Cold executive function processes and their hot analogs in schizotypy.

OBJECTIVE: To examine cold (based on logical reasoning) versus hot (having emotional components) executive function processes in groups with high individual schizotypal traits. METHOD: Two-hundred and forty-seven participants were administered the Schizotypal Personality Questionnaire and were allocated into schizotypal (cognitive-perceptual, paranoid, negative, disorganized) or control groups according to pre-specified criteria. Participants were also administered a battery of tasks examining working memory, complex selective attention, response inhibition, decision-making and fluid intelligence and their affective counterparts. The outcome measures of each task were reduced to one composite variable thus formulating five cold and five hot cognitive domains. Between-group differences in the cognitive domains were examined with repeated measures analyses of covariance. RESULTS: For working memory, the control and the cognitive-perceptual groups outperformed negative schizotypes, while for affective working memory controls outperformed the disorganized group. Controls also scored higher compared with the disorganized group in complex selective attention, while both the control and the cognitive-perceptual groups outperformed negative schizotypes in complex affective selective attention. Negative schizotypes also had striking difficulties in response inhibition, as they scored lower compared with all other groups. Despite the lack of differences in fluid intelligence, controls scored higher compared with all schizotypal groups (except from cognitive-perceptual schizotypes) in emotional intelligence; the latter group reported higher emotional intelligence compared with negative schizotypes. CONCLUSION: Results indicate that there is no categorical association between the different schizotypal dimensions with solely cold or hot executive function processes and support impoverished emotional intelligence as a core feature of schizotypy.

Cognitive Processes and Resting-State Functional Neuroimaging Findings in High Schizotypal Individuals and Schizotypal Personality Disorder Patients: A Systematic Review.

Ample research findings indicate that there is altered brain functioning in the schizophrenia spectrum. Nevertheless, functional neuroimaging findings remain ambiguous for healthy individuals expressing high schizotypal traits and patients with schizotypal personality disorder (SPD). The purpose of this systematic review was to identify patterns of task-related and resting-state neural abnormalities across these conditions. MEDLINE-PubMed and PsycINFO were systematically searched and forty-eight studies were selected. Forty studies assessed healthy individuals with high schizotypal traits and eight studies examined SPD patients with functional neuroimaging techniques (fNIRS; fMRI; Resting-state fMRI). Functional alterations in striatal, frontal and temporal regions were found in healthy individuals with high schizotypal traits. Schizotypal personality disorder was associated with default mode network abnormalities but further research is required in order to better conceive its neural correlates. There was also evidence for functional compensatory mechanisms associated with both conditions. To conclude, the findings suggest that brain dysfunctions are evident in individuals who lie along the subclinical part of the spectrum, further supporting the continuum model for schizophrenia susceptibility. Additional research is required in order to delineate the counterbalancing processes implicated in the schizophrenia spectrum, as this approach will provide promising insights for both conversion and protection from conversion into schizophrenia.

The moderating role of early traumatic experiences on the association of schizotypal traits with visual perception.

The findings on the association of schizotypal traits with the perception of visual illusions are scarce and inconsistent and have not taken into consideration potential effects of childhood traumatic experiences, a risk factor for schizophrenia-spectrum conditions. Thus, the present study addressed the question of potential moderating effects of early traumatic experiences on the association between different aspects of schizotypal traits with the perception of the Müller-Lyer and Navon's Hierarchical Letters (NHL) illusions. The study revealed that (a) increased suspiciousness was associated with increased liability to the Müller-Lyer illusion, when the exposure to traumatic events was high, whereas the opposite pattern was true when the exposure to traumatic events was low; (b) negative schizotypy was associated with more accurate global perception, and high disorganized schizotypy was associated with superior accuracy when target letters were present during the NHL illusion, when early traumatic experiences were at lower levels; and (c) high negative, disorganized, and total schizotypy were associated with lower accuracy when target letters were present in the NHL paradigm, when early traumatic experiences were at higher levels. The findings of the study suggest that early traumatic events differentially moderate the relationship between various aspects of schizotypal traits and visual perceptual processing.

Facial emotion recognition and schizotypal traits: A systematic review of behavioural studies.

AIM: Previous research has indicated that individuals expressing high schizotypal traits and patients with Schizotypal Personality Disorder (SPD), show deficits in facial emotion recognition, compared to low schizotypal or control groups. On the other hand, non-significant findings also exist and the association of facial emotion recognition deficits with the different schizotypal dimensions is not well defined, thus limiting any conclusive outcomes. Therefore, the aim of this systematic review was to further clarify this relationship. METHODS: PsychInfo, Web of Science, Scopus and PubMed were systematically searched, and 23 papers with a cross-sectional design were selected. Nineteen studies examined individuals with high schizotypal traits and four studies evaluated SPD individuals with behavioural facial emotion recognition paradigms and self-report measures or clinical interviews for schizotypal traits. All selected studies were published between 1994 and August 2020. RESULTS: According to the evidence of studies, high schizotypal individuals and SPD patients have poorer performance in facial emotion recognition tasks. Negative schizotypy was related to lower accuracy for positive and negative emotions and faster emotion labeling while positive schizotypy was associated with worse accuracy for positive, negative and neutral emotions and more biases. Disorganized schizotypy was associated with poorer accuracy for negative emotions and suspiciousness with higher accuracy for disgust faces but lower total accuracy. CONCLUSIONS: These findings are consistent with the vulnerability for schizophrenia spectrum disorders and support the idea that emotion recognition deficits are trait markers for these conditions. Thus, the effectiveness of early-intervention programmes could increase by also targeting this class of deficits.

Identifying nootropic drug targets via large-scale cognitive GWAS and transcriptomics.

Broad-based cognitive deficits are an enduring and disabling symptom for many patients with severe mental illness, and these impairments are inadequately addressed by current medications. While novel drug targets for schizophrenia and depression have emerged from recent large-scale genome-wide association studies (GWAS) of these psychiatric disorders, GWAS of general cognitive ability can suggest potential targets for nootropic drug repurposing. Here, we (1) meta-analyze results from two recent cognitive GWAS to further enhance power for locus discovery; (2) employ several complementary transcriptomic methods to identify genes in these loci that are credibly associated with cognition; and (3) further annotate the resulting genes using multiple chemoinformatic databases to identify "druggable" targets. Using our meta-analytic data set (N = 373,617), we identified 241 independent cognition-associated loci (29 novel), and 76 genes were identified by 2 or more methods of gene identification. Actin and chromatin binding gene sets were identified as novel pathways that could be targeted via drug repurposing. Leveraging our transcriptomic and chemoinformatic databases, we identified 16 putative genes targeted by existing drugs potentially available for cognitive repurposing.

Working memory training effects across the lifespan: Evidence from human and experimental animal studies.

Working memory refers to a cognitive function that provides temporary storage and manipulation of the information necessary for complex cognitive tasks. Due to its central role in general cognition, several studies have investigated the possibility that training on working memory tasks could improve not only working memory function but also increase other cognitive abilities or modulate other behaviors. This possibility is still highly controversial, with prior studies providing contradictory findings. The lack of systematic approaches and methodological shortcomings complicates this debate even more. This review highlights the impact of working memory training at different ages on humans. Finally, it demonstrates several findings about the neural substrate of training in both humans and experimental animals, including non-human primates and rodents.

Self-perceived cognitive lapses and psychological well-being in schizotypy: Generalized and domain-specific associations.

A critical link between schizotypy and schizophrenia is impoverished cognitive functioning. In the majority of studies, though: (1) cognition is examined with standard neuropsychological tasks; and (2) high-schizotypal individuals are defined according to criteria applied in the respective study sample. Taking these considerations into account, the aims of the present study were to examine: (1) differences between four pre-defined, according to normative criteria, schizotypal (paranoid, negative, disorganized and cognitive-perceptual) and one control groups in self-perceived cognitive lapses; and (2) associations between schizotypal dimensions, self-perceived cognitive lapses and psychological well-being. Two hundred and sixty-one participants were administered the Schizotypal Personality Questionnaire, the Cognitive Failures Questionnaire (CFQ) and the Flourishing Scale, which assesses psychological well-being. Negative schizotypals reported higher scores in almost all CFQ measures compared with the control group (all p values < 0.01) along with poorer psychological well-being compared with the control and the cognitive-perceptual groups (both p values < 0.001). The disorganized group had higher scores in distractibility, blunders and total CFQ scores compared with the control group (all p values < 0.001). High psychological well-being was significantly associated with low negative schizotypy and CFQ blunders along with high cognitive-perceptual schizotypy (all p values < 0.05). To summarize, negative schizotypy is associated with a profile of "generalized" self-perceived cognitive lapses while disorganized schizotypy is characterized by self-perceived cognitive slips that have previously been shown to be mediated by a fronto-parietal network. Although psychological well-being is negatively associated with social-context specific cognitive failures and negative schizotypy, it is positively associated with cognitive-perceptual schizotypy.

The association of schizotypal traits with Prepulse Inhibition: a double approach exploration.

Introduction: According to the fully-dimensional approach, schizotypy is a personality trait present in the population in a continuous manner while the quasi-dimensional approach emphasises its extreme presentations. In this study we examined the relationship between sensorimotor gating, a core risk-index of the schizophrenia-spectrum, and four schizotypal factors in a dimensional-wise and a dichotomising-wise approach. Methods: Two-hundred and eighty-three participants were assessed with the Schizotypal Personality Questionnaire and were tested for Prepulse Inhibition (PPI). Associations between the schizotypal factors and startle measures were examined with stepwise regressions (dimensional-wise approach). Individuals in the lower 20% or the upper 20% for each schizotypal factor were identified and between-group comparisons were conducted (dichotomising-wise approach). Results: We found that with both approaches, only high paranoid or negative schizotypy were associated with reduced PPI. The low negative schizotypy group had prolonged onset and peak latencies, indicating that prolonged stimulus detection accompanies superior sensorimotor gating in this group. Conclusions: The findings suggest that although differentiating the effects of the various schizotypal factors is primary, the approach employed is secondary. The study also adds evidence in the literature supporting PPI as a useful endophenotypic marker of the schizophrenia-spectrum and highlights the contribution of specific aspects of schizotypy.

Cognitive Functioning and Schizotypy: A Four-Years Study.

Although there is ample evidence from cross-sectional studies indicating cognitive deficits in high schizotypal individuals that resemble the cognitive profile of schizophrenia-spectrum patients, there is still lack of evidence by longitudinal/follow-up studies. The present study included assessments of schizotypal traits and a wide range of cognitive functions at two time points (baseline and 4-years assessments) in order to examine (a) their stability over time, (b) the predictive value of baseline schizotypy on cognition at follow-up and (c) differences in cognition between the two time points in high negative schizotypal and control individuals. Only high negative schizotypal individuals were compared with controls due to the limited number of participants falling in the other schizotypal groups at follow-up. Seventy participants (mean age: 36.17; 70% females) were assessed at baseline and follow-up. Schizotypal traits were evaluated with the Schizotypal Personality Questionnaire. We found that schizotypal traits decreased over time, except in a sub-group of participants ("schizotypy congruent") that includes individuals who consistently meet normative criteria of inclusion in either a schizotypal or control group. In these individuals, negative schizotypy and aspects of cognitive-perceptual and disorganized schizotypy remained stable. The stability of cognitive functioning also varied over time: response inhibition, aspects of cued attention switching, set-shifting and phonemic/semantic verbal fluency improved at follow-up. High negative schizotypy at baseline predicted poorer response inhibition and semantic switching at follow-up while high disorganized schizotypy predicted poorer semantic processing and complex processing speed/set-shifting. The between-group analyses revealed that response inhibition, set-shifting and complex processing speed/set-shifting were poorer in negative schizotypals compared with controls at both time points, while maintaining set and semantic switching were poorer only at follow-up. Taken together, the findings show differential stability of the schizotypal traits over time and indicate that different aspects of schizotypy predict a different pattern of neuropsychological task performance during a 4-years time window. These results are of significant use in the formulation of targeted early-intervention strategies for high-risk populations.

Pleiotropic Meta-Analysis of Cognition, Education, and Schizophrenia Differentiates Roles of Early Neurodevelopmental and Adult Synaptic Pathways.

Susceptibility to schizophrenia is inversely correlated with general cognitive ability at both the phenotypic and the genetic level. Paradoxically, a modest but consistent positive genetic correlation has been reported between schizophrenia and educational attainment, despite the strong positive genetic correlation between cognitive ability and educational attainment. Here we leverage published genome-wide association studies (GWASs) in cognitive ability, education, and schizophrenia to parse biological mechanisms underlying these results. Association analysis based on subsets (ASSET), a pleiotropic meta-analytic technique, allowed jointly associated loci to be identified and characterized. Specifically, we identified subsets of variants associated in the expected ("concordant") direction across all three phenotypes (i.e., greater risk for schizophrenia, lower cognitive ability, and lower educational attainment); these were contrasted with variants that demonstrated the counterintuitive ("discordant") relationship between education and schizophrenia (i.e., greater risk for schizophrenia and higher educational attainment). ASSET analysis revealed 235 independent loci associated with cognitive ability, education, and/or schizophrenia at p < 5 × 10-8. Pleiotropic analysis successfully identified more than 100 loci that were not significant in the input GWASs. Many of these have been validated by larger, more recent single-phenotype GWASs. Leveraging the joint genetic correlations of cognitive ability, education, and schizophrenia, we were able to dissociate two distinct biological mechanisms-early neurodevelopmental pathways that characterize concordant allelic variation and adulthood synaptic pruning pathways-that were linked to the paradoxical positive genetic association between education and schizophrenia. Furthermore, genetic correlation analyses revealed that these mechanisms contribute not only to the etiopathogenesis of schizophrenia but also to the broader biological dimensions implicated in both general health outcomes and psychiatric illness.

Author Correction: Study of 300,486 individuals identifies 148 independent genetic loci influencing general cognitive function.

Christina M. Lill, who contributed to analysis of data, was inadvertently omitted from the author list in the originally published version of this article. This has now been corrected in both the PDF and HTML versions of the article.

Schizotypal traits, neurocognition, and paternal age in unaffected first degree relatives of patients with familial or sporadic schizophrenia.

Studies comparing cognitive processes between familial and sporadic schizophrenia have yielded inconsistent findings. In this study we examined differences in neurocognition and schizotypal traits in unaffected relatives of schizophrenia-spectrum patients with either the familial (multiplex) or the sporadic (simplex) subtype of the disorder, taking paternal age at birth into consideration. Simplex (n = 65; SR), multiplex (n = 35; MR) relatives and controls (n = 114) were compared on several cognitive functions and schizotypal traits; between-group differences were evaluated with and without including paternal age in the analyses. SR and MR had higher negative and paranoid traits compared with controls, but paternal age abolished the differences between the SR and control groups. When taking into account schizotypal traits and participants' age, controls outperformed MR in strategy formation and set-shifting and SR in psychomotor speed, set-shifting and executive working memory. After including paternal age in the analyses, controls outperformed MR in strategy formation, working memory and executive working memory and both groups in psychomotor speed and set-shifting. These findings suggest that multiplex relatives present with a "riskier" personality and cognitive profile when considering the effects of paternal age. Nevertheless, simplex relatives are impaired in fundamental cognitive processes, thus highlighting the detrimental effects of paternal age on neurocognition.

Multi-Trait Analysis of GWAS and Biological Insights Into Cognition: A Response to Hill (2018).

Hill (Twin Research and Human Genetics, Vol. 21, 2018, 84-88) presented a critique of our recently published paper in Cell Reports entitled 'Large-Scale Cognitive GWAS Meta-Analysis Reveals Tissue-Specific Neural Expression and Potential Nootropic Drug Targets' (Lam et al., Cell Reports, Vol. 21, 2017, 2597-2613). Specifically, Hill offered several interrelated comments suggesting potential problems with our use of a new analytic method called Multi-Trait Analysis of GWAS (MTAG) (Turley et al., Nature Genetics, Vol. 50, 2018, 229-237). In this brief article, we respond to each of these concerns. Using empirical data, we conclude that our MTAG results do not suffer from 'inflation in the FDR [false discovery rate]', as suggested by Hill (Twin Research and Human Genetics, Vol. 21, 2018, 84-88), and are not 'more relevant to the genetic contributions to education than they are to the genetic contributions to intelligence'.

Study of 300,486 individuals identifies 148 independent genetic loci influencing general cognitive function.

General cognitive function is a prominent and relatively stable human trait that is associated with many important life outcomes. We combine cognitive and genetic data from the CHARGE and COGENT consortia, and UK Biobank (total N = 300,486; age 16-102) and find 148 genome-wide significant independent loci (P < 5 × 10-8) associated with general cognitive function. Within the novel genetic loci are variants associated with neurodegenerative and neurodevelopmental disorders, physical and psychiatric illnesses, and brain structure. Gene-based analyses find 709 genes associated with general cognitive function. Expression levels across the cortex are associated with general cognitive function. Using polygenic scores, up to 4.3% of variance in general cognitive function is predicted in independent samples. We detect significant genetic overlap between general cognitive function, reaction time, and many health variables including eyesight, hypertension, and longevity. In conclusion we identify novel genetic loci and pathways contributing to the heritability of general cognitive function.

The Network Structure of Schizotypal Personality Traits.

Elucidating schizotypal traits is important if we are to understand the various manifestations of psychosis spectrum liability and to reliably identify individuals at high risk for psychosis. The present study examined the network structures of (1) 9 schizotypal personality domains and (2) 74 individual schizotypal items, and (3) explored whether networks differed across gender and culture (North America vs China). The study was conducted in a sample of 27001 participants from 12 countries and 21 sites (M age = 22.12; SD = 6.28; 37.5% males). The Schizotypal Personality Questionnaire (SPQ) was used to assess 74 self-report items aggregated in 9 domains. We used network models to estimate conditional dependence relations among variables. In the domain-level network, schizotypal traits were strongly interconnected. Predictability (explained variance of each node) ranged from 31% (odd/magical beliefs) to 55% (constricted affect), with a mean of 43.7%. In the item-level network, variables showed relations both within and across domains, although within-domain associations were generally stronger. The average predictability of SPQ items was 27.8%. The network structures of men and women were similar (r = .74), node centrality was similar across networks (r = .90), as was connectivity (195.59 and 199.70, respectively). North American and Chinese participants networks showed lower similarity in terms of structure (r = 0.44), node centrality (r = 0.56), and connectivity (180.35 and 153.97, respectively). In sum, the present article points to the value of conceptualizing schizotypal personality as a complex system of interacting cognitive, emotional, and affective characteristics.

Comparisons of schizotypal traits across 12 countries: Results from the International Consortium for Schizotypy Research.

BACKGROUND: Schizotypal traits are expressions of underlying vulnerability to psychotic disorders which have a potential impact on mental health status, neurocognition, quality of life, and daily functioning. To date, little research has examined epidemiologic landscape of schizotypal traits at the cross-national level. Our aim was to study the expression of schizotypal traits by sex, age, and country in a combined sample gathered from 12 countries. METHODS: A total of 27,001 participants completed the Schizotypal Personality Questionnaire (SPQ). The mean age of participants was 22.12 (SD=6.28); 37.5% (n=10,126) were males. RESULTS: Schizotypal traits varied according to sex, age, and country. Females scored higher than males in the positive dimension, whereas males scored higher in the disorganization dimension. By age, a significant decrease in the positive schizotypal traits was observed. Epidemiological expression of schizotypal traits varied by country. Moreover, several interactions by sex, age, and country were found. CONCLUSIONS: This pattern is similar to those found in patients with psychosis and psychotic-like experiences. These findings provide new insights and the opportunity to explore the phenotypic expression of schizotypal traits at cross-national level.

Brief assessment of schizotypal traits: A multinational study.

The Schizotypal Personality Questionnaire-Brief (SPQ-B) was developed with the aim of examining variations in healthy trait schizotypy, as well as latent vulnerability to psychotic-spectrum disorders. No previous study has studied the cross-cultural validity of the SPQ-B in a large cross-national sample. The main goal of the present study was to analyze the reliability and the internal structure of SPQ-B scores in a multinational sample of 28,426 participants recruited from 14 countries. The mean age was 22.63years (SD=7.08; range 16-68years), 37.7% (n=10,711) were men. The omega coefficients were high, ranging from 0.86 to 0.92 for the total sample. Confirmatory factor analysis revealed that SPQ-B items were grouped either in a theoretical structure of three first-order factors (Cognitive-Perceptual, Interpersonal, and Disorganized) or in a bifactor model (three first-order factors plus a general factor of schizotypal personality). In addition, the results supported configural but not strong measurement invariance of SPQ-B scores across samples. These findings provide new information about the factor structure of schizotypal personality, and support the validity and utility of the SPQ-B, a brief and easy tool for assessing self-reported schizotypal traits, in cross-national research. Theoretical and clinical implications for diagnostic systems, psychosis models, and cross-national mental health strategies are derived from these results.

Meta-analysis on the association between genetic polymorphisms and prepulse inhibition of the acoustic startle response.

Sensorimotor gating measured by prepulse inhibition (PPI) of the acoustic startle response (ASR) has been proposed as one of the most promising electrophysiological endophenotypes of schizophrenia. During the past decade, a number of publications have reported significant associations between genetic polymorphisms and PPI in samples of schizophrenia patients and healthy volunteers. However, an overall evaluation of the robustness of these results has not been published so far. Therefore, we performed the first meta-analysis of published and unpublished associations between gene polymorphisms and PPI of ASR. Unpublished associations between genetic polymorphisms and PPI were derived from three independent samples. In total, 120 single observations from 16 independent samples with 2660 study participants and 43 polymorphisms were included. After correction for multiple testing based on false discovery rate and considering the number of analyzed polymorphisms, significant associations were shown for four variants, even though none of these associations survived a genome-wide correction (P<5∗10-8). These results imply that PPI might be modulated by four genotypes - COMT rs4680 (primarily in males), GRIK3 rs1027599, TCF4 rs9960767, and PRODH rs385440 - indicating a role of these gene variations in the development of early information processing deficits in schizophrenia. However, the overall impact of single genes on PPI is still rather small suggesting that PPI is - like the disease phenotype - highly polygenic. Future genome-wide analyses studies with large sample sizes will enhance our understanding on the genetic architecture of PPI.

Stress-Dependent Association Between Polygenic Risk for Schizophrenia and Schizotypal Traits in Young Army Recruits.

Schizotypal personality traits may increase proneness to psychosis and likely index familial vulnerability to schizophrenia (SZ), implying shared genetic determinants with SZ. Here, we sought to investigate the contribution of common genetic risk variation for SZ on self-reported schizotypy in 2 ethnically homogeneous cohorts of healthy young males during compulsory military service, enrolled in the Athens Study of Proneness and Incidence of Schizophrenia (ASPIS, N = 875) and the Learning on Genetics of Schizophrenia Spectrum study (LOGOS, N = 690). A follow-up psychometric assessment was performed in a sub-sample of the ASPIS (N = 121), 18 months later at military service completion. Polygenic risk scores (PRS) for SZ were derived based on genome-wide association meta-analysis results from the Psychiatric Genomics Consortium. In the ASPIS, higher PRSSZ significantly associated with lower levels of positive (ie, perceptual distortions), disorganization and paranoid facets of schizotypy, whereas no association with negative (ie, interpersonal) facets was noted. Importantly, longitudinal data analysis in the ASPIS subsample revealed that PRSSZ was inversely associated with positive schizotypy at military induction (stressed condition) but not at follow-up (nonstressed condition), providing evidence for environmental rather than SZ-implicated genetic influences. Moreover, consistent with prior reports, PRSSZ was positively correlated with trait anxiety in the LOGOS and additionally the recruits with higher PRSSZ and trait anxiety exhibited attenuated paranoid ideation. Together, these findings do not support an etiological link between increased polygenic liability for SZ and schizotypy, suggesting that psychosocial stress or trait anxiety may impact schizotypal phenotypic expressions among healthy young adults not genetically predisposed to SZ.