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      Enhanced switching and familial susceptibility for psychosis

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          Abstract

          Introduction

          Working Memory and Task‐Switching are essential components of cognitive control, which underlies many symptoms evident across multiple neuropsychiatric disorders, including psychotic and mood disorders. Vulnerability to these disorders has a substantial genetic component, suggesting that clinically unaffected first‐degree relatives may carry some vulnerability‐related traits. Converging evidence from animal and human studies demonstrates that dopamine transmission, striatal and frontal brain regions, and attention and switching behaviors are essential components of a multilevel circuit involved in salience, and disruptions in that circuit may lead to features of psychosis. Yet, it is possible that unaffected relatives may also possess characteristics that protect against development of illness. We hypothesized that reduced switch cost in a cued task‐switching task, may be a behavioral expression of this “resilience” phenotype that will be observable in unaffected relatives.

          Methods

          We tested a large community sample ( n = 536) via the web, to assess different subcomponents of cognitive control, including task‐switching and working memory, as well as risk‐taking, among individuals who report having an affected relative with a psychotic or mood disorder.

          Results

          Healthy individuals with suspected genetic risk due to a self‐reported familial history of a psychotic disorder demonstrated better task‐switching performance compared to healthy people without a psychiatrically ill relative and those with a relative with a mood disorder. This result was specific to illness status and task domain, in that individuals with a personal history of depression or anxiety did not show improved task‐switching performance, and this improvement was selective to task‐switching and not seen in other putative cognitive control domains (working memory or risk taking).

          Conclusions

          Although this study has limitations and independent replication is needed, these preliminary findings suggest a potential avenue for understanding susceptibility to these disorders by highlighting possible protective as well as vulnerability‐related aspects of risk phenotypes.

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          Most cited references 54

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          Lifetime and 12-month prevalence of DSM-III-R psychiatric disorders in the United States. Results from the National Comorbidity Survey.

          This study presents estimates of lifetime and 12-month prevalence of 14 DSM-III-R psychiatric disorders from the National Comorbidity Survey, the first survey to administer a structured psychiatric interview to a national probability sample in the United States. The DSM-III-R psychiatric disorders among persons aged 15 to 54 years in the noninstitutionalized civilian population of the United States were assessed with data collected by lay interviewers using a revised version of the Composite International Diagnostic Interview. Nearly 50% of respondents reported at least one lifetime disorder, and close to 30% reported at least one 12-month disorder. The most common disorders were major depressive episode, alcohol dependence, social phobia, and simple phobia. More than half of all lifetime disorders occurred in the 14% of the population who had a history of three or more comorbid disorders. These highly comorbid people also included the vast majority of people with severe disorders. Less than 40% of those with a lifetime disorder had ever received professional treatment, and less than 20% of those with a recent disorder had been in treatment during the past 12 months. Consistent with previous risk factor research, it was found that women had elevated rates of affective disorders and anxiety disorders, that men had elevated rates of substance use disorders and antisocial personality disorder, and that most disorders declined with age and with higher socioeconomic status. The prevalence of psychiatric disorders is greater than previously thought to be the case. Furthermore, this morbidity is more highly concentrated than previously recognized in roughly one sixth of the population who have a history of three or more comorbid disorders. This suggests that the causes and consequences of high comorbidity should be the focus of research attention. The majority of people with psychiatric disorders fail to obtain professional treatment. Even among people with a lifetime history of three or more comorbid disorders, the proportion who ever obtain specialty sector mental health treatment is less than 50%. These results argue for the importance of more outreach and more research on barriers to professional help-seeking.
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            Effect of COMT Val108/158 Met genotype on frontal lobe function and risk for schizophrenia.

            Abnormalities of prefrontal cortical function are prominent features of schizophrenia and have been associated with genetic risk, suggesting that susceptibility genes for schizophrenia may impact on the molecular mechanisms of prefrontal function. A potential susceptibility mechanism involves regulation of prefrontal dopamine, which modulates the response of prefrontal neurons during working memory. We examined the relationship of a common functional polymorphism (Val(108/158) Met) in the catechol-O-methyltransferase (COMT) gene, which accounts for a 4-fold variation in enzyme activity and dopamine catabolism, with both prefrontally mediated cognition and prefrontal cortical physiology. In 175 patients with schizophrenia, 219 unaffected siblings, and 55 controls, COMT genotype was related in allele dosage fashion to performance on the Wisconsin Card Sorting Test of executive cognition and explained 4% of variance (P = 0.001) in frequency of perseverative errors. Consistent with other evidence that dopamine enhances prefrontal neuronal function, the load of the low-activity Met allele predicted enhanced cognitive performance. We then examined the effect of COMT genotype on prefrontal physiology during a working memory task in three separate subgroups (n = 11-16) assayed with functional MRI. Met allele load consistently predicted a more efficient physiological response in prefrontal cortex. Finally, in a family-based association analysis of 104 trios, we found a significant increase in transmission of the Val allele to the schizophrenic offspring. These data suggest that the COMT Val allele, because it increases prefrontal dopamine catabolism, impairs prefrontal cognition and physiology, and by this mechanism slightly increases risk for schizophrenia.
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              Task switching.

              Everyday life requires frequent shifts between cognitive tasks. Research reviewed in this article probes the control processes that reconfigure mental resources for a change of task by requiring subjects to switch frequently among a small set of simple tasks. Subjects' responses are substantially slower and, usually, more error-prone immediately after a task switch. This 'switch cost' is reduced, but not eliminated, by an opportunity for preparation. It seems to result from both transient and long-term carry-over of 'task-set' activation and inhibition as well as time consumed by task-set reconfiguration processes. Neuroimaging studies of task switching have revealed extra activation in numerous brain regions when subjects prepare to change tasks and when they perform a changed task, but we cannot yet separate 'controlling' from 'controlled' regions.
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                Author and article information

                Contributors
                fws@uoregon.edu
                Journal
                Brain Behav
                Brain Behav
                10.1002/(ISSN)2157-9032
                BRB3
                Brain and Behavior
                John Wiley and Sons Inc. (Hoboken )
                2162-3279
                25 April 2018
                June 2018
                : 8
                : 6 ( doiID: 10.1002/brb3.2018.8.issue-6 )
                Affiliations
                [ 1 ] Lewis Center for Neuroimaging University of Oregon Eugene Oregon
                [ 2 ] Semel Institute for Neuroscience and Human Behavior UCLA Los Angeles California
                [ 3 ] Department of Psychology University of Oregon Eugene Oregon
                [ 4 ] Brain Research Institute UCLA Los Angeles California
                Author notes
                [* ] Correspondence

                Fred W. Sabb, Lewis Center for Neuroimaging, University of Oregon, Eugene, OR.

                Email: fws@ 123456uoregon.edu

                Article
                BRB3988
                10.1002/brb3.988
                5991556
                © 2018 The Authors. Brain and Behavior published by Wiley Periodicals, Inc.

                This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

                Page count
                Figures: 5, Tables: 1, Pages: 13, Words: 10230
                Product
                Funding
                Funded by: National Institute of Mental Health
                Award ID: R01MH091669
                Award ID: P50MH077248
                Funded by: National Alliance for Research on Schizophrenia and Depression
                Funded by: Stagin Family
                Funded by: Miller Family Foundation
                Categories
                Original Research
                Original Research
                Custom metadata
                2.0
                brb3988
                June 2018
                Converter:WILEY_ML3GV2_TO_NLMPMC version:version=5.4.1 mode:remove_FC converted:07.06.2018

                Neurosciences

                vulnerability, heritability, internet, phenotype, resilience, set shifting, cognitive control

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