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Background Child and adolescent mental health problems are urgent health issues in low- and middle-income countries. To promote child and adolescent mental health services, simple validated screening tools are helpful. In Mongolia, the Strengths and Difficulties Questionnaire (SDQ), an internationally used child and adolescent mental health screening tool for children aged 4–17, was translated but not yet validated. To use the questionnaire appropriately, validation is necessary. Methods Children at 4th year at elementary school (community sample) and children visited psychiatric outpatient service (clinical sample) were recruited and their parental version of the SDQ was compared. The discriminating ability of the parental version of the SDQ was examined using Receiver Operating Characteristics (ROC) analysis on the SDQ total difficulties score. The area under the ROC curve (AUC) was used as a measure. Cut-off score was determined by normative banding that categorizes children with the highest 10% score range as abnormal and the second highest 10% as borderline following the original method; this cut-off score was compared with the cut-off score candidates with good balance between sensitivity and specificity using ROC analysis. Results We included 2301 children in the community sample, and 429 children in the clinical sample. Mean age was 9.7 years (SD 0.4, range 8.3–12.0) among the community sample and 10.4 years (SD 3.8, range 4.0–17.8) among the clinical sample. The mean total difficulties score was 12.9 (SD 4.8) among the community sample and 20.4 (SD 6.2) among the clinical sample. A total of 88.8% of the community sample and 98.8% of the clinical sample answered the SDQ. Using ROC analysis, the AUC was 0.82 (95% confident interval 0.80–0.85), which meant moderate discriminating ability. Using normative banding, the borderline cut-off score was 16/17 and abnormal cut-off score was 19/20. For cut-off scores of 16/17 and 19/20, sensitivity was 71.9 and 53.8% and specificity was 78.5 and 90.5%, respectively. The cut-off score candidates by ROC analysis were 16/17 and 17/18. Conclusions The parental version of the SDQ had moderate discriminating ability among Mongolian school-age children. For the screening of mental health problems among community children, cut-off score of 16/17 is recommended.

BackgroundChild and adolescent mental health problems are urgent health issues in low- and middle-income countries (LMICs). To promote mental health services for child and adolescent mental problems, simple validated screening tools are helpful. In Mongolia, the Strengths and Difficulties Questionnaire (SDQ), an internationally used child and adolescent mental health screening tool for children aged 4 to 17, was translated but not yet validated. To use the questionnaire for surveillance, research, and clinical purpose, validation is necessary.MethodsA community sample and a clinical sample were used. The discriminating ability of the parental version of the SDQ was examined using Receiver Operating Characteristics (ROC) analysis on the SDQ total difficulties score. The area under the ROC curve was used as a measure. Cut-off score was determined by normative banding that categorizes children with the highest 10% score range as abnormal and the second highest 10% score as borderline following the original method; this cut-off score was compared with the cut-off score candidates with good balance between sensitivity and specificity using ROC analysis.ResultsWe included 2301 children in the community sample, and 429 children in the clinical sample. Mean age was 9.7 years (SD 0.4) among the community sample and 10.4 years (SD 3.8) among the clinical sample. A total of 88.8% of the community sample and 98.8% of the clinical sample answered the SDQ. Using ROC analysis, the area under the curve was 0.82 (95% confident interval 0.80-0.85), which meant moderate discriminating ability. The mean total difficulties score was 12.9 (SD 4.8) among the community sample and 20.4 (SD 6.2) among the clinical sample. Using normative banding, the cut-off score between normal and borderline was 16/17 and between borderline and abnormal was 19/20. Sensitivity was 71.9% and 53.8% and specificity was 78.5% and 90.5% for cut-off scores of 16/17 and 19/20, respectively. The cut-off score candidates by ROC analysis was 16/17 and 17/18.ConclusionsThe parental version of the SDQ had moderate discriminating ability in Mongolia. For the screening of mental health problems among community children, cut-off score of 16/17 is recommended.

Background Previous studies have revealed an association between maternal depressive/anxious symptoms and children’s tics. However, the longitudinal relationship between these symptoms remains unclear. We examined the longitudinal relationships between maternal depressive/anxious symptoms and children’s tics across early adolescence in a population-based sample. Methods Participants were 3,171 children and their mothers from the Tokyo Teen Cohort study (TTC), a population-representative longitudinal study launched in Tokyo in 2012. Maternal depressive/anxious symptoms and children’s tics were examined using self-report questionnaires at the ages of 10 (time 1, T1) and 12 (time 2, T2). A cross-lagged model was used to explore the relationships between maternal depressive/anxious symptoms and children’s tics. Results As maternal depressive/anxious symptoms at T1 were greater, their children at T2 were more likely to have tics (β = .06, p = .001). Furthermore, the presence of tics at T1 was positively related to maternal depressive/anxious symptoms at T2 (β = .06, p = .001). Conclusions These findings suggest a longitudinal bidirectional relationship between maternal depressive/anxious symptoms and children’s tics during early adolescence which may exacerbate each other over time and possibly create a vicious circle. When an early adolescent has tics, it might be important to identify and care for maternal depressive/anxious symptoms.

Previous structural magnetic resonance imaging studies of psychotic disorders have demonstrated volumetric alterations in subcortical (ie, the basal ganglia, thalamus) and temporolimbic structures, which are involved in high-order cognition and emotional regulation. However, it remains unclear whether individuals at high risk for psychotic disorders with minimal confounding effects of medication exhibit volumetric changes in these regions. This multicenter magnetic resonance imaging study assessed regional volumes of the thalamus, caudate, putamen, nucleus accumbens, globus pallidus, hippocampus, and amygdala, as well as lateral ventricular volume using FreeSurfer software in 107 individuals with an at-risk mental state (ARMS) (of whom 21 [19.6%] later developed psychosis during clinical follow-up [mean = 4.9 years, SD = 2.6 years]) and 104 age- and gender-matched healthy controls recruited at 4 different sites. ARMS individuals as a whole demonstrated significantly larger volumes for the left caudate and bilateral lateral ventricles as well as a smaller volume for the right accumbens compared with controls. In male subjects only, the left globus pallidus was significantly larger in ARMS individuals. The ARMS group was also characterized by left-greater-than-right asymmetries of the lateral ventricle and caudate nucleus. There was no significant difference in the regional volumes between ARMS groups with and without later psychosis onset. The present study suggested that significant volume expansion of the lateral ventricle, caudate, and globus pallidus, as well as volume reduction of the accumbens, in ARMS subjects, which could not be explained only by medication effects, might be related to general vulnerability to psychopathology.

The limited efficacy of available antidepressant therapies may be due to how they affect the underlying brain network. The purpose of this study was to develop a melancholic MDD biomarker to identify critically important functional connections (FCs), and explore their association to treatments. Resting state fMRI data of 130 individuals (65 melancholic major depressive disorder (MDD) patients, 65 healthy controls) were included to build a melancholic MDD classifier, and 10 FCs were selected by our sparse machine learning algorithm. This biomarker generalized to a drug-free independent cohort of melancholic MDD, and did not generalize to other MDD subtypes or other psychiatric disorders. Moreover, we found that antidepressants had a heterogeneous effect on the identified FCs of 25 melancholic MDDs. In particular, it did impact the FC between left dorsolateral prefrontal cortex (DLPFC)/inferior frontal gyrus (IFG) and posterior cingulate cortex (PCC)/precuneus, ranked as the second ‘most important’ FC based on the biomarker weights, whilst other eight FCs were normalized. Given that left DLPFC has been proposed as an explicit target of depression treatments, this suggest that the limited efficacy of antidepressants might be compensated by combining therapies with targeted treatment as an optimized approach in the future.

ObjectiveDisruptions in the dopamine system have been observed in psychiatric disorders. Since dopamine is mainly produced in the ventral tegmental area (VTA), elucidating the differences in the VTA neural network across psychiatric disorders would facilitate a greater understanding of the pathophysiological mechanisms underlying these disorders. However, no study has compared VTA-seed-based functional connectivity across psychiatric disorders. Therefore, we conducted a resting-state functional magnetic resonance imaging (rs-fMRI) study to perform a seed-based fMRI analysis, using the VTA as a seed.MethodsWe included participants with major depressive disorder (MDD; n = 45), schizophrenia (n = 32), and bipolar disorder (BPD; n = 30), along with healthy control participants (n = 46) who were matched for age, gender, and handedness.ResultsThe results showed that patients with MDD and BPD had altered VTA-related connectivity in the superior frontal gyrus, frontal pole regions, hippocampus, cerebellum, and posterior cingulate cortex. Some of these differences in connectivity were also found between affective disorders and schizophrenia; however, there were no differences between the schizophrenia and control groups. Connectivity between the VTA and the hippocampus was correlated with positive symptoms in the schizophrenia group. The connectivity was not associated with medication dose, and the results remained significant after controlling for dose.ConclusionsThe results suggest that altered brain functional connectivity related to VTA networks could be associated with the distinctive pathophysiologies of psychiatric disorders, especially affective disorders.

Suicide is a major cause of death in patients with schizophrenia, particularly among those with recent disease onset. Although brain imaging studies have identified the neuroanatomical correlates of suicidal behavior, functional brain activity correlates particularly in patients with recent-onset schizophrenia (ROSZ) remain unknown. Using near-infrared spectroscopy (NIRS) recording with a high-density coverage of the prefrontal area, we investigated whether prefrontal activity is altered in patients with ROSZ having a history of suicide attempts. A 52-channel NIRS system was used to examine hemodynamic changes in patients with ROSZ that had a history of suicide attempts (n = 24) or that lacked such a history (n = 62), and age- and sex-matched healthy controls (n = 119), during a block-design letter fluency task (LFT). Patients with a history of suicide attempts exhibited decreased activation in the right dorsolateral prefrontal cortex compared with those without such a history. Our findings indicate that specific regions of the prefrontal cortex may be associated with suicidal attempts, which may have implications for early intervention for psychosis.

Several reports have highlighted an association between psychotic experiences (PEs) and autism spectrum disorder/autistic traits; however, no systematic review of the evidence has been done. We searched PubMed, PsycINFO, Web of Science, and Cochrane database on November 20, 2018, for studies providing statistical results on the association between PEs and autism spectrum disorder/autistic traits. Meta-analyses were conducted for both the prevalence of PEs in autism spectrum disorder and the correlation coefficients between PEs and autistic traits. Subgroup analyses were conducted for each PE subtype. Among the 17 included studies, 9 had data about prevalence and 8 had data about correlation. The pooled prevalence of PEs in autism spectrum disorder was 24% (95% confidence interval [CI] 14%–34%). However, subanalyses found that prevalence varied between PE subtypes (hallucinations, 6% [95% CI 1%–11%] and delusions, 45% [95% CI 0%–99%]). Pooled results showed that PEs and autistic traits had a weak to medium correlation (r = .34 [95% CI 0.27–0.41]). Based on our meta-analysis, PEs seem to be more prevalent in individuals with autism spectrum disorder/autistic traits than in the general population, but this finding may vary according to the PE subtype. Future studies should focus on statistical results for each PE subtype separately. More studies should be conducted to clarify the relationship between autism spectrum disorder/autistic traits and PEs by subtype.

A potential association between pet ownership and mental well-being is suggested, but there is a shortage of high-quality longitudinal studies that consider probable differences among different species. We aimed to examine whether ownership of the most popular pets (dogs and cats) would predict mental well-being. The Tokyo Teen Cohort (TTC), a prospective population-based birth cohort study, had dog and cat ownership data at age 10 and mental well-being score at ages 10 and 12 from 2584 adolescents. Linear regression analysis with adjusting for covariates showed that dog ownership had a positive effect on mental well-being compared to no dog ownership, however, cat ownership had a negative effect compared to no cat ownership. Two-factor mixed-design analysis of variance showed that dog ownership predicted maintained mental well-being, while cat ownership predicted progressing decline of mental well-being. Thus, dog and cat ownership may have different effects on adolescents&rsquo, mental well-being, implying that the underlying mechanisms that are activated by these types of ownership may differ.

A discrepancy in oxytocin’s behavioral effects between acute and repeated administrations indicates distinct underlying neurobiological mechanisms. The current study employed a combination of human clinical trial and animal study to compare neurochemical changes induced by acute and repeated oxytocin administrations. Human study analyzed medial prefrontal metabolite levels by using 1H-magnetic resonance spectroscopy, a secondary outcome in our randomized, double-blind, placebo-controlled crossover trial of 6 weeks intranasal administrations of oxytocin (48 IU/day) and placebo within-subject design in 17 psychotropic-free high-functioning men with autism spectrum disorder. Medial prefrontal transcript expression levels were analyzed in adult male C57BL/6J mice after intraperitoneal injection of oxytocin or saline either once (200 ng/100 μL/mouse, n = 12) or for 14 consecutive days (200 ng/100 μL/mouse/day, n = 16). As the results, repeated administration of oxytocin significantly decreased the medial prefrontal N-acetylaspartate (NAA; p = 0.043) and glutamate–glutamine levels (Glx; p = 0.001), unlike the acute oxytocin. The decreases were inversely and specifically associated (r = 0.680, p = 0.004 for NAA; r = 0.491, p = 0.053 for Glx) with oxytocin-induced improvements of medial prefrontal functional MRI activity during a social judgment task not with changes during placebo administrations. In wild-type mice, we found that repeated oxytocin administration reduced medial frontal transcript expression of N-methyl-d-aspartate receptor type 2B (p = 0.018), unlike the acute oxytocin, which instead changed the transcript expression associated with oxytocin (p = 0.0004) and neural activity (p = 0.0002). The present findings suggest that the unique sensitivity of the glutamatergic system to repeated oxytocin administration may explain the differential behavioral effects of oxytocin between acute and repeated administration.

Summary: Compelling evidence in Caucasian populations suggests a role for copy-number variations (CNVs) in autism spectrum disorder (ASD) and schizophrenia (SCZ). We analyzed 1,108 ASD cases, 2,458 SCZ cases, and 2,095 controls in a Japanese population and confirmed an increased burden of rare exonic CNVs in both disorders. Clinically significant (or pathogenic) CNVs, including those at 29 loci common to both disorders, were found in about 8% of ASD and SCZ cases, which was significantly higher than in controls. Phenotypic analysis revealed an association between clinically significant CNVs and intellectual disability. Gene set analysis showed significant overlap of biological pathways in both disorders including oxidative stress response, lipid metabolism/modification, and genomic integrity. Finally, based on bioinformatics analysis, we identified multiple disease-relevant genes in eight well-known ASD/SCZ-associated CNV loci (e.g., 22q11.2, 3q29). Our findings suggest an etiological overlap of ASD and SCZ and provide biological insights into these disorders. : Kushima et al. perform comparative analyses of CNVs in ASD and SCZ in a Japanese population. They identify pathogenic CNVs and biological pathways in each disorder with significant overlap. Patients with pathogenic CNVs have a higher prevalence of intellectual disability. Disease-relevant genes are detected in eight well-known ASD/SCZ-associated CNV loci. Keywords: autism spectrum disorder, schizophrenia, copy-number variation, array comparative genomic hybridization, genetic overlap, Japanese population, oxidative stress response, genome integrity, lipid metabolism, gene ontology

The child-parent relationship is a significant factor in an adolescent’s well-being and functional outcomes. Epidemiological evidence indicates that relationships with the father and mother are differentially associated with specific psychobehavioral problems that manifest differentially between boys and girls. Neuroimaging is expected to bridge the gap in understanding such a complicated mapping between the child-parent relationships and adolescents’ problems. However, possible differences in the effects of child-father and child-mother relationships on sexual dimorphism in children’s brains and psychobehavioral problems have not been examined yet. This study used a dataset of 10- to 13-year-old children (N ​= ​93) to reveal the triad of associations among child-parent relationship, brain, and psychobehavioral problems by separately estimating the respective effects of child-father and child-mother relationships on boys and girls. We first fitted general linear models to identify the effects of paternal and maternal relationships in largely different sets of children’s resting-state functional connectivity, which we term paternal and maternal functional brain connectomes (FBCs). We then performed connectome-based predictive modeling (CPM) to predict children’s externalizing and internalizing problems from these parental FBCs. The models significantly predicted a range of girls’ internalizing problems, whereas the prediction of boys’ aggression was also significant using a more liberal uncorrected threshold. A series of control analyses confirmed that CPMs using FBCs associated with peer relationship or family socioeconomic status failed to make significant predictions of psychobehavioral problems. Lastly, a causal discovery method identified causal paths from daughter-mother relationship to maternal FBC, and then to daughter’s internalizing problems. These observations indicate sex-dependent mechanisms linking child-parent relationship, brain, and psychobehavioral problems in the development of early adolescence.

Introduction Bullying among adolescents can cause depression and suicidality. Identifying the risk factors for bullying in early adolescence, when its prevalence tends to increase, would assist in its prevention. Although certain parenting styles are known to be associated with bullying, the association of slapping as a parental disciplinary practice with early adolescent bullying is not sufficiently understood. Furthermore, little is known about how warm parenting modifies this association although slapping and warm parenting are not mutually exclusive. The aim of this study was to investigate the association of slapping with the experience of early adolescent bullying––categorized in terms of victims, bullies, and bully-victims––while considering how warm parenting modifies this association. Methods This study used data from the Tokyo Early Adolescence Survey, a cross-sectional survey of 4478 children aged 10 from the general population. Data were collected from both children and their primary parent using self-administered questionnaires and face-to-face interviews. Responses from 4326 participants with no missing data were usable for the current analysis (mean age, 10.2 ± 0.3 years; 53 % boys). Results Frequent and occasional slapping was associated with increased odds of youth being identified as bullies or bully-victims, even after adjusting for warm parenting. The likelihood of being victims, bullies or bully-victims increased as the frequency of slapping increased. Conclusion Disciplinary slapping was associated with increased odds of bullying in early adolescence, regardless of whether warm parenting was present or not.

Depressive disorders in epilepsy often present characteristic clinical manifestations atypical in primary, endogenous depression. Here, we report a case of a 64-year-old woman with right mesial temporal lobe epilepsy, who complained of bizarre, antipsychotic-refractory cenesthetic hallucinations in her interictal phase, and was hospitalized after a suicide attempt. Detailed clinical observations revealed mood symptoms, which led to the diagnosis of interictal dysphoric disorder comorbid with interictal psychosis. Sertraline with low-dose aripiprazole markedly alleviated both depressive and psychotic symptoms. This case suggested that the two diagnostic entities may overlap and that depressive symptoms tend to be concurrent when concurring with psychosis, which hampers the appropriate choice of a treatment option., Highlights • Prominent psychosis overshadowed symptoms of interictal dysphoric disorder (IDD). • Interictal psychosis (IIP) may be more severe form of IDD. • Self-report inventories may miss IDD with psychotic features. • Sertraline with low-dose aripiprazole may be a promising pharmacological treatment in severe IDD.

Recent studies have shown that microRNAs (miRNAs) play a role as regulators of neurodevelopment by modulating gene expression. Altered miRNA expression has been reported in various psychiatric disorders, including schizophrenia. However, the changes in the miRNA expression profile that occur during the initial stage of schizophrenia have not been fully investigated. To explore the global alterations in miRNA expression profiles that may be associated with the onset of schizophrenia, we first profiled miRNA expression in plasma from 17 patients with first-episode schizophrenia and 17 healthy controls using microarray analysis. Among the miRNAs that showed robust changes, the elevated expression of has-miR-223-3p (miR-223) was validated via quantitative reverse transcription-polymerase chain reaction (qRT-PCR) using another independent sample set of 21 schizophrenia patients and 21 controls. To identify the putative targets of miR-223, we conducted a genome-wide gene expression analysis in neuronally differentiated SK-N-SH cells with stable miR-223 overexpression and an in silico analysis. We found that the mRNA expression levels of four genes related to the cytoskeleton or cell migration were significantly downregulated in miR-223-overexpressing cells, possibly due to interactions with miR-223. The in silico analysis suggested the presence of miR-223 target sites in these four genes. Lastly, a luciferase assay confirmed that miR-223 directly interacted with the 3′ untranslated regions (UTRs) of all four genes. Our results reveal an increase in miR-223 in plasma during both the first episode and the later stage of schizophrenia, which may affect the expression of cell migration-related genes targeted by miR-223.

Objective Uncovering molecular bases for auditory language processing in the human brain is a fundamental scientific challenge. The power and latency of the magnetic mismatch field (MMF) elicited by phoneme change, which are magnetoencephalographic indices of language function in its early stage of information processing, are theoretically thought to be modulated by N-methyl- d -aspartate-type glutamate receptor (NMDAR) function, but no study has yet assessed this possibility. We have thus sought to demonstrate an association between phonetic MMF power/latency and levels of plasma d -serine, an intrinsic co-agonist of glycine binding sites on NMDAR, in adults. Methods The MMF response to phoneme changes was recorded using 204-channel magnetoencephalography in 61 healthy, right-handed, Japanese adults. Plasma levels of d - and l -serine were measured for each participant. Results We did not find a significant correlation between MMF power/latency and plasma serine levels. Conclusions Despite a sufficient sample size, we failed to find an association between the physiological markers of the early stage of information processing of language in the auditory cortex and biomarkers indexing glutamatergic function. Significance Our study did not indicate that a molecular index of glutamatergic function could be a surrogate marker for the early stage of information processing of language in humans.

Although small-scale studies have described the effects of oxytocin on social deficits in autism spectrum disorder (ASD), no large-scale study has been conducted. In this randomized, parallel-group, multicenter, placebo-controlled, double-blind trial in Japan, 106 ASD individuals (18–48 y.o.) were enrolled between Jan 2015 and March 2016. Participants were randomly assigned to a 6-week intranasal oxytocin (48IU/day, n = 53) or placebo (n = 53) group. One-hundred-three participants were analyzed. Since oxytocin reduced the primary endpoint, Autism Diagnostic Observation Schedule (ADOS) reciprocity, (from 8.5 to 7.7; P

Although advanced paternal and maternal age at birth (PA/MA) increases the risk of autism spectrum disorder (ASD), the underlying neurobiological mechanisms are not fully understood. To explore the neuroanatomical correlates of advanced PA/MA, the current study conducted brain morphometric analyses in 39 high-functioning adult males with ASD and 39 age-, intellectual level-, and parental socioeconomic background-matched, typically developed (TD) males. Whole-brain analysis revealed that the regional gray matter volume (GMV) in bilateral posterior cingulate cortex (PCC) and precuneus (PCU) were significantly smaller in the individuals with ASD than in TD subjects (false discovery rate-corrected P = 0.014). Additional analyses of the constituents of GMV reduction in these brain regions revealed that the cortical thickness of the right ventral PCC was significantly thinner (P = 0.014) and the surface area of bilateral PCU was significantly smaller (left: P = 0.001; right: P = 0.049) in the adults with ASD, compared with TD subjects. Although the analyses were exploratory, the thinner cortical thickness of right ventral PCC was significantly correlated with older PA in the ASD individuals (P = 0.028). The current findings shed new light on the neurobiological mechanisms underlying the link between advanced PA and ASD.

Impulsive behaviours are common symptoms of attention-deficit hyperactivity disorder (ADHD). Although previous studies have suggested functional models of impulsive behaviour, a full explanation of impulsivity in ADHD remains elusive. To investigate the detailed mechanisms behind impulsive behaviour in ADHD, we applied an economic intertemporal choice task involving gains and losses to adults with ADHD and healthy controls and measured brain activity by functional magnetic resonance imaging. In the intertemporal choice of future gains, we observed no behavioural or neural difference between the two groups. In the intertemporal choice of future losses, adults with ADHD exhibited higher discount rates than the control participants. Furthermore, a comparison of brain activity representing the sensitivity of future loss in the two groups revealed significantly lower activity in the striatum and higher activity in the amygdala in adults with ADHD than in controls. Our preliminary findings suggest that an altered size sensitivity to future loss is involved in apparent impulsive choice behaviour in adults with ADHD and shed light on the multifaceted impulsivity underlying ADHD.

Changes in the surface morphology of the orbitofrontal cortex (OFC), such as a fewer orbital sulci and altered sulcogyral pattern of the 'H-shaped' orbital sulcus, have been reported in schizophrenia, possibly reflecting abnormal neurodevelopment during gestation. However, whether high-risk subjects for developing psychosis also exhibit these gross morphologic anomalies is not well documented. This multicenter MRI study from four scanning sites in Japan investigated the distribution of the number of intermediate and posterior orbital sulci, as well as the OFC sulcogyral pattern, in 125 individuals with an at-risk mental state (ARMS) [of whom 22 later developed psychosis (ARMS-P) and 89 did not (ARMS-NP)] and 110 healthy controls. The ARMS group as a whole had a significantly lower number of intermediate and posterior orbital sulci compared with the controls, which was associated with prodromal symptomatology. However, there was no group difference in OFC pattern distribution. The ARMS-P and -NP groups did not differ in OFC surface morphology. These results suggest that gross morphology of the OFC in high-risk subjects may at least partly reflect neurodevelopmental pathology related to vulnerability to psychosis.

Aim Schizophrenia (SZ) and bipolar disorder (BD) have been known to share genetic and environmental risk factors, and complex gene-environmental interactions may contribute to their pathophysiology. In contrast to high genetic overlap between SZ and BD, as revealed by genome-wide association studies, the extent of epigenetic overlap remains largely unknown. In the present study, we explored whether SZ and BD share epigenetic risk factors in the same manner as they share genetic components. Methods We performed DNA methylation analyses of the CpG sites in the top five candidate regions (FAM63B, ARHGAP26, CTAGE11P, TBC1D22A, and intergenic region [IR] on chromosome 16) reported in a previous methylome-wide association study (MWAS) of SZ, using whole blood samples from subjects with BD and controls. Results Among the five candidate regions, the CpG sites in FAM63B and IR on chromosome 16 were significantly hypomethylated in the samples from subjects with BD as well as those from subjects with SZ. On the other hand, the CpG sites in TBC1D22A were hypermethylated in the samples from subjects with BD, in contrast to hypomethylation in the samples from subjects with SZ. Conclusion Hypomethylation of FAM63B and IR on chromosome 16 could be common epigenetic risk factors for SZ and BD. Further comprehensive epigenetic studies for BD, such as MWAS, will uncover the extent of similarity and uniqueness of epigenetic alterations.

Aim Somatic mutations in the human brain are hypothesized to contribute to the functional diversity of brain cells as well as the pathophysiology of neuropsychiatric diseases. However, there are still few reports on somatic mutations in non-neoplastic human brain tissues. This study attempted to unveil the landscape of somatic mutations in the human brain. Methods We explored the landscape of somatic mutations in human brain tissues derived from three individuals with no neuropsychiatric diseases by whole-genome deep sequencing at a depth of around 100. The candidate mutations underwent multi-layered filtering, and were validated by ultra-deep target amplicon sequencing at a depth of around 200 000. Results Thirty-one somatic mutations were identified in the human brain, demonstrating the utility of whole-genome sequencing of bulk brain tissue. The mutations were enriched in neuron-expressed genes, and two-thirds of the identified somatic single nucleotide variants in the brain tissues were cytosine-to-thymine transitions, half of which were in CpG dinucleotides. Conclusion Our developed filtering and validation approaches will be useful to identify somatic mutations in the human brain. The vulnerability of neuron-expressed genes to mutational events suggests their potential relevance to neuropsychiatric diseases.

Aim Hypofunction of N-methyl-D-aspartate receptors (NMDAR) may contribute to the pathophysiology of schizophrenia (SCZ). Recently, the glycine cleavage system (GCS) was shown to affect NMDAR function in the brain. GCS functional defects cause nonketotic hyperglycinemia, the atypical phenotype of which presents psychiatric symptoms similar to SCZ. Here, we examined the involvement of GCS in SCZ. Methods First, to identify the rare variants and the exonic deletions, we resequenced all the coding exons and the splice sites of four GCS genes (GLDC, AMT, GCSH, and DLD) in 474 patients with SCZ and 475 controls and performed multiplex ligation-dependent probe amplification analysis in SCZ. Next, we performed metabolome analysis using plasma of patients harboring GCS variants (n = 5) and controls (n = 5) by capillary electrophoresis time-of-flight mass spectrometry. The correlation between plasma metabolites and Positive and Negative Syndrome Scale score was further examined. Results Possibly damaging variants were observed in SCZ: A203V, S801N in GLDC, near the atypical nonketotic hyperglycinemia causative mutations (A202V, A802V); G825D in GLDC, a potential neural tube defect causative mutation; and R253X in AMT. Marked elevation of plasma 5-oxoproline (pyroglutamic acid), aspartate, and glutamate, which might affect NMDAR function, was observed in patients harboring GCS variants. The aspartate level inversely correlated with negative symptoms (r = -0.942, P = 0.0166). Conclusion These results suggest that GCS rare variants possibly contribute to the pathophysiology of SCZ by affecting the negative symptoms through elevation of aspartate.

Major depressive disorder is a common psychiatric disorder that is thought to be triggered by both genetic and environmental factors. Depressive symptoms are an important public health problem and contribute to vulnerability to major depression. Although a substantial number of genetic and epigenetic studies have been performed to date, the detailed etiology of depression remains unclear and there are no validated biomarkers. DNA methylation is one of the major epigenetic modifications that play diverse roles in the etiology of complex diseases. In this study, we performed an epigenome-wide association study (EWAS) of DNA methylation on subjects with (N = 20) or without (N = 27) depressive symptoms in order to examine whether different levels of DNA methylation were associated with depressive tendencies. Employing methylation-array technology, a total of 363,887 methylation sites across the genomes were investigated and several candidate CpG sites associated with depressive symptoms were identified, especially annotated to genes linked to a G-protein coupled receptor protein signaling pathway. These data provide a strong impetus for validation studies using a larger cohort and support the possibility that G-protein coupled receptor protein signaling pathways are involved in the pathogenesis of depression.

The association between emotional stimuli and temporal lobe epilepsy (TLE) is largely unknown. Here, we report the case of a depressed, 50-year-old female complaining of episodes of a “spaced out” experience precipitated by emotional stimuli. Psychogenic non-epileptic attacks were suspected. However, video-EEG coupled with emotional stimuli-provoked procedures and MRI findings of amygdala enlargement, led to the diagnosis of left TLE. Accurate diagnosis and explanation improved her subjective depression and seizure frequency. This case demonstrated that emotional stimuli can provoke seizures in TLE and suggested the involvement of the enlarged amygdala and the modulation of emotion-related neural circuits., Highlights • Emotional stimuli provoked seizures in TLE with amygdala enlargement. • Amygdala enlargement may be associated with the mechanism that elicits seizures. • Optimizing anti-seizure drugs and emotional stimuli management were crucial. • A correct diagnosis may resolve the distress of patients with PNEA and/or TLE. • Thorough investigation is needed before the diagnosis of PNEA is confirmed.

Background The effect of duration of illness and antipsychotic medication on the volumes of subcortical structures in schizophrenia is inconsistent among previous reports. We implemented a large sample analysis utilizing clinical data from 11 institutions in a previous meta-analysis. Methods Imaging and clinical data of 778 schizophrenia subjects were taken from a prospective meta-analysis conducted by the COCORO consortium in Japan. The effect of duration of illness and daily dose and type of antipsychotics were assessed using the linear mixed effect model where the volumes of subcortical structures computed by FreeSurfer were used as a dependent variable and age, sex, duration of illness, daily dose of antipsychotics and intracranial volume were used as independent variables, and the type of protocol was incorporated as a random effect for intercept. The statistical significance of fixed-effect of dependent variable was assessed. Results Daily dose of antipsychotics was positively associated with left globus pallidus volume and negatively associated with right hippocampus. It was also positively associated with laterality index of globus pallidus. Duration of illness was positively associated with bilateral globus pallidus volumes. Type of antipsychotics did not have any effect on the subcortical volumes. Discussion A large sample size, uniform data collection methodology and robust statistical analysis are strengths of the current study. This result suggests that we need special attention to discuss about relationship between subcortical regional brain volumes and pathophysiology of schizophrenia because regional brain volumes may be affected by antipsychotic medication., Graphical abstract Image 2, Highlights • The imaging data as well as prescription data and demographics from 778 patients with schizophrenia from 11 institutions were included. • The effect of protocol was cooperated as random-effect in the linear mixed-effect model. • Significant positive association were found between daily dose of antipsychotics and left globus pallidus volume. • Significant negative association was found between daily dose of antipsychotics and right hippocampus volume. • Significant positive associations were found between duration of illness and bilateral volumes of globus pallidus.

Memory performance is severely impaired in individuals with schizophrenia. Although several studies have reported a relationship between memory performance and hippocampal volume, only a few structural magnetic resonance imaging (MRI) studies have investigated the relationship between memory performance and subcortical structures other than hippocampus in patients with schizophrenia. We investigated the relationship between memory performance and subcortical regional volumes in a large sample of patients with schizophrenia. Participants included 174 patients with schizophrenia and 638 healthy comparison subjects (HCS). The Wechsler Memory Scale-Revised (WMS-R) has three memory indices (verbal immediate recall, visual immediate recall, and delayed recall (verbal plus visual)) and one control neurocognitive index (attention/concentration). We obtained T1-weighted MRI data and measured the bilateral volumes of the hippocampus, amygdala, thalamus, nucleus accumbens (NA), caudate, putamen, and globus pallidus. Patients with schizophrenia had significantly lower scores for all of the indices of the WMS-R than the HCS. They had more severe impairments in verbal immediate recall and delayed recall than in visual immediate recall and attention/concentration. Verbal immediate recall/delayed recall scores in patients with schizophrenia were significantly correlated not only with hippocampal volume (left: r = 0.34; right: r = 0.28/left: r = 0.33; right: r = 0.31), but also with NA volume (left: r = 0.24; right: r = 0.25/left: r = 0.26; right: r = 0.27). The present investigation with a large sample size did not only replicate hippocampal volume and memory association, but also found that NA volume is associated with memory performances in schizophrenia.

Patients with schizophrenia can exhibit intelligence decline, which is an important element of cognitive impairment. Previous magnetic resonance imaging (MRI) studies have demonstrated that patients with schizophrenia have altered gray matter structures and functional connectivity associated with intelligence decline defined by a difference between premorbid and current intelligence quotients (IQs). However, it has remained unclear whether white matter microstructures are related to intelligence decline. In the present study, the indices of diffusion tensor imaging (DTI) obtained from 138 patients with schizophrenia and 554 healthy controls were analyzed. The patients were classified into three subgroups based on intelligence decline: deteriorated (94 patients), preserved (42 patients), and compromised IQ (2 patients) groups. Given that the DTI of each subject was acquired using either one of two different MRI scanners, we analyzed DTI indices separately for each scanner group. In the comparison between the deteriorated IQ group and the healthy controls, differences in some DTI indices were noted in three regions of interest irrespective of the MRI scanners, whereas differences in only one region of interest were noted between the preserved IQ group and the healthy controls. However, the comparisons between the deteriorated and preserved IQ groups did not show any reproducible differences. Together with the previous findings, it is thought that gray matter structures and functional connectivity are more promising as markers of intelligence decline in schizophrenia than white matter microstructures.

Retrotransposon long interspersed nuclear element-1 (LINE-1) occupies a large proportion of the mammalian genome, comprising approximately 100,000 genomic copies in mice. Epigenetic status of the 5′ untranslated region (5′-UTR) of LINE-1 is critical for its promoter activity. DNA methylation levels in the 5′-UTR of human active LINE-1 subfamily can be measured by well-established methods, such as a pyrosequencing-based assay. However, because of the considerable sequence and structural diversity in LINE-1 among species, methods for such assays should be adapted for the species of interest. Here we developed pyrosequencing-based assays to examine methylcytosine (mC) and hydroxymethylcytosine (hmC) levels of the three active LINE-1 subfamilies in mice (TfI, A, and GfII). Using these assays, we quantified mC and hmC levels in four brain regions and four nonbrain tissues including tail, heart, testis, and ovary. We observed tissue- and subfamily-specific mC and hmC differences. We also found that mC levels were strongly correlated among different brain regions, but mC levels of the testis showed a poor correlation with those of other tissues. Interestingly, mC levels in the A and GfII subfamilies were highly correlated, possibly reflecting their close evolutionary relationship. Our assays will be useful for exploring the epigenetic regulation of the active LINE-1 subfamilies in mice.

The limited efficacy of available antidepressant therapies may be due to how they affect the underlying brain network. The purpose of this study was to develop a melancholic MDD biomarker to identify critically important functional connections (FCs), and explore their association to treatments. Resting state fMRI data of 130 individuals (65 melancholic major depressive disorder (MDD) patients, 65 healthy controls) were included to build a melancholic MDD classifier, and 10 FCs were selected by our sparse machine learning algorithm. This biomarker generalized to a drug-free independent cohort of melancholic MDD, and did not generalize to other MDD subtypes or other psychiatric disorders. Moreover, we found that antidepressants had a heterogeneous effect on the identified FCs of 25 melancholic MDDs. In particular, it did impact the FC between left dorsolateral prefrontal cortex (DLPFC)/inferior frontal gyrus (IFG) and posterior cingulate cortex (PCC)/precuneus, ranked as the second 'most important' FC based on the biomarker weights, whilst other eight FCs were normalized. Given that left DLPFC has been proposed as an explicit target of depression treatments, this suggest that the limited efficacy of antidepressants might be compensated by combining therapies with targeted treatment as an optimized approach in the future.

Motor tics are sudden, rapid, recurrent, non-rhythmic movements. There is a lack of quantitative assessment methods for the motor tics despite severe neck complications. We aimed to provide an improved quantitative method for neck tic assessment in motor tic disorders. We recorded neck motor tics in patients with motor tic disorders and voluntary neck movements in healthy controls. The maximum peak angular velocities and angular accelerations were calculated. Motor tics were assessed in three orthogonal planes (yaw, pitch, and roll) separately, and compared between the patients with motor tic disorders and controls. Correlations between the maximum angular velocities/accelerations and tic counts were also assessed. In the pitch plane, motor tics of the patients showed higher angular velocities/accelerations than voluntary movements of the controls. Angular acceleration in the yaw, and roll planes showed positive correlations with tic count. Some of the observed tics were comparable to the movements experienced in contact sports. Our findings may aid in the identification of populations at a high risk for severe neck complications among motor tic disorder patients.

Aim Research efforts aiming at neuroimaging-aided differential diagnosis for psychiatric disorders have been progressing rapidly. A previous multisite study has developed supplementary diagnostic system using functional near-infrared spectroscopy (fNIRS) that can be easily applied to clinical settings. However, few neuroimaging biomarkers have been developed for psychosis spectrum with various clinical stages. Methods We employed the fNIRS as a clinical examination device for 143 participants, comprising 47 ultra-high risk (UHR) individuals, 30 patients with first-episode psychosis (FEP), 34 patients with chronic schizophrenia (ChSZ), and 33 healthy controls, who were independent of the previous study. A 12-month follow-up measurement was also carried out on 34 UHR individuals (72%), 21 patients with FEP (70%), and 33 controls. The fNIRS algorithm variables used for classification were the intensity and timing of prefrontal activation following the start of the cognitive task as used in the previous multisite study. Results Discrimination rate by timing of activation was modest but it became acceptable after adjusting confounding factors. Discrimination by intensity of activation was not improved by similar adjustment. 63.8%, 86.7%, and 81.3% were classified to patient group in the UHR, FEP, and ChSZ groups, respectively; and 85.1%, 86.7%, and 71.9% were classified as psychosis spectrum. In the follow-up measurement, 88.2% individuals with UHR and 95.0% patients with FEP were successfully classified into psychosis spectrum group. Conclusion The fNIRS for supplementary clinical examination could be validly applied to differentiating people with the psychosis spectrum in various clinical stages. The fNIRS is a candidate biological marker for aiding diagnosis of psychosis spectrum in routine clinical settings.

Aim There is an increasing need for identifying neurocognitive predictors of global functional outcome in early psychosis toward optimizing early intervention strategy. Methods We conducted a longitudinal observational study to investigate an association between neurocognitive assessments at baseline and global functional outcome at an average of one-year follow-up. Participants included ultra-high-risk for psychosis (UHR) individuals who had not converted to psychosis during the follow-up period (UHR-NP), and those with first-episode psychosis (FEP) individuals. We evaluated neurocognition at baseline using the Brief Assessment of Cognition in Schizophrenia Japanese version (BACS-J), including verbal memory, working memory, motor speed, verbal fluency, attention/processing speed, and executive function. We also assessed global functional outcome using modified Global Assessment of Functioning (mGAF) scale both at baseline and after the follow-up period. Results 34 UHR-NP individuals (34/47, 72%) and 29 FEP individuals (29/36, 81%) completed assessment of neurocognitive function at baseline and functional outcome at follow-up. In the UHR-NP group, attention/processing speed was significantly associated with the mGAF score at follow-up. In the FEP group, executive function was significantly associated with the average mGAF score during the follow-up. Conclusion The attention/processing speed and executive function at baseline may predict global functional outcome of early psychosis. These neurocognitive tests are easy to incorporate in clinical settings and, if replicated in independent samples, may be included in routine clinical assessments for prediction of functional outcome in early psychosis.

Psychiatry research has long experienced a stagnation stemming from a lack of understanding of the neurobiological underpinnings of phenomenologically defined mental disorders. Recently, the application of computational neuroscience to psychiatry research has shown great promise in establishing a link between phenomenological and pathophysiological aspects of mental disorders, thereby recasting current nosology in more biologically meaningful dimensions. In this review, we highlight recent investigations into computational neuroscience that have undertaken either theory- or data-driven approaches to quantitatively delineate the mechanisms of mental disorders. The theory-driven approach, including reinforcement learning models, plays an integrative role in this process by enabling correspondence between behavior and disorder-specific alterations at multiple levels of brain organization, ranging from molecules to cells to circuits. Previous studies have explicated a plethora of defining symptoms of mental disorders, including anhedonia, inattention, and poor executive function. The data-driven approach, on the other hand, is an emerging field in computational neuroscience seeking to identify disorder-specific features among high-dimensional big data. Remarkably, various machine-learning techniques have been applied to neuroimaging data, and the extracted disorder-specific features have been used for automatic case–control classification. For many disorders, the reported accuracies have reached 90% or more. However, we note that rigorous tests on independent cohorts are critically required to translate this research into clinical applications. Finally, we discuss the utility of the disorder-specific features found by the data-driven approach to psychiatric therapies, including neurofeedback. Such developments will allow simultaneous diagnosis and treatment of mental disorders using neuroimaging, thereby establishing ‘theranostics’ for the first time in clinical psychiatry.

Inferring beliefs and social emotions of others has different neural substrates and possibly different roles in the pathophysiology of different clinical phases of schizophrenia. The current study investigated the neural basis for inferring others’ beliefs and social emotions, as individual concepts, in 17 subjects at ultra-high risk for psychosis (UHR), 16 patients with schizophrenia and 20 healthy controls. Brain activity significantly differed from normal in both the left superior temporal sulcus (STS) and the inferior frontal gyrus (IFG) in the schizophrenia group while inferring others’ beliefs, whereas those of UHR group were in the middle of those in the schizophrenia and healthy-control groups. Brain activity during inferring others’ social emotions significantly differed in both the left STS and right IFG among individuals at UHR; however, there was no significant difference in the schizophrenia group. In contrast, brain activity differed in the left IFG of those in both the schizophrenia and UHR groups while inferring social emotion. Regarding the difference in direction of the abnormality, both the UHR and schizophrenia groups were characterized by hyper-STS and hypo-IFG activations when inferring others’ beliefs and emotions. These findings might reflect different aspects of the same pathophysiological process at different clinical phases of psychosis.

Background Previous magnetic resonance imaging (MRI) studies in patients with schizophrenia have demonstrated reduced cortical thickness predominantly in the fronto-temporal regions, but several MRI studies of regional cortical thickness in individuals at clinical high-risk for psychosis have reported inconsistent results. In addition, it remains elusive whether abnormalities of the cortical thickness in individuals at risk of psychosis, if present, are related to their functional outcome. Methods T1-weighted structural MR scans were obtained from 107 individuals with at-risk mental state (ARMS), of whom 21 (19.6%) later developed psychosis during clinical follow-up (mean = 4.9 years, SD = 2.6 years), as well as 104 age- and gender- matched healthy control subjects recruited at 4 scanning sites (University of Toyama, Toho University, Tohoku University, and The University of Tokyo). ARMS individuals were subdivided into good (ARMS-G, n = 77) and poor (ARMS-P, n = 13) outcome groups based on the Global Assessment of Functioning (GAF) scores both at baseline and 1-year follow-up. After preprocessing MR images using FreeSurfer software (ver.5.3.), we continuously measured the cortical thickness of entire cortex. A general linear model controlling for age, gender, and sites was used to estimate group differences. To correct for multiple comparisons, a Monte Carlo simulation procedure was used. This study was approved by the Committees on Medical Ethics of each site. After a complete description of the study was provided, written informed consent was obtained from all subjects. Results Compared with the controls, ARMS individuals exhibited significantly reduced cortical thickness in the superior and inferior frontal gyri, parahippocampal gyri, fusiform gyri, temporal pole cortices, and insula cortices bilaterally, as well as in the left middle frontal gyrus and right precuneus cortex. ARMS individuals also showed significantly increased cortical thickness in the left pre- and postcentral gyrus and right pericalcarine cortex in comparison to the controls. Within ARMS population, ARMS-P individuals had significantly reduced cortical thickness in the right paracentral lobule compared with ARMS-G individuals. Discussion Cortical thinning in the fronto-temporal regions as well as cortical thickening in the posterior cortices seen in ARMS individuals might be associated with general vulnerability to psychopathology. Furthermore, cortical thickness of the right paracentral lobule could be a predictive marker for functional outcome in ARMS population.

Aim Studies have reported that cognitive decline occurs after the onset of schizophrenia despite heterogeneity in cognitive function among patients. The aim of this study was to investigate the degree of estimated cognitive decline in patients with schizophrenia by comparing estimated premorbid intellectual functioning and current intellectual functioning. Methods A total of 446 patients with schizophrenia (228 male, 218 female), consisting of three sample sets obtained from 11 psychiatric facilities, and 686 healthy controls participated in this study. The Wechsler Adult Intelligence Scale-III (WAIS-III) was used to measure the participants’ current full-scale IQ (FSIQ). The premorbid IQ was estimated using the Japanese Adult Reading Test-25. Estimated cognitive decline (difference score) was defined as the difference between the estimated premorbid IQ and the current FSIQ. Results Patients with schizophrenia showed greater estimated cognitive decline, a lower FSIQ, and a lower premorbid IQ compared with the healthy controls. The mean difference score, FSIQ, and estimated premorbid IQ were −16.3, 84.2, and 100.5, respectively, in patients with schizophrenia. Furthermore, 39.7% of the patients had a difference score of 20 points or greater decline. A discriminant analysis showed that the difference score accurately predicted 81.6% of the patients and healthy controls. Conclusion These results show the distribution of difference score in patients with schizophrenia. These findings may contribute to assessing the severity of estimated cognitive decline and identifying patients with schizophrenia who suffer from cognitive decline.

Several recent gene expression studies on schizophrenia, including one using monozygotic twins discordant for the disease, have reported the upregulation of adrenomedullin (ADM), which was initially identified as a vasodilator hormone. It has been hypothesized that upregulation of ADM may be a susceptibility factor for schizophrenia, although the exact role of ADM in the central nervous system remains unclear. In this study, we used a microarray analysis to investigate the changes in global gene expression induced by the administration of exogenous ADM in SK-N-SH cells, which allowed us to evaluate the effects of elevated ADM on the central nervous system. A quantitative reverse-transcription PCR study showed that the levels of HSPA1A/1B mRNA, another gene that has been associated with schizophrenia, were significantly suppressed after exogenous ADM treatment. These results indicate that elevated ADM may be involved in the etiology of schizophrenia through the regulation of heat shock protein signaling.

Aim Studies have shown that eye movement abnormalities are possible neurophysiological biomarkers for schizophrenia. The aim of this study was to investigate the utility of eye movement abnormalities in identifying patients with schizophrenia from healthy controls. Methods Eighty-five patients with schizophrenia and 252 healthy controls participated in this study. Eye movement measures were collected from free viewing, fixation stability, and smooth pursuit tests. In an objective and stepwise method, eye movement measures were extracted to create an integrated eye movement score. Results The discriminant analysis resulted in three eye movement measures; the scanpath length during the free viewing test, the horizontal position gain during the fast Lissajous paradigm of the smooth pursuit test, and the duration of fixations during the far distractor paradigm of the fixation stability test. An integrated score using these variables can distinguish patients with schizophrenia from healthy controls with 82% accuracy. The integrated score was correlated with Wechsler Adult Intelligence Scale-Third Edition full scale IQ, Positive and Negative Syndrome Scale scores, and chlorpromazine equivalents, with different correlation patterns in the three eye movement measures used. The discriminant analysis in subgroups matched for age, sex, years of education, and premorbid IQ revealed a sustained classification rate. Conclusion We established an integrated eye movement score with high classification accuracy between patients with schizophrenia and healthy controls, although there was a significant effect of medication. This study provides further evidence of the utility of eye movement abnormalities in schizophrenia pathology and treatment.

Brain/MINDS (Brain Mapping by Integrated Neurotechnologies for Disease Studies) is a national brain project started by Japan in 2014. With the goal of developing the common marmoset as a model animal for neuroscience, the project aims to build a multiscale marmoset brain map, develop new technologies for experimentalists, create transgenic lines for brain disease modeling, and integrate translational findings from the clinical biomarker landscape. Brain/MINDS will collaborate with global brain projects to share technologies and resources.

Aim Neurofeedback has been studied with the aim of controlling cerebral activity. Near-infrared spectroscopy is a non-invasive neuroimaging technique used for measuring hemoglobin concentration changes in cortical surface areas with high temporal resolution. Thus, near-infrared spectroscopy may be useful for neurofeedback, which requires real-time feedback of repeated brain activation measurements. However, no study has specifically targeted neurofeedback, using near-infrared spectroscopy, in the frontal pole cortex. Methods We developed an original near-infrared spectroscopy neurofeedback system targeting the frontal pole cortex. Over a single day of testing, each healthy participant (n = 24) received either correct or incorrect (Sham) feedback from near-infrared spectroscopy signals, based on a crossover design. Results Under correct feedback conditions, significant activation was observed in the frontal pole cortex (P = 0.000073). Additionally, self-evaluation of control and metacognitive beliefs were associated with near-infrared spectroscopy signals (P = 0.006). Conclusion The neurofeedback system developed in this study might be useful for developing control of frontal pole cortex activation.

Multichannel near-infrared spectroscopy (NIRS) is a functional neuroimaging modality that enables easy-to-use and noninvasive measurement of changes in blood oxygenation levels. We developed a clinically-applicable method for estimating resting state functional connectivity (RSFC) with NIRS using a partial correlation analysis to reduce the influence of extraneural components. Using a multi-distance probe arrangement NIRS, we measured resting state brain activity for 8min in 17 healthy participants. Independent component analysis was used to extract shallow and deep signals from the original NIRS data. Pearson's correlation calculated from original signals was significantly higher than that calculated from deep signals, while partial correlation calculated from original signals was comparable to that calculated from deep (cerebral-tissue) signals alone. To further test the validity of our method, we also measured 8min of resting state brain activity using a whole-head NIRS arrangement consisting of 17 cortical regions in 80 healthy participants. Significant RSFC between neighboring, interhemispheric homologous, and some distant ipsilateral brain region pairs was revealed. Additionally, females exhibited higher RSFC between interhemispheric occipital region-pairs, in addition to higher connectivity between some ipsilateral pairs in the left hemisphere, when compared to males. The combined results of the two component experiments indicate that partial correlation analysis is effective in reducing the influence of extracerebral signals, and that NIRS is able to detect well-described resting state networks and sex-related differences in RSFC.

Aims Many studies have shown that natural disasters affect mental health; however, longitudinal data on post-disaster mental health problems are scarce. The aims of our study were to investigate the trend in psychological distress and alcoholism after The Great East Japan Earthquake and tsunami in north eastern Japan, in March 2011. Methods A longitudinal study was conducted using annual health check data for the general population, in the city of Higashi-Matsushima, which was affected by the high impact of tsunami. In 2012 and 2013, the Kessler Psychological Distress Scale and the CAGE questionnaire (for screening for alcoholism) were used to assess psychological distress and prevalence of alcoholism. Results Of 11,855 total eligible residents, 2192 received the annual check in 2012 and 2013. The prevalence of mental illness and the mean score of alcoholism tendency increased during the follow-up period. The majority of respondents (43.8%) with baseline serious mental illness (SMI) continued to have SMI at follow-up; only 16.7% reported recovering. Older age, female sex, and severity of home damage predicted higher psychological distress, while male sex was a risk factor for alcoholism at follow-up. Conclusions Psychological distress deteriorated 2 years after the huge natural disaster, compared with 1 year after the disaster. Long-term mental health care is needed for those affected by natural disasters, particularly those who have suffered loss., Highlights • Long-term trends in psychological distress and alcoholism tendency after natural disasters are unclear. • We examined the trends in psychological distress and alcoholism after a natural disaster in 2011 by a longitudinal study. • The prevalence of mental illness and the mean score of alcoholism tendency increased between 2012 and 2013. • Almost half of individuals with baseline serious mental illness (SMI) continued to have SMI at follow-up. • Older age, being female, and house damage increased psychological distress, and male sex increased alcoholism tendency.

Our previous study showed that enhanced carbonyl stress is closely related to schizophrenia. The endogenous secretory receptor for advanced glycation end-products (esRAGE) is a splice variant of the AGER gene and is one of the soluble forms of RAGE. esRAGE is considered to be a key molecule for alleviating the burden of carbonyl stress by entrapping advanced glycation end-products (AGEs). In the current study, we conducted genetic association analyses focusing on AGER, in which we compared 212 schizophrenic patients to 214 control subjects. We also compared esRAGE levels among a subgroup of 104 patients and 89 controls and further carried out measurements of total circulating soluble RAGE (sRAGE) in 25 patients and 49 healthy subjects. Although the genetic association study yielded inconclusive results, multiple regression analysis indicated that a specific haplotype composed of rs17846798, rs2071288, and a 63 bp deletion, which were in perfect linkage disequilibrium (r2 = 1), and rs2070600 (Gly82Ser) were significantly associated with a marked decrease in serum esRAGE levels. Furthermore, compared to healthy subjects, schizophrenia showed significantly lower esRAGE (p = 0.007) and sRAGE (p = 0.03) levels, respectively. This is the first study to show that serum esRAGE levels are regulated by a newly identified specific haplotype in AGER and that a subpopulation of schizophrenic patients are more vulnerable to carbonyl stress.

Eye movements are indispensable for the collection of visual information in everyday life. Many findings regarding the neural basis of eye movements have been accumulated from neurophysiological and psychophysical studies. In the field of psychiatry, studies on eye movement characteristics in mental illnesses have been conducted since the early 1900s. Participants with schizophrenia are known to have characteristic eye movements during smooth pursuit, saccade control, and visual search. Recently, studies evaluating eye movement characteristics as biomarkers for schizophrenia have attracted considerable attention. In this article, we review the neurophysiological basis of eye movement control and eye movement characteristics in schizophrenia. Furthermore, we discuss the prospects for eye movements as biomarkers for mental illnesses., In this paper, we review recent research on eye movements in schizophrenia and discuss the prospects for eye movements as biomarkers for mental illnesses.