NMDA receptor function in large-scale anticorrelated neural systems with implications for cognition and schizophrenia

Alan Anticevic; Mark Gancsos; John D Murray; Grega Repovs; Naomi R Driesen; Debra J Ennis; Mark J Niciu; Peter T Morgan; Toral S Surti; Michael H Bloch; Ramachandran Ramani; Mark A Smith; Xiao-Jing Wang; John H Krystal; Philip R Corlett

doi:10.1073/pnas.1208494109

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NMDA receptor function in large-scale anticorrelated neural systems with implications for cognition and schizophrenia

Journal article

Open access

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NMDA receptor function in large-scale anticorrelated neural systems with implications for cognition and schizophrenia

Alan Anticevic, Mark Gancsos, John D Murray, Grega Repovs, Naomi R Driesen, Debra J Ennis, Mark J Niciu, Peter T Morgan, Toral S Surti, Michael H Bloch, …

Proceedings of the National Academy of Sciences - PNAS, Vol.109(41), pp.16720-16725

10/09/2012

DOI: 10.1073/pnas.1208494109

PMCID: PMC3478611

PMID: 23012427

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Abstract

Glutamatergic neurotransmission mediated by N -methyl- d -aspartate (NMDA) receptors is vital for the cortical computations underlying cognition and might be disrupted in severe neuropsychiatric illnesses such as schizophrenia. Studies on this topic have been limited to processes in local circuits; however, cognition involves large-scale brain systems with multiple interacting regions. A prominent feature of the human brain’s global architecture is the anticorrelation of default-mode vs. task-positive systems. Here, we show that administration of an NMDA glutamate receptor antagonist, ketamine, disrupted the reciprocal relationship between these systems in terms of task-dependent activation and connectivity during performance of delayed working memory. Furthermore, the degree of this disruption predicted task performance and transiently evoked symptoms characteristic of schizophrenia. We offer a parsimonious hypothesis for this disruption via biophysically realistic computational modeling, namely cortical disinhibition. Together, the present findings establish links between glutamate’s role in the organization of large-scale anticorrelated neural systems, cognition, and symptoms associated with schizophrenia in humans.

Biological Sciences

task-based deactivation

fMRI

Social Sciences

pharmacological manipulation

task-based activation

default-mode network

Details

Title: Subtitle: NMDA receptor function in large-scale anticorrelated neural systems with implications for cognition and schizophrenia
Creators: Alan Anticevic - Connecticut Mental Health Center
Mark Gancsos - Connecticut Mental Health Center
John D Murray - Yale University School of Medicine
Grega Repovs - University of Ljubljana
Naomi R Driesen - Connecticut Mental Health Center
Debra J Ennis - Study Management & Operations
Mark J Niciu - Connecticut Mental Health Center
Peter T Morgan - Connecticut Mental Health Center
Toral S Surti - Connecticut Mental Health Center
Michael H Bloch - Connecticut Mental Health Center
Ramachandran Ramani - Yale University School of Medicine
Mark A Smith - Medical Science, AstraZeneca Pharmaceuticals, Wilmington, DE 19803
Xiao-Jing Wang - Yale University School of Medicine
John H Krystal - VA Connecticut Healthcare System
Philip R Corlett - Connecticut Mental Health Center
Resource Type: Journal article
Publication Details: Proceedings of the National Academy of Sciences - PNAS, Vol.109(41), pp.16720-16725
DOI: 10.1073/pnas.1208494109
PMID: 23012427
PMCID: PMC3478611
NLM abbreviation: Proc Natl Acad Sci U S A
ISSN: 0027-8424
eISSN: 1091-6490
Publisher: National Academy of Sciences
Alternative title: Ketamine disrupts anticorrelated neural systems
Language: English
Date published: 10/09/2012
Academic Unit: Psychiatry; Iowa Neuroscience Institute
Record Identifier: 9984003438802771

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