title: Altered white matter connectivity as a neural substrate for social impairment in Autism Spectrum Disorder.
abstract: BACKGROUND
  Autism Spectrum Disorder (ASD) symptoms have been hypothesized to result from altered brain connectivity. The 'disconnectivity' hypothesis has been used to explain characteristic impairments in socio-emotional function, observed clinically in ASD. Here, we review the evidence for impaired white matter connectivity as a neural substrate for socio-emotional dysfunction in ASD. A review of diffusion tensor imaging (DTI) studies, and focused discussion of relevant post-mortem, structural, and functional neuroimaging studies, is provided.
  
  
  METHODS
  Studies were identified using a sensitive search strategy in MEDLINE, Embase and PsycINFO article databases using the OvidSP database interface. Search terms included database subject headings for the concepts of pervasive developmental disorders, and DTI. Seventy-two published DTI studies examining white matter microstructure in ASD were reviewed. A comprehensive discussion of DTI studies that examined white matter tracts linking socio-emotional structures is presented.
  
  
  RESULTS
  Several DTI studies reported microstructural differences indicative of developmental alterations in white matter organization, and potentially myelination, in ASD. Altered structure within long-range white matter tracts linking socio-emotional processing regions was implicated. While alterations of the uncinate fasciculus and frontal and temporal thalamic projections have been associated with social symptoms in ASD, few studies examined association of tract microstructure with core impairment in this disorder.
  
  
  CONCLUSIONS
  The uncinate fasciculus and frontal and temporal thalamic projections mediate limbic connectivity and integrate structures responsible for complex socio-emotional functioning. Impaired development of limbic connectivity may represent one neural substrate contributing to ASD social impairments. Future efforts to further elucidate the nature of atypical white matter development, and its relationship to core symptoms, may offer new insights into etiological mechanisms contributing to ASD impairments and uncover novel opportunities for targeted intervention.
authors.affiliation: The Hospital for Sick Children, Department of Psychiatry, University of Toronto, Toronto, Ontario, Canada; Child, Youth and Family Program, Research Imaging Centre, The Campbell Family Mental Health Institute, The Centre for Addiction and Mental Health, University of Toronto, Toronto, Ontario, Canada. Electronic address: stephanie.ameis@mail.utoronto.ca.
authors.forename: Stephanie H
authors.initials: SH
authors.lastname: Ameis
authors.affiliation: NATBRAINLAB, Department of Forensic and Neurodevelopmental Sciences, Institute of Psychiatry PO50, King's College London, London, UK. Electronic address: marco.1.catani@kcl.ac.uk.
authors.forename: Marco
authors.initials: M
authors.lastname: Catani
mesh_terms: D001921:Brain / Q000503:physiopathology; D002659:Child Development Disorders, Pervasive / Q000503:physiopathology*; D056324:Diffusion Tensor Imaging; D059907:Functional Neuroimaging; D006801:Humans; D008032:Limbic System / Q000503:physiopathology*; D008279:Magnetic Resonance Imaging; D009434:Neural Pathways / Q000503:physiopathology; D066107:Social Skills; D066127:White Matter / Q000503:physiopathology*
keywords: Autism Spectrum Disorder; Connectivity; Diffusion tensor imaging; Limbic network; Social impairment; Tractography; White matter