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

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish (US)
Pages (from-to)16720-16725
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number41
StatePublished - Oct 9 2012


  • Default-mode network
  • Pharmacological manipulation
  • Task-based activation
  • Task-based deactivation
  • fMRI

ASJC Scopus subject areas

  • General


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