1. Aldegheri L, Kharrat F, Conti A, Monica F, Busa F, Campisciano G, Zanotta N, Cason C, Comar M. Impact of Human Milk Oligosaccharides and Probiotics on Gut Microbiome and Mood in Autism: A Case Report. Microorganisms;2024 (Aug 9);12(8)

Recent evidence has highlighted the role of the gut-brain axis in the progression of autism spectrum disorder (ASD), with significant changes in the gut microbiome of individuals with this condition. This report investigates the effects of probiotics and human milk oligosaccharide (HMO) supplements on the gut microbiome, inflammatory cytokine profile, and clinical outcomes in an ASD adolescent with chronic gastrointestinal dysfunction and cognitive impairment. Following treatment, we observed a decrease in proinflammatory cytokines’ concentration alongside Sutterella relative abundance, a bacterium reported to be linked with gastrointestinal diseases. Also, we reported a notable increase in mood stability. The study aims to evaluate the use of gut microbiome-based therapy in selected ASD patients, highlighting its potential to improve related clinical symptoms.

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2. Alegría PL, Landim SF, Branco BHM, Carmine F, Birditt K, Sandoval C, González MM. Dental Hygiene Challenges in Children with Autism: Correlation with Parental Stress: A Scoping Review. J Clin Med;2024 (Aug 9);13(16)

Children diagnosed with autism spectrum disorders are shown to have poor periodontal health and dental hygiene habits. Extensive research has revealed that parents of children with autism spectrum disorder (ASD) frequently encounter heightened levels of stress, despair, and anxiety in comparison to parents of neurotypical children. The aim was to understand the relationship between the dental hygiene of children with ASD and the stress generated in their parents. Methods: A scoping review was carried out to identify any gaps or research opportunities for clinical practice concerning oral care and stress levels in parents in the PubMed, Medline, ScienceDirect, and Scopus databases. Results: A total of 139 articles were reviewed. Of these, only 10 met the selection criteria for inclusion. Our results reveal a lack of studies presenting evidence on the topic of poor dental hygiene in children with ASD and high stress levels in their parents. Discussion: There is ample evidence that children with ASD have poor dental hygiene, as well as higher levels of stress in their parents. However, little or no evidence links these two variables. Future studies should focus on this link, which could have practical implications for improving dental care for children with ASD.

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3. Avolio E, Olivito I, Leo A, De Matteo C, Guarnieri L, Bosco F, Mahata SK, Minervini D, Alò R, De Sarro G, Citraro R, Facciolo RM. Vasostatin-1 restores autistic disorders in an idiopathic autism model (BTBR T+ Itpr3(tf)/J mice) by decreasing hippocampal neuroinflammation. Prog Neuropsychopharmacol Biol Psychiatry;2024 (Aug 30);135:111131.

Chromogranin A (CgA), a ∼ 49 kDa acidic secretory protein, is ubiquitously distributed in endocrine and neuroendocrine cells and neurons. As a propeptide, CgA is proteolytically cleaved to generate several peptides of biological importance, including pancreastatin (PST: hCgA(250)(-)(301)), Vasostatin 1 (VS1: hCgA(1-76)), and catestatin (CST: CgA (352)(-)(372)). VS1 represents the most conserved fragment of CgA. A 20 amino acid domain within VS1 (CgA 47-66) exhibits potent antimicrobial and anti-inflammatory activities. Autism is known to be associated with inflammation. Therefore, we seek to test the hypothesis that VS1 modulates autism behaviors by reducing inflammation in the hippocampus. Treatment of C57BL/6 (B6) and BTBR (a mouse model of idiopathic autism) mice with VS1 revealed the following: BTBR mice showed a significant decrease in chamber time in the presence of a stranger or a novel object. Treatment with VS1 significantly increased chamber time in both cases, underscoring a crucial role for VS1 in improving behavioral deficits in BTBR mice. In contrast to chamber time, sniffing time in BTBR mice in the presence of a stranger was less compared to B6 control mice. VS1 did not improve this latter parameter. Surprisingly, sniffing time in BTBR mice in the presence of a novel object was comparable with B6 mice. Proinflammatory cytokines such as IL-6 and IL-1b, as well as other inflammatory markers, were elevated in BTBR mice, which were dramatically reduced after supplementation with VS1. Interestingly, even Beclin-1/p62, pAKT/AKT, and p-p70-S6K/p70-S6K ratios were notably reduced by VS1. We conclude that VS1 plays a crucial role in restoring autistic spectrum disorders (ASD) plausibly by attenuating neuroinflammation.

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4. Baldwin E, Kinsella S, Byrne PJ. The Reliability of Field-Based Static and Dynamic Balance Tests in Primary School-Aged Autistic Children. Behav Sci (Basel);2024 (Jul 25);14(8)

Previous research has proven that the balance of autistic children is poor. However, the reliability of assessing balance in this cohort has been inadequately researched. This study therefore aimed to examine if field-based static and dynamic balance tests can be reliably assessed in autistic children, to determine the number of familiarisation sessions required and whether autistic severity impacts on the reliability of these balance tests. The balance of eighteen primary school-aged autistic children was assessed three times a week over five weeks, using the flamingo balance test, a modified version of the balance error scoring system (BESS), the low beam walking test, and the heel to toe walking test. Reliability criteria included an intraclass correlation coefficient (ICC) level of ≥0.75 and a coefficient of variance (CV%) of ≤46% for the low beam walking test, the heel to toe walking test, and the BESS, and a CV% of ≤82% or the flamingo balance test. Inter-session reliability was achieved and required the least number of familiarisation sessions for the flamingo balance test, compared to the low beam walking test, which required a greater number of familiarisation sessions to achieve inter-session reliability. The heel to toe walking test and the BESS achieved inter-session reliability and familiarisation in an acceptable time frame. Due to the large CV% values reported in the current study, practitioners need to be aware that balance interventions need to achieve improvements greater than the CV% in this cohort.

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5. Bausela-Herreras E. Autism Spectrum Disorder and BRIEF-P: A Review and Meta-Analysis. Children (Basel);2024 (Aug 13);11(8)

BACKGROUND: This research can facilitate the development of early detection tools for ASD by identifying specific patterns of deficits in executive functioning, validating the use of the BRIEF-P as a detection tool, and complementing information obtained from other evaluation instruments (Autism Diagnostic Interview-ADI-and Autism Diagnostic Observation Schedule-ADOS). AIMS: To gain knowledge of the application and usefulness of the BRIEF-P in the evaluation of executive functions (EFs) in people with ASD in the early years of the life cycle. METHOD: In order to systematically examine this hypothesis, a meta-analysis was conducted to identify the executive profile (strengths and weaknesses) of children with ASD. Out of a total of 161,773 potentially eligible published articles from different databases, 13 appropriate articles were revised and 4 articles were selected. Studies that were included evaluated samples involving individuals with ASD aged 2 to 8 years and were published in English or Spanish during the period of 2012-2022. RESULTS: The executive profile obtained from the application of the BRIEF-P in individuals with ASD was analyzed. It was identified that children with ASD, compared to typically developing children, show significantly clinical scores on the flexibility, inhibition, and global executive functioning scales. The results support the hypothesis of an executive deficit, with flexibility and inhibition being diagnostic markers for early and prompt identification of autism. CONCLUSIONS AND DISCUSSION: The results confirm deficits in flexibility, although they are not conclusive. This may be due to aspects related to methodology, whereby the studies (i) include very large and heterogeneous age groups, (ii) do not discriminate based on the level of competence, and (iii) use instruments for evaluating executive functions that are not validated or adapted for people with ASD. Another reason is the lack of consensus in the very operational definition of the executive functions construct, with the studies focusing mainly on the cold dimension while ignoring the hot dimension. From the perspective of therapeutic and treatment implications, executive dysfunction can impact adaptive skills in daily life and consequently the person’s autonomy.

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6. Bedford R, Green J, Gliga T, Jones EH, Elsabbagh M, Pasco G, Wan MW, Slonims V, Charman T, Pickles A, Johnson MH. Parent-mediated intervention in infants with an elevated likelihood for autism reduces dwell time during a gaze-following task. Autism Res;2024 (Aug 28)

Cognitive markers may in theory be more sensitive to the effects of intervention than overt behavioral measures. The current study tests the impact of the Intervention with the British Autism Study of Infant Siblings-Video Interaction for Promoting Positive Parenting (iBASIS-VIPP) on an eye-tracking measure of social attention: dwell time to the referred object in a gaze following task. The original two-site, two-arm, assessor-blinded randomized controlled trial (RCT) of this intervention to increase parental awareness, and responsiveness to their infant, was run with infants who have an elevated familial likelihood for autism (EL). Fifty-four EL infants (28 iBASIS-VIPP intervention, 26 no intervention) were enrolled, and the intervention took place between 9 months (baseline) and 15 months (endpoint), with gaze following behavior measured at 15 months. Secondary intention to treat (ITT) analysis showed that the intervention was associated with significantly reduced dwell time to the referent of another person’s gaze (β = -0.32, SE = 0.14, p = 0.03) at 15-month treatment endpoint. Given the established link between gaze following and language, the results are considered in the context of a previously reported, non-significant and transient trend toward lower language scores at the treatment endpoint (Green et al. (2015) The Lancet Psychiatry, 2(2), 133-140). Future intervention trials should aim to include experimental cognitive measures, alongside behavioral measures, to investigate mechanisms associated with intervention effects.

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7. Benevides TW, Cook B, Klinger LG, McLean KJ, Wallace GL, Carey ME, Lee WL, Ventimiglia J, Schiff LD, Shea L. Brief Report: Under-Identification of Symptomatic Menopause in Publicly-Insured Autistic People. J Autism Dev Disord;2024 (Aug 29)

Menopause is a normal part of aging and in the general population is associated with chronic conditions that impact health, mortality, and well-being. Menopause is experienced differently by autistic individuals, although no studies have investigated this topic in a large sample. The purpose of this study was to investigate rates of, and factors associated with symptomatic menopause among autistic individuals and to identify the prevalence of co-occurring conditions in symptomatic individuals. We included autistic females aged 35-70 years enrolled for 10 + months in 2014-2016 Medicare and/or Medicaid (n = 26,904), excluding those with gender dysphoria. Those with symptomatic menopause were compared to a non-symptomatic reference group on demographic, enrollment characteristics, and co-occurring conditions through logistic regression. Approximately 4% of publicly-insured autistic females aged 46-70 years had symptomatic menopause in their medical records. Intellectual disability was associated with a lower likelihood of symptomatic menopause, and being Medicare-enrolled or dual-enrolled was associated with higher likelihood of having symptomatic menopause recorded. In adjusted models, rates of ADHD, anxiety and depressive disorders, headache/migraine, altered sensory experiences, altered sexual function, and sleep disturbance were significantly higher in the symptomatic menopause sample compared to the reference group. More work to better support autistic women in discussing menopausal symptoms and co-occurring conditions with primary care providers is needed, particularly among those for whom self-report of symptoms are more challenging to ascertain. Factors associated with specific types of health care coverage warrant greater investigation to support better identification.

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8. BF AL, Alrashdi BAT, Mallick A, Alruwaili TAM, Alanazi MF, Alruwaili HFS, Alanazi WF, Alanazi WM, Altaymani AFM. Knowledge, Attitude, and Perception towards Autism Spectrum Disorders among Parents in Sakaka, Al-Jouf Region, Saudi Arabia: A Cross-Sectional Study. Healthcare (Basel);2024 (Aug 10);12(16)

Parents are an essential element of family intervention for all children, including those with autism spectrum disorders (ASDs). We can better understand and address parents’ knowledge gaps about ASD through in-depth research and inquiry into parents’ current level of understanding, attitude, and perception. We aimed to assess the knowledge, attitude, and perception of ASD and influencing factors towards ASD among a group of parents with and without a child diagnosed with ASD in Sakaka, Al-Jouf Region, Saudi Arabia. Using the cross-sectional study design, information from the parents was gathered using a pretested questionnaire that included validated scales for measuring knowledge, attitudes, and perceptions related to ASD. The required number of participants was selected using the convenience sampling method. We used Spearman’s correlation test to determine the strength and direction of correlation between each domain. As a last step, we analyzed the influencing factors using binomial logistic regression. Among the 400 participants, 41.2% had high knowledge, 69.1% had a positive attitude, and 60.3% had a high perception of ASD. We found that knowledge was significantly higher among the parents with autistic individuals in the family (p = 038). The high and positive attitude was significantly greater among females (p = 0.010) and parents with high income (p = 0.007), and the perception was significantly associated with females (p = 0.037) and highly educated participants (p = 0.046). Furthermore, we found a positive correlation between knowledge, attitude, and perception. Overall, only less than half of the participants had a high knowledge of ASD. Hence, we recommend awareness-raising programs for the parents in this region. Furthermore, a prospective study involving parents from all provinces of Saudi Arabia is recommended.

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9. Bitsika V, Sharpley CF, Evans ID, Vessey KA. Neurological Validation of ASD Diagnostic Criteria Using Frontal Alpha and Theta Asymmetry. J Clin Med;2024 (Aug 18);13(16)

Background/Objectives: Diagnosis of Autism Spectrum Disorder (ASD) relies on the observation of difficulties in social communication and interaction, plus the presence of repetitive and restrictive behaviors. The identification of neurological correlates of these symptoms remains a high priority for clinical research, and has the potential to increase the validity of diagnosis of ASD as well as provide greater understanding of how the autistic brain functions. This study focused on two neurological phenomena that have been previously associated with psychiatric disorders (alpha- and theta-wave asymmetry across the frontal region of the brain), and tested for their association with the major diagnostic criteria for ASD. Methods: A total of 41 male autistic youth underwent assessment with the Autism Diagnostic Observation Schedule (ADOS-2) and 3 min of eyes-closed resting EEG to collect alpha- and theta-wave data from right and left frontal brain sites. Results: Different associations were found for theta versus alpha asymmetry and the ADOS-2 subscales, across different brain regions responsible for a varying range of cognitive functions. In general, theta asymmetry was associated with conversation with others, sharing of enjoyment, and making social overtures, whereas alpha asymmetry was linked with making eye contact, reporting events to others, and engaging in reciprocal social communication. Specific brain regions involved are identified, as well as implications for clinical practice. Conclusions: Specific autism symptoms may be associated with selected brain region activity, providing a neurological basis for diagnosis and treatment.

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10. Bourque VR, Schmilovich Z, Huguet G, England J, Okewole A, Poulain C, Renne T, Jean-Louis M, Saci Z, Zhang X, Rolland T, Labbé A, Vorstman J, Rouleau GA, Baron-Cohen S, Mottron L, Bethlehem RAI, Warrier V, Jacquemont S. Integrating genomic variants and developmental milestones to predict cognitive and adaptive outcomes in autistic children. medRxiv;2024 (Aug 1)

Although the first signs of autism are often observed as early as 18-36 months of age, there is a broad uncertainty regarding future development, and clinicians lack predictive tools to identify those who will later be diagnosed with co-occurring intellectual disability (ID). Here, we developed predictive models of ID in autistic children (n=5,633 from three cohorts), integrating different classes of genetic variants alongside developmental milestones. The integrated model yielded an AUC ROC=0.65, with this predictive performance cross-validated and generalised across cohorts. Positive predictive values reached up to 55%, accurately identifying 10% of ID cases. The ability to stratify the probabilities of ID using genetic variants was up to twofold greater in individuals with delayed milestones compared to those with typical development. These findings underscore the potential of models in neurodevelopmental medicine that integrate genomics and clinical observations to predict outcomes and target interventions.

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11. Bove M, Sikora V, Santoro M, Agosti LP, Palmieri MA, Dimonte S, Tucci P, Schiavone S, Morgese MG, Trabace L. Sex differences in the BTBR idiopathic mouse model of Autism Spectrum Disorders: behavioural and redox-related hippocampal alterations. Neuropharmacology;2024 (Aug 27):110134.

Autism spectrum disorders (ASD) are highly heterogeneous neurodevelopmental diseases. Epidemiological data report that males have been diagnosed with autism more frequently than females. However, recent studies hypothesize that females’ low incidence might be underestimated due to standard clinical measures of ASD behavioural symptoms, mostly derived from males. Indeed, up to now, ASD mouse models focused mainly only on males, considering the prevalence of the diagnosis in that sex. Regarding ASD aetiopathogenesis, it has been recently reported that oxidative stress might be implicated in its onset and development, suggesting an association with ASD typical repetitive behaviours that still need to be disentangled. Here, we investigated possible behavioural and molecular sex-related differences by using the BTBR mouse model of idiopathic ASD. To this aim, animals were exposed to behavioural tests related to different ASD core symptoms and comorbidities, i.e.Marble Burying, Hole Board, Open Field, Elevated Zero Maze and Social Interaction tests stereotyped repertoire, social dysfunctions, hyperlocomotion and risk-taking behaviours. Moreover, we analysed hippocampal levels of pro-oxidant and anti-oxidant enzymes, together with biomarkers of oxidative stress and lipid peroxidation. Our results showed that BTBR females did not display the same patterns for repetitive behaviours as the male counterpart. From a biomolecular point of view, we found an increase in oxidative stress and pro-oxidant enzymes, accompanied by deficient enzymatic anti-oxidant response, only in BTBR males compared to C57BL/6 male mice, while no differences were retrieved in females. Overall, our study suggests that in females there is an urgent need to depict the distinct ASD symptomatology, accompanied by the identification of sex-specific pharmacological targets.

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12. Bright MA, Ortega DP, Bodi CB, Walsh K. School-Based Victimization Prevention Education Programs for Children and Youth With Intellectual and Developmental Disabilities: A Scoping Review. Child Maltreat;2024 (Aug 29):10775595241276412.

Youth with intellectual and developmental disabilities (IDD) are at significantly higher risk of experiencing multiple types of interpersonal victimization across their lifespan compared to their peers without IDD. Despite the extensive literature on efficacy of prevention education programs for children without IDD, very little is known about comparable programs for children with IDD. In this scoping review, we synthesized the literature on existing programs for children with IDD. We identified thirteen programs which we critically assessed against established best practice criteria for prevention and special education and evaluation. The current literature on prevention education programs for children with IDD exhibits significant limitations, such as weak research designs and poor measurement of outcomes.

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13. Carpita B, Amatori G, Cremone IM, Bonelli C, Nardi B, Massimetti G, Pini S, Dell’Osso L. Major Depressive Disorder with Catatonia: A Phenotype Related to Autistic Traits and High Suicidality. J Clin Med;2024 (Aug 14);13(16)

Background: Major Depressive Disorder (MDD) represents a significant global health concern, often complicated by comorbidities such as catatonia and autism spectrum disorder (ASD). Recognizing the interplay among these conditions and their impact on suicidal tendencies is crucial for effective clinical management. Methods: A total sample of 147 subjects with MDD was divided into Significant Catatonia (SC) and Non-Significant Catatonia (NSC) groups based on Catatonia Spectrum (CS) scores. Participants were evaluated through the Structured Clinical Interview for DSM-5, Research Version (SCID-5-RV), the Adult Autism Subtreshold Spectrum (AdAS Spectrum), and the Mood Spectrum-Self Report questionnaires. Statistical analyses included Mann-Whitney U test, Chi-square test, logistic regression analyses, and a decision tree model. Results: The SC group exhibited higher CS, AdAS Spectrum, and MOODS-SR total and domain scores compared to the NSC group. Individuals with significant autistic traits were over-represented in the SC group, as well as participants with higher suicidality, suicidal ideation, and a history of suicide attempts. The total AdAS Spectrum and MOOD-SR score, the AdAS domain « Hyper-hypo reactivity to sensory input », and the « Cognitive depressive » MOOD-SR domain were predictive of belonging to the SC group. Suicidality levels appeared to be higher in clinically significant ASD, intermediate in subjects with autistic traits (AT), and low in the absence of AT. Conclusions: the study suggests the existence of a specific phenotype of MDD associated with catatonia, characterized by elevated autistic traits and suicide risk.

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14. Carter A, Klinner C, Young A, Strnadová I, Wong H, Vujovich-Dunn C, Newman CE, Davies C, Skinner SR, Danchin M, Hynes S, Guy R. « I Thought It Was Better to Be Safe Than Sorry »: Factors Influencing Parental Decisions on HPV and Other Adolescent Vaccinations for Students with Intellectual Disability and/or Autism in New South Wales, Australia. Vaccines (Basel);2024 (Aug 16);12(8)

The uptake of human papilloma virus (HPV) and other adolescent vaccinations in special schools for young people with disability is significantly lower than in mainstream settings. This study explored the factors believed to influence parental decision making regarding vaccine uptake for students with intellectual disability and/or on the autism spectrum attending special schools in New South Wales, Australia, from the perspective of all stakeholders involved in the program. Focus groups and interviews were conducted with 40 participants, including parents, school staff, and immunisation providers. The thematic analysis identified two themes: (1) appreciating diverse parental attitudes towards vaccination and (2) educating parents and managing vaccination questions and concerns. While most parents were described as pro-vaccination, others were anti-vaccination or vaccination-hesitant, articulating a marked protectiveness regarding their child’s health. Reasons for vaccine hesitancy included beliefs that vaccines cause autism, concerns that the vaccination may be traumatic for the child, vaccination fatigue following COVID-19, and assumptions that children with disability will not be sexually active. Special school staff regarded the vaccination information pack as inadequate for families, and nurses described limited educational impact resulting from minimal direct communication with parents. More effective communication strategies are needed to address vaccine hesitancy among parents with children with disability.

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15. Casella R, Miniello A, Buta F, Yacoub MR, Nettis E, Pioggia G, Gangemi S. Atopic Dermatitis and Autism Spectrum Disorders: Common Role of Environmental and Clinical Co-Factors in the Onset and Severity of Their Clinical Course. Int J Mol Sci;2024 (Aug 16);25(16)

Increasing evidence suggests an association between atopic dermatitis, the most chronic inflammatory disease of the skin, and autism spectrum disorders, which are a group of neurodevelopmental diseases. Inflammation and immune dysregulation associated with genetic and environmental factors seem to characterize the pathophysiological mechanisms of both conditions. We conducted a literature review of the PubMed database aimed at identifying the clinical features and alleged risk factors that could be used in clinical practice to predict the onset of ASD and/or AD or worsen their prognosis in the context of comorbidities.

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16. Castro K, Frye RE, Silva E, Vasconcelos C, Hoffmann L, Riesgo R, Vaz J. Feeding-Related Early Signs of Autism Spectrum Disorder: A Narrative Review. J Pers Med;2024 (Aug 2);14(8)

Feeding difficulties are prevalent among individuals with autism spectrum disorder (ASD). Nevertheless, the knowledge about the association between feeding-related early signs and child development remains limited. This review aimed to describe the signs and symptoms related to feeding during child development and to explore their relevance to the diagnosis of ASD. Specialists in nutrition and/or ASD conducted a search of MEDLINE, PsycINFO, and Web of Science databases. Although studies in typically developing children demonstrate age-related variations in hunger and satiety cues, the literature about early feeding indicators in ASD is scarce. Challenges such as shortened breastfeeding duration, difficulties in introducing solid foods, and atypical mealtime behaviors are frequently observed in children with ASD. The eating difficulties experienced during childhood raise concerns for caregivers who base their feeding practices on their perceptions of food acceptance or refusal. Considering the observed associations between feeding difficulties and ASD, the importance of recognizing feeding-related signs according to developmental milestones is emphasized to alert medical professionals that deviation in the formation of feeding habits and skills could indicate the need for ASD diagnostic investigation.

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17. Chair SY, Chow KM, Chan CW, Chan JY, Law BM, Waye MM. Structural Variations Identified in Patients with Autism Spectrum Disorder (ASD) in the Chinese Population: A Systematic Review of Case-Control Studies. Genes (Basel);2024 (Aug 15);15(8)

Autistic spectrum disorder (ASD) is a neurodevelopmental disability characterised by the impairment of social interaction and communication ability. The alarming increase in its prevalence in children urged researchers to obtain a better understanding of the causes of this disease. Genetic factors are considered to be crucial, as ASD has a tendency to run in families. In recent years, with technological advances, the importance of structural variations (SVs) in ASD began to emerge. Most of these studies, however, focus on the Caucasian population. As a populated ethnicity, ASD shall be a significant health issue in China. This systematic review aims to summarise current case-control studies of SVs associated with ASD in the Chinese population. A list of genes identified in the nine included studies is provided. It also reveals that similar research focusing on other genetic backgrounds is demanded to manifest the disease etiology in different ethnic groups, and assist the development of accurate ethnic-oriented genetic diagnosis.

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18. Chow BJ, Raharja A, Dahir R, Khaier A, Posner M. Understanding the diagnostic challenges of Miller Fisher syndrome in children: a case report from an ophthalmological perspective. Br J Hosp Med (Lond);2024 (Aug 30);85(8):1-5.

We report a case of a 6-year-old boy with autism spectrum disorder presenting with new-onset squint and ‘ptosis’ following a recent infection. Clinical examination revealed ataxia and areflexia alongside a dilated pupil poorly reactive to light. Subsequently, his eye movements deteriorated to near-complete ophthalmoplegia at 1-week review. Further investigations inclusive of a magnetic resonance imaging (MRI) brain scan, a computed tomography (CT) venogram and a lumbar puncture were conducted to consider and rule out differential diagnoses. Cerebrospinal fluid analysis revealed an albuminocytologic dissociation. The clinical triad of progressive ophthalmoplegia, areflexia and areflexia alongside albuminocytologic dissociation led to the diagnosis of Miller Fisher syndrome. The patient was commenced on intravenous immunoglobulin and his symptoms showed significant improvement. We use this interesting case to provide context for key learning points about diagnosing Miller Fisher syndrome in children.

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19. Climent-Pérez P, Martínez-González AE, Andreo-Martínez P. Contributions of Artificial Intelligence to Analysis of Gut Microbiota in Autism Spectrum Disorder: A Systematic Review. Children (Basel);2024 (Jul 31);11(8)

BACKGROUND: Autism spectrum disorder (ASD) is a highly heterogeneous neurodevelopmental disorder whose etiology is not known today, but everything indicates that it is multifactorial. For example, genetic and epigenetic factors seem to be involved in the etiology of ASD. In recent years, there has been an increase in studies on the implications of gut microbiota (GM) on the behavior of children with ASD given that dysbiosis in GM may trigger the onset, development and progression of ASD through the microbiota-gut-brain axis. At the same time, significant progress has occurred in the development of artificial intelligence (AI). METHODS: The aim of the present study was to perform a systematic review of articles using AI to analyze GM in individuals with ASD. In line with the PRISMA model, 12 articles using AI to analyze GM in ASD were selected. RESULTS: Outcomes reveal that the majority of relevant studies on this topic have been conducted in China (33.3%) and Italy (25%), followed by the Netherlands (16.6%), Mexico (16.6%) and South Korea (8.3%). CONCLUSIONS: The bacteria Bifidobacterium is the most relevant biomarker with regard to ASD. Although AI provides a very promising approach to data analysis, caution is needed to avoid the over-interpretation of preliminary findings. A first step must be taken to analyze GM in a representative general population and ASD samples in order to obtain a GM standard according to age, sex and country. Thus, more work is required to bridge the gap between AI in mental health research and clinical care in ASD.

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20. Corey J, Tsai JM, Mhadeshwar A, Srinivasan S, Bhat A. Digital motor intervention effects on motor performance of individuals with developmental disabilities: a systematic review. J Intellect Disabil Res;2024 (Aug 29)

BACKGROUND: Individuals (i.e. children/young adults) with developmental disabilities (DDs) and intellectual disabilities (IDs) often display a variety of physical and motor impairments. It is well known that participation in motor activities can positively impact the development of children’s cognitive and social skills. Recently, virtual and digital technologies (e.g. video conferencing applications, virtual reality and video gaming) have been increasingly used to promote better physical/motor outcomes. The efficacy of digital technologies in improving motor outcomes for those with DD/ID varies depending on the technology and population, and the comparative effects of various technologies are unknown. The aim of our study is to conduct a systematic review to comprehensively examine the quantitative and qualitative results of current studies reporting the efficacy of digitally based motor interventions on motor outcomes in individuals with DD/ID. METHODS: Literature published from 1900 to 2024 was searched in four health sciences databases: PubMed, PsycINFO, Scopus and CINAHL. Articles that examined the effects of gross motor/physical activity training using technologies such as exergaming (i.e. exercise through video gaming such as the Wii and Xbox Kinect), virtual reality or telehealth video conferencing applications (i.e. Zoom, Webex or mobile health apps) on the standardised or game-specific gross motor performance of individuals with DD/ID diagnoses that do not typically experience significant walking challenges using experimental or quasi-experimental study designs were included. Thirty relevant articles were retrieved from a search of the databases PubMed (914), PsycINFO (1201), Scopus (1910) and CINAHL (948). RESULTS: Our quantitative synthesis of this published literature suggests strong and consistent evidence of small-to-large improvements in motor skill performance following digital movement interventions. CONCLUSIONS: Our review supports the use of digital motor interventions to support motor skill performance in individuals with DD without ID. Digital technologies can provide a more engaging option for therapists to promote motor skill development in individuals with DD or for caregivers to use as an adjunct to skilled therapy.

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21. Daghmash RM, Khanfar MS, Darweesh RS. Risperidone Pellets, Pycnogenol(®), and Glucomannan Gummy Formulation for Managing Weight Gain and ADHD in Autistic Children. Pharmaceutics;2024 (Aug 13);16(8)

Gummy formulations are defined as gradually or slowly released solid oral dosage forms. Risperidone is an atypical antipsychotic medication used to treat schizophrenia and autism-related irritability. This study presents the development of visually appealing, patient-tailored medicated gummies that act as a novel pharmaceutical form of Risperidone for pediatrics. In this study, two gummy bases were used, one containing Glucomannan and the other containing Gelatin as a gelling agent, where these gummy bases were loaded with coated Risperidone pellets with a controlled release layer. The final products were evaluated for their pH, viscosity, content uniformity, drug content, and dissolution profile. Both formulas showed proper rheology and met content and weight uniformity standards. The release rates for F1 and F2 in the acidic media were 25% and 11%, respectively, after 2 h. At the same time, a full-release profile for Risperidone was noticed in both formulae at pH 6.8 where the release lasts for 24 h. It can be concluded that the chewable semi-solid dosages (gummies) filled with coated pellets are suitable for pediatric patients since pediatrics have drug-related problems which can be solved using high gastro-resistance coated pellets, which also shows a proper release profile for the drug.

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22. Demirci SC, Barun S, Özaslan A, Gülbahar Ö, Bulut TSD, Çamurdan AD, İşeri E. Investigating the Relationship of Serum CD163, YKL40 and VILIP-1 Levels with Autism Severity and Language-cognitive Development in Preschool Children with Autism. Clin Psychopharmacol Neurosci;2024 (Aug 31);22(3):473-483.

OBJECTIVE: This study aimed to compare serum levels of CD163, YKL-40, and VILIP-1 between children with autism spectrum disorder (ASD) and healthy controls, while also investigating their association with the severity of ASD and language development. METHODS: The study included 40 ASD-diagnosed patients (aged 18-72 months) and 40 age-matched healthy controls. Childhood Autism Rating Scale, Preschool Language Scale-4, and Ankara Development Screening Inventory were administered to children in the ASD group. Serum CD163, YKL-40 and VILIP-1 levels were measured with an enzyme- linked immunosorbent assay kit. RESULTS: In the ASD group compared to the control group, serum VILIP-1 levels were significantly higher (p = 0.046). No significant differences were observed in mean serum CD163 and YKL-40 levels between patients and controls (p = 0.613, p = 0.769). Interestingly, a positive correlation was observed between CD163 and YKL-40 levels and ASD severity (p < 0.001 for both). Additionally, CD163 and YKL-40 levels showed significant predictive value for ASD severity. While no significant associations were found between CD163 and YKL-40 levels and language development, a negative correlation was observed between VILIP-1 levels and language development (p < 0.001). CONCLUSION: Our findings highlight that the levels of CD163 and YKL-40 significantly predicted ASD severity, indicating a potential role of neuroinflammation in the development of ASD.

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23. Fusar-Poli L, Avanzato C, Maccarone G, Di Martino E, Avincola G, Grasso S, Rapisarda G, Guarnieri F, Signorelli MS. The Association between Attention-Deficit-Hyperactivity Disorder and Autistic Traits with Psychotic-like Experiences in Sample of Youths Who Were Referred to a Psychiatric Outpatient Service. Brain Sci;2024 (Aug 22);14(8)

The aim of this study is to identify autism spectrum disorder (ASD) and attention-deficit-hyperactivity disorder (ADHD) traits in adolescents who experience psychotic-like experiences (PLEs), often ignored in clinical practice but widely prevalent in the general population. A total of 57 adolescents and young adults (aged between 16 and 24 years old) were recruited consecutively in the outpatient services. A total of 37 were females (64.9%), 18 were males (31.6%), and two participants (3.5%) were non-binary or gender non-conforming, with a mean age at referral of 18.26 ± 2.06. To investigate these symptoms, three sets of standardized questionnaires were used, as follows: the Autism Spectrum Quotient-short form (AQ-10), the Community Assessment of Psychic Experiences (CAPE-42), and the Adult ADHD Self-Report Scale (ASRS). We found significant associations between the ASRS and AQ-10 total scores and all CAPE scales. The model which explained the highest variance was CAPE Score’s Total Frequency score (p < 0.001). Our findings underline the importance of investigating the presence of subthreshold ASD and ADHD symptoms in clinical populations, particularly in the period of adolescence and young adulthood, to promptly identify the presence of PLEs and, thus, prevent the onset of a frank psychotic disorder, particularly in the presence of a comorbid psychopathological condition, leading to better diagnosis and treatment for individuals with two or more of these conditions.

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24. Gao L, Cao Y, Zhang Y, Liu J, Zhang T, Zhou R, Guo X. Sex differences in the flexibility of dynamic network reconfiguration of autism spectrum disorder based on multilayer network. Brain Imaging Behav;2024 (Aug 30)

Dynamic network reconfiguration alterations in the autism spectrum disorder (ASD) brain have been frequently reported. However, since the prevalence of ASD in males is approximately 3.8 times higher than that in females, and previous studies of dynamic network reconfiguration of ASD have predominantly used male samples, it is unclear whether sex differences exist in dynamic network reconfiguration in ASD. This study used resting-state functional magnetic resonance imaging data from the Autism Brain Imaging Data Exchange database, which included balanced samples of 64 males and 64 females with ASD, along with 64 demographically-matched typically developing control (TC) males and 64 TC females. The multilayer network analysis was used to explore the flexibility of dynamic network reconfiguration. The two-way analysis of variance was further performed to examine the sex-related changes in ASD in flexibility of dynamic network reconfiguration. A diagnosis-by-sex interaction effect was identified in the cingulo-opercular network (CON), central executive network (CEN), salience network (SN), and subcortical network (SUB). Compared with TC females, females with ASD showed lower flexibility in CON, CEN, SN, and SUB. The flexibility of CEN and SUB in males with ASD was higher than that in females with ASD. In addition, the flexibility of CON, CEN, SN, and SUB predicted the severity of social communication impairments and stereotyped behaviors and restricted interests only in females with ASD. These findings highlight significant sex differences in the flexibility of dynamic network reconfiguration in ASD and emphasize the importance of further study of sex differences in future ASD research.

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25. Gholamalizadeh H, Amiri-Shahri M, Rasouli F, Ansari A, Baradaran Rahimi V, Reza Askari V. DNA Methylation in Autism Spectrum Disorders: Biomarker or Pharmacological Target?. Brain Sci;2024 (Jul 23);14(8)

Autism spectrum disorder (ASD) is a group of heterogeneous neurodevelopmental disabilities with persistent impairments in cognition, communication, and social behavior. Although environmental factors play a role in ASD etiopathogenesis, a growing body of evidence indicates that ASD is highly inherited. In the last two decades, the dramatic rise in the prevalence of ASD has interested researchers to explore the etiologic role of epigenetic marking and incredibly abnormal DNA methylation. This review aimed to explain the current understanding of the association between changes in DNA methylation signatures and ASD in patients or animal models. We reviewed studies reporting alterations in DNA methylation at specific genes as well as epigenome-wide association studies (EWASs). Finally, we hypothesized that specific changes in DNA methylation patterns could be considered a potential biomarker for ASD diagnosis and prognosis and even a target for pharmacological intervention.

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26. Harker SA, Baxter LC, Gallegos SM, Mitchell MM, Zerga L, Matthews NL, Braden BB. Adapting the PEERS(®) for Young Adults Program for Autistic Adults across the Lifespan. Healthcare (Basel);2024 (Aug 9);12(16)

The Program for the Education and Enrichment of Relational Skills (PEERS(®)) is an evidence-based intervention developed for autistic individuals to support social communication, peer interactions, independence, and interpersonal relationships. Despite a demonstrated effectiveness for young autistic individuals in the US and several other countries, PEERS has yet to be modified to support the needs of autistic adults across the lifespan. The present study describes how our team sought autistic voices to adapt PEERS for adults of any age. Specifically, we aimed to address the needs of middle-aged and older adults and adapt the curriculum to be more neurodiversity-affirming. Between two cohorts that completed the program consecutively, we evaluated the acceptability of the adapted PEERS program and made refinements based on feedback from autistic participants and their study partners. Results indicated that Cohort 2 reported higher satisfaction with the PEERS components and overall program than Cohort 1, suggesting effective refinement. We present a framework of adaptations that more specifically address the needs of middle-aged and older adults in a neurodiverse-affirming way compared to previous iterations. Our approach to implementing an adapted PEERS curriculum across the adult lifespan may serve as a model for improved clinical care and cultivate the acceptance of neurodiversity in the interpersonal domains of autistic adults’ lives.

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27. Hou Y, Song Z, Deng J, Song X. The impact of exercise intervention on social interaction in children with autism: a network meta-analysis. Front Public Health;2024;12:1399642.

BACKGROUND: Extensive research has documented the positive impacts of physical activity on children and adolescents with Autism Spectrum Disorders (ASD). However, the specific benefits of various sports on the social functioning of children with ASD remain ambiguous. This study aims to employ a network meta-analysis to investigate the effects of different sports on the social functioning of children and adolescents with ASD and to establish a ranking of their effectiveness. METHODS: This study conducted a comprehensive online search across Web of Science, PubMed, Cochrane, and Embase databases for randomized controlled trials and quasi-experimental studies focusing on social functioning outcomes. Data were synthesized using a Bayesian framework. RESULTS: Sixteen relevant studies encompassing 560 participants were included. According to Cohen’s classification, mini-basketball (SMD = 0.84, 95% CI: 0.46, 1.20), SPARK (SMD = 0.88, 95% CI: 0.06, 1.70), and Karate (SMD = 1.10, 95% CI: 0.27, 2.00) demonstrated high effect sizes, with Karate identified as the most effective intervention. Conversely, Combined Exercise and Nei Yang Gong interventions exhibited the least significant effects, falling below small effect sizes. CONCLUSION: Physical activity interventions have been shown to enhance social functioning in children and adolescents with ASD to varying extents, with Karate emerging as the most efficacious.

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28. Jahani A, Jahani I, Khadem A, Braden BB, Delrobaei M, MacIntosh BJ. Twinned neuroimaging analysis contributes to improving the classification of young people with autism spectrum disorder. Sci Rep;2024 (Aug 29);14(1):20120.

Autism spectrum disorder (ASD) is diagnosed using comprehensive behavioral information. Neuroimaging offers additional information but lacks clinical utility for diagnosis. This study investigates whether multi-forms of magnetic resonance imaging (MRI) contrast can be used individually and in combination to produce a categorical classification of young individuals with ASD. MRI data were accessed from the Autism Brain Imaging Data Exchange (ABIDE). Young participants (ages 2-30) were selected, and two group cohorts consisted of 702 participants: 351 ASD and 351 controls. Image-based classification was performed using one-channel and two-channel inputs to 3D-DenseNet deep learning networks. The models were trained and tested using tenfold cross-validation. Two-channel models were twinned with combinations of structural MRI (sMRI) maps and amplitude of low-frequency fluctuations (ALFF) or fractional ALFF (fALFF) maps from resting-state functional MRI (rs-fMRI). All models produced classification accuracy that exceeded 65.1%. The two-channel ALFF-sMRI model achieved the highest mean accuracy of 76.9% ± 2.34. The one-channel ALFF-based model alone had mean accuracy of 72% ± 3.1. This study leveraged the ABIDE dataset to produce ASD classification results that are comparable and/or exceed literature values. The deep learning approach was conducive to diverse neuroimaging inputs. Findings reveal that the ALFF-sMRI two-channel model outperformed all others.

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29. Jeglum SR, Cicero A, DeBrine J, Livingston CP. Emergency Department Utilization Due to Challenging Behavior in Children and Adolescents Diagnosed with Autism Spectrum Disorder. Behav Sci (Basel);2024 (Aug 2);14(8)

Children and adolescents with autism spectrum disorder (ASD) are at a greater risk of seeking emergency department (ED) services during behavioral crises, such as acute aggression, suicidal or homicidal ideation, self-injury, or other types of challenging behavior (e.g., pica, dangerous behaviors). Research demonstrates children and adolescents with ASD often return to the ED due to challenging behavior, suggesting that gaps in care exist (e.g., follow-up appointments, referrals). However, the current knowledge basis is largely based on data from other countries. Given the unique landscape of healthcare in the United States, it is prudent to elucidate characteristics of children and adolescents with ASD who are seeking emergency care due to challenging behavior, as well as systems-level factors that both contribute to our understanding of challenging behavior and ASD in ED settings. In this study, we focus on frequency and characteristics of children and adolescents with ASD presenting to the ED with challenging behavior over the course of a 6-year period in the Midwest region of the United States. Clinical implications for ED staff are discussed.

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30. Jones JP, 3rd, Williamson L, Konsoula Z, Anderson R, Reissner KJ, Parker W. Evaluating the Role of Susceptibility Inducing Cofactors and of Acetaminophen in the Etiology of Autism Spectrum Disorder. Life (Basel);2024 (Jul 23);14(8)

More than 20 previously reported lines of independent evidence from clinical observations, studies in laboratory animal models, pharmacokinetic considerations, and numerous temporal and spatial associations indicate that numerous genetic and environmental factors leading to inflammation and oxidative stress confer vulnerability to the aberrant metabolism of acetaminophen during early development, leading to autism spectrum disorder (ASD). Contrary to this conclusion, multivariate analyses of cohort data adjusting for inflammation-associated factors have tended to show little to no risk of acetaminophen use for neurodevelopment. To resolve this discrepancy, here we use in silico methods to create an ideal (virtual) population of 120,000 individuals in which 50% of all cases of virtual ASD are induced by oxidative stress-associated cofactors and acetaminophen use. We demonstrate that Cox regression analysis of this ideal dataset shows little to no risk of acetaminophen use if the cofactors that create aberrant metabolism of acetaminophen are adjusted for in the analysis. Further, under-reporting of acetaminophen use is shown to be a considerable problem for this analysis, leading to large and erroneously low calculated risks of acetaminophen use. In addition, we argue that factors that impart susceptibility to acetaminophen-induced injury, and propensity for acetaminophen use itself, can be shared between the prepartum, peripartum, and postpartum periods, creating additional difficulty in the analysis of existing datasets to determine risks of acetaminophen exposure for neurodevelopment during a specific time frame. It is concluded that risks of acetaminophen use for neurodevelopment obtained from multivariate analysis of cohort data depend on underlying assumptions in the analyses, and that other evidence, both abundant and robust, demonstrate the critical role of acetaminophen in the etiology of ASD.

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31. K CR, Patel NR, Thurmon AN, Lorino MG, Tiemroth AS, Kulstad I, Morrison V, Akumuo M, Shenoy A, Meadows SM, Galazo MJ. Loss of Zmiz1 in mice leads to impaired cortical development and autistic-like behaviors. bioRxiv;2024 (Aug 18)

De novo mutations in transcriptional regulators are emerging as key risk factors contributing to the etiology of neurodevelopmental disorders. Human genetic studies have recently identified ZMIZ1 and its de novo mutations as causal of a neurodevelopmental syndrome strongly associated with intellectual disability, autism, ADHD, microcephaly, and other developmental anomalies. However, the role of ZMIZ in brain development or how ZMIZ1 mutations cause neurological phenotypes is unknown. Here, we generated a forebrain-specific Zmiz1 mutant mouse model that develops brain abnormalities, including cortical microcephaly, corpus callosum dysgenesis, and abnormal differentiation of upper-layer cortical neurons. Behaviorally, Zmiz1 mutant mice show alterations in motor activity, anxiety, communication, and social interactions with strong sex differences, resembling phenotypes associated with autism. Molecularly, Zmiz1 deficiency leads to transcriptomic changes disrupting neurogenesis, neuron differentiation programs, and synaptic signaling. We identified Zmiz1-mediated downstream regulation of key neurodevelopmental factors, including Lhx2, Auts2, and EfnB2. Importantly, reactivation of the EfnB2 pathway by exogenous EFNB2 recombinant protein rescues the dendritic outgrowth deficits in Zmiz1 mutant cortical neurons. Overall, our in vivo findings provide insight into Zmiz1 function in cortical development and reveal mechanistic underpinnings of ZMIZ1 syndrome, thereby providing valuable information relevant to future studies on this neurodevelopmental disorder.

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32. Khan NA, Shang X. ASD-GANNet: A Generative Adversarial Network-Inspired Deep Learning Approach for the Classification of Autism Brain Disorder. Brain Sci;2024 (Jul 29);14(8)

The classification of a pre-processed fMRI dataset using functional connectivity (FC)-based features is considered a challenging task because of the set of high-dimensional FC features and the small dataset size. To tackle this specific set of FC high-dimensional features and a small-sized dataset, we propose here a conditional Generative Adversarial Network (cGAN)-based dataset augmenter to first train the cGAN on computed connectivity features of NYU dataset and use the trained cGAN to generate synthetic connectivity features per category. After obtaining a sufficient number of connectivity features per category, a Multi-Head attention mechanism is used as a head for the classification. We name our proposed approach « ASD-GANNet », which is end-to-end and does not require hand-crafted features, as the Multi-Head attention mechanism focuses on the features that are more relevant. Moreover, we compare our results with the six available state-of-the-art techniques from the literature. Our proposed approach results using the « NYU » site as a training set for generating a cGAN-based synthetic dataset are promising. We achieve an overall 10-fold cross-validation-based accuracy of 82%, sensitivity of 82%, and specificity of 81%, outperforming available state-of-the art approaches. A sitewise comparison of our proposed approach also outperforms the available state-of-the-art, as out of the 17 sites, our proposed approach has better results in the 10 sites.

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33. Kliemann D, Galdi P, Van De Water AL, Egger B, Jarecka D, Adolphs R, Ghosh SS. Resting-State Functional Connectivity of the Amygdala in Autism: A Preregistered Large-Scale Study. Am J Psychiatry;2024 (Aug 29):appiajp20230249.

OBJECTIVE: Three leading neurobiological hypotheses about autism spectrum disorder (ASD) propose underconnectivity between brain regions, atypical function of the amygdala, and generally higher variability between individuals with ASD than between neurotypical individuals. Past work has often failed to generalize, because of small sample sizes, unquantified data quality, and analytic flexibility. This study addressed these limitations while testing the above three hypotheses, applied to amygdala functional connectivity. METHODS: In a comprehensive preregistered study, the three hypotheses were tested in a subset (N=488 after exclusions; N=212 with ASD) of the Autism Brain Imaging Data Exchange data sets. The authors analyzed resting-state functional connectivity (FC) from functional MRI data from two anatomically defined amygdala subdivisions, in three hypotheses with respect to magnitude, pattern similarity, and variability, across different anatomical scales ranging from whole brain to specific regions and networks. RESULTS: A Bayesian approach to hypothesis evaluation produced inconsistent evidence in ASD for atypical amygdala FC magnitude, strong evidence that the multivariate pattern of FC was typical, and no consistent evidence of increased interindividual variability in FC. The results strongly depended on analytic choices, including preprocessing pipeline for the neuroimaging data, anatomical specificity, and subject exclusions. CONCLUSIONS: A preregistered set of analyses found no reliable evidence for atypical functional connectivity of the amygdala in autism, contrary to leading hypotheses. Future studies should test an expanded set of hypotheses across multiple processing pipelines, collect deeper data per individual, and include a greater diversity of participants to ensure robust generalizability of findings on amygdala FC in ASD.

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34. Lawson RJ, Lipovsek NJ, Brown SP, Jena AK, Osko JJ, Ransdell JL. Selective deletion of Tsc1 from mouse cerebellar Purkinje neurons drives sex-specific behavioral impairments linked to autism. bioRxiv;2024 (Aug 7)

There is a striking sex bias in the prevalence and severity of autism spectrum disorder (ASD) with 80% of diagnoses occurring in males. Because the molecular etiology of ASD is likely combinatorial, including interactions across multiple genetic and environmental factors, it is difficult to investigate the physiological mechanisms driving sex-specific differences. Loss of function mutations in TSC1 result in dysregulated mTORC1 signaling and underlie a multi-system disorder known as tuberous sclerosis (TSC). Interestingly, more than 50% of individuals diagnosed with TSC are also diagnosed with ASD, making TSC mutations one of the most prevalent monogenic causes of ASD. Mice harboring targeted deletion of Tsc1 selectively in cerebellar Purkinje neurons, referred to here as Tsc1 (mut/mut) , have multiple ASD-linked behavioral impairments, including deficits in social interactions, motor coordination, and vocalizations. However, these ASD-linked behavioral deficits have only been investigated using male Tsc1 (mut/mut) animals. Here, we used cohorts of male and female Tsc1 (mut/mut) animals to determine if behavioral impairments, previously identified in this model, are similar across sex. Specifically, we measured balance and motor coordination and social interaction behaviors in two age groups across sex. W e determined balance and motor coordination deficits are similar in male and female Tsc1 (mut/mut) mice, and that deficits in the firing of Tsc1 (mut/mut) Purkinje neurons located in the cerebellar vermis are also similar across sex. However, impairments in social approach behavior were found to be significantly more severe in Tsc1 (mut/mut) males compared to females. These results indicate the selective deletion of Tsc1 in Purkinje neurons differentially impairs cerebellar circuits based on sex.

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35. Le Bras A. Metformin treatment for fragile X syndrome. Lab Anim (NY);2024 (Sep);53(9):218.

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36. Li BZ, Poleg S, Ridenour M, Tollin D, Lei T, Klug A. Computational model for synthesizing auditory brainstem responses to assess neuronal alterations in aging and autistic animal models. bioRxiv;2024 (Aug 7)

The auditory brainstem response (ABR) is a widely used objective electrophysiology measure for non-invasively assessing auditory function and neural activities in the auditory brainstem, but its ability to reflect detailed neuronal processes is limited due to the averaging nature of the electroencephalogram recordings. This study addresses this limitation by developing a computational model of the auditory brainstem which is capable of synthesizing ABR traces based on a large, population scale neural extrapolation of a spiking neuronal network of auditory brainstem neural circuitry. The model was able to recapitulate alterations in ABR waveform morphology that have been shown to be present in two medical conditions: animal models of autism and aging. Moreover, in both of these conditions, these ABR alterations are caused by known distinct changes in auditory brainstem physiology, and the model could recapitulate these changes. In the autism model, the simulation revealed myelin deficits and hyperexcitability, which caused a decreased wave III amplitude and a prolonged wave III-V interval, consistent with experimentally recorded ABRs in Fmr1-KO mice. In the aging model, the model recapitulated ABRs recorded in aged gerbils and indicated a reduction in activity in the medial nucleus of the trapezoid body (MNTB), a finding validated by confocal imaging data. These results demonstrate not only the model’s accuracy but also its capability of linking features of ABR morphologies to underlying neuronal properties and suggesting follow-up physiological experiments. SIGNIFICANCE STATEMENT: This study presents a novel computational model of the auditory brainstem, capable of synthesizing auditory brainstem response (ABR) traces by simulating large-scale neuronal activities. Addressing limitations of traditional ABR measurements, the model links ABR waveform features to underlying neuronal properties. Validated using empirical ABRs from animal models of autism and aging, the model accurately reproduced observed ABR alterations, revealing influences of myelin deficits and hyperexcitability in Fragile X syndrome, and degraded inhibitory activity in aging. These findings, supported by experimental data, demonstrate the model’s potential for predicting changes in auditory brainstem physiology and guiding further physiological investigations, thus advancing our understanding of auditory neural processes.

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37. Li J, Zheng W, Fu X, Zhang Y, Yang S, Wang Y, Zhang Z, Hu B, Xu G. Individual Deviation-Based Functional Hypergraph for Identifying Subtypes of Autism Spectrum Disorder. Brain Sci;2024 (Jul 24);14(8)

Heterogeneity has been one of the main barriers to understanding and treatment of autism spectrum disorder (ASD). Previous studies have identified several subtypes of ASD through unsupervised clustering analysis. However, most of them primarily depicted the pairwise similarity between individuals through second-order relationships, relying solely on patient data for their calculation. This leads to an underestimation of the complexity inherent in inter-individual relationships and the diagnostic information provided by typical development (TD). To address this, we utilized an elastic net model to construct an individual deviation-based hypergraph (ID-Hypergraph) based on functional MRI data. We then conducted a novel community detection clustering algorithm to the ID-Hypergraph, with the aim of identifying subtypes of ASD. By applying this framework to the Autism Brain Imaging Data Exchange repository data (discovery: 147/125, ASD/TD; replication: 134/132, ASD/TD), we identified four reproducible ASD subtypes with roughly similar patterns of ALFF between the discovery and replication datasets. Moreover, these subtypes significantly varied in communication domains. In addition, we achieved over 80% accuracy for the classification between these subtypes. Taken together, our study demonstrated the effectiveness of identifying subtypes of ASD through the ID-hypergraph, highlighting its potential in elucidating the heterogeneity of ASD and diagnosing ASD subtypes.

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38. Lineberry S, Bogenschutz M, Broda M. Proxy Responses in Research on COVID-19 Among People With Intellectual and Developmental Disabilities. Am J Intellect Dev Disabil;2024 (Sep 1);129(5):346-361.

Researchers and advocates have long called for improved research methods that better include people with intellectual and developmental disabilities (IDD), but challenges to doing so persist. Proxy responses are frequently used to circumvent some of these challenges, but may not fully capture the perspectives of people with IDD. The COVID-19 pandemic highlighted the possibility of consequences due to a lack of research about health outcomes for people with IDD, with documented disproportionate impact but little understanding about specific experiences for people with IDD. Using exploratory graph analysis (EGA) we explored the use of proxy responses on the COVID-19 Supplement of the National Core Indicators In-Person Survey. Findings suggest significant differences in response patterns between people who answered independently, via proxy, and with a mix of response types beyond what would be expected due to demographic differences in participants.

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39. Ludyga S, Bruggisser F, Leuenberger R, Ishihara T, Kamijo K, Brotzmann M, Trescher S, Förster M, Gerber M. Acute effects of exercise on gaze fixation and affective response inhibition in children with autism spectrum disorder: A randomized cross-over study. Autism Res;2024 (Aug 30)

Children with autism spectrum disorder (ASD) show impairments in response inhibition, especially in socio-emotional contexts. A single aerobic exercise session has the potential to temporarily reduce such impairments as findings from neurotypical children support acute benefits of this exercise type for inhibitory control and emotion recognition. In children with ASD, we therefore aimed to investigate the effects of an aerobic exercise bout on response inhibition in an emotional Go/NoGo task and gaze fixation as possible mechanism underlying changes in performance. Using a cross-over design, 29 patients completed a 20-min aerobic exercise bout at moderate intensity on a cycling ergometer and a control condition in a randomized order. An emotional Go/NoGo task was administered before and after both experimental conditions. Eye-tracking was performed during the cognitive task to assess the duration of gaze fixation of eyes and mouth parts of faces expressing happy or sad emotions. The results support no beneficial effect of exercise on performance on the emotional Go/NoGo task. Instead, patients showed a greater decrease in accuracy on Go trials displaying happy faces in the exercise compared to the control condition. This change was associated with a more pronounced decrease in the fixation duration of the eyes for faces expressing either happy or sad emotions. In conclusion, while a single session of moderately intense aerobic exercise does not affect response inhibition, it temporarily aggravates ASD-specific deficits in the processing of and response to facial emotions.

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40. Lundy KM, Fischer AJ, Illapperuma-Wood CR, Schultz B. Understanding autistic youths’ menstrual product preferences and caregivers’ product choices. Autism;2024 (Aug 30):13623613241275280.

There is little research exploring the menstrual product preferences of autistic youth, especially those who recently started their period. Study authors surveyed caregivers’ choice of menstrual products for their autistic children. They provided popular menstrual materials to autistic youth to try, then asked them which product(s) they preferred, did not try, and why they did not try it. Caregivers selected sensory impact as the most important feature they consider when choosing a menstrual product for their child, and youth participants preferred to use period underwear. Therefore, autistic youth may benefit from purchasing and using period underwear, and caregivers, clinicians, and companies should consider the impact of menstrual product features, like sensory sensitivities, on young autistic menstruators and how best to support them.

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41. Makale MT, Nybo C, Blum K, Dennen CA, Elman I, Murphy KT. Pilot Study of Personalized Transcranial Magnetic Stimulation with Spectral Electroencephalogram Analyses for Assessing and Treating Persons with Autism. J Pers Med;2024 (Aug 12);14(8)

Autism spectrum condition (ASC) is a neurodevelopmental condition that is only partly responsive to prevailing interventions. ASC manifests core challenges in social skills, communication, and sensory function and by repetitive stereotyped behaviors, along with imbalances in the brain’s excitatory (E) and inhibitory (I) signaling. Repetitive transcranial magnetic stimulation (rTMS) has shown promise in ASC and may be a useful addition to applied behavioral analysis (ABA), a gold-standard psychotherapeutic intervention. We report an open-label clinical pilot (initial) study in which ABA-treated ASC persons (n = 123) received our personalized rTMS protocol (PrTMS). PrTMS uses low TMS pulse intensities and continuously updates multiple cortical stimulation locales and stimulation frequencies based on the spectral EEG and psychometrics. No adverse effects developed, and 44% of subjects had ASC scale scores reduced to below diagnostic cutoffs. Importantly, in PrTMS responders, the spectral EEG regression flattened, implying a more balanced E/I ratio. Moreover, with older participants, alpha peak frequency increased, a positive correlate of non-verbal cognition. PrTMS may be an effective ASC intervention, offering improved cognitive function and overall symptomatology. This warrants further research into PrTMS mechanisms and specific types of subjects who may benefit, along with validation of the present results and exploration of broader clinical applicability.

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42. McLean KJ, Bishop L. Chronic Health Conditions Among Adults With Intellectual and Developmental Disabilities in a State Medicaid System. Am J Intellect Dev Disabil;2024 (Sep 1);129(5):331-345.

Despite a growing number of adults with intellectual and developmental disabilities (IDD) and documented risk for adverse outcomes as they age, little is known about the health and healthcare patterns of adults with different IDD throughout adulthood. This study uses Wisconsin Medicaid claims data to characterize health conditions among adults with IDD. Results indicate high prevalence of asthma, diabetes, heart disease, and hypertension. Heart disease rates were particularly high, having been observed among 39% of autistic adults, 64% of autistic adults with intellectual disability (ID), 67% of adults with Down syndrome, and 75% of adults with ID only. Given there are no known biological differences underlying increased morbidities among most people with IDD, developing inclusive prevention measures should be prioritized in future research.

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43. Meera SS, Srikar M, Raju R, Swaminathan D, Johnson RE, Watson LR, Nair DB, Kommu JVS, Chopra-McGowan J, Vasuki PP. Feasibility and acceptability of a caregiver-mediated early support program, delivered online, for infants at elevated familial likelihood for autism: A feasibility randomized controlled trial. Autism Res;2024 (Aug 28)

Preliminary evidence indicates potential benefit of providing caregiver-mediated intervention, prior to diagnosis, for infants at elevated familial likelihood for autism and related developmental delays including language delay (EL-A). However, delivering such interventions online and in low-resource settings like India has not been reported. This study aimed to evaluate the feasibility and acceptability of delivering a novel manualized caregiver-mediated early support program, the « LiL’ STEPS, » online in India, for EL-A infants. LiL’ STEPS stands for Language development & Intervention Lab’s (LiL’) Supporting Early social-communication and language by Promoting caregiver Sensitive responsiveness (STEPS). The program comprised 14 sessions with a focus on social-communication and language, conducted over 12-weeks using demonstration and video feedback. Families of 36 EL-A infants aged 9 to 15-months participated in this feasibility randomized controlled trial (RCT). Families were randomized in a 2:1 ratio (n = 24 LiL’ STEPS and n = 12 care as usual groups). Information on feasibility and acceptability was collated following a mixed methods approach from caregiver interviews, fidelity forms, session notes, and study register. Findings indicated the LiL’ STEPS study trial as feasible and acceptable with recruitment rate of 4 per month, 100% willingness for randomization, 8.3% attrition, and 3.03% loss of blinding. Interventionist and caregiver fidelity was maintained above 80%. Despite challenges like interruptions during sessions, 100% families found the program acceptable and satisfactory, 86% said they would recommend the program to others, and 71% preferred online modality. Caregivers’ perspectives on beneficial components and experience attending the program have been described. Accordingly, recommendations for future definitive RCTs have been presented.

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44. Mitrakos AK, Kosma K, Makrythanasis P, Tzetis M. The Phenotypic Spectrum of 16p11.2 Recurrent Chromosomal Rearrangements. Genes (Basel);2024 (Aug 10);15(8)

The human 16p11.2 chromosomal region is rich in segmental duplications which mediate the formation of recurrent CNVs. CNVs affecting the 16p11.2 region are associated with an increased risk for developing neuropsychiatric disorders, including autism spectrum disorder (ASD), schizophrenia, and intellectual disability (ID), as well as abnormal body weight and head circumference and dysmorphic features, with marked phenotypic variability and reduced penetrance. CNVs affecting the 16p11.2 region mainly affect a distal interval of ~220 Kb, between Breakpoints 2 and 3 (BP2-BP3), and a proximal interval of ~593 Kb (BP4-BP5). Here, we report on 15 patients with recurrent 16p11.2 rearrangements that were identified among a cohort of 1600 patients (0.9%) with neurodevelopmental disorders. A total of 13 deletions and two duplications were identified, of which eight deletions included the proximal 16p11.2 region (BP4-BP5) and five included the distal 16p11.2 region (BP2-BP3). Of the two duplications that were identified, one affected the proximal and one the distal 16p11.2 region; however, both patients had additional CNVs contributing to phenotypic severity. The features observed and their severity varied greatly, even between patients within the same family. This article aims to further delineate the clinical spectrum of patients with 16p11.2 recurrent rearrangements in order to aid the counselling of patients and their families.

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45. Mohammadi A, Ghazavi Z, Moghadam MF. The Effect of a Happiness Education Program on the Expressed Emotion and Quality of Life of Mothers of Children with Autism Spectrum Disorder. Iran J Nurs Midwifery Res;2024 (Jul-Aug);29(4):446-451.

BACKGROUND: The mental health of the parents of Autism Spectrum Disorder (ASD), particularly the mothers, is poor due to the severity and complex nature of this condition, and they encounter numerous issues. This investigation aimed to determine whether happiness education affected mothers of children with ASD’s Expressed Emotions (EE) and Quality of Life (QoL). MATERIALS AND METHODS: A total of 70 mothers of children with ASD aged 3 to 13 years participated in this clinical trial study research. The experimental group received the Fordyce happiness training program once every 6 weeks via WhatsApp. In three stages, data were collected using a demographic form, the Family Questionnaire (FQ), and the World Health Organization Quality Of Life Instrument, Short Form (WHOQOL-BREF) (before the intervention, immediately afterward, and 1 month later). In the Statistical Package for Social Sciences (SPSS) software, the acquired data were analyzed using independent-sample t-tests, Chi-square tests, and repeated-measures Analysis of Variance (ANOVA). RESULTS: There was no significant difference in EE and QoL mean scores between the two groups before the intervention, but after, the intervention group’s mean score of EE (20.91 (4.355)) was substantially lower than the control group’s (44.74 (4.77)) (p < 0.001). In comparison, the intervention group's mean score of QoL and its dimensions was more significant than the control group's (p < 0.001). CONCLUSIONS: Given the efficacy of the happiness education program in reducing EE and enhancing QoL in mothers of children with ASD, such treatment strategies should be developed and used.

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46. Mohammadkhani R, Salehi I, Safari S, Ghahremani R, Komaki A, Asaad Karimi S. Continuous exercise training rescues hippocampal long-term potentiation in the VPA rat model of Autism: Uncovering sex-specific effects. Neuroscience;2024 (Aug 28)

Long-term potentiation (LTP) impairment has been reported in many studies of autistic models. The aim of the present study was to investigate the effects of interval training (IT) and continuous training (CT) exercises on LTP in the hippocampal dentate gyrus (DG) neurons of valproic acid (VPA) rat model of autism. To induce an autism-like model, pregnant rats were injected 500 mg/kg NaVPA (intraperitoneal) on the embryonic day 12.5. IT and CT aerobic exercises started on postnatal day 56 in the offspring. Four weeks after IT and/or CT exercises, the offspring were urethane-anesthetized and placed into a stereotaxic apparatus for surgery, electrode implantation, and field potential recording. In the DG region, excitatory post synaptic potentials (EPSP) slope and population spike (PS) amplitude were measured. Sex differences in LTP were evident for control rats but not for VPA-exposed offspring. LTP was significantly smaller in VPA-exposed male offspring compared with control male rats. In contrast to males, there was no difference between VPA-exposed female offspring and control female rats. Interestingly, we observed a sex difference in the response to exercise between VPA-exposed male and female offspring. CT exercise training (but not IT) increased LTP in VPA-exposed male offspring. Both IT and CT exercise trainings had no effect on intact LTP in VPA-exposed female offspring. Our work suggests that there may be differences in the benefits of exercise interventions based on sex, and CT exercise training could be more beneficial for LTP improvements.

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47. Nakip OS, Kesici S, Konuskan GD, Yazici MU, Konuskan B, Bayrakci B. Neurodevelopmental Outcomes of Pediatric Cardiac Extracorporeal Membrane Oxygenation Survivors With Central Cannulation. Am J Intellect Dev Disabil;2024 (Sep 1);129(5):377-386.

Extracorporeal life support, such as pediatric cardiac extracorporeal membrane oxygenation (ECMO), is associated with significant mortality and morbidity risk. This study evaluated cardiac ECMO survivors with central cannulation and found that 51.1% were discharged from the hospital. The study also revealed high rates of developmental delay (82.7%), motor dysfunction (58.8%), and cognitive dysfunction (70.6%) among survivors. No significant correlation was found between the duration of ECMO, age at ECMO, pre-ECMO maximum lactate levels, and cognitive scores. Participants with motor dysfunction were significantly younger (p = 0.04). PRISM scores of those with an abnormal developmental status were significantly higher (p = 0.03). Logistic regression analysis did not show a significantly increased risk. Factors such as age, disease severity, and ECMO itself were identified as potential contributors to neurodevelopmental delay.

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48. Neul JL, Benke TA, Marsh ED, Suter B, Fu C, Ryther RC, Skinner SA, Lieberman DN, Feyma T, Beisang A, Heydemann P, Peters SU, Ananth A, Percy AK. Clinical Features and Disease Progression in Older Individuals with Rett Syndrome. Genes (Basel);2024 (Aug 22);15(8)

Although long-term survival in Rett syndrome (RTT) has been observed, limited information on older people with RTT exists. We hypothesized that increased longevity in RTT would be associated with genetic variants in MECP2 associated with milder severity, and that clinical features would not be static in older individuals. To address these hypotheses, we compared the distribution of MECP2 variants and clinical severity between younger individuals with Classic RTT (under 30 years old) and older individuals (over 30 years old). Contrary to expectation, enrichment of a severe MECP2 variant (R106W) was observed in the older cohort. Overall severity was not different between the cohorts, but specific clinical features varied between the cohorts. Overall severity from first to last visit increased in the younger cohort but not in the older cohort. While some specific clinical features in the older cohort were stable from the first to the last visit, others showed improvement or worsening. These data do not support the hypothesis that mild MECP2 variants or less overall severity leads to increased longevity in RTT but demonstrate that clinical features change with increasing age in adults with RTT. Additional work is needed to understand disease progression in adults with RTT.

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49. Öz F, Kaya İ, Tanır Y, Küçükgergin C, Aydın AF. Comparison of Serum Neurofilament Light Chain and Tau Protein Levels in Cases with Autism Spectrum Disorder and Their Healthy Siblings and Healthy Controls. Clin Psychopharmacol Neurosci;2024 (Aug 31);22(3):502-511.

OBJECTIVE: : There is a growing interest among clinicians and researchers in identifying potential biomarkers associated with autism. Neurofilament light chain (NfL) and Tau protein, which are proteins associated with neurodegeneration and neuroaxonal degeneration, are particularly promising potential biomarker candidates in this field. METHODS: : In this study, we compared serum NfL (sNfL) and serum Tau (sTau) levels in Autism spectrum disorder (ASD) patients, their healthy siblings (HS), and healthy controls (HC), aimed to investigate their relationship with ASD severity. Our study included 43 ASD-diagnosed participants, 43 HS participants and 42 HC participants. Clinical characteristics of the participants were assesed by Kiddie Schedule for Affective Disorders and Schizophrenia, Childhood Autism Rating Scale, Aberrant Behavior Checklist, and Strengths and Difficulties Questionnaire. Serum samples were subjected to analysis via enzyme-linked immunosorbent assay to quantitatively measure the levels of NfL and Tau protein. RESULTS: : sNfL levels in the ASD group were significantly higher than both of the control groups. Regarding sTau levels, no significant difference was found between study and control groups. In addition, NfL and Tau levels were not significantly correlated with ASD symptom severity. CONCLUSION: : Our findings may indicate that the sNfl levels associated with neuroaxonal damage may constitue a potential clinical biomarker rather than being an endophenotype phenomena.

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50. Peristeri E, Drakoulaki K, Boznou A, Nerantzini M, Gena A, Lengeris A, Varlokosta S. What Silent Pauses Can ‘Tell’ Us About the Storytelling Skills of Autistic Children: Relations Between Pausing, Language Skills and Executive Functions. J Autism Dev Disord;2024 (Aug 29)

Silent pauses may serve communicative purposes such as demarcating boundaries between discourse units in language production. Previous research has shown that autistic children differ in their pausing behavior from typically-developing (TD) peers, however, the factors behind this difference remain underexplored. The current study was aimed at comparing the use of silent pauses in the narrative production of autistic children and age-matched TD children, and also to identify possible relations between pausing behavior and the children’s language and executive function abilities. According to the study’s findings, the autistic children did not differ from their TD peers in the use of grammatical pauses, however, the former tended to produce significantly less syntactically complex narratives than the TD group, which increased the likelihood that the autistic group would pause appropriately at phrasal boundaries. Though we have found low rates of ungrammatical silent pauses and omitted pauses in obligatory discourse contexts across both groups, autistic children with lower cognitive flexibility tended to use more ungrammatical pauses than their peers with higher cognitive flexibility scores. Also, the autistic group tended to omit obligatory silent pauses more often as their narration became more complex. The results demonstrate that syntactic complexity in narrative production modulated autistic children’s pausing behavior, and that structurally simple narrations boosted the autistic group’s appropriate use of grammatical pauses. The overall findings also demonstrate the importance of studying silent pauses in the narrative discourse of autistic children, and also highlight the links between silent pauses and the children’s syntactic and cognitive skills.

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51. Rahaie Z, Rabiee HR, Alinejad-Rokny H. CNVDeep: deep association of copy number variants with neurocognitive disorders. BMC Bioinformatics;2024 (Aug 29);25(1):283.

BACKGROUND: Copy number variants (CNVs) have become increasingly instrumental in understanding the etiology of all diseases and phenotypes, including Neurocognitive Disorders (NDs). Among the well-established regions associated with ND are small parts of chromosome 16 deletions (16p11.2) and chromosome 15 duplications (15q3). Various methods have been developed to identify associations between CNVs and diseases of interest. The majority of methods are based on statistical inference techniques. However, due to the multi-dimensional nature of the features of the CNVs, these methods are still immature. The other aspect is that regions discovered by different methods are large, while the causative regions may be much smaller. RESULTS: In this study, we propose a regularized deep learning model to select causal regions for the target disease. With the help of the proximal [20] gradient descent algorithm, the model utilizes the group LASSO concept and embraces a deep learning model in a sparsity framework. We perform the CNV analysis for 74,811 individuals with three types of brain disorders, autism spectrum disorder (ASD), schizophrenia (SCZ), and developmental delay (DD), and also perform cumulative analysis to discover the regions that are common among the NDs. The brain expression of genes associated with diseases has increased by an average of 20 percent, and genes with homologs in mice that cause nervous system phenotypes have increased by 18 percent (on average). The DECIPHER data source also seeks other phenotypes connected to the detected regions alongside gene ontology analysis. The target diseases are correlated with some unexplored regions, such as deletions on 1q21.1 and 1q21.2 (for ASD), deletions on 20q12 (for SCZ), and duplications on 8p23.3 (for DD). Furthermore, our method is compared with other machine learning algorithms. CONCLUSIONS: Our model effectively identifies regions associated with phenotypic traits using regularized deep learning. Rather than attempting to analyze the whole genome, CNVDeep allows us to focus only on the causative regions of disease.

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52. Reyes-Martín J, Simó-Pinatella D, Andrés A. Emotional Reactions of Professionals to Challenging Behaviors in People with Intellectual and Developmental Disability. Behav Sci (Basel);2024 (Aug 13);14(8)

Professionals working with people with intellectual and developmental disability (IDD) can be exposed to challenging behaviors (CBs), which may result in professionals exhibiting emotional reactions that can impact their practices. This study examined these reactions and analyzed how they are influenced by the individual characteristics of people with IDD (gender, age, and level of IDD) and the variables related to CB (type of behavior and its frequency and behavioral function). A total of 125 professionals assessed 293 people with IDD who exhibited CBs. The professionals were asked to complete the Behavior Problems Inventory-Short Form, the Emotional Reactions to Challenging Behavior Scale, and the Questions About Behavior Function measure. It was revealed that positive emotional reactions predominated over negative ones. Significant results were found regarding the level of disability and the age of people with IDD. Emotional reactions were related to the severity of CBs, especially self-injurious and aggressive/destructive behavior, as well as certain behavioral functions. The severity of CBs and the age of people with IDD emerge as key predictors of the emotional reactions of professionals. In short, these reactions vary according to different variables, highlighting the importance of interventions that address professionals’ emotional needs.

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53. Reynolds M, Faron N, Hoekel J, Tychsen L. Refractive surgery to correct visual impairments in 267 children with autism spectrum and related neuro-developmental disorders: improvements in vision and behavior. Med Hypothesis Discov Innov Ophthalmol;2024 (Summer);13(2):88-95.

BACKGROUND: Children with autism spectrum disorder (ASD) may have impaired vision owing to high refractive errors and aversion to spectacles or contact lenses. Visual blurring is caused by near-sighted myopia, far-sighted hyperopia, or astigmatism in one or both eyes. Refractive surgery can restore sharp vision and eliminate the need for spectacles and contact lenses. Restoration of sharp vision may improve ASD behavior. We aimed to determine the refractive outcomes in this cohort using ophthalmic measures and behavioral and school performance alterations after refractive surgery by employing parent-proxy reports. METHODS: This interventional, retrospective case series included data from 267 children with refractive errors and neurodevelopmental disorders (NDDs) diagnosed as ASD alone or NDD with ASD-like behaviors over a 15-year period. One of three refractive surgery methods was employed, with the choice of method uniquely tailored to the child’s eye anatomy. Laser photorefractive keratectomy (PRK) was performed in 131 children, implantation of a phakic intraocular lens (pIOL) in 115 children, and removal of the crystalline lens and implantation of an intraocular lens (refractive lens exchange, RLE) in 21 children. All procedures were performed under brief general anesthesia, with the child returning home on the same day. RESULTS: The median age at surgery was 10.9 years and the median follow-up period was 3.1 years. Pre-operative refractive errors ranged from a mean (standard deviation) +7.5 (0.09) D to -14.3 (4.8) D. Surgery corrected 87% of the children to normal focal length (± 1 D). Visual acuity improved an average of 0.6 logarithm of the minimum angle of resolution, the equivalent of 6 lines on a standard eye chart. Change in visual acuity was significant (all P < 0.01) between baseline and the most recent follow-up examination in each of subgroups. Change in spherical equivalent refractive error at 3, 12, 24, 36, 60, and > 60 months post-operatively were significant (all P < 0.01) between baseline and each follow-up visit in each of subgroups. Social interactions and ASD behaviors improved in 72% (192) of the treated children (P < 0.01). The incidence of sight-threatening complications was low. CONCLUSIONS: Refractive surgery improves both visual function and behavior in most children with ASD and major myopia, hyperopia, or astigmatism. The PRK, pIOL, and RLE procedures appear to be effective and reasonably safe methods for improving refractive error, visual acuity, and behavior in many ametropic children with ASD and ASD-like NDDs.

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54. Sannar EM, Winter JR, Franke RK, Werner E, Rochowiak R, Romani PW, Miller OS, Bainbridge JL, Enabulele O, Thompson T, Natvig C, Mikulich-Gilbertson SK, Tartaglia NR. Cannabidiol for treatment of Irritability and Aggressive Behavior in Children and Adolescents with ASD: Background and Methods of the CAnnabidiol Study in Children with Autism Spectrum DisordEr (CASCADE) Study. medRxiv;2024 (Aug 13)

INTRODUCTION: Autism spectrum disorder (ASD) is a neurodevelopmental disorder commonly associated with behavioral challenges. There are few evidence based pharmacological interventions available for the treatment of behavioral symptoms associated with ASD. Cannabidiol (CBD), the non-psychoactive component of cannabis, has potential neuroprotective, antiepileptic, anxiolytic, and antipsychotic effects and may be useful in treating the behavioral symptoms of ASD. METHODS: We describe the research methods of a 27-week double-blind placebo-controlled cross-over trial of cannabidiol for the treatment of irritability and aggression associated with ASD, utilizing the irritability subscale of the Aberrant Behavior Checklist-2nd edition (ABC-2) as the primary outcome measure. Adverse effects and safety monitoring protocols are included. Several secondary and exploratory outcomes measures also include anxiety, communication, repetitive behaviors, attention, hyperactivity, autism family experience, and telehealth functional behavior assessment. CONCLUSION: There is a significant need for clinical research exploring alternative medications for the treatment of behavioral symptoms of ASD. Cannabidiol (CBD) is being studied for the management of irritability, aggression, and other problem behaviors associated with ASD.

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55. Santomauro DF, Hedley D, Sahin E, Brugha TS, Naghavi M, Vos T, Whiteford HA, Ferrari AJ, Stokes MA. The global burden of suicide mortality among people on the autism spectrum: A systematic review, meta-analysis, and extension of estimates from the Global Burden of Disease Study 2021. Psychiatry Res;2024 (Aug 20);341:116150.

We aimed to quantify the risk, mortality, and burden of suicide among autistic persons. We searched PubMed, Embase, and PsycINFO on 5(th) April 2023 for sources reporting the relative risk (RR) of suicide or suicide attempt among autistic persons (PROSPERO registration: CRD42021265313). Autism spectrum prevalence and suicide mortality and years of life lost (YLLs), were sourced from the Global Burden of Disease Study 2021. RRs pooled via meta-regression and health metrics estimates were used to estimate the excess suicide mortality and YLLs among autistic persons. We sourced 983 unique studies of which ten studies met inclusion criteria, consisting of 10.4 million persons. The pooled RR for suicide for autistic persons was 2·85 (95% UI: 2·05-4·03), which was significantly higher for autistic females than autistic males. No evidence of publication bias was detected via inspection of funnel plot and Egger’s test. Globally, we estimated 13 400 excess suicide deaths among autistic persons in 2021, equating to 1·8% of all suicide deaths and 621 000 excess YLLs. Studies were limited in number and geographical coverage. Effective suicide prevention strategies for autistic persons may substantially reduce the fatal burden of suicides globally and reduce the health burden experienced within this population.

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56. Traetta ME, Chaves Filho AM, Akinluyi ET, Tremblay M. Neurodevelopmental and Neuropsychiatric Disorders. Adv Neurobiol;2024;37:457-495.

This chapter will focus on microglial involvement in neurodevelopmental and neuropsychiatric disorders, particularly autism spectrum disorder (ASD), schizophrenia and major depressive disorder (MDD). We will describe the neuroimmune risk factors that contribute to the etiopathology of these disorders across the lifespan, including both in early life and adulthood. Microglia, being the resident immune cells of the central nervous system, could play a key role in triggering and determining the outcome of these disorders. This chapter will review preclinical and clinical findings where microglial morphology and function were examined in the contexts of ASD, schizophrenia and MDD. Clinical evidence points out to altered microglial morphology and reactivity, as well as increased expression of pro-inflammatory cytokines, supporting the idea that microglial abnormalities are involved in these disorders. Indeed, animal models for these disorders found altered microglial morphology and homeostatic functions which resulted in behaviours related to these disorders. Additionally, as microglia have emerged as promising therapeutic targets, we will also address in this chapter therapies involving microglial mechanisms for the treatment of neurodevelopmental and neuropsychiatric disorders.

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57. Vannelli A, Mariano V, Bagni C, Kanellopoulos AK. Activation of the 5-HT1A Receptor by Eltoprazine Restores Mitochondrial and Motor Deficits in a Drosophila Model of Fragile X Syndrome. Int J Mol Sci;2024 (Aug 13);25(16)

Neurons rely on mitochondrial energy metabolism for essential functions like neurogenesis, neurotransmission, and synaptic plasticity. Mitochondrial dysfunctions are associated with neurodevelopmental disorders including Fragile X syndrome (FXS), the most common cause of inherited intellectual disability, which also presents with motor skill deficits. However, the precise role of mitochondria in the pathophysiology of FXS remains largely unknown. Notably, previous studies have linked the serotonergic system and mitochondrial activity to FXS. Our study investigates the potential therapeutic role of serotonin receptor 1A (5-HT1A) in FXS. Using the Drosophila model of FXS, we demonstrated that treatment with eltoprazine, a 5-HT1A agonist, can ameliorate synaptic transmission, correct mitochondrial deficits, and ultimately improve motor behavior. While these findings suggest that the 5-HT1A-mitochondrial axis may be a promising therapeutic target, further investigation is needed in the context of FXS.

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58. Wang L, Clark EA, Hanratty L, Koblan KS, Foley A, Dedic N, Bristow LJ. TAAR1 and 5-HT(1B) receptor agonists attenuate autism-like irritability and aggression in rats prenatally exposed to valproic acid. Pharmacol Biochem Behav;2024 (Aug 26):173862.

Despite the rising prevalence of autism spectrum disorder (ASD), there remains a significant unmet need for pharmacotherapies addressing its core and associative symptoms. While some atypical antipsychotics have been approved for managing associated irritability and aggression, their use is constrained by substantial side effects. This study aimed firstly to develop behavioral measures to explore frustration, irritability and aggression phenotypes in the rat prenatal valproic acid (VPA) model of ASD. Additionally, we investigated the potential of two novel mechanisms, 5-HT(1B) and TAAR1 agonism, to alleviate these behaviors. Male offspring exposed to prenatal VPA were trained to achieve stable performance on a cued operant task, followed by pharmacological assessment in an operant frustration test, bottle brush test and resident intruder test. VPA exposed rats demonstrated behaviors indicative of frustration and irritability, as well as increased aggression compared to controls. The irritability-like behavior and aggression were further exacerbated in animals previously experiencing a frustrative event during the operant test. Single administration of the 5-HT(1B) agonist CP-94253 or TAAR1 agonist RO5263397 attenuated the frustration-like behavior compared to vehicle. Additionally, both agonists reduced irritability-like behavior under both normal and frustrative conditions. While CP-94253 reduced aggression in the resident intruder test under both conditions, RO5263397 only produced effects in rats that previously experienced a frustrative event. Our study describes previously uncharacterized phenotypes of frustration, irritability, and aggression in the rat prenatal VPA model of ASD. Administration of selective TAAR1 or 5-HT(1B) receptor agonists alleviated these deficits, warranting further exploration of both targets in ASD treatment.

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59. Wang PJ, Liao HF, Chen LC, Kang LJ, Lu L, Barrett KC. Child and Family Predictors for Mastery Motivation in Children With Developmental Delays. Am J Intellect Dev Disabil;2024 (Sep 1);129(5):387-404.

Motivation is a key factor for child development, but very few studies have examined child and family predictors of both child task and perceived motivation. Thus, the three aims of this 6-month longitudinal study in preschoolers with global developmental delays (GDD) were to explore: 1) differences between task and perceived motivation in cognitive domain; 2) differences among three domains of perceived motivation: cognitive, gross motor, and social; and 3) early child and family predictors of cognitive task motivation and the three domains of perceived motivation 6 months later. Results indicated that preschoolers with GDD showed higher cognitive task motivation than cognitive perceived motivation, and lower perceived cognitive motivation than the other two perceived motivation domains. Different child and family factors predicted cognitive task motivation and the three domains of perceived motivation. Practitioners should educate caregivers on how to observe children’s motivation to enhance children’s active participation.

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60. Wilpert NM, Thamm R, Thamm M, Kratzsch J, Seelow D, Vogel M, Krude H, Schuelke M. Normal Values for the fT3/fT4 Ratio: Centile Charts (0-29 Years) and Their Application for the Differential Diagnosis of Children with Developmental Delay. Int J Mol Sci;2024 (Aug 6);25(16)

Primary congenital hypothyroidism is easily diagnosed on the basis of elevated plasma levels of thyroid-stimulating hormone (TSH). In contrast, in the rare disorders of thyroid hormone resistance, TSH and, in mild cases, also thyroid hormone levels are within the normal range. Thyroid hormone resistance is caused by defects in hormone metabolism, transport, or receptor activation and can have the same serious consequences for child development as congenital hypothyroidism. A total of n = 23,522 data points from a large cohort of children and young adults were used to generate normal values and sex-specific percentiles for the ratio of free triiodothyronine (T3) to free thyroxine (T4), the fT3/fT4 ratio. The aim was to determine whether individuals with developmental delay and genetically confirmed thyroid hormone resistance, carrying defects in Monocarboxylate Transporter 8 (MCT8), Thyroid Hormone Receptor alpha (THRα), and Selenocysteine Insertion Sequence-Binding Protein 2 (SECISBP2), had abnormal fT3/fT4 ratios. Indeed, we were able to demonstrate a clear separation of patient values for the fT3/fT4 ratio from normal and pathological controls (e.g., children with severe cerebral palsy). We therefore recommend using the fT3/fT4 ratio as a readily available screening parameter in children with developmental delay for the identification of thyroid hormone resistance syndromes. The fT3/fT4 ratio can be easily plotted on centile charts using our free online tool, which accepts various SI and non-SI units for fT3, fT4, and TSH.

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61. Wright B, Bell KJ, Blackwell JE, Teige C, Mandefield L, Wang HI, Welch C, Scantlebury A, Watson J, McMillan D, Standley E, Attwell L, Carrick H, Taylor A, Taylor O, Hodkinson R, Edwards H, Pearson H, Parrott S, Marshall D, Varley D, Hargate R, McLaren A, Elizabeth Hewitt C. Impact of Social Stories on social and emotional health of autism spectrum primary school children: the ASSSIST2 RCT with economic evaluation. Health Technol Assess;2024 (Aug);28(39):1-121.

BACKGROUND: Differences in the way autistic children experience the world can contribute to anxiety and stress. Carol Gray’s Social Stories™ are a highly personalised intervention to support children by providing social information about specific situations in an individual story. OBJECTIVES: This randomised controlled trial aimed to establish whether Social Stories are clinically effective and cost-effective in improving social responsiveness and social and emotional health in children on the autism spectrum in schools. DESIGN: A multisite pragmatic cluster randomised controlled trial comparing Social Stories with care as usual. SETTING: Eighty-seven schools (clusters) across Yorkshire and the Humber. PARTICIPANTS: Two hundred and forty-nine children were randomised via a bespoke system hosted at York Trials Unit (129 Social Stories and 120 care as usual). Recruitment was completed in May 2021. Participants were children aged 4-11 years with a diagnosis of autism, alongside teachers, interventionists and caregivers. Recruitment was via schools, NHS trusts, support groups and local publicity. INTERVENTION: The intervention included training for educational professionals and caregivers covering psychoeducation and implementation of Social Stories. Stories were written around contextualised goals around the child’s need for social information. Interventionists read the Social Story™ with the child at least six times over 4 weeks during school. MAIN OUTCOME MEASURE: The primary outcome was the Social Responsiveness Scale-2 completed by teachers at 6 months (the primary end point), which measures social awareness, cognition, communication and behaviour. Data were collected from caregivers and educational professionals at 6 weeks and 6 months through questionnaires. Blinding of participants was not possible. RESULTS: At 6 months, the estimated difference in expected teacher-reported Social Responsiveness Scale-2 T-score (the primary end point) was -1.61 (95% confidence interval -4.18 to 0.96, p = 0.220), slightly favouring the intervention group. The estimated differences for the parent-reported secondary outcomes at 6 months were small and generally favoured the control group except the measure of children’s quality-adjusted life-year (+ 0.001, 95% confidence interval -0.032 to 0.035) and parental stress (-1.49, 95% confidence interval -5.43 to 2.46, p = 0.460), which favoured the intervention group. Children in the intervention group met their individual goals more frequently than children who received usual care alone (0.97 confidence interval 0.21 to 1.73, p = 0.012). The intervention is likely to save small costs (-£191 per child, 95% confidence interval -767.7 to 337.7) and maintain a similar quality of life compared to usual care. The probability of Social Stories being a preferred option is 75% if the society is willing to pay £20,000 per quality-adjusted life-year gained. Limitations include considerable disruptions during the coronavirus disease 2019 pandemic. CONCLUSION: Social Stories are used in schools and represent a low-cost intervention. There is no clinically evident impact on social responsiveness, anxiety and/or depression, parental stress or general health. Benefits were observed for specific behavioural goals as assessed by the teacher, and Social Stories may serve as a useful tool for facilitating dialogue between children and school staff to address specific behavioural challenges. Usage should be at the school’s discretion. FUTURE WORK: Given the uncertainty of the results in light of coronavirus disease 2019, further work to establish the impact of Social Stories is merited. TRIAL REGISTRATION: This trial is registered as ISRCTN11634810. FUNDING: This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (NIHR award ref: 16/111/91) and is published in full in Health Technology Assessment; Vol. 28, No. 39. See the NIHR Funding and Awards website for further award information. Autism affects the way children experience the world, and some children find social situations stressful. We wanted to know whether Social Stories™, developed by Carol Gray, helped children with their social skills and behaviour in school and whether they offered value for money. A randomised controlled trial design was used, which gave schools an equal chance of being asked to deliver Social Stories or to continue providing care as usual. Two hundred and forty-nine children from 87 schools took part and we trained school staff and parents to write and deliver Social Stories. We agreed with teachers and parents, what each child needed help with and wrote stories with this in mind. Trained staff read the Social Story with the child at least six times over 4 weeks. Follow-up information was collected from parents and school staff at the start of the study, after 6 weeks and 6 months. After 6 months, teachers completed a questionnaire called the Social Responsiveness Scale-2 which measures the child’s social skills. Using these measures, the results suggest that Social Stories do not lead to any significant changes in social skills, mental health, parent stress, general health or quality of life but children in schools allocated to Social Stories met their goal more frequently and incurred less costs than children who did not. Parents and educational professionals found the Social Stories intervention and training beneficial. Based on our findings, Social Stories do not appear to improve general social skills in primary-aged autistic children. Benefits were observed for specific goals, and school-based costs were reduced. eng

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62. Zanin J, Tomlin D, Rance G. Effectiveness of Noise Cancelling Earbuds in Reducing Hearing and Auditory Attention Deficits in Children with Autism. J Clin Med;2024 (Aug 14);13(16)

Background/Objectives: Autism spectrum disorder (ASD) is a lifelong neurodevelopmental condition characterised by impairments in social communication, sensory abnormalities, and attentional deficits. Children with ASD often face significant challenges with speech perception and auditory attention, particularly in noisy environments. This study aimed to assess the effectiveness of noise cancelling Bluetooth earbuds (Nuheara IQbuds Boost) in improving speech perception and auditory attention in children with ASD. Methods: Thirteen children aged 6-13 years diagnosed with ASD participated. Pure tone audiometry confirmed normal hearing levels. Speech perception in noise was measured using the Consonant-Nucleus-Consonant-Word test, and auditory/visual attention was evaluated via the Integrated Visual and Auditory Continuous Performance Task. Participants completed these assessments both with and without the IQbuds in situ. A two-week device trial evaluated classroom listening and communication improvements using the Listening Inventory for Education-Revised (teacher version) questionnaire. Results: Speech perception in noise was significantly poorer for the ASD group compared to typically developing peers and did not change with the IQbuds. Auditory attention, however, significantly improved when the children were using the earbuds. Additionally, classroom listening and communication improved significantly after the two-week device trial. Conclusions: While the noise cancelling earbuds did not enhance speech perception in noise for children with ASD, they significantly improved auditory attention and classroom listening behaviours. These findings suggest that Bluetooth earbuds could be a viable alternative to remote microphone systems for enhancing auditory attention in children with ASD, offering benefits in classroom settings and potentially minimising the stigma associated with traditional assistive listening devices.

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