Psychiatry - Research Publications
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ItemNo Preview AvailableBiological insights from 108 schizophrenia-associated genetic loci(NATURE PORTFOLIO, 2014-07-24)Schizophrenia is a highly heritable disorder. Genetic risk is conferred by a large number of alleles, including common alleles of small effect that might be detected by genome-wide association studies. Here we report a multi-stage schizophrenia genome-wide association study of up to 36,989 cases and 113,075 controls. We identify 128 independent associations spanning 108 conservatively defined loci that meet genome-wide significance, 83 of which have not been previously reported. Associations were enriched among genes expressed in brain, providing biological plausibility for the findings. Many findings have the potential to provide entirely new insights into aetiology, but associations at DRD2 and several genes involved in glutamatergic neurotransmission highlight molecules of known and potential therapeutic relevance to schizophrenia, and are consistent with leading pathophysiological hypotheses. Independent of genes expressed in brain, associations were enriched among genes expressed in tissues that have important roles in immunity, providing support for the speculated link between the immune system and schizophrenia.
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ItemPredicting the diagnosis of autism spectrum disorder using gene pathway analysis(NATURE PUBLISHING GROUP, 2014-04)Autism spectrum disorder (ASD) depends on a clinical interview with no biomarkers to aid diagnosis. The current investigation interrogated single-nucleotide polymorphisms (SNPs) of individuals with ASD from the Autism Genetic Resource Exchange (AGRE) database. SNPs were mapped to Kyoto Encyclopedia of Genes and Genomes (KEGG)-derived pathways to identify affected cellular processes and develop a diagnostic test. This test was then applied to two independent samples from the Simons Foundation Autism Research Initiative (SFARI) and Wellcome Trust 1958 normal birth cohort (WTBC) for validation. Using AGRE SNP data from a Central European (CEU) cohort, we created a genetic diagnostic classifier consisting of 237 SNPs in 146 genes that correctly predicted ASD diagnosis in 85.6% of CEU cases. This classifier also predicted 84.3% of cases in an ethnically related Tuscan cohort; however, prediction was less accurate (56.4%) in a genetically dissimilar Han Chinese cohort (HAN). Eight SNPs in three genes (KCNMB4, GNAO1, GRM5) had the largest effect in the classifier with some acting as vulnerability SNPs, whereas others were protective. Prediction accuracy diminished as the number of SNPs analyzed in the model was decreased. Our diagnostic classifier correctly predicted ASD diagnosis with an accuracy of 71.7% in CEU individuals from the SFARI (ASD) and WTBC (controls) validation data sets. In conclusion, we have developed an accurate diagnostic test for a genetically homogeneous group to aid in early detection of ASD. While SNPs differ across ethnic groups, our pathway approach identified cellular processes common to ASD across ethnicities. Our results have wide implications for detection, intervention and prevention of ASD.
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ItemFunctional and structural alterations in the cingulate motor area relate to decreased fronto-striatal coupling in major depressive disorder with psychomotor disturbances(FRONTIERS MEDIA SA, 2014-12-04)Psychomotor disturbances are a classic feature of major depressive disorders. These can manifest as lack of facial expressions and decreased speech production, reduced body posture and mobility, and slowed voluntary movement. The neural correlates of psychomotor disturbances in depression are poorly understood but it has been suggested that outputs from the cingulate motor area (CMA) to striatal motor regions, including the putamen, could be involved. We used functional and structural magnetic resonance imaging to conduct a region-of-interest analysis to test the hypotheses that neural activation patterns related to motor production and gray matter volumes in the CMA would be different between depressed subjects displaying psychomotor disturbances (n = 13) and matched healthy controls (n = 13). In addition, we conducted a psychophysiological interaction analysis to assess the functional coupling related to self-paced finger-tapping between the caudal CMA and the posterior putamen in patients compared to controls. We found a cluster of increased neural activation, adjacent to a cluster of decreased gray matter volume in the caudal CMA in patients compared to controls. The functional coupling between the left caudal CMA and the left putamen during finger-tapping task performance was additionally decreased in patients compared to controls. In addition, the strength of the functional coupling between the left caudal CMA and the left putamen was negatively correlated with the severity of psychomotor disturbances in the patient group. In conclusion, we found converging evidence for involvement of the caudal CMA and putamen in the generation of psychomotor disturbances in depression.
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ItemDelayed sleep onset in depressed young people(BMC, 2014-02-08)BACKGROUND: The circadian abnormality of delayed sleep phase has been suggested to characterise a subgroup of depressed young adults with different risk factors and course of illness. We aim to assess the prevalence and factors, particularly substance use, associated with such delay in a large help-seeking cohort of young people with mental health problems. METHODS: From a consecutively recruited sample of 802 help-seeking young people, 305 (38%) had at least moderate depressive symptoms (QIDS-C16 >10), sleep data and did not have a chronic severe mental illness. Demographic and clinical characteristics were evaluated through self report and clinical interview. Delayed sleep phase was defined as a sleep onset between the hours of 02:00 a.m. - 06:00 a.m. and the characteristics of this group were compared to normal phase sleepers. RESULTS: Delayed sleep onset was reported amongst 18% (n = 56/305) of the depressed group compared to 11% of the non-depressed young people. Amongst the depressed group, delayed sleep onset was associated with tobacco, alcohol and cannabis misuse and short sleep duration (x̅: 5.8 hrs vs. x̅: 7.8 hrs). There were no differences in demographic factors, personality traits or symptoms. Tobacco smoking was very common: In logistic regression analyses only tobacco use (OR 2.28, 95% CI: 1.04 - 5.01) was associated with delayed sleep onset. There was no interaction with age. CONCLUSIONS: Delayed sleep onset was twice as common in depressed young people as the general population and young people with other mental health problems, and is a potential marker for a subgroup of mood disorders. Those with delayed sleep onset were not more severely depressed but had short sleep duration, a risk for chronic psychological ill health, and higher levels of tobacco use. Nicotine use was common in this group, has biological evidence as a sleep disrupter, and requires specifically addressing in this population.
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ItemDisruption of structure-function coupling in the schizophrenia connectome(ELSEVIER SCI LTD, 2014)Neuroimaging studies have demonstrated that the phenomenology of schizophrenia maps onto diffuse alterations in large-scale functional and structural brain networks. However, the relationship between structural and functional deficits remains unclear. To answer this question, patients with established schizophrenia and matched healthy controls underwent resting-state functional and diffusion weighted imaging. The network-based statistic was used to characterize between-group differences in whole-brain functional connectivity. Indices of white matter integrity were then estimated to assess the structural correlates of the functional alterations observed in patients. Finally, group differences in the relationship between indices of functional and structural brain connectivity were determined. Compared to controls, patients with schizophrenia showed decreased functional connectivity and impaired white matter integrity in a distributed network encompassing frontal, temporal, thalamic, and striatal regions. In controls, strong interregional coupling in neural activity was associated with well-myelinated white matter pathways in this network. This correspondence between structure and function appeared to be absent in patients with schizophrenia. In two additional disrupted functional networks, encompassing parietal, occipital, and temporal cortices, the relationship between function and structure was not affected. Overall, results from this study highlight the importance of considering not only the separable impact of functional and structural connectivity deficits on the pathoaetiology of schizophrenia, but also the implications of the complex nature of their interaction. More specifically, our findings support the core nature of fronto-striatal, fronto-thalamic, and fronto-temporal abnormalities in the schizophrenia connectome.
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ItemBiomarkers and clinical staging in psychiatry(WILEY, 2014-10)Personalized medicine is rapidly becoming a reality in today's physical medicine. However, as yet this is largely an aspirational goal in psychiatry, despite significant advances in our understanding of the biochemical, genetic and neurobiological processes underlying major mental disorders. Preventive medicine relies on the availability of predictive tools; in psychiatry we still largely lack these. Furthermore, our current diagnostic systems, with their focus on well-established, largely chronic illness, do not support a pre-emptive, let alone a preventive, approach, since it is during the early stages of a disorder that interventions have the potential to offer the greatest benefit. Here, we present a clinical staging model for severe mental disorders and discuss examples of biological markers that have already undergone some systematic evaluation and that could be integrated into such a framework. The advantage of this model is that it explicitly considers the evolution of psychopathology during the development of a mental illness and emphasizes that progression of illness is by no means inevitable, but can be altered by providing appropriate interventions that target individual modifiable risk and protective factors. The specific goals of therapeutic intervention are therefore broadened to include the prevention of illness onset or progression, and to minimize the risk of harm associated with more complex treatment regimens. The staging model also facilitates the integration of new data on the biological, social and environmental factors that influence mental illness into our clinical and diagnostic infrastructure, which will provide a major step forward in the development of a truly pre-emptive psychiatry.
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ItemNo Preview AvailableCognitive deficits in youth with familial and clinical high risk to psychosis: a systematic review and meta-analysis(WILEY, 2014-07)OBJECTIVE: It is likely that cognitive deficits are vulnerability markers for developing schizophrenia, as these deficits are already well-established findings in first-episode psychosis. Studies at-risk adolescents and young adults are likely to provide information about cognitive deficits that predate the onset of the illness. METHOD: We conducted meta-analyses of studies comparing familial-high risk (FHR) or ultra-high risk (UHR; n = 2113) and healthy controls (n = 1748) in youth studies in which the mean age was between 15 and 29. RESULTS: Compared with controls, high risk subjects were impaired in each domain in both UHR (d = 0.34-0.71) and FHR (d = 0.24-0.81). Heterogeneity of effect sizes across studies was modest, increasing confidence to the findings of the current meta-analysis (I(2) = 0-0.18%). In both risk paradigms, co-occurrence of genetic risk with attenuated symptoms was associated with more severe cognitive dysfunction. In UHR, later transition to psychosis was associated with more severe cognitive deficits in all domains (d = 0.31-0.49) except sustained attention. However, cognitive impairment has a limited capacity to predict the outcome of high-risk patients. CONCLUSION: Cognitive deficits are already evident in adolescents and young adults who have familial or clinical risk for psychosis. Longitudinal developmental studies are important to reveal timing and trajectory of emergence of such deficits.
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ItemThe neural cascade of olfactory processing: A combined fMRI-EEG study(ELSEVIER SCIENCE BV, 2014-12-01)Olfaction is dependent on respiration for the delivery of odorants to the nasal cavity. Taking advantage of the time-locked nature of inspiration and olfactory processing, electroencephalogram dipole modeling (EEG/DT) has previously been used to identify a cascade of inspiration-triggered neural activity moving from primary limbic olfactory regions to frontal cortical areas during odor perception. In this study, we leverage the spatial resolution of functional magnetic resonance imaging (fMRI) alongside the temporal resolution of EEG to replicate and extend these findings. Brain activation identified by both modalities converged within association regions of the orbitofrontal cortex that were activated from approximately 150-300 ms after inspiration onset. EEG/DT was additionally sensitive to more transient activity in primary olfactory regions, including the parahippocampal gyrus and amygdala, occurring approximately 50 ms post-inspiration. These results provide a partial validation of the spatial profile of the olfactory cascade identified by EEG source modeling, and inform novel future directions in the investigation of human olfaction.
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ItemResponse to Belgard et al.(SPRINGERNATURE, 2014-04)
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ItemNo Preview AvailableAltered Striatal Functional Connectivity in Subjects With an At-Risk Mental State for Psychosis(OXFORD UNIV PRESS, 2014-07)Recent functional imaging work in individuals experiencing an at-risk mental state (ARMS) for psychosis has implicated dorsal striatal abnormalities in the emergence of psychotic symptoms, contrasting with earlier findings implicating the ventral striatum. Our aims here were to characterize putative dorsal and ventral striatal circuit-level abnormalities in ARMS individuals using resting-state functional magnetic resonance imaging (fMRI) and to investigate their relationship to positive psychotic symptoms. Resting-state fMRI was acquired in 74 ARMS subjects and 35 matched healthy controls. An established method for mapping ventral and dorsal striatal functional connectivity was used to examine corticostriatal functional integrity. Positive psychotic symptoms were assessed using the Comprehensive Assessment of At-Risk Mental State and the Positive and Negative Syndrome Scale. Compared with healthy controls, ARMS subjects showed reductions in functional connectivity between the dorsal caudate and right dorsolateral prefrontal cortex, left rostral medial prefrontal cortex, and thalamus, and between the dorsal putamen and left thalamic and lenticular nuclei. ARMS subjects also showed increased functional connectivity between the ventral putamen and the insula, frontal operculum, and superior temporal gyrus bilaterally. No differences in ventral striatal (ie, nucleus accumbens) functional connectivity were found. Altered functional connectivity in corticostriatal circuits were significantly correlated with positive psychotic symptoms. Together, these results suggest that risk for psychosis is mediated by a complex interplay of alterations in both dorsal and ventral corticostriatal systems.