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Bipolar disorder (BD) is frequently misdiagnosed as major depressive disorder (MDD) due to overlapping depressive symptoms. This study investigated whether serum platelet-derived growth factor BB (PDGF-BB) is a differential diagnostic biomarker for BD and MDD. An initial SOMAscan proteomics assay of 1311 proteins in small samples from patients with BD and MDD and healthy controls (HCs) suggested that serum levels of PDGF-BB differed between BD and MDD. We then conducted a two-step, exploratory, cross-sectional, case–control study at our institute and five sites that included a total of 549 participants (157 with BD, 144 with MDD, and 248 HCs). Clinical symptoms were assessed using the Hamilton Depression Rating Scale and the Young Mania Rating Scale. In the initial analysis at our institute, serum PDGF-BB levels in the MDD group (n = 36) were significantly lower than those in the BD (n = 39) and HC groups (n = 36). In the multicenter study, serum PDGF-BB levels in the MDD group were again significantly lower than those in the BD and HC groups, with no significant difference between the BD and HC groups. Treatment with sodium valproate was associated with significantly lower serum PDGF-BB levels in patients with BD. After controlling for confounding factors (sex, age, body mass index, clinical severity, and valproate medication), serum PDGF-BB levels were lower in the MDD group than in the BD group regardless of mood state. Our findings suggest that serum PDGF-BB may be a potential biomarker to differentiate BD and MDD.

Impairment in verbal communication abilities has been reported in autism spectrum disorder (ASD). Dysfunction of the serotonergic system has also been reported in ASD. However, it is still unknown how the brain serotonergic system relates to impairment in verbal communication abilities in individuals with ASD. In the present study, we investigated the correlation between brain serotonergic condition and brain sensitivity to paralinguistic stimuli (i.e., amplitude in the human voice prosodic change-evoked mismatch field) measured by magnetoencephalography (MEG) or verbal ability in 10 adults with ASD. To estimate the brain serotonergic condition, we measured the serotonin transporter nondisplaceable binding potential cerebrum-wide using positron emission tomography with [11C]N,N-dimethyl-2-(2-amino-4-cyanophenylthio)benzylamine ([11C] DASB). The results demonstrated a significant positive correlation between brain activity to paralinguistic stimuli and brain serotonin transporter binding potential in the left lingual gyrus, left fusiform gyrus and left calcarine cortex. In addition, there were significant positive correlations between verbal ability and serotonergic condition in the right anterior insula, right putamen and right central operculum. These results suggested that the occipital cortex is implicated in recognition of the prosodic change in ASD, whereas the right insula-involved serotonergic system is important in nurturing verbal function in ASD.Trial registration: UMIN000011077.

Technological agents could be effective tools to be used in interventions for enhancing social orienting for some young children with ASD. We examined response to social bids in preschool children with ASD and typical development (TD) at a very early age (i.e., around 3 years) using social prompts presented by technological agents of various forms and human comparisons. Children with ASD demonstrated less response overall to social bids compared to TD controls, across agents or human. They responded more often to a simple humanoid robot and the simple avatar compared to the human. These results support the potential utilization of specific robotic and technological agents for harnessing and potentially increasing motivation to socially-relevant behaviors in some young children with ASD.

Social recognition is the sensitive domains of complex behavior critical for identification, interpretation and storage of socially meaningful information. Social recognition develops throughout childhood and adolescent, and is affected in a wide variety of psychiatric disorders. Recently, new data appeared on the molecular mechanisms of these processes, particularly, the excitatory-inhibitory (E/I) ratio which is modified during development, and then E/I balance is established in the adult brain. While E/I imbalance has been proposed as a mechanism for schizophrenia, it also seems to be the common mechanism in autism spectrum disorder (ASD). In addition, there is a strong suggestion that the oxytocinergic system is related to GABA-mediated E/I control in the context of brain socialization. In this review, we attempt to summarize the underpinning molecular mechanisms of E/I balance and its imbalance, and related biomarkers in the brain in healthiness and pathology. In addition, because there are increasing interest on oxytocin in the social neuroscience field, we will pay intensive attention to the role of oxytocin in maintaining E/I balance from the viewpoint of its effects on improving social impairment in psychiatric diseases, especially in ASD.

金沢大学医薬保健総合研究域医学系 / Graduate School of Medical Sciences, PMID: 30247542, Visuospatial working memory (WM), which is impaired in schizophrenia, depends on a distributed network including visual, posterior parietal, and dorsolateral prefrontal cortical regions. Within each region, information processing is differentially regulated by subsets of γ-aminobutyric acid (GABA) neurons that express parvalbumin (PV), somatostatin (SST), or vasoactive intestinal peptide (VIP). In schizophrenia, WM impairments have been associated with alterations of PV and SST neurons in the dorsolateral prefrontal cortex. Here, we quantified transcripts selectively expressed in GABA neuron subsets across four cortical regions in the WM network from comparison and schizophrenia subjects. In comparison subjects, PV mRNA levels declined and SST mRNA levels increased from posterior to anterior regions, whereas VIP mRNA levels were comparable across regions except for the primary visual cortex (V1). In schizophrenia subjects, each transcript in PV and SST neurons exhibited similar alterations across all regions, whereas transcripts in VIP neurons were unaltered in any region except for V1. These findings suggest that the contribution of each GABA neuron subset to inhibitory regulation of local circuitry normally differs across cortical regions of the visuospatial WM network and that in schizophrenia alterations of PV and SST neurons are a shared feature across these regions, whereas VIP neurons are affected only in V1., Embargo Period 12 months

Background A growing body of anecdotal evidence indicates that the use of robots may provide unique opportunities for assisting children with autism spectrum disorders (ASD). However, previous studies investigating the effects of interventions using robots on joint attention (JA) in children with ASD have shown insufficient results. The robots used in these studies could not turn their eyes, which was a limitation preventing the robot from resembling a human agent. Methods We compared the behavior of children with ASD with that of children with typical development (TD) during a JA elicitation task while the children interacted with either a human or a robotic agent. We used the robot “CommU,” which has clear eyes and can turn its eyes, for the robotic intervention. The age range of the participants was limited to 5–6 years. Results Sixty-eight participants participated in this study, including 30 (10 females and 20 males) children with ASD and 38 (13 females and 25 males) children with TD. The participants were randomly assigned to one of the following two groups: the robotic intervention group or the control group. JA in the children with ASD was better during the robotic intervention than during the human agent intervention. These children exhibited improved performance in the JA task with human after interacting with the robot CommU. JA was differentially facilitated by the human and robotic agents between the ASD and TD children. Conclusions The findings of this study significantly contribute to the literature on the impact of robots on JA and provide information regarding the suitability of specific robot types for therapeutic use.

Glial cell line-derived neurotrophic factor (GDNF) plays an important role in the pathophysiology of neuropsychiatric disorders. We examined serum GDNF levels in bipolar disorder (BD) patients and major depressive disorder (MDD) patients and their association with response to lithium therapy. We used a multicenter (six sites), exploratory, cross-sectional case-control design and recruited 448 subjects: 143 BD patients, 116 MDD patients, and 158 healthy controls (HCs). We evaluated the patients' clinical severity using the Clinical Global Impression (CGI), and responses to lithium therapy using the Alda scale. The serum GDNF levels were significantly decreased in the BD and MDD groups compared to the HCs, with no significant difference between the BD and MDD groups. After adjustment, the serum GDNF levels in the BD and MDD patients in remission or depressive states were decreased compared to the HC values. Lower serum GDNF levels in BD patients were associated with higher CGI and Alda scores (i.e., severe illness and good response to lithium therapy, respectively). Our findings suggest that the serum GDNF level may be a biomarker for both BD and MDD in remission or depressive states. The serum GDNF level may be associated with the lithium response of BD patients.

Evaluation of depressive states in children can be challenging. Most of the studies that have investigated cognitive function and cerebral blood volume changes using functional MRI (fMRI) in bipolar disorder (BD) have been confined to BDI or heterogeneous cohorts with attention-deficit/hyperactivity disorder (ADHD). This study investigated cognitive functions in adolescents with BDII and without ADHD using near-infrared spectroscopy (NIRS) and a Das-Naglieri Cognitive Assessment System (DN-CAS). Ten patients with BDII and without ADHD symptoms and 10 age- and gender-matched healthy controls were enrolled in the present study. NIRS was used to detect hemoglobin concentration changes during a verbal fluency test (VFT). In addition, the DN-CAS was used to evaluate cognitive function in four domains: planning, attention, simultaneous, and successive processing. Significant differences between the BDII and control groups in [oxy-Hb] changes during the early phase of VFT were observed in the lower prefrontal cortex but not in cognitive functioning. Furthermore, there was a significant correlation between planning and attention scores in BD subjects.

Understanding the nature of olfactory abnormalities is crucial for optimal interventions in children with autism spectrum disorders (ASD). However, previous studies that have investigated odor identification in children with ASD have produced inconsistent results. The ability to correctly identify an odor relies heavily on visual inputs in the general population. We tested odor identification in eight children with ASD and eight age-matched children with typical development (TD). After confirming that all children were able to identify each odor without visual input, we measured odor identification under the visual-distractor condition. Odor identification was hindered by visual distractors for all children with ASD but was not affected in all children with TD. Our results improve understanding of odor identification in ASD.

Aim The early detection of autistic tendencies in children is essential for providing proper care and education. The auditory steady-state response (ASSR) provides a passive, non-invasive technique for assessing neural synchrony at specific response frequencies in many mental disorders, including autism spectrum disorder (ASD), but few studies have investigated its use in young children. This study investigated the ASSR at 20 Hz and 40 Hz in typically developing (TD) children and children with ASD aged 5-7 years. Methods The participants were 23 children with ASD and 32 TD children aged 5-7 years. Using a custom-made magnetoencephalography device, we measured ASSR at 20 Hz and 40 Hz, compared the results between groups, and evaluated the association with intellectual function as measured by Kaufmann Assessment Battery for Children. Results Responses to 20 Hz and 40 Hz were clearly detected in both groups with no significant difference identified. Consistent with previous findings, right dominance of the 40-Hz ASSR was observed in both groups. In the TD children, the right-side 40-Hz ASSR was correlated with age. The Kaufmann Assessment Battery for Children score was correlated with the left-side 40-Hz ASSR in both groups. Conclusion Right-dominant ASSR was successfully detected in young TD children and children with ASD. No difference in ASSR was observed between the children with ASD and the TD children, although the right-side 40-Hz ASSR increased with age only in the TD children. Left-side 40-Hz ASSR was associated with intelligence score in both groups.

Children with autism spectrum disorder (ASD) reportedly suffer from sleep problems at a higher rate than typically developing (TD) children. Several previous studies have reported differences in sleep indices (e.g., sleep latency) in children with ASD. However, no previous studies have focused specifically on the time course of body movements. In the present study, we investigated the time course of body movements in young TD children and young children with ASD as well as the relationship between body movements during night and social ability. Seventeen TD children and 17 children with ASD participated in this study (5 to 8 years old). We used an accelerometer attached to the waist to record movements during night and measured the average time course of body movements for 3 nights. Our results demonstrated that the rate of body movement 2 to 3 hours after the onset of body stillness was higher in children with ASD than in TD children. In addition, the higher rate of body movement at 0.5 to 1 hour after the onset of body stillness was associated with a lower social ability in the children with ASD. Our results suggested that the time course of body movements is an objective behavioural index for young children with ASD.

Transcranial direct-current stimulation (tDCS) to the dorsolateral prefrontal cortex (DLPFC) has been established as an effective and noninvasive method to modulate cognitive function. Nevertheless, the mechanisms causing those cognitive changes under the tDCS remain largely unknown. We strove to elucidate the cognito-biological relation under the tDCS condition by examining whether the dopamine system activated by tDCS is involved in cognitive changes in human participants, or not. To evaluate the dopamine system, we used [11C]-raclopride positron emission tomography (PET) scanning: 20 healthy men underwent two [11C]-raclopride PET scans and subsequent neuropsychological tests. One scan was conducted after tDCS to the DLPFC. One was conducted after sham stimulation (control). Results of [11C]-raclopride PET measurements demonstrate that tDCS to the DLPFC caused dopamine release in the right ventral striatum. Neuropsychological tests for attentiveness revealed that tDCS to the DLPFC-enhanced participants’ accuracy. Moreover, this effect was correlated significantly with dopamine release. This finding provides clinico-biological evidence, demonstrating that enhancement of dopamine signaling by tDCS in the ventral striatum is associated with attention enhancement.

The core symptoms of autism spectrum disorder (ASD) comprise impairments of social communication and social interactions as well as restricted and repetitive patterns of interests and activities. No definitive treatments for these core symptoms currently exist. Oxytocin, a highly conserved peptide, has been suggested to moderate inter-individual relationships based on the results of many vertebrate studies. Recently, oxytocin has received a great deal of attention as a promising candidate for the treatment of ASD. Here, we review studies on the role of oxytocin in ASD. Numerous randomized controlled trials (RCTs) have shown single- dose oxytocin administration to have significantly favorable effects compared with placebo for both neuro-typical individuals and individuals with ASD. Furthermore, extended administra- tion of oxytocin was associated with effects that significantly exceeded those of a placebo in three of five published RCTs for ASD. Moreover, approximately 20 RCTs investigating whether oxytocin is favorable for ASD participants are in progress, according to clinical trial registries certified by the World Health Organization. The results of these RCTs may elucidate the issues regarding favorable and adverse effects, appropriate doses and treatment durations, participant selection, and specifically how to assess the changes in impairments of social com- munication and social interactions. In addition, it is necessary to consider which version of the Diagnostic and Statistical Manual of Mental Disorders (DSM) is used for the diagnosis of ASD in each RCT because the range of individuals diagnosed with ASD has become gradually nar- rower with each DSM revision, i. e., the Fourth Edition, the Fourth Edition Text Revision, and the Fifth Edition.

Extensive evidence shows that a core neurobiological mechanism of autism spectrum disorder (ASD) involves aberrant neural connectivity. Recent advances in the investigation of brain signal variability have yielded important information about neural network mechanisms. That information has been applied fruitfully to the assessment of aging and mental disorders. Multiscale entropy (MSE) analysis can characterize the complexity inherent in brain signal dynamics over multiple temporal scales in the dynamics of neural networks. For this investigation, we sought to characterize the magnetoencephalography (MEG) signal variability during free watching of videos without sound using MSE in 43 children with ASD and 72 typically developing controls (TD), emphasizing early childhood to older childhood: a critical period of neural network maturation. Results revealed an age‐related increase of brain signal variability in a specific timescale in TD children, whereas atypical age‐related alteration was observed in the ASD group. Additionally, enhanced brain signal variability was observed in children with ASD, and was confirmed particularly for younger children. In the ASD group, symptom severity was associated region‐specifically and timescale‐specifically with reduced brain signal variability. These results agree well with a recently reported theory of increased brain signal variability during development and aberrant neural connectivity in ASD, especially during early childhood. Results of this study suggest that MSE analytic method might serve as a useful approach for characterizing neurophysiological mechanisms of typical‐developing and its alterations in ASD through the detection of MEG signal variability at multiple timescales. Hum Brain Mapp 37:1038–1050, 2016. © 2015 The Authors Human Brain Mapping Published by Wiley Periodicals, Inc.

The elucidation of odour awareness in children with autism spectrum disorders (ASD) is important. We compared the odour awareness of young children with ASD with those of typical development (TD) children using the Children’s Olfactory Behavior in Everyday Life (COBEL) questionnaire, which is a self-report measure that mainly assesses odour awareness. Forty-five young boys (aged 5–6 years), including 20 children with ASD and 25 TD children, participated in this study. The total COBEL score of the young children with ASD was lower than that of the TD children (p

The social interactions between caregivers and their children play a crucial role in childhood development; therefore, caregivers' feelings for children are critical for the development of social minds. Mothers of children with autism spectrum disorder (ASD) are known to experience higher levels of stress. However, knowledge regarding mothers' feelings for their children before receiving a clinical diagnosis is limited. This study retrospectively investigated the time course of mothers' feelings from the time of birth and the effect of protective factors. The participants were 5- to 8-year-old children with an ASD diagnosis and their mothers. The mothers of the children with ASD had less positive feelings toward their children than the mothers of the typically developed (TD) children before receiving a clinical diagnosis. Intriguingly, prior knowledge of ASD may relieve maternal mental distress during the child-rearing years and at the time of diagnosis.

Olfactory traits in individuals with autism spectrum disorder (ASD) are considered the strongest predictors of social impairment. Compared to other sensory abnormalities, olfactory abnormalities in individuals with ASD are poorly understood. In this chapter, we provide an overview of the current assessment in individuals with ASD. Several confounding factors have to be considered when conducting research on olfaction in individuals with ASD. Qualitative measures of olfaction contain only limited information about the olfactory stimuli. In addition, little systematic information is available about individual's actual uses of olfaction in daily life. Only a limited number of experimental studies have performed quantitative measurements of olfactory abnormalities in ASD. Therefore, clarifying the relationship between olfactory traits and the influence of real-life situations in a laboratory setting is very difficult. Some new methodologies for measuring olfactory traits are gradually becoming available. New methods that reveal important links between ASD and olfactory traits should be developed in the future.

The effects of transcranial direct current stimulation (tDCS) likely depend on cortical N-methyl-D-aspartic acid (NMDA) neurotransmission; however, no previous studies have reported tDCS-mediated modulation of cortical NMDA neurotransmission in humans. The gamma-band auditory steady-state response (ASSR) to a 40 Hz stimulation likely reflects the integrity of cortical NMDA neurotransmission. The present study tested whether the effect of tDCS is reflected in gamma-band ASSRs during a 40 Hz stimulation. Using a double-blind, randomized, crossover study, we performed magnetoencephalography (MEG) and measured the ASSR in 24 healthy participants during 40 Hz of auditory stimulation after prefrontal tDCS (2 mA) or sham (i.e., placebo) treatment. Our results failed to reveal significant differences in any brain between the two conditions after the application of a frequency of approximately 40 Hz. Based on these results, the ASSR is an insufficient method to detect the effect of tDCS on cortical NMDA neurotransmission. Unexpectedly, the results revealed an enhanced beta-band event-related spectral perturbation (ERSP) in the left motor cortex after tDCS compared with that observed after the sham stimuli. Given that beta-band oscillations reflect many functions in motor cortices, the tDCS for the frontal areas had some effect on the left motor cortex while the participants were focusing on not pressing the button with their right index finger. An additional study with an adequate psychological task is necessary to draw a conclusion regarding this unexpected result.

The inferior frontal and superior temporal areas in the left hemisphere are crucial for human language processing. In the present study, we investigated the magnetic mismatch field (MMF) evoked by voice stimuli in 3- to 5-year-old typically developing (TD) children and children with autism spectrum disorder (ASD) using child-customized magnetoencephalography (MEG). The children with ASD exhibited significantly decreased activation in the left superior temporal gyrus compared with the TD children for the MMF amplitude. If we classified the children with ASD according to the presence of a speech onset delay (ASD - SOD and ASD - NoSOD, respectively) and compared them with the TD children, both ASD groups exhibited decreased activation in the left superior temporal gyrus compared with the TD children. In contrast, the ASD - SOD group exhibited increased activity in the left frontal cortex (i.e., pars orbitalis) compared with the other groups. For all children with ASD, there was a significant negative correlation between the MMF amplitude in the left pars orbitalis and language performance. This investigation is the first to show a significant difference in two distinct MMF regions in ASD – SOD children compared with TD children.

Identification of meaningful endophenotypes may be critical to unraveling the etiology and pathophysiology of autism spectrum disorders (ASD). We investigated whether impressions of "humanness" for android robot might represent a candidate characteristic of an ASD endophenotype. We used a female type of android robot with an appearance similar to that of a real person. Significant differences in overall impressions of 'humanness' for android robot were found between adolescents with ASD and typical development (TD) controls, as well as parents of children with ASD and parents of TD controls. Our current work does suggest robotic systems could potentially play an intelligent role in dissecting ASD heterogeneity.

The relationship between language development in early childhood and the maturation of brain functions related to the human voice remains unclear. Because the development of the auditory system likely correlates with language development in young children, we investigated the relationship between the auditory evoked field (AEF) and language development using non-invasive child-customized magnetoencephalography (MEG) in a longitudinal design. Twenty typically developing children were recruited (aged 36-75 months old at the first measurement). These children were re-investigated 11-25 months after the first measurement. The AEF component P1m was examined to investigate the developmental changes in each participant's neural brain response to vocal stimuli. In addition, we examined the relationships between brain responses and language performance. P1m peak amplitude in response to vocal stimuli significantly increased in both hemispheres in the second measurement compared to the first measurement. However, no differences were observed in P1m latency. Notably, our results reveal that children with greater increases in P1m amplitude in the left hemisphere performed better on linguistic tests. Thus, our results indicate that P1m evoked by vocal stimuli is a neurophysiological marker for language development in young children. Additionally, MEG is a technique that can be used to investigate the maturation of the auditory cortex based on auditory evoked fields in young children. This study is the first to demonstrate a significant relationship between the development of the auditory processing system and the development of language abilities in young children.

Recent rapid technological advances have enabled robots to fulfill a variety of human-like functions, leading researchers to propose the use of such technology for the development and subsequent validation of interventions for individuals with autism spectrum disorder (ASD). Although a variety of robots have been proposed as possible therapeutic tools, the physical appearances of humanoid robots currently used in therapy with these patients are highly varied. Very little is known about how these varied designs are experienced by individuals with ASD. In this study, we systematically evaluated preferences regarding robot appearance in a group of 16 individuals with ASD (ages 10-17). Our data suggest that there may be important differences in preference for different types of robots that vary according to interaction type for individuals with ASD. Specifically, within our pilot sample, children with higher-levels of reported ASD symptomatology reported a preference for specific humanoid robots to those perceived as more mechanical or mascot-like. The findings of this pilot study suggest that preferences and reactions to robotic interactions may vary tremendously across individuals with ASD. Future work should evaluate how such differences may be systematically measured and potentially harnessed to facilitate meaningful interactive and intervention paradigms.

Treating schizophrenia patients who fail to respond to antipsychotics is a major challenge, and the percentage of treatment-resistant patients is estimated to be 20-25 %. Recent studies indicate that yokukansan (YKS; D2 and 5HT1A partial agonist and 5HT2A and glutamate antagonist) to be safe and useful in treating behavioral and psychological symptoms associated with dementia and other neuropsychiatric conditions. We aimed at evaluating both the efficacy and safety of YKS in patients with treatment-resistant schizophrenia.This randomized, multicenter, double-blind, placebo-controlled study was conducted between May 2010 and August 2012. One hundred twenty antipsychotic-treated inpatients from 34 psychiatric hospitals in Japan were included. Patients were randomized to adjuvant treatment with YKS 7.5 g/day or placebo. During a 4-week follow-up, psychopathology was assessed using the Positive and Negative Syndrome Scale (PANSS) with five factors [excitement/hostility (P4, P7, G8, and G14), depression/anxiety (G1, G2, G3, G4, and G6), cognition (P2, N5, N7, G5, G10, G11, G12, G13, and G15], positive (P1, P3, P5, P6, and G9), and negative (N1, N2, N3, N4, N6, G7, and G16]]. Other assessments included, Clinical Global Impression-Severity (CGI-S), Global Assessment of Functioning (GAF), and Drug-Induced Extrapyramidal Symptoms Scale (DIEPSS). The primary efficacy outcome was the change in PANSS five-factor scores. The secondary outcomes were changes in the scores of CGI-S. The analysis was made on a modified intention to treat basis with the help of a last observation carried forward method.YKS showed a tendency of superiority to placebo in reducing total all PANSS five-factor scores in treatment-resistant schizophrenia, but the difference was not statistically significant in total, depression/anxiety, cognition, positive, and negative factors. However, compared to the placebo group, the YKS group showed statistically significant improvements in the PANSS excitement/hostility factor scores (p0.05). No substantial side effects were recorded.The results of the present study indicate YKS to be a potential adjunctive treatment strategy for treatment-resistant schizophrenia, particularly to improve excitement/hostility symptoms.

Objective Altered brain connectivity has been theorized as a key neural underpinning of autism spectrum disorder (ASD), but recent investigations have revealed conflicting patterns of connectivity, particularly hyper-connectivity and hypo-connectivity across age groups. The application of graph theory to neuroimaging data has become an effective approach for characterizing topographical patterns of large-scale functional networks. We used a graph approach to investigate alteration of functional networks in childhood ASD. Method Magnetoencephalographic signals were quantified using graph-theoretic metrics with a phase lag index (PLI) for specific bands in 24 children with autism spectrum disorder and 24 typically developing controls. Results No significant group difference of PLI was found. Regarding topological organization, enhanced and reduced small-worldness, representing the efficiency of information processing, were observed respectively in ASD children, particularly in the gamma band and delta band. Conclusions Analyses revealed frequency-dependent atypical neural network topologies in ASD children. Significance Our findings underscore the recently proposed atypical neural network theory of ASD during childhood. Graph theory with PLI applied to magnetoencephalographic signals might be a useful approach for characterizing the frequency-specific neurophysiological bases of ASD.

Oxytocin (OT) and the serotonergic system putatively play important roles in autism spectrum disorder (ASD) etiology and symptoms, but no direct neurobiological evidence exists for long-term OT administration effects on the brain's serotonergic system. This pilot study examined 10 male participants with ASD who were administered OT intranasally for 8–10 weeks in an open-label, single-arm, nonrandomized, and uncontrolled manner. Positron emission tomography (PET) with a radiotracer (11C)−3-amino-4-(2-[(dimethylamino)methyl]phenylthio)benzonitrile (11C-DASB) was used before and after OT treatment. The binding potential of serotonin transporter (11C-DASB BPND) was then estimated. The main outcome measures were changes in 11C-DASB BPND and their correlation with changes in symptoms. ASD participants showed significantly elevated 11C-DASB BPND in the left inferior frontal gyrus extending to the left middle frontal gyrus. No significant correlation was found between the change in any clinical symptom and the change in 11C-DASB BPND. This report of a pilot study is the first describing long-term effects of OT on the brain's serotonin system in ASD. Additional randomized controlled studies must be conducted to confirm whether activation of the serotonergic system contributes to the prosocial effect of OT in people with ASD. Autism Res 2017, 10: 821–828. © 2017 International Society for Autism Research, Wiley Periodicals, Inc.

Previously, we demonstrated that CD38, a transmembrane protein with ADP-ribosyl cyclase activity, plays a critical role in mouse social behavior by regulating the release of oxytocin (OXT), which is essential for mutual recognition. When CD38 was disrupted, social amnesia was observed in Cd38 knockout mice. The autism spectrum disorders (ASDs), characterized by defects in reciprocal social interaction and communication, occur either sporadically or in a familial pattern. However, the etiology of ASDs remains largely unknown. Therefore, the theoretical basis for pharmacological treatments has not been established. Hence, there is a rationale for investigating single nucleotide polymorphisms (SNPs) in the human CD38 gene in ASD subjects. We found several SNPs in this gene. The SNP rs3796863 (C > A) was associated with high-functioning autism (HFA) in American samples from the Autism Gene Resource Exchange. Although this finding was partially confirmed in low-functioning autism subjects in Israel, it has not been replicated in Japanese HFA subjects. The second SNP of interest, rs1800561 (4693C > T), leads to the substitution of an arginine (R) at codon 140 by tryptophan (W; R140W) in CD38. This mutation was found in four probands of ASD and in family members of three pedigrees with variable levels of ASD or ASD traits. The plasma levels of OXT in ASD subjects with the R140W allele were lower than those in ASD subjects lacking this allele. The OXT levels were unchanged in healthy subjects with or without this mutation. One proband with the R140W allele receiving intranasal OXT for approximately 3 years showed improvement in areas of social approach, eye contact and communication behaviors, emotion, irritability, and aggression. Five other ASD subjects with mental deficits received nasal OXT for various periods; three subjects showed improved symptoms, while two showed little or no effect. These results suggest that SNPs in CD38 may be possible risk factors for ASD by abrogating OXT function and that some ASD subjects can be treated with OXT in preliminary clinical trials. © 2011 Elsevier Ltd. All rights reserved.

Spontaneous face-to-face interactions between mothers and their children play crucial roles in the development of social minds; however, these inter-brain dynamics are still unclear. In this pilot study, we measured MEG mu suppression during face-to-face spontaneous non-linguistic interactions between mothers and their children with autism spectrum disorder (ASD) using the MEG hyperscanning system (i.e., simultaneous recording). The results demonstrated significant correlations between the index of mu suppression (IMS) in the right precentral area and the traits (or severity) of ASD in 13 mothers and 8 children (MEG data from 5 of the children could not be obtained due to motion noise). In addition, higher IMS values (i.e., strong mu suppression) in mothers were associated with higher IMS values in their children. To evaluate the behavioral contingency between mothers and their children, we calculated cross correlations between the magnitude of the mother and child head-motion during MEG recordings. As a result, in mothers whose head motions tended to follow her child’s head motion, the magnitudes of mu suppression in the mother’s precentral area were large. Further studies with larger sample sizes, including typically developing children, are necessary to generalize this result to typical interactions between mothers and their children.

There have been a number of inconsistent previous reports indicating that mood disorder patients are relatively sensitive or conversely insensitive to physical pain. However, there have been few such studies examining pain using neurophysiological techniques. The present study was performed to investigate the differences in tactile sense recognition between mood disorder patients and control subjects using a tactile sense recognition P300 measuring system. Tactile stimuli were delivered to the index finger as frequent stimuli and to the ring finger as infrequent stimuli. Subjects were requested to press a button promptly and accurately in response to infrequent stimuli. N140 and P300 were measured in the event-related potential to infrequent stimulus paradigm. The subjects evaluated stimuli on a visual analog scale (VAS). The amplitudes of P300 were smaller for the mood disorder patients than for control subjects. The VAS scores of mood disorder patients were significantly higher than those of control subjects. In mood disorder patients, the amplitude of P300 was negatively correlated with the HAM-D score. These results suggest dysfunction of tactile sense recognition in mood disorder patients. In addition, the amplitude of P300 may be useful as a biological marker for psychological conditions in mood disorder patients.

The auditory-evoked P1m, recorded by magnetoencephalography, reflects a central auditory processing ability in human children. One recent study revealed that asynchrony of P1m between the right and left hemispheres reflected a central auditory processing disorder (i.e., attention deficit hyperactivity disorder, ADHD) in children. However, to date, the relationship between auditory P1m right-left hemispheric synchronization and the comorbidity of hyperactivity in children with autism spectrum disorder (ASD) is unknown. In this study, based on a previous report of an asynchrony of P1m in children with ADHD, to clarify whether the P1m right-left hemispheric synchronization is related to the symptom of hyperactivity in children with ASD, we investigated the relationship between voice-evoked P1m right-left hemispheric synchronization and hyperactivity in children with ASD. In addition to synchronization, we investigated the right-left hemispheric lateralization. Our findings failed to demonstrate significant differences in these values between ASD children with and without the symptom of hyperactivity, which was evaluated using the Autism Diagnostic Observational Schedule, Generic (ADOS-G) subscale. However, there was a significant correlation between the degrees of hemispheric synchronization and the ability to keep still during 12-minute MEG recording periods. Our results also suggested that asynchrony in the bilateral brain auditory processing system is associated with ADHD-like symptoms in children with ASD., Highlights • The auditory-evoked P1m reflects a central auditory processing ability in children. • This study showed the relationship between P1m and hyperactivity in ASD children. • There was a correlation between hemispheric synchronization and the ability to keep still during MEG measurement. • A shorter P1m latency in the right hemisphere was associated with hyperactivity. • Asynchrony in the brain auditory processing predicts the comorbidity in children with ASD.

Some individuals with autism spectrum (AS) perform better on visual reasoning tasks than would be predicted by their general cognitive performance. In individuals with AS, mechanisms in the brain’s visual area that underlie visual processing play a more prominent role in visual reasoning tasks than they do in normal individuals. In addition, increased connectivity with the visual area is thought to be one of the neural bases of autistic visual cognitive abilities. However, the contribution of such brain connectivity to visual cognitive abilities is not well understood, particularly in children. In this study, we investigated how functional connectivity between the visual areas and higher-order regions, which is reflected by alpha, beta and gamma band oscillations, contributes to the performance of visual reasoning tasks in typically developing (TD) (n = 18) children and AS children (n = 18). Brain activity was measured using a custom child-sized magneto-encephalograph. Imaginary coherence analysis was used as a proxy to estimate the functional connectivity between the occipital and other areas of the brain. Stronger connectivity from the occipital area, as evidenced by higher imaginary coherence in the gamma band, was associated with higher performance in the AS children only. We observed no significant correlation between the alpha or beta bands imaginary coherence and performance in the both groups. Alpha and beta bands reflect top-down pathways, while gamma band oscillations reflect a bottom-up influence. Therefore, our results suggest that visual reasoning in AS children is at least partially based on an enhanced reliance on visual perception and increased bottom-up connectivity from the visual areas.

If the brain structural coordinates could be estimated using the individual head shape, magnetoencephalograph and near-infrared spectroscopy would be more ideal brain functional imaging methods especially for young human children. First, we propose an algorithm to estimate brain coordinates with reference to the head surface shape in preschool children. Second, we examined its spatial error range using a leave-one-out procedure within 38 samples of child head and brain structures. The mean error of landmarks was 13.6 ± 5.3 mm on the head surface and 18.5 ± 12.4 mm in the intracranial structure between estimated and actual brain coordinates.

Purpose The purpose of this study was to assess cortical hemodynamic response patterns in 3- to 7-year-old children listening to two speech modes: normally vocalized and whispered speech. Understanding whispered speech requires processing of the relatively weak, noisy signal, as well as the cognitive ability to understand the speaker's reason for whispering. Method Near-infrared spectroscopy (NIRS) was used to assess changes in cortical oxygenated hemoglobin from 16 typically developing children. Results A profound difference in oxygenated hemoglobin levels between the speech modes was found over left ventral sensorimotor cortex. In particular, over areas that represent speech articulatory body parts and motion, such as the larynx, lips, and jaw, oxygenated hemoglobin was higher for whisper than for normal speech. The weaker stimulus, in terms of sound energy, thus induced the more profound hemodynamic response. This, moreover, occurred over areas involved in speech articulation, even though the children did not overtly articulate speech during measurements. Conclusion Because whisper is a special form of communication not often used in daily life, we suggest that the hemodynamic response difference over left ventral sensorimotor cortex resulted from inner (covert) practice or imagination of the different articulatory actions necessary to produce whisper as opposed to normal speech.

Brain β-amyloid (Aβ) deposition during normal aging is highlighted as an initial pathogenetic event in the development of Alzheimer's disease. Many recent brain imaging studies have focused on areas deactivated during cognitive tasks [the default mode network (DMN), i.e., medial frontal gyrus/anterior cingulate cortex and precuneus/posterior cingulate cortex], where the strength of functional coordination was more or less affected by cerebral Aβ deposits. In the present positron emission tomography study, to investigate whether regional glucose metabolic alterations and Aβ deposits seen in nondemented elderly human subjects (n= 22) are of pathophysiological importance in changes of brain hemodynamic coordination in DMN during normal aging, we measured cerebral glucose metabolism with [18F]FDG, Aβ deposits with [11C]PIB, and regional cerebral blood flow during control and working memory tasks by H215O on the same day. Data were analyzed using both region of interest and statistical parametric mapping. Our results indicated that the amount of Aβ deposits was negatively correlated with hemodynamic similarity between medial frontal and medial posterior regions, and the lower similarity was associated with poorer working memory performance. In contrast, brain glucose metabolism was not related to this medial hemodynamic similarity. These findings suggest that traceable Aβ deposition, but not glucose hypometabolism, in the brain plays an important role in occurrence of neuronal discoordination in DMN along with poor working memory in healthy elderly people.

In this study we used near-infrared spectroscopy (NIRS) to measure relative changes in cortical hemodynamics from 19 adult and 19 preschool children (aged 3–4 years old), while they watched epochs of static and motion pictures extracted from TV programs. The spatio-temporal characteristics of oxygenated and deoxygenated hemoglobin volumes (oxy- and deoxy-Hb) of both subject groups were described and compared where appropriate for five regions of interest (ROIs). These were striate, left and right middle temporal, and left and right temporo-parietal areas. Over these areas, deoxy-Hb volumes did not differ between both groups. Preschool data showed significant increases in oxy-Hb over striate, middle temporal and temporo-parietal areas in response to visual motion stimuli. Static stimuli caused a significant oxy-Hb increase over striate and left middle temporal areas. Surprisingly, changes in adult oxy-Hb were not profound and did not show a significant oxy-Hb increase in striate and middle temporal areas in response to the motion stimuli, warranting further research. In spite of oxy-Hb volume differences, oxy-Hb recovery to baseline followed a similar pattern in both groups in response to both static and motion stimuli. Together, the results suggest that near-infrared spectroscopy is a viable method to investigate cortical development of preschool children by monitoring their hemodynamic response patterns.

Power spectral analysis of electrocardiogram (ECG) R-R intervals is useful for the detection of autonomic dysfunction in various clinical disorders. Although both panic disorder (PD) and major depressive disorder (MDD) are known to have effects on the cardiac autonomic nervous system, no previous study has tested this among drug-naïve (i.e. no history of treatment) patients with MDD and PD in the same study. The purpose of this study was to compare cardiac autonomic functions among drug-naïve patients with MDD and PD and those of healthy controls. Subjects were 17 drug-naïve PD patients, 15 drug-naïve MDD patients and 15 normal controls. ECGs were recorded under both supine resting and supine deep-breathing conditions (10-12 breaths/min; 0.17-0.20 Hz). We measured the low-frequency power (LF; 0.05-0.15 Hz), which may reflect baroreflex function, the high-frequency power (HF; 0.15-0.40 Hz), which reflects cardiac parasympathetic activity, as well as the LF/HF ratio. As expected, deep breathing induced an increase in HF power and a decrease in the LF/HF ratio in healthy controls. Compared to these controls, however, the MDD group had a lower response to regular deep breathing in LF power and in LF/HF ratio. PD patients showed intermediate results between normal controls and MDD patients. The results indicate that the reactivity to deep breathing revealed diminished cardiac autonomic reactivity in drug-naïve MDD patients.

Pathophysiological role of endoplasmic reticulum (ER) stress response signaling has been suggested for bipolar disorder. The goal of this study was to test the genetic association between bipolar disorder and an ER chaperone gene, HSP90B1 (GRP94/gp96), which is located on a candidate locus, 12q23.3. We tested the genetic association between bipolar disorder and HSP90B1 by case-control studies in two independent Japanese sample sets and by a transmission disequilibrium test (TDT) in NIMH Genetics initiative bipolar trio samples (NIMH trios). We also performed gene expression analysis of HSP90B1 in lymphoblastoid cells. Among the 11 SNPs tested, rs17034977 showed significant association in both Japanese sample sets. The frequency of the SNP was lower in NIMH samples than in Japanese samples and there was no significant association in NIMH trios. Gene expression analysis of HSP90B1 in lymphoblastoid cells suggested a possible relationship between the associated SNP and mRNA levels. HSP90B1 may have a pathophysiological role in bipolar disorder in the Japanese population, though further study will be needed to understand the underlying functional mechanisms.

Disrupted in schizophrenia 1 (DISC1) and its molecular cascade are implicated in the pathophysiology of schizophrenia and bipolar disorder. As interacting-proteins with DISC1, Nudel, ATF4, ATF5, LIS1, α-tubulin, PDE4B, eIF3, FEZ1, Kendrin, MAP1A and MIPT3 were identified. We previously showed the down-regulation of ATF5 in the lymphoblastoid cells derived from affected co-twin of monozygotic twins discordant for bipolar disorder. We also suggested the contribution of endoplasmic reticulum stress response pathway to the illness, and ATF4 is one of major components in the pathway. Truncated mutant DISC1 reportedly cannot interact with ATF4 and ATF5. These findings suggest the role of these genes in the pathophysiology of bipolar disorder. In this study, we tested genetic association of ATF4 and ATF5 genes with bipolar disorder by a case–control study in Japanese population (438 patients and 532 controls) and transmission disequilibrium test in 237 trio samples from NIMH Genetics Initiative Pedigrees. We also performed gene expression analysis in lymphoblastoid cells. We did not find any significant association in both genetic study and expression analysis. By the exploratory haplotype analysis, nominal association of ATF4 with bipolar II patients was observed, but it was not significant after correction of multiple testing. Contribution of common variations of ATF4 and ATF5 to the pathophysiology of bipolar disorder may be minimal if any.

Magnetoencephalography (MEG) is a non-invasive neuroimaging technique that provides a measure of cortical neural activity on a millisecond timescale with high spatial resolution. MEG has been clinically applied to various neurological diseases, including epilepsy and cognitive dysfunction. In the past decade, MEG has also emerged as an important investigatory tool in neurodevelopmental studies. It is therefore an opportune time to review how MEG is able to contribute to the study of atypical brain development. We limit this review to autism spectrum disorder (ASD). The relevant published work for children was accessed using PubMed on 5 January 2015. Case reports, case series, and papers on epilepsy were excluded. Owing to their accurate separation of brain activity in the right and left hemispheres and the higher accuracy of source localization, MEG studies have added new information related to auditory-evoked brain responses to findings from previous electroencephalography studies of children with ASD. In addition, evidence of atypical brain connectivity in children with ASD has accumulated over the past decade. MEG is well suited for the study of neural activity with high time resolution even in young children. Although further studies are still necessary, the detailed findings provided by neuroimaging methods may aid clinical diagnosis and even contribute to the refinement of diagnostic categories for neurodevelopmental disorders in the future.

The P1m component of the auditory evoked magnetic field is the earliest cortical response associated with language acquisition. However, the growth curve of the P1m component is unknown in both typically developing (TD) and atypically developing children. The aim of this study is to clarify the developmental pattern of this component when evoked by binaural human voice stimulation using child-customized magnetoencephalography. A total of 35 young TD children (32-121 months of age) and 35 children with autism spectrum disorder (ASD) (38-111 months of age) participated in this study. This is the first report to demonstrate an inverted U-shaped growth curve for the P1m dipole intensity in the left hemisphere in TD children. In addition, our results revealed a more diversified age-related distribution of auditory brain responses in 3- to 9-year-old children with ASD. These results demonstrate the diversified growth curve of the P1m component in ASD during young childhood, which is a crucial period for first language acquisition. Autism Res 2016, 9: 1216-1226. © 2016 International Society for Autism Research, Wiley Periodicals, Inc.

Autism spectrum disorder (ASD) has been postulated to involve impaired neuronal cooperation in large-scale neural networks, including cortico-cortical interhemispheric circuitry. In the context of ASD, alterations in both peripheral and central auditory processes have also attracted a great deal of interest because these changes appear to represent pathophysiological processes; therefore, many prior studies have focused on atypical auditory responses in ASD. The auditory evoked field (AEF), recorded by magnetoencephalography, and the synchronization of these processes between right and left hemispheres was recently suggested to reflect various cognitive abilities in children. However, to date, no previous study has focused on AEF synchronization in ASD subjects. To assess global coordination across spatially distributed brain regions, the analysis of Omega complexity from multichannel neurophysiological data was proposed. Using Omega complexity analysis, we investigated the global coordination of AEFs in 3-8-year-old typically developing (TD) children (n = 50) and children with ASD (n = 50) in 50-ms time-windows. Children with ASD displayed significantly higher Omega complexities compared with TD children in the time-window of 0-50 ms, suggesting lower whole brain synchronization in the early stage of the P1m component. When we analyzed the left and right hemispheres separately, no significant differences in any time-windows were observed. These results suggest lower right-left hemispheric synchronization in children with ASD compared with TD children. Our study provides new evidence of aberrant neural synchronization in young children with ASD by investigating auditory evoked neural responses to the human voice.

Deficits in attentional-inhibitory control have been reported to correlate to anger, hostility, and aggressive behavior; therefore, inhibitory control appears to play an important role in prosocial behavior. Moreover, recent studies have demonstrated that oxytocin (OT) exerts a prosocial effect (e.g., decreasing negative behaviors, such as aggression) on humans. However, it is unknown whether the positively valenced effect of OT on sociality is associated with enhanced attentional-inhibitory control. In the present study, we hypothesized that OT enhances attentional-inhibitory control and that the positively valenced effect of OT on social cognition is associated with enhanced attentional-inhibitory control. In a single-blind, placebo-controlled crossover trial, we tested this hypothesis using 20 healthy male volunteers. We considered a decrease in the hostility detection ratio, which reflects the positively valenced interpretation of other individuals' facial expressions, to be an index of the positively valenced effects of OT (we reused the results of our previously published study). As a measure of attentional-inhibitory control, we employed a modified version of the flanker task (i.e., a shorter conflict duration indicated higher inhibitory control). These results failed to demonstrate any significant behavioral effects of OT (i.e., neither a positively valenced effect on facial cognition nor an effect on attentional-inhibitory control). However, the enhancement of attentional-inhibitory control after OT administration significantly correlated to the positively valenced effects on the interpretation of uncertain facial cognition (i.e., neutral and ambiguous facial expressions).

The present study explored minor physical anomaly items relevant to schizophrenia in order to establish a scale that can distinguish schizophrenia from controls using newly identified items along with items from the refined Waldrop scale. Seven items were significantly more frequent among schizophrenia patients (N=218) than controls (N=226). Among these seven items, two novel features, strabismus and 'cuspidal ear' showed markedly different prevalence rates between schizophrenia and control groups. A six-item scale, including the newly identified strabismus and cuspidal ear, was selected for most accurately discriminating patients with schizophrenia from controls. This scale correctly classified 59.6% of patients and 78.9% of control subjects. This new scale is procedurally more exacting and quantitative, and more relevant to schizophrenia than the original Waldrop scale. The validity of this scale should be sound since it was tested on a larger number of cohorts than used in previous research. Our scale can be used as a biomarker for predicting risk for future development of schizophrenia. The scale may also facilitate the identification of schizophrenia susceptibility genetic/environmental factors by stratifying etiologically heterogeneous patients according to physical abnormalities.

Objective A series of methamphetamine psychosis reveals two kinds of clinical courses of methamphetamine psychosis: transient type and prolonged type. Furthermore, paranoid psychosis sometimes recurs without methamphetamine reuse, referred to as spontaneous relapse. Dysfunction of central dopaminergic neurotransmission has been implicated in the pathogenesis of these psychiatric states. Catechol-O-methyl transferase appears to play a unique role in regulating synaptic dopaminergic activity. This study aimed to investigate whether a functional polymorphism of the catechol-O-methyl transferase gene would be involved in the development of these psychiatric states. Basic methods We examined the functional polymorphism of val 158 met (catechol-O-methyl transferase) in 143 patients with methamphetamine psychosis and 200 healthy controls in Japan. The patients were divided into subgroups by several characteristic clinical features. Main results We found a significant difference in the catechol-O-methyl transferase allele frequency between patients with spontaneous relapse and the controls (P=0.018, odds ratio=1.67). Odds ratio implied that the patients with spontaneous relapse had a nearly 1.7-fold higher rate of the low activity alleles (met) than the controls. Conclusions Our results indicate that the met allele frequency of the catechol-O-methyl transferase is associated with patients who experienced methamphetamine psychosis and spontaneous relapse, suggesting that patients with a met allele appear to be at increased risk of an adverse response to methamphetamine.

Background Genetic variations in the serotonin receptor 3A (HTR3A) and 3B (HTR3B) genes, positioned in tandem on chromosome 11q23.2, have been shown to be associated with psychiatric disorders in samples of European ancestry. But the polymorphisms highlighted in these reports map to different locations in the two genes, therefore it is unclear which gene exerts a stronger effect on susceptibility. Methods To determine the haplotype block structure in the genomic regions of HTR3A and HTR3B, and to examine whether genetic variations in the region show evidence of association with schizophrenia and affective disorder in the Japanese, we performed haplotype-based case-control analysis using 29 polymorphisms. Results Two haplotype blocks each were revealed for HTR3A and HTR3B in Japanese samples. In HTR3B, haplotype block 2 that included a nonsynonymous single nucleotide polymorphism (SNP), yielded evidence of association with major depression in females (global p = .0023). Analysis employing genome-wide SNPs using the STRUCTURE program did not detect population stratification in the samples. Conclusions Our results suggest an important role for HTR3B in major depression in women and also raise the possibility that previously proposed disease-associated SNPs in the HTR3A/B region in Caucasians are in linkage disequilibrium with haplotype block 2 of HTR3B in the Japanese.

Altered endoplasmic reticulum stress (ER) response signaling is suggested in bipolar disorder. Previously, we preliminarily reported the genetic association of HSPA5 (GRP78/BiP) with bipolar disorder. Here, we extended our analysis by increasing the number of Japanese case-control samples and NIMH Genetics Initiative bipolar trio samples (NIMH trios), and also analyzed schizophrenia samples. In Japanese, nominally significant association of one haplotype was observed in extended samples of bipolar disorder but not in schizophrenia. In NIMH trios, no association was found in total samples. However, an exploratory analysis suggested that the other haplotype was significantly over-transmitted to probands only from the paternal side. The associated haplotype in Japanese or NIMH pedigrees shared three common polymorphisms in the promotor, which was found to alter promotor activity. These findings suggested promotor polymorphisms of HSPA5 may affect the interindividual variability of ER stress response and may confer a genetic risk factor for bipolar disorder.

We previously reported that expression level of LIM (ENH, PDLIM5) was significantly and commonly increased in the brains of patients with bipolar disorder, schizophrenia, and major depression. Expression of LIM was decreased in the lymphoblastoid cells derived from patients with bipolar disorders and schizophrenia. LIM protein reportedly plays an important role in linking protein kinase C with calcium channel. These findings suggested the role of LIM in the pathophysiology of bipolar disorder and schizophrenia. To further investigate the role of LIM in these mental disorders, we performed a replication study of gene expression analysis and performed genetic association studies. Upregulation of LIM was confirmed in the independent sample set obtained from Stanley Array Collection. No effect of sample pH or medication was observed. Genetic association study revealed the association of single nucleotide polymorphism (SNP)1 (rs10008257) with bipolar disorder. In an independent sample set, SNP2 (rs2433320) close to SNP1 was associated with bipolar disorder. In total samples, haplotype of these two SNPs was associated with bipolar disorder. No association was observed in case-control analysis and family-based association analysis in schizophrenia. These results suggest that SNPs in the upstream region of LIM may confer the genetic risk for bipolar disorder.

Objective Advanced paternal age at birth as a risk for schizophrenia in the adult offspring has been reported in previous studies exclusively conducted in Western countries and Israel. The question has arisen whether this finding could be replicated in countries with socially and culturally different attitudes toward marriage, including factors such as age at marriage. To address this question, we conducted a case-control study of a Japanese population. Methods The subjects were representative inpatients with a DSM-IV diagnosis of schizophrenia. Unrelated healthy volunteers were recruited as control subjects. This study was conducted as one of a series of the projects by use of “The Mother and Child Health Handbooks (MCHHs),” from which information on parental characteristics around the time of birth, including parental ages at birth, had been extracted and recorded on computer. Results Ninety-nine subjects with schizophrenia and 381 healthy control subjects enrolled for the study. Advanced paternal, but not maternal, age was associated with an elevated risk for schizophrenia. Reproducibility of the association across different cultures is suggestive of a causal link.

Background We previously reported a reduction in serum levels of d -serine, an endogenous co-agonist of the N-methyl-D-aspartate (NMDA) receptor, in schizophrenia, supporting the hypofunction hypothesis of NMDA neurotransmission in schizophrenia. In this study, we examined the genetic roles of serine racemase (SRR), an enzyme catalyzing the formation of d -serine from l -serine, and d -amino-acid oxidase (DAO) in the susceptibility to schizophrenia and the regulation of serum d -serine levels. Methods We determined the complete cDNA and genomic structures of SRR and performed mutation screening. Single nucleotide polymorphisms (SNPs) in SRR and DAO were tested for their association with schizophrenia in both case-control and family-based designs and for correlation with serum levels of d -serine. Results Genomic analyses revealed that human brain SRR transcripts consist of four isoforms with one major species, which were derived from alternative use of various 5’ end exons. Genetic association analyses showed no significant association between SRR/DAO and schizophrenia. We replicated the decreased serum d -serine levels in schizophrenia in the sample set, but d -serine levels did not correlate with SRR/DAO genotypes. Conclusions The SRR/DAO are not likely to be major genetic determinants in the development of schizophrenia or control of serum d -serine levels.

Dysfunction of the N-methyl-D-aspartate (NMDA) type glutamate receptor has been proposed as a mechanism in the etiology of schizophrenia. Recently, we identified a variable (GT)n repeat in the promoter region of the NMDA NR2A subunit gene (GRIN2A), and showed its association with schizophrenia in a case-control study, together with a correlation between the length of the repeat and severity of chronic outcome. In this study, we extended our analyses, by increasing the number of case-control samples to a total of 672 schizophrenics and 686 controls, and excluded potential sample stratification effects. We confirmed the significant allelic association between the repeat polymorphism and disease (P = 0.011), and as in the previous study, we observed an over-representation of longer alleles in schizophrenia. These results suggest a probable genetic effect for the GRIN2A promoter (GT)n variation on the predisposition to schizophrenia in Japanese cohorts.

Background DISC1 has been suggested as a causative gene for psychoses in a large Scottish family. We recently identified FEZ1 as an interacting partner for DISC1. To investigate the role of FEZ1 in schizophrenia and bipolar disorder, case–control association analyses were conducted in Japanese cohorts. Methods We performed a mutation screen of the FEZ1 gene and detected 15 polymorphisms. Additional data on informative polymorphisms were obtained from public databases. Eight single nucleotide polymorphisms (SNPs) were analyzed in 119 bipolar disorder and 360 schizophrenic patients and age- and gender-matched control subjects. All genotypes were determined with the TaqMan assay, and selected samples were confirmed by sequencing. Results The two adjacent polymorphisms displayed a nominally significant association with schizophrenia (IVS2+1587G>A, p = .014; 396T p = .024). Homozygotes with the Glu123 allele were observed in only a small portion (2%) of schizophrenia patients but not in control subjects or bipolar patients. Conversely, no SNPs displayed allelic, genotypic, or haplotypic associations with bipolar disorder. Conclusions A modest association between FEZ1 and schizophrenia suggests that this gene and the DISC1-mediated molecular pathway might play roles in the development of schizophrenia, with FEZ1 affecting only a small subset of Japanese schizophrenia patients.