title: Dynamic brain network reconfiguration as a potential schizophrenia genetic risk mechanism modulated by NMDA receptor function.
abstract: 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.
authors: Department of Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany; urs.braun@zi-mannheim.de heike.tost@zi-mannheim.de.
authors: Urs
authors: U
authors: Braun
authors: Department of Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany.
authors: Axel
authors: A
authors: Schäfer
authors: Department of Bioengineering, University of Pennsylvania, Philadelphia, PA 19104.|Department of Electrical & Systems Engineering, University of Pennsylvania, Philadelphia, PA 19104.
authors: Danielle S
authors: 0000-0002-6183-4493
authors: DS
authors: Bassett
authors: Department of Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany.
authors: Franziska
authors: F
authors: Rausch
authors: Department of Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany.
authors: Janina I
authors: JI
authors: Schweiger
authors: Department of Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany.
authors: Edda
authors: E
authors: Bilek
authors: Department of Psychiatry and Psychotherapy, Charité-University Medicine Berlin, Campus Mitte, Berlin, Germany.
authors: Susanne
authors: S
authors: Erk
authors: Department of Psychiatry and Psychotherapy, Charité-University Medicine Berlin, Campus Mitte, Berlin, Germany.
authors: Nina
authors: N
authors: Romanczuk-Seiferth
authors: Department of Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany.
authors: Oliver
authors: O
authors: Grimm
authors: Department of Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany.
authors: Lena S
authors: LS
authors: Geiger
authors: Department of Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany.
authors: Leila
authors: L
authors: Haddad
authors: Department of Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany.
authors: Kristina
authors: K
authors: Otto
authors: Department of Psychiatry and Psychotherapy, Charité-University Medicine Berlin, Campus Mitte, Berlin, Germany.
authors: Sebastian
authors: S
authors: Mohnke
authors: Department of Psychiatry and Psychotherapy, Charité-University Medicine Berlin, Campus Mitte, Berlin, Germany.
authors: Andreas
authors: A
authors: Heinz
authors: Department of Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany.
authors: Mathias
authors: M
authors: Zink
authors: Department of Psychiatry and Psychotherapy, Charité-University Medicine Berlin, Campus Mitte, Berlin, Germany.
authors: Henrik
authors: H
authors: Walter
authors: Department of Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany.
authors: Emanuel
authors: E
authors: Schwarz
authors: Department of Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany.
authors: Andreas
authors: A
authors: Meyer-Lindenberg
authors: Department of Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany; urs.braun@zi-mannheim.de heike.tost@zi-mannheim.de.
authors: Heike
authors: H
authors: Tost
mesh_terms: D000293:Adolescent; D000328:Adult; D001921:Brain / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology*; D001931:Brain Mapping; D003915:Dextromethorphan / Q000627:therapeutic use; D018691:Excitatory Amino Acid Antagonists / Q000627:therapeutic use; D005260:Female; D006801:Humans; D008279:Magnetic Resonance Imaging / Q000379:methods; D008297:Male; D008570:Memory, Short-Term / Q000187:drug effects / Q000502:physiology; D009415:Nerve Net / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology*; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D012559:Schizophrenia / Q000235:genetics / Q000503:physiopathology*; D055815:Young Adult
chemical_list: D018691:Excitatory Amino Acid Antagonists; D016194:Receptors, N-Methyl-D-Aspartate; D003915:Dextromethorphan
keywords: NMDA receptor function; dynamic network neuroscience; intermediate phenotype; schizophrenia; working memory