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

Glutamate signaling through NMDA receptors is essential for brain computations that support cognition, and its disruption may contribute to schizophrenia. Using ketamine, an NMDA receptor antagonist, the study found that the normal anticorrelation between the default-mode and task-positive brain systems was disrupted during a working memory task. The degree of this disruption predicted task performance and produced schizophrenia-like symptoms. A computational model suggests that cortical disinhibition underlies this effect, linking glutamate's role in large-scale brain organization to cognition and psychiatric symptoms.

Study at a glance

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.