1. Allely CS, Gillberg C, Wilson P. {{Neurobiological abnormalities in the first few years of life in individuals later diagnosed with autism spectrum disorder: a review of recent data}}. {Behav Neurol};2014;2014:210780.
Background. Despite the widely-held understanding that the biological changes that lead to autism usually occur during prenatal life, there has been relatively little research into the functional development of the brain during early infancy in individuals later diagnosed with autism spectrum disorder (ASD). Objective. This review explores the studies over the last three years which have investigated differences in various brain regions in individuals with ASD or who later go on to receive a diagnosis of ASD. Methods. We used PRISMA guidelines and selected published articles reporting any neurological abnormalities in very early childhood in individuals with or later diagnosed with ASD. Results. Various brain regions are discussed including the amygdala, cerebellum, frontal cortex, and lateralised abnormalities of the temporal cortex during language processing. This review discusses studies investigating head circumference, electrophysiological markers, and interhemispheric synchronisation. All of the recent findings from the beginning of 2009 across these different aspects of defining neurological abnormalities are discussed in light of earlier findings. Conclusions. The studies across these different areas reveal the existence of atypicalities in the first year of life, well before ASD is reliably diagnosed. Cross-disciplinary approaches are essential to elucidate the pathophysiological sequence of events that lead to ASD.
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2. Birch RC, Cornish KM, Hocking DR, Trollor JN. {{Understanding the Neuropsychiatric Phenotype of Fragile X-Associated Tremor Ataxia Syndrome: a Systematic Review}}. {Neuropsychol Rev};2014 (May 15)
Fragile X-associated tremor ataxia syndrome (FXTAS) is a recently identified X-linked neurodegenerative disorder affecting a proportion of premutation carriers of the Fragile X Mental Retardation 1 (FMR1) gene. Previous research suggests that cognitive and psychiatric features of FXTAS may include primary impairments in executive function and increased vulnerability to mood and anxiety disorders. A number of these reports, however, are based on overlapping cohorts or have produced inconsistent findings. A systematic review was therefore conducted to further elucidate the neuropsychiatric features characteristic of FXTAS. Fourteen papers met inclusion criteria for the review and were considered to represent nine independent FXTAS cohorts. Findings from the review suggest that the neuropsychiatric phenotype of FXTAS is characterised primarily by poorer performance on measures of executive function, working memory, information processing speed, and fine motor control when compared to matched comparison groups. Two studies were identified in which psychiatric symptoms in FXTAS were compared with controls, and these yielded mixed results. Overall the results of this review support previous reports that the neuropsychiatric profile of FXTAS is consistent with a dysexecutive fronto-subcortical syndrome. However, additional controlled studies are required to progress our understanding of FXTAS and how the neuropsychiatric profile relates to underlying pathological mechanisms.
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3. Bissonnette JM, Schaevitz LR, Knopp SJ, Zhou Z. {{Respiratory phenotypes are distinctly affected in mice with common Rett syndrome mutations MeCP2 T158A and R168X}}. {Neuroscience};2014 (May 16);267:166-176.
Respiratory disturbances are a primary phenotype of the neurological disorder, Rett syndrome (RTT), caused by mutations in the X-linked gene encoding methyl-CpG-binding protein 2 (MeCP2). Mouse models generated with null mutations in Mecp2 mimic respiratory abnormalities in RTT girls. Large deletions, however, are seen in only approximately 10% of affected human individuals. Here we characterized respiration in heterozygous females from two mouse models that genetically mimic common RTT point mutations, a missense mutation T158A (Mecp2(T158A/)(+)) or a nonsense mutation R168X (Mecp2(R168X/+)). MeCP2 T158A shows decreased binding to methylated DNA, while MeCP2 R168X retains the capacity to bind methylated DNA but lacks the ability to recruit complexes required for transcriptional repression. We found that both Mecp2(T158A/+) and Mecp2(R168X/+) heterozygotes display augmented hypoxic ventilatory responses and depressed hypercapnic responses, compared to wild-type controls. Interestingly, the incidence of apnea was much greater in Mecp2(R168X/+) heterozygotes, 189 per hour, than Mecp2(T158A/+) heterozygotes, 41 per hour. These results demonstrate that different RTT mutations lead to distinct respiratory phenotypes, suggesting that characterization of the respiratory phenotype may reveal functional differences between MeCP2 mutations and provide insights into the pathophysiology of RTT.
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4. Choi JE, Widjaja F, Careaga M, Bent S, Ashwood P, Hendren RL. {{Change in Plasma Cytokine Levels During Risperidone Treatment in Children with Autism}}. {J Child Adolesc Psychopharmacol};2014 (May 14)
Abstract Background: Atypical antipsychotics decrease irritability in autism. They also affect the cytokine network. Psychological stress, depression, and, possibly, autism spectrum disorder (ASD) are associated with the production of pro-inflammatory cytokines. We sought to determine if risperidone treatment led to changes in plasma cytokine levels. Methods: Forty-five subjects from an open-label study of risperidone treatment of children and adolescents with ASD, ages 4-18 years, had an analysis of 27 different cytokines at baseline and after 8 weeks of treatment using multiplex assays (Millipore) and read on the Luminex 100 platform. We examined changes in each of the cytokine levels in the entire group, and also compared changes in cytokines in responders versus nonresponders. Results: After 8 weeks of risperidone treatment, 2 of the 27 plasma cytokines showed statistically significant decreases in median levels: Eotaxin (p=0.0003) and monocyte chemoattractant protein-1 (MCP-1) (p=0.0024). Six of the 48 subjects met two criteria for responders to risperidone, and the median values of interleukin (IL)-5 were significantly higher (p=0.005) in the overall responder group than in nonresponders. Conclusions: Two cytokines, eotaxin and MCP-1, which have previously been identified as abnormally elevated in children with autism, decreased during treatment with risperidone. This suggests a possible mechanism of action of risperidone treatment and a balancing of the immune system in affected subjects in this very preliminary study.
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5. Cooper M, Thapar A, Jones DK. {{White Matter Microstructure Predicts Autistic Traits in Attention-Deficit/Hyperactivity Disorder}}. {J Autism Dev Disord};2014 (May 15)
Traits of autism spectrum disorder (ASD) in children with attention-deficit/hyperactivity disorder (ADHD) have previously been found to index clinical severity. This study examined the association of ASD traits with diffusion parameters in adolescent males with ADHD (n = 17), and also compared WM microstructure relative to controls (n = 17). Significant associations (p < 0.05, corrected) were found between fractional anisotropy/radial diffusivity and ASD trait severity (positive and negative correlations respectively), mostly in the right posterior limb of the internal capsule/corticospinal tract, right cerebellar peduncle and the midbrain. No case-control differences were found for the diffusion parameters investigated. This is the first report of a WM microstructural signature of autistic traits in ADHD. Thus, even in the absence of full disorder, ASD traits may index a distinctive underlying neurobiology in ADHD.
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6. Cozzolino R, De Magistris L, Saggese P, Stocchero M, Martignetti A, Di Stasio M, Malorni A, Marotta R, Boscaino F, Malorni L. {{Use of solid-phase microextraction coupled to gas chromatography-mass spectrometry for determination of urinary volatile organic compounds in autistic children compared with healthy controls}}. {Anal Bioanal Chem};2014 (May 15)
Autism spectrum disorders (ASDs) are a group of neurodevelopmental disorders which have a severe life-long effect on behavior and social functioning, and which are associated with metabolic abnormalities. Their diagnosis is on the basis of behavioral and developmental signs usually detected before three years of age, and there is no reliable biological marker. The objective of this study was to establish the volatile urinary metabolomic profiles of 24 autistic children and 21 healthy children (control group) to investigate volatile organic compounds (VOCs) as potential biomarkers for ASDs. Solid-phase microextraction (SPME) using DVB/CAR/PDMS sorbent coupled with gas chromatography-mass spectrometry was used to obtain the metabolomic information patterns. Urine samples were analyzed under both acid and alkaline pH, to profile a range of urinary components with different physicochemical properties. Multivariate statistics techniques were applied to bioanalytical data to visualize clusters of cases and to detect the VOCs able to differentiate autistic patients from healthy children. In particular, orthogonal projections to latent structures discriminant analysis (OPLS-DA) achieved very good separation between autistic and control groups under both acidic and alkaline pH, identifying discriminating metabolites. Among these, 3-methyl-cyclopentanone, 3-methyl-butanal, 2-methyl-butanal, and hexane under acid conditions, and 2-methyl-pyrazine, 2,3-dimethyl-pyrazine, and isoxazolo under alkaline pH had statistically higher levels in urine samples from autistic children than from the control group. Further investigation with a higher number of patients should be performed to outline the metabolic origins of these variables, define a possible association with ASDs, and verify the usefulness of these variables for early-stage diagnosis.
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7. Fitzpatrick EM, Lambert L, Whittingham J, Leblanc E. {{Examination of characteristics and management of children with hearing loss and autism spectrum disorders}}. {Int J Audiol};2014 (May 16):1-10.
Objective: Up to 40% of children with hearing loss present with other developmental disabilities. The purpose of this study was to document the prevalence of autism spectrum disorders (ASD) in children with permanent hearing loss, to describe the audiologic characteristics, and to examine clinical management. Design: Prospective data related to clinical characteristics of children identified with hearing loss and ASD were examined. A retrospective chart review was also conducted to explore clinical management and uptake of amplification. Study sample: The study included all children in one Canadian region identified with permanent hearing loss and followed from 2002-2010. Results: Of a total of 785 children with permanent hearing loss, 2.2% (n = 17) also received a diagnosis of ASD. The 13 boys and 4 girls presented with a range of audiologic profiles from unilateral to profound bilateral hearing loss. Four of five children with unilateral hearing loss experienced progression to bilateral loss. Amplification was recommended for all but one child and 9 of 16 children continued to use their hearing devices. Conclusions: The higher prevalence rate of ASD in this clinical population is consistent with previous reports. Our findings suggest that some children with autism can derive benefits from the use of amplification.
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8. Jeste SS, Kirkham N, Senturk D, Hasenstab K, Sugar C, Kupelian C, Baker E, Sanders AJ, Shimizu C, Norona A, Paparella T, Freeman SF, Johnson SP. {{Electrophysiological evidence of heterogeneity in visual statistical learning in young children with ASD}}. {Dev Sci};2014 (May 13)
Statistical learning is characterized by detection of regularities in one’s environment without an awareness or intention to learn, and it may play a critical role in language and social behavior. Accordingly, in this study we investigated the electrophysiological correlates of visual statistical learning in young children with autism spectrum disorder (ASD) using an event-related potential shape learning paradigm, and we examined the relation between visual statistical learning and cognitive function. Compared to typically developing (TD) controls, the ASD group as a whole showed reduced evidence of learning as defined by N1 (early visual discrimination) and P300 (attention to novelty) components. Upon further analysis, in the ASD group there was a positive correlation between N1 amplitude difference and non-verbal IQ, and a positive correlation between P300 amplitude difference and adaptive social function. Children with ASD and a high non-verbal IQ and high adaptive social function demonstrated a distinctive pattern of learning. This is the first study to identify electrophysiological markers of visual statistical learning in children with ASD. Through this work we have demonstrated heterogeneity in statistical learning in ASD that maps onto non-verbal cognition and adaptive social function.
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9. Libero LE, Stevens CE, Jr., Kana RK. {{Attribution of emotions to body postures: An independent component analysis study of functional connectivity in autism}}. {Hum Brain Mapp};2014 (May 16)
The ability to interpret others’ body language is a vital skill that helps us infer their thoughts and emotions. However, individuals with autism spectrum disorder (ASD) have been found to have difficulty in understanding the meaning of people’s body language, perhaps leading to an overarching deficit in processing emotions. The current fMRI study investigates the functional connectivity underlying emotion and action judgment in the context of processing body language in high-functioning adolescents and young adults with autism, using an independent components analysis (ICA) of the fMRI time series. While there were no reliable group differences in brain activity, the ICA revealed significant involvement of occipital and parietal regions in processing body actions; and inferior frontal gyrus, superior medial prefrontal cortex, and occipital cortex in body expressions of emotions. In a between-group analysis, participants with autism, relative to typical controls, demonstrated significantly reduced temporal coherence in left ventral premotor cortex and right superior parietal lobule while processing emotions. Participants with ASD, on the other hand, showed increased temporal coherence in left fusiform gyrus while inferring emotions from body postures. Finally, a positive predictive relationship was found between empathizing ability and the brain areas underlying emotion processing in ASD participants. These results underscore the differential role of frontal and parietal brain regions in processing emotional body language in autism. Hum Brain Mapp, 2014. (c) 2014 Wiley Periodicals, Inc.
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10. Maloney A, Mick EO, Frazier J. {{Aripiprazole Decreases Irritability in 12 out of 14 Youth with Autism Spectrum Disorders}}. {J Child Adolesc Psychopharmacol};2014 (May 14)
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11. Njelesani J, Leckie K, Drummond J, Cameron D. {{Parental perceptions of barriers to physical activity in children with developmental disabilities living in Trinidad and Tobago}}. {Disabil Rehabil};2014 (May 14):1-6.
Abstract Background: Parents have a strong influence on their child’s engagement in physical activities, especially for children with developmental disabilities, as these children are less likely to initiate physical activity. Knowledge is limited regarding parents’ perceptions of this phenomenon in low- and middle-income countries (LMICs); yet many rehabilitation providers work with children with developmental disabilities and their parents in these contexts. Purpose: The aim of this study was to explore the barriers perceived by parents of children with developmental disabilities to their children’s engagement in physical activity. Methods: An occupational perspective was used to explore how parents speak about barriers to their child’s engagement in physical activity. Interviews were conducted with nine parents in Port-of-Spain, Trinidad and Tobago. Findings: Parent’s perceived barriers were categorized into four themes: family priorities, not an option in our environment, need to match the activity to the child’s ability, and need for specialized supports. Conclusions: Findings provide opportunities for future rehabilitation and community programming in LMICs. Implications for Rehabilitation Children living with a developmental disability may engage more in solitary and sedentary pursuits as a result of parents choosing activities that do not present extensive social and physical demands for their child. Therapists can play an important role in providing knowledge to parents of appropriate physical activity and the benefits of physical activity for children with developmental disabilities in order to promote children’s participation. In environments where there is limited social support for families, therapists need to consider and be particularly supportive of parental priorities and schedules.
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12. Panerai S, Tasca D, Ferri R, Genitori D’Arrigo V, Elia M. {{Executive Functions and Adaptive Behaviour in Autism Spectrum Disorders with and without Intellectual Disability}}. {Psychiatry J};2014;2014:941809.
Executive functions (EF) in autism spectrum disorders (ASD) have been often investigated, although results seem to be rather inconsistent. The first aim of this study was to detect which EF components are common to the ASD continuum (from high- to low-functioning ASD) and identify a possible EF profile for ASD people. Planning, mental flexibility, inhibition of response, generativity, and ecologic EF were investigated. This study was extended not only to high-functioning ASD, but also to ASD with intellectual disability (ID). The second aim was to find EF aspects correlating with adaptive skills in ASD. A total of 61 children participated in the study (27 ASD with and without ID and 34 controls). Results highlight an executive profile characterised by impaired flexibility and deficient planning; these deficits are associated with decreased adaptive ability, particularly socialization, and a deficient shifting in ecologic conditions. These features are present in all ASD subgroups with and without ID; for this reason, they might be assumed as being specific features in ASD.
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13. Tonnsen BL, Cornish KM, Wheeler AC, Roberts JE. {{Maternal predictors of anxiety risk in young males with fragile X}}. {Am J Med Genet B Neuropsychiatr Genet};2014 (May 16)
Children with fragile X syndrome (FXS) demonstrate high rates of anxiety disorders, with 65-83% meeting diagnostic criteria. The severity of anxiety symptoms in FXS has been shown to be partially predicted by elevated negative affect across early childhood [Tonnsen et al. (2013a); J Abnorm Child Psychol 41:267-280]. This association suggests that biologically driven vulnerability emerges early in development, as is reported in non-clinical populations. However, anxiety emergence is likely moderated by multifaceted genetic, biological and environmental risk and protective factors. Mothers with the FMR1 premutation have been shown to exhibit elevated parenting stress and internalizing symptoms, which have each been associated with child behavior problems [Bailey et al. (2008a); Am J Med Genet Part A 146A:2060-2069 and Bailey et al. (2008b) Am J Med Genet Part A 146A:720-729]. Despite these findings, it is unclear whether maternal factors directly relate to anxiety vulnerability in high-risk children with FXS, a question essential to informing targeted, family-sensitive treatment. The present study examines how maternal protective and risk factors relate to child inhibition reflected in (1) child anxiety symptoms, (2) child trajectories of negative affect, and (3) the association between child anxiety and negative affect. Primary predictors include maternal parenting stress, indicators of mental health risk (anxiety and depressive symptoms), and maternal optimism. We also examine genetic correlates in mothers (CGG repeats, activation ratio, mRNA). Our findings suggest that behavioral inhibition in young children with FXS is associated with higher parenting stress and lower optimism, and higher parenting stress is associated with lower maternal X-activation ratio. These findings underscore the need for family-sensitive treatment strategies for anxiety disorders in children with FXS. (c) 2014 Wiley Periodicals, Inc.
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14. Urbano M, Okwara L, Manser P, Hartmann K, Herndon A, Deutsch SI. {{A trial of d-cycloserine to treat stereotypies in older adolescents and young adults with autism spectrum disorder}}. {Clin Neuropharmacol};2014 (May-Jun);37(3):69-72.
OBJECTIVES: Autism spectrum disorders (ASDs) have core impairments in social communication as well as the presence of repetitive, stereotypic behaviors and restricted interests. Older adolescents and young adults are particularly impacted by these deficits. Preclinical data implicate glutamatergic dysfunction in the pathophysiology of ASDs. D-Cycloserine (DCS), a partial glycineB agonist at the N-methyl-D-aspartic acid receptor site, has been shown to improve sociability in mouse models and a small human study. The sensitivity of the obligatory glycineB co-agonist binding site may change with daily administration of DCS as a result of agonist-induced desensitization. The efficacy of a « pulsed » once-weekly administration versus « daily » administration of DCS was compared. METHODS: Males and females, ages 14 to 25 years, with a Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition Text Revision diagnosis of an ASD were enrolled in a double-blind, randomized 10-week trial consisting of 8 weeks of active drug with either weekly or daily administration of 50 mg of DCS followed by a 2-week follow-up visit. RESULTS: For the purposes of this study, no statistical or clinical differences existed between the 2 dosage groups on the Aberrant Behavior Checklist subscale 3, which measures stereotypies/repetitive movements. When combining groups, a statistically significant decrease of 37% was found from baseline to week 8 when study drug was completed using a linear mixed effects model (P = 0.003). CONCLUSIONS: D-Cycloserine was shown to be effective in improving stereotypic symptoms in older adolescents and young adults with ASDs measured by the Aberrant Behavior Checklist subscale 3. In addition, DCS was safe and well tolerated.
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15. Wakil N, Fitzpatrick EM, Olds J, Schramm D, Whittingham J. {{Long-term outcome after cochlear implantation in children with additional developmental disabilities}}. {Int J Audiol};2014 (May 14):1-8.
Objective: Candidacy criteria for cochlear implants have expanded to include children with complex developmental disabilities. The aim of this study was to determine the long-term benefits of cochlear implantation for this clinical population. Design: The study involved a retrospective chart review. Study sample: The review identified 21 children with complex disabilities who had received cochlear implants in a pediatric center prior to 2004. Length of cochlear implant use was between 7.3 and 19.0 years. Long-term functional auditory abilities were assessed pre and post-operatively using measures appropriate to the child’s level of functioning. Cognitive assessments and developmental data were also available for the children. Results: Children’s long-term speech recognition outcomes depended highly on their developmental status. Children with severe developmental delay showed no open-set speech recognition abilities while children with mild to moderate delays achieved open-set scores ranging from 48 to 94% on open-set word testing. Five of 13 (38%) children with complex needs had discontinued use of their cochlear implant. Conclusions: Long-term speech recognition abilities following cochlear implantation for children with complex developmental issues seem to be highly related to their developmental profile. Developmental status is an important consideration in counselling families as part of the cochlear implant decision process.
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16. Yang CJ, Tan HP, Du YJ. {{The developmental disruptions of serotonin signaling may involved in autism during early brain development}}. {Neuroscience};2014 (May 16);267C:1-10.
Autism is a developmental disorder defined by the presence of a triad of communication, social and stereo typical behavioral characteristics with onset before 3years of age. In spite of the fact that there are potential environmental factors for autistic behavior, the dysfunction of serotonin during early development of the brain could be playing a role in this prevalence rise. Serotonin can modulate a number of developmental events, including cell division, neuronal migration, cell differentiation and synaptogenesis. Hyperserotonemia during fetal development results in the loss of serotonin terminals through negative feedback. The increased serotonin causes a decrease of oxytocin in the paraventricular nucleus of the hypothalamus and an increase in calcitonin gene-related peptide (CGRP) in the central nucleus of the amygdale, which are associated with social interactions and vital in autism. However, hyposerotonemia may be also relevant to the development of sensory as well as motor and cognitive faculties. And the paucity of placenta-derived serotonin should have potential importance when the pathogenesis of autism is considered. This review briefly summarized the developmental disruptions of serotonin signaling involved in the pathogenesis of autism during early development of the brain.
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17. Youngster I, Zachor DA, Gabis LV, Bar-Chaim A, Benveniste-Levkovitz P, Britzi M, Soback S, Ziv-Baran T, Berkovitch M. {{CYP2D6 genotyping in paediatric patients with autism treated with risperidone: a preliminary cohort study}}. {Dev Med Child Neurol};2014 (May 15)
AIM: To evaluate the association between cytochrome P450 2D6 (CYP2D6) phenotypes in paediatric patients with autistic spectrum disorders (ASD) treated with risperidone, adverse drug reactions (ADRs), and drug efficacy. METHOD: An observational cohort study of 40 children (34 males, six females; median age 7y range 3-18y) with autistic disorder, pervasive developmental disorder not otherwise specified, or Asperger syndrome diagnosed using the Autism Diagnostic Interview-Revised and treated with risperidone for at least 3 months. Charts were reviewed for demographic and clinical information, response to treatment was assessed by parents and the treating neurologist on a three-point scale, and information about ADRs was collected. Trough plasma levels of risperidone and its metabolites were determined and CYP2D6 genotyping was performed. RESULTS: Twenty-six patients responded to therapy and 11 patients exhibited ADRs. CYP2D6 genotyping showed two patients to be poor metabolizers, two ultra-rapid metabolizers, seven intermediate metabolizers, and 29 extensive metabolizers. Both ultra-rapid metabolizer patients were non-responders and had no ADRs. In contrast, both poor metabolizer patients were responders but experienced ADRs. No correlation was found between risperidone dosage and either risperidone or drug metabolite plasma levels. There was no difference in risperidone or metabolite plasma levels when comparing responders to non-responders, or when comparing patients with or without ADRs. INTERPRETATION: In patients with ASD treated with risperidone, a CYP2D6 phenotype may be associated with response to treatment and development of ADRs.
