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.     

Ocular motor delayed-response task performance among patients with schizophrenia and their biological relatives

Schizophrenia patients and their relatives have saccadic abnormalities characterized by problems inhibiting a response. The dorsolateral prefrontal cortex and its associated circuitry ostensibly mediate inhibition and support correct delayed response performance. In this context, two components of delayed response task performance are of interest: memory saccade metrics and error saccades made during the delay. To evaluate these variables, an ocular motor delayed response task was presented to 23 schizophrenia patients, 25 of their first-degree biological relatives, and 19 normal subjects. The measure that best differentiated groups was an increased frequency of error saccades generated during the delay by schizophrenia subjects and relatives. Decreased memory saccade gain also characterized patients and relatives. The similar pattern of results demonstrated by the patients with schizophrenia and their relatives suggests that performance on ocular motor delayed response tasks, either alone or in combination with other saccadic variables, may provide useful information about neural substrates associated with a liability for developing schizophrenia.     

Abnormal mechanisms of antisaccade generation in schizophrenia patients and unaffected biological relatives of schizophrenia patients

Although errant saccadic eye movements may mark genetic factors in schizophrenia, little is known about abnormal brain activity that precedes saccades in individuals with genetic liability for schizophrenia. We investigated electrophysiological activity preceding prosaccades and antisaccades in schizophrenia patients, first‐degree biological relatives of schizophrenia patients, and control subjects. Prior to antisaccades, patients had reduced potentials over lateral prefrontal cortex. Smaller potentials were associated with worse antisaccade performance. Relatives also exhibited reduced pre‐saccadic potentials over lateral frontal cortex but additionally had reduced potentials over parietal cortex. Both patients and relatives tended toward increased activity over orbital frontal cortex prior to saccades. Results are consistent with lateral prefrontal dysfunction marking genetic liability for schizophrenia and underlying deficient saccadic control.     

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.     

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.     

The effect of fixation condition manipulations on antisaccade performance in schizophrenia: studies of diagnostic specificity

 This series of studies evaluated (1) hypotheses that poor antisaccade performance is attributable to confounding variables (e.g., visual attention deficits, incomplete understanding of task demands) and (2) the specificity of poor antisaccade performance to schizophrenia. In addition to self-correcting errors before being cued to do so, schizophrenia patients also showed the expected saccadic reaction time changes to fixation condition manipulations: decreased latencies for gap and increased latencies for overlap trials. These data suggest that schizophrenia patients are adequately engaged in and understand the antisaccade task. Schizophrenia patients made fewer correct antisaccade responses than other psychiatric patients (obsessive-compulsive and bipolar disorder) and normal subjects. The first-degree relatives of schizophrenia patients also generated a decreased proportion of correct antisaccade responses compared with normal subjects. For schizophrenia patients who performed below the range of normal subjects, 26% of their relatives also performed below the normal range. Conversely, patients who performed normally did not have a single poor-performing relative. These data suggest that increased antisaccade error rates may index a liability for schizophrenia within a subset of families. Received: 18 June 1996 / Accepted: 23 December 1996     

The relation between antisaccade errors,fixation stability and prosaccade errors in schizophrenia

Whether antisaccade errors in schizophrenia are due to defects in implementing saccadic inhibition or difficulty in generating novel responses is uncertain. We investigated whether antisaccade errors were related to difficulty in inhibiting saccades when subjects were asked to maintain steady fixation, a situation that does not require a novel response. We examined the ocular motor data of 15 schizophrenia subjects and 16 healthy subjects. We assessed fixation in two situations: first, during the period before target onset during each saccadic trial, and second, during fixation trials that were interspersed with saccadic trials. We found that schizophrenia subjects had higher rates of fixation losses than control subjects in both situations. Second, both in healthy and schizophrenia subjects, antisaccade error rate was positively correlated with the frequency of fixation losses in the preparatory period of saccadic trials, but not with the frequency of fixation losses during fixation trials. Third, antisaccade errors were more likely to occur in trials with unstable fixation than in trials with stable fixation. Last, antisaccade error rate was also correlated with prosaccade error rate. We conclude that antisaccade errors are related to difficulties with implementing inhibitory control in the saccadic system. However, the finding of a correlation between the error rates for antisaccades and prosaccades suggests that this is not specifically concerned with inhibiting the automatic prosaccade, but a more general deficit in implementing goal-oriented behavior.     

Shared and distinct oculomotor function deficits in schizophrenia and obsessive compulsive disorder

Detailed analysis of oculomotor function phenotypes in antisaccade, smooth eye pursuit, and active fixation tasks was performed in a sample of 44 patients with schizophrenia, 34 patients with obsessive compulsive disorder (OCD), and 45 matched healthy controls. A common pattern of performance deficits in both schizophrenia and OCD emerged including higher antisaccade error rate, increased latency for corrective antisaccades, as well as higher rates of unwanted saccades in smooth eye pursuit compared to healthy controls. This common pattern could be related to the dysfunction of a network of cognitive control that is present in both disorders, including the dorsolateral prefrontal cortex, the posterior parietal cortex, and the anterior cingulate cortex. In contrast, only patients with schizophrenia showed a specific increase for correct antisaccade mean latency and the intrasubject variability of latency for error prosaccades as well as a decrease in the gain for smooth eye pursuit, suggesting a specific deficit in saccadic motor control and the frontal eye field in schizophrenia that is not present in OCD. A specific deficit in fixation stability (increased frequency of unwanted saccades during active fixation) was observed only for OCD patients pointing to a deficit in the frontostriatal network controlling fixation. This deficit was pronounced for OCD patients receiving additional antipsychotic medication. In conclusion, oculomotor function showed shared and distinct patterns of deviance for schizophrenia and OCD pointing toward shared and specific neurobiological substrates for these psychiatric disorders.     

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.     

Behavioral and brain imaging studies of saccadic performance in schizophrenia.

Data are reviewed from a series of saccadic studies demonstrating that schizophrenia subjects have normal performance on some types, and abnormal performance on other types, of tasks. Normal refixation saccade characteristics and BOLD signal change among schizophrenia subjects suggest that basic saccade generating circuitry is functionally intact among these subjects. Schizophrenia patients and their relatives, however, demonstrate difficulty with saccadic inhibition, a function ostensibly mediated by DLPFC circuitry. We review additional evidence for saccadic inhibition being associated with prefrontal circuitry provided by EEG and fMRI data. Minimum norm analysis of EEG data suggests that dipolar activity preceding correct antisaccades occurred preferentially in prefrontal cortex. Furthermore, there is an indication from the fMRI data that prefrontal activity may be increased in normal, but not in schizophrenia, subjects during antisaccade tasks. These data suggest that a research program relying on multiple functional imaging technologies may be helpful for furthering our understanding of schizophrenia's essential neuropathology.     

Altered control of visual fixation and saccadic eye movements in attention-deficit hyperactivity disorder

Attention-deficit hyperactivity disorder (ADHD) is characterized by the overt symptoms of impulsiveness, hyperactivity, and inattention. A frontostriatal pathophysiology has been hypothesized to produce these symptoms and lead to reduced ability to inhibit unnecessary or inappropriate behavioral responses. Oculomotor tasks can be designed to probe the ability of subjects to generate or inhibit reflexive and voluntary responses. Because regions of the frontal cortex and basal ganglia have been identified in the control of voluntary responses and saccadic suppression, we hypothesized that children and adults diagnosed with ADHD may have specific difficulties in oculomotor tasks requiring the suppression of reflexive or unwanted saccadic eye movements. To test this hypothesis, we measured eye movement performance in pro- and anti-saccade tasks of 114 ADHD and 180 control participants ranging in age from 6 to 59 yr. In the pro-saccade task, participants were instructed to look from a central fixation point toward an eccentric visual target. In the anti-saccade task, stimulus presentation was identical, but participants were instructed to suppress the saccade to the stimulus and instead look from the central fixation point to the side opposite the target. The state of fixation was manipulated by presenting the target either when the central fixation point was illuminated (overlap condition) or at some time after it disappeared (gap condition). In the pro-saccade task, ADHD participants had longer reaction times, greater intra-subject variance, and their saccades had reduced peak velocities and increased durations. In the anti-saccade task, ADHD participants had greater difficulty suppressing reflexive pro-saccades toward the eccentric target, increased reaction times for correct anti-saccades, and greater intra-subject variance. In a third task requiring prolonged fixation, ADHD participants generated more intrusive saccades during periods when they were required to maintain steady fixation. The results suggest that ADHD participants have reduced ability to suppress unwanted saccades and control their fixation behavior voluntarily, a finding that is consistent with a fronto-striatal pathophysiology. The findings are discussed in the context of recent neurophysiological data from nonhuman primates that have identified important control signals for saccade suppression that emanate from frontostriatal circuits.     

Saccadic instabilities and voluntary saccadic behaviour

Primary gaze fixation is never perfectly stable but can be interrupted by involuntary, conjugate saccadic intrusions (SI). SI have a high prevalence in the normal population and are characterised by a horizontal fast eye movement away from the desired eye position, followed, after a variable duration, by a return saccade or drift. Amplitudes are usually below 1° and they often exhibit a directional bias. The aim of the present study was to investigate the aetiology of SI in relation to saccadic behaviour. It was hypothesised that if SI resulted from deficits in the saccadic system (i.e. reduced inhibitory mechanisms), changes in voluntary saccade behaviour may be apparent and related to SI frequency. To examine this, synchrony (no gap), gap, overlap and antisaccade tasks were conducted on ten normal subjects. No significant correlations were found between SI frequency and voluntary saccade latencies, the percentage of express saccades, or the percentage of antisaccade errors. In addition, no significant correlations were found between SI directional biases and saccade latency directional biases, express saccade biases or antisaccade error biases. These results suggest that an underlying alteration to saccadic behaviour is unlikely to be involved in SI production, and that the SI command signal may arise from the influence of attention on an intact saccadic system. Specifically, descending corticofugal signals relating to attention level and orientation may alter the balance between fixation and saccade generation, so determining SI characteristics.     

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     

Effects of age on latency and error generation in internally mediated saccades

Most studies on the effects of ageing on saccades have examined reflexive saccades; the only commonly studied volitional task has been the antisaccade task, with contradictory results. We examined in both young and elderly normal subjects the latency of anti-, memory-guided, and predictable saccades and the timing of self-paced saccades; we also evaluated errors made on the first two tasks. We expected errors to be correlated between tasks; we also expected antisaccade latencies and errors to be inversely correlated. We also expected antisaccade and memory-guided saccade latencies to be longer in individuals with a high self-paced rate. Except for predictable saccades, mean latencies were significantly higher in the elderly. However, their performance was more variable. Errors were also significantly more frequent on anti- and memory-guided saccade tasks. Most of the hypothesised correlations were not observed. Analysis of error latencies showed that whilst most antisaccade errors were reflexive, for memory-guided saccades both express errors and errors with latencies between 0.4 and 2.5 s were observed. The latter appeared to be a premature release of what would otherwise have been a properly planned response. Age thus impaired all but the predictable saccade task; nevertheless, there were few relationships between measures across tasks. This suggests that a range of processes mediate peoples' performance on these saccade paradigms.     

Role of the rostral superior colliculus in active visual fixation and execution of express saccades.

1. In the rostral pole of the monkey superior colliculus (SC) a subset of neurons (fixation cells) discharge tonically when a monkey actively fixates a target spot and pause during the execution of saccadic eye movements. 2. To test whether these fixation cells are necessary for the control of visual fixation and saccade suppression, we artificially inhibited them with a local injection of muscimol, an agonist of the inhibitory neurotransmitter gamma-aminobutyric acid (GABA). After injection of muscimol into the rostral pole of one SC, the monkey was less able to suppress the initiation of saccades. Many unwanted visually guided saccades were initiated less than 100 ms after onset of a peripheral visual stimulus and therefore fell into the range of express saccades. 3. We propose that fixation cells in the rostral SC form part of a fixation system that facilitates active visual fixation and suppresses the initiation of unwanted saccadic eye movements. Express saccades can only occur when activity in this fixation system is reduced.     

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.     

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.     

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     

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.     

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