Predictive smooth eye pursuit in a population of young men: I. Effects of age, IQ, oculomotor and cognitive tasks.

Smooth eye pursuit is believed to involve the integration of an extraretinal signal formed by an internal representation of the moving target and a retinal signal using the visual feedback to evaluate performance. A variation of the smooth eye pursuit paradigm (in which the moving target is occluded for a short period of time and subjects are asked to continue tracking) designed to isolate the predictive processes that drive the extraretinal signal was performed by 1,187 young men. The latency to the onset of change in pursuit speed, the time of decelerating eye-movement speed and the steady state residual gain were measured for each subject and correlated with measures of other oculomotor (closed-loop smooth eye pursuit, saccade, antisaccade, active fixation) and cognitive tasks (measuring sustained attention and working memory). Deceleration time increased with increasing age, while education, general IQ and cognitive variables had no effect on predictive pursuit performance. Predictive pursuit indices were correlated to those of closed-loop pursuit and antisaccade performance, but these correlations were very weak except for a positive correlation of residual gain to saccade frequency in the fixation task with distracters. This correlation suggested that the maintenance of active fixation is negatively correlated with the ability to maintain predictive pursuit speed. In conclusion, this study presents predictive pursuit performance in a large sample of apparently healthy individuals. Surprisingly, predictive pursuit was weakly if at all related to closed-loop pursuit or other oculomotor and cognitive tasks, supporting the usefulness of this phenotype in the study of frontal lobe integrity in normal and patient populations.

Predictive smooth eye pursuit in a population of young men: II. Effects of schizotypy, anxiety and depression.

Smooth pursuit eye movement dysfunction is considered to be a valid schizophrenia endophenotype. Recent studies have tried to refine the phenotype in order to identify the specific neurophysiological deficits associated with schizophrenia. We used a variation of the smooth eye pursuit paradigm, during which the moving target is occluded for a short period of time and subjects are asked to continue tracking. This is designed to isolate the predictive processes that drive the extraretinal signal, a process previously reported to be defective in schizophrenia patients as well as their healthy relatives. In the current study, we investigated the relationship between predictive pursuit performance indices and age, education, non-verbal IQ, schizotypy and state anxiety, depression in 795 young Greek military conscripts. State anxiety was related to better predictive pursuit performance (increase in residual pursuit gain), while disorganized schizotypy was related to deficient predictive pursuit performance (decreased residual gain). This effect was independent of the effect of disorganized schizotypy on other oculomotor functions supporting the hypothesis that predictive pursuit might be specifically affected in schizophrenia spectrum disorders and could be considered as a distinct oculomotor endophenotype.

Monitoring antisaccades: inter-individual differences in cognitive control and the influence of COMT and DRD4 genotype variations.

Conscious monitoring of behavior is an essential control function for adaptation and learning. Antisaccade performance was investigated in a large sample of young healthy men in two tasks, one that required conscious error monitoring and one that did not. Conscious error monitoring did not lead to changes in error rate between the two tasks, while other antisaccade parameters were significantly modulated. Application of signal detection theory showed a large inter-individual variability in error detection sensitivity: the majority of individuals were unable to monitor antisaccade errors (chance error detection group), while a minority that successfully monitored their errors (non-chance error detection group) were worse in antisaccade performance in both tasks. These results were explained by the hypothesis of two modes of antisaccade processing favored by each one of the two groups: a mode of conscious cortical cognitive control leading to error monitoring, worse performance and no post-error adaptation and a mode of non-conscious subcortical control leading to chance error monitoring, post-error slowing and better performance of the antisaccade task. This hypothesis was corroborated by the results of the genotype analysis. Error-monitoring sensitivity in the non-chance error detection group was modulated by COMT genotype variations that in turn did not have an effect on error rate. On the other hand, DRD4 genotype variations were related to differences in antisaccade error rate while not affecting error-monitoring sensitivity.

Familial and socioeconomic contributions to premorbid functioning in psychosis: Impact on age at onset and treatment response.

BACKGROUND: Premorbid adjustment (PA) abnormalities in psychotic disorders are associated with an earlier age at onset (AAO) and unfavorable clinical outcomes, including treatment resistance. Prior family studies suggest that familial liability, likely reflecting increased genetic risk, and socioeconomic status (SES) contribute to premorbid maladjustment. However, their joint effect possibly indicating gene-environment interaction has not been evaluated. METHODS: We examined whether family history of psychosis (FHP) and parental SES may predict PA and AAO in unrelated cases with first-episode psychosis (n = 108) and schizophrenia (n = 104). Premorbid academic and social functioning domains during childhood and early adolescence were retrospectively assessed. Regression analyses were performed to investigate main effects of FHP and parental SES, as well as their interaction. The relationships between PA, AAO, and response to antipsychotic medication were also explored. RESULTS: Positive FHP associated with academic PA difficulties and importantly interacted with parental SES to moderate social PA during childhood (interaction p = 0.024). Positive FHP and parental SES did not predict differences in AAO. Nevertheless, an earlier AAO was observed among cases with worse social PA in childhood (ß = -0.20; p = 0.005) and early adolescence (ß = -0.19; p = 0.007). Further, confirming evidence emerged for an association between deficient childhood social PA and poor treatment response (p = 0.04). CONCLUSIONS: Familial risk for psychosis may interact with parental socioeconomic position influencing social PA in childhood. In addition, this study supports the link between social PA deviations, early psychosis onset, and treatment resistance, which highlights premorbid social functioning as a promising clinical indicator.

Arm movement metrics influence saccade metrics when looking and pointing towards a memorized target location.

Saccades are known to influence subsequent arm movements. There is less information to suggest that the characteristics of saccades depend on the reaching movements they accompany. To explore this issue, we studied the systematic errors of saccades generated by two adult female Rhesus monkeys (Macaca Mulata), which were trained to perform center-out saccades and reaching arm movements to the memorized location of targets. The mean error of saccades executed in isolation differed significantly from that of saccades that were executed towards the same target location and accompanied a reaching movement. This difference was observed in both animals whether they used their right or left arm, whether the size of the movement was equal to 10 or 15 degrees and whether there was no delay or a 3 s delay between the extinction of a visual target and the cue to move. Moreover, the endpoints of saccades and those of the arm-reaching movements in the reaching task were significantly correlated. These data suggest that signals specifying the metrics of limb movements influence those specifying the metrics of preceding saccades at a programming stage.

Premorbid adjustment predictors of cognitive dysfunction in schizophrenia.

Premorbid adjustment (PA) in academic and social domain is a key-predictor of cognitive performance in schizophrenia. Prior studies provided inconsistent findings regarding the differential relationships of PA domains with post-illness cognition. Multivariate associations of academic and social PA in each developmental stage (childhood, early and late adolescence) with post-onset cognitive variables were explored. Furthermore, possible differential relationships of PA domain deterioration courses with post-onset cognitive dysfunction were investigated. Seventy-five schizophrenia patients were evaluated with Premorbid Adjustment Scale (PAS). General cognitive ability, verbal IQ, verbal memory and learning, processing speed, working memory, executive function and premorbid IQ were assessed. Canonical Correlation Analyses revealed that poorer academic PA across childhood and early adolescence was related to worse post-onset verbal IQ, working memory, verbal learning and executive function, while academic PA deterioration between early and late adolescence was associated with poorer verbal learning and executive function and, as further analysis indicated, predicts IQ decline. Academic PA was exclusively associated with post-onset cognitive impairment. New evidence emerged for the specificity of each developmental period in constructing academic PA in its relation to post-illness cognition. Early premorbid academic maladjustment possibly constitutes the onset of a cognitive dysmaturational process which results to post-diagnosis impaired cognition.

Increased intra-subject reaction time variability in the volitional control of movement in schizophrenia.

Increased Reaction Time (RT) studies intra-subject variability is an emerging and consistent finding in RT studies of schizophrenia. A group of 23 patients suffering from DSM-IV schizophrenia and a group of 23 age-matched control subjects performed two RT tasks requiring basic sensorimotor processing and engaging two different motor systems: the Finger Lift Reaction Time task and the Voluntary Saccade Reaction Time task. The Ex-Gaussian model was applied to the RT distributions measuring the mean (mu), and standard deviation (sigma) of a Gaussian component thought to reflect sensorimotor processing and an exponential component (tau), thought to reflect an intermediate decision process. In both tasks, a significantly larger RT intra-subject variability effectively dissociated patients from controls. RT intra-subject variability in the two tasks was highly correlated only for patients. Both sigma and tau were significantly higher in the patient group with tau being the best predictor of schizophrenia. Furthermore, only in the patient group were sigma and tau highly correlated between the two tasks. The results reflect a deficit in information processing that may not be confined to decision processes related to the frontal cortex; rather, they may indicate dysfunction in distributed neural networks modulating adaptive regulation of performance.

Schizophrenia-related neuregulin-1 single-nucleotide polymorphisms lead to deficient smooth eye pursuit in a large sample of young men.

Neuregulin-1 (NRG1) variations have been shown to modulate schizophrenia candidate endophenotypes related to brain structure and function. The aim of this study was to determine the effect of NRG1 on several oculomotor schizophrenia endophenotypes. The effects of 5 core single-nucleotide polymorphisms (SNPs) within the NRG1 gene to oculomotor parameters in a battery of oculomotor tasks (saccade, antisaccade, smooth eye pursuit, fixation) were investigated in a sample of 2243 young male military conscripts. Additive regression models, bootstrap and permutation techniques, were used as well as structural equation modeling and haplotype analysis. A deficit in global smooth eye pursuit performance measured using the root-mean-square error (RMSE) was related to the risk allele of SNP8NRG243177, and a deficit in global smooth eye pursuit performance measured using the saccade frequency was related with the risk allele of SNP8NRG433E1006. Structural equation modeling confirmed a global effect of NRG1 genotype on smooth eye pursuit performance using the RMSE, while the effect on saccade frequency was not confirmed. Haplotype analysis further confirmed the prediction from the structural equation modeling that a combination of alleles corresponding to the Icelandic high-risk haplotype was related to a deficit in global pursuit performance. NRG1 genotype variations were related to smooth eye pursuit variations both at the SNP level and at the haplotype level adding to the validation of this gene as a candidate gene for the disorder.

Smooth pursuit eye movements in 1,087 men: effects of schizotypy, anxiety, and depression.

Individuals with schizotypal personality disorder or high scores in questionnaires measuring schizotypy are at high risk for the development of schizophrenia and they also share some of the same phenotypic characteristics such as eye-tracking dysfunction (ETD). The question arises whether these individuals form a distinct high-risk group in the general population or whether schizotypy and ETD co-vary in the general population with no distinct cutoff point for a high-risk group. A large sample of military conscripts aged 18-25 were screened using oculomotor, cognitive and psychometric tools for the purposes of a prospective study on predisposing factors for the development of psychosis. Schizotypy measured using the perceptual aberration scale (PAS) and the schizotypal personality questionnaire (SPQ), anxiety and depression, measured using the Symptom Checklist 90-R, had no effect on pursuit performance in the total sample. Small groups of individuals with very high scores in schizotypy questionnaires were then identified. These groups were not mutually exclusive. The high PAS group had higher root-mean-square error scores (a quantitative measure for pursuit quality) than the total sample, and the high disorganized factor of SPQ group had lower gain and higher saccade frequencies in pursuit than the total sample. The presence of significant differences in pursuit performance only for predefined high schizotypy groups favors the hypothesis that individuals with high schizotypy might present one or more high-risk groups, distinct from the general population, that are prone to ETD as that observed in schizophrenia.