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Background and Objectives: Deficits in metacognition, the ability to monitor one's own mental states, are key elements of the functional pathology of schizophrenia spectrum disorders. Little is known, however, about the integrity of metacognitive processes in subclinical schizotypy. The purpose of the present investigation was two-fold: First, we conducted a preregistered, systematic literature review to synthesize previous research efforts on the role of metacognition in schizotypy. Second, we investigated the relationship between self-reported dimensions of schizotypy and psychometric as well as behavioral measures of metacognition in a preregistered online study., Methods: A large sample (N = 330) completed a questionnaire battery and an episodic memory experiment; task-based metacognition was tapped via trial-by-trial confidence ratings., Results: In keeping with findings from our literature review, higher schizotypy was associated with diminished introspective insight and an overly self-referential and maladaptive metacognitive style in metacognition questionnaires. Importantly, low task-based metacognitive efficiency was predictive of high levels of cognitive disorganization, whereas task-related overconfidence (i.e., increased metacognitive bias) was linked with positive schizotypy., Limitations: Due to the comparatively small number of k = 20 studies meeting our inclusion criteria, the systematic literature review provides only preliminary indications for potential conclusions. Furthermore, control over potential disturbing influences in the experimental study was limited due to its online format., Conclusions: Overall, we provide evidence for specific metacognitive deficits in schizotypy and discuss a potential continuity of preserved and impaired aspects of metacognitive monitoring along the psychosis continuum., Competing Interests: Declaration of competing interest None., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Background: Schizophrenia is a heterogeneous disorder with substantial heritability. The use of endophenotypes may help clarify its aetiology. Measures from the smooth pursuit and antisaccade eye movement tasks have been identified as endophenotypes for schizophrenia in twin and family studies. However, the genetic basis of the overlap between schizophrenia and these oculomotor markers is largely unknown. Here, we tested whether schizophrenia polygenic risk scores (PRS) were associated with oculomotor performance in the general population., Methods: Analyses were based on the data of 2956 participants (aged 30-95) of the Rhineland Study, a community-based cohort study in Bonn, Germany. Genotyping was performed on Omni-2.5 exome arrays. Using summary statistics from a recent meta-analysis based on the two largest schizophrenia genome-wide association studies to date, we quantified genetic risk for schizophrenia by creating PRS at different p value thresholds for genetic markers. We examined associations between PRS and oculomotor performance using multivariable regression models., Results: Higher PRS were associated with higher antisaccade error rate and latency, and lower antisaccade amplitude gain. PRS showed inconsistent patterns of association with smooth pursuit velocity gain and were not associated with saccade rate during smooth pursuit or performance on a prosaccade control task., Conclusions: There is an overlap between genetic determinants of schizophrenia and oculomotor endophenotypes. Our findings suggest that the mechanisms that underlie schizophrenia also affect oculomotor function in the general population.

Background: Schizotypy is a putative risk phenotype for psychosis liability, but the overlap of its genetic architecture with schizophrenia is poorly understood., Methods: We tested the hypothesis that dimensions of schizotypy (assessed with the SPQ-B) are associated with a polygenic risk score (PRS) for schizophrenia in a sample of 623 psychiatrically healthy, non-clinical subjects from the FOR2107 multi-centre study and a second sample of 1133 blood donors., Results: We did not find correlations of schizophrenia PRS with either overall SPQ or specific dimension scores, nor with adjusted schizotypy scores derived from the SPQ (addressing inter-scale variance). Also, PRS for affective disorders (bipolar disorder and major depression) were not significantly associated with schizotypy., Conclusions: This important negative finding demonstrates that despite the hypothesised continuum of schizotypy and schizophrenia, schizotypy might share less genetic risk with schizophrenia than previously assumed (and possibly less compared to psychotic-like experiences).

Neuroanatomical abnormalities have been reported along a continuum from at-risk stages, including high schizotypy, to early and chronic psychosis. However, a comprehensive neuroanatomical mapping of schizotypy remains to be established. The authors conducted the first large-scale meta-analyses of cortical and subcortical morphometric patterns of schizotypy in healthy individuals, and compared these patterns with neuroanatomical abnormalities observed in major psychiatric disorders. The sample comprised 3004 unmedicated healthy individuals (12-68 years, 46.5% male) from 29 cohorts of the worldwide ENIGMA Schizotypy working group. Cortical and subcortical effect size maps with schizotypy scores were generated using standardized methods. Pattern similarities were assessed between the schizotypy-related cortical and subcortical maps and effect size maps from comparisons of schizophrenia (SZ), bipolar disorder (BD) and major depression (MDD) patients with controls. Thicker right medial orbitofrontal/ventromedial prefrontal cortex (mOFC/vmPFC) was associated with higher schizotypy scores (r = 0.067, p FDR  = 0.02). The cortical thickness profile in schizotypy was positively correlated with cortical abnormalities in SZ (r = 0.285, p spin  = 0.024), but not BD (r = 0.166, p spin  = 0.205) or MDD (r = -0.274, p spin  = 0.073). The schizotypy-related subcortical volume pattern was negatively correlated with subcortical abnormalities in SZ (rho = -0.690, p spin  = 0.006), BD (rho = -0.672, p spin  = 0.009), and MDD (rho = -0.692, p spin  = 0.004). Comprehensive mapping of schizotypy-related brain morphometry in the general population revealed a significant relationship between higher schizotypy and thicker mOFC/vmPFC, in the absence of confounding effects due to antipsychotic medication or disease chronicity. The cortical pattern similarity between schizotypy and schizophrenia yields new insights into a dimensional neurobiological continuity across the extended psychosis phenotype., (© 2021. The Author(s).)

Background: Subclinical psychotic-like experiences (PLE), resembling key symptoms of psychotic disorders, are common throughout the general population and possibly associated with psychosis risk. There is evidence that such symptoms are also associated with structural brain changes., Methods: In 672 healthy individuals, we assessed PLE and associated distress with the symptom-checklist-90R (SCL-90R) scales 'schizotypal signs' (STS) and 'schizophrenia nuclear symptoms' (SNS) and analysed associations with voxel- and surfaced-based brain structural parameters derived from structural magnetic resonance imaging at 3 T with CAT12., Results: For SNS, we found a positive correlation with the volume in the left superior parietal lobule and the precuneus, and a negative correlation with the volume in the right inferior temporal gyrus [p < 0.05 cluster-level Family Wise Error (FWE-corrected]. For STS, we found a negative correlation with the volume of the left and right precentral gyrus (p < 0.05 cluster-level FWE-corrected). Surface-based analyses did not detect any significant clusters with the chosen statistical threshold of p < 0.05. However, in exploratory analyses (p < 0.001, uncorrected), we found a positive correlation of SNS with gyrification in the left insula and rostral middle frontal gyrus and of STS with the left precuneus and insula, as well as a negative correlation of STS with gyrification in the left temporal pole., Conclusions: Our results show that brain structures in areas implicated in schizophrenia are also related to PLE and its associated distress in healthy individuals. This pattern supports a dimensional model of the neural correlates of symptoms of the psychotic spectrum.

Schizotypal personality traits show similarity with schizophrenia at various levels of analysis. It is generally agreed that schizotypal personality is multidimensional; however, it is still debated whether impulsive nonconformity should be incorporated into theories and measurement of schizotypy. In addition, relatively little is known about the network structure of the four-dimensional model of schizotypal personality. To estimate the network structure of schizotypy, we used data from participants recruited from the community (N = 11,807) who completed the short version of the Oxford-Liverpool Inventory of Feelings and Experiences, a widespread self-report instrument that assesses the positive, negative, disorganised and impulsive domains of schizotypy. We performed community detection, then examined differences between communities in terms of centralities and compared the strength of edges within and between communities. We found communities that almost perfectly corresponded to the a priori-defined subscales (93% overlap, normalised mutual information = 0.74). Items in the disorganisation community had higher closeness centrality relative to items in the other communities (Cliff's Δs ranged from 0.55 to 0.83) and weights of edges within the disorganisation community were stronger as compared to the negative schizotypy and impulsive nonconformity communities (Cliff's Δs = 0.33). Our findings imply that the inclusion of impulsive nonconformity items does not dilute the classical three-factor structure of positive, negative and disorganised schizotypy. The high closeness centrality of disorganisation concurs with theories positing that cognitive slippage and associative loosening are core features of the schizophrenic phenotype.

Background: Schizotypy, a putative schizophrenia endophenotype, has been associated with brain-structural variations partly overlapping with those in psychotic disorders. Variations in precuneus structure have been repeatedly reported, whereas the involvement of fronto-striatal networks - as in schizophrenia - is less clear. While shared genetic architecture is thought to increase vulnerability to environmental insults, beneficial factors like general intelligence might buffer their effect., Methods: To further investigate the role of fronto-striatal networks in schizotypy, we examined the relationship of voxel- and surface-based brain morphometry and a measure of schizotypal traits (Schizotypal Personality Questionnaire, with subscores Cognitive-Perceptual, Interpersonal, Disorganised) in 115 healthy participants [54 female, mean age (s.d.) = 27.57(8.02)]. We tested intelligence (MWT-B) as a potential moderator., Results: We found a positive association of SPQ Cognitive-Perceptual with putamen volume (p = 0.040, FWE peak level-corrected), moderated by intelligence: with increasing IQ, the correlation of SPQ Cognitive-Perceptual and striatal volume decreased (p = 0.022). SPQ Disorganised was positively correlated with precentral volume (p = 0.013, FWE peak level-corrected). In an exploratory analysis (p < 0.001, uncorrected), SPQ total score was positively associated with gyrification in the precuneus and postcentral gyrus, and SPQ Disorganised was negatively associated with gyrification in the inferior frontal gyrus., Conclusions: Our findings support the role of fronto-striatal networks for schizotypal features in healthy individuals, and suggest that these are influenced by buffering factors like intelligence. We conclude that protective factors, like general cognitive capacity, might attenuate the psychosis risk associated with schizotypy. These results endorse the idea of a continuous nature of schizotypy, mirroring similar findings in schizophrenia.

In recent years there has been a surge of interest and corresponding accumulation of knowledge about the role of sleep disturbance in schizophrenia. In this review, we provide an update on the current status of experimentally controlled sleep deprivation (SD) as an experimental medicine model of psychosis, and also consider, given the complexity and heterogeneity of schizophrenia, whether this (state) model can be usefully combined with other state or trait model systems to more powerfully model the pathophysiology of psychosis. We present evidence of dose-dependent aberrations that qualitatively resemble positive, negative and cognitive symptoms of schizophrenia as well as deficits in a range of translational biomarkers for schizophrenia, including prepulse inhibition, smooth pursuit and antisaccades, following experimentally controlled SD, relative to standard sleep, in healthy volunteers. Studies examining the combination of SD and schizotypy, a trait model of schizophrenia, revealed only occasional, task-dependent superiority of the combination model, relative to either of the two models alone. Overall, we argue that experimentally controlled SD is a valuable experimental medicine model of schizophrenia to advance our understanding of the pathophysiology of the clinical disorder and discovery of more effective or novel treatments. Future studies are needed to test its utility in combination with other, especially state, model systems of psychosis such as ketamine., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2020 The Authors. Published by Elsevier B.V. All rights reserved.)

Several studies suggest that highly schizotypal individuals display a deficit in smooth pursuit eye movements (SPEM), which are considered an important biomarker of schizophrenia. In schizophrenia, abnormal SPEM is thought to be driven by impairments in motion perception. In schizotypy, the processes underlying reduced SPEM performance have not been examined so far, and there are no studies on motion perception deficits in schizotypy. Thus, in this registered report, we aimed to investigate whether motion perception is impaired in highly schizotypal individuals, and how it contributes to SPEM performance. On an exploratory basis, we were interested in the association between schizotypy and prediction, another mechanism underlying SPEM. To address this issue, participants with high total scores of the Oxford-Liverpool Inventory of Feelings and Experiences (O-LIFE short form) and control participants with low scores (N = 86 in each group) performed a standard sinusoidal SPEM task, random dot kinematograms to measure motion perception, and a blanking SPEM task to assess prediction abilities. Group comparisons as well as mediator analyses were carried out to identify whether motion perception or prediction are responsible for SPEM performance in schizotypy. We found reduced blanking SPEM performance in schizotypes compared to controls, but no group differences regarding sinusoidal SPEM and motion perception. Although no significant mediators were identified for SPEM performance in schizotypes, an exploratory analysis revealed an association between motion perception and SPEM gain in high, but not in low schizotypy. Our findings imply that despite the schizotypy-related impairment in prediction, motion perception seems to be a more important predictor of SPEM performance in schizotypes. A deficit in prediction that does not relate to SPEM performance suggests that protective factors (e.g., other cognitive processes) might operate in schizotypal individuals to maintain SPEM performance on a healthy level., Competing Interests: Declaration of Competing Interest None., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Background: Anticipatory anhedonia is one of the key deficits found in patients with schizophrenia (SCZ). However, the underlying mechanism of this deficit remains unclear. The present study examined whether representation activation and maintenance capacity influenced anticipatory experiences in SCZ patients., Methods: We recruited 46 SCZ patients (26 males) and 45 matched healthy controls (24 males). The Reward Representation Activation and Maintenance (RRAM) Task was administrated to assess anticipatory experience and representation activation and maintenance capacity., Results: SCZ patients exhibited lower subjective arousal than controls in anticipation of rewards with high probability when representation activation and maintenance were difficult to accomplish. SCZ patients also tended to reduce their button presses more than HC when they were required to maintain reward representation., Conclusions: Our findings suggest that representation activation and maintenance may partially account for anticipatory anhedonia observed in SCZ patients., Competing Interests: Declaration of competing interest The authors reported no conflicts of interest with this work., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Saccadic eye movements are well-described markers of cerebral function and have been widely studied in schizophrenia spectrum populations. However, less is known about saccades in individuals clinically at risk for schizophrenia. Therefore, we studied individuals in an at-risk mental state (ARMS) (N = 160), patients in their first episode of schizophrenia (N = 32) and healthy controls (N = 75). N = 88 ARMS participants showed an early at-risk mental state (E-ARMS), defined by cognitive-perceptive basic symptoms (COPER) or a combination of risk and loss of function, whereas N = 72 were in a late at-risk mental state (L-ARMS), defined by attenuated psychotic symptoms or brief limited intermittent psychotic symptoms. We examined prosaccades, reflecting overt attentional shifts, and antisaccades, measuring inhibitory control, as well as their relationship as an indicator of the interplay of bottom-up and top-down influences. L-ARMS but not E-ARMS participants had increased antisaccade latencies compared to controls. First-episode patients had higher antisaccade error rates compared to E-ARMS participants and controls, and increased latencies compared to all other groups. Prosaccade latencies did not differ between groups. We observed the expected negative correlation between prosaccade latency and antisaccade error rate, indicating that individuals with shorter prosaccade latencies made more antisaccade errors. The magnitude of the association did not differ between groups. No saccadic measure predicted conversion to psychosis within 2 years. These findings confirm the existence of antisaccade impairments in patients with schizophrenia and provide evidence that volitional response generation in the antisaccade task may be affected even before onset of clinically overt psychosis.

The latent structure of schizotypy and psychosis-spectrum symptoms remains poorly understood. Furthermore, molecular genetic substrates are poorly defined, largely due to the substantial resources required to collect rich phenotypic data across diverse populations. Sample sizes of phenotypic studies are often insufficient for advanced structural equation modeling approaches. In the last 50 years, efforts in both psychiatry and psychological science have moved toward (1) a dimensional model of psychopathology (eg, the current Hierarchical Taxonomy of Psychopathology [HiTOP] initiative), (2) an integration of methods and measures across traits and units of analysis (eg, the RDoC initiative), and (3) powerful, impactful study designs maximizing sample size to detect subtle genomic variation relating to complex traits (the Psychiatric Genomics Consortium [PGC]). These movements are important to the future study of the psychosis spectrum, and to resolving heterogeneity with respect to instrument and population. The International Consortium of Schizotypy Research is composed of over 40 laboratories in 12 countries, and to date, members have compiled a body of schizotypy- and psychosis-related phenotype data from more than 30000 individuals. It has become apparent that compiling data into a protected, relational database and crowdsourcing analytic and data science expertise will result in significant enhancement of current research on the structure and biological substrates of the psychosis spectrum. The authors present a data-sharing infrastructure similar to that of the PGC, and a resource-sharing infrastructure similar to that of HiTOP. This report details the rationale and benefits of the phenotypic data collective and presents an open invitation for participation.

The ability to inhibit inappropriate responses and suppress irrelevant information is a core feature of executive control. In this study, we provide a detailed analysis of prepotent response inhibition and interference in patients with schizophrenia. To further test the role of genetic factors and subclinical schizophrenia-like traits, we additionally studied clinically unaffected, first-degree relatives of schizophrenia patients and assessed dimensions of schizotypy in both relatives and healthy controls. Inhibition and interference control were assessed using a battery comprising the antisaccade, Stroop, stop signal, go/no-go, flanker, and Simon tasks. Schizophrenia patients differed from both relatives and controls in making more errors on the antisaccade task and having longer response times on the Stroop task, especially the incongruent condition. Patients also had general, that is, condition independent, increases in reaction times on the go/no-go and flanker tasks and made more errors on the flanker and Simon tasks, suggesting general performance impairments independent of inhibitory demand. Relatives were characterized by hypometric antisaccade amplitude gain despite normal prosaccades, suggesting a selective deficit in non-standard sensorimotor transformations. Schizotypy was correlated with inhibitory performance across a number of tasks in both relatives and controls. Generally, these effects were independent of verbal intelligence levels. Overall, the findings point to rather selective impairments of inhibitory control in the schizophrenia spectrum and confirm a previously observed deficit in antisaccade spatial accuracy as an endophenotype of schizophrenia., (© 2017 The British Psychological Society.)

The ability to follow spoken instructions is important to everyday functioning but has seldom been studied in patients with schizophrenia (SZ). Recent evidence suggests that action-based processing may facilitate the ability to follow instructions, which relies largely on working memory. In this study, we tested the hypothesis that SZ patients may also benefit from action-based advantages in following instructions. Forty-eight clinically stable SZ patients and 48 demographic- and IQ-matched controls completed a following spoken instruction span task involving varied encoding and recall conditions. While SZ patients were impaired in the overall performance of following spoken instructions, this deficit could be attributed to working memory impairment. More importantly, SZ patients showed action-based advantages both at the encoding and retrieval stage to the same extent as healthy controls. Specifically, both healthy controls and SZ patients showed improved memory performance when they additionally performed the actions, or watched the experimenter carrying out the actions compared with simply listening to spoken instructions during the encoding stage. During the retrieval stage, memory was improved when they recalled the instructions by physical enactment compared with oral repetition. The present study provides the first empirical evidence for the impairment in the ability to follow instructions in SZ. We have shown that involving action-based processing in the encoding and retrieval stage facilitated memory of instructions, indicating that the enactment advantage in working memory also applies to SZ patients. These findings provide useful insights for clinical interventions and cognitive remediation for SZ patients., (© The Author(s) 2017. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

In this chapter, we present an overview of studies of oxytocin (OXT) in schizophrenia and the schizophrenia spectrum. We first outline the current state of pharmacological treatment of the symptoms of schizophrenia and point to unmet clinical needs. These relate particularly to the debilitating negative symptoms and social cognitive deficits that are frequently observed in patients suffering from schizophrenia. We argue that new treatments are needed to alleviate these impairments. As OXT has been proposed and investigated as a putative treatment, we will then summarise evidence from studies in patients with schizophrenia that have investigated the effects of OXT at several levels, i.e. at the levels of clinical symptoms, social cognitive function as assessed with experimental and neuropsychological tasks, and brain function as assessed using functional magnetic resonance imaging (fMRI). Finally, we will introduce the concept of the schizophrenia spectrum and highlight the importance of studying OXT effects in subclinical spectrum samples, such as in people with high levels of schizotypal personality. We conclude that the evidence of beneficial effects of OXT in schizophrenia is inconsistent, calling for further research in this field.

Background: Reductions in whole brain and grey matter volumes are robust features of schizophrenia, yet their etiological influences are unclear., Methods: We investigated the association between the genetic and environmental risk for schizophrenia and brain volumes. Whole brain, grey matter and white matter volumes were established from structural MRIs from twins varying in their zygosity and concordance for schizophrenia. Hippocampal volumes were measured manually. We conducted between-group testing and full genetic modelling., Results: We included 168 twins in our study. Whole brain, grey matter, white matter and right hippocampal volumes were smaller in twins with schizophrenia. Twin correlations were larger for whole brain, grey matter and white matter volumes in monozygotic than dizygotic twins and were significantly heritable, whereas hippocampal volume was the most environmentally sensitive. There was a significant phenotypic correlation between schizophrenia and reductions in all the brain volumes except for that of the left hippocampus. For whole brain, grey matter and the right hippocampus the etiological links with schizophrenia were principally associated with the shared familial environment. Lower birth weight and perinatal hypoxia were both associated with lower whole brain volume and with lower white matter and grey matter volumes, respectively., Limitations: Scan data were collected across 2 sites, and some groups were modest in size., Conclusion: Whole brain, grey matter and right hippocampal volume reductions are linked to schizophrenia through correlated familial risk (i.e., the shared familial environment). The degree of influence of etiological factors varies between brain structures, leading to the possibility of a neuroanatomically specific etiological imprint.

Cognitive impairment, particularly in attention, memory and executive function domains, is commonly present and associated with poor functional outcomes in schizophrenia. In healthy adults, environmental noise adversely affects many cognitive domains, including those known to be compromised in schizophrenia. This pilot study examined whether environmental noise causes further cognitive deterioration in a small sample of people with schizophrenia. Eighteen outpatients with schizophrenia on stable doses of antipsychotics and 18 age and sex-matched healthy participants were assessed on a comprehensive cognitive battery including measures of psychomotor speed, attention, executive functioning, working memory, and verbal learning and memory under three different conditions [quiet: ~30dB(A); urban noise: building site noise, 68-78dB(A); and social noise: background babble and footsteps from a crowded hall without any discernible words, 68-78dB(A)], 7-14days apart, with counter-balanced presentation of noise conditions across participants of both groups. The results showed widespread cognitive impairment in patients under all conditions, and noise-induced impairments of equal magnitude on specific cognitive functions in both groups. Both patient and healthy participant groups showed significant disruption of delayed verbal recall and recognition by urban and social noise, and of working memory by social noise, relative to the quiet condition. Performance under urban and social noise did not differ significantly from each other for any cognitive measure in either group. We conclude that noise has adverse effects on the verbal and working memory domains in schizophrenia patients and healthy participants. This may be particularly problematic for patients as it worsens their pre-existing cognitive deficits., (Copyright © 2016 The Authors. Published by Elsevier B.V. All rights reserved.)

Neuropsychological deficits are candidate endophenotypes of schizophrenia which can assist to explain the neurocognitive impact of genetic risk variants. The identification of endophenotypes is often based on the familiality of these phenotypes. Several studies demonstrate neuropsychological deficits in unaffected biological relatives of schizophrenia patients without differentiating between genetic and non-genetic factors underlying these deficits. We assessed N=129 unaffected biological parents of schizophrenia patients, N=28 schizophrenia patients (paranoid subtype), and N=143 controls without a family history of schizophrenia with an extensive neuropsychological test battery. Direct comparison of N=22 parents with an ancestral history of schizophrenia (more likely carriers, MLC) and N=17 of their spouses without such a history (less likely carriers, LLC) allowed the separation of genetic and non-genetic aspects in cognition. Overall, parents showed significant deficits in neuropsychological tasks from all cognitive domains with medium effect sizes. Direct comparisons of MLC- and LLC-parents showed that attentional and executive tasks were most strongly affected by genetic loading. To conclude, unaffected parents of schizophrenia patients showed modest yet significant impairments in attention, memory, and executive functioning. In particular, attentional and executive impairments varied most strongly with genetic loading for schizophrenia, prioritising these dysfunctions for genotype-endophenotype analyses., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

Development of drugs for the treatment of the clinical symptoms and cognitive deficits of schizophrenia is unsatisfactory, with many initially promising compounds not showing beneficial effects in clinical studies. Experimental model systems of schizophrenia combined with well-validated biomarkers are urgently needed to provide early indicators of effectiveness. Herein, we argue that experimentally controlled sleep deprivation represents a translational model system that can be studied in combination with neurocognitive biomarkers. Specifically, we review data on the psychotomimetic effects of sleep deprivation in healthy human beings and provide evidence of the psychosis-like deficits in translational inhibitory biomarkers-prepulse inhibition and antisaccades-that occur after sleep deprivation. These data support the use of the sleep deprivation model in combination with biomarkers with excellent psychometric properties and well-characterised neural mechanisms, such as prepulse inhibition and antisaccades, to substantially advance development of drugs with antipsychotic or pro-cognitive effects., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Rationale: Most cognitive domains show only minimal improvement following typical or atypical antipsychotic treatments in schizophrenia, and some may even worsen. One domain that may worsen is procedural learning, an implicit memory function relying mainly on the integrity of the fronto-striatal system., Objectives: We investigated whether switching to atypical antipsychotics would improve procedural learning and task-related neural activation in patients on typical antipsychotics. Furthermore, we explored the differential effects of the atypical antipsychotics risperidone and olanzapine., Methods: Thirty schizophrenia patients underwent functional magnetic resonance imaging during a 5-min procedural (sequence) learning task on two occasions: at baseline and 7-8 weeks later. Of 30 patients, 10 remained on typical antipsychotics, and 20 were switched randomly in equal numbers to receive either olanzapine (10-20 mg) or risperidone (4-8 mg) for 7-8 weeks., Results: At baseline, patients (all on typical antipsychotics) showed no procedural learning. At follow-up, patients who remained on typical antipsychotics continued to show a lack of procedural learning, whereas those switched to atypical antipsychotics displayed significant procedural learning (p = 0.001) and increased activation in the superior-middle frontal gyrus, anterior cingulate and striatum (cluster-corrected p < 0.05). These neural effects were present as a linear increase over five successive 30-s blocks of sequenced trials. A switch to either risperidone or olanzapine resulted in comparable performance but with both overlapping and distinct task-related activations., Conclusions: Atypical antipsychotics restore procedural learning deficits and associated neural activity in schizophrenia. Furthermore, different atypical antipsychotics produce idiosyncratic task-related neural activations, and this specificity may contribute to their differential long-term clinical profiles.

Noise stress (NS) is detrimental to many aspects of human health and behavior. Understanding the effect of noise stressors on human cognitive function is a growing area of research and is crucial to helping clinical populations, such as those with schizophrenia, which are particularly sensitive to stressors. A review of electronic databases for studies assessing the effect of acute NS on cognitive functions in healthy adults revealed 31 relevant studies. The review revealed (1) NS exerts a clear negative effect on attention, working memory and episodic recall, and (2) personality characteristics, in particular neuroticism, and sleep influence the impact of noise stressors on performance in interaction with task complexity. Previous findings of consistent impairment in NS-relevant cognitive domains, heightened sensitivity to stressors, elevated neuroticism and sleep disturbances in schizophrenia, taken together with the findings of this review, highlight the need for empirical studies to elucidate whether NS, a common aspect of urban environments, exacerbates cognitive deficits and other symptoms in schizophrenia and related clinical populations.

Nicotine has been proposed to be a cognitive enhancer, particularly in schizophrenia patients. So far, the published studies of nicotine effects on antisaccade performance in schizophrenia patients only tested participants who were deprived smokers. Thus, we aimed to test both smoking and non-smoking patients as well as healthy controls in order to extend previous findings. Moreover, we employed a paradigm using standard and delayed trials. We hypothesized that, if nicotine is a genuine cognitive enhancer, its administration would improve antisaccade performance both in smoking and non-smoking participants. A total of 22 patients with schizophrenia (12 smokers and 10 non-smokers) and 26 controls (14 smokers and 12 non-smokers) completed the study. The effects of a nicotine patch (14 mg for smokers, 7 mg for non-smokers) on antisaccade performance were tested in a randomized, double-blind, placebo-controlled, cross-over trial. Schizophrenia patients made significantly more antisaccade errors than controls (p = 0.03). Both patients and controls made fewer antisaccade errors in the delayed trials than in the standard trials (p < 0.0001). Nicotine significantly reduced antisaccade error rate in the standard trials, but not in the delayed trials (p = 0.02). Smoking status did not influence the nicotine effect on antisaccade error rate (p = 0.10) indicating an equal procognitive effect of nicotine in smokers and non-smokers. Overall the present findings indicate that beneficial effects of nicotine on antisaccade performance are not confined to smoking schizophrenia patients. Instead, the findings likely represent genuine nicotine-induced enhancement of cognitive performance.

Schizophrenia patients have deficits in cognitive control as well as in a number of emotional domains. The antisaccade task is a measure of cognitive control that requires the inhibition of a reflex-like eye movement to a peripheral stimulus. Antisaccade performance has been shown to be modulated by the emotional content of the peripheral stimuli, with emotional stimuli leading to higher error rates than neutral stimuli, reflecting an implicit emotion processing effect. The aim of the present study was to investigate the impact on antisaccade performance of threat-related emotional facial stimuli in schizophrenia patients, first-degree relatives of schizophrenia patients and healthy controls. Fifteen patients, 22 relatives and 26 controls, matched for gender, age and verbal intelligence, carried out an antisaccade task with pictures of faces displaying disgusted, fearful and neutral expressions as peripheral stimuli. We observed higher antisaccade error rates in schizophrenia patients compared to first-degree relatives and controls. Relatives and controls did not differ significantly from each other. Antisaccade error rate was influenced by the emotional nature of the stimuli: participants had higher antisaccade error rates in response to fearful faces compared to neutral and disgusted faces. As this emotional influence on cognitive control did not differ between groups we conclude that implicit processing of emotional faces is intact in patients with schizophrenia and those at risk for the illness., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Recent research using individual task settings suggests that a major problem in schizophrenia is a dysfunctional theory of mind system leading to false mental state attributions. However, if a more low-level deficit to integrate own and other's actions (action blindness) is present in schizophrenia is still unknown. Using a social Simon task, we tested if schizophrenia patients have a deficit in self-other integration. Further, we tested for a possible genetic bias of this dysfunction by studying clinically unaffected first-degree relatives of schizophrenia patients. While schizophrenia patients showed no Social Simon effect, we found a reliable social Simon effect in healthy participants and first-degree relatives of schizophrenia patients. Joint task performance differed statistically between patients and healthy controls. We did not find any differences in the size of the social Simon effects of relatives and healthy controls. The present findings suggest that schizophrenia patients have severe problems with self-other integration, which may lead to problems in social interactions. Since first-degree relatives of schizophrenia patients showed a reliable social Simon effect, the evidence for a genetic bias of this social dysfunction in schizophrenia however is weak., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Objectives: Schizophrenia is associated with replicable grey matter volume reductions in fronto-temporo-limbic and subcortical regions. Psychometric schizotypy refers to a set of behavioural traits and cognitions thought to represent the subclinical manifestation of schizophrenia in the general population. While there is evidence of a continuum between schizophrenia and schizotypy at phenotypic, genetic and cognitive levels, no previous study has observed grey matter volume reductions associated with increased psychometric schizotypy levels in healthy individuals. Such evidence would provide further support for a relationship between non-clinical schizophrenia-like traits in the general population and the full-blown clinical condition of schizophrenia., Methods: We used magnetic resonance imaging to investigate the relationship between psychometric schizotypy and brain structure in 55 clinically unaffected and unmedicated volunteers. We performed a voxel-based morphometry analysis of grey matter volume data obtained at 1.5 Tesla., Results: Covarying for age and gender, higher scores of self-report positive schizotypy were significantly associated with reduced grey matter volume in medial prefrontal, orbitofrontal, and temporal cortical regions., Conclusions: These findings show that psychometric schizotypy in healthy individuals is associated with volume reductions in cortical areas known to be altered in schizophrenia, thereby providing neurobiological evidence of a continuum between schizotypy and schizophrenia.

This study sought to systematically investigate whether prefrontal cortex grey matter volume reductions are valid endophenotypes for schizophrenia, specifically investigating their presence in unaffected relatives, heritability, genetic overlap with the disorder itself and finally to contrast their performance on these criteria with putative neuropsychological indices of prefrontal functioning. We used a combined twin and family design and examined four prefrontal cortical regions of interest. Superior and inferior regions were significantly smaller in patients. However, the volumes of these same regions were normal in unaffected relatives and therefore, we could confirm that such deficits were not due to familial effects. Volumes of the prefrontal and orbital cortices were, however, moderately heritable, but neither shared a genetic overlap with schizophrenia. Total prefrontal cortical volume reductions shared a significant unique environmental overlap with the disorder, suggesting that the reductions were not familial. In contrast, prefrontal (executive) functioning deficits were present in the unaffected relatives, were moderately heritable and shared a substantial genetic overlap with liability to schizophrenia. These results suggest that the well recognized prefrontal volume reductions are not related to the same familial influences that increase schizophrenia liability and instead may be attributable to illness related biological changes or indeed confounded by illness trajectory, chronicity, medication or substance abuse, or in fact a combination of some or all of them.

Dimensional models of psychosis assume a continuum between schizotypy and schizophrenia. However, little is known about the overlap in brain functional alterations between schizotypy and schizophrenia. Fifty-four healthy volunteers underwent functional magnetic resonance imaging during an antisaccade task, a measure of cognitive control known to be impaired in schizophrenia, and a prosaccade task. Higher positive schizotypy was correlated with higher antisaccade error rates. Associations between reduced blood oxygenation level dependent signal and higher schizotypy were found during antisaccades in the putamen, thalamus, cerebellum, and visual cortex and during prosaccades in the visual cortex, supplementary eye field, and posterior intraparietal sulcus. These findings show that increased schizotypy is associated with decreased antisaccade performance and reduced brain function in regions also affected in schizophrenia, therefore providing evidence of neurocognitive and neurophysiological overlap between schizotypy and schizophrenia., (Copyright © 2011 Society for Psychophysiological Research.)

Frontostriatal networks mediating important cognitive and motor functions have been shown to be abnormal structurally and functionally in schizophrenia. However, the influence of genetic risk for schizophrenia on structural abnormalities in these areas is not well established. This study therefore aimed to investigate prefrontal and striatal volume alterations in schizophrenia and to define the extent to which they are dependent on genetic vulnerability for the condition. We employed structural magnetic resonance imaging (sMRI) in monozygotic (MZ) twins with or without schizophrenia. A sample of 129 twins completed sMRI, consisting of 21 MZ twin pairs concordant for schizophrenia, 17 MZ schizophrenic twins and 18 MZ nonschizophrenic twins drawn from 19 pairs discordant for schizophrenia, and 26 MZ control twin pairs without schizophrenia. Groups did not significantly differ in age, gender, handedness, height, level of education, parental socioeconomic status, and ethnicity. Using a region-of-interest approach, we measured the gray matter volumes (in cm(3)) of superior, middle, inferior, and orbital frontal cortices (SFC, MFC, IFC, and OFC, respectively); the caudate; and putamen. Covarying for whole-brain volume, age, and gender, we found that concordant but not discordant twins with schizophrenia had significantly lower volumes of MFC and OFC than control twins. In contrast, both patient groups had significantly lower SFC volumes than both groups of nonschizophrenic twins. There were no significant group differences in IFC and the striatum. We conclude that the prefrontal cortex shows a heterogeneous pattern of genetic influences on volumetric reductions in schizophrenia.

Antipsychotic drugs are the mainstay of treatment for schizophrenia but they have little effect on core negative symptoms or cognitive impairment. To meet the deficiencies of current treatments, novel potential compounds are emerging from preclinical research but translation to clinical success has been poor. This article evaluates the possibility that cognitive and physiological abnormalities in schizophrenia can be used as central nervous system biomarkers to predict, in healthy volunteers, the likely efficacy of entirely new pharmacological approaches to treatment. Early detection of efficacy would focus resource on rapidly developing, effective drugs. We review the relevance of selected cognitive and physiological abnormalities as biomarkers in schizophrenia and three of its surrogate populations: (i) healthy volunteers with high trait schizotypy; (ii) unaffected relatives of patients; and (iii) healthy volunteers in a state of cortical glutamate disinhibition induced by low-dose ketamine. Several biomarkers are abnormal in these groups and in some instances there has been exploratory work to determine their sensitivity to drug action. They are generally insensitive to current antipsychotics and therefore their predictive validity cannot be established until novel, therapeutically useful drugs are discovered. Until then such biomarker studies can provide evidence of drugs engaging with the mechanism of interest and encouragement of the concept.

Rationale: Working memory dysfunction is frequently observed in schizophrenia. The neural mechanisms underlying this dysfunction remain unclear, with functional neuroimaging studies reporting increased, decreased or unchanged activation compared to controls., Objectives: We investigated the neural correlates of spatial working memory in schizophrenia with particular consideration of effects of antipsychotic treatment and relation to performance levels in the patient group., Method: We used functional magnetic resonance imaging and studied the blood-oxygen-level-dependent (BOLD) response of 45 schizophrenia outpatients and 19 healthy controls during a parametric spatial n-back task., Results: Performance in both groups deteriorated with increasing memory load (0-back, 1-back, 2-back), but the two groups did not significantly differ in performance overall or as a function of load. Patients produced stronger BOLD signal in occipital and lateral prefrontal cortex during task performance than controls. This difference increased with increasing working memory load in the prefrontal areas. We also found that in patients with good task performance, the BOLD response in left prefrontal cortex showed a stronger parametric increase with working memory load than in patients with poor performance. Second-generation antipsychotics were independently associated with left prefrontal BOLD increase in response to working memory load, whereas first-generation antipsychotics were associated with BOLD decrease with increasing load in this area., Conclusions: Together, these findings suggest that in schizophrenia patients, normal working memory task performance may be achieved through compensatory neural activity, especially in well-performing patients and in those treated with second-generation antipsychotics.

Background: Reduced power and phase locking of the early auditory gamma-band response (EAGBR) have been reported in schizophrenia, but findings are equivocal. Further, little is known about genetic (heritability) and environmental influences on the EAGBR or its potential as an endophenotype of schizophrenia. The present study used a twin design to examine whether EAGBR power and phase locking are heritable and reduced in schizophrenic patients and their unaffected co-twins and thus putative endophenotypes of schizophrenia., Methods: The study sample included a total of 194 individuals, consisting of 15 monozygotic [MZ] twin pairs concordant for schizophrenia, 9 MZ twin pairs discordant for schizophrenia, and 42 MZ and 31 dizygotic (DZ) control pairs. Evoked power and phase-locking factor of the EAGBR were computed on Morlet wavelet-transformed electroencephalogram responses to standard tones during an auditory oddball target detection task. Structural equation modeling was applied to estimate heritability and genetic and environmental correlations with schizophrenia for the EAGBR measures., Results: Both evoked power and phase-locking phenotypes were heritable traits (power: h(2) = 0.65; phase locking: h(2) = 0.63). Impaired EAGBR measures were significantly associated with schizophrenia. Patients with schizophrenia and their unaffected identical co-twins exhibited significantly reduced EAGBR power compared with control subjects. In each phenotype, shared genetic factors were likely the source of the observed associations with schizophrenia., Conclusions: Our results support EAGBR measures as putative endophenotypes of schizophrenia, likely reflecting an ubiquitous local cortical circuit deficit.

In a large-scale meta-analysis, it has been recently shown that the transcription factor 4 (TCF4) gene is among the most prominent susceptibility genes for schizophrenia. Moreover, transgenic mice overexpressing TCF4 in the brain display a reduction of sensorimotor gating measured by prepulse inhibition (PPI) of the acoustic startle response (ASR). PPI is heritable and has been established as an important translational endophenotype of schizophrenia. We therefore investigated the impact of the schizophrenia susceptibility gene TCF4 (rs9960767) on sensorimotor gating of the ASR in healthy humans and in patients with a schizophrenia spectrum disorder. We assessed PPI, startle reactivity, and habituation of the ASR in two independent samples. The first sample consisted of 107 healthy volunteers from London, UK. The second sample was a schizophrenia spectrum group (n = 113) of 73 schizophrenia patients and 40 individuals at high risk for schizophrenia from Bonn, Germany (total sample n = 220). In both samples, PPI was strongly decreased in carriers of the schizophrenia risk allele C of the TCF4 gene (meta-analysis across both samples: p = 0.00002), whereas startle reactivity and habituation were unaffected by TCF4 genotype. Sensorimotor gating is modulated by TCF4 genotype, indicating an influential role of TCF4 gene variations in the development of early information-processing deficits in schizophrenia.

Background: There is strong evidence for significant contributions of genetic factors to the risk of schizophrenia. In the past 10 years, studies employing linkage and association approaches have identified multiple putative schizophrenia risk genes. For most of these, the evidence for association with schizophrenia remains weak and attempts of replication not always successful nor easy to interpret., Aim: To give an overview of new developments in genetic research of schizophrenia., Methods: The present literature on schizophrenia genetics was reviewed with special emphasis on new developments such as genome-wide association studies (GWAS), associations of copy number variations (CNVs) with schizophrenia and the role of endophenotypes in genetic research., Results: The first GWAS of schizophrenia have identified new putative candidate risk genes and opened avenues for investigating how multiple genes may act in functional biological pathways forming the genetic basis of schizophrenia and other complex diseases. There is growing evidence that rare de novo CNVs as well as some inherited CNVs contribute to the susceptibility to several neuropsychiatric disorders including schizophrenia. Schizophrenia endophenotypes, which possibly better represent biological phenomena than the complex clinical phenotype, are turning out to be helpful for investigating neurobiological pathways of putative risk genes., Conclusions: Recent studies suggest that individual common gene variants make relatively small contributions to risk of schizophrenia but some rare CNVs may be associated with much higher risk when present. Future studies employing new technologies for identifying common and rare risk markers are likely to deepen our understanding of the genetic architecture of schizophrenia.

Attentional gating deficits, commonly measured by prepulse inhibition (PPI) of the acoustic startle response (ASR), have been established as an endophenotype of schizophrenia. Prepulse inhibition is heritable and has been associated with polymorphisms in serotonin and dopamine system genes. Prepulse inhibition can be enhanced by nicotine, and therefore it has been proposed that schizophrenia patients smoke to ameliorate their early attentional deficits. The PPI-enhancing effects of nicotine in rodents are strain dependent, suggesting a genetic contribution to PPI within the nicotinic acetylcholine receptor (nAChR) system. Recent human genetic studies also imply that tobacco dependence is affected by polymorphisms in the alpha3/alpha5 subunits of the nAChR (CHRNA3/CHRNA5) gene cluster. We, therefore, investigated the impact of two common CHRNA3 polymorphisms (rs1051730/rs1317286) on PPI, startle reactivity, and habituation of the ASR in two independent samples of 107 healthy British volunteers and 73 schizophrenia patients hailing from Germany. In both samples, PPI was influenced by both CHRNA3 polymorphisms (combined p-value=0.0027), which were strongly linked. Moreover, CHRNA3 genotype was associated with chronicity, treatment, and negative symptoms in the schizophrenia sample. These results suggest that sensorimotor gating is influenced by variations of the CHRNA3 gene, which might also have an impact on the course and severity of schizophrenia.

Background: Alterations in gray matter volume (GMV) are a robust feature of schizophrenia. However, it is not clear to what extent these abnormalities are correlates of the genetic liability to the disorder, as opposed to environmental factors and the disorder itself. We investigated the influence of genetic and environmental risk on GMV in monozygotic (MZ) twin pairs concordant and discordant for schizophrenia., Methods: Total and regional GMVs were measured from magnetic resonance images of 80 twins: 14 MZ pairs concordant for schizophrenia, 9 pairs discordant for schizophrenia, and 17 healthy MZ twin pairs., Results: Total GMV was smaller in twins with schizophrenia (t = -3.17, p = .003) and nonpsychotic cotwins from discordant pairs (t = -2.66, p = .011) than in healthy control twins. Twin pairs concordant for schizophrenia displayed reduced regional GMV in the inferior frontal, medial frontal, and anterior cingulate gyri; the caudate; lingual gyrus; and cerebellum relative to healthy twins (p < .05, corrected). Within discordant pairs, twins with schizophrenia had less GMV than their nonpsychotic cotwins in the insula; superior/medial frontal, pre/postcentral, cingulate, and superior temporal gyri; and the paracentral lobule. There were no significant differences in regional GMV between nonpsychotic cotwins and healthy control subjects., Conclusions: The presence of schizophrenia was specifically related to reduced GMV in frontal, insular, cingulate, medial parietal, and temporal cortex, over and above effects of genetic risk for the disorder. These changes could be related to the pathophysiology of the disorder itself or to unique environmental factors acting etiologically or because of the illness., (Copyright 2010 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Neuregulin-1 (NRG-1) is a putative susceptibility gene for schizophrenia but the neurocognitive processes that may involve NRG-1 in schizophrenia are unknown. Deficits in antisaccade (AS) and smooth pursuit eye movements (SPEM) are promising endophenotypes, which may be associated with brain dysfunctions underlying the pathophysiology of schizophrenia. The aim of this study was to investigate the associations of NRG-1 genotypes with AS and SPEM in schizophrenia patients and healthy controls. Patients (N = 113) and controls (N = 106) were genotyped for two NRG-1 single nucleotide polymorphisms (SNPs); SNP8NRG222662, a surrogate marker for the originally described Icelandic NRG-1 risk haplotype, and SNP8NRG243177, which has recently been associated with individual differences in brain function. Subjects underwent infrared oculographic assessment of AS and SPEM. The study replicates previous findings of impaired AS and SPEM performance in schizophrenia patients (all P < 0.005; all d = 0.5-1.5). SNP8NRG243177 risk allele carriers had marginally increased variability of AS spatial error (P = 0.050, d = 0.3), but there were no significant genotype effects on other eye movement variables and no significant diagnosis-by-genotype interactions. Generally, risk allele carriers (G allele for SNP8NRG222662 and T allele for SNP8NRG243177) had numerically worse performance than non-carriers on most AS and SPEM variables. The results do not suggest that NRG-1 genotype significantly affects AS and SPEM task performance. However, the power of the sample to identify small effects is limited and the possibility of a type II error must be kept in mind. Larger samples may be needed to reliably investigate such gene effects on oculomotor endophenotypes.

The catechol-O-methyltransferase (COMT) enzyme catabolizes dopamine. The val(158)met single nucleotide polymorphism (rs4680) in the COMT gene has received considerable attention as a candidate gene for schizophrenia as well as for frontally mediated cognitive functions. Antisaccade performance is a good measure of frontal lobe integrity. Deficits on the task are considered a trait marker for schizophrenia. The aim of this study was to investigate the association of COMT val(158)met polymorphism with antisaccade eye movements in schizophrenia patients and healthy controls. Schizophrenia patients (N = 105) and healthy controls (N = 95) underwent infrared oculographic assessment of antisaccades. Subjects were genotyped for COMT val(158)met and divided into 3 groups according to genotype (val/val, val/met, and met/met). Patients displayed significantly more reflexive errors, longer and more variable latency, and lower amplitude gain than controls (all P < 0.02). A greater number of val(158) alleles was associated with shorter (P = 0.045) and less variable (P = 0.028) antisaccade latency and, nonsignificantly, with lower reflexive error rate (P = 0.056). None of these variables showed a group-by-genotype interaction (P > 0.1). There were no significant associations of genotype with measures of amplitude gain or spatial error (P > 0.2). The results suggest that COMT val(158) carrier status is associated with better performance on the antisaccade task. Possible explanations of this finding are discussed.

Schizophrenia is a complex disorder, caused by both genetic and environmental factors and their interactions. Research on pathogenesis has traditionally focused on neurotransmitter systems in the brain, particularly those involving dopamine. Schizophrenia has been considered a separate disease for over a century, but in the absence of clear biological markers, diagnosis has historically been based on signs and symptoms. A fundamental message emerging from genome-wide association studies of copy number variations (CNVs) associated with the disease is that its genetic basis does not necessarily conform to classical nosological disease boundaries. Certain CNVs confer not only high relative risk of schizophrenia but also of other psychiatric disorders. The structural variations associated with schizophrenia can involve several genes and the phenotypic syndromes, or the 'genomic disorders', have not yet been characterized. Single nucleotide polymorphism (SNP)-based genome-wide association studies with the potential to implicate individual genes in complex diseases may reveal underlying biological pathways. Here we combined SNP data from several large genome-wide scans and followed up the most significant association signals. We found significant association with several markers spanning the major histocompatibility complex (MHC) region on chromosome 6p21.3-22.1, a marker located upstream of the neurogranin gene (NRGN) on 11q24.2 and a marker in intron four of transcription factor 4 (TCF4) on 18q21.2. Our findings implicating the MHC region are consistent with an immune component to schizophrenia risk, whereas the association with NRGN and TCF4 points to perturbation of pathways involved in brain development, memory and cognition.

Deletions within the neurexin 1 gene (NRXN1; 2p16.3) are associated with autism and have also been reported in two families with schizophrenia. We examined NRXN1, and the closely related NRXN2 and NRXN3 genes, for copy number variants (CNVs) in 2977 schizophrenia patients and 33 746 controls from seven European populations (Iceland, Finland, Norway, Germany, The Netherlands, Italy and UK) using microarray data. We found 66 deletions and 5 duplications in NRXN1, including a de novo deletion: 12 deletions and 2 duplications occurred in schizophrenia cases (0.47%) compared to 49 and 3 (0.15%) in controls. There was no common breakpoint and the CNVs varied from 18 to 420 kb. No CNVs were found in NRXN2 or NRXN3. We performed a Cochran-Mantel-Haenszel exact test to estimate association between all CNVs and schizophrenia (P = 0.13; OR = 1.73; 95% CI 0.81-3.50). Because the penetrance of NRXN1 CNVs may vary according to the level of functional impact on the gene, we next restricted the association analysis to CNVs that disrupt exons (0.24% of cases and 0.015% of controls). These were significantly associated with a high odds ratio (P = 0.0027; OR 8.97, 95% CI 1.8-51.9). We conclude that NRXN1 deletions affecting exons confer risk of schizophrenia.

Disturbances of the oculomotor system are promising endophenotypes for schizophrenia. Increased error rates in the antisaccade task and prolonged antisaccade latencies have been found in patients with schizophrenia and their first degree relatives. We investigated oculomotor performance in 41 parents of schizophrenia patients and 22 controls with a prosaccade task and an antisaccade task. Parents were grouped into parents with a positive family history for schizophrenia (N=9) and parents with a negative family history for schizophrenia (N=32). An overlap-paradigm was applied; eye movements were recorded using infrared oculography. The combined group of parents made more antisaccade direction errors than controls (p=0.005) and there was a linear increase in direction errors from controls via negative family history parents to positive family history parents (p=0.008). Antisaccade latencies were prolonged in the combined parent group (p=0.057) compared to controls and there was a linear increase in latency with genetic loading (p=0.018). No group differences were found for prosaccade parameters. These results support the hypothesis that antisaccade impairment is associated with genetic loading for schizophrenia.

Background: Deficits in antisaccade (AS) and smooth pursuit eye movements (SPEM) are promising endophenotypes in genetic studies of schizophrenia. The Icelandic population lends itself ideally to genetic studies due to its ethnic homogeneity and well-documented genealogy. The primary aim of this study was to assess AS and SPEM performance in a large Icelandic sample. Additional aims were to investigate the relationship between AS and SPEM task performance and to assess internal consistency, within-session performance changes and effects of SPEM target velocity on performance., Method: Patients with schizophrenia (N = 118) and healthy controls (N = 109) matched for age and gender underwent infrared oculographic assessment of AS and SPEM (at target velocities of 12 degrees , 24 degrees and 36 degrees /s)., Results: On the AS task patients displayed significantly more reflexive errors, longer latency, increased intra-individual latency variability, and reduced amplitude gain compared to controls. On the SPEM task, patients had significantly lower velocity gain and more frequent saccades during pursuit at all velocities, but group differences in velocity gain increased with increasing target velocity. Internal consistency of performance was high for all variables in both groups (Cronbach's alpha >0.77 for AS and >0.85 for SPEM) except for AS spatial error in patients (alpha = 0.38). A moderate association was found between AS and SPEM performance. By and large, patients and controls showed similar patterns of systematic within-session performance changes., Conclusions: Our findings confirm the existence of robust eye movement deficits in schizophrenia in a large sample. These measures may be studied as endophenotypes in future studies of potential schizophrenia risk genotypes in the genetically homogenous Icelandic population.

Background: P300 amplitude reduction is reliably seen in schizophrenia. Inconsistent reports of isolated frontal and/or parietal deficits in unaffected family members may be clarified using a task that places greater load on frontal function., Method: Go and No-Go versions of the auditory oddball task were performed by eighteen schizophrenia patients, age-matched unaffected siblings and healthy controls matched closely to unaffected siblings on age, sex, education, socioeconomic-status, handedness and ethnicity. Groups were compared on P300 and N100 amplitude and latency. Spearman correlations were used to test the relationship between ERP amplitudes and neuropsychological measures of executive function and memory. The relationship between schizotypy--as measured using the structured interview--and ERPs was explored in a combined group of siblings and controls., Results: Independent of task, patients had lower P300 than controls and reduced parietal amplitude compared to siblings. Siblings had enhanced frontocentral N100 compared to controls. No-Go P300 amplitude and N100 latency was associated with executive function measures. There were significant intraclass correlations between patients and siblings for No-Go P300 amplitude, particularly at the central midline electrode. Frontocentral N100 and P300 amplitude were positively correlated with anxiety-related aspects of schizotypy., Conclusion: Enhanced N100 is present in unaffected siblings. Parietal P300 is intact in unaffected siblings, but reduced in patients. The No-Go-oddball is more sensitive than the Go-oddball to executive function deficits in patients and as an index of heritability.

Context: The use of endophenotypes, biological traits that increase the liability to a disorder, represents one strategy to facilitate the detection of susceptibility genes for complex behavioral disorders such as schizophrenia. Establishing that a candidate trait is both heritable and linked genetically to schizophrenia is integral to its validity as an endophenotypic marker. Neurocognitive deficits are among the most promising indicators of increased risk for schizophrenia; however, it is not clear to what extent these deficits are genetically linked to the disorder., Objectives: To quantify the genetic and environmental contributions to the variability of selected neurocognitive measures and to estimate the genetic relationship between these and schizophrenia., Design: Genetic model fitting to monozygotic and dizygotic twin data., Setting: United Kingdom psychiatric research institute., Participants: Two hundred sixty-seven monozygotic and dizygotic twins concordant and discordant for schizophrenia, and healthy monozygotic and dizygotic control twin pairs., Main Outcome Measures: The heritabilities of intelligence, working memory, processing speed, perceptual organization, and verbal comprehension were estimated, and the genetic relationship between each of these and schizophrenia was quantified., Results: Genetic influences contributed substantially to all of the cognitive domains, but intelligence and working memory were the most heritable. A significant correlation was found between intelligence and schizophrenia (r = -0.61; 95% confidence interval, -0.71 to -0.48), with shared genetic variance accounting for 92% of the covariance between the two. Genetic influences also explained most of the covariance between working memory and schizophrenia. Significant but lesser portions of covariance between the other cognitive domains and schizophrenia were also found to be genetically shared. Environmental effects, although separately linked to neurocognition and schizophrenia, did not generally contribute to their covariance., Conclusion: Genomewide searches using factorial designs stratifying for levels of intelligence and working memory will assist in the search for finding quantitative trait loci for schizophrenia.

Objective: Several components of event-related potentials--P50 suppression, P300 amplitude and latency, and mismatch negativity--have been proposed as potential endophenotypes for schizophrenia on the basis of family studies. The present study used a twin design to estimate the extent of genetic overlap between these indices and the liability to schizophrenia., Method: The authors measured mismatch negativity, P300, and P50 suppression in 16 monozygotic twin pairs concordant for schizophrenia, nine monozygotic twin pairs discordant for schizophrenia, and 78 healthy comparison twin pairs. The study design was based on a power calculation. Structural equation modeling was used to quantify the genetic and environmental contributions to the phenotypic covariance between schizophrenia and each of the event-related potential indices., Results: Significant phenotypic correlation with schizophrenia was found for each of the event-related potential components. Genetic factors were the main source of the phenotypic correlations. P50 suppression had the greatest genetic correlation with schizophrenia, followed by P300 amplitude, P300 latency, and mismatch negativity., Conclusions: All four event-related potential indices are potentially valid endophenotypes for schizophrenia, but P50 suppression and P300 amplitude show the closest genetic relationship to schizophrenia.

Context: Abnormalities of the thalamus are thought to be central to the pathophysiology of schizophrenia. These abnormalities include altered structure and shape of the thalamus itself and possibly changes to the adhesio interthalamica (or massa intermedia), the gray matter bridge connecting the 2 thalamic lobes. However, it is not clear to what extent these abnormalities are determined by the genetic liability for schizophrenia., Objective: To investigate thalamic volume and the presence of the adhesio interthalamica in monozygotic (MZ) twins concordant or discordant for schizophrenia., Design: Study of MZ twins., Setting: Patients were drawn from inpatient and outpatient clinics. Twin controls were recruited from a volunteer twin register and through media advertisements., Participants: A total of 123 twins participated: 19 MZ twin pairs concordant for schizophrenia, 15 MZ schizophrenic twins and 16 MZ nonschizophrenic twins drawn from 17 pairs discordant for schizophrenia, and 27 MZ twin pairs without schizophrenia. Groups were matched for age, sex, handedness, level of education, parental socioeconomic status, and ethnicity., Main Outcome Measures: The volume of the thalamus (including right and left hemispheres) was measured (in cubic centimeters) and the presence of the adhesio interthalamica was ascertained from structural magnetic resonance images., Results: Concordant twin pairs displayed significantly reduced thalamic volume compared with control twins, even when covarying for effects of whole-brain volume, age, and sex. There was a significant linear decrease in thalamic volume (control greater than discordant nonschizophrenic greater than discordant schizophrenic greater than concordant). In all groups, right thalamus was larger than left thalamus. There was no difference across groups in the frequency of the adhesio interthalamica., Conclusions: Volumetric thalamic abnormalities in schizophrenia occur in twin pairs concordant for schizophrenia. These abnormalities may mark the substantial genetic contribution to the illness seen in concordant twin pairs, whereas the adhesio interthalamica is unlikely to be affected in schizophrenia.

Objective: Deficiency in antisaccade performance has been proposed as a schizophrenia endophenotype., Method: The authors assessed performance on an antisaccade task (and a prosaccade control condition) by 10 monozygotic twin pairs discordant for DSM-IV schizophrenia and 10 monozygotic healthy twin pairs matched for age, sex, and parental socioeconomic status. The authors computed antisaccade gain, latency, and error rate, as well as prosaccade gain and latency., Results: The schizophrenic twins made more antisaccade reflexive errors than the nonschizophrenic co-twins and comparison twins, who did not significantly differ from each other. The nonschizophrenic members of discordant pairs performed worse than the comparison twins on antisaccade gain and latency but did not differ from their schizophrenic co-twins on these variables. There were no differences on prosaccade performance. Antisaccade errors were correlated with negative symptoms in the patients., Conclusions: Antisaccade spatial accuracy and latency deficits may serve as markers of genetic liability for schizophrenia.

We investigated whether prepulse inhibition of the startle response is reduced in siblings of schizophrenia patients compared to age- and sex-matched healthy controls. Nineteen unaffected biological siblings and 19 controls were assessed on prepulse inhibition by monaural and binaural acoustic prepulse stimuli, with the startle stimuli always presented binaurally. There was significantly less prepulse inhibition in siblings, compared to controls, with binaural prepulse stimuli, as also seen previously in schizophrenia patients. The difference between siblings and controls in prepulse inhibition with the left or right ear prepulse stimuli was not significant because of a pronounced increase in prepulse inhibition with monaural, relative to binaural, prepulses in the sibling group. High schizotypal ratings were mildly associated with reduced prepulse inhibition. Prepulse inhibition may provide a useful measure in the search for schizophrenia genes.

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.

Objective: The authors investigated the structural brain correlates of antisaccade performance., Method: Magnetic resonance imaging was used to measure the volumes of the prefrontal, premotor, sensorimotor, and occipitoparietal cortices as well as the caudate, thalamus, cerebellar vermis, and cerebrum in 20 first-episode psychosis patients and 18 healthy comparison subjects. Antisaccades were recorded by using infrared oculography., Results: Groups significantly differed in terms of antisaccade error rate and amplitude gain and tended to differ in terms of latency but not brain region volumes. Premotor cortex volume predicted antisaccade error rate among comparison subjects. In the patient group, caudate volume was related to latency and amplitude gain. Negative symptoms, independent of structural volumes, predicted error rate., Conclusions: These findings point to altered structure-function relationships in first-episode psychosis.

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.