title: Connectivity, pharmacology, and computation: toward a mechanistic understanding of neural system dysfunction in schizophrenia.
abstract: Neuropsychiatric diseases such as schizophrenia and bipolar illness alter the structure and function of distributed neural networks. Functional neuroimaging tools have evolved sufficiently to reliably detect system-level disturbances in neural networks. This review focuses on recent findings in schizophrenia and bipolar illness using resting-state neuroimaging, an advantageous approach for biomarker development given its ease of data collection and lack of task-based confounds. These benefits notwithstanding, neuroimaging does not yet allow the evaluation of individual neurons within local circuits, where pharmacological treatments ultimately exert their effects. This limitation constitutes an important obstacle in translating findings from animal research to humans and from healthy humans to patient populations. Integrating new neuroscientific tools may help to bridge some of these gaps. We specifically discuss two complementary approaches. The first is pharmacological manipulations in healthy volunteers, which transiently mimic some cardinal features of psychiatric conditions. We specifically focus on recent neuroimaging studies using the NMDA receptor antagonist, ketamine, to probe glutamate synaptic dysfunction associated with schizophrenia. Second, we discuss the combination of human pharmacological imaging with biophysically informed computational models developed to guide the interpretation of functional imaging studies and to inform the development of pathophysiologic hypotheses. To illustrate this approach, we review clinical investigations in addition to recent findings of how computational modeling has guided inferences drawn from our studies involving ketamine administration to healthy subjects. Thus, this review asserts that linking experimental studies in humans with computational models will advance to effort to bridge cellular, systems, and clinical neuroscience approaches to psychiatric disorders.
authors.affiliation: Department of Psychiatry, Yale University School of Medicine , New Haven, CT , USA ; NIAAA Center for the Translational Neuroscience of Alcoholism , New Haven, CT , USA ; Abraham Ribicoff Research Facilities, Connecticut Mental Health Center , New Haven, CT , USA ; Interdepartmental Neuroscience Program, Yale University , New Haven, CT , USA ; Olin Neuropsychiatry Research Center, Institute of Living, Hartford Hospital , Hartford, CT , USA ; Department of Psychology, Yale University , New Haven, CT , USA.
authors.forename: Alan
authors.initials: A
authors.lastname: Anticevic
authors.affiliation: Department of Psychology, Washington University in St. Louis , St. Louis, MO , USA.
authors.forename: Michael W
authors.initials: MW
authors.lastname: Cole
authors.affiliation: Department of Psychology, University of Ljubljana , Ljubljana , Slovenia.
authors.forename: Grega
authors.initials: G
authors.lastname: Repovs
authors.affiliation: Department of Psychiatry, University of Zagreb School of Medicine , Zagreb , Croatia.
authors.forename: Aleksandar
authors.initials: A
authors.lastname: Savic
authors.affiliation: Department of Psychiatry, Yale University School of Medicine , New Haven, CT , USA.
authors.forename: Naomi R
authors.initials: NR
authors.lastname: Driesen
authors.affiliation: Department of Psychiatry, Yale University School of Medicine , New Haven, CT , USA ; Interdepartmental Neuroscience Program, Yale University , New Haven, CT , USA.
authors.forename: Genevieve
authors.initials: G
authors.lastname: Yang
authors.affiliation: Department of Psychiatry, Yale University School of Medicine , New Haven, CT , USA.
authors.forename: Youngsun T
authors.initials: YT
authors.lastname: Cho
authors.affiliation: Center for Neural Science, New York University , New York, NY , USA.
authors.forename: John D
authors.initials: JD
authors.lastname: Murray
authors.affiliation: Department of Psychiatry, Yale University School of Medicine , New Haven, CT , USA ; Olin Neuropsychiatry Research Center, Institute of Living, Hartford Hospital , Hartford, CT , USA.
authors.forename: David C
authors.initials: DC
authors.lastname: Glahn
authors.affiliation: Center for Neural Science, New York University , New York, NY , USA.
authors.forename: Xiao-Jing
authors.initials: XJ
authors.lastname: Wang
authors.affiliation: Department of Psychiatry, Yale University School of Medicine , New Haven, CT , USA ; NIAAA Center for the Translational Neuroscience of Alcoholism , New Haven, CT , USA ; Abraham Ribicoff Research Facilities, Connecticut Mental Health Center , New Haven, CT , USA ; Department of Neurobiology, Yale University School of Medicine , New Haven, CT , USA.
authors.forename: John H
authors.initials: JH
authors.lastname: Krystal
keywords: NMDA receptors; computational modeling; functional connectivity; glutamate; pharmacology; schizophrenia; thalamus