The critical role of ASD-related gene CNTNAP3 in regulating synaptic development and social behavior in mice.

Accumulated genetic evidences indicate that the contactin associated protein-like (CNTNAP) family is implicated in autism spectrum disorders (ASD). In this study, we identified genetic mutations in the CNTNAP3 gene from Chinese Han ASD cohorts and Simons Simplex Collections. We found that CNTNAP3 interacted with synaptic adhesion proteins Neuroligin1 and Neuroligin2, as well as scaffolding proteins PSD95 and Gephyrin. Significantly, we found that CNTNAP3 played an opposite role in controlling the development of excitatory and inhibitory synapses in vitro and in vivo, in which ASD mutants exhibited loss-of-function effects. In this study, we showed that the male Cntnap3-null mice exhibited deficits in social interaction， spatial learning and prominent repetitive behaviors. These evidences elucidate the pivotal role of CNTNAP3 in synapse development and social behaviors, providing mechanistic insights into ASD.

MicroRNA-197 controls ADAM10 expression to mediate MeCP2's role in the differentiation of neuronal progenitors.

Duplication of MECP2 (Methyl-CpG-binding protein 2) causes severe mental illness called MECP2 duplication syndrome (MDS), yet the underlying mechanism remains elusive. Here we show, in Tg(MECP2) transgenic mouse brain or cultured neural progenitor cells (NPCs), that elevated MeCP2 expression promotes NPC differentiation into neurons. Ectopic expression of MeCP2 inhibits ADAM10 and thus the NOTCH pathway during NPC differentiation. In human cells, this downregulation on ADAM10 was mediated by miRNA-197, which is upregulated by MeCP2. Surprisingly, miR-197 binds to the ADAM10 3'-UTR via its 3' side, not the canonical seed sequence on the 5' side. In mouse cells, a noncoding RNA Gm28836 is used to replace the function of miR-197 between MeCP2 and ADAM10. Similar to MeCP2, overexpressing miR-197 also promotes NPCs differentiation into neurons. Interestingly, three rare missense mutations (H371R, E394K, and G428S) in MECP2, which we identified in a Han Chinese autism spectrum disorders (ASD) cohort showed loss-of-function effects in NPC differentiation assay. These mutations cannot upregulate miR-197. Overexpressing miR-197 together with these MeCP2 mutations could rescue the downregulation on ADAM10. Not only the inhibitor of miR-197 could reverse the effect of overexpressed MeCP2 on NPCs differentiation, but also overexpression of miR-197 could reverse the NPCs differentiation defects caused by MECP2 mutations. Our results revealed that a regulatory axis involving MeCP2, miR-197, ADAM10, and NOTCH signaling is critical for NPC differentiation, which is affected by both MeCP2 duplication and mutation.

Suspiciousness in young minds: Convergent evidence from non-clinical, clinical and community twin samples.

BACKGROUND: We validated the Social Mistrust Scale (SMS) and utilized it to examine the structure, prevalence, and heritability of social mistrust in a large sample of Chinese children and adolescents. METHODS: In Study 1, a large sample of healthy twins (N=2094) aged 8 to 14years (M=10.27years, SD=2) completed the SMS. Structural equation modeling (SEM) was conducted to assess the structure of the SMS and to estimate the heritability of social mistrust in a sub-sample of twins (n=756 pairs). In Study 2, 32 adolescents with childhood-onset schizophrenia were compared with 34 healthy controls on levels of suspiciousness and clinical symptoms to examine the associations between the SMS and the Positive and Negative Syndrome Scale (PANSS). RESULTS: We found a three-factor structure for social mistrust (home, school, and general mistrust). Social mistrust was found to be moderately - heritable (19%-40%), with mistrust at home most strongly influenced by genetic factors. Compared with 11.76% of the healthy controls, 56.25% of the adolescents with early-onset schizophrenia exhibited very high levels of social mistrust on all three subscales of the SMS. The SMS exhibited good discriminant validity in distinguishing adolescents with childhood-onset schizophrenia from healthy controls and showed associations with a broad range of symptoms assessed by the PANSS. CONCLUSIONS: Social mistrust assessed by the SMS may be heritable. The SMS demonstrates good discriminant validity with clinical diagnoses of schizophrenia. However, it seems to be correlated with multiple aspects of psychopathology in the schizophrenia group, rather than being specific to delusional ideation/paranoia.

Identification of autism-related MECP2 mutations by whole-exome sequencing and functional validation.

BACKGROUND: Methyl-CpG-binding protein-2 (MeCP2) is a critical regulator for neural development. Either loss- or gain-of-function leads to severe neurodevelopmental disorders, such as Rett syndrome (RTT) and autism spectrum disorder (ASD). We set out to screen for MECP2 mutations in patients of ASD and determine whether these autism-related mutations may compromise the proper function of MeCP2. METHODS: Whole-exome sequencing was performed to screen MECP2 and other ASD candidate genes for 120 patients diagnosed with ASD. The parents of patients who were identified with MECP2 mutation were selected for further Sanger sequencing. Each patient accomplished the case report form including general information and clinical scales applied to assess their clinical features. Mouse cortical neurons and HEK-293 cells were cultured and transfected with MeCP2 wild-type (WT) or mutant to examine the function of autism-associated MeCP2 mutants. HEK-293 cells were used to examine the expression of MeCP2 mutant constructs with Western blot. Mouse cortical neurons were used to analyze neurites and axon outgrowth by immunofluorescence experiments. RESULTS: We identified three missense mutations of MECP2 from three autism patients by whole-exome sequencing: p.P152L (c.455C>T), p.P376S (c.1162C>T), and p.R294X (c.880C>T). Among these mutations, p.P152L and p.R294X were de novo mutations, whereas p.P376S was inherited maternally. The diagnosis of RTT was excluded in all three autism patients. Abnormalities of dendritic and axonal growth were found after autism-related MeCP2 mutants were expressed in mouse cortical neurons; suggesting that autism-related MECP2 mutations impair the proper development of neurons. CONCLUSIONS: Our study identified genetic mutations of the MECP2 gene in autism patients, which were previously considered to be associated primarily with RTT. This finding suggests that loss-of-function mutations of MECP2 may also lead to autism spectrum disorders.

Relationships between behavioral symptoms of non-medicated Chinese children with attention deficit hyperactivity disorder and parenting stress: Comparison of different subtypes and comorbidities.

INTRODUCTION: To identify the characteristics of behavior problems among children with attention deficit hyperactivity disorder (ADHD) and their relation with parenting stress. METHODS: The Conners Parent Symptom Questionnaire (PSQ) and Parenting Stress Index (PSI) were used to assess the symptoms and parenting stress of 132 non-medicated children with ADHD as compared with 88 healthy controls. RESULTS: Every PSQ factor of ADHD children was higher than in the control group; children with the combined subtype of ADHD had the highest scores in conduct and learning problems, impulsivity/hyperactivity, and overall hyperactivity index; the PSI total stress, child domain, and parent domain scores were all higher in the ADHD group than in the control group; children with the combined subtype of ADHD had the highest score in the competence subscale of the parent domain, whereas the PSI total stress score of parents of children with ADHD and comorbid oppositional defiant disorder (ODD) was higher than that of parents of children with only ADHD. The PSI total stress score was positively correlated with all PSQ factor scores. The PSQ factors of conduct problems and learning problems were found to be significant predictors in a regression analysis. DISCUSSION: The children with ADHD exhibited abnormal parenting stress compared with healthy controls, which was much more pronounced when the children had comorbid ODD. Furthermore, parenting stress was related with the severity of ADHD symptoms, suggesting that children with the combined subtype of ADHD require particular attention in the future.

Decreased prefrontal lobe interhemispheric functional connectivity in adolescents with internet gaming disorder: a primary study using resting-state FMRI.

PURPOSES: Recent neuroimaging studies have shown that people with Internet gaming disorder (IGD) have structural and functional abnormalities in specific brain areas and connections. However, little is known about the alterations of the interhemispheric resting-state functional connectivity (rsFC) in participants with IGD. In the present study, we used a newly developed voxel-mirrored homotopic connectivity (VMHC) method to investigate the interhemispheric rsFC of the whole brain in participants with IGD. METHODS: We compared interhemispheric rsFC between 17 participants with IGD and 24 healthy controls, group-matched on age, gender, and education status. All participants were provided written informed consent. Resting-state functional and structural magnetic resonance images were acquired for all participants. The rsFC between bilateral homotopic voxels was calculated. Regions showing abnormal VMHC in IGD participants were adopted as regions of interest for correlation analyses. RESULTS: Compared to healthy controls, IGD participants showed decreased VMHC between the left and right superior frontal gyrus (orbital part), inferior frontal gyrus (orbital part), middle frontal gyrus and superior frontal gyrus. Further analyses showed Chen Internet Addiction Scale (CIAS)-related VMHC in superior frontal gyrus (orbital part) and CIAS (r = -0.55, p = 0.02, uncorrected). CONCLUSIONS: Our findings implicate the important role of altered interhemispheric rsFC in the bilateral prefrontal lobe in the neuropathological mechanism of IGD, and provide further supportive evidence for the reclassification of IGD as a behavioral addiction.

Parent Ratings of ADHD Symptoms in Chinese Urban Schoolchildren: Assessment With the Chinese ADHD Rating Scale-IV: Home Version.

OBJECTIVE: The objective of this study was to assess the psychometric properties of the Chinese ADHD Rating Scale-IV (ADHD RS-IV): Home Version and to explore parent ratings of ADHD symptoms in a large sample of urban schoolchildren in China. METHOD: Parents of a representative sample of 1,616 schoolchildren (aged 6-17) in 12 Chinese cities completed the ADHD RS-IV: Home Version. RESULTS: The Chinese ADHD RS-IV: Home Version demonstrated satisfactory internal consistency, test-retest reliability, parent-teacher correlation, discriminant validity, and convergent validity. Factor analysis revealed the DSM-IV two-factor model with "inattention" and "hyperactivity-impulsivity" dimensions, accounting for equal variances. Parent ratings revealed lower/similar scores for Chinese schoolchildren compared with the U.S. CONCLUSION: The ADHD RS-IV: Home Version is a reliable and valid ADHD rating scale in China. The factor structure is similar but not identical to the U.S. STUDY: Normative data reveal cultural differences in some aspects of the parent ratings of ADHD.

Trait impulsivity and impaired prefrontal impulse inhibition function in adolescents with internet gaming addiction revealed by a Go/No-Go fMRI study.

BACKGROUND: Recent studies suggest that Internet gaming addiction (IGA) is an impulse disorder, or is at least related to impulse control disorders. In the present study, we hypothesized that different facets of trait impulsivity may be specifically linked to the brain regions with impaired impulse inhibition function in IGA adolescents. METHODS: Seventeen adolescents with IGA and seventeen healthy controls were scanned during performance of a response-inhibition Go/No-Go task using a 3.0 T MRI scanner. The Barratt Impulsiveness Scale (BIS)-11 was used to assess impulsivity. RESULTS: There were no differences in the behavioral performance on the Go/No-Go task between the groups. However, the IGA group was significantly hyperactive during No-Go trials in the left superior medial frontal gyrus, right anterior cingulate cortex, right superior/middle frontal gyrus, left inferior parietal lobule, left precentral gyrus, and left precuneus and cuneus. Further, the bilateral middle temporal gyrus, bilateral inferior temporal gyrus, and right superior parietal lobule were significantly hypoactive during No-Go trials. Activation of the left superior medial frontal gyrus was positively associated with BIS-11 and Chen Internet Addiction Scale (CIAS) total score across IGA participants. CONCLUSIONS: Our data suggest that the prefrontal cortex may be involved in the circuit modulating impulsivity, while its impaired function may relate to high impulsivity in adolescents with IGA, which may contribute directly to the Internet addiction process.

Brief report: effects of solution-focused brief therapy group-work on promoting post-traumatic growth of mothers who have a child with ASD.

The study evaluated the impact of solution-focused brief therapy (SFBT) group-work on the post-traumatic growth (PTG) of mothers who have a child with ASD. A quasi-experimental design was used in which 43 mothers participated. 18 mothers in 2 SFBT groups (n = 9 in each group) received a 6-session SFBT group therapy while 25 mothers in a control group received no treatment. The Post-traumatic Growth Inventory was used to measure the PTG levels of the participants at baseline, post-treatment and 6-month follow-up assessments. Mothers who attended SFBT group-work reported higher PTG scores both at post-treatment (t = 4.065, p = .001) and 6-month follow-up (t = 2.980, p = .006) assessments. Further investigations to prove whether SFBT in groups can increase the positivity of clients would promote the use of SFBT.

Comparison of psychological symptoms and serum levels of neurotransmitters in Shanghai adolescents with and without internet addiction disorder: a case-control study.

BACKGROUND: Internet addiction disorder (IAD) is now recognized internationally and is known to be linked with academic and social impairment. To date, we know little about its associated main biological factors. This study aimed to collect a carefully defined group of adolescents with IAD and an age- and gender-matched typically developing comparison group. We hypothesized that the young people with IAD would have higher rates of self-reported anxiety and depressive symptoms, have altered levels of peripheral blood dopamine, norepinephrine and serotonin. In addition, we hypothesized the hours spent online are correlated with the severity of depression and anxiety among these young people with IAD. METHODOLOGY/PRINCIPAL FINDING: A cross-sectional study of 20 adolescents who met Beard's criteria for IAD and 15 typically developing adolescents (comparison group) was conducted. All the participants completed the Self Rating Depression Scale (SDS), Self Rating Anxiety Scale (SAS), and the Screen for Child Anxiety Related Emotional Disorders (SCARED). Peripheral blood dopamine, serotonin and norepinephrine were assayed. The mean level of norepinephrine was lower in the IAD group than that in the typically developing participants, while dopamine and serotonin levels did not differ. The SDS, SAS and SCARED symptom scores were increased in the adolescents with IAD. A logistic regression analysis revealed that a higher SAS score and lower level of norepinephrine independently predicted IAD group membership. There was no significant correlation between hours spent online and scores of SAS/SDS in IAD group. CONCLUSIONS/SIGNIFICANCE: Increased self-reported anxiety and lower peripheral blood norepinephrine are independently associated with IAD.

Altered default network resting-state functional connectivity in adolescents with Internet gaming addiction.

PURPOSE: Excessive use of the Internet has been linked to a variety of negative psychosocial consequences. This study used resting-state functional magnetic resonance imaging (fMRI) to investigate whether functional connectivity is altered in adolescents with Internet gaming addiction (IGA). METHODS: Seventeen adolescents with IGA and 24 normal control adolescents underwent a 7.3 minute resting-state fMRI scan. Posterior cingulate cortex (PCC) connectivity was determined in all subjects by investigating synchronized low-frequency fMRI signal fluctuations using a temporal correlation method. To assess the relationship between IGA symptom severity and PCC connectivity, contrast images representing areas correlated with PCC connectivity were correlated with the scores of the 17 subjects with IGA on the Chen Internet Addiction Scale (CIAS) and Barratt Impulsiveness Scale-11 (BIS-11) and their hours of Internet use per week. RESULTS: There were no significant differences in the distributions of the age, gender, and years of education between the two groups. The subjects with IGA showed longer Internet use per week (hours) (p<0.0001) and higher CIAS (p<0.0001) and BIS-11 (p = 0.01) scores than the controls. Compared with the control group, subjects with IGA exhibited increased functional connectivity in the bilateral cerebellum posterior lobe and middle temporal gyrus. The bilateral inferior parietal lobule and right inferior temporal gyrus exhibited decreased connectivity. Connectivity with the PCC was positively correlated with CIAS scores in the right precuneus, posterior cingulate gyrus, thalamus, caudate, nucleus accumbens, supplementary motor area, and lingual gyrus. It was negatively correlated with the right cerebellum anterior lobe and left superior parietal lobule. CONCLUSION: Our results suggest that adolescents with IGA exhibit different resting-state patterns of brain activity. As these alterations are partially consistent with those in patients with substance addiction, they support the hypothesis that IGA as a behavioral addiction that may share similar neurobiological abnormalities with other addictive disorders.

Gray matter abnormalities in Internet addiction: a voxel-based morphometry study.

BACKGROUND: This study aims to investigate brain gray matter density (GMD) changes in adolescents with Internet addiction (IA) using voxel-based morphometry (VBM) analysis on high-resolution T1-weighted structural magnetic resonance images. METHODS: Eighteen IA adolescents and 15 age- and gender-matched healthy controls took part in this study. High-resolution T1-weighted magnetic resonance imaging scans were performed on the two groups. VBM analysis was used to compare the GMD between the two groups. RESULTS: Compared with healthy controls, IA adolescents had lower GMD in the left anterior cingulate cortex, left posterior cingulate cortex, left insula, and left lingual gyrus. CONCLUSIONS: Our findings suggested that brain structural changes were present in IA adolescents, and this finding may provide a new insight into the pathogenesis of IA.

[Association of DNA methyltransferase 3B gene polymorphism with early-onset schizophrenia].

OBJECTIVE: To investigate the association of DNA methyltransferase 3B (DNMT3B) gene polymorphism with the development of early-onset schizophrenia. METHODS: A single nucleotide polymorphism (rs6119954) of DNMT3B gene was genotyped in 279 early-onset schizophrenic patients and 395 healthy controls, using TaqMan SNP Genotyping Assays. To detect the interaction between the DNMT3B gene and environmental factors, the prenatal information of the patients was collected. RESULTS: Genotype distribution of the rs6119954 locus was significantly different between patients and controls (Chi-square = 12.27, P< 0.01). The frequency of the G allele of this locus was significantly higher in patients than in controls (Chi-square = 12.76, P< 0.01). The G allele was highly associated with an earlier age of onset (P= 0.026). No interaction between the DNMT3B gene and environmental factors was found. CONCLUSION: DNMT3B gene is associated with early-onset schizophrenia and rs6119954 may plays an important role in age of onset of schizophrenia.

Longer term effect of randomized, controlled group cognitive behavioural therapy for Internet addiction in adolescent students in Shanghai.

OBJECTIVE: The aim of the present study was to evaluate the therapeutic effectiveness of group cognitive behavioural therapy (CBT) for Internet addiction in adolescents. METHOD: A total of 56 patients, who met Beard's diagnostic criteria for Internet addiction, aged 12-17 years, were divided randomly into an active treatment group (n = 32) and a clinical control group (n = 24). Participants in the active treatment group were treated with an eight-session multimodal school-based group CBT while participants in the clinical control group received no intervention. Internet use, time management, emotional, cognitive and behavioural measures were assessed for both groups at baseline, immediately after the intervention and at 6 month follow up by investigators blind to the participants' group status. RESULTS: Internet use decreased in both groups while only the multimodal school-based group CBT evinced improved time management skills and better emotional, cognitive and behavioural symptoms. CONCLUSIONS: Multimodal school-based group CBT is effective for adolescents with Internet addiction, particularly in improving emotional state and regulation ability, behavioural and self-management style.

[Gene-gene interaction between DNMT3B and DRD1 in schizophrenia].

OBJECTIVE: to identify the impact of gene-gene interaction between DNMT3B and DRD1 on the risk of schizophrenia. METHODS: two SNPs (rs2424908 and rs6119954) within DNMT3B and five SNPs (rs4532, rs5326, rs2168631, rs6882300 and rs267418) within DRD1 were genotyped in 365 schizophrenic patients and 365 healthy controls. The gene-gene interaction between DNMT3B and DRD1 was analyzed by Multifactor Dimensionality Reduction (MDR) software. RESULTS: the frequency of genotypes of rs6119954 within DNMT3B was significantly higher in patients than that in controls (χ(2) = 8.06, P = 0.018). MDR revealed that the significance were shown in patterns with 2 SNPs (rs6119954-rs267418) (OR = 1.79, 95%CI: 1.29 - 2.47; χ(2) = 12.51, P = 0.0004), 3 SNPs (rs6119954-rs5326-rs267418) (OR = 2.36, 95%CI: 1.73 - 3.22; χ(2) = 29.33, P < 0.0001) and 4 SNPs (rs2424908-rs6119954-rs5326-rs267418) (OR = 3.08, 95%CI: 2.24 - 4.24;χ(2) = 48.88, P < 0.0001). CONCLUSION: the gene-gene interaction between DNMT3B and DRD1 may exist and increase the risk for schizophrenia.

Randomized double-blind multicentre placebo-controlled clinical trial of the clonidine adhesive patch for the treatment of tic disorders.

OBJECTIVE: The aim of the present study was to evaluate the therapeutic effectiveness and safety of the clonidine adhesive patch in treating tic disorders. METHOD: A total of 437 patients, who met Chinese Classification of Mental Disorders-third edition diagnostic criteria for transient tic disorder (5%), chronic motor or vocal tic disorder (40%) or Tourette disorder (55%), aged 6-18 years, were divided randomly into an active treatment group and a clinical control group. Participants in the active treatment group were treated with a clonidine adhesive patch and participants in the clinical control group with a placebo adhesive patch for 4 weeks. The dosage of the clonidine adhesive patch was 1.0mg, 1.5mg or 2.0mg per week, depending on each participant's bodyweight. Participants whose Yale Global Tic Severity Scale (YGTSS) score decreased <30% and Clinical Global Impression score was > or =4 by the end of week 3 were withdrawn from the trial. RESULTS: After 4 weeks of treatment the active treatment group participants' YGTSS score was significantly lower than that of the clinical control group (F=4.63, p=0.03). Further, the active treatment group had a significantly better therapeutic response than the clinical control group (chi(2)=9.15, p=0.003). The response rate in the active treatment group was 68.85% compared to 46.85% in the clinical control group (chi(2)=16.98, p=0.0001). The rate of adverse events was low (active treatment group, 3.08%; clinical control group, 7.21%) and did not differ between the two groups. CONCLUSIONS: The clonidine adhesive patch is effective and safe for tic disorders.