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1.  Autism Spectrum Disorder is associated with ventricular enlargement in a Low Birth Weight Population 
The Journal of pediatrics  2013;163(1):73-78.
To determine the relation of neonatal cranial ultrasound abnormalities to autism spectrum disorders (ASD) in low birthweight (LBW) adult survivors, a population at increased ASD risk.
Study design
This is a secondary analysis of a prospectively-followed regional birth cohort of 1105 LBW infants systematically screened for perinatal brain injury with cranial ultrasound in the first week of life and later assessed for ASD using a two-stage process [screening at age 16 years (N=623) followed by diagnostic assessment at age 21 years of a systematically selected subgroup of those screened (N=189)]; 14 cases of ASD were identified. For this analysis, cranial ultrasound abnormalities were defined as ventricular enlargement (indicative of diffuse white matter injury), parenchymal lesions (indicative of focal white matter injury) and isolated germinal matrix/intraventricular hemorrhage (GM/IVH).
Compared with no cranial ultrasound abnormalities, any type of white matter injury (ventricular enlargement and/or parenchymal lesion) tripled the risk for screening positively for ASD [3.0 ( 2.2, 4.1)]. However, the risk of being diagnosed with ASD depended on type of white matter injury. With ventricular enlargement, the risk of ASD diagnosis was almost seven-fold that of no cranial ultrasound abnormality [6.7 (2.3, 19.7)], and no elevated risk was found for parenchymal lesion without ventricular enlargement [1.8 (0.2, 13.6)]. Isolated GM/IVH did not increase risk for a positive ASD screen or diagnosis.
In LBW neonates, cranial ultrasound evidence of ventricular enlargement is a strong, and significant risk factor for subsequent development of rigorously-diagnosed ASD.
PMCID: PMC4122247  PMID: 23410601
preterm; autism screening; ventricular enlargement; autism diagnosis
2.  Maturational differences in thalamocortical white matter microstructure and auditory evoked response latencies in autism spectrum disorders 
Brain research  2013;1537:79-85.
White matter diffusion anisotropy in the acoustic radiations was characterized as a function of development in autistic and typically developing children. Auditory-evoked neuromagnetic fields were also recorded from the same individuals and the latency of the left and right middle latency superior temporal gyrus auditory ~50ms response (M50)1 was measured. Group differences in structural and functional auditory measures were examined, as were group differences in associations between white matter pathways, M50 latency, and age. Acoustic radiation white matter fractional anisotropy did not differ between groups. Individuals with autism displayed a significant M50 latency delay. Only in typically developing controls, white matter fractional anisotropy increased with age and increased white matter anisotropy was associated with earlier M50 responses. M50 latency, however, decreased with age in both groups. Present findings thus indicate that although there is loss of a relationship between white matter structure and auditory cortex function in autism spectrum disorders, and although there are delayed auditory responses in individuals with autism than compared with age-matched controls, M50 latency nevertheless decreases as a function of age in autism, parallel to the observation in typically developing controls (although with an overall latency delay). To understand auditory latency delays in autism and changes in auditory responses as a function of age in controls and autism, studies examining white matter as well as other factors that influence auditory latency, such as synaptic transmission, are of interest.
PMCID: PMC3970268  PMID: 24055954
Magnetoencephalography; Autism spectrum disorder; Auditory evoked response; Fractional anisotropy; White matter; M50
3.  Missing and Delayed Auditory Responses in Young and Older Children with Autism Spectrum Disorders 
Background: The development of left and right superior temporal gyrus (STG) 50 ms (M50) and 100 ms (M100) auditory responses in typically developing (TD) children and in children with autism spectrum disorder (ASD) was examined. Reflecting differential development of primary/secondary auditory areas and supporting previous studies, it was hypothesized that whereas left and right M50 STG responses would be observed equally often in younger and older children, left and right M100 STG responses would more often be absent in younger than older children. In ASD, delayed neurodevelopment would be indicated via the observation of a greater proportion of ASD than TD subjects showing missing M100 but not M50 responses in both age groups. Missing M100 responses would be observed primarily in children with ASD with language impairment (ASD + LI) (and perhaps concomitantly lower general cognitive abilities).
Methods: Thirty-five TD controls, 63 ASD without language impairment (ASD − LI), and 38 ASD + LI were recruited. Binaural tones were presented. The presence or absence of a STG M50 and M100 was scored. Subjects were grouped into younger (6–10 years old) and older groups (11–15 years old).
Results: Although M50 responses were observed equally often in older and younger subjects and equally often in TD and ASD, left and right M50 responses were delayed in ASD − LI and ASD + LI. Group comparisons showed that in younger subjects M100 responses were observed more often in TD than ASD + LI (90 versus 66%, p = 0.04), with no differences between TD and ASD − LI (90 versus 76%, p = 0.14) or between ASD − LI and ASD + LI (76 versus 66%, p = 0.53). In older subjects, whereas no differences were observed between TD and ASD + LI, responses were observed more often in ASD − LI than ASD + LI. Findings were similar when splitting the ASD group into lower- and higher-cognitive functioning groups.
Conclusion: Although present in all groups, M50 responses were delayed in ASD. Examining the TD data, findings indicated that by 11 years, a right M100 should be observed in 100% of subjects and a left M100 in 80% of subjects. Thus, by 11 years, lack of a left and especially right M100 offers neurobiological insight into sensory processing that may underlie language or cognitive impairment.
PMCID: PMC4047517  PMID: 24936181
autism spectrum disorders; M50; M100; superior temporal gyrus; magnetoencephalography
4.  Autism 
Lancet  2009;374(9701):1627-1638.
Autism spectrum disorders are characterised by severe deficits in socialisation, communication, and repetitive or unusual behaviours. Increases over time in the frequency of these disorders (to present rates of about 60 cases per 10 000 children) might be attributable to factors such as new administrative classifications, policy and practice changes, and increased awareness. Surveillance and screening strategies for early identification could enable early treatment and improved outcomes. Autism spectrum disorders are highly genetic and multifactorial, with many risk factors acting together. Genes that affect synaptic maturation are implicated, resulting in neurobiological theories focusing on connectivity and neural effects of gene expression. Several treatments might address core and comorbid symptoms. However, not all treatments have been adequately studied. Improved strategies for early identification with phenotypic characteristics and biological markers (eg, electrophysiological changes) might hopefully improve effectiveness of treatment. Further knowledge about early identification, neurobiology of autism, effective treatments, and the effect of this disorder on families is needed.
PMCID: PMC2863325  PMID: 19819542
5.  “Complementary and Alternative Medicine Treatments for Children with Autism Spectrum Disorders” 
Complementary and alternative medical treatments are commonly used for children with autism spectrum disorders. This review discusses the evidence supporting the most frequently used treatments, including categories of mind-body medicine, energy medicine, biologically based, manipulative and body-based practices, with the latter two the most commonly selected by families. It is important for clinical providers to understand the evidence for efficacy (or lack thereof) and potential side effects. Some CAM practices have evidence to reject their use, such as secretin, others have emerging evidence to support their use, like melatonin. Most treatments, however, have not been adequately studied and do not have evidence to support their use.
PMCID: PMC2597185  PMID: 18775371
autism; autism spectrum; complementary and alternative treatments; evidence based
6.  Investigation of Autistic Features Among Individuals With Mild to Moderate Cornelia de Lange Syndrome 
Cornelia de Lange syndrome (CdLS) is a congenital disorder characterized by distinctive facial features, growth retardation, limb abnormalities, intellectual disability, and behavioral problems. Autism has been reported to occur frequently in CdLS, but the frequency of autism in individuals with the milder CdLS phenotype is not well studied. We investigated autistic features by using a screening tool and a diagnostic interview in 49 individuals with the mild to moderate phenotype from a CdLS research database at the Children’s Hospital of Philadelphia. The Social Communication Questionnaire (SCQ), a screening instrument for autistic disorder, was completed for all individuals. For individuals who screened positive and a subset of those that screened negative, the Autism Diagnostic Interview-Revised (ADI-R) was administered. Autistic symptom severity was not significantly different by gender, age groups, and genotypes. There was a significant correlation between higher levels of adaptive functioning and lower scores of autistic symptoms. The estimated prevalence of significant autistic features by ADI-R criteria was 43% in our cohort of individuals with the mild to moderate CdLS phenotype, which suggests that prevalence of autistic disorder may be higher than previously described among individuals with mild to moderate phenotype of CdLS. Clinicians who take care of individuals with CdLS should have a high index of suspicion for autistic features, and refer for further evaluation when these features are present in order to expedite appropriate intervention.
PMCID: PMC3557850  PMID: 22740374
Cornelia de Lange syndrome (CdLS); autism; behavioral phenotype; NIPBL; SMC1A; SMC3
7.  Prevalence of Autism Spectrum Disorder in Adolescents Born Weighing <2000 Grams 
Pediatrics  2011;128(5):883-891.
To estimate the diagnostic prevalence of autism spectrum disorders (ASDs) in a low birth weight (LBW) cohort.
Participants belonged to a regional birth cohort of infants (N = 1105) born weighing <2000 g between October 1, 1984, and July 3, 1989, and followed up by periodic assessments to 21 years of age. At 16 years (n = 623), adolescents were screened for ASD using a wide net (previous professional diagnosis of an ASD or a score above a liberal cutoff on the Social Communication Questionnaire or the Autism Spectrum Symptoms Questionnaire). At 21 years (n = 189), 60% of screen positives and 24% of screen negatives were assessed for diagnoses of ASD by the Autism Diagnostic Observation Schedule or the Autism Diagnostic Interview–Revised.
Samples retained at ages 16 and 21 years were representative of samples assessed at earlier ages except for lower levels of social risk. Of positive screens, 11 of 70 had ASD; of negative screens, 3 of 119 had ASD. The fractions of the 2 screening groups with ASD (14.3% in screen-positives and 2.5% in screen negatives) were weighted by fractions of screen-positives and screen-negatives among the adolescents (18.8% and 81.2%, respectively). This calculation produced an estimated prevalence rate of ASD in the entire cohort of 5% (31 of 623).
The diagnostic prevalence of ASD in this LBW preterm cohort was higher than that reported by the Centers for Disease Control and Prevention for 8-year-olds in the general US population in 2006.
PMCID: PMC3208957  PMID: 22007018
low birth weight; preterm; autism spectrum; screening; diagnosis; outcome
8.  Auditory Magnetic Mismatch Field Latency: A Biomarker for Language Impairment in Autism 
Biological psychiatry  2011;70(3):263-269.
Auditory processing abnormalities are frequently observed in Autism Spectrum Disorders (ASD), and these abnormalities may have sequelae in terms of clinical language impairment (LI). The present study assessed associations between language impairment and the amplitude and latency of the superior temporal gyrus magnetic mismatch field (MMF) in response to changes in an auditory stream of tones or vowels.
51 children with ASD and 27 neurotypical controls, all aged 6-15 years, underwent neuropsychological evaluation, including tests of language function, as well as magnetoencephalographic (MEG) recording during presentation of tones and vowels. The MMF was identified in the difference waveform obtained from subtraction of responses to standard stimuli from deviant stimuli.
MMF latency was significantly prolonged (p<0.001) in children with ASD compared to neurotypical controls. Furthermore, this delay was most pronounced (∼50ms) in children with concomitant LI, with significant differences in latency between children with ASD with LI and those without (p<0.01). Receiver operator characteristic analysis indicated a sensitivity of 82.4% and specificity of 71.2% for diagnosing LI based on MMF latency.
Neural correlates of auditory change detection (the MMF) are significantly delayed in children with ASD, and especially those with concomitant LI suggesting both a neurobiological basis for LI as well as a clinical biomarker for LI in ASD.
PMCID: PMC3134608  PMID: 21392733
autism spectrum disorders; mismatch negativity; language impairment; magnetoencephalography; biomarker; electrophysiology
9.  Infant siblings and the investigation of autism risk factors 
Infant sibling studies have been at the vanguard of autism spectrum disorders (ASD) research over the past decade, providing important new knowledge about the earliest emerging signs of ASD and expanding our understanding of the developmental course of this complex disorder. Studies focused on siblings of children with ASD also have unrealized potential for contributing to ASD etiologic research. Moving targeted time of enrollment back from infancy toward conception creates tremendous opportunities for optimally studying risk factors and risk biomarkers during the pre-, peri- and neonatal periods. By doing so, a traditional sibling study, which already incorporates close developmental follow-up of at-risk infants through the third year of life, is essentially reconfigured as an enriched-risk pregnancy cohort study. This review considers the enriched-risk pregnancy cohort approach of studying infant siblings in the context of current thinking on ASD etiologic mechanisms. It then discusses the key features of this approach and provides a description of the design and implementation strategy of one major ASD enriched-risk pregnancy cohort study: the Early Autism Risk Longitudinal Investigation (EARLI).
PMCID: PMC3436647  PMID: 22958474
Autism; Cohort; Epidemiology; Pregnancy; Prospective; Sibling; Study Design
10.  MEG Detection of Delayed Auditory Evoked Responses in Autism Spectrum Disorders: Towards an Imaging Biomarker for Autism 
Motivated by auditory and speech deficits in autism spectrum disorders (ASD), the frequency dependence of superior temporal gyrus (STG) 50 msec (M50) and 100 msec (M100) neuromagnetic auditory evoked field responses in children with ASD and typically developing controls were evaluated. Whole-cortex magnetoencephalography (MEG) was obtained from 17 typically developing children and 25 children with ASD. Subjects were presented tones with frequencies of 200, 300, 500, and 1,000 Hz, and left and right STG M50 and M100 STG activity was examined. No M50 latency or amplitude Group differences were observed. In the right hemisphere, a Group × Frequency ANOVA on M100 latency produced a main effect for Group (P 5 0.01), with an average M100 latency delay of 11 msec in children with ASD. In addition, only in the control group was the expected association of earlier M100 latencies in older than younger children observed. Group latency differences remained significant when hierarchical regression analyses partialed out M100 variance associated with age, IQ, and language ability (all P-values < 0.05). Examining the right-hemisphere 500 Hz condition (where the largest latency differences were observed), a sensitivity of 75%, a specificity of 81%, and a positive predictive value (PPV) of 86% was obtained at a threshold of 116 msec. The M100 latency delay indicates disruption of encoding simple sensory information. Given similar findings in language impaired and nonlanguage impaired ASD subjects, a right-hemisphere M100 latency delay appears to be an electrophysiological endophenotype for autism.
PMCID: PMC3099241  PMID: 20063319
autism spectrum disorders; M50; M100; magnetoencephalography; language impairment; auditory evoked response
11.  Common genetic variants on 5p14.1 associate with autism spectrum disorders 
Nature  2009;459(7246):528-533.
Autism spectrum disorders (ASDs) represent a group of childhood neurodevelopmental and neuropsychiatric disorders characterized by deficits in verbal communication, impairment of social interaction, and restricted and repetitive patterns of interests and behaviour. To identify common genetic risk factors underlying ASDs, here we present the results of genome-wide association studies on a cohort of 780 families (3,101 subjects) with affected children, and a second cohort of 1,204 affected subjects and 6,491 control subjects, all of whom were of European ancestry. Six single nucleotide polymorphisms between cadherin 10 (CDH10) and cadherin 9 (CDH9)—two genes encoding neuronal cell-adhesion molecules—revealed strong association signals, with the most significant SNP being rs4307059 (P = 3.4 × 10−8, odds ratio = 1.19). These signals were replicated in two independent cohorts, with combined P values ranging from 7.4 × 10−8 to 2.1 × 10−10. Our results implicate neuronal cell-adhesion molecules in the pathogenesis of ASDs, and represent, to our knowledge, the first demonstration of genome-wide significant association of common variants with susceptibility to ASDs.
PMCID: PMC2943511  PMID: 19404256
12.  Autism genome-wide copy number variation reveals ubiquitin and neuronal genes 
Nature  2009;459(7246):569-573.
Autism spectrum disorders (ASDs) are childhood neurodevelopmental disorders with complex genetic origins1–4. Previous studies focusing on candidate genes or genomic regions have identified several copy number variations (CNVs) that are associated with an increased risk of ASDs5–9. Here we present the results from a whole-genome CNV study on a cohort of 859 ASD cases and 1,409 healthy children of European ancestry who were genotyped with ~550,000 single nucleotide polymorphism markers, in an attempt to comprehensively identify CNVs conferring susceptibility to ASDs. Positive findings were evaluated in an independent cohort of 1,336 ASD cases and 1,110 controls of European ancestry. Besides previously reported ASD candidate genes, such as NRXN1 (ref. 10) and CNTN4 (refs 11, 12), several new susceptibility genes encoding neuronal cell-adhesion molecules, including NLGN1 and ASTN2, were enriched with CNVs in ASD cases compared to controls (P = 9.5 × 10−3). Furthermore, CNVs within or surrounding genes involved in the ubiquitin pathways, including UBE3A, PARK2, RFWD2 and FBXO40, were affected by CNVs not observed in controls (P = 3.3 × 10−3). We also identified duplications 55 kilobases upstream of complementary DNA AK123120 (P = 3.6 × 10−6). Although these variants may be individually rare, they target genes involved in neuronal cell-adhesion or ubiquitin degradation, indicating that these two important gene networks expressed within the central nervous system may contribute to the genetic susceptibility of ASD.
PMCID: PMC2925224  PMID: 19404257
13.  Socioeconomic Inequality in the Prevalence of Autism Spectrum Disorder: Evidence from a U.S. Cross-Sectional Study 
PLoS ONE  2010;5(7):e11551.
This study was designed to evaluate the hypothesis that the prevalence of autism spectrum disorder (ASD) among children in the United States is positively associated with socioeconomic status (SES).
A cross-sectional study was implemented with data from the Autism and Developmental Disabilities Monitoring Network, a multiple source surveillance system that incorporates data from educational and health care sources to determine the number of 8-year-old children with ASD among defined populations. For the years 2002 and 2004, there were 3,680 children with ASD among a population of 557 689 8-year-old children. Area-level census SES indicators were used to compute ASD prevalence by SES tertiles of the population.
Prevalence increased with increasing SES in a dose-response manner, with prevalence ratios relative to medium SES of 0.70 (95% confidence interval [CI] 0.64, 0.76) for low SES, and of 1.25 (95% CI 1.16, 1.35) for high SES, (P<0.001). Significant SES gradients were observed for children with and without a pre-existing ASD diagnosis, and in analyses stratified by gender, race/ethnicity, and surveillance data source. The SES gradient was significantly stronger in children with a pre-existing diagnosis than in those meeting criteria for ASD but with no previous record of an ASD diagnosis (p<0.001), and was not present in children with co-occurring ASD and intellectual disability.
The stronger SES gradient in ASD prevalence in children with versus without a pre-existing ASD diagnosis points to potential ascertainment or diagnostic bias and to the possibility of SES disparity in access to services for children with autism. Further research is needed to confirm and understand the sources of this disparity so that policy implications can be drawn. Consideration should also be given to the possibility that there may be causal mechanisms or confounding factors associated with both high SES and vulnerability to ASD.
PMCID: PMC2902521  PMID: 20634960
14.  Disparities in Diagnoses Received Prior to a Diagnosis of Autism Spectrum Disorder 
This study estimated differences by ethnicity in the diagnoses assigned prior to the diagnosis of autism. In this sample of 406 Medicaid-eligible children, African-Americans were 2.6 times less likely than white children to receive an autism diagnosis on their first specialty care visit. Among children who did not receive an autism diagnosis on their first visit, ADHD was the most common diagnosis. African-American children were 5.1 times more likely than white children to receive a diagnosis of adjustment disorder than of ADHD, and 2.4 times more likely to receive a diagnosis of conduct disorder than of ADHD. Differences in diagnostic patterns by ethnicity suggest possible variations in parents’ descriptions of symptoms, clinician interpretations and expectations, or symptom presentation.
PMCID: PMC2861330  PMID: 17160456
Autistic disorder; Autism spectrum disorder; African-Americans; Minorities; Child health services; Community mental health services
15.  Electrophysiological Signatures: Magnetoencephalographic Studies of the Neural Correlates of Language Impairment in Autism Spectrum Disorders 
While magnetoencephalography (MEG) is of increasing utility in the assessment of pediatric patients with seizure disorders, this indication reflects only a part of the clinical potential of the technology. Beyond epilepsy, a broad range of developmental psychiatric disorders require the combined offerings of spatial and temporal resolution, along with direct sensitivity to neural electrical activity, that are offered by MEG. This article reviews the application of MEG in the study of auditory processing as an aspect of language impairment in children. Potential application is elaborated in the clinical case of autism spectrum disorders, a devastating disorder with prevalence of 1 in 150, poorly served by alternative imaging modalities. MEG offers both spatial and temporal insights, tentatively described as “electrophysiological signatures”. Results demonstrate the sensitivity of MEG for detection of abnormalities of auditory processing in ASD and their clinical correlates. These findings offer promise for the comprehensive assessment of developmental neuropsychiatric disorders such as autism, but also suggest avenues for the development of MEG technology to adequately meet the needs of such populations, as well as providing conduits to basic sciences including neurobiology and genetics.
PMCID: PMC2397446  PMID: 18336941

Results 1-15 (15)