Direction of saccadic and smooth eye movements induced by electrical stimulation of the human frontal eye field: effect of orbital position

The present study reports on the direction of saccadic and smooth eye movements, which were induced electrically from the human dorsolateral frontal cortex including the human frontal eye field (FEF). The eye position prior to stimulation was varied in order to examine its effect on induced eye movement direction. The five patients of the study underwent invasive presurgical evaluation for pharmacoresistant epilepsy. The present data show that the direction of electrically induced eye movements was always contralateral and either horizontal or oblique upward if the eye started from the primary position. The elicited direction was changed if the eyes started from an eccentric position. The frequency of oblique eye movements was increased and oblique downward responses were induced, which were not observed if the eye started from the primary position. This was found for saccades and, especially, for smooth eye movements. Head movements, which were almost exclusively induced with saccades, did not depend on initial orbital position. Four conclusions can be drawn. Firstly, saccades and smooth eye movements induced from the human dorsolateral cortex including the human FEF have the same directional bias. Secondly, the frequent upward responses and the absence of downward responses induced from the primary position suggests either a more numerous or a more superficial representation of neurons that code for the former direction. Thirdly, at some sites the direction of saccades and smooth eye movements varies depending on the initial orbital position. Since these directional changes were observed without changes in eye-head coordination, our data suggest that stimulation of the FEF might evoke goal-directed saccades or interferes with a resettable saccade integrator. Fourthly, human studies that investigate eye movements induced from the lateral frontal cortex need to control eye position prior to stimulation. Electronic Publication     

The frontal eye field provides the goal of saccadic eye movement

Summary Microstimulation of oculomotor regions in primate cortex normally evokes saccadic eye movements of stereotypic directions and amplitudes. The fixed-vector nature of the evoked movements is compatible with the creation of either an artificial retinal or motor error signal. However, when microstimulation is applied during an ongoing natural saccade, the starting eye position of the evoked movement differs from the eye position at stimulation onset (due to the latency of the evoked saccade). An analysis of the effect of this eye position discrepancy on the trajectory of the eventual evoked saccade can clarify the oculomotor role of the structure stimulated. The colliding saccade paradigm of microstimulation was used in the present study to investigate the type of signals conveyed by visual, visuomovement, and movement unit activities in the primate frontal eye field. Colliding saccades elicited from all sites were found to compensate for the portion of the initial movement occurring between stimulation and evoked movement onset, plus a portion of the initial movement occurring before stimulation. This finding suggests that activity in the frontal eye field encodes a retinotopic goal that is converted by a downstream structure into the vector of the eventual saccade. Offprint requests to: J. Schlag, Department of Anatomy and Cell Biology     

Anticipatory smooth eye movements and predictive pursuit after unilateral lesions in human brain

Anticipatory smooth eye movements precede expected changes in target motion. It has been questioned whether anticipatory smooth eye movements are a component of the smooth pursuit system. Five subjects with unilateral brain lesions and five control subjects were tested with predictable double-ramp stimuli to determine whether these lesions have a similar effect on horizontal, visually guided smooth pursuit, anticipatory smooth eye movements, and the predictive component of smooth pursuit. All four subjects with a brain lesion involving the parietal or parietal-frontal lobe had parallel velocity asymmetries in all three forms of smooth eye movements, with lowest velocities toward the side of the lesion. A similar uniformity and magnitude of smooth eye movement directional asymmetries were not found in control subjects. Unidirectional attenuation of these three forms of smooth eye movements provides evidence that they are part of a unified smooth eye movement system.     

Frontal eye field lesions impair predictive and visually-guided pursuit eye movements

Summary The study initially explored the frontal eye field's (FEF) control of predictive eye movements, i.e., eye movements driven by previous rather than current sensory signals. Five monkeys were trained to pursue horizontal target motion, including sinusoidal targets and random-walk targets which sometimes deviated from a sine motion. Some subjects also tracked other target trajectories and optokinetic motion. FEF ablations or cold lesions impaired predictive pursuit, but also degraded visually guided foveal pursuit of all targets. Unilateral lesions impaired pursuit of targets moving in both horizontal orbital fields and in both directions of movement. Saccadic estimates of target motion were generally accurate. The slow-phase velocity of optokinetic pursuit (collected after 54 s of OKN) also appeared normal. Pursuit recovered over 1–3 weeks after surgery but the deficits were then reinstated by removal of FEF in the other hemisphere. Thereafter, a slight deficit persisted for up to 10 weeks of observation in two subjects. The pattern of symptoms suggests that FEF lies subsequent to parietal area MST and prior to the pontine nuclei in controlling pursuit eye movements.     

Effects of frontal eye field stimulation upon activities of the lateral geniculate body of the cat

Summary Effects of electrical stimulation of the frontal eye field (FEF) upon activities of the lateral geniculate body (LG) were studied in encéphale isolé cats. In some experiments the effects were examined by recording field responses of the dorsal nucleus of LG (LGd) and the visual cortex (VC) to electrical stimulation of the optic chiasm (OX). Conditioning repetitive stimulation of FEF exerted no significant effects on the r₁ wave of LGd responses but had a facilitatory effect on the r₂ wave. FEF-induced facilitation of VC responses was prominent in the late postsynaptic components. These effects had latencies of 50–100 msec and durations of 200–500 msec. Transection of the midbrain showed that most of the FEF-effect was not mediated via the brainstem reticular formation.Extracellular unitary recordings were made from 125 neurons, of which 91 were LGd neurons, 23 neurons of the caudal part of the thalamic reticular nucleus (TRc) and 11 neurons of the ventral nucleus of LG (LGv). In 30 of 87 LGd relay neurons FEF stimuli increased response probabilities to OX stimuli and their spontaneous discharges. These FEF-facilitated LGd neurons were distinguished from the non-affected ones in that the former had longer OX-latencies than the latter. The FEF-facilitated neurons probably correspond to X neurons of LGd.In 17 TRc neurons the effects were inhibitory. Their time courses were similar to those of the facilitation in the LGd relay neurons. Seven LGv neurons received facilitatory effects from FEF. Among them 5 neurons showed short-latency (6.7–17 msec) responses to FEF single shocks.The FEF sites inducing conjugate lateral eye movements exerted stronger facilitatory effects than those inducing upward or centering eye movements did.It is suggested that the effects may subserve to cancel the inhibitory convergence onto X-cells just after saccadic eye movements so as to improve visual information transmission through LGd during the eye fixation.     

Control of fixation and saccades during an anti-saccade task: an investigation in humans with chronic lesions of oculomotor cortex

Fourteen patients with a chronic, unilateral lesion restricted to the frontal lobe (twelve involving the frontal eye field (FEF)), nine patients with a chronic, unilateral lesion restricted to posterior association cortex (eight involving the intraparietal sulcus (IPS)), and twelve neurologically normal control subjects were studied in an anti-saccade task. A combination of manipulating cuing and fixation offset enabled us to examine the effects of chronic oculomotor lesions on both saccade preparation and voluntary control over ocular fixation. Patients with lesions of the FEF made more errors (reflexive glances) toward contralesional targets, whereas patients with IPS lesions made fewer errors toward contralesional targets. Patients with IPS lesions had increased latencies to initiate saccades away from contralesional targets. For FEF patients, the presence of a fixation point inhibited the initiation of contralesionally directed saccades less than those directed ipsilesionally. Saccade preparation in response to a cue did not reduce the inhibitory effect of a fixation point on initiating anti-saccades directed either ipsilesionally or contralesionally for either patient group. We conclude that chronic IPS lesions result in a reduced contralesional visual grasp reflex (VGR) and delayed utilization of visual signals in the contralesional field for planning voluntary eye movements. In contrast, patients with chronic FEF lesions are impaired in inhibiting the VGR toward contralesional signals, and manifest an asymmetry in the balance between fixation and saccade activity. Moreover, voluntary control of fixation is compromised after chronic damage to either frontal or parietal oculomotor cortex.     

Relationship of presaccadic activity in frontal eye field and supplementary eye field to saccade initiation in macaque: Poisson spike train analysis

The purpose of this study was to investigate the temporal relationship between presaccadic neuronal discharges in the frontal eye fields (FEF) and supplementary eye fields (SEF) and the initiation of saccadic eye movements in macaque. We utilized an analytical technique that could reliably identify periods of neuronal modulation in individual spike trains. By comparing the observed activity of neurons with the random Poisson distribution generated from the mean discharge rate during the trial period, the period during which neural activity was significantly elevated with a predetermined confidence level was identified in each spike train. In certain neurons, bursts of action potentials were identified by determining the period in each spike train in which the activation deviated most from the expected Poisson distribution. Using this method, we related these defined periods of modulation to saccade initiation in specific cell types recorded in FEF and SEF. Cells were recorded in SEF while monkeys made saccades to targets presented alone. Cells were recorded in FEF while monkeys made saccades to targets presented alone or with surrounding distractors. There were no significant differences in the time-course of activity of the population of FEF presaccadic movement cells prior to saccades generated to singly presented or distractor-embedded targets. The discharge of presaccadic movement cells in FEF and SEF could be subdivided quantitatively into an early prelude followed by a high-rate burst of activity that occurred at a consistent interval before saccade initiation. The time of burst onset relative to saccade onset in SEF presaccadic movement cells was earlier and more variable than in FEF presaccadic movement cells. The termination of activity of another population of SEF neurons, known as preparatory set cells, was time-locked to saccade initiation. In addition, the cessation of SEF preparatory set cell activity coincided precisely with the beginning of the burst of SEF presaccadic movement cells. This finding raises the possibility that SEF preparatory set cells may be involved in saccade initiation by regulating the activation of SEF presaccadic movement cells. These results demonstrate the utility of the Poisson spike train analysis to relate periods of neuronal modulation to behavior.     

Initiation of smooth pursuit in humans

We examined the influence of target saliency on the initiation of smooth pursuit. The eye movements of five human subjects were recorded with the scleral search-coil technique. A video-projection system was used to create a pursuit target, consisting of a cluster of 14 red or green dots (0.5 degrees squares) extending randomly over a 3 degrees x3 degrees region, and a surrounding background, consisting of stationary, random dots of the same size and density extending over an area 70 degrees x 40 degrees. When the dots in the background and the target were of the same color, the target was indistinguishable from the background until it started to move. On the other hand, when the colors were different, the target was salient, even when stationary. We measured the changes in eye position over the 70-ms interval starting 70 ms after the onset of target motion (initial tracking response). When the target moved toward the fovea (centripetal motion), the initial tracking responses developed earlier when the dots in the target and background were of different color than when the two sets of dots were of the same color. However, in order to see this effect of target salience, it was critical that the colors be different before the onset of motion, but not afterwards. When the target moved away from the fovea (centrifugal motion), the initial tracking responses were independent of whether the colors of the target and the background were the same or different. Our data indicate that the initiation of tracking responses is very sensitive to the saliency of the target before the onset of target motion when that motion is toward the fovea.     

The effect of attentive fixation on eye movements evoked by electrical stimulation of the frontal eye fields

Summary Electrical stimulation of the frontal eye fields of the rhesus monkey evokes saccadic eye movements. Both the amplitude of electrically elicited saccades and the threshold current for eliciting them are primarily determined by the location of the stimulating electrode within the frontal eye fields; however, threshold and amplitude also are systematically affected by the monkey's behavioral state when the stimulation is applied. If the monkey is alert, but not performing a task, saccade amplitudes are largest and thresholds are lowest. Conversely, if the monkey actively fixates a visual target, elicited saccades are smaller and threshold currents are higher. Saccades evoked during fixation have slower velocities appropriate for their reduced amplitude. Phase plane plots of eye velocity versus eye position indicate that these saccades are originally programmed to be smaller and slower, and hence are not large saccades voluntarily braked in mid-flight. As opposed to their amplitude and threshold, the direction of electrically evoked saccades is unaffected by the state of fixation. The state of attentive fixation, but not the visual fixation target itself, is the responsible factor for these effects. These results suggest that there is a difference between the state of active fixation and the state of having the eye still in the orbit without active fixation. The oculomotor system in the latter case is relatively more susceptible to signals from the cerebral cortex.     

Scaling of smooth anticipatory eye velocity in response to sequences of discrete target movements in humans

We investigated the ability to generate anticipatory smooth pursuit to sequences of constant velocity (ramp) stimuli of increasing complexity. Previously, it was shown that repeated presentation of sequences composed of four ramps with two speeds in two directions, evoked anticipatory smooth pursuit after only one or two presentations. Here, sequences of four or six ramps, each having a choice of four speeds and either one or two directions (uni- or bi-directional) were examined. The components of each sequence were presented as discrete ramps (duration: 400 ms; randomised velocity: 10–40°/s), each starting from the centre with 1,200 ms periods of central fixation between ramps, allowing anticipatory activity to be segregated from prior eye movement. Auditory warning cues occurred 600 ms prior to each target presentation. Anticipatory smooth eye velocity was assessed by calculating eye velocity 50 ms after target onset (V ₅₀), prior to the availability of visual feedback. Despite being required to re-fixate centre during inter-ramp gaps, subjects could still generate anticipatory smooth pursuit with V ₅₀ comparable to single speed control sequences, but with less accuracy. In the steady state V ₅₀ was appropriately scaled in proportion to upcoming target velocity for each ramp component and thus truly predictive. Only one to two repetitions were required to attain a steady-state for unidirectional sequences (four or six ramps), but three or four repeats were required for bi-directional sequences. Results suggest working memory can be used to acquire multiple levels of velocity information for prediction, but its use in rapid prediction is compromised when direction as well as speed must be retained.     

On the gap effect for saccades evoked by electrical microstimulation of frontal eye fields in monkeys

To investigate the mechanisms of fixation disengagement and saccade initiation, we electrically stimulated the macaque frontal eye fields (FEF) while monkeys performed a visual fixation task. We tested the effect of introducing a temporal gap between fixation target offset and the onset of the electrical stimulus. We found that the duration of the gap had a pronounced effect on the probability of producing electrically evoked saccades at a given current level. The highest probability was found for gaps of 200 ms duration. There were also effects of gap duration on saccade latency and amplitude for most of the stimulation sites. The increase in saccade probability may be associated with lower current thresholds for evoking saccades.     

Reversible inactivation of macaque frontal eye field

 The macaque frontal eye field (FEF) is involved in the generation of saccadic eye movements and fixations. To better understand the role of the FEF, we reversibly inactivated a portion of it while a monkey made saccades and fixations in response to visual stimuli. Lidocaine was infused into a FEF and neural inactivation was monitored with a nearby microelectrode. We used two saccadic tasks. In the delay task, a target was presented and then extinguished, but the monkey was not allowed to make a saccade to its location until a cue to move was given. In the step task, the monkey was allowed to look at a target as soon as it appeared. During FEF inactivation, monkeys were severely impaired at making saccades to locations of extinguished contralateral targets in the delay task. They were similarly impaired at making saccades to locations of contralateral targets in the step task if the target was flashed for ≤100 ms, such that it was gone before the saccade was initiated. Deficits included increases in saccadic latency, increases in saccadic error, and increases in the frequency of trials in which a saccade was not made. We varied the initial fixation location and found that the impairment specifically affected contraversive saccades rather than affecting all saccades made into head-centered contralateral space. Monkeys were impaired only slightly at making saccades to contralateral targets in the step task if the target duration was 1000 ms, such that the target was present during the saccade: latency increased, but increases in saccadic error were mild and increases in the frequency of trials in which a saccade was not made were insignificant. During FEF inactivation there usually was a direct correlation between the latency and the error of saccades made in response to contralateral targets. In the delay task, FEF inactivation increased the frequency of making premature saccades to ipsilateral targets. FEF inactivation had inconsistent and mild effects on saccadic peak velocity. FEF inactivation caused impairments in the ability to fixate lights steadily in contralateral space. FEF inactivation always caused an ipsiversive deviation of the eyes in darkness. In summary, our results suggest that the FEF plays major roles in (1) generating contraversive saccades to locations of extinguished or flashed targets, (2) maintaining contralateral fixations, and (3) suppressing inappropriate ipsiversive saccades. Received: 2 February 1996 / Accepted: 26 February 1997     

The frontal eye field is involved in spatial short-term memory but not in reflexive saccade inhibition

Physiological studies in monkeys have shown that the frontal eye field (FEF) is involved in the preparation and triggering of purposive saccades. However, several questions of FEF function remain unclear: the role of the FEF in visual short-term memory, its ability to update its spatial map and its role in reflexive saccade inhibition. We have addressed these issues in a patient with a small acute ischemic lesion whose location corresponded very accurately to the region of the left FEF according to the most recent cerebral blood flow studies. An initial study was conducted on days 7 and 8 after the stroke, i.e., before substantial recovery. A first group of paradigms (smooth pursuit, simple saccade tasks) was performed to assess FEF dysfunction. In a second group of paradigms, (1) visual short-term memory was tested by means of memory-guided saccade paradigms with short and long delays (1 and 7 s), (2) spatial updating abilities were tested by a double-step saccade task and two memory-guided saccade tasks in which the central fixation point was displaced during the memorization delay, and (3) reflexive saccade inhibition was tested by the antisaccade task. Results show that the FEF is involved in short-term memorization of the parameters of the forthcoming memory-guided saccade encoded in oculocentric coordinates. Normal results in the antisaccade task suggest that the FEF is not involved in reflexive saccade inhibition. Received: 26 January 1999 / Accepted: 3 June 1999     

Ocular limit cycles induced by delayed retinal feedback

Lisberger's and Robinson's models of smooth pursuit predict very different results from altering retinal feedback delay. We have therefore investigated the effects of increasing the retinal feedback time delay in three normal human subjects by means of an artificial feedback paradigm. When additional delays were incorporated into the retinal feedback path a threshold was reached beyond which the eye exhibited sustained self-excited oscillations or limit cycles. The oscillation period increased linearly (as the added delay was increased) with slopes ranging from 1.41 to 1.6 with zero-delay intercepts of between 212 and 306 ms. Contrary to our experimental findings the Robinson and Lisberger models predict that the plot of oscillation period against added delay should have a slope of 3.4 and 2.7 and an intercept of 479 and 554 ms, respectively. Neither model produced comparable limit cycles, both being unstable at delays greater than 280 ms. Our results imply that the models of smooth pursuit need to incorporate predictive control.     

Eye movement and visual motion perception in schizophrenia I: Apparent motion evoked smooth pursuit eye movement reveals a hidden dysfunction in smooth pursuit eye movement in schizophrenia

To date, smooth pursuit eye movement in schizophrenia has only been investigated using a target stimulus in continuous motion. However, smooth pursuit can also be evoked by an oscillating jumping dot that appears to be in apparent motion and although there is no continuous motion on the retinal surface this apparently moving stimulus can effortlessly elicit smooth-pursuit eye movement. In the first of two experiments smooth pursuit eye movement was evoked by target stimuli in continuous (real) motion at seven target velocities from 5.0 to 35.0 deg/s, and in a second experiment it was measured in response to an oscillating jumping dot in apparent motion at eight target velocities from 5.0 to 25.0 deg/s in a group with mixed-symptoms in schizophrenia and in a control group. The results of Experiment 1 provided no evidence for a dysfunction in continuous motion evoked smooth pursuit eye movement in the group with schizophrenia. However, following the removal of saccadic eye movements in smooth pursuit, the group with schizophrenia showed significantly lower smooth pursuit eye velocity at target velocities from 20.0 to 35.0 deg/s. The results of Experiment 2 revealed that apparent motion evoked smooth pursuit eye velocity in the group with schizophrenia was significantly lower in comparison with normal observers at all target velocities up to 25.0 deg/s with the inclusion or exclusion of saccadic eye movements. The findings demonstrate that overall smooth pursuit eye movement evoked in response to a continuous (real) motion target in the group with schizophrenia may nevertheless contain a hidden temporal resolution and integration dysfunction that is revealed when smooth pursuit eye movement is evoked in response to an oscillating jumping dot in apparent motion. The findings also demonstrate that normal smooth pursuit eye movement in normal observers can be made to resemble the dysfunctional smooth pursuit eye movement that is naturally found in some people with schizophrenia by using a target stimulus in apparent motion.     

A model of smooth pursuit eye movement deficit associated with the schizophrenia phenotype

Smooth pursuit eye movement (SPEM) abnormalities in schizophrenia, although well described, are poorly understood. SPEMs are initiated by motion of an object image on the retina. During initiation, the eyes accelerate until they approximate target velocity and a state of minimal retinal motion is achieved. Pursuit is maintained through predictive eye movements based on extraretinal signals and corrections based on deviations from the fovea. Here, initiation and predictive pursuit responses were used to estimate the contributions of retinal and extraretinal signals to pursuit maintenance in schizophrenia patients' relatives. Relatives exhibited normal initiation, but had lower predictive pursuit gain compared with controls. Relatives had normal gain during pursuit maintenance, presumably by greater reliance on retinal error. This was confirmed by group differences in regression coefficients for retinal and extraretinal measures, and suggests that schizophrenia SPEM deficits involve reduced ability to maintain or integrate extraretinal signals, and that retinal error may be used to compensate.     

Interactions between eye movement systems in cats and humans

Eye movements can be broadly classified into target-selecting and gaze-stabilizing eye movements. How do the different systems interact under natural conditions? Here we investigate interactions between the optokinetic and the target-selecting system in cats and humans. We use combinations of natural and grating stimuli. The natural stimuli are movies and pictures taken from the cat’s own point of view with a head-mounted camera while it moved about freely in an outdoor environment. We superimpose linear global motion on the stimuli and use measurements of optokinetic nystagmus as a probe to study the interaction between the different systems responsible for controlling eye movements. Cats display higher precision stabilizing eye movements in response to natural pictures as compared to drifting gratings. In contrast, humans perform similarly under these two conditions. This suggests an interaction of the optokinetic and the pursuit system. In cats, the natural movies elicit very weak optokinetic responses. In humans, by contrast, the natural movie stimuli elicit effectively stabilizing eye movements. In both species, we find a unimodal distribution of saccades for all stimulus velocities. This suggests an early interaction of target-selecting and gaze-stabilizing saccades. Thus, we argue for a more integrated view in humans of the different eye movement systems.     

Activity of pursuit neurons in the caudal part of the frontal eye fields during static roll-tilt

The smooth-pursuit system and vestibular system interact to keep the retinal target image on the fovea during head and/or whole body movements. The caudal part of the frontal eye fields (FEF) in the fundus of arcuate sulcus contains pursuit neurons and the majority of them respond to vestibular stimulation induced by whole-body rotation, that activates primarily semi-circular canals, and by whole-body translation, that activates otoliths. To examine whether coordinate frames representing FEF pursuit signals are orbital or earth-vertical, we compared preferred directions during upright and static, whole-body roll-tilt in head- and trunk-restrained monkeys. Preferred directions (re monkeys’ head/trunk axis) of virtually all pursuit neurons tested (n = 21) were similar during upright and static whole-body roll-tilt. The slight shift of preferred directions of the majority of neurons could be accounted for by ocular counter-rolling. The mean (±SD) differences in preferred directions between upright and 40° right ear down and between upright and 40° left ear down were 6° (±6°) and 5° (±5°), respectively. Visual motion preferred directions were also similar in five pursuit neurons tested. To examine whether FEF pursuit neurons could signal static whole-body roll-tilt, we compared mean discharge rates of 29 neurons during fixation of a stationary spot while upright and during static, whole-body roll-tilt. Virtually all neurons tested (28/29) did not exhibit a significant difference in mean discharge rates between the two conditions. These results suggest that FEF pursuit neurons do not signal static roll-tilt and that they code pursuit signals in head/trunk-centered coordinates.     

Impairment of extraretinal eye position signals after central thalamic lesions in humans

Accuracy of four different types of memory-guided saccades was studied in two patients with a small central thalamic lesion, probably involving the region of the internal medullary lamina (IML), and in a control group. In the first paradigm, the eyes and head remained immobile between the time of the presentation of the visual target to be remembered and the memory-guided saccade. In the other three paradigms, the eyes were displaced during the same period (before the memory-guided saccade) by either visually-guided saccades, a smooth pursuit eye movement or a body movement (with vestibulo-ocular reflex suppression). Therefore, in these three paradigms, the initial eye displacement required the use of extraretinal eye position to produce accurate memory-guided saccades. Compared with the control group, the two patients had normal accuracy in the first memory-guided saccade paradigm, in which there was no initial eye displacement, but markedly impaired saccade accuracy in the other three paradigms. These results suggest that the cortical areas triggering saccades did not receive correct extraretinal eye position signals. They are consistent with an impairment of the efference copy, which could be distributed to the cortical ocular motor areas by the IML.