Auditory Hallucinations in Schizophrenia: The Role of Cognitive, Brain Structural and Genetic Disturbances in the Left Temporal Lobe

In this article we review research in our laboratory on auditory hallucinations using behavioral and MRI measure. The review consists of both previously published and new data that for the first time is presented together in a cohesive way. Auditory hallucinations are among the most common symptoms in schizophrenia, affecting more than 70% of the patients. We here advance the hypothesis that auditory hallucinations are internally generated speech perceptions that are lateralized to the left temporal lobe, in the peri-Sylvian region. From this we predict that hallucinating patients should have problems identifying a simultaneously presented external speech sound, as measured through performance on the dichotic listening (DL) paradigm with consonant–vowel syllables, since this technique lateralizes the stimulus input. Across a series of behavioral experiments, we have shown that patients with schizophrenia who experience frequent auditory hallucinations fail to demonstrate an expected right ear advantage on the dichotic listening test. Absence of a right ear advantage is indicative of a functional deficit in the left peri-Sylvian region. The results also revealed that patients with ongoing auditory hallucinations were more impaired than patients with previous hallucinations, and that a higher score on the hallucination item in a standard symptom rating scale (BPRS) correlated negatively with number of correct reports for the right ear stimulus. Moreover, we have found that schizophrenia patients fail to shift attention to the left ear stimulus, when explicitly instructed to focus on the right or left ear stimulus only, thus showing a deficit in inhibition of attention and response-inhibition. The behavioral DL data are substantiated in two MR morphometry studies that revealed significant reductions in grey matter density in the left peri-Sylvian region in hallucinating patients, and patients with reduced left temporal lobe grey matter density. Hallucinating patients also failed to show a right ear advantage in the dichotic listening test. Ongoing fMRI studies are focused on the underlying synaptic and molecular mechanisms by investigating the effects of the glutamate antagonist drug memantine on auditory perception and speech lateralization, and examination of temporal cortex-specific gene expression in the left peri-Sylvian region

Evaluation of five different cDNA labeling methods for microarrays using spike controls

BACKGROUND: Several different cDNA labeling methods have been developed for microarray based gene expression analysis. We have examined the accuracy and reproducibility of such five commercially available methods in detection of predetermined ratio values from target spike mRNAs (A. thaliana) in a background of total RNA. The five different labeling methods were: direct labeling (CyScribe), indirect labeling (FairPlay™ – aminoallyl), two protocols with dendrimer technology (3DNA(® )Array 50™ and 3DNA(® )submicro™), and hapten-antibody enzymatic labeling (Micromax™ TSA™). Ten spike controls were mixed to give expected Cy5/Cy3 ratios in the range 0.125 to 6.0. The amounts of total RNA used in the labeling reactions ranged from 5 – 50 μg. RESULTS: The 3DNA array 50 and CyScribe labeling methods performed best with respect to relative deviation from the expected values (16% and 17% respectively). These two methods also displayed the best overall accuracy and reproducibility. The FairPlay method had the lowest total experimental variation (22%), but the estimated values were consistently higher than the expected values (36%). TSA had both the largest experimental variation and the largest deviation from the expected values (45% and 48% respectively). CONCLUSION: We demonstrate the usefulness of spike controls in validation and comparison of cDNA labeling methods for microarray experiments

Neurogenetic Effects on Cognition in Aging Brains: A Window of Opportunity for Intervention?

Knowledge of genetic influences on cognitive aging can constrain and guide interventions aimed at limiting age-related cognitive decline in older adults. Progress in understanding the neural basis of cognitive aging also requires a better understanding of the neurogenetics of cognition. This selective review article describes studies aimed at deriving specific neurogenetic information from three parallel and interrelated phenotype-based approaches: psychometric constructs, cognitive neuroscience-based processing measures, and brain imaging morphometric data. Developments in newer genetic analysis tools, including genome wide association, are also described. In particular, we focus on models for establishing genotype–phenotype associations within an explanatory framework linking molecular, brain, and cognitive levels of analysis. Such multiple-phenotype approaches indicate that individual variation in genes central to maintaining synaptic integrity, neurotransmitter function, and synaptic plasticity are important in affecting age-related changes in brain structure and cognition. Investigating phenotypes at multiple levels is recommended as a means to advance understanding of the neural impact of genetic variants relevant to cognitive aging. Further knowledge regarding the mechanisms of interaction between genetic and preventative procedures will in turn help in understanding the ameliorative effect of various experiential and lifestyle factors on age-related cognitive decline

Sex-Specific Effect of Serum Lipids and Body Mass Index on Psychotic Symptoms, a Cross-Sectional Study of First-Episode Psychosis Patients

Background: Schizophrenia is a disorder with considerable heterogeneity in course and outcomes, which is in part related to the patients' sex. Studies report a link between serum lipids, body mass index (BMI), and therapeutic response. However, the role of sex in these relationships is poorly understood. In a cross-sectional sample of first-episode psychosis (FEP) patients, we investigated if the relationship between serum lipid levels (total cholesterol, HDL-C, LDL-C, and triglycerides), BMI, and symptoms differs between the sexes. Methods: We included 435 FEP patients (males: N = 283, 65%) from the ongoing Thematically Organized Psychosis (TOP) study. Data on clinical status, antipsychotics, lifestyle, serum lipid levels, and BMI were obtained. The Positive and Negative Syndrome Scale (PANSS) and the Calgary Depression Scale for Schizophrenia (CDSS) were used to assess psychotic and depressive symptoms. General linear models were employed to examine the relationship between metabolic variables and symptomatology. Results: We observed a female-specific association between serum HDL-C levels and negative symptoms (B = −2.24, p = 0.03) and between triglycerides levels (B = 1.48, p = 0.04) and BMI (B = 0.27, p = 0.001) with depressive symptoms. When controlling for BMI, only the association between serum HDL-C levels and negative symptoms remained significant. Moreover, the HDL-C and BMI associations remained significant after controlling for demography, lifestyle, and illness-related factors. Conclusion: We found a relationship between metabolic factors and psychiatric symptoms in FEP patients that was sex-dependent.publishedVersio

Global Gene Expression Profiling of Human Osteosarcomas Reveals Metastasis-Associated Chemokine Pattern

Global gene expression analysis was performed on a panel of 23 osteosarcoma samples of primary and metastatic origin using the Applied Biosystems Gene Expression Array System. When comparing the primary tumours with the metastases, we found a significantly increased expression of genes involved in immunological processes, for example coding for cytokines and chemokines, in the metastatic samples. In addition, a comparison of the gene expression in primary samples from patients with or without metastases demonstrated that patients who later developed metastases had high expression of the chemokine (C-X-C motif) receptor 4 (CXCR4), similar to the metastatic samples, suggesting that these signal molecules play an important role in promoting metastasis. Increased knowledge of mechanisms and interactions between specified molecular signalling pathways in osteosarcomas could lead to a more rational strategy for development of targeted therapy

Constructing the Immune Signature of Schizophrenia for Clinical Use and Research; An Integrative Review Translating Descriptives Into Diagnostics

Schizophrenia is considered a syndrome comprised by several disease phenotypes, covering a range of underlying pathologies. One of these disease mechanisms seems to involve immune dysregulation and neuroinflammation. While the current dopamine receptor-blocking antipsychotic drugs decrease psychotic symptoms and prevent relapse in the majority of patients with schizophrenia, there is a huge need to explore new treatment options that target other pathophysiological pathways. Such studies should aim at identifying robust biomarkers in order to diagnose and monitor the immune biophenotype in schizophrenia and develop better selection procedures for clinical trials with anti-inflammatory and immune-modulating drugs. In this focused review, we describe available methods to assess inflammatory status and immune disturbances in vivo. We also outline findings of immune disturbances and signs of inflammation at cellular, protein, and brain imaging levels in patients with schizophrenia. Furthermore, we summarize the results from studies with anti-inflammatory or other immune-modulating drugs, highlighting how such studies have dealt with participant selection. Finally, we propose a strategy to construct an immune signature that may be helpful in selecting and monitoring participants in studies with immune modulating drugs and also applicable in regular clinical work

Variants in Doublecortin- and Calmodulin Kinase Like 1, a Gene Up-Regulated by BDNF, Are Associated with Memory and General Cognitive Abilities

Human memory and general cognitive abilities are complex functions of high heritability and wide variability in the population. The brain-derived neurotrophic factor (BDNF) plays an important role in mammalian memory formation.Based on the identification of genes markedly up-regulated during BDNF-induced synaptic consolidation in the hippocampus, we selected genetic variants that were tested in three independent samples, from Norway and Scotland, of adult individuals examined for cognitive abilities. In all samples, we show that markers in the doublecortin- and calmodulin kinase like 1 (DCLK1) gene, are significantly associated with general cognition (IQ scores) and verbal memory function, resisting multiple testing. DCLK1 is a complex gene with multiple transcripts which vary in expression and function. We show that the short variants are all up-regulated after BDNF treatment in the rat hippocampus, and that they are expressed in the adult human brain (mostly in cortices and hippocampus). We demonstrate that several of the associated variants are located in potential alternative promoter- and cis-regulatory elements of the gene and that they affect BDNF-mediated expression of short DCLK1 transcripts in a reporter system.These data present DCLK1 as a functionally pertinent gene involved in human memory and cognitive functions

A Genetic Deconstruction of Neurocognitive Traits in Schizophrenia and Bipolar Disorder

Background: Impairments in cognitive functions are common in patients suffering from psychiatric disorders, such as schizophrenia and bipolar disorder. Cognitive traits have been proposed as useful for understanding the biological and genetic mechanisms implicated in cognitive function in healthy individuals and in the dysfunction observed in psychiatric disorders. Methods: Sets of genes associated with a range of cognitive functions often impaired in schizophrenia and bipolar disorder were generated from a genome-wide association study (GWAS) on a sample comprising 670 healthy Norwegian adults who were phenotyped for a broad battery of cognitive tests. These gene sets were then tested for enrichment of association in GWASs of schizophrenia and bipolar disorder. The GWAS data was derived from three independent single-centre schizophrenia samples, three independent single-centre bipolar disorder samples, and the multi-centre schizophrenia and bipolar disorder samples from the Psychiatric Genomics Consortium. Results: The strongest enrichments were observed for visuospatial attention and verbal abilities sets in bipolar disorder. Delayed verbal memory was also enriched in one sample of bipolar disorder. For schizophrenia, the strongest evidence of enrichment was observed for the sets of genes associated with performance in a colour-word interference test and for sets associated with memory learning slope. Conclusions: Our results are consistent with the increasing evidence that cognitive functions share genetic factors with schizophrenia and bipolar disorder. Our data provides evidence that genetic studies using polygenic and pleiotropic models can be used to link specific cognitive functions with psychiatric disorders