1. Albein-Urios N, Youssef GJ, Kirkovski M, Enticott PG. {{Autism Spectrum Traits Linked with Reduced Performance on Self-Report Behavioural Measures of Cognitive Flexibility}}. {J Autism Dev Disord}. 2018.
Deficits in cognitive flexibility are thought to underpin the core symptom of repetitive and restricted patterns of behaviour in autism spectrum disorder (ASD). Studies investigating this relationship, however, report inconsistent results. This is partly due to the variable nature of measures used to assess the construct of flexibility. The main purpose of this study was to investigate whether ASD traits differentially predict cognitive flexibility performance on lab-based neurocognitive measures relative to behavioural self-reports in a non-clinical sample of young adults. Our results indicate that ASD traits exclusively predict performance on behavioural self-reports of cognitive flexibility. These findings highlight the possibility that behavioural self-reports are a better index than lab-based neurocognitive measures to capture cognitive flexibility impairments in individuals with ASD.
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2. Bi XA, Wang Y, Shu Q, Sun Q, Xu Q. {{Classification of Autism Spectrum Disorder Using Random Support Vector Machine Cluster}}. {Front Genet}. 2018; 9: 18.
Autism spectrum disorder (ASD) is mainly reflected in the communication and language barriers, difficulties in social communication, and it is a kind of neurological developmental disorder. Most researches have used the machine learning method to classify patients and normal controls, among which support vector machines (SVM) are widely employed. But the classification accuracy of SVM is usually low, due to the usage of a single SVM as classifier. Thus, we used multiple SVMs to classify ASD patients and typical controls (TC). Resting-state functional magnetic resonance imaging (fMRI) data of 46 TC and 61 ASD patients were obtained from the Autism Brain Imaging Data Exchange (ABIDE) database. Only 84 of 107 subjects are utilized in experiments because the translation or rotation of 7 TC and 16 ASD patients has surpassed +/-2 mm or +/-2 degrees . Then the random SVM cluster was proposed to distinguish TC and ASD. The results show that this method has an excellent classification performance based on all the features. Furthermore, the accuracy based on the optimal feature set could reach to 96.15%. Abnormal brain regions could also be found, such as inferior frontal gyrus (IFG) (orbital and opercula part), hippocampus, and precuneus. It is indicated that the method of random SVM cluster may apply to the auxiliary diagnosis of ASD.
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3. Cezar LC, Kirsten TB, da Fonseca CCN, de Lima APN, Bernardi MM, Felicio LF. {{Zinc as a therapy in a rat model of autism prenatally induced by valproic acid}}. {Prog Neuropsychopharmacol Biol Psychiatry}. 2018; 84(Pt A): 173-80.
Autism is characterized by numerous behavioral impairments, such as in communication, socialization and cognition. Recent studies have suggested that valproic acid (VPA), an anti-epileptic drug with teratogenic activity, is related to autism. In rodents, VPA exposure during pregnancy induces autistic-like effects. Exposure to VPA may alter zinc metabolism resulting in a transient deficiency of zinc. Therefore, we selected zinc as a prenatal treatment to prevent VPA-induced impairments in a rat model of autism. Wistar female rats received either saline solution or VPA (400mg/kg, i.p) on gestational day (GD) 12.5. To test the zinc supplementation effect, after 1h of treatment with saline or VPA, a dose of zinc (2mg/kg, s.c.) was injected. The offspring were tested for abnormal communication behaviors with an ultrasound vocalization task on postnatal day (PND) 11, repetitive behaviors and cognitive ability with a T-maze task on PND 29, and social interaction with a play behavior task on PND 30. Tyrosine hydroxylase protein (TH) expression was evaluated in the striatum. Prenatal VPA decreased ultrasonic vocalization, induced repetitive/restricted behaviors and cognitive inflexibility, impaired socialization, and reduced striatal TH levels compared with control group. Zinc treatment reduced VPA-induced autistic-like behaviors. However, we found no evidence of an effect of zinc on the VPA-induced reduction in TH expression. The persistence of low TH expression in the VPA-Zn group suggests that Zn-induced behavioral improvement in autistic rats may not depend on TH activity.
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4. Hanish AE, Cohen MZ, Starr LJ. {{Autism spectrum disorder and genetic testing: Parental perceptions and decision-making}}. {Journal for specialists in pediatric nursing : JSPN}. 2018.
PURPOSE: Advances in genomic technology and research have led to genetic testing being recognized as an essential component of the etiological workup for children with autism spectrum disorder (ASD). Chromosomal microarray analysis (CMA) is a first-tier diagnostic test for patients with ASD, as recommended by the American College of Medical Genetics and other professional societies. An accurate underlying medical diagnosis for ASD has many potential benefits, including appropriate medical management, detailed therapeutic recommendations, and accurate recurrence risk. Genetic testing is relatively complicated, expensive, and, currently, in the majority of the cases, does not provide any organic improvement in the management of symptoms. DESIGN AND METHODS: We conducted semistructured interviews with 20 parents to explore the decision-making process of genetic testing from the perspectives and experiences of parents of children with ASD. Data were analyzed using qualitative content analysis. RESULTS: Parents had limited knowledge of genetic testing for ASD prior to a genetics clinic visit. The majority of the participants thought genetic testing would be beneficial for their child, their reproductive choices, and potential future generations. PRACTICE IMPLICATIONS: Various stakeholders (geneticists, primary care providers, nurses, and families) would benefit from future establishment of educational strategies to inform parental decision-making regarding genetic testing for children with ASD.
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5. Kumazaki H, Kikuchi M, Yoshimura Y, Miyao M, Okada KI, Mimura M, Minabe Y. {{Relationship Between Odor Identification and Visual Distractors in Children with Autism Spectrum Disorders}}. {J Autism Dev Disord}. 2018.
Understanding the nature of olfactory abnormalities is crucial for optimal interventions in children with autism spectrum disorders (ASD). However, previous studies that have investigated odor identification in children with ASD have produced inconsistent results. The ability to correctly identify an odor relies heavily on visual inputs in the general population. We tested odor identification in eight children with ASD and eight age-matched children with typical development (TD). After confirming that all children were able to identify each odor without visual input, we measured odor identification under the visual-distractor condition. Odor identification was hindered by visual distractors for all children with ASD but was not affected in all children with TD. Our results improve understanding of odor identification in ASD.
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6. Mancini J, Dubus JC, Jouve E, Roux JC, Franco P, Lagrue E, Castelnau P, Cances C, Chaix Y, Rougeot-Jung C, Cornu C, Desportes V, Vallee L, Bahi-Buisson N, Truillet R, Attolini L, Villard L, Blin O, Micallef J. {{Effect of desipramine on patients with breathing disorders in RETT syndrome}}. {Annals of clinical and translational neurology}. 2018; 5(2): 118-27.
Objective: Rett Syndrome (RTT) is a severe neurodevelopmental condition with breathing disorders, affecting around one in 10,000 female births. Desipramine, a noradrenaline reuptake inhibitor, reduced the number of apneas in Mecp2-deficient mice, a model of RTT. We planned a phase 2 trial to test its efficacy and its safety on breathing patterns in 36 girls with RTT. Methods: The trial was a 6-month, multicenter, randomized, double-blind, placebo-controlled study registered with ClinicalTrials.gov, number NCT00990691. Girls diagnosed according to clinical examination and confirmed by genotyping were randomly assigned in a 1:1:1 ratio to receive 2-3 mg/kg Desipramine per day (high Desipramine), 1-2 mg/kg Desipramine per day (low Desipramine), or a placebo. The primary outcome was the change of apnea hypopnea index (AHI), defined by the number of apnea and hypopnea events per hour, assessed at 6 months from baseline. Intention-to-treat analysis was applied. Results: The median change in AHI from baseline to 6 months was -31 (IQR: -37 to -11) for the high Desipramine, -17.5 (IQR: -31 to 13) for the low Desipramine, and -13 (IQR:-31 to 0) for the placebo group. We did not find any significant difference in these changes between the groups (P = 0.781). A significant inverse correlation between Desipramine plasma concentration and AHI (r = -0.44; P = 0.0002) was underlined. Interpretation: This first clinical trial of desipramine did not show clinical efficacy. Although required further studies, the significant correlation between Desipramine concentrations and improvement of AHI provided additional and relevant reasons to test the noradrenergic pathway in RTT.
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7. Masiran R. {{Stimming behaviour in a 4-year-old girl with autism spectrum disorder}}. {BMJ case reports}. 2018; 2018.
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8. Mor-Shaked H, Eiges R. {{Reevaluation of FMR1 Hypermethylation Timing in Fragile X Syndrome}}. {Front Mol Neurosci}. 2018; 11: 31.
Fragile X syndrome (FXS) is one of the most common heritable forms of cognitive impairment. It results from a fragile X mental retardation protein (FMRP) protein deficiency caused by a CGG repeat expansion in the 5′-UTR of the X-linked FMR1 gene. Whereas in most individuals the number of CGGs is steady and ranges between 5 and 44 units, in patients it becomes extensively unstable and expands to a length exceeding 200 repeats (full mutation). Interestingly, this disease is exclusively transmitted by mothers who carry a premutation allele (55-200 CGG repeats). When the CGGs reach the FM range, they trigger the spread of abnormal DNA methylation, which coincides with a switch from active to repressive histone modifications. This results in epigenetic gene silencing of FMR1 presumably by a multi-stage, developmentally regulated process. The timing of FMR1 hypermethylation and transcription silencing is still hotly debated. There is evidence that hypermethylation varies considerably between and within the tissues of patients as well as during fetal development, thus supporting the view that FMR1 silencing is a post-zygotic event that is developmentally structured. On the other hand, it may be established in the female germ line and transmitted to the fetus as an integral part of the mutation. This short review summarizes the data collected to date concerning the timing of FMR1 epigenetic gene silencing and reassess the evidence in favor of the theory that gene inactivation takes place by a developmentally regulated process around the 10th week of gestation.
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9. Richter M, Murtaza N, Scharrenberg R, White SH, Johanns O, Walker S, Yuen RKC, Schwanke B, Bedurftig B, Henis M, Scharf S, Kraus V, Dork R, Hellmann J, Lindenmaier Z, Ellegood J, Hartung H, Kwan V, Sedlacik J, Fiehler J, Schweizer M, Lerch JP, Hanganu-Opatz IL, Morellini F, Scherer SW, Singh KK, Calderon de Anda F. {{Altered TAOK2 activity causes autism-related neurodevelopmental and cognitive abnormalities through RhoA signaling}}. {Mol Psychiatry}. 2018.
Atypical brain connectivity is a major contributor to the pathophysiology of neurodevelopmental disorders (NDDs) including autism spectrum disorders (ASDs). TAOK2 is one of several genes in the 16p11.2 microdeletion region, but whether it contributes to NDDs is unknown. We performed behavioral analysis on Taok2 heterozygous (Het) and knockout (KO) mice and found gene dosage-dependent impairments in cognition, anxiety, and social interaction. Taok2 Het and KO mice also have dosage-dependent abnormalities in brain size and neural connectivity in multiple regions, deficits in cortical layering, dendrite and synapse formation, and reduced excitatory neurotransmission. Whole-genome and -exome sequencing of ASD families identified three de novo mutations in TAOK2 and functional analysis in mice and human cells revealed that all the mutations impair protein stability, but they differentially impact kinase activity, dendrite growth, and spine/synapse development. Mechanistically, loss of Taok2 activity causes a reduction in RhoA activation, and pharmacological enhancement of RhoA activity rescues synaptic phenotypes. Together, these data provide evidence that TAOK2 is a neurodevelopmental disorder risk gene and identify RhoA signaling as a mediator of TAOK2-dependent synaptic development.
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10. Tillmann J, Ashwood K, Absoud M, Bolte S, Bonnet-Brilhault F, Buitelaar JK, Calderoni S, Calvo R, Canal-Bedia R, Canitano R, De Bildt A, Gomot M, Hoekstra PJ, Kaale A, McConachie H, Murphy DG, Narzisi A, Oosterling I, Pejovic-Milovancevic M, Persico AM, Puig O, Roeyers H, Rommelse N, Sacco R, Scandurra V, Stanfield AC, Zander E, Charman T. {{Evaluating Sex and Age Differences in ADI-R and ADOS Scores in a Large European Multi-site Sample of Individuals with Autism Spectrum Disorder}}. {J Autism Dev Disord}. 2018.
Research on sex-related differences in Autism Spectrum Disorder (ASD) has been impeded by small samples. We pooled 28 datasets from 18 sites across nine European countries to examine sex differences in the ASD phenotype on the ADI-R (376 females, 1763 males) and ADOS (233 females, 1187 males). On the ADI-R, early childhood restricted and repetitive behaviours were lower in females than males, alongside comparable levels of social interaction and communication difficulties in females and males. Current ADI-R and ADOS scores showed no sex differences for ASD severity. There were lower socio-communicative symptoms in older compared to younger individuals. This large European ASD sample adds to the literature on sex and age variations of ASD symptomatology.
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11. Van der Hallen R, Chamberlain R, de-Wit L, Wagemans J. {{Superior Disembedding in Children with ASD: New Tests Using Abstract, Meaningful, and 3D Contexts}}. {J Autism Dev Disord}. 2018.
Since its initial development, the embedded figures test (EFT) has been used extensively to measure local-global perceptual style. However, little is known about the perceptual factors that influence target detection. The current study aimed to investigate disembedding in children with and without ASD, aged 8-15 years, using the newly developed, stimulus-controlled L-EFT, M-EFT and D-EFT. Firstly, results revealed superior disembedding for children with ASD, irrespective of the type of target or embedding context, although the ASD group took more time in both the M-EFT and D-EFT. Secondly, the number of target lines continuing into the context proved more of a hindrance for the controls. Taken together, these findings provide strong evidence to support the notion of superior disembedding in ASD.
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12. Zhu P, Li J, Zhang L, Liang Z, Tang B, Liao WP, Yi YH, Su T. {{Development-related aberrations in Kv1.1 alpha-subunit exert disruptive effects on bioelectrical activities of neurons in a mouse model of fragile X syndrome}}. {Prog Neuropsychopharmacol Biol Psychiatry}. 2018; 84(Pt A): 140-51.
Kv1.1, a Shaker homologue potassium channel, plays a critical role in homeostatic regulation of neuronal excitability. Aberrations in the functional properties of Kv1.1 have been implicated in several neurological disorders featured by neuronal hyperexcitability. Fragile X syndrome (FXS), the most common form of inherited mental retardation, is characterized by hyperexcitability in neural network and intrinsic membrane properties. The Kv1.1 channel provides an intriguing mechanistic candidate for FXS. We investigated the development-related expression pattern of the Kv1.1 alpha-subunit by using a Fmr1 knockout (KO) mouse model of FXS. Markedly decreased protein expression of Kv1.1 was found in neonatal and adult stages when compared to age-matched wild-type (WT) mice. Immunohistochemical investigations supported the delayed development-related increases in Kv1.1 expression, especially in CA3 pyramidal neurons. By applying a Kv1.1-specific blocker, dendrotoxin-kappa (DTX-kappa), we isolated the Kv1.1-mediated currents in the CA3 pyramidal neurons. The isolated DTX-kappa-sensitive current of neurons from KO mice exhibited decreased amplitude, lower threshold of activation, and faster recovery from inactivation. The equivalent reduction in potassium current in the WT neurons following application of the appropriate amount of DTX-kappa reproduced the enhanced firing abilities of KO neurons, suggesting the Kv1.1 channel as a critical contributor to the hyperexcitability of KO neurons. The role of Kv1.1 in controlling neuronal discharges was further supported by the parallel developmental trajectories of Kv1.1 expression, current amplitude, and discharge impacts, with a significant correlation between the amplitude of Kv1.1-mediated currents and Kv1.1-blocking-induced firing enhancement. These data suggest that the expression of the Kv1.1 alpha-subunit has a profound pathological relevance to hyperexcitability in FXS, as well as implications for normal development, maintenance, and control of neuronal activities.
