1. Ameis SH, Blumberger DM, Croarkin PE, Mabbott DJ, Lai MC, Desarkar P, Szatmari P, Daskalakis ZJ. {{Treatment of Executive Function Deficits in autism spectrum disorder with repetitive transcranial magnetic stimulation: A double-blind, sham-controlled, pilot trial}}. {Brain stimulation}. 2020; 13(3): 539-47.
BACKGROUND: In youth and young adults with autism spectrum disorder (ASD), executive function (EF) deficits may be a promising treatment target with potential impact on everyday functioning. OBJECTIVE: To conduct a pilot randomized, double-blind, parallel, controlled trial evaluating repetitive transcranial magnetic stimulation (rTMS) for EF deficits in ASD. METHOD: In Toronto, Ontario (November 2014 to June 2017), a 20-session, 4-week course of 20 Hz rTMS targeting dorsolateral prefrontal cortex (DLPFC) (90%RMT) was compared to sham stimulation in 16-35 year-olds with ASD (28 male/12 female), without intellectual disability, who had impaired everyday EF performance (n = 20 active/n = 20 sham). Outcome measures evaluated protocol feasibility and clinical effects of active vs. sham rTMS on EF performance. The moderating effect of baseline functioning was explored. RESULTS: Of eligible participants, 95% were enrolled and 95% of randomized participants completed the protocol. Adverse events across treatment arms were mild-to-moderate. There was no significant difference between active vs. sham rTMS on EF performance. Baseline adaptive functioning moderated the effect of rTMS, such that participants with lower baseline functioning experienced significant EF improvement in the active vs. sham group. CONCLUSIONS: Our pilot RCT demonstrated the feasibility and acceptability of using high frequency rTMS targeting DLPFC in youth and young adults with autism. No evidence for efficacy of active versus sham rTMS on EF performance was found. However, we found promising preliminary evidence of EF performance improvement following active versus sham rTMS in participants with ASD with more severe adaptive functioning deficits. Future work could focus on examining efficacy of rTMS in this higher-need population. CLINICAL TRIAL REGISTRATION: Repetitive Transcranial Magnetic Stimulation (rTMS) for Executive Function Deficits in Autism Spectrum Disorder and Effects on Brain Structure: A Pilot Study; https://clinicaltrials.gov/ct2/show/NCT02311751?term = ameis&rank = 1; NCT02311751. The trial was funded by: an American Academy of Child and Adolescent Psychiatry (AACAP) Pilot Research Award, the Innovation Fund from the Alternate Funding Plan of the Academic Health Sciences Centres of Ontario, and an Ontario Mental Health Foundation (OMHF) Project A Grant and New Investigator Fellowship.
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2. Carlsson E, Asberg Johnels J, Gillberg C, Miniscalco C. {{Narrative Skills in Primary School Children with Autism in Relation to Language and Nonverbal Temporal Sequencing}}. {Journal of psycholinguistic research}. 2020.
Recent research has suggested that temporal sequencing of narrative events might be a domain-general ability that underlies oral narrative capacities. The current study investigated this issue in a group of children with known pragmatic and narrative difficulties, namely Autism Spectrum Disorder (ASD). We hypothesized (1) that children with ASD (n = 45) would retell narratives of poorer quality than both chronological age-matched (CAM) children and younger children matched on sentence-level language skills (LM), and (2) that nonverbal temporal sequencing skills would uniquely predict individual differences in oral narrative performance in children with ASD. The results show that children with ASD performed poorer on all measures of oral narrative quality compared with the CAM group, and on eight of ten measures compared with the LM group. Thus, our first hypothesis was confirmed, suggesting that narrative difficulties in ASD cannot be fully explained by impaired language. The second hypothesis was only partly confirmed: nonverbal temporal sequencing explained significant or marginally significant variance in some, but not all, aspects of oral narrative performance of children with ASD. These results are discussed from theoretical and clinical/educational perspectives, in relation to the heterogeneity of language skills in ASD and to domain-general features of narrative processing.
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3. Cucchiara F, Frumento P, Banfi T, Sesso G, Di Galante M, D’Ascanio P, Valvo G, Sicca F, Faraguna U. {{Electrophysiological features of sleep in children with Kir4.1 channel mutations and Autism-Epilepsy phenotype: a preliminary study}}. {Sleep}. 2020; 43(4).
STUDY OBJECTIVES: Recently, a role for gain-of-function (GoF) mutations of the astrocytic potassium channel Kir4.1 (KCNJ10 gene) has been proposed in subjects with Autism-Epilepsy phenotype (AEP). Epilepsy and autism spectrum disorder (ASD) are common and complexly related to sleep disorders. We tested whether well characterized mutations in KCNJ10 could result in specific sleep electrophysiological features, paving the way to the discovery of a potentially relevant biomarker for Kir4.1-related disorders. METHODS: For this case-control study, we recruited seven children with ASD either comorbid or not with epilepsy and/or EEG paroxysmal abnormalities (AEP) carrying GoF mutations of KCNJ10 and seven children with similar phenotypes but wild-type for the same gene, comparing period-amplitude features of slow waves detected by fronto-central bipolar EEG derivations (F3-C3, F4-C4, and Fz-Cz) during daytime naps. RESULTS: Children with Kir4.1 mutations displayed longer slow waves periods than controls, in Fz-Cz (mean period = 112,617 ms +/- SE = 0.465 in mutated versus mean period = 105,249 ms +/- SE = 0.375 in controls, p < 0.001). An analog result was found in F3-C3 (mean period = 125,706 ms +/- SE = 0.397 in mutated versus mean period = 120,872 ms +/- SE = 0.472 in controls, p < 0.001) and F4-C4 (mean period = 127,914 ms +/- SE = 0.557 in mutated versus mean period = 118,174 ms +/- SE = 0.442 in controls, p < 0.001). CONCLUSION: This preliminary finding suggests that period-amplitude slow wave features are modified in subjects carrying Kir4.1 GoF mutations. Potential clinical applications of this finding are discussed. Lien vers le texte intégral (Open Access ou abonnement)
4. Fu L, Wang Y, Fang H, Xiao X, Xiao T, Li Y, Li C, Wu Q, Chu K, Xiao C, Ke X. {{Longitudinal Study of Brain Asymmetries in Autism and Developmental Delays Aged 2-5Years}}. {Neuroscience}. 2020; 432: 137-49.
Some previous studies have demonstrated atypical brain lateralization in autism spectrum disorder (ASD). However, most of these reports have focused on language-related asymmetries in adults, and the developmental trajectory of hemispheric asymmetries in the important phase that occurs at 2-5years of age remains unclear. Thus, we used structural magnetic resonance imaging and diffusion tensor imaging (DTI) in a longitudinal study of grey matter (GM) asymmetries across all cortical parcellation units (PUs) and white matter (WM) lateralization across the WM skeleton using voxel-based morphometry and tract-based spatial statistics (TBSS) in 34 toddlers with ASD and a matched group of 26 toddlers with developmental delay (DD) at 2-3years old and with follow-up at 4-5years of age. We found the total brain volume and fractional anisotropy (FA) of WM was higher in the ASD group than in the DD group at baseline and 2years later. The ASD and DD groups showed a rightward asymmetry in a large number of cortical PUs and in the WM skeleton at both time points. GM lateralization was associated with the social and communicative disturbances observed in ASD at baseline, while WM asymmetry was significantly related to social disturbances and repetitive behaviours seen at 4-5years of age. In conclusion, both ASD and DD toddlers had widespread rightward asymmetry, and the patterns of lateralization were similar across the groups. GM and WM showed asynchronous development of hemispheric asymmetries at 2-5years of age, and this lateralization was associated with ASD symptoms.
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5. Garre JM, Silva HM, Lafaille JJ, Yang G. {{P2X7 receptor inhibition ameliorates dendritic spine pathology and social behavioral deficits in Rett syndrome mice}}. {Nat Commun}. 2020; 11(1): 1784.
Dysregulated immunity has been implicated in the pathogenesis of neurodevelopmental disorders but its contribution to synaptic and behavioral deficits in Rett syndrome (RTT) remains unknown. P2X7 receptors (P2X7Rs) are unique purinergic receptors with pro-inflammatory functions. Here, we report in a MECP2-deficient mouse model of RTT that the border of the cerebral cortex exhibits increased number of inflammatory myeloid cells expressing cell-surface P2X7Rs. Total knockout of P2X7Rs in MECP2 deficient mice decreases the number of inflammatory myeloid cells, restores cortical dendritic spine dynamics, and improves the animals’ neurological function and social behavior. Furthermore, either genetic depletion of P2X7Rs in bone-marrow derived leukocytes or pharmacological block of P2X7Rs primarily outside of the central nervous system parenchyma, recapitulates the beneficial effects of total P2X7R depletion on the social behavior. Together, our results highlight the pathophysiological roles of P2X7Rs in a mouse model of RTT.
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6. Haem E, Doostfatemeh M, Firouzabadi N, Ghazanfari N, Karlsson MO. {{A longitudinal item response model for Aberrant Behavior Checklist (ABC) data from children with autism}}. {Journal of pharmacokinetics and pharmacodynamics}. 2020.
This manuscript aims to present the first item response theory (IRT) model within a pharmacometric framework to characterize the longitudinal changes of Aberrant Behavior Checklist (ABC) data in children with autism. Data were obtained from 120 patients, which included 20,880 observations of the 58 items for up to three months. Observed scores for each ABC item were modeled as a function of the subject’s disability. Longitudinal IRT models with five latent disability variables based on ABC subscales were used to describe the irritability, lethargy, stereotypic behavior, hyperactivity, and inappropriate speech over time. The IRT pharmacometric models could accurately describe the longitudinal changes of the patient’s disability while estimating different time-course of disability for the subscales. For all subscales, model-estimated disability was reduced following initiation of therapy, most markedly for hyperactivity. The developed framework provides a description of ABC longitudinal data that can be a suitable alternative to traditional ABC data collected in autism clinical trials. IRT is a powerful tool with the ability to capture the heterogeneous nature of ABC, which results in more accurate analysis in comparison to traditional approaches.
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7. Iandolo G, Lopez-Florit L, Venuti P, Neoh MJY, Bornstein MH, Esposito G. {{Story contents and intensity of the anxious symptomatology in children and adolescents with Autism Spectrum Disorder}}. {International journal of adolescence and youth}. 2020; 25(1): 725-40.
This study aimed to analyse and compare the storytelling of 25 children with Autism Spectrum Disorder (ASD) with a comparison group of 25 children with typical development. Children’s narratives were transcribed verbatim, and their forms and contents were analysed. The two groups were matched according to the narrative cohesion of the story using the Bears Family Projective Test, equivalent verbal age, sex, and socioeconomic level. No differences in the forms of the stories emerged, but compared with the narratives of the typical development group, the narrative contents of the ASD group showed more adaptive and maladaptive behaviours of the characters, more problems, and less use of the atmosphere outside the home. These contents are related to the intensity of the anxious symptomatology indicated by the ASD group, their family members and teachers.
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8. Imamura A, Morimoto Y, Ono S, Kurotaki N, Kanegae S, Yamamoto N, Kinoshita H, Tsujita T, Okazaki Y, Ozawa H. {{Genetic and environmental factors of schizophrenia and autism spectrum disorder: insights from twin studies}}. {J Neural Transm (Vienna)}. 2020.
Twin studies of psychiatric disorders such as schizophrenia and autism spectrum disorder have employed epidemiological approaches that determine heritability by comparing the concordance rate between monozygotic twins (MZs) and dizygotic twins. The basis for these studies is that MZs share 100% of their genetic information. Recently, biological studies based on molecular methods are now being increasingly applied to examine the differences between MZs discordance for psychiatric disorders to unravel their possible causes. Although recent advances in next-generation sequencing have increased the accuracy of this line of research, there has been greater emphasis placed on epigenetic changes versus DNA sequence changes as the probable cause of discordant psychiatric disorders in MZs. Since the epigenetic status differs in each tissue type, in addition to the DNA from the peripheral blood, studies using DNA from nerve cells induced from postmortem brains or induced pluripotent stem cells are being carried out. Although it was originally thought that epigenetic changes occurred as a result of environmental factors, and thus were not transmittable, it is now known that such changes might possibly be transmitted between generations. Therefore, the potential possible effects of intestinal flora inside the body are currently being investigated as a cause of discordance in MZs. As a result, twin studies of psychiatric disorders are greatly contributing to the elucidation of genetic and environmental factors in the etiology of psychiatric conditions.
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9. Kildahl AN, Helverschou SB, Bakken TL, Oddli HW. {{« If we do not look for it, we do not see it »: Clinicians’ experiences and understanding of identifying post-traumatic stress disorder in adults with autism and intellectual disability}}. {J Appl Res Intellect Disabil}. 2020.
BACKGROUND: Individuals with autism spectrum disorder (ASD) and intellectual disability (ID) are at increased risk of potentially traumatic events and may be at increased risk of post-traumatic stress disorder (PTSD). However, knowledge regarding identification of PTSD in this population is limited. The aim of this study was to investigate clinical experience regarding PTSD and trauma assessment in individuals with co-occurring ASD and ID. METHOD: Interpretative phenomenological analysis was used to explore experiences of identifying PTSD in this population among 18 mental health clinicians working with ASD and ID. RESULTS: Informants viewed PTSD in individuals with ASD and ID as equivalent to PTSD in the general population, but with causes and expressions potentially differing. Several factors were described to contribute to challenges in identification. CONCLUSIONS: Trauma may have severe impact in individuals with ASD and ID. Multidimensional, individualized assessment strategies seem necessary to recognize PTSD or trauma-related symptoms in this population.
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10. Ledbetter-Cho K, O’Reilly M, Watkins L, Lang R, Lim N, Davenport K, Murphy C. {{The Effects of a Teacher-Implemented Video-Enhanced Activity Schedule Intervention on the Mathematical Skills and Collateral Behaviors of Students with Autism}}. {J Autism Dev Disord}. 2020.
This study used a multiple probe design to evaluate the effects of a teacher-implemented video-schedule intervention on the mathematical skills and untargeted challenging behaviors of five elementary-school students with autism. Results indicated that the intervention was effective in improving participants’ academic performance, and a decrease in the level of challenging behaviors and stereotypy was observed for participants following the introduction of intervention. Additionally, academic gains generalized across academic problems and to a small group setting, suggesting that this technology-based intervention is an efficient use of instructional time. Future research targeting a variety of academic skills and examining intervention implementation by additional practitioners (e.g., teaching assistants) is warranted.
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11. Lim SY, Ishiura H, Ramli N, Shibata S, Almansour MA, Tan AH, Houlden H, Lang AE, Tsuji S. {{Adult-onset neuronal intranuclear inclusion disease mimicking Fragile X-associated tremor-ataxia syndrome in ethnic Chinese patients}}. {Parkinsonism & related disorders}. 2020; 74: 25-7.
Two ethnic Chinese men with clinico-radiologic features of Fragile X-associated tremor-ataxia syndrome (FXTAS) were found on genetic testing to have neuronal intranuclear inclusion disease (NIID), highlighting that NIID should be considered in the differential diagnosis of FXTAS. NIID may also be much more common than FXTAS in certain Asian populations.
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12. Mehdizadefar V, Ghassemi F, Fallah A. {{Brain Connectivity Reflected in Electroencephalogram Coherence in Individuals With Autism: A Meta-Analysis}}. {Basic Clin Neurosci}. 2019; 10(5): 409-17.
Introduction: Many theories have been proposed about the etiology of autism. One is related to brain connectivity in patients with autism. Several studies have reported brain connectivity changes in autism disease. This study was performed on Electroencephalogram (EEG) studies that evaluated patients with autism, using functional brain connectivity, and compared them with typically-developing individuals. Methods: Three scientific databases of ScienceDirect, Medline (PubMed), and BioMed Central were systematically searched through their online search engines. Comprehensive Meta-analysis software analyzed the obtained data. Results: The systematic search led to 10 papers, in which EEG coherence was used to obtain the brain connectivity of people with autism. To determine the effect size, Cohen’s d parameter was used. In the first meta-analysis, the study of the maximum effect size was considered, and all significant effect sizes were evaluated in the second meta-analysis. The effect size was assessed using a random-effects model in both meta-analyses. The results of the first meta-analysis indicated that heterogeneity was not present among the studies (Q=13.345, P>0.1). The evaluation of all effect sizes in the second meta-analysis showed a significant lack of homogeneity among the studies (Q=56.984, P=0.0001). Conclusion: On the whole, autism was found to be related to neural connectivity, and the present research showed the difference in the EEG coherence of people with autism and healthy people. These conclusions require further studies with more extensive data, considering different brain regions, and novel analysis techniques for assessing brain connectivity.
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13. Mollajani R, Joghataei MT, Tehrani-Doost M. {{Bumetanide Therapeutic Effect in Children and Adolescents With Autism Spectrum Disorder: A Review Study}}. {Basic Clin Neurosci}. 2019; 10(5): 433-41.
Introduction: Autism Spectrum Disorder (ASD) is characterized by several impairments in communications and social interactions, as well as restricted interests or stereotyped behaviors. Interventions applied for this disorder are based on multi-modal approaches, including pharmacotherapy. No definitive cure or medication has been introduced so far; therefore, researchers still investigate potential drugs for treating ASD. One of the new medications introduced for this purpose is bumetanide. The present article aimed to review the efficacy of this drug on the core symptoms of ASD and its potential side effects. Methods: We searched all papers reported on pharmacokinetics, pharmacodynamics, efficacy, and adverse effects of bumetanide on animal models and humans with ASD. The papers were extracted from the main databases of PubMed, Web of Science, and Scopus. Results: The findings revealed that cortical neurons have high Chloride ion (Cl-)i and excitatory actions of gamma-aminobutyric acid in the valproic acid animal model with ASD and mice with fragile X syndrome. Bumetanide, which has been introduced as a diuretic, is also a high-affinity-specific Na+-K+-Cl- cotransporter (NKCC1) antagonist that can reduce Cl- level. The results also indicate that bumetanide can attenuate behavioral features of autism in both animal and human models. Moreover, the studies showed that such medication could activate fusiform face area in individuals with ASD while viewing emotional faces. Also, recent findings suggest that a dose of 1 mg/d of this drug, taken twice daily, might be the best compromise between safety and efficacy. Conclusion: Recent studies provided some evidence that bumetanide can be a novel pharmacological agent in treating core symptoms of ASD. Future studies are required to confirm the efficacy of this medication in individuals with ASD.
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14. Morris S, O’Reilly G, Byrne MK. {{Understanding Our Peers with Pablo: Exploring the Merit of an Autism Spectrum Disorder De-stigmatisation Programme Targeting Peers in Irish Early Education Mainstream Settings}}. {J Autism Dev Disord}. 2020.
The political drive for inclusion means there are increasing numbers of children with autism spectrum disorder (ASD) being educated alongside their neurotypical peers. Pervasive victimisation has prompted the development of peer interventions targeting stigma. This study evaluated the ‘Understanding Our Peers with Pablo’ programme for effects on knowledge, attitudes and behavioural intentions of infant schoolchildren (N = 222) towards autistic peers. Classes were randomly assigned to an intervention or waitlist control condition. Change over time in knowledge of autism and attitudes and behavioural intentions towards familiar and unfamiliar peers was analysed using mixed analyses of variance. The intervention condition showed gains in knowledge and increased positive attitudes towards unfamiliar autistic peers (maintained over three-months). There were significant improvements in attitudes towards familiar autistic peers, and time-limited decreases in behavioural intentions across both conditions. Overall, results support the use of this programme in early-years education.
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15. Scheerer NE, Shafai F, Stevenson RA, Iarocci G. {{Affective Prosody Perception and the Relation to Social Competence in Autistic and Typically Developing Children}}. {Journal of abnormal child psychology}. 2020.
Individuals diagnosed with autism spectrum disorder (ASD) have difficulty perceiving and expressing emotions. Since prosodic changes in speech (i.e. changes in intonation, stress, rhythm, etc.) are crucial for extracting information about the emotional state of a speaker, an inability to perceive and interpret these prosodic changes may be related to impairments in social communication. This study used non-verbal emotional voice-clips to examine the ability of autistic and typically-developing children (7-13 years old) to extract affect from changes in prosody. This research also explored whether difficulty extracting affective intent from changes in prosody may be related to social competence. Autistic (n = 26) and typically-developing (n = 26) children accurately matched emotional voice-clips to emotion words, suggesting autistic children can accurately extract the affective meaning conveyed by changes in prosody. Autistic children were less accurate at matching the voice-clips to emotional faces, suggesting that autistic children may struggle to make use of prosodic information in a social context. Across both autistic and typically-developing children, prosody-face matching accuracy was found to predict overall social competence, as well as social inferencing abilities, suggesting that the inability to utilize affective information derived from a speaker’s voice may interfere with effective social communication.
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16. Schnabel A, Hallford DJ, Stewart M, McGillivray JA, Forbes D, Austin DW. {{An Initial Examination of Post-Traumatic Stress Disorder in Mothers of Children with Autism Spectrum Disorder: Challenging Child Behaviors as Criterion A Traumatic Stressors}}. {Autism Res}. 2020.
Parenting a child with autism spectrum disorder (ASD) is associated with high levels of stress. Several studies have conceptualized this as a traumatic stress response to challenging child behaviors such as self-harm, suicidal ideation, and physical aggression toward caregivers. In the present study, we explored the relevance of a trauma-based diagnostic framework to a sample of 30 mothers (M age = 42.97, SD = 5.82) of children with ASD (M age = 12.43, SD = 3.15). Participants were interviewed using the Clinician-Administered PTSD Scale for DSM-5 (CAPS-5) for post-traumatic stress disorder (PTSD) and an abbreviated Mini International Neuropsychiatric Interview to assess for comorbidity. Three participants were excluded as they met criteria for PTSD from a traumatic event unrelated to their parenting experience. Of the remaining 27 participants, 6 (22.2%) met criteria for PTSD in the context of traumatic parenting experiences. Descriptions of traumatic events experienced are summarized. Results suggest that, for some parents, challenging child behaviors such as physical violence toward the caregiver from the child, self-injurious behaviors, and suicidal behaviors function as traumatic stressors as per Criterion A of PTSD (American Psychiatric Association [2013]. Diagnostic and statistical manual of mental disorders [DSM-5]. Arlington, VA). This has implications for health professionals engaged with parents of children with ASD, who should consider the possibility of PTSD when challenging behaviors of a potentially traumatic nature are present. Autism Res 2020. (c) 2020 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: This study found that some challenging behaviors exhibited by children with autism spectrum disorder can be traumatic for parents and lead to the development of post-traumatic stress disorder. Some of these behaviors included self-harming behaviors like head banging, expressing suicidal urges, and becoming physically aggressive toward parents during meltdowns.
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17. Siracusano M, Riccioni A, Abate R, Benvenuto A, Curatolo P, Mazzone L. {{Vitamin D Deficiency and Autism Spectrum Disorder}}. {Current pharmaceutical design}. 2020.
Vitamin D is a neurosteroid hormone crucially involved in neurodevelopment. Neural cell proliferation, neurotransmission, oxydative stress and immune function, represent the main mechanisms mediated by vitamin D in the Central Nervous System. Therefore, its deficiency during pregnancy and early childhood may significantly impact on a developing brain, leading to possible adverse neuropsychological outcomes including Autism Spectrum Disorder (ASD). Significant vitamin D deficiency is described within children affected by ASD and in pregnant mothers whose offspring will later develop ASD, suggesting a possible role of the hormone as a contributing risk factor in the etiopathogenesis of ASD. We reviewed the actual literature on the potential contributing role of prenatal and early postnatal vitamin D deficiency in ASD etiopathogenesis, at both genetic and environmental level, and the possible effect of vitamin D supplementation in autistic children. Conflicting but promising results emerged on the topic. Further Randomized Controlled Trials studies carried out during pregnancy and early infancy are necessary for better understanding the possible contribution of vitamin D deficiency in the etiopathogenesis of autism and the potential efficacy of the hormone supplementation on the improvement of ASD core symptoms.
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18. Strydom A, Bosco A, Vickerstaff V, Hunter R, Hassiotis A. {{Clinical and cost effectiveness of staff training in the delivery of Positive Behaviour Support (PBS) for adults with intellectual disabilities, autism spectrum disorder and challenging behaviour – randomised trial}}. {BMC Psychiatry}. 2020; 20(1): 161.
BACKGROUND: Although Positive Behaviour Support (PBS) is a widely used intervention for ameliorating challenging behaviour (CB), evidence for its use in adults with intellectual disability (ID) and comorbid autism (ASD) is lacking. We report a planned subsidiary analysis of adults with both ASD and ID who participated in a randomised trial of PBS delivered by health professionals. METHODS: The study was a multicentre, cluster randomised trial conducted in 23 community ID services in England, participants were randomly allocated to either the delivery of PBS (n = 11 clusters) or to treatment as usual (TAU; n = 12). One-hundred and thirteen participants (46% of all participants in the trial) had a diagnosis of ID, autism spectrum disorder and CB (ASD+); (47 allocated to the intervention arm, and 66 to the control). CB (primary outcome) was measured with the Aberrant Behaviour Checklist total score (ABC-CT). Secondary outcomes included mental health status, psychotropic medication use, health and social care costs and quality adjusted life years (QALYs) over 12 months. RESULTS: There were no statistically significant differences in ABC-CT between ASD+ groups randomised to the two arms over 12 months (adjusted mean difference = – 2.10, 95% CI: – 11.3 7.13, p = 0.655) or other measures. The mean incremental cost of the intervention per participant was pound628 (95% CI – pound1004 to pound2013). There was a difference of 0.039 (95% CI – 0.028 to 0.103) for QALYs and a cost per QALY gained of pound16,080. CONCLUSIONS: Results suggest lack of clinical effectiveness for PBS delivered by specialist ID clinical teams. Further evidence is needed from larger trials, and development of improved interventions. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01680276.
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19. Xu ZX, Kim GH, Tan JW, Riso AE, Sun Y, Xu EY, Liao GY, Xu H, Lee SH, Do NY, Lee CH, Clipperton-Allen AE, Kwon S, Page DT, Lee KJ, Xu B. {{Elevated protein synthesis in microglia causes autism-like synaptic and behavioral aberrations}}. {Nat Commun}. 2020; 11(1): 1797.
Mutations that inactivate negative translation regulators cause autism spectrum disorders (ASD), which predominantly affect males and exhibit social interaction and communication deficits and repetitive behaviors. However, the cells that cause ASD through elevated protein synthesis resulting from these mutations remain unknown. Here we employ conditional overexpression of translation initiation factor eIF4E to increase protein synthesis in specific brain cells. We show that exaggerated translation in microglia, but not neurons or astrocytes, leads to autism-like behaviors in male mice. Although microglial eIF4E overexpression elevates translation in both sexes, it only increases microglial density and size in males, accompanied by microglial shift from homeostatic to a functional state with enhanced phagocytic capacity but reduced motility and synapse engulfment. Consequently, cortical neurons in the mice have higher synapse density, neuroligins, and excitation-to-inhibition ratio compared to control mice. We propose that functional perturbation of male microglia is an important cause for sex-biased ASD.
