期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 113, 期 44, 页码 12568-12573出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1608819113
关键词
dynamic network neuroscience; schizophrenia; NMDA receptor function; intermediate phenotype; working memory
资金
- BMBF [01GQ1102]
- Deutsche Forschungsgemeinschaft (DFG) (Collaborative Research Center) [SFB 636, B7]
- German Federal Ministry of Education and Research (BMBF) through the Integrated Network IntegraMent (Integrated Understanding of Causes and Mechanisms in Mental Disorders) under the auspices of the e:Med Programme (BMBF) [01ZX1314G]
- Innovative Medicines Initiative Joint Undertaking (IMI) [115300, 602805]
- John D. and Catherine T. MacArthur Foundation
- Alfred P. Sloan Foundation
- Army Research Laboratory
- Army Research Office [W911NF-10-2-0022, W911NF-14-1-0679]
- National Institute of Mental Health [2-R01-DC-009209-11]
- National Institute of Child Health and Human Development [1R01HD086888-01]
- Office of Naval Research
- National Science Foundation [Grants Faculty Early Career Development (CAREER)] [PHY-1554488, BCS-1441502, BCS-1430087]
- DFG [ZI 1253/3-1, ZI 1253/3-2]
- DFG (Emmy Noether Program) [SCHW 1768/1-1]
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.
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