Medical Education - Research Publications
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ItemNo Preview AvailableDrug-induced psychosis: how to avoid star gazing in schizophrenia research by looking at more obvious sources of light.(Frontiers Media SA, 2011)The prevalent view today is that schizophrenia is a syndrome rather than a specific disease. Liability to schizophrenia is highly heritable. It appears that multiple genetic and environmental factors operate together to push individuals over a threshold into expressing the characteristic clinical picture. One environmental factor which has been curiously neglected is the evidence that certain drugs can induce schizophrenia-like psychosis. In the last 60 years, improved understanding of the relationship between drug abuse and psychosis has contributed substantially to our modern view of the disorder suggesting that liability to psychosis in general, and to schizophrenia in particular, is distributed trough the general population in a similar continuous way to liability to medical disorders such as hypertension and diabetes. In this review we examine the main hypotheses resulting from the link observed between the most common psychotomimetic drugs (lysergic acid diethylamide, amphetamines, cannabis, phencyclidine) and schizophrenia.
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ItemWhite Matter and Cognition in Adults Who Were Born Preterm(PUBLIC LIBRARY SCIENCE, 2011-10-12)BACKGROUND AND PURPOSE: Individuals born very preterm (before 33 weeks of gestation, VPT) are at risk of damage to developing white matter, which may affect later cognition and behaviour. METHODS: We used diffusion tensor MRI (DT-MRI) to assess white matter microstructure (fractional anisotropy; FA) in 80 VPT and 41 term-born individuals (mean age 19.1 years, range 17-22, and 18.5 years, range 17-22 years, respectively). VPT individuals were part of a 1982-1984 birth cohort which had been followed up since birth; term individuals were recruited by local press advertisement. General intellectual function, executive function and memory were assessed. RESULTS: The VPT group had reduced FA in four clusters, and increased FA in four clusters relative to the Term group, involving several association tracts of both hemispheres. Clusters of increased FA were associated with more severe neonatal brain injury in the VPT group. Clusters of reduced FA were associated with lower birth weight and perinatal hypoxia, and with reduced adult cognitive performance in the VPT group only. CONCLUSIONS: Alterations of white matter microstructure persist into adulthood in VPT individuals and are associated with cognitive function.
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ItemPattern of neural responses to verbal fluency shows diagnostic specificity for schizophrenia and bipolar disorder.(Springer Science and Business Media LLC, 2011-01-28)BACKGROUND: Impairments in executive function and language processing are characteristic of both schizophrenia and bipolar disorder. Their functional neuroanatomy demonstrate features that are shared as well as specific to each disorder. Determining the distinct pattern of neural responses in schizophrenia and bipolar disorder may provide biomarkers for their diagnoses. METHODS: 104 participants underwent functional magnetic resonance imaging (fMRI) scans while performing a phonological verbal fluency task. Subjects were 32 patients with schizophrenia in remission, 32 patients with bipolar disorder in an euthymic state, and 40 healthy volunteers. Neural responses to verbal fluency were examined in each group, and the diagnostic potential of the pattern of the neural responses was assessed with machine learning analysis. RESULTS: During the verbal fluency task, both patient groups showed increased activation in the anterior cingulate, left dorsolateral prefrontal cortex and right putamen as compared to healthy controls, as well as reduced deactivation of precuneus and posterior cingulate. The magnitude of activation was greatest in patients with schizophrenia, followed by patients with bipolar disorder and then healthy individuals. Additional recruitment in the right inferior frontal and right dorsolateral prefrontal cortices was observed in schizophrenia relative to both bipolar disorder and healthy subjects. The pattern of neural responses correctly identified individual patients with schizophrenia with an accuracy of 92%, and those with bipolar disorder with an accuracy of 79% in which mis-classification was typically of bipolar subjects as healthy controls. CONCLUSIONS: In summary, both schizophrenia and bipolar disorder are associated with altered function in prefrontal, striatal and default mode networks, but the magnitude of this dysfunction is particularly marked in schizophrenia. The pattern of response to verbal fluency is highly diagnostic for schizophrenia and distinct from bipolar disorder. Pattern classification of functional MRI measurements of language processing is a potential diagnostic marker of schizophrenia.
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ItemDisease-associated epigenetic changes in monozygotic twins discordant for schizophrenia and bipolar disorder.(Oxford University Press (OUP), 2011-12-15)Studies of the major psychoses, schizophrenia (SZ) and bipolar disorder (BD), have traditionally focused on genetic and environmental risk factors, although more recent work has highlighted an additional role for epigenetic processes in mediating susceptibility. Since monozygotic (MZ) twins share a common DNA sequence, their study represents an ideal design for investigating the contribution of epigenetic factors to disease etiology. We performed a genome-wide analysis of DNA methylation on peripheral blood DNA samples obtained from a unique sample of MZ twin pairs discordant for major psychosis. Numerous loci demonstrated disease-associated DNA methylation differences between twins discordant for SZ and BD individually, and together as a combined major psychosis group. Pathway analysis of our top loci highlighted a significant enrichment of epigenetic changes in biological networks and pathways directly relevant to psychiatric disorder and neurodevelopment. The top psychosis-associated, differentially methylated region, significantly hypomethylated in affected twins, was located in the promoter of ST6GALNAC1 overlapping a previously reported rare genomic duplication observed in SZ. The mean DNA methylation difference at this locus was 6%, but there was considerable heterogeneity between families, with some twin pairs showing a 20% difference in methylation. We subsequently assessed this region in an independent sample of postmortem brain tissue from affected individuals and controls, finding marked hypomethylation (>25%) in a subset of psychosis patients. Overall, our data provide further evidence to support a role for DNA methylation differences in mediating phenotypic differences between MZ twins and in the etiology of both SZ and BD.