title: Delayed Development of Brain Connectivity in Adolescents With Schizophrenia and Their Unaffected Siblings.
abstract: OBJECTIVE
  Abnormalities in structural brain connectivity have been observed in patients with schizophrenia. Mapping these abnormalities longitudinally and understanding their genetic risk via sibship studies will provide crucial insight into progressive developmental changes associated with schizophrenia.
  
  
  OBJECTIVE
  To identify corticocortical connections exhibiting an altered developmental trajectory in adolescents with childhood-onset schizophrenia (COS) and to determine whether similar alterations are found in patients' unaffected siblings.
  
  
  METHODS
  Using prospective structural brain magnetic resonance imaging, large-scale corticocortical connectivity was mapped from ages 12 to 24 years in 109 patients with COS (272 images), 86 of their unaffected siblings (184 images), and 102 healthy controls (262 images) over a 20-year period beginning January 1, 1991, through April 30, 2011, as part of the ongoing COS study at the National Institute of Mental Health.
  
  
  METHODS
  Structural connectivity between pairs of cortical regions was estimated using a validated technique based on across-subject covariation in magnetic resonance imaging-derived cortical thickness measurements.
  
  
  RESULTS
  Compared with normally developing controls, significant left-hemisphere occipitotemporal deficits in cortical thickness correlations were found in patients with COS as well as their healthy siblings (P < .05). Deficits in siblings normalized by mid-adolescence, whereas patients with COS showed significantly longer maturational delays, with cortical thickness correlations between the left temporal lobe and left occipital cortex not showing evidence of development until early adulthood. The normalization of deficits with age in patients with COS correlated with improvement in symptoms. Compared with controls, left-hemisphere occipitotemporal thickness correlations in a subgroup of patients with high positive symptoms were significantly reduced from age 14 to 18 years (P < .05); however, other patients with low positive symptoms showed no significant deficits.
  
  
  CONCLUSIONS
  Delayed maturation of occipitotemporal connectivity appears to be a trait marker in patients with COS, with a milder endophenotype in unaffected siblings associated with resilience to developing schizophrenia. These findings indicate genetically influenced and connection-specific developmental abnormalities in the schizophrenia connectome, and lead to the hypothesis that visual hallucinations in patients with COS may be because of delayed development of the inferior longitudinal fasciculus, a prominent occipitotemporal fiber.
authors.affiliation: Melbourne Neuropsychiatry Centre, The University of Melbourne and Melbourne Health, Victoria, Australia.
authors.forename: Andrew
authors.initials: A
authors.lastname: Zalesky
authors.affiliation: Melbourne Neuropsychiatry Centre, The University of Melbourne and Melbourne Health, Victoria, Australia.
authors.forename: Christos
authors.initials: C
authors.lastname: Pantelis
authors.affiliation: Melbourne Neuropsychiatry Centre, The University of Melbourne and Melbourne Health, Victoria, Australia.
authors.forename: Vanessa
authors.initials: V
authors.lastname: Cropley
authors.affiliation: Melbourne Neuropsychiatry Centre, The University of Melbourne and Melbourne Health, Victoria, Australia2Monash Clinical and Imaging Neuroscience, School of Psychology and Psychiatry and Monash Biomedical Imaging, Monash University, Melbourne, Australia.
authors.forename: Alex
authors.initials: A
authors.lastname: Fornito
authors.affiliation: Queensland Brain Institute, The University of Queensland, Brisbane, Australia.
authors.forename: Luca
authors.initials: L
authors.lastname: Cocchi
authors.affiliation: Child Psychiatry Branch, National Institute of Mental Health, Bethesda, Maryland.
authors.forename: Harrison
authors.initials: H
authors.lastname: McAdams
authors.affiliation: Child Psychiatry Branch, National Institute of Mental Health, Bethesda, Maryland.
authors.forename: Liv
authors.initials: L
authors.lastname: Clasen
authors.affiliation: Child Psychiatry Branch, National Institute of Mental Health, Bethesda, Maryland.
authors.forename: Deanna
authors.initials: D
authors.lastname: Greenstein
authors.affiliation: Child Psychiatry Branch, National Institute of Mental Health, Bethesda, Maryland.
authors.forename: Judith L
authors.initials: JL
authors.lastname: Rapoport
authors.affiliation: Child Psychiatry Branch, National Institute of Mental Health, Bethesda, Maryland.
authors.forename: Nitin
authors.initials: N
authors.lastname: Gogtay
mesh_terms: D000293:Adolescent; D001931:Brain Mapping; D016022:Case-Control Studies; D002540:Cerebral Cortex / Q000254:growth & development / Q000503:physiopathology; D002648:Child; D002658:Developmental Disabilities / Q000473:pathology / Q000503:physiopathology; D058068:Endophenotypes; D005260:Female; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D009434:Neural Pathways / Q000254:growth & development / Q000503:physiopathology; D009778:Occipital Lobe / Q000254:growth & development* / Q000503:physiopathology; D009929:Organ Size; D011446:Prospective Studies; D012559:Schizophrenia / Q000473:pathology* / Q000503:physiopathology; D035781:Siblings; D013702:Temporal Lobe / Q000254:growth & development* / Q000503:physiopathology; D013997:Time Factors; D055815:Young Adult