title: Functional brain networks in treatment-resistant schizophrenia.
abstract: Up to 20% of individuals with schizophrenia show minimal or no response to medication and are considered to have 'treatment-resistant' schizophrenia (TRS). Unlike early and established schizophrenia, few studies have investigated resting-state functional connectivity (rs-FC) in TRS. Here, we test for disruptions in FC and altered efficiency of functional brain networks in a well-characterized cohort of TRS patients.
  
  
  
  Resting-state functional magnetic resonance imaging was used to investigate functional brain networks in 42 TRS participants prescribed clozapine (30 males, mean age=41.3(10)) and 42 healthy controls (24 males, mean age=38.4(10)). Graph analysis was used to characterize between-group differences in local and global efficiency of functional brain network organization as well as the strength of FC.
  
  
  
  Global brain FC was reduced in TRS patients (p=0.0001). Relative to controls, 3.4% of all functional connections showed reduced strength in TRS (p<0.001), predominantly involving fronto-temporal, fronto-occipital and temporo-occipital connections. Global efficiency was reduced in TRS (p=0.0015), whereas local efficiency was increased (p=0.0042).
  
  
  
  TRS is associated with widespread reductions in rs-FC and altered network topology. Increased local functional network efficiency coupled with decreased global efficiency suggests that hub-to-hub connections are preferentially affected in TRS. These findings further our understanding of the neurobiological impairments in TRS.
authors.affiliation: Melbourne Neuropsychiatry Centre, Department of Psychiatry, The University of Melbourne and Melbourne Health, Carlton South, Victoria, Australia; Orygen, The National Centre of Excellence in Youth Mental Health, Victoria, Australia; The Centre for Youth Mental Health, The University of Melbourne, Victoria, Australia; The Cooperative Research Centre (CRC) for Mental Health, Victoria, Australia; North Western Mental Health, Melbourne Health, Parkville, Victoria, Australia. Electronic address: e.ganella@student.unimelb.edu.au.
authors.forename: Eleni P
authors.initials: EP
authors.lastname: Ganella
authors.affiliation: Melbourne Neuropsychiatry Centre, Department of Psychiatry, The University of Melbourne and Melbourne Health, Carlton South, Victoria, Australia; Orygen, The National Centre of Excellence in Youth Mental Health, Victoria, Australia; The Centre for Youth Mental Health, The University of Melbourne, Victoria, Australia.
authors.forename: Cali F
authors.initials: CF
authors.lastname: Bartholomeusz
authors.affiliation: Melbourne Neuropsychiatry Centre, Department of Psychiatry, The University of Melbourne and Melbourne Health, Carlton South, Victoria, Australia.
authors.forename: Caio
authors.initials: C
authors.lastname: Seguin
authors.affiliation: Melbourne Neuropsychiatry Centre, Department of Psychiatry, The University of Melbourne and Melbourne Health, Carlton South, Victoria, Australia.
authors.forename: Sarah
authors.initials: S
authors.lastname: Whittle
authors.affiliation: Melbourne Neuropsychiatry Centre, Department of Psychiatry, The University of Melbourne and Melbourne Health, Carlton South, Victoria, Australia; The Cooperative Research Centre (CRC) for Mental Health, Victoria, Australia; Florey Institute for Neurosciences and Mental Health, Parkville, Victoria, Australia; Swinburne University of Technology, Centre for Human Psychopharmacology, Hawthorne, Victoria, Australia; The University of Melbourne, Department of General Practice, Parkville, Victoria, Australia.
authors.forename: Chad
authors.initials: C
authors.lastname: Bousman
authors.affiliation: Melbourne Neuropsychiatry Centre, Department of Psychiatry, The University of Melbourne and Melbourne Health, Carlton South, Victoria, Australia.
authors.forename: Christina
authors.initials: C
authors.lastname: Phassouliotis
authors.affiliation: The Cooperative Research Centre (CRC) for Mental Health, Victoria, Australia; North Western Mental Health, Melbourne Health, Parkville, Victoria, Australia; Florey Institute for Neurosciences and Mental Health, Parkville, Victoria, Australia; Centre for Neural Engineering, Department of Electrical and Electronic Engineering, University of Melbourne, Carlton South, Victoria, Australia; Melbourne School of Engineering, The University of Melbourne, Parkville, Victoria, Australia.
authors.forename: Ian
authors.initials: I
authors.lastname: Everall
authors.affiliation: Melbourne Neuropsychiatry Centre, Department of Psychiatry, The University of Melbourne and Melbourne Health, Carlton South, Victoria, Australia; The Cooperative Research Centre (CRC) for Mental Health, Victoria, Australia; North Western Mental Health, Melbourne Health, Parkville, Victoria, Australia; Florey Institute for Neurosciences and Mental Health, Parkville, Victoria, Australia; Centre for Neural Engineering, Department of Electrical and Electronic Engineering, University of Melbourne, Carlton South, Victoria, Australia; Melbourne School of Engineering, The University of Melbourne, Parkville, Victoria, Australia.
authors.forename: Christos
authors.initials: C
authors.lastname: Pantelis
authors.affiliation: Melbourne Neuropsychiatry Centre, Department of Psychiatry, The University of Melbourne and Melbourne Health, Carlton South, Victoria, Australia; Melbourne School of Engineering, The University of Melbourne, Parkville, Victoria, Australia.
authors.forename: Andrew
authors.initials: A
authors.lastname: Zalesky
mesh_terms: D000328:Adult; D002540:Cerebral Cortex / Q000000981:diagnostic imaging / Q000503:physiopathology*; D063132:Connectome / Q000379:methods*; D004351:Drug Resistance; D005260:Female; D006801:Humans; D008279:Magnetic Resonance Imaging / Q000379:methods; D008297:Male; D008875:Middle Aged; D012559:Schizophrenia / Q000000981:diagnostic imaging / Q000503:physiopathology*; D055815:Young Adult
keywords: Functional connectivity; Network efficiency; Treatment-resistant schizophrenia; fMRI