Antisaccade task performance in patients at ultra high risk for developing psychosis

doi:10.1016/j.schres.2007.06.022

Schizophrenia Research

Volume 95, Issues 1–3, September 2007, Pages 54-60

https://doi.org/10.1016/j.schres.2007.06.022 Get rights and content

Abstract

Patients with schizophrenia consistently perform worse than healthy controls on the antisaccade task in which the subject is required to inhibit a reflexive saccade to a suddenly appearing visual target and look in the opposite direction. To our knowledge there is no research yet showing how patients at ultra high risk (UHR) for developing psychosis perform on the antisaccade task. The aim of the present study was to investigate antisaccade task performance in UHR patients. Patients were eligible for the study when they met criteria for one or more of the following groups: Attenuated symptoms or brief limited intermitted psychotic symptoms or a first-degree family member with a psychotic disorder and reduced functioning or basic symptoms. In 35 UHR patients we assessed antisaccades, neuropsychological test performance and symptomatology. Antisaccade task results were compared with those obtained in 42 age- and intelligence-matched patients with recent-onset schizophrenia and 28 matched healthy controls. Antisaccade error rate was significantly higher in the UHR patients than in the controls. Schizophrenia patients performed worse than the UHR patients and the control subjects. We found a trend towards higher antisaccade error rate at baseline in the UHR patients who later made the transition to psychosis compared to the UHR patients who did not make the transition to psychosis. Poor spatial working memory function was related to increased antisaccade errors in the UHR group. Abnormal antisaccade task performance is also present in patients at UHR for developing psychosis. Subsequent research needs to clarify if increased antisaccade error rate is predictive of a psychotic episode. In UHR patients, poor antisaccade performance may reflect working memory dysfunction.

Introduction

The antisaccade task generates the most frequently observed volitional saccade abnormality in schizophrenia (Crawford et al., 1996, Fukushima et al., 1990). In the antisaccade task, subjects are asked not to look at a suddenly appearing visual target but to make a saccade in the opposite direction at a similar distance from the central fixation point. It has been suggested that the dorsolateral prefrontal cortex is involved in suppressing reflexive saccades, and that the frontal eye fields trigger the correct saccade to the opposite side (Muri et al., 1998). It is unknown how patients at ultra high risk (UHR) for developing psychosis perform on the antisaccade test.

The development of schizophrenia is generally preceded by a prodromal phase in which there is a clear deterioration from a previous level in functioning. The length of this prodromal phase is extremely variable and varies from weeks to years.

The mechanism by which this prodromal state evolves into psychosis is not really understood (Hodges et al., 1999). Additionally, to predict whether the symptoms of a prodromal state evolve in a psychosis or not, is also not yet possible. The retrospective term ‘prodrome’ therefore cannot appropriately be applied to prospective investigations (Yung et al., 2003). The term ‘ultra high risk’ has been used to indicate a subthreshold syndrome that can be regarded as a risk factor for subsequent psychosis within the next year, but that psychosis is not inevitable (Yung et al., 2003).

McGorry et al. (1995) were able to define three groups thought to be at ultra high risk of developing a psychotic disorder. Group 1: Attenuated psychotic symptoms defines a group of people who have symptoms that deviate from normal phenomena but which are not frankly psychotic e.g. ideas of reference, odd beliefs and paranoid ideation. Group 2: Brief Limited Intermittent Psychotic Symptoms (BLIPS), defines a group that has symptoms of psychotic intensity but which are very infrequent, or which have a total duration of less than 7 days before resolving spontaneously. Group 3: Trait and state risk factors, defines a group who have non-specific symptoms such as lowered mood or anxiety symptoms plus some trait-risk factors for psychotic disorder, either a schizotypical personality disorder or a family history of a psychotic disorder in a first-degree relative. The non-specific symptoms must have a duration of at least 1 month and must be associated with marked disability or decrease in functioning. 20 of 49 subjects considered as belonging to an ultra high risk group as mentioned above (40.8%) developed a psychotic disorder within 12 months (Yung et al., 2003). Thus 59% did not. If UHR patients would be treated with antipsychotic medication, 59% would receive medication that was not indicated. Therefore, it is important that the percentage correct prediction of psychosis is increased.

Cognitive abnormalities have been reported in UHR subjects. Hawkins et al. (2004) found that UHR patients performed at levels intermediate to population norms and data reported for schizophrenia samples on a comprehensive neuropsychological exam. In the context of normal intelligence, this intermediate status suggests that, as a group, these subjects are not fully normal in neuropsychological functioning. Wood et al. (2003) found spatial working memory disorders in UHR patients. Working memory is fundamental to the human ability to reason and make judgments that rely on remembered contextual information and is thought to be mediated mainly by the dorsolateral prefrontal cortex (Beardsley, 1997). The relationship between antisaccade errors and neuropsychological test performance in UHR subjects is yet unexplored.

The first aim of the present study was to investigate antisaccade task performance in patients at UHR for developing psychosis. If antisaccade task performance is reduced in UHR patients, further research is warranted to elucidate if this test could enhance the percentage correct prediction of psychosis. The second aim was to investigate the relationship between neuropsychological tests and antisaccade task performance to gain insight into underlying pathological mechanisms of antisaccade task performance in UHR patients.

Section snippets

Subjects

Thirty-five patients (five women) with a UHR of developing psychosis were assessed with the antisaccade test. Mean age was 20.1 years ± 3.7, SD. The UHR patients were referred to the Academic Medical Center, Amsterdam, Netherlands by psychiatrists and psychologists for a second opinion with the question whether a psychotic development was taking place. The exclusion criteria were: previous psychotic episode for more than one week (as assessed with the Structured Clinical Interview for Diagnosis,

Results

Fig. 1 depicts the number of UHR patients falling into the four inclusion groups. Most patients fell in more than one inclusion category.

Examples of antisaccades in an UHR patient and a control are shown in Fig. 2. Three wrong antisaccades are depicted in the registration of the UHR patient and three correct antisaccades in the control subject.

Mean and standard deviation of the antisaccade and neuropsychological outcome variables in the UHR and schizophrenia patients and control subjects are

Discussion

We found antisaccade error rate in a group of UHR patients to be significantly higher than in controls but not as high as in a matched schizophrenia sample. Furthermore, our results showed a trend towards higher antisaccade error rate at baseline in the UHR patients who later made the transition to psychosis compared to the UHR patients who did not make the transition to psychosis. The percentage of errors in the antisaccade task increased with decreased working memory function (SWMT) in the

Role of the funding source

This study was funded by grant QLGU-CT-2001-01081 from the European Commission in Brussels, Belgium. The European Commission had no further role in the study design; in the collection, analysis and interpretation of data; in the writing of the report; and in the decision to submit the paper for publication.

Contributors

Author Hiske Becker included patients in the study and was involved in clinical assessments concerning transition to psychosis. Reinaud van de Fliert was involved in recruiting patients into the study and clinical assessments. Niels Plat assessed patients neurophysiologically and contributed to the statistical analysis of these data. Lo Bour wrote the eye movement recording protocol and supervised eye movement recording and analysis. Hans Koelman was involved in the design of the study. Maria

Conflict of interest

All authors declare that they have no conflicts of interest.

Acknowledgement

We thank Thijs Boerée for his help with the analysis of the eye movement data.

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Antisaccade error rates in first-episode psychosis, ultra-high risk for psychosis and unaffected relatives of schizophrenia: A systematic review and meta-analysis
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Antisaccade, which is described as looking at the opposite location of the target, is an eye movements paradigm used for assessing cognitive functions in schizophrenia. Initiation and sustainment of saccades in antisaccade are managed by frontal and parietal cortical areas. Antisaccade abnormalities are well-established findings in schizophrenia. However, studies in the early phases of psychotic disorders and clinical/familial risk for psychosis reported inconsistent findings. The current systematic review aimed to review the results of studies investigating antisaccade error rates in first-episode psychosis (FEP), individuals with ultra-high-risk for psychosis (UHRP), and familial-high-risk for psychosis (FHRP) compared to healthy controls.
A meta-analysis of 17 studies was conducted to quantitatively review antisaccade errors in FEP, UHR-P and FHRP. The error rate (Hedges'g) was compared between the total of 860 FEP, UHRP, FHRP, and 817 healthy controls. Hedges' g for effect size, I² for estimating the percentage of variability, and publication bias were evaluated through the R software.
The outcomes of this meta-analysis suggested that FEP is associated with a robust deficit in the antisaccade error rate (g = 1.16, CI = 0.95–1.38). Additionally, both the clinical and familial high-risk groups showed small but significant increases in AS errors (g = 0.26, CI = 0.02–0.52 and g = 0.34, CI = 0.13–0.55, respectively).
The large effect size estimated for FEP was compatible with previously reported results in chronic schizophrenia patients. Additionally, relatives had abnormalities with small to medium effect sizes and significant differences. The current findings suggest that antisaccade errors might be a potential endophenotype for psychotic disorders.
Reduced task-evoked pupillary response in preparation for an executive cognitive control response among individuals across the psychosis spectrum
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Task-evoked pupillary response (TEPR) is a measure of physiological arousal modulated by cognitive demand. Healthy individuals demonstrate greater TEPR prior to correct versus error antisaccade trials and correct antisaccade versus visually guided saccade (VGS) trials. The relationship between TEPR and antisaccade performance in individuals with psychotic disorders and their relatives has not been investigated.
Probands with schizophrenia, schizoaffective disorder, psychotic bipolar disorder, their first-degree relatives, and controls from the B-SNIP study completed antisaccade and VGS tasks. TEPR prior to execution of responses on these tasks was evaluated among controls compared to probands and relatives according to diagnostic groups and neurobiologically defined subgroups (biotypes).
Controls demonstrated greater TEPR on antisaccade correct versus error versus VGS trials. TEPR was not differentiated between antisaccade correct versus error trials in bipolar or schizophrenia probands, though was greater on antisaccade compared to prosaccade trials. There was no modulation of TEPR in schizoaffective probands. Relatives of schizophrenia and schizoaffective probands and those with elevated psychosis spectrum traits failed to demonstrate differential TEPR on antisaccade correct versus error trials. No proband or relative biotypes demonstrated differential TEPR on antisaccade correct versus error trials, and only proband biotype 3 and relative biotypes 3 and 2 demonstrated greater TEPR on antisaccade versus VGS trials.
Our findings suggest that aberrant modulation of preparatory activity prior to saccade execution contributes to impaired executive cognitive control across the psychosis spectrum, including nonpsychotic relatives with elevated clinical risk. Reduced pupillary modulation under cognitive challenge may thus be a biomarker for the psychosis phenotype.
The impact of COVID-19 pandemic on individuals at clinical high-risk for psychosis: Evidence from eye-tracking measures
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Evidence suggested that aberrant performances of eye movement were also observed prior to the onset of psychosis. For instance, altered indicators, including increased error rates of the anti-saccade (Nieman et al., 2007; Obyedkov et al., 2019), pro-saccade (Obyedkov et al., 2019), and memory-guided saccade tests (Caldani et al., 2017) along with prolonged anti-saccade latency (Kleineidam et al., 2019), were frequently reported in CHR population. Additionally, eye movement indexes were observed to be associated with levels of psychological stress in intensive care unit nurses (Ahmadi et al., 2022) and were also altered in the individuals diagnosed with posttraumatic stress disorder (PTSD) (Coll et al., 2022), suggesting the potential of eye movement metrics as markers of psychological stress (Skaramagkas et al., 2021).
Emerging evidence suggested that people with severe mental disorders were more vulnerable to the negative effects of the COVID-19 pandemic. However, few researches investigated the influence of global pandemics on people at clinical high risk (CHR) for psychosis. This study aimed to investigate the impact of the COVID-19 pandemic on clinical symptoms, psychological distress, and eye-tracking characteristics in CHR individuals and healthy participants. Forty-nine CHR individuals and 50 healthy controls (HC) were assessed by PTSD Checklist for DSM-5 (PCL-5), Perceived Stress Scale, 10-item version (PSS-10), and Coronavirus Impact Scale (CIS). Eye movement performances were measured by the tests of fixation stability, free-viewing, and anti-saccade. According to the mean score of CIS, participants were stratified into high-impact (n = 35) and low-impact (n = 64) subgroups. Compared with the HC group, CHR participants reported significantly higher levels of post-traumatic symptoms caused by the COVID-19 pandemic and showed abnormalities in most of the eye movement indexes. Among the altered indexes, the saccade amplitude of fixation stability test (far distractor), the scan path length of free-viewing test, and the accuracy of anti-saccade test were negatively affected by the severity of impact level in the CHR group. Moreover, the altered eye movement indexes were significantly associated with the total scores of CIS, PCL-5, and subscales of the Scale of Prodromal Syndromes (SOPS) among CHR individuals. Overall, our findings suggested the negative impact of the COVID-19 pandemic on the eye movement characteristics of CHR individuals. The present study provides valuable information on physiological distress related to the COVID-19 pandemic and sensitive neuropsychological biomarkers that interacted with social and environment stress in the CHR population.
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The phosphoinositide-3-kinase (PI3K) family plays a major role in cell signaling and is predominant in leukocytes. Gain-of-function (GOF) mutations in the PIK3CD gene lead to the development of activated PI3Kδ syndrome (APDS), a rare primary immunodeficiency disorder. A subset of APDS patients also displays neurodevelopmental delay symptoms, suggesting a potential role of PIK3CD in cognitive and behavioural function. However, the extent and nature of the neurodevelopmental deficits has not been previously quantified. Here, we assessed the cognitive functions of two APDS patients, and investigated the causal role of the PIK3CD GOF mutation in neurological deficits using a murine model of this disease. We used p110δ^E1020K knock-in mice, harbouring the most common APDS mutation in patients. We found that APDS patients present with visuomotor deficits, exacerbated by autism spectrum disorder comorbidity, whereas p110δ^E1020K mice exhibited impairments in motor behaviour, learning and repetitive behaviour patterning. Our data indicate that PIK3CD GOF mutations increase the risk for neurodevelopmental deficits, supporting previous findings on the interplay between the nervous and the immune system. Further, our results validate the knock-in mouse model, and offer an objective assessment tool for patients that could be incorporated in diagnosis and in the evaluation of treatments.
Neurocognitive and neurophysiological endophenotypes in schizophrenia: An overview
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Physiological mechanism underlying AS are complex and appear to depend on competitive stimulus selection in the superior colliculus [60]. Patients suffering from SCZ show longer latencies to correct eye movements in AS tasks, when compared to HC [61], which likely reflects a lack of inhibitor control [62]. Studies in unaffected FDR of SCZ probands have reported an intermediate degree of AS deficits in those individuals [63].
Schizophrenia (SCZ) is a severe psychotic disorder that affects up to 1% of the US population and it is associated with progressive impairment in social functioning and cognition. Nonetheless, despite its high burden, the pathophysiology of SCZ, including the genetic and biological mechanisms underlying the development and manifestation of the disorder, remains largely elusive. Endophenotypes are subtypes of biological markers that are more closely related to the genetic vulnerability for a disorder (e.g., SCZ). Recently, research on endophenotypes has identified several parameters that may prove useful in shedding light over the underlying neurobiology of SCZ. In this article, we provide an overview of the most established SCZ endophenotypes in the domains of neurocognition (attention deficits, working and verbal declarative memory dysfunctions) and neurophysiology (pre-pulse inhibition, anti-saccade impairment, event-related potential deficits) along with some novel, sleep-based measures (reduced sleep spindles and sleep slow waves). We also discuss recent conceptual advances in the field that may lead to novel, personalized treatment interventions for patients affected by this devastating mental illness.
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Alteration of visual scanpaths under emotional facial expression in schizophrenia patients has been described in recent years; however, it is not clear whether such results are different when they transfer to faces in natural social scenes. The present study was designed to investigate the effects of emotional faces in natural social scenes on the gaze patterns of patients with schizophrenia, compared to gaze at isolated faces. A novel theme identification task was used where participants selected a positive, neutral or negative word to describe an emotional picture. Participants were 29 patients with schizophrenia and 31 healthy controls. The Positive and Negative Syndrome Scale (PANSS) and the Scale of Social Function in Psychosis Inpatients (SSPI) were used to assess symptoms and social functioning. In total, patients with schizophrenia showed significantly fewer fixations, saccades numbers and decreased fixations in areas of interest. As expected, patients showed shorter scanpath length, but only in the pictures with social settings. Furthermore, the effect size of scanpaths parameters under social scene was all greater than isolated face. In addition, patients compared to controls showed more abnormal scanpath parameters processing negative and neutral faces than positive faces, especially in social scene. The present study suggests that scanpath length for social scene faces may be more sensitive than for isolated face pictures. Our findings further support restricted scanpath whilst recognizing emotional facial expressions in natural social scenes as a favorable topic for further investigation as a trait marker.

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Antisaccade task performance in patients at ultra high risk for developing psychosis

Abstract

Introduction

Section snippets

Subjects

Results

Discussion

Role of the funding source

Contributors

Conflict of interest

Acknowledgement

Biol. Psychiatry

Schizophr. Res.

Biol. Psychiatry

Magn. Reson. Imaging

Schizophr. Res.

Schizophr. Res.

DSM-IV: Diagnostic and Statistical Manual of Mental Disorders

The machinery of thought

Sci. Am.

The double magnetic induction method for measuring eye movements—results in monkey and man

IEEE Trans. Biomed. Eng.

Physiological characteristics of capacity constraints in working memory as revealed by functional MRI

Cereb. Cortex

Saccadic abnormalities in psychotic patients. I. Neuroleptic-free psychotic patients

Psychol. Med.

Abnormal saccadic distractibility in patients with schizophrenia: a 99mTc-HMPAO SPET study

Psychol. Med.

People at risk of schizophrenia: sample characteristics of the first 100 cases in Edinburgh high-risk study

Br. J. Psychiatry

Abnormal saccadic distractibility in patients with schizophrenia: a ^99mTc-HMPAO SPET study