title: NMDA receptor function in large-scale anticorrelated neural systems with implications for cognition and schizophrenia.
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.
authors.affiliation: Department of Psychiatry, Yale University School of Medicine, New Haven, CT 06510, USA.
authors.forename: Alan
authors.initials: A
authors.lastname: Anticevic
authors.forename: Mark
authors.initials: M
authors.lastname: Gancsos
authors.forename: John D
authors.initials: JD
authors.lastname: Murray
authors.forename: Grega
authors.initials: G
authors.lastname: Repovs
authors.forename: Naomi R
authors.initials: NR
authors.lastname: Driesen
authors.forename: Debra J
authors.initials: DJ
authors.lastname: Ennis
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Niciu
authors.forename: Peter T
authors.initials: PT
authors.lastname: Morgan
authors.forename: Toral S
authors.initials: TS
authors.lastname: Surti
authors.forename: Michael H
authors.initials: MH
authors.lastname: Bloch
authors.forename: Ramachandran
authors.initials: R
authors.lastname: Ramani
authors.forename: Mark A
authors.initials: MA
authors.lastname: Smith
authors.forename: Xiao-Jing
authors.initials: XJ
authors.lastname: Wang
authors.forename: John H
authors.initials: JH
authors.lastname: Krystal
authors.forename: Philip R
authors.initials: PR
authors.lastname: Corlett
mesh_terms: D000328:Adult; D000465:Algorithms; D001921:Brain / Q000187:drug effects / Q000502:physiology*; D003071:Cognition / Q000187:drug effects / Q000502:physiology*; D004311:Double-Blind Method; D018691:Excitatory Amino Acid Antagonists / Q000008:administration & dosage / Q000494:pharmacology; D005260:Female; D006801:Humans; D007262:Infusions, Intravenous; D007649:Ketamine / Q000008:administration & dosage / Q000494:pharmacology; D008279:Magnetic Resonance Imaging; D008297:Male; D008568:Memory / Q000187:drug effects / Q000502:physiology; D008959:Models, Neurological; D010364:Pattern Recognition, Visual / Q000187:drug effects / Q000502:physiology; D011597:Psychomotor Performance / Q000187:drug effects / Q000502:physiology; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors / Q000502:physiology*; D012559:Schizophrenia / Q000503:physiopathology*; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology; D055815:Young Adult
chemical_list: D018691:Excitatory Amino Acid Antagonists; D016194:Receptors, N-Methyl-D-Aspartate; D007649:Ketamine