Jessica Brian

Behavioral manifestations of autism in the first year of life

In the interest of more systematically documenting the early signs of autism, and of testing specific hypotheses regarding their underlying neurodevelopmental substrates, we have initiated a longitudinal study of high‐risk infants, all of whom have an older sibling diagnosed with an autistic spectrum disorder. Our sample currently includes 150 infant siblings, including 65 who have been followed to age 24 months, who are the focus of this paper. We have also followed a comparison group of low‐risk infants. Our measures include a novel observational scale (the first, to our knowledge, that is designed to assess autism‐specific behavior in infants), a computerized visual orienting task, and standardized measures of temperament, cognitive and language development. Our preliminary results indicate that by 12 months of age, siblings who are later diagnosed with autism may be distinguished from other siblings and low‐risk controls on the basis of: (1) several specific behavioral markers, including atypicalities in eye contact, visual tracking, disengagement of visual attention, orienting to name, imitation, social smiling, reactivity, social interest and affect, and sensory‐oriented behaviors; (2) prolonged latency to disengage visual attention; (3) a characteristic pattern of early temperament, with marked passivity and decreased activity level at 6 months, followed by extreme distress reactions, a tendency to fixate on particular objects in the environment, and decreased expression of positive affect by 12 months; and (4) delayed expressive and receptive language. We discuss these findings in the context of various neural networks thought to underlie neurodevelopmental abnormalities in autism, including poor visual orienting. Over time, as we are able to prospectively study larger numbers and to examine interrelationships among both early‐developing behaviors and biological indices of interest, we hope this work will advance current understanding of the neurodevelopmental origins of autism.

Clinical assessment of autism in high-risk 18-month-olds

Earlier intervention improves outcomes for children with autism spectrum disorders (ASDs), but existing identification tools are at the limits of standardization with 18-month-olds. We assessed potential behavioural markers of ASD at 18 months in a high-risk cohort of infant siblings of children with ASD. Prospective data were collected using the Autism Diagnostic Observation Schedule (ADOS) and Autism Observation Scale for Infants (AOSI) on 155 infant siblings and 73 low-risk controls at 18 months. Infants were classified into three groups (ASD sibs, non-ASD sibs, controls) based on blind best-estimate diagnosis at age 3. Fishers exact tests, followed by discriminant function analyses, revealed that the majority of informative ADOS items came from the social and behavioural domains, and AOSI items measuring behavioural reactivity and motor control contributed additional information. Findings highlight the importance of considering not only social-communication deficits, but also basic dimensions of temperament including state regulation and motor control when assessing toddlers with suspected ASD.

Speech and language impairment and oromotor dyspraxia due to deletion of 7q31 that involves FOXP2

We report detailed clinical, cytogenetic, and molecular findings in a girl with a deletion of chromosome 7q31‐q32. This child has a severe communication disorder with evidence of oromotor dyspraxia, dysmorphic features, and mild developmental delay. She is unable to cough, sneeze, or laugh spontaneously. Her deletion is on the paternally inherited chromosome and includes the FOXP2 gene, which has recently been associated with speech and language impairment and a similar form of oromotor dyspraxia in at least three other published cases. We hypothesize that our patients communication disorder and oromotor deficiency are due to haploinsufficiency for FOXP2 and that her dysmorphism and developmental delay are a consequence of the absence of the other genes involved in the microdeletion. We propose that this patient, together with others reported in the literature, may define a new contiguous gene deletion syndrome encompassing the 7q31‐FOXP2 region. Cytogenetic and molecular analysis of this region should be considered for other individuals displaying similar characteristics.

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

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 × 10−4). 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.

Diagnostic stability in young children at risk for autism spectrum disorder: a baby siblings research consortium study.

BACKGROUND The diagnosis of autism spectrum disorder (ASD) made before age 3 has been found to be remarkably stable in clinic- and community-ascertained samples. The stability of an ASD diagnosis in prospectively ascertained samples of infants at risk for ASD due to familial factors has not yet been studied, however. The American Academy of Pediatrics recommends intensive surveillance and screening for this high-risk group, which may afford earlier identification. Therefore, it is critical to understand the stability of an ASD diagnosis made before age 3 in young children at familial risk. METHODS Data were pooled across seven sites of the Baby Siblings Research Consortium. Evaluations of 418 later-born siblings of children with ASD were conducted at 18, 24, and 36 months of age and a clinical diagnosis of ASD or Not ASD was made at each age. RESULTS The stability of an ASD diagnosis at 18 months was 93% and at 24 months was 82%. There were relatively few children diagnosed with ASD at 18 or 24 months whose diagnosis was not confirmed at 36 months. There were, however, many children with ASD outcomes at 36 months who had not yet been diagnosed at 18 months (63%) or 24 months (41%). CONCLUSIONS The stability of an ASD diagnosis in this familial-risk sample was high at both 18 and 24 months of age and comparable with previous data from clinic- and community-ascertained samples. However, almost half of the children with ASD outcomes were not identified as being on the spectrum at 24 months and did not receive an ASD diagnosis until 36 months. Thus, longitudinal follow-up is critical for children with early signs of social-communication difficulties, even if they do not meet diagnostic criteria at initial assessment. A public health implication of these data is that screening for ASD may need to be repeated multiple times in the first years of life. These data also suggest that there is a period of early development in which ASD features unfold and emerge but have not yet reached levels supportive of a diagnosis.

Magnetoencephalography identifies rapid temporal processing deficit in autism and language impairment.

Deficient rapid temporal processing may contribute to impaired language development by interfering with the processing of brief acoustic transitions crucial for speech perception. Using magnetoencephalography, evoked neural activity (M50, M100) to two 40 ms tones passively presented in rapid succession was recorded in 10 neurologically normal adults and 40 8–17-year-olds with autism, specific language impairment, Asperger syndrome or typical development. While 80% of study participants with intact language (Asperger syndrome, typical development, adults) showed identifiable responses to the second tone, which presented rapid temporal processing demands, 65% of study participants with impaired language (autism, specific language impairment) did not, despite having shown identifiable responses to the first tone. Rapid temporal processing impairments may be fundamentally associated with impairments in language rather than autism spectrum disorder.

Autism spectrum disorder: advances in evidence-based practice

Autism spectrum disorder (ASD) encompasses wide variation in symptom severity and functional impact. The core features of ASD include impairments in social communication, repetitive behaviours and restricted interests. Not all people with ASD identify their challenges as a disorder. Autism spectrum

Intranasal oxytocin in the treatment of autism spectrum disorders: A review of literature and early safety and efficacy data in youth

BACKGROUND There is a paucity of treatments targeting core symptom domains in Autism Spectrum Disorder (ASD). Several animal models and research in typically developing volunteers suggests that manipulation of the oxytocin system may have therapeutic potential for the treatment of social deficits. We review the literature for oxytocin and ASD and report on early dosing, safety and efficacy data of multi-dose oxytocin on aspects of social cognition/function, as well as repetitive behaviors and co-occurring anxiety within ASD. METHODS Fifteen children and adolescents with verbal IQs≥70 were diagnosed with ASD using the ADOS and the ADI-R. They participated in a modified maximum tolerated dose study of intranasal oxytocin (Syntocinon). Data were modeled using repeated measures regression analysis controlling for week, dose, age, and sex. RESULTS Among 4 doses tested, the highest dose evaluated, 0.4 IU/kg/dose, was found to be well tolerated. No serious or severe adverse events were reported and adverse events reported/observed were mild to moderate. Over 12 weeks of treatment, several measures of social cognition/function, repetitive behaviors and anxiety showed sensitivity to change with some measures suggesting maintenance of effect 3 months past discontinuation of intranasal oxytocin. CONCLUSIONS This pilot study suggests that daily administration of intranasal oxytocin at 0.4 IU/kg/dose in children and adolescents with ASD is safe and has therapeutic potential. Larger studies are warranted. This article is part of a Special Issue entitled Oxytocin and Social Behav.

A Prospective Study of Autistic-Like Traits in Unaffected Siblings of Probands With Autism Spectrum Disorder

CONTEXT The presence of autistic-like traits in relatives of individuals with autism spectrum disorder (ASD) is well recognized, but, to our knowledge, the emergence of these traits early in development has not been studied. OBJECTIVE To prospectively investigate the emergence of autistic-like traits in unaffected (no ASD diagnosis) infant siblings of probands diagnosed as having ASD. DESIGN Two groups of children unaffected with ASD were assessed prospectively-siblings of probands diagnosed as having ASD (high risk [HR]) and control subjects with no family history of ASD (low risk [LR]). Scores on a measure of autistic-like traits at 12 months of age were used in a cluster analysis of the entire sample. SETTING A prospective study of infant siblings of probands with ASD from 3 diagnostic centers in Canada. PARTICIPANTS The study included 170 HR and 90 LR children, none of whom was diagnosed as having ASD at age 3 years. MAIN OUTCOME MEASURES The Autism Observation Scale for Infants was used to measure autistic-like traits and derive clusters at 12 months of age. Clusters were compared on ASD symptoms, cognitive abilities, and social-emotional difficulties at age 3 years. RESULTS Two clusters were identified. Cluster 1 (n = 37; 14.2% of total sample) had significantly higher levels of autistic-like traits compared with cluster 2. Within cluster 1, 33 children came from the siblings (19.4% of HR group) and only 4 came from the control subjects (4.5% of LR group). At age 3 years, children from cluster 1 had more social-communication impairment (effect size > 0.70; P < .001), lower cognitive abilities (effect size = -0.59; P < .005), and more internalizing problems (effect size = 0.55; P = .01). Compared with control subjects, HR siblings had a relative risk of 4.3 (95% CI,1.6-11.9) for membership in cluster 1. CONCLUSIONS Study findings suggest the emergence of autistic-like traits resembling a broader autism phenotype by 12 months of age in approximately 19% of HR siblings who did not meet ASD diagnostic criteria at age 3 years.

Inhibitory mechanisms in autism spectrum disorders: typical selective inhibition of location versus facilitated perceptual processing.

BACKGROUND This study examined the inhibitory control mechanisms of selective attention in autism spectrum disorders. Two issues were engaged: First, we extend previous findings of normal inhibition of distractor identity in autism by examining whether inhibition of spatial location is also spared. The second issue concerns the selectivity of inhibition. In non-clinical participants inhibition is selectively directed to the properties of the distractor that compete for the control of action; we examined whether individuals with autism also show normal selectivity of inhibition. METHOD A negative priming task was used to examine selective spatial inhibition in participants with autism relative to matched non-clinical controls. RESULTS We discovered that inhibition of distractor spatial location is within normal limits in autism, as is the ability to selectively direct inhibition to task-relevant stimulus features. In addition, we unexpectedly found that the irrelevant perceptual feature of colour produced a facilitation effect in autism, which has not been observed previously in typical controls. CONCLUSIONS Evidence of colour facilitation implicates more fluent, but presumably less adaptive, perceptual processes in autism.