Working memory in schizophrenia and mania: Correlation with symptoms during the acute and subacute phases

Objective: The aims of this study were to examine working memory in the acute-subacute phase of schizophrenia and mania and to examine correlations between working memory and specific symptom domains. Method: Visuospatial working memory and symptom profiles were assessed in three groups (schizophrenia group, n=19; mania, n=12; controls, n=19) on two occasions separated by 4 weeks. Results: Both patient groups had significant deficits on working memory compared to the well controls and the schizophrenia and mania groups were equally impaired. All groups showed equivalent improvement over time. In the patient groups, impaired working memory was significantly correlated with the presence of both negative symptoms and positive thought disorder. Conclusion: Impaired wet-king memory is found in both schizophrenia and mania during the acute-subacute phases. Further research is required in order to clarify the neurocognitive mechanisms linking impaired working memory with both negative symptoms and positive thought disorder.

Binocular rivalry and the cerebral hemispheres with a note on the correlates and constitution of visual consciousness

In addressing the scientific study of consciousness, Crick and Koch state, "It is probable that at any moment some active neuronal processes in your head correlate with consciousness, while others do not: what is the difference between them?" (1998, p. 97). Evidence from electrophysiological and brain-imaging studies of binocular rivalry supports the premise of this statement and answers to some extent, the question posed. I discuss these recent developments and outline the rationale and experimental evidence for the interhemispheric switch hypothesis of perceptual rivalry. According to this model, the perceptual alternations of rivalry reflect hemispheric alternations, suggesting that visual consciousness of rivalling stimuli may be unihemispheric at any one time (Miller et al., 2000). However, in this paper, I suggest that interhemispheric switching could involve alternating unihemispheric attentional selection of neuronal processes for access to visual consciousness. On this view, visual consciousness during rivalry could be bihemispheric because the processes constitutive of attentional selection may be distinct from those constitutive of visual consciousness. This is a special case of the important distinction between the neuronal correlates and constitution of visual consciousness.

Jules Cotard (1840-1889) - His life and the unique syndrome which bears his name

Dr. Jules Cotard (1840-1889) was a Parisian neurologist who first described the delire des negations. Cotard's syndrome or Cotard's delusion comprises any one of a series of delusions ranging from the fixed and unshakable belief that one has lost organs, blood, or body parts to believing that one has lost one's soul or is dead. In its most profound form, the delusion takes the form of a professed belief that one does not exist. Encountered primarily in psychoses such as schizophrenia and bipolar disorder, Cotard's syndrome has also been described in organic lesions of the nondominant temporoparietal cortex as well as in migraine. Cotard's delusion is the only self-certifiable syndrome of delusional psychosis. Jules Cotard, a Parisian neurologist and psychiatrist and former military surgeon, was one of the first to induce cerebral atrophy by the experimental embolization of cerebral arteries in animals and a pioneer in studies of the clinicopathologic correlates of cerebral atrophy secondary to perinatal and postnatal pathologic changes. He was the first to record that unilateral cerebral atrophy in infancy does not necessarily lead to aphasia and was also the pioneer of studies of altered conscious states in diabetic hyperglycemia.

Long-term trends in sunshine duration and its association with schizophrenia birth rates and age at first registration - data from Australia and the Netherlands

Back ground. Based on the well-described excess of schizophrenia births in winter and spring, we hypothesised that individuals with schizophrenia (a) would be more likely to be born during periods of decreased perinatal sunshine, and (b) those born during periods of less sunshine would have an earlier age of first registration. Methods. We undertook an ecological analysis of long-term trends in perinatal sunshine duration and schizophrenia birth rates based on two mental health registers (Queensland. Australia n = 6630; The Netherlands n = 24, 474). For each of the 480 months between 1931 and 1970, the agreement between slopes of the trends in psychosis and long-term sunshine duration series were assessed. Age at first registration was assessed by quartiles of long-term trends in perinatal sunshine duration, Males and females were assessed separately. Results. Both the Dutch and Australian data showed a statistically significant association between falling long-term trends in sunshine duration around the time of birth and rising schizophrenia birth rates for males only. In both the Dutch and Australian data there were significant associations between earlier age of first registration and reduced long-term trends in sunshine duration around the time of birth for both males and females, Conclusions. A measure of long-term trends in perinatal sunshine duration was associated with two epidemiological features of schizophrenia in two separate data sets. Exposures related to sunshine duration warrant further consideration in schizophrenia research. (C) 2002 Elsevier Science B.V. All rights reserved.

Age-at-first-registration and heterogeneity in affective psychoses

Background: Previous research into age of onset in affective disorders has produced conflicting results. This paper examines the influence of heterogeneity on the age-at-first-registration distribution for the ICD-9 diagnostic group 'affective psychosis'. Method: For 1979-1991, data for age-at-first-registration for 4985 individuals diagnosed with affective psychosis (ICD-9 296.x) were extracted from a name-linked mental health register. These data were divided into (i) '296.1 only', a category used to code unipolar depression (males = 700; females = 1321); and (ii) '296 other', all 296 cases other than 296.1 (males = 1280; females = 1684). Inception rates for each 5-year age division were adjusted for the background population age-structure as a rate per 100 000 population. Results: The age-at-first-registration distribution for affective psychosis has a wide age range, with women outnumbering men. There is a near-linear increase in inception rates for both men and women with 296.1 only, while the bulk of those with affective psychoses (296 other) have an inverted U-shaped age distribution. Males have an earlier modal age-at-first-registration for 296 other compared to females. Conclusion: The heterogeneity in terms of subtypes and sex in affective psychosis clouds the interpretation of age-at-first-registration. Separating those with unipolar psychotic depression from other subclassifications and differentiating by sex may provide clues to factors that precipitate the onset of affective psychosis.

Psychiatric genetics in Australia

Australian research in psychiatric genetics covers molecular genetic studies of depression, anxiety, alcohol dependence, Alzheimer's disease, bipolar disorder, schizophrenia, autism, and attention deficit hyperactivity disorder. For each disorder, a variety of clinical cohorts have been recruited including affected sib pair families, trios, case/controls, and twins from a large population-based twin registry. These studies are taking place both independently and in collaboration with international groups. Microarray studies now complement DNA investigations, while animal models are in development An Australian government genome facility provides a high throughput genotyping and mutation detection service to the Australian scientific community, enhancing the contribution of Australian psychiatric genetics groups to gene discovery. (C) 2003 Lippincott Williams Wilkins.

A systematic review and meta-analysis of Northern Hemisphere season of birth studies in schizophrenia

Based on the epidemiological finding that individuals with schizophrenia tend to be born in winter/spring when compared to the general population, we examined (1) the strength and timing of this effect in Northern Hemisphere sites, and (2) the correlation between the season of birth effect size and latitude. Studies were located via electronic data sources, published citations, and letters to authors. Inclusion criteria were that studies specify the diagnostic criteria used, that studies specify the counts of schizophrenia and general population births for each month, and that subjects and the general population be drawn from the same birth years and catchment area. We extracted data from eight studies based on 126,196 patients with schizophrenia and 86,605,807 general population births and drawn from 27 Northern Hemisphere sites. Comparing winter/spring versus summer/autumn births, we found a significant excess for winter/spring births (pooled odds ratio = 1.07; 95% confidence interval 1.05, 1.08; population attributable risk = 3.3%). There was a small but significant positive correlation between the odds ratios for the season of birth comparison and latitude (r = 0.271, p < 0.005). Furthermore, the shape of the seasonality in schizophrenia births varied by latitude band. These variations may encourage researchers to generate candidate seasonally fluctuating exposures.

The Cotard syndrome. Report of two patients: with a review of the extended spectrum of 'délire des négations'

The Cotard syndrome is characterized by the delusion where an individual insists that he has died or part of his body has decayed. Although described classically in schizophrenia and bipolar disorder, physical disorders including migraine, tumour and trauma have also been associated with the syndrome. Two new cases are described here, the one associated with arteriovenous malformations and the other with probable multiple sclerosis. The delusion has been embarrassing to each patient. Study of such cases may have wider implications for the understanding of the psychotic interpretation of body image, for example that occurring in anorexia nervosa.

Polymorphisms in the trace amine receptor 4 (TRAR4) gene on chromosome 6q23.2 are associated with susceptibility to schizophrenia

Several linkage studies across multiple population groups provide convergent support for a susceptibility locus for schizophrenia - and, more recently, for bipolar disorder - on chromosome 6q13-q26. We genotyped 192 European-ancestry and African American (AA) pedigrees with schizophrenia from samples that previously showed linkage evidence to 6q13-q26, focusing on the MOXD1-STX7-TRARs gene cluster at 6q23.2, which contains a number of prime candidate genes for schizophrenia. Thirty-one screening single-nucleotide polymorphisms (SNPs) were selected, providing a minimum coverage of at least 1 SNP/20 kb. The association observed with rs4305745 (P = .0014) within the TRAR4 (trace amine receptor 4) gene remained significant after correction for multiple testing. Evidence for association was proportionally stronger in the smaller AA sample. We performed database searches and sequenced genomic DNA in a 30-proband subsample to obtain a high-density map of 23 SNPs spanning 21.6 kb of this gene. Single-SNP analyses and also haplotype analyses revealed that rs4305745 and/or two other polymorphisms in perfect linkage disequilibrium (LD) with rs4305745 appear to be the most likely variants underlying the association of the TRAR4 region with schizophrenia. Comparative genomic analyses further revealed that rs4305745 and/or the associated polymorphisms in complete LD with rs4305745 could potentially affect gene expression. Moreover, RT-PCR studies of various human tissues, including brain, confirm that TRAR4 is preferentially expressed in those brain regions that have been implicated in the pathophysiology of schizophrenia. These data provide strong preliminary evidence that TRAR4 is a candidate gene for schizophrenia; replication is currently being attempted in additional clinical samples.

Multicenter linkage study of schizophrenia loci on chromosome 22q

The hypothesis of the existence of one or more schizophrenia susceptibility loci on chromosome 22q is supported by reports of genetic linkage and association, meta-analyses of linkage, and the observation of elevated risk for psychosis in people with velocardiofacial syndrome, caused by 22q11 microdeletions. We tested this hypothesis by evaluating 10 microsatellite markers spanning 22q in a multicenter sample of 779 pedigrees. We also incorporated age at onset and sex into the analysis as covariates. No significant evidence for linkage to schizophrenia or for linkage associated with earlier age at onset, gender, or heterogeneity across sites was observed. We interpret these findings to mean that the population-wide effects of putative 22q schizophrenia susceptibility loci are too weak to detect with linkage analysis even in large samples.

Modulating the rate and rhythmicity of perceptual rivalry alternations with the mixed 5-HT2A and 5-HT1A agonist psilocybin

Binocular rivalry occurs when different images are presented simultaneously to corresponding points within the left and right eyes. Under these conditions, the observer's perception will alternate between the two perceptual alternatives. Motivated by the reported link between the rate of perceptual alternations, symptoms of psychosis and an incidental observation that the rhythmicity of perceptual alternations during binocular rivalry was greatly increased 10 h after the consumption of LSD, this study aimed to investigate the pharmacology underlying binocular rivalry and to explore the connection between the timing of perceptual switching and psychosis. Psilocybin (4-phosphoryloxy-N,N-dimethyltryptamine, PY) was chosen for the study because, like LSD, it is known to act as an agonist at serotonin (5-HT)(1A) and 5-HT2A receptors and to produce an altered state sometimes marked by psychosis-like symptoms. A total of 12 healthy human volunteers were tested under placebo, low-dose ( 115 mg/kg) and high-dose ( 250 mg/kg) PY conditions. In line with predictions, under both low- and high-dose conditions, the results show that at 90 min postadministration ( the peak of drug action), rate and rhythmicity of perceptual alternations were significantly reduced from placebo levels. Following the 90 min testing period, the perceptual switch rate successively increased, with some individuals showing increases well beyond pretest levels at the final testing, 360 min postadministration. However, as some subjects had still not returned to pretest levels by this time, the mean phase duration at 360 min was not found to differ significantly from placebo. Reflecting the drug-induced changes in rivalry phase durations, subjects showed clear changes in psychological state as indexed by the 5D-ASC ( altered states of consciousness) rating scales. This study suggests the involvement of serotonergic pathways in binocular rivalry and supports the previously proposed role of a brainstem oscillator in perceptual rivalry alternations and symptoms of psychosis.

Genomewide Linkage Scan of 409 European-ancestry and African American Families with Schizophrenia: Suggestive Evidence of Linkage at 8p23.3-p21.2 and 11p13.1-q14.1 in the Combined Sample

We report the clinical characteristics of a schizophrenia sample of 409 pedigrees-263 of European ancestry ( EA) and 146 of African American ancestry ( AA)-together with the results of a genome scan ( with a simple tandem repeat polymorphism interval of 9 cM) and follow-up fine mapping. A family was required to have a proband with schizophrenia ( SZ) and one or more siblings of the proband with SZ or schizoaffective disorder. Linkage analyses included 403 independent full-sibling affected sibling pairs ( ASPs) ( 279 EA and 124 AA) and 100 all-possible half-sibling ASPs ( 15 EA and 85 AA). Nonparametric multipoint linkage analysis of all families detected two regions with suggestive evidence of linkage at 8p23.3-q12 and 11p11.2-q22.3 ( empirical Z likelihood-ratio score [ Z(lr)] threshold >= 2.65) and, in exploratory analyses, two other regions at 4p16.1-p15.32 in AA families and at 5p14.3-q11.2 in EA families. The most significant linkage peak was in chromosome 8p; its signal was mainly driven by the EA families. Z(lr) scores >= 2.0 in 8p were observed from 30.7 cM to 61.7 cM ( Center for Inherited Disease Research map locations). The maximum evidence in the full sample was a multipoint Z(lr) of 3.25 ( equivalent Kong-Cox LOD of 2.30) near D8S1771 ( at 52 cM); there appeared to be two peaks, both telomeric to neuregulin 1 ( NRG1). There is a paracentric inversion common in EA individuals within this region, the effect of which on the linkage evidence remains unknown in this and in other previously analyzed samples. Fine mapping of 8p did not significantly alter the significance or length of the peak. We also performed fine mapping of 4p16.3-p15.2, 5p15.2-q13.3, 10p15.3-p14, 10q25.3-q26.3, and 11p13-q23.3. The highest increase in Z(lr) scores was observed for 5p14.1-q12.1, where the maximum Z(lr) increased from 2.77 initially to 3.80 after fine mapping in the EA families.

Identification of the semaphorin receptor PLXNA2 as a candidate for susceptibility to schizophrenia

The discovery of genetic factors that contribute to schizophrenia susceptibility is a key challenge in understanding the etiology of this disease. Here, we report the identification of a novel schizophrenia candidate gene on chromosome 1q32, plexin A2 (PLXNA2), in a genome-wide association study using 320 patients with schizophrenia of European descent and 325 matched controls. Over 25 000 single-nucleotide polymorphisms (SNPs) located within approximately 14 000 genes were tested. Out of 62 markers found to be associated with disease status, the most consistent finding was observed for a candidate locus on chromosome 1q32. The marker SNP rs752016 showed suggestive association with schizophrenia (odds ratio (OR) = 1.49, P = 0.006). This result was confirmed in an independent case control sample of European Americans (combined OR = 1.38, P = 0.035) and similar genetic effects were observed in smaller subsets of Latin Americans (OR = 1.26) and Asian Americans (OR = 1.37). Supporting evidence was also obtained from two family-based collections, one of which reached statistical significance (OR = 2.2, P = 0.02). High-density SNP mapping showed that the region of association spans approximately 60 kb of the PLXNA2 gene. Eight out of 14 SNPs genotyped showed statistically significant differences between cases and controls. These results are in accordance with previous genetic findings that identified chromosome 1q32 as a candidate region for schizophrenia. PLXNA2 is a member of the transmembrane semaphorin receptor family that is involved in axonal guidance during development and may modulate neuronal plasticity and regeneration. The PLXNA2 ligand semaphorin 3A has been shown to be upregulated in the cerebellum of individuals with schizophrenia. These observations, together with the genetic results, make PLXNA2 a likely candidate for the 1q32 schizophrenia susceptibility locus.

Neuropsychological assessment of an eighty-nine year old man

A case of first onset of the symptoms of mania in an eighty-nine year old man is reported. Organic contributions appear to be particularly important in cases of mania in older adults. In cases of first onset of mania in older adults the major differential diagnosis is between primary mania and a wide range of possible secondary etiological factors. This man had no known history of affective disorder and at the time of initial examination no organic explanation for his symptoms could be identified. While lateonset bipolar disorder has been reported in the literature, such cases are rare and are usually proceeded by a history of major depressive disorder or dysthymia. A range of neuropsychological assessment instruments were administered as part of a comprehensive inpatient examination of this man, commenting on his cognitive functioning and competence to manage his affairs. This assessment indicated that while his functioning was intact in some areas, there were areas of significant difficulty. The case illustrates the difficulties in interpreting neuropsychological assessment results obtained during a manic phase, and highlights some of the difficulties of conducting research with older adults.