The brain is an inherently dynamic system, and executive cognition requires dynamically reconfiguring, highly evolving networks of brain regions that interact in complex and transient communication patterns. However, a precise characterization of these reconfiguration processes during cognitive function in humans remains elusive. Here, we use a series of techniques developed in the field of "dynamic network neuroscience" to investigate the dynamics of functional brain networks in 344 healthy subjects during a working-memory challenge (the "n-back" task). In contrast to a control condition, in which dynamic changes in cortical networks were spread evenly across systems, the effortful working-memory condition was characterized by a reconfiguration of frontoparietal and frontotemporal networks. This reconfiguration, which characterizes "network flexibility," employs transient and heterogeneous connectivity between frontal systems, which we refer to as "integration." Frontal integration predicted neuropsychological measures requiring working memory and executive cognition, suggesting that dynamic network reconfiguration between frontal systems supports those functions. Our results characterize dynamic reconfiguration of large-scale distributed neural circuits during executive cognition in humans and have implications for understanding impaired cognitive function in disorders affecting connectivity, such as schizophrenia or dementia.

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. S chizophrenia is a highly heritable mental disorder for which aberrant interactions between brain regions or "dysconnectivity" have been proposed as a core neural mechanism (1). Functional magnetic resonance imaging (fMRI) studies demonstrate alterations in specific neural subcircuits in schizophrenia (2, 3) that are under genetic control (4), although recent data from network neuroscience point to more widespread disturbances in the dynamics of large-scale brain networks (5, 6). Uhlhaas (5), Uhlhaas and Singer (6), and Phillips and Silverstein (7) have proposed a plausible pathophysiological mechanism for these phenomena: They argue that alterations in the cellular excitation-inhibitory balance may lead to disturbances in the neural synchrony of large-scale cell ensembles and give rise to the dysconnectivity phenomena at the level of neural ensembles.The neural excitation-inhibitory balance is highly dependent on glutamatergic N-methyl-D-aspartate (NMDA) receptor function (8), and alterations in NMDA receptor signaling have been associated with schizophrenia risk (9), disorder-related cognitive abnormalities (10, 11), and deficits in the temporal coordination of large-scale bra...