Inflammatory profiles in the BTBR mouse: How relevant are they to autism spectrum disorders?

Autism spectrum disorders (ASD) are a group of disorders characterized by core behavioral features including stereotyped interests, repetitive behaviors and impairments in communication and social interaction. In addition, widespread changes in the immune systems of individuals with ASD have been identified, in particular increased evidence of inflammation in the periphery and central nervous system. While the etiology of these disorders remains unclear, it appears that multiple gene and environmental factors are involved. The need for animal models paralleling the behavioral and immunological features of ASD is paramount to better understand the link between immune system dysregulation and behavioral deficits observed in these disorders. As such, the asocial BTBR mouse strain displays both ASD relevant behaviors and persistent immune dysregulation, providing a model system that has and continues to be instructive in understanding the complex nature of ASD.     

Epilepsy and autism spectrum disorders: Are there common developmental mechanisms?

Autistic spectrum disorders (ASD) and epilepsies are heterogeneous disorders that have diverse etiologies and pathophysiologies. The high rate of co-occurrence of these disorders suggest potentially shared underlying mechanisms. A number of well-known genetic disorders share epilepsy and autism as prominent phenotypic features, including tuberous sclerosis, Rett syndrome, and fragile X. In addition, mutations of several genes involved in neurodevelopment, including ARX, DCX, neuroligins and neuropilin2 have been identified in children with epilepsy, ASD or often both. Finally, in animal models, early-life seizures can result in cellular and molecular changes that could contribute to learning and behavioral disabilities as seen in ASD. Increased understanding of the common genetic, molecular and cellular mechanisms of ASD and epilepsy may provide insight into their underlying pathophysiology and elucidate new therapeutic approaches of both conditions.     

Sex differences in oxytocin and vasopressin: implications for autism spectrum disorders?

Autism spectrum disorders (ASD) are male-biased and characterized by deficits in social behavior and social communication, excessive anxiety or hyperreactivity to stressful experiences, and a tendency toward repetitiveness. The purpose of this review is to consider evidence for a role for two sexually dimorphic neuropeptides, oxytocin (OT) and arginine vasopressin (VP), in these features of ASD. Both VP and OT play a role in normal development. VP is androgen-dependent and of particular importance to male behavior. Excess VP or disruptions in the VP system could contribute to the male vulnerability to ASD. Alternatively, protective processes mediated via OT or the OT receptor might help to explain the relatively rare occurrence of ASD in females. Disruptions in either OT or VP or their receptors could result from genetic variation or epigenetic modifications of gene expression, especially during early development. Deficits in other developmental growth factors, such as reelin, which may in turn regulate or be regulated by OT or VP, are additional candidates for a role in ASD.     

Understanding autism and related disorders: what has imaging taught us?

Structural imaging studies of autism have documented increased total brain volume and early acceleration in brain growth. Functional MR imaging (fMRI) studies in autism have also led to the view of autism as a disorder of cortical functioning in which functional connectivity or synchronization of brain regions and cortical activity are disturbed with atypical cortical specialization.     

Pre-school children with suspected autism spectrum disorders: Do girls and boys have the same profiles?

The male to female ratio is raised in autism spectrum disorders (ASD). Previous studies have suggested that girls with ASD have more problems with communication than boys, but boys show more repetitive behaviours than girls. In this study, 20 girls, 1.8–3.9 years of age were matched for chronological and developmental age with 20 boys with suspected ASD. All the children were recruited after population screening and referral by Child Health Care Services to a specialised neuropsychiatry clinic, where they underwent comprehensive neuropsychiatric assessments. Comparisons were made with regard to diagnosis, developmental profiles and global disability. No significant gender differences were found. There were strong correlations between results obtained in different developmental areas. The results suggest that either (1) previous studies finding clear gender differences may have overrated discrepancies between girls and boys in ASD, or that (2) there may be girls, who will not be identified in the early years with our current screening instruments. More research with a much larger population representative study samples is required.     

Prader�CWilli syndrome and autism spectrum disorders: an evolving story

Prader-Willi syndrome (PWS) is well-known for its genetic and phenotypic complexities. Caused by a lack of paternally derived imprinted material on chromosome 15q11-q13, individuals with PWS have mild to moderate intellectual disabilities, repetitive and compulsive behaviors, skin picking, tantrums, irritability, hyperphagia, and increased risks of obesity. Many individuals also have co-occurring autism spectrum disorders (ASDs), psychosis, and mood disorders. Although the PWS 15q11-q13 region confers risks for autism, relatively few studies have assessed autism symptoms in PWS or directly compared social, behavioral, and cognitive functioning across groups with autism or PWS. This article identifies areas of phenotypic overlap and difference between PWS and ASD in core autism symptoms and in such comorbidities as psychiatric disorders, and dysregulated sleep and eating. Though future studies are needed, PWS provides a promising alternative lens into specific symptoms and comorbidities of autism.     

What distinguishes autism spectrum disorders from other developmental disorders before the age of four years?

Abstract The increasing recognition of the benefits of early intervention for children with autism spectrum disorder (ASD) stresses the importance of early identification of children who might benefit from those programs. However, in the early years of life it may be difficult to distinguish children with ASD from children with other developmental disorders. The aim of the present study was to identify behavioural patterns that could facilitate this differentiation. Prior to diagnostic assessment, 2- and 3-year-old children (n=30), all referred to a clinic for possible autism, were observed in a semi-structured play interaction, and their parents were interviewed about the childrens early development from 0 to 24 months. Following diagnostic assessment, the 17 children fulfilling the ICD-10 criteria for ASD were compared to the 13 children diagnosed with other developmental disorders (outside the autism spectrum). On the basis of parent reports only a few distinguishing signs of ASD were found before 24 months of age. On the basis of professional observations in a semi-structured play interaction several distinguishing signs were found for the 2- and 3-year-olds; smiles in response, responds to name, follows pointing, looks to read faces, initiates requesting verbal and nonverbal behaviours, and functional play.     

Who benefits from early intervention in autism spectrum disorders?

Research in autism spectrum disorders (ASD) described individual differences in response to intervention. This study explored child and parental characteristics at baseline that predict outcomes in adaptive skills and acquisition of cognitive gains. Seventy-eight children aged 15–35 months diagnosed with ASD by standardized diagnostic tools were included. Evaluations of verbal and non-verbal abilities, adaptive skills and autism severity were obtained at pre-intervention (T1) and after one year of intervention (T2). At T2, children improved significantly in their verbal ability and the severity of autism symptoms was reduced. Outcome in adaptive skills was best predicted by baseline verbal ability and maternal age. Better verbal ability especially in those with severe autism symptoms, and older maternal age predicted better adaptive skills outcome. T1 autism severity, child's age and maternal age and educational attainment best predicted cognitive gains. Less severe autism symptoms, younger child's age at start of intervention, older maternal age and higher maternal education predicted greater cognitive gains with intervention. The study suggests biological factors including age, language abilities and autism severity and environmental factors including maternal age and education, impact the ability to benefit from early intervention in ASD.     

Gastrointestinal disease in children with autism spectrum disorders: Etiology or consequence?

Chronic gastrointestinal (GI) symptoms and disorders are common in children with autism spectrum disorder and have been shown to be significantly correlated with the degree of behavioral and cognitive impairment. In this unique population, GI symptoms often arise very early in development, during infancy or toddlerhood, and may be misdiagnosed - or not diagnosed at all – due in part to the challenges associated with recognition of symptoms in a minimally or non-communicative child. Evidence demonstrating that the gut-brain-axis can communicate gut dysbiosis and systemic immune dysregulation in a bidirectional manner raises the question as to whether an untreated gastrointestinal disorder can directly impact neurodevelopment or, conversely, whether having a neurodevelopmental disorder predisposes a child to chronic GI issues. From the data presented in this mini review, we conclude that the preponderance of available evidence would suggest the former scenario is more strongly supported.     

Do autism spectrum disorders differ from each other and from non-spectrum disorders on emotion recognition tests?

 We tested whether dimensional measures of empathic ability, theory of mind, and intelligence would differentiate autism spectrum disorders from each other and from non-spectrum disorders. Tests were administered to children with a diagnosis of Autistic Disorder (AutD; n = 20), Asperger's Disorder (AspD; n = 28), Attention Deficit/Hyperactivity Disorder (Inattentive Type) (ADHD; n = 35), Mental Retardation (Mild) (MR; n = 34), Anxiety Disorder (AnxD; n = 14), or No Psychological Disorder (NPD; n = 36). Results showed that empathic ability discriminated among groups on the autism spectrum (AutD < AspD < NPD). Because empathic ability is not independent of intelligence (AutD < AspD < NPD on intelligence; MR < ADHD < NPD on empathic ability), both dimensions are necessary to discriminate autism spectrum from non-spectrum disorders. When intelligence is covaried, empathic ability discriminated AutD, but not AspD, from other disorders (AutD < MR < ADHD <  NPD = AnxD = AspD). Accepted: 11 October 2000     

Overlap between functional GI disorders and other functional syndromes: what are the underlying mechanisms?

Abstract Background Irritable bowel syndrome and other gastrointestinal (GI) and non‐GI disorders such as functional dyspepsia, fibromyalgia, temporomandibular joint disorder, interstitial cystitis/painful bladder syndrome, and chronic fatigue syndrome are known as functional pain syndromes. They commonly coexist within the same individual. The pathophysiologic mechanisms of these disorders are not well understood, but it has been hypothesized that they share a common pathogenesis. Purpose The objective of this review is to discuss the proposed pathophysiologic mechanisms, which have been similarly studied in these conditions. These mechanisms include enhanced pain perception, altered regional brain activation, infectious etiologies, dysregulations in immune and neuroendocrine function, and genetic susceptibility. Studies suggest that these functional disorders are multifactorial, but factors which increase the vulnerability of developing these conditions are shared.     

Do risk factors for autism spectrum disorders affect gender representation?

To examine the M:F ratio in several known risk factors to demonstrate insights regarding autism spectrum disorders (ASD) etiology and sex. The study included 615 participants aged 18 months to 18 years age (mean = 49.8 months, SD = 28.4 months) diagnosed with ASD. Cognitive, adaptive and assessment of ASD were obtained using standardized tests. Detailed birth, familial, medical and developmental histories were obtained from the parents. Risk factors included ASD in the family (having a first-order family member with ASD); advanced maternal age (≥35 years); advanced paternal age (≥38 years); birth order (first-born versus third-born); low birth weight (LBW) (<2500 g); prematurity (gestational age <36 weeks). The M:F ratio (4.4:1) in the LBW group was lower than the M:F ratio (7.1:1) in the >2500 g group; however the difference showed only a statistical trend. No significant differences in M:F ratio were found between the ASD groups with and without the other examined risk factors. It is possible that the absence of a major association between most of the examined risk factors and sex representation points to the relatively minor role of these risk factors in ASD.     

How can epidemiological studies contribute to understanding autism spectrum disorders?

More and more studies on the frequency of autism spectrum disorders (ASD) have been published recently, most of which show the increase in prevalence data. In this review, the author pointed out factors and parameters to be considered in analyzing frequency data, i.e., the enlargement of the concept of autism, prevalence and incidence, accuracy and precision in the initial screening, and the effect of the “vaccine debate”. The proportion of high-functioning ASD has been growing higher and higher due to better recognition in the last few years, and the apparent increase might still be the tip of an iceberg. Future epidemiological studies should include themes on diversity of the longitudinal course and re-conceptualization of ASD by dimensional diagnosis.     

Do children with autism spectrum disorders have motor learning difficulties?

Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by social and communication impairments as well as a wide range of behavioral symptoms. For years, motor disturbance reported in ASD has not been treated as a core deficit because of the overwhelming problems in sociability and communication. Recent studies, however, reveal that motor deficits are also fundamental to ASD presentation and contribute to the core symptoms of ASD. Untreated motor problems can persist well into adolescence and adulthood, resulting in long-term physical, psychological, and behavioral issues in individuals with ASD. Thus, the ability to understand and address the overall picture of a child with ASD, including motor dysfunction, has become a critical need. This review focuses on sensorimotor adaptation and motor sequence learning in children with ASD and presents related evidence that compromised motor learning may play a critical role in motor dysfunctions of ASD. It addresses possible factors that explain controversial findings in the literature and discusses potential strategies for facilitating motor learning. Future intervention studies should address the importance of motor learning beyond social and language domains in ASD.     

Effects of season of birth on autism spectrum disorders: fact or fiction?

OBJECTIVE: This study attempted to examine the relationship between month and season of birth and risk for autism spectrum disorders. METHOD: The cohort included all Jewish individuals born in Israel over 5 consecutive years (N=311,169) and assessed by the Israeli Draft Board as part of the mandatory assessment of eligibility for military service conducted at age 17. The outcome of autism spectrum disorders was ascertained from the Draft Board Medical Registry, which contains information about medical and psychiatric disorders for this population of adolescents. RESULTS: There was no association between month or season of birth and the prevalence of autistic spectrum disorders. CONCLUSIONS: The findings from this historical, population-based cohort study do not support an association between season of birth and autistic spectrum disorders.     

Variability of cortical oscillation patterns: A possible endophenotype in autism spectrum disorders?

Autism spectrum disorders (ASD) have been associated with altered neural oscillations, especially fast oscillatory activity in the gamma frequency range, suggesting fundamentally disturbed temporal coordination of activity during information processing. A detailed review of available cortical oscillation studies in ASD does not convey a clear-cut picture with respect to dysfunctional oscillation patterns in the gamma or other frequency ranges. Recent evidence suggests that instead of a general failure to activate or synchronize the cortex, there is greater intra-participant variability across behavioral, fMRI and EEG responses in ASD. Intra-individual fluctuations from one trial to another have been largely ignored in task-related neural oscillation studies of ASD, which instead have focused on mean changes in power. We highlight new avenues for the analysis of cortical oscillation patterns in ASD which are sensitive to trial-to-trial variability within the participant, in order to validate the significance of increased response variability as possible endophenotype of the disorder.