Schizophrenia is associated with a pattern of spatial working memory deficits consistent with cortical disinhibition
Martina Starc, John D Murray, Nicole Santamauro, Aleksandar Savic, Caroline Diehl, Youngsun T Cho, Vinod Srihari, Peter T Morgan, John H Krystal, Xiao-Jing Wang, Grega Repovs, Alan Anticevic, Martina Starc, John D Murray, Nicole Santamauro, Aleksandar Savic, Caroline Diehl, Youngsun T Cho, Vinod Srihari, Peter T Morgan, John H Krystal, Xiao-Jing Wang, Grega Repovs, Alan Anticevic
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.
Keywords: Cognitive deficits; Computational modeling; Disinhibition; Excitation/inhibition balance; Schizophrenia; Working memory.
Conflict of interest statement
Financial conflicts of interest
J.H.K. consults for several pharmaceutical and biotechnology companies with compensation less than $10,000 per year. He also has stock options in two companies, each valued less than $2000 and three patents for pharmacotherapies for psychiatric disorders. None of these financial interests are directly related to this paper. All other authors declare that they have no conflict of interest.
Copyright © 2016. Published by Elsevier B.V.
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Source: PubMed