Aspects Of Autism Spectrum Disorder Research Articles

Experiences of families with children diagnosed with Autism Spectrum Disorder in World Health Organization Afro-Regions: A scoping review.

A scoping review on Autism Spectrum Disorder (ASD) and its impact on the families of affected children was undertaken due to insufficient information available on the diverse experiences impacting their lives. Using the Joanna Briggs Institute methodology, eligibility criteria were guided by Population (families), Concept (family experiences), and Context (African region). English-language articles were sought from a variety of databases and search engines. The publication date of the identified articles ranged from 2003 to 2021 with most published in 2020 (n = 10), and the majority using qualitative methodologies (n = 51). Most family members involved were parents (n = 51) and their ages ranged from 18 to 75 years. The families experienced various challenges related to their child with regard to education, healthcare, and the broader community including lack of support. Family coping strategies included believing in God, attending counseling sessions, adapting, and accepting the situation. Healthcare professionals should be prepared and positioned to educate families and siblings on various aspects of ASD. There is a need for active, continued research on families within most countries of World Health Organization Afro-region.

Phenotypical divergence between self-reported and clinically ascertained autism.

While allowing for rapid recruitment of large samples, online psychiatric and neurodevelopmental research relies heavily on participants' self-report of neuropsychiatric symptoms, foregoing the rigorous clinical characterization of laboratory settings. Autism spectrum disorder (ASD) research is one example where the clinical validity of such an approach remains elusive. Here, we compared participants characterized online via self-reports against in-person participants evaluated by clinicians. Despite having comparable self-reported autism symptoms, the online high-trait group reported significantly more social anxiety and avoidant behavior than in-person ASD subjects. Within the in-person sample, there was no relationship between self-rated and clinician-rated autism symptoms, suggesting these approaches may capture different aspects of ASD. The online high-trait and in-person ASD participants also differed in their behavior in well-validated social decision-making tasks: the in-person group perceived having less social control and acted less affiliative towards virtual characters. Our study aimed to draw comparisons at three levels: methodological platform (online versus in-person), symptom measurement (self- versus clinician-report), and social behavior. We identified a lack of agreement between self- and clinician-rated measures of symptoms and divergent social tendencies in groups ascertained by each method, highlighting the need for differentiation between in-person versus online samples in autism research.

A39Managing transitions from CAMHS for people with autism spectrum disorder (ASD) – interactive simulation training course

Transitions from CAMHS services to adult mental health care present a challenge to patients, carers, and professionals alike and are often managed poorly by services, leading to avoidable anxiety and adverse experiences for service users [1]. For patients with autism, transitions can be extremely distressing and require careful consideration and planning to ensure continuity of care. There is a lack of clarity for professionals and services users about what resources are available and appropriate for people with autism. This course is designed to provide professionals working in both CAMHS and adult mental health with a better understanding of autism and introduce strategies to improve the management of transitions and care of individuals with autism. Maudsley Learning, in collaboration with the ESTIA Centre, offered an online simulation training program on two occasions. The course aimed to provide participants with a clinical understanding of autism and autistic persons’ lived experiences, to equip participants with person-centred strategies to support individuals with autism, address the challenges faced by autistic individuals during child-to-adult transitions, and implement strategies to improve the care of individuals with autism who have co-morbid mental and physical illnesses. The training began with group icebreakers and a didactic introduction to simulation training to establish psychological safety followed by five scenarios covering different aspects of ASD and the challenges faced by individuals with ASD during transition. To add higher fidelity and better learning experience, we involved actors with autism and intellectual disability. The Maudsley debrief model was used to provide constructive feedback to participants on their contributions and facilitate positive learning experiences. Participants completed a questionnaire before and after the course assessing their confidence in skills related to the course. They also provided qualitative feedback on their experience and their willingness to apply their learning. Paired samples t-tests did not find a significant difference in scores for course-specific questions between pre-course (M =16.75 SD = 2.50) and post-course (M = 20.25, SD =.50), t(2.64)=3 p >.0.05, 95% CI [-7.70,.70]. 100% of the participants reported that they would recommend the course. This course was co-produced and involved actors with autism and intellectual disability for better learning. The score improved slightly, but not significantly due to a small number of participants. All participants found the course helpful for their clinical practice and would recommend it. The course is best conducted in-person for optimal learning experiences. Authors confirm that all relevant ethical standards for research conduct and dissemination have been met. The submitting author confirms that relevant ethical approval was granted, if applicable.

Autism spectrum disorder and GABA levels in children with succinic semialdehyde dehydrogenase deficiency.

To elucidate the etiological aspects of autism spectrum disorder (ASD) in succinic semialdehyde dehydrogenase deficiency (SSADHD), related to dysregulation of γ-aminobutyric acid (GABA) and the imbalance of excitatory and inhibitory neurotransmission. In this prospective, international study, individuals with SSADHD underwent neuropsychological assessments, as well as biochemical, neurophysiological, and neuroimaging evaluations. Of the 29 individuals (17 females) enrolled (median age [IQR] 10 years 5 months [5 years 11 months-18 years 1 month]), 16 were diagnosed with ASD. ASD severity significantly increased with age (r = 0.67, p < 0.001) but was inversely correlated with plasma GABA (r = -0.67, p < 0.001) and γ-hydroxybutyrate levels (r = -0.538, p = 0.004), and resting motor threshold as measured by transcranial magnetic stimulation (r = -0.44, p = 0.03). A discriminative analysis indicated that an age older than 7 years 2 months (p = 0.004) and plasma GABA levels less than 2.47 μM (p = 0.01) are the threshold values beyond which the likelihood of ASD presenting in individuals with SSADHD is increased. ASD is prevalent but not universal in SSADHD, and it can be predicted by lower levels of plasma GABA and GABA-related metabolites. ASD severity in SSADHD increases with age and the loss of cortical inhibition. These findings add insight into the pathophysiology of ASD and may facilitate its early diagnosis and intervention in individuals with SSADHD.

Connectome-based prediction of the severity of autism spectrum disorder.

Autism spectrum disorder (ASD) is characterized by social and behavioural deficits. Current diagnosis relies on behavioural criteria, but machine learning, particularly connectome-based predictive modelling (CPM), offers the potential to uncover neural biomarkers for ASD. This study aims to predict the severity of ASD traits using CPM and explores differences among ASD subtypes, seeking to enhance diagnosis and understanding of ASD. Resting-state functional magnetic resonance imaging data from 151 ASD patients were used in the model. CPM with leave-one-out cross-validation was conducted to identify intrinsic neural networks that predict Autism Diagnostic Observation Schedule (ADOS) scores. After the model was constructed, it was applied to independent samples to test its replicability (172 ASD patients) and specificity (36 healthy control participants). Furthermore, we examined the predictive model across different aspects of ASD and in subtypes of ASD to understand the potential mechanisms underlying the results. The CPM successfully identified negative networks that significantly predicted ADOS total scores [r (df=150) = 0.19, P=0.008 in all patients; r (df=104) = 0.20, P=0.040 in classic autism] and communication scores [r (df=150) = 0.22, P=0.010 in all patients; r (df=104) = 0.21, P=0.020 in classic autism]. These results were reproducible across independent databases. The networks were characterized by enhanced inter- and intranetwork connectivity associated with the occipital network (OCC), and the sensorimotor network (SMN) also played important roles. A CPM based on whole-brain resting-state functional connectivity can predicted the severity of ASD. Large-scale networks, including the OCC and SMN, played important roles in the predictive model. These findings may provide new directions for the diagnosis and intervention of ASD, and maybe could be the targets in novel interventions.

GC1f Vitamin D Binding Protein Isoform as a Marker of Severity in Autism Spectrum Disorders.

Autism spectrum disorders (ASD) are characterized by a wide spectrum of clinical, behavioral, and cognitive manifestations. It is, therefore, crucial to investigate possible biomarkers associated with specific ASD phenotypes. Ample literature suggests a possible role for vitamin D (VD) in influencing ASD clinical phenotypes. We analyzed three vitamin D binding protein gene (DBP) functional polymorphisms (rs2282679, rs7041, and rs4588), which are involved in the modulation of vitamin D serum concentration in 309 ASD children and 831 healthy controls. Frequency comparisons of single nucleotide polymorphisms (SNPs) alleles, genotypes, and GC isoforms (GC1f, G1s, and GC2)—generated by the combination of rs7041 and rs4588 alleles—were correlated with ASD diagnostic, behavioral, and functioning scales. The GC1f isoform was significantly more frequent in ASD compared with controls (18.6% vs. 14.5% pc = 0.02). Significantly higher scores for item 15 of the Childhood Autism Rating Scale (CARS) and lower ones for the Children’s Global Assessment Scale (CGAS) functioning scales were seen in ASD carrying the GC1f isoform. In GC phenotype analysis, a gradient of severity for overall CARS scores and CARS item 15 was observed, with scores decreasing according to the presence of GC1f-GC1f > GC1f-GC1s > GC1s-GC1s > GC1f-GC2 > GC2-GC2 isoforms. Similarly, lower CGAS scores were seen in carriers of the GC1f-GC1f isoform, whereas higher scores were present in those carrying GC2-GC2 (p = 0.028). This is the first study to evaluate possible relationships between GC variants and the different aspects of ASD in Italian ASD children. Results, although needing to be validated in ampler cohorts, suggest that the GC1f isoform could be a marker of severity in ASD that may be useful in establishing the intensity of therapeutic and rehabilitative protocols.

Aspects of autism spectrum disorder and correlation with neuroimaging findings in tuberous sclerosis complex

BackgroundTuberous sclerosis complex (TSC) patients may have different specific neuropsychological deficits related to the location of the tubers. Autism spectrum disorders (ASD) are common in TSC patients but the relationship between these diagnoses has not been formally explored. In this study we sought to examine brain Magnetic Resonance Imaging (MRI) findings in TSC patients with ASD. MethodsWe evaluated 34 TSC patients on the basis of DSM-V diagnostic criteria for ASD, Wechsler Intelligence Scale for Children (WISC-R), psychiatrist’s examination and also structured parent interviews. The number and localization of the tubers, postcontrast signal characteristics of the tubers, SWI findings, DWI findings on brain MRI were recorded. Demographic features, epilepsy histories, number of antiseizure medications, cognitive status were eveluated also. Patients were divided into two groups: ASD group, which represented group 1 and group 2 consisting of patients without any ASD symptoms. ResultsIn our study, the mean number of tuber count was 21.8 in patients with ASD patients (Group 1, n = 13) and 12.4 in other TSC patients without ASD (Group 2, n = 21). Rate of tubers in prefrontal cortex/whole tubers (0.51) in patients with ASD was determined to be higher in group 1 (p = 0.003). Also a significant difference was detected between generalize epileptiform activities on EEG and the rate of DRE (p = 0.002; p = 0.001) between groups. Cognitive disturbances and infantile spasm history were similar between groups. TSC2 mutations have been identified in 29 (86%) patients. ConclusionThe mean of total tuber count and the rate of the location in the prefrontal cortex were determined to be higher in TSC patients with ASD. Specific areas on brain MRI may help understanding the development of ASD in TSC patients.

41 Content Analysis of the Recommendations from Project Echo Ontario Autism

Abstract Background The rising prevalence of autism spectrum disorder (ASD) diagnoses has caused an increased number of community practitioners to care for this population. However, community practitioners report a lack of knowledge and confidence in treating these patients, resulting in unmet healthcare needs. The Extension of Community Healthcare Outcomes (ECHO) Autism model aims to address this through case-based and didactic learning to help guide community practitioners in providing comprehensive, best-practice care for ASD screening, diagnosis, and management of co-occurring conditions. Each ECHO session involves a case presentation followed by a list of recommendations generated by community participants and an interdisciplinary ‘hub’ team. While ECHO Autism has been shown to improve physicians' abilities to care for children with ASD in their practices, recommendations stemming from ECHO cases have yet to be characterized and may help guide future care. Objectives To quantify and characterize the common categories within ECHO Autism Ontario case recommendations. Design/Methods A content analysis of 422 recommendations from 61 ECHO cases was conducted to identify categories of recommendations and their frequencies. Three researchers independently coded recommendations from five ECHO cases, from which an original coding guide was developed. The researchers then independently coded the remaining cases and met regularly with the ECHO lead to modify and consolidate the codes and coding guide. From there, categories and sub-categories from the various codes were identified. Finally, the frequencies of each code and category were calculated. Results Fifty-seven codes were included in the final coding guide and grouped into eight broad categories. Categories included: 1) diagnosis; 2) concurrent mental and physical health conditions; 3) referrals to allied health providers and other specialists; 4) accessing community resources, such as parent and sibling support groups; 5) providing education and guidance to physicians, patients, and families; 6) management strategies such as nutrition, physical activity, and social skills; and 7) patient and family-centered care. A COVID-19 category was added, as many of the later recommendations were adapted to online service delivery. An analysis of the frequency of codes found that 1,384 total in-text codes were distributed amongst the various categories. The three highest frequencies of categories were providing general guidance and education (22%), accessing resources (16%), and referrals (15%). Conclusion This is the first time recommendations from ECHO Autism have been characterized and quantified. Our results, particularly the most common category of providing general guidance and education about ASD, show there is still important work to be done with educating clinicians and families about aspects of ASD. Furthermore, findings from this study should inform Pediatrics residency programs about real-world knowledge gaps in ASD care, and may help create more tailored ASD training programs and educational materials.

Connecting phenotype to genotype: PheWAS-inspired analysis of autism spectrum disorder.

Autism Spectrum Disorder (ASD) is extremely heterogeneous clinically and genetically. There is a pressing need for a better understanding of the heterogeneity of ASD based on scientifically rigorous approaches centered on systematic evaluation of the clinical and research utility of both phenotype and genotype markers. This paper presents a holistic PheWAS-inspired method to identify meaningful associations between ASD phenotypes and genotypes. We generate two types of phenotype-phenotype (p-p) graphs: a direct graph that utilizes only phenotype data, and an indirect graph that incorporates genotype as well as phenotype data. We introduce a novel methodology for fusing the direct and indirect p-p networks in which the genotype data is incorporated into the phenotype data in varying degrees. The hypothesis is that the heterogeneity of ASD can be distinguished by clustering the p-p graph. The obtained graphs are clustered using network-oriented clustering techniques, and results are evaluated. The most promising clusterings are subsequently analyzed for biological and domain-based relevance. Clusters obtained delineated different aspects of ASD, including differentiating ASD-specific symptoms, cognitive, adaptive, language and communication functions, and behavioral problems. Some of the important genes associated with the clusters have previous known associations to ASD. We found that clusters based on integrated genetic and phenotype data were more effective at identifying relevant genes than clusters constructed from phenotype information alone. These genes included five with suggestive evidence of ASD association and one known to be a strong candidate.

Psychophysiological aspects of autism spectrum disorder

Autism spectrum disorder is a neurodevelopmental illness marked by chronic difficulties with mutual social interaction and communication, as well as restricted or repetitive patterns of behavior, interests, or activities. ASD symptoms commonly appear in early childhood and can be identified by the age of 2 years. Early detection of ASD allows for better therapeutic interventions and management, which has been shown to lessen children's long-term intellectual, behavioral, and functional deficits while also improving family consequences. In the present review, we are focusing on important psychophysiological aspects of autism spectrum disorders.

Structure-function relationships of the disease-linked A218T oxytocin receptor variant

Various single nucleotide polymorphisms (SNPs) in the oxytocin receptor (OXTR) gene have been associated with behavioral traits, autism spectrum disorder (ASD) and other diseases. The non-synonymous SNP rs4686302 results in the OXTR variant A218T and has been linked to core characteristics of ASD, trait empathy and preterm birth. However, the molecular and intracellular mechanisms underlying those associations are still elusive. Here, we uncovered the molecular and intracellular consequences of this mutation that may affect the psychological or behavioral outcome of oxytocin (OXT)-treatment regimens in clinical studies, and provide a mechanistic explanation for an altered receptor function. We created two monoclonal HEK293 cell lines, stably expressing either the wild-type or A218T OXTR. We detected an increased OXTR protein stability, accompanied by a shift in Ca2+ dynamics and reduced MAPK pathway activation in the A218T cells. Combined whole-genome and RNA sequencing analyses in OXT-treated cells revealed 7823 differentially regulated genes in A218T compared to wild-type cells, including 429 genes being associated with ASD. Furthermore, computational modeling provided a molecular basis for the observed change in OXTR stability suggesting that the OXTR mutation affects downstream events by altering receptor activation and signaling, in agreement with our in vitro results. In summary, our study provides the cellular mechanism that links the OXTR rs4686302 SNP with genetic dysregulations associated with aspects of ASD.

Assistive technology for an inclusive school for schoolchildren with special needs: autism spectrum disorders

Background: The debate and research over autism spectrum disorders (ASD) encounter a theoretical and interpretive impasse that reflects our inability to provide a coherent definition. This challenge is confirmed by the current description of the condition as a spectrum, and its management stretches the limits of the various relevant fields of knowledge and research, including medicine, psychology, language and communication, education, sociology, human rights, ethics and legal issues, philosophy. Objectives: In the diagnostic and therapeutic approach to persons with physical disabilities, technology has been tool. In the case of ASD, however, although some lines of research are focused on the study of sensory defects, the cause appears to lie, not only in perception, but also in interpretation of stimuli from the outside world. Since we entered the “digital era”, the use of technology as an assistive tool in interpretation of the surrounding world appears to provide a borderline between our knowledge and the dark area of our ignorance. For tackling this, an interdisciplinary approach is required. Which kind of assistive technology (AT) should be employed in the case of ASD, which leads us to an encounter with the theoretical and institutional void that the stormy pace of the digital transformation and evolution has created. Methods: Searching was through PubMed, National Institute of Health (NIH) publications, the official websites of European Union , Autism Europe, resources were found in the library of the University of Macedonia. Ninety eight papers were identified through the literature review in the period 2000-2021 Results: A features of postmodern society that is taking shape under the influence of the digital technology could be the crossing from the physical reality into the virtual realm. Another feature might be the reference to symbolic language that characterizes the various different fields of knowledge, together with their protocols and communication jargon. This entails the creation of hybrid knowledge which is expanding our physical world, and which makes possible intercommunication between isolated disciplinary fields. People with ASD feel more at ease when dealing with digital entities than in interaction with other people. Also individuals who are involved in the digital realm for long periods present characteristics similar to those of ASD. Could the creation of a virtual realm be possible, which would act as a common locus between the so-called normal and people with ASD. Conclusion: We conducted a preliminary study to explore the possibility of an interdisciplinary research program with the participation of experts from the various fields involved in the many aspects of ASD.

What Exactly Is Inherited in Autism?

What Exactly Is Inherited in Autism?

A BIBLIOMETRIC ANALYSIS OF COHESIVE SPEECH RESEARCH OF PRESCHOOLERS FROM 1970 TO 2020

Cohesive speech has commonly become regarded as one of the essential aspects of language development, especially for pre-schoolers. This study aimed to shed light on the cohesive speech of pre-schoolers (CSP) knowledge base. Three hundred ninety-five publications close related cohesive speech research of 5-6-year-old children were collected from the Scopus database. By using the bibliometric approach, the results showed the growth rate of publications over time from 1970 to 2020. In this period, the top five countries, the United States, the United Kingdom, Australia, Brazil and France, have published over 60% of total documents. Besides, four main interests of authors in this field were discovered: “language development”, “speech pathology outcomes”, “speech therapy”, “language intervention”. Among these themes, “speech pathology outcomes” was the most relevant one. Another finding, in recent years, scholars focused on aspects of autism spectrum disorder of pre-schoolers. More importantly, the achievements of this discipline have considerably made positive contributions to various fields both in terms of theory and practice, especially in language and linguistics, speech and hearing, psychology, and medicine. Overall, these studies highlight the need for many other studies, particularly relevant to pre-schooling when new generations should be better prepared to be happy in school by their future cognitive developments. Keywords: language development, language intervention, speech pathology outcomes, speech therapy

Autism Spectrum Disorder (ASD) and the Family Inclusive Airport Design Experience.

The literature on air travellers with psychiatric disorders is limited. This perspective article highlights various travel-related aspects of autism spectrum disorder (ASD). The airport experience can be stressful for families of children with autism spectrum disorder (FwASDs). The aim of this study was to explore the airport experience of FwASDs using the value co-creation process approach to assist airport managers in designing improved experiences for this specific passenger segment. This study responds to the current climate in which airports are developing awareness programmes in relation to children who require special assistance at airports. The prevalence of children with ASD is 1/68. While a number of airports throughout the world have adopted procedures addressing the needs of those with cognitive impairment, these advances are far from universal. As part of an academic–industry collaboration between Vueling airlines and the Spanish airport operator Aena, 25 FwASDs took part in an inclusive airport research project in the city of Barcelona from November 2015 to April 2016. Employing a qualitative methodology that incorporated focus groups, ethnographic techniques, and post-experience surveys, the study contributes to extending the body of knowledge on the management of the value co-creation process for challenging passenger segments within the airport context. The study explains how ensuring adequate resource allocation to this passenger segment can improve the family-inclusive design of the airport experience and offers managerial recommendations.

025 Sleep Disruption on an Orbital Shaker alters Glutamate in Prairie Vole Prefrontal Cortex

Abstract Introduction Glutamate concentrations in the cortex fluctuate with the sleep wake cycle in both rodents and humans. Altered glutamatergic signaling, as well as the early life onset of sleep disturbances have been implicated in neurodevelopmental disorders such as autism spectrum disorder. In order to study how sleep modulates glutamate activity in brain regions relevant to social behavior and development, we disrupted sleep in the socially monogamous prairie vole (Microtus ochrogaster) rodent species and quantified markers of glutamate neurotransmission within the prefrontal cortex, an area of the brain responsible for advanced cognition and complex social behaviors. Methods Male and female prairie voles were sleep disrupted using an orbital shaker to deliver automated gentle cage agitation at continuous intervals. Sleep was measured using EEG/EMG signals and paired with real time glutamate concentrations in the prefrontal cortex using an amperometric glutamate biosensor. This same method of sleep disruption was applied early in development (postnatal days 14–21) and the long term effects on brain development were quantified by examining glutamatergic synapses in adulthood. Results Consistent with previous research in rats, glutamate concentration in the prefrontal cortex increased during periods of wake in the prairie vole. Sleep disruption using the orbital shaker method resulted in brief cortical arousals and reduced time in REM sleep. When applied during development, early life sleep disruption resulted in long-term changes in both pre- and post-synaptic components of glutamatergic synapses in the prairie vole prefrontal cortex including increased density of immature spines. Conclusion In the prairie vole rodent model, sleep disruption on an orbital shaker produces a sleep, behavioral, and neurological phenotype that mirrors aspects of autism spectrum disorder including altered features of excitatory neurotransmission within the prefrontal cortex. Studies using this method of sleep disruption combined with real time biosensors for excitatory neurotransmitters will enhance our understanding of modifiable risk factors, such as sleep, that contribute to the altered development of glutamatergic synapses in the brain and their relationship to social behavior. Support (if any) NSF #1926818, VA CDA #IK2 BX002712, Portland VA Research Foundation, NIH NHLBI 5T32HL083808-10, VA Merit Review #I01BX001643

Impact of COVID-19 on autism spectrum disorder management - a therapist perspective

IntroductionTherapist led interventions form a core element in the management of children with Autism Spectrum Disorder (ASD) in India. COVID-19 pandemic has disrupted several aspects of ASD management.ObjectivesThis study aims to understand the impact of COVID-19 pandemic on ASD therapies from a therapist perspective.MethodsAn online survey was conducted using a google form questionnaire disseminated among ASD therapists. The form was open for response between 23rd of June and 23rd of July 2020. The responses were extracted into an excel sheet and analysed using descriptive statistics.Results41 out of 75 therapists with mean age of 44 years (21 – 58 years) responded to the survey. 48% were women. Majority of them were either special educators (49%) or ASD therapists (32%) with professional experience of &gt;5 years (63%). Majority of the therapists felt that there is significant disruption during the pandemic with reduction in conventional therapies (63% to 17%) and increase in online therapies (15% to 61%). They also felt that this disruption had moderate to severe impact on child’s learning (73%) and parents emotional and psychological well being (85%). Only 22% of therapists were using digital based therapy (DBT) before the pandemic. Although 51% of the therapists were not entirely sure whether DBT augments parents and therapists’ efforts, majority (65%) were willing to use them.ConclusionsCOVID-19 pandemic has significantly disrupted ASD therapy in India. Willingness to use online and digital based therapies could open up a new dimension. Reliable and effective Artificial-Intelligence based therapies are the need of the day.DisclosureMedical advisor for CognitiveBotics

Disrupted nocturnal melatonin in autism: Association with tumor necrosis factor and sleep disturbances.

Sleep disturbances, abnormal melatonin secretion, and increased inflammation are aspects of autism spectrum disorder (ASD) pathophysiology. The present study evaluated the daily urinary 6-sulfatoxymelatonin (aMT6s) excretion profile and the salivary levels of tumor necrosis factor (TNF) and interleukin-6 (IL-6) in 20 controls and 20 ASD participants, as well as correlating these measures with sleep disturbances. Although 60% of ASD participants showed a significant night-time rise in aMT6s excretion, this rise was significantly attenuated, compared to controls (P<.05). The remaining 40% of ASD individuals showed no significant increase in nocturnal aMT6s. ASD individuals showed higher nocturnal levels of saliva TNF, but not IL-6. Dysfunction in the initiation and maintenance of sleep, as indicated by the Sleep Disturbance Scale for Children, correlated with night-time aMT6s excretion (r=-.28, P<.05). Dysfunction in sleep breathing was inversely correlated with aMT6s (r=-.31, P<.05) and positively associated with TNF level (r=.42, P<.01). Overall such data indicate immune-pineal axis activation, with elevated TNF but not IL-6 levels associated with disrupted pineal melatonin release and sleep dysfunction in ASD. It is proposed that circadian dysregulation in ASD is intimately linked to heightened immune-inflammatory activity. Such two-way interactions of the immune-pineal axis may underpin many aspects of ASD pathophysiology, including sleep disturbances, as well as cognitive and behavioral alterations.

CD103 Deficiency Promotes Autism (ASD) and Attention-Deficit Hyperactivity Disorder (ADHD) Behavioral Spectra and Reduces Age-Related Cognitive Decline.

The incidence of autism spectrum disorders (ASD) and attention deficit hyperactivity disorder (ADHD), which frequently co-occur, are both rising. The causes of ASD and ADHD remain elusive, even as both appear to involve perturbation of the gut-brain-immune axis. CD103 is an integrin and E-cadherin receptor most prominently expressed on CD8 T cells that reside in gut, brain, and other tissues. CD103 deficiency is well-known to impair gut immunity and resident T cell function, but it's impact on neurodevelopmental disorders has not been examined. We show here that CD8 T cells influence neural progenitor cell function, and that CD103 modulates this impact both directly and potentially by controlling CD8 levels in brain. CD103 knockout (CD103KO) mice exhibited a variety of behavioral abnormalities, including superior cognitive performance coupled with repetitive behavior, aversion to novelty and social impairment in females, with hyperactivity with delayed learning in males. Brain protein markers in female and male CD103KOs coincided with known aspects of ASD and ADHD in humans, respectively. Surprisingly, CD103 deficiency also decreased age-related cognitive decline in both sexes, albeit by distinct means. Together, our findings reveal a novel role for CD103 in brain developmental function, and identify it as a unique factor linking ASD and ADHD etiology. Our data also introduce a new animal model of combined ASD and ADHD with associated cognitive benefits, and reveal potential therapeutic targets for these disorders and age-related cognitive decline.

Induction of core symptoms of autism spectrum disorder by in vivo CRISPR/Cas9-based gene editing in the brain of adolescent rhesus monkeys

Although CRISPR/Cas9-mediated gene editing is widely applied to mimic human disorders, whether acute manipulation of disease-causing genes in the brain leads to behavioral abnormalities in non-human primates remains to be determined. Here we induced genetic mutations in MECP2, a critical gene linked to Rett syndrome (RTT) and autism spectrum disorders (ASD), in the hippocampus (DG and CA1–4) of adolescent rhesus monkeys (Macaca mulatta) in vivo via adeno-associated virus (AAV)-delivered Staphylococcus aureus Cas9 with small guide RNAs (sgRNAs) targeting MECP2. In comparison to monkeys injected with AAV-SaCas9 alone (n = 4), numerous autistic-like behavioral abnormalities were identified in the AAV-SaCas9-sgMECP2-injected monkeys (n = 7), including social interaction deficits, abnormal sleep patterns, insensitivity to aversive stimuli, abnormal hand motions, and defective social reward behaviors. Furthermore, some aspects of ASD and RTT, such as stereotypic behaviors, did not appear in the MECP2 gene-edited monkeys, suggesting that different brain areas likely contribute to distinct ASD symptoms. This study showed that acute manipulation of disease-causing genes via in vivo gene editing directly led to behavioral changes in adolescent primates, paving the way for the rapid generation of genetically engineered non-human primate models for neurobiological studies and therapeutic development.