Dynamic brain network reconfiguration as a potential schizophrenia genetic risk mechanism modulated by NMDA receptor function
Significance Converging evidence points to a role for glutamate and altered brain network dynamics in schizophrenia, but the molecular and genetic contributions are poorly understood. Here, we applied dynamic network neuroscience methods to neuroimaging working memory data to identify potential alterations in brain network flexibility related to schizophrenia genetic risk and N methyl d aspartate (NMDA) receptor hypofunction. Consistent with altered network dynamics, we detected significant increases in brain network flexibility in patients with schizophrenia, healthy first degree relatives, and healthy subjects receiving a single dose of an NMDA receptor antagonist. Our data identify a potential dynamic network intermediate phenotype related to the genetic risk for schizophrenia and point to a critical role for glutamate in the temporal coordination of neural networks and the pathophysiology of schizophrenia. Schizophrenia is increasingly recognized as a disorder of distributed neural dynamics, but the molecular and genetic contributions are poorly understood. Recent work highlights a role for altered N methyl d aspartate (NMDA) receptor signaling and related impairments in the excitation inhibitory balance and synchrony of large scale neural networks. Here, we combined a pharmacological intervention with novel techniques from dynamic network neuroscience applied to functional magnetic resonance imaging (fMRI) to identify alterations in the dynamic reconfiguration of brain networks related to schizophrenia genetic risk and NMDA receptor hypofunction. We quantified "network flexibility," a measure of the dynamic reconfiguration of the community structure of time variant brain networks during working memory performance. Comparing 28 patients with schizophrenia, 37 unaffected first degree relatives, and 139 healthy controls, we detected significant differences in network flexibility [F(2,196) 6.541, P 0.002] in a pattern consistent with the assumed genetic risk load of the groups (highest for patients, intermediate for relatives, and lowest for controls) In an observer blinded, placebo controlled, randomized, cross over pharmacological challenge study in 37 healthy controls, we further detected a significant increase in network flexibility as a result of NMDA receptor antagonism with 120 mg dextromethorphan [F(1,34) 5.291, P 0.028] Our results identify a potential dynamic network intermediate phenotype related to the genetic liability for schizophrenia that manifests as altered reconfiguration of brain networks during working memory. The phenotype appears to be influenced by NMDA receptor antagonism, consistent with a critical role for glutamate in the temporal coordination of neural networks and the pathophysiology of schizophrenia.
Proceedings of the National Academy of Sciences