Pubmed du 08/05/19

mercredi 8 mai 2019

1. Chabbert D, Caubit X, Roubertoux PL, Carlier M, Habermann B, Jacq B, Salin P, Metwaly M, Frahm C, Fatmi A, Garratt AN, Severac D, Dubois E, Kerkerian-Le Goff L, Fasano L, Gubellini P. Postnatal Tshz3 Deletion Drives Altered Corticostriatal Function and Autism Spectrum Disorder-like Behavior. Biol Psychiatry. 2019.

BACKGROUND : Heterozygous deletion of the TSHZ3 gene, encoding for the teashirt zinc-finger homeobox family member 3 (TSHZ3) transcription factor that is highly expressed in cortical projection neurons (CPNs), has been linked to an autism spectrum disorder (ASD) syndrome. Similarly, mice with Tshz3 haploinsufficiency show ASD-like behavior, paralleled by molecular changes in CPNs and corticostriatal synaptic dysfunctions. Here, we aimed at gaining more insight into "when" and "where" TSHZ3 is required for the proper development of the brain, and its deficiency crucial for developing this ASD syndrome. METHODS : We generated and characterized a novel mouse model of conditional Tshz3 deletion, obtained by crossing Tshz3(flox/flox) with CaMKIIalpha-Cre mice, in which Tshz3 is deleted in CPNs from postnatal day 2 to 3 onward. We characterized these mice by a multilevel approach combining genetics, cell biology, electrophysiology, behavioral testing, and bioinformatics. RESULTS : These conditional Tshz3 knockout mice exhibit altered cortical expression of more than 1000 genes, approximately 50% of which have their human orthologue involved in ASD, in particular genes encoding for glutamatergic synapse components. Consistently, we detected electrophysiological and synaptic changes in CPNs and impaired corticostriatal transmission and plasticity. Furthermore, these mice showed strong ASD-like behavioral deficits. CONCLUSIONS : Our study reveals a crucial postnatal role of TSHZ3 in the development and functioning of the corticostriatal circuitry and provides evidence that dysfunction in these circuits might be determinant for ASD pathogenesis. Our conditional Tshz3 knockout mouse constitutes a novel ASD model, opening the possibility for an early postnatal therapeutic window for the syndrome linked to TSHZ3 haploinsufficiency.

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2. De Vane CL, Charles JM, Abramson RK, Williams JE, Carpenter LA, Raven S, Gwynette F, Stuck CA, Geesey ME, Bradley C, Donovan JL, Hall AG, Sherk ST, Powers NR, Spratt E, Kinsman A, Kruesi MJ, Bragg JE, Jr. Pharmacotherapy of Autism Spectrum Disorder : Results from the Randomized BAART Clinical Trial. Pharmacotherapy. 2019.

STUDY OBJECTIVE : The objective of this trial-Biomarkers in Autism of Aripiprazole and Risperidone Treatment (BAART)-was to provide support and guidance for an evidence-based approach for the selection and monitoring of initial pharmacotherapy in patients with autism by assessing predictors of efficacy, tolerability, and safety. DESIGN : Randomized, double-blind, parallel-group study. SETTING : Three academic medical centers and a single private pediatric practice. PATIENTS : Eighty children or adolescents (aged 6-17 years) with autistic disorder were enrolled, and 61 patients were randomized to study drug. Of those patients, 51 completed the 10-week trial, and 31 completed an optional 12-week blinded extension phase. INTERVENTION : All patients were treated with 2 weeks of placebo before random assignment to receive aripiprazole (31 patients) or risperidone (30 patients) for 10 weeks. Sixteen placebo responders (20%) were excluded from further analysis. Drug dosing followed United States Food and Drug Administration (FDA) labeling, and weekly dosage adjustments were allowed until week 4 ; patients were then maintained on a fixed dose for 6 additional weeks. MEASUREMENTS AND MAIN RESULTS : Safety, physical, and psychological assessments were recorded weekly or every two weeks. No significant differences in severity of illness between the aripiprazole and risperidone groups were noted at baseline. All patients significantly improved on the Aberrant Behavior Checklist irritability subscale after one week and continued for the remaining 9 weeks and the extension phase. Improvement was greatest in the risperidone group at every assessment period and was statistically significantly better than that in the aripiprazole group at weeks 3 and 6 (p<0.05). No dose-limiting adverse events occurred during the dose-titration period. Mean weight gain in the aripiprazole group was significantly less than that in the risperidone group at week 4 (0.62 vs 1.38 kg, p=0.033) and week 10 (1.61 vs 3.31 kg, p<0.001), but the difference became nonsignificant for the 31 patients completing the 3-month extension phase (4.36 vs 5.55 kg, p=0.26). CONCLUSION : Pharmacotherapy of patients with autism spectrum disorder resulted in behavioral improvement within one week and lasted at least 22 weeks. Weight gain occurred to a greater degree with risperidone than aripiprazole initially, but the differences became nonsignificant by the end of the trial. Our trial supports previous results of drug efficacy and safety in patients with autism spectrum disorder from other trials and extends the evidence-based support for choosing an FDA-approved drug for initial pharmacotherapy for autism spectrum disorder. This article is protected by copyright. All rights reserved.

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3. de Vega M, Padron I, Moreno IZ, Garcia-Marco E, Dominguez A, Marrero H, Hernandez S. Both the mirror and the affordance systems might be impaired in adults with high autistic traits. Evidence from EEG mu and beta rhythms. Autism Res. 2019.

The association of autism spectrum disorder (ASD) with an altered mirror neuron system is still controversial. At the same time, the processing of object affordances by persons with ASD is a neglected issue. In this electroencephalographic study, adults differing in their autism quotient (AQ) scores were selected. We found anomalous modulation of mu and beta rhythms in high-AQ, compared to low-AQ persons, while they watched a set of goal-directed manual actions. This confirms that observing actions involving implicit intentions most clearly reveals the impairment of the mirror neurons system (MNS). The high-AQ group also showed anomalous mu and beta modulation when they looked at pictures of manipulable objects, indicating a deficit in processing motor affordances. We conclude that high-AQ adults have neural impairment of both the MNS and the affordance systems, which could underlie their relational problems with both people and objects. Autism Res 2019. (c) 2019 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY : Adults with autistic traits (high-autism quotient [AQ] scores) and matched controls (low-AQ) observed intentional hand actions, and pictures of manipulable and non-manipulable objects. The high-AQ group compared to the control group, showed anomalous modulation of the electroencephalographic motoric rhythms (mu and beta) while observing familiar goal-directed actions, confirming an impairment of their mirror neuron system. Also, their brain rhythms were anomalous when they watched manipulable objects, which suggest a dysfunction in their relation with objects (affordance system).

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4. Hannant P, Cassidy S, Renshaw D, Joyce A. A double-blind, placebo-controlled, randomised-designed GABA tea study in children diagnosed with autism spectrum conditions : a feasibility study clinical trial registration : ISRCTN 72571312. Nutr Neurosci. 2019 : 1-17.

OBJECTIVE : The research has shown an association with sensorimotor integration and symptomology of Autism Spectrum Conditions (ASC). Specific areas of the brain that are involved in sensorimotor integration, such as the cerebellum and basal ganglia, are pathologically different in individuals with ASC in comparison to typically developing (TD) peers. These brain regions contain GABAergic inhibitory neurons that release an inhibitory neurotransmitter, gamma-Aminobutyric acid (GABA). Brain GABA levels are decreased in ASC. This study explored the effect of introducing a non-invasive GABA substitute, in the form of GABA Oolong tea, on sensorimotor skills, ASC profiles, anxieties and sleep of children with ASC. METHODS : Nine children took part : (5 male, 4 female). Each child participated in three tea conditions : high GABA, high L-Theanine (a compound that increases GABA), placebo with low GABA. A double-blind, repeated measures design was employed. Measures were taken after each tea condition. Sensory and ASC profiles were scored using parental questionnaires. Motor skills were assessed using a gold standard coordination assessment. Sleep was monitored using an actiwatch and anxiety measured through cortisol assays. Subjective views were sought from parents on ’best’ tea. RESULTS : The results showed significant improvement in manual dexterity and some large individual improvements in balance, sensory responsivity, DSM-5 criteria and cortisol levels with GABA tea. Improvements were also seen in the L-Theanine condition although they were more sporadic. CONCLUSIONS : These results suggest that sensorimotor abilities, anxiety levels and DSM-5 symptomology of children with ASC can benefit from the administration of GABA in the form of Oolong tea.

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5. Hillman H. Home-Based Video Modeling on Food Selectivity of Children With an Autism Spectrum Disorder. Phys Occup Ther Pediatr. 2019 : 1-13.

AIM : The purpose of this study was to evaluate the effects of video modeling - in the home setting - on food selectivity of three children with an autism spectrum disorder. METHODS : Using a multiple baseline experimental design, the researcher implemented an in home video modeling intervention during dinner for all three participants. Intervention consisted of a video modeling condition, a video modeling plus reinforcement condition, and follow-up probes conducted for five months after the departure of the researcher. RESULTS : The video modeling alone resulted in an increased acceptance of food by participants. When reinforcement was added to the video modeling, a higher level of food acceptance occurred for all three participants. CONCLUSION : The results suggest that video modeling was effective in increasing food acceptance, but food acceptance was higher for all three participants when reinforcement was added. Follow-up probes conducted for five months after the departure of the researcher suggest that the video modeling intervention was responsible for the increased food acceptance.

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6. Loyacono N, Ferreira ML, Iermoli R. Humanism in medicine : The critical role of pediatricians in autism spectrum disorder. Archivos argentinos de pediatria. 2019 ; 117(3) : 195-7.

In this article, we describe the importance of coexisting medical problems in the diagnosis of autism spectrum disorder (ASD). It is worth noting the role of pediatricians as health care providers trained to assess, test, diagnose, and treat such conditions during childhood. The population diagnosed with ASD is systemically vulnerable. ASD is the name given to a group of symptoms resulting from a systemic, dynamic, chronic encephalopathy according to the model proposed by Martha Herbert, M.D. (Harvard, USA). Based on this model, we may describe the circumstances of patients’ families who, in Argentina, are unable to find answers on the coexisting medical problems in the diagnosis of ASD according to the psychoanalytic, genetic, and neurodiversity models. It is necessary to review current models in the setting of humanism in medicine because, so far, results have not been as expected.

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7. Naito N, Kikuchi M, Yoshimura Y, Kumazaki H, Kitagawa S, Ikeda T, Hasegawa C, Saito DN, Tomiyama S, Minabe Y. Atypical body movements during night in young children with autism spectrum disorder : a pilot study. Sci Rep. 2019 ; 9(1) : 6999.

Children with autism spectrum disorder (ASD) reportedly suffer from sleep problems at a higher rate than typically developing (TD) children. Several previous studies have reported differences in sleep indices (e.g., sleep latency) in children with ASD. However, no previous studies have focused specifically on the time course of body movements. In the present study, we investigated the time course of body movements in young TD children and young children with ASD as well as the relationship between body movements during night and social ability. Seventeen TD children and 17 children with ASD participated in this study (5 to 8 years old). We used an accelerometer attached to the waist to record movements during night and measured the average time course of body movements for 3 nights. Our results demonstrated that the rate of body movement 2 to 3 hours after the onset of body stillness was higher in children with ASD than in TD children. In addition, the higher rate of body movement at 0.5 to 1 hour after the onset of body stillness was associated with a lower social ability in the children with ASD. Our results suggested that the time course of body movements is an objective behavioural index for young children with ASD.

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8. Okuno M, Uehara T. [Behavioral assessments in infancy/toddlerhood and autism spectrum disorder : Effectiveness of a semi-structured behavioral observation incorporated into a legal health examination]. [Nihon koshu eisei zasshi] Japanese journal of public health. 2019 ; 66(4) : 177-89.

ObjectivesWe investigated the relationship between the diagnosis of autism spectrum disorder (ASD) based on legal health examinations and semi-structured behavioral observations conducted by the Social Attention and Communication Surveillance-Japan (SACS-J), wherein public health nurses evaluated sociality, verbal communication development, and tool employment in infants and toddlers through interactive play.MethodsPublic health nurses evaluated the behavioral features of 372 babies. These babies were born in 2011 or 2012 in a town, received a routine of legal health examinations at one and a half year (20 months) and at three years (38 months), and remained traceable until December 2016. The nurses used SACS-J items and the babies underwent routines of the examinations at 15, 20, 27, and 38 months. We statistically compared the relationships of the behavioral features at each of the above-mentioned months between two groups : Children with ASD and children with typical development.ResultsEight children were medically diagnosed with ASD, while five children received a diagnosis other than ASD. We compared gender, conditions at birth, physical development, and SACS-J behavioral observation items between the ASD group and the typical-development group. The ratio of the mean of the results from the ASD group was high (P<0.05), which indicates that the ASD group was significantly slower than the typical-development group in acquisition timing of "the sitting" and "the walk" (P<0.05). Significant differences in SACS-J items were "eye contact" at 15 months (P<0.05), at 20, 27, and 38 months (P<0.001) and "joint attention" at 15 months (P<.001). Further significant differences were "joint attention - adults do" at 20 months (P<0.05), "joint attention - children do" at 20 months (P<0.01), "pointing" at 20 months (P<0.05), "showing" at 27 months (P<0.001), "verbal development" at 15 months (P<0.01), "Use of language" at 20 months (P<0.01), "2-word sentence" at 27 months, and "3-word sentence" at 38 months (P<0.001). The ASD group scored significantly higher than the typical-development group in "fine motor skill" at 15 months (P<0.001) and at 27 months (P<0.01).ConclusionIntroducing an evaluation of standardized behavioral observations by public nurses in the early stages of development, prior to the legal health examination of babies at one and a half year, revealed the possibility of the early identification of children suspected of ASD at the public health activity level by a local government. Related health guidance and upbringing-and-development support are necessary in the community.

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9. Ormazabal M, Solari A, Espeche L, Castro T, Buzzalino N. [Fragile X syndrome and other entities associated with the FMR1 gene : Study of 28 affected families]. Archivos argentinos de pediatria. 2019 ; 117(3) : e257-e62.

The fragile X syndrome occurs due to an expansion of CGG trinucleotides, called full mutation, which is found at the Xq27.3 locus of the FMR1 gene. It is the most common cause of inherited intellectual disability. Associated with autistic spectrum disorders in one third of the patients, it affects males with higher prevalence. It also leads to hypermethylation of the gene promoter, silencing it and reducing the expression levels of FMRP, a protein involved in synaptic maturation and plasticity. A lower expansion causes primary ovarian failure syndrome as well as tremor and ataxia syndrome characterized by progressive cerebellar ataxia of late onset and intention tremor. In the present case-control study we analyze the segregation of mutations of the FMR1 gene in different families and the variability of expression that led to the genetic consultation.

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10. Pagani M, Bertero A, Liska A, Galbusera A, Sabbioni M, Barsotti N, Colenbier N, Marinazzo D, Scattoni ML, Pasqualetti M, Gozzi A. Deletion of autism risk gene Shank3 disrupts prefrontal connectivity. J Neurosci. 2019.

Mutations in the synaptic scaffolding protein Shank3 are a major cause of autism, and are associated with prominent intellectual and language deficits. However, the neural mechanisms whereby SHANK3 deficiency affects higher order socio-communicative functions remain unclear. Using high-resolution functional and structural MRI in adult male mice, here we show that loss of Shank3 (Shank3B (-/-)) results in disrupted local and long-range prefrontal and fronto-striatal functional connectivity. We document that prefrontal hypo-connectivity is associated with reduced short-range cortical projections density, and reduced gray matter volume. Finally, we show that prefrontal disconnectivity is predictive of social communication deficits, as assessed with ultrasound vocalization recordings. Collectively, our results reveal a critical role of SHANK3 in the development of prefrontal anatomy and function, and suggest that SHANK3 deficiency may predispose to intellectual disability and socio-communicative impairments via dysregulation of higher-order cortical connectivity.SignificanceMutations in the synaptic scaffolding protein SHANK3 are commonly associated with autism, intellectual and language deficits. Previous research has linked SHANK3 deficiency to basal ganglia dysfunction, motor stereotypies and social deficits. However, the neural mechanism whereby Shank3 gene mutations affects cortical functional connectivity and higher order socio-communicative functions remain unclear. Here we show that loss of SHANK3 in mice results in largely disrupted functional connectivity and abnormal gray matter anatomy in prefrontal areas. We also show that prefrontal connectivity disruption is tightly linked to socio-communicative deficits. Our findings suggest that SHANK3 is a critical orchestrator of fronto-cortical function, and that disrupted connectivity of prefrontal areas may underpin socio-communicative impairments observed in SHANK3 mutation carriers.

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11. Thomas RP, Wang LAL, Guthrie W, Cola M, McCleery JP, Pandey J, Schultz RT, Miller JS. What’s in a name ? A preliminary event-related potential study of response to name in preschool children with and without autism spectrum disorder. PLoS One. 2019 ; 14(5) : e0216051.

The ability to selectively respond to one’s own name is important for social and language development, and is disrupted in atypically developing populations (e.g., autism spectrum disorder). Research with typically developing samples using event-related potentials (ERPs) has demonstrated that the subject’s own name (SON) is differentiated from other stimuli at both early sensory and later cognitive stages of auditory processing. While neural indices of response to name have been researched extensively in adults, no such studies have been conducted with typically developing preschool children or children with autism spectrum disorder (ASD). The present study investigated ERP response to name in a sample of typically developing (TD) preschoolers (n = 19 ; mean age = 4.3 years) as well as a small, exploratory comparison group of preschoolers with ASD (n = 13 ; mean age = 4.4 years). TD preschoolers exhibited significantly greater negativity to SON over frontal regions than to an unfamiliar nonsense name, consistent with the adult SON negativity component. This component was present whether the name was spoken by a parent or an unfamiliar adult, suggesting that it reflects SON-specific processing rather than broad self-relevant information processing. Comparing preschoolers with ASD to the TD children revealed a significant SON negativity component across both groups. The amplitude of the SON negativity response was significantly correlated with social variables in the ASD group, though these correlations did not survive correction for multiple comparisons. This study is the first to demonstrate the presence of the SON component in preschool children with and without ASD.

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