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Background There have been concerns about the potential cardiovascular (CV) adverse effects associated with methylphenidate (MTH) use. However, only limited evidence exists on the long-term safety of MTH.Objective To evaluate whether MTH use is associated with long-term CV risk.Methods This was a retrospective cohort study using 2003–2017 data from the Health and Welfare Database in Taiwan. Patients newly diagnosed with attention deficit and hyperactivity disorder (ADHD) and between 3 and 18 years of age were included. Two treatment statuses were assessed: initial treatment ≥7 days and ≥180 days. Patients treated with MTH were compared with those receiving non-medication therapy. One-to-one propensity score matching was used to balance between-group differences. Study outcomes included major CV events, chronic CV disease, cardiogenic shock and all-cause mortality. Cox proportional hazard models were used to estimate HRs between the two groups.Results We began with 307 459 patients with ADHD. After exclusion, 224 732 patients were included in the final cohort. The results showed that compared with non-ADHD medication users, patients who were treated with MTH for more than 7 days had a similar risk of major CV events (HR 0.85, 95% CI 0.72 to 0.99; p=0.040). Identical trends were found in groups who were treated for more than 180 days (HR 0.83, 95% CI 0.69 to 1.00; p=0.050). The results of the sensitivity analyses were consistent with the main analyses across all groups and individual outcomes.Conclusion Short-term MTH use did not increase CV risk among patients with ADHD. More evidence on long-term MTH use and risk of cardiogenic shock and death is warranted.

Background Few previous studies have established Snaith–Hamilton Pleasure Scale (SHAPS) cut-off values using receiver operating characteristic curve analysis and applied these values to compare predictors of anhedonia between clinical and nonclinical groups. Aims To determine the optimal cut-off values for the SHAPS and use them to identify predictors of anhedonia in clinical and nonclinical groups in Taiwan. Method This cross-sectional and correlational study used convenience sampling to recruit 160 patients from three hospitals and 412 students from two universities in northern Taiwan. Data analysis included receiver operating characteristic curve, univariate and multivariate analyses. Results The optimal SHAPS cut-off values were 29.5 and 23.5 for the clinical and nonclinical groups, respectively. Moreover, two-stage analysis revealed that participants in the clinical group who perceived themselves as nondepressed, and participants in the nonclinical group who did not skip classes and whose fathers exhibited higher levels of care and protection were less likely to attain the cut-off values. Conversely, participants in the nonclinical group who reported lower academic satisfaction and were unwilling to seek help from family or friends were more likely to attain the cut-off values. Conclusions Our findings highlight the importance of optimal cut-off values in screening for depression risk within clinical and nonclinical groups. Accordingly, the development of comprehensive, individualised programmes to monitor variation trends in SHAPS scores and relevant predictors of anhedonia across different target populations is crucial.

Background: The sex-differential prevalence of attention-deficit/hyperactivity disorder (ADHD) varies across the lifespan, but little is known about sex differences in executive functions in adults with ADHD. Methods: We assessed 261 adults, aged 18–40 years, diagnosed with ADHD (170 males [assigned at birth], aged 25.81 ± 5.49; 91 females, aged 27.76 ± 5.42) and 308 neurotypical adults (176 males, aged 24.62 ± 5.14; 132 female, aged 25.37 ± 5.42) via psychiatric interviews to confirm ADHD and other psychiatric diagnoses. They were assessed by the Cambridge Neuropsychological Testing Automated Battery (CANTAB) on Reaction Time (arousal/processing speed), Rapid Visual Information Processing (sustained attention), Spatial Span (spatial memory), Spatial Working Memory, Intradimentional/Extradimensional Shift (set-shifting), and Stocking of Cambridge (spatial planning). The primary analyses were adjusted for age, full-scale IQ, and co-occurring psychiatric conditions. Results: Adults with ADHD had various co-occurring psychiatric conditions without sex differences in ADHD-neurotypical differences. Both adult males and females with ADHD performed poorer in all CANTAB tasks than same-sex neurotypical adults. Significant sex-moderating effects were observed in neuropsychological performance, including greater ADHD-neurotypical differences in arousal for females than males and in location memory for spatial tasks in males than females. Conclusion: There were no sex-moderating effects in the presence of co-occurring psychiatric conditions in adult ADHD. However, there were sex-moderating effects on how ADHD related to neuropsychological functioning in adulthood. ADHD was associated with more challenges in arousal/processing speed in females and more challenges in strategy use or inhibition in spatial memory in males.

Background: Although the neural mechanisms of the theory of mind (ToM) in children with autism spectrum disorder (ASD) through fMRI using the social animation task have been investigated, little is known in adults with ASD. Therefore, the present study aimed to explore the neural substrates of ToM in adults with ASD. Moreover, we aimed to elucidate the relationship between brain activation and behavior of social interaction in adults with ASD. Methods: Twenty-four healthy controls and 24 adults with the clinical diagnosis of ASD were recruited. Participants were asked to complete the social animation task in functional magnetic resonance imaging. The imaging analyses of within (whole brain analysis) and between (5 regions of interest) group comparisons were conducted to explore the process of ToM. The correlation analyses were further conducted to explore the relationship between neural activations associated with ToM and social interaction abilities assessed by ADI-R. Results: The ASD group showed greater activation in the left precuneus and right superior temporal gyrus (STG) than the control group. For correlation analyses, greater right STG activation was positively correlated with autistic symptoms assessed by the ADI-R in the ASD group. Conclusion: ASD adults might spend a lot of effort on identification processing, thereby influencing social communication skills. Also, the neural deficits of ToM in ASD adults might be associated with their social interaction difficulties.

Background/purpose: The diagnosis of autism spectrum disorder (ASD), involving multiple components of clinical assessments, is challenging. The Autism Diagnostic Observation Schedule-Generic (ADOS-G), one of the standardized and validated instruments for ASD diagnostic evaluation, has been widely used in many countries. With the preparation of the Mandarin version of the ADOS-G (Mandarin-ADOS-G), this study aims to examine its psychometric properties, including reliability and validity. Methods: The sample included 554 individuals clinically diagnosed with ASD (477 males, 86.1%) and 50 typically developing (TD) individuals (29 males, 58.0%) who were assessed with different modules of the Mandarin-ADOS-G between 4.1 and 34.0 years old with a mean age of 13.0 years (Module 1, n = 40; Module 2, n = 46; Module 3, n = 275; Module 4, n = 243). We evaluated the inter-rater reliability, test-retest reliability, internal consistency, and concurrent validity with the Chinese Autism Diagnostic Interview-Revised (ADI-R) and Social Responsiveness Scale (SRS) caregiver-report and self-report forms. The discriminative validity of Mandarin-ADOS-G was also examined. Results: The Mandarin-ADOS-G demonstrated good inter-rater reliability (agreement of ADOS classification 0.91), good test-retest reliability (intraclass correlations 0.55–0.73), and low to high good internal consistency (Cronbach's alpha 0.27–0.86). The concurrent validity showed significant correlations with ADI-R (Pearson correlations 0.22–0.37) and the SRS caregiver-report form (Pearson correlations 0.15–0.23). Moreover, all Mandarin-ADOS-G domains successfully differentiated autistic individuals from TD individuals (all p-values

This study documented the prescribing patterns of methylphenidate and atomoxetine among patients aged 3 to 18 in Taiwan diagnosed with attention deficit hyperactivity disorder (ADHD) between 2004 and 2017. Initial treatment for ADHD, the time between the first diagnosis and the first prescription, and medication-switching patterns were investigated. The final cohort consisted of 256,882 patients, and 147,210 (57.3%) of them received medication treatment. Most of the patients (98.2%) received methylphenidate. Atomoxetine use increased from 0.1% in 2007 to 5.5% in 2017. The median time between the ADHD diagnosis and the first prescription was 21 days (IQR: 0–212 days). In patients who initiated methylphenidate, 12,406 (8.4%) patients switched to atomoxetine; 850 (31.3%) of the children began with atomoxetine and switched to methylphenidate. In conclusion, methylphenidate was the predominant treatment for ADHD in 2004–2017. However, the prevalence of pharmacotherapy for ADHD was relatively low. Further investigation on the reasons behind this pattern is recommended.

We investigated whether the upper limb muscle stiffness quantified by the acoustic radiation force impulse shear wave elastography (ARFI/SWE) is a potential biomarker for age-related muscle alteration and functional decline in patients with Duchenne muscular dystrophy (DMD). 37 patients with DMD and 30 typically developing controls (TDC) were grouped by age (3–8, 9–11, and 12–18 years). ARFI/SWE measured the biceps and deltoid muscle's shear wave velocities (SWVs). Performance of Upper Limb Module (PUL 1.2 module) assessed muscle function in DMD patients. Mann Whitney test compared muscle SWVs between DMD and TDC, stratified by three age groups. We used analysis of variance with Bonferroni correction to compare muscle SWVs between DMD and TDC and correlated muscle SWVs with PUL results in the DMD group. Results showed that the SWVs of biceps differentiated DMD patients from TDC across age groups. Younger DMD patients (3–8 years) exhibited higher SWVs (p = 0.013), but older DMD patients (12–18 years) showed lower SWVS (p = 0.028) than same-aged TDC. DMD patients had decreasing biceps SWVs with age (p

Background/purpose: Youths with autism spectrum disorder (ASD) are at a high risk of involvement in school bully. The study investigated whether comorbid psychopathologies mediated the link between ASD and bullying involvement. Methods: We assessed 353 youths (mean age, 11.8 ± 3.1 years), including 121 youths with ASD and 232 typically developing (TD) controls, using semi-structured diagnostic interviews on ASD and other psychiatric conditions. Follow-up assessments took place 2–5 years (37.6 ± 15 months) later. Meanwhile, their parents reported on the Social Adjustment Inventory for Children and Adolescents about bullying involvement statuses. We identified significant mediators by simple mediation models, followed by multiple mediation models to scrutinize the mediation effects of selected mediators. Results: The results showed a sevenfold increased risk of bullying involvement among youths with ASD compared with TD controls at follow-up. In general, psychopathologies mediated the link between ASD and bullying involvement, even independent of age and sex. Specifically, we found mediating effects of social problems on victimization-only and aggressive behaviors on victimization-perpetration. Conclusion: Our findings strongly suggest the link between ASD and later bullying involvement is mediated by pre-existing comorbid psychiatric conditions, besides the direct effect of ASD on bullying victimization. Hence, early identification and intervention of these psychopathologies are highly suggested.

Background: Theta burst stimulation (TBS), a patterned repetitive transcranial magnetic stimulation (rTMS) protocol with shorter simulation duration and lower stimulus intensity, could be a better protocol for individuals with autism spectrum disorder (ASD). Our study aimed to explore the impacts of intermittent TBS (iTBS) over the bilateral posterior superior temporal sulcus (pSTS) on intellectually able adults with ASD. Methods: In this randomized, single-blinded, sham-controlled crossover trial, 13 adults with ASD completed iTBS for 5 consecutive days over the bilateral pSTS and inion (as a sham control) in a 16-weeks interval and in a randomly assigned order. The neuropsychological function was measured with the Wisconsin Card Sorting Test (WCST) for cognitive flexibility while the clinical outcomes were measured with both self-rate and parents-rate Autism Spectrum Quotient (AQ) before and after 5-day iTBS interventions. Results: The results revealed significantly immediate effects of multi-session iTBS over the bilateral pSTS on parent-rate autistic symptoms in adults with ASD. The post-hoc analysis revealed the impacts of multi-session iTBS on cognitive flexibility were affected by baseline social-communicative impairment and baseline cognitive performance. Besides, the impacts of multi-session iTBS on clinical symptoms was affected by the concurrent psychotropic medication use and baseline autistic symptoms. Conclusions: Given the caveat of the small sample size and discrepancy of multiple informants, this pilot study suggests the therapeutic potential of 5-day multi-session iTBS over the pSTS in adults with ASD. Individual factors modulating the response to rTMS should be explicitly considered in the future trial.

Abstract Background Neuroimage literature of autism spectrum disorder (ASD) has a moderate-to-high risk of bias, partially because those combined with intellectual impairment (II) and/or minimally verbal (MV) status are generally ignored. We aimed to provide more comprehensive insights into white matter alterations of ASD, inclusive of individuals with II (ASD-II-Only) or MV expression (ASD-MV). Methods Sixty-five participants with ASD (ASD-Whole; 16.6 ± 5.9 years; comprising 34 intellectually able youth, ASD-IA, and 31 intellectually impaired youth, ASD-II, including 24 ASD-II-Only plus 7 ASD-MV) and 38 demographic-matched typically developing controls (TDC; 17.3 ± 5.6 years) were scanned in accelerated diffusion-weighted MRI. Fixel-based analysis was undertaken to investigate the categorical differences in fiber density (FD), fiber cross section (FC), and a combined index (FDC), and brain symptom/cognition associations. Results ASD-Whole had reduced FD in the anterior and posterior corpus callosum and left cerebellum Crus I, and smaller FDC in right cerebellum Crus II, compared to TDC. ASD-IA, relative to TDC, had no significant discrepancies, while ASD-II showed almost identical alterations to those from ASD-Whole vs. TDC. ASD-II-Only had greater FD/FDC in the isthmus splenium of callosum than ASD-MV. Autistic severity negatively correlated with FC in right Crus I. Nonverbal full-scale IQ positively correlated with FC/FDC in cerebellum VI. FD/FDC of the right dorsolateral prefrontal cortex showed a diagnosis-by-executive function interaction. Limitations We could not preclude the potential effects of age and sex from the ASD cohort, although statistical tests suggested that these factors were not influential. Our results could be confounded by variable psychiatric comorbidities and psychotropic medication uses in our ASD participants recruited from outpatient clinics, which is nevertheless closer to a real-world presentation of ASD. The outcomes related to ASD-MV were considered preliminaries due to the small sample size within this subgroup. Finally, our study design did not include intellectual impairment-only participants without ASD to disentangle the mixture of autistic and intellectual symptoms. Conclusions ASD-associated white matter alterations appear driven by individuals with II and potentially further by MV. Results suggest that changes in the corpus callosum and cerebellum are key for psychopathology and cognition associated with ASD. Our work highlights an essential to include understudied subpopulations on the spectrum in research.

Abstract Background Features of autism spectrum disorder (ASD) include difficulties in processing and interpreting socioemotional information. The "Reading the Mind in the Eyes" test (RMET) is a validated measurement for processing socioemotional ability. However, previous RMET studies did not explore patterns of incorrect answers and the emotional valence of the test items. This study used the Taiwanese version of the RMET and the network analysis methods to examine the differences in underlying mechanisms of socioemotional processes between 30 males with autism spectrum disorder (ASD) (mean age = 18 years) and 30 healthy control males (mean age = 17 years). For each test item, a picture of a person's eyes and partial face was shown with four words describing the emotional status on picture corners. Participants were instructed to choose one of the four words that best matched the person's thinking or feeling. We further classified the words into three valences of emotional categories to examine socioemotional processes. Results Our results showed that ASD males performed poorer on the RMET than the controls. ASD males had higher network density and in-degree scores, especially in negative words, than control males. Conclusions The findings suggest that males with ASD might have deficits in mapping the best emotional concept words to the target item, especially for processing negative emotion.

Background/purpose: Increased intra-individual variability (IIV) in reaction time (RT) is a key feature of attention-deficit/hyperactivity disorder (ADHD). However, little is known about neurobiology underpinnings of IIV in ADHD. Methods: We assessed 55 youths with ADHD, and 55 individually-matched typically developing control (TDC) with the MRI and Conners' Continuous Performance Test. The ex-Gaussian distribution of RT was estimated to capture IIV with the parameters σ (sigma) and τ (tau). The regional brain volumes, analyzed by voxel-based morphometry, were correlated with IIV parameters. Results: We found both distinct and shared correlations among ADHD and TDC. For grey matter, there were significant σ-by-group interactions in the cingulate cortex and thalamus and also a τ-by-group interaction in the right inferior frontal gyrus. There was also shared negative associations between σ and regional volumes of the right posterior cerebellum and a positive association between τ and the right anterior insula. For white matter, there was a significant σ-by-group interaction in the genu of the corpus callosum and significant τ-by-group interactions in the right anterior corona radiata, the left splenium of the corpus callosum, and bilateral posterior cerebellum. There were also shared patterns that increased τ was associated with increased regional volumes of the right anterior corona radiata and decreased regional volumes of the right posterior limb of the internal capsule. Conclusion: This study highlights that brain regions responsible for the motor, salience processing and multimodal information integration are associated with increased IIV in youths with ADHD.

Objectives: The symptoms of attention-deficit/hyperactivity disorder (ADHD) have been positively documented to be correlated with unintentional mind-wandering (MW) in the literature. In this study, we intended to explore the link between the types of MW and the attention laboratory performance in adults with ADHD symptoms. Methods: We recruited 24 adult patients with ADHD and 30 controls: (a) to receive a semi-structured psychiatric interview for ADHD and other diagnoses, (b) to complete questionnaires about adult ADHD symptoms and other psychiatric symptoms, (c) to receive intelligence assessment, (d) to have thought probes during a Sustained Attention to Response Task (SART), and (e) to be assessed with the MW: Spontaneous Scale (WM-S). Results: Adult patients with ADHD symptoms showed a more impulsive SART response style (increased commission errors and fast response speed) and unintentional MW. Increased unintentional MW was associated with reduced task performance. A positive association existed between MW-S scores and unintentional MW during the SART. Conclusion: Spontaneous MW may be significant impairment in adults with ADHD. Different measurements of MW had the associated and consistent findings measured by cognitive laboratory task with thought probe or WM-S measurement.

Following the published behavioral and cognitive results of this single-blind parallel sham-controlled randomized clinical trial, the current study aimed to explore the impact of intermittent theta burst stimulation (iTBS), a variant of excitatory transcranial magnetic stimulation, over the bilateral posterior superior temporal sulci (pSTS) on white matter macro/microstructure in intellectually able children and adolescents with autism. Participants were randomized and blindly received active or sham iTBS for 4 weeks (the single-blind sham-controlled phase). Then, all participants continued to receive active iTBS for another 4 weeks (the open-label phase). The clinical results were published elsewhere. Here, we present diffusion magnetic resonance imaging data on potential changes in white matter measures after iTBS. Twenty-two participants in Active-Active group and 27 participants in Sham-Active group underwent multi-shell high angular resolution diffusion imaging (64-direction for b = 2000 & 1000 s/mm2, respectively) at baseline, week 4, and week 8. With longitudinal fixel-based analysis, we found no white matter changes following iTBS from baseline to week 4 (a null treatment by time interaction and a null within-group paired comparison in the Active-Active group), nor from baseline to week 8 (null within-group paired comparisons in both Active-Active and Sham-Active groups). As for the brain-symptoms relationship, we did not find baseline white matter metrics associated with symptom changes at week 4 in either group. Our results raise the question of what the minimal cumulative stimulation dose required to induce the white matter plasticity is.

Long-term neurological and neurodevelopmental sequelae are a concerning issue for people with Enterovirus A71 (EV-A71) central nervous system (CNS) infection. Unfortunately, no longitudinal prospective clinical study has systematically investigated the consequences of EV-A71 CNS infection during early life on the later development of other psychiatric disorders. In this naturalistic longitudinal follow-up design, we followed forty-three youth, who got EV-A71 CNS involvement 6–18 years ago and were enrolled in other EV-A71 clinical studies then. Their psychiatric presentation, emotional/behavioral problems, and cognitive issues were examined using a psychiatrist-conducted diagnostic interview, parent- and self-rated questionnaires, and neuropsychological tests, respectively. We compared the prevalence of psychiatric disorders in youth with EV-A71 CNS involvement to a nationally representative cohort. Emotion/behavior and cognition in EV-A71-CNS-infected youth were compared to those in a matched community-based sample of healthy controls and youth with attention-deficit/hyperactivity disorder (ADHD). Compared to a national sample (absolute ADHD prevalence 10.1%), youth with EV-A71 CNS involvement had three times the odds of receiving an ADHD diagnosis (standardized prevalence ratio, 95% CI = 1.8, 4.2; absolute ADHD prevalence 34.9%). No other psychiatric diagnoses were more common in EV-A71-CNS-infected youth. Compared to community-based ADHD youth, EV-A71-CNS-infected youth with psychiatric disorders showed comparable core ADHD symptoms, opposition/defiance, autistic features, and suboptimal sustained attention performance (based on the Conners’ Continuous Performance Test), all of which were more severe than healthy controls. EV-A71-CNS-infected youth without psychiatric disorders showed comparable autistic features to EV-A71-CNS-infected youth with psychiatric disorders and ADHD youth. EV-A71 CNS involvement may cause long-term, adverse psychiatric outcomes that develop into an ADHD diagnosis alongside social/communication/emotion problems and autistic features. We recommend earlier identification and intervention of these problems among these children.

Individuals diagnosed with autism spectrum disorder (ASD) are more likely to have suicidal thoughts and behaviors. However, little research delineates the temporal and mechanistic associations between potential risk factors and suicidality in autistic individuals. We assessed 129 autistic and 121 age-matched and sex-assigned-at-birth-matched typically developing (TD) children and youth at baseline and follow-up. We evaluated internalizing/externalizing problems, bullying experiences, and three executive function tasks at a mean baseline age of 13.4 years (standard deviation: 4.2 years). After an average of 5.8 years (standard deviation: 1.7 years), we evaluated their suicidal thoughts and behaviors. The experiences of being bullied partially mediated the temporal relationship between pre-existing ASD and later-reported suicidal thoughts. Several cognitive flexibility and sustained attention indices mediated the temporal relationship between pre-existing ASD and later-reported suicidal thoughts. A multiple mediation model confirmed that bullying victimization and cognitive flexibility jointly mediated the temporal relationship between ASD and suicidal thoughts. Better cognitive flexibility and experiences of bullying victimization in autistic children/youth were both associated with higher risks of later-reported suicidal thoughts in adolescence/adulthood. School bullying-prevention programs and tailored clinical support for autistic youth with better cognitive flexibility are warranted for personalized suicide prevention for the autistic population.

Abstract Background Despite the effectiveness of methylphenidate for treating ADHD, up to 30% of individuals with ADHD show poor responses to methylphenidate. Neuroimaging biomarkers to predict medication responses remain elusive. This study characterized neuroanatomical features that differentiated between clinically good and poor methylphenidate responders with ADHD. Methods Using a naturalistic observation design selected from a larger cohort, we included 79 drug-naive individuals (aged 6–42 years) with ADHD without major psychiatric comorbidity, who had acceptable baseline structural MRI data quality. Based on a retrospective chart review, we defined responders by individuals’ responses to at least one-month treatment with methylphenidate. A nonparametric mass-univariate voxel-based morphometric analysis was used to compare regional gray matter volume differences between good and poor responders. A multivariate pattern recognition based on the support vector machine was further implemented to identify neuroanatomical indicators to predict an individual’s response. Results 63 and 16 individuals were classified in the good and poor responder group, respectively. Using the small-volume correction procedure based on the hypothesis-driven striatal and default-mode network masks, poor responders had smaller regional volumes of the left putamen as well as larger precuneus volumes compared to good responders at baseline. The machine learning approach identified that volumetric information among these two regions alongside the left frontoparietal regions, occipital lobes, and posterior/inferior cerebellum could predict clinical responses to methylphenidate in individuals with ADHD. Conclusion Our results suggest regional striatal and precuneus gray matter volumes play a critical role in mediating treatment responses in individuals with ADHD.

Background/Purpose: With globalization, transnational marriages become more and more common in the world. The mental health of the offspring of immigrants is a significant public health issue. The present study aimed to investigate whether children of immigrant mothers demonstrate more emotional and behavioral problems than those of native mothers in Taiwan. Methods: In a sample of 6242 children in grade 3, grade 5, and grade 7 from a national epidemiological study of child mental disorders, 617 (9.9%) children were born by immigrant mothers (Chinese, Vietnam, Indonesia, and other countries) and 5625 children by Taiwanese parents. The children reported on Achenbach Youth Self-report, and their parents reported about them on the Child Behavior Checklist, Parental Bonding Inventory, and Family APGAR for assessing emotional and behavioral problems, mother's parenting style, and perceived family support. Results: Compared with children of native mothers, children of immigrant mothers reported themselves and were reported by their parents to have more externalizing and internalizing problems. However, after considering the effects of sociodemographics, parenting style, and family function, only significant differences in externalizing problems between children with native or immigrant mothers were found. Conclusion: Our findings indicate that right parenting style and family support; may offset emotional and behavioral problems in children of immigrant mothers, and suggest that improving maternal parenting and family function is beneficial to child development, regardless of immigrant or native mothers. Keywords: Immigrant, Offspring, Child behaviors, Parenting, Family function

Socio-cognitive difficulties in individuals with autism spectrum disorder (ASD) are heterogenuous and often co-occur with irritability symptoms, such as angry/grouchy mood and temper outbursts. However, the specific relations between individual symptoms are not well-represented in conventional methods analyzing aggregated autistic symptoms and ASD diagnosis. Moreover, the cognitive-behavioral mechanisms linking ASD to irritability are largely unknown. This study investigated the dynamics between autistic (Social Responsiveness Scale) and irritability (Affective Reactivity Index) symptoms and executive functions (Cambridge Neuropsychological Test Automated Battery) in a sample of children and adolescents with ASD, their unaffected siblings, and neurotypical peers (N = 345, aged 6-18 years, 78.6% male). Three complementary networks across the entire sample were computed: (1) Gaussian graphical network estimating the conditional correlations between symptom nodes; (2) Relative importance network computing relative influence between symptoms; (3) Bayesian directed acyclic graph estimating predictive directionality between symptoms. Networks revealed numerous partial correlations within autistic (rs = 0.07-0.56) and irritability (rs = 0.01-0.45) symptoms and executive functions (rs = -0.83 to 0.67) but weak connections between clusters. This segregated pattern converged in all directed and supplementary networks. Plausible predictive paths were found between social communication difficulties to autism mannerisms and between "angry frequently" to "lose temper easily." Autistic and irritability symptoms are two relatively independent families of symptoms. It is unlikely that executive dysfunctions explain elevated irritability in ASD. Findings underscore the need for researching other mood and cognitive-behavioral bridge symptoms, which may inform individualized treatments for co-occurring irritability in ASD.

Abstract During recent 20 years, enterovirus A71 (EV-A71) has emerged as a major concern among pediatric infectious diseases, particularly in the Asia-Pacific region. The clinical manifestations of EV-A71 include uncomplicated hand, foot, and mouth disease, herpanina or febrile illness and central nervous system (CNS) involvement such as aseptic meningitis, myoclonic jerk, polio-like syndrome, encephalitis, encephalomyelitis and cardiopulmonary failure due to severe rhombencephalitis. In follow-up studies of patients with EV-A 71 CNS infection, some still have hypoventilation and need tracheostomy with ventilator support, some have dysphagia and need nasogastric tube or gastrostomy feeding, some have limb weakness/astrophy, cerebellar dysfunction, neurodevelopmental delay, lower cognition, or attention deficiency hyperactivity disorder. Long term sequelae may be related to greater severity of CNS involvement or neuron damage, hypoxia and younger age of onset.

Objectives: The identification of subgroups of autism spectrum disorder (ASD) may partially remedy the problems of clinical heterogeneity to facilitate the improvement of clinical management. The current study aims to use machine learning algorithms to analyze microarray data to identify clusters with relatively homogeneous clinical features.Methods: The whole-genome gene expression microarray data were used to predict communication quotient (SCQ) scores against all probes to select differential expression regions (DERs). Gene set enrichment analysis was performed for DERs with a fold-change >2 to identify hub pathways that play a role in the severity of social communication deficits inherent to ASD. We then used two machine learning methods, random forest classification (RF) and support vector machine (SVM), to identify two clusters using DERs. Finally, we evaluated how accurately the clusters predicted language impairment.Results: A total of 191 DERs were initially identified, and 54 of them with a fold-change >2 were selected for the pathway analysis. Cholesterol biosynthesis and metabolisms pathways appear to act as hubs that connect other trait-associated pathways to influence the severity of social communication deficits inherent to ASD. Both RF and SVM algorithms can yield a classification accuracy level >90% when all 191 DERs were analyzed. The ASD subtypes defined by the presence of language impairment, a strong indicator for prognosis, can be predicted by transcriptomic profiles associated with social communication deficits and cholesterol biosynthesis and metabolism.Conclusion: The results suggest that both RF and SVM are acceptable options for machine learning algorithms to identify AD subgroups characterized by clinical homogeneity related to prognosis.

Tai Chi Chuan (TCC) exercise has been shown to improve cognitive task-switching performance in older adults, but the extent of this positive effect varies among individuals. Past research also shows that brain white matter integrity could predict behavioral gains of cognitive and motor learning. Therefore, in this randomized controlled trial (NCT02270320), we examined whether baseline integrity of three target white matter tract groups was predictive of task-switching improvement after 12-week TCC training in middle-aged and older adults. Thirty-eight eligible participants were randomly assigned to a TCC group (n = 19) and a control group (n = 19). Cognitive task-switching and physical performances were collected before and after training. Brain diffusion spectrum MR images were acquired before training and the general fractional anisotropy (GFA) of each target white matter tract group was calculated to indicate baseline white matter integrity of that group. Correlation and regression analyses between these GFAs and post-training task-switching improvement were analyzed using adjusted p-values. After 12 weeks, significant task-switching and physical performance improvements were found only in the TCC group. Moreover, higher baseline GFA of the prefronto-striato-thalamo-prefrontal loop fibers (r = −0.63, p = 0.009), but not of the prefronto-parietal/occipital (r = −0.55, p = 0.026) and callosal (r = −0.35, p = 0.189) fiber groups, was associated with greater reductions of task-switching errors after the TCC training. Multiple regression analysis revealed that baseline GFA of the prefronto-striato-thalamo-prefrontal loop fibers was the only independent white matter integrity predictor of task-switching error reductions after TCC training (β = −0.620, adjusted R2 change = 0.265, p = 0.009). These findings not only highlight the important role of baseline integrity of the prefronto-striatal circuits in influencing the extent of positive cognitive task-switching effects from short-term TCC training, but also implicate that preserving good white matter integrity in the aging process may be crucial in order to gain the best cognitive effects of exercise interventions.

Backgrounds: Although evidence suggests that the activity of the anterior cingulate cortex involves social cognition, there are inconsistent findings regarding the aberrant cingulate gray matter (GM) and scanty evidence about altered cortical thickness and white matter (WM) of cingulate in individuals with autism spectrum disorder (ASD). Evidence supports the association between the genetic variants of CNTNAP2 and altered brain connectivity. This study investigated the cingulate substructure and its association with social awareness deficits and the CNTNAP2 variants in individuals with ASD and typically-developing controls (TDC). Methods: We assessed 118 individuals with ASD and 122 TDC with MRI and clinical evaluation. The GM, WM volumes and cortical thickness of the cingulate gyrus were compared between ASD and TDC based on fine parcellation. Five SNPs of the CNTNAP2 linked to ASD and brain structural abnormality were genotyped, and rs2710102, rs2538991, rs2710126 passed quality control filters. Results: ASD individuals showed thinner cortical thickness in bilateral cingulate subregions than TDC without significant group differences in GM and WM volumes. The WM volume of the right anterior cingulate gyrus was correlated with social awareness deficits in ASD. The CNTNAP2 variant demonstrated a main effect on the WM volumes of the right middle cingulate gyrus. Besides, the CNTNAP2 variants interacted with ASD diagnosis and age on the cortical thickness of the left anterior middle cingulate cortex. Conclusions: Our findings suggest that aberrant cingulate structure in ASD might be associated with the social awareness deficits and genetic variants of the CNTNAP2. These novel findings need validation.

A variety of tools and methods have been used to measure behavioral symptoms of attention-deficit/hyperactivity disorder (ADHD). Missing data is a major concern in ADHD behavioral studies. This study used a deep learning method to impute missing data in ADHD rating scales and evaluated the ability of the imputed dataset (i.e., the imputed data replacing the original missing values) to distinguish youths with ADHD from youths without ADHD. The data were collected from 1220 youths, 799 of whom had an ADHD diagnosis, and 421 were typically developing (TD) youths without ADHD, recruited in Northern Taiwan. Participants were assessed using the Conners’ Continuous Performance Test, the Chinese versions of the Conners’ rating scale-revised: short form for parent and teacher reports, and the Swanson, Nolan, and Pelham, version IV scale for parent and teacher reports. We used deep learning, with information from the original complete dataset (referred to as the reference dataset), to perform missing data imputation and generate an imputation order according to the imputed accuracy of each question. We evaluated the effectiveness of imputation using support vector machine to classify the ADHD and TD groups in the imputed dataset. The imputed dataset can classify ADHD vs. TD up to 89% accuracy, which did not differ from the classification accuracy (89%) using the reference dataset. Most of the behaviors related to oppositional behaviors rated by teachers and hyperactivity/impulsivity rated by both parents and teachers showed high discriminatory accuracy to distinguish ADHD from non-ADHD. Our findings support a deep learning solution for missing data imputation without introducing bias to the data.

Abstract Background Impaired social interaction is one of the essential features of autism spectrum disorder (ASD). Our previous copy number variation (CNV) study discovered a novel deleted region associated with ASD. One of the genes included in the deleted region is ARHGEF10. A missense mutation of ARHGEF10 has been reported to be one of the contributing factors in several diseases of the central nervous system. However, the relationship between the loss of ARHGEF10 and the clinical symptoms of ASD is unclear. Methods We generated Arhgef10 knockout mice as a model of ASD and characterized the social behavior and the biochemical changes in the brains of the knockout mice. Results Compared with their wild-type littermates, the Arhgef10-depleted mice showed social interaction impairment, hyperactivity, and decreased depression-like and anxiety-like behavior. Behavioral measures of learning in the Morris water maze were not affected by Arhgef10 deficiency. Moreover, neurotransmitters including serotonin, norepinephrine, and dopamine were significantly increased in different brain regions of the Arhgef10 knockout mice. In addition, monoamine oxidase A (MAO-A) decreased in several brain regions. Conclusions These results suggest that ARHGEF10 is a candidate risk gene for ASD and that the Arhgef10 knockout model could be a tool for studying the mechanisms of neurotransmission in ASD. Trial registration Animal studies were approved by the Institutional Animal Care and Use Committee of National Taiwan University (IACUC 20150023). Registered 1 August 2015.

Background/Purpose: This study aimed to evaluate neuropsychological functioning of attention-deficit/hyperactivity disorder (ADHD) with and without comorbidities of oppositional defiant disorder (ODD) and/or conduct disorder (CD) and the mediation effects of the neuropsychological functions in the relationship between ADHD and ODD/CD symptoms to increase our understanding about these frequently co-occurring disorders. Methods: Adolescents aged 11â18Â years were interviewed by the Kiddie epidemiologic version of the Schedule for Affective Disorders and Schizophrenia to confirm their previous and current ADHD status and other psychiatric diagnoses. The performance of the Cambridge Neuropsychological Testing Automated Battery was compared among four groups: (1) ADHD with CD (ADHD+CD), regardless of ODD; (2) ADHD with ODD (ADHD+ODD) without CD; (3) ADHD without ODD/CD (ADHD-only); and (4) typically developing controls. Mediation effects of neuropsychological functioning were tested. Results: All three ADHD groups had impaired spatial working memory and short-term memory. Deficits in verbal memory and response inhibition were found in ADHD+ODD, but not in ADHD-only. ADHD+CD did not differ from typically developing controls in verbal working memory, signal detectability, and response inhibition. Spatial working memory partially mediated the association between ADHD and CD symptoms and alerting/signal detectability of arousal partially mediated the association between ADHD and ODD symptoms. Conclusion: There were both common and distinct neuropsychological deficits between adolescents with ADHD who developed ODD only and who developed CD. ADHD comorbid with CD may be a different disease entity and needs different treatment strategies in addition to treating ADHD, while ADHD+ODD may be a severe form of ADHD and warrants intensive treatment for ADHD symptoms. Keywords: arousal, attention-deficit/hyperactivity disorder, conduct disorder, mediator, oppositional defiant disorder, spatial working memory

Central nervous system (CNS) patterning genes are recognized as candidate genes for autism spectrum disorders (ASDs) based on neuroimaging and neuropathological evidence. Several genes that regulate CNS development are shown to be associated with ASD. Our previous family-based association study also revealed that a specific haplotype of WNT2 (wingless-type MMTV integration site family member 2) gene was overtransmitted to probands with ASD. Whether the CNS patterning genes moderate the clinical phenotype of ASD is unclear. This study investigated the genetic associations of WNT2, engrailed 2 (EN2), and forkhead box P2 (FOXP2) with the clinical symptom severity. Methods: The sample included 391 patients (males, 88.3%; mean age±standard deviation, 9.5±4.4 years) diagnosed with ASDs. Tag single nucleotide polymorphisms (SNPs) of EN2, WNT2, and FOXP2 were genotyped. The single-locus and multilocus markers were tested for association. Results: We found that multilocus markers of WNT2 were associated with stereotyped behaviors whereas the markers of FOXP2 tended to be associated with social deficits. Moreover, an SNP of WNT2 showed a trend to be associated with less inattentive symptoms. Conclusion: Our findings that WNT2 and FOXP2 may moderate the clinical phenotypes of ASD provide evidence to support the possible universal effect of WNT2 and FOXP2 on neurodevelopmental symptom dimensions. Such findings warrant further validation in other independent samples. Trial registration: Clinical trial registration identifier: NCT00494754

Changes of diagnostic coverage and criteria for psychiatric disorders in the fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) published in 2013 cause a need for updating the Kiddie-Schedule for Affective Disorders and Schizophrenia-Epidemiological version (K-SADS-E). This study examined the preliminary psychometric properties, including inter-rater reliability, and convergent and divergent validity of the modified K-SADS-E for DSM-5. Methods: A national survey of a school-based sample of 3242 students in grade 3, 5, and 7 from 44 schools was conducted in Northern, Central, and Southern Taiwan. Psychiatric diagnoses were made by the K-SADS-E interviews. Clinical questionnaires for attention deficit hyperactivity disorder (ADHD), autism spectrum disorder (ASD), and emotional and behavioral problems were examined using the Chinese version of the Swanson, Nolan, and Pelham IV scale, Social Responsiveness Scale, and Child Behavior Checklist. Results: The K-SADS-E showed satisfactory inter-rater reliability (prevalence adjusted bias adjusted kappa = 0.80–1.00) among eight interviewers. The diagnoses of K-SADS-E demonstrated good convergent and divergent validity with most corresponding clinical questionnaires. Conclusion: Our finding suggests that the K-SADS-E is a reliable and valid instrument for diagnosing child and adolescent psychiatric disorders based on DSM-5. Further study will examine the sensitivity, specificity, and test–retest reliability of the K-SADS-E in clinical and community samples.

Abstract Background The presence of attention-deficit/hyperactive disorder (ADHD) symptoms and impaired attention performance are commonly noted in individuals with autism spectrum disorder (ASD). However, little is known about attention performance in their unaffected siblings. This study aimed to investigate the ADHD-related traits and attention performance in unaffected siblings of probands with autism and Asperger syndrome (AS), as well as the clinical correlates of ADHD-related traits. Methods We assessed the intention, hyperactivity-impulsivity, and oppositional symptoms, and attention profiles of 199 probands with a diagnosis of ASD (122 autism, 77 AS), their unaffected siblings, and 196 typically developing controls (TD) by their parents’ reports on the ADHD-related symptoms and the Connors' Continuous Performance Test (CCPT), respectively. Results Compared to TD, unaffected siblings of ASD probands were more hyperactive/impulsive and oppositional, particularly unaffected siblings of AS probands. In CCPT, unaffected siblings of AS have intermediate levels of performance between probands with AS and TD on focused attention and sustained attention but were not statistically different from AS probands or TD in these attention profiles. In contrast, unaffected siblings of autism probands have significantly better CCPT performance when compared to autism probands but not to TD. In addition, stereotyped behaviors predicted ADHD-related traits in both sibling groups, but distinctive patterns of other correlates for ADHD-related traits were found between the two sibling groups. Conclusions This work suggested that unaffected siblings of AS, but not autism, have more hyperactive/impulsive traits and a trend of pervasive attention deficits assessed by CCPT which might serve as potential endophenotypes for genetic studies in AS. Trial registration ClinicalTrials.gov, NCT01582256

Abstract Background Several longitudinal studies have shown the partial symptomatic persistence of attention-deficit hyperactivity disorder (ADHD) in clinic-based samples. However, little is known about the patterns and trajectories of ADHD symptoms in community-based populations. Methods To differentiate developmental trajectories of ADHD symptoms over 1 year, with a four-wave quarterly follow-up in children and adolescents in the community of Taiwan, we conducted this prospective study in 1281 students in grade 3, 5, and 8. All the students in the regular classes rather than special educational classes were eligible and recruited to the study. Inattention, hyperactivity–impulsivity, and opposition-defiance were rated by parent reports on the Chinese version of the Swanson, Nolan, and Pelham Version IV Scale (SNAP-IV). Group-based trajectory modeling and multivariable regression analyses were used to explore the individual, family and social factors associated with differential trajectories. Results Trajectories were classified as Low (29.9–40.6%), Intermediate (52.5–58.5%) and High (6.9–12.5%) based on the symptom severity of ADHD symptoms assessed by the SNAP-IV. The proportion of children in the high ADHD trajectory might approximately reflect the prevalence of ADHD in Taiwan. The following factors differentiated High from Low trajectories: male gender, more externalizing problems, fewer prosocial behaviors, school dysfunction, more home behavioral problems, and less perceived family support. Conclusions Our findings that the concurrent conditions of emotional or externalizing problems, as well as impaired school and home function at baseline, might differentiate the high ADHD symptoms trajectory from others could help developing the specific measures for managing high ADHD symptoms over time in a school setting.

The aims of the current study were to determine whether patients with conduct disorder (CD) showed an abnormal availability of serotonin reuptake transporter (SERT), and if their hyperkinetic symptoms, impulsivity, and quality of life were correlated with the availability of SERT. Methods: We recruited 14 drug-naïve patients with CD and eight age-matched healthy controls (HCs). The adult attention-deficit/hyperactivity disorder (ADHD) self-report scale (ASRS), Barrett impulsivity scale (BIS), and the World Health Organization quality of life-brief version (WHOQOL-BREF) scale were administered. Positron emission tomography (PET) of the brain with 4-[18F]-ADAM was arranged for SERT imaging. Results: SERT availability was significantly reduced in the striatum and midbrain of patients with CD. Quality of life and inattention symptoms were also significantly correlated with the availability of SERT in the prefrontal cortex. Conclusion: The study suggested that a reduction in the availability of SERT might be associated with CD and could potentially predict poor quality of life or symptoms of inattention for these patients. The implications of our results might be limited to individuals with CD; a future study with a larger sample to validate our preliminary results is warranted.

Objectives: Methylphenidate (MPH) is highly effective in controlling the symptoms of attention-deficit/hyperactivity disorder (ADHD), but some children with ADHD either do not respond to, or do not tolerate, treatment. Dextromethorphan (DM) is a neuroprotective agent which has been used in the treatment of neuropsychiatric disorders. This clinical trial had examined the effect of DM on the use of MPH in the children with ADHD.Methods: This randomized double-blind clinical trial had evaluated 44 male outpatients, aged between 6 and 12 years, with a diagnosis of ADHD. The study subjects were randomly assigned into one of the two groups: receiving MPH alone (15–60 mg per day) or MPH plus DM (30–60 mg per day) for 8 weeks. Assessments, comprising the Chinese version of the Child Behavior Checklist (CBCL-C) scale and the Swanson, Nolan and Pelham Questionnaire (SNAP)-IV rating tests conducted by parents and the serum cytokines measured by microarray and enzyme-linked immunosorband assay (ELISA), were compared between groups at baseline and at 8 weeks after the medication was started.Results: There were a significant decrease at the mean scores of both CBCL-C and SNAP-IV scales after 8 weeks of treatment, but no significant differences between MPH and MPH+DM groups. Compared with the MPH-only group, the mean scores of some psychometric parameters reported on the CBCL-C and SNAP-IV scales regarding time effects as well as the attention problems on the CBCL-C scale regarding group effect were significantly higher in the DM+MPH group. Although there were no significant differences in the levels of various serum cytokines between groups, the subjects in the DM-MPH group had relatively fewer and lower levels of adverse effects. Significant interactions were found between the withdrawn/depression item reported on the CBCL-C scale and tumor necrosis factor α (ခTNF-α) (p = 0.027), as well as between thought problems item on the CBCL-C and TNF-α (p = 0.028) in subjects who had received DM+MPH treatment.Conclusion: Following the trial, DM+MPH was not superior to MPH alone for the treatment of children with ADHD, yet DM may potentially have negative effects on ADHD symptoms when combined with MPH.Clinical Trial Registration: Clinicaltrials.gov, trial number: NCT01787136.

Psychiatric comorbidities are common in individuals with attention-deficit/hyperactivity disorder (ADHD). In this study, we sought to evaluate the effects of medication and childhood ADHD subtypes on psychiatric comorbidities among adults with ADHD as compared to healthy adult controls. We assessed 121 drug-naïve adults with ADHD, 93 treated adults with ADHD, and 145 healthy controls (age 18-36 years) using semi-structured psychiatric interviews, intelligence tests, and medical records. Drug-naïve adults with ADHD had more comorbidities than treated adults with ADHD and controls. Childhood ADHD-combined subtype, relative to ADHD-inattentive subtype, was associated with higher risks of comorbidities. Current medication treatment was associate with a higher risk for anxiety disorders, and longer treatment duration was associated with lower risks of mood disorders and sleep disorders. Our results indicate that no medication treatment, short treatment duration, and childhood ADHD-combined subtype are associated with increased risks for psychiatric comorbidities among adults with ADHD.

An amendment to this paper has been published and can be accessed via the original article.

Abstract Background Our purpose was to examine the reliability and validity of the Chinese version of the Patient Health Questionnaire-15 (PHQ-15) in Taiwan, and to explore its relation to somatoform disorders (DSM-IV) and to somatic symptom and related disorders (DSM-5). Methods We recruited 471 individuals, 151 with somatoform disorders and 200 with somatic symptom and related disorders. Subjects completed the Chinese version of the PHQ-15, Beck Depression Inventory-II (BDI-II), Beck Anxiety Inventory (BAI), and received a DSM-IV- and DSM-5-based diagnostic interview. We performed exploratory factor analysis and assessed test-retest reliability, internal consistency, and correlation with BDI-II/BAI to confirm reliability and validity, and carried out ROC curve analysis to determine suitability for evaluation or screening purposes. PHQ-15 scores were compared between patients with various DSM-IV psychiatric diagnoses (such as DSM-IV somatoform disorders, panic disorder, other anxiety/depressive disorders) or no DSM-IV diagnosis and patients with DSM-5 somatic symptom and related disorders or no DSM-5 diagnosis. Results The Chinese version identified cardiopulmonary, pain-fatigue, and gastrointestinal as major factors and had good reliability (0.803–0.930), internal consistency (0.637–0.861), and correlation coefficients with BDI-II/BAI (0.407–0.619, 0.536–0.721, respectively). The PHQ-15 scores were similar in patients with somatoform disorders and patients with panic disorder; higher in patients with somatoform disorders and panic disorder than in patients with other anxiety/depressive disorders; and significantly higher in patients with somatic symptom and related disorders than in patients without this diagnosis. The AUC of the PHQ-15 was 0.678 (cutoff 6/7) for screening somatoform disorders (DSM-IV) and 0.725 (cutoff 4/5) for screening somatic symptom and related disorders (DSM-5). Conclusions The Chinese version of the PHQ-15 is suitable for evaluating somatic symptom and related disorders. The preponderance of somatic symptom disorder in our sample, lack of evaluation of functional disorders, and recruitment solely from psychiatric clinics are possible limitations.

Microdeletion at 22q11.2, a common copy number variation (CNV) noted in neurodevelopmental disorders, may be associated with cognitive impairment. However, cognitive function in individuals with microduplication remains unclear. This work presents the genetic, clinical, and brain structural data of two men out of 335 probands with autistic spectrum disorder (ASD) who had different CNV dosages at 22q11.2, and comparison with their siblings, 55 ASD probands, and 73 controls. Both showed severe autistic symptoms, but the proband with microduplication demonstrated better cognitive functions. Furthermore, different cingulate gyrus volume changes were noted, indicating that the proband with 22q11.2 microduplication had a different pattern of cingulate gyrus structure. Our comprehensive characterization of the behavioral, cognitive, and imaging phenotypes of ASD probands with different CNV dosage at 22q11.2 contribute to how copy number changes at 22q11.2 mediate the phenotypes in ASD, and pave the way for future clinical and functional study on these variants.

The mediators of real-world executive functions in autism during the transition into adulthood are mainly unknown. This study aimed to identify the mediators for the behavioral and cognitive domains of real-world executive functions in late adolescent and young adult autistic populations. We followed up 289 autistic children (aged 11.6 ± 3.8, male 82.2%) and 203 non-autistic controls (10.7 ± 2.9, 66.5%) to their ages of 16.9 ± 4.7 and 15.8 ± 3.9, respectively. The Behavior Rating Inventory of Executive Function, comprising two global scales (Behavioral Regulation Index and the Metacognitive Index), was used to assess real-world executive functions at Time 2. Mediators of behavior regulation and metacognition were explored among a wide range of clinical correlates and parental bonding. We found that the autistic group had lower executive functions than the non-autistic group with lower behavior regulation and metacognition subscores. Several childhood factors were significant mediators. Multiple mediation analyses revealed that childhood inattention remained a significant mediator for both behavior regulation and metacognition in late adolescence, and peer problems were the specific mediators of metacognition. Our findings suggest several childhood factors may mediate real-world executive functions during late adolescence. Treating common mediators such as inattention may improve real-world executive functions in autistic individuals during adulthood.

Studies have shown that Tai Chi Chuan (TCC) training has benefits on task-switching ability. However, the neural correlates underlying the effects of TCC training on task-switching ability remain unclear. Using task-related functional magnetic resonance imaging (fMRI) with a numerical Stroop paradigm, we investigated changes of prefrontal brain activation and behavioral performance during task-switching before and after TCC training and examined the relationships between changes in brain activation and task-switching behavioral performance. Cognitively normal older adults were randomly assigned to either the TCC or control (CON) group. Over a 12-week period, the TCC group received three 60-min sessions of Yang-style TCC training weekly, whereas the CON group only received one telephone consultation biweekly and did not alter their life style. All participants underwent assessments of physical functions and neuropsychological functions of task-switching, and fMRI scans, before and after the intervention. Twenty-six (TCC, N = 16; CON, N = 10) participants completed the entire experimental procedure. We found significant group by time interaction effects on behavioral and brain activation measures. Specifically, the TCC group showed improved physical function, decreased errors on task-switching performance, and increased left superior frontal activation for Switch > Non-switch contrast from pre- to post-intervention, that were not seen in the CON group. Intriguingly, TCC participants with greater prefrontal activation increases in the switch condition from pre- to post-intervention presented greater reductions in task-switching errors. These findings suggest that TCC training could potentially provide benefits to some, although not all, older adults to enhance the function of their prefrontal activations during task-switching.

Parent and teacher ratings of child behaviors are often discrepant, and these discrepancies may be correlated with parenting stress. The present study explored whether various parenting stress factors are associated with discrepancies between parent and teacher ratings of attention-deficit/hyperactivity disorder and oppositional defiant disorder (ODD) as well as internalizing symptoms in preschool children. We recruited 299 Taiwanese preschool children (aged 4-6 years) from the community or via clinical referrals. A structural equation modeling was used to analyze the relationships among three factors derived from the Parenting Stress Index-Short Form and informant discrepancies on symptoms of inattention, hyperactivity/impulsivity, ODD, and internalizing behaviors. Scores reported by parents were higher for each of the symptoms examined than those reported by teachers, and the degree of agreement between informants ranged from low to moderate. The parental distress factor of parenting stress was associated only with parent ratings, whereas other factors of parenting stress-parent-child dysfunctional interaction and parents' stress resulted from their child's temperament-were correlated with both parent and teacher ratings. Only parental distress factor predicted informant discrepancies for all behavioral symptoms assessed. Our findings suggest that parental distress should be considered when parent rating scores show significant discrepancies from that of teacher rating scores.

The majority of studies on parent-child discrepancies in the assessment of adolescent emotional and behavioral problems have been conducted in Western countries. It is believed that parent-adolescent agreement would be higher in societies with a strong culture of familism. We examined whether parent-adolescent discrepancies in the rating of adolescent emotional and behavioral problems are related to parental and family factors in Taiwan. Participants included 1,421 child-parent pairs of 7th-grade students from 12 middle schools in Northern Taiwan and their parents. We calculated Pearson's correlation coefficients to assess the relationship between parental (Child Behavior Checklist, CBCL) and adolescent (Youth Self Report, YSR) report of emotional/behavioral problem syndromes. Regression models were used to assess parent-adolescent differences in relation to parental psychopathology and family factors. We found that parent-adolescent agreement was moderate (r = 0.37). Adolescents reported higher symptom scores than their parents (Mean Total Problem Score: CBCL: 20.79, YSR: 33.14). Parental psychopathology was related to higher parental ratings and better informant agreement. Parents with higher socioeconomic status (SES) tended to report lower scores for adolescent problem syndromes, resulting in higher levels of disagreement. Greater maternal care was related to higher parent-adolescent agreement. Based on our study findings, we conclude that familism values do not seem to improve parent-child agreement in the assessment of adolescent problem syndromes. The finding that higher SES was related to increased discrepancies speaks to the need to explore the culture-specific mechanisms giving rise to informant discrepancies.

Diagnosis disclosure is an important clinical issue in developmental disabilities, which may influence parents' ability to cope with their child's conditions. This paper presents the content and patterns of diagnosis-informed counseling for mothers of children with autism and investigates the determinants for maternal satisfaction with this counseling, in order to improve clinical practice. Methods: Mothers of 151 children, aged 3–12 years, with DSM-IV autistic disorder, confirmed by the Chinese version of the Autism Diagnostic Interview—Revised, were assessed. We collected information about the mothers' experience with diagnosis-informed counseling, their personality characteristics, and the extent to which they were satisfied with the counseling. Results: Satisfaction with diagnosis-informed counseling was related more to the context of the counseling, including the attitude of the counselors and the timing and duration of counseling, than to its content. Parents' social desirability, educational level, and employment status were negatively associated with their satisfaction with counseling. However, immediate emotion, neuroticism, and extroversion did not have a significant effect on the satisfaction with counseling. Approximately 60% of the mothers preferred to be informed of having an autistic child after the diagnosis had been confirmed. Conclusion: Our findings suggest that more efforts are needed to improve the quality of diagnosis-informed counseling in autism, particularly in the context of breaking the news to mothers of children with autism. Future study could further examine the moderating effect of diagnostic subtype of autism spectrum disorders, treatment response, or social support on maternal satisfaction with diagnosis-informed counseling (ClinicalTrials.gov number, NCT00494754).

Little is known about whether Asian children with epilepsy have more attention-deficit hyperactivity disorder (ADHD)-related symptoms, emotional/ behavioral problems, and physical conditions compared with those described in Western studies. The authors investigated the rates of ADHD-related symptoms, emotional/behavioral problems, and physical conditions among pediatric patients with epilepsy. Methods: We recruited 61 patients with epilepsy, aged 6–16 years, and 122 age-, sex-, and parental education-matched school controls. Data on demographics, parental reports on the Child Behavior Checklist (CBCL) and Swanson, Nolan, and Pelham, version IV scale (SNAP-IV), and medical records were collected. Results: The average full-scale intelligence quotient of the case group was 95.8. There were 11 (18.0%), 7 (11.5%), 26 (42.6%), and 26 (42.6%) of children with epilepsy ever clinically diagnosed with developmental delay, overt ADHD symptoms, allergies reported by physicians, and behavior problems measured by the CBCL, respectively. Those children with epilepsy had more severe ADHD-related symptoms and a wider range of emotional/behavioral problems than controls (Cohen’s d 0.36–0.80). The rate of potential cases of ADHD among children with epilepsy was 24.6%. A history of developmental delay predicted ADHD- related symptoms and internalizing and externalizing problems. Among children with epilepsy, a longer duration of treatment with antiepileptic drugs predicted externalizing problems, and an earlier onset of epilepsy predicted inattention and hyperactivity/impulsivity. Conclusion: Our findings imply that clinicians should assess physical and emotional/behavioral problems among children with epilepsy in order to provide interventions to offset possible adverse psychiatric outcomes.

Genomic imprinting is an epigenetic mechanism causing monoallelic expression in a parent-of-origin-specific manner. Disruption of imprinted genes causes various neurological and psychiatric disorders. However, the role of imprinted genes in the brain is largely unknown. Different cell types within distinct brain regions can influence the genomic imprinting status, but imprinted genes in single cell types within distinct brain regions have not been characterized on a genome-wide scale. To address this critical question, we used a multi-stage approach, which combined genetically engineered mice with fluorescence-based laser capture microdissection (LCM) to capture excitatory neurons, inhibitory neurons and astrocytes as single cells in layer 2/3 of mouse visual cortex. RNA sequencing determined parental expression patterns on a genome-wide scale in the captured cells within specific brain regions. The expression level of cell-type-specific genes for excitatory neurons (13 genes), inhibitory neurons (16 genes) and astrocytes (20 genes) confirmed the LCM-captured cells maintained their cellular identities. The parent-of-origin-specific expression pattern of imprinted genes, including maternally expressed Meg3 and paternally expressed Peg3, provided evidence that the status of known imprinted genes was also maintained. Although our platform remains to be improved, our findings demonstrate the parental expression pattern can be analysed not only at the level of a single cell type but also at the level of specific cortical layers. Our approach has the potential to reveal novel regulatory modules associated with plasticity through genomic imprinting mechanisms in different cell types, not only in the visual cortex but also in other brain regions.

Dysfunction of RBFOX3 has been identified in neurodevelopmental disorders such as autism spectrum disorder, cognitive impairments and epilepsy and a causal relationship with these diseases has been previously demonstrated with Rbfox3 homozygous knockout mice. Despite the importance of RBFOX3 during neurodevelopment, the function of RBFOX3 regarding neurogenesis and synaptogenesis remains unclear. To address this critical question, we profiled the developmental expression pattern of Rbfox3 in the brain of wild-type mice and analyzed brain volume, disease-relevant behaviors, neurogenesis, synaptic plasticity, and synaptogenesis in Rbfox3 homozygous knockout mice and their corresponding wild-type counterparts. Here we report that expression of Rbfox3 differs developmentally for distinct brain regions. Moreover, Rbfox3 homozygous knockout mice exhibited cold hyperalgesia and impaired cognitive abilities. Focusing on hippocampal phenotypes, we found Rbfox3 homozygous knockout mice displayed deficits in neurogenesis, which was correlated with cognitive impairments. Furthermore, RBFOX3 regulates the exons of genes with synapse-related function. Synaptic plasticity and density, which are related to cognitive behaviors, were altered in the hippocampal dentate gyrus of Rbfox3 homozygous knockout mice; synaptic plasticity decreased and the density of synapses increased. Taken together, our results demonstrate the important role of RBFOX3 during neural development and maturation. In addition, abnormalities in synaptic structure and function occur in Rbfox3 homozygous knockout mice. Our findings may offer mechanistic explanations for human brain diseases associated with dysfunctional RBFOX3.

The literature has documented maternal distress and behavioral problems among children with Down syndrome (DS), however, little is known about paternal adjustment and behavioral problems among the siblings of children with DS. Here, we examined parental psychopathology, parenting style and emotional/behavioral problems among children with DS, their siblings, and controls in Taiwan. Methods: We recruited 45 families of children with DS (age, 2-14 years) and 50 families of normally developing children (age, 3-15 years). If there were more than two children in the case family, the sibling whose age was closest to the child with DS was recruited (age, 3-18 years). Both parents completed self-administered measures of their personality characteristics, psychopathology, family functioning, parenting styles, and child behavioral problems, using the Chinese versions of the Maudsley Personality Inventory, Brief Symptom Rating Scale, Family Adaptability and Cohesion Evaluation Scale, Parental Bonding Instrument, and Child Behavioral Checklist, respectively. Results: Children with DS demonstrated significantly more severe symptoms than normal children of a wide range of behavioral problems such as attention problems, delinquency, social problems, somatic complaints, thought problems, and withdrawal compared with the other two groups, and obtained similar parental treatment, except for paternal overprotection. Their parents suffered from more psychopathology and their mothers were less often employed than their counterparts. The siblings of children with DS obtained less overprotection from their mothers than children with DS and less maternal care and control than normal children. There was no difference in emotional/behavioral problems between the siblings and normal controls. Conclusion: Our findings suggest that in addition to the physical, educational and psychological needs of children with DS, the psychological care of their mothers, fathers and siblings also needs to be evaluated. Moreover, parenting counseling should focus not only on children with DS, but their siblings as well.

The literature has suggested timing processing as a potential endophenotype for attention deficit/hyperactivity disorder (ADHD); however, whether the subjective internal clock speed presented by verbal estimation and limited attention capacity presented by time reproduction could be endophenotypes for ADHD is still unknown. We assessed 223 youths with DSM-IV ADHD (age range: 10-17 years), 105 unaffected siblings, and 84 typically developing (TD) youths using psychiatric interviews, intelligence tests, verbal estimation and time reproduction tasks (single task and simple and difficult dual tasks) at 5-second, 12-second, and 17-second intervals. We found that youths with ADHD tended to overestimate time in verbal estimation more than their unaffected siblings and TD youths, implying that fast subjective internal clock speed might be a characteristic of ADHD, rather than an endophenotype for ADHD. Youths with ADHD and their unaffected siblings were less precise in time reproduction dual tasks than TD youths. The magnitude of estimated errors in time reproduction was greater in youths with ADHD and their unaffected siblings than in TD youths, with an increased time interval at the 17-second interval and with increased task demands on both simple and difficult dual tasks versus the single task. Increased impaired time reproduction in dual tasks with increased intervals and task demands were shown in youths with ADHD and their unaffected siblings, suggesting that time reproduction deficits explained by limited attention capacity might be a useful endophenotype of ADHD.

BACKGROUND:Autism spectrum disorder (ASD) is a neurodevelopmental disorder with strong genetic components. Several recent genome-wide association (GWA) studies in Caucasian samples have reported a number of gene regions and loci correlated with the risk of ASD--albeit with very little consensus across studies. METHODS:A two-stage GWA study was employed to identify common genetic variants for ASD in the Taiwanese Han population. The discovery stage included 315 patients with ASD and 1,115 healthy controls, using the Affymetrix SNP array 6.0 platform for genotyping. Several gene regions were then selected for fine-mapping and top markers were examined in extended samples. Single marker, haplotype, gene-based, and pathway analyses were conducted for associations. RESULTS:Seven SNPs had p-values ranging from 3.4~9.9*10-6, but none reached the genome-wide significant level. Five of them were mapped to three known genes (OR2M4, STYK1, and MNT) with significant empirical gene-based p-values in OR2M4 (p = 3.4*10(-5)) and MNT (p = 0.0008). Results of the fine-mapping study showed single-marker associations in the GLIS1 (rs12082358 and rs12080993) and NAALADL2 (rs3914502 and rs2222447) genes, and gene-based associations for the OR2M3-OR2T5 (olfactory receptor genes, p = 0.02), and GLIPR1/KRR1 gene regions (p = 0.015). Pathway analyses revealed important pathways for ASD, such as olfactory and G protein-coupled receptors signaling pathways. CONCLUSIONS:We reported Taiwanese Han specific susceptibility genes and variants for ASD. However, further replication in other Asian populations is warranted to validate our findings. Investigation in the biological functions of our reported genetic variants might also allow for better understanding on the underlying pathogenesis of autism.

PurposeThe aim of this study was to evaluate the concordance between claims records in the National Health Insurance Research Database and patient self-reports on clinical diagnoses, medication use, and health system utilization.MethodsIn this study, we used the data of 15,574 participants collected from the 2005 Taiwan National Health Interview Survey. We assessed positive agreement, negative agreement, and Cohen's kappa statistics to examine the concordance between claims records and patient self-reports.ResultsKappa values were 0.43, 0.64, and 0.61 for clinical diagnoses, medication use, and health system utilization, respectively. Using a strict algorithm to identify the clinical diagnoses recorded in claims records could improve the negative agreement; however, the effect on positive agreement and kappa was diverse across various conditions.ConclusionWe found that the overall concordance between claims records in the National Health Insurance Research Database and patient self-reports in the Taiwan National Health Interview Survey was moderate for clinical diagnosis and substantial for both medication use and health system utilization.