Antisaccade Deficits Research Articles

Uncorrected errors and correct saccades in the antisaccade task distinguish between early-stage Alzheimer’s disease dementia, amnestic mild cognitive impairment, and normal aging

ABSTRACT Alzheimer’s disease (AD) dementia is a degenerative illness that is characterized by a gradual decline in cognitive abilities. Amnestic mild cognitive impairment (aMCI) is seen as a precursor to AD. The changes in antisaccade performance that can be seen in MCI may provide important clues in the early detection of AD. Therefore, the antisaccade deficits in AD and aMCI remain a research question. This study aimed to examine antisaccade responses and the relationship between antisaccade and cognitive function in AD, aMCI, and healthy controls (HC). This study included 30 patients with early-stage AD, 34 with aMCI, and 32 HC. Patients with AD showed higher rates of uncorrected error, anticipatory saccades and corrected errors, as well as decreased correct saccade rates, and shortened saccade latency compared to aMCI and HC in this study. Patients with aMCI exhibited increased rates of express saccades relative to HC. The antisaccade task and cognitive domains were found to be significantly related. Our study showed that the rate of correct saccades has the capacity to distinguish AD from HC with 87% sensitivity and 86% specificity (AUC = 0.93, p < 0.001). In addition, the rate of uncorrected errors was found to be capable of distinguishing AD from HC with 84% sensitivity and 83% specificity (AUC = 0.91, p < 0.001). This study presented promising findings that these parameters can be used clinically to differentiate AD and aMCI from healthy older individuals.

Prosaccade and Antisaccade Behavior in Fragile X-Associated Tremor/Ataxia Syndrome Progression.

Quantitative measurement of eye movements can reveal subtle progression in neurodegenerative diseases. To determine if quantitative measurements of eye movements may reveal subtle progression of fragile X-associated tremor and ataxia (FXTAS). Prosaccade (PS) and antisaccade (AS) behavior was analyzed in 25 controls, 57 non-FXTAS carriers, and 46 carriers with FXTAS. Symptomatic individuals with FXTAS had longer AS latencies, increased rates of AS errors, and increased AS dysmetria relative to non-FXTAS carriers and controls. These deficits, along with PS latency and velocity, were greater in advanced FXTAS stages. AS deficits differentiated FXTAS from non-FXTAS premutation carriers implicating top-down control and frontostriatal deterioration. However, the absence of group differences between non-FXTAS carriers and controls in AS and PS markers suggests saccade performance may not be a sensitive enough measure for detecting conversion to FXTAS, but instead more helpful as translational biomarkers of FXTAS progression.

Positive and Negative Symptoms Are Associated with Distinct Effects on Predictive Saccades.

The predictive saccade task is a motor learning paradigm requiring saccades to track a visual target moving in a predictable pattern. Previous research has explored extensively anti-saccade deficits observed across psychosis, but less is known about predictive saccade-related mechanisms. The dataset analysed came from the studies of Crawford et al, published in 1995, where neuroleptically medicated schizophrenia and bipolar affective disorder patients were compared with non-medicated patients and control participants using a predictive saccade paradigm. The participant groups consisted of medicated schizophrenia patients (n = 40), non-medicated schizophrenia patients (n = 18), medicated bipolar disorder patients (n = 14), non-medicated bipolar disorder patients (n = 18), and controls (n = 31). The current analyses explore relationships between predictive saccades and symptomatology, and the potential interaction of medication. Analyses revealed that the schizophrenia and bipolar disorder diagnostic categories are indistinguishable in patterns of predictive control across several saccadic parameters, supporting a dimensional hypothesis. Once collapsed into predominantly high-/low- negative/positive symptoms, regardless of diagnosis, differences were revealed, with significant hypometria and lower gain in those with more negative symptoms. This illustrates how the presentation of the deficits is homogeneous across diagnosis, but heterogeneous when surveyed by symptomatology; attesting that a diagnostic label is less informative than symptomatology when exploring predictive saccades.

Neural modeling of antisaccade performance of healthy controls and early Huntington's disease patients.

Huntington's disease (HD), a genetically determined neurodegenerative disease, is positively correlated with eye movement abnormalities in decision making. The antisaccade conflict paradigm has been widely used to study response inhibition in eye movements, and reliable performance deficits in HD subjects have been observed, including a greater number and timing of direction errors. We recorded the error rates and response latencies of early HD patients and healthy age-matched controls performing the mirror antisaccade task. HD participants displayed slower and more variable antisaccade latencies and increased error rates relative to healthy controls. A competitive accumulator-to-threshold neural model was then employed to quantitatively simulate the controls' and patients' reaction latencies and error rates and uncover the mechanisms giving rise to the observed HD antisaccade deficits. Our simulations showed that (1) a more gradual and noisy rate of accumulation of evidence by HD patients is responsible for the observed prolonged and more variable antisaccade latencies in early HD; (2) the confidence level of early HD patients making a decision is unaffected by the disease; and (3) the antisaccade performance of healthy controls and early HD patients is the end product of a neural lateral competition (inhibition) between a correct and an erroneous decision process, and not the end product of a third top-down stop signal suppressing the erroneous decision process as many have speculated.

Antisaccade Deficits in Schizophrenia Can Be Driven by Attentional Relevance of the Stimuli.

The antisaccade task is considered a test of cognitive control because it creates a conflict between the strong bottom-up signal produced by the cue and the top-down goal of shifting gaze to the opposite side of the display. Antisaccade deficits in schizophrenia are thought to reflect impaired top-down inhibition of the prepotent bottom-up response to the cue. However, the cue is also a highly task-relevant stimulus that must be covertly attended to determine where to shift gaze. We tested the hypothesis that difficulty in overcoming the attentional relevance of the cue, rather than its bottom-up salience, is key in producing impaired performance in people with schizophrenia (PSZ). We implemented 3 versions of the antisaccade task in which we varied the bottom-up salience of the cue while holding its attentional relevance constant. We found that difficulty in performing a given antisaccade task-relative to a prosaccade version using the same stimuli-was largely independent of the cue's bottom-up salience. The magnitude of impairment in PSZ relative to control subjects was also independent of bottom-up salience. The greatest impairment was observed in a version where the cue lacked bottom-up salience advantage over other locations. These results indicate that the antisaccade deficit in PSZ does not reflect an impairment in overcoming bottom-up salience of the cue, but PSZ are instead impaired at overcoming its attentional relevance. This deficit may still indicate an underlying inhibitory control impairment but could also reflect a hyperfocusing of attentional resources on the cue.

Anti-saccade error rates as a measure of attentional bias in cocaine dependent subjects

Cocaine-dependent (CD) subjects show attentional bias toward cocaine-related cues, and this form of cue-reactivity may be predictive of craving and relapse. Attentional bias has previously been assessed by models that present drug-relevant stimuli and measure physiological and behavioral reactivity (often reaction time). Studies of several CNS diseases outside of substance use disorders consistently report anti-saccade deficits, suggesting a compromise in the interplay between higher-order cortical processes in voluntary eye control (i.e., anti-saccades) and reflexive saccades driven more by involuntary midbrain perceptual input (i.e., pro-saccades). Here, we describe a novel attentional-bias task developed by using measurements of saccadic eye movements in the presence of cocaine-specific stimuli, combining previously unique research domains to capitalize on their respective experimental and conceptual strengths. CD subjects (N=46) and healthy controls (N=41) were tested on blocks of pro-saccade and anti-saccade trials featuring cocaine and neutral stimuli (pictures). Analyses of eye-movement data indicated (1) greater overall anti-saccade errors in the CD group; (2) greater attentional bias in CD subjects as measured by anti-saccade errors to cocaine-specific (relative to neutral) stimuli; and (3) no differences in pro-saccade error rates. Attentional bias was correlated with scores on the obsessive–compulsive cocaine scale. The results demonstrate increased saliency and differential attentional to cocaine cues by the CD group. The assay provides a sensitive index of saccadic (visual inhibitory) control, a specific index of attentional bias to drug-relevant cues, and preliminary insight into the visual circuitry that may contribute to drug-specific cue reactivity.

Heritability and molecular genetic basis of antisaccade eye tracking error rate: a genome-wide association study.

Antisaccade deficits reflect abnormalities in executive function linked to various disorders including schizophrenia, externalizing psychopathology, and neurological conditions. We examined the genetic bases of antisaccade error in a sample of community-based twins and parents (N = 4,469). Biometric models showed that about half of the variance in the antisaccade response was due to genetic factors and half due to nonshared environmental factors. Molecular genetic analyses supported these results, showing that the heritability accounted for by common molecular genetic variants approximated biometric estimates. Genome-wide analyses revealed several SNPs as well as two genes-B3GNT7 and NCL-on Chromosome 2 associated with antisaccade error. SNPs and genes hypothesized to be associated with antisaccade error based on prior work, although generating some suggestive findings for MIR137, GRM8, and CACNG2, could not be confirmed.

Preparatory neural networks are impaired in adults with attention-deficit/hyperactivity disorder during the antisaccade task.

Adults with attention-deficit/hyperactivity disorder (ADHD) often display executive function impairments, particularly in inhibitory control. The antisaccade task, which measures inhibitory control, requires one to suppress an automatic prosaccade toward a salient visual stimulus and voluntarily make an antisaccade in the opposite direction. ADHD patients not only have longer saccadic reaction times, but also make more direction errors (i.e., a prosaccade was executed toward the stimulus) during antisaccade trials. These deficits may stem from pathology in several brain areas that are important for executive control. Using functional MRI with a rapid event-related design, adults with combined subtype of ADHD (coexistence of attention and hyperactivity problems), who abstained from taking stimulant medication 20 h prior to experiment onset, and age-match controls performed pro- and antisaccade trials that were interleaved with pro- and anti-catch trials (i.e., instruction was presented but no target appeared, requiring no response). This method allowed us to examine brain activation patterns when participants either prepared (during instruction) or executed (after target appearance) correct pro or antisaccades. Behaviorally, ADHD adults displayed several antisaccade deficits, including longer and more variable reaction times and more direction errors, but saccade metrics (i.e., duration, velocity, and amplitude) were normal. When preparing to execute an antisaccade, ADHD adults showed less activation in frontal, supplementary, and parietal eye fields, compared to controls. However, activation in these areas was normal in the ADHD group during the execution of a correct antisaccade. Interestingly, unlike controls, adults with ADHD produced greater activation than controls in dorsolateral prefrontal cortex during antisaccade execution, perhaps as part of compensatory mechanisms to optimize antisaccade production. Overall, these data suggest that the saccade deficits observed in adults with ADHD do not result from an inability to execute a correct antisaccade but rather the failure to properly prepare (i.e., form the appropriate task set) for the antisaccade trial. The data support the view that the executive impairments, including inhibitory control, in ADHD adults are related to poor response preparation.

Impaired executive function signals in motor brain regions in Parkinson's disease

Recent evidence has shown that patients with Parkinson's disease (PD) often display deficits in executive functions, such as planning for future behavior, and these deficits may stem from pathologies in prefrontal cortex and basal ganglia circuits that are critical to executive control. Using the antisaccade task (look away from a visual stimulus), we show that when the preparatory 'readiness' to perform a given action is dissociated from the actual execution of that action, PD patients off and on dopamine medication display behavioral impairments and reduced cortical brain activation that cannot be explained by a pathology related to dysfunction in movement execution. Rather, they show that the appropriate task set signals were not in place in motor regions prior to execution, resulting in impairments in the control of subsequent voluntary movement. This is the first fMRI study of antisaccade deficits in Parkinson's disease, and importantly, the findings point to a critical role of the basal ganglia in translating signals related to rule representation (executive) into those governing voluntary motor behavior.

Executive control in chronic schizophrenia: A perspective from manual stimulus-response compatibility task performance

Background Antisaccade deficits are a well-documented pathophysiological characteristic in schizophrenia. However, it is yet unclear whether these findings reflect a specific oculomotor deficit, general psychomotor impairment or disturbance in executive control mechanisms. Methods Performance in a manual stimulus-response compatibility (SRC) task and a neuropsychological test-battery covering different cognitive and motor domains were obtained in 28 patients with chronic schizophrenia. It was compared with a normative cohort of healthy subjects and validated by comparison with a sub-sample of that cohort consisting of 28 age, gender and education matched controls. Results Patients showed significantly worse performance than controls in tests requiring maintenance or manipulating of multiple components but were unimpaired in simple motor, memory or executive tasks. In the SRC task patients had a significantly worse performance in the congruent condition and also a significantly higher increase in error rate from the congruent to the incongruent condition. There were, however, neither a group difference nor a group-by-condition interaction with respect to reaction times. Interpretation : Our results provide evidence against an isolated oculomotor deficit but also against an undifferentiated psychomotor dysfunction in chronic schizophrenia. Rather, in synopsis with previous reports on antisaccade performance, it becomes evident that the degree of impairment follows closely the amount of executive control required in a task, which in turn may relate to dysfunctional top-down bias of the prefrontal cortex arising from unstable task instructions.

Executive impairment in Parkinson's disease: Response automaticity and task switching

Patients with Parkinson's disease (PD) show slowed movement initiation and can have deficits in executive function, leading to impairments in controlling involuntary behavior. This results in difficulties performing an antisaccade, which requires one to suppress an automatic eye movement (a prosaccade) to a visual stimulus, and execute a voluntary eye movement in the opposite direction. Antisaccade deficits are similar to those seen in task switching, whereby one is required to change a response after performing a different behavior. Both antisaccade ( Hood et al., 2007) and task switching ( Cools, Barker, Sahakian, & Robbins, 2001) deficits in PD have been attributed to fronto-basal ganglia (BG) dysfunction. Previously, we demonstrated with functional magnetic resonance imaging that BG circuitry is important to both task switching and voluntary saccade generation, as greater caudate activation was seen when healthy young adults first prepared a prosaccade, but then switched to an antisaccade ( Cameron, Coe, et al., 2009). Therefore, we hypothesized that PD patients would have difficulty switching from one saccade response to the other, with particular impairment in switching from a pro to an antisaccade. Here, we not only confirmed this prediction, but also showed that PD patients performed better than controls in switching from an anti to a prosaccade. This suggests that task switching deficits in PD are particularly pronounced when more automatic behavior needs to be overridden with alternative behavior. We suggest that this occurs primarily at the level of establishing the appropriate task set, which is an internalized rule that governs how to respond.

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.

Antisaccade deficits in subjects either genetically or clinically at risk for schizophrenia

Antisaccade deficits in subjects either genetically or clinically at risk for schizophrenia

Do antisaccade deficits in schizophrenia provide evidence of a specific inhibitory function?

Despite its inhibitory control requirements, antisaccade deficits have been consistently associated with working memory impairments in schizophrenia. We investigated whether variance in antisaccade performance could be better accounted for in terms of a specific inhibitory function. We assessed 48 clinically stable out-patients with schizophrenia on an antisaccade task, as well as on measures of spatial and verbal working memory, sustained selective attention, and a simple motoric go/no-go measure of response inhibition. In a stepwise multiple regression analysis, go/no-go task performance accounted for a considerably greater percentage of variance in antisaccade performance (25.3%) than either working memory (8.4%) or sustained selective attention task (9.1%). We conclude that antisaccade deficits in schizophrenia appear to be better understood in terms of a specific deficit of inhibitory control than in terms of more general difficulties with context maintenance or goal neglect.

Successful multi-site measurement of antisaccade performance deficits in schizophrenia

The antisaccade task is a promising schizophrenia endophenotype; it is stable over time and reflects neurophysiological deficits present in both schizophrenia subjects and their first-degree relatives. Meaningful genetic research requires large sample sizes that are best ascertained using multi-site study designs. To establish the criterion validity of the antisaccade task in a multi-site design, the Consortium on the Genetics of Schizophrenia (COGS) examined whether seven sites could detect previously reported antisaccade deficits in schizophrenia subjects. Investigators presented 3 blocks of 20 antisaccade stimuli to 143 schizophrenia subjects and 195 comparison subjects. Frequent collaborator communication, standardized training, and ongoing quality assurance optimized testing uniformity. Data were discarded from only 1.2% of subjects due to poor quality, reflecting the high fidelity of data collection and scoring methods. All sites detected a significant difference in the proportion of correct antisaccades between schizophrenia and comparison subjects ( p < .02 at all sites); group differences in gain and latency were less robust. Regression analyses to adjust for the effects of group, site, age, gender, smoking, and parental education on the proportion of correct antisaccades revealed a significant effect of group, site, and age but no effect of gender, smoking, or parental education, and no group-by-site interactions. Intraclass correlations between proportion of correct antisaccades across the blocks of stimuli ranged from 0.87 to 0.93, demonstrating good within-session reliability at sites. These results confirm previous findings of antisaccade deficits in schizophrenia subjects and support the use of the antisaccade task as a potential schizophrenia endophenotype in multi-site genetic studies.

Neural correlates of antisaccade deficits in schizophrenia, an fMRI study

Schizophrenia patients were known to have oculomotor abnormalities for decades and several studies had found antisaccade impairment to be a biological marker of schizophrenia. In this study, we used functional magnetic resonance imaging (fMRI) to investigate the neural circuits responsible for antisaccade deficits in schizophrenia. Ten normal controls and 10 DSM-IV schizophrenia patients performed antisaccade tasks and control tasks during fMRI. Data were analyzed and task-specific activations were identified using Statistical Parametric Mapping (SPM-2). In normal subjects, antisaccade tasks activated bilateral frontal eye fields, supplementary eye fields, inferior frontal gyrus, superior parietal lobules, inferior parietal lobules, occipital visual cortex, cerebellum, thalamus, and lentiform nuclei ( P < 0.001). By contrast, schizophrenia patients failed to show activation in bilateral lentiform nucleus, bilateral thalamus, and left inferior frontal gyrus during antisaccade performance. Our findings suggest that schizophrenic antisaccade deficits are associated with dysfunction of fronto-striatal-thalamo-cortical circuits previously demonstrated to be responsible for suppression of the reflexive saccade. Left inferior frontal gyrus, which was known to be responsible for response inhibition on “go/no-go” testing, also plays an important role in schizophrenic antisaccade deficit.

The antisaccade task as a research tool in psychopathology: A critical review

The antisaccade task is a measure of volitional control of behavior sensitive to fronto-striatal dysfunction. Here we outline important issues concerning antisaccade methodology, consider recent evidence of the cognitive processes and neural mechanisms involved in task performance, and review how the task has been applied to study psychopathology. We conclude that the task yields reliable and sensitive measures of the processes involved in resolving the conflict between volitional and reflexive behavioral responses, a key cognitive deficit relevant to a number of neuropsychiatric conditions. Additionally, antisaccade deficits may reflect genetic liability for schizophrenia. Finally, the ease and accuracy with which the task can be administered, combined with its sensitivity to fronto-striatal dysfunction and the availability of suitable control conditions, may make it a useful benchmark tool for studies of potential cognitive enhancers.

Antisaccade and smooth pursuit performance in positive- and negative-symptom schizotypy

Schizophrenic patients have well-documented abnormalities in smooth pursuit eye movements and antisaccade performance. In populations at risk for schizophrenia, smooth pursuit abnormalities are also well documented. Antisaccade deficits have been replicated in high-risk populations as well, but the findings are more variable and the reasons for the variability are not clear. Some evidence suggests that antisaccade deficits increase in high-risk populations in relation to the presence of positive symptoms. Whether antisaccade deficits increase in relation to negative symptoms in high-risk populations is relatively uninvestigated. We evaluated antisaccade and pursuit performance in “psychometric schizotypes” who had elevated scores on either the Perceptual Aberration Scale (PerAb; i.e., positive symptoms) or the Physical Anhedonia Scale (PhysAnh; i.e., negative symptoms) but not both, and in normal controls. We used the standard version of the antisaccade task, for which results in positive-symptom schizotypes have previously been reported, and investigated performance on a gap and overlap version. We replicated the finding that a significantly larger percentage of positive-symptom schizotypes than controls have elevated antisaccade error rates on the standard antisaccade task ( P=0.03); the percentage of negative-symptom schizotypes with elevated antisaccade error rates did not differ from that of control subjects. Neither schizotypal group was impaired on the gap or overlap versions of the task. On the pursuit task, a higher percentage of positive- and negative-symptom schizotypes were classified as having deviant performance than control subjects (both Ps<0.04). These findings suggest that antisaccade deficits may be better at identifying high-risk subjects with positive symptoms. Pursuit deficits identified both positive- and negative-symptom schizotypes, but was better at identifying the latter.

Lack of association between prepulse inhibition and antisaccadic deficits in chronic schizophrenia: implications for identification of schizophrenia endophenotypes

Individuals with schizophrenia, compared to healthy individuals, are known to exhibit deficient prepulse inhibition (PPI) of the startle response as well as reduced performance on the antisaccade task. There is evidence for genetic transmission of both PPI and antisaccadic abnormalities in schizophrenia. It has been suggested that PPI and antisaccade measures identify separate endophenotypes, on the basis of a lack of relationship between PPI and antisaccade deficits in patients with schizotypal personality disorder. However, given that patients with schizotypal personality disorder are unlikely to manifest all the abnormalities associated with schizophrenia, it is important to determine that there is no relationship present between these two abnormalities in people affected with schizophrenia. The main objective of this investigation therefore was to establish the lack of the association between PPI and antisaccade deficits in schizophrenia in two independent studies. Study 1 involved 39 patients with schizophrenia and 14 healthy controls and study 2 involved 35 patients with schizophrenia and 22 healthy controls. PPI (uninstructed paradigm) of the acoustically elicited startle (eye blink) was measured electromyographically. Antisaccadic eye movements (standard, non-overlap version) were measured using infrared oculography. Patients displayed reduced PPI and a lower percentage of correct antisaccades relative to healthy controls in both studies. As expected, no relationship occurred between PPI and the percentage of correct antisaccade responses in either group. It is concluded that PPI and antisaccade abnormalities in schizophrenia represent separate endophenotypes, reflecting the functions of different genetic aetiologies and different or only partially overlapping neural systems.

Smooth pursuit and antisaccade eye movements in siblings discordant for schizophrenia

Smooth pursuit eye movement (SPEM) and antisaccade deficits have been proposed as endophenotypes in the search for schizophrenia genes. We assessed these measures in 24 schizophrenia patients, 24 of their healthy siblings, and 24 healthy controls closely matched to the siblings. Between-group differences were assessed using a random effects regression model taking into account the relatedness between patients and siblings. Patients showed reduced SPEM gain, increased frequency of saccades during pursuit, increased antisaccade error rate, and reduced antisaccade gain compared to controls. Siblings performed intermediate, i.e. between patients and controls, on most measures, but were particularly characterised by reduced antisaccade gain. SPEM gain at one target velocity was significantly correlated between patients and siblings, highlighting the necessity of taking into account within-family correlations in the statistical analysis of between-group differences. It is concluded that subtle SPEM and antisaccade deficits are observed in clinically unaffected siblings of schizophrenia patients; these deficits may be useful markers of genetic liability to schizophrenia.