title: Schizophrenia is associated with a pattern of spatial working memory deficits consistent with cortical disinhibition.
abstract: Schizophrenia is associated with severe cognitive deficits, including impaired working memory (WM). A neural mechanism that may contribute to WM impairment is the disruption in excitation-inhibition (E/I) balance in cortical microcircuits. It remains unknown, however, how these alterations map onto quantifiable behavioral deficits in patients. Based on predictions from a validated microcircuit model of spatial WM, we hypothesized two key behavioral consequences: i) increased variability of WM traces over time, reducing performance precision; and ii) decreased ability to filter out distractors that overlap with WM representations. To test model predictions, we studied N=27 schizophrenia patients and N=28 matched healthy comparison subjects (HCS) who performed a spatial WM task designed to test the computational model. Specifically, we manipulated delay duration and distractor distance presented during the delay. Subjects used a high-sensitivity joystick to indicate the remembered location, yielding a continuous response measure. Results largely followed model predictions, whereby patients exhibited increased variance and less WM precision as the delay period increased relative to HCS. Schizophrenia patients also exhibited increased WM distractibility, with reports biased toward distractors at specific spatial locations, as predicted by the model. Finally, the magnitude of the WM drift and distractibility were significantly correlated, indicating a possibly shared underlying mechanism. Effects are consistent with elevated E/I ratio in schizophrenia, establishing a framework for translating neural circuit computational model of cognition to human experiments, explicitly testing mechanistic behavioral hypotheses of cellular-level neural deficits in patients.
authors.affiliation: Department of Psychiatry, Yale University School of Medicine, 300 George Street, New Haven, CT 06511, USA; Department of Psychology, University of Ljubljana, Ljubljana, Slovenia.
authors.forename: Martina
authors.initials: M
authors.lastname: Starc
authors.affiliation: Department of Psychiatry, Yale University School of Medicine, 300 George Street, New Haven, CT 06511, USA; Center for Neural Science, New York University, New York, NY 06510, USA.
authors.forename: John D
authors.initials: JD
authors.lastname: Murray
authors.affiliation: Department of Psychiatry, Yale University School of Medicine, 300 George Street, New Haven, CT 06511, USA.
authors.forename: Nicole
authors.initials: N
authors.lastname: Santamauro
authors.affiliation: Department of Psychiatry, Yale University School of Medicine, 300 George Street, New Haven, CT 06511, USA; University Psychiatric Hospital Vrapce, University of Zagreb, Zagreb 10000, Croatia.
authors.forename: Aleksandar
authors.initials: A
authors.lastname: Savic
authors.affiliation: Department of Psychiatry, Yale University School of Medicine, 300 George Street, New Haven, CT 06511, USA; Department of Psychology, University of Ljubljana, Ljubljana, Slovenia.
authors.forename: Caroline
authors.initials: C
authors.lastname: Diehl
authors.affiliation: Department of Psychiatry, Yale University School of Medicine, 300 George Street, New Haven, CT 06511, USA.
authors.forename: Youngsun T
authors.initials: YT
authors.lastname: Cho
authors.affiliation: Department of Psychiatry, Yale University School of Medicine, 300 George Street, New Haven, CT 06511, USA.
authors.forename: Vinod
authors.initials: V
authors.lastname: Srihari
authors.affiliation: Department of Psychiatry, Yale University School of Medicine, 300 George Street, New Haven, CT 06511, USA.
authors.forename: Peter T
authors.initials: PT
authors.lastname: Morgan
authors.affiliation: Department of Psychiatry, Yale University School of Medicine, 300 George Street, New Haven, CT 06511, USA; Department of Neurobiology, Yale University, New Haven, CT, USA.
authors.forename: John H
authors.initials: JH
authors.lastname: Krystal
authors.affiliation: Center for Neural Science, New York University, New York, NY 06510, USA.
authors.forename: Xiao-Jing
authors.initials: XJ
authors.lastname: Wang
authors.affiliation: Department of Psychology, University of Ljubljana, Ljubljana, Slovenia.
authors.forename: Grega
authors.initials: G
authors.lastname: Repovs
authors.affiliation: Department of Psychiatry, Yale University School of Medicine, 300 George Street, New Haven, CT 06511, USA; Abraham Ribicoff Research Facilities, Connecticut Mental Health Center, New Haven, CT 06519, USA; Interdepartmental Neuroscience Program, Yale University, New Haven, CT 06520, USA; NIAAA Center for the Translational Neuroscience of Alcoholism, New Haven, CT 06519, USA; Department of Psychology, Yale University, 2 Hillhouse Avenue, CT 06520, USA. Electronic address: alan.anticevic@yale.edu.
authors.forename: Alan
authors.initials: A
authors.lastname: Anticevic
mesh_terms: D000328:Adult; D002540:Cerebral Cortex / Q000503:physiopathology*; D003198:Computer Simulation; D005260:Female; D006801:Humans; D008297:Male; D008570:Memory, Short-Term / Q000502:physiology*; D008959:Models, Neurological; D009483:Neuropsychological Tests; D011618:Psychotic Disorders / Q000503:physiopathology / Q000523:psychology; D012559:Schizophrenia / Q000503:physiopathology*; D012565:Schizophrenic Psychology
keywords: Cognitive deficits; Computational modeling; Disinhibition; Excitation/inhibition balance; Schizophrenia; Working memory