1. Buxbaum Grice AS, Sloofman L, Levy T, Walker H, Ganesh G, Rodriguez de Los Santos M, Amini P, Buxbaum JD, Kolevzon A, Kostic A, Breen MS. Transient peripheral blood transcriptomic response to ketamine treatment in children with ADNP syndrome. Transl Psychiatry;2024 (Jul 25);14(1):307.

Activity-dependent neuroprotective protein (ADNP) syndrome is a rare neurodevelopmental disorder resulting in intellectual disability, developmental delay and autism spectrum disorder (ASD) and is due to mutations in the ADNP gene. Ketamine treatment has emerged as a promising therapeutic option for ADNP syndrome, showing safety and apparent behavioral improvements in a first open label study. However, the molecular perturbations induced by ketamine remain poorly understood. Here, we investigated the longitudinal effect of ketamine on the blood transcriptome of 10 individuals with ADNP syndrome. Transcriptomic profiling was performed before and at multiple time points after a single low-dose intravenous ketamine infusion (0.5 mg/kg). We show that ketamine triggers immediate and profound gene expression alterations, with specific enrichment of monocyte-related expression patterns. These acute alterations encompass diverse signaling pathways and co-expression networks, implicating upregulation of immune and inflammatory-related processes and down-regulation of RNA processing mechanisms and metabolism. Notably, these changes exhibit a transient nature, returning to baseline levels 24 hours to 1 week after treatment. These findings enhance our understanding of ketamine’s molecular effects and lay the groundwork for further research elucidating its specific cellular and molecular targets. Moreover, they contribute to the development of therapeutic strategies for ADNP syndrome and potentially, ASD more broadly.

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2. Dias C, Mo A, Cai C, Sun L, Cabral K, Brownstein CA, Rockowitz S, Walsh CA. Cell-type-specific effects of autism-associated 15q duplication syndrome in the human brain. Am J Hum Genet;2024 (Jul 25)

Recurrent copy-number variation represents one of the most well-established genetic drivers in neurodevelopmental disorders, including autism spectrum disorder. Duplication of 15q11-q13 (dup15q) is a well-described neurodevelopmental syndrome that increases the risk of autism more than 40-fold. However, the effects of this duplication on gene expression and chromatin accessibility in specific cell types in the human brain remain unknown. To identify the cell-type-specific transcriptional and epigenetic effects of dup15q in the human frontal cortex, we conducted single-nucleus RNA sequencing and multi-omic sequencing on dup15q-affected individuals (n = 6) as well as individuals with non-dup15q autism (n = 7) and neurotypical control individuals (n = 7). Cell-type-specific differential expression analysis identified significantly regulated genes, critical biological pathways, and differentially accessible genomic regions. Although there was overall increased gene expression across the duplicated genomic region, cellular identity represented an important factor mediating gene-expression changes. As compared to other cell types, neuronal subtypes showed greater upregulation of gene expression across a critical region within the duplication. Genes that fell within the duplicated region and had high baseline expression in control individuals showed only modest changes in dup15q, regardless of cell type. Of note, dup15q and autism had largely distinct signatures of chromatin accessibility but shared the majority of transcriptional regulatory motifs, suggesting convergent biological pathways. However, the transcriptional binding-factor motifs implicated in each condition implicated distinct biological mechanisms: neuronal JUN and FOS networks in autism vs. an inflammatory transcriptional network in dup15q microglia. This work provides a cell-type-specific analysis of how dup15q changes gene expression and chromatin accessibility in the human brain, and it finds evidence of marked cell-type-specific effects of this genetic driver. These findings have implications for guiding therapeutic development in dup15q syndrome, as well as understanding the functional effects of copy-number variants more broadly in neurodevelopmental disorders.

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3. Fields VL, Tian LH, Wiggins LD, Soke GN, Overwyk K, Moody E, Reyes N, Shapira SK, Schieve LA. Prevalence of Developmental, Psychiatric, and Neurologic Conditions in Older Siblings of Children with and without Autism Spectrum Disorder: Study to Explore Early Development. J Autism Dev Disord;2024 (Jul 25)

This study evaluated developmental, psychiatric, and neurologic conditions among older siblings of children with and without autism spectrum disorder (ASD) to understand the extent of familial clustering of these diagnoses. Using data from the Study to Explore Early Development, a large multi-site case-control study, the analyses included 2,963 children aged 2-5 years with ASD, other developmental disabilities (DD group), and a population-based control group (POP). Percentages of index children with older siblings with select developmental, psychiatric, and neurologic conditions were estimated and compared across index child study groups using chi-square tests and multivariable modified Poisson regression. In adjusted analyses, children in the ASD group were significantly more likely than children in the POP group to have one or more older siblings with ASD, developmental delay, attention-deficit/hyperactivity disorder, intellectual disability, sensory integration disorder (SID), speech/language delays, or a psychiatric diagnosis (adjusted prevalence ratio [aPR] range: 1.4-3.7). Children in the DD group were significantly more likely than children in the POP group to have an older sibling with most of the aforementioned conditions, except for intellectual disability and psychiatric diagnosis (aPR range: 1.4-2.2). Children in the ASD group were significantly more likely than children in the DD group to have one or more older siblings with ASD, developmental delay, SID, or a psychiatric diagnosis (aPR range: 1.4-1.9). These findings suggest that developmental disorders cluster in families. Increased monitoring and screening for ASD and other DDs may be warranted when an older sibling has a DD diagnosis or symptoms.

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4. Fletcher-Watson S. Reporting participatory methods and author positionality in autism. Autism;2024 (Jul 25):13623613241266950.

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5. Hosseini SJ, Ramezani M, Ashrafzadeh F, Jamali J. Motivation in caregiving among mothers of children with intellectual and developmental disabilities in Iran: A qualitative study. BMC Pediatr;2024 (Jul 25);24(1):472.

BACKGROUND: The motivation of caregivers plays a crucial role in the treatment, follow-up, and care of children with intellectual and developmental disabilities. Previous studies have focused on the older people and end-stage diseases, while giving less attention to the motivation of mothers caring for children with special needs. This study aimed to explore the motivations of mothers caring for children with intellectual and developmental disabilities in Iran. METHODS: This study employed a qualitative approach, guided by the Self-Determination Theory. Purposeful sampling was initially used, followed by theoretical sampling until data saturation was achieved. Data were collected through semi-structured interviews with 26 mothers of children with intellectual and developmental disabilities. Mayring’s seven-step directed content analysis approach was utilized for coding and categorization. The research adhered to ethical standards and ensured data trustworthiness through credibility, dependability, confirmability, and transferability measures. RESULTS: The findings revealed that mothers’ caregiving motivations could be classified into four main categories: (I) intrinsic, (II) identified-extrinsic, (III) introjected-extrinsic, and (IV) external-extrinsic. Additionally, twelve sub-categories were identified within these four main categories. CONCLUSION: The findings revealed that mothers demonstrated varying levels of intrinsic and extrinsic motivations in caring for children with intellectual and developmental disabilities. By recognizing and enhancing the diverse sources of motivation, healthcare providers and policymakers can better support mothers in their caregiving roles, ultimately contributing to improved outcomes for both the mothers and their children.

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6. Lee EAL, Milbourn B, Afsharnejad B, Chitty E, Jannings AM, Kealy R, McWhirter T, Girdler S. ‘We are all bringing, like a unique sort of perspective’: The core elements of a strengths-based digital arts mentoring program for autistic adolescents from the perspective of their mentors. Aust Occup Ther J;2024 (Jul 25)

INTRODUCTION: While the adoption of strengths-based approaches to supporting autistic adolescents is growing in popularity, the application of this approach to a digital arts mentoring program has yet to be explored. This study reports on the core elements contributing to the success of a community digital arts mentoring program for autistic adolescents from the mentors’ perspective. This paper presents an in-depth exploration of mentors’ experiences, comprising a component of a broader line of research investigating a digital arts mentoring program for autistic adolescents emphasising positive youth development. METHODS: The digital arts mentoring program spanned 20 weeks across two Australian school terms and was attended by two groups of autistic adolescents (N = 18) aged between 11 and 17 years. A qualitative approach was utilised in exploring the perspective of their mentors (N = 6). Qualitative data were collected at the end of each school term for each group with the mentors using an interpretive phenomenological approach and Colaizzi’s seven-step analysis method. Thirteen individual interviews were conducted with six mentors. CONSUMER AND COMMUNITY INVOLVEMENT: This research was conducted with a disability arts provider to provide a digital arts mentoring program to autistic adolescents. The mentors employed have lived experience with disorders such as attention deficit hyperactivity disorder (ADHD) and anxiety. RESULTS: Five primary themes emerged from the data: positive connections, mentor knowledge and experience, mentoring approaches, autism education, program organisation, resources and environment. Subthemes underpinned the primary themes related to positive connections (three subthemes), mentoring approaches (four subthemes) and program organisation, resources and environment (three subthemes). CONCLUSION: The findings suggest that prior experience, sufficient training, a supportive environment and a flexible and adaptable approach were essential for success. Understanding the core elements of a strengths-based digital arts program in occupational therapy provides a comprehensive framework for utilising clients’ inherent strengths and creativity as therapeutic tool, creating an empowering environment, fostering meaningful outcomes for clients.

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7. Lee KS, Long EL, Catmur C, Hauser TU, Bird G. Information gathering: Dissociable effects of autistic and alexithymic traits in youths aged 6-25 years. Emotion;2024 (Jul 25)

Autistic youths tend to react negatively to uncertain events. Little is known about the cognitive processes associated with this intolerance of uncertainty, most notably the tendency to actively gather information to minimize uncertainty. Past research has relied on self-report measures that may not allow investigation of the multifaceted processes associated with intolerance of uncertainty, including information gathering. Alexithymia (difficulties in identifying and describing one’s own emotions) commonly co-occurs with autistic traits, but its role in information gathering has rarely been considered. Accordingly, 97 typically developing youths (aged 6-25 years) performed an information gathering task in which they were asked to gather information to infer socioemotional (emotional state) and nonsocial (clothing preference) information about another person when information gathering was costly versus not costly. Dimensional autistic traits were associated with more information gathering regardless of costs and information type. Computational modeling suggested this may be because of the delayed emergence of subjective costs of information gathering in high autistic trait individuals, resulting in later guesses. Alexithymia was uniquely associated with inconsistent emotional responses to rewards and losses and to reduced information gathering about emotional states when assessed using parent-report measures. Future validation in youths diagnosed with autism is warranted to test the generalizability of the findings. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

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8. Longmore A, Anagnostou E, Georgiages S, Jones J, Kelley E, Baribeau D. Predictors of Depressive Symptoms in Autistic Youth-A Longitudinal Study From the Province of Ontario Neurodevelopmental Disorders (POND) Network: Prédicteurs des symptômes dépressifs chez les jeunes autistes-une étude longitudinale du Réseau des troubles neurodéveloppementaux de la province de l’Ontario (réseau POND). Can J Psychiatry;2024 (Jul 25):7067437241259925.

OBJECTIVE: The objective of this study was to identify longitudinal predictors of depressive symptoms in autistic children and youth. METHODS: Participants were youth with a diagnosis of autism who were part of the Province of Ontario Neurodevelopmental Disorders Network longitudinal substudy. Depressive symptoms were assessed using the child behaviour checklist (CBCL) affective problems subscale. Univariate and multivariable logistic regression models were used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for the associations between clinical and demographic characteristics at baseline (T1) and clinically elevated depressive symptoms (CEDS) approximately 4 years later (T2). RESULTS: The mean age of participants (n = 75) at T1 was 9.8 years (SD = 2.7) and at T2 was 14.1 years (SD = 2.8). A total of 37% and 35% of participants had CEDS at T1 and T2, respectively. Additionally, 24% of participants had CEDS at both T1 and T2. T1 characteristics associated with T2 CEDS were: loneliness (OR = 3.0, 95% CI, 1.1 to 8.8), self-harm (OR = 4.0, 95% CI, 1.1 to 16.9), suicidal ideation (OR = 3.9, 95% CI, 1.0 to 16.5), more social and adaptive skills (OR = 0.3, 95% CI, 0.1 to 0.9), elevated restricted and repetitive behaviours (OR = 3.8, 95% CI, 1.3 to 11.6), psychotropic medication use (OR = 3.0, 95% CI, 1.1 to 8.4), attention-deficient/hyperactivity disorder (OR = 2.8, 95% CI, 1.1 to 7.8), and T1 CEDS (OR = 8.8, 95% CI, 3.1 to 27.0) (uncorrected for multiple comparisons). Associations persisted after adjusting for age and intelligence quotient (IQ) differences. Age, sex, IQ, teasing/bullying on the CBCL, family psychiatric history and family income were not associated with T2 CEDS. CONCLUSION: Our results highlight both high prevalence and high potential for the persistence of depressive symptoms in autism and emphasize the importance of early support to address loneliness and social participation. Study assessing risk factors for depression in autistic youthPlain Language SummaryObjectiveThe goal of this study was to find risk factors for depression in autistic youth.MethodsThe study included autistic youth who were part of the Province of Ontario Neurodevelopmental Disorders Network. Symptoms of depression were identified using mental health surveys and screening tools completed by parents. We studied 75 youth over two time points, to understand what factors might predict greater depression risk.ResultsThe average age of our study population at the first visit was 10 years old, and 14 years old at the second visit. Our study found that 37% of participants had elevated symptoms of depression at the first visit, and 35% at the second visit. Factors associated with future depressive symptoms included: loneliness, self-harm, suicidal ideation, high levels of restrictive/repetitive behaviours, depressive symptoms at the first visit, and ADHD. Factors that protected against depressive symptoms included high levels of social skills.ConclusionOur results show high levels of depressive symptoms among autistic youth, and the potential for this to persist over time in this population. Our findings emphasize the importance of early supports to address loneliness and social participation. eng

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9. Maes P, La Valle C, Tager-Flusberg H. Frequency and characteristics of echoes and self-repetitions in minimally verbal and verbally fluent autistic individuals. Autism Dev Lang Impair;2024 (Jan-Dec);9:23969415241262207.

BACKGROUND AND AIMS: Nongenerative speech is the rote repetition of words or phrases heard from others or oneself. The most common manifestations of nongenerative speech are immediate and delayed echolalia, which are a well-attested clinical feature and a salient aspect of atypical language use in autism. However, there are no current estimates of the frequency of nongenerative speech, and the individual characteristics associated with nongenerative speech use in individuals across the autistic spectrum are poorly understood. In this study, we aim to measure and characterize spontaneous and nongenerative speech use in minimally verbal and verbally fluent autistic children and adolescents. METHODS: Participants were 50 minimally verbal and 50 verbally fluent autistic individuals aged 6 to 21 years. Spontaneous and nongenerative speech samples were derived from SALT transcripts of ADOS-2 assessments. Participants’ intelligible speech utterances were categorized as spontaneous or nongenerative. Spontaneous versus nongenerative utterances were compared between language subgroups on frequency of use and linguistic structure. Associations between nongenerative speech use and a series of individual characteristics (ADOS-2 subscale scores, nonverbal IQ, receptive vocabulary, and chronological age) were investigated over the whole sample and for each language subgroup independently. RESULTS: Almost all participants produced some nongenerative speech. Minimally verbal individuals produced significantly more nongenerative than spontaneous utterances, and more nongenerative utterances compared to verbally fluent individuals. Verbally fluent individuals produced limited rates of nongenerative utterances, in comparison to their much higher rates of spontaneous utterances. Across the sample, nongenerative utterance rates were associated with nonverbal IQ and receptive vocabulary, but not separately for the two language subgroups. In verbally fluent individuals, only age was significantly inversely associated with nongenerative speech use such that older individuals produced fewer nongenerative utterances. In minimally verbal individuals, there were no associations between any of the individual characteristics and nongenerative speech use. In terms of linguistic structure, the lexical diversity of nongenerative and spontaneous utterances of both language subgroups was comparable. Morphosyntactic complexity was higher for spontaneous compared to nongenerative utterances in verbally fluent individuals, while no differences emerged between the two utterance types in minimally verbal individuals. CONCLUSIONS: Nongenerative speech presents differently in minimally verbal and verbally fluent autistic individuals. Although present in verbally fluent individuals, nongenerative speech appears to be a major feature of spoken language in minimally verbal children and adolescents. IMPLICATIONS: Our results advocate for more research on the expressive language profiles of autistic children and adolescents who remain minimally verbal and for further investigations of nongenerative speech, which is usually excluded from language samples. Given its prevalence in the spoken language of minimally verbal individuals, nongenerative speech could be used as a way to engage in and maintain communication with this subgroup of autistic individuals.

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10. Meulien C, Baghdadli A. A Systematic Review of the Stigma Experienced by People with Autism Spectrum Disorder Associated with Intellectual Disabilities and by Their Family Caregivers. J Autism Dev Disord;2024 (Jul 25)

The purpose of this paper was to explore the social stigma experienced by individuals diagnosed with ASD+ID, and to identify knowledge gaps for future studies by conducting a systematic review of peer-reviewed literature. In this systematic review, we included 12 studies exploring the experience of stigma among people with ASD+ID and/or their caregivers. Our aim was to better understand this experience, but also to explore the strategies used to cope with stigma in this population. Our results confirmed that people with ASD+ID and their caregivers experience at least low to moderate levels of stigma, and that this experience is modulated by internal and external factors (such as parental age, mindfulness traits, ASD symptoms…). In addition, our results show the impact of stigma on community integration, psychological well-being and help-seeking behaviour. The role of family, friends and professional support, as well as the formation of networks to share information, appear in our results to be protective factors against stigma. To our knowledge, this study is the first systematic review to examine the stigmatisation of people with ASD+ID and/or their caregivers. Further research is needed to understand the perspective of people with ASD+ID themselves and to explore other factors that modulate this experience, in particular gender and ethnicity.

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11. Sun H, Shen Y, Ni P, Liu X, Li Y, Qiu Z, Su J, Wang Y, Wu M, Kong X, Cao JL, Xie W, An S. Autism-associated neuroligin-3 deficiency in medial septum causes social deficits and sleep loss in mice. J Clin Invest;2024 (Jul 25)

Patients with autism spectrum disorder (ASD) frequently experience sleep disturbance. Genetic mutations in Neuroligin-3 (NLG3) genes are highly correlative with ASD and sleep disturbance. However, the cellular and neural circuit bases of this correlation remain elusive. Here, we find the conditional knockout of NLG3 (NLG3-CKO) in the medial septum (MS) impairs social memory and reduces sleep. NLG3 knockout in MS causes hyperactivity of MS-GABA neurons during social avoidance and wakefulness. Activation of MSGABA neurons induces social memory deficits and sleep loss in C57BL/6 mice. In contrast, inactivation of these neurons ameliorates social memory deficits and sleep loss in NLG3-CKO mice. Sleep deprivation leads to social memory deficits, while social isolation causes sleep loss, both resulting in a reduction of NLG3 expression and an increase in activity of GABAergic neurons in MS from C57BL/6 mice. Furthermore, MS-GABA-innervated CA2 neurons specifically regulate social memory without impacting sleep, whereas MSGABA-innervating neurons in the preoptic area selectively control sleep without affecting social behavior. Together, these findings demonstrate that the hyperactive MS-GABA neurons impair social memory and disrupt sleep resulting from NLG3 knockout in MS, and achieve the modality specificity through their divergent downstream targets.

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12. Thakur A, Bobbette N, Bond V, Gonzales A, Lake J, Lefkowitz G, Mia N, Niel U, Sockalingam S, Streisslberger E, Thomson K, Volpe T, Lunsky Y. Bridging the gap: national virtual education programme for professionals caring for adults with intellectual and developmental disabilities at the time of COVID-19. BJPsych Open;2024 (Jul 25);10(4):e130.

BACKGROUND: The COVID-19 pandemic significantly impacted the mental health of adults with intellectual and developmental disabilities (IDD). During this period of uncertainty and need for up-to-date information, various virtual training programmes demonstrated the role of tele-mentoring programmes. AIM: The aim of this paper is to describe the educational evaluation of the National Extension for Community Healthcare Outcomes – Adults with Intellectual and Developmental Disabilities (ECHO-AIDD), a programme for service providers working with adults with IDD during COVID-19. METHOD: The programme consisted of six sessions, conducted weekly, over two cycles. Each session included didactic teaching by hub team members, COVID-19 news updates, wellness check-ins and a brief mindfulness activity, followed by a 30 to 45 min case-based discussion. The hub structure had an inter-professional approach to team expertise. Those with lived experience were an integral part of the content experts’ hub. Pre-, post- and follow-up evaluation data were collected. RESULTS: Care providers from health and social care sectors (n = 230) participated in the programme. High levels of engagement and satisfaction were reported. Self-efficacy ratings improved from pre- to post-, and were maintained at 8-week follow-up; improvement from pre- to post- was significant (P < 0.0001). CONCLUSION: Exposure to National ECHO-AIDD educational intervention led to improvement in perceived competencies. This study also shows the valuable role of people with lived experience in fostering adaptive expertise in learners. The outreach and scalability support the feasibility of building a national virtual community of practice for IDD service providers. Future studies should focus on studying the impact of these programmes on the health outcomes of people with IDD.

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13. Zhou Y, Jia G, Ren Y, Ren Y, Xiao Z, Wang Y. Advancing ASD identification with neuroimaging: a novel GARL methodology integrating Deep Q-Learning and generative adversarial networks. BMC Med Imaging;2024 (Jul 25);24(1):186.

Autism Spectrum Disorder (ASD) is a neurodevelopmental condition that affects an individual’s behavior, speech, and social interaction. Early and accurate diagnosis of ASD is pivotal for successful intervention. The limited availability of large datasets for neuroimaging investigations, however, poses a significant challenge to the timely and precise identification of ASD. To address this problem, we propose a breakthrough approach, GARL, for ASD diagnosis using neuroimaging data. GARL innovatively integrates the power of GANs and Deep Q-Learning to augment limited datasets and enhance diagnostic precision. We utilized the Autistic Brain Imaging Data Exchange (ABIDE) I and II datasets and employed a GAN to expand these datasets, creating a more robust and diversified dataset for analysis. This approach not only captures the underlying sample distribution within ABIDE I and II but also employs deep reinforcement learning for continuous self-improvement, significantly enhancing the capability of the model to generalize and adapt. Our experimental results confirmed that GAN-based data augmentation effectively improved the performance of all prediction models on both datasets, with the combination of InfoGAN and DQN’s GARL yielding the most notable improvement.

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