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Model systems of psychosis play an important role in pathophysiology and drug development research. Schizotypal individuals display similar cognitive impairments as schizophrenia patients in several domains. Therefore, schizotypy may be interpreted as a trait model system of psychosis. In addition, experimentally controlled sleep deprivation is a putative state psychosis model that evokes subclinical psychosis-like states. We aimed to further validate these model systems by examining them in relation to central cognitive biomarkers of schizophrenia. Most of all, we were interested in investigating, for the first time, effects of their combination on cognitive function. Healthy subjects with high (N = 17) or low (N = 19) levels of schizotypy performed a cognitive task battery after one night of normal sleep and after 24 h of sleep deprivation. Sleep deprivation impaired performance in the go/nogo and n-back tasks relative to the normal sleep control condition. No differences between groups or interactions of group with sleep condition were found. The role of sleep deprivation as a model of psychosis is thus supported to some extent by impairments in inhibitory control. However, classical measures of cognition may be less able to detect deficits in schizotypy, in line with evidence of more basic information processing dysfunctions in schizotypy., (Copyright © 2018 Elsevier B.V. All rights reserved.)

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.

Only a few common variants in the sequence of the genome have been shown to impact cognitive traits. Here we demonstrate that polygenic scores of educational attainment predict specific aspects of childhood cognition, as measured with IQ. Recently, three sequence variants were shown to associate with educational attainment, a confluence phenotype of genetic and environmental factors contributing to academic success. We show that one of these variants associating with educational attainment, rs4851266-T, also associates with Verbal IQ in dyslexic children (P = 4.3 × 10 -4 , β = 0.16 s.d.). The effect of 0.16 s.d. corresponds to 1.4 IQ points for heterozygotes and 2.8 IQ points for homozygotes. We verified this association in independent samples consisting of adults (P = 8.3 × 10 -5 , β = 0.12 s.d., combined P = 2.2 x 10 -7 , β = 0.14 s.d.). Childhood cognition is unlikely to be affected by education attained later in life, and the variant explains a greater fraction of the variance in verbal IQ than in educational attainment (0.7% vs 0.12%,. P = 1.0 × 10 -5 )., Competing Interests: B.G., G.A.J., G.B., P.S., S.K., B.Ke., O.G., H.H., P.I., S.O., M.F., G.Þ., S.A., B.S., U.Th., A.K., D.F.G., H.S., B.V.H. and K.S. are employees of deCODE Genetics/Amgen.

Environmental noise causes cognitive impairment, particularly in executive function and episodic memory domains, in healthy populations. However, the possible moderating influences on this relationship are less clear. This study assessed 54 healthy participants (24 men) on a cognitive battery (measuring psychomotor speed, attention, executive function, working memory, and verbal learning and memory) under three (quiet, urban, and social) noise conditions. IQ, subjective noise sensitivity, sleep, personality, paranoia, depression, anxiety, stress, and schizotypy were assessed on a single occasion. We found significantly slower psychomotor speed (urban), reduced working memory and episodic memory (urban and social), and more cautious decision-making (executive function, urban) under noise conditions. There was no effect of sex. Variance in urban noise-induced changes in psychomotor speed, attention, Trail Making B-A (executive function), and immediate recall and social noise-induced changes in verbal fluency (executive function) and immediate recall were explained by a combination of baseline cognition and paranoia, noise sensitivity, sleep, or cognitive disorganization. Higher baseline cognition (but not IQ) predicted greater impairment under urban and social noise for most cognitive variables. Paranoia predicted psychomotor speed, attention, and executive function impairment. Subjective noise sensitivity predicted executive function and memory impairment. Poor sleep quality predicted less memory impairment. Finally, lower levels of cognitive disorganization predicted slower psychomotor speed and greater memory impairment. The identified moderators should be considered in studies aiming to reduce the detrimental effects of occupational and residential noise. These results highlight the importance of studying noise effects in clinical populations characterized by high levels of the paranoia, sleep disturbances, noise sensitivity, and cognitive disorganization.

Saccadic tasks are widely used to study cognitive processes, effects of pharmacological treatments, and mechanisms underlying psychiatric disorders. In genetic studies, it is assumed that saccadic endophenotypes are traits. While internal consistency and temporal stability of saccadic performance is high for most of the measures, the magnitude of underlying trait components has not been estimated, and influences of situational aspects and person by situation interactions have not been investigated. To do so, 68 healthy participants performed prosaccades, antisaccades, and memory-guided saccades on three occasions at weekly intervals at the same time of day. Latent state-trait modeling was applied to estimate the proportions of variance reflecting stable trait components, situational influences, and Person × Situation interaction effects. Mean variables for all saccadic tasks showed high to excellent reliabilities. Intraindividual standard deviations were found to be slightly less reliable. Importantly, an average of 60% of variance of a single measurement was explained by trans-situationally stable person effects, while situation aspects and interactions between person and situation were found to play a negligible role. We conclude that saccadic variables, in standard laboratory settings, represent highly reliable measures that are largely unaffected by situational influences. Extending previous reliability studies, these findings clearly demonstrate the trait-like nature of these measures and support their role as endophenotypes., (© 2015 Society for Psychophysiological Research.)

The gene coding for the dopamine transporter (DAT), SLC6A3, contains a 40-base pair variable number of tandem repeats (VNTR) polymorphism (rs28363170) in its 3' untranslated region. This VNTR has been associated with attention deficit hyperactivity disorder (ADHD) and has been investigated in relation to cognition and brain function. Here, we report the results of a comprehensive meta-analysis with meta-regression examining the association of the VNTR with different domains of cognition in healthy adults. We extracted data from 28 independent studies and carried out meta-analyses for associations with working memory (k=10 samples, N=1193 subjects), inhibition (k=8 samples, N=829 subjects), executive functions including inhibition (k=10 samples, N=984 subjects), attention (k=6 samples, N=742 subjects) and declarative long-term memory (k=5 samples, N=251 subjects). None of the investigated dimensions showed significant associations with the VNTR (all p>0.26). Meta-regression including year of publication, gender, age, ethnicity and percentage of 10R-homozygotes similarly did not attain significance. We conclude that there is no evidence that rs28363170 may be a significant predictor of cognitive function in healthy adults., (Copyright © 2015 Elsevier Ltd. 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.)

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.)

The catechol-O-methyltransferase (COMT) val(158)met single nucleotide polymorphism (rs4680) has been shown to be associated with brain activation during a number of neurocognitive and emotional tasks. The present study evaluated genotypic associations with brain function during measurement of cognitive stability (prosaccades) and plasticity (antisaccades). A total of 36 healthy volunteers were genotyped for rs4680 and underwent functional magnetic resonance imaging (fMRI) at 1.5 T. Individuals with at least one val(158) allele (val(158) carriers, N=24) showed lower blood oxygen level-dependent (BOLD) response in ventromedial and dorsomedial prefrontal cortex during antisaccades compared to val(158) noncarriers, whereas met(158) homozygotes (N=12) showed lower BOLD response in a cluster in the posterior cingulate and precuneus during prosaccades compared to val(158) carriers. These findings suggest that associations of COMT val(158)met genotype with brain function may be mediated by task characteristics. The findings may be compatible with a hypothesis on the role of COMT val(158)met genotype in tonic and phasic dopamine levels in brain and differential effects on cognitive measures of stability (eg prosaccades) and plasticity (eg antisaccades).

The antisaccade task is a model of the conflict between an unwanted reflexive response (which must be inhibited) and a complex volitional response (which must be generated). The present experiment aimed to investigate separately the neural correlates of these cognitive components using a delayed saccade paradigm to dissociate saccade inhibition from generation. Seventeen healthy volunteers completed event-related functional magnetic resonance imaging at 1.5 T during saccades to and away from a peripheral visual target (prosaccades and antisaccades, respectively). Saccades were requested in response to an auditory go signal on average 12 s after peripheral target appearance. It was found that the right supramarginal gyrus showed significantly greater activation during the inhibition phase than the generation phase of the paradigm for both antisaccade and prosaccade trials, suggesting a role in saccade inhibition or stimulus detection. On the other hand, the right lateral frontal eye field and bilateral intraparietal sulcus showed evidence of selective involvement in antisaccade generation. Ventrolateral and dorsolateral prefrontal cortices showed comparable levels of activation in both phases of the task. These areas likely fulfill a more general supervisory role in the volitional control of eye movements, such as stimulus appraisal, task set, and decision making.

Mean pupil size during fixation has been suggested to reflect interindividual differences in working memory and fluid intelligence. However, due to small samples with limited age range (17–35 years) and suboptimal light conditions in previous studies, these associations are still controversial and it is unclear whether they are observed at older ages. Therefore, we assessed whether interindividual differences in cognitive performance are reflected in pupil diameter during fixation and whether these associations are age‐dependent. We analyzed pupillometry and cognition data of 4560 individuals aged 30–95 years of the community‐based Rhineland Study. Pupillometry data were extracted from a one‐minute fixation task. The cognitive test battery included tests of oculomotor control, working memory, episodic verbal memory, processing speed, executive function, and crystallized intelligence. For data analysis, we used multivariable regression models. Working memory and global cognition were not associated with pupil diameter during fixation. Better processing speed performance was associated with larger pupil diameter during fixation. Associations between cognition and pupil diameter during fixation hardly varied with age, but pupil diameter during fixation declined linearly with age (adjusted decline: 0.33 mm per 10 years of age). There were no significant sex differences in pupil size. We conclude that interindividual differences in mean pupil diameter during fixation may partly reflect interindividual differences in the speed of processing and response generation. We could not confirm that interindividual differences in working memory and fluid intelligence are reflected in pupil size during fixation; however, our sample differed in age range from previous studies. Our study contributes to the intense debate on whether or not interindividual differences in working memory capacity and fluid intelligence are reflected in mean pupil size during fixation. In our large dataset of 4560 participants aged 30 to 95 years, we could not confirm that mean pupil size during fixation reflects interindividual differences in working memory capacity or fluid intelligence. However, our findings suggest that mean pupil diameter during fixation may inform about interindividual differences in levels of preparatory neural activity for motor responses. [ABSTRACT FROM AUTHOR]

Rationale: Nicotine has been widely studied for its pro-dopaminergic effects. However, at the behavioural level, past investigations have yielded heterogeneous results concerning effects on cognitive, affective, and motor outcomes, possibly linked to individual differences at the level of genetics. A candidate polymorphism is the 40-base-pair variable number of tandem repeats polymorphism (rs28363170) in the SLC6A3 gene coding for the dopamine transporter (DAT). The polymorphism has been associated with striatal DAT availability (9R-carriers > 10R-homozygotes), and 9R-carriers have been shown to react more strongly to dopamine agonistic pharmacological challenges than 10R-homozygotes. Objectives: In this preregistered study, we hypothesized that 9R-carriers would be more responsive to nicotine due to genotype-related differences in DAT availability and resulting dopamine activity. Methods: N=194 non-smokers were grouped according to their genotype (9R-carriers, 10R-homozygotes) and received either 2-mg nicotine or placebo gum in a between-subject design. Spontaneous blink rate (SBR) was obtained as an indirect measure of striatal dopamine activity and smooth pursuit, stop signal, simple choice and affective processing tasks were carried out in randomized order. Results: Reaction times were decreased under nicotine compared to placebo in the simple choice and stop signal tasks, but nicotine and genotype had no effects on any of the other task outcomes. Conditional process analyses testing the mediating effect of SBR on performance and how this is affected by genotype yielded no significant results. Conclusions: Overall, we could not confirm our main hypothesis. Individual differences in nicotine response could not be explained by rs28363170 genotype. [ABSTRACT FROM AUTHOR]

Intertemporal choice involves deciding between smaller, sooner and larger, later rewards. People tend to prefer smaller rewards that are available earlier to larger rewards available later, a phenomenon referred to as temporal or delay discounting. Despite its ubiquity in human and non-human animals, temporal discounting is subject to considerable individual differences. Here, we provide a critical narrative review of this literature and make suggestions for future work. We conclude that temporal discounting is associated with key socio-economic and health-related variables. Regarding personality, large-scale studies have found steeper temporal discounting to be associated with higher levels of self-reported impulsivity and extraversion; however, effect sizes are small. Temporal discounting correlates negatively with future-oriented cognitive styles and inhibitory control, again with small effect sizes. There are consistent associations between steeper temporal discounting and lower intelligence, with effect sizes exceeding those of personality or cognitive variables, although socio-demographic moderator variables may play a role. Neuroimaging evidence of brain structural and functional correlates is not yet consistent, neither with regard to areas nor directions of effects. Finally, following early candidate gene studies, recent Genome Wide Association Study (GWAS) approaches have revealed the molecular genetic architecture of temporal discounting to be more complex than initially thought. Overall, the study of individual differences in temporal discounting is a maturing field that has produced some replicable findings. Effect sizes are small-to-medium, necessitating future hypothesis-driven work that prioritizes large samples with adequate power calculations. More research is also needed regarding the neural origins of individual differences in temporal discounting as well as the mediating neural mechanisms of associations of temporal discounting with personality and cognitive variables. [ABSTRACT FROM AUTHOR]

Previous research has suggested reduced parasympathetic cardiac regulation during cognitive activity in major depressive disorder (MDD). However, little is known about possible abnormalities in sympathetic control and cardiovascular reactivity. This study aimed to provide a comprehensive analysis of autonomic cardiovascular control in the context of executive functions in MDD. Thirty six MDD patients and 39 healthy controls participated. Parameters of sympathetic (pre‐ejection period, PEP) and parasympathetic control (high and low frequency heart rate variability, HF HRV, LF HRV; and baroreflex sensitivity, BRS) as well as RR interval were obtained at rest and during performance of executive function tasks (number‐letter task, n‐back task, continuous performance test, and Stroop task). Patients, as compared to controls, exhibited lower HF HRV and LF HRV during task execution and smaller shortenings in PEP and RR interval between baseline and tasks. They displayed longer reaction times during all conditions of the tasks and more omission errors and false alarms on the continuous performance test. In the total sample, on‐task HF HRV, LF HRV and BRS, and reactivity in HF HRV, LF HRV, and PEP, were positively associated with task performance. As performance reduction arose independent of executive function load of the tasks, the behavioral results reflect impairments in attention and processing speed rather than executive dysfunctions in MDD. Abnormalities in cardiovascular control during cognition in MDD appear to involve both divisions of the autonomic nervous system. Low tonic parasympathetic control and blunted sympathetic reactivity imply reduced physiological adjustment resources and, by extension, provide suboptimal conditions for cognitive performance. This study investigated autonomic cardiovascular control during cognitive activity in MDD. In addition to impaired cognitive performance, patients showed reduced HRV, smaller decreases in pre‐ejection period and RR interval during task execution. On‐task HRV and reactivity in HRV, baroreflex sensitivity, and pre‐ejection period correlated positively with task performance. The study, for the first time, documented that that low tonic parasympathetic control and blunted sympathetic reactivity characterizing MDD may provide suboptimal conditions for cognitive performance. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Schizotypy is defined as a time-stable multidimensional personality trait consisting of positive, negative, and disorganized facets. Schizotypy is considered as a model system of psychosis, as there is considerable overlap between the 2 constructs. High schizotypy is associated with subtle but fairly widespread cognitive alterations, which include poorer performance in tasks measuring cognitive control. Similar but more pronounced impairments in cognitive control have been described extensively in psychosis. We here sought to provide a quantitative estimation of the effect size of impairments in schizotypy in the updating, shifting, and inhibition dimensions of cognitive control. We included studies of healthy adults from both general population and college samples, which used either categorical or correlative designs. Negative schizotypy was associated with significantly poorer performance on shifting (g = 0.32) and updating (g = 0.11). Positive schizotypy was associated with significantly poorer performance on shifting (g = 0.18). There were no significant associations between schizotypy and inhibition. The divergence in results for positive, negative, and disorganized schizotypy emphasizes the importance of examining relationships between cognition and the facets of schizotypy rather than using the overall score. Our findings also underline the importance of more detailed research to further understand and define this complex personality construct, which will also be of importance when applying schizotypy as a model system for psychosis. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Executive function impairments have been frequently observed in depressive disorders. Moreover, reduced heart rate variability (HRV) has repeatedly been described, especially in the high frequency band (i.e., respiratory sinus arrhythmia, RSA), suggesting lower vagal cardiac outflow. The study tested the hypothesis of involvement of low vagal tone in executive dysfunction in depression. In addition to RSA, HRV in the low frequency (LF) band was assessed. In 36 patients with depression and 36 healthy subjects, electrocardiography recordings were accomplished at rest and during performance of five executive function tasks (number-letter task, n-back task, continuous performance test, flanker task, and antisaccade task). Patients displayed increased error rates and longer reaction times in the task-switching condition of the number-letter task, in addition to increased error rates in the n-back task and the final of two blocks of the antisaccade task. In patients, both HRV parameters were lower during all experimental phases. RSA correlated negatively with reaction time during task-switching. This finding confirms reduced performance across different executive functions in depression and suggests that, in addition to RSA, LF HRV is also diminished. However, the hypothesis of involvement of low parasympathetic tone in executive dysfunction related to depression received only limited support. [ABSTRACT FROM AUTHOR]

Schizotypy refers to a set of personality traits thought to reflect the subclinical expression of the signs and symptoms of schizophrenia. Here, we review the cognitive and brain functional profile associated with high questionnaire scores in schizotypy. We discuss empirical evidence from the domains of perception, attention, memory, imagery and representation, language, and motor control. Perceptual deficits occur early and across various modalities. While the neural mechanisms underlying visual impairments may be linked to magnocellular dysfunction, further effects may be seen downstream in higher cognitive functions. Cognitive deficits are observed in inhibitory control, selective and sustained attention, incidental learning, and memory. In concordance with the cognitive nature of many of the aberrations of schizotypy, higher levels of schizotypy are associated with enhanced vividness and better performance on tasks of mental rotation. Language deficits seem most pronounced in higher-level processes. Finally, higher levels of schizotypy are associated with reduced performance on oculomotor tasks, resembling the impairments seen in schizophrenia. Some of these deficits are accompanied by reduced brain activation, akin to the pattern of hypoactivations in schizophrenia spectrum individuals. We conclude that schizotypy is a construct with apparent phenomenological overlap with schizophrenia and stable interindividual differences that covary with performance on a wide range of perceptual, cognitive, and motor tasks known to be impaired in schizophrenia. The importance of these findings lies not only in providing a fine-grained neurocognitive characterization of a personality constellation known to be associated with real-life impairments, but also in generating hypotheses concerning the aetiology of schizophrenia. [ABSTRACT FROM AUTHOR]

Schizotypy refers to a constellation of personality traits that are believed to mirror the subclinical expression of schizophrenia in the general population. Evidence from pharmacological studies indicates that dopamine (DA) is involved in the etiology of schizophrenia. Based on the assumption of a continuum between schizophrenia and schizotypy, researchers have begun investigating the association between DA and schizotypy using a wide range of methods. In this article, we review published studies on this association from the following areas of work: (1) experimental investigations of the interactive effects of dopaminergic challenges and schizotypy on cognition, motor control, and behavior (2), dopaminergically supported cognitive functions (3), studies of associations between schizotypy and polymorphisms in genes involved in dopaminergic neurotransmission, and (4) molecular imaging studies of the association between schizotypy and markers of the DA system. Together, data from these lines of evidence suggest that DA is important to the expression and experience of schizotypy and associated behavioral biases. An important observation is that the experimental designs, methods, and manipulations used in this research are highly heterogeneous. Future studies are required to replicate individual observations, to enlighten the link between DA and different schizotypy dimensions (positive, negative, cognitive disorganization), and to guide the search for solid DA-sensitive behavioral markers. Such studies are important in order to clarify inconsistencies between studies. Morework is also needed to identify differences between dopaminergic alterations in schizotypy compared to the dysfunctions observed in schizophrenia. [ABSTRACT FROM AUTHOR]

The catechol-O-methyltransferase (COMT) val158met single nucleotide polymorphism (rs4680) has been shown to be associated with brain activation during a number of neurocognitive and emotional tasks. The present study evaluated genotypic associations with brain function during measurement of cognitive stability (prosaccades) and plasticity (antisaccades). A total of 36 healthy volunteers were genotyped for rs4680 and underwent functional magnetic resonance imaging (fMRI) at 1.5 T. Individuals with at least one val158 allele (val158 carriers, N=24) showed lower blood oxygen level-dependent (BOLD) response in ventromedial and dorsomedial prefrontal cortex during antisaccades compared to val158 noncarriers, whereas met158 homozygotes (N=12) showed lower BOLD response in a cluster in the posterior cingulate and precuneus during prosaccades compared to val158 carriers. These findings suggest that associations of COMT val158met genotype with brain function may be mediated by task characteristics. The findings may be compatible with a hypothesis on the role of COMT val158met genotype in tonic and phasic dopamine levels in brain and differential effects on cognitive measures of stability (eg prosaccades) and plasticity (eg antisaccades).Neuropsychopharmacology (2008) 33, 3046–3057; doi:10.1038/sj.npp.1301658; published online 30 January 2008 [ABSTRACT FROM AUTHOR]

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

Neurological soft signs (NSS) are nonspecific indicators of brain dysfunction that are found to be in excess and correlated with cognitive dysfunction and psychopathology in patients with schizophrenia. The aim of the study was to examine whether the severity of NSS determines the efficacy of atypical antipsychotics in schizophrenia. Forty-three patients with schizophrenia were assessed on psychopathology and cognitive domains of executive functioning, memory, attention, and psychomotor speed at baseline and 6 months after they had been switched from typical to atypical antipsychotics. NSS were examined at baseline. The high-NSS group showed more severe psychopathology and greater impaired cognitive function than the low-NSS group at baseline. Following treatment, there were improvements in cognitive functioning and psychopathology with the low-NSS group, which showed significant improvements on measures of verbal fluency, memory, and psychomotor speed and negative symptoms. The high-NSS group also showed improvements on most of these measures, but the improvement was less than that seen in the low-NSS group. The presence of high NSS in schizophrenia patients impedes the improvement in cognitive function with atypical antipsychotics treatment. [ABSTRACT FROM PUBLISHER]

Smooth pursuit eye movement (SPEM) and antisaccade deficits are observed in the schizophrenia spectrum and have been used to study the pathophysiology as well as the genetic basis of this condition. The neurotransmitter acetylcholine has been implicated in a number of cognitive processes thought to underlie SPEM and antisaccade performance. This study investigates effects on eye movements of procyclidine, an anticholinergic drug often administered to schizophrenic patients. A total of 13 patients completed a double-blind placebo-controlled crossover design, receiving 15 mg procyclidine and placebo. Seven participants received procyclidine first and placebo second, six participants were tested in the reverse order. SPEM and antisaccade (as well as fixation and prosaccade) eye movements were recorded using infrared oculography. Results showed that procyclidine overall, relative to placebo, mildly worsened SPEM performance, as indicated by nonsignificantly reduced gain (p=0.08) and increased frequency of intrusive anticipatory saccades during pursuit (p=0.06). A significant interaction of group and order of administration indicated that procyclidine increased the rate of antisaccade reflexive errors only when administered first; the opposite pattern was observed when placebo was administered first, likely due to the operation of practice effects at second assessment. These findings indicate that acute administration of a clinically relevant dose of procyclidine leads to mild impairments in eye movement performance in schizophrenic patients, suggesting the need to consider this compound in oculomotor studies in schizophrenia. The action of this anticholinergic drug on oculomotor performance is consistent with the hypothesized role of the cholinergic system in the cognitive mechanisms of attention and working memory, processes thought to underlie SPEM and antisaccade performance. Effects of order of administration and practice on the antisaccade task suggest that these factors need to be taken into consideration in future pharmacological studies. [ABSTRACT FROM AUTHOR]

• We linked three genetic polymorphisms with behaviorally measured metacognition. • We found higher metacognitive bias in S/L G -allele carriers in the 5-HTTLPR genotype. • This is discussed with regard to the role of the S-allele as a plasticity variant. • The serotonergic system partially mediates metacognitive bias. There is a striking lack of studies on the molecular genetic basis of metacognition, i.e., the higher-order ability to monitor mental processes. Here, an initial step toward resolving this issue was undertaken by investigating functional polymorphisms from three genes of the dopaminergic or serotonergic systems (DRD4, COMT , and 5-HTTLPR) in relation to behaviorally assessed metacognition in six paradigms across three cognitive domains. We report evidence for a task-dependent higher average confidence level (metacognitive bias) in carriers of at least one S or L G -allele in the 5-HTTLPR genotype and integrate these findings within a differential susceptibility framework. [ABSTRACT FROM AUTHOR]

Abstract: A number of compounds aimed at improving cognition in schizophrenia have failed to demonstrate efficacy in Phase 2 clinical trials. Translational studies using biomarkers in surrogate populations, such as schizotypy, could be used to assess the efficacy of novel compounds. In this study, we aimed to validate the sensitivity and inter-site reliability of cognitive biomarkers (working memory (N-back), spatial working memory (SWM) and verbal fluency (VF) tasks) to detect the schizotypy phenotype and its reversal by psychotropic drugs. Healthy volunteers scoring high or average on a schizotypal personality measure (122 in each group) were randomized to receive a single dose of risperidone, amisulpride, nicotine or placebo in a double-blind, between-subject design. We found evidence for a poorer performance on N-back and VF tasks in the high schizotypy group, replicating previous research. This effect was counteracted by amisulpride on N-back: it improved working memory in high schizotypy group but impaired the controls. A similar pattern was seen in SWM and VF. We interpret this finding in the light of the dopamine enhancing action of amisulpride when given in low doses. In contrast, risperidone impaired both groups and nicotine had a beneficial effect for the low baseline performers only. These effects were consistent across sites. These data demonstrates the utility of biomarkers in detecting the effect of schizotypy and its reversal by drugs that enhance dopamine and cholinergic function. Studies using similar design could help the early assessment of potential of compounds designed to improve cognition in schizophrenia. [Copyright &y& Elsevier]