title: Early-course unmedicated schizophrenia patients exhibit elevated prefrontal connectivity associated with longitudinal change.
abstract: Strong evidence implicates prefrontal cortex (PFC) as a major source of functional impairment in severe mental illness such as schizophrenia. Numerous schizophrenia studies report deficits in PFC structure, activation, and functional connectivity in patients with chronic illness, suggesting that deficient PFC functional connectivity occurs in this disorder. However, the PFC functional connectivity patterns during illness onset and its longitudinal progression remain uncharacterized. Emerging evidence suggests that early-course schizophrenia involves increased PFC glutamate, which might elevate PFC functional connectivity. To test this hypothesis, we examined 129 non-medicated, human subjects diagnosed with early-course schizophrenia and 106 matched healthy human subjects using both whole-brain data-driven and hypothesis-driven PFC analyses of resting-state fMRI. We identified increased PFC connectivity in early-course patients, predictive of symptoms and diagnostic classification, but less evidence for "hypoconnectivity." At the whole-brain level, we observed "hyperconnectivity" around areas centered on the default system, with modest overlap with PFC-specific effects. The PFC hyperconnectivity normalized for a subset of the sample followed longitudinally (n = 25), which also predicted immediate symptom improvement. Biologically informed computational modeling implicates altered overall connection strength in schizophrenia. The initial hyperconnectivity, which may decrease longitudinally, could have prognostic and therapeutic implications.
authors.affiliation: Huaxi MR Research Center (HMRRC), Departments of Radiology, Psychiatry, and Psychology,West China Hospital and Schools of Clinical Medicine and Public Administration, Sichuan University, Chengdu, Sichuan, 610041 China, Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut 06511, Departments of Psychiatry and Oncology, Stat Key Laboratory of Biotherapy, West China Hospital of Sichuan University, Chengdu, Sichuan, 610041 China, Abraham Ribicoff Research Facilities, Connecticut Mental Health Center, New Haven, Connecticut 06519, Interdepartmental Neuroscience Program, Yale University, New Haven, Connecticut 06520, Department of Psychology, Yale University, New Haven, Connecticut 06520.
authors.forename: Alan
authors.initials: A
authors.lastname: Anticevic
authors.affiliation: Huaxi MR Research Center (HMRRC), Departments of Radiology, Psychiatry, and Psychology,West China Hospital and Schools of Clinical Medicine and Public Administration, Sichuan University, Chengdu, Sichuan, 610041 China.
authors.forename: Xinyu
authors.initials: X
authors.lastname: Hu
authors.affiliation: Huaxi MR Research Center (HMRRC), Departments of Radiology, Psychiatry, and Psychology,West China Hospital and Schools of Clinical Medicine and Public Administration, Sichuan University, Chengdu, Sichuan, 610041 China.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Xiao
authors.affiliation: Departments of Psychiatry and Oncology, Stat Key Laboratory of Biotherapy, West China Hospital of Sichuan University, Chengdu, Sichuan, 610041 China.
authors.forename: Junmei
authors.initials: J
authors.lastname: Hu
authors.affiliation: Huaxi MR Research Center (HMRRC), Departments of Radiology, Psychiatry, and Psychology,West China Hospital and Schools of Clinical Medicine and Public Administration, Sichuan University, Chengdu, Sichuan, 610041 China.
authors.forename: Fei
authors.initials: F
authors.lastname: Li
authors.affiliation: Departments of Psychiatry and Oncology, Stat Key Laboratory of Biotherapy, West China Hospital of Sichuan University, Chengdu, Sichuan, 610041 China.
authors.forename: Feng
authors.initials: F
authors.lastname: Bi
authors.affiliation: Center for Molecular and Behavioral Neuroscience, Rutgers University, Newark, New Jersey 07102.
authors.forename: Michael W
authors.initials: MW
authors.lastname: Cole
authors.affiliation: University Psychiatric Hospital Vrapce, University of Zagreb, Zagreb 10000, Croatia.
authors.forename: Aleksandar
authors.initials: A
authors.lastname: Savic
authors.affiliation: Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut 06511, Interdepartmental Neuroscience Program, Yale University, New Haven, Connecticut 06520.
authors.forename: Genevieve J
authors.initials: GJ
authors.lastname: Yang
authors.affiliation: Department of Psychology, University of Ljubljana, 1000 Ljubljana, Slovenia, and.
authors.forename: Grega
authors.initials: G
authors.lastname: Repovs
authors.affiliation: Center for Neural Science, New York University, New York, New York 06510.
authors.forename: John D
authors.initials: JD
authors.lastname: Murray
authors.affiliation: Center for Neural Science, New York University, New York, New York 06510.
authors.forename: Xiao-Jing
authors.initials: XJ
authors.lastname: Wang
authors.affiliation: Huaxi MR Research Center (HMRRC), Departments of Radiology, Psychiatry, and Psychology,West China Hospital and Schools of Clinical Medicine and Public Administration, Sichuan University, Chengdu, Sichuan, 610041 China.
authors.forename: Xiaoqi
authors.initials: X
authors.lastname: Huang
authors.affiliation: Huaxi MR Research Center (HMRRC), Departments of Radiology, Psychiatry, and Psychology,West China Hospital and Schools of Clinical Medicine and Public Administration, Sichuan University, Chengdu, Sichuan, 610041 China.
authors.forename: Su
authors.initials: S
authors.lastname: Lui
authors.affiliation: Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut 06511.
authors.forename: John H
authors.initials: JH
authors.lastname: Krystal
authors.affiliation: Huaxi MR Research Center (HMRRC), Departments of Radiology, Psychiatry, and Psychology,West China Hospital and Schools of Clinical Medicine and Public Administration, Sichuan University, Chengdu, Sichuan, 610041 China, Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut 06511, qiyonggong@hmrrc.org.cn.
authors.forename: Qiyong
authors.initials: Q
authors.lastname: Gong
mesh_terms: D000293:Adolescent; D000328:Adult; D042241:Early Diagnosis; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D008137:Longitudinal Studies; D008297:Male; D009415:Nerve Net / Q000502:physiology*; D017397:Prefrontal Cortex / Q000502:physiology*; D012559:Schizophrenia / Q000175:diagnosis* / Q000503:physiopathology*; D012565:Schizophrenic Psychology; D055815:Young Adult
keywords: computational modeling; first episode; hyperconnectivity; longitudinal; prefrontal cortex; schizophrenia