Pubmed du 08/06/20

lundi 8 juin 2020

1. Bruining H, Hardstone R, Juarez-Martinez EL, Sprengers J, Avramiea AE, Simpraga S, Houtman SJ, Poil SS, Dallares E, Palva S, Oranje B, Matias Palva J, Mansvelder HD, Linkenkaer-Hansen K. Measurement of excitation-inhibition ratio in autism spectrum disorder using critical brain dynamics. Sci Rep ;2020 (Jun 8) ;10(1):9195.

Balance between excitation (E) and inhibition (I) is a key principle for neuronal network organization and information processing. Consistent with this notion, excitation-inhibition imbalances are considered a pathophysiological mechanism in many brain disorders including autism spectrum disorder (ASD). However, methods to measure E/I ratios in human brain networks are lacking. Here, we present a method to quantify a functional E/I ratio (fE/I) from neuronal oscillations, and validate it in healthy subjects and children with ASD. We define structural E/I ratio in an in silico neuronal network, investigate how it relates to power and long-range temporal correlations (LRTC) of the network’s activity, and use these relationships to design the fE/I algorithm. Application of this algorithm to the EEGs of healthy adults showed that fE/I is balanced at the population level and is decreased through GABAergic enforcement. In children with ASD, we observed larger fE/I variability and stronger LRTC compared to typically developing children (TDC). Interestingly, visual grading for EEG abnormalities that are thought to reflect E/I imbalances revealed elevated fE/I and LRTC in ASD children with normal EEG compared to TDC or ASD with abnormal EEG. We speculate that our approach will help understand physiological heterogeneity also in other brain disorders.

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2. Feng C, Zhao J, Ji F, Su L, Chen Y, Jiao J. TCF20 dysfunction leads to cortical neurogenesis defects and autistic-like behaviors in mice. EMBO Rep ;2020 (Jun 8):e49239.

Recently, de novo mutations of transcription factor 20 (TCF20) were found in patients with autism by large-scale exome sequencing. However, how TCF20 modulates brain development and whether its dysfunction causes ASD remain unclear. Here, we show that TCF20 deficits impair neurogenesis in mouse. TCF20 deletion significantly reduces the number of neurons, which leads to abnormal brain functions. Furthermore, transcriptome analysis and ChIP-qPCR reveal that the DNA demethylation factor TDG is a downstream target gene of TCF20. As a nonspecific DNA demethylation factor, TDG potentially affects many genes. Combined TDG ChIP-seq and GO analysis of TCF20 RNA-Seq identifies T-cell factor 4 (TCF-4) as a common target. TDG controls the DNA methylation level in the promoter area of TCF-4, affecting TCF-4 expression and modulating neural differentiation. Overexpression of TDG or TCF-4 rescues the deficient neurogenesis of TCF20 knockdown brains. Together, our data reveal that TCF20 is essential for neurogenesis and we suggest that defects in neurogenesis caused by TCF20 loss are associated with ASD.

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3. Frank HE, Kagan ER, Storch EA, Wood JJ, Kerns CM, Lewin AB, Small BJ, Kendall PC. Accommodation of Anxiety in Youth with Autism Spectrum Disorder : Results from the TAASD Study. J Clin Child Adolesc Psychol ;2020 (Jun 8):1-11.

OBJECTIVE : Accommodation, or the ways in which families modify their routines and expectations in response to a child’s anxiety, is common and interferes with anxiety treatment outcomes. However, little research has examined family accommodation among youth with autism spectrum disorder and anxiety. The current study aimed to (a) identify pre-treatment correlates of accommodation, (b) examine changes in accommodation after treatment, and (c) assess relationships between accommodation and post-treatment anxiety severity. METHOD : The sample consisted of 167 youth (mean age = 9.90 years ; 79.6% male ; 18% Latinx) with clinically significant anxiety and a diagnosis of autism spectrum disorder who were enrolled in a randomized clinical trial comparing two cognitive behavioral therapy interventions for anxiety and treatment-as-usual. Participants were evaluated for symptom severity and family accommodation at pre- and post-treatment. RESULTS : Results indicated that clinician-rated anxiety severity and parent-rated externalizing behaviors and autism spectrum disorder severity significantly predicted pre-treatment accommodation. Accommodation significantly decreased from pre- to post-treatment and non-responders showed significantly higher accommodation at post-treatment compared to responders. Finally, youth with higher pre-treatment accommodation had higher post-treatment anxiety. CONCLUSIONS : Findings indicate that accommodation for anxiety is common among youth with autism spectrum disorder and anxiety. Furthermore, accommodation is implicated in treatment outcomes and should be targeted in treatment for youth with autism spectrum disorder and anxiety.

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4. Frasca A, Spiombi E, Palmieri M, Albizzati E, Valente MM, Bergo A, Leva B, Kilstrup-Nielsen C, Bianchi F, Di Carlo V, Di Cunto F, Landsberger N. MECP2 mutations affect ciliogenesis : a novel perspective for Rett syndrome and related disorders. EMBO Mol Med ;2020 (Jun 8) ;12(6):e10270.

Mutations in MECP2 cause several neurological disorders of which Rett syndrome (RTT) represents the best-defined condition. Although mainly working as a transcriptional repressor, MeCP2 is a multifunctional protein revealing several activities, the involvement of which in RTT remains obscure. Besides being mainly localized in the nucleus, MeCP2 associates with the centrosome, an organelle from which primary cilia originate. Primary cilia function as "sensory antennae" protruding from most cells, and a link between primary cilia and mental illness has recently been reported. We herein demonstrate that MeCP2 deficiency affects ciliogenesis in cultured cells, including neurons and RTT fibroblasts, and in the mouse brain. Consequently, the cilium-related Sonic Hedgehog pathway, which is essential for brain development and functioning, is impaired. Microtubule instability participates in these phenotypes that can be rescued by HDAC6 inhibition together with the recovery of RTT-related neuronal defects. Our data indicate defects of primary cilium as a novel pathogenic mechanism that by contributing to the clinical features of RTT might impact on proper cerebellum/brain development and functioning, thus providing a novel therapeutic target.

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5. Gudbrandsen M, Bletsch A, Mann C, Daly E, Murphy CM, Stoencheva V, Blackmore CE, Rogdaki M, Kushan L, Bearden CE, Murphy DGM, Craig MC, Ecker C. Neuroanatomical underpinnings of autism symptomatology in carriers and non-carriers of the 22q11.2 microdeletion. Mol Autism ;2020 (Jun 8) ;11(1):46.

BACKGROUND : A crucial step to understanding the mechanistic underpinnings of autism spectrum disorder (ASD), is to examine if the biological underpinnings of ASD in genetic high-risk conditions, like 22q11.2 deletion syndrome (22q11.2DS), are similar to those in idiopathic illness. This study aimed to examine if ASD symptomatology in 22q11.2DS is underpinned by the same-or distinct-neural systems that mediate these symptoms in non-deletion carriers. METHODS : We examined vertex-wise estimates of cortical volume (CV), surface area (SA), and cortical thickness across 131 individuals between 6 and 25 years of age including (1) 50 individuals with 22q11.2DS, out of which n = 25 had a diagnosis of ASD, (2) 40 non-carriers of the microdeletion with a diagnosis of ASD (i.e., idiopathic ASD), and (3) 41 typically developing (TD) controls. We employed a 2-by-2 factorial design to identify neuroanatomical variability associated with the main effects of 22q11.2DS and ASD, as well as their interaction. Further, using canonical correlation analysis (CCA), we compared neuroanatomical variability associated with the complex (i.e., multivariate) clinical phenotype of ASD between 22q11.2 deletion carriers and non-carriers. RESULTS : The set of brain regions associated with the main effect of 22q11.2DS was distinct from the neuroanatomical underpinnings of the main effect of ASD. Moreover, significant 22q11.2DS-by-ASD interactions were observed for CV and SA in the dorsolateral prefrontal cortex, precentral gyrus, and posterior cingulate cortex, suggesting that the neuroanatomy of ASD is significantly modulated by 22q11.2DS (p < 0.01). We further established that the multivariate patterns of neuroanatomical variability associated with differences in symptom profiles significantly differed between 22q11.2 deletion carriers and non-carriers. LIMITATIONS : We employed a multicenter design to overcome single-site recruitment limitations ; however, FreeSurfer-derived measures of surface anatomy have been shown to be highly reliable across scanner platforms and field strengths. Further, we controlled for gender to address the differing distribution between idiopathic ASD individuals and the other groups. Nonetheless, the gender distribution in our sample reflects that of the respective populations, adding to the generalizability of our results. Last, we included individuals with a relatively wide age range (i.e., 6-25 years). CONCLUSIONS : Our findings indicate that neuroanatomical correlates of ASD symptomatology in carriers of the 22q11.2 microdeletion diverge from those in idiopathic ASD.

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6. Hill JR, Ziviani J, Driscoll C. "The connection just happens" : Therapists’ perspectives of canine-assisted occupational therapy for children on the autism spectrum. Aust Occup Ther J ;2020 (Jun 8)

INTRODUCTION : The inclusion of a therapy dog has been suggested as a means of facilitating therapy engagement for children on the autism spectrum within occupational therapy sessions. The aim of this study was to seek an understanding of possible benefits and challenges of this practice from the perspectives of occupational therapists, trained in canine-assisted therapy. METHOD : This study adopted an interpretive descriptive design. Six therapists participated in a semi-structured, telephone interview to describe their experience of working as canine-assisted occupational therapists with children on the autism spectrum. An inductive thematic analysis was used to analyse the data. RESULTS : Two overarching themes emerged. The first captured how therapists incorporated their therapy dog into sessions to accelerate children’s initial motivation to engage within the therapy process. Specifically, therapists discussed how involving their therapy dog facilitated the development of a secure relationship, supported autonomous task involvement and increased children’s sense of confidence. Second, they identified challenges inherent in their practice, such as the therapist’s ability to maintain a goal-directed focus when including a therapy dog. Beyond the challenges within their own practice sessions, therapists reflected on issues thought to impact the occupational therapy profession since starting practice as a canine-assisted occupational therapist. CONCLUSION : Findings from this study contribute to the current understanding of how occupational therapists incorporate therapy dogs into their practice with children on the autism spectrum. The specific challenges noted by the therapists highlighted the importance of canine-assisted occupational therapy being viewed as an advanced scope of practice within Australia and, therefore, the need for training and practice guidelines to be established.

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