1. Atmar K, Defrancq A, Hermans M, van Vliet C, Kasius M. [Catatonia in youth with developmental disabilities: challenges in recognition and management]. Tijdschr Psychiatr;2024;66(1):46-50.

Catatonia in children and adolescents is not rare and, as in adults, has a favorable outcome, provided it is recognized and treated promptly. Nevertheless, in clinical practice we encounter several obstacles in terms of diagnosis and treatment in this population of patients. We describe a 14-year-old boy with an intellectually disability and autism spectrum disorder (ASD) in which clinicians did not diagnose catatonia until 1 year after the development of symptoms. Moreover, hesitations surrounding the correct treatment led to its delayed initiation. With this case report we aim to contribute to reduced reluctance and increased alertness in the treatment of catatonia in adolescents with developmental disorders.

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2. Banke TG, Traynelis SF, Barria A. Early Expression of GluN2A-Containing NMDA Receptors in A Model of Fragile X Syndrome. J Neurophysiol;2024 (Feb 21)

NMDA-type glutamate receptors (NMDARs) play a crucial role in synaptogenesis, circuit development, and synaptic plasticity, serving as fundamental components in cellular models of learning and memory. Their dysregulation has been implicated in several neurological disorders and synaptopathies. NMDARs are heterotetrameric complexes composed of two GluN1 and two GluN2 subunits. The composition of GluN2 subunits determines the main biophysical properties of the channel, such as calcium permeability and gating kinetics, and influences the ability of the receptor to interact with postsynaptic proteins involved in normal synaptic physiology and plasticity, including scaffolding proteins and signaling molecules. During early development, NMDARs in the forebrain contain solely the GluN2B subunit, a necessary subunit for proper synaptogenesis and synaptic plasticity. As the animal matures, the expression of the GluN2A subunit increases, leading to a partial replacement of GluN2B-containing synaptic NMDARs with GluN2A-containing receptors. The switch in the synaptic GluN2A/GluN2B ratio has a significant impact on the kinetics of excitatory postsynaptic currents and diminishes the synaptic plasticity capacity. In this study, we present findings indicating that GluN2A expression occurs earlier in a mouse model of FXS. This altered timing of GluN2A expression affects various important parameters of NMDAR-mediated excitatory postsynaptic currents, including maximal current amplitude, decay time, and response to consecutive stimuli delivered in close temporal proximity. These observations suggest that the early expression of GluN2A during a critical period when synapses and circuits are developing could be an underlying factor contributing to the formation of pathological circuits in the FXS mouse model.

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3. Choi B, Rowe ML. The Role of Gesture in Language Development for Neurotypical Children and Children With or at Increased Likelihood of Autism. Top Cogn Sci;2024 (Feb 21)

For young children, gesture is found to precede and predict language development. However, we are still building a knowledge base about the specific nature of the relationship between gesture and speech. While much of the research on this topic has been conducted with neurotypical children, there is a growing body of work with children who have or are at increased likelihood of autism spectrum disorder (ASD). Here, we summarize the literature on relations between gesture and speech, including the role of child gesture production as well as that of gesture exposure (caregiver gesture). We include literature on both neurotypical children and children with or at likelihood of ASD, highlight the similarities and differences across populations, and offer implications for research as well as early identification and intervention.

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4. Del Río M, de Lange FP, Fritsche M, Ward J. Perceptual confirmation bias and decision bias underlie adaptation to sequential regularities. J Vis;2024 (Feb 1);24(2):5.

Our perception does not depend exclusively on the immediate sensory input. It is also influenced by our internal predictions derived from prior observations and the temporal regularities of the environment, which can result in choice history biases. However, it is unclear how this flexible use of prior information to predict the future influences perceptual decisions. Prior information may bias decisions independently of the current sensory input, or it may modulate the weight of current sensory input based on its consistency with the expectation. To address this question, we used a visual decision-making task and manipulated the transitional probabilities between successive noisy grating stimuli. Using a reverse correlation analysis, we evaluated the contribution of stimulus-independent decision bias and stimulus-dependent sensitivity modulations to choice history biases. We found that both effects coexist, whereby there was increased bias to respond in line with the predicted orientation alongside modulations in perceptual sensitivity to favor perceptual information consistent with the prediction, akin to selective attention. Furthermore, at the individual differences level, we investigated the relationship between autistic-like traits and the adaptation of choice history biases to the sequential statistics of the environment. Over two studies, we found no convincing evidence of reduced adaptation to sequential regularities in individuals with high autistic-like traits. In sum, we present robust evidence for both perceptual confirmation bias and decision bias supporting adaptation to sequential regularities in the environment.

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5. Edwards C, Gibbs V, Love AMA, Brown L, Cai RY. A qualitative exploration of an autism-specific self-compassion program: The ASPAA. Autism;2024 (Feb 21):13623613241234097.

Autistic people often struggle to find the right support for their mental health. We wanted to change that by trying a new approach to help autistic adults with their emotions and well-being. We focused on something called « self-compassion, » which is a way of being kind and understanding toward ourselves. This approach has worked well for many people, but we didn’t know if it would work for autistic individuals. We invited 39 autistic adults to join an online program that taught them about self-compassion. The program lasted 5 weeks and included educational materials, meditation exercises, and self-reflection activities. We asked the participants for feedback each week and at the end of the program. From their responses, we discovered four important things. First, self-compassion had a big positive impact on the well-being of autistic adults. Second, they faced some challenges during the program. Third, they saw self-compassion as a journey that takes time and practice. Finally, they described how they valued changes to help autistic people engage with the program. Our findings show that self-compassion can really help autistic adults. We learned about the benefits they experienced and the difficulties they faced. Most importantly, we found that personalized support is crucial for autistic individuals. By creating programs that consider their specific needs, we can improve their mental health and make their lives better.

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6. Eygnor A, Angulo A, Cobian M, Wilson R, Coan E, Reynolds A, Friedman S, Boles RE. Assessing Community Needs for Autism Spectrum Disorder: A Review of Rural/Frontier Needs Through Community Outreach With Developmental Pediatrics. Clin Pediatr (Phila);2024 (Feb 20):99228241233803.

Early intervention is known to improve long-term outcomes for individuals with autism spectrum disorder (ASD). Access barriers to care limit timely engagement with supportive services. This report characterized the community needs and supportive services for children and families with suspected or diagnosed ASD. Families and providers participating in outreach clinics identified available services and their attitudes about support for ASD diagnosis. Chart reviews provided referral history, insurance, and current services. Children were nearly 6 years old, 95% of families relied on public health insurance, whereas 50% reported traveling 11 miles or greater for supportive services. Most providers (83%) were medically trained in primary care and placed 1-5 referrals per month to a tertiary referral hospital. Providers reported travel difficulty as the primary reason for referring patients for evaluation. Multiple barriers for supportive services were identified, highlighting the importance to increase the capacity and availability of local ASD supportive services.

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7. Frye RE, Rose S, Voinsky I, Gurwitz D. Nitrosative Stress in Autism: Supportive Evidence and Implications for Mitochondrial Dysfunction. Adv Sci (Weinh);2024 (Feb 21):e2304439.

A recent study by the Amal team published in this journal in May 2023 proved for the first time the link of nitric oxide (NO) with autism spectrum disorder (ASD), thereby opening new venues for the potential use of neuronal nitric oxide synthase (nNOS) inhibitors as therapeutics for improving the neurological and behavioral symptoms of ASD. The authors conclude that their findings demonstrate that NO plays a significant role in ASD. Indeed, earlier studies support elevated NO and its metabolites, nitrite, and peroxynitrite, in individuals diagnosed with ASD. Dysregulated NOS activity may underlie the well-documented mitochondrial dysfunction in a subset of individuals with ASD. Strategies for treating ASD shall also consider NO effects on mitochondrial respiration in modulating NOS activity. Further experimental evidence and controlled clinical trials with NOS modifiers are required for assessing their therapeutic potential for individuals with ASD.

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8. Giua G, Iezzi D, Caceres-Rodriguez A, Strauss B, Chavis P, Manzoni OJ. Sex-specific modulation of early life vocalization and cognition by Fmr1 gene dosage in a mouse model of Fragile X Syndrome. Biol Sex Differ;2024 (Feb 21);15(1):18.

BACKGROUND: Pup-dam ultrasonic vocalizations (USVs) are essential to cognitive and socio-emotional development. In autism and Fragile X Syndrome (FXS), disruptions in pup-dam USV communication hint at a possible connection between abnormal early developmental USV communication and the later emergence of communication and social deficits. METHODS: Here, we gathered USVs from PND 10 FXS pups during a short period of separation from their mothers, encompassing animals of all possible genotypes and both sexes (i.e., Fmr1-/y vs. Fmr1+/y males and Fmr1+/+, +/-, and -/- females). This allowed comparing the influence of sex and gene dosage on pups’ communication capabilities. Leveraging DeepSqueak and analyzing vocal patterns, intricate vocal behaviors such as call structure, duration, frequency modulation, and temporal patterns were examined. Furthermore, homing behavior was assessed as a sensitive indicator of early cognitive development and social discrimination. This behavior relies on the use of olfactory and thermal cues to navigate and search for the maternal or nest odor in the surrounding space. RESULTS: The results show that FMRP-deficient pups of both sexes display an increased inclination to vocalize when separated from their mothers, and this behavior is accompanied by significant sex-specific changes in the main features of their USVs as well as in body weight. Analysis of the vocal repertoire and syntactic usage revealed that Fmr1 gene silencing primarily alters the USVs’ qualitative composition in males. Moreover, sex-specific effects of Fmr1 silencing on locomotor activity and homing behavior were observed. FMRP deficiency in females increased activity, reduced nest-reaching time, and extended nest time. In males, it prolonged nest-reaching time and reduced nest time without affecting locomotion. CONCLUSIONS: These findings highlight the interplay between Fmr1 gene dosage and sex in influencing communicative and cognitive skills during infancy. In this study, we investigated ultrasonic vocalizations (USVs) and homing behavior in a mouse model of Fragile X Syndrome (FXS), a leading genetic cause of autism spectrum disorder (ASD) caused by a mutation of the X-chromosome linked Fmr1 gene. Disruptions in pup-dam USV communication and cognitive skills may be linked to the later emergence of communication and social deficits in ASD. USVs were collected from 10-day-old FXS pups of all possible genotypes and both sexes during a short period of separation from their mothers. We utilized DeepSqueak, an advanced deep learning system, to examine vocal patterns and intricate vocal behaviors, including call structure, duration, frequency modulation, and their temporal patterns. Homing, a sensitive indicator of early cognitive development and social discrimination was assessed at P13. The results showed that FXS pups of both sexes displayed an increased inclination to vocalize when separated from their mothers. Examination of the vocal repertoire and its syntactic usage revealed that the silencing of the Fmr1 gene primarily alters the qualitative composition of ultrasonic communication in males. The sex-specific changes observed in USVs were accompanied by modifications in body weight. Regarding homing behavior, the deficiency of FMRP led to opposite deficits in activity, time to reach the nest, and nesting time depending on sex. Taken together, these findings highlight the interplay between Fmr1 gene dosage and sex in shaping communication and cognition during infancy. eng

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9. Jaswal VK, Lampi AJ, Stockwell KM. Literacy in nonspeaking autistic people. Autism;2024 (Feb 21):13623613241230709.

Many autistic people who do not talk cannot tell other people what they know or what they are thinking. As a result, they might not be able to go to the schools they want, share feelings with friends, or get jobs they like. It might be possible to teach them to type on a computer or tablet instead of talking. But first, they would have to know how to spell. Some people do not believe that nonspeaking autistic people can learn to spell. We did a study to see if they can. We tested 31 autistic teenagers and adults who do not talk much or at all. They played a game on an iPad where they had to tap flashing letters. After they played the game, we looked at how fast they tapped the letters. They did three things that people who know how to spell would do. First, they tapped flashing letters faster when the letters spelled out sentences than when the letters made no sense. Second, they tapped letters that usually go together faster than letters that do not usually go together. This shows that they knew some spelling rules. Third, they paused before tapping the first letter of a new word. This shows that they knew where one word ended and the next word began. These results suggest that many autistic people who do not talk can learn how to spell. If they are given appropriate opportunities, they might be able to learn to communicate by typing.

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10. Kollayan BY, Cansiz D, Beler M, Unal I, Emekli-Alturfan E, Yalcinkaya SE. Effects of low-dose ionizing radiation on the molecular pathways linking neurogenesis and autism spectrum disorders in zebrafish embryos. Drug Chem Toxicol;2024 (Feb 21):1-14.

Prenatal exposure to environmental factors may play an important role in the aetiopathogenesis of autism spectrum disorder (ASD). We aim to investigate the potential effects of low-dose x-rays from dental diagnostic x-rays on neurodevelopment and molecular mechanisms associated with ASD in developing zebrafish embryos. Zebrafish embryos were divided into four groups and exposed using a dental x-ray unit: control, 0.08, 0.15 and 0.30 seconds, which are exemplary exposure settings for periapical imaging. These exposure times were measured as 7.17, 23.17 and 63.83 mSv using optical stimulated luminescence dosimeters. At the end of 72 hours post-fertilization, locomotor activity, oxidant-antioxidant status, and acetylcholine esterase (AChE) activity were analyzed. Expression of genes related to apoptosis (bax, bcl2a, p53), neurogenesis (α1-tubulin, syn2a, neurog1, elavl3) and ASD (eif4eb, adsl2a, shank3) was determined by RT-PCR. Even at reduced doses, developmental toxicity was observed in three groups as evidenced by pericardial edema, yolk sac edema and scoliosis. Deleterious effects of dental x-rays on neurogenesis through impaired locomotor activity, oxidative stress, apoptosis and alterations in genes associated with neurogenesis and ASD progression were more pronounced in the 0.30s exposure group. Based on these results we suggest that the associations between ASD and low-dose ionizing radiation need a closer look.

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11. Konishi S, Kuwata M, Matsumoto Y, Yoshikawa Y, Takata K, Haraguchi H, Kudo A, Ishiguro H, Kumazaki H. Self-administered questionnaires enhance emotion estimation of individuals with autism spectrum disorders in a robotic interview setting. Front Psychiatry;2024;15:1249000.

BACKGROUND: Robots offer many unique opportunities for helping individuals with autism spectrum disorders (ASD). Determining the optimal motion of robots when interacting with individuals with ASD is important for achieving more natural human-robot interactions and for exploiting the full potential of robotic interventions. Most prior studies have used supervised machine learning (ML) of user behavioral data to enable robot perception of affective states (i.e., arousal and valence) and engagement. It has previously been suggested that including personal demographic information in the identification of individuals with ASD is important for developing an automated system to perceive individual affective states and engagement. In this study, we hypothesized that assessing self-administered questionnaire data would contribute to the development of an automated estimation of the affective state and engagement when individuals with ASD are interviewed by an Android robot, which will be linked to implementing long-term interventions and maintaining the motivation of participants. METHODS: Participants sat across a table from an android robot that played the role of the interviewer. Each participant underwent a mock job interview. Twenty-five participants with ASD (males 22, females 3, average chronological age = 22.8, average IQ = 94.04) completed the experiment. We collected multimodal data (i.e., audio, motion, gaze, and self-administered questionnaire data) to train a model to correctly classify the state of individuals with ASD when interviewed by an android robot. We demonstrated the technical feasibility of using ML to enable robot perception of affect and engagement of individuals with ASD based on multimodal data. RESULTS: For arousal and engagement, the area under the curve (AUC) values of the model estimates and expert coding were relatively high. Overall, the AUC values of arousal, valence, and engagement were improved by including self-administered questionnaire data in the classification. DISCUSSION: These findings support the hypothesis that assessing self-administered questionnaire data contributes to the development of an automated estimation of an individual’s affective state and engagement. Given the efficacy of including self-administered questionnaire data, future studies should confirm the effectiveness of such long-term intervention with a robot to maintain participants’ motivation based on the proposed method of emotion estimation.

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12. Marquardt MD, Gibbs D, Grossbach A, Keister A, Munjal V, Moranville R, Mallory N, Toop N, Dhaliwal J, Marquardt H, Xu D, Viljoen S. Impact of obesity on adult spinal deformity (ASD) long-segment spinal fusion radiographic and clinical outcomes. Clin Neurol Neurosurg;2024 (Feb 21);238:108187.

STUDY DESIGN: Retrospective chart review of patients receiving long-segment fusion during a five-year period. OBJECTIVE: To determine whether obese patients receive comparable benefits when receiving long-segment fusion compared to non-obese patients and to identify factors that may predict hardware failure and post-surgical complications among obese patients. METHODS: Demographic, spinopelvic radiographic, patient-reported outcome measures (PROMs), and complications data was retrospectively collected from 120 patients who underwent long-segment fusion during a five-year period at one tertiary care medical center. Radiographic measurements were pelvic incidence, pelvic tilt (PT), lumbar lordosis, L4-S1 lordosis, thoracic kyphosis, sagittal vertical axis, PI-LL mismatch, and proximal junction cobb angle at upper instrumented vertebrae + 2 (UIV+2). PROMs were Oswestry disability index, numeric rating scale (NRS) Back Pain, NRS Leg Pain, RAND SF-36 pain, and RAND SF-36 physical functioning. Included patients were adults and had at least 2-years of postoperative follow-up. Descriptive and multivariate statistical analysis was performed with α = 0.05. RESULTS: Patients with a BMI ≥ 30 (n=63) and patients with a BMI < 30 (n=57) demonstrated comparable improvements (P>0.05) for all spinopelvic radiographic measurements and PROMs. Each cohort demonstrated significant improvements from pre-assessment to post-assessment on nearly all spinopelvic radiographic measurements and PROMs (P<0.05), except PT and L4-S1 lordosis where neither group improved (p=0.95 and 0.58 for PT and P=0.23 and 0.11 for L4-S1 lordosis fornon-obese and obese cohorts respectively) and SF-36 physical functioning where the non-obese cohort not statistically improve (P=0.08). Patients with a BMI ≥ 30 demonstrated an increased incidence of cardiovascular complications (P=0.0293), acute kidney injury (P=0.0241), rod fractures (P=0.0293), and reoperations (P=0.0241) when compared to patients with a BMI < 30. CONCLUSION: This study adds to a growing body of evidence linking demographic factors with risks of hardware failure. Further, this data challenges the assumption that obese patients may not receive sufficient benefit to be long-segment surgical candidates. However, given their elevated risk for post-operative and delayed hardware complications, obese patients should be appropriately counseling before undergoing surgery.

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13. McFayden TC, Rutsohn J, Cetin G, Forsen E, Swanson MR, Meera SS, Wolff JJ, Elison JT, Shen MD, Botteron K, Dager SR, Estes A, Gerig G, McKinstry RC, Pandey J, Schultz R, St John T, Styner M, Truong Y, Zwaigenbaum L, Hazlett HC, Piven J, Girault JB. White matter development and language abilities during infancy in autism spectrum disorder. Mol Psychiatry;2024 (Feb 21)

White matter (WM) fiber tract differences are present in autism spectrum disorder (ASD) and could be important markers of behavior. One of the earliest phenotypic differences in ASD are language atypicalities. Although language has been linked to WM in typical development, no work has evaluated this association in early ASD. Participants came from the Infant Brain Imaging Study and included 321 infant siblings of children with ASD at high likelihood (HL) for developing ASD; 70 HL infants were later diagnosed with ASD (HL-ASD), and 251 HL infants were not diagnosed with ASD (HL-Neg). A control sample of 140 low likelihood infants not diagnosed with ASD (LL-Neg) were also included. Infants contributed expressive language, receptive language, and diffusion tensor imaging data at 6-, 12-, and 24 months. Mixed effects regression models were conducted to evaluate associations between WM and language trajectories. Trajectories of microstructural changes in the right arcuate fasciculus were associated with expressive language development. HL-ASD infants demonstrated a different developmental pattern compared to the HL-Neg and LL-Neg groups, wherein the HL-ASD group exhibited a positive association between WM fractional anisotropy and language whereas HL-Neg and LL-Neg groups showed weak or no association. No other fiber tracts demonstrated significant associations with language. In conclusion, results indicated arcuate fasciculus WM is linked to language in early toddlerhood for autistic toddlers, with the strongest associations emerging around 24 months. To our knowledge, this is the first study to evaluate associations between language and WM development during the pre-symptomatic period in ASD.

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14. Miletic K, Servais M, Cardy JO, Denusik L. Do Caregiver Perceptions of the Virtual More Than Words® Program Differ Based on Autistic Children’s Attributes?. Am J Speech Lang Pathol;2024 (Feb 21):1-15.

PURPOSE: More Than Words® (MTW) is a caregiver-mediated intervention program led by a speech-language pathologist (SLP) who teaches caregivers strategies to support their autistic child’s early social communication and play development. The program includes group sessions composed of multiple families with children of varying profiles. We explored whether caregiver experiences and perceived outcomes of the virtual MTW program differed depending on the child’s age and social communication stage. METHOD: As part of a program evaluation of virtual MTW delivered to over 2,000 families in Ontario, Canada, between 2020 and 2021, we randomly selected 31 families across four social communication stages and two age groups using stratified sampling (n = 4, in all but one subgroup). The Final Reflection and Evaluation form was analyzed both qualitatively and quantitatively, and a modified RE-AIM framework guided our analyses, including theme development. RESULTS: Child attributes did not appear to impact caregivers’ experiences, but perceived child skill improvements varied by children’s social communication stage. The majority of caregivers reported changes in how they interact with their child. Four themes emerged: (a) perceived child skill improvements differed by social communication stage, (b) caregivers gained new knowledge and strategies regardless of child attributes, (c) SLPs effectively managed families’ individual needs, and (d) program components were appropriate for a variety of families. CONCLUSIONS: Findings suggest that the content taught in the MTW program was relevant for a variety of children, including those beyond the program’s intended age of 5 years and under. Grouping families of children with varying profiles does not appear to negatively influence caregivers’ experiences or perceived outcomes. SUPPLEMENTAL MATERIAL: https://doi.org/10.23641/asha.25237009.

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15. Moore R, Poulsen J, Reardon L, Samples-Morris C, Simmons H, Ramsey KM, Whatley ML, Lane JB. Managing Gastrointestinal Symptoms Resulting from Treatment with Trofinetide for Rett Syndrome: Caregiver and Nurse Perspectives. Adv Ther;2024 (Feb 20)

Rett syndrome (RTT) is a rare genetic neurodevelopmental disorder mainly affecting female individuals. Trofinetide was recently approved as the first treatment for RTT, largely on the basis of results from the phase 3 LAVENDER trial, in which trofinetide showed improvements in core symptoms of RTT compared with placebo. However, gastrointestinal (GI) symptoms such as diarrhea and vomiting were commonly reported side effects, and taste was also a reported issue. The objective of this article is to describe the perspectives of five caregivers of girls in trofinetide clinical trials as well as those of three nurse trial coordinators, with a focus on management of GI symptoms of trofinetide treatment.Audio Abstract available for this article. Audio Abstract: Jane Lane provides an overview and discusses key findings of the article titled « Managing Gastrointestinal Symptoms Resulting from Treatment with Trofinetide for Rett Syndrome: Caregiver and Nurse Perspectives. » (MP4 83274 KB).

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16. Ntoulas G, Brakatselos C, Nakas G, Asprogerakas MZ, Delis F, Leontiadis LJ, Trompoukis G, Papatheodoropoulos C, Gkikas D, Valakos D, Vatsellas G, Politis PK, Polissidis A, Antoniou K. Multi-level profiling of the Fmr1 KO rat unveils altered behavioral traits along with aberrant glutamatergic function. Transl Psychiatry;2024 (Feb 20);14(1):104.

Fragile X syndrome (FXS) is the most common cause of inherited intellectual disabilities and the most prevalent monogenic cause of autism. Although the knockout (KO) of the Fmr1 gene homolog in mice is primarily used for elucidating the neurobiological substrate of FXS, there is limited association of the experimental data with the pathophysiological condition in humans. The use of Fmr1 KO rats offers additional translational validity in this regard. Therefore, we employed a multi-level approach to study the behavioral profile and the glutamatergic and GABAergic neurotransmission status in pathophysiology-associated brain structures of Fmr1 KO rats, including the recordings of evoked and spontaneous field potentials from hippocampal slices, paralleled with next-generation RNA sequencing (RNA-seq). We found that these rats exhibit hyperactivity and cognitive deficits, along with characteristic bidirectional glutamatergic and GABAergic alterations in the prefrontal cortex and the hippocampus. These results are coupled to affected excitability and local inhibitory processes in the hippocampus, along with a specific transcriptional profile, highlighting dysregulated hippocampal network activity in KO rats. Overall, our data provide novel insights concerning the biobehavioral profile of FmR1 KO rats and translationally upscales our understanding on pathophysiology and symptomatology of FXS syndrome.

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17. Pramanik S, Bala A, Pradhan A. Zebrafish in understanding molecular pathophysiology, disease modeling, and developing effective treatments for Rett syndrome. J Gene Med;2024 (Feb);26(2):e3677.

Rett syndrome (RTT) is a rare but dreadful X-linked genetic disease that mainly affects young girls. It is a neurological disease that affects nerve cell development and function, resulting in severe motor and intellectual disabilities. To date, no cure is available for treating this disease. In 90% of the cases, RTT is caused by a mutation in methyl-CpG-binding protein 2 (MECP2), a transcription factor involved in the repression and activation of transcription. MECP2 is known to regulate several target genes and is involved in different physiological functions. Mouse models exhibit a broad range of phenotypes in recapitulating human RTT symptoms; however, understanding the disease mechanisms remains incomplete, and many potential RTT treatments developed in mouse models have not shown translational effectiveness in human trials. Recent data hint that the zebrafish model emulates similar disrupted neurological functions following mutation of the mecp2 gene. This suggests that zebrafish can be used to understand the onset and progression of RTT pathophysiology and develop a possible cure. In this review, we elaborate on the molecular basis of RTT pathophysiology in humans and model organisms, including rodents and zebrafish, focusing on the zebrafish model to understand the molecular pathophysiology and the development of therapeutic strategies for RTT. Finally, we propose a rational treatment strategy, including antisense oligonucleotides, small interfering RNA technology and induced pluripotent stem cell-derived cell therapy.

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18. Restoy D, Oriol-Escudé M, Alonzo-Castillo T, Magán-Maganto M, Canal-Bedia R, Díez-Villoria E, Gisbert-Gustemps L, Setién-Ramos I, Martínez-Ramírez M, Ramos-Quiroga JA, Lugo-Marín J. Emotion regulation and emotion dysregulation in children and adolescents with Autism Spectrum Disorder: A meta-analysis of evaluation and intervention studies. Clin Psychol Rev;2024 (Feb 21);109:102410.

Children and adolescents with Autism Spectrum Disorder (ASD) often experience challenges in emotion regulation (ER) and emotion dysregulation (ED) which can interfere with their adaptive functioning. This study aimed to systematically review and meta-analyze the evidence on ER/ED in children and/or adolescents with ASD, examining its relationship with the following variables: internalizing and externalizing symptoms, cognitive function and social skills, and the effectiveness of non-pharmacological interventions addressing ER difficulties. Both electronic and manual searches were conducted to identify potential studies. Fifty-five studies were included in the meta-analysis. A statistically significant between-group difference was found, suggesting greater ER/ED challenges in the ASD group. Also, the ASD group showed more maladaptive ER strategies and fewer adaptive ER strategies compared to the non-ASD participants. Additionally, more severe ASD and poorer social skills were associated with greater ED and poorer ER skills, respectivelly. Furthermore, there was a significant correlation between internalizing symptomatology and both adaptive and maladaptive ER strategies. Studies of non-pharmacological interventions showed significant improvement in both ER and ED. These results imply that assessing ER/ED in children and adolescents with ASD should be part of the evaluation process, and it should also be a focal point for intervention in this population.

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19. Samadi SA. Handedness in autism spectrum disorders and intellectually disabled children and adolescents – Contrasting caregivers’ reports with assessments of hand preference. Heliyon;2024 (Feb 29);10(4):e25935.

BACKGROUND: A higher rate of atypical handedness prevalence (non-right-handedness or left-, mixed-hand dominance) has been recurrently reported in individuals diagnosed with autism spectrum disorder (ASD) compared to individuals with other types of developmental disabilities. However, the exact magnitude of this difference as well as the presence of possible contributing factors remained unknown. The main aim of this study was to understand caregivers’ impression of the handedness of their child with developmental disabilities and its relationship with assessments of the child using a hand preference scale. METHODS AND PROCEDURES: The sample of the present study was 1116 individuals with developmental disabilities from two countries, 541 (51.5%) individuals from Iran and 575 (48.5%) individuals from the Kurdistan Region of Iraq (KRI). The handedness of the sample was evaluated based on the parental report and utilizing a standardized scale (The Hand-Preference Demonstration Test « HPDT »). OUTCOMES AND RESULTS: There was a statistically significant difference between caregivers’ reports on their dependents’ handedness and the application of a valid hand preference scale and they do not necessarily overlap. There was a statistically significant relationship between handedness and type of developmental disabilities based on caregivers’ reports and individuals with ASD were more non-right-handed compared to individuals with ID based on the caregivers’ report. Hence similar difference was not seen between the ASD and ID groups when HDTP was applied as a diagnostic scale. While left-handedness in the ASD and ID group was similar (23-24%), mixed-handedness in the ASD group was 38% compared to 33% in the ID group. CONCLUSIONS AND IMPLICATIONS: The Hand-Preference Demonstration Test (HPDT) was a valid way to determine the hand preference of individuals with ASD and ID. It is concluded that parental reports on their offspring with ASD’s hand preference need to be approved through the application of a scale and caregivers and professionals need to be more aware of early motor symptoms such as handedness. Further research should focus on the role of handedness in the development of fine motor skills and eye-hand coordination in children with differing developmental disabilities and variations among those differing impairments.

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20. Takada R, Toritsuka M, Yamauchi T, Ishida R, Kayashima Y, Nishi Y, Ishikawa M, Yamamuro K, Ikehara M, Komori T, Noriyama Y, Kamikawa K, Saito Y, Okano H, Makinodan M. Granulocyte macrophage colony-stimulating factor-induced macrophages of individuals with autism spectrum disorder adversely affect neuronal dendrites through the secretion of pro-inflammatory cytokines. Mol Autism;2024 (Feb 21);15(1):10.

BACKGROUND: A growing body of evidence suggests that immune dysfunction and inflammation in the peripheral tissues as well as the central nervous system are associated with the neurodevelopmental deficits observed in autism spectrum disorder (ASD). Elevated expression of pro-inflammatory cytokines in the plasma, serum, and peripheral blood mononuclear cells of ASD has been reported. These cytokine expression levels are associated with the severity of behavioral impairments and symptoms in ASD. In a prior study, our group reported that tumor necrosis factor-α (TNF-α) expression in granulocyte-macrophage colony-stimulating factor-induced macrophages (GM-CSF MΦ) and the TNF-α expression ratio in GM-CSF MΦ/M-CSF MΦ (macrophage colony-stimulating factor-induced macrophages) was markedly higher in individuals with ASD than in typically developed (TD) individuals. However, the mechanisms of how the macrophages and the highly expressed cytokines affect neurons remain to be addressed. METHODS: To elucidate the effect of macrophages on human neurons, we used a co-culture system of control human-induced pluripotent stem cell-derived neurons and differentiated macrophages obtained from the peripheral blood mononuclear cells of five TD individuals and five individuals with ASD. All participants were male and ethnically Japanese. RESULTS: Our results of co-culture experiments showed that GM-CSF MΦ affect the dendritic outgrowth of neurons through the secretion of pro-inflammatory cytokines, interleukin-1α and TNF-α. Macrophages derived from individuals with ASD exerted more severe effects than those derived from TD individuals. LIMITATIONS: The main limitations of our study were the small sample size with a gender bias toward males, the use of artificially polarized macrophages, and the inability to directly observe the interaction between neurons and macrophages from the same individuals. CONCLUSIONS: Our co-culture system revealed the non-cell autonomous adverse effects of GM-CSF MΦ in individuals with ASD on neurons, mediated by interleukin-1α and TNF-α. These results may support the immune dysfunction hypothesis of ASD, providing new insights into its pathology.

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21. Tang X, Ma Z, SiuChing K, Xu L, Liu Q, Yang L, Wang Y, Cao Q, Li X, Liu J. Altered Intrinsic Brain Spontaneous Activities in Children With Autism Spectrum Disorder Comorbid ADHD. J Atten Disord;2024 (Feb 20):10870547241233207.

OBJECTIVE: The study involved 17 children with Autism Spectrum Disorder (ASD), 21 with ADHD, 30 with both (ASD + ADHD), and 28 typically developing children (TD). METHODS: The amplitude of low-frequency fluctuations (ALFF) was measured as a regional brain function index. Intrinsic functional connectivity (iFC) was also analyzed using the region of interest (ROI) identified in ALFF analysis. Statistical analysis was done via one-way ANCOVA, Gaussian random field (GRF) theory, and post-hoc pair-wise comparisons. RESULTS: The ASD + ADHD group showed increased ALFF in the left middle frontal gyrus (MFG.L) compared to the TD group. In terms of global brain function, the ASD group displayed underconnectivity in specific regions compared to the ASD + ADHD and TD groups. CONCLUSION: The findings contribute to understanding the neural mechanisms underlying ASD + ADHD.

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22. Voldsbekk I, Kjelkenes R, Frogner ER, Westlye LT, Alnaes D. Testing the sensitivity of diagnosis-derived patterns in functional brain networks to symptom burden in a Norwegian youth sample. Hum Brain Mapp;2024 (Feb 15);45(3):e26631.

Aberrant brain network development represents a putative aetiological component in mental disorders, which typically emerge during childhood and adolescence. Previous studies have identified resting-state functional connectivity (RSFC) patterns reflecting psychopathology, but the generalisability to other samples and politico-cultural contexts has not been established. We investigated whether a previously identified cross-diagnostic case-control and autism spectrum disorder (ASD)-specific pattern of RSFC (discovery sample; aged 5-21 from New York City, USA; n = 1666) could be validated in a Norwegian convenience-based youth sample (validation sample; aged 9-25 from Oslo, Norway; n = 531). As a test of generalisability, we investigated if these diagnosis-derived RSFC patterns were sensitive to levels of symptom burden in both samples, based on an independent measure of symptom burden. Both the cross-diagnostic and ASD-specific RSFC pattern were validated across samples. Connectivity patterns were significantly associated with thematically appropriate symptom dimensions in the discovery sample. In the validation sample, the ASD-specific RSFC pattern showed a weak, inverse relationship with symptoms of conduct problems, hyperactivity and prosociality, while the cross-diagnostic pattern was not significantly linked to symptoms. Diagnosis-derived connectivity patterns in a developmental clinical US sample were validated in a convenience sample of Norwegian youth, however, they were not associated with mental health symptoms.

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23. Zhou K, Liu X, Li S, Zhang Y, An R, Ma S. The use of Treatment and Education of Autistic and Related Communication Handicapped Children in schools to improve the ability of children with autism to complete tasks independently: A single-case meta-analysis. Child Care Health Dev;2024 (Mar);50(2):e13234.

OBJECTIVE: To investigate the effectiveness of a Treatment and Education of Autistic and Related Communication Handicapped Children (TEACCH) intervention in schools for improving independent task performance in children with autism spectrum disorders (ASD). METHODS: We screened relevant studies published up to December 2022 from Web of science, ERIC, PsycINFO and other databases using predefined inclusion/exclusion criteria to identify suitable intervention studies for meta-analysis. Tau-U effect sizes were calculated for each A-B comparison extracted from the included experiments. Moderated analyses were conducted to examine the type of intervention (independent variable), intervention target behaviours (dependent variable), participant characteristics, setting characteristics and intervener characteristics. RESULTS: A total of 14 studies (38 participants) met the criteria and were included in the meta-analysis. The analysis results showed that TEACCH had a significant intervention effect, and the overall intervention effect size was Tau-U = 0.85[0.77, 0.91]. There were significant differences in the intervention target behaviour variables (p < 0.01), limited variation in the intervention type variables, but no differences in participant characteristics, setting characteristics and intervenor characteristics. CONCLUSION: The use of TEACCH is effective in improving independent task completion in children with ASD and provides evidence-based recommendations for its extended use in schools.

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