Frontal eye field activity preceding aurally guided saccades.

The frontal eye field (FEF) is a cortical structure involved in cognitive aspects of eye movement control. Neurons in the FEF, as in most of cerebral cortex, primarily represent contralateral space. They fire for visual stimuli in the contralateral field and for saccadic eye movements made to those stimuli. Yet many FEF neurons engage in sophisticated functions that require flexible spatial representations such as shifting receptive fields and vector subtraction. Such functions require knowledge about all of space, including the ipsilateral hemifield. How does the FEF gain access to ipsilateral information? Here we provide evidence that one source of ipsilateral information may be the opposite superior colliculus (SC) in the midbrain. We physiologically identified neurons in the FEF that receive input from the opposite SC, same-side SC, or both. We found a striking structure-function relationship: the laterality of an FEF neuron's response field was predicted by the laterality of its SC inputs. FEF neurons with input from the opposite SC had ipsilateral fields, while neurons with input from the same-side SC had contralateral fields. FEF neurons with input from both SCs had lateralized fields that could point in any direction. The results suggest that signals from the two SCs provide each FEF with information about all of visual space, a prerequisite for higher level sensorimotor computations.

The frontal eye field (FEF) contributes to directing visual attention and saccadic eye movement through intrinsic processing, interactions with extrastriate visual cortical areas (e.g., V4), and projections to subcortical structures (e.g., superior colliculus, SC). Several models have been proposed to describe the relationship between the allocation of visual attention and the production of saccades. We obtained anatomical information that might provide useful constraints on these models by evaluating two characteristics of FEF. First, we investigated the laminar distribution of efferent connections from FEF to visual areas V4 + TEO and to SC. Second, we examined the laminar distribution of different populations of GABAergic neurons in FEF. We found that the neurons in FEF that project to V4 + TEO are located predominantly in the supragranular layers, colocalized with the highest density of calbindin- and calretinin-immunoreactive inhibitory interneurons. In contrast, the cell bodies of neurons that project to SC are found only in layer 5 of FEF, colocalized primarily with parvalbumin inhibitory interneurons. None of the neurons in layer 5 that project to V4 + TEO also project to SC. These results provide useful constraints for cognitive models of visual attention and saccade production by indicating that different populations of neurons project to extrastriate visual cortical areas and to SC. This finding also suggests that FEF neurons projecting to visual cortex and SC are embedded in different patterns of intracortical circuitry.

An internal model for predictive saccades in frontal cortex was investigated by recording neurons in monkey frontal eye field during an inferred motion task. Monkeys were trained to make saccades to the extrapolated position of a small moving target that was rendered temporarily invisible and whose trajectory was altered. On roughly two-thirds of the trials, monkeys made multiple saccades while the target was invisible. Primary saccades were correlated with extrapolated target position. Secondary saccades significantly reduced residual errors resulting from imperfect accuracy of the first saccade. These observations suggest that the second saccade was corrective. As there was no visual feedback, corrective saccades could only be driven by an internally generated error signal. Neuronal activity in the frontal eye field was directionally tuned prior to both primary and secondary saccades. Separate subpopulations of cells encoded either saccade direction or direction error prior to the second saccade. These results suggest that FEF neurons encode the error after the first saccade, as well as the direction of the second saccade. Hence, FEF appears to contribute to detecting and correcting movement errors based on internally generated signals.

Schizophrenia is thought to arise from the interaction of genetically mediated and environmentally triggered abnormalities in brain function. Reduced frontal activation, reported in schizophrenic patients, may be one expression of genetic risk. The present study investigated whether frontal activation in relatives of schizophrenic patients would be related to eye tracking deficits (ETD), which are considered a behavioral marker of risk for schizophrenia. Subjects were first-degree relatives of schizophrenic patients (n = 17) and controls (n = 11). Relatives were divided into those with normal and abnormal pursuit based on qualitative ratings. Subjects were scanned using positron emission tomography and the H(2)15O bolus subtraction technique while performing smooth pursuit and fixation. Brain areas more active in pursuit than fixation were identified in the 3 groups. Correlations were used to investigate the relationship between activation of pursuit regions and pursuit gain in the relatives. Controls significantly activated frontal eye fields (FEFs) and posterior areas, including the motion processing area, V5, and cuneus. The 2 groups of relatives activated the same posterior regions as controls, but differed from each other in activation of FEFs. Relatives with normal tracking activated right dorsal FEFs while relatives with ETD did not. Individual subtractions revealed that 90% of controls and 100% of the relatives with normal tracking activated FEFs during pursuit compared with 42% of relatives with ETD (P = .009). Pursuit gain was significantly and selectively associated with percent activation of right dorsal FEFs (r = 0.74). Subtle frontal dysfunction seems to be a pathophysiological substrate of ETD in relatives of schizophrenic patients, and may be one aspect of genetically mediated differences in brain function relevant to schizophrenia.

Both the frontal eye field (FEF) in the prefrontal cortex and the superior colliculus (SC) on the roof of the midbrain participate in the generation of rapid or saccadic eye movements and both have projections to the premotor circuits of the brain stem where saccades are ultimately generated. In the present experiments, we tested the contributions of the pathway from the FEF to the premotor circuitry in the brain stem that bypasses the SC. We assayed the contribution of the FEF to saccade generation by evoking saccades with direct electrical stimulation of the FEF. To test the role of the SC in conveying information to the brain stem, we inactivated the SC, thereby removing the circuit through the SC to the brain stem, and leaving only the direct FEF-brain stem pathway. If the contributions of the direct pathway were substantial, removal of the SC should have minimal effect on the FEF stimulation, whereas if the FEF stimulation were dependent on the SC, removal of the SC should alter the effect of FEF stimulation. By acutely inactivating the SC, instead of ablating it, we were able to test the efficiency of the direct FEF-brain stem pathway before substantial compensatory mechanisms could mask the effect of removing the SC. We found two striking effects of SC inactivation. In the first, we stimulated the FEF at a site that evoked saccades with vectors that were very close to those evoked at the site of the SC inactivation, and with such optimal alignment, we found that SC inactivation eliminated the saccades evoked by FEF stimulation. The second effect was evident when the FEF evoked saccades were disparate from those evoked in the SC, and in this case we observed a shift in the direction of the evoked saccade that was consistent with the SC inactivation removing a component of a vector average. Together these observations lead to the conclusion that in the nonablated monkey the direct FEF-brain stem pathway is not functionally sufficient to generate accurate saccades in the absence of the indirect pathway that courses from the FEF through the SC to the brain stem circuitry. We suggest that the recovery of function following SC ablation that has been seen in previous studies must result not from the use of an already functioning parallel pathway but from neural plasticity within the saccadic system.

We investigated the link between neuronal activity in the frontal eye field (FEF) and the enhancement of visual processing associated with covert spatial attention in the absence of eye movements. We correlated activity recorded in the FEF of monkeys manually reporting the identity of a visual search target to performance accuracy and reaction time. Monkeys were cued to the most probable target location with a cue array containing a popout color singleton. Neurons exhibited spatially selective responses for the popout cue stimulus and for the target of the search array. The magnitude of activity related to the location of the cue prior to the presentation of the search array was correlated with trends in behavioral performance across valid, invalid, and neutral cue trial conditions. However, the speed and accuracy of the behavioral report on individual trials were predicted by the magnitude of spatial selectivity related to the target to be identified, not for the spatial cue. A minimum level of selectivity was necessary for target detection and a higher level for target identification. Muscimol inactivation of FEF produced spatially selective perceptual deficits in the covert search task that were correlated with the effectiveness of the inactivation and were strongest on invalid cue trials that require an endogenous attention shift. These results demonstrate a strong functional link between FEF activity and covert spatial attention and suggest that spatial signals from FEF directly influence visual processing during the time that a stimulus to be identified is being processed by the visual system.

1. Monkeys were trained to look to brief visual targets presented in a completely darkened room. On some trials, after the visual target disappeared but before a saccade to the target could be initiated, the eyes were driven to another position in the orbit by electrical stimulation of the superior colliculus. Retinocentric models of the saccadic system predict that a saccade with a predetermined distance and direction based entirely on retinal error will occur. If this were the case, gaze would miss the target location by a distance and direction equal to the vector of the stimulation-induced movement. Spatial models assume that the retinal error signal will be combined with information about the change in eye position produced by stimulation and predict that the animal will look to the position of the target in space. 2. Results confirm the predictions of spatial models. Animals compensated for the stimulation-induced perturbation by looking to the position of the target in space. The result predicted by retinocentric models-a saccade with a direction and amplitude based on retinal error alone-was never observed. 3. The eye movement that compensated for the change in eye position produced by stimulation was a saccade, not a passive, lowvelocity movement to an orbital position of mechanical equilibrium established by a tonic pattern of motoneuron activation specified by the visual target. This indicates that a new saccade command, based on stored information about the location of the retinal image and information about the new position of the eyes, had been issued. Computation of the vector of the compensatory saccade does not necessarily increase the latency of target acquisition. The interval between the end of a stimulation-induced saccade and the beginning of the compensatory saccade was frequently 20 ms or less, permitting the animal to acquire the target with a normal latency.

The dorsolateral prefrontal cortex (DLPFC) and the frontal eye fields (FEF) have both been implicated in the executive control of saccades, yet possible dissociable roles of each region have not been established. Specifically, both establishing a “task set” as well as suppressing an inappropriate response have been linked to DLPFC and FEF activity, with behavioral outcome measures of these mechanisms mainly being the percentage of pro-saccade errors made on anti-saccade trials. We used continuous theta-burst stimulation (cTBS) to disrupt FEF or DLPFC function in humans during an anti-saccade task to assess the causal role of these regions in these executive control processes, and in programming saccades towards (pro-saccade) or away (anti-saccade) from visual targets. After right FEF cTBS, as compared to control cTBS to the right primary somatosensory cortex (rS1), anti-saccade amplitude of the first saccade decreased and the number of anti-saccades to acquire final position increased; however direction errors to the visual target were not different. In contrast, after left DLPFC cTBS, as compared to left S1 cTBS, subjects displayed greater direction errors for contralateral anti-saccades; however, there were no impairments on the number of saccades or the saccade amplitude. These results are consistent with the notion that DLPFC is necessary for executive control of saccades, whereas FEF is necessary for visuo-motor aspects of anti-saccade programming.

Previous neurophysiological studies of the frontal eye field (FEF) in monkeys have focused on its role in saccade target selection and gaze shift control. It has been argued that FEF neurons indicate the locations of behaviorally significant visual stimuli and are not inherently sensitive to specific features of the visual stimuli per se. Here, for the first time, we directly examined single cell responses to simple, two-dimensional shapes and found that shape selectivity exists in a substantial number of FEF cells during a passive fixation task or during the sample, delay (memory), and eye movement periods in a delayed match to sample (DMTS) task. Our data demonstrate that FEF neurons show sensory and mnemonic selectivity for stimulus shape features whether or not they are behaviorally significant for the task at hand. We also investigated the extent and localization of activation in the FEF using a variety of shape stimuli defined by static or dynamic cues employing functional magentic resonance imaging (fMRI) in anesthetized and paralyzed monkeys. Our fMRI results support the electrophysiological findings by showing significant FEF activation for a variety of shape stimuli and cues in the absence of attentional and motor processing. This shape selectivity in FEF is comparable to previous reports in the ventral pathway, inviting a reconsideration of the functional organization of the visual system.

Voluntary attention is often allocated according to internally maintained goals. Recent evidence indicates that the frontal eye field (FEF) participates in the deployment of spatial attention, even in the absence of saccadic eye movements. In addition, many FEF neurons maintain persistent representations of impending saccades. However, the role of persistent activity in the general maintenance of spatial information, and its relationship to spatial attention, has not been explored. We recorded the responses of single FEF neurons in monkeys trained to remember cued locations in order to detect changes in targets embedded among distracters in a task that did not involve saccades. We found that FEF neurons persistently encoded the cued location throughout the trial, both during the delay period when no visual stimuli were present, and during visual discrimination. Furthermore, FEF activity reliably predicted whether monkeys would detect the target change. Population analyses revealed that FEF neurons with persistent activity were better at selecting the target from among distracters than neurons lacking persistent activity. These results demonstrate that FEF neurons maintain spatial information in the absence of saccade preparation and suggest that this maintenance contributes to the selection of relevant visual stimuli.

Optogenetic methods have been highly effective for suppressing neural activity and modulating behavior in rodents, but effects have been much smaller in primates, which have much larger brains. Here, we present a suite of technologies to use optogenetics effectively in primates and apply these tools to a classic question in oculomotor control. First, we measured light absorption and heat propagation in vivo, optimized the conditions for using the red-light-shifted halorhodopsin Jaws in primates, and developed a large-volume illuminator to maximize light delivery with minimal heating and tissue displacement. Together, these advances allowed for nearly universal neuronal inactivation across more than 10 mm3 of the cortex. Using these tools, we demonstrated large behavioral changes (i.e., up to several fold increases in error rate) with relatively low light power densities (≤100 mW/mm2) in the frontal eye field (FEF). Pharmacological inactivation studies have shown that the FEF is critical for executing saccades to remembered locations. FEF neurons increase their firing rate during the three epochs of the memory-guided saccade task: visual stimulus presentation, the delay interval, and motor preparation. It is unclear from earlier work, however, whether FEF activity during each epoch is necessary for memory-guided saccade execution. By harnessing the temporal specificity of optogenetics, we found that FEF contributes to memory-guided eye movements during every epoch of the memory-guided saccade task (the visual, delay, and motor periods).

We tested the hypothesis that frontal eye field (FEF) visual activity integrates visual information with a template of a target by examining whether a target that is not present in a search display influences the target selection in FEF. Neural activity was recorded in FEF of macaque monkeys performing visual search for a singleton target defined by color or direction of motion. The target remained constant throughout, but not across experimental sessions. Trials with distractors dissimilar to the target were interleaved with trials with distractors similar to the target. The hypothesis was tested by measuring the magnitude of activity in randomly interleaved trials with the target absent and only distractors in the display. We found that the response to the distractors was significantly greater when presented with displays consisting of distractors that resembled the absent target than when presented with displays consisting of distractors most different from the absent target. The influence of target-distractor similarity on FEF activity was also observed when the target was present, as reported previously. These data suggest that a template of the absent target can influence the selection process in FEF. This provides more direct evidence that FEF integrates visual information and knowledge of the target to determine the goal of a saccade.

Almost all cortical areas in the vertebrate brain take part in recurrent connections through the subcortical basal ganglia (BG) nuclei, through parallel inhibitory and excitatory loops. It has been suggested that these circuits can modulate our reactions to external events such that appropriate reactions are chosen from many available options, thereby imposing volitional control over behavior. The saccade system is an excellent model system to study cortico-BG interactions. In this study two possible pathways were investigated that might regulate automaticity of eye movements in the human brain; the cortico-tectal pathway, running directly between the frontal eye fields (FEF) and superior colliculus (SC) and the cortico-striatal pathway from the FEF to the SC involving the caudate nucleus (CN) in the BG. In an event-related functional magnetic resonance imaging (fMRI) paradigm participants made pro- and anti-saccades. A diffusion tensor imaging (DTI) scan was made for reconstruction of white matter tracts between the FEF, CN and SC. DTI fiber tracts were used to divide both the left and right FEF into two sub-areas, projecting to either ipsilateral SC or CN. For each of these FEF zones an event-related fMRI timecourse was extracted. In general activity in the FEF was larger for anti-saccades. This increase in activity was lateralized with respect to anti-saccade direction in FEF zones connected to the SC but not for zones only connected to the CN. These findings suggest that activity along the contralateral FEF–SC projection is responsible for directly generating anti-saccades, whereas the pathway through the BG might merely have a gating function withholding or allowing a pro-saccade.

Spatial attention is known to gate entry into visual short-term memory, and some evidence suggests that spatial signals may also play a role in binding features or protecting object representations during memory maintenance. To examine the persistence of spatial signals during object short-term memory, the activity of neurons in the Frontal Eye Field (FEF) of macaque monkeys was recorded during an object-based delayed match-to-sample (DMS) task. In this task monkeys were trained to remember an object image over a brief delay, irrespective of the locations of the sample or target presentation. FEF neurons exhibited visual, delay, and target period activity, including selectivity for sample location and target location. Delay period activity represented the sample location throughout the delay, despite the irrelevance of spatial information for successful task completion. Furthermore, neurons continued to encode sample position in a variant of the task in which the matching stimulus never appeared in their response field, confirming that FEF maintains sample location independent of subsequent behavioral relevance. FEF neurons also exhibited target-position-dependent anticipatory activity immediately prior to target onset, suggesting that monkeys predicted target position within blocks. These results show that FEF neurons maintain spatial information during short-term memory, even when that information is irrelevant for task performance.

We examined whether the frontal eye fields (FEF) are involved in the suppression of reflexive saccades. Simultaneous recording of horizontal eye movements and functional magnetic resonance imaging enabled us to perform a randomized pro- and antisaccade task and to sort blood oxygenation level dependent (BOLD) time series on the basis of task performance. Saccadic reaction time distributions were comparable across tasks indicating a similar effort in preprocessing of the saccades. Furthermore, we found similar BOLD activation in FEF during both correctly performed pro- and antisaccades. Frontal eye field activation started prior to target presentation and saccade generation. While we observed only few erroneous antisaccades, these were associated with a decrease in BOLD activity prior to target presentation, and increased BOLD activity after target presentation relative to correctly performed antisaccades. These findings are consistent with a role of the FEF in the suppression of reflexive saccades. The increase in activity after target presentation for antisaccade errors can only be indirectly linked to such a role but may also reflect activity related to the generation of a correction saccade. Frontal eye field BOLD activity may further represent general arousal, preparatory set, short-term memory, or salience-map related activity.