title: Multivariate characterization of white matter heterogeneity in autism spectrum disorder.
abstract: The complexity and heterogeneity of neuroimaging findings in individuals with autism spectrum disorder has suggested that many of the underlying alterations are subtle and involve many brain regions and networks. The ability to account for multivariate brain features and identify neuroimaging measures that can be used to characterize individual variation have thus become increasingly important for interpreting and understanding the neurobiological mechanisms of autism. In the present study, we utilize the Mahalanobis distance, a multidimensional counterpart of the Euclidean distance, as an informative index to characterize individual brain variation and deviation in autism. Longitudinal diffusion tensor imaging data from 149 participants (92 diagnosed with autism spectrum disorder and 57 typically developing controls) between 3.1 and 36.83 years of age were acquired over a roughly 10-year period and used to construct the Mahalanobis distance from regional measures of white matter microstructure. Mahalanobis distances were significantly greater and more variable in the autistic individuals as compared to control participants, demonstrating increased atypicalities and variation in the group of individuals diagnosed with autism spectrum disorder. Distributions of multivariate measures were also found to provide greater discrimination and more sensitive delineation between autistic and typically developing individuals than conventional univariate measures, while also being significantly associated with observed traits of the autism group. These results help substantiate autism as a truly heterogeneous neurodevelopmental disorder, while also suggesting that collectively considering neuroimaging measures from multiple brain regions provides improved insight into the diversity of brain measures in autism that is not observed when considering the same regions separately. Distinguishing multidimensional brain relationships may thus be informative for identifying neuroimaging-based phenotypes, as well as help elucidate underlying neural mechanisms of brain variation in autism spectrum disorders.
authors.affiliation: Waisman Center, University of Wisconsin-Madison, Madison, WI, USA.
authors.forename: D C
authors.initials: DC
authors.lastname: Dean
authors.affiliation: Department of Psychiatry, Harvard School of Medicine, Boston, MA, USA; Child and Adolescent Psychiatry, McLean Hospital, Belmont, MA, USA.
authors.forename: N
authors.initials: N
authors.lastname: Lange
authors.affiliation: Waisman Center, University of Wisconsin-Madison, Madison, WI, USA; Occupational Therapy Program, Department of Kinesiology, University of Wisconsin-Madison, Madison, WI, USA.
authors.forename: B G
authors.initials: BG
authors.lastname: Travers
authors.affiliation: Department of Radiology, University of Utah, Salt Lake City, UT, USA; Department of Pediatrics, University of Utah and Primary Children's Medical Center, Salt Lake City, UT, USA.
authors.forename: M B
authors.initials: MB
authors.lastname: Prigge
authors.affiliation: Department of Human Genetics, University of Utah, Salt Lake City, UT, USA.
authors.forename: N
authors.initials: N
authors.lastname: Matsunami
authors.affiliation: Waisman Center, University of Wisconsin-Madison, Madison, WI, USA; Department of Psychology, University of Wisconsin-Madison, Madison, WI, USA.
authors.forename: K A
authors.initials: KA
authors.lastname: Kellett
authors.affiliation: Waisman Center, University of Wisconsin-Madison, Madison, WI, USA.
authors.forename: A
authors.initials: A
authors.lastname: Freeman
authors.affiliation: Waisman Center, University of Wisconsin-Madison, Madison, WI, USA.
authors.forename: K L
authors.initials: KL
authors.lastname: Kane
authors.affiliation: Waisman Center, University of Wisconsin-Madison, Madison, WI, USA.
authors.forename: N
authors.initials: N
authors.lastname: Adluru
authors.affiliation: Waisman Center, University of Wisconsin-Madison, Madison, WI, USA; Department of Psychiatry, University of Wisconsin-Madison, Madison, WI, USA.
authors.forename: D P M
authors.initials: DP
authors.lastname: Tromp
authors.affiliation: Waisman Center, University of Wisconsin-Madison, Madison, WI, USA.
authors.forename: D J
authors.initials: DJ
authors.lastname: Destiche
authors.affiliation: Waisman Center, University of Wisconsin-Madison, Madison, WI, USA.
authors.forename: D
authors.initials: D
authors.lastname: Samsin
authors.affiliation: Department of Pediatrics, University of Utah and Primary Children's Medical Center, Salt Lake City, UT, USA; Department of Neurology, University of Utah, Salt Lake City, UT, USA.
authors.forename: B A
authors.initials: BA
authors.lastname: Zielinski
authors.affiliation: Scientific Computing and Imaging Institute, University of Utah, Salt Lake City, UT, USA; School of Computing, University of Utah, Salt Lake City, UT, USA.
authors.forename: P T
authors.initials: PT
authors.lastname: Fletcher
authors.affiliation: Department of Radiology, University of Utah, Salt Lake City, UT, USA; Interdepartmental Program in Neuroscience, University of Utah, Salt Lake City, UT, USA.
authors.forename: J S
authors.initials: JS
authors.lastname: Anderson
authors.affiliation: School of Computing, University of Utah, Salt Lake City, UT, USA.
authors.forename: A L
authors.initials: AL
authors.lastname: Froehlich
authors.affiliation: Department of Human Genetics, University of Utah, Salt Lake City, UT, USA.
authors.forename: M F
authors.initials: MF
authors.lastname: Leppert
authors.affiliation: Department of Psychology, Brigham Young University, Provo, UT, USA; Neuroscience Center, Brigham Young University, Provo, UT 84602, USA.
authors.forename: E D
authors.initials: ED
authors.lastname: Bigler
authors.affiliation: Waisman Center, University of Wisconsin-Madison, Madison, WI, USA; Department of Psychiatry, University of Wisconsin-Madison, Madison, WI, USA.
authors.forename: J E
authors.initials: JE
authors.lastname: Lainhart
authors.affiliation: Waisman Center, University of Wisconsin-Madison, Madison, WI, USA; Department of Psychiatry, University of Wisconsin-Madison, Madison, WI, USA; Department of Medical Physics, University of Wisconsin-Madison, Madison, WI, USA.
authors.forename: A L
authors.initials: AL
authors.lastname: Alexander
mesh_terms: D000293:Adolescent; D000328:Adult; D016880:Anisotropy; D000067877:Autism Spectrum Disorder / Q000000981:diagnostic imaging*; D002648:Child; D002675:Child, Preschool; D038524:Diffusion Magnetic Resonance Imaging; D005260:Female; D006801:Humans; D007091:Image Processing, Computer-Assisted; D008137:Longitudinal Studies; D008297:Male; D009434:Neural Pathways / Q000000981:diagnostic imaging*; D066127:White Matter / Q000000981:diagnostic imaging*; D055815:Young Adult
keywords: Autism spectrum disorder; Brain variability; Diffusion tensor imaging; Mahalanobis distance; White matter microstructure