Behavioral and Brain Functions - Latest articles

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

2008-10-03

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.

Persistent spatial working memory deficits in rats with bilateral cortical microgyria

R. Holly Fitch, Heather Breslawski, Glenn D. Rosen and James J. Chrobak — 2008-10-01

Background: Anomalies of cortical neuronal migration (e.g., microgyria (MG) and/or ectopias) are associated with a variety of language and cognitive deficits in human populations. In rodents, postnatal focal freezing lesions lead to the formation of cortical microgyria similar to those seen in human dyslexic brains, and also cause subsequent deficits in rapid auditory processing similar to those reported in human language impaired populations. Thus convergent findings support the ongoing study of disruptions in neuronal migration in rats as a putative model to provide insight on human language disability. Since deficits in working memory using both verbal and non-verbal tasks also characterize dyslexic populations, the present study examined the effects of neonatally induced bilateral cortical microgyria (MG) on working memory in adult male rats. Methods: A delayed match-to-sample radial-arm water maze task, in which the goal arm was altered among eight locations on a daily basis, was used to assess working memory performance in MG (n=8) and sham (n=10) littermates. Results: Over a period of 60 sessions of testing (each session comprising one pre-delay sample trial, and one post-delay test trial), all rats showed learning as evidenced by a significant decrease in overall test errors. However, MG rats made significantly more errors than shams during initial testing, and this memory deficit was still evident after 60 days (12 weeks) of testing. Analyses performed on daily error patterns showed that over the course of testing, MG rats utilized a strategy similar to shams, but with less effectiveness, as indicated by more errors. Conclusions: These results indicate persistent abnormalities in the spatial working memory system in rats with induced disruptions of neocortical neuronal migration.

Evidence of Inflammatory Immune Signaling in Chronic Fatigue Syndrome: A Pilot Study of Gene Expression in Peripheral Blood

Anne L Aspler, Carly Bolshin, Suzanne D Vernon and Gordon Broderick — 2008-09-26

Background: Genomic profiling of peripheral blood reveals altered immunity in chronic fatigue syndrome (CFS) however interpretation remains challenging without immune demographic context. The object of this work is to identify modulation of specific immune functional components and restructuring of co-expression networks characteristic of CFS using the quantitative genomics of peripheral blood. Methods: Gene sets were constructed a priori for CD4+ T cells, CD8+ T cells, CD19+ B cells, CD14+ monocytes and CD16+ neutrophils from published data. A group of 111 women were classified using empiric case definition (U.S. Centers for Disease Control and Prevention) and unsupervised latent cluster analysis (LCA). Microarray profiles of peripheral blood were analyzed for expression of leukocyte-specific gene sets and characteristic changes in co-expression identified from topological evaluation of linear correlation networks. Results: Median expression for a set of 6 genes preferentially up-regulated in CD19+ B cells was significantly lower in CFS (p=0.01) due mainly to PTPRK and TSPAN3 expression. Although no other gene set was differentially expressed at p<0.05, patterns of co-expression in each group differed markedly. Significant co-expression of CD14+ monocyte with CD16+ neutrophil (p=0.01) and CD19+ B cell sets (p=0.00) characterized CFS and fatigue phenotype groups. Also in CFS was a significant negative correlation between CD8+ and both CD19+ up-regulated (p=0.02) and NK gene sets (p=0.08). These patterns were absent in controls. Conclusions: Dissection of blood microarray profiles points to B cell dysfunction with coordinated immune activation supporting persistent inflammation and antibody-mediated NK cell modulation of T cell activity. This has clinical implications as the CD19+ genes identified could provide robust and biologically meaningful basis for the early detection and unambiguous phenotyping of CFS.

Cortical and subcortical anatomy of chronic spatial neglect following vascular damage

Laetitia Golay, Armin Schnider and Radek Ptak — 2008-09-22

Background: The role of the inferior parietal lobule (IPL) and superior temporal gyrus (STG) or subcortical pathways as possible anatomical correlates of spatial neglect is currently intensely discussed. Some of the conflicting results might have arisen because patients were examined in the acute stage of disease. Methods: We examined the anatomical basis of spatial neglect in a sample of patients examined in the post-acute stage following right-hemispheric vascular brain damage. Lesions of 28 patients with chronic spatial neglect were contrasted to lesions of 22 control patients without neglect using lesion subtraction techniques and voxel-wise comparisons. Results: The comparisons identified the temporo-parietal junction (TPJ) with underlying white matter, the supramarginal gyrus, the posterior STG, and the insula as brain regions damaged significantly more often in neglect compared to non-neglect patients. In a subgroup of neglect patients showing particularly large cancellation bias together with small errors on line bisection damage was prevalent deep in the frontal lobe while damage of patients with the reverse pattern was located in the white matter of the TPJ. Conclusion: Considering our results and the findings of previous studies, spatial neglect appears to be associated with a network of regions involving the TPJ, inferior IPL, posterior STG, the insular cortex, and posterior-frontal projections. Frontal structures or projections may be of particular relevance for spatial exploration, while the IPL may be important for object-based attention as required for line bisection.

Recessive genetic mode of an ADH4 variant in substance dependence in African-Americans: A model of utility of the HWD test

2008-09-18

Background: In our previous studies, we reported positive associations between seven ADH4 polymorphisms and substance dependence [i.e., alcohol dependence (AD) and/or drug dependence (DD)] in European-Americans (EAs). In the present study, we address the relationship between ADH4 variation and substance dependence in an African-American (AA) population, and report evidence that supports an association between a different ADH4 polymorphism (rs2226896) and these phenotypes in AAs. Methods: Two family-based association study methods, i.e., TDT and FBAT, were applied to test the relationship between ADH4 variation and substance dependence in Sample 3 (112 small nuclear families) and in Sample 4 (632 pedigrees), respectively. A population-based case-control association study method was also applied to test this relationship in 1303 unrelated subjects, with and without controlling for admixture effects. Finally, a Hardy-Weinberg Disequilibrium (HWD) test was applied to examine the association in the case-only sample, infer the genetic disease models, and distinguish the disease and non-disease factors contributing to HWD. Results: The marker examined was found to be in significant HWD in AA alcoholics (p = 0.0071) and drug dependent subjects (p = 0.0341), but in Hardy-Weinberg Equilibrium (HWE) in all other subgroups. Other association methods failed to detect any association between this variation and phenotypes. The best-fit genetic disease model for this marker is a recessive genetic model. Conclusion: ADH4 variation might play a role in risk for substance dependence in AAs, potentially via a recessive mechanism. Under certain conditions, the HWD test could be a more powerful association method than conventional family-based and population-based case-control association analyses, for which, the present study provides an extreme example.

On the neural networks of empathy: A principal component analysis of an fMRI study

2008-09-17

Background: Human emotional expressions serve an important communicatory role allowing the rapid transmission of valence information among individuals. We aimed at exploring the neural networks mediating the recognition of and empathy with human facial expressions of emotion. Methods: A principal component analysis was applied to event-related functional magnetic imaging (fMRI) data of 14 right-handed healthy volunteers (29 +/- 6 years). During scanning, subjects viewed happy, sad and neutral face expressions in the following conditions: emotion recognition, empathizing with emotion, and a control condition of simple object detection. Functionally relevant principal components (PCs) were identified by planned comparisons at an alpha level of p < 0.001. Results: Four PCs revealed significant differences in variance patterns of the conditions, thereby revealing distinct neural networks: mediating facial identification (PC 1), identification of an expressed emotion (PC 2), attention to an expressed emotion (PC 12), and sense of an emotional state (PC 27). Conclusion: Our findings further the notion that the appraisal of human facial expressions involves multiple neural circuits that process highly differentiated cognitive aspects of emotion.

Does neuregulin-1 play a role in Type A behavior? The cardiovascular risk in young Finns study

2008-09-17

Background: Neuregulin-1 proteins are related to physiological correlates of Type A in terms of cardiac reactivity. Furthermore, neuregulin-1 gene (NRG1) may play a role in cardiovascular disease such as atherosclerosis and coronary heart disease i.e. the suggested "outcomes" of Type A behavior. Therefore, NRG1 is hypothesized to be associated with Type A behavior. Methods: The study examined whether Type A behavior pattern is associated with the single nucleotide polymorphism (SNP) SNP8NRG221533 of the NRG1. The subjects were 631 men and women participating in the population-based Cardiovascular Risk in Young Finns study in 1992 and 2001. Type A was self-assessed with the Framingham Type A Scale and reassessed nine years later. Results: Type A was associated with NRG1 genotype. Carriers of genotype CC scored lower on Type A compared to the others. Conclusion: Our study has pinpointed a SNP in NRG1 that predicts Type A behavior. As previous evidence suggests an association for NRG1 with beta-adrenergic stimulation, its role underlying Type A is discussed.

An association study of ADSS gene polymorphisms with schizophrenia

2008-08-24

Background: Adenylosuccinate synthase (ADSS) catalyzes the first committed step of AMP synthesis. It was suggested that the blood-derived RNA of ADSS was down-regulated in schizophrenia (SZ) and one of the eight putative biomarker genes to discriminate SZ from normal controls. However, it remains unclear whether the reduction of ADSS RNA is due to the polymorphisms of the gene or not. Methods: We attempted to examine the association of ADSS gene with schizophrenia in a Chinese population of 480 schizophrenics and 502 normal controls. Genotyping was performed by the Sequenom platform. Results: The 6 marker SNPs (rs3102460, rs3127459, rs3127460, rs3127465, rs3006001, and rs3003211) were genotyped. The frequencies of alleles, genotypes, and haplotypes were tested between cases and controls. There was no significant difference of genotypic, allelic, or haplotypic distributions of the 6 SNPs between the two groups. Conclusion: Our data did not support ADSS gene as a susceptibility gene for SZ in Chinese Han population. Large sample size study is needed to validate or replicate our association study, especially from other ethnic populations.

Using parametric regressors to disentangle properties of multi-feature processes

Guilherme Wood, Hans-Christoph Nuerk, Denise Sturm and Klaus Willmes — 2008-08-15

FMRI data observed under a given experimental condition may be decomposed into two parts: the average effect and the deviation of single replications from this average effect. The average effect is represented by the mean activation over a specific condition. The deviation from this average effect may be decomposed into two components as well: systematic variation due to known empirical factors and pure measurement error. In most fMRI designs deviations from mean activation may be treated as measurement error. Nevertheless, often deviation from the average also may contain systematic variation that can be distinguished from simple measurement error. In these cases, the average fMRI signal may provide only a coarse picture of real brain activation. The larger the variation within-condition, the coarser the average effect and the more relevant is the impact of deviations from it. Systematic deviation from the mean activation may be examined by defining a set of parametric regressors. Here, the applicability of parametric methods to refine the evaluation of fMRI studies is discussed with special emphasis on (i) examination of the impact of continuous predictors on the fMRI signal, (ii) control for variation within each experimental condition and (iii) isolation of specific contributions by different features of a single complex stimulus, especially in the case of a sampled stimulus. The usefulness and applicability of this method are discussed and an example with real data is presented.

The Frizzled 3 gene is associated with methamphetamine psychosis in the Japanese population

2008-08-15

Background: Frizzled 3 (Fzd3) is a receptor required for the Wnt-signaling pathway, which has been implicated in the development of the central nervous system, including synaptogenesis and structural plasticity. We previously found a significant association between the FZD3 gene and susceptibility to schizophrenia, but subsequent studies showed inconsistent findings. To understand the roles of the FZD3 gene in psychotic disorders further, it should be useful to examine FZD3 in patients with methamphetamine psychosis because the clinical features of methamphetamine psychosis are similar to those of schizophrenia. Methods: Six SNPs of FZD3, rs3757888 in the 3' flanking region, rs960914 in the intron 3, rs2241802, a synonymous SNP in the exon5, rs2323019 and rs352203 in the intron 5, and rs880481 in the intron 7, were selected based on the previous schizophrenic studies and analyzed in 188 patients with methamphetamine psychosis and 240 age- and gender-matched controls. Results: A case-control association analyses revealed that two kinds of FZD3 haplotypes showed strong associations with methamphetamine psychosis (p < 0.00001). Having the G-A-T-G or A-G-C-A haplotype of rs2241802-rs2323019-rs352203-rs880481 was a potent negative risk factor (odds ratios were 0.13 and 0.086, respectively) for methamphetamine psychosis. Conclusion: Our present and previous findings indicate that genetic variants of the FZD3 gene affect susceptibility to two analogous but distinct dopamine-related psychoses, endogenous and substance-induced psychosis.

Knockout mice reveal a role for protein tyrosine phosphatase H1 in cognition

2008-08-12

Background: The present study has investigated the protein tyrosine phosphatase H1 (PTPH1) expression pattern in mouse brain and its impact on CNS functions. Methods: We have previously described a PTPH1-KO mouse, generated by replacing the PTP catalytic and the PDZ domain with a LacZ neomycin cassette. PTPH1 expression pattern was evaluated by LacZ staining in the brain and PTPH1-KO and WT mice (n = 10 per gender per genotype) were also behaviorally tested for CNS functions. Results: In CNS, PTPH1 is expressed during development and in adulthood and mainly localized in hippocampus, thalamus, cortex and cerebellum neurons. The behavioral tests performed on the PTPH1-KO mice showed an impact on working memory in male mice and an impaired learning performance at rotarod in females. Conclusion: These results demonstrate for the first time a neuronal expression of PTPH1 and its functionality at the level of cognition.