Convolutional neural network propagation on electroencephalographic scalograms for detection of schizophrenia.

OBJECTIVE: Electroencephalographic analysis (EEG) has emerged as a powerful tool for brain state interpretation. Studies have shown distinct deviances of patients with schizophrenia in EEG activation at specific frequency bands. METHODS: Evidence is presented for the validation of a Convolutional Neural Network (CNN) model using transfer learning for scalp EEGs of patients and controls during the performance of a speeded sensorimotor task and a working memory task. First, we trained a CNN on EEG data of 41 schizophrenia patients (SCZ) and 31 healthy controls (HC). Secondly, we used a pretrained model for training. Both models were tested in an external validation set of 15 SCZ, 16 HC, and 12 first-degree relatives. RESULTS: Using the layer-wise relevance propagation on the classification decision, a heatmap was produced for each subject, specifying the pixel-wise relevance. The CNN model resulted in the first case in a balanced accuracy of 63.7% and 81.5% in the second case, on the external validation test 64.5% and 83.2%, respectively. CONCLUSIONS: The theta and alpha frequency bands of the EEG signals had significant relevance to the CNN classification decision and predict the first-degree relatives indicating potential heritable functional deviances. SIGNIFICANCE: The proposed methodology results in important advancements for the identification of biomarkers in schizophrenia heritability.

The relation of integrated psychological therapy to resting state functional brain connectivity networks in patients with schizophrenia.

Functional brain dysconnectivity measured with resting state functional magnetic resonance imaging (rsfMRI) has been linked to cognitive impairment in schizophrenia. This study investigated the effects on functional brain connectivity of Integrated Psychological Therapy (IPT), a cognitive behavioral oriented group intervention program, in 31 patients with schizophrenia. Patients received IPT or an equal intensity non-specific psychological treatment in a non-randomized design. Evidence of improvement in executive and social functions, psychopathology and overall level of functioning was observed after treatment completion at six months only in the IPT treatment group and was partially sustained at one-year follow up. Independent Component Analysis and Isometric Mapping (ISOMAP), a non-linear manifold learning algorithm, were used to construct functional connectivity networks from the rsfMRI data. Functional brain dysconnectivity was observed in patients compared to a group of 17 healthy controls, both globally and specifically including the default mode (DMN) and frontoparietal network (FPN). DMN and FPN connectivity were reversed towards healthy control patterns only in the IPT treatment group and these effects were sustained at follow up for DMN but not FPN. These data suggest the use of rsfMRI as a biomarker for accessing and monitoring the therapeutic effects of cognitive remediation therapy in schizophrenia.

Social and non-social gaze cueing in autism spectrum disorder, attention-deficit/hyperactivity disorder and a comorbid group.

Recent trends in literature, along with the changes to the Diagnostic and Statistical Manual (DSM), make it imperative to study Attention-Deficit/Hyperactivity Disorder (ADHD) and Autism Spectrum Disorder (ASD) together, in order to better understand potential aetiological commonalities between these highly comorbid disorders. The present study examines social cueing, a highly studied construct in ASD, and intra-subject variability (ISV), a potential endophenotype of ADHD, in four groups of typically developing (TD), ADHD, ASD- (ASD without ADHD), ASD+ (ASD with ADHD) participants (N = 85) aged 10-13 years. Results showed that social cueing is intact in the 'pure' ASD group when task expectations are clear. The ADHD group showed faster saccadic reaction times, no increased ISV and a pattern of viewing comparable to the TD group. However, the ASD + group showed a differences in processing style and ISV. A secondary analysis gives evidence of non-additive effects of the ASD and ADHD factors.

Examining the Overlap Between ADHD and Autism Spectrum Disorder (ASD) Using Candidate Endophenotypes of ADHD.

Objective: Recent discussions of aetiological overlap between ADHD and Autism Spectrum Disorder (ASD) require comparative studying of these disorders. METHOD: We examined performance of ASD patients with (ASD+) and without (ASD-) comorbid ADHD, ADHD patients, and controls for selected putative endophenotypes of ADHD: Intrasubject Variability (ISV) of reaction times, working memory (WM), inhibition, and temporal processing. RESULTS: We found that patients with ADHD or ASD+, but not ASD-, had elevated ISV across the entire task battery and temporal processing deficits, and that none of the groups were impaired in WM or inhibition. High levels of ISV and generally poor performance in ASD+ patients were only partially due to additive effects of the pure disorders. CONCLUSION: Overall, we conclude that, within our limited but heterogeneous task battery, ISV and temporal processing deficits are most sensitive to ADHD symptomatology and that controlling for ADHD comorbidity is mandatory when assessing ISV in autism.

Visual search in ADHD, ASD and ASD + ADHD: overlapping or dissociating disorders?

Recent debates in the literature discuss commonalities between Attention-Deficit/Hyperactivity Disorder (ADHD) and Autism Spectrum Disorder (ASD) at multiple levels of putative causal networks. This debate requires systematic comparisons between these disorders that have been studied in isolation in the past, employing potential markers of each disorder to be investigated in tandem. The present study, choose superior local processing, typical to ASD, and increased Intra-Subject Variability (ISV), typical to ADHD, for a head-to-head comparison of the two disorders, while also considering the comorbid cases. It directly examined groups of participants aged 10-13 years with ADHD, ASD with (ASD+) or without (ASD-) comorbid ADHD and a typically developing (TD) group (total N = 85). A visual search task consisting of an array of paired words was designed. The participants needed to find the specific pair of words, where the first word in the pair was the cue word. This visual search task was selected to compare these groups on overall search performance and trial-to-trial variability of search performance (i.e., ISV). Additionally, scanpath analysis was also carried out using Recurrence Quantification Analysis (RQA) and the Multi-Match Model. Results show that only the ASD- group exhibited superior search performance; whereas, only the groups with ADHD symptoms showed increased ISV. These findings point towards a double dissociation between ASD and ADHD, and argue against an overlap between ASD and ADHD.

P300 response modulation reflects breaches of non-probabilistic expectations.

In oddball paradigms, infrequent stimuli elicit larger P300 event related potentials (ERPs) than frequent ones. One hypothesis is that P300 modulations reflect the degree of "surprise" associated with unexpected stimuli. That is the P300 represents how unlikely the stimulus is and this signal is then used to update the observer's expectations. It could be hypothesized that P300 is modulated by any factor affecting an observer's expectations, not only target probability. Alternatively, the P300 may reflect an evaluative process engaged whenever a discrepancy between task context and sensory inputs arises, irrespective of the latter probability. In previous ERP studies, stimulus probability was often the only determinant of task set confounding the effects of stimulus probability and set stimulus discrepancy. In this study, we used a speeded luminance detection task. The target was preceded by a central cue that predicted its location. The probability that the target was valid, i.e. would appear at the cued location was manipulated by varying the reliability of the cue. Reaction times were modulated by probabilistic expectations based on cue reliability and target validity while P300 was affected by target validity only. We conclude that increased P300 amplitude reflects primarily breaches of non-probabilistic expectations, rather than target probability.

Studying global processing in autism and attention-deficit/hyperactivity disorder with gaze movements: The example of a copying task.

Recent discussions in the literature, along with the revision of the Diagnostic and Statistical Manual (DSM) (American Psychiatric Association 2013), suggest aetiological commonalities between the highly comorbid Attention-Deficit/Hyperactivity Disorder (ADHD) and Autism Spectrum Disorder (ASD). Addressing this discussion requires studying these disorders together by comparing constructs typical to each of them. In the present study, we investigate global processing, known to be difficult for participants with ASD, and Intra-Subject Variability (ISV), known to be consistently increased in participants with ADHD, in groups, aged 10-13 years, with ADHD (n = 25), ASD without comorbid ADHD (ASD-) (n = 13) and ASD with ADHD (ASD+) (n = 18) in comparison with a typically developing group (n = 22). A Copying task, typically requiring global processing and in this case particularly designed using equally complex stimuli to also measure ISV across trials, was selected. Oculomotor measures in this task proved to be particularly sensitive to group differences. While increased ISV was not observed in the present task in participants with ADHD, both ASD groups looked longer on the figure to be drawn, indicating that global processing takes longer in ASD. However, the ASD+ group fixated on the figure only between drawing movements, whereas the ASD- group did this throughout the drawing process. The present study provides evidence towards ASD and ADHD being separate, not-overlapping, disorders. Since the pure ASD- group was affected more by central coherence problems than the ASD+ group, it may suggest that neuropsychological constructs interact differently in different clinical groups and sub-groups.

Hypo-activity of the dorsolateral prefrontal cortex relates to increased reaction time variability in patients with schizophrenia.

Increased reaction time intra-subject variability (RT-ISV) in fast decision tasks has been confirmed in patients with schizophrenia and has been hypothesized to result from a deficit in the control of attention. Here, an attentional task and functional brain imaging were used to probe the neural correlates of increased RT-ISV in schizophrenia. Thirty patients and 30 age and sex matched controls performed the Eriksen flanker spatial attention task with concurrent measurement of brain activity using functional magnetic resonance imaging (fMRI). The behavioral measures included accuracy, mean, standard deviation of RT (RTSD), coefficient of variation of RT (RTCV) and ex-Gaussian model of RT distribution parameters (mu, sigma and tau). Larger mean RT and Ex-Gaussian mu was observed for patients compared to controls. The group difference was larger for incongruent (attentionally demanding) versus congruent trials confirming a deficit in the control of spatial attention for patients. Significant increase in RT-ISV measures (RTSD, sigma and tau) for patients compared to controls was observed and was not modulated by trial congruency. Attention modulation (congruency effect) resulted in activation of bilateral frontal and parietal areas that was not different between patients and controls. Right middle frontal, right superior temporal and bilateral cingulate areas were more active in controls compared to patients independent of congruency. Activation in ROIs extracted from attention (congruency) and group related areas correlated with RT-ISV measures (especially RTCV and tau). Hypo-activation of the right middle frontal area correlated with increased tau specifically in patients. Hypo-activity of the right prefrontal cortex predicted increased RT-ISV in schizophrenia. This effect was unrelated to the effects of spatial attention and might be linked to a deficit in the inhibitory control of action for these patients.

The impact of the COMT genotype and cognitive demands on facets of intra-subject variability.

Intra-Subject Variability (ISV), a potential index of catecholaminergic regulation, is elevated in several disorders linked with altered dopamine function. ISV has typically been defined as reaction time standard deviation. However, the ex-Gaussian and spectral measures capture different aspects and may delineate different underlying sources of ISV; thus reflecting different facets of the construct. We examined the impact of factors associated with dopamine metabolism, namely, Catechol-O-Methyltransferase Val158Met (COMT) genotype and Working Memory (WM) and response-switching on ISV facets in young healthy adults. The Met allele was associated with overall increased variability. The rather exclusive sensitivity of ex-Gaussian tau to frequencies below 0.025 Hz and the quasi-periodic structure of particularly slow responses support the interpretation of tau as low frequency fluctuations of neuronal networks. Sigma, by contrast, may reflect neural noise. Regarding cognitive demands, a WM load-related increase in variability was present for all genotypes and all ISV facets. Contrastingly, ISV facets reacted differently to variations in response-switching as, across genotypes, sigma was elevated for rare target trials whereas tau was elevated for frequent standard trials, particularly for Met homozygotes. Our findings support the significant role of COMT in regulating behavioural ISV with its facetted structure and presumed underlying neural processes.

Electro-cortical correlates of multisensory integration using ecologically valid emotional stimuli: Differential effects for fear and disgust.

Multisensory integration (MSI) is crucial for human communication and social interaction and has been investigated in healthy populations and neurodevelopmental disorders. However, the use of stimuli with high ecological validity is sparse, especially in event-related potential (ERP) studies. The present study examined the ERP correlates of MSI in healthy adults using short (500 ms) ecologically valid professional actor-produced emotions of fear or disgust as vocal exclamation or facial expression (unimodal conditions) or both (bimodal condition). Behaviourally, our results show a general visual dominance effect (similarly fast responses following bimodal and visual stimuli) and an MSI-related speedup of responses only for fear. Electrophysiologically, both P100 and N170 showed MSI-related amplitude increases only following fear, but not disgust stimuli. Our results show for the first time that the known differential neural processing of fear and disgust also holds for the integration of dynamic auditory and visual information.

Shared variance of oculomotor phenotypes in a large sample of healthy young men.

This study used canonical correlation analysis to investigate patterns of shared variance between parameters measured in seven different occulomotor function tasks, namely the visually guided saccade task, the antisaccade task, the closed-loop smooth-pursuit task, the open-loop smooth-pursuit task, and three active visual fixation tasks. These tasks were performed by 2130 young army recruits. Only a small percentage (1-10%) of shared variance existed between sets of parameters for all oculomotor function tasks measured. The most correlated tasks were the visually guided saccade and the antisaccade. The first common factor correlated with speed of performance between these tasks (latency), while the second and third correlated with accuracy of performance. Better performance in active visual fixation tasks correlated with better performance accuracy (lower error rate) and increased speed (lower latency) in the antisaccade and saccade tasks as well as better performance in the closed-loop smooth-pursuit task (increase in gain and decrease in the rate of unwanted saccades during pursuit). Better performance in the closed-loop smooth-pursuit task (increased gain and decreased number of unwanted saccades) also correlated with increased accuracy and increased speed of performing saccades and antisaccades. Finally, the open-loop fixation task had no correlation with all other oculomotor tasks except for a very weak negative correlation with the closed-loop pursuit task where better performance (increased gain) in one correlated with worse performance (decreased gain) in the other. The results of this analysis showed that a small percentage of variance is shared among different oculomotor function tasks. The structure of this shared variance could be used to derive common oculomotor function indices to study their relation to genetic and other sources of inter-subject variation.

GWAS meta-analysis reveals novel loci and genetic correlates for general cognitive function: a report from the COGENT consortium.

This corrects the article DOI: 10.1038/mp.2016.244.

GWAS meta-analysis reveals novel loci and genetic correlates for general cognitive function: a report from the COGENT consortium.

The complex nature of human cognition has resulted in cognitive genomics lagging behind many other fields in terms of gene discovery using genome-wide association study (GWAS) methods. In an attempt to overcome these barriers, the current study utilized GWAS meta-analysis to examine the association of common genetic variation (~8M single-nucleotide polymorphisms (SNP) with minor allele frequency ⩾1%) to general cognitive function in a sample of 35 298 healthy individuals of European ancestry across 24 cohorts in the Cognitive Genomics Consortium (COGENT). In addition, we utilized individual SNP lookups and polygenic score analyses to identify genetic overlap with other relevant neurobehavioral phenotypes. Our primary GWAS meta-analysis identified two novel SNP loci (top SNPs: rs76114856 in the CENPO gene on chromosome 2 and rs6669072 near LOC105378853 on chromosome 1) associated with cognitive performance at the genome-wide significance level (P<5 × 10-8). Gene-based analysis identified an additional three Bonferroni-corrected significant loci at chromosomes 17q21.31, 17p13.1 and 1p13.3. Altogether, common variation across the genome resulted in a conservatively estimated SNP heritability of 21.5% (s.e.=0.01%) for general cognitive function. Integration with prior GWAS of cognitive performance and educational attainment yielded several additional significant loci. Finally, we found robust polygenic correlations between cognitive performance and educational attainment, several psychiatric disorders, birth length/weight and smoking behavior, as well as a novel genetic association to the personality trait of openness. These data provide new insight into the genetics of neurocognitive function with relevance to understanding the pathophysiology of neuropsychiatric illness.

Modular Patterns of Phase Desynchronization Networks During a Simple Visuomotor Task.

By performing sensor-level analysis on magnetoencephalography (MEG) data we identified the dynamic evolution of the functional connectivity networks during a simple visuomotor task. The functional connectivity networks were constructed using the concept of phase-locking value (PLV). We illustrate that the task-related activity is mediated by distinct complex networks related to the PLV desynchronization that configure their architecture dynamically during the task. These networks are prominent at ß and α band, and are characterized by coherent modular organization. Moreover the time for the development of the desynchronization networks at α band predicts the intra-subject variability of reaction time. Thus, the spatio-temporal dynamics and the structural properties of the emerged functional networks share common characteristics with the mechanism of coactivation and resting state networks.

Temperament and character dimensions assessed in general population, in individuals with psychoactive substance dependence and in young male conscripts.

BACKGROUND: In this work we consider Cloninger's psychobiological model, which measures two dimensions of personality: character and temperament. Temperament refers to the biological basis of personality and its characteristics, while character refers to an individual's attitudes towards own self, towards humanity and as part of the universe. METHODS: The Temperament and Character Inventory-Revised-140 (TCI-R-140) was administered to 3 divergent samples: a general population sample, a sample of male conscripts and a sample of individuals attending a substance abuse rehabilitation programme. Score differences among the three samples were assessed controlling for age and gender and reliability coefficients are reported. The latent structure was studied in all samples, using exploratory and confirmatory factor analysis methods (EFA and CFA respectively). RESULTS: The proposed structure was partially replicated via EFA. CFA however indicated less than satisfactory fit, as in previously reported results. To improve the fit, the path diagram was augmented to account for multiple factor complexity, as suggested by the EFA results in all samples. While retaining the original seven-factor structure, the augmented model provided adequate fit. The consistency of the inventory was satisfactory in all samples. Evidence for the construct validity was found in relation to aggression. CONCLUSIONS: This is the first study to conclude in adequate fit, after allowing for the indicators to load on more than one factor within each dimension. While cross-national differences apply, our results were similar (when comparable) with previously reported ones in the literature.

Myocarditis after administration of clozapine.

OBJECTIVE: Clozapine is an atypical antpsychotic medication with established efficacy in patients diagnosed of resistant schizophrenia. However, clozapine has multiple side effects. Cardiac complications such as myocarditis and cardiomyopathy have always been related with treatment with clozapine. METHODS: A 42 year old Caucasian male, with history of schizophrenia developed a acute myocarditis after commencement of clozapine. RESULTS: The patient recovered with intensive medical support. The symptoms occurred approximately 20 days after starting clozapine. CONCLUSIONS: Myocarditis is an ingreasingly recognized complication associated with clozapine. Use of clozapine must be based on a balance of its risks and benefits on an individual basis which for the most part defines its use in treatment refractory schizophrenia. Appropriate monitoring of adverse events is an essential part of the clinical usage of clozapine and should be charted for at least two years.

COMT Val158Met genotype is associated with fluctuations in working memory performance: converging evidence from behavioural and single-trial P3b measures.

Intra-subject variability in reaction times (ISV) is a promising endophenotype for several psychiatric conditions, but its neural underpinnings are not yet established. Converging evidence from neuroimaging, molecular genetics, and psychopharmacology suggests that ISV could index catecholaminergically-mediated neural noise. The fine-grained temporal resolution of electroencephalography is ideal for investigating ISV, but only if potential neural correlates of ISV can be assessed in single trials. Based on evidence that ISV is associated with dopaminergic functioning, we apply a recently developed method of single-trial P3b analysis to investigate the association of COMT Val(158)Met genotype with measures of ISV on the behavioural and neural levels at different working memory loads. Greater number of Met alleles was associated with poorer and more intra-individually variable performance on the tasks, and greater latency jitter in single-trial P3bs. These converging results at the behavioural and neurophysiological levels confirm previous observations that prefrontal dopamine availability is associated with stability and accuracy of cognitive performance. Together with previous studies, these data imply pleiotropic cognitive effects of COMT genotype.

Cognitive impairments and psychopathological parameters in patients of the schizophrenic spectrum.

Cognitive impairment is a core feature of schizophrenia and it is considered by many researchers as one of the dimensional components of the disorder. Cognitive dysfunction occurs in 85% of schizophrenic patients and it is negatively associated with the outcome of the disorder, the psychosocial functioning of the patients, and non-compliance with treatment. Many different cognitive domains are impaired in schizophrenia, such as attention, memory, executive functions and speech. Nowadays, it is argued that apart from clinical heterogeneity of schizophrenia, there is probable heterogeneity in the accompanying neurocognitive dysfunction. Recent studies for cognitive dysfunction in schizophrenia employ computerized assessment batteries of cognitive tests, designed to assess specific cognitive impairments. Computerized cognitive testing permits for more detailed data collection (e.g. precise timing scores of responses), eliminates researcher's measurement errors and bias, assists the manipulation of data collected, and improves reliability of measurements through standardized data collection methods. The aims of the present study are: the comparison of cognitive performance of our sample of patients and that of healthy controls, on different specific cognitive tests, and the testing for possible association between patients' psychopathological symptoms and specific cognitive impairments, using the Cogtest computerized cognitive assessment battery. 71 male inpatients diagnosed with schizophrenia or other psychotic spectrum disorders (mean = 30.23 ± 7.71 years of age), admitted in a psychiatric unit of the First Department of Psychiatry, Athens University Medical School, Eginition Hospital (continuous admissions) were studied. Patients were excluded from the study if they suffered from severe neurological conditions, severe visual or hearing impairment, mental retardation, or if they abused alcohol or drugs. The patients' diagnoses were based on the semi-structured diagnostic interview "Diagnostic Interview for Psychosis" (DIP) and were clinically confirmed by two independent expert psychiatrists, according to the criteria of DSM-IVTM. Our healthy control group consisted of 20 healthy male participants (mean = 31.65 ± 5.90 years of age), who met the same inclusion criteria for the study as the patient group, as well as the same exclusion criteria from the study, having no history of psychiatric disorders. All statistical analyses were conducted using the statistical package SPSS.17. According to our results, healthy controls cognitively outperform our patient sample in all cognitive tests, with the differences between performances being statistically significant. Results concerning the association between psychotic symptoms and cognitive deficits of our patients indicated that hallucinations, highly organized delusions, persecutory delusions, agitation, catatonia and inappropriate affect did not associate with any subtype of cognitive deficit. Blunted affect associated significantly with response inhibition ("GoNoGo test", p = 0.007), and poor speech associated significantly with declarative memory of faces ("FMT test", p = 0.002). Moreover, psychomotor ability (non-dominant hand) associated significantly with generalized delusions ("TST test", p = 0.033), and with constricted affect ("TST test", p = 0.026). Furthermore, there was a tendency towards significance association between persecutory delusions and executive function ("CPT test", p = 0.053), inappropriate affect and declarative face memory ("FMT test", p = 0.056), and psychomotor ability and poor speech (p = 0.086).

Theory of Mind as a potential trait marker of schizophrenia: a family study.

INTRODUCTION: Although there is some evidence that Theory of Mind (ToM) deficits may be trait markers of schizophrenia it is not clear yet if ToM deficits are primary deficits, that is, to be independent of deficits in general intellectual abilities and executive function. The aim was to examine if ToM deficits may be trait markers of the illness and the effect of cognitive inhibition, general intellectual abilities and depression on ToM abilities of patients with schizophrenia and their unaffected parents. METHODS: We assessed ToM abilities (first-order and second-order ToM stories, The Revised Eyes Test), cognitive inhibition (Stroop Task), general intellectual ability (Standard Progressive Matrices Test Plus) in patients with schizophrenia (N=21) and their unaffected fathers (N=21) and mothers (N=21) in comparison with healthy control families (healthy control males, N=21, healthy control fathers, N=21, healthy control mothers, N=21) RESULTS: Patients showed deficits in first-order ToM tasks but some of these deficits were mediated by general intellectual abilities. Impairments in cognitive inhibition mediated only patients' performance in The Revised Eyes Test. Patients showed deficits in second-order ToM stories independently of deficits in general intellectual abilities and cognitive inhibition. Unaffected parents did not show deficits in first-order ToM tasks, whereas they showed deficits in second-order ToM stories. However, the deficits that unaffected parents showed in second-order ToM stories were mediated by their deficits in general intellectual abilities, and there was an effect of remitted depression on the unaffected mothers' performance. CONCLUSIONS: The results suggest that intact neurocognitive and general intellectual abilities are necessary in order patients and their unaffected parents to pass successfully ToM tasks. Patients and their unaffected parents show ToM deficits but these deficits are not similar. Patients show ToM deficits but these deficits seem to be a component of the pathophysiology of the illness (e.g., deficits in executive function, general intellectual abilities).

Schizophrenia-related RGS4 gene variations specifically disrupt prefrontal control of saccadic eye movements.

BACKGROUND: The gene encoding the regulator of G-protein signaling subtype 4 (RGS4), located on chromosome 1q23-3, has been proposed as a possible susceptibility gene for schizophrenia and has been specifically linked to prefrontal cortical structural and functional integrity. METHOD: The effects of four core single nucleotide polymorphisms (SNPs) within the RGS4 gene on 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. RESULTS: The risk allele of RGS4SNP18 was found to be associated with two variables of antisaccade performance, increased error rate and variation in the correct antisaccade latency. By contrast, the same allele and also the risk allele of RGS4SNP4 led to an improvement in smooth eye pursuit performance (increased gain). Structural equation modeling confirmed that the combined gene variation of RGS4SNP4 and RGS4SNP18 was a significant predictor of antisaccade but not smooth eye pursuit performance. CONCLUSIONS: These results provide evidence for a specific effect of schizophrenia-related RGS4 genotype variations to prefrontal dysfunction measured by oculomotor indices of performance in normal individuals, further validating the hypothesis that RGS4 is related to prefrontal dysfunction in schizophrenia.