title: Abnormal frontoparietal synaptic gain mediating the P300 in patients with psychotic disorder and their unaffected relatives.
abstract: The "dysconnection hypothesis" of psychosis suggests that a disruption of functional integration underlies cognitive deficits and clinical symptoms. Impairments in the P300 potential are well documented in psychosis. Intrinsic (self-)connectivity in a frontoparietal cortical hierarchy during a P300 experiment was investigated. Dynamic Causal Modeling was used to estimate how evoked activity results from the dynamics of coupled neural populations and how neural coupling changes with the experimental factors. Twenty-four patients with psychotic disorder, twenty-four unaffected relatives, and twenty-five controls underwent EEG recordings during an auditory oddball paradigm. Sixteen frontoparietal network models (including primary auditory, superior parietal, and superior frontal sources) were analyzed and an optimal model of neural coupling, explaining diagnosis and genetic risk effects, as well as their interactions with task condition were identified. The winning model included changes in connectivity at all three hierarchical levels. Patients showed decreased self-inhibition-that is, increased cortical excitability-in left superior frontal gyrus across task conditions, compared with unaffected participants. Relatives had similar increases in excitability in left superior frontal and right superior parietal sources, and a reversal of the normal synaptic gain changes in response to targets relative to standard tones. It was confirmed that both subjects with psychotic disorder and their relatives show a context-independent loss of synaptic gain control at the highest hierarchy levels. The relatives also showed abnormal gain modulation responses to task-relevant stimuli. These may be caused by NMDA-receptor and/or GABAergic pathologies that change the excitability of superficial pyramidal cells and may be a potential biological marker for psychosis. Hum Brain Mapp 38:3262-3276, 2017. © 2017 Wiley Periodicals, Inc.
authors.affiliation: Division of Psychiatry, University College London, London, United Kingdom.|Department of Basic Psychology II - Cognitive processes, Faculty of Psychology, Complutense University of Madrid, Madrid, Spain.|Laboratory of Cognitive and Computational Neuroscience - Centre for Biomedical Technology (CTB), Complutense University and Technical University of Madrid, Madrid, Spain.
authors.forename: Álvaro
authors.identifier: 0000-0002-1725-1223
authors.initials: Á
authors.lastname: Díez
authors.affiliation: Division of Psychiatry, University College London, London, United Kingdom.|Psychology & Neuroscience - King's College London, Institute of Psychiatry, London, United Kingdom.
authors.forename: Siri
authors.identifier: 0000-0003-2899-6746
authors.initials: S
authors.lastname: Ranlund
authors.affiliation: The Wellcome Trust Centre for Neuroimaging, Institute of Neurology, University College London, London, United Kingdom.|The Picower Institute for Learning & Memory and Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, Massachusetts.
authors.forename: Dimitris
authors.identifier: 0000-0002-6865-8103
authors.initials: D
authors.lastname: Pinotsis
authors.affiliation: Division of Psychiatry, University College London, London, United Kingdom.
authors.forename: Stella
authors.initials: S
authors.lastname: Calafato
authors.affiliation: North East London NHS Foundation Trust, London, United Kingdom.|Psychology & Neuroscience - King's College London, Institute of Psychiatry, London, United Kingdom.
authors.forename: Madiha
authors.initials: M
authors.lastname: Shaikh
authors.affiliation: Psychosis Neurobiology Laboratory, McLean Hospital, Harvard Medical School, Belmont, Massachusetts.
authors.forename: Mei-Hua
authors.initials: MH
authors.lastname: Hall
authors.affiliation: Division of Psychiatry, University College London, London, United Kingdom.|Psychology & Neuroscience - King's College London, Institute of Psychiatry, London, United Kingdom.
authors.forename: Muriel
authors.identifier: 0000-0001-6829-1105
authors.initials: M
authors.lastname: Walshe
authors.affiliation: Department of Basic Psychology II - Cognitive processes, Faculty of Psychology, Complutense University of Madrid, Madrid, Spain.|Laboratory of Cognitive and Computational Neuroscience - Centre for Biomedical Technology (CTB), Complutense University and Technical University of Madrid, Madrid, Spain.
authors.forename: Ángel
authors.identifier: 0000-0002-1660-8294
authors.initials: Á
authors.lastname: Nevado
authors.affiliation: The Wellcome Trust Centre for Neuroimaging, Institute of Neurology, University College London, London, United Kingdom.
authors.forename: Karl J
authors.identifier: 0000-0001-7984-8909
authors.initials: KJ
authors.lastname: Friston
authors.affiliation: Division of Psychiatry, University College London, London, United Kingdom.|Institute of Cognitive Neuroscience, University College London, London, United Kingdom.
authors.forename: Rick A
authors.identifier: 0000-0002-7661-8881
authors.initials: RA
authors.lastname: Adams
authors.affiliation: Division of Psychiatry, University College London, London, United Kingdom.|Psychology & Neuroscience - King's College London, Institute of Psychiatry, London, United Kingdom.|Institute of Cognitive Neuroscience, University College London, London, United Kingdom.
authors.forename: Elvira
authors.identifier: 0000-0003-1369-5983
authors.initials: E
authors.lastname: Bramon
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D001499:Bayes Theorem; D001931:Brain Mapping; D004569:Electroencephalography; D018913:Event-Related Potentials, P300 / Q000502:physiology*; D005190:Family; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D008959:Models, Neurological; D009415:Nerve Net / Q000000981:diagnostic imaging / Q000503:physiopathology*; D017711:Nonlinear Dynamics; D017397:Prefrontal Cortex / Q000000981:diagnostic imaging / Q000503:physiopathology*; D011569:Psychiatric Status Rating Scales; D011618:Psychotic Disorders / Q000473:pathology* / Q000503:physiopathology*; D055815:Young Adult
keywords: DCM; GABA; NMDA; P300; cortical excitability; dynamic causal modeling; effective connectivity; genetic risk; intrinsic connectivity; psychosis; schizophrenia; self-inhibition; synaptic gain; unaffected relatives