La revue Brain and Development propose un dossier spécial consacré à l’autisme dans le cadre d’une conférence internationale qui s’est tenue à Tokyo en décembre 2011 :

Exploring Autism Research Collaboration between Japan and United States Joint Academic Conference on Autism Spectrum Disorders (ASD)

1. Kaga M. Exploring autism research collaboration between Japan and United States Joint Academic Conference on Autism Spectrum Disorders, December, 2011. Brain and Development ;2013 ;35(2):95.

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2. Senju A. Atypical development of spontaneous social cognition in autism spectrum disorders. Brain and Development ;2013 ;35(2):96-101.

Individuals with autism spectrum disorders (ASD) have profound impairment in the development of social interaction and communication. However, it is also known that some ‘high-functioning’ individuals with ASD show apparently typical capacity to process social information in a controlled experimental settings, despite their difficulties in daily life. The current paper overviews the spontaneous social cognition, spontaneous processing of social information in the absence of explicit instruction or task demand, in individuals with ASD. Three areas of the researches, false belief attribution, imitation/mimicry, and eye gaze processing, have been reviewed. The literatures suggest that high-functioning individuals with ASD (a) do not spontaneously attribute false belief to others, even though they can easily do so when explicitly instructed, (b) can imitate others’ goal-directed actions under explicit instruction and show spontaneous mimicry of others’ actions when they attend to the action, but are less likely to show spontaneous mimicry without the task structure to navigate attention to others’ action and (c) can process others’ gaze direction and shift attention to others’ gaze directions, but fail to spontaneously attend to another person’s eyes in social and communicative context, and less likely to be prompted to respond in response to perceived eye contact. These results are consistent with the claim that individuals with ASD do not spontaneously attend to socially relevant information, even though they can easily process the same information when their attention is navigated towards it.

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3. Honda H. How can epidemiological studies contribute to understanding autism spectrum disorders ?. Brain and Development ;2013 ;35(2):102-105.

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.

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4. Uchino S, Waga C. SHANK3 as an autism spectrum disorder-associated gene. Brain and Development ;2013 ;35(2):106-110.

SHANK3 is a synaptic scaffolding protein enriched in the postsynaptic density of excitatory synapses, and plays important roles in the formation, maturation, and maintenance of synapses. Haploinsufficiency of the SHANK3 gene causes a developmental disorder, 22q13.3 deletion syndrome (known as Phelan–McDermid syndrome), that is characterized by severe expressive language and speech delay, hypotonia, global developmental delay, and autistic behavior. Since several SHANK3 mutations have been identified in a particular phenotypic group in patients with autism spectrum disorder (ASD), the SHANK3 is strongly suspected of being involved in the pathogenesis and neuropathology of ASD. Five CpG-islands have been identified in the SHANK3 gene, and tissue-specific expression of SHANK3 is regulated by DNA methylation in an epigenetic manner. Cumulative evidence has shown that several SHANK3 variants are expressed in the developing rodent brain and that their expression is regulated by DNA methylation of intragenic promoters. We identified novel SHANK3 transcripts whose transcription started at the vicinity of the CpG-island 2 in the mouse brain. Shank3 mutant mice exhibit autistic-like behaviors, including impaired social interaction and repetitive behaviors. In this article we review recent findings in regard to higher brain functions of SHANK3, epigenetic regulation of SHANK3 expression, and SHANK3-related ASD that were obtained from genetic analyses in ASD patients, molecular biological studies using developing mouse brains, and studies of Shank3 mutant mice.

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5. Yamasue H. Function and structure in social brain regions can link oxytocin-receptor genes with autistic social behavior. Brain and Development ;2013 ;35(2):111-118.

Difficulties in appropriate social and communicative behaviors are the most prevalent and core symptoms of autism spectrum disorders (ASDs). Although recent intensive research has focused on the neurobiological background of these difficulties, many aspects of them were not yet elucidated. Recent studies have employed multimodal magnetic resonance imaging (MRI) indices as intermediate phenotypes of this behavioral phenotype to link candidate genes with the autistic social difficulty. As MRI indices, functional MRI (fMRI), structural MRI, and MR-spectroscopy have been examined in subjects with autism spectrum disorders. As candidate genes, this mini-review has much interest in oxytocin-receptor genes (OXTR), since recent studies have repeatedly reported their associations with normal variations in social cognition and behavior as well as with their extremes, autistic social dysfunction. Through previous increasing studies, medial prefrontal cortex, hypothalamus and amygdala have repeatedly been revealed as neural correlates of autistic social behavior by MRI multimodalities and their relationship to OXTR. For further development of this research area, this mini-review integrates recent accumulating evidence about human behavioral and neural correlates of OXTR.

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6. Benvenuto A, Battan B, Porfirio MC, Curatolo P. Pharmacotherapy of autism spectrum disorders. Brain and Development ;2013 ;35(2):119-127.

Although no pharmacological or behavioral therapy has currently proven effective for treating all core symptoms of autism, many dysfunctional behaviors may be treated pharmacologically. Drug treatments should always be part of a comprehensive management plan that includes behavioral and educational interventions, and should be focused on specific targets. Several classes of psychotropic medications have been used to decrease the wide range of “maladaptive” or “interfering” behaviors and associated medical problems that can interfere with relationships and physical health and hinder the implementation of various non-pharmacological interventions. Atypical neuroleptics have been shown to be useful in the treatment of behavioral symptoms in autism. Attention deficit and hyperactivity disorder medications may be effective for counteracting the additional features of hyperactivity and short attention span. Antiepileptic drugs and selective serotonin reuptake inhibitors have shown promising results, but there are no specific indications for them as of yet. With respect to potential drug targets, some clinical features are caused by a dysfunction in neurochemical signaling systems, and thus may improve with selective pharmacological interventions acting on specific abnormal neurobiological pathways. Recent animal studies can be useful models for understanding the common pathogenic pathways leading to autism spectrum disorders (ASDs), and have the potential to offer new biologically focused treatment options.

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7. Neville B. Role of ESSENCE for preschool children with neurodevelopmental disorders. Brain and Development ;2013 ;35(2):128-132.

Early Symptomatic Syndromes Eliciting Neurodevelopmental Examinations (ESSENCE) has been proposed as a guide to the neurodevelopmental needs of the under 5s. The problems are their multiplicity, the presence of partial features of specific conditions e.g. autism spectrum disorder and attention deficit/hyperactivity disorder and the young age of the children. For these reasons, child development teams often leave families to cope with very difficult situations. This paper includes epilepsy and the cerebral palsies to see if providing precise diagnostic categories and therapeutic targets can be achieved. It includes a discussion of causal sequences which have yet to be applied comprehensively to the neurodevelopment disorders.

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8. Estes A, Olson E, Sullivan K, Greenson J, Winter J, Dawson G, Munson J. Parenting-related stress and psychological distress in mothers of toddlers with autism spectrum disorders. Brain and Development ;2013 ;35(2):133-138.

Background:Parents of children with autism spectrum disorders (ASDs) are at risk for higher stress levels than parents of children with other developmental disabilities and typical development. Recent advances in early diagnosis have resulted in younger children being diagnosed with ASDs but factors associated with parent stress in this age group are not well understood. Aims : The present study examined parenting-related stress and psychological distress in mothers of toddlers with ASD, developmental delay without ASD (DD), and typical development. The impact of child problem behavior and daily living skills on parenting-stress and psychological distress were further investigated. Methods : Participants were part of a larger research study on early ASD intervention. Results : Parent self-report of parenting-related stress and psychological distress was utilized. Parents of toddlers with ASD demonstrated increased parenting-related stress compared with parents of toddlers with DD and typical development. However, psychological distress did not differ significantly between the groups. Child behavior problems, but not daily living skills emerged as a significant predictor of parenting-related stress and psychological distress. This was true for both mothers of children with ASD and DD. Conclusions : These finding suggest that parents’ abilities to manage and reduce behavior problems is a critical target for interventions for young children with ASD and DD in order to improve child functioning and decrease parenting-related stress.

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9. Mori K, Toda Y, Ito H, Mori T, Goji A, Fujii E, Miyazaki M, Harada M, Kagami S. A proton magnetic resonance spectroscopic study in autism spectrum disorders : Amygdala and orbito-frontal cortex. Brain and Development ;2013 ;35(2):139-145.

We previously reported neural dysfunction in the anterior cingulate cortex and dorsolateral prefrontal cortex in autistic patients using proton magnetic resonance spectroscopy (1H-MRS). In this investigation, we measured chemical metabolites in the left amygdala and the bilateral orbito-frontal cortex (OFC), which are the main components of the social brain. We also examined the association between these metabolic findings and social abilities in subjects with autism. The study group included 77 autistic patients (3–6 years old ; mean age 4.1 ; 57 boys and 20 girls). The control subjects were 31 children (3–6 years old ; mean age 4.0 ; 23 boys and 8 girls). Conventional proton MR spectra were obtained using the STEAM sequence with parameters of TR = 5 sec and TE = 15 msec by a 1.5-tesla clinical MRI system. We analyzed the concentrations of N-acetylaspartate (NAA), creatine/phosphocreatine (Cr), and choline-containing compounds (Cho) using LCModel (Ver. 6.1). The concentrations of NAA in the left amygdala and the bilateral OFC in autistic patients were significantly decreased compared to those in the control group. In the autistic patients, the NAA concentrations in these regions correlated with their social quotient. These findings suggest the presence of neuronal dysfunction in the amygdala and OFC in autism. Dysfunction in the amygdala and OFC may contribute to the pathogenesis of autism.

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10. Pecorelli A, Leoncini S, De Felice C, Signorini C, Cerrone C, Valacchi G, Ciccoli L, Hayek J. Non-protein-bound iron and 4-hydroxynonenal protein adducts in classic autism. Brain and Development ;2013 ;35(2):146-154.

A link between oxidative stress and autism spectrum disorders (ASDs) remains controversial with opposing views on its role in the pathogenesis of the disease. We investigated for the first time the levels of non-protein-bound iron (NPBI), a pro-oxidant factor, and 4-hydroxynonenal protein adducts (4-HNE PAs), as a marker of lipid peroxidation-induced protein damage, in classic autism. Patients with classic autism (n = 20, mean age 12.0 ± 6.2 years) and healthy controls (n = 18, mean age 11.7 ± 6.5 years) were examined. Intraerythrocyte and plasma NPBI were measured by high performance liquid chromatography (HPLC), and 4-HNE PAs in erythrocyte membranes and plasma were detected by Western blotting. The antioxidant defences were evaluated as erythrocyte glutathione (GSH) levels using a spectrophotometric assay. Intraerythrocyte and plasma NPBI levels were significantly increased (1.98- and 3.56-folds) in autistic patients, as compared to controls (p = 0.0019 and p < 0.0001, respectively) ; likewise, 4-HNE PAs were significantly higher in erythrocyte membranes and in plasma (1.58- and 1.6-folds, respectively) from autistic patients than controls (p = 0.0043 and p = 0.0001, respectively). Erythrocyte GSH was slightly decreased (−10.34%) in patients compared to controls (p = 0.0215). Our findings indicate an impairment of the redox status in classic autism patients, with a consequent imbalance between oxidative stress and antioxidant defences. Increased levels of NPBI could contribute to lipid peroxidation and, consequently, to increased plasma and erythrocyte membranes 4-HNE PAs thus amplifying the oxidative damage, potentially contributing to the autistic phenotype.

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11. Miyajima T, Kumada T, Saito K, Fujii T. Autism in siblings with autosomal dominant nocturnal frontal lobe epilepsy. Brain and Development ;2013 ;35(2):155-157.

In 1999, Hirose et al. reported a Japanese family with autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) associated with a neuronal nicotinic acetylcholine receptor α4 subunit mutation (S252L). We followed the siblings of this family, and found that the elder brother had Asperger’s disorder without mental retardation (MR) and the younger brother had autistic disorder with profound MR. The clinical epileptic features of the siblings were very similar, and both had deficits in socialization, but their cognitive development differed markedly. It thus seems that epilepsy is the direct phenotype of the S252L mutation, whereas other various factors modulate the cognitive and social development. No patients with ADNFLE have previously been reported to have autism spectrum disorder or profound MR.

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