Cortical Eye Fields and Saccades

1. Cortical Pathways for Visually Guided Saccades

In primates, the cerebral cortex is a very important part of the saccadic circuitry. Although the SC seems to be the premier structure for visually guided saccades, it is not a critical component of saccade generation because the effects of SC lesions are largely transient, whereas the saccade structures downstream are vital. Thus, lesions of the saccade generator structures in the pontine and midbrain reticular formation permanently eliminate all rapid eye movements, including visually guided saccades, whereas SC lesions do not eliminate visually guided saccades at all. Following an acute period of visual neglect, there are few lasting oculomotor deficits following SC lesions in monkeys and man, with the most consistent lasting deficit being a modest increase in latency of visually guided saccades.

Visually guided saccades survive SC lesions because the primate also has an elaborate neocortical network for visually guided saccades. The connectivity diagram of Fig. 13 summarizes these cortical pathways and helps explain most effects of experimental lesions. For example, the sparing of visually guided saccades following SC lesions is mediated by FEF projections to the brain stem saccade generator; however, the SC normally provides a shorter path via its direct retinal projections, which explains the increase in saccade latency after SC damage. FEF lesions alone also spare visually guided saccades; however, FEF lesions combined with SC lesions eliminate most visually guided saccades. Thus, the SC and FEF provide parallel pathways for visual stimuli to activate the brain stem saccade generator for the purpose of accurate, foveat-ing saccades. It is also the case that visually guided saccades are spared following lesions of primary visual cortex (V1) even though conscious awareness of the visual world is lost. However, combined V1 and SC lesions eliminate visually guided saccades most likely because, as Fig. 13 indicates, V1 removal eliminates most visual inputs to FEF and, hence, renders FEF incapable of triggering visually guided saccades.

2. Frontal Eye Field Anatomy and Physiology

David Ferrier discovered (~ 1875) that electrical stimulation in the frontal lobe of macaque monkeys deviated the eyes toward the contralateral side, and it was soon confirmed that many primate species, including man, have such an FEF. These electrically elicited eye movements are indistinguishable from naturally occurring saccadic eye movements, and each site in FEF yields saccades of a characteristic direction and amplitude, with the set of all possible contralat-erally directed saccades represented in each hemisphere's FEF. The macaque FEF lies primarily in the anterior bank of the arcuate sulcus; the human FEF lies in the precentral sulcus, behind the middle frontal gyrus and in front of the hand representation in the precentral gyrus (Fig. 14).

FEF is not the only cortex specialized for eye movements. There is also the parietal eye field (PEF),

Parietal Eye Field

Figure 13 Pathways for visually guided saccades. Anatomical connections between cortical and subcortical structures involved in the control and generation of saccadic eye movements. The frontal eye field (FEF) receives visual information via pathways originating in the striate cortex, as does the parietal eye field (PEF) and the supplementary eye field (SEF). Notice that all these cortical areas project to the superior colliculus (SC), with FEF, PEF, and SEF all projecting primarily to its intermediate layers. In contrast, the superficial layers of SC receive direct visual projections from the retina and indirect visual projections from the striate and extrastriate cortices. The brain stem saccade generator is in the paramedian pontine reticular formation (PPRF) and in the rostral interstitial nucleus of the medial longitudinal fasciculus (riMLF). The brain stem neural integrator is in the medial vestibular nucleus (MVN), the adjacent nucleus prepositus hypoglossi (NPH), and the interstitial nucleus of Cajal (INC). Additional structures and pathways involved in saccades, such as the thalamus and basal ganglia, are omitted for simplicity.

Figure 13 Pathways for visually guided saccades. Anatomical connections between cortical and subcortical structures involved in the control and generation of saccadic eye movements. The frontal eye field (FEF) receives visual information via pathways originating in the striate cortex, as does the parietal eye field (PEF) and the supplementary eye field (SEF). Notice that all these cortical areas project to the superior colliculus (SC), with FEF, PEF, and SEF all projecting primarily to its intermediate layers. In contrast, the superficial layers of SC receive direct visual projections from the retina and indirect visual projections from the striate and extrastriate cortices. The brain stem saccade generator is in the paramedian pontine reticular formation (PPRF) and in the rostral interstitial nucleus of the medial longitudinal fasciculus (riMLF). The brain stem neural integrator is in the medial vestibular nucleus (MVN), the adjacent nucleus prepositus hypoglossi (NPH), and the interstitial nucleus of Cajal (INC). Additional structures and pathways involved in saccades, such as the thalamus and basal ganglia, are omitted for simplicity.

located in the lateral bank of the intraparietal sulcus in the macaque, and the supplementary eye field (SEF), located in the frontal lobe near the midline. FEF, SEF, and PEF are reciprocally interconnected with each other; however, FEF seems to be the principal cortical eye field. FEF has the lowest thresholds for electrically elicited saccades, oculomotor behavior after FEF lesions is generally more impaired than after lesions of the other eye fields, and FEF is indispensable for visually guided saccades if the SC is damaged.

3. Effects of FEF Lesions

Gordon Holmes found that patients with frontal lesions had difficulty moving their eyes in response to verbal commands, even though they could follow visual objects and understood the verbal commands. In a 1938 lecture, he concluded that ''the frontal centers make possible the turning of gaze in any desired direction and the exploration of space, but they also keep under control, or inhibit, reflexes that are not appropriate.'' In 1985, Daniel Guitton and colleagues used the antisaccade paradigm to demonstrate that ''frontal lobe lesions in man cause difficulties in suppressing reflexive glances and in generating goal-directed saccades.'' In other words, their subjects could not launch saccades in the direction opposite the visual target (antisaccades), even though they understood that to be the task. Instead, they made inappropriate saccades toward the visual targets (prosaccades), exactly what they were instructed not to do. Similarly, subjects with FEF lesions have difficulty making memory saccades and in making predictive saccades to square-wave target motion. Thus, lesion studies show that FEF is important for ''purposive'' saccades, particularly when there is no visual target present to trigger the visual grasp reflex.

Saccade Brain Frontal Eye Field

Figure 14 Cortex for eye movements in man and monkey. Cortical regions important for saccade and smooth-pursuit eye movements are highlighted on lateral views of a monkey brain (top) and human brain (bottom). In both monkey and man, FEF is in front of premotor cortex for the hand and neck and mostly lies within the sulcus marking the anterior limit of the precentral gyrus. In both species, the smooth-pursuit region of FEF is just posterior to the saccadic region of FEF. A dorsolateral view is used for the monkey brain in order to minimize distortion of the frontal lobe sulci.

Figure 14 Cortex for eye movements in man and monkey. Cortical regions important for saccade and smooth-pursuit eye movements are highlighted on lateral views of a monkey brain (top) and human brain (bottom). In both monkey and man, FEF is in front of premotor cortex for the hand and neck and mostly lies within the sulcus marking the anterior limit of the precentral gyrus. In both species, the smooth-pursuit region of FEF is just posterior to the saccadic region of FEF. A dorsolateral view is used for the monkey brain in order to minimize distortion of the frontal lobe sulci.

4. FEF Bursts Precede All Types of Purposive Saccades

During the past three decades, single-neuron recordings in trained macaque monkeys have resulted in a detailed picture of FEF activity during all manner of voluntary oculomotor behavior. Presaccadic bursts are the signature activity of FEF and are manifest in more than 30% of FEF neurons. These bursts begin prior to saccade initiation, usually end sharply just after the saccade is completed, and are always tuned for particular saccade vectors, similar to saccade related bursters in the SC and vectorial LLBNs in the pons. Presaccadic bursts seem to constitute the FEF command to the saccade generator (both directly and through the SC), providing both an impetus to saccade and a saccade vector specification. Indeed, electrical stimulation through a recording microelectrode in FEF elicits natural-looking saccades that closely match the vector for the optimal presaccadic burst of nearby cells. Moreover, FEF-elicited saccades are very insistent and are still elicited with low currents even when subjects are intently fixating a stationary light.

a. Visually Guided Saccades FEF neurons have robust presaccadic bursts in conjunction with visually guided saccades. The average response of 51 FEF cells recorded in a single monkey during a ''stable-target'' type of saccade task is shown in Fig. 15A. This task was chosen to separate any phasic visual response to the appearance of the peripheral target from the presaccadic burst. This provides a baseline for assessing presaccadic bursts made without an overt target.

b. Memory Saccades Presaccadic bursts of FEF neurons in conjunction with saccades made to remembered targets are generally equivalent to bursts associated with visually guided saccades on the stable-target task. In this paradigm, as shown for a representative visuomovement neuron in Fig. 15B, a peripheral cue appears only briefly, and the saccade is made some time later and hence must be guided by a short-term memory of the cue.

c. Antisaccades FEF neurons also have robust presaccadic bursts in conjunction with antisaccades, as shown in Fig. 15C for another representative visuomovement neuron. The cell discharged preceding antisaccades into its visuomovement RF, even though the visual cue had been on the opposite side and thus not at all in the cell's RF.

d. Other Purposive Saccades FEF cells have also been demonstrated to reliably burst for some other types of purposive saccades (e.g., saccades made to the locations of sounds). It is interesting to speculate that FEF lesions might disrupt socially motivated saccades and that FEF cells would burst in conjunction with such saccades, but this has not been tested.

e. Spontaneous Saccades In contrast with most purposive saccades, FEF bursts are usually weaker in conjunction with spontaneous saccades made in the dark, presumably because such saccades are usually not purposive.

5. FEF Activities and Circuits

Just as the basic VOR reflex has a set of associated assisting circuits, a diverse set of functional activities and cortical circuits underlie FEF's programming of purposive saccades in the monkey. These serve to facilitate the generation of appropriate presaccadic bursts in diverse situations and paradigms.

a. Visual Activity More than half the neurons in FEF are visually responsive. Typically, they have large RFs centered in the contralateral hemifield and respond to the appearance of any stimulus within their RF, without much selectivity for color or form. Moreover, FEF visual responses do not require overt attention to the stimulus or the RF location or that the stimulus has functional significance to the monkey.

b. Alignment of Visual and Presaccadic Movement Fields Visuomovement FEF cells have both visual and presaccadic burst activities, and their visual RF generally corresponds with the optimal saccade vector for their burst (i.e., movement field) and also to the electrically elicited saccadic eye movement vector obtained at the cell's location. Thus, the FEF default is a foveating saccade. However, the presaccadic burst is independent of the location and/or the presence of RF stimulation as shown by the memory saccade and antisaccade tasks (Fig. 15B,C). Moreover, a minority of FEF cells are discordant with nonmatching, or even nonoverlapping, visual and movement fields.

c. Tonic Visual Activity The strongest aggregate visual response in FEF is to the initial appearance of visual targets, and many visual cells only respond to this appearance. However, other visual cells tonically respond as long as the target remains in their RF. Notice in Fig. 15A that the composite spike rate was elevated throughout the wait period (between the phasic visual response and the eventual presaccadic burst). Thus, FEF visual activity can guide saccades to old, ''stable'' visual targets as well as newly appearing targets.

d. Mnemonic Activity Usually tonic visual FEF activity is maintained even after the visual cue is extinguished, and this activity could provide a short-term memory of the visual cue location in the memory saccade test. Many individual FEF cells have robust mnemonic responses (Fig. 15B). However, when many FEF cells are averaged, the mnemonic signal is only a modest elevation of the overall spike rate, especially when compared to the size of the presaccadic burst. Tonic neural activity has a high metabolic cost; therefore, it is economical for overall tonic visual and tonic mnemonic activity to be minimal—just robust enough to inform spatially appropriate saccades whenever the go signal finally arrives.

e. Postsaccadic Activity Coding Executed Saccades (Efferent Copy) Postsaccadic activity in the FEF was first described by Emilio Bizzi, and ~25% of FEF neurons are excited after particular saccadic eye movements. This postsaccadic activity seems to be an efferent copy of saccades actually executed because it reliably follows every saccade made into the cell's postsaccadic movement field, even spontaneous saccades made in the dark or rapid phases of nystagmus. A timely efferent copy of saccadic displacements, as coded by postsaccadic activity in FEF, is critical for several of the following circuits. Interestingly, many FEF cells with presaccadic (visual, movement, or

Saccades Activity

Figure 15 Frontal eye field activity for purposive saccades. (A) Aggregate activity of 51 FEF neurons recorded from one monkey during the stable-target type of visually guided saccade task. (Top) Task events: Shortly after the monkey fixates a central light, a peripheral target appears in the neuron's response field (RF). This target remains on for the remainder of the trial, but no saccade is permitted until the fixation light is extinguished at the end of the wait period. Thus, the target is a stable presence at the time of the saccade. (Bottom) The histogram aligned on the target appearance (left) shows the aggregate visual response. The histogram aligned on the saccade start (right) shows the large aggregate burst that starts just prior to the saccade. Thus, FEF activity manifests both visual (phasic and tonic) andmovement activities (H. R. Friedman and C. J. Bruce, unpublished data). (B) Activity of a visuomovement FEF neuron from a second monkey tested on memory-saccade task. (Top) Task events: Shortly after the monkey fixates a central light, a peripheral cue briefly appears. Then, after a delay period, the fixation light is extinguished and the monkey must saccade to the location where the peripheral cue had been shown earlier. Thus, unlike in A, there is no visual target present at the time of the saccade. (Bottom) Rasters (by trial) and histograms of spike activity aligned on cue onset (left) show the burst of activity elicited by the visual stimulus and aligned on saccade onset (right) show the large burst of activity preceding the saccades. Note that the visual response has three components: a phasic high-rate burst to the initial appearance of the visual stimulus (with a latency of ~ 50 msec), a robust tonic visual discharge while the cue remained on, and then, starting ~ 50 msec after the cue was extinguished, a medium-level tonic mnemonic response that was maintained above the cell's baseline level of activity throughout the delay interval (M. S. Kraus, H. R. Friedman, and C.J. Bruce, unpublished data). (C) Activity of a visuomovement FEF neuron, from a third monkey, tested on an antisaccade task (memory version). As in B, the monkey must remember the position of a brief visual cue across a delay interval. However, unlike in B, the correct response (once the fixation light goes off) is a saccade to the location opposite to where the cue was shown. The visual RF of this cell was on the left when tested with conventional ''prosaccade'' tasks and its presaccadic bursts were maximal for leftward saccades. (Top, left) The cell discharged preceding leftward antisaccades, even though the visual cue had been in the right side and thus not in its RF. (Bottom, left) The neuron was silent before rightward antisaccades even though the visual cue had been in its RF. Interestingly, its bursts were completely predictive of erroneous prosaccades mistakenly made on some trials (right). (H. R. Friedman and C. J. Bruce, unpublished data).

both) activity also have postsaccadic activity for saccades directed opposite their presaccadic RF. This provides a mechanism for readily returning to the previous fixation (i.e., glances).

f. Suppression of Presaccadic Activities by Saccade Execution A striking aspect of FEF presaccadic activity of all types (e.g., anticipatory, visual, mnemonic, and movement) is that it quickly ceases upon the execution of a saccade into the RF. Notice in Fig. 15 that saccade execution actively suppresses both tonic visual (Fig. 15A) and mnemonic (Fig. 15B) activity as well as the presaccadic bursts.

This suppression could come from the postsaccadic coding of prior saccades (efferent copy) previously described. Such suppression is very important because visual or mnemonic activity coding a peripheral cue location becomes invalid once the monkey foveates the peripheral location. Without prompt suppression, persistent activity could lead to multiple triggering of the same saccade, much like the ''staircase'' of saccades evoked by continued electrical stimulation in FEF.

g. Fixation Status Signals (Tonic Foveation and Eye Position Activity) Some FEF cells provide tonic signals concerning the current fixation target rather than pertaining to possible saccade targets. One class is excited by fixation (foveal) stimulation; their activity could play a role in suppressing other saccade cells in FEF and elsewhere in the interest of maintaining fixation. Another class has the inverse activity, being suppressed by foveal stimulation and active thereafter, and thus signaling the extinction of the current fixation light. A small minority of cells tonically respond as a linear function of absolute eye position (e.g., elevation); they could be receiving an efferent copy from the common neural integrator, and some have foveal responses that are modulated by the current eye position.

h. Other Saccade-Related Activities and Responses Many FEF cells show anticipatory activity for predictable saccadic situations. This activity could decrease saccade latency by biasing FEF in favor of the predicted saccade dimensions. Sometimes, anticipatory activity is purely guessing. For example, in the ''gap'' paradigm, wherein the signal to saccade (e.g., fixation light off) precedes the peripheral target appearance by 100-200 msec, FEF neurons with presaccadic motor bursts will first discharge at an intermediate level in response to the fixation light extinction and then drastically accelerate or suppress their rate after the peripheral target comes in the neuron's RF or opposite it. Saccade latencies in the gap paradigm are typically shorter than in conventional saccade tasks and are termed express saccades.

Cells in and near the medial FEF have responses to sound. Their auditory RFs are partially remapped from a craniocentric to a retinocentric framework, which should facilitate FEF bursts known to precede aurally guided saccades. Moreover, there is a pinna movement region adjacent to the medial FEF of the monkey (Fig. 14).

Finally, saccades to moving targets are usually directed at a predicted target location, based on both retinal position and velocity. Visual and movement RFs of FEF neurons evidence this predictive process, indicating that target motion information is being utilized.

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