S. Monkey dorsolateral prefrontal cortex sends taskselective signals directly to the superior colliculus. J Neurosci 26: 12471– 12478, 2006. Johnston K, Everling S. Task-relevant output signals are sent from monkey dorsolateral prefrontal cortex to the superior colliculus during a visuospatial working memory task. J Cogn Neurosci 21: 1023–1038, 2009. Johnston K, Koval MJ, Lomber SG, Everling S. Macaque dorsolateral prefrontal cortex does not suppress saccade-related activity in the superior colliculus. Cereb Cortex. In press, 2013. Johnston K, Levin HM, Koval MJ, Everling S. Top-down control-signal dynamics in anterior cingulate and prefrontal cortex neurons following task switching. Neuron 53: 453– 462, 2007. Juan CH, Muggleton NG, Tzeng OJ, Hung DL, Cowey A, Walsh V. Segregation of visual selection and saccades in human frontal eye fields. Cereb Cortex 18: 2410 –2415, 2008. Juan CH, Shorter-Jacobi SM, Schall JD. Dissociation of spatial attention and saccade preparation. Proc Natl Acad Sci U S A 101: 15541–15544, 2004. Kaping D, Vinck M, Hutchison RM, Everling S, Womelsdorf T. Specific contributions of ventromedial, anterior cingulate, and lateral prefrontal cortex for attentional selection and stimulus valuation. PLoS Biol 9: e1001224, 2011. Kennerley SW, Walton ME, Behrens TE, Buckley MJ, Rushworth MF. Optimal decision making and the anterior cingulate cortex. Nat Neurosci 9: 940 –947, 2006. Klier EM, Martinez-Trujillo JC, Medendorp WP, Smith MA, Crawford JD. Neural control of 3-D gaze shifts in the primate. Prog Brain Res 142: 109 –124, 2003.


802


Koval MJ, Lomber SG, Everling S. Prefrontal cortex deactivation in macaques alters activity in the superior colliculus and impairs voluntary control of saccades. J Neurosci 31: 8659 – 8668, 2011. Lau HC, Rogers RD, Ramnani N, Passingham RE. Willed action and attention to the selection of action. Neuroimage 21: 1407–1415, 2004. Lebedev MA, Messinger A, Kralik JD, Wise SP. Representation of attended versus remembered locations in prefrontal cortex. PLoS Biol 2: e365, 2004. Leichnetz GR, Spencer RF, Hardy SG, Astruc J. The prefrontal corticotectal projection in the monkey; an anterograde and retrograde horseradish peroxidase study. Neuroscience 6: 1023–1041, 1981. Lennert T, Martinez-Trujillo J. Strength of response suppression to distracter stimuli determines attentional-filtering performance in primate prefrontal neurons. Neuron 70: 141–152, 2011. Leopold DA, Maier A. Ongoing physiological processes in the cerebral cortex. Neuroimage 62: 2190 –2200, 2012. Li CS, Mazzoni P, Andersen RA. Effect of reversible inactivation of macaque lateral intraparietal area on visual and memory saccades. J Neurophysiol 81: 1827–1838, 1999. Lomber SG, Payne BR, Horel JA. The cryoloop: an adaptable reversible cooling deactivation method for behavioral or electrophysiological assessment of neural function. J Neurosci Methods 86: 179 –194, 1999. Luna B, Thulborn KR, Strojwas MH, McCurtain BJ, Berman RA, Genovese CR, Sweeney JA. Dorsal cortical regions subserving visually guided saccades in humans: an fMRI study. Cereb Cortex 8: 40 – 47, 1998. Lynch JC, Graybiel AM, Lobeck LJ. The differential projection of two cytoarchitectonic subregions of the inferior parietal lobule of macaque upon the deep layers of the superior colliculus. J Comp Neurol 235: 241–254, 1985. Manly T, Owen AM, McAvinue L, Datta A, Lewis GH, Scott SK, Rorden C, Pickard J, Robertson IH. Enhancing the sensitivity of a sustained attention task to frontal damage: convergent clinical and functional imaging evidence. Neurocase 9: 340 –349, 2003. Martinez-Trujillo JC, Klier EM, Wang H, Crawford JD. Contribution of head movement to gaze command coding in monkey frontal cortex and superior colliculus. J Neurophysiol 90: 2770 –2776, 2003a. Martinez-Trujillo JC, Wang H, Crawford JD. Electrical stimulation of the supplementary eye fields in the head-free macaque evokes kinematically normal gaze shifts. J Neurophysiol 89: 2961–2974, 2003b. McDowell JE, Dyckman KA, Austin BP, Clementz BA. Neurophysiology and neuroanatomy of reflexive and volitional saccades: evidence from studies of humans. Brain Cogn 68: 255–270, 2008. Mennes M, Kelly C, Colcombe S, Castellanos FX, Milham MP. The extrinsic and intrinsic functional architectures of the human brain are not equivalent. Cereb Cortex 23: 223–229, 2013. Milea D, Lehericy S, Rivaud-Pechoux S, Duffau H, Lobel E, Capelle L, Marsault C, Berthoz A, Pierrot-Deseilligny C. Antisaccade deficit after anterior cingulate cortex resection. Neuroreport 14: 283–287, 2003. Miller EK, Cohen JD. An integrative theory of prefrontal cortex function. Annu Rev Neurosci 24: 167–202, 2001. Monteon JA, Constantin AG, Wang H, Martinez-Trujillo J, Crawford JD. Electrical stimulation of the frontal eye fields in the head-free macaque evokes kinematically normal 3D gaze shifts. J Neurophysiol 104: 3462– 3475, 2010. Morecraft RJ, Van Hoesen GW. Frontal granular cortex input to the cingulate (M3), supplementary (M2) and primary (M1) motor cortices in the rhesus monkey. J Comp Neurol 337: 669 – 689, 1993. Munakata Y, Herd SA, Chatham CH, Depue BE, Banich MT, O’Reilly RC. A unified framework for inhibitory control. Trends Cogn Sci 15: 453– 459, 2011. Munoz DP, Dorris MC, Pare M, Everling S. On your mark, get set: brainstem circuitry underlying saccadic initiation. Can J Physiol Pharmacol 78: 934 –944, 2000. Munoz DP, Everling S. Look away: the anti-saccade task and the voluntary control of eye movement. Nat Rev Neurosci 5: 218 –228, 2004. Munoz DP, Guitton D. Presaccadic burst discharges of tecto-reticulo-spinal neurons in the alert head-free and -fixed cat. Brain Res 398: 185–190, 1986. Munoz DP, Istvan PJ. Lateral inhibitory interactions in the intermediate layers of the monkey superior colliculus. J Neurophysiol 79: 1193–1209, 1998. Muri RM, Nyffeler T. Neurophysiology and neuroanatomy of reflexive and volitional saccades as revealed by lesion studies with neurological patients and transcranial magnetic stimulation (TMS). Brain Cogn 68: 284 –292, 2008.

Niki H, Watanabe M. Prefrontal and cingulate unit activity during timing behavior in the monkey. Brain Res 171: 213–224, 1979. Owen AM, Evans AC, Petrides M. Evidence for a two-stage model of spatial working memory processing within the lateral frontal cortex: a positron emission tomography study. Cereb Cortex 6: 31–38, 1996. Palmer LM, Schulz JM, Murphy SC, Ledergerber D, Murayama M, Larkum ME. The cellular basis of GABA(B)-mediated interhemispheric inhibition. Science 335: 989 –993, 2012. Paus T. Primate anterior cingulate cortex: where motor control, drive and cognition interface. Nat Rev Neurosci 2: 417– 424, 2001. Paus T, Castro-Alamancos MA, Petrides M. Cortico-cortical connectivity of the human mid-dorsolateral frontal cortex and its modulation by repetitive transcranial magnetic stimulation. Eur J Neurosci 14: 1405–1411, 2001. Petrides M, Alivisatos B, Frey S. Differential activation of the human orbital, mid-ventrolateral, and mid-dorsolateral prefrontal cortex during the processing of visual stimuli. Proc Natl Acad Sci U S A 99: 5649 –5654, 2002. Petrides M, Pandya DN. Dorsolateral prefrontal cortex: comparative cytoarchitectonic analysis in the human and the macaque brain and corticocortical connection patterns. Eur J Neurosci 11: 1011–1036, 1999. Phillips JM, Johnston K, Everling S. Effects of anterior cingulate microstimulation on pro- and antisaccades in nonhuman primates. J Cogn Neurosci 23: 481– 490, 2011. Picard N, Strick PL. Motor areas of the medial wall: a review of their location and functional activation. Cereb Cortex 6: 342–353, 1996. Pierrot-Deseilligny C, Milea D, Muri RM. Eye movement control by the cerebral cortex. Curr Opin Neurol 17: 17–25, 2004. Pierrot-Deseilligny C, Rosa A, Masmoudi K, Rivaud S, Gaymard B. Saccade deficits after a unilateral lesion affecting the superior colliculus. J Neurol Neurosurg Psychiatry 54: 1106 –1109, 1991. Polli FE, Barton JJ, Cain MS, Thakkar KN, Rauch SL, Manoach DS. Rostral and dorsal anterior cingulate cortex make dissociable contributions during antisaccade error commission. Proc Natl Acad Sci U S A 102: 15700 –15705, 2005. Pouget P, Stepniewska I, Crowder EA, Leslie MW, Emeric EE, Nelson MJ, Schall JD. Visual and motor connectivity and the distribution of calcium-binding proteins in macaque frontal eye field: implications for saccade target selection. Front Neuroanat 3: 2, 2009. Procyk E, Joseph JP. Characterization of serial order encoding in the monkey anterior cingulate sulcus. Eur J Neurosci 14: 1041–1046, 2001. Procyk E, Tanaka YL, Joseph JP. Anterior cingulate activity during routine and non-routine sequential behaviors in macaques. Nat Neurosci 3: 502– 508, 2000. Rainer G, Asaad WF, Miller EK. Selective representation of relevant information by neurons in the primate prefrontal cortex. Nature 393: 577–579, 1998. Rizzolatti G, Riggio L, Dascola I, Umilta C. Reorienting attention across the horizontal and vertical meridians: evidence in favor of a premotor theory of attention. Neuropsychologia 25: 31– 40, 1987. Rohrer WH, White JM, Sparks DL. Saccade-related burst cells in the superior colliculus: Relationship of activity with saccadic velocity. Soc Neurosci Abstr 13: 1092, 1987. Rowe JB, Passingham RE. Working memory for location and time: activity in prefrontal area 46 relates to selection rather than maintenance in memory. Neuroimage 14: 77– 86, 2001. Rowe JB, Toni I, Josephs O, Frackowiak RS, Passingham RE. The prefrontal cortex: response selection or maintenance within working memory? Science 288: 1656 –1660, 2000. Sato TR, Schall JD. Effects of stimulus-response compatibility on neural selection in frontal eye field. Neuron 38: 637– 648, 2003. Schlag J, Dassonville P, Schlag-Rey M. Interaction of the two frontal eye fields before saccade onset. J Neurophysiol 79: 64 –72, 1998. Schlag J, Schlag-Rey M. Evidence for a supplementary eye field. J Neurophysiol 57: 179 –200, 1987. Scudder CA, Kaneko CS, Fuchs AF. The brainstem burst generator for saccadic eye movements: a modern synthesis. Exp Brain Res 142: 439 – 462, 2002. Selemon LD, Goldman-Rakic PS. Common cortical and subcortical targets of the dorsolateral prefrontal and posterior parietal cortices in the rhesus monkey: evidence for a distributed neural network subserving spatially guided behavior. J Neurosci 8: 4049 – 4068, 1988. Selemon LD, Goldman-Rakic PS. Longitudinal topography and interdigitation of corticostriatal projections in the rhesus monkey. J Neurosci 5: 776 –794, 1985.


SACCADIC EFFECTS OF COOLING dlPFC AND ACC Shen K, Bezgin G, Hutchison RM, Gati JS, Menon RS, Everling S, McIntosh AR. Information processing architecture of functionally defined clusters in the macaque cortex. J Neurosci 32: 17465–17476, 2012. Shibutani H, Sakata H, Hyvarinen J. Saccade and blinking evoked by microstimulation of the posterior parietal association cortex of the monkey. Exp Brain Res 55: 1– 8, 1984. Shmuel A, Leopold DA. Neuronal correlates of spontaneous fluctuations in fMRI signals in monkey visual cortex: implications for functional connectivity at rest. Hum Brain Mapp 29: 751–761, 2008. Smith SM, Fox PT, Miller KL, Glahn DC, Fox PM, Mackay CE, Filippini N, Watkins KE, Toro R, Laird AR, Beckmann CF. Correspondence of the brain’s functional architecture during activation and rest. Proc Natl Acad Sci U S A 106: 13040 –13045, 2009. Sommer MA, Tehovnik EJ. Reversible inactivation of macaque frontal eye field. Exp Brain Res 116: 229 –249, 1997. Sparks DL. The brainstem control of saccadic eye movements. Nat Rev Neurosci 3: 952–964, 2002. Stanford TR, Freedman EG, Sparks DL. Site and parameters of microstimulation: evidence for independent effects on the properties of saccades evoked from the primate superior colliculus. J Neurophysiol 76: 3360 –3381, 1996. Stanton GB, Goldberg ME, Bruce CJ. Frontal eye field efferents in the macaque monkey. II. Topography of terminal fields in midbrain and pons. J Comp Neurol 271: 493–506, 1988. Sweeney JA, Mintun MA, Kwee S, Wiseman MB, Brown DL, Rosenberg DR, Carl JR. Positron emission tomography study of voluntary saccadic eye movements and spatial working memory. J Neurophysiol 75: 454 – 468, 1996. Takahashi M, Sugiuchi Y, Izawa Y, Shinoda Y. Commissural excitation and inhibition by the superior colliculus in tectoreticular neurons projecting to omnipause neuron and inhibitory burst neuron regions. J Neurophysiol 94: 1707–1726, 2005. Thompson KG, Bichot NP, Schall JD. Dissociation of visual discrimination from saccade programming in macaque frontal eye field. J Neurophysiol 77: 1046 –1050, 1997.

803

Thompson KG, Biscoe KL, Sato TR. Neuronal basis of covert spatial attention in the frontal eye field. J Neurosci 25: 9479 –9487, 2005. van den Heuvel MP, Mandl RC, Kahn RS, Hulshoff Pol HE. Functionally linked resting-state networks reflect the underlying structural connectivity architecture of the human brain. Hum Brain Mapp 30: 3127–3141, 2009. Van Essen DC. Surface-based approaches to spatial localization and registration in primate cerebral cortex. Neuroimage 23, Suppl 1: S97–S107, 2004. Van Essen DC, Drury HA, Dickson J, Harwell J, Hanlon D, Anderson CH. An integrated software suite for surface-based analyses of cerebral cortex. J Am Med Inform Assoc 8: 443– 459, 2001. Van Essen DC, Glasser MF, Dierker DL, Harwell J. Cortical parcellations of the macaque monkey analyzed on surface-based atlases. Cereb Cortex 22: 2227–2240, 2012. Van Opstal AJ, Van Gisbergen JA, Smit AC. Comparison of saccades evoked by visual stimulation and collicular electrical stimulation in the alert monkey. Exp Brain Res 79: 299 –312, 1990. Vincent JL, Patel GH, Fox MD, Snyder AZ, Baker JT, Van Essen DC, Zempel JM, Snyder LH, Corbetta M, Raichle ME. Intrinsic functional architecture in the anaesthetized monkey brain. Nature 447: 83– 86, 2007. Wang Y, Matsuzaka Y, Shima K, Tanji J. Cingulate cortical cells projecting to monkey frontal eye field and primary motor cortex. Neuroreport 15: 1559 –1563, 2004. Wardak C, Olivier E, Duhamel JR. Saccadic target selection deficits after lateral intraparietal area inactivation in monkeys. J Neurosci 22: 9877–9884, 2002. Wegener SP, Johnston K, Everling S. Microstimulation of monkey dorsolateral prefrontal cortex impairs antisaccade performance. Exp Brain Res 190: 463– 473, 2008. Wurtz RH, Goldberg ME. Activity of superior colliculus in behaving monkey. IV. Effects of lesions on eye movements. J Neurophysiol 35: 587–596, 1972.


Neuronal activity related to saccadic eye movements in the monkey's dorsolateral prefrontal cortex.

b Isoform Levels in Human Brain Dorsolateral Prefrontal Cortex and Anterior Cingulate Cortex.

The effects of TMS over dorsolateral prefrontal cortex on trans-saccadic memory of multiple objects.

Motivation and affective judgments differentially recruit neurons in the primate dorsolateral prefrontal and anterior cingulate cortex.

Visual space is compressed in prefrontal cortex before eye movements.

Molecular influences on working memory circuits in dorsolateral prefrontal cortex.

Prefrontal thinning affects functional connectivity and regional homogeneity of the anterior cingulate cortex in depression.

Exon microarray analysis of human dorsolateral prefrontal cortex in alcoholism.

Multiple signals in anterior cingulate cortex.

Functional linkage between the electrical activity in the vermal cerebellar cortex and saccadic eye movements.

Effects of post-traumatic growth on the dorsolateral prefrontal cortex after a disaster.

The effects of transcranial direct current stimulation over the dorsolateral prefrontal cortex on cognitive inhibition.

Effects of mild to moderate sedation on saccadic eye movements.

Light therapy and serotonin transporter binding in the anterior cingulate and prefrontal cortex.

Ultrastructural analysis of parvalbumin synapses in human dorsolateral prefrontal cortex.

Impairment of Neuroplasticity in the Dorsolateral Prefrontal Cortex by Alcohol.

Crack cocaine use impairs anterior cingulate and prefrontal cortex function in women with HIV infection.

Anterior Cingulate Cortex Cells Identify Process-Specific Errors of Attentional Control Prior to Transient Prefrontal-Cingulate Inhibition.

Theta and beta synchrony coordinate frontal eye fields and anterior cingulate cortex during sensorimotor mapping.

Saccadic eye movements on Béla Julesz' figure.

Anterior cingulate cortex sulcation and its differential effects on conflict monitoring in bilinguals and monolinguals.

Opioid modulation of resting-state anterior cingulate cortex functional connectivity.

Reading without saccadic eye movements.

Influence of dorsolateral prefrontal cortex and ventral striatum on risk avoidance in addiction: a mediation analysis.