1. Ajram LA, Horder J, Mendez MA, Galanopoulos A, Brennan LP, Wichers RH, Robertson DM, Murphy CM, Zinkstok J, Ivin G, Heasman M, Meek D, Tricklebank MD, Barker GJ, Lythgoe DJ, Edden RAE, Williams SC, Murphy DGM, McAlonan GM. {{Shifting brain inhibitory balance and connectivity of the prefrontal cortex of adults with autism spectrum disorder}}. {Transl Psychiatry};2017 (May 23);7(5):e1137.
Currently, there are no effective pharmacologic treatments for the core symptoms of autism spectrum disorder (ASD). There is, nevertheless, potential for progress. For example, recent evidence suggests that the excitatory (E) glutamate and inhibitory (I) GABA systems may be altered in ASD. However, no prior studies of ASD have examined the ‘responsivity’ of the E-I system to pharmacologic challenge; or whether E-I modulation alters abnormalities in functional connectivity of brain regions implicated in the disorder. Therefore, we used magnetic resonance spectroscopy ([1H]MRS) to measure prefrontal E-I flux in response to the glutamate and GABA acting drug riluzole in adult men with and without ASD. We compared the change in prefrontal ‘Inhibitory Index’-the GABA fraction within the pool of glutamate plus GABA metabolites-post riluzole challenge; and the impact of riluzole on differences in resting-state functional connectivity. Despite no baseline differences in E-I balance, there was a significant group difference in response to pharmacologic challenge. Riluzole increased the prefrontal cortex inhibitory index in ASD but decreased it in controls. There was also a significant group difference in prefrontal functional connectivity at baseline, which was abolished by riluzole within the ASD group. Our results also show, for we believe the first time in ASD, that E-I flux can be ‘shifted’ with a pharmacologic challenge, but that responsivity is significantly different from controls. Further, our initial evidence suggests that abnormalities in functional connectivity can be ‘normalised’ by targeting E-I, even in adults.
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2. Bao VA, Doobay V, Mottron L, Collignon O, Bertone A. {{Multisensory Integration of Low-level Information in Autism Spectrum Disorder: Measuring Susceptibility to the Flash-Beep Illusion}}. {J Autism Dev Disord};2017 (May 23)
Previous studies have suggested audiovisual multisensory integration (MSI) may be atypical in Autism Spectrum Disorder (ASD). However, much of the research having found an alteration in MSI in ASD involved socio-communicative stimuli. The goal of the current study was to investigate MSI abilities in ASD using lower-level stimuli that are not socio-communicative in nature by testing susceptibility to auditory-guided visual illusions. Adolescents and adults with ASD and typically-developing (TD) individuals were shown to have similar susceptibility to a fission illusion. However, the ASD group was significantly more susceptible to the fusion illusion. Results suggest that individuals with ASD demonstrate MSI on the flash-beep illusion task but that their integration of audiovisual sensory information may be less selective than for TD individuals.
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3. Bradshaw J, Koegel LK, Koegel RL. {{Improving Functional Language and Social Motivation with a Parent-Mediated Intervention for Toddlers with Autism Spectrum Disorder}}. {J Autism Dev Disord};2017 (May 23)
Recent research suggests that children with autism spectrum disorder (ASD) may now be reliably identified in later infancy, highlighting the need for empirically-validated interventions for infants and toddlers with early symptoms of ASD. Using a multiple baseline design across 15- to 21-month-old toddlers, this study implemented a brief, parent-mediated, Pivotal Response Treatment program, focusing on improving expressive communication. The results indicated that verbal communication improved as a consequence of the intervention, with concomitant improvements in untreated areas for all participants. Following the intervention, symptoms of autism decreased and parents reported satisfaction with the program’s ease of implementation and observed child gains. The results are discussed in terms of developing very early interventions to improve developmental trajectories for infants and toddlers.
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4. Cantor RM, Navarro L, Won H, Walker RL, Lowe JK, Geschwind DH. {{ASD restricted and repetitive behaviors associated at 17q21.33: genes prioritized by expression in fetal brains}}. {Mol Psychiatry};2017 (May 23)
Autism spectrum disorder (ASD) is a behaviorally defined condition that manifests in infancy or early childhood as deficits in communication skills and social interactions. Often, restricted and repetitive behaviors (RRBs) accompany this disorder. ASD is polygenic and genetically complex, so we hypothesized that focusing analyses on intermediate core component phenotypes, such as RRBs, can reduce genetic heterogeneity and improve statistical power. Applying this approach, we mined Caucasian genome-wide association studies (GWAS) data from two of the largest ASD family cohorts, the Autism Genetics Resource Exchange and Autism Genome Project (AGP). Of the 12 RRBs measured by the Autism Diagnostic Interview-Revised, seven were found to be significantly familial and substantially variable, and hence, were tested for genome-wide association in 3104 ASD-affected children from 2045 families. Using a stringent significance threshold (P<7.1 x 10-9), GWAS in the AGP revealed an association between 'the degree of the repetitive use of objects or interest in parts of objects' and rs2898883 (P<6.8 x 10-9), which resides within the sixth intron of PHB. To identify the candidate target genes of the associated single-nucleotide polymorphisms at that locus, we applied chromosome conformation studies in developing human brains and implicated three additional genes: SLC35B1, CALCOCO2 and DLX3. Gene expression, brain imaging and fetal brain expression quantitative trait locus studies prioritize SLC35B1 and PHB. These analyses indicate that GWAS of single heritable features of genetically complex disorders followed by chromosome conformation studies in relevant tissues can be successful in revealing novel risk genes for single core features of ASD.Molecular Psychiatry advance online publication, 23 May 2017; doi:10.1038/mp.2017.114. Lien vers le texte intégral (Open Access ou abonnement)
5. Coleman-Fountain E. {{Uneasy encounters: Youth, social (dis)comfort and the autistic self}}. {Soc Sci Med};2017 (May 12);185:9-16.
Notions of deficit and ‘faultiness’ shape depictions of the association between autism and uneasy social relationships. That framing has been the focus of critique by autistic activists and scholars who, exploring autistic people’s sociality, reframe issues of social difficulty in terms of inequality and discomfort. Located within this set of debates, the article analyses data from a UK based study of mental health narratives derived from semi-structured interviews with 19 autistic young adults aged 23 to 24. The NIHR funded the study, and a UK National Health Service Research Ethics Committee gave ethical approval. Sociality and social difficulties, feelings of discomfort, and perceptions of the autistic self as ‘faulty’ were themes of the study. Exploring the nexus of inequality, non-autistic social power, fears about social performance and (dis)comfort that underpinned the accounts, the article explores the conclusions the young adults reached about social difficulty. Critically examining notions of improvability, the article contributes to debates about sociality, social difficulty and comfort by questioning the assumption that social dysfunction is due to autistic ‘fault’. The article concludes with a discussion of inequality in autistic and non-autistic encounters, and of the social dynamics that deny autistic people social comfort.
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6. Custodio CS, Mello BSF, Filho A, de Carvalho Lima CN, Cordeiro RC, Miyajima F, Reus GZ, Vasconcelos SMM, Barichello T, Quevedo J, de Oliveira AC, de Lucena DF, Macedo DS. {{Neonatal Immune Challenge with Lipopolysaccharide Triggers Long-lasting Sex- and Age-related Behavioral and Immune/Neurotrophic Alterations in Mice: Relevance to Autism Spectrum Disorders}}. {Mol Neurobiol};2017 (May 23)
Early-life challenges, particularly infections and stress, are related to neuropsychiatric disorders such as autism and schizophrenia. Here, we conducted a wide range of behavioral tests in periadolescent (postnatal day (PN) 35) and adult (PN70) Swiss mice neonatally challenged with LPS on PN5 and -7, to unveil behavioral alterations triggered by LPS exposure. Immune and neurotrophic (brain-derived neurotrophic factor-BDNF) alterations were determined in the prefrontal cortex (PFC), hippocampus (HC), and hypothalamus (HT). Since the incidence and clinical manifestations of neurodevelopmental disorders present significant sex-related differences, we sought to distinctly evaluate male and female mice. While on PN35, LPS-challenged male mice presented depressive, anxiety-like, repetitive behavior, and working memory deficits; on PN70, only depressive- and anxiety-like behaviors were observed. Conversely, females presented prepulse inhibition (PPI) deficits in both ages studied. Behavioral changes in periadolescence and adulthood were accompanied, in both sexes, by increased levels of interleukin (IL-4) (PFC, HC, and HT) and decreased levels of IL-6 (PFC, HC, and HT). BDNF levels increased in both sexes on PN70. LPS-challenged male mice presented, in both ages evaluated, increased HC myeloperoxidase activity (MPO); while when adult increased levels of interferon gamma (IFNgamma), nitrite and decreased parvalbumin were observed. Alterations in innate immunity and parvalbumin were the main LPS-induced remarks between males and females in our study. We concluded that neonatal LPS challenge triggers sex-specific behavioral and neurochemical alterations that resemble autism spectrum disorder, constituting in a relevant model for the mechanistic investigation of sex bias associated with the development of this disorder.
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7. Freitag CM. {{[Genetic findings in autism spectrum disorders]}}. {Nervenarzt};2017 (May 23)
Autism spectrum disorders (ASD) are pervasive developmental disorders comprising problems in social interaction, communication, and stereotyped behavior and interests. They show a prevalence of around 0.8% in children, adolescents, and adults, and a skewed sex distribution (about 4:1 = male:female). ASD are predominantly genetically determined disorders. Heritability estimates from twin studies range between 64 and 91%. Recurrence risk in siblings is 20-fold elevated. De novo and inherited monogenetic disorders, mutations, sex chromosomal abnormalities, cytogenetic and imprinting disorders as well as common variants are associated with ASD. Genetic disorders implicating a specific additional intervention are of specific clinical relevance. Genetic testing and counselling should be provided for all families and individuals with ASD. This article gives an overview on current basic genetic research in ASD, its clinical relevance and genetic counselling in ASD.
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8. Hodges A, Davis T, Crandall M, Phipps L, Weston R. {{Using Shaping to Increase Foods Consumed by Children with Autism}}. {J Autism Dev Disord};2017 (May 23)
The current study used differential reinforcement and shaping to increase the variety of foods accepted by children with autism who demonstrated significant feeding inflexibility. Participants were introduced to four new food items via a hierarchical exposure, which involved systematically increasing the desired response with the food item. Level of food consumption was evaluated using a combined multiple baseline plus changing criterion design. Following intervention, all participants accepted all foods targeted, expanding upon the number of foods consumed.
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9. Isaksson J, Pettersson E, Kostrzewa E, Diaz Heijtz R, Bolte S. {{Brief Report: Association Between Autism Spectrum Disorder, Gastrointestinal Problems and Perinatal Risk Factors Within Sibling Pairs}}. {J Autism Dev Disord};2017 (May 23)
Autism spectrum disorder (ASD) has been associated with gastrointestinal (GI) problems, but the nature of this association is unclear. Parents to siblings, concordant or discordant for ASD (N = 217), participated in a web survey covering mother’s weight gain during pregnancy, maternal viral/bacterial infection and use of antibiotics, duration of breastfeeding, mode of delivery, birth weight and child GI problems. ASD was associated with GI problems and perinatal environmental risk, based on a summation of maternal infection and antibiotic use during pregnancy and/or the breastfeeding period. The association between GI problems and ASD remained within the sibling pairs (beta = 1.23; p < .001) in the adjusted model. Our results indicate non-shared environmental effects on the ASD/GI association, but none of the factors examined explained the link. Lien vers le texte intégral (Open Access ou abonnement)
10. Kong HE, Zhao J, Xu S, Jin P, Jin Y. {{Fragile X-Associated Tremor/Ataxia Syndrome: From Molecular Pathogenesis to Development of Therapeutics}}. {Front Cell Neurosci};2017;11:128.
Fragile X-associated tremor/ataxia syndrome (FXTAS) is a neurodegenerative disorder caused by a premutation CGG repeat expansion (55-200 repeats) within the 5′ UTR of the fragile X gene (FMR1). FXTAS is characterized by intension tremor, cerebellar ataxia, progressive neurodegeneration, parkinsonism and cognitive decline. The development of transgenic mouse and Drosophila melanogaster models carrying an expanded CGG repeat has yielded valuable insight into the pathophysiology of FXTAS. To date, we know of two main molecular mechanisms of this disorder: (1) a toxic gain of function of the expanded CGG-repeat FMR1 mRNA, which results in the binding/sequestration of the CGG-binding proteins; and (2) CGG repeat-associated non-AUG-initiated (RAN) translation, which generates a polyglycine peptide toxic to cells. Besides these CGG-mediated mechanisms, recent studies have shed light on additional mechanisms of pathogenesis, such as the antisense transcript ASFMR1, mitochondrial dysfunction, DNA damage from R-loop formation and 5-hydroxymethylcytosine (5hmC)-mediated epigenetic modulation. Here we summarize the recent progress towards understanding the etiology of FXTAS and provide an overview of potential treatment strategies.
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11. Marschik PB, Lemcke S, Einspieler C, Zhang D, Bolte S, Townend GS, Lauritsen MB. {{Early development in Rett syndrome – the benefits and difficulties of a birth cohort approach}}. {Dev Neurorehabil};2017 (May 23):1-5.
PURPOSES: Typically, early (pre-diagnostic) development in individuals later diagnosed with Rett syndrome (RTT) has been investigated retrospectively using parent reports, medical records and analysis of home videos. In recent years, prospective research designs have been increasingly applied to the investigation of early development in individuals with late phenotypical onset disorders, for example, autism spectrum disorder. METHODS: In this study, data collected by the Danish National Birth Cohort lent itself to prospective exploration of the early development of RTT, in particular early motor-, speech-language, and socio-communicative behaviors, mood, and sleep. RESULTS AND CONCLUSIONS: Despite limitations, this quasi prospective methodology proved promising. In order to add substantially to the body of knowledge, however, specific questions relating to peculiarites in early development could usefully be added to future cohort studies. As this involves considerable work, it may be more realistic to consider a set of indicators which point to a number of developmental disorders rather than to one.
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12. McKenzie R, Dallos R. {{Autism and attachment difficulties: Overlap of symptoms, implications and innovative solutions}}. {Clin Child Psychol Psychiatry};2017 (May 01):1359104517707323.
This article explores overlap of symptoms between autism and attachment difficulties and suggests innovative solutions based on formulation. Currently, clinicians express difficulties in differentiating between these conditions contributing to misdiagnosis. Research into the prevalence of attachment difficulties among children with autism often fails to reflect detailed knowledge of attachment theory. Consequently, studies in this area employ questionable modifications to attachment measures and methods of analysis. The findings of such studies are confusing and inconsistent. Children with autism and their parents are, however, known to be at high risk of developing insecure attachment patterns. Clinical assessments based on formulation may be helpful in these cases, as they include consideration of developmental and relational factors contributing to symptom presentation. Research suggests that where parents of children with autism establish secure relationships with their children outcomes are improved. Consequently, interventions, which improve dyadic synchrony and sensitivity of parents, are likely to benefit families living with autism and attachment difficulties.
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13. Quintana DS, Westlye LT, Hope S, Naerland T, Elvsashagen T, Dorum E, Rustan O, Valstad M, Rezvaya L, Lishaugen H, Stensones E, Yaqub S, Smerud KT, Mahmoud RA, Djupesland PG, Andreassen OA. {{Dose-dependent social-cognitive effects of intranasal oxytocin delivered with novel Breath Powered device in adults with autism spectrum disorder: a randomized placebo-controlled double-blind crossover trial}}. {Transl Psychiatry};2017 (May 23);7(5):e1136.
The neuropeptide oxytocin has shown promise as a treatment for symptoms of autism spectrum disorders (ASD). However, clinical research progress has been hampered by a poor understanding of oxytocin’s dose-response and sub-optimal intranasal delivery methods. We examined two doses of oxytocin delivered using a novel Breath Powered intranasal delivery device designed to improve direct nose-to-brain activity in a double-blind, crossover, randomized, placebo-controlled trial. In a randomized sequence of single-dose sessions, 17 male adults with ASD received 8 international units (IU) oxytocin, 24IU oxytocin or placebo followed by four social-cognitive tasks. We observed an omnibus main effect of treatment on the primary outcome measure of overt emotion salience as measured by emotional ratings of faces (eta2=0.18). Compared to placebo, 8IU treatment increased overt emotion salience (P=0.02, d=0.63). There was no statistically significant increase after 24IU treatment (P=0.12, d=0.4). The effects after 8IU oxytocin were observed despite no significant increase in peripheral blood plasma oxytocin concentrations. We found no significant effects for reading the mind in the eyes task performance or secondary outcome social-cognitive tasks (emotional dot probe and face-morphing). To our knowledge, this is the first trial to assess the dose-dependent effects of a single oxytocin administration in autism, with results indicating that a low dose of oxytocin can significantly modulate overt emotion salience despite minimal systemic exposure.
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14. Righi G, Benevides J, Mazefsky C, Siegel M, Sheinkopf SJ, Morrow EM. {{Predictors of Inpatient Psychiatric Hospitalization for Children and Adolescents with Autism Spectrum Disorder}}. {J Autism Dev Disord};2017 (May 23)
Autism Spectrum Disorder (ASD) is associated with significant healthcare expenditures and a greater utilization of psychiatric health services. High utilization may not be evenly distributed across individuals with ASD. The objective of this study was to identify individual and family characteristics that increase the risk of psychiatric hospitalization. Naturalistic study of two age- and gender-matched ASD cohorts, inpatients enrolled in the Autism Inpatient Collection (AIC) and outpatients enrolled in the Rhode Island Consortium of Autism Research and Treatment (RI-CART), revealed a number of factors associated with hospitalization. Multiple logistic regression analyses revealed that adaptive functioning, ASD symptom severity, primary caregiver’s marital status, the presence of mood disorders, and the presence of sleep problems independently increased the risk of psychiatric hospitalization.
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15. Viktorin A, Uher R, Reichenberg A, Levine SZ, Sandin S. {{Autism risk following antidepressant medication during pregnancy}}. {Psychol Med};2017 (May 22):1-10.
BACKGROUND: Previous studies have examined if maternal antidepressant medication during pregnancy increase the risk of autism spectrum disorder (ASD) in the offspring, but the results have been conflicting. METHODS: In a population-based cohort of 179 007 children born in 2006 and 2007 and followed through 2014 when aged 7 and 8, we estimated relative risks (RRs) of ASD and 95% confidence intervals (CIs) from Cox regression in children exposed to any antidepressant medication during pregnancy, and nine specific antidepressant drugs. Analyses were adjusted for potential confounders and were conducted in the full population sample, and in a clinically relevant sub-sample of mothers with at least one diagnosis of depression or anxiety during life. RESULTS: The adjusted RR of ASD in children of mothers who used antidepressant medication during pregnancy was estimated at 1.23 (95% CI 0.96-1.57), and at 1.07 (95% CI 0.80-1.43) in women with a history of depression or anxiety. Analyses of specific antidepressants initially revealed increased RRs of offspring ASD confined to citalopram and escitalopram (RR: 1.47; 95% CI 0.92-2.35) and clomipramine (RR: 2.86; 95% CI 1.04-7.82). CONCLUSION: Medication with antidepressants during pregnancy does not appear to be causally associated with an increased risk of ASD in the offspring. Instead, the results suggest that the association is explained by factors related to the underlying susceptibility to psychiatric disorders. Based on these findings, the risk of ASD in the offspring should not be a consideration to withhold treatment with commonly used antidepressant drugs from pregnant women.
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16. Warren LR, Rao PA, Paton DC. {{A Pilot Observational Study of an Acupressure/Acupuncture Intervention in Children with Autism Spectrum Disorder}}. {J Altern Complement Med};2017 (May 22)
OBJECTIVES: To determine whether children with autism spectrum disorder (ASD) would tolerate an acupressure/acupuncture intervention and whether parents would adhere to a twice-weekly, 8-week intervention protocol. Second, to further understand best measures to use to capture impact of intervention on behavioral and regulatory functions. DESIGN: This is an observational pilot study with pre-, mid-, and postintervention measures. SETTINGS/LOCATION: The intervention was carried out in a private practice office in a large metropolitan area. SUBJECTS: A total of 10 children of ages 3-10 years with ASD and one of their parents participated. INTERVENTIONS: A total of 16 biweekly treatment sessions of acupressure and/or acupuncture were carried out by a licensed acupuncturist, and a daily home-based acupressure intervention was carried out by a parent. OUTCOME MEASURES: Attendance, tolerance of intervention, parent compliance with home program, and parent compliance in completing daily diary and five standardized measures of behavioral and regulatory functions pre-, mid-, and postintervention were recorded. RESULTS: The 10 children in this observational study, collectively, tolerated the intervention and parents adhered to the 16 sessions, biweekly protocol, and home protocol, as well as completing daily diary and five standardized measures at three different time intervals. The five measurements appeared to be sensitive to behavioral and regulatory functions that may improve with this type of intervention. CONCLUSIONS: The results of this observational pilot study suggest that acupressure/acupuncture is a feasible intervention for children with ASD that merits rigorous evaluation through a randomized controlled trial.
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17. Wu Z, Qin J, You Y, Ma Y, Jia M, Wang L, Lu T, Yue W, Ruan Y, Zhang D, Li J, Wang L. {{Genetic variants in the transcription regulatory region of MEGF10 are associated with autism in Chinese Han population}}. {Sci Rep};2017 (May 23);7(1):2292.
Multiple epidermal growth factor-like-domains 10 (MEGF10), a critical member of the apoptotic engulfment pathway, mediates axon pruning and synapse elimination during brain development. Previous studies indicated that synaptic pruning deficit was associated with autism-related phenotypes. However, the relationship between MEGF10 and autism remains poorly understood. Disease-associated variants are significantly enriched in the transcription regulatory regions. These include the transcription start site (TSS) and its cis-regulatory elements. To investigate the role of MEGF10 variants with putative transcription regulatory function in the etiology of autism, we performed a family-based association study in 410 Chinese Han trios. Our results indicate that three single nucleotide polymorphisms (SNPs), rs4836316, rs2194079 and rs4836317 near the TSS are significantly associated with autism following Bonferroni correction (p = 0.0011, p = 0.0088, and p = 0.0023, respectively). Haplotype T-A-G (rs4836316-rs2194079-rs4836317) was preferentially transmitted from parents to affected offspring (p permutation = 0.0055). Consistently, functional exploration further verified that the risk allele and haplotype might influence its binding with transcription factors, resulting in decreased transcriptional activity of MEGF10. Our findings indicated that the risk alleles and haplotype near the MEGF10 TSS might modulate transcriptional activity and increase the susceptibility to autism.
