Incidence, prevalence, and global burden of ADHD from 1990 to 2019 across 204 countries: data, with critical re-analysis, from the Global Burden of Disease study.

Data on incidence, prevalence and burden of ADHD are crucial for clinicians, patients, and stakeholders. We present the incidence, prevalence, and burden of ADHD globally and across countries from 1990 to 2019 from the Global Burden of Disease (GBD) study. We also: (1) calculated the ADHD prevalence based on data actually collected as opposed to the prevalence estimated by the GBD with data imputation for countries without prevalence data; (2) discussed the GBD estimated ADHD burden in the light of recent meta-analytic evidence on ADHD-related mortality. In 2019, GBD estimated global age-standardized incidence and prevalence of ADHD across the lifespan at 0.061% (95%UI = 0.040-0.087) and 1.13% (95%UI = 0.831-1.494), respectively. ADHD accounted for 0.8% of the global mental disorder DALYs, with mortality set at zero by the GBD. From 1990 to 2019 there was a decrease of -8.75% in the global age-standardized prevalence and of -4.77% in the global age-standardized incidence. The largest increase in incidence, prevalence, and burden from 1990 to 2019 was observed in the USA; the largest decrease occurred in Finland. Incidence, prevalence, and DALYs remained approximately 2.5 times higher in males than females from 1990 to 2019. Incidence peaked at age 5-9 years, and prevalence and DALYs at age 10-14 years. Our re-analysis of data prior to 2013 showed a prevalence in children/adolescents two-fold higher (5.41%, 95% CI: 4.67-6.15%) compared to the corresponding GBD estimated prevalence (2.68%, 1.83-3.72%), with no significant differences between low- and middle- and high-income countries. We also found meta-analytic evidence of significantly increased ADHD-related mortality due to unnatural causes. While it provides the most detailed evidence on temporal trends, as well as on geographic and sex variations in incidence, prevalence, and burden of ADHD, the GBD may have underestimated the ADHD prevalence and burden. Given the influence of the GBD on research and policies, methodological issues should be addressed in its future editions.

Incidence, prevalence, and global burden of autism spectrum disorder from 1990 to 2019 across 204 countries.

Autism spectrum disorder (ASD) substantially contributes to the burden of mental disorders. Improved awareness and changes in diagnostic criteria of ASD may have influenced the diagnostic rates of ASD. However, while data on trends in diagnostic rates in some individual countries have been published, updated estimates of diagnostic rate trends and ASD-related disability at the global level are lacking. Here, we used the Global Burden of Diseases, Injuries, and Risk Factors Study data to address this gap, focusing on changes in prevalence, incidence, and disability-adjusted life years (DALYs) of ASD across the world. From 1990 to 2019, overall age-standardized estimates remained stable globally. Both prevalence and DALYs increased in countries with high socio-demographic index (SDI). However, the age-standardized incidence decreased in some low SDI countries, indicating a need to improve awareness. The male/female ratio decreased between 1990 and 2019, possibly accounted for by increasing clinical attention to ASD in females. Our results suggest that ASD detection in low SDI countries is suboptimal, and that ASD prevention/treatment in countries with high SDI should be improved, considering the increasing prevalence of the disorder. Additionally, growing attention is being paid to ASD diagnosis in females, who might have been left behind by ASD epidemiologic and clinical research previously. ASD burden estimates are underestimated as GBD does not account for mortality in ASD.

Correlations between sleep problems, core symptoms, and behavioral problems in children and adolescents with autism spectrum disorder: a systematic review and meta-analysis.

Children and adolescents with autism spectrum disorder (ASD) experience various sleep problems. Sleep problems co-occur in a bidirectional relationship with ASD core symptoms and behavioral problems. However, studies on how these three factors are intricately linked to each other are limited. This meta-analysis examined the differential relationship between specific sleep problems, core symptoms, and behavioral problems in this population. This study was registered in PROSPERO (CRD42022339695). We systematically searched the PubMed/MEDLINE, Web of Science, and Scopus databases from inception to April 27, 2022. Observational studies that reported correlations between measures of sleep problems, ASD core symptoms, or ASD behavioral problems were included, and participants aged 18 years or below were enrolled. The correlation coefficient (r) was assessed as the primary effect metric. Total 22 cross-sectional studies were included, which comprised 2655 participants (mean age = 6.60 years old; mean percentage of boys = 80.64%). We found correlations between total sleep problems and total core symptoms (r 0.293 [95% confidence interval - 0.095 to 0.604]), total sleep problems and total behavioral problems (r 0.429 [0.299-0.544]), and total core symptoms and total behavioral problems (r - 0.050 [- 0.177 to 0.079]) and identified statistically significant correlations between specific components of sleep problems, ASD core symptoms, and ASD behavioral problems. Each specific sleep problem showed a unique association with core symptoms and behavioral problems. Sleep problems in ASD should be explored in detail, and the closely linked core symptoms and behavioral problems should be common therapeutic targets.

Investigation of gene-environment interactions in relation to tic severity.

Tourette syndrome (TS) is a neuropsychiatric disorder with involvement of genetic and environmental factors. We investigated genetic loci previously implicated in Tourette syndrome and associated disorders in interaction with pre- and perinatal adversity in relation to tic severity using a case-only (N = 518) design. We assessed 98 single-nucleotide polymorphisms (SNPs) selected from (I) top SNPs from genome-wide association studies (GWASs) of TS; (II) top SNPs from GWASs of obsessive-compulsive disorder (OCD), attention-deficit/hyperactivity disorder (ADHD), and autism spectrum disorder (ASD); (III) SNPs previously implicated in candidate-gene studies of TS; (IV) SNPs previously implicated in OCD or ASD; and (V) tagging SNPs in neurotransmitter-related candidate genes. Linear regression models were used to examine the main effects of the SNPs on tic severity, and the interaction effect of these SNPs with a cumulative pre- and perinatal adversity score. Replication was sought for SNPs that met the threshold of significance (after correcting for multiple testing) in a replication sample (N = 678). One SNP (rs7123010), previously implicated in a TS meta-analysis, was significantly related to higher tic severity. We found a gene-environment interaction for rs6539267, another top TS GWAS SNP. These findings were not independently replicated. Our study highlights the future potential of TS GWAS top hits in gene-environment studies.

Child and adolescent psychiatry in the Far East: A 5-year follow up on the Consortium on Academic Child and Adolescent Psychiatry in the Far East (CACAP-FE) study.

AIM: Data pertaining to child and adolescent psychiatry (CAP) training systems are limited as extant research has mostly been derived from one-time data collection. This 5-year follow-up survey collects updated information on CAP training systems in the Far East, allowing for the tracking of system changes over the past 5 years. METHODS: Data were obtained from 18 countries, or functionally self-governing areas, in the Far East, 17 of which were also included in the original study. An online questionnaire was completed by leading CAP professionals in each country. Questions were expanded in the present study to capture the contents of CAP training. RESULTS: When compared to data from the original study, there has been progress in CAP training systems in the last 5 years. Specifically, there has been an increase in the number of countries with CAP training programs and national guidelines for the training. In addition, the number of CAP departments/divisions affiliated with academic institutions/universities has increased. Findings from 12 of 18 countries in the present study provide data on clinical contents. All informants of the present study reported the need for more child and adolescent psychiatrists and allied professionals. CONCLUSION: Despite progress in CAP training systems over the last 5 years, the need for more professionals in child and adolescent mental health care in all the relevant areas in this region have yet to be adequately addressed. Continued national efforts and international collaborations are imperative to developing and sustaining new CAP training systems while facilitating improvements in existing programs.

Investigation of previously implicated genetic variants in chronic tic disorders: a transmission disequilibrium test approach.

Genetic studies in Tourette syndrome (TS) are characterized by scattered and poorly replicated findings. We aimed to replicate findings from candidate gene and genome-wide association studies (GWAS). Our cohort included 465 probands with chronic tic disorder (93% TS) and both parents from 412 families (some probands were siblings). We assessed 75 single nucleotide polymorphisms (SNPs) in 465 parent-child trios; 117 additional SNPs in 211 trios; and 4 additional SNPs in 254 trios. We performed SNP and gene-based transmission disequilibrium tests and compared nominally significant SNP results with those from a large independent case-control cohort. After quality control 71 SNPs were available in 371 trios; 112 SNPs in 179 trios; and 3 SNPs in 192 trios. 17 were candidate SNPs implicated in TS and 2 were implicated in obsessive-compulsive disorder (OCD) or autism spectrum disorder (ASD); 142 were tagging SNPs from eight monoamine neurotransmitter-related genes (including dopamine and serotonin); 10 were top SNPs from TS GWAS; and 13 top SNPs from attention-deficit/hyperactivity disorder, OCD, or ASD GWAS. None of the SNPs or genes reached significance after adjustment for multiple testing. We observed nominal significance for the candidate SNPs rs3744161 (TBCD) and rs4565946 (TPH2) and for five tagging SNPs; none of these showed significance in the independent cohort. Also, SLC1A1 in our gene-based analysis and two TS GWAS SNPs showed nominal significance, rs11603305 (intergenic) and rs621942 (PICALM). We found no convincing support for previously implicated genetic polymorphisms. Targeted re-sequencing should fully appreciate the relevance of candidate genes.

The effect of epilepsy on autistic symptom severity assessed by the social responsiveness scale in children with autism spectrum disorder.

BACKGROUND: As the prevalence of autism spectrum disorders in people with epilepsy ranges from 15 to 47 % (Clarke et al. in Epilepsia 46:1970-1977, 2005), it is speculated that there is a special relationship between the two disorders, yet there has been a lack of systematic studies comparing the behavioral phenotype between autistic individuals and autistic individuals with epilepsy. This study aims to investigate how the co-occurrence of epilepsy and Autism Spectrum Disorder (ASD) affects autistic characteristics assessed by the Social Responsiveness Scale (SRS), which has been used as a measure of autism symptoms in previous studies. In this research we referred to all individuals with Autism or Autistic Disorder as individuals with ASD. METHODS: We reviewed the complete medical records of 182 participants who presented to a single tertiary care referral center from January 1, 2013 to July 28, 2015, and subsequently received complete child and adolescent psychiatric assessments. Of the 182 participants, 22 were diagnosed with Autism Spectrum Disorder and epilepsy. Types of epilepsy observed in these individuals included complex partial seizure, generalized tonic-clonic seizure, or infantile spasm. Using 'Propensity Score Matching' we selected 44 children, diagnosed with only Autism Spectrum Disorder, whose age, gender, and intelligence quotient (IQ) were closely matched with the 22 children diagnosed with Autism Spectrum Disorder and epilepsy. Social functioning of participants was assessed by the social responsiveness scale, which consists of five categories: social awareness, social cognition, social communication, social motivation, and autistic mannerisms. Bivariate analyses were conducted to compare the ASD participants with epilepsy group with the ASD-only group on demographic and clinical characteristics. Chi square and t test p values were calculated when appropriate. RESULTS: There was no significant difference in age (p = 0.172), gender (p > 0.999), IQ (FSIQ, p = 0.139; VIQ, p = 0.114; PIQ, p = 0.295) between the two groups. ASD participants with epilepsy were significantly more impaired than ASD participants on some measures of social functioning such as social awareness (p = 0.03) and social communication (p = 0.027). ASD participants with epilepsy also scored significantly higher on total SRS t-score than ASD participants (p = 0.023). CONCLUSIONS: Understanding the relationship between ASD and epilepsy is critical for appropriate management (e.g. social skills training, seizure control) of ASD participants with co-occurring epilepsy. Results of this study suggest that mechanisms involved in producing epilepsy may play a role in producing or augmenting autistic features such as poor social functioning. Prospective study with larger sample sizes is warranted to further explore this association.

Exploring the Clinical Characteristics and Comorbid Disorders of Borderline Intellectual Functioning.

Borderline intellectual functioning (BIF) is characterized by cognitive impairment and deficits in adaptive functioning. Despite affecting a significant proportion of the population, BIF still remains underdiagnosed and poorly understood. In addition to cognitive impairments across a range of domains, individuals with BIF face a greater risk of academic failure and often require special educational support. They suffer from emotional problems, such as difficulties with emotional awareness, anxiety, depressed mood, and unhappiness. Individuals with BIF are more likely to have an impairment of social and adaptive functioning. Furthermore, individuals with BIF are at higher risk of physical and mental health problems, often receive inadequate treatment, and have a poorer prognosis. This review aims to enhance the understanding of clinicians, educators, and policymakers by providing an overview of the characteristics of BIF and its associated challenges, ultimately contributing to the improvement of support systems for individuals with BIF.

Epidemiology and Diagnosis of Slow Learners (Borderline Intellectual Functioning).

The definitions of "slow learners" and "borderline intellectual functioning (BIF)" have not reached a consensus and have continually evolved in terminology. The criteria for diagnosing BIF include the Full-Scale Intelligence Quotient, adaptive functioning, and onset of symptoms from the developmental period; however, specific standards have not been provided. Until the Diagnostic and Statistical Manual of Mental Disorders-IV, a range for the Full-Scale Intelligence Quotient was provided, but due to its limitations in reflecting the actual functioning of individuals with BIF, this criterion was removed from the Diagnostic and Statistical Manual of Mental Disorders-5. The absence of specific diagnostic criteria complicates the identification of individuals with BIF, highlighting the need for a more precise classification and definition.

Association of self-harm and suicidality with psychiatric co-occurring conditions in autistic individuals: a systematic review and pooled analysis.

Background: Autistic individuals frequently experience psychiatric co-occurring conditions, but the association with self-harm/suicidality according to these conditions was not yet elucidated. We aimed to summarize the association between self-harm/suicidality and psychiatric co-occurring conditions in autistic people. Methods: We systematically searched PubMed, Scopus, Embase, Web of Science, and Cochrane Database of Systematic Reviews until June 4, 2024 (PROSPERO registration number: CRD42023412860). Observational studies were included that provided information to calculate the odds ratio (OR) regarding the association between self-harm/suicidality and psychiatric co-occurring conditions in autistic individuals. We summarized the identified associations by presenting OR range or meta-analyzing when 7 or more estimates are available. Findings: The systematic search found 20 eligible studies with 301,841 participants. Our findings suggested that autistic individuals with any psychiatric disorder (k = 1; OR 3.55; 95% CI 1.27-9.98), ADHD (k = 3; OR range: 1.07-1.65), or mood disorder (k = 1; OR 1.26; 95% CI 1.05-1.51) may be associated with higher odds of self-harm than those without these conditions. We identified potential positive associations between suicidality and the following co-occurring conditions: any psychiatric disorder (k = 1; OR 11.65; 95% CI 10.68-12.71), psychotic disorder (k = 4; OR range: 1.95-10.97), mood disorder (k = 3; OR range: 1.75-9.82), bipolar disorder (k = 2; OR range: 2.55-4.95), depressive disorder (k = 10; pooled OR 2.29; 95% CI 1.39-3.77), trauma- and stress-related disorder (k = 2; OR range: 1.28-10.47), and adjustment disorder (k = 1; OR 3.52; 95% CI 2.89-4.28). Interpretation: We found psychiatric co-occurring conditions that may be associated with higher odds of self-harm/suicidality in autistic individuals. However, our findings should be interpreted with caution considering the limited number of included studies. We suggested that clinicians should remain vigilant for autistic individuals with psychiatric co-occurring conditions for their potentially higher likelihood of self-harm and suicidality. Funding: This research was supported by a grant of the R&D project, funded by the National Center for Mental Health (grant number: MHER22A01).

Alterations in Plasma Cytokine Levels in Korean Children with Autism Spectrum Disorder.

PURPOSE: Numerous studies have supported the role of the immune dysfunction in the pathogenesis of autism spectrum disorder (ASD); however, to our knowledge, no study has been conducted on plasma cytokine levels in children with ASD in South Korea. In this study, we aimed to analyze the immunological characteristics of Korean children with ASD through plasma cytokine analysis. MATERIALS AND METHODS: Blood samples were collected from 94 ASD children (mean age 7.1; 81 males and 13 females) and 48 typically developing children (TDC) (mean age 7.3; 30 males and 18 females). Plasma was isolated from 1 mL of blood by clarifying with centrifugation at 8000 rpm at 4℃ for 10 min. Cytokines in plasma were measured with LEGENDplex HU Th cytokine panel (BioLegend, 741028) and LEGENDplex HU cytokine panel 2 (BioLegend, 740102). RESULTS: Among 25 cytokines, innate immune cytokine [interleukin (IL)-33] was significantly decreased in ASD children compared with TDC. In acute phase proteins, tumor necrosis factor α (TNF-α) was significantly increased, while IL-6, another inflammation marker, was decreased in ASD children compared with TDC. The cytokines from T cell subsets, including interferon (IFN)-γ, IL-5, IL-13, and IL-17f, were significantly decreased in ASD children compared to TDC. IL-10, a major anti-inflammatory cytokine, and IL-9, which modulates immune cell growth and proliferation, were also significantly decreased in ASD children compared to TDC. CONCLUSION: We confirmed that Korean children with ASD showed altered immune function and unique cytokine expression patterns distinct from TDC.

Pharmacological and non-pharmacological interventions for irritability in autism spectrum disorder: a systematic review and meta-analysis with the GRADE assessment.

BACKGROUND: Numerous interventions for irritability in autism spectrum disorder (ASD) have been investigated. We aimed to appraise the magnitude of pharmacological and non-pharmacological interventions for irritability in ASD without any restrictions in terms of eligible interventions. METHODS: We systematically searched PubMed/MEDLINE, Scopus, and Web of Science until April 15, 2023. We included randomized controlled trials (RCTs) with a parallel design that examined the efficacy of interventions for the treatment of irritability in patients of any age with ASD without any restrictions in terms of eligible interventions. We performed a random-effects meta-analysis by pooling effect sizes as Hedges' g. We classified assessed interventions as follows: pharmacological monotherapy, risperidone plus adjuvant therapy versus risperidone monotherapy, non-pharmacological intervention, and dietary intervention. We utilized the Cochrane tool to evaluate the risk of bias in each study and the GRADE approach to assess the certainty of evidence for each meta-analyzed intervention. RESULTS: Out of 5640 references, we identified 60 eligible articles with 45 different kinds of interventions, including 3531 participants, of which 80.9% were males (mean age [SD] = 8.79 [3.85]). For pharmacological monotherapy, risperidone (Hedges' g - 0.857, 95% CI - 1.263 to - 0.451, certainty of evidence: high) and aripiprazole (Hedges' g - 0.559, 95% CI - 0.767 to - 0.351, certainty of evidence: high) outperformed placebo. Among the non-pharmacological interventions, parent training (Hedges' g - 0.893, 95% CI - 1.184 to - 0.602, certainty of evidence: moderate) showed a significant result. None of the meta-analyzed interventions yielded significant effects among risperidone + adjuvant therapy and dietary supplementation. However, several novel molecules in augmentation to risperidone outperformed risperidone monotherapy, yet from one RCT each. LIMITATIONS: First, various tools have been utilized to measure the irritability in ASD, which may contribute to the heterogeneity of the outcomes. Second, meta-analyses for each intervention included only a small number of studies and participants. CONCLUSIONS: Only risperidone, aripiprazole among pharmacological interventions, and parent training among non-pharmacological interventions can be recommended for irritability in ASD. As an augmentation to risperidone, several novel treatments show promising effects, but further RCTs are needed to replicate findings. Trial registration PROSPERO, CRD42021243965.

Identifying major predictors for parenting stress in a caregiver of autism spectrum disorder using machine learning models.

Introduction: Previous studies have investigated predictive factors for parenting stress in caregivers of autism spectrum disorder (ASD) patients using traditional statistical approaches, but their study settings and results were inconsistent. Herein, this study aimed to identify major predictors for parenting stress in this population by developing explainable machine learning models. Methods: Study participants were collected from the Department of Child and Adolescent Psychiatry, Severance Hospital, Yonsei University College of Medicine, Seoul, the Republic of Korea between March 2016 and October 2020. A total of 36 model features were used, which include subscales of the Minnesota Multiphasic Personality Inventory-2 (MMPI-2) for caregivers' psychopathology, Social Responsiveness Scale-2 for core symptoms, and Child Behavior Checklist (CBCL) for behavioral problems. Machine learning classifiers [eXtreme Gradient Boosting (XGBoost), random forest (RF), logistic regression, and support vector machine (SVM) classifier] were generated to predict severe total parenting stress and its subscales (parental distress, parent-child dysfunctional interaction, and difficult child). Model performance was assessed by area under the receiver operating curve (AUC), sensitivity, specificity, accuracy, positive predictive value, and negative predictive value. We utilized the SHapley Additive exPlanations tree explainer to investigate major predictors. Results: A total of 496 participants were included [mean age of ASD patients 6.39 (SD 2.24); 413 men (83.3%)]. The best-performing models achieved an AUC of 0.831 (RF model; 95% CI 0.740-0.910) for parental distress, 0.814 (SVM model; 95% CI 0.720-0.896) for parent-child dysfunctional interaction, 0.813 (RF model; 95% CI 0.724-0.891) for difficult child, and 0.862 (RF model; 95% CI 0.783-0.930) for total parenting stress on the test set. For the total parenting stress, ASD patients' aggressive behavior and anxious/depressed, and caregivers' depression, social introversion, and psychasthenia were the top 5 leading predictors. Conclusion: By using explainable machine learning models (XGBoost and RF), we investigated major predictors for each subscale of the parenting stress index in caregivers of ASD patients. Identified predictors for parenting stress in this population might help alert clinicians whether a caregiver is at a high risk of experiencing severe parenting stress and if so, providing timely interventions, which could eventually improve the treatment outcome for ASD patients.

Development of Deep Ensembles to Screen for Autism and Symptom Severity Using Retinal Photographs.

Importance: Screening for autism spectrum disorder (ASD) is constrained by limited resources, particularly trained professionals to conduct evaluations. Individuals with ASD have structural retinal changes that potentially reflect brain alterations, including visual pathway abnormalities through embryonic and anatomic connections. Whether deep learning algorithms can aid in objective screening for ASD and symptom severity using retinal photographs is unknown. Objective: To develop deep ensemble models to differentiate between retinal photographs of individuals with ASD vs typical development (TD) and between individuals with severe ASD vs mild to moderate ASD. Design, Setting, and Participants: This diagnostic study was conducted at a single tertiary-care hospital (Severance Hospital, Yonsei University College of Medicine) in Seoul, Republic of Korea. Retinal photographs of individuals with ASD were prospectively collected between April and October 2022, and those of age- and sex-matched individuals with TD were retrospectively collected between December 2007 and February 2023. Deep ensembles of 5 models were built with 10-fold cross-validation using the pretrained ResNeXt-50 (32×4d) network. Score-weighted visual explanations for convolutional neural networks, with a progressive erasing technique, were used for model visualization and quantitative validation. Data analysis was performed between December 2022 and October 2023. Exposures: Autism Diagnostic Observation Schedule-Second Edition calibrated severity scores (cutoff of 8) and Social Responsiveness Scale-Second Edition T scores (cutoff of 76) were used to assess symptom severity. Main Outcomes and Measures: The main outcomes were participant-level area under the receiver operating characteristic curve (AUROC), sensitivity, and specificity. The 95% CI was estimated through the bootstrapping method with 1000 resamples. Results: This study included 1890 eyes of 958 participants. The ASD and TD groups each included 479 participants (945 eyes), had a mean (SD) age of 7.8 (3.2) years, and comprised mostly boys (392 [81.8%]). For ASD screening, the models had a mean AUROC, sensitivity, and specificity of 1.00 (95% CI, 1.00-1.00) on the test set. These models retained a mean AUROC of 1.00 using only 10% of the image containing the optic disc. For symptom severity screening, the models had a mean AUROC of 0.74 (95% CI, 0.67-0.80), sensitivity of 0.58 (95% CI, 0.49-0.66), and specificity of 0.74 (95% CI, 0.67-0.82) on the test set. Conclusions and Relevance: These findings suggest that retinal photographs may be a viable objective screening tool for ASD and possibly for symptom severity. Retinal photograph use may speed the ASD screening process, which may help improve accessibility to specialized child psychiatry assessments currently strained by limited resources.

Subjective and objective sleep alterations in medication-naïve children and adolescents with autism spectrum disorder: a systematic review and meta-analysis.

AIMS: This study aimed to summarize the evidence on sleep alterations in medication-naïve children and adolescents with autism spectrum disorder (ASD). METHODS: We systematically searched PubMed/Medline, Embase and Web of Science databases from inception through March 22, 2021. This study was registered with PROSPERO (CRD42021243881). Any observational study was included that enrolled medication-naïve children and adolescents with ASD and compared objective (actigraphy and polysomnography) or subjective sleep parameters with typically developing (TD) counterparts. We extracted relevant data such as the study design and outcome measures. The methodological quality was assessed through the Newcastle-Ottawa Scale (NOS). A meta-analysis was carried out using the random-effects model by pooling effect sizes as Hedges' g. To assess publication bias, Egger's test and p-curve analysis were done. A priori planned meta-regression and subgroup analysis were also performed to identify potential moderators. RESULTS: Out of 4277 retrieved references, 16 studies were eligible with 981 ASD patients and 1220 TD individuals. The analysis of objective measures showed that medication-naïve ASD patients had significantly longer sleep latency (Hedges' g 0.59; 95% confidence interval [95% CI] 0.26 to 0.92), reduced sleep efficiency (Hedges' g -0.58; 95% CI -0.87 to -0.28), time in bed (Hedges' g -0.64; 95% CI -1.02 to -0.26) and total sleep time (Hedges' g -0.64; 95% CI -1.01 to -0.27). The analysis of subjective measures showed that they had more problems in daytime sleepiness (Hedges' g 0.48; 95% CI 0.26 to 0.71), sleep latency (Hedges' g 1.15; 95% CI 0.72 to 1.58), initiating and maintaining sleep (Hedges' g 0.86; 95% CI 0.39 to 1.33) and sleep hyperhidrosis (Hedges' g 0.48; 95% CI 0.29 to 0.66). Potential publication bias was detected for sleep latency, sleep period time and total sleep time measured by polysomnography. Some sleep alterations were moderated by age, sex and concurrent intellectual disability. The median NOS score was 8 (interquartile range 7.25-8.75). CONCLUSION: We found that medication-naïve children and adolescents with ASD presented significantly more subjective and objective sleep alterations compared to TD and identified possible moderators of these differences. Future research requires an analysis of how these sleep alterations are linked to core symptom severity and comorbid behavioural problems, which would provide an integrated therapeutic intervention for ASD. However, our results should be interpreted in light of the potential publication bias.

One-year Cohort Follow-up on the Diagnosis and Posttraumatic Symptoms in Child Sexual Assault Victims in Korea.

OBJECTIVE: The victims and their families of child sexual abuse (CSA) may confront persistent psychological sequela. We aimed to investigate the psychological symptoms, diagnosis, and family functions in children and adolescents with CSA. METHODS: We assessed the symptom scales at 6-month intervals, and conducted diagnostic re-assessments at 1-year intervals. Trauma Symptom Checklist for Children (TSCC), Trauma Symptom Checklist for Young Children (TSCYC), Family Adaptability and Cohesion Evaluation Scales IV (FACES-IV), and Family Communication Scale (FCS) scores were reported by children or parents. RESULTS: We found in parent-reported TSCYC, that posttraumatic stress symptoms domain scores significantly decreased with time progression. The scores decreased more in the evidence-based treatment group over time in anxiety and posttraumatic stress symptom domains of TSCC. In FACES-IV and FCS scores, indices of family function have been gradually increasing both after 6 months and after 1 year compared to the initial evaluation. Further, about 64% of the children diagnosed with psychiatric diseases, including posttraumatic stress disorder (PTSD) at the initial assessment maintained the same diagnosis at follow-up. CONCLUSION: We observed changes in psychological symptoms and family functioning in sexually abused children with time progression during 1 year. It is postulated that PTSD may be a persistent major mental illness in the victims of CSA.

Pilot study of a mobile application-based intervention to induce changes in neural activity in the frontal region and behaviors in children with attention deficit hyperactivity disorder and/or intellectual disability.

Children with neurodevelopmental disorders, such as attention deficit hyperactivity disorder (ADHD) and intellectual disability (ID), need early intervention and continuous treatment. We aimed to investigate the feasibility and acceptability of mobile application-based interventions in children with ADHD and ID in supporting attention and cognitive function. Twenty-six children with ADHD and/or ID with attention and cognition difficulties were recruited. Participants completed a 12-week mobile application-based intervention. To assess whether digital intervention improved attention and cognitive function, we used the Comprehensive Attention Test (CAT), Cambridge Neuropsychological Tests Automated Battery (CANTAB), and electroencephalography (EEG) to examine direct changes in children's behavior and neural activity. Clinicians and parents assessed changes using the Behavior Rating Inventory of Executive Function, Second Edition (BRIEF-2), Korean version of the ADHD Rating Scale (K-ARS), Clinical Global Impression-Improvement Scale, and parental questionnaires. The intervention induced changes in neural activities on EEG and behavior but there were no significant changes in CAT and CANTAB results. Relative theta and alpha power were significantly lower post-intervention in the eyes-open (EO) condition of EEG recording and these changes were mainly observed in the frontal regions of the brain. Parental reports using the BRIEF-2 and K-ARS noted significant improvements in executive function, attention, and hyperactivity-impulsivity. In addition, the clinical impression improved in 60% of participants. These results provide evidence that a mobile application-based intervention has the benefit of supporting children with ADHD and/or ID. Digital intervention could change neural activity and improve children's attention and cognitive function. Given our findings, we suggested that mobile application-based digital therapeutics may have great potential for helping children with neurodevelopmental disorders who need continuous treatment.

Association between autism spectrum disorder and inflammatory bowel disease: A systematic review and meta-analysis.

Children with autism spectrum disorder (ASD) are frequently diagnosed with co-occurring medical conditions including inflammatory bowel disease (IBD). To investigate the association, we conducted a systematic review registered in PROSPERO (ID:CRD42021236263) with a random-effects meta-analysis. We searched PubMed, Embase, and PsycInfo (last search on January 25, 2021), and manually searched relevant publications. We included observational studies measuring the association between ASD and IBD. The primary outcome was the association (odds ratio, OR) between ASD and later development of IBD. Sensitivity analyses were conducted by quality, confounding adjustment, and study design. We performed meta-regression analyses and assessed heterogeneity, publication bias, and quality of studies with the Newcastle-Ottawa Scale. Overall, we included six studies consisting of eight datasets, including over 11 million participants. We found that ASD was significantly associated with subsequent incident IBD (any IBD, OR = 1.66, 95% confidence interval[CI] = 1.25-2.21, p < 0.001; ulcerative colitis, OR = 1.91, 95%CI = 1.41-2.6, p < 0.001; Crohn's disease, OR = 1.47, 95%CI = 1.15-1.88, p = 0.002). ASD and IBD were also associated regardless of temporal sequence of diagnosis (any IBD, OR = 1.57, 95%CI = 1.28-1.93, p < 0.001; ulcerative colitis, OR = 1.7, 95%CI = 1.36-2.12, p < 0.001; Crohn's disease, OR = 1.37, 95%CI = 1.12-1.69, p = 0.003). Sensitivity analyses confirmed the findings of the main analysis. Meta-regression did not identify any significant moderators. Publication bias was not detected. Quality was high in four datasets and medium in four. In conclusion, our findings highlight the need to screen for IBD in individuals with ASD, and future research should identify who, among those with ASD, has the highest risk of IBD, and elucidate the shared biological mechanisms between ASD and IBD. LAY SUMMARY: This systematic review and meta-analysis of eight observational datasets found that individuals with autism spectrum disorder (ASD) are more likely to develop any inflammatory bowel disease, ulcerative colitis, or Crohn's disease. Our findings highlight the need to screen for inflammatory bowel disease in patients with ASD and elucidate the shared biological mechanisms between the two disorders.

The 1287 G/A polymorphism of the norepinephrine transporter gene (NET) is involved in commission errors in Korean children with attention deficit hyperactivity disorder.

BACKGROUND: Previous evidence supports the role of noradrenergic systems in ADHD, and norepinephrine transporter (NET) is critical in regulating the noradrenergic system. The present study aimed to investigate the association between NET gene polymorphism and the performance measures of the Continuous Performance Test (CPT) in Korean ADHD children. METHODS: Eighty-seven children (mean age = 9.23 ± 1.99 years) with ADHD were recruited from a university hospital. Genotypes of G1287A of the NET gene (SLC6A2) were analyzed. All participants completed the CPT, with performance measures of omission errors, commission errors, reaction time and reaction standardization computed. The relationship between G1287A polymorphisms and CPT performance measures was examined. RESULTS: There were 46 subjects with the G/G genotype, 35 subjects with the G/A genotype and 6 subjects with the A/A genotype. Among the three groups, there were no significant differences in the performance of CPTs. When dichotomized according to whether the subjects have the rare allele or not, subjects with the homozygous G/G genotype showed significantly lower commission errors compared to those without G/G genotypes (by independent T-test, t = -2.18, p = 0.026). DISCUSSION: Our study found a significant association between commission errors of the CPT and the G1287A genotype of the NET gene in Korean ADHD children. These findings suggest a protective role of the G/G genotype of the NET polymorphisms in the deficits of response inhibition in ADHD children.

The Role of Ion Channel-Related Genes in Autism Spectrum Disorder: A Study Using Next-Generation Sequencing.

The clinical heterogeneity of autism spectrum disorder (ASD) is closely associated with the diversity of genes related to ASD pathogenesis. With their low effect size, it has been hard to define the role of common variants of genes in ASD phenotype. In this study, we reviewed genetic results and clinical scores widely used for ASD diagnosis to investigate the role of genes in ASD phenotype considering their functions in molecular pathways. Genetic data from next-generation sequencing (NGS) were collected from 94 participants with ASD. We analyzed enrichment of cellular processes and gene ontology using the Database for Annotation, Visualization, and Integrated Discovery (DAVID). We compared clinical characteristics according to genetic functional characteristics. We found 266 genes containing nonsense, frame shift, missense, and splice site mutations. Results from DAVID revealed significant enrichment for "ion channel" with an enrichment score of 8.84. Moreover, ASD participants carrying mutations in ion channel-related genes showed higher total IQ (p = 0.013) and lower repetitive, restricted behavior (RRB)-related scores (p = 0.003) and mannerism subscale of social responsiveness scale scores, compared to other participants. Individuals with variants in ion channel genes showed lower RRB scores, suggesting that ion channel genes might be relatively less associated with RRB pathogenesis. These results contribute to understanding of the role of common variants in ASD and could be important in the development of precision medicine of ASD.