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Attention deficit hyperactive disorder (ADHD) is a highly heritable neurodevelopmental disorder, and excessive daytime sleepiness is frequently observed in ADHD patients. Excessive daytime sleepiness is also a core symptom of narcolepsy and essential hypersomnia (EHS), which are also heritable conditions. Psychostimulants are effective for the symptomatic control of ADHD (primary recommended intervention) and the two sleep disorders (frequent off-label use). However, the common biological mechanism for these disorders has not been well understood. Using a previously collected genome-wide association study of narcolepsy and EHS, we calculated polygenic risk scores (PRS) for each individual. We investigated a possible genetic association between ADHD and narcolepsy traits in the Hamamatsu Birth Cohort for mothers and children (HBC study) (n = 876). Gene-set enrichment analyses were used to identify common pathways underlying these disorders. Narcolepsy PRS were significantly associated with ADHD traits both in the hyperactivity domain (e.g., P-value threshold P = 0.002) and inattention domain (e.g., P-value threshold P = 0.004). However, EHS PRS was not significantly associated with either domain of ADHD traits. Gene-set enrichment analyses revealed that pathways related to dopaminergic signaling, immune systems, iron metabolism, and glial cell function involved in both ADHD and narcolepsy. Findings indicate that ADHD and narcolepsy are genetically related, and there are possible common underlying biological mechanisms for this relationship. Future studies replicating these findings would be warranted to elucidate the genetic vulnerability for daytime sleepiness in individuals with ADHD.

Objective Pain is one of the main symptoms of patients with rheumatoid arthritis (RA). Pain in RA is caused by specific physical changes, such as joint destruction, and is therefore used as a disease activity marker. Although pain can also be influenced by emotional factors, neither the effect of emotional health nor the indirect effect of the physical state mediated by emotional health on pain has been quantified. Methods A total of 548 patients with RA participated. Emotional health was assessed using the Hospital Anxiety and Depression Scale (HADS). Measures routinely used in practice were used to evaluate the physical state and pain. To quantify the effects of the physical state on emotional health, and the effects of both physical and emotional health on pain, we used structural equation modeling, with emotional health, physical state, and pain as latent variables. Results The prevalence of anxiety and depression (HADS score ≥8 for each) among patients with RA was 18.7% and 29.4%, respectively. Emotional health was significantly influenced by the physical state (β = 0.21). Pain was affected by physical (β = 0.54) and emotional health (β = 0.29). The effect of the physical state on pain was mediated by emotional health, with this mediation effect (β = 0.06) accounting for 10.2% of the total effect. Conclusion The magnitude of pain in RA is determined by the mediation effect of emotional health as well as the direct physical state. Our findings suggest that emotional factors should be taken into account when assessing RA disease activity.

Background Little is known about the extent to which neurodevelopmental trajectories in infancy predict a later diagnosis of autism spectrum disorder (ASD). Methods We investigated the association between the neurodevelopmental trajectory classes identified using a latent class growth analysis and the distal clinical outcome. Participants included 952 infants from the Hamamatsu Birth Cohort for Mothers and Children (HBC study). Neurodevelopment was measured using the Mullen Scales of Early Learning, which contains five subscales (gross motor, fine motor, visual reception, receptive language, and expressive language), at seven time points from 1 to 24 months of age. ASD was diagnosed in 3.1% of the children at 32 months of age. The clinical outcome was included in our analysis model. Results Five neurodevelopmental classes were identified: high normal (11.5%), normal (49.2%), low normal (21.2%), delayed (14.1%), and markedly delayed (4.0%). The probability of a diagnosis of ASD in the markedly delayed class was highest (32.6%) when compared with the other classes. The probabilities of receiving a diagnosis of ASD in the delayed and low normal classes were 6.4% and 4.0%, respectively, whereas the probabilities in the normal and high normal classes were both 0%. Conclusions A diagnosis of ASD may be predicted by the neurodevelopmental trajectories during infancy, which can be evaluated both routinely and objectively in clinical settings. In this representative population, children diagnosed with ASD showed early signs in neurodevelopmental domains during the first 2 years of life.

Previous studies have reported interaction effects of oxytocin receptor genotype (rs53576) and environmental factors on mental health in youth. However, the findings are mixed, especially regarding the type of allele (i.e., A vs. G), and it remains unanswered whether such an interaction presents at an early stage of development. Thus, using a unique longitudinal birth cohort sample in Japan (n = 568), we examined whether there was an effect of the interaction between the OXTR rs53576 genotype and maternal postpartum depression, as an environmental risk, on behavioural problems in children. Child behavioural problems (internalising and externalising problems) were ascertained using the Strengths and Difficulties Questionnaire when children were 6 years old. Maternal postpartum depression was measured using the Edinburgh Postnatal Depression Scale when children were at 2 months and 10 months of age. The results revealed a significant effect in the interaction between OXTR rs53576 genotype and maternal postpartum depression on externalising problems in children with AA genotype (β = 0.136, 95% CI 0.032 to 0.240), but not in those with GG/GA genotype. This indicates that an interaction of vulnerable genotypes (i.e., A allele of OXTR rs53576) with an environmental burden (i.e. maternal postpartum depression) may be one of the potential elements that predisposes the infant to developing behavioural problems early in life. Hence, special attention needs to be paid to children exposed to environmental risks such as maternal postpartum depression, to facilitate the provision of appropriate care.

It is unclear whether neurodevelopmental progress from infancy to early childhood remains stable. Moreover, little is known about the risk factors, if any, affecting neurodevelopmental descending transition patterns and the relationship between these patterns and later childhood adaptive behaviours. We used data of 875 children from the Hamamatsu Birth Cohort Study in Japan. Children’s neurodevelopment at 18 and 32 months and adaptive behaviours at 40 months were evaluated. Perinatal factors and infant overweight status at 18 months were investigated to identify descending-transition-associated risk factors. In the latent transition analysis, ultimately, three classes were identified for each time point, resulting in nine transition patterns; among them, 10.4% of children showed descending class shifts (normal to delayed class). Such decelerated growth was predicted by maternal pre-pregnancy overweight status (odds ratio [OR] = 2.49; 95% confidence interval [CI]: 1.23, 5.02), low maternal educational history (OR = 1.20; 95% CI: 1.04, 1.36), and infant overweight status at 18 months (OR = 5.89; 95% CI: 1.26, 27.45). Children with descending transition showed poor functioning in adaptive behaviours at the age of 40 months. Interventions targeting children with risk factors for descending transition patterns may prevent decelerated growth and subsequent poor adaptive functioning.

Background Both genetic and pre- and perinatal factors, including birth weight, have been implicated in the onset of attention deficit hyperactivity disorder (ADHD) traits among children. This study aimed to elucidate to what extent the genetic risk of ADHD moderates the association between birth weight and ADHD traits among Japanese children. Methods We conducted a longitudinal birth cohort study (Hamamatsu Birth Cohort for Mother and Children Study) to investigate the association of genetic risk for ADHD and low birth weight with ADHD traits among Japanese children. Out of 1258 children, we included 796 who completed follow-ups at 8 to 9 years of age. Birth weight was categorized as Results Birth weight of 2000–2499 g was not associated with ADHD traits. Birth weight under 2000 g was significantly associated with both inattention and hyperactivity. When accounting for higher and lower genetic risk for ADHD, only those with higher genetic risk and birth weight < 2000 g were associated with inattention (rate ratio [RR] 1.56, 95% CI 1.07–2.27) and hyperactivity (RR 1.87, 95% CI 1.14–3.06). Conclusions Birth weight under 2000 g, together with the genetic risk of ADHD, contributes to higher levels of ADHD traits among Japanese children aged 8 to 9 years. The suggested association between low birth weight and ADHD is confined to children with a genetic susceptibility to ADHD, indicating the relevance of genetic-environmental interactions in the etiology.

BackgroundPostpartum depression (PPD) is a common and highly heritabledisorder in the postnatal period of new mothers. The development of PPD is shown to affectneurodevelopment in children and recent evidence suggests thatthe trajectory of PPDisalso associated with children’s neurodevelopment and mental conditions. Thus, early identification and intervention for individuals at high risk of PPD are urgently needed.Additionally, it is not clear whether genetic factors affect thetrajectory of PPD. Therefore, using a polygenic risk score (PRS) approach, we investigated if PRS for depression (Depression-PRS) and bipolar disorder (Bipolar-PRS) are associated with the development and clinical course of PPD.Methods Usingrecent large genome-wide association studies(GWAS) of depression and bipolar disorder as discovery cohorts, we calculatedDepression-PRS and Bipolar-PRS in each individual. Then, we investigated the possible association between Depression-PRS and Bipolar-PRS with the development andtrajectory of PPD insubjects from the Hamamatsu Birth Cohort for mothers and children (n = 136). Depressive symptoms were assessed using the Edinburgh Postpartum Depression Scale. Gene-set enrichment analyses were used to identify pathways underlying these conditions. ResultsDepression-PRS was significantly higher in subjects with PPD than in those without PPD(t = -3.283, P = 0.002)and logistic analysis showed that Depression-PRS significantly increases therisk of developing PPD(OR [SE] = 2.274 [0.585], P = 0.002). Furthermore, Depression-PRS was positively associated with continuity of PPD (β [SE]=1.621 [0.672]; P = 0.032).Gene-set enrichment analyses revealed that pathways such as“response to hormone”(β[SE] -2.285[1.002], P < 0.001) and “epigenetic regulation”(β[SE] 2.831 [1.317], P < 0.001) were involved in the continuity of PPD. ConclusionThese preliminary findings indicate that the genetic component plays an important role not only in the development but also inthe continuity of PPD. A polygenic risk score approach could be useful to identify subjects at risk for PPD, especially for persistent PPD,who needcareful monitoring and intervention after delivery.

School climate is a significant determinant of students&rsquo, behavioral problems and academic achievement. In this study, we developed the Japan School Climate Inventory (JaSC) to see whether it measures school climate properly. To do so, we investigated whether or not the measurement with JaSC varies across sub-groups of varying grade and of gender and examined the relationship between the perception of school climate and the psychological and behavioral traits at individual levels in a sample of Japanese elementary and junior high school students (n = 1399, grade 4&ndash, 9). The results showed that the measurement was consistent, since single-factor structures, factor loadings and thresholds of the items were found not to vary across sub-groups of the participants. The participants&rsquo, perception of school climate was associated positively with quality of life, especially in school (&beta, = 0.152, p &lt, 0.001) and associated negatively with involvement in ijime (bullying) as &ldquo, victim&rdquo, and &ldquo, bully/victim&rdquo, (&beta, = &minus, 0.098, p = 0.001, &beta, 0.188, p = 0.001, respectively) and peer relationship problems (&beta, 0.107, p = 0.025). JaSC was found to measure school climate consistently among varying populations of Japanese students, with satisfactory validity.

Autism spectrum disorder (ASD) is highly heritable, and modest contributions of common genetic variants to ASD have been reported. However, the association of genetic risks derived from common risk variants with ASD traits in children from the general population is not clear, and the association of these genetic risks with neurodevelopment in infants has not been well understood.To test whether a polygenic risk score (PRS) for ASD is associated with neurodevelopmental progress at age 18 months and ASD traits at age 6 years among children from the general population.In this cohort study, 876 children in the Hamamatsu Birth Cohort for Mothers and Children in Hamamatsu, Japan, underwent testing for the association of an ASD PRS with neurodevelopmental progress and ASD traits. Data collection began in December 2007 and is ongoing. Data analysis was conducted from April to December 2019.Summary data from the largest genome-wide association study were used to generate ASD PRSs, and significance of thresholds was calculated for each outcome. The Autism Diagnostic Observation Schedule 2 was used to measure ASD traits at age 6 years, and the Mullen Scales of Early Learning was used to measure neurodevelopmental progress at age 18 months.Of 876 participants (mean [SD] gestational age at birth, 38.9 [1.6] weeks; 438 [50.0%] boys; 868 [99.1%] Japanese), 734 were analyzed. The ASD PRS was associated with ASD traits (R2 = 0.024; β, 0.71; SE, 0.24; P = .03). The association of ASD PRS with infant neurodevelopment was most pronounced in gross motor (R2 = 0.015; β, -1.25; SE, 0.39; P = .01) and receptive language (R2 = 0.014; β, -1.19; SE, 0.39; P = .02) scores on the Mullen Scales of Early Learning. Gene set enrichment analyses found that several pathways, such as cell maturation (R2 = 0.057; β, -5.28; SE, 1.40; P .001) and adenylyl cyclase activity and cyclic adenosine monophosphate concentration (R2 = 0.064; β, -5.30; SE 1.30; P .001), were associated with ASD traits. Gene sets associated with inflammation were commonly enriched with ASD traits and gross motor skills (eg, chemokine motif ligand 2 production: R2 = 0.051; β, -6.04; SE, 1.75; P = .001; regulation of monocyte differentiation: R2 = 0.052; β, -6.63; SE, 1.90; P = .001; and B-cell differentiation: R2 = 0.051; β, 7.37; SE, 2.15; P = .001); glutamatergic signaling-associated gene sets were commonly enriched with ASD traits and receptive language skills (eg, regulation of glutamate secretion: R2 = 0.052; β, -5.82; SE, 1.68; P = .001; ionotropic glutamate receptor signaling pathway: R2 = 0.047; β, 3.54; SE, 1.09; P = .001; and negative regulation of glutamate secretion: R2 = 0.045; β, -5.38; SE, 1.74; P = .002).In this study, the ASD PRS was associated with ASD traits among children from the general population. Genetic risks for ASD might be associated with delays in some neurodevelopmental domains, such as gross motor and receptive language skills.

Whereas the term 'deinstitutionalisation' being obsolete in the West, the prolonged hospitalisation of patients with schizophrenia remains a major public health concern in Japan. According to the Organisation for Economic Cooperation and Development (OECD), Japan had 2.61 psychiatric beds per 1,000 persons in 2018, which was much higher than in other OECD countries (mean: 0.61 psychiatric beds per 1,000 persons; range: 0.03-1.35).1 This figure is almost identical to the number of beds in Japan in 1998 (2.84 per 1,000 persons)1 and shows that there has been no active movement to reduce the number of psychiatric beds in the last two decades. The Japanese Ministry of Health, Labour and Welfare (JMHLW) indicated that there were 272,100 inpatients in psychiatric hospitals or units as of 30 June 2019; more than half of these patients had schizophrenia (n = 143,600). Furthermore, about 45% of inpatients with schizophrenia (n = 64,600) had been institutionalised for more than 5 years.

Previous studies have led to the assumption that maternal problems in reciprocal social behavior might play an important role in infantile aggression. This study investigated whether maternal problems in reciprocal social behavior were predictive of higher infantile aggression at 18 months of age, and whether maternal postpartum depressive symptoms mediated the association. Participants were 769 mother-child dyads enrolled in the Hamamatsu Birth Cohort for Mothers and Children, in Hamamatsu, Japan. Maternal problems in reciprocal social behavior were evaluated during mid-pregnancy; maternal postpartum depressive symptoms were assessed at 4 weeks after childbirth; and infantile aggression was evaluated at 18 months of age. The results of mediation analysis using structural equation modeling showed that maternal problems in reciprocal social behavior directly increased infantile aggression (estimate = 0.100, 95% CI [0.011, 0.186]), and indirectly increased infantile aggression via maternal postpartum depressive symptoms (estimate = 0.027, 95% CI [0.010, 0.054]), even after controlling for covariates. This is the first study to demonstrate two separate processes in the effects of maternal problems in reciprocal social behavior on early infantile aggression.

Aim The present study aimed at developing a novel scale, the Japan Ijime Scale (JaIS), to measure bullying in Japan with substantial reliability and validity, with which we estimated the prevalence of bullying among children and adolescents of school age. Methods The JaIS is a self-report questionnaire and consists of three parts: subscales measuring victimization and witnessing, and an item measuring perpetration. To test the reliability and validity of the two subscales, the authors analyzed responses to the JaIS from 2334 school students (Grades 4-9) in six elementary and three junior high schools in a middle-sized industrial city in central Japan, using exploratory factor analysis, item response theory, and examination of the external validity of the items. The prevalence of bullying victimization, witnessing, and perpetration was estimated. Results Item response theory models revealed that both the Victimization and Witness subscales have sufficient discrimination power and measurement precision, and the external validity of each scale has been confirmed. Using the JaIS, we found that 35.8% of students had been victims of bullying every 2-3 months (27.6% were solely victims and 8.3% were bully/victims), 32.8% had witnessed some type of bullying act, and 11.8% had perpetrated some type of bullying (3.5% as perpetrators, and 8.3% as bully/victims). Conclusion The JaIS is a reliable and valid measure. Using this scale, we found a high prevalence of bullying victimization in Japanese schools.

The broader autism phenotype (BAP), which refers to the expression of behavioral and cognitive propensities that are milder but qualitatively similar to those defining autism spectrum disorder, can play a crucial role in postpartum depression (PPD). We investigated whether pregnant women's BAP would increase the risk for PPD, using a representative birth cohort in Japan. Pregnant women were enrolled in the Hamamatsu Birth Cohort (HBC) Study during their mid-gestation (N=841) and were followed up until 3 months after delivery. BAP was measured mainly during the 2nd trimester of the pregnancy by using the Broader Phenotype Autism Symptoms Scale. Participants scoring 9 points or higher on the Edinburgh Postnatal Depression Scale at least once during the first 3 months after childbirth were diagnosed with PPD. Among participants, 128 (15.2%) women were found to have PPD. Multiple logistic regression analyses showed that BAP were associated with PPD (OR=1.19, 95% CI [1.07–1.31]), even after controlling for other potential confounders. In addition, the association was not moderated by history of depression and/or anxiety disorders, including concurrent depressive and anxiety symptoms during pregnancy. The findings suggest that pregnant women with BAP have an elevated risk for PPD.

Background A growing body of evidence suggests that the aberrant cholinergic system may underlie the pathophysiology in schizophrenia. Nicotinic acetylcholine receptor (nAChR) subtype α7 (henceforth ‘α7 nAChR’) is located in presynaptic and postsynaptic constructs in the cerebral cortex and considered to play a key role in the regulation of learning and memory. Additionally, α7 nAChR is deemed to exert neuroprotective effects. Therefore, α7 nAChR is one of the potent therapeutic targets for negative symptoms and cognitive impairment in schizophrenia. In effect, several randomised trials to assess the efficacy and safety of α7 nAChR agonists are currently underway. There is some evidence in support of aberrant α7 nAChR in schizophrenia. In postmortem studies, protein levels of α7 nAChR in the frontal cortex (Guan et al., 1999) have been reported to be decreased in patients with schizophrenia. However, the availability of α7 nAChR in individuals with schizophrenia has yet to be examined in vivo. In this pilot study, we aim to clarify availability of α7 nAChR in the brains of patients with schizophrenia using positron emission tomography (PET) with a ligand of [11C](R)-2-methylamino-benzoic acid 1-aza-bicyclo[2.2.2]oct-3-yl ester ([11C](R)-MeQAA). Methods All participants provided informed consent. Inclusion criteria included diagnosis of schizophrenia according to the Diagnostic and Statistical Manual of Mental Disorders-Fifth Edition (DSM-5, 2013). Patients were excluded if they had (1) full IQ under 69 measured with the Wechsler Adult Intelligent Scale-III; (2) current or past history of tobacco smoking; (3) history of neurological disorder or structural brain abnormality; (4) use of benzodiazepines, antidepressants, or anticholinergics in the past 6 months; and (5) substance abuse. Although scanning drug-free or drug-naïve patients for investigation is optimal, it is extremely difficult to attain this. Consequently, participants with schizophrenia comprised medicated cases. We evaluated the availability of α7 nAChR by estimating non-displaceable binding potential (BPND) of the tracer using PET with [11C] (R)-MeQAA, a selective PET tracer for α7 nAChR. Four patients with schizophrenia (age: range 27–39; m/f: 2/2) and 5 age-matched healthy adults (age: range 22–32; m/f: 2/3) underwent the PET scan. The level of BPND in patients with schizophrenia was compared with that for control participants by applying regions of interest (ROIs) approach. In this pilot study, we opted for 4 cortical areas, the superior frontal, middle frontal, parietal, and temporal cortices, for ROIs. This study was approved by the Hamamatsu University School of Medicine Ethics Committee. Results We found the levels of [11C] (R)-MeQAA BPND significantly lower in the middle frontal cortex (p = 0.036) in patients with schizophrenia. Additionally, there was a trend towards a decreased level of BPND in the temporal cortex (p = 0.067) and parietal cortex (p = 0.087) in the brains of schizophrenia patients, although it failed to reach statistical significance. There was no difference in the superior frontal cortex. Discussion To our knowledge, this represents the first demonstration of anomalies in the acetylcholinergic system in the in vivo brains of schizophrenia patients. However, this is regarded as a pilot study, and further recruitment of schizophrenia patients with a recent onset and minimal use of antipsychotic medication, followed by scanning and data analyses, will be continued.

Aim The local expression of two isoenzymes of 11β-hydroxysteroid dehydrogenase, type 1 (11βHSD-1) and type 2 (11βHSD-2), regulates the access of glucocorticoid hormones to their target cells. Reports on the association between the placental expression of 11βHSD and infantile growth are limited. The aim of the present study was to investigate if the placental gene expression of 11βHSD affects infantile growth at 10 months of age. Methods Placentas and umbilical venous cord blood were obtained from 42 singleton cases of cesarean deliveries between 31 and 40 weeks of gestation at Hamamatsu University Hospital between March 2009 and June 2010. The gene expression of both 11βHSD-1 and 11βHSD-2 was measured by quantitative reverse transcription polymerase chain reaction. Adiponectin and leptin levels in umbilical cord blood were measured using enzyme-linked immunoassay. Results 11βHSD-1 and 11βHSD-2 gene expression in human placentas did not correlate with bodyweight or the ponderal index (PI) at 10 months of age, whereas the gene expression of 11βHSD-1, but not 11βHSD-2, correlated with birthweight as well as PI at birth. Adiponectin levels in umbilical cord blood significantly correlated with the placental gene expression of 11βHSD-1 as well as bodyweight and PI at 10 months of age, although no direct correlation was observed between them. Conclusion No direct correlation was observed between the placental gene expression of 11βHSD and infantile growth at 10 months of age. However, the placental gene expression of 11βHSD-1 may be indirectly connected with infantile growth via adiponectin-associated metabolic regulation represented by adiponectin levels in umbilical cord blood.

Background Previous research has demonstrated that the season of birth may predict development of emotional and behavioral regulation during childhood or adolescence. This study examined whether the season of birth predicts effortful control (i.e., the ability to voluntarily choose course of actions during conflict and to plan for the future) and aggression (i.e., the use of physical force and expression of anger toward others) in 18-month-old infants. Methods Participants included 885 infants who were enrolled in the Hamamatsu Birth Cohort for Mothers and Children in Hamamatsu, Japan. Seasons of birth were categorized into winter (December, January, and February), spring (March, April, and May), summer (June, July, and August), and autumn (September, October, and November). At 18 months of age, effortful control was assessed using the Early Childhood Behavior Questionnaire, and aggression was measured using the Cardiff Infant Contentiousness Scale. Structural equation modeling analysis with measurement and structural equations was conducted to test our prediction. Results Effortful control was higher in infants born in spring [B = 0.095, 95% CI (0.014 to 0.175), p = 0.021, β = 0.146] and summer [B = 0.078, 95% CI (0.001 to 0.156), p = 0.049, β = 0.118] than in those born in winter. In addition, aggression was lower in those born in spring [B = −0.286, 95% CI (−0.551 to −0.021), p = 0.035, β = −0.135] than those born in winter, even after controlling for seven covariates. Conclusion The findings suggest that season of birth may determine development of emotional and behavioral regulation skills during early infancy. Future research should pay more attention to the underlying mechanisms of the effects of birth season on development of emotional and behavioral regulation during infancy.

We investigated the potential relationship between maternal depressive symptoms during the postpartum period and non-verbal communication skills of infants at 14 months of age in a birth cohort study of 951 infants and assessed what factors may influence this association. Maternal depressive symptoms were measured using the Edinburgh Postnatal Depression Scale, and non-verbal communication skills were measured using the MacArthur-Bates Communicative Development Inventories, which include Early Gestures and Later Gestures domains. Infants whose mothers had a high level of depressive symptoms (13+ points) during both the first month postpartum and at 10 weeks were approximately 0.5 standard deviations below normal in Early Gestures scores and 0.5-0.7 standard deviations below normal in Later Gestures scores. These associations were independent of potential explanations, such as maternal depression/anxiety prior to birth, breastfeeding practices, and recent depressive symptoms among mothers. These findings indicate that infants whose mothers have postpartum depressive symptoms may be at increased risk of experiencing delay in non-verbal development.

BACKGROUND We investigate patterns of neurodevelopmental trajectories in infants, using a representative population, and identify risk factors that predict delayed growth. METHODS Participating infants (n = 952; 82.8% of the total sample) were assessed by Mullen Scales of Early Learning at seven time points, from 1 month to 24 months of age. Mothers were recruited in early pregnancy and data on demographic characteristics were collected during pregnancy. Trajectory patterns were investigated using latent class growth analysis, and risk factors for the derived trajectory classes were investigated by multinomial logistic regression. RESULTS Participants were found to be a fairly representative sample with respect to their demographic characteristics. Five classes of high normal (11.5%), normal (49.2%), low normal (21.2%), delayed (14.1%), and markedly delayed (4.0%) were identified. The markedly delayed class was characterized by overall delay from the early developmental stages; notably, such delay first became salient in motor domains and was then exceeded by language domains, especially receptive language. This class was predicted by male sex (odds ratio 4.0; 95% confidence interval 1.7-9.1), small for gestational age (2.8; 1.0-7.5), low placenta-to-birthweight ratio (2.8; 1.2-6.4) and low maternal education (4.7; 1.2-19.0). The delayed class was characterized by gradual downward deviation after the first birthday, and was predicted by male sex (2.5; 1.5-4.2), preterm birth (4.4; 1.6-12.6) and advanced paternal age (1.9; 1.0-3.5). CONCLUSIONS Our results demonstrate that about 1 out of 5 infants exhibits delayed neurodevelopment. Infants with distinct patterns of delayed trajectories and varying risk factors are considered to have different pathophysiological mechanisms.

The muscarinic cholinergic receptor (mAChR) antagonist scopolamine was used to induce transient cognitive impairment in monkeys trained in a delayed matching to sample task. The temporal relationship between the occupancy level of central mAChRs and cognitive impairment was determined. Three conscious monkeys (Macaca mulatta) were subjected to positron emission tomography (PET) scans with the mAChR radioligand N-[(11)C]methyl-3-piperidyl benzilate ([(11)C](+)3-MPB). The scan sequence was pre-, 2, 6, 24, and 48 h post-intramuscular administration of scopolamine in doses of 0.01 and 0.03 mg/kg. Occupancy levels of mAChR were maximal 2 h post-scopolamine in cortical regions innervated primarily by the basal forebrain, thalamus, and brainstem, showing that mAChR occupancy levels were 43-59 and 65-89% in doses of 0.01 and 0.03 mg/kg, respectively. In addition, dose-dependent impairment of working memory performance was measured 2 h after scopolamine. A positive correlation between the mAChR occupancy and cognitive impairment 2 and 6 h post-scopolamine was the greatest in the brainstem (P0.00001). Although cognitive impairment was not observed 24 h post-scopolamine, sustained mAChR occupancy (11-24%) was found with both doses in the basal forebrain and thalamus, but not in the brainstem. These results indicate that a significant degree of mAChRs occupancy is needed to produce cognitive impairment by scopolamine. Furthermore, the importance of the brainstem cholinergic system in working memory in monkey is described.

Autism is a pervasive developmental disorder diagnosed in early childhood. Abnormalities of serotonergic neurotransmission have been reported in autism. Serotonin transporter (5-HTT), which modulates serotonin levels, is a major therapeutic target in autism. Therefore, factors that regulate 5-HTT expression might be implicated in autism. One candidate 5-HTT-regulatory protein is the presynaptic protein, syntaxin 1A (STX1A). We examined the association of STX1A with autism in a trio association study using DNA samples from Japanese trios with autistic probands. In TDT analysis, rs69510130 ( p = 0.027) showed nominal associations with autism; modest haplotype association was also observed. We further compared STX1A mRNA expression between the autistic and control groups in the postmortem brain. In the anterior cingulate gyrus region, STX1A expression in the autism group was found to be significantly lower than that of the control group. Thus, we suggest a possible role of STX1A in the pathogenesis of autism.

Objective: According to the DSM-IV-TR, the concept of taijin-kyofusho (fear of interpersonal relations) is both unique to East Asia and a culture-bound syndrome. In the indigenous diagnostic classification system in Japan, taijin-kyofusho consists of four subtypes, i.e. sekimen-kyofu (phobia of blushing), shubo-kyofu (phobia of a deformed face/body), jiko-shu-kyofu (phobia of one's own foul body odour), and jiko-shisen-kyofu (phobia of one's own glance). Each subtype except for phobia of one's own glance can be adequately assigned to a respective existing category in the DSM-IV-TR. The aim of the study was to introduce clinical features of phobia of one's own glance to western psychiatrists. Methods: Description of a series of cases with jiko-shisen-kyofu (phobia of one's own glance). Results: All of our cases shared the unique feature that they suffered from the preoccupation that their own glance was offensive to others, and as a result were socially withdrawn themselves. Conclusions: To our best knowledge, no cases with a clear picture of phobia of one's own glance have been reported in the West to date. The controversial issue of the classification of phobia of one's own glance as an east Asian culture-related specific syndrome was addressed.

The aim of the present study was to investigate metabolite alterations in the hippocampal formation as they relate to aggression in high-functioning adults with autism. We measured concentrations of N-acetylaspartate (NAA), choline-containing compounds (Cho), and creatine plus phosphocreatine (Cr+ PCr) in the hippocampal formation by proton magnetic resonance spectroscopy in 12 non-medicated male subjects with autism and 12 age- and sex-matched controls. Aggression was scored in the autistic subjects using the Buss-Perry Aggression Questionnaire. The concentrations of Cho and Cr+PCr in the hippo- campal formation in autistic subjects were significantly higher than the corresponding values in control subjects, and a significant positive correlation was observed between the concentrations of these metab- olites in the hippocampal formation and scores on the Buss-Perry Aggression Questionnaire in autistic subjects. Results suggest that high-functioning adult subjects with autism have abnormal metabolite concentrations in the hippocampal formation, which may in part account for their aggression.

School teaching is regarded as a stressful occupation. The present study aimed to compare the likelihood of having minor psychiatric disorders (MPD) among school teachers with that among civil servants, and to investigate what factors were specifically associated with MPD in teachers. We conducted a questionnaire-based survey of 403 teachers employed at state schools and 611 civil servants as a comparison group in a medium-sized city in Japan. The response rate was 59.6% for teachers and 62.0% for civil servants. Mental health was assessed using the 28-item General Health Questionnaire (GHQ-28), according to which those with a score of six or higher were considered to have MPD. Logistic regression analysis was used to identify the factors associated with MPD. Although the proportion of subjects with MPD among teachers was greater than that among civil servants, the difference in the proportion was not statistically significant in the multiple logistic regression analysis adjusted for potential confounders. In a separate analysis of the teachers, reduced job satisfaction and shorter time spent of leisure were significantly associated with an increased likelihood of having MPD. In the group of civil servants, longer working hours, reduced life satisfaction, a history of sick leave, and physical illness were associated with an increased likelihood of having MPD. When this analysis was conducted separately for male and female teachers, job dissatisfaction alone was associated with MPD only in female teachers. Poor mental health of Japanese school teachers, female teachers in particular, was found to be associated with job dissatisfaction.

Autism is a pervasive neurodevelopmental disorder diagnosed in early childhood. Growth factors have been found to play a key role in the cellular differentiation and proliferation of the central and peripheral nervous systems. Epidermal growth factor (EGF) is detected in several regions of the developing and adult brain, where, it enhances the differentiation, maturation, and survival of a variety of neurons. Transforming growth factor-beta (TGFbeta) isoforms play an important role in neuronal survival, and the hepatocyte growth factor (HGF) has been shown to exhibit neurotrophic activity. We examined the association of EGF, TGFbeta1, and HGF genes with autism, in a trio association study, using DNA samples from families recruited to the Autism Genetic Resource Exchange; 252 trios with a male offspring scored for autism were selected for the study. Transmission disequilibrium test revealed significant haplotypic association of EGF with autism. No significant SNP or haplotypic associations were observed for TGFbeta1 or HGF. Given the role of EGF in brain and neuronal development, we suggest a possible role of EGF in the pathogenesis of autism.

To clarify whether reelin signaling is involved in dopaminergic neurotransmission in the adult mouse brain, we investigated dopamine function in mice lacking reelin (reeler). We found that methamphetamine-induced locomotor activity is significantly attenuated in reeler mice. To elucidate the mechanism of this phenomenon, we first investigated presynaptic dopamine release; however, there were no significant differences in wildtype, heterozygous reeler and homozygous reeler mice. Next, we examined the locomotor response to intra-accumbens injection of dopamine D1 and D2 receptor agonists, and found that lack of reelin signaling results in decreases in both D1 and D2 receptor-mediated dopaminergic functions. In addition, we measured dopamine receptor binding in the striatum, and found that both D1 and D2 classes of dopamine receptors are reduced in reeler mice. Furthermore, we found that the phosphorylation levels of DARPP-32 are also changed by lack of reelin signaling. Finally, to distinguish between a developmental role of reelin or an acute role of reelin in adult mouse, we intraventricularly infused CR-50, a monoclonal antibody against reelin. Interestingly, infusion of CR-50 also significantly reduced methamphetamine-induced hyperlocomotion in wildtype mice, showing that reelin has an acute role in the dopaminergic system. These results indicate that reelin signaling plays a pivotal role in the dopaminergic system in adult mice, especially in postsynaptic levels.

Several previous studies have reported a significant linkage between markers in the alpha 7 nicotinic cholinergic receptor subunit ( CHRNA7 ) gene and either schizophrenia or the P50 sensory gating deficit, a schizophrenia endophenotype. However, CHRFAM7A , a partially duplicated gene 1.6 Mb upstream of the CHRNA7 gene, has complicated further genetic analysis. We genotyped 14 polymorphic markers throughout the full-length CHRNA7 gene and the duplicated region in 188 unrelated Han Chinese patients with schizophrenia and 188 controls. The duplicated regions were assessed by genotyping up- and down-stream polymorphic markers in the vicinity of each region and analyzing the linkage disequilibrium (LD) between each pair of markers. No evidence of risk variants for schizophrenia in either the CHRNA7 gene or the partially duplicated region was found in the LD analysis. A significant deviation from the Hardy–Weinberg equilibrium (HWE) was found only in the genotypic distribution of SNP9 (IVS4-1912) in patients ( p = 0.00829), but not in controls. In conclusion, our LD analysis did not reveal any association between schizophrenia in our Han Chinese population and the CHRNA7 gene or its partially duplicated region. However, we could not exclude the possibility of a weak genetic effect due to the small sample size. Analyses of larger samples and higher-density markers, particularly around SNP9 (IVS4-1912), are still needed.

Preface Part 1: Russia and Central Asia Overview: Psychiatry in Russia and Central Asia 1. The Republic of Kazakhstan 2. Kyrgyz Republic: In Between the Soviet Past and a Vague Future 3. Russian Federation 4. The Republic of Uzbekistan Part 2: Indian Subcontinent Overview: Diversity in Unity and Adversity 5. Bangladesh 6. Bhutan 7. India: Epidemiology, Services and Health Systems 8. India: Training and Explanatory Models 9. Nepal 10. Pakistan 11. Sri Lanka Part 3: Greater China Overview 12. China 13. Taiwan 4. Hong Kong Part 4: Far East Overview 15. Japan 16. South Korea 17. North Korea Part 5: South East, Philippines and Indonesia Overview 18. Indonesia 19. Malaysia 20. Philippines 21. Singapore Part 6: Thailand and Nearby Countries Overview 22. Cambodia 23. Lao People's Democratic Republic 24. Myanmar 25. Thailand 26. Vietnam

Epidemiologic studies demonstrate significant environmental impact of maternal viral infection and obstetric complications on the risk of schizophrenia and indicate their detrimental influences on brain development in this disorder. Based on these findings, animal models for schizophrenia have been established using double stranded RNA, bacterial lipopolysaccharides, hippocampal lesion, or prenatal/perinatal ischemia. Key molecules regulating such immune/inflammatory reactions are cytokines, which are also involved in brain development, regulating dopaminergic and GABAergic differentiation, and synaptic maturation. Specific members of the cytokine family, such as interleukin-1, epidermal growth factor, and neuregulin-1, are induced after infection and brain injury; therefore, certain cytokines are postulated to have a central role in the neurodevelopmental defects of schizophrenia. Recently, to test this hypothesis, a variety of cytokines were administered to rodent pups. Cytokines administered in the periphery penetrated the immature blood-brain barrier and perturbed phenotypic neural development. Among the many cytokines examined, epidermal growth factor (or potentially other ErbB1 ligands) and interleukin-1 specifically induced the most severe and persistent behavioral and cognitive abnormalities, most of which were ameliorated by antipsychotics. These animal experiments illustrate that, during early development, these cytokine activities in the periphery perturbs normal brain development and impairs later psychobehavioral and/or cognitive traits. The neurodevelopmental and behavioral consequences of prenatal/perinatal cytokine activity are compared with those of other schizophrenia models and cytokine interactions with genes are also discussed in this review.