Pubmed du 11/05/20

lundi 11 mai 2020

1. Al-Harbi NO, Nadeem A, Ahmad SF, Al-Ayadhi LY, Al-Harbi MM, As Sobeai HM, Ibrahim KE, Bakheet SA. Elevated expression of toll-like receptor 4 is associated with NADPH oxidase-induced oxidative stress in B cells of children with autism. International immunopharmacology. 2020 ; 84 : 106555.

Autism spectrum disorder (ASD) is a childhood disorder with neurodevelopmental dysfunction which manifests as impairment in social behavior and communication skills. B cells play an important role in immune dysfunction where toll-like receptor 4 (TLR4) may contribute through oxidative inflammatory process. TLR4 related signaling and oxidative stress have been reported in the periphery of ASD subjects, however it has not been evaluated in peripheral B cells of ASD subjects and compared with typically developing control (TDC) children. This study evaluated TLR4 expression and related signaling [Bruton’s tyrosine kinase (BTK), spleen tyrosine kinase (SYK), NF-kB, NADPH oxidase (NOX2), nitrotyrosine, superoxide dismutase (SOD)] in ASD and TDC subjects. Current investigation in B cells shows that ASD subjects have increased TLR4 expression and oxidative stress as exhibited by upregulated NOX2 and nitrotyrosine expression as compared to TDC subjects. B cell relevant pathways, BTK/SYK/NF-kB were also upregulated in B cells of ASD group. Treatment with TLR4 agonist, LPS led to upregulation of NOX2 and nitrotyrosine in B cells of ASD whereas it had no significant effect on TDC subjects. Treatment with NF-kB inhibitor caused inhibition of LPS-induced upregulation of NOX2 and nitrotyrosine in B cells of ASD. Therefore, current investigation proposes the notion that TLR4 expression is elevated in B cells which is associated with increased NF-kB signaling and oxidant stress in ASD subjects. In short, peripheral B cells could contribute to systemic oxidative inflammation and contribute to the immune dysfunction in ASD.

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2. Bangerter A, Chatterjee M, Manfredonia J, Manyakov NV, Ness S, Boice MA, Skalkin A, Goodwin MS, Dawson G, Hendren R, Leventhal B, Shic F, Pandina G. Automated recognition of spontaneous facial expression in individuals with autism spectrum disorder : parsing response variability. Mol Autism. 2020 ; 11(1) : 31.

BACKGROUND : Reduction or differences in facial expression are a core diagnostic feature of autism spectrum disorder (ASD), yet evidence regarding the extent of this discrepancy is limited and inconsistent. Use of automated facial expression detection technology enables accurate and efficient tracking of facial expressions that has potential to identify individual response differences. METHODS : Children and adults with ASD (N = 124) and typically developing (TD, N = 41) were shown short clips of "funny videos." Using automated facial analysis software, we investigated differences between ASD and TD groups and within the ASD group in evidence of facial action unit (AU) activation related to the expression of positive facial expression, in particular, a smile. RESULTS : Individuals with ASD on average showed less evidence of facial AUs (AU12, AU6) relating to positive facial expression, compared to the TD group (p < .05, r = - 0.17). Using Gaussian mixture model for clustering, we identified two distinct distributions within the ASD group, which were then compared to the TD group. One subgroup (n = 35), termed "over-responsive," expressed more intense positive facial expressions in response to the videos than the TD group (p < .001, r = 0.31). The second subgroup (n = 89), ("under-responsive"), displayed fewer, less intense positive facial expressions in response to videos than the TD group (p < .001 ; r = - 0.36). The over-responsive subgroup differed from the under-responsive subgroup in age and caregiver-reported impulsivity (p < .05, r = 0.21). Reduced expression in the under-responsive, but not the over-responsive group, was related to caregiver-reported social withdrawal (p < .01, r = - 0.3). LIMITATIONS : This exploratory study does not account for multiple comparisons, and future work will have to ascertain the strength and reproducibility of all results. Reduced displays of positive facial expressions do not mean individuals with ASD do not experience positive emotions. CONCLUSIONS : Individuals with ASD differed from the TD group in their facial expressions of positive emotion in response to "funny videos." Identification of subgroups based on response may help in parsing heterogeneity in ASD and enable targeting of treatment based on subtypes. TRIAL REGISTRATION :, NCT02299700. Registration date : November 24, 2014.

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3. Benevides TW, Shore SM, Andresen ML, Caplan R, Cook B, Gassner DL, Erves JM, Hazlewood TM, King MC, Morgan L, Murphy LE, Purkis Y, Rankowski B, Rutledge SM, Welch SP, Wittig K. Interventions to address health outcomes among autistic adults : A systematic review. Autism. 2020 : 1362361320913664.

LAY ABSTRACT : Autistic adults have more health problems then their same-aged peers. Yet little research has been conducted that focuses on addressing these health problems. In order to guide future research, it is important to know what intervention studies have been done to improve health outcomes among autistic adults. The project team and student assistants read studies that were published between 2007 and 2018 in the online research database, PubMed. We looked for studies published in English, which were peer-reviewed and included (1) an intervention, (2) an outcome that was related to health, and (3) a study group that included autistic adults. We did not include studies that had outcomes about employment (unless there was a health outcome), studies about caregivers or caregiving, or expert opinions about interventions. Of 778 reviewed articles, 19 studies met all of the criteria above. Within these studies, two approaches were found to have emerging evidence for their use in autistic adults : cognitive behavioral interventions and mindfulness-based approaches for improved mental health outcomes. The remaining intervention approaches did not have enough articles to support their use. Many of the outcomes were about reduced symptoms of co-occurring mental health diagnoses (e.g. reduced anxiety, depression). Most of the participants in these studies were male and did not have intellectual disability. Most study participants were adults younger than 40. There are not many intervention studies that address health outcomes among autistic adults. More research is needed on interventions which are desired by the adult autism community and address preferred health outcomes such as increased quality of life or well-being.

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4. Bouck EC, Long H. Teaching students with intellectual and developmental disabilities to calculate cost after discounts via schematic diagrams. Res Dev Disabil. 2020 ; 102 : 103656.

BACKGROUND/AIMS/METHODS : Life skills instruction is important for students with intellectual and developmental disabilities (IDD) and an emerging research base exists in which schema instruction is used to support students with IDD. In this single-case multiple probe across participants study, researchers explored the use of a schematic diagram in conjunction with the system of least prompts (SLP) to support the acquisition, fluency, maintenance, and generalization of life skills mathematics for secondary students with IDD. PROCEDURES/OUTCOMES : Researchers collected data relative to student accuracy and independence in solving problems involving finding the cost of an item after a discount (i.e., sale or coupon). Researchers collected data across baseline, intervention, maintenance, and generalization phases. RESULTS/CONCLUSION : Researchers found a functional relation between the intervention package and accuracy for all three students. Students were successful with the schematic diagram, however, the data for generalization to when no schema was provided were more idiosyncratic. IMPLICATIONS : This research holds implications for the use of a schematic diagram to support students with IDD learning life-skills mathematical problem solving.

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5. Chetcuti L, Uljarevic M, Varcin KJ, Boutrus M, Wan MW, Slonims V, Green J, Segal L, Iacono T, Dissanayake C, Whitehouse AJO, Hudry K. The Role of Negative Affectivity in Concurrent Relations Between Caregiver Psychological Distress and Social-Emotional Difficulties in Infants With Early Signs of Autism. Autism Res. 2020.

Recent evidence suggests the link between caregiver psychological distress and offspring social-emotional difficulties may be accounted for by offspring temperament characteristics. However, existing studies have only focused on neurotypical children ; thus, the current study sought to provide an initial examination of this process among children with varying levels of early autism features. Participants included 103 infants aged 9-16 months (M = 12.39, SD = 1.97 ; 68% male) and their primary caregiver (96% mothers) referred to a larger study by community healthcare professionals. We utilized caregiver-reported measures of psychological distress (Depression Anxiety Stress Scales), infant temperament (Infant Behavior Questionnaire-Revised) and internalizing and externalizing symptoms (Infant-Toddler Social and Emotional Assessment) and administered the Autism Observation Schedule for Infants (AOSI) at an assessment visit to quantify autism features. Infant negative affectivity was found to mediate positive concurrent relations between caregiver psychological distress and infant internalizing and externalizing symptoms, irrespective of the infants’ AOSI score. While preliminary and cross-sectional, these results replicate and extend previous findings suggesting that the pathway from caregiver psychological distress to negative affectivity to social-emotional difficulties might also be apparent among infants with varying levels of autism features. More rigorous tests of causal effects await future longitudinal investigation. LAY SUMMARY : Offspring of caregivers experiencing psychological distress (i.e., symptoms of depression, anxiety, and/or stress) may themselves be at increased risk of poor mental health outcomes. Several previous studies conducted with neurotypical children suggest that this link from caregiver-to-child may be facilitated by children’s temperament qualities. This study was a preliminary cross-sectional exploration of these relationships in infants with features of autism. We found that infants’ elevated negative emotions were involved in the relation between caregiver heightened psychological distress and children’s mental health difficulties, consistent with neurotypical development.

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6. Culotta L, Penzes P. Exploring the mechanisms underlying excitation/inhibition imbalance in human iPSC-derived models of ASD. Mol Autism. 2020 ; 11(1) : 32.

Autism spectrum disorder (ASD) is a range of neurodevelopmental disorders characterized by impaired social interaction and communication, and repetitive or restricted behaviors. ASD subjects exhibit complex genetic and clinical heterogeneity, thus hindering the discovery of pathophysiological mechanisms. Considering that several ASD-risk genes encode proteins involved in the regulation of synaptic plasticity, neuronal excitability, and neuronal connectivity, one hypothesis that has emerged is that ASD arises from a disruption of the neuronal network activity due to perturbation of the synaptic excitation and inhibition (E/I) balance. The development of induced pluripotent stem cell (iPSC) technology and recent advances in neuronal differentiation techniques provide a unique opportunity to model complex neuronal connectivity and to test the E/I hypothesis of ASD in human-based models. Here, we aim to review the latest advances in studying the different cellular and molecular mechanisms contributing to E/I balance using iPSC-based in vitro models of ASD.

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7. Donnelly LJ, Cervantes PE, Okparaeke E, Stein CR, Filton B, Kuriakose S, Havens J, Horwitz SM. Staff Perceptions and Implementation Fidelity of an Autism Spectrum Disorder Care Pathway on a Child/Adolescent General Psychiatric Inpatient Service. J Autism Dev Disord. 2020.

While youth with autism spectrum disorder (ASD) are psychiatrically hospitalized at high rates, general psychiatric settings are not designed to meet their unique needs. Previous evaluations of an ASD-Care Pathway (ASD-CP) on a general psychiatric unit revealed sustained reductions in crisis interventions (intramuscular medication use, holds/restraints ; Cervantes et al. in J Autism Dev Disord 49(8):3173-3180,, 2019 ; Kuriakose et al. in J Autism Dev Disord 48(12):4082-4089,, 2018). The current study investigated staff perceptions of the ASD-CP (N = 30), and examined rates of ASD-CP implementation fidelity in relation to patient outcomes (N = 28). Staff identified visual communication aids and reward strategies as most helpful. The number of days of reward identification early in the inpatient stay was associated with fewer crisis interventions later in a patient’s stay.

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8. Fuentes J, Basurko A, Isasa I, Galende I, Muguerza MD, Garcia-Primo P, Garcia J, Fernandez-Alvarez CJ, Canal-Bedia R, Posada de la Paz M. The ASDEU autism prevalence study in northern Spain. Eur Child Adolesc Psychiatry. 2020.

The prevalence of autism spectrum disorders (ASD) was studied in children in the County of Gipuzkoa (Basque Country, Spain) as part of the European Union’s Autism Spectrum Disorder in Europe project (ASDEU- To identify cases in a total community sample of 7- to 9-year-old pupils (N = 14,734), a multistage approach was adopted : in the first stage, a teacher nomination (TN) form was completed by school teachers ; and in the second stage, all families with a child nominated by their teachers were invited to complete the Social Communication Questionnaire (SCQ). A total of 108 (59%) schools participated fully, yielding a final sample of 9177 of 14.734 (61.9%) pupils. A total of 212 (2.3%) children were nominated via the TN form, and of these, 105 (49.5%) returned the completed SCQ. Twenty-five (23.8%) cases with SCQ scores >/= 15 were invited to undergo a free clinical assessment, and 10 (40%) new cases of ASD were identified. The prevalence estimate included the 55 cases already being supported by the Gipuzkoa’s only ASD association, the Gipuzkoa Autism Society (Asociacion Guipuzcoana de Autismo/GAUTENA)), as well as the 10 new subjects identified by the ASDEU field diagnostic process. A sensitivity analysis was performed to estimate new potential ASD cases among the non-participant schools, leading to a final figure of 87 cases of ASD in this age-bracket at the date of the study. This global probabilistic estimate, including non-participating schools, would thus provide a population prevalence of 0.59% (95% CI 0.48-0.73), a result lower than those reported by some other studies. Attrition rates in cross-sectional studies are challenging and support the need for developing longitudinal ASD incidence surveillance study areas (ASD observatories).

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9. Hawco C, Yoganathan L, Voineskos AN, Lyon R, Tan T, Daskalakis ZJ, Blumberger DM, Croarkin PE, Lai MC, Szatmari P, Ameis SH. Greater Individual Variability in Functional Brain Activity during Working Memory Performance in young people with Autism and Executive Function Impairment. Neuroimage Clin. 2020 ; 27 : 102260.

BACKGROUND : Individuals with autism spectrum disorder (ASD) often present with executive functioning (EF) deficits, including spatial working memory (SWM) impairment, which impedes real-world functioning. The present study examined task-related brain activity, connectivity and individual variability in fMRI-measured neural response during an SWM task in older youth and young adults with autism and clinically significant EF impairment. METHODS : Neuroimaging was analyzed in 29 individuals with ASD without intellectual disability who had clinically significant EF impairment on the Behavior Rating Inventory of Executive Function, and 20 typically developing controls (participant age range=16-34). An SWM N-Back task was performed during fMRI. SWM activity (2-Back vs. 0-Back) and task-related dorsolateral prefrontal cortex (DLPFC) connectivity was examined within and between groups. Variability of neural response during SWM was also examined. RESULTS : During SWM performance both groups activated the expected networks, and no group differences in network activation or task-related DLPFC-connectivity were found. However, greater individual variability in the pattern of SWM activity was found in the ASD versus the typically developing control group. CONCLUSIONS : While there were no group differences in SWM task-evoked activity or connectivity, fronto-parietal network engagement was found to be more variable/idiosyncratic in ASD. Our results suggest that the fronto-parietal network may be shifted or sub-optimally engaged during SWM performance in participants with ASD with clinically significant EF impairment, with implications for developing targeted interventions for this subgroup.

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10. Howard K, Gibson J, Katsos N. Parental Perceptions and Decisions Regarding Maintaining Bilingualism in Autism. J Autism Dev Disord. 2020.

A growing body of evidence suggests that bilingual exposure does not negatively impact children on the autism spectrum. This study sought to illuminate parents’ perceptions and choices regarding maintaining bilingualism in autism. Semi-structured interviews were conducted with 16 family members in England and Wales. Data were analysed using interpretative phenomenological analysis (IPA). Although parents expressed positive attitudes towards bilingualism, these views were not always congruent with their language practices. Instead, several factors influenced decisions about language maintenance in autism, including the severity of the child’s autism, advice received, and the importance of English as the dominant societal language. This article calls for greater support for families in making language decisions that are suitable for the individual child and their family.

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11. Li X, Wang L, Qin B, Zhang Y, Zhou Z, Qin Y, Bao G, Huang J, Cai J. A Sleeping rs-fMRI Study of Preschool Children with Autism Spectrum Disorders. Current medical imaging. 2020.

OBJECTIVES : The brain functional network of autism spectrum disorders (ASDs) in the earlier stages of life has been almost unknown due to difficulties in obtaining a resting-state functional magnetic resonance imaging (rs-fMRI). This study aimed to perform rs-MRI under a sedated sleep state and reveal possible alterations in the brain functional network. METHODS : Rs-fMRI was performed in a group of preschool children (aged 2-6 years, 53 with ASD, 63 as controls) under a sedated sleeping state. Based on graph theoretical analysis, global and local topological metrics were calculated to investigate alterations in brain functional networks. In addition, correlation analyses were conducted between the abnormal attribute values and Childhood Autism Rating Scale (CARS) scores. RESULTS : The graph theoretical analysis showed that the nodal degree of the right medial frontal gyrus and the nodal efficiency of the right lingual gyrus in the ASD group were higher than those in the control group (P<0.05). There was a statistically significant positive correlation (R=0.318, P<0.05) between the right midfrontal gyrus nodal degree values and CARS scores in the ASD patients. CONCLUSION : Alterations of some nodal attributes in the brain network has occurred in preschool autistic children and could serve as potential imaging biomarkers for evaluating ASD in earlier stages.

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12. Renard E, Leheup B, Gueant-Rodriguez RM, Oussalah A, Quadros EV, Gueant JL. Folinic acid improves the score of Autism in the EFFET placebo-controlled randomized trial. Biochimie. 2020.

Autism spectrum disorders (ASD) are influenced by interacting maternal and environmental risk factors. High-dose folinic acid has shown improvement in verbal communication in ASD children. The EFFET randomized placebo-controlled trial (NCT02551380) aimed to evaluate the efficacy of folinic acid (FOLINORAL(R)) at a lower dose of 5mg twice daily. Nineteen children were included in the EFFET trial. The primary efficacy outcome was improvement of Autism Diagnostic Observation Schedule (ADOS) score. The secondary outcomes were the improvement in ADOS sub scores communication, social interactions, Social Responsiveness Score (SRS) and treatment safety. The global ADOS score and social interaction and communication sub scores were significantly improved at week 12 compared to baseline in the folinic acid group (P=0.003, P=0.004 and P=0.022, respectively), but not in the placebo group (P=0.574, P=0.780, P=0.269, respectively). We observed a greater change of ADOS global score (-2.78 vs. -0.4 points) and (-1.78 vs. 0.20 points) in the folinic acid group, compared to the placebo group. No serious adverse events were observed. This pilot study showed significant efficacy of folinic acid with an oral formulation that is readily available. It opens a perspective of therapeutic intervention with folinic acid but needs to be confirmed by a multi-center trial on a larger number of children.

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13. Ribeiro MC, Moore SM, Kishi N, Macklis JD, MacDonald JL. Vitamin D supplementation rescues aberrant NF-kappaB pathway activation and partially ameliorates Rett syndrome phenotypes in Mecp2 mutant mice. eNeuro. 2020.

Rett syndrome (RTT) is a severe, progressive X-linked neurodevelopmental disorder caused by mutations in the transcriptional regulator MECP2 We previously identified aberrant NF-kappaB pathway up-regulation in brains of Mecp2-null mice and demonstrated that genetically attenuating NF-kappaB rescues some characteristic neuronal RTT phenotypes. These results raised the intriguing question of whether NF-kappaB pathway inhibitors might provide a therapeutic avenue in RTT. Here, we investigate whether the known NF-kappaB pathway inhibitor vitamin D ameliorates neuronal phenotypes in Mecp2-mutant mice. Vitamin D deficiency is prevalent among RTT patients, and we find that Mecp2-null mice similarly have significantly reduced 25(OH)D serum levels compared to wildtype littermates. We identify that vitamin D rescues aberrant NF-kappaB pathway activation and reduced neurite outgrowth of Mecp2 knockdown cortical neurons in vitro Further, dietary supplementation with vitamin D in early symptomatic male Mecp2 hemizygous null and female Mecp2 heterozygous mice ameliorates reduced neocortical dendritic morphology and soma size phenotypes, and modestly improves reduced lifespan of Mecp2-nulls. These results elucidate fundamental neurobiology of RTT and provide foundation that NF-kappaB pathway inhibition might be a therapeutic target for RTT.Significance Statement There is currently no effective treatment for Rett syndrome (RTT) ; however, selectively re-expressing Mecp2 in adult mice has shown that RTT symptoms can be partially reversed, suggesting that restoration of homeostasis of downstream targets of MeCP2 could also reverse or alleviate RTT symptoms. One such potential target is the NF-kappaB pathway, which is aberrantly up-regulated in the brain of Mecp2-mutant mice. Genetically reducing NF-kappaB signaling in these mice improves neuronal phenotypes. Here, we identify that the known NF-kappaB inhibitor vitamin D reduces the aberrant NF-kappaB signaling in Mecp2 knockdown neurons, and partially ameliorates neuronal size and complexity phenotypes in both male and female Mecp2-mutant mice. Thus, this simple, cost-effective dietary supplement could contribute toward a partial therapeutic avenue in RTT.

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14. Rivera P, Renziehausen J, Garcia JM. Effects of an 8-Week Judo Program on Behaviors in Children with Autism Spectrum Disorder : A Mixed-Methods Approach. Child Psychiatry Hum Dev. 2020.

Prior studies suggest that a combination of physical activity and mind-body exercises, often seen in martial arts, may attenuate negative behaviors in youth with Autism Spectrum Disorder (ASD). Therefore, the aim of this study was to examine the effects of an 8-week judo program on behavioral factors in children with ASD, using a mixed-methods approach. A total of 25 children (ages 8-17), diagnosed with ASD, participated in an 8-week judo program (1 x week). Parents of participants were given the Aberrant Behavior Checklist (ABC) to compare the severity of ASD-related behavior at baseline and at the end of the program. A subset of parents (n = 9) participated in semi-structured interviews that focused on their child’s behaviors during the judo program. Non-parametric paired t-tests were conducted to compare differences in the ABC scores from at baseline and at the end of the program. Interviews were coded independently by two trained researchers and categorized into behavioral themes. Participants attended an average of 7.04 +/- 1.06 classes (out of 8 sessions). There were no significant changes in ABC scores, however, parent interviews revealed that 78% of parents observed improvements in both social skills and self-esteem as a result of the judo program. Despite no significant differences in ABC scores pre and post-judo, data from parent interviews indicate improvements in self-esteem and social skills. Future studies should further examine the effects of judo in a larger sample of youth with ASD, and include control conditions (e.g. no-exercise group) for comparison purposes.

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15. Shalev M, Hetzroni OE. Factors predicting school staff’s responsivity toward students with intellectual and developmental disability and complex communication needs. Res Dev Disabil. 2020 ; 102 : 103677.

BACKGROUND : Children with significant intellectual and developmental disabilities (IDD) are characterized by substantial language delays. Responsivity, the quantity and quality of the communication partner’s responses to child’s behaviors, is a key component in communication development. AIMS : The aim of the study was to map multidimensional factors predicting school staff’s responsivity toward communication of students with IDD with complex communication needs. METHOD : Interactions between 120 school staff members and 43 students ages 9-16, were videotaped, during group and individual routine sessions in school. Staff’s behaviors were transcribed and coded to form responsivity scores. Statistical tests were performed to map variables predicting staff’s responsivity. RESULTS : Analysis revealed the type of session (individual/group) as a main predictor of responsivity. Separate analysis of individual and group sessions revealed that while in the individual session students’ speech level was the main predictor for responsivity, in group sessions, group size, number of sessions per week, staff’s attitudes and students’ disability level were among the variables predicting responsivity. CONCLUSIONS : Results emphasize group setting as more complex where multidimensional factors influence the communication process, whereas students’ speech ability is important in promoting staff’s responsivity in individual sessions. Implications for designing conditions to promote responsivity are discussed.

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16. Vidal V, McAllister A, DeThorne L. Communication Profile of a Minimally Verbal School-Age Autistic Child : A Case Study. Language, speech, and hearing services in schools. 2020 : 1-16.

Purpose The present clinical focus draws on an intrinsic case study to provide a thick description of the communication profile of John, a 9-year-old minimally verbal autistic student. Method Specifically, traditional behavioral assessments, classroom video observations, and semistructured interviews were used to gather information regarding John’s communication profile and potential sensory-motor differences. Results Convergent evidence indicated that John’s expressive profile was characterized by single words, emergent word combinations, some conventional gestures, and a low frequency of communicative initiations. Concomitant language comprehension challenges and poor intelligibility associated with motor speech impairment were also indicated. His sensory-motor profile was marked by fine motor impairment, relative strengths in gross motor abilities, and sensory differences across visual, hearing, and tactile modalities. Conclusion Direct implications for supporting minimally verbal autistic students like John include the need to (a) consider sensory-motor influences on social interaction and (b) support flexible use of multimodal communication resources, including augmentative and alternative communication. Supplemental Material

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17. Wong NML, Findon JL, Wichers RH, Giampietro V, Stoencheva V, Murphy CM, Blainey S, Ecker C, Murphy DG, McAlonan GM, Daly E. Serotonin differentially modulates the temporal dynamics of the limbic response to facial emotions in male adults with and without autism spectrum disorder (ASD) : a randomised placebo-controlled single-dose crossover trial. Neuropsychopharmacology. 2020.

Emotion processing-including signals from facial expressions-is often altered in individuals with autism spectrum disorder (ASD). The biological basis of this is poorly understood but may include neurochemically mediated differences in the responsivity of key ’limbic’ regions (including amygdala, ventromedial prefrontal cortex (vmPFC) and nucleus accumbens (NAc)). Emerging evidence also suggests that ASD may be a disorder of brain temporal dynamics. Moreover, serotonin (5-HT) has been shown to be a key regulator of both facial-emotion processing and brain dynamics, and 5-HT abnormalities have been consistently implicated in ASD. To date, however, no one has examined how 5-HT influences the dynamics of facial-emotion processing in ASD. Therefore, we compared the influence of 5-HT on the responsivity of brain dynamics during facial-emotion processing in individuals with and without ASD. Participants completed a facial-emotion processing fMRI task at least 8 days apart using a randomised double-blind crossover design. At each visit they received either a single 20-mg oral dose of the selective serotonin reuptake inhibitor (SSRI) citalopram or placebo. We found that citalopram (which increases levels of 5-HT) caused sustained activation in key limbic regions during processing of negative facial emotions in adults with ASD-but not in neurotypical adults. The neurotypical adults’ limbic response reverted more rapidly to baseline following a 5-HT-challenge. Our results suggest that serotonergic homoeostatic control of the temporal dynamics in limbic regions is altered in adults with ASD, and provide a fresh perspective on the biology of ASD.

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18. Zhou MS, Nasir M, Farhat LC, Kook M, Artukoglu BB, Bloch MH. Meta-analysis : Pharmacologic Treatment of Restricted and Repetitive Behaviors in Autism Spectrum Disorders. J Am Acad Child Adolesc Psychiatry. 2020.

OBJECTIVE : To examine the efficacy of pharmacological treatments for restricted and repetitive behaviors (RRBs) in autism spectrum disorder (ASD). METHOD : We searched PubMed, Embase, and CENTRAL to identify all double-blind, randomized, placebo-controlled trials that examined the efficacy of pharmacological agents in the treatment of autism spectrum disorders and measured restricted and repetitive behaviors as an outcome. Our primary outcome was standardized mean difference in rating scales of RRBs. RESULTS : We identified 64 randomized, placebo-controlled trials involving 3,499 participants with ASD. Antipsychotics significantly improved RRB outcomes compared to placebo [standardized mean difference (SMD)=0.28 (95% Confidence Interval (CI) : 0.08-0.49), z=2.77, p=0.01] demonstrating a small effect size. Larger significant positive effects on RRBs in ASD were seen in individual studies with fluvoxamine, buspirone, bumetanide, divalproex, guanfacine, and folinic acid that have not been replicated. Other frequently studied pharmacological treatments in ASD including oxytocin, omega-3 fatty acids, selective serotonin reuptake inhibitors (SSRI) and methylphenidate did not demonstrate significant benefit in reducing RRB compared to placebo [oxytocin : SMD=0.23 (95% CI : -0.01-0.47), z=1.85, p= 0.06 ; omega-3 fatty acids : SMD = 0.19 (95% CI : -0.05-0.43), z= 1.54, p = 0.12 ; SSRI : SMD=0.09 (95% CI : -0.21-0.39), z=0.60, p=0.56 ; methylphenidate : SMD=0.18 (95% CI : -0.11-0.46), z=1.23, p=0.22]. CONCLUSION : The results of the present meta-analysis suggest that currently available pharmacological agents have at best only a modest benefit for the treatment of RRBs in ASD with the most evidence supporting antipsychotic medications. Additional RCTs with standardized study designs and consistent and specific assessment tools for RRBs, are needed to further understand how we can best help ameliorate these behaviors in individuals with ASD.

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