The NeuroDevNet Autism Spectrum Disorders Demonstration Project

doi:10.1016/j.spen.2011.02.003

Seminars in Pediatric Neurology

Volume 18, Issue 1, March 2011, Pages 40-48

https://doi.org/10.1016/j.spen.2011.02.003 Get rights and content

The NeuroDevNet Autism Spectrum Disorder Demonstration Project interfaces at many levels with the network's research themes and priorities. Our interdisciplinary team aims to improve understanding of genetic factors underlying vulnerability to autism spectrum disorders (ASDs) to develop better diagnostic strategies and, ultimately, to pinpoint molecular pathways relevant to developing biologically based treatments. Linking our existing longitudinal ASD cohorts with both genetics and neuroimaging studies will provide, for the first time, integrated data on how the genetic variation influences brain and behavioral development in ASD. Importantly, as our science progresses and we translate this information to the health care system, we will also educate policy makers, media, and business, so an informed society is prepared to capitalize on new genomic advances and effectively integrate these into health services for the broader community. We believe that this research has the potential to transform assessment and care for individuals with ASD.

Section snippets

Public Health Significance of ASD

There has been a several-fold increase in the estimated prevalence of ASD over the past 20 years, from less than 1 in 1,0002, 3, 4 to nearly 1 in 100.5, 6 The degree to which prevalence increases can be attributed to expanded diagnostic criteria, younger age at diagnosis, and improved efficiency of case ascertainment is not known although it likely accounts for a large part of the increase.7, 8 Regardless, the rising prevalence of ASD has profound population health and social-economic

Overview

Our interdisciplinary Canadian NeuroDevNet team will leverage extensive clinical infrastructure and national/international collaborations to discover, characterize, and validate rare DNA variants underlying susceptibility to ASD and associated variation in brain and behavioral development. Identifying genetic biomarkers informative for ASD could transform clinical practice, facilitating earlier diagnosis, more effective and individualized treatment planning, and, ultimately, the development of

Summary and Future Directions

NeuroDevNet has provided an unprecedented opportunity for scientists from across Canada to come together to advance our understanding of the fundamental mechanisms underlying neurodevelopmental dysfunction in ASD. We will discover and characterize de novo DNA variants detected in ASD cohorts using state-of-the-art DNA sequencing techniques, prioritize mutations based on replication in independent clinical cohorts and functional relevance based on MRI-based neural connectivity studies, and then

References (109)

A. Wazana et al.
The autism epidemic: fact or artifact?
J Am Acad Child Adolesc Psychiatry
(2007)
N. Risch et al.
A genomic screen of autism: Evidence for a multilocus etiology
Am J Hum Genet
(1999)
M. Auranen et al.
A genomewide screen for autism-spectrum disorders: Evidence for a major susceptibility locus on chromosome 3q25-27
Am J Hum Genet
(2002)
J. Liu et al.
A genomewide screen for autism susceptibility loci
Am J Hum Genet
(2001)
C.R. Marshall et al.
Structural variation of chromosomes in autism spectrum disorder
Am J Hum Genet
(2008)
R. Moessner et al.
Contribution of SHANK3 mutations to autism spectrum disorder
Am J Hum Genet
(2007)
H.G. Kim et al.
Disruption of neurexin 1 associated with autism spectrum disorder
Am J Hum Genet
(2008)
D.E. Arking et al.
A common genetic variant in the neurexin superfamily member CNTNAP2 increases familial risk of autism
Am J Hum Genet
(2008)
B. Bakkaloglu et al.
Molecular cytogenetic analysis and resequencing of contraction associated protein-like 2 in autism spectrum disorders
Am J Hum Genet
(2008)
J.E. Lainhart et al.
Macrocephaly in children and adults with autism
J Am Acad Child Adolesc Psychiatry
(1997)

J. Piven et al.

Regional brain enlargement in autism: A magnetic resonance imaging study

J Am Acad Child Adolesc Psychiatry

(1996)

H.C. Hazlett et al.

Cortical gray and white brain tissue volume in adolescents and adults with autism

Biol Psychiatry

(2006)

J. Piven et al.

Magnetic resonance imaging in autism: Measurement of the cerebellum, pons, and fourth ventricle

Biol Psychiatry

(1992)

A.Y. Hardan et al.

A preliminary longitudinal magnetic resonance imaging study of brain volume and cortical thickness in autism

Biol Psychiatry

(2009)

E.A. Varga et al.

The prevalence of PTEN mutations in a clinical pediatric cohort with autism spectrum disorders, developmental delay, and macrocephaly

Genet Med

(2009)

C.H. Kwon et al.

PTEN regulates neuronal arborization and social interaction in mice

Neuron

(2006)

L. Zwaigenbaum et al.

Behavioral manifestations of autism in the first year of life

Int J Dev Neurosci

(2005)

P.T. Shattuck et al.

Timing of identification among children with an autism spectrum disorder: Findings from a population-based surveillance study

J Am Acad Child Adolesc Psychiatry

(2009)

S. Mori et al.

Stereotaxic white matter atlas based on diffusion tensor imaging in an ICBM template

Neuroimage

(2008)

S. Jbabdi et al.

A Bayesian framework for global tractography

Neuroimage

(2007)

S. Baron-Cohen et al.

Prevalence of autism-spectrum conditions: UK school-based population study

Br J Psychiatry

(2009)

S.E. Bryson et al.

First report of a Canadian epidemiological study of autistic syndromes

J Child Psychol Psychiatry

(1988)

C. Gillberg et al.

Is autism more common now than ten years ago?

Br J Psychiatry

(1991)

E.R. Ritvo et al.

The UCLA-University of Utah epidemiologic survey of autism: Recurrence risk estimates and genetic counseling

Am J Psychiatry

(1989)

Principal Investigators; Centers for Disease Control and Prevention (CDC)Prevalence of Autism Spectrum Disorders—Autism and Developmental Disabilities Monitoring Network, United States, 2006

MMWR Surveill Summ

(2009)

T. Lazoff et al.

Prevalence of pervasive developmental disorders among children at the English Montreal School Board

Can J Psychiatry

(2010)

E. Fombonne

Epidemiological surveys of autism and other pervasive developmental disorders: an update

J Autism Dev Disord

(2003)

J.L. Sanders et al.

Family stress and adjustment as perceived by parents of children with autism or Down syndrome: Implications for interventions

Child Fam Behav Ther

(1997)

M.J. Weiss

Harrdiness and social support as predictors of stress in mothers of typical children, children with autism, and children with mental retardation

Autism

(2002)

R. Bouma et al.

The impact of chronic childhood illness on family stress: A comparison between autism and cystic fibrosis

J Clin Psychol

(1990)

M. Ganz

The lifetime distribution of the incremental societal costs of autism

Arch Pediatr Adolesc Med

(2007)

G. King et al.

Belief systems of families of children with autism spectrum disorders or Down syndrome

Focus Autism Other Dev Disabl

(2009)

J. Bromley et al.

Mothers supporting children with autistic spectrum disorders: Social support, mental health status and satisfaction with services

Autism

(2004)

E. Dale et al.

Mothers' attributions following their child's diagnosis of autistic spectrum disorder: Exploring links with maternal levels of stress, depression and expectations about their child's future

Autism

(2006)

A. Estes et al.

Parenting stress and psychological functioning among mothers of preschool children with autism and developmental delay

Autism

(2009)

A. Bailey et al.

Autism as a strongly genetic disorder: Evidence from a British twin study

Psychol Med

(1995)

S. Folstein et al.

Infantile autism: A genetic study of 21 twin pairs

J Child Psychol Psychiatry

(1977)

A. Le Couteur et al.

A broader phenotype of autism: The clinical spectrum in twins

J Child Psychol Psychiatry

(1996)

E.R. Ritvo et al.

Concordance for the syndrome of autism in 40 pairs of afflicted twins

Am J Psychiatry

(1985)

R.E. Rosenberg et al.

Characteristics and concordance of autism spectrum disorders among 277 twin pairs

Arch Pediatr Adolesc Med

(2009)

S. Steffenburg et al.

A twin study of autism in Denmark, Finland, Iceland, Norway and Sweden

J Child Psychol Psychiatry

(1989)

H. Taniai et al.

Genetic influences on the broad spectrum of autism: Study of proband-ascertained twins

Am J Med Genet B Neuropsychiatr Genet

(2008)

A genomewide screen for autism: Strong evidence for linkage to chromosomes 2q, 7q, and 16p

Am J Hum Genet

(2001)

A full genome screen for autism with evidence for linkage to a region on chromosome 7qInternational Molecular Genetic Study of Autism Consortium

Hum Mol Genet

(1998)

S. Barrett et al.

An autosomal genomic screen for autismCollaborative linkage study of autism

Am J Med Genet

(1999)

K. Wang et al.

Common genetic variants on 5p14.1 associate with autism spectrum disorders

Nature

(2009)

L.A. Weiss et al.

Gene Discovery Project of Johns Hopkins and the Autism Consortium, Daly MJ, Chakravarti AA genome-wide linkage and association scan reveals novel loci for autism

Nature

(2009)

R. Anney et al.

A genome-wide scan for common alleles affecting risk for autism

Hum Mol Genet

(2010)

S. Berkel et al.

Mutations in the SHANK2 synaptic scaffolding gene in autism spectrum disorder and mental retardation

Nat Genet

(2010)

D. Pinto et al.

Functional impact of global rare copy number variation in autism spectrum disorders

Nature

(2010)

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This database will allow for detailed mapping of gene to neural expression across adolescence and adulthood in individuals with ADHD (von Rhein et al., 2015). The NeuroDevNet ASD Demonstration Project aims to identify genetic variants that are risk factors for ASD, and then compare ASD probands with and without the genetic variants using measurements of cortical thickness, volume, and area (Zwaigenbaum et al., 2011). Further efforts to integrate genetics and neuroimaging in larger samples will greatly improve our understanding of how genes that concur risk for NDDs impact neural structure and function.
Recent years have witnessed the proliferation of neuroimaging studies of neurodevelopmental disorders (NDDs), particularly of children with autism spectrum disorder (ASD), attention-deficit/hyperactivity disorder (ADHD), and Tourette’s syndrome (TS). Neuroimaging offers immense potential in understanding the biology of these disorders, and how it relates to clinical symptoms. Neuroimaging techniques, in the long run, may help identify neurobiological markers to assist clinical diagnosis and treatment. However, methodological challenges have affected the progress of clinical neuroimaging. This paper reviews the methodological challenges involved in imaging children with NDDs. Specific topics include correcting for head motion, normalization using pediatric brain templates, accounting for psychotropic medication use, delineating complex developmental trajectories, and overcoming smaller sample sizes. The potential of neuroimaging-based biomarkers and the utility of implementing neuroimaging in a clinical setting are also discussed. Data-sharing approaches, technological advances, and an increase in the number of longitudinal, prospective studies are recommended as future directions. Significant advances have been made already, and future decades will continue to see innovative progress in neuroimaging research endeavors of NDDs.
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Data from 9 subjects (4 ASD, 5 TD) was removed due to excessive head motion (greater than 2 mm in any direction), leaving 30 ASD (M age = 16 ± 3.0) and 32 TD subjects (M age = 15 ± 3.0) in the final analysis (Table 4). Subjects were recruited as a part of the NeuroDevNet Autism Demonstration Project, a multisite study to examine brain structural and behavioural development in children with ASD (Zwaigenbaum et al., 2011). All subjects gave written informed consent/assent where applicable.
The purpose of the current study was to examine how repetitive behaviour in Autism Spectrum Disorder (ASD) is related to intrinsic functional connectivity patterns in a number of large-scale, neural networks. Resting-state fMRI scans from thirty subjects with ASD and thirty-two age-matched, typically developing control subjects were analysed. Seed-to-voxel and ROI-to-ROI functional connectivity analyses were used to examine resting-state connectivity in a number of cortical and subcortical neural networks. Bivariate correlation analysis was performed to examine the relationship between repetitive behaviour scores from the Repetitive Behaviour Scale – Revised and intrinsic functional connectivity in ASD subjects. Compared to control subjects, ASD subjects displayed marked over-connectivity of the thalamus with several cortical sensory processing areas, as well as over-connectivity of the basal ganglia with somatosensory and motor cortices. Within the ASD group, significant correlations were found between functional connectivity patterns and total RBS-R scores as well as one principal component analysis-derived score from the RBS-R. These results suggest that thalamocortical resting-state connectivity is altered in individuals with ASD, and that resting-state functional connectivity is associated with ASD symptomatology.
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Two groups of children participated in the present study: 1) 31 boys with ASD and 2) 23 TD boys that were matched on a group level for age (ASD: mean 11.5 years, SD 2.8, range 6.9–15.6; TD: mean 11.1 years, SD 3.1 range 6.8–15.7; p = 0.60) and intelligence quotient (IQ; ASD [n = 30]: mean 108.5, SD 13.7, range 84–146; TD: mean 114.2, SD 10.4, range 88–133; p = 0.10). Participants were recruited as part of the “NeuroDevNet Autism Demonstration Project”, a multi-site initiative to study brain structural and behavioral development in children with ASD (Zwaigenbaum et al., 2011). Participants were recruited and tested at two sites: 1) in Montreal, Canada at the Montreal Neurological Institute (14 ASD, 15 TD), and, 2) in Toronto, Canada at the Holland Bloorview Kids Rehabilitation Hospital and Toronto Sick Kids Hospital (17 ASD, 8 TD).
Autism spectrum disorder (ASD) is characterized by difficulties in social and communication skills as well as atypical sensory perception and motor skills. Sensorimotor abilities such as auditory-motor integration are essential for social interaction and communication. The goal of this research was to investigate the development of auditory-motor rhythm synchronization for the first time in ASD versus typically-developing (TD) children.
Participants were 31 boys with ASD and 23 TD boys that were matched in age and IQ. Participants were tested on an auditory-motor rhythm synchronization task in which they tapped in synchrony with rhythms of varying metrical complexity.
Both children with ASD and TD performed similarly on this task and both groups performed better with age.
This work demonstrates that non-verbal rhythm synchronization is intact in ASD over the course of childhood development. This research serves to better understand sensorimotor interactions in ASD and to better define sensory phenotypes in ASD.
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Multicenter use of a standardized testing protocol would permit cross syndrome comparisons. It would also permit comparisons to children with severe postpartum issues such as fetal alcohol spectrum disorder, cerebral palsy, and autism spectrum disorder who are commonly investigated using the sophisticated, non-invasive testing methods we adapted for our PE-F1 pilot study [76–78]. Data from our laboratory and others suggest a possible mechanistic link between low gestational PGF, PE, and fetal impairment of brain vascular and structural development.
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Two groups of children participated in the present study: 38 boys with ASD and 46 TD boys. Participants were recruited as part of the NeuroDevNet Autism Demonstration Project, a multisite initiative to study brain structural and behavioral development in ASD.31 Participants were assessed at two collaborating sites: (1) Montreal, Canada at the Montreal Children's Hospital and Montreal Neurological Institute, and (2) Toronto, Canada, at the Holland Bloorview Kids Rehabilitation Hospital and Toronto Sick Kids Hospital.
Autism spectrum disorder is a complex neurodevelopmental disorder characterized by impaired social interaction and communication, repetitive behaviors, and restricted interests. Gray matter differences linked to autism spectrum disorder have been studied using a variety of structural imaging methods, but yielded little consensus; the extent to which disparate results reflect differences in methodology or heterogeneity within autism spectrum disorder is not yet clear. Moreover, very few studies have examined gray matter changes as a function of age in autism spectrum disorder.
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: Dr Zwaigenbaum is supported by the Stollery Children's Hospital Foundation Chair in Autism research and by a Health Scholar Award from the Alberta Innovates—Health Solutions. Dr Scherer is supported by the GlaxoSmithKline-Canadian Institutes of Health Research Endowed Chair in Genetics and Genomics. Dr Bryson, is supported by the Jack and Joan Craig Chair in Autism research, and Dr Szatmari by the Chedoke Health Chair in Child psychiatry. Drs Fombonne is supported by a Canada research Chairs in Child psychiatry and Dr Vaillancourt, by a Canada research Chair in children's mental health and Violence Protection. The research described in this paper is supported by the Canadian Institutes of Health Research, Autism Speaks Canada, the Sinneave Family Foundation and the University of Alberta women's and children's Research Institute, as well as NeuroDevNet, which is supported by the Networks of Centres of Excellence of Canada.

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