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Objective Atomoxetine and fluoxetine are psychopharmacologic agents associated with loss of appetite and weight. Adenosine monophosphate-activated protein kinase (AMPK) is the cellular energy sensor that regulate metabolism and energy, being activated by fasting and inhibited by feeding in the hypothalamus.Methods Human brain cell lines (SH-SY5Y and U-87 MG cells) were used to study the outcome of atomoxetine and fluoxetine treatment in the activity of AMPK-acetyl-CoA carboxylase (ACC)- carnitine palmitoyl transferase 1 (CPT1) pathway and upstream regulation by calcium/calmodulin-dependent kinase kinase β (CaMKKβ) using immunoblotting and CPT1 enzymatic activity measures.Results Phosphorylation of AMPK and ACC increased significantly after atomoxetine and fluoxetine treatment in the first 30–60 minutes of treatment in the two cell lines. Activation of AMPK and inhibition of ACC was associated with an increase by 5-fold of mitochondrial CPT1 activity. Although the neuronal isoform CPT1C could be detected by immunoblotting, activity was not changed by the drug treatments. In addition, the increase in phospho-AMPK and phospho-ACC expression induced by atomoxetine was abolished by treatment with STO-609, a CaMKKβ inhibitor, indicating that AMPK-ACC-CPT1 pathway is activated through CaMKKβ phosphorylation.Conclusion These findings indicate that at the cellular level atomoxetine and fluoxetine treatments may activate AMPK-ACC-CPT1 pathways through CaMKKβ in human SH-SY5Y and U-87 MG cells.

Intangible cultural heritage (ICH) is problematic as it is ‘intangible and not yet fixed in any medium’ (Ivey), however, it opens new possibilities for illustrators to shape and form its intangibility. This article explores the role of illustration in preserving disappearing culture, with reference to my recent project, Tamnarok: The Record of Tamna. This project aims to investigate illustration as both a research method and an artistic mode of disseminating knowledge of endangered cultural heritage, specifically with case studies around female free divers Jeju haenyeo and the distinctive language Jejueo in South Korea. Positioning illustration as a participatory and creative practice for communicating, understanding, facilitating and disseminating lived experience, this article proposes that illustration is an effective way of processing and manifesting ICH.

Moesin-like gene 1 antisense was increased in the postmortem cortex of patients with autism spectrum disorders. Overexpression of moesin-like gene 1 antisense induces downregulation of moesin expression in cortical neurons, resulting in decreased neurite numbers and length. However, moesin knockout (KO) mice have not been reported about behavioral abnormalities or delayed brain development, indicating autism spectrum disorders. Here, we generated moesin KO mice by using the CRISPR/CAS9 system and observed their behaviors. Moesin KO mice exhibited abnormal developmental behaviors at 7 days, cognitive decline in the passive avoidance and Y maze tests, and anxiety symptoms in the open field test compared to wild-type mice at 3 months. Moreover, the primary cortical neurons of moesin KO mice showed a low cell survival rate and low expression of proteins involved in neuronal development and growth, such as MAP2, DCX, SOX2, SNAP25, and PSD95. Western blot analysis also revealed the downregulation of various synaptic proteins, such as syntaxin 1A and CDK5, in the brain of moesin KO adult mice. Moreover, the phosphorylation levels of synapsin I, MUNC18, ERK, and CREB were downregulated in the brains of moesin-KO mice. Furthermore, risperidone reversed the impaired memory function and synapsin I and ERK phosphorylation in the cortical tissue of moesin-KO mice. Thus, these results suggest that moesin affects neurodevelopmental and cognitive processes, plays an important role in the synaptic plasticity showing normal synapse structure and function, and that risperidone can reverse these synaptopathy and neurodevelopmental disorders.

Objective We sought to determine if the links between and within the default mode network (DMN) and dorsal attention network (DAT) exhibited different conditions according to catechol-O-methyltransferase (COMT) gene polymorphism in relationship to attention-deficit hyperactivity disorder (ADHD) symptoms.Methods Fifty-seven children with ADHD and 48 healthy controls (HCs) were administered an intelligence test, the Children’s Depression Inventory, the Korean ADHD rating scale, and continuous performance test. Resting-state brain functional MRI scans were obtained, and COMT genotyping was performed to distinguish valine carriers and methionine homozygotes.Results Compared to controls, children with ADHD showed increased ADHD scale scores, increased visual commission errors, and increased functional connectivity (FC) within the DMN and DAT. Compared to all children with ADHD, children with the methionine homozygote and those who were valine carriers showed increased FC within the DMN and DAT and decreased FC between the DMN and DAT. FC within the DMN was also increased in HC valine carriers compared to HC children with the methionine homozygote, and in children with ADHD who were valine carriers compared to HC valine carriers.Conclusion We observed increased brain connectivity within the DMN and DAT and altered brain connectivity within and between the DMN and DAT associated with COMT polymorphism in children with ADHD.

Objective This study aimed to examine personality profiles and behavioral problems of children with nail biting (NB) to gain insight into the developmental trajectory of pathological NB.Methods 681 elementary school students were divided into non NB (n=436), occasional NB (n=173) and frequent NB group (n=72) depending on the frequency of NB reported in Child Behavioral Checklist (CBCL). Children’s personality was assessed using the Junior Temperament and Character Inventory (JTCI), and behavioral problems were assessed using the CBCL. Latent Profile Analysis (LPA) was performed using JTCI profiles to classify personalities of the children with NB (belonging to frequent and occasional NB group, n=245).Results For subscale scores of CBCL, the total, internalizing, externalizing, anxious/depressed withdrawn/depressed, depression, thought, rule-breaking, and aggressive behavior problems, were most severe in the frequent NB group followed by occasional NB and non NB group. LPA of personality profile in children with NB revealed four classes (‘adaptiveness,’ ‘high reward dependence,’ ‘low self-directedness,’ and ‘maldaptiveness’). The four personality classes demonstrated significant group differences in all of the CBCL subscales. Children who showed low self-directedness and cooperativeness and high novelty seeking and harm avoidance personality profiles demonstrated highest tendency for problematic behavior irrespective of the frequency of NB.Conclusion Children with NB reported significantly more problematic behaviors compared to children without NB. Children with specific personality profile demonstrated higher tendency for problematic behavior irrespective of the frequency of NB. Therefore, accompanying personality profiles should be considered when assessing behavioral problems in children with NB.

Significance: Our current knowledge of the pathophysiology and molecular mechanisms causing psychiatric disorders is modest, but genetic susceptibility and environmental factors are central to the etiology of these conditions. Autism, schizophrenia, bipolar disorder and major depressive disorder show genetic gene risk overlap and share symptoms and metabolic comorbidities. The identification of such common features may provide insights into the development of these disorders. Recent Advances: Multiple pieces of evidence suggest that brain energy metabolism, mitochondrial functions and redox balance are impaired to various degrees in psychiatric disorders. Since mitochondrial metabolism and redox signaling can integrate genetic and environmental environmental factors affecting the brain, it is possible that they are implicated in the etiology and progression of psychiatric disorders. Critical Issue: Evidence for direct links between cellular mitochondrial dysfunction and disease features are missing. Future Directions: A better understanding of the mitochondrial biology and its intracellular connections to the nuclear genome, the endoplasmic reticulum and signaling pathways, as well as its role in intercellular communication in the organism, is still needed. This review focuses on the findings that implicate mitochondrial dysfunction, the resultant metabolic changes and oxidative stress as important etiological factors in the context of psychiatric disorders. We also propose a model where specific pathophysiologies of psychiatric disorders depend on circuit-specific impairments of mitochondrial dysfunction and redox signaling at specific developmental stages.

Objective Synaptic vesicle mobilization and neurite outgrowth regulation molecules were examined in modulation of effects of methylphenidate (MPH) in Spontaneous Hypertensive Rats (SHRs), a model for attention-deficit hyperactivity disorder (ADHD). Methods We compared the changes in the protein expression level of Cyclin dependent kinase 5 (Cdk5) and molecular substrates of Cdk5; tropomyosin receptor kinase B (TrkB), syntaxin 1A (STX1A) and synaptosomal-associated protein 25 (SNAP25). Comparisons were made in prefrontal cortex of vehicle (distilled water i.p. for 7 days)-treated SHRs, vehicle-treated Wistar Kyoto Rats (WKYs) and MPH (2 mg/kg i.p. for 7 days) treated SHRs. Results The Cdk5 level of vehicle-treated SHRs was significantly decreased compared to the Cdk5 level of vehicle-treated WKY rats, but was restored to the expression level of vehicle-treated WKYs in MPH-treated SHR. The ratio of p25/p35 was significantly decreased in MPH-treated SHR compared to vehicle-treated SHR. Moreover, TrkB, STX1A and SNAP25 of vehicle-treated SHRs were significantly decreased compared to vehicle-treated WKY rats, but were restored to the expression level of vehicle-treated WKYs in MPH-treated SHR. Conclusion The results show that Cdk5, TrkB, STX1A, and SNAP25 were involved in the modulation of MPH effects in prefrontal cortex of SHRs and play important role in treatment of ADHD.

International audience; Bipolar disorder (BD) is a psychiatric condition characterized by depressive and manic episodes that affect 2% of the world population. The first-line long-term treatment for mood stabilization is lithium (Li). Induced pluripotent stem cell modeling of BD using hippocampal dentate gyrus-like neurons derived from Li-responsive (LR) and Li-non-responsive (NR) patients previously showed neuronal hyperexcitability. Li treatment reversed hyperexcitability only on the LR neurons. In this study we searched for specific targets of Li resistance in NR neurons and found that the activity of Wnt/β-catenin signaling pathway was severely affected, with a significant decrease in expression of LEF1. Li targets the Wnt/βcatenin signaling pathway by inhibiting GSK-3β and releasing β-catenin that forms a nuclear complex with TCF/LEF1, activating the Wnt/β-catenin transcription program. Therefore, we propose that downregulation of LEF1 may account for Li resistance in NR neurons. Our results show that valproic acid (VPA), a drug used to treat NR patients that also acts downstream of GSK-3β, upregulated LEF1 and Wnt/β-catenin gene targets, increased transcriptional activity of complex β-catenin/TCF/LEF1 and reduced excitability in NR neurons. Additionally, decreasing LEF1 expression in control neurons using shLEF1 caused hyperexcitability, confirming that the impact of VPA on excitability in NR neurons was connected to changes in LEF1 and in the Wnt/β-catenin pathway. Our results suggest that LEF1 may be a useful target for the discovery of new drugs for BD treatment.

Bipolar disorder (BD) is a psychiatric condition characterized by depressive and manic episodes that affect 2% of the world population. The first-line long-term treatment for mood stabilization is lithium (Li). Induced pluripotent stem cell modeling of BD using hippocampal dentate gyrus-like neurons derived from Li-responsive (LR) and Li-non-responsive (NR) patients previously showed neuronal hyperexcitability. Li treatment reversed hyperexcitability only on the LR neurons. In this study we searched for specific targets of Li resistance in NR neurons and found that the activity of Wnt/β-catenin signaling pathway was severely affected, with a significant decrease in expression of LEF1. Li targets the Wnt/β-catenin signaling pathway by inhibiting GSK-3β and releasing β-catenin that forms a nuclear complex with TCF/LEF1, activating the Wnt/β-catenin transcription program. Therefore, we propose that downregulation of LEF1 may account for Li resistance in NR neurons. Our results show that valproic acid (VPA), a drug used to treat NR patients that also acts downstream of GSK-3β, upregulated LEF1 and Wnt/β-catenin gene targets, increased transcriptional activity of complex β-catenin/TCF/LEF1, and reduced excitability in NR neurons. In addition, decreasing LEF1 expression in control neurons using shLEF1 caused hyperexcitability, confirming that the impact of VPA on excitability in NR neurons was connected to changes in LEF1 and in the Wnt/β-catenin pathway. Our results suggest that LEF1 may be a useful target for the discovery of new drugs for BD treatment.

Objective Association between home environment and the behavioral and neurocognitive development of children from a community childcare center for low-income families was examined (aged 6 to 12 years, n=155). Methods The parents performed a questionnaire on home environment (K-HOME-Q) to assess home environment including parenting attitude and the Child Behavior Checklist (K-CBCL). The children performed the Wechsler Intelligence (IQ) Scale, Stroop interference test (Stroop), word fluency test (WF), and design fluency test (DF) to assess their neurocognitive development. Results 'Nurturing of Development' and 'Variety of Language Interaction' scores from the K-HOME-Q, were inversely associated with total behavior problems, externalization, rule-breaking, and aggressive behavior subscales of K-CBCL, and 'Emotional atmosphere' and 'Tolerance toward the child' scores showed inverse associations with the total behavior problems, rule-breaking, aggressive behavior, and withdrawn/depressed subscales. Despite economic hardship, the mean scores of the neurocognitive tests were comparable to the average level of Korean children's normative sample. However, 'Nurturing of Development' and 'Tolerance toward the Child' score of K-HOME-Q were associated with better executive function (IQ, WF, DF). Conclusion These results suggest that parental stimulation of development and tolerant parenting attitude may offer protection against the negative effects of suboptimal economic environment on children's behavior and neurocognitive development.

Objective This study was conducted to investigate the reliability and validity of the Korean version of Autism-Spectrum Quotient (AQ). Methods 20 participants with high-functioning autism (HFA) and 99 normal participants were recruited. All participants were completed the AQ and Empathy Quotient (EQ), and parents of the HFA group completed the parent-report AQ. For testing the reliability, we examined Cronbach's alpha, performed item analysis, and compared self versus parent report score of HFA participants. For testing the validity, we compared the difference of the score of AQ among HFA and control group using independent t-tests, and performed correlation analysis between AQ and EQ. The receiver operation characteristic curve analysis was performed to determine a cut-off. Results The Korean version of the AQ exhibited adequate internal consistency, and in most items, the HFA group scored higher in comparison to the control group. It was demonstrated that AQ has good discriminant validity through the confirmation of the significant difference in the AQ score between two groups. The concurrent validity was established through the significant correlation between AQ and EQ in the HFA group. The best estimate cut-off score of AQ for screening was 23. Conclusion The Korean version of the AQ was determined as a reliable and valid instrument to assess HFA in Korean population.

Objectives: We aimed to assess the test-retest reliability, internal consistency, and validity of the Korean version of the Quantitative Checklist for Autism in Toddlers (Q-CHAT). Methods: The Korean version of the Q-CHAT and the Korean version of the Child Behavior Checklist (CBCL) 1.5-5 were completed by parents of 24 toddlers and preschoolers with autism spectrum disorder (ASD) and 80 unselected toddlers and preschoolers. Parents of the ASD group also completed the Social Communication Questionnaire (SCQ), and Childhood Autism Rating Scale (CARS) scores were obtained from medical records. Results: The ASD group scored higher on the Q-CHAT than the unselected group. The Cronbach’s alpha coefficient of the Q-CHAT was 0.658, and test-retest reliability was calculated to be 0.836. The estimated area under the curve was 0.793. The total scores of the Q-CHAT in the ASD group demonstrated significant positive correlations with findings regarding pervasive development problems in the CBCL, SCQ, and CARS. A total score of 33.5 may be a useful cutoff point to use when identifying toddlers at risk of ASD. Conclusion: The Korean version of the Q-CHAT has good reliability and validity and can be used as a screening tool in order to identify toddlers and preschool children at risk of ASD.

Objectives In this prospective cohort study, the effects of prenatal Hg exposure on neurocognitive development during the first 3 years of life were investigated. Methods The maternal blood levels of Hg were assessed during pregnancy and in cord blood. Maternal fish intake was assessed by interviewing the weekly frequency of fish intake during pregnancy. Maternal n-3 and n-6 fatty acid intake was estimated based on 24 h recall food intake interview. The mental (MDI) and psychomotor (PDI) development index scores were assessed using the Bayley Scales of Infant Development at 6, 12, 24, 36 months of age. Results The geometric mean of the maternal blood Hg concentration was 3.3 μg/L (10th percentile = 1.81; 90th = 5.91) during the early pregnancy, 3.0 μg/L (10th = 1.68; 90th = 5.57) during late pregnancy, and 5.1 μg/L (10th = 2.94; 90th = 8.93) in cord blood. After adjusting for weekly frequency of fish intake, the blood Hg concentrations during early pregnancy showed association with the adjusted MDI (β = − 0.408, p = 0.048) and PDI scores (β = − 0.550, p = 0.031) at 6 months. After further adjusting for n-3 and n-6 fatty acids estimated based on 24 h recall of food intake, the blood Hg concentrations during early pregnancy showed association with the MDI (β = − 0.489, p = 0.026) and PDI (β = − 0.664, p = 0.015) at 6 months. Conclusion These results show that prenatal Hg exposure during early pregnancy adversely associated with early neurodevelopment during infancy, after adjusting for fish and n-3, n-6 fatty acid intake. Consuming fish high in fatty acids and low in Hg during early pregnancy may be important to neurocognitive development at early infancy.

Objectives Problem behaviors pose a great obstacle to daily functioning in children with neurodevelopmental deficits and are an important target for treatment. In this study, we translated the Behavior Problems Inventory (BPI)-01 into Korean language and tested its psychometric properties. Methods We attained the approval of the BPI author and performed standard translation-back translation. Then, professional caregivers examined appropriateness according to cultural and situational contexts in order to make necessary modifications of the Korean version of the BPI. Results The BPI-01, Korea-Scales of Independent Behavior-Revised (K-SIB-R), and Child Behavior Checklist were completed for 98 autistic spectrum disorder or intellectual development disorder participants (mean age=28.3, standard deviation=7.3, range=10.1-51.7). The inter-rater reliability of the BPI-01 was found to be high (r=0.992-1.000). As for the results for concurrent validity for subscale items of BPI-01 and scales of SIB, correlations between SIB and BPI-01 subscales were statistically significant (r=0.357-0.672). Discussion The Korean version of the BPI-01 showed good psychometric properties with high reliability and sufficient convergent validity. Further examination of the validity of BPI-01 should be carried out with inclusion of younger aged children and a closer look at less frequently occurring symptoms.

Background: The Mothers and Children's Environmental Health study (MOCEH) is a multi-centric prospective birth cohort study investigating effects of various environmental pollutants like heavy metals, endocrine disruptors, air pollutants, nutrition and lifestyle on birth outcomes, growth and development, health and disease of children. In this study, we report all the outcomes from the MOCEH study describing the different environmental pollutants affecting children’s health and disease. Methods: In MOCEH study, 1,751 pregnant women in their first trimester were recruited at 3 centers from 2006 to 2010 in South Korea. The children were followed from birth up to 6 years. Information on health outcomes of children including birth parameters, demographic characteristics, medical and child-rearing history, and nutritional status, were repeatedly obtained through the follow-ups by questionnaires administration, clinical evaluation, and biological specimen collection and measurements. Prenatal and postnatal measurement in biospecimen, i.e., lead, mercury, cadmium, manganese, 1-hydroxypyrene, 2-naphthol, malonadialdehyde, hippuric acid, bisphenol A and phthalate metabolites, and measurement in air samples, i.e., particulate matter, nitrogen dioxide, and total volatile organic compounds were performed. Results: The results show the adverse effect of prenatal exposure to heavy metals like mercury, lead and cadmium on children’s physical, cognitive and neurobehavioral development. Exposure to endocrine disruptors, air pollution, second hand smoke, and mother’s lifestyle during pregnancy affects children’s growth and development. We also identified specific window periods of exposure of pollutants significantly related to children’s health outcomes. Conclusion: The collective results from MOCEH study provide strong scientific evidence that exposures to prenatal and postnatal environmental pollutants have a negative effect on growth and development of children, which will be useful in implementing effective national policy to improve children’s environmental health. Keywords: Birth cohort, Children Environmental health, Environmental pollutants

Objective Problematic online gaming (POG) and problematic Internet use (PIU) have become a serious public mental health problem, with Internet gaming disorder (IGD) included in “Conditions for further study” section of DSM-5. Although higher immersive tendency is observed in people affected by POG, little is known about the simultaneous effect of immersive tendency and its highly comorbid mental disorder, attention deficit/hyperactivity disorder (ADHD). This study aimed to assess the relationship between immersive tendency, ADHD, and IGD.Methods Cross-sectional interview study was conducted in Seoul, Korea with 51 male undergraduate students; 23 active gamers and 28 controls.Results Current ADHD symptoms showed partial mediation effect on the path of immersive tendency on POG and PIU. The mediation model with inattention explained variance in both POG and PIU better than other current ADHD symptom models (R2=69.2 in POG; 69.3 in PIU). Childhood ADHD symptoms models demonstrated mediation effect on both POG and PIU which explained less variance than current ADHD symptom models (R2=53.7 in POG; 52.1 in PIU). Current ADHD symptoms, especially inattention, appear to mediate the effect of immersive tendency on POG/PIU.Conclusion Immersive tendencies may entail greater susceptibility to IGD, and comorbidity with ADHD may mediate the effect of immersive tendency on IGD.

Background and aims Previous studies have suggested that mercury exposure and folate levels during pregnancy may influence early childhood neurodevelopment. Rapid catch-up growth in children is associated with an increased risk of pathological nervous system development. We evaluated whether the association between prenatal folate and mercury-related neuropsychological dysfunction was modified by growth velocity during childhood. Methods The Mothers and Children's Environmental Health (MOCEH) birth cohort study began in 2006 and by 2010, 1751 women had been enrolled before the second trimester of their pregnancy along with their partners. Participants visited the research center at birth and 6, 12, 24, and 36 months. We measured mercury levels in maternal and cord blood and folate in maternal serum. Questionnaires to evaluate the environment and health of their child were administered and anthropometric factors including body weight and height were measured. Certified investigators used the Bayley test to measure neurobehavioral outcomes. We calculated postnatal growth change as the change in infant weight for-age z-score between birth and 3 years. Multiple linear regression and mixed models were used to examine the association between mercury exposure and children's neurodevelopment as well as the modifying effects of folate and growth velocity. Results A total of 30.6% of children experienced rapid growth during the first 3 years of life. Median values of mercury in the low folate group were significantly higher in rapid growers (3.41 μg/L in maternal blood and 5.63 μg/L in cord blood) than in average/slow growers (3.05 μg/L in maternal blood and 5.19 μg/L in cord blood). Rapid growers were also significantly associated with decreased psychomotor development scores during the first 3 years of life and with having mothers who had low prenatal folate levels, even after adjusting for potential confounders. Conclusion Prenatal mercury exposure adversely affects infant neurodevelopment and is associated with rapid growth during the first 3 years of life. This effect was limited to children whose mothers had low prenatal folate levels, suggesting a protective effect of folate against developmental neurotoxicity due to mercury exposure and rapid catch-up growth.

Objectives Neurotoxic effects of phthalate during pregnancy on immature brain of the offspring or mature brains of the mothers remain unclear. We examined the effect of dibutyl phthalate (DBP) exposure during gestation and lactation on the maternal behavior of mother mice and neurodevelopment in pups. Methods Pregnant mice were treated orally with DBP (0, 50 and 100 mg/kg/day, N = 20 per group) from gestational day 13 to postnatal day (PND) 15. Maternal behavior was measured using pup retrieval and nest shape test at postpartum day 4. For the pups, the neurodevelopment was measured using negative geotaxis, cliff avoidance at PND 7, swimming test and olfactory orientation at PND 14. RNA and protein expressions in the brain cortex of 50 mg/kg/day and control group (0 mg/kg/day) were analyzed using microarray and Western blot analysis. Nissl-stained sections at the coronal level of interaural 2.56 mm, bregma −1,23 mm, were used for counting of dark cortical neurons in mother and pup mice. Results DBP treated mother mice (50 and 100 mg/kg/day) showed poor maternal behavior, poor nesting and retrieval behavior compared to the control group (0 mg/kg/day). In brain cortex, DBP-treated mothers showed decrease in protein expression of Nr4a3, Egr1, Arc, BDNF and phosphorylation of AKT and CREB, were also decreased in cortex of DBP-treated mothers. Pups exposed to DBP showed significantly decreased scores in negative geotaxis at PND 7 and swimming scores and olfactory orientation tests at PND 14. The cortex of the DBP exposed pups showed increase in expression of dopamine receptor D2 gene. Nissl staining showed that the dark neurons were increased in cortex of DBP treated mothers and DBP exposed pups. Suggesting that phthalate may delay pup development indirectly through inadequate mothering as well as direct phthalate exposure on the brain. Conclusion DBP exposure during gestation and lactation cause impairment in maternal behaviors and downregulation of neuronal plasticity and survival signals. Pups of mothers with exposed to DBP, showed delayed neurodevelopment and dark neurons increase in brain cortex, suggesting that phthalate may delay pup development indirectly through inadequate mothering as well as direct phthalate exposure on the brain.

Table S1. Comparison of general characteristics between children with K-BSID-II scores and children without K-BSID-II scores at 24 months. Table S2. Association between maternal urine cotinine in early pregnancy and children’s neurodevelopment at 24 months without adjusting for creatinine level. Table S3. Association between maternal urine cotinine in early pregnancy and children’s neurodevelopment at 24 months stratified by genetic polymorphism and breastfeeding behavior without adjusting for creatinine level. Figure S1. Unadjusted associations of ln-transformed maternal urinary cotinine levels and Bayley scores in infants at 24 months of age stratified by genetic polymorphism and breastfeeding behavior. (DOCX 562 kb)

Auditory verbal hallucinations (AVHs) constitute a frequent and distressing symptom of schizophrenia, associated with physical, emotional, and cognitive challenges. Despite their clinical importance, changes in the multiple dimensions of AVHs during treatment have rarely been examined, and subjective views thereof have received minimal attention. Here, we evaluated 87 patients with schizophrenia-related AVHs using the Hamilton Program for Schizophrenia Voices Questionnaire (HPSVQ; a self-report questionnaire) and the Psychotic Symptom Rating Scales-Auditory Hallucination Subscale (PSYRATS-AH; a clinician-rated scale) at baseline and after 6 months and 1 year of treatment. We explored dimensions that changed from the perspectives of both clinicians and patients and the relationships between these perceptions over the year. The test–retest reliabilities of the HPSVQ and PSYRATS-AH were generally fair. Improvements in AVHs were evident over the first 6 months; the PSYRATS-AH revealed a broader range of symptom improvement than did the HPSVQ. The “interference with life” dimension on the HPSVQ was not reduced, but the “disruption to life” score on the PSYRATS-AH was. At both baseline and 6 months, the physical characteristics of AVHs (frequency, duration, and loudness) were significantly correlated with both distress and life interference/disruption; all correlations except that for frequency were reduced at 1 year. The clinician-rated and self-reported personal perspectives on AVHs exhibited both differences and similarities; physical AVH components and subjective distressful experiences changed in different ways in those with chronic, persistent AVHs. The HPSVQ and PSYRATS-AH data were complementary, improving our understanding of the clinical implications of AVHs and subjective patient distress.

Autism Spectrum Disorders is a syndrome with multiple causes and different mechanisms leading to abnormal development. Only a few longitudinal studies have investigated the associ...

Alzheimer's disease (AD) is a progressive degenerative condition. In order to treat AD, the use of a "drug repositioning" or "repurposing" approach with potential disease-modifying compounds has been increased. The new generation antipsychotics are commonly used in AD and other dementias for the treatment of psychosis and behavioral symptoms, and several animal models have shown the effects of these potential disease-modifying compounds. In this study, we examined whether long-term clozapine treatment could reduce amyloid beta (Aβ) deposition and cognitive impairment in transgenic mice of AD, Tg-APPswe/PS1dE9. AD mice were fed clozapine at 20 mg/kg/day for 3 months from 4.5 months of age. Intake of clozapine improved the Aβ-induced memory impairment and suppressed Aβ levels and plaque deposition in the brain of AD mice. Clozapine upregulated Trk, brain-derived neurotrophic factor, cyclin-dependent kinase-5, and p35 in the cortex and hippocampus of AD mice and activated AMP-activated protein kinase (AMPK). As a downstream effector of AMPK, beta-secretase expression was decreased by clozapine administration. Moreover, clozapine-phosphorylated synapsin I at Ser9 and Ser549 sites in the hippocampus and cortex of AD mice, which may be involved in synaptic strength. This study suggests that as one of candidate for multi-target approach of AD treatment, clozapine is proposed as a therapeutic drug for treatment of AD patients.

We develop a charge-modified PVDF UF/MF membrane that restricts membrane fouling derived from charged water contaminants. The charge-modified membranes are fabricated through surface assembly of various charged hyperbranched polyglycerols (HPGs), which act as anti-fouling agents. The native HPGs are neutrally charged polymers with a lot of hydroxyl end groups that can be modified with specific charges. We prepare three types of charged HPGs, i.e., neutrally charged HPGs without end group modifications, positively charged HPG with quaternary ammonium groups, and negatively charged HPG with sulfonate groups. The combined results for 1H NMR, FT-IR, and XPS results show that the charged HPGs are successfully synthesized and bound to the surfaces of the PVDF membrane. The surface hydrophilicity improves upon assembly of the hydrophilic charged HPGs. As expected, zeta potential results disclose that the differently charged HPGs provide the desired electrical properties to the membrane surface. In addition, the surface-assembled charged HPGs effectively suppress the attachment and accumulation of foulants having the same charge due to electrostatic repulsion and improved surface hydrophilicity.

Objectives : We retrospectively investigated the efficacy and tolerability of risperidone monotherapy in subjects with autism spectrum disorder (ASD). In addition, we did mixed effect model analysis of the effects of risperidone in patients with ASDs naturalistically treated in a routine clinical setting to determine whether the clinical effects were maintained and the side effects were tolerable. Methods : This retrospective study assessed children and adolescents with ASD, who were on risperidone monotherapy from July 2010 to July 2011 at the Child and Adolescent ASD Clinic at Seoul National Hospital. Outcome measures included the Clinical Global Impression-Severity of Illness (CGI-S) and the CGI-Improvement (CGI-I) scales along with other clinical indices: dosage, target symptoms, and side effects. Results : The mean dose of risperidone in 47 children and adolescents with ASD (40 males, 7 females; age range 5-19 years) who were on risperidone monotherapy was , and the mean duration of the treatment period was . Aggressive behavior, stereotypic behavior, irritability, and self-injurious behavior were the most frequent target symptoms of risperidone. The most common side effects were weight gain followed by somnolence and extrapyramidal symptoms. In a mixed effects model analysis of CGI-I scores, the mean CGI-I score at the 1 month follow-up was significantly different from the mean CGI-I score of the 3-month follow-up (p

Objective To investigate relationships among oral mucosal epithelial MUC1 expression, salivary stress markers, and female gonadal hormones throughout the menstrual cycle. Subjects and Methods Thirty healthy women (25.9 ± 2.1 years) with regular menstrual cycle were included. Unstimulated (UWS) and stimulated whole saliva (SWS) were collected during the menstrual cycle. The expression level of oral mucosal MUC1 was analyzed. 17β-Estradiol, progesterone, dehydroepiandrosterone (DHEA), cortisol, chromogranin A (CgA), and blood contamination levels were measured from UWS and SWS. Results Significant positive correlations were observed between 17β-estradiol and DHEA in UWS, cortisol and CgA in UWS, MUC1 expression and DHEA in SWS, and among cortisol, progesterone, and DHEA in UWS and SWS. Significant negative correlations were observed between MUC1 and cortisol/DHEA ratio in UWS and SWS. When each phase was analyzed individually, MUC1 expression showed significant negative correlations with cortisol, progesterone, and cortisol/DHEA ratio in UWS and with progesterone and cortisol/DHEA ratio in SWS during the mid-luteal phase. A significant negative correlation was also observed between MUC1 and cortisol/DHEA ratio in UWS during the late luteal phase. Conclusions Stress-related psychoendocrinological interactions throughout the menstrual cycle resulted in a decrease in oral mucosal epithelial MUC1 expression and a weakening of oral mucosal defense.

Autism spectrum disorder (ASD) is a neurodevelopmental disorder marked by impaired social communication and repetitive, restricted behaviors and activities. The prevalence of ASD has been increasing for the past 2 decades, but evidence-based therapeutic approaches are lacking for patients with ASD. To date, there is no cure for the core symptoms of ASD, and the existing treatments focus on improving the patient’s function and adaptation by using behavioral intervention methods. Behavioral interventions have been proven to show the greatest effect when applied before the age of 2 years, for at least 40?60 hours per week. Many clinicians and ASD families are unfamiliar with the treatment methods, and consequently, may seek unproven and potentially hazardous methods. The purpose of this article was to present an extensive and updated review on evidence-based ASD behavioral interventions that are commonly used in clinical settings.

Background This study aimed to examine the environmental tobacco smoke (ETS) exposure at home and associated problem behaviors in Korean children and adolescents. Methods Approximately 2,167 children aged 3–18 years were included in the study after excluding 163 active smokers from the Korean Environmental Health Survey in Children and Adolescents (2012–2014). ETS data were obtained using a questionnaire; problem behaviors were measured using the Child Behavior Checklist administered to parents. The relationship between ETS exposure and problem behavior was evaluated using a survey regression model adjusted for region, age, sex, income, and father's education. The population-attributable fraction (PAF%) was calculated based on problem behaviors related to ETS exposure at home. Results The rates of ETS exposure at home were 20%, 28%, and 39% in children aged 3–5, 6–11, and 12–18 years, respectively; ETS exposure at home was associated with behavioral problems: the exposed group having higher total behavioral problem score (95% confidence interval [CI]) than the non-exposed by 2.46 (0.60–4.32) and 2.74 (0.74–4.74) in children aged 6–11 and 12–18 years, respectively, with no significant association in those aged 3–5 years. The PAF% (95% CI) of total problem behaviors for ETS exposure at home were 2.68 (−10.11–17.78), 10.66 (3.25–17.55), and 11.62 (3.03–18.96) in children aged 3–5, 6–11, and 12–18 years, respectively. Children with externalizing problems had higher PAF% than those with internalizing problems. Conclusion In Korea, ETS exposure at home is associated with problem behaviors in children and adolescents with about more than 10% population attributable fraction., Graphical Abstract

Background Although the association between lead exposure and children's neurodevelopment has been studied, gender differences remain to be investigated. We examined the effects of lead exposure on the neurobehavioral development of 5-year-old children to identify the vulnerable time window of exposure and potential gender difference. Method A total of 1751 pregnant women and children participated in the prospective birth cohort study, Mothers and Children's Environmental Health study, since 2006. Lead levels were measured in the maternal blood in early and late pregnancies, in cord blood at birth, and in 2-, 3-, and 5-year-old children's blood. The behavior of 575 children aged 5 years were assessed using the Korean Child Behavior Checklist. The association between the blood lead level at each time window and behavior was examined using a generalized linear model adjusted for potential confounders and covariates. Results Lead levels at late pregnancy were significantly associated with increased risk of behavioral problems in males. Lead levels in 2- and 5-year-old children's blood significantly increased behavioral risks in females: for a 1-μg/dL increase in blood lead levels, the score for total behavioral problems increased by 3.00 (95% confidence interval [CI]: 0.56–5.45) during the late pregnancy in males, whereas it increased by 3.82 (95% CI: 1.25–6.39) at 2 years and by 5.72 (95% CI: 0.44–10.99) at 5 years in females with a stronger effect in attention and sleep problems. Conclusion Effects of lead toxicity on children's neurobehavioral development showed gender differences. Males were more susceptible to prenatal exposure, while females were more susceptible to postnatal exposure with stronger effects in attention and sleep problems.

Prenatal exposure to volatile organic compounds may restrict fetal development and adversely influence infants' life. Therefore, we investigated the relationship between prenatal exposure to total volatile organic compounds (TVOC) and postnatal neurobehavioral development. A subsample of 383 pregnant participants was chosen from the prospective birth cohort study of Mother and Children's Environmental Health Study; MOCEH (N=1,751) from three regions of the Republic of Korea (Seoul, Cheon-an, and Ulsan). Participants were enrolled during their first trimester with informed consent. We investigated maternal characteristics including socio-economic and obstetrical history using questionnaires. An environmental hygienist measured participating mothers' personal TVOC exposure using passive samplers during pregnancy. Participants visited the research center at 6, 12, 24 and 36 months. At each visit, questionnaires about infantile environment and health conditions were answered and a neurobehavioral test (BSID-II) was conducted by certified investigators. We conducted multiple general linear and mixed model analyses to investigate the relationship between TVOC and infantile neurobehavioral development (SAS 9.3). Mean prenatal TVOC exposure was 284.2μg/m3. In longitudinal analyses on infantile neurobehavioral development, adjusted mean psychomotor development index and mental developmental index scores in high TVOC exposure group (cut off at Q3: 374.0 ug/m3) were 3 points lower than the low exposure group. Results suggested exposure to higher TVOC during the fetal period may adversely influence neurobehavioral development in the early life stage.

Results:The social skills training program improved the 'helping' behaviors in boys (t=-2.355, p

Aims Antipsychotic-induced autonomic dysregulation may lead to a wide range of subjective side-effects in schizophrenia patients. Using heart rate variability (HRV) measures, we prospectively examined the relationship between subjective side-effects and cardiac autonomic regulation in unmedicated schizophrenia patients. Methods Forty-five unmedicated schizophrenia patients were assessed for antipsychotic-associated side-effects and HRV parameters at baseline and after 6 weeks of treatment. Psychiatric symptoms and subjective side-effects were assessed using the Positive and Negative Syndrome Scale (PANSS) and the Liverpool University Neuroleptic Side-effect Rating Scale (LUNSERS). Results Correlations between subjective adverse effects and HRV measures at baseline and at week 6 varied. Nonetheless, the changes in the psychic side-effects domain were significantly correlated with the changes in time-domain HRV measures and sample entropy (SampEn). In addition, the change in SampEn was significantly associated with that in the scores of extrapyramidal, anticholinergic, miscellaneous, and red herring domains as well as the mean total LUNSERS score. Conclusion Baseline HRV measures may predict clinical response and adverse events associated with treatment adherence. Also, subjective side-effects may correspond well with the changes in neurocardiac dynamics, and the changes in SampEn may effectively reflect subjective discomfort in patients receiving antipsychotic treatment.

Although there is some evidence supporting the existence of an association between prenatal maternal or postnatal child's urine phthalate metabolite concentrations and poor attentional performances, the interaction between urine phthalate metabolite levels and genetic variation for neuropsychological deficit of attention-deficit hyperactivity disorder (ADHD) has not been examined. The aim of this study was to determine whether phthalate metabolites in urine are associated with poor neuropsychological performance in children with ADHD, and whether such association is affected by genotype-phthalate interaction. A cross-sectional examination of urine phthalate metabolite concentrations and the continuous performance test (CPT) were performed in 179 Korean children with ADHD recruited from department of psychiatry of university hospital. Correlations between urine phthalate metabolite concentrations and the CPT scores were investigated, and the interaction of phthalate metabolite levels with the selected polymorphisms at major candidate genes for ADHD, namely dopamine receptor D4 (DRD4), dopamine transporter, alpha-2A-adrenergic receptor, and norepinephrine transporter genes. For the subjects with the DRD4 4/4 genotype, there were significant associations of the urine phthalate metabolite concentrations with the number of omission errors, the number of commission errors, and the response time variability scores on the CPT. However, for the subjects without the DRD4 4/4 genotype, no significant associations were found. The results of this study suggest a possible association between phthalate metabolite concentrations and poor attentional performances of ADHD as well as a genetic influence on this association. Further prospective and epigenetic studies are needed to investigate causality and pathophysiological mechanisms.