Josef Parnas

A Global Perspective on Genetic Variation at the ADH Genes Reveals Unusual Patterns of Linkage Disequilibrium and Diversity

Variants of different Class I alcohol dehydrogenase (ADH) genes have been shown to be associated with an effect that is protective against alcoholism. Previous work from our laboratory has shown that the two sites showing the association are in linkage disequilibrium and has identified the ADH1B Arg47His site as causative, with the ADH1C Ile349Val site showing association only because of the disequilibrium. Here, we describe an initial study of the nature of linkage disequilibrium and genetic variation, in population samples from different regions of the world, in a larger segment of the ADH cluster (including the three Class I ADH genes and ADH7). Linkage disequilibrium across approximately 40 kb of the Class I ADH cluster is moderate to strong in all population samples that we studied. We observed nominally significant pairwise linkage disequilibrium, in some populations, between the ADH7 site and some Class I ADH sites, at moderate values and at a molecular distance as great as 100 kb. Our data indicate (1) that most ADH-alcoholism association studies have failed to consider many sites in the ADH cluster that may harbor etiologically significant alleles and (2) that the relevance of the various ADH sites will be population dependent. Some individual sites in the Class I ADH cluster show Fst values that are among the highest seen among several dozen unlinked sites that were studied in the same subset of populations. The high Fst values can be attributed to the discrepant frequencies of specific alleles in eastern Asia relative to those in other regions of the world. These alleles are part of a single haplotype that exists at high (>65%) frequency only in the eastern-Asian samples. It seems unlikely that this haplotype, which is rare or unobserved in other populations, reached such high frequency because of random genetic drift alone.

Parallel Factor Analysis as an exploratory tool for wavelet transformed event-related EEG

In the decomposition of multi-channel EEG signals, principal component analysis (PCA) and independent component analysis (ICA) have widely been used. However, as both methods are based on handling two-way data, i.e. two-dimensional matrices, multi-way methods might improve the interpretation of frequency transformed multi-channel EEG of channel x frequency x time data. The multi-way decomposition method Parallel Factor (PARAFAC), also named Canonical Decomposition (CANDECOMP), was recently used to decompose the wavelet transformed ongoing EEG of channel x frequency x time (Miwakeichi, F., Martinez-Montes, E., Valdes-Sosa, P.A., Nishiyama, N., Mizuhara, H., Yamaguchi, Y., 2004. Decomposing EEG data into space-time-frequency components using parallel factor analysis. Neuroimage 22, 1035-1045). In this article, PARAFAC is used for the first time to decompose wavelet transformed event-related EEG given by the inter-trial phase coherence (ITPC) encompassing ANOVA analysis of differences between conditions and 5-way analysis of channel x frequency x time x subject x condition. A flow chart is presented on how to perform data exploration using the PARAFAC decomposition on multi-way arrays. This includes (A) channel x frequency x time 3-way arrays of F test values from a repeated measures analysis of variance (ANOVA) between two stimulus conditions; (B) subject-specific 3-way analyses; and (C) an overall 5-way analysis of channel x frequency x time x subject x condition. The PARAFAC decompositions were able to extract the expected features of a previously reported ERP paradigm: namely, a quantitative difference of coherent occipital gamma activity between conditions of a visual paradigm. Furthermore, the method revealed a qualitative difference which has not previously been reported. The PARAFAC decomposition of the 3-way array of ANOVA F test values clearly showed the difference of regions of interest across modalities, while the 5-way analysis enabled visualization of both quantitative and qualitative differences. Consequently, PARAFAC is a promising data exploratory tool in the analysis of the wavelets transformed event-related EEG.

Schizophrenia, neurodevelopment and corpus callosum.

The Zeitgeist favors an interpretation of schizophrenia as a condition of abnormal connectivity of cortical neurons, particularly in the prefrontal and temporal cortex. The available evidence points to reduced connectivity, a possible consequence of excessive synaptic pruning in development. A decreased thalamic input to the cerebral cortex appears likely, and developmental studies predict that this decrease should entail a secondary loss of both long- and short-range cortico-cortical connections, including connections between the hemispheres. Indeed, morphological, electrophysiological and neuropsychological studies over the last two decades suggest that the callosal connections are altered in schizophrenics. However, the alterations are subtle and sometimes inconsistent across studies, and need to be investigated further with new methodologies.

Anomalies of subjective experience in schizophrenia and psychotic bipolar illness

Objective: Contemporary psychopathology, as a result of behaviourally dominated epistemological stance, downplays anomalies of the patients subjectivity. This neglect has probably deleterious consequences for research in the causes and the boundaries of the schizophrenia spectrum conditions. The purpose of this study is to explore frequency of qualitative, not‐yet‐psychotic, anomalies of subjective experience in patients with residual schizophrenia and psychotic bipolar illness in remission.

Anomalous Subjective Experience among First-Admitted Schizophrenia Spectrum Patients: Empirical Investigation

Our research group has for several years conducted philosophically informed, phenomenological-empirical studies of morbid alterations of conscious experience (subjectivity) in schizophrenia (Sz) and its spectrum of disorders. Some of these experiential alterations constitute, in our view, the vulnerability markers to Sz – indicators that are intrinsic to this disorder and which were historically considered as constituting the phenotypic anchor of the very concept and the diagnostic validity of Sz spectrum disorders. In a more pragmatic clinical context, these indicators, considered here as symptoms, may be potentially effective for early differential diagnosis. In this study, 151 consecutive first-admitted patients (with bipolar, melancholic and organic patients excluded) diagnosed according to the ICD-10, were evaluated on a number of expressive and experiential psychopathological dimensions, with special emphasis on the experiences of perplexity, disorders of self-awareness, perceptual disorders and anomalous bodily experiences. The a priori scales derived from the item pool of a slightly modified OPCRIT and BSABS were used for analyses. Sz and schizotypal disorder scored equally on the subjective dimensions, suggesting a basic phenomenological affinity of these disorders. In contrast, anomalies of subjective experience were clearly more pronounced among the patients within, as compared to those outside the Sz spectrum.

Haplotypes and linkage disequilibrium at the phenylalanine hydroxylase locus, PAH, in a global representation of populations.

Because defects in the phenylalanine hydroxylase gene (PAH) cause phenylketonuria (PKU), PAH was studied for normal polymorphisms and linkage disequilibrium soon after the gene was cloned. Studies in the 1980s concentrated on European populations in which PKU was common and showed that haplotype-frequency variation exists between some regions of the world. In European populations, linkage disequilibrium generally was found not to exist between RFLPs at opposite ends of the gene but was found to exist among the RFLPs clustered at each end. We have now undertaken the first global survey of normal variation and disequilibrium across the PAH gene. Four well-mapped single-nucleotide polymorphisms (SNPs) spanning approximately 75 kb, two near each end of the gene, were selected to allow linkage disequilibrium across most of the gene to be examined. These SNPs were studied as PCR-RFLP markers in samples of, on average, 50 individuals for each of 29 populations, including, for the first time, multiple populations from Africa and from the Americas. All four sites are polymorphic in all 29 populations. Although all but 5 of the 16 possible haplotypes reach frequencies >5% somewhere in the world, no haplotype was seen in all populations. Overall linkage disequilibrium is highly significant in all populations, but disequilibrium between the opposite ends is significant only in Native American populations and in one African population. This study demonstrates that the physical extent of linkage disequilibrium can differ substantially among populations from different regions of the world, because of both ancient genetic drift in the ancestor common to a large regional group of modern populations and recent genetic drift affecting individual populations.

A Disappearing Heritage: The Clinical Core of Schizophrenia

This article traces the fundamental descriptive features of schizophrenia described in the European continental literature form Kraepelin and Bleuler, culminating with the creation of the International Classification of Diseases (ICD)-8 (1974). There was a consensus among the researchers that the specificity and typicality of schizophrenia was anchored to its “fundamental” clinical core (with trait status) and not to positive psychotic features, which were considered as “state”, “accessory” phenomena. The clinical core of schizophrenia was, in a diluted form, constitutive of the spectrum conditions (“schizoidia” and “latent schizophrenia”). The fundamental features are manifest across all domains of consciousness: subjective experience, expression, cognition, affectivity, behavior, and willing. Yet, the specificity of the core was only graspable at a more comprehensive Gestalt-level, variously designated (eg, discordance, autism, “Spaltung”), and not on the level of single features. In other words, the phenomenological specificity was seen as being expressive of a fundamental structural or formal change of the patient’s mentality (consciousness, subjectivity). This overall change transpires through the single symptoms and signs, lending them a characteristic phenomenological pattern. This concept of schizophrenia bears little resemblance to the current operational definitions. The Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, and ICD-10 seem to diagnose a subset of patients with chronic paranoid-hallucinatory variant of schizophrenia.

Looking at the Schizophrenia Spectrum Through the Prism of Self-disorders: An Empirical Study

Nonpsychotic anomalies of subjective experience were emphasized in both classic literature and phenomenological psychiatry as essential clinical features of schizophrenia. However, only in recent years, their topicality with respect to the construct validity of the concept of the schizophrenia spectrum has been explicitly acknowledged, mainly as a consequence of the increasing focus on early detection and prevention of psychosis. The current study tested the hypothesis of a specific aggregation of self-disorders (SDs, various anomalies of self-awareness) in schizophrenia-spectrum conditions, comparing different diagnostic groups; 305 subjects, previously assessed in the Copenhagen Schizophrenia Linkage Study, were grouped into 4 experimental samples, according to their Diagnostic and Statistical Manual of Mental Disorders (Third Edition Revised) main diagnosis: schizophrenia, (n = 29), schizotypal personality disorder (n = 61), other mental illness not belonging to the schizophrenia spectrum (n = 112), and no mental illness (n = 103). The effect of diagnostic grouping on the level of SDs was explored via general linear model and logistic regression. The diagnosis of schizophrenia and schizotypy predicted higher levels of SDs, and SDs scores were significantly different between spectrum and nonspectrum samples; the likelihood of experiencing SDs increased as well with the diagnostic severity. The findings support the assumption that SDs are a discriminant psychopathological feature of the schizophrenia spectrum and suggest their incorporation to strengthen its construct validity, with potential benefit for both early detection and pathogenetic research.

Sodium Valproate, Serum Level and Clinical Effect in Epilepsy: A Controlled Study

Summary: Clinical effects at three different serum levels of sodium valproate (VPA) were compared in a triple‐blind, multiple crossover trial comprising 13 epileptic inpatients. Patients were selected regardless of seizure type, and all were in concomitant antiepileptic treatment, which was kept constant throughout the study. A significant relationship between the decrease in number of seizures and increasing VPA serum level was demonstrated. The relationship between VPA dose and serum level was curvilinear. Statistical evaluation of patients by seizure type in relation to clinical effect of VPA was only possible for secondary generalized seizures. Between phenytoin, phenobarbital, and carbamazepine and the different VPA serum levels no interactions could be demonstrated. Recorded side effects were always mild and transient. No obvious correlation between side effects and VPA serum level was established.

Reliability of clinical ICD-10 schizophrenia diagnoses.

Concern has been expressed as to the reliability of clinical ICD-10 diagnosis of schizophrenia. This study was designed to assess the diagnostic reliability of the clinical ICD-10 diagnosis of schizophrenia in a random sample of Danish in- and outpatients with a history of psychosis. A sample of 100 subjects was assessed using the operational criteria OPCRIT checklist for psychotic and affective illness. The most recent principal and clinical ICD-10 diagnosis was compared with diagnoses generated by the OPCRIT instrument. Data documented very high sensitivity (93%) and positive predictive value (87%) of ICD-10 schizophrenia and an overall good agreement between clinical and OPCRIT-derived diagnoses (κ=0.60). An even higher positive predictive value was obtained when diagnoses were amalgamated into a diagnostic entity of schizophrenia-spectrum disorders (98%). Near perfect agreement was seen between OPCRIT-derived ICD-10 and DSM-IV diagnoses (κ=0.87). Thus, this study demonstrates high reliability of the clinical diagnosis of schizophrenia and even more so of the diagnosis of schizophrenia-spectrum disorder.