Publications by authors named "Rob Nicolson"

38 Publications

Exploring sensory phenotypes in autism spectrum disorder.

Mol Autism 2021 Oct 12;12(1):67. Epub 2021 Oct 12.

Brain and Mind Institute, Western University, 1151 Richmond St, London, ON, N6A 3K7, Canada.

Background: Atypical reactions to the sensory environment are often reported in autistic individuals, with a high degree of variability across the sensory modalities. These sensory differences have been shown to promote challenging behaviours and distress in autistic individuals and are predictive of other functions including motor, social, and cognitive abilities. Preliminary research suggests that specific sensory differences may cluster together within individuals creating discrete sensory phenotypes. However, the manner in which these sensory differences cluster, and whether the resulting phenotypes are associated with specific cognitive and social challenges is unclear.

Methods: Short sensory profile data from 599 autistic children and adults between the ages of 1 and 21 years were subjected to a K-means cluster analysis. Analysis of variances compared age, adaptive behaviour, and traits associated with autism, attention-deficit and hyperactivity disorder, and obsessive and compulsive disorder across the resultant clusters.

Results: A five-cluster model was found to minimize error variance and produce five sensory phenotypes: (1) sensory adaptive, (2) generalized sensory differences, (3) taste and smell sensitivity, (4) under-responsive and sensation seeking, and (5) movement difficulties with low energy. Age, adaptive behaviour, and traits associated with autism, attention-deficit and hyperactivity disorder, and obsessive and compulsive disorder were found to differ significantly across the five phenotypes.

Limitations: The results were based on parent-report measures of sensory processing, adaptive behaviour, traits associated with autism, attention-deficit and hyperactivity disorder, and obsessive and compulsive disorder, which may limit the generalizability of the findings. Further, not all measures are standardized, or psychometrically validated with an autism population. Autistic individuals with an intellectual disability were underrepresented in this sample. Further, as these data were obtained from established records from a large provincial database, not all measures were completed for all individuals.

Conclusions: These findings suggest that sensory difficulties in autistic individuals can be clustered into sensory phenotypes, and that these phenotypes are associated with behavioural differences. Given the large degree of heterogeneity in sensory difficulties seen in the autistic population, these sensory phenotypes represent an effective way to parse that heterogeneity and create phenotypes that may aid in the development of effective treatments and interventions for sensory difficulties.
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http://dx.doi.org/10.1186/s13229-021-00471-5DOI Listing
October 2021

Cortical Gyrification Morphology in ASD and ADHD: Implication for Further Similarities or Disorder-Specific Features?

Cereb Cortex 2021 Sep 21. Epub 2021 Sep 21.

Bloorview Research Institute, Holland Bloorview Kids Rehabilitation Hospital, Toronto M4G 1R8, Canada.

Shared etiological pathways are suggested in ASD and ADHD given high rates of comorbidity, phenotypic overlap and shared genetic susceptibility. Given the peak of cortical gyrification expansion and emergence of ASD and ADHD symptomology in early development, we investigated gyrification morphology in 539 children and adolescents (6-17 years of age) with ASD (n=197) and ADHD (n=96) compared to typically developing controls (n=246) using the local Gyrification Index (lGI) to provide insight into contributing etiopathological factors in these two disorders. We also examined IQ effects and functional implications of gyrification by exploring the relation between lGI and ASD and ADHD symptomatology beyond diagnosis. General Linear Models yielded no group differences in lGI, and across groups, we identified an age-related decrease of lGI and greater lGI in females compared to males. No diagnosis-by-age interactions were found. Accounting for IQ variability in the model (n=484) yielded similar results. No significant associations were found between lGI and social communication deficits, repetitive and restricted behaviours, inattention or adaptive functioning. By examining both disorders and controls using shared methodology, we found no evidence of atypicality in gyrification as measured by the lGI in these conditions.
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http://dx.doi.org/10.1093/cercor/bhab326DOI Listing
September 2021

Amygdala subnuclei development in adolescents with autism spectrum disorder: Association with social communication and repetitive behaviors.

Brain Behav 2021 08 1;11(8):e2299. Epub 2021 Aug 1.

Neuroscience, Schulich School of Medicine and Dentistry, Western University, London, Canada.

Introduction: The amygdala subnuclei regulate emotional processing and are widely implicated in social cognitive impairments often seen in children with autism spectrum disorder (ASD). Dysregulated amygdala development has been reported in young children with ASD; less is known about amygdala maturation in later adolescence, a sensitive window for social skill development.

Methods: The macrostructural development of the amygdala subnuclei was assessed at two time points in a longitudinal magnetic resonance imaging (MRI) study of adolescents with ASD (n = 23) and typically-developing adolescents (n = 15) . In adolescents with ASD, amygdala subnuclei growth was assessed in relation to ASD symptomatology based on standardized diagnostic assessments. Participants were scanned with MRI at median age of 12 years and returned for a second scan at a median age of 15 years. The volumes of nine amygdala subnuclei were extracted using an automatic segmentation algorithm.

Results: When examining the longitudinal data acquired across two time points, adolescents with ASD had larger basolateral amygdala (BLA) nuclei volumes compared to typically developing adolescents (B = 46.8, p = 0.04). When examining ASD symptomatology in relation to the growth of the amygdala subnuclei, reciprocal social interaction scores on the ADI-R were positively associated with increased growth of the BLA nuclei (B = 8.3, p < 0.001). Growth in the medial nucleus negatively predicted the communication (B = -46.9, p = 0.02) and social (B = -47.7, p < 0.001) domains on the ADOS-G. Growth in the right cortical nucleus (B = 26.14, p = 0.02) positively predicted ADOS-G social scores. Central nucleus maturation (B = 29.9, p = 0.02) was associated with the repetitive behaviors domain on the ADOS-G.

Conclusions: Larger BLA volumes in adolescents with ASD may reflect underlying alterations in cellular density previously reported in post-mortem studies. Furthermore, findings demonstrate an association between regional growth in amygdala subnuclei volumes and ASD symptomatology. Improved understanding of the developmental trajectories of the amygdala subnuclei may aid in identifying key windows for interventions, particularly for social communication, in adolescents with ASD.
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http://dx.doi.org/10.1002/brb3.2299DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8413788PMC
August 2021

An Epigenetically Distinct Subset of Children With Autism Spectrum Disorder Resulting From Differences in Blood Cell Composition.

Front Neurol 2021 16;12:612817. Epub 2021 Apr 16.

Genetics and Genome Biology, The Hospital for Sick Children, Toronto, ON, Canada.

Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder that often involves impaired cognition, communication difficulties and restrictive, repetitive behaviors. ASD is extremely heterogeneous both clinically and etiologically, which represents one of the greatest challenges in studying the molecular underpinnings of ASD. While hundreds of ASD-associated genes have been identified that confer varying degrees of risk, no single gene variant accounts for >1% of ASD cases. Notably, a large number of ASD-risk genes function as epigenetic regulators, indicating potential epigenetic dysregulation in ASD. As such, we compared genome-wide DNA methylation (DNAm) in the blood of children with ASD ( = 265) to samples from age- and sex-matched, neurotypical controls ( = 122) using the Illumina Infinium HumanMethylation450 arrays. While DNAm patterns did not distinctly separate ASD cases from controls, our analysis identified an epigenetically unique subset of ASD cases ( = 32); these individuals exhibited significant differential methylation from both controls than the remaining ASD cases. The CpG sites at which this subset was differentially methylated mapped to known ASD risk genes that encode proteins of the nervous and immune systems. Moreover, the observed DNAm differences were attributable to altered blood cell composition, i.e., lower granulocyte proportion and granulocyte-to-lymphocyte ratio in the ASD subset, as compared to the remaining ASD cases and controls. This ASD subset did not differ from the rest of the ASD cases in the frequency or type of high-risk genomic variants. Within our ASD cohort, we identified a subset of individuals that exhibit differential methylation from both controls and the remaining ASD group tightly associated with shifts in immune cell type proportions. This is an important feature that should be assessed in all epigenetic studies of blood cells in ASD. This finding also builds on past reports of changes in the immune systems of children with ASD, supporting the potential role of altered immunological mechanisms in the complex pathophysiology of ASD. The discovery of significant molecular and immunological features in subgroups of individuals with ASD may allow clinicians to better stratify patients, facilitating personalized interventions and improved outcomes.
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http://dx.doi.org/10.3389/fneur.2021.612817DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8085304PMC
April 2021

Mostly worse, occasionally better: impact of COVID-19 pandemic on the mental health of Canadian children and adolescents.

Eur Child Adolesc Psychiatry 2021 Feb 26. Epub 2021 Feb 26.

Department of Psychiatry, Hospital for Sick Children, Peter Gilgan Centre for Research and Learning, 686 Bay Street, 6th Floor, Toronto, On, M5G 0A4, Canada.

This large cross-sectional study examined the impact of COVID-19 emergency measures on child/adolescent mental health for children/adolescents with and without pre-existing psychiatric diagnoses. Using adapted measures from the CRISIS questionnaire, parents of children aged 6-18 (N = 1013; 56% male; 62% pre-existing psychiatric diagnosis) and self-reporting children/adolescents aged 10-18 (N = 385) indicated changes in mental health across six domains: depression, anxiety, irritability, attention, hyperactivity, and obsessions/compulsions. Changes in anxiety, irritability, and hyperactivity were calculated for children aged 2-5 years using the Strengths and Difficulties Questionnaire. COVID-19 exposure, compliance with emergency measures, COVID-19 economic concerns, and stress from social isolation were measured with the CRISIS questionnaire. Prevalence of change in mental health status was estimated for each domain; multinomial logistic regression was used to determine variables associated with mental health status change in each domain. Depending on the age group, 67-70% of children/adolescents experienced deterioration in at least one mental health domain; however, 19-31% of children/adolescents experienced improvement in at least one domain. Children/adolescents without and with psychiatric diagnoses tended to experience deterioration during the first wave of COVID-19. Rates of deterioration were higher in those with a pre-exiting diagnosis. The rate of deterioration was variable across different age groups and pre-existing psychiatric diagnostic groups: depression 37-56%, anxiety 31-50%, irritability 40-66%, attention 40-56%, hyperactivity 23-56%, obsessions/compulsions 13-30%. Greater stress from social isolation was associated with deterioration in all mental health domains (all ORs 11.12-55.24). The impact of pre-existing psychiatric diagnosis was heterogenous, associated with deterioration in depression, irritability, hyperactivity, obsession/compulsions for some children (ORs 1.96-2.23) but also with improvement in depression, anxiety, and irritability for other children (ORs 2.13-3.12). Economic concerns were associated with improvement in anxiety, attention, and obsessions/compulsions (ORs 3.97-5.57). Children/adolescents with and without pre-existing psychiatric diagnoses reported deterioration. Deterioration was associated with increased stress from social isolation. Enhancing social interactions for children/adolescents will be an important mitigation strategy for current and future COVID-19 waves.
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http://dx.doi.org/10.1007/s00787-021-01744-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7909377PMC
February 2021

DNA Methylation of the Oxytocin Receptor Across Neurodevelopmental Disorders.

J Autism Dev Disord 2021 Oct 4;51(10):3610-3623. Epub 2021 Jan 4.

Genetics and Genome Biology, Hospital for Sick Children, Toronto, ON, Canada.

Many neurodevelopmental disorders (NDDs) share common learning and behavioural impairments, as well as features such as dysregulation of the oxytocin hormone. Here, we examined DNA methylation (DNAm) in the 1st intron of the oxytocin receptor gene, OXTR, in patients with autism spectrum (ASD), attention deficit and hyperactivity (ADHD) and obsessive compulsive (OCD) disorders. DNAm of OXTR was assessed for cohorts of ASD (blood), ADHD (saliva), OCD (saliva), which uncovered sex-specific DNAm differences compared to neurotypical, tissue-matched controls. Individuals with ASD or ADHD exhibiting extreme DNAm values had lower IQ and more social problems, respectively, than those with DNAm within normative ranges. This suggests that OXTR DNAm patterns are altered across NDDs and may be correlated with common clinical outcomes.
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http://dx.doi.org/10.1007/s10803-020-04792-xDOI Listing
October 2021

Sex Differences in Age of Diagnosis and First Concern among Children with Autism Spectrum Disorder.

J Clin Child Adolesc Psychol 2021 Sep-Oct;50(5):645-655. Epub 2020 Nov 2.

Department of Psychiatry, Western University.

Objective: Early identification of autism spectrum disorder (ASD) is an essential healthcare priority. Girls may be at risk for late diagnosis, although research is equivocal regarding how sex and other factors relate to ASD identification. The goals of the current investigation were to (1) identify how child sex, cognitive abilities, and demographic factors relate to age of first concern (AOC) and age of diagnosis (AOD), (2) evaluate trends in AOC/AOD over time, and (3) consider whether main effects of sex on AOC/AOD are moderated by cognitive abilities or time.

Method: Children (N = 365; 20% female; 85.6% identified as White) with ASD participated through the Province of Ontario Neurodevelopmental Disorders (POND) Network. Study records included AOD, date/timing of diagnosis (between 1996 and 2017), age of first parent concern, demographics, and standardized cognitive testing results (24.7% of children had IQ scores below standard scores of 70).

Results: Average AOC occurred before 2 years of age whereas average AOD occurred after 5 years of age. Girls did not differ on AOC but had a later AOD than boys. Higher verbal IQ was associated with later AOD more strongly in girls than boys. Regarding time-related changes, average AOC and AOD increased across the study period, more strongly for girls.

Conclusions: Results support that sex is a key factor underlying delays in ASD identification and highlight the urgent need to improve diagnostic practices among girls. Limitations and implications for improving the diagnostic process are discussed.

ASD=autism spectrum disorder; IQ=intelligence quotient; AOC=parental report of age of first concern; AOD=age of diagnosis.
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http://dx.doi.org/10.1080/15374416.2020.1823850DOI Listing
November 2020

Concurrent Validity of the ABAS-II Questionnaire with the Vineland II Interview for Adaptive Behavior in a Pediatric ASD Sample: High Correspondence Despite Systematically Lower Scores.

J Autism Dev Disord 2021 May;51(5):1417-1427

Department of Psychiatry, University of Toronto, Toronto, ON, Canada.

We examined the correlation between interviewer-administered Vineland Adaptive Behavior Scale II (VABS-II) and the parent-rated Adaptive Behavior Assessment System II (ABAS-II) questionnaire in 352 participants (ages 1.5-20.8 years) with autism spectrum disorder (ASD) to determine if ABAS could be used as a screen to reduce the number of VABS interviews. Corresponding domain scores between the two measures were highly correlated but scores were significantly lower on the ABAS-II. Screening with ABAS-II significantly reduced the number of VABS-II interviews required with little cost to overall accuracy. The ABAS-II provides a cost- and time-saving alternative to the VABS-II to rule out functional impairment; however, scores are not strictly comparable between the two measures.
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http://dx.doi.org/10.1007/s10803-020-04597-yDOI Listing
May 2021

Concurrent Validity of the ABAS-II Questionnaire with the Vineland II Interview for Adaptive Behavior in a Pediatric ASD Sample: High Correspondence Despite Systematically Lower Scores.

J Autism Dev Disord 2021 May;51(5):1417-1427

Department of Psychiatry, University of Toronto, Toronto, ON, Canada.

We examined the correlation between interviewer-administered Vineland Adaptive Behavior Scale II (VABS-II) and the parent-rated Adaptive Behavior Assessment System II (ABAS-II) questionnaire in 352 participants (ages 1.5-20.8 years) with autism spectrum disorder (ASD) to determine if ABAS could be used as a screen to reduce the number of VABS interviews. Corresponding domain scores between the two measures were highly correlated but scores were significantly lower on the ABAS-II. Screening with ABAS-II significantly reduced the number of VABS-II interviews required with little cost to overall accuracy. The ABAS-II provides a cost- and time-saving alternative to the VABS-II to rule out functional impairment; however, scores are not strictly comparable between the two measures.
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http://dx.doi.org/10.1007/s10803-020-04597-yDOI Listing
May 2021

A large data resource of genomic copy number variation across neurodevelopmental disorders.

NPJ Genom Med 2019 7;4:26. Epub 2019 Oct 7.

Hamilton Health Sciences, Ron Joyce Children's Health Centre, Hamilton, On Canada.

Copy number variations (CNVs) are implicated across many neurodevelopmental disorders (NDDs) and contribute to their shared genetic etiology. Multiple studies have attempted to identify shared etiology among NDDs, but this is the first genome-wide CNV analysis across autism spectrum disorder (ASD), attention deficit hyperactivity disorder (ADHD), schizophrenia (SCZ), and obsessive-compulsive disorder (OCD) at once. Using microarray (Affymetrix CytoScan HD), we genotyped 2,691 subjects diagnosed with an NDD (204 SCZ, 1,838 ASD, 427 ADHD and 222 OCD) and 1,769 family members, mainly parents. We identified rare CNVs, defined as those found in <0.1% of 10,851 population control samples. We found clinically relevant CNVs (broadly defined) in 284 (10.5%) of total subjects, including 22 (10.8%) among subjects with SCZ, 209 (11.4%) with ASD, 40 (9.4%) with ADHD, and 13 (5.6%) with OCD. Among all NDD subjects, we identified 17 (0.63%) with aneuploidies and 115 (4.3%) with known genomic disorder variants. We searched further for genes impacted by different CNVs in multiple disorders. Examples of NDD-associated genes linked across more than one disorder (listed in order of occurrence frequency) are , , , , , , , , , , and long non-coding RNAs: and . We demonstrated that CNVs impacting the same genes could potentially contribute to the etiology of multiple NDDs. The CNVs identified will serve as a useful resource for both research and diagnostic laboratories for prioritization of variants.
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http://dx.doi.org/10.1038/s41525-019-0098-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6779875PMC
October 2019

Structural neuroimaging correlates of social deficits are similar in autism spectrum disorder and attention-deficit/hyperactivity disorder: analysis from the POND Network.

Transl Psychiatry 2019 02 4;9(1):72. Epub 2019 Feb 4.

Department of Paediatrics, University of Toronto, Toronto, ON, Canada.

Autism spectrum disorder (ASD), attention-deficit/hyperactivity disorder (ADHD), and obsessive-compulsive disorder (OCD) have been associated with difficulties recognizing and responding to social cues. Neuroimaging studies have begun to map the social brain; however, the specific neural substrates contributing to social deficits in neurodevelopmental disorders remain unclear. Three hundred and twelve children underwent structural magnetic resonance imaging of the brain (controls = 32, OCD = 44, ADHD = 77, ASD = 159; mean age = 11). Their social deficits were quantified on the Social Communication Questionnaire (SCQ) and the Reading the Mind in the Eyes Test (RMET). Multivariable regression models were used to examine the structural neuroimaging correlates of social deficits, with both a region of interest and a whole-brain vertex-wise approach. For the region of interest analysis, social brain regions were grouped into three networks: (1) lateral mentalization (e.g., temporal-parietal junction), (2) frontal cognitive (e.g., orbitofrontal cortex), and (3) subcortical affective (e.g., limbic system) regions. Overall, social communication deficits on the SCQ were associated with thinner cortices in the left lateral regions and the right insula, and decreased volume in the ventral striatum, across diagnostic groups (p = 0.006 to <0.0001). Smaller subcortical volumes were associated with more severe social deficits on the SCQ in ASD and ADHD, and less severe deficits in OCD. On the RMET, larger amygdala/hippocampal volumes were associated with fewer deficits across groups. Overall, patterns of associations were similar in ASD and ADHD, supporting a common underlying biology and the blurring of the diagnostic boundaries between these disorders.
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http://dx.doi.org/10.1038/s41398-019-0382-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6361977PMC
February 2019

Oxytocin Receptor Polymorphisms are Differentially Associated with Social Abilities across Neurodevelopmental Disorders.

Sci Rep 2017 09 14;7(1):11618. Epub 2017 Sep 14.

Department of Paediatrics, University of Toronto, Toronto, Ontario, Canada.

Oxytocin is a pituitary neuropeptide that affects social behaviour. Single nucleotide polymorphisms (SNPs) in the oxytocin receptor gene (OXTR) have been shown to explain some variability in social abilities in control populations. Whether these variants similarly contribute to the severity of social deficits experienced by children with neurodevelopmental disorders is unclear. Social abilities were assessed in a group of children with autism spectrum disorder (ASD, n = 341) or attention deficit hyperactivity disorder (ADHD, n = 276) using two established social measures. Scores were compared by OXTR genotype (rs53576, rs237887, rs13316193, rs2254298). Unexpectedly, the two most frequently studied OXTR SNPs in the general population (rs53576 and rs2254298) were associated with an increased severity of social deficits in ASD (p < 0.0001 and p = 0.0005), yet fewer social deficits in ADHD (p = 0.007 and p < 0.0001). We conclude that these genetic modifier alleles are not inherently risk-conferring with respect to their impact on social abilities; molecular investigations are greatly needed.
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http://dx.doi.org/10.1038/s41598-017-10821-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5599599PMC
September 2017

Variable phenotype expression in a family segregating microdeletions of the and autism spectrum disorder susceptibility genes.

NPJ Genom Med 2017 May;2

Program in Genetics and Genome Biology, The Centre for Applied Genomics, The Hospital for Sick Children, Toronto, ON, Canada.

Autism Spectrum Disorder (ASD) is a developmental condition of early childhood onset, which impacts socio-communicative functioning and is principally genetic in etiology. Currently, more than 50 genomic loci are deemed to be associated with susceptibility to ASD, showing and inherited unbalanced copy number variants (CNVs) and smaller insertions and deletions (indels), more complex structural variants (SVs), as well as single nucleotide variants (SNVs) deemed of pathological significance. However, the phenotypes associated with many of these genes are variable, and penetrance is largely unelaborated in clinical descriptions. This case report describes a family harboring two CNV microdeletions, which affect regions of and - each well-established in association with risk of ASD and other neurodevelopmental disorders. Although each CNV would likely be categorized as pathologically significant, both genomic alterations are transmitted in this family from an unaffected father to the proband, and shared by an unaffected sibling. This family case illustrates the importance of recognizing that phenotype can vary among exon overlapping variants of the same gene, and the need to evaluate penetrance of such variants in order to properly inform on risks.
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http://dx.doi.org/10.1038/s41525-017-0020-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5482711PMC
May 2017

Whole genome sequencing resource identifies 18 new candidate genes for autism spectrum disorder.

Nat Neurosci 2017 Apr 6;20(4):602-611. Epub 2017 Mar 6.

The Centre for Applied Genomics, Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Canada.

We are performing whole-genome sequencing of families with autism spectrum disorder (ASD) to build a resource (MSSNG) for subcategorizing the phenotypes and underlying genetic factors involved. Here we report sequencing of 5,205 samples from families with ASD, accompanied by clinical information, creating a database accessible on a cloud platform and through a controlled-access internet portal. We found an average of 73.8 de novo single nucleotide variants and 12.6 de novo insertions and deletions or copy number variations per ASD subject. We identified 18 new candidate ASD-risk genes and found that participants bearing mutations in susceptibility genes had significantly lower adaptive ability (P = 6 × 10). In 294 of 2,620 (11.2%) of ASD cases, a molecular basis could be determined and 7.2% of these carried copy number variations and/or chromosomal abnormalities, emphasizing the importance of detecting all forms of genetic variation as diagnostic and therapeutic targets in ASD.
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http://dx.doi.org/10.1038/nn.4524DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5501701PMC
April 2017

Molecular characterization of NRXN1 deletions from 19,263 clinical microarray cases identifies exons important for neurodevelopmental disease expression.

Genet Med 2017 01 19;19(1):53-61. Epub 2016 May 19.

Cytogenetics Laboratory, Department of Pediatric Laboratory Medicine, the Hospital for Sick Children, Toronto, Ontario, Canada.

Purpose: The purpose of the current study was to assess the penetrance of NRXN1 deletions.

Methods: We compared the prevalence and genomic extent of NRXN1 deletions identified among 19,263 clinically referred cases to that of 15,264 controls. The burden of additional clinically relevant copy-number variations (CNVs) was used as a proxy to estimate the relative penetrance of NRXN1 deletions.

Results: We identified 41 (0.21%) previously unreported exonic NRXN1 deletions ascertained for developmental delay/intellectual disability that were significantly greater than in controls (odds ratio (OR) = 8.14; 95% confidence interval (CI): 2.91-22.72; P < 0.0001). Ten (22.7%) of these had a second clinically relevant CNV. Subjects with a deletion near the 3' end of NRXN1 were significantly more likely to have a second rare CNV than subjects with a 5' NRXN1 deletion (OR = 7.47; 95% CI: 2.36-23.61; P = 0.0006). The prevalence of intronic NRXN1 deletions was not statistically different between cases and controls (P = 0.618). The majority (63.2%) of intronic NRXN1 deletion cases had a second rare CNV at a prevalence twice as high as that for exonic NRXN1 deletion cases (P = 0.0035).

Conclusions: The results support the importance of exons near the 5' end of NRXN1 in the expression of neurodevelopmental disorders. Intronic NRXN1 deletions do not appear to substantially increase the risk for clinical phenotypes.Genet Med 19 1, 53-61.
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http://dx.doi.org/10.1038/gim.2016.54DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4980119PMC
January 2017

Examining and comparing social perception abilities across childhood-onset neurodevelopmental disorders.

J Am Acad Child Adolesc Psychiatry 2015 Jun 30;54(6):479-86.e1. Epub 2015 Mar 30.

Bloorview Research Institute and the University of Toronto. Electronic address:

Objective: Several neurodevelopmental disorders are associated with social processing deficits. The objective of this study was to compare patterns of social perception abilities across obsessive-compulsive disorder (OCD), attention-deficit/hyperactivity disorder (ADHD), autism spectrum disorder (ASD), and control participants.

Method: A total of 265 children completed the Reading the Mind in the Eyes Test-Child Version (RMET). Parents or caregivers completed established trait/symptom scales. The predicted percentage of accuracy on the RMET was compared across disorders and by item difficulty and item valence (i.e., positive/negative/neutral mental states), then analyzed for associations with trait/symptom scores.

Results: The percentage of correct RMET scores varied significantly between diagnostic groups (p < .0001). On pairwise group comparisons controlling for age and sex, children with ADHD and ASD scored lower than the other groups (p < .0001). When IQ was also controlled for in the model, participants with OCD performed better than controls (p < .001), although differences between other groups were less pronounced. Participants with ASD scored lowest on easy items. Those with ASD and ADHD scored significantly lower than other groups on items with positive valence (p < .01). Greater social communication impairment and hyperactivity/impulsivity, but not OCD traits/symptoms, were associated with lower scores on the RMET, irrespective of diagnosis.

Conclusion: Social perception abilities in neurodevelopmental disorders exist along a continuum. Children with ASD have the greatest deficits, whereas children with OCD may be hypersensitive to social information. Social communication deficits and hyperactive/impulsive traits are associated with impaired social perception abilities; these findings highlight overlapping cognitive and behavioral manifestations across disorders.
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http://dx.doi.org/10.1016/j.jaac.2015.03.016DOI Listing
June 2015

Mapping brain abnormalities in boys with autism.

Hum Brain Mapp 2009 Dec;30(12):3887-900

Laboratory of Neuro Imaging, Department of Neurology, UCLA School of Medicine, Los Angeles, California 90095-7332, USA.

Children with autism spectrum disorder (ASD) exhibit characteristic cognitive and behavioral differences, but no systematic pattern of neuroanatomical differences has been consistently found. Recent neurodevelopmental models posit an abnormal early surge in subcortical white matter growth in at least some autistic children, perhaps normalizing by adulthood, but other studies report subcortical white matter deficits. To investigate the profile of these alterations in 3D, we mapped brain volumetric differences using a relatively new method, tensor-based morphometry. 3D T1-weighted brain MRIs of 24 male children with ASD (age: 9.5 years +/- 3.2 SD) and 26 age-matched healthy controls (age: 10.3 +/- 2.4 SD) were fluidly registered to match a common anatomical template. Autistic children had significantly enlarged frontal lobes (by 3.6% on the left and 5.1% on the right), and all other lobes of the brain were enlarged significantly, or at trend level. By analyzing the applied deformations statistically point-by-point, we detected significant gray matter volume deficits in bilateral parietal, left temporal and left occipital lobes (P = 0.038, corrected), trend-level cerebral white matter volume excesses, and volume deficits in the cerebellar vermis, adjacent to volume excesses in other cerebellar regions. This profile of excesses and deficits in adjacent regions may (1) indicate impaired neuronal connectivity, resulting from aberrant myelination and/or an inflammatory process, and (2) help to understand inconsistent findings of regional brain tissue excesses and deficits in autism.
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http://dx.doi.org/10.1002/hbm.20814DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2790012PMC
December 2009

Three-dimensional mapping of the lateral ventricles in autism.

Psychiatry Res 2008 Jul 27;163(2):106-15. Epub 2008 May 27.

Laboratory of Neuro Imaging, Brain Mapping Division, Department Neurology, UCLA School of Medicine, Los Angeles, California, USA.

In this study, a computational mapping technique was used to examine the three-dimensional profile of the lateral ventricles in autism. T1-weighted three-dimensional magnetic resonance images of the brain were acquired from 20 males with autism (age: 10.1+/-3.5 years) and 22 male control subjects (age: 10.7+/-2.5 years). The lateral ventricles were delineated manually and ventricular volumes were compared between the two groups. Ventricular traces were also converted into statistical three-dimensional maps, based on anatomical surface meshes. These maps were used to visualize regional morphological differences in the thickness of the lateral ventricles between patients and controls. Although ventricular volumes measured using traditional methods did not differ significantly between groups, statistical surface maps revealed subtle, highly localized reductions in ventricular size in patients with autism in the left frontal and occipital horns. These localized reductions in the lateral ventricles may result from exaggerated brain growth early in life.
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http://dx.doi.org/10.1016/j.pscychresns.2007.11.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2770439PMC
July 2008

Structural variation of chromosomes in autism spectrum disorder.

Am J Hum Genet 2008 Feb 17;82(2):477-88. Epub 2008 Jan 17.

The Centre for Applied Genomics, The Hospital for Sick Children, Department of Molecular and Medical Genetics, University of Toronto, Toronto, Ontario M5G 1L7, Canada.

Structural variation (copy number variation [CNV] including deletion and duplication, translocation, inversion) of chromosomes has been identified in some individuals with autism spectrum disorder (ASD), but the full etiologic role is unknown. We performed genome-wide assessment for structural abnormalities in 427 unrelated ASD cases via single-nucleotide polymorphism microarrays and karyotyping. With microarrays, we discovered 277 unbalanced CNVs in 44% of ASD families not present in 500 controls (and re-examined in another 1152 controls). Karyotyping detected additional balanced changes. Although most variants were inherited, we found a total of 27 cases with de novo alterations, and in three (11%) of these individuals, two or more new variants were observed. De novo CNVs were found in approximately 7% and approximately 2% of idiopathic families having one child, or two or more ASD siblings, respectively. We also detected 13 loci with recurrent/overlapping CNV in unrelated cases, and at these sites, deletions and duplications affecting the same gene(s) in different individuals and sometimes in asymptomatic carriers were also found. Notwithstanding complexities, our results further implicate the SHANK3-NLGN4-NRXN1 postsynaptic density genes and also identify novel loci at DPP6-DPP10-PCDH9 (synapse complex), ANKRD11, DPYD, PTCHD1, 15q24, among others, for a role in ASD susceptibility. Our most compelling result discovered CNV at 16p11.2 (p = 0.002) (with characteristics of a genomic disorder) at approximately 1% frequency. Some of the ASD regions were also common to mental retardation loci. Structural variants were found in sufficiently high frequency influencing ASD to suggest that cytogenetic and microarray analyses be considered in routine clinical workup.
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http://dx.doi.org/10.1016/j.ajhg.2007.12.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2426913PMC
February 2008

Evidence for cortical dysfunction in autism: a proton magnetic resonance spectroscopic imaging study.

Biol Psychiatry 2007 Feb;61(4):465-73

Department of Medical Biophysics, The University of Western Ontario, London, Ontario, Canada.

Background: Although brain imaging studies have reported neurobiological abnormalities in autism, the nature and distribution of the underlying neurochemical irregularities are unknown. The purpose of this study was to examine cerebral gray and white matter cellular neurochemistry in autism with proton magnetic resonance spectroscopic imaging (MRSI).

Methods: Proton MRSI examinations were conducted in 26 males with autism (age 9.8 +/- 3.2 years) and 29 male comparison subjects (age 11.1 +/- 2.4 years). Estimates of cerebral gray and white matter concentrations of N-acetylaspartate (NAA), creatine + phosphocreatine, choline-containing compounds, myo-inositol, and glutamate + glutamine (Glx) were made by linear regression analysis of multi-slice MRSI data and compared between groups. Regional estimates of metabolite concentration were also made with multivariate linear regression, allowing for comparisons of frontal, temporal, and occipital gray matter, cerebral white matter, and the cerebellum.

Results: Patients with autism exhibited significantly lower levels of gray matter NAA and Glx than control subjects. Deficits were widespread, affecting most cerebral lobes and the cerebellum. No significant differences were detected in cerebral white matter or cerebellar metabolite levels.

Conclusions: These results suggest widespread reductions in gray matter neuronal integrity and dysfunction of cortical and cerebellar glutamatergic neurons in patients with autism.
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http://dx.doi.org/10.1016/j.biopsych.2006.07.022DOI Listing
February 2007

A prospective, open-label trial of galantamine in autistic disorder.

J Child Adolesc Psychopharmacol 2006 Oct;16(5):621-9

Department of Psychiatry, University of Western Ontario, London, Ontario, Canada.

Objective: Post-mortem studies have reported abnormalities of the cholinergic system in autism. The purpose of this study was to assess the use of galantamine, an acetylcholinesterase inhibitor and nicotinic receptor modulator, in the treatment of interfering behaviors in children with autism.

Methods: Thirteen medication-free children with autism (mean age, 8.8 +/- 3.5 years) participated in a 12-week, open-label trial of galantamine. Patients were rated monthly by parents on the Aberrant Behavior Checklist (ABC) and the Conners' Parent Rating Scale-Revised, and by a physician using the Children's Psychiatric Rating Scale and the Clinical Global Impressions scale.

Results: Patients showed a significant reduction in parent-rated irritability and social withdrawal on the ABC as well as significant improvements in emotional lability and inattention on the Conners' Parent Rating Scale--Revised. Similarly, clinician ratings showed reductions in the anger subscale of the Children's Psychiatric Rating Scale. Eight of 13 participants were rated as responders on the basis of their improvement scores on the Clinical Global Impressions scale. Overall, galantamine was well-tolerated, with no significant adverse effects apart from headaches in one patient.

Conclusion: In this open trial, galantamine was well-tolerated and appeared to be beneficial for the treatment of interfering behaviors in children with autism, particularly aggression, behavioral dyscontrol, and inattention. Further controlled trials are warranted.
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http://dx.doi.org/10.1089/cap.2006.16.621DOI Listing
October 2006

Detection and mapping of hippocampal abnormalities in autism.

Psychiatry Res 2006 Nov 23;148(1):11-21. Epub 2006 Oct 23.

Department of Psychiatry, The University of Western Ontario, London, Ontario, Canada.

Brain imaging studies of the hippocampus in autism have yielded inconsistent results. In this study, a computational mapping strategy was used to examine the three-dimensional profile of hippocampal abnormalities in autism. Twenty-one males with autism (age: 9.5+/-3.3 years) and 24 male controls (age: 10.3+/-2.4 years) underwent a volumetric magnetic resonance imaging scan at 3 Tesla. The hippocampus was delineated, using an anatomical protocol, and hippocampal volumes were compared between the two groups. Hippocampal traces were also converted into three-dimensional parametric surface meshes, and statistical brain maps were created to visualize morphological differences in the shape and thickness of the hippocampus between groups. Parametric surface meshes and shape analysis revealed subtle differences between patients and controls, particularly in the right posterior hippocampus. These deficits were significant even though the groups did not differ significantly with traditional measures of hippocampal volume. These results suggest that autism may be associated with subtle regional reductions in the size of the hippocampus. The increased statistical and spatial power of computational mapping methods provided the ability to detect these differences, which were not found with traditional volumetric methods.
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http://dx.doi.org/10.1016/j.pscychresns.2006.02.005DOI Listing
November 2006

Mapping corpus callosum deficits in autism: an index of aberrant cortical connectivity.

Biol Psychiatry 2006 Aug 7;60(3):218-25. Epub 2006 Feb 7.

Laboratory of Neuro Imaging, Brain Mapping Division, Department of Neurology, UCLA School of Medicine, Los Angeles, California 90095-7332, USA.

Background: Volumetric studies have reported reductions in the size of the corpus callosum (CC) in autism, but the callosal regions contributing to this deficit have differed among studies. In this study, a computational method was used to detect and map the spatial pattern of CC abnormalities in male patients with autism.

Methods: Twenty-four boys with autism (aged 10.0 +/- 3.3 years) and 26 control boys (aged 11.0 +/- 2.5 years) underwent a magnetic resonance imaging (MRI) scan at 3 Tesla. Total and regional areas of the CC were determined using traditional morphometric methods. Three-dimensional (3D) surface models of the CC were also created from the MRI scans. Statistical maps were created to visualize morphologic variability of the CC and to localize regions of callosal thinning in autism.

Results: Traditional morphometric methods detected a significant reduction in the total callosal area and in the anterior third of the CC in patients with autism; however, 3D maps revealed significant reductions in both the splenium and genu of the CC in patients.

Conclusions: Statistical maps of the CC revealed callosal deficits in autism with greater precision than traditional morphometric methods. These abnormalities suggest aberrant connections between cortical regions, which is consistent with the hypothesis of abnormal cortical connectivity in autism.
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http://dx.doi.org/10.1016/j.biopsych.2005.11.011DOI Listing
August 2006

Dynamically spreading frontal and cingulate deficits mapped in adolescents with schizophrenia.

Arch Gen Psychiatry 2006 Jan;63(1):25-34

Laboratory of Neuro Imaging, Brain Mapping Division, Department of Neurology, David Geffen School of Medicine at UCLA, 90095-1769, USA.

Context: We previously detected a dynamic wave of gray matter loss in childhood-onset schizophrenia that started in parietal association cortices and proceeded frontally to envelop dorsolateral prefrontal and temporal cortices, including superior temporal gyri.

Objective: To map gray matter loss rates across the medial hemispheric surface, including the cingulate and medial frontal cortex, in the same cohort studied previously.

Design: Five-year longitudinal study.

Setting: National Institute of Mental Health, Bethesda, Md. Subjects Twelve subjects with childhood-onset schizophrenia, 12 healthy controls, and 9 medication- and IQ-matched subjects with psychosis not otherwise specified.

Interventions: Three-dimensional magnetic resonance imaging at baseline and follow-up.

Main Outcome Measures: Gyral pattern and shape variations encoded by means of high-dimensional elastic deformation mappings driving each subject's cortical anatomy onto a group average; changes in cortical gray matter mapped by computing warping fields that matched sulcal patterns across hemispheres, subjects, and time.

Results: Selective, severe frontal gray matter loss occurred bilaterally in a dorsal-to-ventral pattern across the medial hemispheric surfaces in the schizophrenic subjects. A sharp boundary in the pattern of gray matter loss separated frontal regions and cingulate-limbic areas.

Conclusion: Frontal and limbic regions may not be equally vulnerable to gray matter attrition, which is consistent with the cognitive, metabolic, and functional vulnerability of the frontal cortices in schizophrenia.
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http://dx.doi.org/10.1001/archpsyc.63.1.25DOI Listing
January 2006

Brain magnetic resonance spectroscopy in Tourette's disorder.

J Am Acad Child Adolesc Psychiatry 2005 Dec;44(12):1301-8

Department of Medical Biophysics, University of Western Ontario, London, Ontario, Canada.

Objective: Although abnormalities of neural circuits involving the cortex, striatum, and thalamus are hypothesized to underlie Tourette's disorder, the neuronal abnormalities within components of these circuits are unknown. The purpose of this study was to examine the cellular neurochemistry within these circuits in Tourette's disorder using proton magnetic resonance spectroscopy, a method that has not previously been used in neurobiological investigations of the disorder.

Method: Proton magnetic resonance spectroscopic imaging examinations were conducted in 25 males with Tourette's disorder (age 10.9 +/- 2.0 years) and 32 male comparison subjects (age 11.5 +/- 2.7 years). Spectra from frontal cortex, caudate nucleus, putamen, and thalamus were analyzed, and N-acetylaspartate, creatine, choline, myoinositol, and glutamate + glutamine were quantified and compared between the groups.

Results: Patients with Tourette's disorder demonstrated a reduction in N-acetylaspartate and choline in the left putamen, along with reduced levels of creatine bilaterally in the putamen. In the frontal cortex, patients had significantly lower concentrations of N-acetylaspartate bilaterally, lower levels of creatine on the right side, and reduced myoinositol on the left side.

Conclusions: The results of this study suggest compromised neuronal integrity and deficits in density of neuronal and nonneuronal cells in components of the neural circuits implicated in Tourette's disorder.
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http://dx.doi.org/10.1097/01.chi.0000181046.52078.f4DOI Listing
December 2005

Structural MRI and brain development.

Int Rev Neurobiol 2005 ;67:285-323

Laboratory of Neuro Imaging, Brain Mapping Division, Department of Neurology, University of California, Los Angeles School of Medicine, Los Angeles, California 90095-1769, USA.

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http://dx.doi.org/10.1016/S0074-7742(05)67009-2DOI Listing
May 2006

White matter abnormalities in autism detected through transverse relaxation time imaging.

Neuroimage 2006 Feb 7;29(4):1049-57. Epub 2005 Oct 7.

Department of Medical Biophysics, The University of Western Ontario, London, Ontario, Canada.

While neuroimaging studies have reported neurobiological abnormalities in autism, the underlying tissue abnormalities remain unclear. Quantitative transverse relaxation time (T2) imaging permits the examination of tissue abnormalities in vivo, with increased T2 largely reflecting increased tissue water. Blood flow and the presence of tissue iron may also affect T2. In this study, we used voxel-based relaxometry of the cerebrum and global averages to examine T2 abnormalities in autism. Nineteen males with autism (age: 9.2 +/- 3.0 years) and 20 male controls (age: 10.7 +/- 2.9 years) underwent magnetic resonance imaging at 3.0 T. Quantitative T2 maps, generated through gradient echo sampling of the free induction decay and echo, were segmented into gray matter, white matter, and cerebrospinal fluid. Average cerebral gray and white matter T2 were determined and compared between groups. To assess localized T2 differences, the quantitative T2 maps were warped to a template created for this study, smoothed, and compared using statistical parametric mapping. Patients with autism had an increase in average cerebral white matter T2, although no group differences were seen in average cerebral gray matter T2. Patients with autism also had bilateral regional T2 increases in the gray matter and associated white matter of the parietal lobes (primary sensory association areas) and occipital lobes (visual association areas) and in the white matter within the supplementary motor areas in the frontal lobes. The regional and global elevations in white matter T2 suggest abnormalities of white matter tissue water content in autism, which may represent a neurobiological basis for the aberrant cortical connectivity hypothesized to underlie the disorder.
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http://dx.doi.org/10.1016/j.neuroimage.2005.08.039DOI Listing
February 2006

Parental perception of sleep problems in children of normal intelligence with pervasive developmental disorders: prevalence, severity, and pattern.

J Am Acad Child Adolesc Psychiatry 2005 Aug;44(8):815-22

Department of Psychiatry, University of Western Ontario, London, Ontario, Canada.

Objective: This study compares parents' perceptions of the prevalence, severity, and pattern of sleep problems in children of normal intelligence with pervasive developmental disorders (PDDs) with a normative comparison group of children.

Method: A survey including the Children's Sleep Habits Questionnaire was mailed to a sample of parents of children (age range 5-12 years) with PDDs (diagnosed by the Autism Diagnostic Interview-Revised) obtained by chart review of the past 7 years and to parents of comparison children matched on age, gender, and postal code.

Results: The response rate in the PDD group was 82.2% (37/45) and 55.8% (43/77) in the comparison group. By individually matching, 23 pairs were obtained. The prevalence of sleep problems in the PDD group was reported by parents as being significantly higher than in the comparison group (78% and 26%, respectively; p < .002), as was the severity (mean score 48.2 and 39.0, respectively; p < .001). Values for four of eight sleep subscales including sleep onset delay, sleep duration, sleep anxiety, and parasomnias were significantly higher in the PDD group.

Conclusions: Parents report that sleep problems are significantly more prevalent and severe in children of normal intelligence with PDDs compared with normally developing children, and the pattern appears diverse. Sleep problems in children with PDDs require further research and clinical attention.
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http://dx.doi.org/10.1097/01.chi.0000166377.22651.87DOI Listing
August 2005

A randomized, double-blind, placebo-controlled trial of metoclopramide for the treatment of Tourette's disorder.

J Am Acad Child Adolesc Psychiatry 2005 Jul;44(7):640-6

Department of Psychiatry, The University of Western Ontario, London, Ontario, Canada.

Objective: The pattern of dopamine antagonism by metoclopramide suggests benefits in the treatment of tic disorders. The purpose of this study was to examine the efficacy and safety of metoclopramide in the treatment of children and adolescents with tic disorders.

Method: Twenty-seven medication-free patients (age 11.9 +/- 2.7 years) with Tourette's disorder or a chronic tic disorder participated in an 8-week double-blind, randomized, placebo-controlled trial of metoclopramide. Metoclopramide was started at 5 mg daily and titrated as needed to a maximum dose of 40 mg daily. Tics were rated every 2 weeks, and adverse effects, including weight, cardiac, and laboratory measures, were monitored.

Results: After 8 weeks of treatment, subjects receiving metoclopramide showed a 39% reduction in their total tic score on the Yale Global Tic Severity Scale, while subjects receiving placebo showed only a 13% reduction in tic severity (p = .001). Metoclopramide was well tolerated with no significant laboratory or cardiac changes noted other than an increase in serum prolactin.

Conclusions: The results of this small controlled study suggest that metoclopramide is an effective and well-tolerated treatment for children and adolescents with tic disorders. Further trials are needed to confirm its efficacy and safety in pediatric patients and adults.
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http://dx.doi.org/10.1097/01.chi.0000163279.39598.44DOI Listing
July 2005

Childhood-onset schizophrenia: smooth pursuit eye-tracking dysfunction in family members.

Schizophr Res 2005 Mar;73(2-3):243-52

Child Psychiatry Branch, National Institute of Mental Health, National Institute of Health, Bldg 10, Rm 3N202, Bethesda, MD 20892, USA.

Background: Childhood-onset schizophrenia (COS), a severe form of the disorder, is of interest for etiologic studies. Smooth pursuit eye-tracking dysfunction (ETD) is a biological marker for schizophrenia.

Aims: To compare familial eye-tracking abnormalities for COS and adult-onset schizophrenia (AOS).

Method: Eye-tracking performance for 70 COS parents, 64 AOS parents and 20 COS siblings was compared to their respective age-matched control groups.

Results: COS and AOS parents had higher rate of dichotomously rated eye-tracking dysfunction than their respective controls (16% vs. 1% and 22% vs. 4%, respectively). COS parents and siblings also differed from controls on several continuous measures. However, scores for COS, AOS and control groups overlapped extensively.

Conclusions: Genetic factors underlying eye-tracking dysfunction appear more salient for COS. However, eye-tracking measures have to be used with caution for endophenotypic definition due to low predictive power.

Declaration Of Interest: The study was done at the National Institutes of Health.
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http://dx.doi.org/10.1016/j.schres.2004.07.020DOI Listing
March 2005
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