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Background: Social isolation during critical periods of development is associated with alterations in behavior and neuronal circuitry. This study aimed to investigate the immediate and developmental effects of social isolation on firing properties, neuronal activity-regulated pentraxin (NARP) and parvalbumin (PV) expression in the prefrontal cortex (PFC), social behavior in juvenile socially isolated mice, and the biological relevance of NARP expression in autism spectrum disorder (ASD). Methods: Mice were subjected to social isolation during postnatal days 21-35 (P21-P35) and were compared with group-housed control mice. Firing properties in the PFC pyramidal neurons were altered in P35 socially isolated mice, which might be associated with alterations in NARP and PV expression. Results: In adulthood, mice that underwent juvenile social isolation exhibited difficulty distinguishing between novel and familiar mice during a social memory task, while maintaining similar levels of social interaction as the control mice. Furthermore, a marked decrease in NARP expression in lymphoblastoid cell lines derived from adolescent humans with ASD as compared to typically developing (TD) humans was found. Conclusion: Our study highlights the role of electrophysiological properties, as well as NARP and PV expression in the PFC in mediating the developmental consequences of social isolation on behavior. [ABSTRACT FROM AUTHOR]

Catatonia is a complex neuropsychiatric syndrome involving a constellation of psychomotor disturbances including catalepsy, waxy flexibility, stupor, mutism, negativism, agitation, posturing, stereotypes, mannerisms, grimacing, echolalia, and echopraxia. Catatonia occurs in several conditions including psychotic, affective and neurodevelopmental disorders such as autism spectrum disorder (ASD). ASD is a neurodevelopmental disorder characterized by persistent deficits in communication, social interaction, restricted interests, repetitive behaviours and sensory sensitivities. Catatonia can occur in response to life stressors such as extreme fear or threat, interpersonal conflict, tragic events or following significant loss. Those with ASD may be particularly vulnerable to the negative impact of stressors and the link between catatonia and ASD is being increasingly recognized. The overlapping features of catatonia and ASD make it difficult to differentiate often resulting in delayed or missed diagnosis. Catatonia in ASD remains a significant clinical challenge; it is difficult to diagnose and can pose debilitating difficulties for those affected. Catatonia is a treatable condition and prompt recognition is vital in securing the best possible outcome. We report a complex and unique case of a 15-year-old boy who presented with severe cognitive and functional decline with a background history of significant bullying and deterioration in his mental state. This case posed a diagnostic conundrum leading to a diagnosis of underlying ASD, anxiety and trauma. [ABSTRACT FROM AUTHOR]

This case study examines the effective use of Augmentative and Alternative Communication (AAC) tools in enhancing communication skills in a 15-year-old male with Autism Spectrum Disorder (ASD). Initially exhibiting non-verbal tendencies, the subject experienced significant improvements in communication and social interaction following the introduction of a letter board and subsequent transition to an iPad. These AAC tools facilitated a marked development in his ability to articulate thoughts, engage in academic activities, and express complex ideas, particularly in science. The study highlights the role of AAC in expanding the communicative capabilities of individuals with limited or no verbal language, demonstrating notable advancements in both verbal expression and cognitive engagement. The findings underscore the transformative impact of personalized AAC interventions and suggest the potential for broader application in ASD support strategies. This case highlights the need for further research, including randomized controlled trials, to explore the efficacy of AAC tools in diverse ASD contexts. [ABSTRACT FROM AUTHOR]

Introduction: Autism SpectrumDisorder (ASD) is a common neurodevelopmental disorder emerging in early childhood, with heterogeneous clinical outcomes across individuals. This study aims to recognize neuroimaging genetic factors associated with outcomes of ASD after a 4-year follow-up. Methods: A total of 104 ASD children were included in this study; they underwent clinical assessments, MRI data acquisition, and the whole exome sequencing (WES). Exome functional risk score (EFRS) was calculated based on WES; and two modalities of brain connectivity were constructed based on MRI data, that is functional connectivity (FC) for functional MRI (fMRI), and individual differential structural covariance network (IDSCN) for structural MRI (sMRI), to explore the neuroimaging genetic biomarker of outcomes of ASD children. Results: Regression analysis found EFRS predicts social adaptability at the 4-year follow-up (Y = -0.013X + 9.29, p = 0.003). We identified 19 pairs of FC associated with autism symptoms severity at follow-up, 10 pairs of FC and 4 pairs of IDSCN associated with social adaptability at follow-up, and 10 pairs of FC associated with ASD EFRS by support vector regression (SVR). Related brain regions with prognostic predictive effects are mainly distributed in superior frontal gyrus, occipital cortex, temporal cortex, parietal cortex, paracentral lobule, pallidum, and amygdala for FC, and temporal cortex, thalamus, and hippocampus for IDSCN. Mediation model showed that ASD EFRS affects the social communication of ASD children through the mediation of FC between left middle occipital gyrus and left pallidum (RMSEA=0.126, CMIN=80.66, DF=42, p< 0.001, CFI=0.867, AIC=152). Discussion: Our findings underscore that both EFRS and brain connectivity can predict social adaptability, and that brain connectivity serving as mediator in the relationship of EFRS and behaviors of ASD, suggesting the intervention targets in the future clinical application. [ABSTRACT FROM AUTHOR]

The hippocampus is one of the brain areas affected by autism spectrum disorder (ASD). Individuals with ASD typically have impairments in hippocampusdependent learning, memory, language ability, emotional regulation, and cognitive map creation. However, the pathological changes in the hippocampus that result in these cognitive deficits in ASD are not yet fully understood. In the present review, we will first summarize the hippocampal involvement in individuals with ASD. We will then provide an overview of hippocampal structural and functional abnormalities in genetic, environmentinduced, and idiopathic animal models of ASD. Finally, we will discuss some pharmacological and non-pharmacological interventions that show positive impacts on the structure and function of the hippocampus in animal models of ASD. A further comprehension of hippocampal aberrations in ASD might elucidate their influence on the manifestation of this developmental disorder and provide clues for forthcoming diagnostic and therapeutic innovation. [ABSTRACT FROM AUTHOR]

Background: Restricted interests and repetitive behavior are characteristics of autism spectrum disorder (ASD). The likelihood that persons with ASD will respond adversely to unfamiliar situations is great. The novel coronavirus outbreak has resulted in disruptions to all aspects of routine and behavior. Hence, this study proposed to investigate the impact of the outbreak on the eating behavior and routines of childrenwith ASD in Saudi Arabia through the perceptions of their parents. Method: A cross-sectional study with a quantitative approach was utilized to obtain data from 150 parents of children with ASD aged =18 years in Saudi Arabia. The data collected included demographic data of the parents, the ASD status of the family, impact of COVID-19 to the family, eating behavior of the children with ASD, and daily routines of the children with ASD. Moreover, parents were able to provide comments regarding their children's eating behavior or daily routines. Results: The study found that changes in the eating behavior of children with ASD were found to differ significantly (p<0.05) based on the number of children with ASD, the age of the children with ASD, the gender of the children with ASD, and the severity of their ASD symptoms. Moreover, changes to dinner-time routines were found to differ significantly (p<0.05) based on the age of the children with ASD. Also, changes to morning routines were found to differ significantly (p<0.05) based on the age of the children with ASD, their gender, and the severity of their ASD symptoms. Additionally, impact of COVID-19 to the family had a significant impact to eating behavior and daily routines of the children with ASD. Conclusion: This study found that the eating behavior and daily routines of children with ASD in Saudi Arabia have been considerably worsened and changed. The study recommends the collaboration of multidisciplinary teams and parents to modify or design interventions that help to change their eating behavior and routine can be implemented in the home. It also recommends the provision of virtual helplines to aid parents of children with ASD in such cases. [ABSTRACT FROM AUTHOR]

Background: The aim of the study was to investigate the level of fear of the COVID-19 pandemic and to detect a possible correlation between the autistic traits and the level of fear and to learn about other factors that may affect the level of fear. Methods: The study utilised a questionnaire and was conducted online in the period from 16.02.2021 to 11.06.2021. The test group consisted of 214 respondents with an average age of 23.78 years (95%CI: 22.48 - 25.08; max: 61, min: 14) from the general population. The study used The Autism-Spectrum Quotient (AQ) questionnaire to assess the degree of autistic traits in the general population and The Fear of COVID-19 Scale, which was used to assess the level of fear of COVID-19. Results: Among the respondents, 9 people scored =32 on the AQ test and were considered to have a high degree of autistic traits. In multiple regression (R2 = 0.1, p<0.0001), a positive relationship between the severity of fear of COVID-19 and the autistic traits (p=0.01) and age (p<0.001) was obtained. Additionally, a second multiple regression (R2 = 0.1, p<0.000001) including the subscales of AQ was performed and a positive relationship between the severity of fear of COVID-19 and the difficulties in attention switching (p=0.0004) and age (p=0.00001) was obtained. Conclusion: People with higher autistic traits present greater fear of the COVID-19 pandemic. We suggest that it might be caused by cognitive stiffness and disorders in emotions regulation, according to the literature. The elderly also present higher levels of fear. The other variables did not affect the level of fear of the COVID-19 pandemic. [ABSTRACT FROM AUTHOR]

Catatonia is a complex neuropsychiatric syndrome involving a constellation of psychomotor disturbances including catalepsy, waxy flexibility, stupor, mutism, negativism, agitation, posturing, stereotypes, mannerisms, grimacing, echolalia, and echopraxia. Catatonia occurs in several conditions including psychotic, affective and neurodevelopmental disorders such as autism spectrum disorder (ASD). ASD is a neurodevelopmental disorder characterized by persistent deficits in communication, social interaction, restricted interests, repetitive behaviours and sensory sensitivities. Catatonia can occur in response to life stressors such as extreme fear or threat, interpersonal conflict, tragic events or following significant loss. Those with ASD may be particularly vulnerable to the negative impact of stressors and the link between catatonia and ASD is being increasingly recognized. The overlapping features of catatonia and ASD make it difficult to differentiate often resulting in delayed or missed diagnosis. Catatonia in ASD remains a significant clinical challenge; it is difficult to diagnose and can pose debilitating difficulties for those affected. Catatonia is a treatable condition and prompt recognition is vital in securing the best possible outcome. We report a complex and unique case of a 15-year-old boy who presented with severe cognitive and functional decline with a background history of significant bullying and deterioration in his mental state. This case posed a diagnostic conundrum leading to a diagnosis of underlying ASD, anxiety and trauma.

This case study examines the effective use of Augmentative and Alternative Communication (AAC) tools in enhancing communication skills in a 15-year-old male with Autism Spectrum Disorder (ASD). Initially exhibiting non-verbal tendencies, the subject experienced significant improvements in communication and social interaction following the introduction of a letter board and subsequent transition to an iPad. These AAC tools facilitated a marked development in his ability to articulate thoughts, engage in academic activities, and express complex ideas, particularly in science. The study highlights the role of AAC in expanding the communicative capabilities of individuals with limited or no verbal language, demonstrating notable advancements in both verbal expression and cognitive engagement. The findings underscore the transformative impact of personalized AAC interventions and suggest the potential for broader application in ASD support strategies. This case highlights the need for further research, including randomized controlled trials, to explore the efficacy of AAC tools in diverse ASD contexts.

BackgroundRestricted interests and repetitive behavior are characteristics of autism spectrum disorder (ASD). The likelihood that persons with ASD will respond adversely to unfamiliar situations is great. The novel coronavirus outbreak has resulted in disruptions to all aspects of routine and behavior. Hence, this study proposed to investigate the impact of the outbreak on the eating behavior and routines of children with ASD in Saudi Arabia through the perceptions of their parents.MethodA cross-sectional study with a quantitative approach was utilized to obtain data from 150 parents of children with ASD aged ≤18 years in Saudi Arabia. The data collected included demographic data of the parents, the ASD status of the family, impact of COVID-19 to the family, eating behavior of the children with ASD, and daily routines of the children with ASD. Moreover, parents were able to provide comments regarding their children’s eating behavior or daily routines.ResultsThe study found that changes in the eating behavior of children with ASD were found to differ significantly (p

BackgroundThe aim of the study was to investigate the level of fear of the COVID-19 pandemic and to detect a possible correlation between the autistic traits and the level of fear and to learn about other factors that may affect the level of fear.MethodsThe study utilised a questionnaire and was conducted online in the period from 16.02.2021 to 11.06.2021. The test group consisted of 214 respondents with an average age of 23.78 years (95%CI: 22.48 – 25.08; max: 61, min: 14) from the general population. The study used The Autism-Spectrum Quotient (AQ) questionnaire to assess the degree of autistic traits in the general population and The Fear of COVID-19 Scale, which was used to assess the level of fear of COVID-19.ResultsAmong the respondents, 9 people scored ≥32 on the AQ test and were considered to have a high degree of autistic traits. In multiple regression (R2 = 0.1, p

Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by social communication and social interaction impairments accompanied by restrictive and repetitive behaviors or interests. Co-occurring conditions may greatly impact overall functioning and intervention needs, and contribute to individual variability and etiologic subtypes. Clinical care of individuals with ASD requires gathering a breadth of information across multiple domains. The neurodevelopmental parent report for outcome monitoring (ND-PROM) was developed to assess symptoms across core features of ASD as well as frequent concerns and comorbidities. The current study expands upon the initially reported psychometric properties of the ND-PROM and evaluates a proposed a clinically derived 12-factor structure of the ND-PROM. Methods and procedures: The ND-PROM was completed for 246 children with ASD ands tested using confirmatory factor analysis (CFA) and measurement invariance based on sex. Outcomes and results: A 12-factor correlated structure was found (expressive language, receptive language, nonverbal communication, social emotional understanding, social interaction, independent play, adaptive/toileting skills, restrictive and repetitive behaviors and interests, sensory processes, challenging behaviors, impulse/ADHD, and mental health), which did not vary by sex. Conclusions and implications: The ND-PROM captures a range of distinct aspects of developmental and behavioral functioning in ASD that can be used to track independent functioning across domains. [ABSTRACT FROM AUTHOR]

Introduction: Autism spectrum disorder (ASD) is a neurodevelopmental disorder that persists into adulthood with both social and cognitive disturbances. Asperger's syndrome (AS) was a distinguished subcategory of autism in the DSM-IV-TR defined by specific symptoms including difficulties in social interactions, inflexible thinking patterns, and repetitive behaviour without any delay in language or cognitive development. Studying the functional brain organization of individuals with these specific symptoms may help to better understand Autism spectrum symptoms. Methods: The aim of this study is therefore to investigate functional connectivity as well as functional network organization characteristics using graph-theory measures of the whole brain in male adults with AS compared to healthy controls (HC) (AS: n = 15, age range 21–55 (mean ± sd: 39.5 ± 11.6), HC: n = 15, age range 22–57 [mean ± sd: 33.5 ± 8.5]). Results: No significant differences were found when comparing the region-by-region connectivity at the whole-brain level between the AS group and HC. However, measures of “transitivity,” which reflect local information processing and functional segregation, and “assortativity,” indicating network resilience, were reduced in the AS group compared to HC. On the other hand, global efficiency, which represents the overall effectiveness and speed of information transfer across the entire brain network, was increased in the AS group. Discussion: Our findings suggest that individuals with AS may have alterations in the organization and functioning of brain networks, which could contribute to the distinctive cognitive and behavioural features associated with this condition. We suggest further research to explore the association between these altered functional patterns in brain networks and specific behavioral traits observed in individuals with AS, which could provide valuable insights into the underlying mechanisms of its symptomatology. [ABSTRACT FROM AUTHOR]

Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by social communication and social interaction impairments accompanied by restrictive and repetitive behaviors or interests. Co-occurring conditions may greatly impact overall functioning and intervention needs, and contribute to individual variability and etiologic subtypes. Clinical care of individuals with ASD requires gathering a breadth of information across multiple domains. The neurodevelopmental parent report for outcome monitoring (ND-PROM) was developed to assess symptoms across core features of ASD as well as frequent concerns and comorbidities. The current study expands upon the initially reported psychometric properties of the ND-PROM and evaluates a proposed a clinically derived 12-factor structure of the ND-PROM.Methods and proceduresThe ND-PROM was completed for 246 children with ASD ands tested using confirmatory factor analysis (CFA) and measurement invariance based on sex.Outcomes and resultsA 12-factor correlated structure was found (expressive language, receptive language, nonverbal communication, social emotional understanding, social interaction, independent play, adaptive/toileting skills, restrictive and repetitive behaviors and interests, sensory processes, challenging behaviors, impulse/ADHD, and mental health), which did not vary by sex.Conclusions and implicationsThe ND-PROM captures a range of distinct aspects of developmental and behavioral functioning in ASD that can be used to track independent functioning across domains.

IntroductionAutism spectrum disorder (ASD) is a neurodevelopmental disorder that persists into adulthood with both social and cognitive disturbances. Asperger's syndrome (AS) was a distinguished subcategory of autism in the DSM-IV-TR defined by specific symptoms including difficulties in social interactions, inflexible thinking patterns, and repetitive behaviour without any delay in language or cognitive development. Studying the functional brain organization of individuals with these specific symptoms may help to better understand Autism spectrum symptoms.MethodsThe aim of this study is therefore to investigate functional connectivity as well as functional network organization characteristics using graph-theory measures of the whole brain in male adults with AS compared to healthy controls (HC) (AS: n = 15, age range 21–55 (mean ± sd: 39.5 ± 11.6), HC: n = 15, age range 22–57 [mean ± sd: 33.5 ± 8.5]).ResultsNo significant differences were found when comparing the region-by-region connectivity at the whole-brain level between the AS group and HC. However, measures of “transitivity,” which reflect local information processing and functional segregation, and “assortativity,” indicating network resilience, were reduced in the AS group compared to HC. On the other hand, global efficiency, which represents the overall effectiveness and speed of information transfer across the entire brain network, was increased in the AS group.DiscussionOur findings suggest that individuals with AS may have alterations in the organization and functioning of brain networks, which could contribute to the distinctive cognitive and behavioural features associated with this condition. We suggest further research to explore the association between these altered functional patterns in brain networks and specific behavioral traits observed in individuals with AS, which could provide valuable insights into the underlying mechanisms of its symptomatology.

Background: We performed a pilot study on whether tablet-based measures of manual dexterity can provide behavioral markers for detection of first-episode psychosis (FEP), and whether cortical excitability/inhibition was altered in FEP. Methods: Behavioral and neurophysiological testing was undertaken in persons diagnosed with FEP (N = 20), schizophrenia (SCZ, N = 20), autism spectrum disorder (ASD, N = 20), and in healthy control subjects (N = 20). Five tablet tasks assessed different motor and cognitive functions: Finger Recognition for effector (finger) selection and mental rotation, Rhythm Tapping for temporal control, Sequence Tapping for control/memorization of motor sequences, Multi Finger Tapping for finger individuation, and Line Tracking for visuomotor control. Discrimination of FEP (from other groups) based on tablet-based measures was compared to discrimination through clinical neurological soft signs (NSS). Cortical excitability/inhibition, and cerebellar brain inhibition were assessed with transcranial magnetic stimulation. Results: Compared to controls, FEP patients showed slower reaction times and higher errors in Finger Recognition, and more variability in Rhythm Tapping. Variability in Rhythm Tapping showed highest specificity for the identification of FEP patients compared to all other groups (FEP vs. ASD/SCZ/Controls; 75% sensitivity, 90% specificity, AUC = 0.83) compared to clinical NSS (95% sensitivity, 22% specificity, AUC = 0.49). Random Forest analysis confirmed FEP discrimination vs. other groups based on dexterity variables (100% sensitivity, 85% specificity, balanced accuracy = 92%). The FEP group had reduced short-latency intra-cortical inhibition (but similar excitability) compared to controls, SCZ, and ASD. Cerebellar inhibition showed a non-significant tendency to be weaker in FEP. Conclusion: FEP patients show a distinctive pattern of dexterity impairments and weaker cortical inhibition. Easy-to-use tablet-based measures of manual dexterity capture neurological deficits in FEP and are promising markers for detection of FEP in clinical practice. [ABSTRACT FROM AUTHOR]

Introduction: Hikikomori, a form of pathological social withdrawal, has been suggested to have comorbidity with autism spectrum disorder (ASD). This study aimed to clarify how characteristics of ASD are associated with hikikomori. Methods: Thirty-nine adult male patients with a diagnosis of ASD attending our outpatient clinic for neurodevelopmental disabilities were subjected to a structured interview regarding social withdrawal, various self-administered questionnaires, and blood tests. Through structured interviews, the subjects were divided into two groups: (Group 1) ASD with hikikomori condition and (Group 2) ASD without hikikomori condition. Sixteen subjects qualified as hikikomori and 23 subjects qualified as subjects without hikikomori. Age, sex, autism spectrumquotient (AQ), AutismDiagnosticObservation Schedule (ADOS), and FIQ were matched. Results: Compared to non-hikikomori controls, hikikomori cases were likely to have stronger sensory symptoms, lower uric acid (UA) (p = 0.038), and higher rates of atopic dermatitis (p = 0.01). Cases showed more severe depressive and social anxiety symptoms based on self-rated scales: Patient Heath Questionnaire 9 (PHQ-9) (p < 0.001) and Liebowitz Social Anxiety Scale Japanese Version (LSAS-J) (p=0.04). Tarumi'sModern-Type Depression Trait Scale (TACS-22), which measure traits of Modern-Type Depression (MTD), were significantly higher in cases (p = 0.003). Conclusion: The present study has suggested that ASD patients with hikikomori weremore likely to have higher sensory abnormalities, comorbid atopic dermatitis, lower UA, stronger depressive, and anxiety tendency. Evaluating and approaching these aspects are important for appropriate interventions in ASD with hikikomori. Further investigations should be conducted to validate our pilot findings. [ABSTRACT FROM AUTHOR]

Introduction: Investigating the pathological mechanisms of developmental disorders is a challenge because the symptoms are a result of complex and dynamic factors such as neural networks, cognitive behavior, environment, and developmental learning. Recently, computational methods have started to provide a unified framework for understanding developmental disorders, enabling us to describe the interactions among those multiple factors underlying symptoms. However, this approach is still limited because most studies to date have focused on cross-sectional task performance and lacked the perspectives of developmental learning. Here, we proposed a new research method for understanding the mechanisms of the acquisition and its failures in hierarchical Bayesian representations using a state-of-the-art computational model, referred to as in silico neurodevelopment framework for atypical representation learning. Methods: Simple simulation experiments were conducted using the proposed framework to examine whether manipulating the neural stochasticity and noise levels in external environments during the learning process can lead to the altered acquisition of hierarchical Bayesian representation and reduced flexibility. Results: Networks with normal neural stochasticity acquired hierarchical representations that reflected the underlying probabilistic structures in the environment, including higher-order representation, and exhibited good behavioral and cognitive flexibility. When the neural stochasticity was high during learning, top-down generation using higher-order representation became atypical, although the flexibility did not differ from that of the normal stochasticity settings. However, when the neural stochasticity was low in the learning process, the networks demonstrated reduced flexibility and altered hierarchical representation. Notably, this altered acquisition of higher-order representation and flexibility was ameliorated by increasing the level of noises in external stimuli. Discussion: These results demonstrated that the proposed method assists in modeling developmental disorders by bridging between multiple factors, such as the inherent characteristics of neural dynamics, acquisitions of hierarchical representation, flexible behavior, and external environment. [ABSTRACT FROM AUTHOR]

Cul3 encodes Cullin-3, a core component of the ubiquitin E3 ligase that is involved in protein ubiquitination. Recent studies have identified Cul3 as a high-confidence risk gene in neurodevelopmental disorders (NDDs), especially autism spectrum disorder (ASD). Different strategies have been used to generate animal models with Cul3 deficiency in the central nervous system, including whole-brain knockout (KO), cell-type specific conditional KO (cKO), and brain region-specific knockdown. In this review, we revisited the basic properties of CUL3 and its function under physiological and pathological conditions. Recent clinical studies including case reports and large cohort sequencing studies related to CUl3 in NDDs have been summarized. Moreover, we characterized the behavioral, electrophysiological, and molecular changes in newly developed Cul3 deficiency models. This would guide further studies related to Cul3 in CNS and provide potential therapeutic targets for Cul3-deficiency-induced NDDs, including ASD.

BackgroundWe performed a pilot study on whether tablet-based measures of manual dexterity can provide behavioral markers for detection of first-episode psychosis (FEP), and whether cortical excitability/inhibition was altered in FEP.MethodsBehavioral and neurophysiological testing was undertaken in persons diagnosed with FEP (N = 20), schizophrenia (SCZ, N = 20), autism spectrum disorder (ASD, N = 20), and in healthy control subjects (N = 20). Five tablet tasks assessed different motor and cognitive functions: Finger Recognition for effector (finger) selection and mental rotation, Rhythm Tapping for temporal control, Sequence Tapping for control/memorization of motor sequences, Multi Finger Tapping for finger individuation, and Line Tracking for visuomotor control. Discrimination of FEP (from other groups) based on tablet-based measures was compared to discrimination through clinical neurological soft signs (NSS). Cortical excitability/inhibition, and cerebellar brain inhibition were assessed with transcranial magnetic stimulation.ResultsCompared to controls, FEP patients showed slower reaction times and higher errors in Finger Recognition, and more variability in Rhythm Tapping. Variability in Rhythm Tapping showed highest specificity for the identification of FEP patients compared to all other groups (FEP vs. ASD/SCZ/Controls; 75% sensitivity, 90% specificity, AUC = 0.83) compared to clinical NSS (95% sensitivity, 22% specificity, AUC = 0.49). Random Forest analysis confirmed FEP discrimination vs. other groups based on dexterity variables (100% sensitivity, 85% specificity, balanced accuracy = 92%). The FEP group had reduced short-latency intra-cortical inhibition (but similar excitability) compared to controls, SCZ, and ASD. Cerebellar inhibition showed a non-significant tendency to be weaker in FEP.ConclusionFEP patients show a distinctive pattern of dexterity impairments and weaker cortical inhibition. Easy-to-use tablet-based measures of manual dexterity capture neurological deficits in FEP and are promising markers for detection of FEP in clinical practice.

Background: Reduced or absence of the response to name (RTN) has been widely reported as an early specific indicator for autism spectrum disorder (ASD), while few studies have quantified the RTN of toddlers with ASD in an automatic way. The present study aims to apply a multimodal machine learning system (MMLS) in early screening for toddlers with ASD based on the RTN. Methods: A total of 125 toddlers were recruited, including ASD (n = 61), developmental delay (DD, n = 31), and typical developmental (TD, n = 33). Procedures of RTN were, respectively, performed by the evaluator and caregiver. Behavioral data were collected by eight-definition tripod-mounted cameras and coded by the MMLS. Response score, response time, and response duration time were accurately calculated to evaluate RTN. Results: Total accuracy of RTN scores rated by computers was 0.92. In both evaluator and caregiver procedures, toddlers with ASD had significant differences in response score, response time, and response duration time, compared to toddlers with DD and TD (all P-values < 0.05). The area under the curve (AUC) was 0.81 for the computerrated results, and the AUC was 0.91 for the human-rated results. The accuracy in the identification of ASD based on the computer- and human-rated results was, respectively, 74.8 and 82.9%. There was a significant difference between the AUC of the human-rated results and computer-rated results (Z = 2.71, P-value = 0.007). Conclusion: The multimodal machine learning system can accurately quantify behaviors in RTN procedures and may effectively distinguish toddlers with ASD from the non-ASD group. This novel system may provide a low-cost approach to early screening and identifying toddlers with ASD. However, machine learning is not as accurate as a human observer, and the detection of a single symptom like RTN is not sufficient enough to detect ASD. [ABSTRACT FROM AUTHOR]

Type 1 diabetes and neurodevelopmental disorders are common chronic conditions in childhood and adolescence, and having one may lead to an increased chance of developing the other. Type 1 diabetes mellitus is mainly manifested by elevated blood glucose, while neurodevelopmental diseases are composed of a variety of diseases, which are relatively complex. The purpose of this meta-analysis was to find out the prevalence of type 1 diabetes-related neurodevelopmental disorders in children and adolescents and to explore the potential association between neurodevelopmental disorders and type 1 diabetes. PubMed, Embase and Web of science databases were searched from the inception to May 22, 2022 to identify relevant studies, Finally, 24 original studies were included in the meta-analysis. Prevalence estimates for neurodevelopmental disorders in the type 1 diabetes adolescent and their 95% confidence intervals were pooled using random effects models. The pooled estimates for autism spectrum disorders (ASD) and attention deficit hyperactivity disorder (ADHD) in the type 1 diabetes population were 1.2 and 5.3%, respectively, both of which are higher than the 2019 global prevalence of ASD and ADHD in the general population. The results of the subgroup analysis showed that the prevalence of ASD and ADHD in the T1DM population tended to increase with age. In conclusion, there may be a potential link between the occurrence of type 1 diabetes mellitus and the development of neurodevelopmental disorders in children and adolescents, but more relevant studies are needed to understand the link between the underlying pathogenesis of type 1 diabetes and neurodevelopmental disorders.Systematic review registration[https://www.crd.york.ac.uk/PROSPERO/], identifier [CDR42022333443].

The comorbidity of autism spectrum disorder (ASD) and attention-deficit/hyperactivity disorder (ADHD) diagnoses is well established. An ASD diagnosis is associated with elevated ADHD traits and symptoms, as well as strengths in attention. In the ASD literature, attentional strengths have been described as maladaptive (e.g., hyperfocus), in contrast with positive portrayals in the typically developing population (e.g., flow). The objective of this study was to (1) compare profiles of attentional strengths and weaknesses in ASD and ADHD and (2) determine whether attentional strengths in ASD are associated with impairment, poorer cognitive flexibility, and perseveration/perfectionism. In a community sample of 5,744 children and youth, 131 children were reported as having a diagnosis of ASD (mean age 10.3 years) and 346 children were reported as having a diagnosis of ADHD (mean age 10.7 years). We used the Strengths and Weaknesses of Attention-Deficit/Hyperactivity-symptoms and Normal-behaviors (SWAN) rating scale to calculate attentional and hyperactive/impulse control strength and weakness counts and scores. The Autism-Spectrum Quotient Switching factor served as a measure of cognitive flexibility. Impairment was assessed with the Columbia Impairment Scale. We used the symmetry/ordering factor on the Toronto Obsessive-Compulsive Scale as a measure of perseveration/perfectionism. No differences were found between the ADHD and ASD groups in SWAN weakness scores, symptoms, or hyperactive/impulse control strengths; however, autistic children had higher rates of attentional strengths [odds ratio: 5.7, 95% CI (2.8, 11.6), p < 0.0001]. Post-hoc pairwise testing identified four attentional strengths with significantly higher rates in ASD than in ADHD. Attentional strength scores were not associated with impairment or poor cognitive flexibility, but predicted levels of perseveration/perfectionism. The effect of attentional strengths on impairment and cognitive flexibility did not differ between autistic and Control children, but the higher perseveration/perfectionism scores seen in ASD were not found in Control children. ASD is associated with a pattern of attentional strengths that is not found in ADHD Characterizing the full range of attentional abilities in autistic children may explain variability in outcomes such as quality-of-life indicators and identify protective factors, providing targets for strength-based behavioral interventions. The clinical and etiological implications of the subgroup of autistic children with attentional strengths require further investigation. [ABSTRACT FROM AUTHOR]

The comorbidity of autism spectrum disorder (ASD) and attention-deficit/hyperactivity disorder (ADHD) diagnoses is well established. An ASD diagnosis is associated with elevated ADHD traits and symptoms, as well as strengths in attention. In the ASD literature, attentional strengths have been described as maladaptive (e.g., hyperfocus), in contrast with positive portrayals in the typically developing population (e.g., flow). The objective of this study was to (1) compare profiles of attentional strengths and weaknesses in ASD and ADHD and (2) determine whether attentional strengths in ASD are associated with impairment, poorer cognitive flexibility, and perseveration/perfectionism. In a community sample of 5,744 children and youth, 131 children were reported as having a diagnosis of ASD (mean age 10.3 years) and 346 children were reported as having a diagnosis of ADHD (mean age 10.7 years). We used the Strengths and Weaknesses of Attention-Deficit/Hyperactivity-symptoms and Normal-behaviors (SWAN) rating scale to calculate attentional and hyperactive/impulse control strength and weakness counts and scores. The Autism-Spectrum Quotient Switching factor served as a measure of cognitive flexibility. Impairment was assessed with the Columbia Impairment Scale. We used the symmetry/ordering factor on the Toronto Obsessive-Compulsive Scale as a measure of perseveration/perfectionism. No differences were found between the ADHD and ASD groups in SWAN weakness scores, symptoms, or hyperactive/impulse control strengths; however, autistic children had higher rates of attentional strengths [odds ratio: 5.7, 95% CI (2.8, 11.6), p < 0.0001]. Post-hoc pairwise testing identified four attentional strengths with significantly higher rates in ASD than in ADHD. Attentional strength scores were not associated with impairment or poor cognitive flexibility, but predicted levels of perseveration/perfectionism. The effect of attentional strengths on impairment and cognitive flexibility did not differ between autistic and Control children, but the higher perseveration/perfectionism scores seen in ASD were not found in Control children. ASD is associated with a pattern of attentional strengths that is not found in ADHD Characterizing the full range of attentional abilities in autistic children may explain variability in outcomes such as quality-of-life indicators and identify protective factors, providing targets for strength-based behavioral interventions. The clinical and etiological implications of the subgroup of autistic children with attentional strengths require further investigation.

Background: Belgium is one of very few countries that legally allow euthanasia for suffering caused by psychiatric illness. In the first criminal trial in Belgium of physicians involved in euthanasia, three physicians recently faced the accusation of "murder by poisoning," for allegedly having failed to comply with several requirements of the Belgian Euthanasia Law in granting the euthanasia request a woman suffering from psychiatric illness. Although all three physicians were acquitted, the case generated much debate among policy makers, medical professionals, and the general public. Method: We use this trial as the starting point for a critical analysis of the adequacy of the three-level control system established in the Euthanasia Law, as it is applied in the evaluation of euthanasia requests from persons who suffer unbearably from a psychiatric illness. This analysis is based on information presented during the criminal trial as well as information on the euthanasia that was published in the press. Results: Our analysis highlights substantial problems in the assessment and granting of the euthanasia request. The patient was euthanized without it having been substantiated that her psychiatric illness had no prospect of improvement and that her suffering could not be alleviated. The three-step control system enshrined in the Law and promoted by the Federal Control and Evaluation Commission for Euthanasia appears to have failed at each level. Conclusion: To evaluate requests for euthanasia for mental suffering caused by psychiatric illness, the requirements of the Belgian Euthanasia Law should be complemented by mandating the advice of two psychiatrists, and face-to-face discussions between all physicians involved. In parallel with the process of evaluating the euthanasia request, a treatment track should be guaranteed where reasonable evidence-based treatments and recoveryoriented options are tried. [ABSTRACT FROM AUTHOR]

Introduction: The past decade has seen key advances in early intervention for autistic children in high-income countries, with most evidence based on specialist delivery of interventions. The care gap seen in low- and middle-income countries (LMIC) remains close to 100%. A key challenge in addressing this care gap concerns the paucity of specialists available to deliver services. Task-sharing provides an important potential solution; there is a need to identify interventions that are suitable for scaled-up delivery through task-sharing in low-resourced settings. We aimed to conduct a scoping review to identify studies which reported autism intervention delivered by non-specialists within LMIC and, using established frameworks, specify intervention components with evidence of successful non-specialist delivery. Methods: A scoping literature search, conducted within four databases, generated 2,535 articles. Duplicates were removed, followed by screening of titles and abstracts, with 10% double-rated for reliability. 50 full text articles were then screened independently by two raters. Articles were included if studies: (a) were conducted in LMIC; (b) included samples of autistic children (age < 10); (c) evaluated psycho-social interventions delivered by non-specialists; (d) reported child outcomes; and (e) were peer-reviewed full-texts in English. Two established frameworks - @Practicewise and NDBI-Fi framework - were then used to ascertain the commonly delivered components of these interventions. Results: Two studies met the inclusion criteria. Both studies evaluated parent-mediated interventions delivered by non-specialists in South Asia. Through the two frameworks, we identified elements and techniques that had been delivered successfully by nonspecialists. Conclusion: There is evidence from two acceptability and feasibility trials that non-specialists can be trained to deliver some intervention elements and techniques within parent-mediated interventions, with good fidelity and acceptability and evidence of effectiveness. The review points up the lack of a widespread evidence base in this area and need for further research in low resourced settings, including well-powered trials and mechanistic analyses to identify active ingredients. A focus on the pre-requisites for non-specialist delivery is critical to reduce inequity and provide universal health coverage within resource-constrained health systems. [ABSTRACT FROM AUTHOR]

IntroductionThe past decade has seen key advances in early intervention for autistic children in high-income countries, with most evidence based on specialist delivery of interventions. The care gap seen in low- and middle-income countries (LMIC) remains close to 100%. A key challenge in addressing this care gap concerns the paucity of specialists available to deliver services. Task-sharing provides an important potential solution; there is a need to identify interventions that are suitable for scaled-up delivery through task-sharing in low-resourced settings. We aimed to conduct a scoping review to identify studies which reported autism intervention delivered by non-specialists within LMIC and, using established frameworks, specify intervention components with evidence of successful non-specialist delivery.MethodsA scoping literature search, conducted within four databases, generated 2,535 articles. Duplicates were removed, followed by screening of titles and abstracts, with 10% double-rated for reliability. 50 full text articles were then screened independently by two raters. Articles were included if studies: (a) were conducted in LMIC; (b) included samples of autistic children (age < 10); (c) evaluated psycho-social interventions delivered by non-specialists; (d) reported child outcomes; and (e) were peer-reviewed full-texts in English. Two established frameworks – @Practicewise and NDBI-Fi framework - were then used to ascertain the commonly delivered components of these interventions.ResultsTwo studies met the inclusion criteria. Both studies evaluated parent-mediated interventions delivered by non-specialists in South Asia. Through the two frameworks, we identified elements and techniques that had been delivered successfully by non-specialists.ConclusionThere is evidence from two acceptability and feasibility trials that non-specialists can be trained to deliver some intervention elements and techniques within parent-mediated interventions, with good fidelity and acceptability and evidence of effectiveness. The review points up the lack of a widespread evidence base in this area and need for further research in low resourced settings, including well-powered trials and mechanistic analyses to identify active ingredients. A focus on the pre-requisites for non-specialist delivery is critical to reduce inequity and provide universal health coverage within resource-constrained health systems.

Autism spectrum disorder (ASD) is characterized as a very heterogeneous child-onset disorder, whose heterogeneity is partly determined by differences in intelligence quotient (IQ). Older epidemiological studies suggested that the IQ-related spectrum tends to be skewed to the left, i.e., a larger proportion of individuals with ASD have below average intelligence, while only few individuals with ASD may have an IQ above average. This picture changed over time with broadening the spectrum view. Within the present perspective article, we discuss discrepancies in IQ profiles between epidemiological and clinical studies and identify potential underlying aspects, for example, the influence of external factors such as sample biases or differences in availability of autism health services. Additionally, we discuss the validity and reciprocal influences of ASD diagnostics and IQ measurement. We put the impact of these factors for diagnostic as well as care and support situations of patients into perspective and want to encourage further research to contribute to the conceptualization of "autism" more comprehensively including the IQ as well as to examine broader (life) circumstances, interacting factors and diagnostic requirements of given diagnoses in childhood as compared to adulthood. [ABSTRACT FROM AUTHOR]

This study was performed to evaluate the effects of prenatal baclofen (a GABAB receptor agonist) treatment on the inheritance of autism-like behaviors in valproic acid (VPA)-exposed mice. VPA model mice (first generation, F1) that were prenatally exposed to VPA exhibited robust core autism-like behaviors, and we found that oral administration of baclofen to F1 mice corrected their autism-like behavioral phenotypes at an early age. Based on a previous epigenetics study, we mated the F1 male offspring with litter females to produce the second generation (F2). The F2 male mice showed obvious inheritance of autism-like phenotypes from F1 mice, implying the heritability of autism symptoms in patients with prenatal VPA exposure. Furthermore, we found prenatal baclofen administration was associated with beneficial effects on the autism-like phenotype in F2 male mice. This may have involved corrections in the density of total/mature dendritic spines in the hippocampus (HC) and medial prefrontal cortex (mPFC), normalizing synaptic plasticity. In this research, GABAB receptor agonist administration corrected the core autism-like behaviors of F1 mice and protected against the inheritance of neurodevelopmental disorders in the offspring of F1 mice, suggesting the potential of early intervention with GABAB receptor agonists in the treatment of neurodevelopmental disorders. [ABSTRACT FROM AUTHOR]

Maternal immune activation (MIA) is triggered by infection or autoimmune predisposition during pregnancy, and cytokines produced by MIA are transmitted through the placenta to the fetal brain, implicating at the onset risks and vulnerability for developmental and psychiatric disorders, such as autism spectrum disorder (ASD) and schizophrenia. To address these kinds of problem in child health, we have developed a silicon (Si)-based hydrogen-producing antioxidant (Si-based agent) that continuously and effectively produces hydrogen in the body. Medical hydrogen is known to have antioxidative, anti-inflammatory, and antiapoptotic effects, therefore we applied our Si-based agent as a potential therapeutic agent to MIA. Using a MIA mouse model, we found that the Si-based agent improved the social communication of MIA offspring mice. We also found that the Si-based agent suppressed the expressions of inflammation-associated genes Ifna1 and Il-6 in the mouse brain. These results demonstrate that the Si-based agent is an effective prophylactic agent against MIA during pregnancy, suggesting that our Si-based agent may be a preventative or therapeutic agent for ASD and other disease risks in child health suppressing MIA damage. [ABSTRACT FROM AUTHOR]

Autism spectrum disorder (ASD) and generalised joint hypermobility (GJH) share a number of clinical manifestations including proprioceptive impairment, motor difficulties, sensory hypersensitivity, and autonomic dysfunction. Clinical observations suggest that GJH is overrepresented in ASD. However, there are currently few systematic studies available. Knowledge about comorbidities may unfold common aetiopathological pathways underlying the association and improve the clinical management. The aim of this large, cross-sectional comparative study is to evaluate the relationship between ASD and GJH in adults. Data on joint hypermobility, symptoms associated with both hypermobility spectrum disorders (HSD) and hypermobile Ehlers-Danlos syndrome (hEDS), lifetime psychiatric diagnoses, psychiatric rating scales for ASD and attention deficit hyperactivity disorder (ADHD), and socio-demographics was collected for 199 individuals with ASD and 419 non-ASD community controls. Logistic regression models adjusting for covariates (age, sex, ethnicity) revealed a significant relationship between ASD and GJH and between ASD and symptomatic GJH, with adjusted odds ratios of 3.1 (95% CI: 1.9, 5.2; p < 0.001) and 4.9 (95% CI: 2.6, 9.0; p < 0.001), respectively. However, the high prevalence of comorbid ADHD in the study sample reduces the generalizability of the results among individuals with ASD without comorbid ADHD. Possibly, an additional ADHD phenotype is the primary driver of the association between ASD and GJH. Furthermore, GJH with additional self-reported symptoms, suggestive of HSD/hEDS, showed a stronger association with ASD than did non-specified GJH, indicating that symptomatic GJH plays a greater role in the relationship than non-specified GJH does. Therefore, the current study underscores the need of careful sample subclassifications. ASD with GJH may represent a novel subgroup of ASD in terms of aetiopathology and clinical presentation. Future research should elucidate the aetiological factors behind the association between ASD and GJH and evaluate how the comorbidity of GJH affects ASD outcomes. [ABSTRACT FROM AUTHOR]

Epidemiological evidence in humans has suggested that maternal infections and maternal autoimmune diseases are involved in the pathogenesis of autism spectrum disorder. Animal studies supporting human results have shown that maternal immune activation causes brain and behavioral alterations in offspring. Several underlying mechanisms, including interleukin-17A imbalance, have been identified. Apart from the pro-inflammatory effects of interleukin-17A, there is also evidence to support the idea that it activates neuronal function and defines cognitive behavior. In this review, we examined the signaling pathways in both immunological and neurological contexts that may contribute to the improvement of autism spectrum disorder symptoms associated with maternal blocking of interleukin-17A and adult exposure to interleukin-17A. We first describe the epidemiology of maternal immune activation then focus on molecular signaling of the interleukin-17 family regarding its physiological and pathological roles in the embryonic and adult brain. In the future, it may be possible to use interleukin-17 antibodies to prevent autism spectrum disorder. [ABSTRACT FROM AUTHOR]

This study was performed to evaluate the effects of prenatal baclofen (a GABAB receptor agonist) treatment on the inheritance of autism-like behaviors in valproic acid (VPA)-exposed mice. VPA model mice (first generation, F1) that were prenatally exposed to VPA exhibited robust core autism-like behaviors, and we found that oral administration of baclofen to F1 mice corrected their autism-like behavioral phenotypes at an early age. Based on a previous epigenetics study, we mated the F1 male offspring with litter females to produce the second generation (F2). The F2 male mice showed obvious inheritance of autism-like phenotypes from F1 mice, implying the heritability of autism symptoms in patients with prenatal VPA exposure. Furthermore, we found prenatal baclofen administration was associated with beneficial effects on the autism-like phenotype in F2 male mice. This may have involved corrections in the density of total/mature dendritic spines in the hippocampus (HC) and medial prefrontal cortex (mPFC), normalizing synaptic plasticity. In this research, GABAB receptor agonist administration corrected the core autism-like behaviors of F1 mice and protected against the inheritance of neurodevelopmental disorders in the offspring of F1 mice, suggesting the potential of early intervention with GABAB receptor agonists in the treatment of neurodevelopmental disorders.

Maternal immune activation (MIA) is triggered by infection or autoimmune predisposition during pregnancy, and cytokines produced by MIA are transmitted through the placenta to the fetal brain, implicating at the onset risks and vulnerability for developmental and psychiatric disorders, such as autism spectrum disorder (ASD) and schizophrenia. To address these kinds of problem in child health, we have developed a silicon (Si)-based hydrogen-producing antioxidant (Si-based agent) that continuously and effectively produces hydrogen in the body. Medical hydrogen is known to have antioxidative, anti-inflammatory, and antiapoptotic effects, therefore we applied our Si-based agent as a potential therapeutic agent to MIA. Using a MIA mouse model, we found that the Si-based agent improved the social communication of MIA offspring mice. We also found that the Si-based agent suppressed the expressions of inflammation-associated genes Ifna1 and Il-6 in the mouse brain. These results demonstrate that the Si-based agent is an effective prophylactic agent against MIA during pregnancy, suggesting that our Si-based agent may be a preventative or therapeutic agent for ASD and other disease risks in child health suppressing MIA damage.

Autism spectrum disorder (ASD) is characterized as a very heterogeneous child-onset disorder, whose heterogeneity is partly determined by differences in intelligence quotient (IQ). Older epidemiological studies suggested that the IQ-related spectrum tends to be skewed to the left, i.e., a larger proportion of individuals with ASD have below average intelligence, while only few individuals with ASD may have an IQ above average. This picture changed over time with broadening the spectrum view. Within the present perspective article, we discuss discrepancies in IQ profiles between epidemiological and clinical studies and identify potential underlying aspects, for example, the influence of external factors such as sample biases or differences in availability of autism health services. Additionally, we discuss the validity and reciprocal influences of ASD diagnostics and IQ measurement. We put the impact of these factors for diagnostic as well as care and support situations of patients into perspective and want to encourage further research to contribute to the conceptualization of “autism” more comprehensively including the IQ as well as to examine broader (life) circumstances, interacting factors and diagnostic requirements of given diagnoses in childhood as compared to adulthood.

Epidemiological evidence in humans has suggested that maternal infections and maternal autoimmune diseases are involved in the pathogenesis of autism spectrum disorder. Animal studies supporting human results have shown that maternal immune activation causes brain and behavioral alterations in offspring. Several underlying mechanisms, including interleukin-17A imbalance, have been identified. Apart from the pro-inflammatory effects of interleukin-17A, there is also evidence to support the idea that it activates neuronal function and defines cognitive behavior. In this review, we examined the signaling pathways in both immunological and neurological contexts that may contribute to the improvement of autism spectrum disorder symptoms associated with maternal blocking of interleukin-17A and adult exposure to interleukin-17A. We first describe the epidemiology of maternal immune activation then focus on molecular signaling of the interleukin-17 family regarding its physiological and pathological roles in the embryonic and adult brain. In the future, it may be possible to use interleukin-17 antibodies to prevent autism spectrum disorder.

Autism spectrum disorder (ASD) and generalised joint hypermobility (GJH) share a number of clinical manifestations including proprioceptive impairment, motor difficulties, sensory hypersensitivity, and autonomic dysfunction. Clinical observations suggest that GJH is overrepresented in ASD. However, there are currently few systematic studies available. Knowledge about comorbidities may unfold common aetiopathological pathways underlying the association and improve the clinical management. The aim of this large, cross-sectional comparative study is to evaluate the relationship between ASD and GJH in adults. Data on joint hypermobility, symptoms associated with both hypermobility spectrum disorders (HSD) and hypermobile Ehlers-Danlos syndrome (hEDS), lifetime psychiatric diagnoses, psychiatric rating scales for ASD and attention deficit hyperactivity disorder (ADHD), and socio-demographics was collected for 199 individuals with ASD and 419 non-ASD community controls. Logistic regression models adjusting for covariates (age, sex, ethnicity) revealed a significant relationship between ASD and GJH and between ASD and symptomatic GJH, with adjusted odds ratios of 3.1 (95% CI: 1.9, 5.2; p < 0.001) and 4.9 (95% CI: 2.6, 9.0; p < 0.001), respectively. However, the high prevalence of comorbid ADHD in the study sample reduces the generalizability of the results among individuals with ASD without comorbid ADHD. Possibly, an additional ADHD phenotype is the primary driver of the association between ASD and GJH. Furthermore, GJH with additional self-reported symptoms, suggestive of HSD/hEDS, showed a stronger association with ASD than did non-specified GJH, indicating that symptomatic GJH plays a greater role in the relationship than non-specified GJH does. Therefore, the current study underscores the need of careful sample subclassifications. ASD with GJH may represent a novel subgroup of ASD in terms of aetiopathology and clinical presentation. Future research should elucidate the aetiological factors behind the association between ASD and GJH and evaluate how the comorbidity of GJH affects ASD outcomes.

Sleep disorder emerges as a common comorbidity in children with autism spectrum disorder (ASD), and the interaction between the core symptoms of ASD and its sleep disorder remains unclear. Repetitive transcranial magnetic stimulation (rTMS) was used on the bilateral dorsolateral prefrontal cortex (DLPFC) to investigate the efficacy of rTMS on the core symptoms of ASD and comorbid sleep problems as well as the mediation role of the ASD symptoms between rTMS intervention and sleep improvement. A total of 41 Chinese children with ASD and who met the criteria in the fifth edition of the American Diagnostic and Statistical Manual of Mental Disorders were recruited, and 39 of them (mean age: 9.0 ± 4.4 years old; the male–female ratio was 3.9: 1) completed the study with the stimulating protocol of high frequency on the left DLPFC and low frequency on the right DLPFC. They were all assessed three times (before, at 4 weeks after, and at 8 weeks after the stimulation) by the Children's Sleep Habits Questionnaire (CSHQ), Strengths and Difficulties Questionnaire (SDQ), Childhood Autism Rating Scale, Repetitive Behavior Questionnaire-2, and Short Sensory Profile (SSP). The repeated-measures ANOVA showed that the main effect of "intervention time" of CSHQ (F = 25.103, P < 0.001), SSP (F = 6.345, P = 0.003), and SDQ (F = 9.975, P < 0.001) was statistically significant. By Bayesian mediation analysis, we only found that the total score of SSP mediated the treating efficacy of rTMS on CSHQ (αβ = 5.11 ± 1.51, 95% CI: 2.50–8.41). The percentage of mediation effect in total effect was 37.94%. Our results indicated the treating efficacy of rTMS modulation on bilateral DLPFC for both autistic symptoms and sleep disturbances. The sensory abnormality of ASD mediated the improvement of rTMS on sleep problems of ASD. [ABSTRACT FROM AUTHOR]

Background: Early intervention and prevention of psychiatric comorbidities of children with autism spectrum disorder (ASD) and attention-deficit/hyperactivity disorder (ADHD) are urgent issues. However, the differences in the diagnoses of ASD and ADHD and psychiatric comorbidities associated with age, long-term healthcare utilization trajectories, and its associated diagnostic features have not been fully elucidated in Japan. Method: We conducted a retrospective observational study using the medical records. Member hospitals of three major consortiums of hospitals providing child and adolescent psychiatric services in Japan were recruited for the study. Children who accessed the psychiatry services of the participating hospitals in April 2015 were followed up for 5 years, and data on their clinical diagnoses, consultation numbers, and hospitalizations were collected. Non-hierarchical clustering was performed using two 10-timepoint longitudinal variables: consultation numbers and hospitalization. Among the major clusters, the differences in the prevalence of ASD, ADHD, comorbid intellectual disability, neurotic disorders, and other psychiatric disorders were assessed. Results: A total of 44 facilities participated in the study (59.5%), and 1,003 participants were enrolled. Among them, 591 diagnosed with ASD and/or ADHD (58.9%) and 589 without missing data were assessed. The mean age was 10.1 years, and 363 (70.9%) were boys. Compared with the pre-schoolers, the school-aged children and adolescents had fewer ASD, more ADHD, and fewer comorbid intellectual disability diagnoses, as well as more diagnoses of other psychiatric disorders. A total of 309 participants (54.7%) continued consultation for 2 years, and 207 (35.1%) continued for 5 years. Clustering analysis identified three, two, and three major clusters among pre-schoolers, school-aged children, and adolescents, respectively. The largest cluster was characterized by early termination of the consultation and accounted for 55.4, 70.6, and 73.4% of pre-schoolers, school-aged children, and adolescents, respectively. Among the school-aged children, the diagnosis of ADHD was associated with a cluster that required longer periods of consultations. Among the adolescents, comorbid psychiatric disorders other than intellectual disability and neurotic disorders were associated with clusters that required hospitalization. Conclusion: Continuous healthcare needs were common and psychiatric comorbidities were associated with complex trajectory among adolescents. The promotion of early intervention and prevention of comorbidities are important. [ABSTRACT FROM AUTHOR]

Background: Limited success of previous clinical trials for Fragile X syndrome (FXS) has led researchers to consider combining different drugs to correct the pleiotropic consequences caused by the absence of the Fragile X mental retardation protein (FMRP). Here, we report the results of the LovaMiX clinical trial, the first trial for FXS combining two disease-modifying drugs, lovastatin, and minocycline, which have both shown positive effects when used independently. Aim: The main goals of the study were to assess the safety and efficacy of a treatment combining lovastatin and minocycline for patients with FXS. Design: Pilot Phase II open-label clinical trial. Patients with a molecular diagnostic of FXS were first randomized to receive, in two-step titration either lovastatin or minocycline for 8 weeks, followed by dual treatment with lovastatin 40 mg and minocycline 100 mg for 2 weeks. Clinical assessments were performed at the beginning, after 8 weeks of monotherapy, and at week 20 (12 weeks of combined therapy). Outcome Measures: The primary outcome measure was the Aberrant Behavior Checklist-Community (ABC-C) global score. Secondary outcome measures included subscales of the FXS specific ABC-C (ABC-CFX), the Anxiety, Depression, and Mood Scale (ADAMS), the Social Responsiveness Scale (SRS), the Behavior Rating Inventory of Executive Functions (BRIEF), and the Vineland Adaptive Behavior Scale second edition (VABS-II). Results: Twenty-one individuals out of 22 completed the trial. There were no serious adverse events related to the use of either drugs alone or in combination, suggesting good tolerability and safety profile of the combined therapy. Significant improvement was noted on the primary outcome measure with a 40% decrease on ABC-C global score with the combined therapy. Several outcome measures also showed significance. Conclusion: The combination of lovastatin and minocycline is safe in patients for FXS individuals and appears to improve several elements of the behavior. These results set the stage for a larger, placebo-controlled double-blind clinical trial to confirm the beneficial effects of the combined therapy. [ABSTRACT FROM AUTHOR]

The concept of "acquired autism" refers to the hypothesis that amongst the massive heterogeneity that encompasses autism spectrum disorder (ASD) there may be several phenotypes that are neither syndromic nor innate. Strong and consistent evidence has linked exposure to various pharmacological and infective agents with an elevated risk of a diagnosis of ASD including maternal valproate use, rubella and herpes encephalitis. Autoimmune encephalitis (AE) describes a group of conditions characterised by the body's immune system mounting an attack on healthy brain cells causing brain inflammation. The resultant cognitive, psychiatric and neurological symptoms that follow AE have also included ASD or autism-like traits and states. We review the current literature on AE and ASD. Drawing also on associated literature on autoimmune psychosis (AP) and preliminary evidence of a psychosis-linked subtype of ASD, we conclude that AE may either act as a potentially causative agent for ASD, and/or produce symptoms that could easily be mistaken for or misdiagnosed as autism. Further studies are required to discern the connection between AE and autism. Where autism is accompanied by regression and atypical onset patterns, it may be prudent to investigate whether a differential diagnosis of AE would be more appropriate. [ABSTRACT FROM AUTHOR]

Background: Limited success of previous clinical trials for Fragile X syndrome (FXS) has led researchers to consider combining different drugs to correct the pleiotropic consequences caused by the absence of the Fragile X mental retardation protein (FMRP). Here, we report the results of the LovaMiX clinical trial, the first trial for FXS combining two disease-modifying drugs, lovastatin, and minocycline, which have both shown positive effects when used independently.Aim: The main goals of the study were to assess the safety and efficacy of a treatment combining lovastatin and minocycline for patients with FXS.Design: Pilot Phase II open-label clinical trial. Patients with a molecular diagnostic of FXS were first randomized to receive, in two-step titration either lovastatin or minocycline for 8 weeks, followed by dual treatment with lovastatin 40 mg and minocycline 100 mg for 2 weeks. Clinical assessments were performed at the beginning, after 8 weeks of monotherapy, and at week 20 (12 weeks of combined therapy).Outcome Measures: The primary outcome measure was the Aberrant Behavior Checklist-Community (ABC-C) global score. Secondary outcome measures included subscales of the FXS specific ABC-C (ABC-CFX), the Anxiety, Depression, and Mood Scale (ADAMS), the Social Responsiveness Scale (SRS), the Behavior Rating Inventory of Executive Functions (BRIEF), and the Vineland Adaptive Behavior Scale second edition (VABS-II).Results: Twenty-one individuals out of 22 completed the trial. There were no serious adverse events related to the use of either drugs alone or in combination, suggesting good tolerability and safety profile of the combined therapy. Significant improvement was noted on the primary outcome measure with a 40% decrease on ABC-C global score with the combined therapy. Several outcome measures also showed significance.Conclusion: The combination of lovastatin and minocycline is safe in patients for FXS individuals and appears to improve several elements of the behavior. These results set the stage for a larger, placebo-controlled double-blind clinical trial to confirm the beneficial effects of the combined therapy.

BackgroundEarly intervention and prevention of psychiatric comorbidities of children with autism spectrum disorder (ASD) and attention-deficit/hyperactivity disorder (ADHD) are urgent issues. However, the differences in the diagnoses of ASD and ADHD and psychiatric comorbidities associated with age, long-term healthcare utilization trajectories, and its associated diagnostic features have not been fully elucidated in Japan.MethodWe conducted a retrospective observational study using the medical records. Member hospitals of three major consortiums of hospitals providing child and adolescent psychiatric services in Japan were recruited for the study. Children who accessed the psychiatry services of the participating hospitals in April 2015 were followed up for 5 years, and data on their clinical diagnoses, consultation numbers, and hospitalizations were collected. Non-hierarchical clustering was performed using two 10-timepoint longitudinal variables: consultation numbers and hospitalization. Among the major clusters, the differences in the prevalence of ASD, ADHD, comorbid intellectual disability, neurotic disorders, and other psychiatric disorders were assessed.ResultsA total of 44 facilities participated in the study (59.5%), and 1,003 participants were enrolled. Among them, 591 diagnosed with ASD and/or ADHD (58.9%) and 589 without missing data were assessed. The mean age was 10.1 years, and 363 (70.9%) were boys. Compared with the pre-schoolers, the school-aged children and adolescents had fewer ASD, more ADHD, and fewer comorbid intellectual disability diagnoses, as well as more diagnoses of other psychiatric disorders. A total of 309 participants (54.7%) continued consultation for 2 years, and 207 (35.1%) continued for 5 years. Clustering analysis identified three, two, and three major clusters among pre-schoolers, school-aged children, and adolescents, respectively. The largest cluster was characterized by early termination of the consultation and accounted for 55.4, 70.6, and 73.4% of pre-schoolers, school-aged children, and adolescents, respectively. Among the school-aged children, the diagnosis of ADHD was associated with a cluster that required longer periods of consultations. Among the adolescents, comorbid psychiatric disorders other than intellectual disability and neurotic disorders were associated with clusters that required hospitalization.ConclusionContinuous healthcare needs were common and psychiatric comorbidities were associated with complex trajectory among adolescents. The promotion of early intervention and prevention of comorbidities are important.

Sleep disorder emerges as a common comorbidity in children with autism spectrum disorder (ASD), and the interaction between the core symptoms of ASD and its sleep disorder remains unclear. Repetitive transcranial magnetic stimulation (rTMS) was used on the bilateral dorsolateral prefrontal cortex (DLPFC) to investigate the efficacy of rTMS on the core symptoms of ASD and comorbid sleep problems as well as the mediation role of the ASD symptoms between rTMS intervention and sleep improvement. A total of 41 Chinese children with ASD and who met the criteria in the fifth edition of the American Diagnostic and Statistical Manual of Mental Disorders were recruited, and 39 of them (mean age: 9.0 ± 4.4 years old; the male–female ratio was 3.9: 1) completed the study with the stimulating protocol of high frequency on the left DLPFC and low frequency on the right DLPFC. They were all assessed three times (before, at 4 weeks after, and at 8 weeks after the stimulation) by the Children's Sleep Habits Questionnaire (CSHQ), Strengths and Difficulties Questionnaire (SDQ), Childhood Autism Rating Scale, Repetitive Behavior Questionnaire-2, and Short Sensory Profile (SSP). The repeated-measures ANOVA showed that the main effect of “intervention time” of CSHQ (F = 25.103, P < 0.001), SSP (F = 6.345, P = 0.003), and SDQ (F = 9.975, P < 0.001) was statistically significant. By Bayesian mediation analysis, we only found that the total score of SSP mediated the treating efficacy of rTMS on CSHQ (αβ = 5.11 ± 1.51, 95% CI: 2.50–8.41). The percentage of mediation effect in total effect was 37.94%. Our results indicated the treating efficacy of rTMS modulation on bilateral DLPFC for both autistic symptoms and sleep disturbances. The sensory abnormality of ASD mediated the improvement of rTMS on sleep problems of ASD.

The concept of “acquired autism” refers to the hypothesis that amongst the massive heterogeneity that encompasses autism spectrum disorder (ASD) there may be several phenotypes that are neither syndromic nor innate. Strong and consistent evidence has linked exposure to various pharmacological and infective agents with an elevated risk of a diagnosis of ASD including maternal valproate use, rubella and herpes encephalitis. Autoimmune encephalitis (AE) describes a group of conditions characterised by the body's immune system mounting an attack on healthy brain cells causing brain inflammation. The resultant cognitive, psychiatric and neurological symptoms that follow AE have also included ASD or autism-like traits and states. We review the current literature on AE and ASD. Drawing also on associated literature on autoimmune psychosis (AP) and preliminary evidence of a psychosis-linked subtype of ASD, we conclude that AE may either act as a potentially causative agent for ASD, and/or produce symptoms that could easily be mistaken for or misdiagnosed as autism. Further studies are required to discern the connection between AE and autism. Where autism is accompanied by regression and atypical onset patterns, it may be prudent to investigate whether a differential diagnosis of AE would be more appropriate.

Background: Multiple prenatal factors have been associated with autism spectrum disorder (ASD) risk. However, current data about the association between antimicrobial use during pregnancy and ASD is limited.Methods: A nested matched case-control study of children with ASD (cases), and children without ASD or other psychiatric or genetic disorders (controls). We compared the use of antimicrobial therapy during the 3 months before conception or during pregnancy between mothers of cases and controls and used multivariate conditional logistic regression models to assess the independent association between maternal use of antimicrobials during pregnancy and the risk of ASD in their offspring.Results: More than half of the mothers in the study (54.1%) used antimicrobial drugs during the 3 months before conception or during pregnancy. Rates of antimicrobial use were lower for mothers of children with ASD compared to mothers of controls (49.0 vs. 55.1%, respectively; p = 0.02), especially during the third trimester of pregnancy (18.8 vs. 22.9%, respectively; p = 0.03), and for the use of penicillins (15.7 vs. 19.7%, respectively; p = 0.06). These case–control differences suggest that antimicrobial administration during pregnancy was associated with a reduced risk of ASD in the offspring (aOR = 0.75, 95% CI = 0.61–0.92). Interestingly, this association was seen only among Jewish but not for the Bedouin mothers (aOR = 0.62, 95% CI = 0.48–0.79 and aOR = 1.21, 95% CI = 0.82–1.79).Conclusions: The reduced risk of ASD associated with prenatal antimicrobials use only in the Jewish population suggest the involvement of other ethnic differences in healthcare services utilization in this association.

Mental disorders are heterogeneous and psychiatric comorbidities are common. Previous studies have suggested a link between inflammation and mental disorders. This link can manifest as increased levels of proinflammatory mediators in circulation and as signs of neuroinflammation. Furthermore, there is strong evidence that individuals suffering from psychiatric disorders have increased risk of developing metabolic comorbidities. Our group has previously shown that, in a cohort of low-functioning individuals with serious mental disorders, there is increased expression of genes associated with the NLRP3 inflammasome, a known sensor of metabolic perturbations, as well as increased levels of IL-1-family cytokines. In the current study, we set out to explore the interplay between disease-specific changes in lipid metabolism and known markers of inflammation. To this end, we performed mass spectrometry-based lipidomic analysis of plasma samples from low-functioning individuals with serious mental disorders (n = 39) and matched healthy controls (n = 39). By identifying non-spurious immune-lipid associations, we derived a partial correlation network of inflammatory markers and molecular lipids. We identified levels of lipids as being altered between individuals with serious mental disorders and controls, showing associations between lipids and inflammatory mediators, e.g., osteopontin and IL-1 receptor antagonist. These results indicate that, in low-functioning individuals with serious mental disorders, changes in specific lipids associate with immune mediators that are known to affect neuroinflammatory diseases.