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.

Maternal sleep disturbances during late pregnancy and child neuropsychological and behavioral development in early childhood.

The present study aims to explore the association of maternal sleep disturbances during late pregnancy on child neuropsychological and behavioral development in preschool years. The study included 638 mother-child pairs from the prospective Rhea mother-child cohort in Crete, Greece. Information on antenatal sleep disturbances was collected through a computer-assisted interview. Children's neuropsychological and behavioral development was assessed using the McCarthy Scales of Children's Abilities (MSCA), the Attention-Deficit Hyperactivity Disorder Test (ADHDT), and the Strengths and Difficulties Questionnaire (SDQ). Multivariate analysis showed that maternal sleep duration less than 8 h was associated with reduced scores in the general cognitive scale (ß = -2.28, 95% CI -4.54, -0.02, R2 = 0.417) and memory span (ß = -3.24, 95% CI -5.72, -0.77, R2 = 0.304), while mild-severe daytime sleepiness was associated with reduced scores in the memory scale (ß = -5.42, 95% CI -10.47, -0.37, R2 = 0.304), memory span (ß = -5.44, 95% CI -10.68, -0.21, R2 = 0.304), nd functions of posterior cortex (ß = -5.55, 95% CI -10.40, -0.70, R2 = 0.393) of MSCA. Snoring in late pregnancy was related to higher child hyperactivity scores in SDQ (ß = 1.05, 95% CI 0.16, 1.95, R2 = 0.160). An interaction between child sex and maternal sleep duration in response to ADHD symptoms was also found (p for interaction < 0.05). Stratified analysis revealed increased hyperactivity, inattention, and ADHD total scores for girls of mothers with sleep duration less than 8 h. Maternal sleep disturbances during pregnancy may be associated with impaired child neuropsychological and behavioral development during the preschool years. Early detection and intervention is necessary to reduce sleep disturbances habits in pregnancy and improve child neurodevelopment.

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.

Association between high levels of inflammatory markers and cognitive outcomes at 4 years of age: The Rhea mother-child cohort study, Crete, Greece.

There is growing evidence associating inflammatory markers in complex, higher order neurological functions, such as cognition and memory. We examined whether high levels of various inflammatory markers are associated with cognitive outcomes at 4 years of age in a mother-child cohort in Crete, Greece (Rhea study). We included 642 children in this cross-sectional study. Levels of several inflammatory markers (IFN-γ, IL-1ß, IL-6, IL-8, IL-17α, IL-10, MIP-1α, TNF-α and the ratios of IL-6 to IL-10 and TNF-α to IL-10) were determined in child serum via immunoassay. Neurodevelopment at 4 years was assessed by means of the McCarthy Scales of Children's Abilities. Multivariate linear regression analyses were used to estimate the associations between the exposures and outcomes of interest after adjustment for various confounders. Our results indicate that children with high TNF-α concentrations (≥90th percentile) in serum demonstrated decreased scores in memory (adjusted ß = -4.0; 95% CI: -7.7, -0.2), working memory (adjusted ß = -4.0; 95% CI: -8.0, -0.1) as well as in memory span scale (adjusted ß = -4.0; 95% CI: -7.9, -0.1). We also found that children with high IFN-γ serum levels showed lower scores in memory span scale (adjusted ß = -3.4; 95% CI: -7.3, -0.4). Children with elevated TNF-α/IL-10 ratio demonstrated decreased quantitative (adjusted ß = -4.3; 95% CI: -8.2, -0.4), motor (adjusted ß = -3.5; 95% CI: -7.5, -0.5), executive function (adjusted ß = -4.8; 95% CI: -8.5, -1.1), general cognitive (adjusted ß = -3.6; 95% CI: -7.3, -0.1), memory (adjusted ß = -3.8; 95% CI: -7.6, -0), working memory (adjusted ß = -3.5; 95% CI: -7.5, -0.5) and memory span scores (adjusted ß = -5.3; 95% CI: -9.1, -1.4) The findings suggest that high levels of TNF-α may contribute to reduced memory performance at preschool age.

Associations of differential schizotypal dimensions with executive working memory: A moderated-mediation analysis.

BACKGROUND: Increased schizotypal traits are observed in a percentage of the general population and in the schizophrenia-spectrum and have been associated with impairments in working memory. In this study we examined the effects of four schizotypal dimensions [Negative (NegS), Paranoid (ParS), Cognitive-Perceptual (CPS), Disorganized (DiS)] on executive working memory (EWM), as mediated by set-shifting, planning and control inhibition. We also examined whether these associations are moderated by family-history of psychosis. METHODS: Our sample consisted of 110 unaffected first-degree relatives of schizophrenia-spectrum patients and 120 control individuals. Schizotypy was assessed with the Schizotypal Personality Questionnaire. Participants were also tested with the Letter-Number Sequencing, Wisconsin Card Sorting, Stroop Color-Word and Stockings of Cambridge tasks. The effects of set-shifting, control inhibition and planning on the relationship between schizotypy and EWM were examined with mediation analyses. Moderated-mediation analyses examined potential moderating effects of group membership (unaffected relative/community participant). RESULTS: All mediators were significant in the relationship between NegS and EWM. The effects of ParS were mediated only by set-shifting and planning. Planning and control inhibition were the only significant mediators on the effects of CPS and DiS on EWM, respectively. The moderated-mediation analyses revealed that these findings apply only in the community group. CONCLUSIONS: We found that the effects of different schizotypal dimensions on EWM are mediated by other cognitive processes in individuals without personal/family history of psychosis. This is probably due to either more severe impairments in the cognitive processes of the relatives or restrictions in our sample and study-design.

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.

Independent evidence for an association between general cognitive ability and a genetic locus for educational attainment.

Cognitive deficits and reduced educational achievement are common in psychiatric illness; understanding the genetic basis of cognitive and educational deficits may be informative about the etiology of psychiatric disorders. A recent, large genome-wide association study (GWAS) reported a genome-wide significant locus for years of education, which subsequently demonstrated association to general cognitive ability ("g") in overlapping cohorts. The current study was designed to test whether GWAS hits for educational attainment are involved in general cognitive ability in an independent, large-scale collection of cohorts. Using cohorts in the Cognitive Genomics Consortium (COGENT; up to 20,495 healthy individuals), we examined the relationship between g and variants associated with educational attainment. We next conducted meta-analyses with 24,189 individuals with neurocognitive data from the educational attainment studies, and then with 53,188 largely independent individuals from a recent GWAS of cognition. A SNP (rs1906252) located at chromosome 6q16.1, previously associated with years of schooling, was significantly associated with g (P = 1.47 × 10(-4) ) in COGENT. The first joint analysis of 43,381 non-overlapping individuals for this a priori-designated locus was strongly significant (P = 4.94 × 10(-7) ), and the second joint analysis of 68,159 non-overlapping individuals was even more robust (P = 1.65 × 10(-9) ). These results provide independent replication, in a large-scale dataset, of a genetic locus associated with cognitive function and education. As sample sizes grow, cognitive GWAS will identify increasing numbers of associated loci, as has been accomplished in other polygenic quantitative traits, which may be relevant to psychiatric illness.

Antenatal maternal mental health as determinant of postpartum depression in a population based mother-child cohort (Rhea Study) in Crete, Greece.

PURPOSE: Antenatal maternal mental health has been identified as an important determinant of postpartum depression (PPD). We investigated the occurrence of depression both antenatally and postnatally and examined whether maternal trait anxiety and depression during pregnancy were associated with PPD at 8 weeks postpartum in a prospective mother-child cohort (Rhea Study) in Crete, Greece. METHODS: 438 women completed the Edinburgh Postnatal Depression Scale (EPDS) and the Trait subscale of the State-Trait Anxiety Inventory (STAI-Trait) questionnaires assessing antenatal depression and anxiety, respectively, during the third trimester of pregnancy as well as the EPDS at 8 weeks postpartum. RESULTS: The prevalence of women with probable depression (EPDS score ≥13) was 16.7 % at 28-32 weeks of pregnancy and 13.0 % at 8 weeks postpartum. A per 5 unit increase in the STAI-Trait subscale increased the odds for PPD by 70 % (OR = 1.70, 95 % CI 1.41, 2.05), whereas a per unit increase in EPDS during pregnancy increased the odds for PPD by 27 % (OR = 1.27, 95 % CI 1.19, 1.36). CONCLUSIONS: Our findings suggest that antenatal maternal psychological well-being has a significant effect on PPD, which might have important implications for early detection during pregnancy of women at risk for postpartum depression.

Risk factors for new onset and persistence of multi-site musculoskeletal pain in a longitudinal study of workers in Crete.

OBJECTIVES: To explore occupational and psychological risk factors for the incidence and persistence of multi-site musculoskeletal pain. METHODS: We conducted a longitudinal investigation of three occupational groups in Crete, Greece. Baseline information was obtained at interview about pain in the past year at each of six anatomical sites, and about possible risk factors for subsequent symptoms. Twelve months later, subjects were re-interviewed about pain at the same anatomical sites in the past month. Pain at two or more sites was classed as multi-site. Associations with new development and persistence of multi-site pain at follow-up were assessed by logistic regression. RESULTS: Analysis was based on 518 subjects (87% of those originally selected for study). At follow-up, multi-site pain persisted in 217 (62%) of those who had experienced it in the year before baseline, and was newly developed in 27 (17%) of those who had not. Persistence of multi-site pain was significantly related to physical loading at work, somatising tendency and beliefs about work as a cause of musculoskeletal pain, with OR (95% CI) for the highest relative to the lowest exposure categories of 2.3 (1.0 to 5.6), 2.6 (1.5 to 4.6) and 1.9 (1.1 to 3.3) respectively. Development of new multi-site pain was most strongly associated with working for ≥40 h per week (OR 5.0, 95% CI 1.1 to 24.0). CONCLUSIONS: Our findings confirm the importance of both physical loading at work and somatising tendency as risk factors for multi-site pain, and suggest that persistence of pain is also influenced by adverse beliefs about work causation.

Antenatal and postnatal maternal mental health as determinants of infant neurodevelopment at 18 months of age in a mother-child cohort (Rhea Study) in Crete, Greece.

PURPOSE: A growing body of evidence links poor maternal mental health with negative outcomes on early child development. We examined the effect of antenatal and postnatal maternal mental health on infant neurodevelopment at age 18 months in a population-based mother-child cohort (Rhea Study) in Crete, Greece. METHODS: Self-reported measures of maternal depression (EPDS), trait anxiety (STAI-Trait) and personality traits (EPQ-R) were assessed in a sample of women during pregnancy and at 8 weeks postpartum (n = 223). An additional sample of 247 mothers also completed the EPDS scale at 8 weeks postpartum (n = 470). Neurodevelopment at 18 months was assessed with the use of Bayley Scales of Infant and Toddler Development (3rd edition). RESULTS: Multivariable linear regression models adjusted for confounders revealed that antenatal depressive symptoms (EPDS ≥ 13) were associated with decrease in cognitive development independently of postnatal depression. High trait anxiety and extraversion were associated with decrease and increase, respectively, in social-emotional development. Also, high trait anxiety and neuroticism had a positive effect on infants' expressive communication. Finally, postpartum depressive symptoms (EPDS ≥ 13) were associated with decrease in cognitive and fine motor development independently of antenatal depression. CONCLUSIONS: These findings suggest that antenatal and postnatal maternal psychological well-being has important consequences on early child neurodevelopment.

Assessing the burden of caregivers of patients with mental disorders: translating and validating the involvement evaluation questionnaire into Greek.

BACKGROUND: The changes in the organization of mental health care services have made the role of the family even more important in caring for patients with mental disorders. Caring may have serious consequences for family caregivers, with a great impact on the quality of family life. This study reports on the translation, cultural adaptation, and validation of the Involvement Evaluation Questionnaire-European Union (IEQ-EU) into the Greek language. METHODS: Caregivers of patients with major mental disorders were interviewed to test a modified version of the IEQ-EU questionnaire. Psychometric measurements included reliability coefficients, exploratory factor analysis and confirmatory analysis by linear structural relations. To measure the concurrent validity we used the Nottingham Health Profile (NHP). RESULTS: Most caregivers were female (83%), mainly mothers living with the patient (80%), with quite a high level of burden. The Greek version of the IEQ-EU (G-IEQ-EU) demonstrated a good reliability with high internal consistency (α = 0.88), Guttman split-half correlation of 0.71, high test-retest reliability (ICC = 0.82) and good concurrent validity with the NHP. A four-factor structure was confirmed for the G-IEQ-EU, slightly different from the original IEQ. The confirmatory factor analysis demonstrated that the four-factor model offered modest fit to our data. CONCLUSIONS: The G-IEQ-EU is a reasonably valid and reliable tool for use in both clinical and research contexts in order to assess the burden of caregivers of patients with mental disorders.

The CACNA1C and ANK3 risk alleles impact on affective personality traits and startle reactivity but not on cognition or gating in healthy males.

OBJECTIVES: The rs10994336 ANK3 and rs1006737 CACNA1C genetic variants have recently been identified as the most consistent, genome-wide significant risk factors for bipolar disorder, while the CACNA1C variant has also been associated with schizophrenia and major depression. The aim of this study was to examine the phenotypic consequences of the risk CACNA1C and ANK3 alleles in a large homogeneous cohort of healthy young males. METHODS: We recruited 703 randomly selected, healthy army conscripts (mean age 22.1 ± 3.0 years) from the first wave of the Learning on Genetics of Schizophrenia project in Heraklion, Crete. Of those recruited, 530 subjects entered and completed the study. Subjects were assessed for prepulse inhibition (PPI), startle reactivity, neuropsychology, and personality. RESULTS: UNPHASED analysis revealed that the rs1006737 A-allele was associated with lower extraversion and higher harm avoidance, trait anxiety, and paranoid ideation, while the rs10994336 T-allele was associated with lower novelty seeking and behavioral activation scores (p < 0.01). Both alleles were associated with high startle reactivity (p < 0.05). There were no significant associations with any cognitive task performance or PPI. CONCLUSIONS: The CACNA1C genotype was associated with proneness to anxiety and negative mood, while the ANK3 genotype was associated with proneness to anhedonia. Both risk genotypes were associated with high startle reactivity, suggesting a role of these polymorphisms in threat/stress signal processing, probably in the hippocampus and/or amygdala. None of the risk genotypes affected sensorimotor gating or behavioral performance in an extensive battery of executive function tests in this cohort of healthy males.

Evidence of dysregulated affect indicated by high alexithymia in obstructive sleep apnea.

Alexithymia refers to dysregulation of affect characterized by difficulty in identifying and expressing emotions. Obstructive sleep apnea (OSA) is characterized by increased medical/psychiatric comorbidity and possibly by affect dysregulation. In the present case-control study, we examined alexithymia levels with the Toronto Alexithymia Scale (TAS-20) in 23 psychiatrically uncomplicated OSA outpatients and 23 same gender controls one-to-one matched for age, education and subjective depressive symptomatology. General health/quality of life was assessed with the Short-Form 36 Health Survey (SF-36) in the patient group. Hierarchical multivariate regression models were used to evaluate the association of alexithymia with the presence of OSA, and clinical and polysomnographic parameters of this condition. TAS-20 total and subscale scores were associated positively with Beck Depression Inventory (BDI)-21 and negatively with SF-36 scores. After adjusting for all confounders, OSA was positively associated with total TAS-20 score, 'expressing feelings' and 'externally oriented thinking' subscales. The latter was associated with increased sleepiness and reduced blood oxygenation in the OSA group. Finally, 'difficulty describing feelings' and 'externally oriented thinking' significantly predicted risk for OSA. Alexithymia is higher in non-psychiatrically ill patients with OSA compared with carefully matched controls even after adjustment for subjective depressive symptoms and demographic confounders. Total alexithymia is associated with greater subjective depression and poor general health/quality of life, while 'externally oriented thinking' is associated with disease severity and together with 'difficulty describing feelings' may be vulnerability factors for OSA, although reverse causality cannot be excluded.

Dietary patterns during pregnancy and the risk of postpartum depression: the mother-child 'Rhea' cohort in Crete, Greece.

OBJECTIVE: To identify and describe dietary patterns in a cohort of pregnant women, and investigate whether dietary patterns during pregnancy are related to postpartum depression (PPD). DESIGN: The study uses data from the prospective mother-child cohort 'Rhea' study. Pregnant women completed an FFQ in mid-pregnancy and the Edinburg Postpartum Depression Scale (EPDS) at 8-10 weeks postpartum. Dietary patterns during pregnancy ('health conscious', 'Western') were identified using principal component analysis. Associations between dietary patterns categorized in tertiles and PPD symptoms were investigated by multivariable regression models after adjusting for confounders. SETTING: Heraklion, Crete, Greece, 2007-2010. SUBJECTS: A total of 529 women, participating in the 'Rhea' cohort. RESULTS: High adherence to a 'health conscious' diet, characterized by vegetables, fruit, pulses, nuts, dairy products, fish and olive oil, was associated with lower EPDS scores (highest v. lowest tertile: ß-coefficient = -1·75, P = 0·02). Women in the second (relative risk (RR) = 0·52, 95 % CI 0·30, 0·92) or third tertile (RR = 0·51, 95 % CI 0·25, 1·05) of the 'health conscious' dietary pattern were about 50 % less likely to have high levels of PPD symptoms (EPDS ≥ 13) compared with those in the lowest tertile. CONCLUSIONS: This is the first prospective study showing that a healthy diet during pregnancy is associated with reduced risk for PPD. Additional longitudinal studies and trials are needed to confirm these findings.

The Edinburgh Postnatal Depression Scale: translation and validation for a Greek sample.

BACKGROUND: Edinburgh Postnatal Depression Scale (EPDS) is an important screening instrument that is used routinely with mothers during the postpartum period for early identification of postnatal depression. The purpose of this study was to validate the Greek version of EPDS along with sensitivity, specificity and predictive values. METHODS: 120 mothers within 12 weeks postpartum were recruited from the perinatal care registers of the Maternity Departments of 4 Hospitals of Heraklion municipality, Greece. EPDS and Beck Depression Inventory-II (BDI-II) surveys were administered in random order to the mothers. Each mother was diagnosed with depression according to the validated Greek version of BDI-II. The psychometric measurements that were performed included: two independent samples t-tests, One-way analysis of variance (ANOVA), reliability coefficients, Explanatory factor analysis using a Varimax rotation and Principal Components Method. Confirmatory analysis -known as structural equation modelling- of principal components was conducted by LISREL (Linear Structural Relations). A receiver operating characteristic (ROC) analysis was carried out to evaluate the global functioning of the scale. RESULTS: 8 (6.7%) of the mothers were diagnosed with major postnatal depression, 14 (11.7%) with moderate and 38 (31.7%) with mild depression on the basis of BDI-II scores. The internal consistency of the EPDS Greek version -using Chronbach's alpha coefficient- was found 0.804 and that of Guttman split-half coefficient 0.742. Our findings confirm the multidimensionality of EPDS, demonstrating a two-factor structure which contained subscales reflecting depressive symptoms and anxiety. The Confirmatory Factor analysis demonstrated that the two factor model offered a very good fit to our data. The area under ROC curve AUC was found 0.7470 and the logistic estimate for the threshold score of 8/9 fitted the model sensitivity at 76.7% and model specificity at 68.3%. CONCLUSION: Our data confirm the validity of the Greek version of the EPDS in identifying postnatal depression. The Greek EPDS scale could be used as a useful instrument in both clinical practice and research.

Planning, decision-making and the COMT rs4818 polymorphism in healthy males.

Recent evidence suggests that a synonymous polymorphism within the COMT gene (rs4818 C/G) accounts for a greater variation of COMT activity compared to the functional Val158Met polymorphism. This is the first study on the effects of the rs4818 C/G polymorphism on cognition. One hundred and seven healthy males were tested with the Stockings of Cambridge (SoC) and the Iowa Gambling Task (IGT) and then grouped according to their COMT rs4818 C/G status into three groups (G/G, C/G, C/C). ANOVAs showed that C/C individuals had the best performance in the SoC, G/G the worse, while C/G were intermediate. G/G individuals had strikingly better performance in the IGT compared to the other two groups and their performances in the two tasks were inversely related. These results show that the rs4818 C/G polymorphism imparts strong and differential effects on PFC functions. Low prefrontal dopamine levels are disadvantageous for planning in non-emotional problem solving but lead to optimal effects in emotionally informed decision-making. While high prefrontal dopamine levels may be advantageous for non-emotional problem solving, they lead to disadvantageous choices when decision-making depends on processing of emotional feedback.

The 5-min pupillary alertness test is sensitive to modafinil: a placebo controlled study in patients with sleep apnea.

RATIONALE: The extent of pupillary miosis during 5 min in darkness is a simple, recently introduced alertness test which may become useful in the clinical assessment of normal and pathological sleepiness. OBJECTIVES: In this study, we further validated this test by testing its sensitivity to the effects of modafinil, a non-stimulant, alertness-promoting drug. METHODS: Twelve unmedicated patients recently diagnosed with obstructive sleep apnea (OSA) after polysomnography, received placebo or modafinil (200 mg), according to a double-blind, cross-over design. The patients' resting pupil diameter (RPD) was sampled over 5 min in darkness before (10:00 A.M.) and after treatment (2:00 P.M.), and their light reflexes were elicited and recorded in darkness with an infrared video pupillometer. RESULTS: We found a circadian miosis at 2:00 P.M. in the placebo treatment condition, which was reversed by modafinil. This effect correlated with modafinil-induced increase in subjective alertness, and it was greater in the most severely affected patients in terms of lowest oxygen saturation, independently of body mass index, age, or apneic episodes during sleep. Modafinil reduced the light reflex amplitude, suggesting an increase in the inhibitory input at the pupilloconstrictor Edinger-Westphal nucleus. CONCLUSIONS: These effects of modafinil are best explained via an activation of the hypoxia-sensitive nucleus locus coeruleus. The 5-min pupillary alertness test has promising predictive validity, and it holds promise as a fast and sensitive method for the objective assessment of excessive daytime sleepiness, monitoring of disease progression, and response to treatment.

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.

Genome-wide association meta-analysis in 269,867 individuals identifies new genetic and functional links to intelligence.

Intelligence is highly heritable1 and a major determinant of human health and well-being2. Recent genome-wide meta-analyses have identified 24 genomic loci linked to variation in intelligence3-7, but much about its genetic underpinnings remains to be discovered. Here, we present a large-scale genetic association study of intelligence (n = 269,867), identifying 205 associated genomic loci (190 new) and 1,016 genes (939 new) via positional mapping, expression quantitative trait locus (eQTL) mapping, chromatin interaction mapping, and gene-based association analysis. We find enrichment of genetic effects in conserved and coding regions and associations with 146 nonsynonymous exonic variants. Associated genes are strongly expressed in the brain, specifically in striatal medium spiny neurons and hippocampal pyramidal neurons. Gene set analyses implicate pathways related to nervous system development and synaptic structure. We confirm previous strong genetic correlations with multiple health-related outcomes, and Mendelian randomization analysis results suggest protective effects of intelligence for Alzheimer's disease and ADHD and bidirectional causation with pleiotropic effects for schizophrenia. These results are a major step forward in understanding the neurobiology of cognitive function as well as genetically related neurological and psychiatric disorders.