Common genetic variation and schizophrenia polygenic risk influence neurocognitive performance in young adulthood.

Neurocognitive abilities constitute complex traits with considerable heritability. Impaired neurocognition is typically observed in schizophrenia (SZ), whereas convergent evidence has shown shared genetic determinants between neurocognition and SZ. Here, we report a genome-wide association study (GWAS) on neuropsychological and oculomotor traits, linked to SZ, in a general population sample of healthy young males (n = 1079). Follow-up genotyping was performed in an identically phenotyped internal sample (n = 738) and an independent cohort of young males with comparable neuropsychological measures (n = 825). Heritability estimates were determined based on genome-wide single-nucleotide polymorphisms (SNPs) and potential regulatory effects on gene expression were assessed in human brain. Correlations with general cognitive ability and SZ risk polygenic scores were tested utilizing meta-analysis GWAS results by the Cognitive Genomics Consortium (COGENT) and the Psychiatric Genomics Consortium (PGC-SZ). The GWAS results implicated biologically relevant genetic loci encoding protein targets involved in synaptic neurotransmission, although no robust individual replication was detected and thus additional validation is required. Secondary permutation-based analysis revealed an excess of strongly associated loci among GWAS top-ranked signals for verbal working memory (WM) and antisaccade intra-subject reaction time variability (empirical P < 0.001), suggesting multiple true-positive single-SNP associations. Substantial heritability was observed for WM performance. Further, sustained attention/vigilance and WM were suggestively correlated with both COGENT and PGC-SZ derived polygenic scores. Overall, these results imply that common genetic variation explains some of the variability in neurocognitive functioning among young adults, particularly WM, and provide supportive evidence that increased SZ genetic risk predicts neurocognitive fluctuations in the general population.

The influence of an anti-stigma intervention on adolescents' attitudes to schizophrenia: a mixed methodology approach.

BACKGROUND: This study aimed at exploring adolescents' attitudes to schizophrenia and the impact of an educational intervention on improving them, by employing a mixed methodology. METHOD: A total of 1081 secondary-school students were randomly allocated to a control and intervention condition. Stigma endorsement was assessed by a free association card and a questionnaire, before and 2 weeks after the intervention. RESULTS: The intervention yielded substantial changes in students' beliefs, attitudes and social distance levels as well as in their associations with the term 'severe mental illness'. CONCLUSIONS: Educational interventions can contribute substantially to preventing consolidation of unfavourable attitudes towards mental illness.

Medical students' beliefs and attitudes towards schizophrenia before and after undergraduate psychiatric training in Greece.

AIMS: The aim of the present study was to explore medical students' beliefs and attitudes towards people with schizophrenia (PwS) prior to receiving any training in psychiatry and to assess the impact of the psychiatric placement on changing them. METHODS: A questionnaire addressing beliefs, attitudes and desired social distance from PwS was distributed to all final year medical students before the beginning of their 4-week undergraduate psychiatric placement and upon its completion. RESULTS: Students did not endorse stereotypes commonly attached to PwS, such as being dangerous, lazy or of lower intelligence, but they held the view that PwS are unpredictable and suffer from split personality. Furthermore, the baseline level of desired social distance was found to increase as the intimacy of the interaction increased, and the only variable associated with it was personal experience of serious mental illness. Moreover, the placement was found to have either no influence at all or in a negative direction. Upon its completion more students were found to believe that PwS cannot recover, have no insight into their condition, cannot make reasonable decisions, cannot work in regular jobs and are dangerous to the public. No difference was recorded in social distance scores. CONCLUSIONS: A close and critical examination of the various elements of the undergraduate placement in psychiatry is needed in order to develop an evidence-based, fully rounded education with an anti-stigma orientation.

The interference of introversion-extraversion and depressive symptomatology with reasoning performance: a behavioural study.

The objective of this study was to investigate the link between the Eysenck Personality Questionnaire (EPQ) scores and depressive symptomatology with reasoning performance induced by a task including valid and invalid Aristotelian syllogisms. The EPQ and the Zung Depressive Scale (ZDS) were completed by 48 healthy subjects (27 male, 21 female) aged 33.5 ± 9.0 years. Additionally, the subjects engaged into two reasoning tasks (valid vs. invalid syllogisms). Analysis showed that the judgment of invalid syllogisms is a more difficult task than of valid judgments (65.1% vs. 74.6% of correct judgments respectively, p < 0.01). In both conditions, the subjects' degree of confidence is significantly higher when they make a correct judgment than when they make an incorrect judgment (83.8 ± 11.2 vs. 75.3 ± 17.3, p < 0.01). Subjects with extraversion as measured by EPQ and high sexual desire as rated by the relative ZDS subscale are more prone to make incorrect judgments in the valid syllogisms, while, at the same time, they are more confident in their responses. The effects of extraversion/introversion and sexual desire on the outcome measures of the valid condition are not commutative but additive. These findings indicate that extraversion/introversion and sexual desire variations may have a detrimental effect in the reasoning performance.

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

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

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

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

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

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

Perceived social stigma, self-concept, and self-stigmatization of patient with schizophrenia.

The advent of community-based mental health care in Greece emphasized clinicians' need to understand patients' attitudes and their experience of their illness. A 42-item self-administered questionnaire (Self-Stigmatization Questionnaire) with flexible format was designed and administered to 150 outpatients with schizophrenia who fulfilled the criteria for inclusion in the vocational rehabilitation program where the study took place. The patients participated voluntarily. Multivariate regression models were applied to each item to assess the degree of patients' self-stigmatization experience as well as the effect of potential factors such as age, sex, psychopathologic condition, hospitalization, and duration of illness. The options selected by the patients revealed stigmatized attitudes in most items. The odds of selecting these options were mainly influenced by the severity of the patients' psychopathologic condition and the duration of illness and less by sex, age, and hospitalization.

Attitudes to depression and psychiatric medication amid the enduring financial crisis in Attica: Comparison between 2009 and 2014.

BACKGROUND: Only a handful of studies have explored the effect of the financial crisis on public attitudes to mental illness. AIMS: This study examines changes in lay attitudes to depression and psychiatric medication between 2009 and 2014 in Attica region. Furthermore, it explored a potential interaction with employment status. METHODS: Data were drawn from two surveys conducted in 2009 and 2014 using the same sampling procedure, interview mode, and survey instrument. Specifically, a random and representative sample of 586 people was recruited in 2009 and of 604 in 2014. Attitudes to depression were measured by the Personal Stigma subscale of the Depression Stigma Scale and attitudes to psychiatric medication by a self-constructed scale with good psychometric properties. Data collection occurred via telephone. RESULTS: There has been no overall change in lay attitudes to depression. Nonetheless, a positive change was recorded with regard to the belief that depression is a sign of personal weakness and a negative change with respect to people with depression being dangerous. Attitudes to psychiatric medication have worsened during the study period. Employment status was not found to interact with the survey year. CONCLUSION: Anti-stigma efforts should be tailored on counteracting the dangerousness stereotype, while they should prioritize targeting attitudes to psychiatric medication.

Association of RGS4 variants with schizotypy and cognitive endophenotypes at the population level.

BACKGROUND: While association studies on schizophrenia show conflicting results regarding the importance of the regulator of the G-protein signaling 4 (RGS4) gene, recent work suggests that RGS4 may impact on the structural and functional integrity of the prefrontal cortex. We aimed to study associations of common RGS4 variants with prefrontal dependent cognitive performance and schizotypy endophenotypes at the population level. METHODS: Four RGS4 single nucleotide polymorphisms (SNP1 [rs10917670], SNP4 [rs951436], SNP7 [rs951439], and SNP18 [rs2661319]) and their haplotypes were selected. Their associations with self-rated schizotypy (SPQ), vigilance, verbal, spatial working memory and antisaccade eye performance were tested with regressions in a representative population of 2,243 young male military conscripts. RESULTS: SNP4 was associated with negative schizotypy (higher SPQ negative factor for common T allele, p = 0.009; p = 0.031 for differences across genotypes) and a similar trend was seen also for common A allele of SNP18 (p = 0.039 for allele-load model; but p = 0.12 for genotype differences). Haplotype analyses showed a similar pattern with a dose-response for the most common haplotype (GGGG) on the negative schizotypy score with or without adjustment for age, IQ and their interaction (p = 0.011 and p = 0.024, respectively). There was no clear evidence for any association of the RGS4 variants with cognitive endophenotypes, except for an isolated effect of SNP18 on antisaccade error rate (p = 0.028 for allele-load model). CONCLUSION: Common RGS4 variants were associated with negative schizotypal personality traits amongst a large cohort of young healthy individuals. In accordance with recent findings, this may suggest that RGS4 variants impact on the functional integrity of the prefrontal cortex, thus increasing susceptibility for psychotic spectrum disorders.

Local shaping of function in the motor cortex: motor contrast, directional tuning.

In this review we bring together three different lines of evidence to bear on the issue of local shaping of function in the motor cortex. The first line of evidence comes from the description by Cajal (1904) of the recurrent collaterals of pyramidal cell axons in the precentral gyrus. The second line of evidence comes from the electrophysiological study of the functional effects of these collaterals [Stefanis, C., Jasper, H. 1964a. Intracellular microelectrode studies of antidromic responses in cortical pyramidal tract neurons. J. Neurophysiol. 27, 828-854.; Stefanis, C., Jasper, H. 1964b. Recurrent collateral inhibition in pyramidal tract neurons. J. Neurophysiol. 27, 855-877.] and associated interneurons [Stefanis, C. 1969. Interneuronal mechanisms in the cortex. In: The Interneuron, Brazier, M.A.B. (ed.), Berkeley, CA: University of California Press, pp. 497-526.] using intracellular recordings. And third came the discovery of directional tuning in the motor cortex [Georgopoulos, A.P., Kalaska, J.F., Caminiti, R., Massey, J.T. 1982. On the relations between the direction of two-dimensional arm movements and cell discharge in primate motor cortex. J. Neurosci. 2, 1527-1537.] in the behaving monkey. We hazard the hypothesis that the bell-shaped directional tuning curve is the outcome of orderly, local neuronal interactions in the motor cortex in which the recurrent pyramidal cell collaterals play a crucial role. Specifically, we propose that these collaterals and the intercalated interneurons they impinge upon serve to spatially sharpen the motor cortical activation to a locus corresponding to the direction of the intended movement. Thus, the originally proposed role of the pyramidal cell collaterals in enhancing "motor contrast" [Stefanis, C. 1969. Interneuronal mechanisms in the cortex. In: The Interneuron, Brazier, M.A.B. (ed.), Berkeley, CA: University of California Press, pp. 497-526.] would translate to creating a "directional tuning field" on the motor cortical surface, where the enhanced motor contrast would correspond to high activity at the center of directional field, and the suppression of the fringe would correspond to lower activity at the periphery of the field, resulting, together in spatial tuning.

Effect of schizotypy on cognitive performance and its tuning by COMT val158 met genotype variations in a large population of young men.

BACKGROUND: Mirroring schizophrenia, specific dimensions of schizotypy are related to cognitive dysfunction. The relation of schizotypy and state psychopathology to cognitive performance and its link to catechol-O-methyltransferase (COMT) val(158) met genotype variations was studied in a large sample of young men. METHODS: State psychopathology and schizotypy were assessed with self-rated questionnaires. Cognitive performance was assessed with tests of reasoning ability, sustained attention, and verbal and spatial working memory. Subjects were genotyped for the val(158) met polymorphism of the gene for COMT (low enzymatic activity met/met, intermediate met/val, and high val/val). RESULTS: The val/val group had higher scores in measures of state psychopathology as well as negative and disorganized schizotypy dimensions, whereas there was no effect of COMT genotype on cognitive performance measures. Structural equation modeling showed that cognitive performance accuracy but not speed decreased with increasing negative schizotypy, increased with increasing paranoid schizotypy, and was not affected by state psychopathology. Increasing val loading resulted in a dose-dependent increase in the factor loading for the relation between negative schizotypy and cognitive performance accuracy. CONCLUSIONS: Different schizotypal phenotypes had opposing relations to cognitive performance in the population. COMT genotype modulated the relation between the negative schizotypal phenotype and cognitive performance.

Impact of schizophrenia candidate genes on schizotypy and cognitive endophenotypes at the population level.

BACKGROUND: Aspects of cognitive function and schizotypy have been proposed as potential endophenotypes for schizophrenia. It is unknown whether the expression of these endophenotypes at the population level is modulated by the genetic variability of candidate susceptibility genes for schizophrenia. METHODS: We examined the potential impact of 18 single nucleotide polymorphisms (SNPs) within the DTNBP1, NRG1, DAOA/G32, and DAAO genes, on cognition and self-rated schizotypy, in a representative population of 2243 young male military conscripts. Single SNP and haplotype associations were evaluated. RESULTS: The DTNBP1 SNPs rs2619522 and rs760761 exhibited several single marker associations, the minor alleles being associated with lower attention capacity but also a decrease in positive and paranoid schizotypy scores. The DTNBP1 haplotype load had borderline associations with nonverbal IQ, paranoid schizotypy, and sustained attention. For individual NRG1 polymorphisms, isolated but weak signals of association were noted with sustained attention and working memory but not schizotypy. The risk allele of functional SNP8NRG243177 was associated with reduced spatial working memory capacity. An isolated effect of DAAO haplotype variability was noted on negative and disorganization schizotypy. No convincing association of DAOA/G32 variability was detected. CONCLUSIONS: The DTNBP1 and, less so, NRG1 and DAAO variants might exert gene-specific modulating effects on schizophrenia endophenotypes at the population level.

Mixed handedness is associated with the Disorganization dimension of schizotypy in a young male population.

Within the ASPIS (Athens Study of Psychosis Proneness and Incidence of Schizophrenia) we sought out to examine in accordance with previous reports if a deviation from dextrality is associated with an augmented endorsement of self rated schizotypal personality traits in a large population of 1129 young male army recruits. Schizotypal traits were assessed using the Schizotypal Personality Questionnaire and hand preference membership was determined by applying stringent criteria derived from the Annett Handedness Questionnaire and the Porac-Coren questionnaire of lateral preferences. By adopting three different definitions of hand preference membership, we confirmed an association between mixed handedness and increased schizotypal personality traits, and in particular with Disorganization schizotypy that encompasses aspects of self perceived difficulties in verbal communication. Non-verbal cognitive ability, as indexed by measurement of non-verbal IQ, sustained attention and working memory was not associated with hand preference. We argue that a deviation from normal cerebral lateralization, as indexed by mixed handedness, is associated with mild sub clinical language dysfunction, rather than non-verbal cognitive ability, and this might be relevant to the expression of psychosis phenotype.

Lack of genetic association between the phospholipase A2 gene and bipolar mood disorder in a European multicentre case-control study.

The possible association between phospholipase A2 gene and bipolar mood disorder was examined in 557 bipolar patients and 725 controls (all personally interviewed), recruited from seven countries (Belgium, Bulgaria, Croatia, Germany, Greece, Italy, and UK). The frequencies of the eight alleles that were identified did not differ between patients and control individuals in the whole population, while the power to detect an association based on our sample was relatively high. Some differences were noted among the various ethnic groups, but no significant trends existed, suggesting that population stratification by country may not be responsible for a type II error. On the basis of these results, mutations of the phospholipase A2 gene, at least in the region close to the polymorphism examined between exons 1 and 2, are not involved in the pathogenesis of bipolar mood disorder.

Effect of COMT Val158Met polymorphism on the Continuous Performance Test, Identical Pairs Version: tuning rather than improving performance.

OBJECTIVE: It has been suggested that variation in catechol O-methyltransferase (COMT) activity associated with variation in COMT Val158Met genotypes may result in enhanced or reduced cognitive performance, depending on whether the phenotype requires cognitive stability or cognitive flexibility. The authors' goal was to determine whether, in confirmation of this prediction, performance on a measure of cognitive stability would be associated with Met loading. METHOD: COMT genotyping was investigated in relation to a measure of reaction time variability on the Continuous Performance Test, Identical Pairs Version, in a large and representative sample of 527 young men (mean age=21 years). RESULTS: Met loading was associated with reduced reaction time variability. CONCLUSIONS: Met genotype loading may confer enhanced "tuning" or greater stability in performance, possibly by stabilizing active neural representations in the prefrontal cortex during tasks involving working memory.

Neuroticism, social network, stressful life events: association with mood disorders, depressive symptoms and suicidal ideation in a community sample of women.

According to the stress-diathesis hypothesis, depression and suicidal behavior may be precipitated by psychosocial stressors in vulnerable individuals. However, risk factors for mental health are often gender-specific. In the present study, we evaluated common risk factors for female depression in association with depressive symptoms and suicidal ideation in a community sample of women. The sample was composed by 415 women evaluated for mood disorders (MDs), depressive symptoms and suicidal ideation by structured interviews and the Beck depression inventory II (BDI II). All women also filled in the Eysenck personality questionnaire to evaluate neuroticism and were interviewed for social contact frequency and stressful life events (SLEs). In the whole sample, 19% of the women satisfied criteria for MD and suicidal ideation was reported by 12% of the women. Though stressful life events, especially personal and interpersonal problems, and poor social network were associated with all the outcome variables (mood disorder, depressive symptomatology and suicidal ideation), neuroticism survived to all multivariate analyses. Social network, together with neuroticism, also showed strong association with depressive severity, independently from current depressive state. Though we were unable to compare women and men, data obtained from the present study suggest that in women neurotic traits are strongly related to depression and suicidal ideation, and potentially mediate reporting of stressful life events and impaired social network. Independently from a current diagnosis of depression, impaired social network increases depressive symptoms in the women.

Variation in catechol-o-methyltransferase val158 met genotype associated with schizotypy but not cognition: a population study in 543 young men.

BACKGROUND: Increased catechol-O-methyltransferase activity associated with variation in catechol-O-methyltransferase valine158 methionine genotypes may result in reduced dopamine neurotransmission in the prefrontal cortex and thus contribute to the poor performance of frontally mediated cognitive tasks and the occurrence of associated negative symptoms observed in patients with schizophrenia; however, reported associations between catechol-O-methyltransferase valine158 methionine genotypes and measures of cognition have not been consistent. METHODS: Catechol-O-methyltransferase genotyping, measures of schizotypy, cognitive measures of memory and attention, as well as the antisaccade eye movement task, a measure sensitive to prefrontal cortical function, were obtained in a sample of 543 young men representative for that age group (mean age 21 years). RESULTS: None of the cognitive measures was associated with catechol-O-methyltransferase valine158 methionine genotypes; however, there was an effect of high-activity allele loading on schizotypy, in particular the negative and disorganization dimensions. CONCLUSIONS: Previously reported inconsistencies in the relationship between catechol-O-methyltransferase valine158 methionine genotypes and cognition were not resolved; however, catechol-O-methyltransferase genotype may affect expression of negative schizotypy by direct or indirect effects on central dopamine neurotransmitter signaling.