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

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
JournalSchizophrenia Research
DOIs
StateAccepted/In press - Feb 1 2016

Fingerprint

Memory Disorders
Short-Term Memory
Schizophrenia
Healthy Volunteers
Spatial Memory
Aptitude
Cognition

Keywords

  • Cognitive deficits
  • Computational modeling
  • Disinhibition
  • Excitation/inhibition balance
  • Schizophrenia
  • Working memory

ASJC Scopus subject areas

  • Psychiatry and Mental health
  • Biological Psychiatry

Cite this

Schizophrenia is associated with a pattern of spatial working memory deficits consistent with cortical disinhibition. / Starc, Martina; Murray, John D.; Santamauro, Nicole; Savic, Aleksandar; Diehl, Caroline; Cho, Youngsun T.; Srihari, Vinod; Morgan, Peter T.; Krystal, John H.; Wang, Xiao-Jing; Repovs, Grega; Anticevic, Alan.

In: Schizophrenia Research, 01.02.2016.

Research output: Contribution to journalArticle

Starc, M, Murray, JD, Santamauro, N, Savic, A, Diehl, C, Cho, YT, Srihari, V, Morgan, PT, Krystal, JH, Wang, X-J, Repovs, G & Anticevic, A 2016, 'Schizophrenia is associated with a pattern of spatial working memory deficits consistent with cortical disinhibition', Schizophrenia Research. https://doi.org/10.1016/j.schres.2016.10.011
Starc, Martina ; Murray, John D. ; Santamauro, Nicole ; Savic, Aleksandar ; Diehl, Caroline ; Cho, Youngsun T. ; Srihari, Vinod ; Morgan, Peter T. ; Krystal, John H. ; Wang, Xiao-Jing ; Repovs, Grega ; Anticevic, Alan. / Schizophrenia is associated with a pattern of spatial working memory deficits consistent with cortical disinhibition. In: Schizophrenia Research. 2016.
@article{08d526679505421da317abcd27a5e33b,
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.",
keywords = "Cognitive deficits, Computational modeling, Disinhibition, Excitation/inhibition balance, Schizophrenia, Working memory",
author = "Martina Starc and Murray, {John D.} and Nicole Santamauro and Aleksandar Savic and Caroline Diehl and Cho, {Youngsun T.} and Vinod Srihari and Morgan, {Peter T.} and Krystal, {John H.} and Xiao-Jing Wang and Grega Repovs and Alan Anticevic",
year = "2016",
month = "2",
day = "1",
doi = "10.1016/j.schres.2016.10.011",
language = "English (US)",
journal = "Schizophrenia Research",
issn = "0920-9964",
publisher = "Elsevier",

}

TY - JOUR

T1 - Schizophrenia is associated with a pattern of spatial working memory deficits consistent with cortical disinhibition

AU - Starc, Martina

AU - Murray, John D.

AU - Santamauro, Nicole

AU - Savic, Aleksandar

AU - Diehl, Caroline

AU - Cho, Youngsun T.

AU - Srihari, Vinod

AU - Morgan, Peter T.

AU - Krystal, John H.

AU - Wang, Xiao-Jing

AU - Repovs, Grega

AU - Anticevic, Alan

PY - 2016/2/1

Y1 - 2016/2/1

N2 - 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.

AB - 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.

KW - Cognitive deficits

KW - Computational modeling

KW - Disinhibition

KW - Excitation/inhibition balance

KW - Schizophrenia

KW - Working memory

UR - http://www.scopus.com/inward/record.url?scp=84994468187&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84994468187&partnerID=8YFLogxK

U2 - 10.1016/j.schres.2016.10.011

DO - 10.1016/j.schres.2016.10.011

M3 - Article

JO - Schizophrenia Research

JF - Schizophrenia Research

SN - 0920-9964

ER -