Autism is currently defined as a single disorder characterized by impairments in social communication and the presence of restricted interests and repetitive behaviors. However, there is mounting evidence that autism represents a collection of overlapping neurodevelopmental disorders, resulting from a variety of neuroanatomical, neurophysiological, neuroimmunologic and/or genetic abnormalities. The wide range of possible etiologies and the heterogeneity of symptom expression among individuals with autism leads to speculation that there actually are several "autisms", i.e., clinically distinct disorders with similar behavioral presentations but different etiologies, clinical course, and treatments. The PDN research program aims to characterize the behavioral and biological manifestations of these differing presentations of autism and to identify their unique features in order to facilitate development of effective therapeutic and preventive interventions. During the reporting period, this project focused primarily on continuing a longitudinal, phenotyping investigation of 105 young children (ages 1-6 years) with autism, 60 age and sex-matched typically developing controls and a group of 25 children with non-autistic developmental delays (NCT 00298246). Baseline evaluations have been completed for these subjects and they are returning for periodic follow-up assessments. Data from the baseline evluations are now being analyzed, including examinations of potentially meaningful subgroups of patients, such as the comparisons of children with autism who have a history of developmental regression and those without. Interestingly, one of the most striking findings of the preliminary analyses was that regression appears to be a continuous variable, rather than the dichotomous categories previously described. That is, children with a history of developmental regression have frequently had at least some delays in their early development and those with distinct early developmental delays may also lose some social and communication skills. We have also recently explored the measurement of restrictive and repetitive behavior in this cohort, finding that these children are reported to have significantly more restrictive and repetitive behavior than found in similar samples, and that this behavior remains stable over a one year period. Finally, data from this project have also been used to continue validation of appropriate algorithms of diagnostic instruments for children in the preschool age range. In addition to the behavioral assessments, the study includes comprehensive medical and developmental histories;neuropsychological, medical and neurological evaluations;assays of blood, urine and cerebrospinal fluid (CSF) samples;and also a variety of specialized studies, including routine and overnight electroencephalograms(EEGs);modified polysomnography to evaluate sleep architecture;and magnetic resonance imaging (MRI scans);genetic assays;and dysmorphology evaluations. Preliminary results from these evaluations have demonstrated that more than one-half of the children have abnormalities of sleep architecture, particularly notable are relative reductions in the percentage time spent in Rapid Eye Movement (REM) sleep. The low REM findings prompted a therapeutic trial which is described in a separate project report (MH002914-04 PDNB). As expected, genetic abnormalities were found in approximately 10% of the subjects and the aberrations are being evaluated for clinical significance (that is, are they a potential etiologic factor or merely a clinically insignificant variation?) Further, we are engaged in a collaboration that is conducting whole exome sequencing of the cohort, and will begin analyzing exome sequencing data in combination with phenotypic expressions. We have now also analyzed cross-sectional data from MRI scans, which found signals of abnormal myelination in specific brain areas of autism, as well as other indicators of abnormalities in brain white matter and relative cortical thinning in specific key regions in the brain. Evidence of previously found early brain growth in autism has also been investigated, both through imaging as well as head circumference records, with data indicating previous findings may have spuriously overestimated increased head circumference trajectory in autism due to inadequate norms (see Raznahan et al, 2013). The overall overall goal of the phenotyping investigation is to determine if there are distinct groups of individuals within the spectrum of autistic disorders that share common profiles of biological and/or behavioral characteristics. Identification of such subgroups will provide new avenues for clinical and basic science research into the causes and treatments of autism. More information about this study (NCT 00298246) may be found at http://clinicalstudies.info.nih.gov/detail/A_2006-M-0102.html Other phenotyping studies are also underway or have been recently completed. Each of them shares the goal of providing a deeper understanding of the autism phenotype and its relationship to etiology, clinical course and outcome. One completed study, "Identification of Characteristics Associated with Symptom Remission in Autism" (NCT00938054) compared children previously diagnosed with autism whose symptoms have remitted (partially or completely), with a cohort of similarly aged children who received similar interventions but continued to meet criteria for autism. Data are being analyzed and a manuscript reporting the results will be prepared. Another study (NCT01093768) used oxytocin and vasopressin as probes of social cognition among young adults with ASD and age-/sex-matched healthy volunteers. Using functional magnetic resonance imaging (fMRI) and a double-blind, placebo-controlled, crossover design, healthy volunteers and individuals with ASD were scanned to investigate how intranasally-administered oxytocin and vasopressin modulated neural activity during tasks including feedback to the subject. Data are being analyzed to assess the effects of vasopressin and oxytocin (each compared against placebo) on behavioral responses and fMRI brain activity to specific tasks involving social feedback. The most recent PDN phenotyping study is a prospective, longitudinal investigation of toddlers considered to be at-risk for ASD because of the presence of early language delays (NCT01339767). This study aims to delineate early communicative impairments that predict ASD and to distinguish these from non-specific markers of non-autistic developmental delays, as well as examining how communication impairments correlate with brain structure and function, as assessed with structural and functional MRI scans, and overnight EEGs. The longitudinal assessments also include comprehensive behavioral assessments designed to profile strengths and weaknesses in communication and other domains. The goal of these assessments is to identify specific risk and resilience factors for ASD, assessed at the final evaluation at age 3 - 4 years. More information about this study may be found at: www.clinicaltrials.gov/ct2/show/NCT01339767?term=toddlers+autism&rank=2

Project Start
Project End
Budget Start
Budget End
Support Year
8
Fiscal Year
2013
Total Cost
$1,954,272
Indirect Cost
Name
U.S. National Institute of Mental Health
Department
Type
DUNS #
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Zip Code
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Raznahan, Armin; Wallace, Gregory L; Antezana, Ligia et al. (2013) Compared to what? Early brain overgrowth in autism and the perils of population norms. Biol Psychiatry 74:563-75
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