1. Boo C, Alpers-Leon N, McIntyre N, Mundy P, Naigles L. Conversation During a Virtual Reality Task Reveals New Structural Language Profiles of Children with ASD, ADHD, and Comorbid Symptoms of Both. Journal of autism and developmental disorders. 2021.

Many studies have utilized standardized measures and storybook narratives to characterize language profiles of children with Autism Spectrum Disorder (ASD) and Attention Deficit/Hyperactivity Disorder (ADHD). They report that structural language of these children is on par with mental-age-matched typically developing (TD) peers. Few studies have looked at structural language profiles in conversational contexts. This study examines conversational speech produced in a virtual reality (VR) paradigm to investigate the strengths and weaknesses of structural language abilities of these children. The VR paradigm introduced varying social and cognitive demands across phases. Our results indicate that children from these diagnostic groups produced less complex structural language than TD children. Moreover, language complexity decreased in all groups across phases, suggesting a cross-etiology sensitivity to conversational contexts.

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2. Booker SA, Kind PC. Mechanisms regulating input-output function and plasticity of neurons in the absence of FMRP. Brain research bulletin. 2021; 175: 69-80.

The function of brain circuits relies on high-fidelity information transfer within neurons. Synaptic inputs arrive primarily at dendrites, where they undergo integration and summation throughout the somatodendritic domain, ultimately leading to the generation of precise patterns of action potentials. Emerging evidence suggests that the ability of neurons to transfer synaptic information and modulate their output is impaired in a number of neurodevelopmental disorders including Fragile X Syndrome. In this review we summarise recent findings that have revealed the pathophysiological and plasticity mechanisms that alter the ability of neurons in sensory and limbic circuits to reliably code information in the absence of FMRP. We examine which aspects of this transform may result directly from the loss of FMRP and those that a result from compensatory or homeostatic alterations to neuronal function. Dissection of the mechanisms leading to altered input-output function of neurons in the absence of FMRP and their effects on regulating neuronal plasticity throughout development could have important implications for potential therapies for Fragile X Syndrome, including directing the timing and duration of different treatment options.

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3. Corbera S, Wexler BE, Bell MD, Pearlson G, Mayer S, Pittman B, Belamkar V, Assaf M. Predictors of social functioning and quality of life in schizophrenia and autism spectrum disorder. Psychiatry research. 2021; 303: 114087.

Schizophrenia (SZ) and Autism Spectrum Disorder (ASD) show overlap in social cognitive and functioning impairments. Proposed predictors of social functioning (SF) and quality of life (QL) have been symptom severity, IQ and social cognition. Empathy has rarely been compared between ASD and SZ and its predictive power on functional outcomes is unclear. We investigated general, affective, and cognitive empathy in 46 SZ, 30 ASD and 51 healthy controls (HC) and examined their relationship to SF and QL in addition to IQ and symptoms. SZ and ASD shared deficits in general and cognitive empathy, and personal distress, but only SZ showed deficits in affective empathy. Both groups showed lower performance-based empathy scores and only ASD showed slower responses compared to HC. Negative symptoms predicted QL in both groups, the more negative symptoms the worse QL (ASD t=-3.22; SZ t= -3.43; p<0.01), and only in ASD, IQ predicted QL, the higher the IQ the higher QL (t = 2.1; p<0.05). In ASD only, negative symptoms predicted SF, the greater negative symptoms the worse SF (t=-3.45; p<0.01), and communication deficits predicted SF, the higher deficits, the higher SF (t = 2.9; p<0.01). Negative symptoms but not empathy were the shared predictors of functioning across ASD and SZ.

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4. Frith U. When diagnosis hampers research. Autism research : official journal of the International Society for Autism Research. 2021; 14(10): 2235-6.

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5. Hayes J, Ford T, McCabe R, Russell G. Autism diagnosis as a social process. Autism : the international journal of research and practice. 2022; 26(2): 488-98.

When a child or adult is referred for an autism diagnosis, clinicians from different backgrounds work together to make a diagnostic decision. A few studies have asked clinicians in interview how they feel about diagnosis and what the challenges are. We interviewed clinicians in child and adult assessment services in England, and from different professional backgrounds, about the challenges of autism diagnosis and the factors that might influence the assessment process. We found that there were a number of challenges in autism diagnosis, especially when someone coming for diagnosis was considered to be near the diagnostic threshold. Clinicians told us that making a diagnosis was like creating a ‘narrative’: looking at many different factors that told a story about a person, rather than just looking at the results of diagnostic tests. Clinicians do not always agree with the results of those tests and have to use their specialist clinical judgement to make decisions. Clinicians were concerned about the amount of time people have to wait for an autism assessment, and the resulting pressure on the assessment process. The findings of this work can help us to understand how diagnosis happens and consider ways in which it can be improved for adults, children and families coming for assessment, as well as clinicians.

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6. Kamita MK, Silva LAF, Magliaro FCL, Fernandes FD, Matas CG. Auditory Event Related Potentials in children with autism spectrum disorder. International journal of pediatric otorhinolaryngology. 2021; 148: 110826.

OBJECTIVE: To analyze auditory cortical processing in high functioning ASD individuals. METHODS: Thirty individuals were included in the study (15 with Autism Spectrum Disorder and 15 with typical development), and their Auditory Event Related Potentials evaluation, elicited with tone burst and speech stimuli, were analyzed. RESULTS: There were no significant differences between individuals with high-functioning Autism Spectrum Disorder without intellectual disability and those with typical development in the auditory Event-related Potentials elicited with tone bursts or speech stimuli. CONCLUSIONS: The results of Auditory Event Related Potentials did not show any change at the cortical level in individuals with Autism Spectrum Disorder.

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7. Lamônica DAC, Giacheti CM, Dias Hayssi Haduo M, Dias Dos Santos MJ, da Silva NC, Pinato L. Sleep quality, functional skills, and communication in preschool-aged children with autism spectrum disorder. Research in developmental disabilities. 2021; 116: 104024.

AIM: This study aimed to correlate sleep quality, the performance of functional skills (mobility, self-care, and social function), communication, independence, and severity of ASD in children with ASD. METHOD: 58 children between 3 and 5 years and 11 months old were investigated. The Childhood Autism Rating Scale was applied to determine the severity of autism; the Sleep Disturbance Scale for Children was used to investigate sleep quality, and the Pediatric Evaluation of Disability Inventory to investigate functional abilities and independence of the children. RESULTS: 68.9 % of the children showed indicative of sleep disorders. There was no correlation between the different sleep disorders and communication. Sleep disorders showed a negative correlation with functional performance and a positive correlation with ASD severity. INTERPRETATION: The current study offers an exploration between sleep and functional skills in children with ASD. These findings provide important clinical implications in the diagnosis and intervention process of children with ASD and also stimulate reflections on the importance in minimize the impact of sleep disorders and functional abilities on the quality of life of these individuals and their families.

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8. Livingston LA, Shah P, White SJ, Happé F. Further developing the Frith-Happé animations: A quicker, more objective, and web-based test of theory of mind for autistic and neurotypical adults. Autism research : official journal of the International Society for Autism Research. 2021; 14(9): 1905-12.

The Frith-Happé Animations Test, depicting interactions between triangles, is widely used to measure theory of mind (ToM) ability in autism spectrum disorder (ASD). This test began with recording, transcribing, and subjectively scoring participants’ verbal descriptions, which consistently found ToM-specific difficulties in ASD. More recently in 2011, White et al. created a more objective version of this ToM test using multiple-choice questions. However, there has been surprisingly little uptake of this test, hence it is currently unclear if White et al.’s findings replicate. Further, the lack of an online version of the test may be hampering its use in large-scale studies and outside of research settings. Addressing these issues, we report the development of a web-based version of the Frith-Happé Animations Test for autistic and neurotypical adults. An online version of the test was developed in a large general population sample (study 1; N = 285) and online data were compared with those collected in a lab-based setting (study 2; N = 339). The new online test was then administered to adults with a clinical diagnosis of ASD and matched neurotypical controls (study 3; N = 231). Results demonstrated that the test could successfully be administered online to autistic adults, who showed ToM difficulties compared to neurotypical adults, replicating White et al.’s findings. Overall, we have developed a quicker, more objective, and web-based version of the Frith-Happé Animations Test that will be useful for social cognition research within and beyond the field of autism, with potential utility for clinical settings. LAY SUMMARY: Many autistic people find it hard to understand what other people are thinking. There are many tests for this ‘mentalising’ ability, but they often take a long time to complete and cannot be used outside of research settings. In 2011, scientists used short silent animations of moving shapes to create a fast way to measure mentalising ability. We developed this into an online test to use in research and clinics to measure mentalising ability in autism.

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9. Marwick H, Jarvie K, Cowie H, Johnston L, Hammond-Evans N, Cockayne R. Developing Pretend Play in Autistic Children Using the Playboxes Joint Play Approach as Part of Ongoing Practice. Journal of autism and developmental disorders. 2021.

A repeated measures single subject design was used to examine the effectiveness of a joint play approach embedded in professional practice, in supporting pretend play for autistic children. Seven autistic children, aged 5-8 years, with a placement within a specialist educational provision, and who demonstrated restricted play, participated in weekly sessions using the Playboxes approach over a period of 3 months. Pre- and post-approach pretend play abilities were assessed using the Symbolic Play Test and the Test of Pretend Play. Every child gained increased age-equivalent scores on the Test of Pretend Play, ranging from + 8 to + 30 months. Pretend Play abilities can support developmental outcomes and incorporation of this approach into regular practice could be of value for autistic children.

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10. Norris JE, Maras K. Supporting autistic adults’ episodic memory recall in interviews: The role of executive functions, theory of mind, and language abilities. Autism : the international journal of research and practice. 2022; 26(2): 513-24.

Autistic people have difficulties recalling episodic memories (memories of specific events) compared to typically developing people. However, being able to effectively recall such memories is important in many real-world situations, for example, in police interviews, during medical consultations, and in employment interviews. Autistic people’s episodic memory difficulties are most noticeable when they are responding to open, unsupportive questions. However, the ‘Task Support Hypothesis’ indicates that autistic people are able to recall as much information as typically developing people, as long as they are asked more supportive questions. Autistic people also experience difficulties with executive functioning (cognitive abilities which allow us to plan, hold information in mind, inhibit interruptions, etc.), theory of mind (the ability to understand others’ perspectives and intentions), and spoken language. The current study aimed to investigate the impact of these cognitive abilities on memory recall in two previous studies which compared autistic and typically developing adults on how specific their recall was in police, healthcare, and employment interviews, and the quality of responses during an employment interview when both unsupportive and supportive questioning was used. The results show that while typically developing people may rely on theory of mind abilities, autistic people may rely more on language abilities when performing in interviews, potentially to compensate for their episodic memory difficulties, and that this effect is most apparent during more unsupportive recall (e.g. when a brief, open question is asked) compared to when open questions are followed by prompts (e.g. ‘tell me about who as there’, ‘what happened?’, etc.).

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11. Sacchi C, O’Muircheartaigh J, Batalle D, Counsell SJ, Simonelli A, Cesano M, Falconer S, Chew A, Kennea N, Nongena P, Rutherford MA, Edwards AD, Nosarti C. Neurodevelopmental Outcomes following Intrauterine Growth Restriction and Very Preterm Birth. The Journal of pediatrics. 2021; 238: 135-44.e10.

OBJECTIVES: To evaluate whether intrauterine growth restriction (IUGR) adds further neurodevelopmental risk to that posed by very preterm birth alone in terms of alterations in brain growth and poorer toddlerhood outcomes. STUDY DESIGN: Participants were 314 infants of very preterm birth enrolled in the Evaluation of Preterm Imaging Study (e-Prime) who were subsequently followed up in toddlerhood. IUGR was identified postnatally from discharge records (n = 49) and defined according to prenatal evaluation of growth restriction confirmed by birth weight <10th percentile for gestational age and/or alterations in fetal Doppler. Appropriate for gestational age (AGA; n = 265) was defined as birth weight >10th percentile for gestational age at delivery. Infants underwent magnetic resonance imaging at term-equivalent age (median = 42 weeks); T2-weighted images were obtained for voxelwise gray matter volumes. Follow-up assessments were conducted at corrected median age of 22 months using the Bayley Scales of Infant and Toddler Development III and the Modified-Checklist for Autism in Toddlers. RESULTS: Infants of very preterm birth with IUGR displayed a relative volumetric decrease in gray matter in limbic regions and a relative increase in frontoinsular, temporal-parietal, and frontal areas compared with peers of very preterm birth who were AGA. At follow-up, toddlers born very preterm with IUGR had significantly lower cognitive (effect size = 0.42) and motor (effect size = 0.41) scores and were more likely to have a positive Modified-Checklist for Autism in Toddlers screening for autism (OR = 2.12) compared with peers of very preterm birth who were AGA. CONCLUSIONS: IUGR might confer a neurodevelopmental risk that is greater than that posed by very preterm alone, in terms of both alterations in brain growth and poorer toddlerhood outcomes.

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12. Taylor SC, Steeman S, Gehringer BN, Dow HC, Langer A, Rawot E, Perez L, Goodman M, Smernoff Z, Grewal M, Eshraghi O, Pallathra AA, Oksas C, Mendez M, Gur RC, Rader DJ, Bucan M, Almasy L, Brodkin ES. Heritability of quantitative autism spectrum traits in adults: A family-based study. Autism research : official journal of the International Society for Autism Research. 2021; 14(8): 1543-53.

Autism spectrum disorder (ASD) comprises a multi-dimensional set of quantitative behavioral traits expressed along a continuum in autistic and neurotypical individuals. ASD diagnosis-a dichotomous trait-is known to be highly heritable and has been used as the phenotype for most ASD genetic studies. But less is known about the heritability of autism spectrum quantitative traits, especially in adults, an important prerequisite for gene discovery. We sought to measure the heritability of many autism-relevant quantitative traits in adults high in autism spectrum traits and their extended family members. Among adults high in autism spectrum traits (n = 158) and their extended family members (n = 245), we calculated univariate and bivariate heritability estimates for 19 autism spectrum traits across several behavioral domains. We found nearly all tested autism spectrum quantitative traits to be significantly heritable (h(2) = 0.24-0.79), including overall ASD traits, restricted repetitive behaviors, broader autism phenotype traits, social anxiety, and executive functioning. The degree of shared heritability varied based on method and specificity of the assessment measure. We found high shared heritability for the self-report measures and for most of the informant-report measures, with little shared heritability among performance-based cognition tasks. These findings suggest that many autism spectrum quantitative traits would be good, feasible candidates for future genetics studies, allowing for an increase in the power of autism gene discovery. Our findings suggest that the degree of shared heritability between traits depends on the assessment method (self-report vs. informant-report vs. performance-based tasks), as well as trait-specificity. LAY SUMMARY: We found that the scores from questionnaires and tasks measuring different types of behaviors and abilities related to autism spectrum disorder (ASD) were heritable (strongly influenced by gene variants passed down through a family) among autistic adults and their family members. These findings mean that these scores can be used in future studies interested in identifying specific genes and gene variants that are associated with different behaviors and abilities related with ASD.

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13. Zhang Y, Tachtsidis G, Schob C, Koko M, Hedrich UBS, Lerche H, Lemke JR, van Haeringen A, Ruivenkamp C, Prescott T, Tveten K, Gerstner T, Pruniski B, DiTroia S, VanNoy GE, Rehm HL, McLaughlin H, Bolz HJ, Zechner U, Bryant E, McDonough T, Kindler S, Bähring R. KCND2 variants associated with global developmental delay differentially impair Kv4.2 channel gating. Human molecular genetics. 2021; 30(23): 2300-14.

Here, we report on six unrelated individuals, all presenting with early-onset global developmental delay, associated with impaired motor, speech and cognitive development, partly with developmental epileptic encephalopathy and physical dysmorphisms. All individuals carry heterozygous missense variants of KCND2, which encodes the voltage-gated potassium (Kv) channel α-subunit Kv4.2. The amino acid substitutions associated with the variants, p.(Glu323Lys) (E323K), p.(Pro403Ala) (P403A), p.(Val404Leu) (V404L) and p.(Val404Met) (V404M), affect sites known to be critical for channel gating. To unravel their likely pathogenicity, recombinant mutant channels were studied in the absence and presence of auxiliary β-subunits under two-electrode voltage clamp in Xenopus oocytes. All channel mutants exhibited slowed and incomplete macroscopic inactivation, and the P403A variant in addition slowed activation. Co-expression of KChIP2 or DPP6 augmented the functional expression of both wild-type and mutant channels; however, the auxiliary β-subunit-mediated gating modifications differed from wild type and among mutants. To simulate the putative setting in the affected individuals, heteromeric Kv4.2 channels (wild type + mutant) were studied as ternary complexes (containing both KChIP2 and DPP6). In the heteromeric ternary configuration, the E323K variant exhibited only marginal functional alterations compared to homomeric wild-type ternary, compatible with mild loss-of-function. By contrast, the P403A, V404L and V404M variants displayed strong gating impairment in the heteromeric ternary configuration, compatible with loss-of-function or gain-of-function. Our results support the etiological involvement of Kv4.2 channel gating impairment in early-onset monogenic global developmental delay. In addition, they suggest that gain-of-function mechanisms associated with a substitution of V404 increase epileptic seizure susceptibility.

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