Dynamic brain network reconfiguration as a potential schizophrenia genetic risk mechanism modulated by NMDA receptor function.

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TitleDynamic brain network reconfiguration as a potential schizophrenia genetic risk mechanism modulated by NMDA receptor function.
Publication TypeJournal Article
Year of Publication2016
AuthorsBraun, U, Schäfer, A, Bassett, DS, Rausch, F, Schweiger, JI, Bilek, E, Erk, S, Romanczuk-Seiferth, N, Grimm, O, Geiger, LS, Haddad, L, Otto, K, Mohnke, S, Heinz, A, Zink, M, Walter, H, Schwarz, E, Meyer-Lindenberg, A, Tost, H
JournalProc Natl Acad Sci U S A
Date Published2016 11 01
KeywordsAdolescent, Adult, Brain, Brain Mapping, Dextromethorphan, Excitatory Amino Acid Antagonists, Female, Humans, Magnetic Resonance Imaging, Male, Memory, Short-Term, Nerve Net, Receptors, N-Methyl-D-Aspartate, Schizophrenia, Young Adult

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.

Alternate JournalProc. Natl. Acad. Sci. U.S.A.
PubMed ID27791105
PubMed Central IDPMC5098640
Grant ListR01 DC009209 / DC / NIDCD NIH HHS / United States
R01 HD086888 / HD / NICHD NIH HHS / United States