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     

Saccadic disinhibition in schizophrenia patients and their first-degree biological relatives

Several studies have reported that patients with schizophrenia and their relatives perform poorly on antisaccade tasks and have suggested that this deficit represents saccadic disinhibition. If this proposition is correct, then varying task parameters that specifically increase the difficulty with which unwanted saccades can be inhibited should exacerbate deficits. Forty-two schizophrenia patients, 42 of their first-degree biological relatives, 21 psychotic affective disorder patients, and 38 nonpsychiatric comparison subjects were given fixation and antisaccade tasks. The introduction of distracters and the presence of visible fixation stimuli were parameters used to vary the difficulty in suppressing unwanted saccades (inhibitory load). It is known that the presence of a fixation stimulus at the time when a saccade must be inhibited results in fewer reflexive errors on antisaccade tasks. Performance on fixation tasks without (low load) vs with distracters (high load) and antisaccade tasks that had fixation stimuli still visible (low load) vs already extinguished (high load) at the time when the reflexive saccade must be inhibited was compared. The schizophrenia patients and their first-degree biological relatives showed evidence of increased saccadic disinhibition that was most pronounced during high inhibitory load conditions. These data indicate that dysfunctional inhibitory processes, at least in the oculomotor domain, are associated with the liability to schizophrenia. Results also suggest that this genetic liability may be related to dysfunctional prefrontal cortical areas that provide top-down inhibitory control over reflexive saccade generation.     

Event-related fMRI responses in the human frontal eye fields in a randomized pro- and antisaccade task

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.     

Eye movement disorders after frontal eye field lesions in humans

Eye movements were recorded electro-oculographically in three patients with a small ischemic lesion affecting the left frontal eye field (FEF) and in 12 control subjects. Reflexive visually guided saccades (gap and overlap tasks), antisaccades, predictive saccades, memory-guided saccades, smooth pursuit and optokinetic nystagmus (OKN) were studied in the three patients. Staircase saccades and double step saccades were also studied in one of the three patients. For both leftward and rightward saccades, latency in the overlap task (but not in the gap task) and that of correct antisaccades and of memory-guided saccades was significantly increased, compared with the results of controls. There was a significant decrease in the amplitude gain of all rightward saccades programmed using retinotopic coordinates (gap and overlap tasks, predictive and memory-guided saccades), whereas the amplitude gain of corresponding leftward saccades was preserved. Such an asymmetry between leftward and rightward saccades was significant. In the staircase paradigm as well as for the first saccade in the double step paradigm (with the use of retinotopic coordinates in both cases), the amplitude gain of rightward saccades was also significantly lower than that of leftward saccades. Moreover, in the double step paradigm, the amplitude gain of the first rightward saccade was significantly lower than that of the second rightward saccade (programmed using extraretinal signals), which was preserved. The percentage of errors in the antisaccade task did not differ significantly from that of normal subjects. In the predictive saccade paradigm, the percentage of predictive rightward saccades was significantly decreased. The left smooth pursuit gain for all tested velocities, the right smooth pursuit gain for higher velocities, and the left OKN gain were significantly decreased. The results show, for the first time in humans, that the FEF plays an important role in (1) the disengagement from central fixation, (2) the control of contralateral saccades programmed using retinotopic coordinates, (3) saccade prediction and (4) the control of smooth pursuit and OKN, mainly ipsilaterally. In contrast, the left FEF did not appear to be crucial for the control of the only type of saccades programmed using extraretinal signals studied here.     

Abnormalities of internally generated saccades in obsessive-compulsive disorder

BACKGROUND: We aimed to utilize tests of saccadic function to investigate whether cognitive abnormalities in obsessive-compulsive disorder (OCD) arise from a dysfunction of inhibitory processes or whether they reflect a more general difficulty in guiding behaviour on the basis of an internal representation of task goal. METHODS: Twelve patients with OCD and 12 matched controls performed a visually-guided saccade task, a volitional prosaccade task and an antisaccade task. The latency and gain of saccades was compared between groups for the three saccade tasks. The number of antisaccade errors was also calculated and compared between groups. RESULTS: There was no difference for antisaccade error rates between the groups. The latency of visually guided saccades did not differ between groups, however the latency of both volitional prosaccades and antisaccades was significantly slower in the patients with OCD than in controls. The difference in latency between volitional prosacades and antisaccades, however, was equal between groups. CONCLUSIONS: These results suggest that patients with OCD have an abnormality in guiding behaviour on the basis of an internal representation of the task goal, rather than a problem with inhibiting reflexive behaviour.     

Characteristics of contralesional and ipsilesional saccades in hemianopic patients

In order to further our understanding of action-blindsight, four hemianopic patients suffering from visual field loss contralateral to a unilateral occipital lesion were compared to six healthy controls during a double task of verbally reported target detection and saccadic responses toward the target. Three oculomotor tasks were used: a fixation task (i.e., without saccade) and two saccade tasks (eliciting reflexive and voluntary saccades, using step and overlap 600 ms paradigms, respectively), in separate sessions. The visual target was briefly presented at two different eccentricities (5° and 8°), in the right or left visual hemifield. Blank trials were interleaved with target trials, and signal detection theory was applied. Despite their hemifield defect, hemianopic patients retained the ability to direct a saccade toward their contralesional hemifield, whereas verbal detection reports were at chance level. However, saccade parameters (latency and amplitude) were altered by the defect. Saccades to the contralesional hemifield exhibited longer latencies and shorter amplitudes compared to those of the healthy group, whereas only the latencies of reflexive saccades to the ipsilesional hemifield were altered. Furthermore, healthy participants showed the expected latency difference between reflexive and voluntary saccades, with the latter longer than the former. This difference was not found in three out of four patients in either hemifield. Our results show action-blindsight for saccades, but also show that unilateral occipital lesions have effects on saccade generation in both visual hemifields.     

Control of voluntary and reflexive saccades in Parkinson’s disease

Eight patients with idiopathic Parkinson’s disease (PD) were compared with a group of age-matched controls on both reflexive saccade and antisaccade tasks. While reflexive, visually guided saccades led to equivalent performance in both groups, PD patients were slower, made more errors, and showed reduced gain on antisaccades (AS). This is consistent with previous results showing that PD patients have no difficulty with reflexive saccades but show deficiencies in a number of voluntary saccade paradigms. Moreover, visual information in the form of landmarks improves AS performance more for PD patients than controls, a finding analogous to results seen with other motor acts such as target-directed pointing. Results are discussed in terms of a two-process model of attention and eye movements. Received: 13 October 1998 / Accepted: 11 May 1999     

Evidence for a deficit in volitional action generation in patients with obsessive-compulsive disorder

Obsessive-compulsive disorder (OCD) patients show deficits in tasks of executive functioning like the antisaccade (AS) task. These deficits suggest problems in response inhibition or volitional saccade generation. Thirty patients (15 nonmedicated) and 30 healthy subjects performed antisaccades and simple volitional saccades (SVS), that is, centrally cued saccades. In SVS, two aspects of volitional saccade generation were disentangled: response selection and initiation. Latencies of OCD patients were increased in volitional saccades independent of response selection demands. AS performance did not differ. Across groups, latencies in AS were faster than in SVS. Medicated patients did not differ from nonmedicated patients. In sum, response initiation is deficient in OCD patients, which may reflect a general problem in volitional action generation. This deficit did not affect antisaccade performance, possibly due to a lower volitional demand in that task.     

Prepulse inhibition of the acoustic startle reflex and oculomotor control

Prepulse inhibition and the suppression of reflexive saccades on the antisaccade task are thought to tap inhibitory function. Reports of a lack of association between these measures suggest that they reflect different facets of inhibition. This study aimed to reexamine this relationship in a large sample and investigate the association of prepulse inhibition with oculomotor tasks that require inhibition of a reflexive saccade with lower concurrent processing demands than antisaccades, namely the oculomotor delayed response and fixation with distractors tasks. One hundred and seven healthy volunteers took part. Prepulse inhibition was uncorrelated with oculomotor performance. The error rate was highest for antisaccades, intermediate for the delayed response task, and lowest for fixation with distractors, and was correlated across tasks. These findings provide no evidence of a relationship between prepulse inhibition and oculomotor inhibition. Failure in suppressing reflexive saccades toward a peripheral target may represent a common inhibitory component underlying these oculomotor tasks.     

Memory-guided saccade abnormalities in schizophrenic patients and their healthy, full biological siblings

BACKGROUND: Ocular-motor inhibition errors and saccadic hypometria occur at elevated rates in biological relatives of schizophrenic patients. The memory-guided saccade (MS) paradigm requires a subject to inhibit reflexive saccades (RSs) and to programme a delayed saccade towards a remembered target. METHOD: MS, RS, and central fixation (CF) tasks were administered to 16 patients who met the criteria for DSM-IV schizophrenia, 19 of their psychiatrically healthy siblings, and 18 controls. RESULTS: Patients and siblings showed elevated MS error rates reflecting a failure to inhibit RSs to a visible target, as required by the task. In contrast to controls, prior errors did not improve MS accuracy in patients and siblings. CONCLUSIONS: The specific characteristics of the elevated MS error rate help to clarify the nature of the disinhibition impairment found in schizophrenics and their healthy siblings. Failure to inhibit premature saccades and to improve the accuracy of subsequent volitional saccades implicates a deficit in spatial working-memory integration, mental representation and/or motor learning processes in schizophrenia.     

Deficits of cortical oculomotor mechanisms in cerebellar atrophy patients

Commonly, the cerebellum is not associated with cortical components of saccadic eye movement programming. The present study investigates cerebellar effects on visually guided saccades in reflexive tasks (step, gap, overlap) and on internally driven saccades in intentional tasks (anti, memory, short memory sequences of four targets) in five patients with isolated cerebellar atrophy. The cerebellar dysfunction led to impairments in both reflexive and intentional saccades. Cerebellar atrophy patients showed an increase in the gain variability and an increase in the saccade latency. Furthermore, in the memory and anti task, suppression and pro-saccade errors were more frequent in the atrophy group compared to the control group. In the sequence task, patients had difficulties reproducing all four target locations in the order of the displayed sequence. The high variability of the saccade gain is a common observation in cerebellar atrophy patients and can be explained by the general variability present in the saccadic system. The increase in the saccade latency could be due to a cerebellar contribution to cortical processes related to fixation and target selection preceding the initiation of a saccade. Furthermore, the frequent occurrence of saccade errors in the memory and anti task suggests a cerebellar involvement in frontal inhibition of unwanted reflexive saccades. The impaired reproduction of saccade sequences in atrophy patients points to a deficit in short-term memory processes. Thus, this study provides further evidence that the cerebellum is involved in different cortical mechanisms related to the control of saccadic eye movements.     

Effects of anterior cingulate cortex lesions on ocular saccades in humans

Cerebral blood flow studies in humans suggest that the anterior cingulate cortex (ACC) could be involved in eye movement control. In two patients with a small infarction affecting the posterior part of this area (on the right side) and in ten control subjects, we studied several paradigms of saccadic eye movements: gap task, overlap task, antisaccades (using either a 5° or 25° lateral target), memory-guided saccades with a short (1 s) or long (7 s) delay, and sequences of memory-guided saccades. Compared with controls, patients had normal latency in the gap task but increased latency in the other tasks. The gain of memory-guided saccades was markedly decreased, bilaterally, whatever the duration of the delay. Patients made more errors than controls in the antisaccade task when the 5° lateral target was used, and a higher percentage of chronological errors in the sequences of saccades. These results show that the posterior part of the right ACC plays an important role in eye movement control and suggest that this area could correspond to a “cingulate eye field” (CEF). The role of this hypothetical CEF could be an early activation exerted on the frontal ocular motor areas involved in intentional saccades and also a direct action on brainstem ocular premotor structures. Received: 8 November 1996 / Accepted: 14 October 1997     

The mirror antisaccade task: direction–amplitude interaction and spatial accuracy characteristics

In this study we examined the performance of human subjects in three oculomotor tasks: a visually guided saccade task (VST), a simple antisaccade task (SAT) and a mirror antisaccade task (MAT). The stimulus presentation was identical for all three tasks, and the differentiation of the tasks was based on the instruction given to the subjects. Subjects were instructed to either look at a visually presented target location (visually triggered saccade task), or to look at the opposite direction of the visually presented target (simple antisaccade task) or finally to look at the mirror location opposite to the location of the visually presented target (mirror antisaccade task). The loading of the simple antisaccade task with the addition of the amplitude requirement did not affect the percentage of directional errors but slowed down the onset of antisaccade execution by 19 ms. The amplitude of the directionally correct antisaccade in the mirror antisaccade task showed a significant distortion of the true mirror target location. This dysmetria followed the same qualitative pattern to that observed for the visually guided saccades, i.e., a near-target hypermetria together with a far-target hypometria, but both these features were exaggerated in the mirror antisaccade task. This distorted amplitude modulation of mirror antisaccade amplitude was completely lost in corrected antisaccades that followed a directional error.     

Spatial and temporal aspects of eye-hand coordination across different tasks

The way in which saccadic eye movements are elicited influences their latency and accuracy. Accordingly, different tasks elicit different types of saccades. Using the tasks steps, gap, memory, scanning and antisaccade, we analyzed combined eye and hand movements to determine whether both motor systems share control strategies. Errors and latencies were measured to examine whether changes in eye motor behavior are reflected in hand motor behavior. Directional and variable errors of eye and hand changed differently according to the tasks. Moreover, errors of the two systems did not correlate for any of the tasks investigated. Contrary to errors, mean latencies of eye movements were organized in the same pattern as hand movements. A correlation of latencies indicates that both motor systems rely on common information to initiate movement. Temporal coupling was stronger for intentional tasks than for reflexive tasks.     

The effects of task instructions on pro and antisaccade performance

In the antisaccade task participants are required to overcome the strong tendency to saccade towards a sudden onset target, and instead make a saccade to the mirror image location. The task thus provides a powerful tool with which to study the cognitive processes underlying goal directed behaviour, and has become a widely used index of “disinhibition” in a range of clinical populations. Across two experiments we explored the role of top-down strategic influences on antisaccade performance by varying the instructions that participants received. Instructions to delay making a response resulted in a significant increase in correct antisaccade latencies and reduction in erroneous prosaccades towards the target. Instructions to make antisaccades as quickly as possible resulted in faster correct responses, whereas instructions to be as spatially accurate as possible increased correct antisaccade latencies. Neither of these manipulations resulted in a significant change in error rate. In a second experiment, participants made fewer errors in delayed pro and antisaccade tasks than in a standard antisaccade task. The implications of these results for current models of antisaccade performance, and the interpretation of antisaccade deficits in clinical populations are discussed.     

Peak velocities of visually and nonvisually guided saccades in smooth-pursuit and saccadic tasks

 Smooth pursuit typically includes corrective catch-up saccades, but may also include such intrusive saccades away from the target as anticipatory or large overshooting saccades. We sought to differentiate catch-up from anticipatory and overshooting saccades by their peak velocities, to see whether the higher velocities of visually rather than nonvisually guided saccades in saccadic tasks may be found also in saccades in pursuit. In experiment 1, 12 subjects showed catch-up, anticipatory, and overshooting saccades to comprise 70.4% of all saccades in pursuit of periodic, 30°/s constant-velocity targets. Catch-up saccades were faster than the others. Saccadic tasks were run as well, on 19 subjects, including the 12 whose pursuit data were analyzed, with target-onset, target-remaining (saccade to the remaining target when the other three extinguish), and antisaccade tasks. For 17 of the 19 subjects, antisaccade velocities were lower than for either target-onset or target-remaining tasks. Velocities for the target-remaining task were near those for target onset, indicating that target presence, not its onset, defines visually guided saccades. Error and reaction-time data suggest greater cognitive difficulty for target remaining than for target onset, so that the cognitive difficulty of typical nonvisually guided saccade tasks is not sufficient to produce their lowered velocity. To produce reliably, in each subject, catch-up and anticipatory saccades with comparable amplitude distributions, nine new subjects were asked in experiment 2 to make intentional catch-up and anticipatory saccades in pursuit, and were presented with embedded target jumps to elicit catch-up saccades, all with periodic target trajectories of 15°/s and 30°/s. Velocities of intentional anticipatory saccades were lower than velocities of intentional catch-up saccades, while velocities of intentional and embedded catch-up saccades were similar. Target-onset and remembered-target saccadic tasks were run, showing the expected higher velocity for the target-onset task in each subject. Both experiments demonstrate higher peak velocities for catch-up saccades than for anticipatory saccades, suggesting that cortical structures preferentially involved in nonvisually guided saccades may initiate the anticipatory and overshooting saccades in pursuit. Received: 1 December 1995 / Accepted: 25 February 1997     

Effects of direction on saccadic performance in relation to lateral preferences

A sample of 676 healthy young males performed visually guided saccades and antisaccades and completed the Porac-Coren questionnaire measuring lateral preferences. There was no difference in mean latency between rightward versus leftward saccades or for saccades executed in the left versus right hemispace. There was also no right/left asymmetry for individuals with left or right dominance as assessed by the lateral preferences questionnaire. The same results were observed for the latency of antisaccades and for the error rate in the antisaccade task. Finally, we did not confirm any substantial subpopulation of individuals with idiosyncratic left/right latency asymmetries that persisted both in the saccade and antisaccade task. These results suggest that neither latency nor antisaccade error rate are good indicators of lateral preferences in these tasks. Other oculomotor tasks might be more sensitive to hemifield differences, or cerebral hemispheric asymmetry is not present at the level of cortical organization of saccades and antisaccades.     

Ocular motor differences between melancholic and non-melancholic depression

BACKGROUND: Major depressive disorder may be a heterogeneous disorder, yet melancholic depression is the most consistently described subtype, regarded as qualitatively different to non-melancholic depression in terms of cognitive and motor impairments. Eye movement studies in depression are infrequent and findings are inconclusive. METHODS: This study employed a battery of saccadic eye movement tasks to explore reflexive saccades, as well as higher order cognitive aspects of saccades including inhibitory control and spatial working memory. Nineteen patients with major depressive disorder (9 melancholic; 10 non-melancholic) and 15 healthy controls participated. RESULTS: Differences were revealed between melancholic and non-melancholic patients. Melancholia was associated with longer latencies, difficulty increasing peak velocities as target amplitudes increased, and hypometric primary saccades during the predictable protocol. In contrast, the non-melancholic depression group performed similarly to controls on most tasks, but saccadic peak velocity was increased for reflexive saccades at larger amplitudes. LIMITATIONS: Most patients were taking antidepressant medication. CONCLUSIONS: The latency increases, reduced peak velocity and primary saccade hypometria with more severe melancholia may be explained by functional changes in the fronto-striatal-collicular networks, related to dopamine dysfunction. In contrast, the serotonergic system plays a greater role in non-melancholic symptoms and this may underpin the observed increases in saccadic peak velocity. These findings provide neurophysiological support for functional differences between depression subgroups that are consistent with previous motor and cognitive findings.     

Analysis of volition latency on antisaccadic eye movements

The antisaccadic paradigm can be applied to test the suppression of reflexive saccades and the activation of volitional saccades simultaneously. The impaired frontal cortex has been shown to have difficulty in suppressing reflexive saccade (prosaccade) to make a successful antisaccade. Degraded antisaccade performance can also be observed in patients with Parkinson's disease (PD). The studies of PD based on the prosaccadic and antisaccadic paradigms have shown controversial findings; the latency between patients and age-matched controls could be either with or without significant difference. Even with this inconsistency, our previous study and recent analysis have supported that the latency of both prosaccade and antisaccade increases significantly for patients with PD. The objective of this study is to investigate whether prolonged antisaccade latency is caused by the affected volitional decision process (volition latency) or simply by the delayed initiation of saccade with direction opposite to the cue, by measuring prosaccade and antisaccade latency from the intermingled paradigms. Eleven mildly affected patients with idiopathic PD and eight age-matched normal subjects were tested in this study. As compared to the age-matched control, the results showed that prosaccade, antisaccadic, and volition latency of the patients was significantly elevated (P<0.01). We conclude that antisaccade performance for the PD patients was degraded for both the volition decision process and the initiation of saccade with direction opposite to the cue. Also, volition latency analysis is a more objective method than prosaccade and antisaccade latency analysis, which can be compared among results obtained from different analysis methodologies.     

Expectations can modulate the frequency and timing of multiple saccades: a TMS study

This study was undertaken to determine if target predictability could modulate saccadic planning and timing at the level of the frontal eye fields (FEF). To this end, healthy participants performed two gap saccade tasks in which the targets were displaced left or right of the midline in either a predictable or a random fashion. Additionally, half of the participants were informed about this manipulation. Single pulse transcranial magnetic stimulation (TMS) was applied to the left FEF before, during, or after the target onset. We examined both the saccade latency and the frequency of multiple saccades (MS) (i.e., saccades that covered <90 % of the distance to the target and were subsequently followed by a corrective saccade). Findings revealed that saccadic reaction times were quickest to the more predictable target side and also confirmed that MS were released more quickly than single saccades. Further, the frequency of MS differed between target locations; higher frequencies of MS were found on the unpredictable side, showing more vulnerability to TMS disruption. In conclusion, we have demonstrated that target predictability modulates saccade planning and that this modulation takes place at least in part in the FEF. The influence of FEF in these processes is observed both in the latencies with which saccades are executed and in the timing and characteristics of the multiple saccades that are observed under different task constraints. Finally, the timing of the FEF contribution also appears to be influenced by the manipulation of target predictability. Each of these observations serves to further clarify the role of the human FEF in saccade planning.