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      Impaired prefrontal synaptic gain in people with psychosis and their relatives during the mismatch negativity

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          Abstract

          The mismatch negativity (MMN) evoked potential, a preattentive brain response to a discriminable change in auditory stimulation, is significantly reduced in psychosis. Glutamatergic theories of psychosis propose that hypofunction of NMDA receptors (on pyramidal cells and inhibitory interneurons) causes a loss of synaptic gain control. We measured changes in neuronal effective connectivity underlying the MMN using dynamic causal modeling (DCM), where the gain (excitability) of superficial pyramidal cells is explicitly parameterised. EEG data were obtained during a MMN task—for 24 patients with psychosis, 25 of their first‐degree unaffected relatives, and 35 controls—and DCM was used to estimate the excitability (modeled as self‐inhibition) of (source‐specific) superficial pyramidal populations. The MMN sources, based on previous research, included primary and secondary auditory cortices, and the right inferior frontal gyrus. Both patients with psychosis and unaffected relatives (to a lesser degree) showed increased excitability in right inferior frontal gyrus across task conditions, compared to controls. Furthermore, in the same region, both patients and their relatives showed a reversal of the normal response to deviant stimuli; that is, a decrease in excitability in comparison to standard conditions. Our results suggest that psychosis and genetic risk for the illness are associated with both context‐dependent (condition‐specific) and context‐independent abnormalities of the excitability of superficial pyramidal cell populations in the MMN paradigm. These abnormalities could relate to NMDA receptor hypofunction on both pyramidal cells and inhibitory interneurons, and appear to be linked to the genetic aetiology of the illness, thereby constituting potential endophenotypes for psychosis. Hum Brain Mapp 37:351–365, 2016. © 2015 The Authors Human Brain Mapping Published by Wiley Periodicals, Inc.

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          Most cited references 132

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          The positive and negative syndrome scale (PANSS) for schizophrenia.

          The variable results of positive-negative research with schizophrenics underscore the importance of well-characterized, standardized measurement techniques. We report on the development and initial standardization of the Positive and Negative Syndrome Scale (PANSS) for typological and dimensional assessment. Based on two established psychiatric rating systems, the 30-item PANSS was conceived as an operationalized, drug-sensitive instrument that provides balanced representation of positive and negative symptoms and gauges their relationship to one another and to global psychopathology. It thus constitutes four scales measuring positive and negative syndromes, their differential, and general severity of illness. Study of 101 schizophrenics found the four scales to be normally distributed and supported their reliability and stability. Positive and negative scores were inversely correlated once their common association with general psychopathology was extracted, suggesting that they represent mutually exclusive constructs. Review of five studies involving the PANSS provided evidence of its criterion-related validity with antecedent, genealogical, and concurrent measures, its predictive validity, its drug sensitivity, and its utility for both typological and dimensional assessment.
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            Dynamic causal modelling.

            In this paper we present an approach to the identification of nonlinear input-state-output systems. By using a bilinear approximation to the dynamics of interactions among states, the parameters of the implicit causal model reduce to three sets. These comprise (1) parameters that mediate the influence of extrinsic inputs on the states, (2) parameters that mediate intrinsic coupling among the states, and (3) [bilinear] parameters that allow the inputs to modulate that coupling. Identification proceeds in a Bayesian framework given known, deterministic inputs and the observed responses of the system. We developed this approach for the analysis of effective connectivity using experimentally designed inputs and fMRI responses. In this context, the coupling parameters correspond to effective connectivity and the bilinear parameters reflect the changes in connectivity induced by inputs. The ensuing framework allows one to characterise fMRI experiments, conceptually, as an experimental manipulation of integration among brain regions (by contextual or trial-free inputs, like time or attentional set) that is revealed using evoked responses (to perturbations or trial-bound inputs, like stimuli). As with previous analyses of effective connectivity, the focus is on experimentally induced changes in coupling (cf., psychophysiologic interactions). However, unlike previous approaches in neuroimaging, the causal model ascribes responses to designed deterministic inputs, as opposed to treating inputs as unknown and stochastic.
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              Cortical parvalbumin interneurons and cognitive dysfunction in schizophrenia.

              Deficits in cognitive control, a core disturbance of schizophrenia, appear to emerge from impaired prefrontal gamma oscillations. Cortical gamma oscillations require strong inhibitory inputs to pyramidal neurons from the parvalbumin basket cell (PVBC) class of GABAergic neurons. Recent findings indicate that schizophrenia is associated with multiple pre- and postsynaptic abnormalities in PVBCs, each of which weakens their inhibitory control of pyramidal cells. These findings suggest a new model of cortical dysfunction in schizophrenia in which PVBC inhibition is decreased to compensate for an upstream deficit in pyramidal cell excitation. This compensation is thought to rebalance cortical excitation and inhibition, but at a level insufficient to generate the gamma oscillation power required for high levels of cognitive control. Copyright © 2011 Elsevier Ltd. All rights reserved.
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                Author and article information

                Journal
                Hum Brain Mapp
                Hum Brain Mapp
                10.1002/(ISSN)1097-0193
                HBM
                Human Brain Mapping
                John Wiley and Sons Inc. (Hoboken )
                1065-9471
                1097-0193
                27 October 2015
                January 2016
                : 37
                : 1 ( doiID: 10.1002/hbm.v37.1 )
                : 351-365
                Affiliations
                [ 1 ] Division of PsychiatryUniversity College London LondonUnited Kingdom
                [ 2 ]Institute of Cognitive Neuroscience, University College London LondonUnited Kingdom
                [ 3 ] Department of PsychiatryHospital Beatriz Angelo LisbonPortugal
                [ 4 ] The South London and Maudsley NHS Foundation TrustNIHR Biomedical Research Centre for Mental Health at the Institute of Psychiatry, Psychology and Neuroscience, King's College London United Kingdom
                [ 5 ] Psychology Research LaboratoryHarvard Medical School, McLean Hospital Belmont MassachusettsUSA
                [ 6 ] Department of PsychiatryClinical Science Institute, National University of Ireland GalwayIreland
                [ 7 ] Department of PsychiatryClinical and Experimental Science Institute, University of Foggia Italy
                [ 8 ] The South London and Maudsley NHS Foundation TrustUniversity Hospital Lewisham LondonUnited Kingdom
                [ 9 ]Neuroepidemiology and Ageing Research Unit, Imperial College LondonUnited Kingdom
                [ 10 ]The Wellcome Trust Centre for Neuroimaging, Institute of Neurology, University College London LondonUnited Kingdom
                Author notes
                [* ]Correspondence to: Siri Ranlund, Division of Psychiatry, University College London, 6th Floor Maple House, 149 Tottenham Court Road, London W1T 7NF, United Kingdom. Email: s.ranlund@ 123456ucl.ac.uk
                Article
                HBM23035
                10.1002/hbm.23035
                4843949
                26503033
                © 2015 The Authors Human BrainMapping Published byWiley Periodicals, Inc.

                This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

                Page count
                Pages: 15
                Product
                Funding
                Funded by: National Institute for Health Research, UK
                Award ID: PDA/02/06/016
                Categories
                Research Article
                Research Articles
                Custom metadata
                2.0
                hbm23035
                January 2016
                Converter:WILEY_ML3GV2_TO_NLMPMC version:4.8.6 mode:remove_FC converted:25.04.2016

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