Ioannis Evdokimidis

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.

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.

Higher scores of self reported schizotypy in healthy young males carrying the COMT high activity allele.

The gene for COMT is located on chromosome 22q11, an area that has been implicated in the pathogenesis of schizophrenia through linkage studies and through the detection of deletions in schizophrenics and velocardiofacial syndrome patients that often present psychotic symptomatology. Additionally catechol-O-methyl transferase activity has been found increased in schizophrenia and a functional polymorphism in the COMT gene itself has been associated with the disease, as well as with aggression in patients. We tested the hypothesis that COMT genotype for the functional Val158Met might contribute to the variance of self reported schizotypy and aggression scores in the normal population. We genotyped 379 healthy 18- to 24-year-old male individuals who had completed the PAS, SPQ and AQ questionnaires. Our results showed that self-reported schizotypy scores in both questionnaires were significantly related to COMT genotype (P = 0.028 for the PAS and P = 0.015 for the SPQ) with individuals homozygous for the high activity allele showing the highest scores. No significant differences were detected for AQ scores. We conclude that the COMT genotype for the functional Val158Met polymorphism is correlated to self-reported schizotypy in healthy males. This finding is in the same direction as reported findings on schizophrenia and it adds to the list of evidence that COMT or a nearby gene in linkage disequilibrium is involved in the pathogenesis of the disease.

The antisaccade task in a sample of 2,006 young males: II. Effects of task parameters

Abstract. Antisaccade performance was investigated in a sample of 2,006 young males as part of a large epidemiological study investigating psychosis proneness. This report summarizes the effects of task parameters on performance using a sample of 55,678 antisaccade trials collected from a subpopulation of 947 individuals. Neither the amplitude nor the latency of an error prosaccade in the antisaccade task was correlated with the latency of the ensuing corrective antisaccade that almost always followed an error. However, the latency of the corrective antisaccade decreased with increasing stimulus distance. Concerning the effects of specific task parameters, trials with stimuli closer to the central fixation point and trials preceded by shorter fixation intervals resulted in more errors and longer latencies for the antisaccades. Finally, there were learning and fatigue effects reflected mainly in the error rate, which was greater at the beginning and at the end of the 5-min task. We used a model to predict whether an error or a correct antisaccade would follow a particular trial. All task parameters were significant predictors of the trial outcome but their power was negligible. However, when modeled alone, response latency of the first movement predicted 40% of errors. In particular, the smaller this latency was, the higher the probability of an error. These findings are discussed in light of current hypotheses on antisaccade production mechanisms involving mainly the superior colliculus.

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.

COMT Val158Met moderation of stress-induced psychosis

BACKGROUND Exposure to stressful life events increases the risk of developing a psychotic disorder. Moreover, increased reactivity to stress seems to represent part of the vulnerability for psychosis. This study aimed to investigate whether a functional polymorphism in the catechol-O-methyltransferase (COMT Val(158)Met) gene moderates the psychosis-inducing effects of stress. METHOD A semi-experimental stress exposure paradigm was used in a sample of 306 genotyped young men (aged 19-24 years), in whom measures of psychotic symptoms were obtained at recruitment in the Greek army (exposed condition) and again after 18 months of military training (unexposed condition). RESULTS Stress exposure at army induction was associated with an increased level of psychotic symptoms. In addition, carriers of the COMT Val(158)Met Val allele were more susceptible to the effect of stress on the psychosis outcome than those with the Met/Met genotype (test for interaction: chi2 = 5.02, df = 1, p = 0.025). CONCLUSION The COMT Val(158)Met genotype may moderate the effect of stress on psychotic symptoms.

Cortical potentials with antisaccades

The term antisaccade refers to saccades that are performed towards the side opposite to that of target appearance. The performance of antisaccades is considered to be determined by intact frontal inhibitory areas as patients with frontal, and especially prefrontal, lesions show a striking impairment in suppressing an unwanted protarget saccade. We recorded cortical slow potentials from subjects performing saccades and antisaccades in a task, antitask and no move conditions in order to investigate possible topographic differences between these two types of eye movement. Our main findings concern both movement related as well as sensory related potentials. With regard to the saccadic potentials, performance of an antisaccade is preceded by a much more pronounced activity during the last 100 ms prior to the eye movement onset over central-anterior leads with a slight ipsilateral lateralization. As for the sensory potentials, the target related with antisaccade performance is followed by smaller, but nonstatistically significant, exogenous responses while at 300-350 ms after target appearance, the activity associated with the antisaccades target is clearly larger over central midline leads. Although we could not precisely relate the electrical activity obtained with well circumscribed cortical function, the results support the view that the anterior and slightly ipsilateral cortical activation which precedes the performance of an antisaccade could reflect the frontal mechanisms of suppression of the unwanted saccade.

Antisaccade performance of 1,273 men: Effects of schizotypy, anxiety, and depression

A total of 1,273 conscripts of the Greek Air Force performed antisaccades and completed self-reporting questionnaires measuring schizotypy and current state-dependent psychopathology. Only 1.0% of variability in antisaccade performance indices was related to psychometric scores in the population and could be attributed more to current state-dependent symptoms such as anxiety rather than to schizotypy. In contrast, a specific increase of error rate and response latency variability and a high correlation of these 2 variables was observed in a group with very high schizotypy scores. This effect was independent of anxiety and depression, suggesting that a specific group of psychosis-prone individuals has a characteristic deviance in antisaccade performance that is not present in the general population.

Short-term and working memory impairments in aphasia.

The aim of the present study is to investigate short-term memory and working memory deficits in aphasics in relation to the severity of their language impairment. Fifty-eight aphasic patients participated in this study. Based on language assessment, an aphasia score was calculated for each patient. Memory was assessed in two modalities, verbal and spatial. Mean scores for all memory tasks were lower than normal. Aphasia score was significantly correlated with performance on all memory tasks. Correlation coefficients for short-term memory and working memory were approximately of the same magnitude. According to our findings, severity of aphasia is related with both verbal and spatial memory deficits. Moreover, while aphasia score correlated with lower scores in both short-term memory and working memory tasks, the lack of substantial difference between corresponding correlation coefficients suggests a possible primary deficit in information retention rather than impairment in working memory.

A neural model of decision-making by the superior colicullus in an antisaccade task

In the antisaccade paradigm subjects are instructed to perform eye movements in the opposite direction from the location of a visually appearing stimulus while they are fixating on a central stimulus. A recent study investigated saccade reaction times (SRTs) and percentages of erroneous prosaccades (towards the peripheral stimulus) of 2006 young men performing visually guided antisaccades. A unimodal distribution of SRTs (ranging from 80 to 600 ms) as well as an overall 25% of erroneous prosaccade responses was reported in that large sample. In this article, we present a neural model of saccade initiation based on competitive integration of planned and reactive saccade decision signals in the intermediate layer of the superior colliculus. In the model the decision processes grow nonlinearly towards a preset criterion level and when they cross it, a movement is initiated. The resultant model reproduced the unimodal distributions of SRTs for correct antisaccades and erroneous prosaccades as well as the variability of SRTs and the percentage of erroneous prosaccade responses.