title: Functional hierarchy underlies preferential connectivity disturbances in schizophrenia.
abstract: Schizophrenia may involve an elevated excitation/inhibition (E/I) ratio in cortical microcircuits. It remains unknown how this regulatory disturbance maps onto neuroimaging findings. To address this issue, we implemented E/I perturbations within a neural model of large-scale functional connectivity, which predicted hyperconnectivity following E/I elevation. To test predictions, we examined resting-state functional MRI in 161 schizophrenia patients and 164 healthy subjects. As predicted, patients exhibited elevated functional connectivity that correlated with symptom levels, and was most prominent in association cortices, such as the fronto-parietal control network. This pattern was absent in patients with bipolar disorder (n = 73). To account for the pattern observed in schizophrenia, we integrated neurobiologically plausible, hierarchical differences in association vs. sensory recurrent neuronal dynamics into our model. This in silico architecture revealed preferential vulnerability of association networks to E/I imbalance, which we verified empirically. Reported effects implicate widespread microcircuit E/I imbalance as a parsimonious mechanism for emergent inhomogeneous dysconnectivity in schizophrenia.
authors.affiliation: Department of Psychiatry, Yale University School of Medicine, New Haven, CT 06511; Interdepartmental Neuroscience Program, Department of Neurobiology, Yale University, New Haven, CT 06520; Abraham Ribicoff Research Facilities, Department of Psychiatry, Connecticut Mental Health Center, New Haven, CT 06519;
authors.forename: Genevieve J
authors.initials: GJ
authors.lastname: Yang
authors.affiliation: Department of Psychiatry, Yale University School of Medicine, New Haven, CT 06511; Center for Neural Science, New York University (NYU), New York, NY 06510;
authors.forename: John D
authors.initials: JD
authors.lastname: Murray
authors.affiliation: Center for Neural Science, New York University (NYU), New York, NY 06510; New York University-East China Normal University Institute of Brain and Cognitive Science, Department of Neural Science, NYU Shanghai, Pudong, 200122 Shanghai, China;
authors.forename: Xiao-Jing
authors.initials: XJ
authors.lastname: Wang
authors.affiliation: Department of Psychiatry, Yale University School of Medicine, New Haven, CT 06511; Olin Neuropsychiatry Research Center, Institute of Living, Hartford Hospital, CT 06106;
authors.forename: David C
authors.initials: DC
authors.lastname: Glahn
authors.affiliation: Department of Psychiatry, Yale University School of Medicine, New Haven, CT 06511; Olin Neuropsychiatry Research Center, Institute of Living, Hartford Hospital, CT 06106; Department of Neurobiology, Yale University School of Medicine, New Haven, CT 06520;
authors.forename: Godfrey D
authors.initials: GD
authors.lastname: Pearlson
authors.affiliation: Department of Psychology, University of Ljubljana, 1000 Ljubljana, Slovenia;
authors.forename: Grega
authors.initials: G
authors.lastname: Repovs
authors.affiliation: Department of Psychiatry, Yale University School of Medicine, New Haven, CT 06511; Abraham Ribicoff Research Facilities, Department of Psychiatry, Connecticut Mental Health Center, New Haven, CT 06519; Department of Neurobiology, Yale University School of Medicine, New Haven, CT 06520;
authors.forename: John H
authors.initials: JH
authors.lastname: Krystal
authors.affiliation: Department of Psychiatry, Yale University School of Medicine, New Haven, CT 06511; Interdepartmental Neuroscience Program, Department of Neurobiology, Yale University, New Haven, CT 06520; Abraham Ribicoff Research Facilities, Department of Psychiatry, Connecticut Mental Health Center, New Haven, CT 06519; Olin Neuropsychiatry Research Center, Institute of Living, Hartford Hospital, CT 06106; Department of Psychology, Yale University, CT 06520 alan.anticevic@yale.edu.
authors.forename: Alan
authors.initials: A
authors.lastname: Anticevic
mesh_terms: D001921:Brain / Q000503:physiopathology; D003198:Computer Simulation; D005625:Frontal Lobe / Q000503:physiopathology; D006801:Humans; D008959:Models, Neurological; D009415:Nerve Net / Q000503:physiopathology*; D009433:Neural Inhibition / Q000502:physiology; D010296:Parietal Lobe / Q000503:physiopathology; D012559:Schizophrenia / Q000503:physiopathology*
keywords: computational modeling; functional connectivity; schizophrenia