1. Ali M, Kamran M, Talha M, Shad MU. Adiponectin blood levels and autism spectrum disorders: a systematic review. BMC Psychiatry;2024 (Jan 31);24(1):88.

OBJECTIVE: To review the relationship between adiponectin levels and autism spectrum disorders (ASDs) in children. BACKGROUND: ASDs are associated with pervasive social interaction and communication abnormalities. Researchers have studied various pathophysiological mechanisms underlying ASDs to identify predictors for an early diagnosis to optimize treatment outcomes. Immune dysfunction, perhaps mediated by a decrease in anti-inflammatory adipokine, adiponectin, along with changes in other adipokines, may play a central role in increasing the risk for ASDs. However, other factors, such as low maternal vitamin D levels, atherosclerosis, diabetes, obesity, cardio-metabolic diseases, preterm delivery, and oxytocin gene polymorphism may also contribute to increased risk for ASDs. METHODS: Searches on the database; PubMed, Google Scholar, and Cochrane using keywords; adiponectin, adipokines, ASD, autism, autistic disorder, included English-language studies published till September 2022. Data were extracted on mean differences between adiponectin levels in children with and without ASDs. RESULTS: The search yielded six studies providing data on adiponectin levels in young patients with ASDs. As can be seen from Table 1, four of the six studies were positive for an inverse correlation between ASD and adiponectin levels. In addition, two of the four positive and one negative studies found low adiponectin levels associated with and the severity of autistic symptoms. However, results from one reviewed study were insignificant. CONCLUSION: Most studies reviewed yielded lower adiponectin levels in children with ASDs as well as the severity of autistic symptoms.

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2. Basu S, Ro EJ, Liu Z, Kim H, Bennett A, Kang S, Suh H. The Mef2c Gene Dose-Dependently Controls Hippocampal Neurogenesis and the Expression of Autism-Like Behaviors. J Neurosci;2024 (Jan 31);44(5)

Mutations in the activity-dependent transcription factor MEF2C have been associated with several neuropsychiatric disorders. Among these, autism spectrum disorder (ASD)-related behavioral deficits are manifested. Multiple animal models that harbor mutations in Mef2c have provided compelling evidence that Mef2c is indeed an ASD gene. However, studies in mice with germline or global brain knock-out of Mef2c are limited in their ability to identify the precise neural substrates and cell types that are required for the expression of Mef2c-mediated ASD behaviors. Given the role of hippocampal neurogenesis in cognitive and social behaviors, in this study we aimed to investigate the role of Mef2c in the structure and function of newly generated dentate granule cells (DGCs) in the postnatal hippocampus and to determine whether disrupted Mef2c function is responsible for manifesting ASD behaviors. Overexpression of Mef2c (Mef2c(OE) ) arrested the transition of neurogenesis at progenitor stages, as indicated by sustained expression of Sox2(+) in Mef2c(OE) DGCs. Conditional knock-out of Mef2c (Mef2c(cko) ) allowed neuronal commitment of Mef2c(cko) cells; however, Mef2c(cko) impaired not only dendritic arborization and spine formation but also synaptic transmission onto Mef2c(cko) DGCs. Moreover, the abnormal structure and function of Mef2c(cko) DGCs led to deficits in social interaction and social novelty recognition, which are key characteristics of ASD behaviors. Thus, our study revealed a dose-dependent requirement of Mef2c in the control of distinct steps of neurogenesis, as well as a critical cell-autonomous function of Mef2c in newborn DGCs in the expression of proper social behavior in both sexes.

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3. Bennett T, Drmic I, Gross J, Jambon M, Kimber M, Zaidman-Zait A, Andrews K, Frei J, Duku E, Georgiades S, Gonzalez A, Janus M, Lipman E, Pires P, Prime H, Roncadin C, Salt M, Shine R. The Family-Check-Up® Autism Implementation Research (FAIR) Study: protocol for a study evaluating the effectiveness and implementation of a family-centered intervention within a Canadian autism service setting. Front Public Health;2023;11:1309154.

INTRODUCTION: Prevalence rates of emotional and behavior problems (EBP) in autistic children and youth are high (40-70%), and often cause severe and chronic impairment. Furthermore, autistic children are also more likely to experience family « social-ecological » adversity compared to neurotypically developing peers, including social isolation, child maltreatment, caregiver mental illness, and socioeconomic risk. These family stressors increase the risk of co-occurring EBP among autistic children and can often impede access to evidence-based care, thus amplifying long-term health inequities for autistic children and their caregivers. In the current autism services landscape, there are few scalable, evidence-based programs that adequately address these needs. The Family Check-Up (FCU®) is a brief, strength-based, and tailored family-centered intervention that supports positive parenting and explicitly assesses the social determinants of child and family mental health within an ecological framework. Studies have demonstrated long-term positive child and caregiver outcomes in other populations, but the FCU® has not been evaluated in families of autistic children and youth. Therefore, we aimed to evaluate FCU® implementation within an established, publicly funded Autism Program in Ontario, Canada, with delivery by autism therapists, to demonstrate sustainable effectiveness within real-world settings. METHODS: In this study, we outline the protocol for a hybrid implementation-effectiveness approach with two key components: (1) A parallel-arm randomized controlled trial of N = 80 autistic children/youth (ages 6-17 years) and high levels of EBP and their caregivers. Primary and secondary outcomes include child EBP, and caregiver well-being and parenting. (2) A mixed methods implementation study, to describe facilitators and barriers to implementation of the FCU® within an autism service setting. DISCUSSION: Scalable, ecologically focused family-centered interventions offer promise as key components of a public health framework aimed at reducing mental health inequities among autistic children, youth, and their caregivers. Results of this study will inform further program refinement and scale-up.

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4. Bjørklund G, Mkhitaryan M, Sahakyan E, Fereshetyan K, Meguid NA, Hemimi M, Nashaat NH, Yenkoyan K. Linking Environmental Chemicals to Neuroinflammation and Autism Spectrum Disorder: Mechanisms and Implications for Prevention. Mol Neurobiol;2024 (Jan 31)

This article explores the potential link between endocrine-disrupting chemicals (EDCs), neuroinflammation, and the development of autism spectrum disorder (ASD). Neuroinflammation refers to the immune system’s response to injury, infection, or disease in the central nervous system. Studies have shown that exposure to EDCs, such as bisphenol A and phthalates, can disrupt normal immune function in the brain, leading to chronic or excessive neuroinflammation. This disruption of immune function can contribute to developing neurological disorders, including ASD. Furthermore, EDCs may activate microglia, increasing pro-inflammatory cytokine production and astroglia-mediated oxidative stress, exacerbating neuroinflammation. EDCs may also modulate the epigenetic profile of cells by methyltransferase expression, thereby affecting neurodevelopment. This article also highlights the importance of reducing exposure to EDCs and advocating for policies and regulations restricting their use. Further research is needed to understand better the mechanisms underlying the link between EDCs, neuroinflammation, and ASD and to develop new treatments for ASD.

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5. Borreca A, Mantovani C, Desiato G, Corradini I, Filipello F, Elia C, D’Autilia F, Santamaria G, Garlanda C, Morini R, Pozzi D, Matteoli M. Loss of interleukin 1 signaling causes impairment of microglia- mediated synapse elimination and autistic-like behaviour in mice. Brain Behav Immun;2024 (Jan 31)

In the last year, the hypothesis that elevated levels of proinflammatory cytokines contribute to the pathogenesis of neurodevelopmental diseases has gained popularity. IL-1 is one of the main cytokines found to be elevated in ASD Autism spectrum disorder, a complex neurodevelopmental condition characterized by defects in social communication and cognitive impairments. In this study, we demonstrate that mice lacking IL-1 signaling display autistic-like defects associated with an excessive number of synapses. We also show that microglia lacking IL-1 signaling at early neurodevelopmental stages are unable to properly perform the process of synapse engulfment and display excessive activation of mammalian target of rapamycin (mTOR) signaling. Notably, even the acute inhibition of IL-1R1 by IL-1Ra is sufficient to enhance mTOR signaling and reduce synaptosome phagocytosis in WT microglia. Finally, we demonstrate that rapamycin treatment rescues the defects in IL-1R deficient mice. These data unveil an exclusive role of microglial IL-1 in synapse refinement via mTOR signaling and indicate a novel mechanism possibly involved in neurodevelopmental disorders associated with defects in the IL-1 pathway.

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6. Brown CO, Uy JA, Murtaza N, Rosa E, Alfonso A, Dave BM, Kilpatrick S, Cheng AA, White SH, Scherer SW, Singh KK. Disruption of the autism-associated gene SCN2A alters synaptic development and neuronal signaling in patient iPSC-glutamatergic neurons. Front Cell Neurosci;2023;17:1239069.

SCN2A is an autism spectrum disorder (ASD) risk gene and encodes a voltage-gated sodium channel. However, the impact of ASD-associated SCN2A de novo variants on human neuron development is unknown. We studied SCN2A using isogenic SCN2A(-/-) induced pluripotent stem cells (iPSCs), and patient-derived iPSCs harboring a de novo R607* truncating variant. We used Neurogenin2 to generate excitatory (glutamatergic) neurons and found that SCN2A(+/R607*) and SCN2A(-/-) neurons displayed a reduction in synapse formation and excitatory synaptic activity. We found differential impact on actional potential dynamics and neuronal excitability that reveals a loss-of-function effect of the R607* variant. Our study reveals that a de novo truncating SCN2A variant impairs the development of human neuronal function.

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7. Dalton GD, Siecinski SK, Nikolova VD, Cofer GP, Hornburg K, Qi Y, Johnson GA, Jiang YH, Moy SS, Gregory SG. Transcriptome Analysis Identifies An ASD-Like Phenotype In Oligodendrocytes And Microglia From C58/J Amygdala That Is Dependent On Sex and Sociability. bioRxiv;2024 (Jan 16)

BACKGROUND: Autism Spectrum Disorder (ASD) is a group of neurodevelopmental disorders with higher incidence in males and is characterized by atypical verbal/nonverbal communication, restricted interests that can be accompanied by repetitive behavior, and disturbances in social behavior. This study investigated brain mechanisms that contribute to sociability deficits and sex differences in an ASD animal model. METHODS: Sociability was measured in C58/J and C57BL/6J mice using the 3-chamber social choice test. Bulk RNA-Seq and snRNA-Seq identified transcriptional changes in C58/J and C57BL/6J amygdala within which DMRseq was used to measure differentially methylated regions in amygdala. RESULTS: C58/J mice displayed divergent social strata in the 3-chamber test. Transcriptional and pathway signatures revealed immune-related biological processes differ between C58/J and C57BL/6J amygdala. Hypermethylated and hypomethylated genes were identified in C58/J versus C57BL/6J amygdala. snRNA-Seq data in C58/J amygdala identified differential transcriptional signatures within oligodendrocytes and microglia characterized by increased ASD risk gene expression and predicted impaired myelination that was dependent on sex and sociability. RNA velocity, gene regulatory network, and cell communication analysis showed diminished oligodendrocyte/microglia differentiation. Findings were verified using bulk RNA-Seq and demonstrated oxytocin’s beneficial effects on myelin gene expression. LIMITATIONS: Our findings are significant. However, limitations can be noted. The cellular mechanisms linking reduced oligodendrocyte differentiation and reduced myelination to an ASD phenotype in C58/J mice need further investigation. Additional snRNA-Seq and spatial studies would determine if effects in oligodendrocytes/microglia are unique to amygdala or if this occurs in other brain regions. Oxytocin’s effects need further examination to understand its potential as an ASD therapeutic. CONCLUSIONS: Our work demonstrates the C58/J mouse model’s utility in evaluating the influence of sex and sociability on the transcriptome in concomitant brain regions involved in ASD. Our single-nucleus transcriptome analysis elucidates potential pathological roles of oligodendrocytes and microglia in ASD. This investigation provides details regarding regulatory features disrupted in these cell types, including transcriptional gene dysregulation, aberrant cell differentiation, altered gene regulatory networks, and changes to key pathways that promote microglia/oligodendrocyte differentiation. Our studies provide insight into interactions between genetic risk and epigenetic processes associated with divergent affiliative behavior and lack of positive sociability.

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8. Häger LA, Høyland AL, Kropotov JD, Åsberg Johnels J, Weidle B, Hollup S, Gillberg C, Billstedt E, Ogrim G. Is Visual Prediction Impaired in Adolescents with Autism spectrum Disorder? Event-Related Potentials in a Cued Visual GO/NOGO Task. Clin EEG Neurosci;2024 (Jan 31):15500594241227974.

Aim: Deviant visual processing has been observed in autism spectrum disorder (ASD), manifesting as decreased P1 and P2 components of visual event-related potentials (ERPs). Alterations have been attributed to a failure of Bayesian inference, characterized by hypo-activation of top-down predictive abilities. To test this hypothesis, we measured the visual negativity (vN) as an ERP index of visual preparation hypothesized to mirror predictive brain activity. Method: ERPs in a cued visual GO/NOGO task in 63 adolescents with ASD (IQ > 70, attention-deficit hyperactivity disorder excluded) were compared with ERPs in a sex- and age-matched group of 60 typically developing (TD) controls. Results: The behavioral variables (omissions, commissions, reaction time, and reaction time variability), as well as ERP components reflecting, among other processes, cognitive control (contingent negative variation, P3 GO, P3 NOGO, N2 NOGO) did not differ between the groups. There were group differences in visually based ERPs. Besides P1 and P2 differences, the vN component differentiated the 2 groups with the highest effect size (d  =  0.74).Conclusion: This ERP study lends support to the hypothesis suggesting that a Bayesian hypo-prediction could underlie unique perceptual experiences in individuals with ASD. This could lead to a predisposition to perceive the world with reduced influence and modulation from contextual cues, prior experiences, and pre-existing expectations.

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9. Hayward BA. A job analysis of mental health nursing in a school for students with intellectual and developmental disabilities. Int J Ment Health Nurs;2024 (Jan 30)

While schools have become settings for the delivery of mental health supports to students, mental health nursing has not yet described its practice in schools. In the absence of this mental health nursing literature, a quantitative self-reporting job analysis methodology was used to describe the tasks of mental health nursing in a specialist school as an observant-participator in a single-case holistic case study. Additional aims were to compare the results with the general school nursing and the disability nursing literatures and interpret these findings for mental health nursing. Categories of tasks from general school nursing were used to deductively interpret the results. Tasks were recorded across all categories of school nursing. The greatest number of tasks were recorded in the professional performance category, followed by planning, then personnel. The least number of tasks were recorded in the health education and promotion category, followed by practice and treatments, assessment and diagnosis, and management. These results differ from tasks in general school nursing but share similarities with intellectual and developmental disability nursing, particularly related to relationships and communication. Practising effectively as a mental health nurse in a specialist school requires capabilities for working with people with disability, particularly communicating and establishing relationships, in addition to clinical mental health skills. Mental health nursing in schools is an area of practice that requires further exploration to capitalise on emerging policy developments to support student mental health.

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10. Holyfield C, MacNeil S, Caldwell N, O’Neill Zimmerman T, Lorah E, Dragut E, Vucetic S. Leveraging Communication Partner Speech to Automate Augmented Input for Children on the Autism Spectrum Who Are Minimally Verbal: Prototype Development and Preliminary Efficacy Investigation. Am J Speech Lang Pathol;2024 (Jan 30):1-19.

PURPOSE: Augmentative and alternative communication (AAC) technology innovation is urgently needed to improve outcomes for children on the autism spectrum who are minimally verbal. One potential technology innovation is applying artificial intelligence (AI) to automate strategies such as augmented input to increase language learning opportunities while mitigating communication partner time and learning barriers. Innovation in AAC research and design methodology is also needed to empirically explore this and other applications of AI to AAC. The purpose of this report was to describe (a) the development of an AAC prototype using a design methodology new to AAC research and (b) a preliminary investigation of the efficacy of this potential new AAC capability. METHOD: The prototype was developed using a Wizard-of-Oz prototyping approach that allows for initial exploration of a new technology capability without the time and effort required for full-scale development. The preliminary investigation with three children on the autism spectrum who were minimally verbal used an adapted alternating treatment design to compare the effects of a Wizard-of-Oz prototype that provided automated augmented input (i.e., pairing color photos with speech) to a standard topic display (i.e., a grid display with line drawings) on visual attention, linguistic participation, and (for one participant) word learning during a circle activity. RESULTS: Preliminary investigation results were variable, but overall participants increased visual attention and linguistic participation when using the prototype. CONCLUSIONS: Wizard-of-Oz prototyping could be a valuable approach to spur much needed innovation in AAC. Further research into efficacy, reliability, validity, and attitudes is required to more comprehensively evaluate the use of AI to automate augmented input in AAC.

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11. Hsieh CC, Lo YC, Wang HH, Shen HY, Chen YY, Lee YC. Amelioration of the brain structural connectivity is accompanied with changes of gut microbiota in a tuberous sclerosis complex mouse model. Transl Psychiatry;2024 (Jan 31);14(1):68.

Tuberous sclerosis complex (TSC) is a genetic disease that causes benign tumors and dysfunctions in many organs, including the brain. Aside from the brain malformations, many individuals with TSC exhibit neuropsychiatric symptoms. Among these symptoms, autism spectrum disorder (ASD) is one of the most common co-morbidities, affecting up to 60% of the population. Past neuroimaging studies strongly suggested that the impairments in brain connectivity contribute to ASD, whether or not TSC-related. Specifically, the tract-based diffusion tensor imaging (DTI) analysis provides information on the fiber integrity and has been used to study the neuropathological changes in the white matter of TSC patients with ASD symptoms. In our previous study, curcumin, a diet-derived mTOR inhibitor has been shown to effectively mitigate learning and memory deficits and anxiety-like behavior in Tsc2(+/-) mice via inhibiting astroglial proliferation. Recently, gut microbiota, which is greatly influenced by the diet, has been considered to play an important role in regulating several components of the central nervous system, including glial functions. In this study, we showed that the abnormal social behavior in the Tsc2(+/-) mice can be ameliorated by the dietary curcumin treatment. Second, using tract-based DTI analysis, we found that the Tsc2(+/-) mice exhibited altered fractional anisotropy, axial and radial diffusivities of axonal bundles connecting the prefrontal cortex, nucleus accumbens, hypothalamus, and amygdala, indicating a decreased brain network. Third, the dietary curcumin treatment improved the DTI metrics, in accordance with changes in the gut microbiota composition. At the bacterial phylum level, we showed that the abundances of Actinobacteria, Verrucomicrobia, and Tenericutes were significantly correlated with the DTI metrics FA, AD, and RD, respectively. Finally, we revealed that the expression of myelin-associated proteins, myelin bassic protein (MBP) and proteolipid protein (PLP) was increased after the treatment. Overall, we showed a strong correlation between structural connectivity alterations and social behavioral deficits, as well as the diet-dependent changes in gut microbiota composition.

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12. Knight EJ, Altschuler TS, Molholm S, Murphy JW, Freedman EG, Foxe JJ. It’s all in the timing: Delayed feedback in autism may weaken predictive mechanisms during contour integration. bioRxiv;2024 (Jan 19)

Humans rely on predictive mechanisms during visual processing to efficiently resolve incomplete or ambiguous sensory signals. While initial low-level sensory data are conveyed by feedforward connections, feedback connections are believed to shape sensory processing through conveyance of statistical predictions based on prior exposure to stimulus configurations. Individuals with autism spectrum disorder (ASD) show biases in stimulus processing toward parts rather than wholes, suggesting their sensory processing may be less shaped by statistical predictions acquired through prior exposure to global stimulus properties. Investigations of illusory contour (IC) processing in neurotypical (NT) adults have established a well-tested marker of contour integration characterized by a robust modulation of the visually evoked potential (VEP) – the IC-effect – that occurs over lateral occipital scalp during the timeframe of the N1 component. Converging evidence strongly supports the notion that this IC-effect indexes a signal with significant feedback contributions. Using high-density VEPs, we compared the IC-effect in 6-17-year-old children with ASD (n=32) or NT development (n=53). Both groups of children generated an IC-effect that was equivalent in amplitude. However, the IC-effect notably onset 21ms later in ASD, even though timing of initial VEP afference was identical across groups. This suggests that feedforward information predominated during perceptual processing for 15% longer in ASD compared to NT children. This delay in the feedback dependent IC-effect , in the context of known developmental differences between feedforward and feedback fibers, suggests a potential pathophysiological mechanism of visual processing in ASD, whereby ongoing stimulus processing is less shaped by statistical prediction mechanisms. SIGNIFICANCE STATEMENT: Children with autism often present with an atypical visual perceptual style that emphasizes parts or details over the whole. Using electroencephalography (EEG), this study identifies delays in the visual feedback from higher order sensory brain areas to primary sensory regions. Because this type of visual feedback is thought to carry information about prior sensory experiences, individuals with autism may have difficulty efficiently using prior experience and predictions to help make sense of incoming new visual information. This provides empirical neural evidence to support theories of disrupted sensory perception mechanisms in autism.

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13. Li Y, Li R, Gu J, Yi H, He J, Lu F, Gao J. Enhanced group-level dorsolateral prefrontal cortex subregion parcellation through functional connectivity-based distance-constrained spectral clustering with application to autism spectrum disorder. Cereb Cortex;2024 (Jan 31)

The dorsolateral prefrontal cortex (DLPFC) assumes a central role in cognitive and behavioral control, emerging as a crucial target region for interventions in autism spectrum disorder neuroregulation. Consequently, we endeavor to unravel the functional subregions within the DLPFC to shed light on the intricate functions of the brain. We introduce a distance-constrained spectral clustering (SC-DW) methodology that leverages functional connection to identify distinctive functional subregions within the DLPFC. Furthermore, we verify the relationship between the functional characteristics of these subregions and their clinical implications. Our methodology begins with principal component analysis to extract the salient features. Subsequently, we construct an adjacency matrix, which is constrained by the spatial properties of the brain, by linearly combining the distance matrix and a similarity matrix. The quality of spectral clustering is further optimized through multiple cluster evaluation coefficient. The results from SC-DW revealed four uniform and contiguous subregions within the bilateral DLPFC. Notably, we observe a substantial positive correlation between the functional characteristics of the third and fourth subregions in the left DLPFC with clinical manifestations. These findings underscore the unique insights offered by our proposed methodology in the realms of brain subregion delineation and therapeutic targeting.

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14. Longo A, Radford D, Hand BN. A US national update of health condition prevalence among privately-insured autistic adults. J Comp Eff Res;2024 (Jan 31):e230051.

Aim: Previous research using state or regional samples has shown that autistic adults have a higher prevalence of health conditions in comparison to the general population. Methods: To build upon this important previous research, we conducted a cross-sectional retrospective study of 2019-2020 healthcare claims to determine the prevalence of conditions in a US national sample of privately insured autistic adults (n = 30,258) and an age- and sex-matched population comparison (n = 60,516) group of adults without autism diagnoses. Results: Like previous studies, we found that autistic adults had significantly greater odds of most mental and physical health conditions. However, our prevalence estimates differed from previous studies for several mental and physical health conditions. For example, our sample of autistic adults had higher prevalence of anxiety disorders (55%) and attention deficit hyperactivity disorders (34%), but lower prevalence of asthma (9%) and sleep disorders (3%) than previous studies. Discussion & conclusion: Our use of a large US national sample, more recent healthcare claims data, and different methods for identifying health conditions may have contributed to these differences. Our findings alert healthcare providers and policymakers to the health conditions most common among the growing population of autistic adults. We hope these findings lead to improved screening and management of these conditions, inform initiatives to improve access to healthcare, and guide future funding.

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15. MacKenzie KT, Beck KB, Eack SM, Zeglen KN, Conner CM, Mazefsky CA. Developing a Measure of Key Adult Outcomes in Adults with Developmental Disabilities: Conceptual Model and Item Generation of the REALS (Relationships, Employment, Autonomy, and Life Satisfaction). J Autism Dev Disord;2024 (Jan 30)

Employment, social relationships, and autonomy are priorities to people with intellectual and developmental disabilities (IDDs). However, few validated measures exist to systematically assess these key adult outcomes in this population. This research includes first steps to develop self- and proxy report measures of life outcomes for adults with IDDs-the Relationships, Employment, Autonomy, and Life Satisfaction (REALS). A literature search identified existing adult outcome measures, and comparison of their domains informed initial conceptual model development. External consultants revised the model, and items were generated. Autistic adults (n = 15), adults with other IDDs (n = 7), caregivers of autistic adults (n = 13), and caregivers of adults with other IDDs (n = 10) completed in-depth cognitive interviews to assess comprehension of items and response categories, factors influencing how participants respond to items, and the inclusiveness of the item pool. A final conceptual model was generated with three subdomains (social relationships, employment, and autonomy), including assessment of life satisfaction within each domain. Cognitive interviews revealed that response set restructuring and item-level revisions were needed to capture the complexity of adult life and make the measure more accessible across a range of abilities. This study developed a conceptual model of relationships, work, and autonomy specific to adults with IDDs. Future work will involve collecting data from 800 + self-reporters with IDDs and 800 + caregivers of adults with IDDs to conduct psychometric analyses. Improving measurement in this area is critical to better understanding the needs of adults with IDDs and improving services available to them.

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16. Marchetta P, Dapper K, Hess M, Calis D, Singer W, Wertz J, Fink S, Hage SR, Alam M, Schwabe K, Lukowski R, Bourien J, Puel JL, Jacob MH, Munk MHJ, Land R, Rüttiger L, Knipper M. Dysfunction of specific auditory fibers impacts cortical oscillations, driving an autism phenotype despite near-normal hearing. Faseb j;2024 (Jan 31);38(2):e23411.

Autism spectrum disorder is discussed in the context of altered neural oscillations and imbalanced cortical excitation-inhibition of cortical origin. We studied here whether developmental changes in peripheral auditory processing, while preserving basic hearing function, lead to altered cortical oscillations. Local field potentials (LFPs) were recorded from auditory, visual, and prefrontal cortices and the hippocampus of Bdnf(Pax2) KO mice. These mice develop an autism-like behavioral phenotype through deletion of BDNF in Pax2+ interneuron precursors, affecting lower brainstem functions, but not frontal brain regions directly. Evoked LFP responses to behaviorally relevant auditory stimuli were weaker in the auditory cortex of Bdnf(Pax2) KOs, connected to maturation deficits of high-spontaneous rate auditory nerve fibers. This was correlated with enhanced spontaneous and induced LFP power, excitation-inhibition imbalance, and dendritic spine immaturity, mirroring autistic phenotypes. Thus, impairments in peripheral high-spontaneous rate fibers alter spike synchrony and subsequently cortical processing relevant for normal communication and behavior.

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17. Nelson AD, Catalfio AM, Gupta JP, Min L, Caballero-Florán RN, Dean KP, Elvira CC, Derderian KD, Kyoung H, Sahagun A, Sanders SJ, Bender KJ, Jenkins PM. Physical and functional convergence of the autism risk genes Scn2a and Ank2 in neocortical pyramidal cell dendrites. Neuron;2024 (Jan 23)

Dysfunction in sodium channels and their ankyrin scaffolding partners have both been implicated in neurodevelopmental disorders, including autism spectrum disorder (ASD). In particular, the genes SCN2A, which encodes the sodium channel Na(V)1.2, and ANK2, which encodes ankyrin-B, have strong ASD association. Recent studies indicate that ASD-associated haploinsufficiency in Scn2a impairs dendritic excitability and synaptic function in neocortical pyramidal cells, but how Na(V)1.2 is anchored within dendritic regions is unknown. Here, we show that ankyrin-B is essential for scaffolding Na(V)1.2 to the dendritic membrane of mouse neocortical neurons and that haploinsufficiency of Ank2 phenocopies intrinsic dendritic excitability and synaptic deficits observed in Scn2a(+/-) conditions. These results establish a direct, convergent link between two major ASD risk genes and reinforce an emerging framework suggesting that neocortical pyramidal cell dendritic dysfunction can contribute to neurodevelopmental disorder pathophysiology.

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18. Oztan O, Del Rosso LA, Simmons SM, Nguyen DKK, Talbot CF, Capitanio JP, Garner JP, Parker KJ. Naturally occurring low sociality in female rhesus monkeys: A tractable model for autism or not?. Mol Autism;2024 (Jan 31);15(1):8.

BACKGROUND: Autism spectrum disorder (ASD) is characterized by persistent social interaction impairments and is male-biased in prevalence. We have established naturally occurring low sociality in male rhesus monkeys as a model for the social features of ASD. Low-social male monkeys exhibit reduced social interactions and increased autistic-like trait burden, with both measures highly correlated and strongly linked to low cerebrospinal fluid (CSF) arginine vasopressin (AVP) concentration. Little is known, however, about the behavioral and neurochemical profiles of female rhesus monkeys, and whether low sociality in females is a tractable model for ASD. METHODS: Social behavior assessments (ethological observations; a reverse-translated autistic trait measurement scale, the macaque Social Responsiveness Scale-Revised [mSRS-R]) were completed on N = 88 outdoor-housed female rhesus monkeys during the non-breeding season. CSF and blood samples were collected from a subset of N = 16 monkeys across the frequency distribution of non-social behavior, and AVP and oxytocin (OXT) concentrations were quantified. Data were analyzed using general linear models. RESULTS: Non-social behavior frequency and mSRS-R scores were continuously distributed across the general female monkey population, as previously found for male monkeys. However, dominance rank significantly predicted mSRS-R scores in females, with higher-ranking individuals showing fewer autistic-like traits, a relationship not previously observed in males from this colony. Females differed from males in several other respects: Social behavior frequencies were unrelated to mSRS-R scores, and AVP concentration was unrelated to any social behavior measure. Blood and CSF concentrations of AVP were positively correlated in females; no significant relationship involving any OXT measure was found. LIMITATIONS: This study sample was small, and did not consider genetic, environmental, or other neurochemical measures that may be related to female mSRS-R scores. CONCLUSIONS: Dominance rank is the most significant predictor of autistic-like traits in female rhesus monkeys, and CSF neuropeptide concentrations are unrelated to measures of female social functioning (in contrast to prior CSF AVP findings in male rhesus monkeys and male and female autistic children). Although preliminary, this evidence suggests that the strong matrilineal organization of this species may limit the usefulness of low sociality in female rhesus monkeys as a tractable model for ASD.

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19. Palmer JK, van der Pols JC, Sullivan KA, Staudacher HM, Byrne R. A Double-Blind Randomised Controlled Trial of Prebiotic Supplementation in Children with Autism: Effects on Parental Quality of Life, Child Behaviour, Gastrointestinal Symptoms, and the Microbiome. J Autism Dev Disord;2024 (Jan 31)

PURPOSE: Modifying gut bacteria in children with autism may influence behaviour, with potential to improve family functioning. We conducted a randomised controlled trial to assess the effect of prebiotics on behaviour, gastrointestinal symptoms and downstream effects on parental quality of life. METHOD: Children with autism (4-10yrs) were randomised to 2.4 g/d of prebiotic (GOS) or placebo for six weeks. Pre and post stools samples were collected, and validated questionnaires used to measure change in social and mealtime behaviours, GI symptoms and pQOL. Linear mixed models evaluated group differences for behavioural variables, and Mann Whitney U tests were used to compare change between-groups for GI symptoms, differential abundance of genera and alpha diversity of the microbiome. RESULTS: Thirty-three parent-child dyads completed the trial. No group difference was seen for behavioural variables but both groups improved significantly from baseline. There was a medium effect size between groups for GI symptoms (d = 0.47) and pQOL (d = 0.44) driven by greater improvements in the prebiotic group. Bifidobacterium increased threefold following prebiotics (1.4-5.9%, p < 0.001) with no change in controls. Supplements were well tolerated, compliance with dose 94%. CONCLUSION: Prebiotics modify levels of Bifidobacterium and prove well tolerated but in this instance, resulted in only marginal effects on GI symptoms and pQOL. A larger sample of children with more severe symptoms could help to determine the potential of prebiotics in autism. TRIAL REGISTRATION: https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?ACTRN=12619000615189 .

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20. Shamabadi A, Karimi H, Arabzadeh Bahri R, Motavaselian M, Akhondzadeh S. Emerging drugs for the treatment of irritability associated with autism spectrum disorder. Expert Opin Emerg Drugs;2024 (Jan 31)

INTRODUCTION: Autism spectrum disorder (ASD) is an early-onset disorder with a prevalence of 1% among children and reported disability-adjusted life years of 4.31 million. Irritability is a challenging behavior associated with ASD, for which medication development has lagged. More specifically, pharmacotherapy effectiveness may be limited against high adverse effects (considering side effect profiles and patient medication sensitivity); thus, the possible benefits of pharmacological interventions must be balanced against potential adverse events in each patient. AREAS COVERED: After reviewing the neuropathophysiology of ASD-associated irritability, the benefits and tolerability of emerging medications in its treatment based on randomized controlled trials were detailed in light of mechanisms and targets of action. EXPERT OPINION: Succeeding risperidone and aripiprazole, monotherapy with memantine may be beneficial. In addition, N-acetylcysteine, galantamine, sulforaphane, celecoxib, palmitoylethanolamide, pentoxifylline, simvastatin, minocycline, amantadine, pregnenolone, prednisolone, riluzole, propentofylline, pioglitazone, and topiramate, all adjunct to risperidone, and clonidine and methylphenidate outperformed placebo. These effects were through glutamatergic, γ-aminobutyric acidergic, inflammatory, oxidative, cholinergic, dopaminergic, and serotonergic systems. All medications were reported to be safe and tolerable. Considering sample size, follow-up, and effect size, further studies are necessary. Along with drug development, repositioning and combining existing drugs supported by the mechanism of action is recommended.

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21. Stamenkovic V, Lautz JD, Harsh FM, Smith SEP. SRC family kinase inhibition rescues molecular and behavioral phenotypes, but not protein interaction network dynamics, in a mouse model of Fragile X syndrome. Mol Psychiatry;2024 (Jan 31)

Glutamatergic synapses encode information from extracellular inputs using dynamic protein interaction networks (PINs) that undergo widespread reorganization following synaptic activity, allowing cells to distinguish between signaling inputs and generate coordinated cellular responses. Here, we investigate how Fragile X Messenger Ribonucleoprotein (FMRP) deficiency disrupts signal transduction through a glutamatergic synapse PIN downstream of NMDA receptor or metabotropic glutamate receptor (mGluR) stimulation. In cultured cortical neurons or acute cortical slices from P7, P17 and P60 FMR1(-/y) mice, the unstimulated protein interaction network state resembled that of wildtype littermates stimulated with mGluR agonists, demonstrating resting state pre-activation of mGluR signaling networks. In contrast, interactions downstream of NMDAR stimulation were similar to WT. We identified the Src family kinase (SFK) Fyn as a network hub, because many interactions involving Fyn were pre-activated in FMR1(-/y) animals. We tested whether targeting SFKs in FMR1(-/y) mice could modify disease phenotypes, and found that Saracatinib (SCB), an SFK inhibitor, normalized elevated basal protein synthesis, novel object recognition memory and social behavior in FMR1(-/y) mice. However, SCB treatment did not normalize the PIN to a wild-type-like state in vitro or in vivo, but rather induced extensive changes to protein complexes containing Shank3, NMDARs and Fyn. We conclude that targeting abnormal nodes of a PIN can identify potential disease-modifying drugs, but behavioral rescue does not correlate with PIN normalization.

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22. Wan Y, Zhang L, Xu Z, Su Q, Leung TF, Chan D, Wong OWH, Chan S, Chan FKL, Tun HM, Ng SC. Alterations in fecal virome and bacteriome virome interplay in children with autism spectrum disorder. Cell Rep Med;2024 (Jan 31):101409.

Emerging evidence suggests autism spectrum disorder (ASD) is associated with altered gut bacteria. However, less is known about the gut viral community and its role in shaping microbiota in neurodevelopmental disorders. Herein, we perform a metagenomic analysis of gut-DNA viruses in 60 children with ASD and 64 age- and gender-matched typically developing children to investigate the effect of the gut virome on host bacteria in children with ASD. ASD is associated with altered gut virome composition accompanied by the enrichment of Clostridium phage, Bacillus phage, and Enterobacteria phage. These ASD-enriched phages are largely associated with disrupted viral ecology in ASD. Importantly, changes in the interplay between the gut bacteriome and virome seen in ASD may influence the encoding capacity of microbial pathways for neuroactive metabolite biosynthesis. These findings suggest an impaired bacteriome-virome ecology in ASD, which sheds light on the importance of bacteriophages in pathogenesis and the development of microbial therapeutics in ASD.

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23. Zade K, Campbell C, Bach S, Fernandes H, Tropea D. Rett syndrome in Ireland: a demographic study. Orphanet J Rare Dis;2024 (Jan 31);19(1):34.

BACKGROUND: Rett syndrome (RTT) is a rare neurodevelopmental condition associated with mutations in the gene coding for the methyl-CpG-binding protein 2 (MECP2). It is primarily observed in girls and affects individuals globally. The understanding of the neurobiology of RTT and patient management has been improved by studies that describe the demographic and clinical presentation of individuals with RTT. However, in Ireland, there is a scarcity of data regarding individuals with RTT, which impedes the ability to fully characterize the Irish RTT population. Together with the Rett Syndrome Association of Ireland (RSAI), we prepared a questionnaire to determine the characteristics of RTT individuals in Ireland. Twenty-five families have participated in the study to date, providing information about demographics, genetics, familial history, clinical features, and regression. RESULTS: The results show that Irish individuals with RTT have comparable presentation with respect to individuals in other countries; however, they had a better response to anti-epileptic drugs, and fewer skeletal deformities were reported. Nonetheless, seizures, involuntary movements and regression were more frequently observed in Irish individuals. One of the main findings of this study is the limited genetic information available to individuals to support the clinical diagnosis of RTT. CONCLUSIONS: Despite the limited sample size, this study is the first to characterize the RTT population in Ireland and highlights the importance of having a swift access to genetic testing to sharpen the characterization of the phenotype and increase the visibility of Irish individuals in the international RTT community.

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24. Zhang X, Smits M, Curfs L, Spruyt K. Sleep and the Social Profiles of Individuals With Rett Syndrome. Pediatr Neurol;2024 (Jan 8);152:153-161.

BACKGROUND: This study investigates the distinctive social behaviors observed in individuals with Rett syndrome (RTT), characterized by the loss of spoken language, impaired eye gaze communication, gait abnormalities, and sleep issues. The research aims to identify social profiles in RTT and explore their correlation with sleep, sleep-disordered breathing (SDB), and daytime sleepiness. METHODS: Standard overnight sleep macrostructure and respiratory parameters were assessed. Extracting 25 social-related items and one for daytime sleepiness from the Rett Syndrome Behavioral Questionnaire, factor analysis was applied to establish latent social profiles. These profiles were then correlated with sleep parameters. The nonparametric Mann-Whitney U test compared social profiles based on the presence of SDB (defined by an apnea-hypopnea index greater than one per hour) and daytime sleepiness. RESULTS: The study involved 12 female subjects with confirmed RTT diagnoses and MECP2 mutations, aged 8.54 ± 5.30 years. The Rett Syndrome Behavioral Questionnaire revealed a total average score of 25.83 ± 12.34, indicating varying degrees of social impairments. Comprising 25 social-related items, factor analysis yielded four social profiles: « interactive motricity, » « mood change, » « anxiety/agitation, » and « gazing. » Longer sleep onset latency correlated with increased socio-behavioral impairments, particularly in interactive motricity reduction. Conversely, higher rapid eye movement sleep was associated with fewer interactive socio-motor behaviors. No significant differences in social profiles were found concerning the presence of SDB or daytime sleepiness. CONCLUSIONS: The findings suggest four distinct social profiles in RTT individuals, hinting at shared disrupted circuits between sensorimotor functioning and sleep-related neuronal pathways. Despite the absence of differences in SDB or daytime sleepiness, the study highlights the relationship between sleep parameters, such as sleep onset latency and rapid eye movement sleep, and socio-behavioral outcomes in RTT with MECP2 mutations.

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25. Zhu F, Shi Q, Jiang YH, Zhang YQ, Zhao H. Impaired synaptic function and hyperexcitability of the pyramidal neurons in the prefrontal cortex of autism-associated Shank3 mutant dogs. Mol Autism;2024 (Jan 31);15(1):9.

BACKGROUND: SHANK3 gene is a highly replicated causative gene for autism spectrum disorder and has been well characterized in multiple Shank3 mutant rodent models. When compared to rodents, domestic dogs are excellent animal models in which to study social cognition as they closely interact with humans and exhibit similar social behaviors. Using CRISPR/Cas9 editing, we recently generated a dog model carrying Shank3 mutations, which displayed a spectrum of autism-like behaviors, such as social impairment and heightened anxiety. However, the neural mechanism underlying these abnormal behaviors remains to be identified. METHODS: We used Shank3 mutant dog models to examine possible relationships between Shank3 mutations and neuronal dysfunction. We studied electrophysiological properties and the synaptic transmission of pyramidal neurons from acute brain slices of the prefrontal cortex (PFC). We also examined dendrite elaboration and dendritic spine morphology in the PFC using biocytin staining and Golgi staining. We analyzed the postsynaptic density using electron microscopy. RESULTS: We established a protocol for the electrophysiological recording of canine brain slices and revealed that excitatory synaptic transmission onto PFC layer 2/3 pyramidal neurons in Shank3 heterozygote dogs was impaired, and this was accompanied by reduced dendrite complexity and spine density when compared to wild-type dogs. Postsynaptic density structures were also impaired in Shank3 mutants; however, pyramidal neurons exhibited hyperexcitability. LIMITATIONS: Causal links between impaired PFC pyramidal neuron function and behavioral alterations remain unclear. Further experiments such as manipulating PFC neuronal activity or restoring synaptic transmission in Shank3 mutant dogs are required to assess PFC roles in altered social behaviors. CONCLUSIONS: Our study demonstrated the feasibility of using canine brain slices as a model system to study neuronal circuitry and disease. Shank3 haploinsufficiency causes morphological and functional abnormalities in PFC pyramidal neurons, supporting the notion that Shank3 mutant dogs are new and valid animal models for autism research.

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