1. Caires CRS, Martins ALB. Which form of environmental enrichment is most effective in rodent models of autism?. Behav Processes;2023 (Jul 12):104915.

Environmental enrichment (EE) is known to produce experience-dependent changes in the brains and behaviors of rodents, and it has therefore been widely used to study neurodevelopmental disorders, including autism. Current studies show significant protocol variation, such as the presence of running wheels, number of cagemates, duration of enrichment, and the age of the animals at the beginning and end of the enrichment interventions. EE has been shown to have prominent positive effects in animal models of idiopathic and syndromic autism, but little is known about the ideal type of EE and the most efficient protocols for reversing autism spectrum disorder (ASD) behaviors modeled in rodents. This review presents evidence that social enrichment is the most effective way to rescue typical behaviors, and that variables such as onset, duration, and type of induction in the ASD model are important for EE success. Understanding which EE protocols are most beneficial for reversing ASD behaviors modeled in rodents opens up possibilities for the potential treatment of neuropsychiatric disorders characterized by behavioral deficits, such as autism.

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2. Friedman NR, Watkins L, Barnard-Brak L, Barber A, White SW. De-implementation of Low-Value Practices for Autism Spectrum Disorder. Clin Child Fam Psychol Rev;2023 (Jul 14)

Due to a variety of factors, Autism Spectrum Disorder (ASD) has long been tethered to use of low-value practice (LVP), arguably moreso than any other psychiatric or neurodevelopmental condition. Although dissemination of empirically supported treatments (EST) for autistic individuals has expanded markedly over the past decade, there has not been concomitant reduction in the use of LVP. It is critical that clinicians and scientists not only promote the implementation of EST, but also facilitate the de-implementation (abandonment and/or divestment) of ineffective or harmful practices. In this review, we describe a data-driven approach that can be used to identify LVP, drawing from established criteria for identification of evidence-based treatments (e.g., APA Division 12, National Clearinghouse on Autism Evidence and Practice; SAMHSA), as well as broader considerations such as social validity, cost, and parsimony. Herein, a data-based approach to LVP identification is proposed with a goal of improving quality of service access. Within an implementation science framework, we identify specific facilitators that sustain LVP use, and recommendations for subsequent de-implementation strategies are offered.

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3. Habib MZ, Elnahas EM, Aboul-Ela YM, Ebeid MA, Tarek M, Sadek DR, Negm EA, Abdelhakam DA, Aboul-Fotouh S. Risperidone impedes glutamate excitotoxicity in a valproic acid rat model of autism: Role of ADAR2 in AMPA GluA2 RNA editing. Eur J Pharmacol;2023 (Jul 15):175916.

Several reports indicate a plausible role of calcium (Ca(2+)) permeable AMPA glutamate receptors (with RNA hypo-editing at the GluA2 Q/R site) and the subsequent excitotoxicity-mediated neuronal death in the pathogenesis of a wide array of neurological disorders including autism spectrum disorder (ASD). This study was designed to examine the effects of chronic risperidone treatment on the expression of adenosine deaminase acting on RNA 2 (Adar2), the status of AMPA glutamate receptor GluA2 editing, and its effects on oxidative/nitrosative stress and excitotoxicity-mediated neuronal death in the prenatal valproic acid (VPA) rat model of ASD. Prenatal VPA exposure was associated with autistic-like behaviors accompanied by an increase in the apoptotic marker « caspase-3 » and a decrease in the antiapoptotic marker « BCL2 » alongside a reduction in the Adar2 relative gene expression and an increase in GluA2 Q:R ratio in the hippocampus and the prefrontal cortex. Risperidone, at doses of 1 and 3 mg, improved the VPA-induced behavioral deficits and enhanced the Adar2 relative gene expression and the subsequent GluA2 subunit editing. This was reflected on the cellular level where risperidone impeded VPA-induced oxidative/nitrosative stress and neurodegenerative changes. In conclusion, the present study confirms a possible role for Adar2 downregulation and the subsequent hypo-editing of the GluA2 subunit in the pathophysiology of the prenatal VPA rat model of autism and highlights the favorable effect of risperidone on reversing the RNA editing machinery deficits, giving insights into a new possible mechanism of risperidone in autism.

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4. Hughes L, Kargas N, Wilhelm M, Meyerhoff HS, Föcker J. The Impact of Audio-Visual, Visual and Auditory Cues on Multiple Object Tracking Performance in Children with Autism. Percept Mot Skills;2023 (Jul 15):315125231187984.

Previous studies have documented differences in processing multisensory information by children with autism compared to typically developing children. Furthermore, children with autism have been found to track fewer multiple objects on a screen than those without autism, suggesting reduced attentional control. In the present study, we investigated whether children with autism (n = 33) and children without autism (n = 33) were able to track four target objects moving amongst four indistinguishable distractor objects while sensory cues were presented. During tracking, we presented various types of cues – auditory, visual, or audio-visual or no cues while target objects bounced off the inner boundary of a centralized circle. We found that children with autism tracked fewer targets than children without autism. Furthermore, children without autism showed improved tracking performance in the presence of visual cues, whereas children with autism did not benefit from sensory cues. Whereas multiple object tracking performance improved with increasing age in children without autism, especially when using audio-visual cues, children with autism did not show age-related improvement in tracking. These results are in line with the hypothesis that attention and the ability to integrate sensory cues during tracking are reduced in children with autism. Our findings could contribute valuable insights for designing interventions that incorporate multisensory information.

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5. Iniesta J, Verdugo MA, Schalock RL. Organizational change and evidence-based practices in support services for people with intellectual and developmental disabilities. Eval Program Plann;2023 (Jun 20);100:102337.

The impact on support services for persons with intellectual and developmental disabilities of the socioeconomic movements and theoretical reformulations of the last decades has generated the necessity, in order to guarantee their sustainability, to carry out processes of profound change in their organizational culture, intervening in the elements that compose it. Among them are professional practices as the best way to intervene in culture, with the use of comparative analysis between an organization’s current practices and those expected with culture change. In this line, the organizational self-assessment tool « Organizational Effectiveness and Efficiency Scale » (OEES) is applied in a study with 24 organizations, which uses a collaborative assessment approach in the service of a set of evidence-based practices identified as standards in key aspects that guide culture change, specifically, a person-centered approach, participative structures, use of information systems and data management, implementation of quality systems and participative and transformational leadership. The results obtained show that a large majority of organizations have significant discrepancies between their current practices and evidence-based practices. The descriptive analysis allows affirming the usefulness of the scale for an organizational diagnosis and identification of strategies to guide transformational change.

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6. Kourdougli N, Suresh A, Liu B, Juarez P, Lin A, Chung DT, Graven Sams A, Gandal MJ, Martínez-Cerdeño V, Buonomano DV, Hall BJ, Mombereau C, Portera-Cailliau C. Improvement of sensory deficits in fragile X mice by increasing cortical interneuron activity after the critical period. Neuron;2023 (Jul 7)

Changes in the function of inhibitory interneurons (INs) during cortical development could contribute to the pathophysiology of neurodevelopmental disorders. Using all-optical in vivo approaches, we find that parvalbumin (PV) INs and their immature precursors are hypoactive and transiently decoupled from excitatory neurons in postnatal mouse somatosensory cortex (S1) of Fmr1 KO mice, a model of fragile X syndrome (FXS). This leads to a loss of parvalbumin INs (PV-INs) in both mice and humans with FXS. Increasing the activity of future PV-INs in neonatal Fmr1 KO mice restores PV-IN density and ameliorates transcriptional dysregulation in S1, but not circuit dysfunction. Critically, administering an allosteric modulator of Kv3.1 channels after the S1 critical period does rescue circuit dynamics and tactile defensiveness. Symptoms in FXS and related disorders could be mitigated by targeting PV-INs.

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7. Lee KS, Gau SS, Tseng WL. Autistic Symptoms, Irritability, and Executive Dysfunctions: Symptom Dynamics from Multi-Network Models. J Autism Dev Disord;2023 (Jul 15)

Socio-cognitive difficulties in individuals with autism spectrum disorder (ASD) are heterogenuous and often co-occur with irritability symptoms, such as angry/grouchy mood and temper outbursts. However, the specific relations between individual symptoms are not well-represented in conventional methods analyzing aggregated autistic symptoms and ASD diagnosis. Moreover, the cognitive-behavioral mechanisms linking ASD to irritability are largely unknown. This study investigated the dynamics between autistic (Social Responsiveness Scale) and irritability (Affective Reactivity Index) symptoms and executive functions (Cambridge Neuropsychological Test Automated Battery) in a sample of children and adolescents with ASD, their unaffected siblings, and neurotypical peers (N = 345, aged 6-18 years, 78.6% male). Three complementary networks across the entire sample were computed: (1) Gaussian graphical network estimating the conditional correlations between symptom nodes; (2) Relative importance network computing relative influence between symptoms; (3) Bayesian directed acyclic graph estimating predictive directionality between symptoms. Networks revealed numerous partial correlations within autistic (rs = .07-.56) and irritability (rs = .01-.45) symptoms and executive functions (rs = -.83 to .67) but weak connections between clusters. This segregated pattern converged in all directed and supplementary networks. Plausible predictive paths were found between social communication difficulties to autism mannerisms and between « angry frequently » to « lose temper easily. » Autistic and irritability symptoms are two relatively independent families of symptoms. It is unlikely that executive dysfunctions explain elevated irritability in ASD. Findings underscore the need for researching other mood and cognitive-behavioral bridge symptoms, which may inform individualized treatments for co-occurring irritability in ASD.

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8. Li YJ, Zhang K, Sun T, Guo YY, Yang Q, Liu SB, Wu YM, Zhao MG. Improvement of Learning and Memory by Elevating Brain D-Aspartate in a Mouse Model of Fragile X Syndrome. Mol Neurobiol;2023 (Jul 15)

Fragile X syndrome (FXS) is an inherited human mental retardation that arises from expansion of a CGG repeat in the Fmr1 gene, causing loss of the fragile X mental retardation protein (FMRP). It is reported that N-methyl-D-aspartate receptor (NMDAR)-mediated facilitation of long-term potentiation (LTP) and fear memory are impaired in Fmr1 knockout (KO) mice. In this study, biological, pharmacological, and electrophysiological techniques were performed to determine the roles of D-aspartate (D-Asp), a modulator of NMDAR, and its metabolizing enzyme D-aspartate oxidase (DDO) in Fmr1 KO mice. Levels of D-Asp were decreased in the medial prefrontal cortex (mPFC ); however, the levels of its metabolizing enzyme DDO were increased. Electrophysiological recordings indicated that oral drinking of D-Asp recovered LTP induction in mPFC from Fmr1 KO mice. Moreover, chronic oral administration of D-Asp reversed behavioral deficits of cognition and locomotor coordination in Fmr1 KO mice. The therapeutic action of D-Asp was partially through regulating functions of NMDARs and mGluR5/mTOR/4E-BP signaling pathways. In conclusion, supplement of D-Asp may benefit for synaptic plasticity and behaviors in Fmr1 KO mice and offer a potential therapeutic strategy for FXS.

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9. Parent H, Ferranti A, Niswender C. Trofinetide: a pioneering treatment for Rett syndrome. Trends Pharmacol Sci;2023 (Jul 15)

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10. Song AY, Kauffman EM, Hamra GB, Dickerson AS, Croen LA, Hertz-Picciotto I, Schmidt RJ, Newschaffer CJ, Fallin MD, Lyall K, Volk HE. Associations of prenatal exposure to a mixture of persistent organic pollutants with social traits and cognitive and adaptive function in early childhood: Findings from the EARLI study. Environ Res;2023 (Jul 15);229:115978.

BACKGROUND: Literature suggests that maternal exposure to persistent organic pollutants (POPs) may influence child neurodevelopment. Evidence linking prenatal POPs and autism spectrum disorder has been inconclusive and few studies have examined the mixture effect of the POPs on autism-related traits. OBJECTIVE: To evaluate the associations between prenatal exposure to a mixture of POPs and autism-related traits in children from the Early Autism Risk Longitudinal Investigation study. METHODS: Maternal serum concentrations of 17 POPs (11 polychlorinated biphenyls [PCBs], 4 polybrominated diphenyls [PBDEs], and 2 persistent pesticides) in 154 samples collected during pregnancy were included in this analysis. We examined the independent associations of the natural log-transformed POPs with social, cognitive, and behavioral traits at 36 months of age, including Social Responsiveness Scale (SRS), Mullen Scales of Early Learning-Early Learning Composite (MSEL-ELC), and Vineland Adaptive Behavior Scales (VABS) scores, using linear regression models. We applied Bayesian kernel machine regression and quantile g-computation to examine the joint effect and interactions of the POPs. RESULTS: Higher ln-PBDE47 was associated with greater deficits in social reciprocity (higher SRS score) (β = 6.39, 95% CI: 1.12, 11.65) whereas higher ln-p,p’-DDE was associated with lower social deficits (β = -8.34, 95% CI: -15.32, -1.37). Positive associations were observed between PCB180 and PCB187 and cognitive (MSEL-ELC) scores (β = 5.68, 95% CI: 0.18, 11.17; β = 4.65, 95% CI: 0.14, 9.17, respectively). Adaptive functioning (VABS) scores were positively associated with PCB170, PCB180, PCB187, PCB196/203, and p,p’-DDE. In the mixture analyses, we did not observe an overall mixture effect of POPs on the quantitative traits. Potential interactions between PBDE99 and other PBDEs were identified in association with MSEL-ELC scores. CONCLUSIONS: We observed independent effects of PCB180, PCB187, PBDE47, and p,p’ DDE with ASD-related quantitative traits and potential interactions between PBDEs. Our findings highlight the importance of assessing the effect of POPs as a mixture.

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11. Soylu F, May K, Kana R. White and gray matter correlates of theory of mind in autism: a voxel-based morphometry study. Brain Struct Funct;2023 (Jul 15)

Autism spectrum disorder (ASD) is characterized by difficulties in theory of mind (ToM) and social communication. Studying structural and functional correlates of ToM in the brain and how autistic and nonautistic groups differ in terms of these correlates can help with diagnosis and understanding the biological mechanisms of ASD. In this study, we investigated white matter volume (WMV) and gray matter volume (GMV) differences between matching autistic and nonautistic samples, and how these structural features relate to age and ToM skills, indexed by the Reading the Mind in the Eyes (RMIE) measure. The results showed widespread GMV and WMV differences between the two groups in regions crucial for social processes. The autistic group did not express the typically observed negative GMV and positive WMV correlations with age at the same level as the nonautistic group, pointing to abnormalities in developmental structural changes. In addition, we found differences between the two groups in how GMV relates to ToM, particularly in the left frontal regions, and how WMV relates to ToM, mostly in the cingulate and corpus callosum. Finally, GMV in the left insula, a region that is part of the salience network, was found to be crucial in distinguishing ToM performance between the two groups.

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12. Yang Y, Zhou S, Xing Y, Yang G, You M. Impact of pesticides exposure during neurodevelopmental period on autism spectrum disorders – A focus on gut microbiota. Ecotoxicol Environ Saf;2023 (Jul 15);260:115079.

Accumulating evidence indicates exposure to pesticides during the crucial neurodevelopmental period increases susceptibility to many diseases, including the neurodevelopmental disorder known as autism spectrum disorder (ASD). In the last few years, it has been hypothesized that gut microbiota dysbiosis is strongly implicated in the aetiopathogenesis of ASD. Recently, new studies have suggested that the gut microbiota may be involved in the neurological and behavioural defects caused by pesticides, including ASD symptoms. This review highlights the available evidence from recent animal and human studies on the relationship between pesticides that have the potential to disturb intestinal microbiota homeostasis, and ASD symptoms. The mechanisms through which gut microbiota dysbiosis may trigger ASD-like behaviours induced by pesticides exposure during the neurodevelopmental period via the altered production of bacterial metabolites (short chain fatty acids, lipids, retinol, and amino acid) are also described. According to recent research, gut microbiota dysbiosis may be a major contributor to the symptoms of ASD associated with pesticides exposure. However, to determine the detailed mechanism of action of gut microbiota on pesticide-induced ASD behaviours, actual population exposure scenarios from epidemiological studies should be used as the basis for the appropriate exposure pattern and dosage to be used in animal studies.

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13. Yue X, Shen Y, Li Y, Zhang G, Li X, Wei W, Bai Y, Shang Y, Xie J, Luo Z, Wang X, Zhang X, Wang M. Regional Dynamic Neuroimaging Changes of Adults with Autism Spectrum Disorder. Neuroscience;2023 (Jul 15);523:132-139.

Most neuroimaging studies investigating autism spectrum disorder (ASD) have focused on static brain function, but ignored the dynamic features of spontaneous brain activities in the temporal dimension. Research of dynamic brain regional activities might help to fully investigate the mechanisms of ASD patients. This study aimed to examine potential changes in the dynamic characteristics of regional neural activities in adult ASD patients and to detect whether the changes were associated with Autism Diagnostic Observation Schedule (ADOS) scores. Resting-state functional MRI was obtained on 77 adult ASD patients and 76 healthy controls. The dynamic regional homogeneity (dReHo) and dynamic amplitude of low-frequency fluctuations (dALFF) were compared between the two groups. Correlation analyses were also performed between dReHo and dALFF in areas showing group differences and ADOS scores. In ASD group, significant differences in dReHo were observed in the left middle temporal gyrus (MTG.L). Besides, we found increased dALFF in the left middle occipital gyrus (MOG.L), left superior parietal gyrus (SPG.L), left precuneus (PCUN.L), left inferior temporal gyrus (ITG.L), and right inferior frontal gyrus, orbital part (ORBinf.R). Furthermore, a significant positive correlation was found between dALFF in the PCUN.L and the ADOS_TOTAL scores, ADOS_SOCIAL scores; the dALFF in the ITG.L, SPG.L was positively associated with ADOS_SOCIAL scores. In conclusion, adults with ASD have a wide area of dynamic regional brain function abnormalities. These suggested that dynamic regional indexes might be used as a powerful measure to help us obtain a more comprehensive understanding of neural activity in adult ASD patients.

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14. Zane E, Grossman RB. Analysis of Noun Phrase Ambiguity in Narratives Reveals Differences in Referential Establishment But Not Cohesion for Older Autistic Children. J Speech Lang Hear Res;2023 (Jul 14):1-19.

PURPOSE: Stories told by autistic narrators often contain relatively frequent use of ambiguous references. However, it remains unclear whether this ambiguity is driven by ambiguous character establishment (e.g., « Once upon a time, she/the girl… ») and/or ambiguous cohesion (e.g., « Two girls lived in a castle. She/The girl… »). In this study, we directly compared rates of each type of ambiguity within and between narratives told by autistic and non-autistic children, to determine which type of ambiguity is relatively more common in narratives told by autistic children. METHOD: Thirty-three 10- to 17-year-old autistic participants (n = 17) and non-autistic peers (n = 16), who were not statistically different in age, standardized language scores, and IQ scores (p > .8 for all), watched two short animated videos alone and then described the videos’ events to two listeners who were openly unfamiliar with the videos. We transcribed video recordings of narratives and coded all referential noun phrases (NPs) as either clear or ambiguous. We further categorized ambiguous NPs as either ineffective introduction or ineffective cohesion. RESULTS: Autistic children produced significantly higher rates of ambiguous establishment than non-autistic peers, whereas between-group comparisons’ rates of ambiguous cohesion were not statistically significant. CONCLUSIONS: Older children on the autism spectrum show differences in the way they introduce characters, selecting NP types that are only appropriate when their listener is already familiar with the referent. In contrast, once they have introduced characters, they show cohesive skills that are comparable to those of non-autistic peers. Findings support theories arguing that autistic children show differences in their application of social pragmatic principles (listener/context-specific pragmatic rules), whereas their use of linguistic pragmatics (context-independent rules) is similar to that of non-autistic peers.

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15. Zhang M, Yu J, Liu A, Liu QQ, Sun T, Li X, Du Y, Li J, Wang B, Yang Q. Luteolin in the Qi Bi Anshen decoction improves propionic acid-induced autism-like behavior in rats by inhibiting LRP1/MMP9. Phytomedicine;2023 (Jul 10);118:154965.

BACKGROUND: A neurodevelopmental illness with a high frequency and unidentified pathophysiology is known as autism spectrum disorder (ASD). A research hotspot in this field is the identification of disease-specific biomarkers and drug intervention targets. Traditional Chinese medicine (TCM) can eliminate the symptoms of autism by precisely regulating human physiology. The Qi Bi Anshen decoction (QAT) is a commonly used TCM clinical drug commonly-used to treat for treating ASD. However, the primary active ingredients and underlying mechanisms of action of this decoction remain unknown. PURPOSE: This study aimed to investigate the active ingredients and pharmacodynamics of QAT in the treatment of ASD using a Sprague-Dawley rat model that resembled autism. METHODS: Autism-like rat models were established through intracerebroventricular injections of propionic acid (PPA). Subsequently, the rats were treated with QAT, and their efficacy was evaluated using the three-chamber method to analyze social interactions and grooming behavior. Additionally, open-field tests, elevated cross-maze tests, hematoxylin and eosin staining, Nissl staining, and enzyme-linked immunosorbent assays were performed; Western blot analysis was employed to determine the expression of synaptic plasticity-related proteins. Utilizing ultra-high-performance liquid chromatography-mass spectrometry (UPLC-MS), the effectiveness of active QAT components was assessed, and potential QAT targets were screened through molecular docking, surface plasmon resonance, and thermal migration experiments. To better understand the precise processes involved in treating ASD with active QAT components, in vivo and in vitro knockdown tests were also performed. RESULTS: QATexhibited a significant improvement in autism-like behavior and a notable increase in the production of proteins associated with synaptic plasticity. Furthermore, luteolin (LUT), identified as a potentially important active ingredient in QAT for treating ASD, reduced matrix metallopeptidase-9 (MMP9) expression. However, this effect was attenuated by the knockdown of low-density lipoprotein receptor-associated protein 1 (LRP1), which is the target binding site for LUT. CONCLUSIONS: LUT emerges as a potentially crucial active component of QAT in the treatment of ASD, with the ability to antagonize LRP1 and subsequently reduce MMP9 expression.

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16. Zhao Y, Wang Y, Meng F, Chen X, Chang T, Huang H, He F, Zheng Y. Altered Gut Microbiota as Potential Biomarkers for Autism Spectrum Disorder in Early Childhood. Neuroscience;2023 (Jul 15);523:118-131.

Gastrointestinal (GI) disorders are widely recorded in autism spectrum disorder (ASD), and ASD with GI symptoms is a vital subtype of this disease. Growing evidence suggests altered gut microbiota biomarkers in ASD, but little is known about the gut microbiota of individuals with ASD with GI Symptoms, particularly in early childhood. In our study, the gut microbiota of 36 individuals with ASD along with GI symptoms and 40 typically developing (TD) children were compared using 16S rRNA gene sequencing. The microbial diversity and composition were found to differ between the two groups. Compared to TD, the gut microbiota of ASD patients with GI symptoms exhibited decreased alpha diversity and depletion of butyrate-producing bacteria (e.g., Faecalibacterium and Coprococcus). In addition, microbial functional analysis showed abnormality in several gut metabolic models and gut brain models of ASD with GI symptoms, including short-chain fatty acid (SCFA) synthesis/degradation and neurotoxin-related p-cresol degradation, which are closely associated with ASD-related behaviors in animal models. Furthermore, we constructed a Support Vector Machine classification model, which robustly discriminated individuals with ASD and GI symptoms from TD individuals in a validation set (AUC = 0.88). Our findings provide a deep insight into the roles of the disturbed gut ecosystem in individuals with ASD and GI symptoms aged 3-6 years. Our classification model supports gut microbiota as a potential biomarker for the early identification of ASD and interventions targeting particular gut-beneficial microbiota.

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