1. Ambrose K, Simpson K, Adams D. The relationship between social and academic outcomes and anxiety for children and adolescents on the autism spectrum: A systematic review. Clinical psychology review. 2021; 90: 102086.

Anxiety is the most common co-occurring condition in children on the autism spectrum but the potential impacts of anxiety on social and academic outcomes of children on the autism spectrum have not been systematically examined. In this review, 50 studies were identified that explore the relationship between anxiety and scores on social or academic measures in children on the autism spectrum. Social competence was frequently measured, and the findings of these studies were mixed. While other social constructs have received little attention, associations were found between anxiety and victimisation, and anxiety and social relationships. Only three studies focused on the impact of anxiety on scores on academic measures, highlighting the need for further research in this area. Anxiety was most frequently measured using subscales from broader behavioural instruments, which may not capture the range of anxiety symptoms of children on the autism spectrum. Future studies that include multi-informant methodologies and proportional representation of females and children with intellectual disability will further knowledge of the impact of anxiety in children on the spectrum.

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2. Ban Y, Yu T, Wang J, Wang X, Liu C, Baker C, Zou Y. Mutation of the murine Prickle1 (R104Q) causes phenotypes analogous to human symptoms of epilepsy and autism. Experimental neurology. 2022; 347: 113880.

Epilepsy and autism spectrum disorders (ASD) frequently show comorbidity, suggesting shared or overlapping neurobiological basis underlying these conditions. R104Q is the first mutation in the PRICKLE 1(PK1) gene that was discovered in human patients with progressive myoclonus epilepsy (PME). Subsequently, a number of mutations in the PK1 gene were shown to be associated with either epilepsy, autism, or both, as well as other developmental disorders. Using CRISPR-Cas9-mediated gene editing, we generated a PK1(R104Q) mouse line. The mutant mice showed reduced density of excitatory synapses in hippocampus and impaired interaction between PK1 and the repressor element 1(RE-1) silencing transcription factor (REST). They also displayed reduced seizure threshold, impaired social interaction, and cognitive functions. Taken together, the PK1(R104Q) mice display characteristic behavioral features similar to the key symptoms of epilepsy and ASD, providing a useful model for studying the molecular and neural circuit mechanisms underlying the comorbidity of epilepsy and ASD.

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3. Beker S, Foxe JJ, Venticinque J, Bates J, Ridgeway EM, Schaaf RC, Molholm S. Looking for consistency in an uncertain world: test-retest reliability of neurophysiological and behavioral readouts in autism. Journal of neurodevelopmental disorders. 2021; 13(1): 43.

BACKGROUND: Autism spectrum disorders (ASD) are associated with altered sensory processing and perception. Scalp recordings of electrical brain activity time-locked to sensory events (event-related potentials; ERPs) provide precise information on the time-course of related altered neural activity, and can be used to model the cortical loci of the underlying neural networks. Establishing the test-retest reliability of these sensory brain responses in ASD is critical to their use as biomarkers of neural dysfunction in this population. METHODS: EEG and behavioral data were acquired from 33 children diagnosed with ASD aged 6-9.4 years old, while they performed a child-friendly task at two different time-points, separated by an average of 5.2 months. In two blocked conditions, participants responded to the occurrence of an auditory target that was either preceded or not by repeating visual stimuli. Intraclass correlation coefficients (ICCs) were used to assess test-retest reliability of measures of sensory (auditory and visual) ERPs and performance, for the two experimental conditions. To assess the degree of reliability of the variability of responses within individuals, this analysis was performed on the variance of the measurements, in addition to their means. This yielded a total of 24 measures for which ICCs were calculated. RESULTS: The data yielded significant good ICC values for 10 of the 24 measurements. These spanned across behavioral and ERPs data, experimental conditions, and mean as well as variance measures. Measures of the visual evoked responses accounted for a disproportionately large number of the significant ICCs; follow-up analyses suggested that the contribution of a greater number of trials to the visual compared to the auditory ERP partially accounted for this. CONCLUSIONS: This analysis reveals that sensory ERPs and related behavior can be highly reliable across multiple measurement time-points in ASD. The data further suggest that the inter-trial and inter-participant variability reported in the ASD literature likely represents replicable individual participant neural processing differences. The stability of these neuronal readouts supports their use as biomarkers in clinical and translational studies on ASD. Given the minimum interval between test/retest sessions across our cohort, we also conclude that for the tested age-range of ~ 6 to 9.4 years, these reliability measures are valid for at least a 3-month interval. Limitations related to EEG task demands and study length in the context of a clinical trial are considered.

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4. Deb S, Roy M, Lee R, Majid M, Limbu B, Santambrogio J, Roy A, Bertelli MO. Randomised controlled trials of antidepressant and anti-anxiety medications for people with autism spectrum disorder: systematic review and meta-analysis. BJPsych open. 2021; 7(6): e179.

BACKGROUND: Although widely used, the current evidence for the efficacy of antidepressant and anti-anxiety medications for people with autism spectrum disorder (ASD) is limited and conflicting. AIMS: We carried out a systematic review and meta-analysis of randomised controlled trials that assessed the effectiveness of these medications in people with ASD. METHOD: We searched the following databases: Cochrane Library, Medline, EMBASE, CINAHL, PsycINFO, ERIC, DARE and ClinicalTrials.gov. Additionally, we hand-searched 11 relevant journals. We used the Cochrane risk-of-bias tool and Jadad score to assess the quality of each included study. We carried out a meta-analysis using a random effects model. RESULTS: We included 15 randomised controlled trials (13 on antidepressants and two on anti-anxiety medications) for a total of 958 people with ASD. Data showed contradictory findings among the studies, with larger studies mostly showing a non-significant difference in outcomes between the treatment and the placebo groups. Meta-analysis of pooled Yale-Brown Obsessive Compulsive Scale and Clinical Global Impression Scale data from nine studies (60%) did not show any statistically significant inter-group difference on either of the outcome measures. The adverse effects reported were mild and, in most studies, their rates did not show any significant inter-group difference. CONCLUSIONS: Given the methodological flaws in the most included studies and contradictory findings, it is difficult to draw any definitive conclusion about the effectiveness of either antidepressant or anti-anxiety medications to treat either ASD core symptoms or associated behaviours. Robust, large-scale, randomised controlled trials are needed to address this issue.

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5. Dollion N, Toutain M, François N, Champagne N, Plusquellec P, Grandgeorge M. Visual Exploration and Observation of Real-Life Interactions Between Children with ASD and Service Dogs. Journal of autism and developmental disorders. 2021; 51(11): 3785-805.

Two original studies explored relationships between visual attention of children with ASD (candidates for receiving a service dog) and their behaviors during their first interaction with a service dog. The first study consisted in video behavioural analyses of 16 children with ASD interacting with a service dog. During the interaction with a service dog, the time children with ASD spent looking towards social items vs objects was associated with how they interacted with the service dog. The second study was exploratory (i.e. 6 children), using the same behavioural approach but coupled with eye-tracking data. The more children with ASD looked at both their parent and the evaluator, as opposed to inanimate items, the more they interacted with the service dog.

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6. Escher J, Yan W, Rissman EF, Wang HV, Hernandez A, Corces VG. Beyond Genes: Germline Disruption in the Etiology of Autism Spectrum Disorders. Journal of autism and developmental disorders. 2021.

Investigations into the etiology of autism spectrum disorders have been largely confined to two realms: variations in DNA sequence and somatic developmental exposures. Here we suggest a third route-disruption of the germline epigenome induced by exogenous toxicants during a parent’s gamete development. Similar to cases of germline mutation, these molecular perturbations may produce dysregulated transcription of brain-related genes during fetal and early development, resulting in abnormal neurobehavioral phenotypes in offspring. Many types of exposures may have these impacts, and here we discuss examples of anesthetic gases, tobacco components, synthetic steroids, and valproic acid. Alterations in parental germline could help explain some unsolved phenomena of autism, including increased prevalence, missing heritability, skewed sex ratio, and heterogeneity of neurobiology and behavior.

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7. Fastman J, Foss-Feig J, Frank Y, Halpern D, Harony-Nicolas H, Layton C, Sandin S, Siper P, Tang L, Trelles P, Zweifach J, Buxbaum JD, Kolevzon A. A randomized controlled trial of intranasal oxytocin in Phelan-McDermid syndrome. Molecular autism. 2021; 12(1): 62.

BACKGROUND: Phelan-McDermid syndrome (PMS) is a rare neurodevelopmental disorder caused by haploinsufficiency of the SHANK3 gene and characterized by global developmental delays, deficits in speech and motor function, and autism spectrum disorder (ASD). Monogenic causes of ASD such as PMS are well suited to investigations with novel therapeutics, as interventions can be targeted based on established genetic etiology. While preclinical studies have demonstrated that the neuropeptide oxytocin can reverse electrophysiological, attentional, and social recognition memory deficits in Shank3-deficient rats, there have been no trials in individuals with PMS. The purpose of this study is to assess the efficacy and safety of intranasal oxytocin as a treatment for the core symptoms of ASD in a cohort of children with PMS. METHODS: Eighteen children aged 5-17 with PMS were enrolled. Participants were randomized to receive intranasal oxytocin or placebo (intranasal saline) and underwent treatment during a 12-week double-blind, parallel group phase, followed by a 12-week open-label extension phase during which all participants received oxytocin. Efficacy was assessed using the primary outcome of the Aberrant Behavior Checklist-Social Withdrawal (ABC-SW) subscale as well as a number of secondary outcome measures related to the core symptoms of ASD. Safety was monitored throughout the study period. RESULTS: There was no statistically significant improvement with oxytocin as compared to placebo on the ABC-SW (Mann-Whitney U = 50, p = 0.055), or on any secondary outcome measures, during either the double-blind or open-label phases. Oxytocin was generally well tolerated, and there were no serious adverse events. LIMITATIONS: The small sample size, potential challenges with drug administration, and expectancy bias due to relying on parent reported outcome measures may all contribute to limitations in interpreting results. CONCLUSION: Our results suggest that intranasal oxytocin is not efficacious in improving the core symptoms of ASD in children with PMS. Trial registration NCT02710084.

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8. Fernández M, Sánchez-León CA, Llorente J, Sierra-Arregui T, Knafo S, Márquez-Ruiz J, Peñagarikano O. Altered Cerebellar Response to Somatosensory Stimuli in the Cntnap2 Mouse Model of Autism. eNeuro. 2021; 8(5).

Atypical sensory processing is currently included within the diagnostic criteria of autism. The cerebellum is known to integrate sensory inputs of different modalities through its connectivity to the cerebral cortex. Interestingly, cerebellar malformations are among the most replicated features found in postmortem brain of individuals with autism. We studied sensory processing in the cerebellum in a mouse model of autism, knock-out (KO) for the Cntnap2 gene. Cntnap2 is widely expressed in Purkinje cells (PCs) and has been recently reported to regulate their morphology. Further, individuals with CNTNAP2 mutations display cerebellar malformations and CNTNAP2 antibodies are associated with a mild form of cerebellar ataxia. Previous studies in the Cntnap2 mouse model show an altered cerebellar sensory learning. However, a physiological analysis of cerebellar function has not been performed yet. We studied sensory evoked potentials in cerebellar Crus I/II region on electrical stimulation of the whisker pad in alert mice and found striking differences between wild-type and Cntnap2 KO mice. In addition, single-cell recordings identified alterations in both sensory-evoked and spontaneous firing patterns of PCs. These changes were accompanied by altered intrinsic properties and morphologic features of these neurons. Together, these results indicate that the Cntnap2 mouse model could provide novel insight into the pathophysiological mechanisms of autism core sensory deficits.

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9. Galigani M, Fossataro C, Gindri P, Conson M, Garbarini F. Monochannel Preference in Autism Spectrum Conditions Revealed by a Non-Visual Variant of Rubber Hand Illusion. Journal of autism and developmental disorders. 2021.

Individuals with autism spectrum conditions (ASC) are less susceptible to multisensory delusions, such as rubber hand illusion (RHI). Here, we investigate whether a monochannel variant of RHI is more effective in inducing an illusory feeling of ownership in ASC. To this aim, we exploit a non-visual variant of the RHI that, excluding vision, leverages only on the somatosensory channel. While the visual-tactile RHI does not alter the perceived hand position in ASC individuals, the tacto-tactile RHI effectively modulates proprioception to a similar extent as that found in typical development individuals. These findings suggest a more effective integration of multiple inputs originating from the same sensory channel in ASC, revealing a monochannel preference in this population.

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10. Gassner L, Geretsegger M, Mayer-Ferbas J. Effectiveness of music therapy for autism spectrum disorder, dementia, depression, insomnia and schizophrenia: update of systematic reviews. European journal of public health. 2022; 32(1): 27-34.

BACKGROUND: Music therapy (MT) aims at maintaining, restoring and furthering physical/emotional/mental health. This review assesses effectiveness of MT and its methods for autism spectrum disorder (ASD), dementia, depression, insomnia and schizophrenia. METHODS: A search for systematic reviews and health technology assessment reports was conducted and yielded 139 hits. Given the large amount, we focused on five frequent diagnostic groups with available Cochrane reviews. A second search was conducted in four databases. Two authors independently performed study selection, data extraction and assessed methodological quality. Only trials with moderate/low risk of bias (RoB) were selected. RESULTS: Ten randomized controlled trials (1.248 participants) met inclusion criteria. For schizophrenia, no studies with low/moderate RoB were found; therefore, updating was not possible. The Cochrane authors stated that quality of life (QoL), social functioning, global/mental state improved for schizophrenia, but not global functioning. For ASD, MT improved behaviour, social communication, brain connectivity and parent-child relationship. For depression, mood was enhanced, and for insomnia, sleep quality, stress, anxiety, total sleep time, disease severity and psychological QoL improved. MT positively affected mood, neuropsychiatric behaviour, apathy, communication and physical functions for dementia; behavioural/psychological symptoms improved only in severe, and memory and verbal fluency only in mild Alzheimer’s disease. Cognition improved for dementia in one of four studies. Both active (playing music) and receptive (listening to music) methods were used for dementia, whereas for ASD and depression, active methods were applied. For insomnia, only receptive methods were used. CONCLUSION: These findings provide evidence that MT helps patients improving their physical/psychosocial health. More research investigating long-term effects is needed.

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11. Gwynette MF, Koth KA, Marrus N, Hellings JA, Lohr WD, Muhle RA, Vasa RA. Developing Freely Accessible Educational Videos to Enhance Knowledge of Autism Spectrum Disorder and Intellectual Disability. Journal of the American Academy of Child and Adolescent Psychiatry. 2022; 61(1): 1-2.

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12. Porceddu PF, Ciampoli M, Romeo E, Garrone B, Durando L, Milanese C, Di Giorgio FP, Reggiani A. The novel potent GSK3 inhibitor AF3581 reverts fragile X syndrome phenotype. Human molecular genetics. 2022; 31(6): 839-49.

Glycogen-synthase kinase 3 (GSK3) is a kinase mediating phosphorylation on serine and threonine amino acid residues of several target molecules. The enzyme is involved in the regulation of many cellular processes and aberrant activity of GSK3 has been linked to several disease conditions such as fragile X syndrome (FXS). Recent evidences demonstrating an increased activity of GSK3 in murine models of FXS, suggest that dysregulation/hyperactivation of the GSK3 path should contribute to FXS development. A likely possibility could be that in FXS there is a functional impairment of the upstream inhibitory input over GSK3 thus making overactive the kinase. Since GSK3 signaling is a central regulatory node for critical neurodevelopmental pathways, understanding the contribution of GSK3 dysregulation to FXS, may provide novel targets for therapeutic interventions for this disease. In this study we used AF3581, a potent GSK3 inhibitor that we recently discovered, in an in vivo FXS mouse model to elucidate the crucial role of GSK3 in specific behavioral patterns (locomotor activity, sensorimotor gating and social behavior) associated with this disease. All the behavioral alterations manifested by Fmr1 knockout mice were reverted after a chronic treatment with our GSK3 inhibitor, confirming the importance of this pathway as a therapeutic target.

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13. Quinde-Zlibut JM, Williams ZJ, Gerdes M, Mash LE, Heflin BH, Cascio C. Multifaceted empathy differences in children and adults with autism. Scientific reports. 2021; 11(1): 19503.

Although empathy impairments have been reported in autistic individuals, there is no clear consensus on how emotional valence influences this multidimensional process. In this study, we use the Multifaceted Empathy Test for juveniles (MET-J) to interrogate emotional and cognitive empathy in 184 participants (ages 8-59 years, 83 autistic) under the robust Bayesian inference framework. Group comparisons demonstrate previously unreported interaction effects between: (1) valence and autism diagnosis in predictions of emotional resonance, and (2) valence and age group in predictions of arousal to images portraying positive and negative facial expressions. These results extend previous studies using the MET by examining differential effects of emotional valence in a large sample of autistic children and adults with average or above-average intelligence. We report impaired cognitive empathy in autism, and subtle differences in emotional empathy characterized by less distinction between emotional resonance to positive vs. negative facial expressions in autism compared to neurotypicals. Reduced emotional differentiation between positive and negative affect in others could be a mechanism for diminished social reciprocity that poses a universal challenge for people with autism. These component- and valence- specific findings are of clinical relevance for the development and implementation of target-specific social interventions in autism.

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14. Silva GM, Souto JJS, Fernandes TP, Bolis I, Santos NA. Interventions with Serious Games and Entertainment Games in Autism Spectrum Disorder: A Systematic Review. Developmental neuropsychology. 2021; 46(7): 463-85.

The use of serious games and entertainment games was compared as adjuvant tools for intervention in Autism Spectrum Disorder (ASD). A comprehensive search was performed in the MEDLINE, PsycINFO, Scopus, and Web of Science databases. From 295 studies, 53 studies were selected and included in this review. Overall, studies showed improvement after intervention, regardless of the type of video games, mostly for social skills and behavior. However, these changes should be regarded with caution, as they are limited to the tests applied. Furthermore, neither the entertainment nor the serious approach had a therapeutic impact on emotional resilience, representing the current gap in the field. Thus, even considering the limitations, our study is important because it shows that both categories have strengths.

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15. Taylor JL. Transforming care for people with intellectual disabilities and autism in England. The lancet Psychiatry. 2021; 8(11): 942-4.

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16. Voillemont C, Imbault E, Schoenberger M, Di Patrizio P. Care and management of adults with autism spectrum disorder in family practice: difficulties experienced by general practitioners. Family practice. 2021.

BACKGROUND AND OBJECTIVES: Few studies exist regarding the management and support of adults with autism spectrum disorder (ASD) in family practice. Most of them concern the management of children. As a primary care professional however, the general practitioner (GP) has a role to play at every step of the autistic adult’s care pathway. With this study, we sought to identify GPs’ experienced difficulties in caring for and managing their adult patients with ASD. METHODS: We conducted a qualitative study of 11 French GPs caring for adults with ASD via semistructured interviews and a thematic content analysis. GPs were recruited from 5 counties of the Grand Est Region (Marne, Haute-Marne, Meurthe-et-Moselle, Meuse and Vosges). RESULTS: All of the GPs described difficulties with the diagnostic process and the lack of initial training. Most of the respondents expressed difficulties with medical consultations of patients presenting an intellectual disability (ID) and with the lack of communication between GPs and mental health specialists during the patient care process. More than half of the GPs described difficulties with referral pathways for diagnosis due to lengthy delays and patient reluctance to seek psychiatric care. More than half of the respondents also experienced difficulties with providing proper social care, and with responding to patient distress due to their healthcare experiences. CONCLUSION: Improving awareness and training about ASD in adults, as well as harmonizing the diagnostic process and referral pathways, might reduce GPs’ experienced difficulties in caring for this population. Autism spectrum disorder (ASD) is a heterogeneous and lifelong disorder, which impacts the communication and social abilities of the person, including sometimes behavioral challenges. Adults with ASD are consequently exposed to psychiatric complications such as anxiety, depression, and suicide. The general practitioners (GPs) are on the frontline providing care for these patients. However, several studies show that GPs lack confidence in their ability to provide the best care for adults with ASD. We interviewed 11 French GPs from five counties in order to identify their difficulties managing adult patients with ASD. We found that they were challenged mostly by diagnostic and referral processes, by their lack of training, and by the insufficiency of communication with mental health specialists. These results highlight the need to organize and coordinate effective training in ASD and to facilitate the care process. This work also underscores the need for more collaboration and coordination between general practice and psychiatry in regard to a disorder for which both medical fields are needed. Addressing these issues is an opportunity to improve health care experiences for both patients and GPs. eng.

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