Complex Autism Spectrum Disorder Research Articles

​​Auditory Sensitivity in Autism Spectrum Disorder: Assessment, Challenges, and Therapeutic Approaches

In recent years, our understanding of autism spectrum disorders (ASD) has evolved, allowing us to better understand and treat those affected by it. ASD affects behavior, physical aspects, and social development in millions of individuals nationwide. Among ASD the challenges faced by individuals with ASD, hyperacusis (reduced sound tolerance) is commonly found. This paper examines ASD's link to auditory sensitivity, especially hyperacusis, covering symptoms, causes, and interventions. Interventions such as cognitive behavioral therapy (CBT) and desensitization methods show promising results in alleviating symptoms of those with ASD. In conclusion, tailored approaches are needed for complex ASD challenges and treatment varies by individual. In order to better treat ASD, more research must be done to better understand the etiology and intricacies of this disorder. This paper emphasizes the significance of understanding ASD nuances and auditory aspects, promoting research for enhanced autism spectrum lives.

Autism Spectrum Disorder detection framework for children based on federated learning integrated CNN-LSTM

The incidence of Autism Spectrum Disorder (ASD) among children, attributed to genetics and environmental factors, has been increasing daily. ASD is a non-curable neurodevelopmental disorder that affects children’s communication, behavior, social interaction, and learning skills. While machine learning has been employed for ASD detection in children, existing ASD frameworks offer limited services to monitor and improve the health of ASD patients. This paper presents a complex and efficient ASD framework with comprehensive services to enhance the results of existing ASD frameworks. Our proposed approach is the Federated Learning-enabled CNN-LSTM (FCNN-LSTM) scheme, designed for ASD detection in children using multimodal datasets. The ASD framework is built in a distributed computing environment where different ASD laboratories are connected to the central hospital. The FCNN-LSTM scheme enables local laboratories to train and validate different datasets, including Ages and Stages Questionnaires (ASQ), Facial Communication and Symbolic Behavior Scales (CSBS) Dataset, Parents Evaluate Developmental Status (PEDS), Modified Checklist for Autism in Toddlers (M-CHAT), and Screening Tool for Autism in Toddlers and Children (STAT) datasets, on different computing laboratories. To ensure the security of patient data, we have implemented a security mechanism based on advanced standard encryption (AES) within the federated learning environment. This mechanism allows all laboratories to offload and download data securely. We integrate all trained datasets into the aggregated nodes and make the final decision for ASD patients based on the decision process tree. Additionally, we have designed various Internet of Things (IoT) applications to improve the efficiency of ASD patients and achieve more optimal learning results. Simulation results demonstrate that our proposed framework achieves an ASD detection accuracy of approximately 99% compared to all existing ASD frameworks.

Het gesprek over gezondheid met mensen met een autismespectrumstoornis: Wat is daar voor nodig?

Het gesprek over gezondheid met mensen met een autismespectrumstoornis: Wat is daar voor nodig?

Atypical local brain connectivity in pediatric autism spectrum disorder? A coordinate-based meta-analysis of regional homogeneity studies

Despite decades of massive neuroimaging research, the comprehensive characterization of short-range functional connectivity in autism spectrum disorder (ASD) remains a major challenge for scientific advances and clinical translation. From the theoretical point of view, it has been suggested a generalized local over-connectivity that would characterize ASD. This stance is known as the general local over-connectivity theory. However, there is little empirical evidence supporting such hypothesis, especially with regard to pediatric individuals with ASD (age ≤\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$$\\le$$\\end{document} 18 years old). To explore this issue, we performed a coordinate-based meta-analysis of regional homogeneity studies to identify significant changes of local connectivity. Our analyses revealed local functional under-connectivity patterns in the bilateral posterior cingulate cortex and superior frontal gyrus (key components of the default mode network) and in the bilateral paracentral lobule (a part of the sensorimotor network). We also performed a functional association analysis of the identified areas, whose dysfunction is clinically consistent with the well-known deficits affecting individuals with ASD. Importantly, we did not find relevant clusters of local hyper-connectivity, which is contrary to the hypothesis that ASD may be characterized by generalized local over-connectivity. If confirmed, our result will provide a valuable insight into the understanding of the complex ASD pathophysiology.

Heritability of Sound Processing Deficits in Autism: Neural Insights

Heritability of Sound Processing Deficits in Autism: Neural Insights

Sex differences in age of diagnosis of autism spectrum disorder: Preliminary evidence from Uganda.

This study was performed to determine (a) the age at which autism spectrum disorder (ASD) is first diagnosed in Ugandan children receiving mental health services, (b) whether age at diagnosis varies by sex and clinical presentation, and (c) the average age of ASD diagnosis in children manifesting comorbid conditions. A retrospective chart review was performed and demographic as well as clinical data were collected from children with ASD diagnoses who attended two mental health clinics in Uganda between 2014 and 2019. Descriptive statistics such as percentages, means, and standard deviations were used to summarize the data. Independent t-test was also performed to determine differences in the mean age of diagnosis between males and females. Two hundred and thirty-seven (156 males, 81 females) children with ASD were identified. The average age of ASD diagnosis was (6.9 ± 4.0) years. A statistically significant difference in age of ASD diagnosis was found between males and females (t=-2.106, p=0.036), such that on average females received a diagnosis at least 1 year later than males. Of the 237 participants, 53.6% were identified with ASD only, 16.0% had ASD and ADHD, 10.5% were diagnosed with ASD and epilepsy, and 7.2% had a diagnosis of complex ASD. The results confirm delays in access to ASD diagnosis and suggest that females are more likely to receive a ASD diagnosis later than males within the Ugandan context. ASD awareness should be intensified to improve public or professional knowledge about ASD to enhance early identification in Uganda.

Atypical Integration of Sensory-to-Transmodal Functional Systems Mediates Symptom Severity in Autism.

A notable characteristic of autism spectrum disorder (ASD) is co-occurring deficits in low-level sensory processing and high-order social interaction. While there is evidence indicating detrimental cascading effects of sensory anomalies on the high-order cognitive functions in ASD, the exact pathological mechanism underlying their atypical functional interaction across the cortical hierarchy has not been systematically investigated. To address this gap, here we assessed the functional organisation of sensory and motor areas in ASD, and their relationship with subcortical and high-order trandmodal systems. In a resting-state fMRI data of 107 ASD and 113 neurotypical individuals, we applied advanced connectopic mapping to probe functional organization of primary sensory/motor areas, together with targeted seed-based intrinsic functional connectivity (iFC) analyses. In ASD, the connectopic mapping revealed topological anomalies (i.e., excessively more segregated iFC) in the motor and visual areas, the former of which patterns showed association with the symptom severity of restricted and repetitive behaviors. Moreover, the seed-based analysis found diverging patterns of ASD-related connectopathies: decreased iFCs within the sensory/motor areas but increased iFCs between sensory and subcortical structures. While decreased iFCs were also found within the higher-order functional systems, the overall proportion of this anomaly tends to increase along the level of cortical hierarchy, suggesting more dysconnectivity in the higher-order functional networks. Finally, we demonstrated that the association between low-level sensory/motor iFCs and clinical symptoms in ASD was mediated by the high-order transmodal systems, suggesting pathogenic functional interactions along the cortical hierarchy. Findings were largely replicated in the independent dataset. These results highlight that atypical integration of sensory-to-high-order systems contributes to the complex ASD symptomatology.

SyNC, a Computationally Extensive and Realistic Neural Net to Identify Relative Impacts of Synaptopathy Mechanisms on Glutamatergic Neurons and Their Networks in Autism and Complex Neurological Disorders.

Synaptic function and experience-dependent plasticity across multiple synapses are dependent on the types of neurons interacting as well as the intricate mechanisms that operate at the molecular level of the synapse. To understand the complexity of information processing at synaptic networks will rely in part on effective computational models. Such models should also evaluate disruptions to synaptic function by multiple mechanisms. By co-development of algorithms alongside hardware, real time analysis metrics can be co-prioritized along with biological complexity. The hippocampus is implicated in autism spectrum disorders (ASD) and within this region glutamatergic neurons constitute 90% of the neurons integral to the functioning of neuronal networks. Here we generate a computational model referred to as ASD interrogator (ASDint) and corresponding hardware to enable in silicon analysis of multiple ASD mechanisms affecting glutamatergic neuron synapses. The hardware architecture Synaptic Neuronal Circuit, SyNC, is a novel GPU accelerator or neural net, that extends discovery by acting as a biologically relevant realistic neuron synapse in real time. Co-developed ASDint and SyNC expand spiking neural network models of plasticity to comparative analysis of retrograde messengers. The SyNC model is realized in an ASIC architecture, which enables the ability to compute increasingly complex scenarios without sacrificing area efficiency of the model. Here we apply the ASDint model to analyse neuronal circuitry dysfunctions associated with autism spectral disorder (ASD) synaptopathies and their effects on the synaptic learning parameter and demonstrate SyNC on an ideal ASDint scenario. Our work highlights the value of secondary pathways in regard to evaluating complex ASD synaptopathy mechanisms. By comparing the degree of variation in the synaptic learning parameter to the response obtained from simulations of the ideal scenario we determine the potency and time of the effect of a particular evaluated mechanism. Hence simulations of such scenarios in even a small neuronal network now allows us to identify relative impacts of changed parameters and their effect on synaptic function. Based on this, we can estimate the minimum fraction of a neuron exhibiting a particular dysfunction scenario required to lead to complete failure of a neural network to coordinate pre-synaptic and post-synaptic outputs.

CGH Findings in Children with Complex and Essential Autistic Spectrum Disorder.

Autism spectrum disorder (ASD) is a heterogeneous neurodevelopmental condition with a strong genetic basis. We accurately assessed 209 ASD subjects, categorized in complex (47) and essential (162), and performed array comparative genomic hybridization to identify pathogenic and recurrent Copy Number Variants (CNVs). We found 117 CNVs in 75 patients, 11 classified as pathogenic. The complex ASD subjects have higher frequency of pathogenic CNVs with a diagnostic yield of 12.8%. Familiality, cognitive and verbal abilities, severity of autistic symptoms, neuroimaging and neurophysiological findings are not related to genetic data. This study identifies loci of interest for ASD and highlights the importance of a careful phenotypic characterization, as complex ASD is related to higher rate of pathogenic CNVs.

Évaluation clinique des pratiques intégratives dans les troubles du spectre autistique (EPIGRAM) : méthodologie, population à l’inclusion et satisfaction des familles à 12 mois

BackgroundIntegrative care practices (ICPs) in the management of autism spectrum disorders (ASDs) do not currently receive sufficient rigorous evaluation. Moreover, they lack formalisation despite their important place in clinical practice, particularly in France, where they are implemented in day care hospital structures. We present here the methodology of the EPIGRAM study financed by the French General Directorate of Healthcare Organisations (PREPS 2013), the profile of the inclusive population (M0), and the experience of families after 12 months of care. MethodIn order to homogenise practices, a manual has been formalised following the methodology of the clinical pathway and the recommendations of the High Authority of health. We then conducted an open, multi-centre, observational study in a natural environment in routine care evaluating ICPs in ASDs for children aged 3 to 6 years. The main inclusion criteria were the diagnosis (typical or atypical autism, according to the ICD10) and the duration of care (2 to 4 half-days per week) during the first year of care. The children were clinically assessed using several instruments including the PEP-3 (Psychoeducational Profile-3) and the CARS (Children Autism Rating Scale). In order to maintain a blind assessment for the main variable, randomly assigned videos of the PEP-3 were rated by two independent psychologists. A questionnaire, completed separately by the families and the professionals at inclusion and at one year, complemented the study. ResultsWe included 89 children demonstrated to have severe autism through the CARS (mean=44; SD=6.51) and moderate autism through he PEP-3 maladaptive behaviour category (CAT MB) (mean=30; SD=29.89). The children were all diagnosed before the age of 3 years 6 months. Most of the children had severe language impairments. With PEP-3, the impairment is more pronounced in gross motor skills and characteristic verbal behaviours. Thirty percent of the families had a low socioeconomic status and 56 % were first generation immigrants. Seventy-seven percent of the children were enrolled in kindergarten with school life support. Children of immigrant parents have more severe autism (CARS : mean=45.8 (±6.51) vs. 41.2 (±5.58), t-test, P=0.001) in addition to a more marked cognitive deficit (CVP : median=24.5 [min–max: 9.75–45.5] vs. 52 [min–max: 26–76], Wilcoxon, P=0.001). At entry, the collection of the signs at the structured clinical observation met the signs noted by the families as being the object of their concern. With standardised tools, these observations constituted an efficient functional and multidimensional analysis for the integrative care project. At 12 months, the families’ level of satisfaction was high and consistent with that of the practitioners. ConclusionOur results show that the day units take care of a population of children with predominantly severe and complex ASDs, for the most part, from families with low socioeconomic status and first-generation immigration. The relevance of the multidimensional observation and the care project of the ISPs were confirmed by the families at entry and after 12 months of care.

Diagnostic efficacy and new variants in isolated and complex autism spectrum disorder using molecular karyotyping.

Autism spectrum disorder (ASD) is a group of the neurodevelopment disorders presenting as an isolated ASD or more complex forms, where a broader clinical phenotype comprised of developmental delay and intellectual disability is present. Both the isolated and complex forms have a significant causal genetic component and submicroscopic genomic copy number variations (CNV) are the most common identifiable genetic factor in these patients. The data on microarray testing in ASD cohorts are still accumulating and novel loci are often identified; therefore, we aimed to evaluate the diagnostic efficacy of the method and the relevance of implementing it into routine genetic testing in ASD patients. A genome-wide CNV analysis using the Agilent microarrays was performed in a group of 150 individuals with an isolated or complex ASD. Altogether, 11 (7.3%) pathogenic CNVs and 15 (10.0%) variants of unknown significance (VOUS) were identified, with the highest proportion of pathogenic CNVs in the subgroup of the complex ASD patients (14.3%). An interesting case of previously unreported partial UPF3B gene deletion was identified among the pathogenic CNVs. Among the CNVs with unknown significance, four VOUS involved genes with possible correlation to ASD, namely genes SNTG2, PARK2, CADPS2 and NLGN4X. The diagnostic efficacy of aCGH in our cohort was comparable with those of the previously reported and identified an important proportion of genetic ASD cases. Despite the continuum of published studies on the CNV testing in ASD cohorts, a considerable number of VOUS CNVs is still being identified, namely 10.0% in our study.

Syndromic autism spectrum disorders: moving from a clinically defined to a molecularly defined approach

Autism spectrum disorder (ASD) encompasses a group of neurodevelopmental conditions diagnosed solely on the basis of behavioral assessments that reveal social deficits. Progress has been made in understanding its genetic underpinnings, but most ASD-associated genetic variants, which include copy number variants (CNVs) and mutations in ASD-risk genes, account for no more than 1 % of ASD cases. This high level of genetic heterogeneity leads to challenges obtaining and interpreting genetic testing in clinical settings. The traditional definition of syndromic ASD is a disorder with a clinically defined pattern of somatic abnormalities and a neurobehavioral phenotype that may include ASD. Most have a known genetic cause. Examples include fragile X syndrome and tuberous sclerosis complex. We propose dividing syndromic autism into the following two groups: (i) ASD that occurs in the context of a clinically defined syndrome-recognizing these disorders depends on the familiarity of the clinician with the features of the syndrome, and the diagnosis is typically confirmed by targeted genetic testing (eg, mutation screening of FMR1); (ii) ASD that occurs as a feature of a molecularly defined syndrome-for this group of patients, ASD-associated variants are identified by genome-wide testing that is not hypothesis driven (eg, microarray, whole exome sequencing). These ASD groups cannot be easily clinically defined because patients with a given variant have variable somatic abnormalities (dysmorphism and birth defects). In this article, we review common diagnoses from the above categories and suggest a testing strategy for patients, guided by determining whether the individual has essential or complex ASD; patients in the latter group have multiple morphologic anomalies on physical examination. Finally, we recommend that the syndromic versus nonsyndromic designation ultimately be replaced by classification of ASD according to its genetic etiology, which will inform about the associated spectrum and penetrance of neurobehavioral and somatic manifestations.

Molecular Investigation of Autism May Bring Genetic Diagnosis Closer

Back to table of contents Previous article Next article Clinical and Research NewsFull AccessMolecular Investigation of Autism May Bring Genetic Diagnosis CloserAaron LevinAaron LevinSearch for more papers by this authorPublished Online:1 Oct 2015https://doi.org/10.1176/appi.pn.2015.10a16AbstractPatients with autism spectrum disorder may benefit from genetic tests that guide more precise diagnosis and treatment.Clinical observation of behavior and evaluation of certain minor physical anomalies serve to diagnose autism spectrum disorder (ASD), but both diagnosis and treatment might be made more precise with better insight into the underlying genetics of each individual’s version of the disorder.One new study takes another step in that direction by combining two different ways of probing the genome.A team of researchers studied 258 children from Labrador and Newfoundland who were previously diagnosed clinically with ASD. Some had minor physical anomalies, “slight morphological deviations present in less than 5 percent of the normal population,” according to Kristiina Tammimies, Ph.D., of Toronto’s Hospital for Sick Children, and colleagues, writing in JAMA September 1. Sometimes a dysmorphology can identify a specific syndrome, but it usually functions as a clue that something else is going on that requires investigation.The children also were given magnetic resonance brain imaging scans to look for structural brain abnormalities. From that information, the researchers created a total morphological score, dividing the cohort into “essential” (that is, with few anomalies), “complex” (with many anomalies), or “equivocal” (in between) ASD groups.“The premise … is that individuals for whom there is evidence of an insult to early morphogenesis would have developed their autism on a different basis than individuals for whom morphogenesis proceeded normally,” wrote Judith Miles, M.D., Ph.D., a professor emerita of child health and genetics at the University of Missouri in Columbia, in an accompanying editorial.Finally, each child received two genetic tests: chromosomal microarray analysis (CMA) and whole-exome sequencing (WES). CMA identifies copy number variants (duplicated or deleted lengths of DNA), and WES identifies single nucleotide polymorphisms.CMA has been in use for some time, and the American Academy of Genetics recommends its use for all children diagnosed with ASD. The test is usually reimbursed by insurance companies because it yields meaningful information, said Jeremy Veenstra-VanderWeele, M.D., an associate professor of psychiatry at Columbia University, who was not involved with the study. WES has been used so far as a research tool. “But here, it adds information above and beyond the CMA.”The CMA alone revealed that the complex ASD group had a higher proportion of pathologic CNVs (24.5 percent) than the essential group (4.2 percent). For WES, the rates for probands with a molecular diagnosis were 16.7 percent in the complex group and 3.1 percent in the essential group. Using both methods, the combined yield of molecular diagnoses was significantly higher in the complex group than the essential group.“A combined molecular diagnostic yield of 15.8 percent was found in those children who received both tests,” wrote Tammimies. That more than triples the yield relative to results a decade ago. “Our study illustrates the genetic and phenotypic heterogeneity of ASD.”The costs of such genetic tests are coming down, said Veenstra-VanderWeele. The CMA now costs about $300 to $500 per test, and the WES is down to $1,000 per test in research projects.Even now, existing genetic tests can be helpful for the families of patients with ASD, both for guiding treatment decisions and for other reasons, said Veenstra-VanderWeele. “Also, if the mutation is inherited from the parents, they can make decisions about family planning,” said Veenstra-VanderWeele. “And you can’t underestimate the value to the family of providing a reason for ASD or suggesting potential avenues to treatments.”The study of one mutation, for instance, led to hypotheses about dietary adjustments for patients with ASD. Those changes were tested in mice and then in patients and found to ameliorate symptoms.“It seems possible that it will not be too long before the evidence presented by Tammimies et al will prompt a … recommendation to include whole-exome DNA sequencing as a first-tier ASD test, if not for all ASD diagnoses, certainly for children with physical dysmorphology,” concluded Miles. ■“Molecular Diagnostic Yield of Chromosomal Microarray Analysis and Whole-Exome Sequencing in Children With Autism Spectrum Disorder” can be accessed here. “Complex Autism Spectrum Disorders and Cutting-Edge Molecular Diagnostic Tests” is available here. ISSUES NewArchived

Truncating mutations of MAGEL2 cause Prader-Willi phenotypes and autism

Prader-Willi Syndrome (PWS) is caused by the absence of paternally expressed, maternally silenced genes at 15q11-q13. We report four individuals with truncating mutations on the paternal allele of MAGEL2, a gene within the PWS domain. The first subject was ascertained by whole genome sequencing analysis for PWS features. Three additional subjects were identified by reviewing results of exome sequencing of 1248 cases in a clinical laboratory. All four subjects had autism spectrum disorder (ASD), intellectual disability (ID), and a varying degree of clinical and behavioral features of PWS. These findings suggest MAGEL2 is a novel gene causing complex ASDs, and MAGEL2loss of function can contribute to several aspects of the PWS phenotype.

Complex autism spectrum disorder in a patient with a 17q12 microduplication

Autism spectrum disorders (ASDs) are phenotypically complex developmental neuropsychiatric disorders affecting approximately 0.6% of the population. About 30-70% of affected children are also considered to have intellectual disability (ID). The underlying genetic causes of ASDs are diverse with a defined etiology in 16-20%. Array comparative genomic hybridization (aCGH) has proven useful in identifying sub-microscopic chromosome aberrations in a subset of patients, some of which have been shown to be recurrent. One such aberration is the 1.4 Mb microdeletion at chromosome 17q12, which has been reported to be associated with renal disease, growth restriction, diabetes, cognitive impairment, seizures, and in some cases an ASD. Patients with the reciprocal chromosome 17q12 microduplication typically have also been identified with ID and in some cases seizures and behavioral abnormalities. Here we report a patient with a de novo, 1.4 Mb microduplication diagnosed with significant ID involving complex deficits and autism. To our knowledge, this is the first report of a patient with the 17q12 microduplication and a complex ASD phenotype.