NMDA receptor function in large-scale anticorrelated neural systems with implications for cognition and schizophrenia
Alan Anticevic, Mark G. Gancsos, John D. Murray, Grega Repovš, Naomi R. Driesen, Debra J. Ennis, Mark J. Niciu, Peter T Morgan, Toral Surti, Michael H. Bloch, Ramachandran Ramani, Mark A. Smith, Xiao-Jing Wang, John H. Krystal, Philip R. Corlett
Proceedings of the National Academy of Sciences September 25, 2012 DOI: 10.1073/pnas.1208494109 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Experimental study Peer reviewed |
|---|---|
| Population | Humans |
| Intervention | Ketamine |
| Keywords | Nmda receptor Disinhibition Schizophrenia object-oriented programming Cognition Glutamatergic Glutamate receptor Ampa receptor Memantine |
| Citations | 260 |
| Key findings | Ketamine administration disrupted the anticorrelated relationship between default-mode and task-positive brain systems, and this disruption predicted task performance and transient schizophrenia-like symptoms. |
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.