Publications by authors named "Kiyoto Kasai"

376 Publications

Volumetric Differences in Gray and White Matter of Cerebellar Crus I/II across the Different Clinical Stages of Schizophrenia.

Psychiatry Clin Neurosci 2021 Jun 3. Epub 2021 Jun 3.

Center for Evolutionary Cognitive Science, Graduate School of Art and Sciences, The University of Tokyo, 3-8-1 Komaba, Meguro-ku, Tokyo, 153-8902, Japan.

Aim: Schizophrenia is considered to be a disorder of progressive structural brain abnormalities. Previous studies have indicated that the cerebellar Crus I/II plays a critical role in schizophrenia. We aimed to investigate how specific morphological features in the Crus I/II at different critical stages of the schizophrenia spectrum contribute to the disease.

Methods: The study involved 73 participants on the schizophrenia spectrum (28 with ultra-high risk for psychosis [UHR], 17 with first-episode schizophrenia [FES], and 28 with chronic schizophrenia), and 79 healthy controls. We undertook a detailed investigation into differences in Crus I/II volume using a semi-automated segmentation method optimized for the cerebellum. We analyzed the effects of group and sex, as well as their interaction, on Crus I/II volume in gray matter (GM) and white matter (WM).

Results: Significant group × sex interactions were found in WM volumes of the bilateral Crus I/II; the UHR males demonstrated significantly larger WM volumes compared to the other male groups, whereas no significant group differences were found in the female groups. Additionally, WM and GM volumes of the Crus I/II had positive associations with symptom severity in the UHR group, whereas, in contrast, GM volumes in the FES group were negatively associated with symptom severity.

Conclusions: The present findings provide evidence that the morphology of Crus I/II is involved in schizophrenia in a sex- and disease stage-dependent manner. Additionally, alterations of WM volumes of Crus I/II may have potential as a biological marker of early detection and treatment for UHR individuals. This article is protected by copyright. All rights reserved.
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http://dx.doi.org/10.1111/pcn.13277DOI Listing
June 2021

Bidirectional relationship of problematic Internet use with hyperactivity/inattention and depressive symptoms in adolescents: a population-based cohort study.

Eur Child Adolesc Psychiatry 2021 May 22. Epub 2021 May 22.

Department of Neuropsychiatry, The University of Tokyo Hospital, Tokyo, Japan.

Problematic Internet use (PIU), hyperactivity/inattention, and depressive symptoms are comorbid problems in adolescence, but the causal relationships among these issues are unclear. To assess the relationships among PIU, hyperactivity/inattention, and depressive symptoms in adolescents in the general population. This longitudinal cohort study used data from the Tokyo Teen Cohort study in Tokyo, Japan, for two years between October 2012 and January 2015. Of the 3171 pairs of children and parents, 3007 pairs continued to participate in the second wave of the Tokyo Teen Cohort study. A total of 3007 children were included in the analysis (mean [standard deviation] age, 9.7 [0.4] years; 1418 women [47.2%]. Cross-lagged panel analysis revealed that PIU at timepoint 1 was significantly associated with hyperactivity/inattention at timepoint 2 (β = 0.03; 95% confidence interval (CI) 0.01-0.06), and hyperactivity/inattention at timepoint 1 was also significantly associated with PIU at timepoint 2 (β = 0.07; 95% CI 0.04-0.10), even after adjustments were made for depressive symptoms. Furthermore, PIU at timepoint 1 was significantly associated with depressive symptoms at timepoint 2 (β = 0.05; 95% CI 0.01-0.12), and depressive symptoms at timepoint 1 were also significantly associated with PIU at timepoint 2 (β = 0.05; 95% CI 0.02-0.07), even after adjustments were made for hyperactivity/inattention. These results support the bidirectional relationships among PIU, hyperactivity/inattention, and depressive symptoms. PIU may be a target to improve hyperactivity/inattention and depressive symptoms in adolescents.
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http://dx.doi.org/10.1007/s00787-021-01808-4DOI Listing
May 2021

Abnormality of Resting-State Functional Connectivity in Major Depressive Disorder: A Study With Whole-Head Near-Infrared Spectroscopy.

Front Psychiatry 2021 29;12:664859. Epub 2021 Apr 29.

Department of Neuropsychiatry, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.

Near-infrared spectroscopy (NIRS) is a functional neuroimaging modality that has advantages in clinical usage. Previous functional magnetic resonance imaging (fMRI) studies have found that the resting-state functional connectivity (RSFC) of the default mode network (DMN) is increased, while the RSFC of the cognitive control network (CCN) is reduced in patients with major depressive disorder (MDD) compared with healthy controls. This study tested whether the NIRS-based RSFC measurements can detect the abnormalities in RSFC that have been associated with MDD in previous fMRI studies. We measured 8 min of resting-state brain activity in 34 individuals with MDD and 78 age- and gender-matched healthy controls using a whole-head NIRS system. We applied a previously established partial correlation analysis for estimating RSFCs between the 17 cortical regions. We found that MDD patients had a lower RSFC between the left dorsolateral prefrontal cortex and the parietal lobe that comprise the CCN, and a higher RSFC between the right orbitofrontal cortex and ventrolateral prefrontal cortex, compared to those in healthy controls. The RSFC strength of the left CCN was negatively correlated with the severity of depressive symptoms and the dose of antipsychotic medication and positively correlated with the level of social functioning. The results of this study suggest that NIRS-based measurements of RSFCs have potential clinical applications.
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http://dx.doi.org/10.3389/fpsyt.2021.664859DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8116563PMC
April 2021

The Association Between Locus of Control and Psychopathology: A Cross-Cohort Comparison Between a UK (Avon Longitudinal Study of Parents and Children) and a Japanese (Tokyo Teen Cohort) Cohort.

Front Psychol 2021 21;12:600941. Epub 2021 Apr 21.

Unit for Mental Health Promotion, Research Centre for Social Science & Medicine, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan.

An external locus of control (externality) is associated with poorer psychopathology in individualist cultures, but associations are reported to be weaker in collectivist cultures where an external style is less maladaptive. We investigated the prospective association between externality and psychotic-like experiences (PLE) and depressive symptoms (DS) and compared the strength of associations between a UK and a Japanese cohort. Cross-cultural cohort study of a UK (Avon Longitudinal Study of Parents and Children) and a Japanese cohort (Tokyo Teen Cohort). Externality was assessed using the Children's Nowicki and Strickland Internal, External Scale and DS using the Short Moods and Feelings Questionnaire in both cohorts, PLE were assessed with the Psychosis-Like Experiences Questionnaire (ALSPAC), and the Adolescent Psychotic-Like Symptom Screener (TTC). Associations were investigated using multivariable regression models and bivariate regression models to compare the strength of associations. Mean externality in both childhood and adolescence was higher in ALSPAC than in the TTC. Childhood externality was associated with PLE in late childhood and adolescence in both cohorts and adolescent externality was associated with PLE in young adulthood in the ALSPAC cohort. There was a more mixed pattern of association between externality and DS scores. There was little evidence of any differences in the strength of associations between externality and different psychopathologies, or between cohorts. In ALSPAC adolescent externality and early adult psychopathology were more strongly associated than childhood externality and adolescent and early adult psychopathology. There was no evidence that change in externality between childhood and adolescence was associated with new onset PLE or DS in early adulthood. An external locus of control is associated with poor mental health regardless of cultural context.
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http://dx.doi.org/10.3389/fpsyg.2021.600941DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8096915PMC
April 2021

Association of Structural Magnetic Resonance Imaging Measures With Psychosis Onset in Individuals at Clinical High Risk for Developing Psychosis: An ENIGMA Working Group Mega-analysis.

JAMA Psychiatry 2021 May 5. Epub 2021 May 5.

Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, New York.

Importance: The ENIGMA clinical high risk (CHR) for psychosis initiative, the largest pooled neuroimaging sample of individuals at CHR to date, aims to discover robust neurobiological markers of psychosis risk.

Objective: To investigate baseline structural neuroimaging differences between individuals at CHR and healthy controls as well as between participants at CHR who later developed a psychotic disorder (CHR-PS+) and those who did not (CHR-PS-).

Design, Setting, And Participants: In this case-control study, baseline T1-weighted magnetic resonance imaging (MRI) data were pooled from 31 international sites participating in the ENIGMA Clinical High Risk for Psychosis Working Group. CHR status was assessed using the Comprehensive Assessment of At-Risk Mental States or Structured Interview for Prodromal Syndromes. MRI scans were processed using harmonized protocols and analyzed within a mega-analysis and meta-analysis framework from January to October 2020.

Main Outcomes And Measures: Measures of regional cortical thickness (CT), surface area, and subcortical volumes were extracted from T1-weighted MRI scans. Independent variables were group (CHR group vs control group) and conversion status (CHR-PS+ group vs CHR-PS- group vs control group).

Results: Of the 3169 included participants, 1428 (45.1%) were female, and the mean (SD; range) age was 21.1 (4.9; 9.5-39.9) years. This study included 1792 individuals at CHR and 1377 healthy controls. Using longitudinal clinical information, 253 in the CHR-PS+ group, 1234 in the CHR-PS- group, and 305 at CHR without follow-up data were identified. Compared with healthy controls, individuals at CHR exhibited widespread lower CT measures (mean [range] Cohen d = -0.13 [-0.17 to -0.09]), but not surface area or subcortical volume. Lower CT measures in the fusiform, superior temporal, and paracentral regions were associated with psychosis conversion (mean Cohen d = -0.22; 95% CI, -0.35 to 0.10). Among healthy controls, compared with those in the CHR-PS+ group, age showed a stronger negative association with left fusiform CT measures (F = 9.8; P < .001; q < .001) and left paracentral CT measures (F = 5.9; P = .005; q = .02). Effect sizes representing lower CT associated with psychosis conversion resembled patterns of CT differences observed in ENIGMA studies of schizophrenia (ρ = 0.35; 95% CI, 0.12 to 0.55; P = .004) and individuals with 22q11.2 microdeletion syndrome and a psychotic disorder diagnosis (ρ = 0.43; 95% CI, 0.20 to 0.61; P = .001).

Conclusions And Relevance: This study provides evidence for widespread subtle, lower CT measures in individuals at CHR. The pattern of CT measure differences in those in the CHR-PS+ group was similar to those reported in other large-scale investigations of psychosis. Additionally, a subset of these regions displayed abnormal age associations. Widespread disruptions in CT coupled with abnormal age associations in those at CHR may point to disruptions in postnatal brain developmental processes.
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http://dx.doi.org/10.1001/jamapsychiatry.2021.0638DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8100913PMC
May 2021

Validation of the parent version of the Strengths and Difficulties Questionnaire (SDQ) to screen mental health problems among school-age children in Mongolia.

BMC Psychiatry 2021 04 29;21(1):218. Epub 2021 Apr 29.

Department of Health Policy, National Center for Child Health and Development, 2-10-1, Okura, Tokyo, Setagaya, 157-8535, Japan.

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.
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http://dx.doi.org/10.1186/s12888-021-03218-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8086060PMC
April 2021

Global and Parallel Cortical Processing Based on Auditory Gamma Oscillatory Responses in Humans.

Cereb Cortex 2021 Apr 28. Epub 2021 Apr 28.

Department of Neuropsychiatry, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan.

Gamma oscillations are physiological phenomena that reflect perception and cognition, and involve parvalbumin-positive γ-aminobutyric acid-ergic interneuron function. The auditory steady-state response (ASSR) is the most robust index for gamma oscillations, and it is impaired in patients with neuropsychiatric disorders such as schizophrenia and autism. Although ASSR reduction is known to vary in terms of frequency and time, the neural mechanisms are poorly understood. We obtained high-density electrocorticography recordings from a wide area of the cortex in 8 patients with refractory epilepsy. In an ASSR paradigm, click sounds were presented at frequencies of 20, 30, 40, 60, 80, 120, and 160 Hz. We performed time-frequency analyses and analyzed intertrial coherence, event-related spectral perturbation, and high-gamma oscillations. We demonstrate that the ASSR is globally distributed among the temporal, parietal, and frontal cortices. The ASSR was composed of time-dependent neural subcircuits differing in frequency tuning. Importantly, the frequency tuning characteristics of the late-latency ASSR varied between the temporal/frontal and parietal cortex, suggestive of differentiation along parallel auditory pathways. This large-scale survey of the cortical ASSR could serve as a foundation for future studies of the ASSR in patients with neuropsychiatric disorders.
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http://dx.doi.org/10.1093/cercor/bhab103DOI Listing
April 2021

Decreased DNA methylation at promoters and gene-specific neuronal hypermethylation in the prefrontal cortex of patients with bipolar disorder.

Mol Psychiatry 2021 Apr 20. Epub 2021 Apr 20.

Department of Molecular Brain Science, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan.

Bipolar disorder (BD) is a severe mental disorder characterized by repeated mood swings. Although genetic factors are collectively associated with the etiology of BD, the underlying molecular mechanisms, particularly how environmental factors affect the brain, remain largely unknown. We performed promoter-wide DNA methylation analysis of neuronal and nonneuronal nuclei in the prefrontal cortex of patients with BD (N = 34) and controls (N = 35). We found decreased DNA methylation at promoters in both cell types in the BD patients. Gene Ontology (GO) analysis of differentially methylated region (DMR)-associated genes revealed enrichment of molecular motor-related genes in neurons, chemokines in both cell types, and ion channel- and transporter-related genes in nonneurons. Detailed GO analysis further revealed that growth cone- and dendrite-related genes, including NTRK2 and GRIN1, were hypermethylated in neurons of BD patients. To assess the effect of medication, neuroblastoma cells were cultured under therapeutic concentrations of three mood stabilizers. We observed that up to 37.9% of DMRs detected in BD overlapped with mood stabilizer-induced DMRs. Interestingly, mood stabilizer-induced DMRs showed the opposite direction of changes in DMRs, suggesting the therapeutic effects of mood stabilizers. Among the DMRs, 12 overlapped with loci identified in a genome-wide association study (GWAS) of BD. We also found significant enrichment of neuronal DMRs in the loci reported in another GWAS of BD. Finally, we performed qPCR of DNA methylation-related genes and found that DNMT3B was overexpressed in BD. The cell-type-specific DMRs identified in this study will be useful for understanding the pathophysiology of BD.
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http://dx.doi.org/10.1038/s41380-021-01079-0DOI Listing
April 2021

Dietary Restraint Related to Body Weight Maintenance and Neural Processing in Value-Coding Areas in Adolescents.

J Nutr 2021 Apr 13. Epub 2021 Apr 13.

The Center for Integrative Science of Human Behavior (CiSHuB), The University of Tokyo, Tokyo, Japan.

Background: There is an alarming increase in the obesity prevalence among children in an environment of increasing availability of preprocessed high-calorie foods. However, some people maintain a healthy weight even in such obesogenic environments. This difference in body weight management could be attributed to individual differences in dietary restraint; however, its underlying neurocognitive mechanisms in adolescents remain unclear.

Objectives: This study aimed to elucidate these neurocognitive mechanisms in adolescents by examining the relationships between dietary restraint and the food-related value-coding region located in the ventromedial prefrontal cortex (vmPFC).

Methods: The association between dietary restraint and BMI was tested using a multilinear regression analysis in a large early adolescent cohort (n = 2554; age, 12.2 ± 0.3 years; BMI, 17.9 ± 2.5 kg/m2; 1354 boys). Further, an fMRI experiment was designed to assess the association between the vmPFC response to food images and dietary restraint in 30 adolescents (age, 17.6 ± 1.9 years; BMI, 20.7 ± 2.2 kg/m2; 13 boys). Additionally, using 54 individuals from the cohort (age, 14.5 ± 0.6 years; BMI, 18.8 ± 2.6 kg/m2; 31 boys), we assessed the association between dietary restraint and intrinsic vmPFC-related functional connectivity.

Results: In the cohort, adolescents with increased dietary restraint showed a lower BMI (β = -0.38; P < 0.001; B = -0.06; SE = 0.003). The fMRI results showed a decreased vmPFC response to high-calorie food were correlated with greater dietary restraint. Moreover, there was an association of attenuated intrinsic vmPFC-related functional connectivity in the superior and middle frontal gyrus and the middle temporal gyrus with greater dietary restraint.

Conclusions: Our findings suggest that dietary restraint in adolescents could be a preventive factor for weight gain; its effect involves modulating the vmPFC, which is associated with food value coding.
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http://dx.doi.org/10.1093/jn/nxab068DOI Listing
April 2021

Detailed Postmortem Profiling of Inflammatory Mediators Expression Revealed Post-inflammatory Alternation in the Superior Temporal Gyrus of Schizophrenia.

Front Psychiatry 2021 18;12:653821. Epub 2021 Mar 18.

Department of Neuropsychiatry, School of Medicine, Fukushima Medical University, Fukushima, Japan.

Recent studies have lent support to the possibility that inflammation is associated with the pathology of schizophrenia. In the study of measurement of inflammatory mediators, which are markers of inflammation, elevated inflammatory cytokine levels in the brain and blood have been reported in patients with schizophrenia. Several postmortem brain studies have also reported changes in the expression of inflammatory cytokines. However, it is not clear how these elevated inflammatory cytokines interact with other inflammatory mediators, and their association with the pathology of schizophrenia. We comprehensively investigated the expression of 30 inflammatory mediators in the superior temporal gyrus (STG) of 24 patients with schizophrenia and 26 controls using a multiplex method. Overall, inflammatory mediator expression in the STG was mostly unchanged. However, the expression of interleukin (IL)1-α and interferon-gamma-inducible protein (IP)-10 was decreased [IL-1α, median (IQR), 0.51 (0.37-0.70) vs. 0.87 (0.47-1.23), = 0.01; IP-10, 13.99 (8.00-36.64) vs. 30.29 (10.23-134.73), = 0.05], whereas that of IFN-α was increased [2.34 (1.84-4.48) vs. 1.94 (1.39-2.36), = 0.04] in schizophrenia, although these alterations did not remain significant after multiple testing. Clustering based on inflammatory mediator expression pattern and analysis of upstream transcription factors using pathway analysis revealed that the suppression of IL-1α and IP-10 protein expression may be induced by regulation of a common upstream pathway. Neuroinflammation is important in understanding the biology of schizophrenia. While neuroimaging has been previously used, direct observation to determine the expression of inflammatory mediators is necessary. In this study, we identified protein changes, previously unreported, using comprehensive protein analysis in STG. These results provide insight into post-inflammatory alternation in chronic schizophrenia.
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http://dx.doi.org/10.3389/fpsyt.2021.653821DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8012534PMC
March 2021

Brain/MINDS beyond human brain MRI project: A protocol for multi-level harmonization across brain disorders throughout the lifespan.

Neuroimage Clin 2021 Mar 16:102600. Epub 2021 Mar 16.

Laboratory for Brain Connectomics Imaging, RIKEN Center for Biosystems Dynamics Research, Hyogo 650-0047, Japan. Electronic address:

Psychiatric and neurological disorders are afflictions of the brain that can affect individuals throughout their lifespan. Many brain magnetic resonance imaging (MRI) studies have been conducted; however, imaging-based biomarkers are not yet well established for diagnostic and therapeutic use. This article describes an outline of the planned study, the Brain/MINDS Beyond human brain MRI project (BMB-HBM, FY2018 ~ FY2023), which aims to establish clinically-relevant imaging biomarkers with multi-site harmonization by collecting data from healthy traveling subjects (TS) at 13 research sites. Collection of data in psychiatric and neurological disorders across the lifespan is also scheduled at 13 sites, whereas designing measurement procedures, developing and analyzing neuroimaging protocols, and databasing are done at three research sites. A high-quality scanning protocol, Harmonization Protocol (HARP), was established for five high-quality 3 T scanners to obtain multimodal brain images including T1 and T2-weighted, resting-state and task functional and diffusion-weighted MRI. Data are preprocessed and analyzed using approaches developed by the Human Connectome Project. Preliminary results in 30 TS demonstrated cortical thickness, myelin, functional connectivity measures are comparable across 5 scanners, suggesting sensitivity to subject-specific connectome. A total of 75 TS and more than two thousand patients with various psychiatric and neurological disorders are scheduled to participate in the project, allowing a mixed model statistical harmonization. The HARP protocols are publicly available online, and all the imaging, demographic and clinical information, harmonizing database will also be made available by 2024. To the best of our knowledge, this is the first project to implement a prospective, multi-level harmonization protocol with multi-site TS data. It explores intractable brain disorders across the lifespan and may help to identify the disease-specific pathophysiology and imaging biomarkers for clinical practice.
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http://dx.doi.org/10.1016/j.nicl.2021.102600DOI Listing
March 2021

Oxytocin-induced increase in N,N-dimethylglycine and time course of changes in oxytocin efficacy for autism social core symptoms.

Mol Autism 2021 02 23;12(1):15. Epub 2021 Feb 23.

Department of Psychiatry, Hamamatsu University School of Medicine, 1-20-1 Handayama, Higashiku, Hamamatsu City, 431-3192, Japan.

Background: Oxytocin is expected as a novel therapeutic agent for autism spectrum disorder (ASD) core symptoms. However, previous results on the efficacy of repeated administrations of oxytocin are controversial. Recently, we reported time-course changes in the efficacy of the neuropeptide underlying the controversial effects of repeated administration; however, the underlying mechanisms remained unknown.

Methods: The current study explored metabolites representing the molecular mechanisms of oxytocin's efficacy using high-throughput metabolomics analysis on plasma collected before and after 6-week repeated intranasal administration of oxytocin (48 IU/day) or placebo in adult males with ASD (N = 106) who participated in a multi-center, parallel-group, double-blind, placebo-controlled, randomized controlled trial.

Results: Among the 35 metabolites measured, a significant increase in N,N-dimethylglycine was detected in the subjects administered oxytocin compared with those given placebo at a medium effect size (false discovery rate (FDR) corrected P = 0.043, d = 0.74, N = 83). Furthermore, subgroup analyses of the participants displaying a prominent time-course change in oxytocin efficacy revealed a significant effect of oxytocin on N,N-dimethylglycine levels with a large effect size (P = 0.004, d = 1.13, N = 60). The increase in N,N-dimethylglycine was significantly correlated with oxytocin-induced clinical changes, assessed as changes in quantifiable characteristics of autistic facial expression, including both of improvements between baseline and 2 weeks (P = 0.006, r = - 0.485, N = 43) and deteriorations between 2 and 4 weeks (P = 0.032, r = 0.415, N = 37).

Limitations: The metabolites changes caused by oxytocin administration were quantified using peripheral blood and therefore may not directly reflect central nervous system changes.

Conclusion: Our findings demonstrate an association of N,N-dimethylglycine upregulation with the time-course change in the efficacy of oxytocin on autistic social deficits. Furthermore, the current findings support the involvement of the N-methyl-D-aspartate receptor and neural plasticity to the time-course change in oxytocin's efficacy.

Trial Registration: A multi-center, parallel-group, placebo-controlled, double-blind, confirmatory trial of intranasal oxytocin in participants with autism spectrum disorders (the date registered: 30 October 2014; UMIN Clinical Trials Registry: https://upload.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000017703 ) (UMIN000015264).
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http://dx.doi.org/10.1186/s13229-021-00423-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7903697PMC
February 2021

Effects of age and sex on eye movement characteristics.

Neuropsychopharmacol Rep 2021 Jun 21;41(2):152-158. Epub 2021 Feb 21.

Department of Pathology of Mental Diseases, National Institute of Mental Health, National Center of Neurology and Psychiatry, Kodaira, Japan.

Abnormal eye movements are often associated with psychiatric disorders. Eye movements are sensorimotor functions of the brain, and aging and sex would affect their characteristics. A precise understanding of normal eye movements is required to distinguish disease-related abnormalities from natural differences associated with aging or sex. To date, there is no multicohort study examining age-related dependency and sex effects of eye movements in healthy, normal individuals using large samples to ensure the robustness and reproducibility of the results. In this study, we aimed to provide findings showing the impact of age and sex on eye movement measures. The present study used eye movement measures of more than seven hundred healthy individuals from three large independent cohorts. We herein evaluated eye movement measures quantified by using a set of standard eye movement tests that have been utilized for the examination of patients with schizophrenia. We assessed the statistical significance of the effects of age and sex and its reproducibility across cohorts. We found that 4-18 out of 35 eye movement measures were significantly correlated with age, depending on the cohort, and that 10 of those, which are related to the fixation and motor control of smooth pursuit and saccades, showed high reproducibility. On the other hand, the effects of sex, if any, were less reproducible. The present results suggest that we should take age into account when we evaluate abnormalities in eye movements.
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http://dx.doi.org/10.1002/npr2.12163DOI Listing
June 2021

Identification and functional characterization of the extremely long allele of the serotonin transporter-linked polymorphic region.

Transl Psychiatry 2021 Feb 11;11(1):119. Epub 2021 Feb 11.

Department of Molecular Brain Science, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan.

SLC6A4, which encodes the serotonin transporter, has a functional polymorphism called the serotonin transporter-linked polymorphic region (5-HTTLPR). The 5-HTTLPR consists of short (S) and long (L) alleles, each of which has 14 or 16 tandem repeats. In addition, the extralong (XL) and other rare alleles have been reported in 5-HTTLPR. Although they are more frequent in Asian and African than in other populations, the extent of variations and allele frequencies (AFs) were not addressed in a large population. Here, we report the AFs of the rare alleles in a large number of Japanese subjects (N = 2894) consisting of two cohorts. The first cohort (case-control study set, CCSS) consisted of 1366 subjects, including 485 controls and 881 patients with psychosis (bipolar disorder or schizophrenia). The second cohort (the Arao cohort study set, ACSS) consisted of 1528 elderly subjects. During genotyping, we identified 11 novel 5-HTTLPR alleles, including 3 XL alleles. One novel allele had the longest subunit ever reported, consisting of 28 tandem repeats. We named this XL An in vitro luciferase assay revealed that XL has no transcriptional activity. XL was found in two unrelated patients with bipolar disorder in the CCSS and one healthy subject in the ACSS who did not show depressive symptoms or a decline in cognitive function. Therefore, it is unlikely that XL is associated with psychiatric disorders, despite its apparent functional deficit. Our results suggest that unraveling the complex genetic variations of 5-HTTLPR will be important for further understanding its role in psychiatric disorders.
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http://dx.doi.org/10.1038/s41398-021-01242-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7878853PMC
February 2021

Adolescent Problem Gaming and Loot Box Purchasing in Video Games: Cross-sectional Observational Study Using Population-Based Cohort Data.

JMIR Serious Games 2021 Feb 9;9(1):e23886. Epub 2021 Feb 9.

Research Center for Social Science & Medicine, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan.

Background: Video game loot boxes, which can typically be purchased by players or are given as reward, contain random virtual items, or loot, ranging from simple customization options for a player's avatar or character, to game-changing equipment such as weapons and armor. Loot boxes have drawn concern, as purchasing loot boxes might lead to the development of problematic gambling for adolescents. Although parental problem gambling is associated with adolescent problem gambling, no studies have evaluated the prevalence of loot box purchases in adolescents' parents.

Objective: This study investigated the association between loot box purchasing among adolescents and parents, and problem online gaming in population-based samples.

Methods: In total, 1615 adolescent (aged 14 years) gamers from Japan responded to a questionnaire regarding their loot box purchasing and problem online gaming behaviors. Problem online gaming was defined as four or more of the nine addictive behaviors from the Diagnostic and Statistical Manual of Mental Disorders. The adolescents' primary caregivers were asked about their loot box purchasing.

Results: Of the 1615 participants, 57 (3.5%) reported loot box purchasing. This prevalence did not differ according to primary caregivers' loot box purchasing, but adolescents who purchased loot boxes were significantly more likely to exhibit problem online gaming (odds ratio 3.75, 95% CI 2.17-6.48).

Conclusions: Adolescent loot box purchasing is linked to problem online gaming, but not with parents' loot box purchasing. Measures to reduce these behaviors should target reducing addictive symptoms in young video gamers.
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http://dx.doi.org/10.2196/23886DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7902198PMC
February 2021

Development of Metacognition in Adolescence: The Congruency-Based Metacognition Scale.

Front Psychol 2020 6;11:565231. Epub 2021 Jan 6.

Center for Evolutionary Cognitive Sciences, Graduate School of Art and Sciences, The University of Tokyo, Tokyo, Japan.

Introduction: Previous studies on metacognitive ability were explored using self-report questionnaires that are difficult to adequately measure and evaluate when the capacity for self-reference is undeveloped. This study aimed to validate the Congruency-based Metacognition Scale (CMS) to measure metacognition and the feeling of confidence abilities and to investigate the development of metacognition during adolescence.

Methods: The CMS was administered to 633 child-parent pairs in Japan (child, mean age = 16.0 years, 46.0% female; parent, mean age = 48.3 years, 94.9% mother). The CMS metacognition score was assessed based on congruency scores between the self-report of the child from a third-person perspective (3PP) and the parent's report from the first-person perspective (1PP). The CMS self-judgment accuracy score was assessed by the congruency scores between the children's self-report from the 1PP and 3PP. For both measures, the more distant the 3PP on the self-report was from the 1PP on the parent's report and child self-report means low ability. An exploratory factor analysis (EFA) was conducted to examine construct validity and then a confirmatory factor analysis (CFA) was used. Criterion validity was examined by calculating Pearson's correlation coefficients with scores on the Beck Cognitive Insight Scale (BCIS) and Autism Quotient (AQ). We used intraclass correlation and Cronbach's alpha to examine the test-retest and internal consistency reliability.

Results: Based on the results of the EFA and CFA, we adopted one factor structure with five items. The CMS metacognition and CMS self-judgment accuracy showed evidence criterion validity, exhibiting significant correlations with the BCIS self-reflectiveness ( = 0.16) and self-certainty scores ( = 0.17), respectively. Regarding to the AQ, only the CMS metacognition score had significant correlations with the social skills ( = 0.22) and total scale score ( = 0.20). The test-retest reliability showed adequate (intraclass correlation coefficient 0.70-0.81 and the Cronbach's alpha coefficient 0.63-0.59). Adolescents were found to have significantly lower metacognitive ability compared to young adults.

Conclusion: CMS could be a valid and reliable measure to examine metacognitive abilities for adolescents.
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http://dx.doi.org/10.3389/fpsyg.2020.565231DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7815698PMC
January 2021

Shared functional impairment in the prefrontal cortex affects symptom severity across psychiatric disorders.

Psychol Med 2020 Dec 18:1-10. Epub 2020 Dec 18.

University of Tokyo Institute for Diversity & Adaptation of Human Mind (UTIDAHM), Meguro-ku, Tokyo153-8902, Japan.

Background: The prefrontal deficits in psychiatric disorders have been investigated using functional neuroimaging tools; however, no studies have tested the related characteristics across psychiatric disorders considering various demographic and clinical confounders.

Methods: We analyzed 1558 functional brain measurements using a functional near-infrared spectroscopy during a verbal fluency task from 1200 participants with three disease spectra [196 schizophrenia, 189 bipolar disorder (BPD), and 394 major depressive disorder (MDD)] and 369 healthy controls along with demographic characteristics (age, gender, premorbid IQ, and handedness), task performance during the measurements, clinical assessments, and medication equivalent doses (chlorpromazine, diazepam, biperiden, and imipramine) in a consistent manner. The association between brain functions and demographic and clinical variables was tested using a general linear mixed model (GLMM). Then, the direction of relationship between brain activity and symptom severity, controlling for any other associations, was estimated using a model comparison of structural equation models (SEMs).

Results: The GLMM showed a shared functional deficit of brain activity and a schizophrenia-specific delayed activity timing in the prefrontal cortex (false discovery rate-corrected p < 0.05). Comparison of SEMs showed that brain activity was associated with the global assessment of functioning scores in the left inferior frontal gyrus opercularis (IFGOp) in BPD group and the bilateral superior temporal gyrus and middle temporal gyrus, and the left superior frontal gyrus, inferior frontal gyrus triangularis, and IFGOp in MDD group.

Conclusion: This cross-disease large-sample neuroimaging study with high-quality clinical data reveals a robust relationship between prefrontal function and behavioral outcomes across three major psychiatric disorders.
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http://dx.doi.org/10.1017/S0033291720004742DOI Listing
December 2020

Generalizable brain network markers of major depressive disorder across multiple imaging sites.

PLoS Biol 2020 12 7;18(12):e3000966. Epub 2020 Dec 7.

Brain Information Communication Research Laboratory Group, Advanced Telecommunications Research Institutes International, Kyoto, Japan.

Many studies have highlighted the difficulty inherent to the clinical application of fundamental neuroscience knowledge based on machine learning techniques. It is difficult to generalize machine learning brain markers to the data acquired from independent imaging sites, mainly due to large site differences in functional magnetic resonance imaging. We address the difficulty of finding a generalizable marker of major depressive disorder (MDD) that would distinguish patients from healthy controls based on resting-state functional connectivity patterns. For the discovery dataset with 713 participants from 4 imaging sites, we removed site differences using our recently developed harmonization method and developed a machine learning MDD classifier. The classifier achieved an approximately 70% generalization accuracy for an independent validation dataset with 521 participants from 5 different imaging sites. The successful generalization to a perfectly independent dataset acquired from multiple imaging sites is novel and ensures scientific reproducibility and clinical applicability.
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http://dx.doi.org/10.1371/journal.pbio.3000966DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7721148PMC
December 2020

The Association Between Amygdala Subfield-Related Functional Connectivity and Stigma Reduction 12 Months After Social Contacts: A Functional Neuroimaging Study in a Subgroup of a Randomized Controlled Trial.

Front Hum Neurosci 2020 27;14:356. Epub 2020 Aug 27.

University of Tokyo Center for Integrative Science of Human Behavior (CiSHuB), Tokyo, Japan.

Social contact is one of the best methods for reducing stigma, and the effect may be associated with emotional response and social cognition. The amygdala is a key region of these functions and can be divided into three subregions, each of which has a different function and connectivity. We investigated whether the amygdala subregion-related functional connectivity is associated with the effect of anti-stigma interventions on reducing mental health-related stigma in a randomized controlled trial (RCT) over 12 months. Healthy young adults [ = 77, age, mean () = 21.23 (0.94) years; male, = 48], who were subsampled from an RCT ( = 259) investigating the effect of anti-stigma interventions, using filmed social contacts (FSC) or internet self-learning (INS), on reducing stigma, underwent 10 min resting-state functional magnetic resonance imaging between the trial registration and 12 months follow-up. The extent of stigma was assessed at the baseline, post-intervention and 12 month follow-up surveys, using the Japanese-language version of the Social Distance Scale (SDSJ), to assess negative emotional attitude toward people with schizophrenia. We compared associations between amygdala subregion-related functional connectivity and changes in the SDSJ scores for 12 months across the control, INS, and FSC groups. Associations between the change in stigma for 12 months and the superficial (SF) subregion of the amygdala-related connectivity in the intracalcarine cortex [(x, y, z) = (-8, -66, 12), z = 4.21, = 0.0003, cluster size = 192] differed across groups. The analysis showed that the SF-intracalcarine cortex connectivity was negatively correlated with the change in stigma only in the FSC group. The current results indicate that greater SF-intracalcarine cortex connectivity is associated with a better response to the FSC interventions, suggesting that biological variability could underlie the long-term effect of anti-stigma interventions on stigma in the real world.
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http://dx.doi.org/10.3389/fnhum.2020.00356DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7481372PMC
August 2020

The Association Between Amygdala Subfield-Related Functional Connectivity and Stigma Reduction 12 Months After Social Contacts: A Functional Neuroimaging Study in a Subgroup of a Randomized Controlled Trial.

Front Hum Neurosci 2020 27;14:356. Epub 2020 Aug 27.

University of Tokyo Center for Integrative Science of Human Behavior (CiSHuB), Tokyo, Japan.

Social contact is one of the best methods for reducing stigma, and the effect may be associated with emotional response and social cognition. The amygdala is a key region of these functions and can be divided into three subregions, each of which has a different function and connectivity. We investigated whether the amygdala subregion-related functional connectivity is associated with the effect of anti-stigma interventions on reducing mental health-related stigma in a randomized controlled trial (RCT) over 12 months. Healthy young adults [ = 77, age, mean () = 21.23 (0.94) years; male, = 48], who were subsampled from an RCT ( = 259) investigating the effect of anti-stigma interventions, using filmed social contacts (FSC) or internet self-learning (INS), on reducing stigma, underwent 10 min resting-state functional magnetic resonance imaging between the trial registration and 12 months follow-up. The extent of stigma was assessed at the baseline, post-intervention and 12 month follow-up surveys, using the Japanese-language version of the Social Distance Scale (SDSJ), to assess negative emotional attitude toward people with schizophrenia. We compared associations between amygdala subregion-related functional connectivity and changes in the SDSJ scores for 12 months across the control, INS, and FSC groups. Associations between the change in stigma for 12 months and the superficial (SF) subregion of the amygdala-related connectivity in the intracalcarine cortex [(x, y, z) = (-8, -66, 12), z = 4.21, = 0.0003, cluster size = 192] differed across groups. The analysis showed that the SF-intracalcarine cortex connectivity was negatively correlated with the change in stigma only in the FSC group. The current results indicate that greater SF-intracalcarine cortex connectivity is associated with a better response to the FSC interventions, suggesting that biological variability could underlie the long-term effect of anti-stigma interventions on stigma in the real world.
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http://dx.doi.org/10.3389/fnhum.2020.00356DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7481372PMC
August 2020

Bi-Directional Relationships Between Psychological Symptoms and Environmental Factors in Early Adolescence.

Front Psychiatry 2020 3;11:574182. Epub 2020 Sep 3.

Center for Evolutionary Cognitive Sciences, Graduate School of Art and Sciences, University of Tokyo, Tokyo, Japan.

Aim: Bi-directional relationships between various environmental factors and psychological symptoms can be seen from childhood to adolescence; however, there has been little prospective cohort study, which investigated the relationships simultaneously. In this study, we first distinguished specific psychological symptoms from general psychopathology using bifactor modeling and then tested the relationships between psychological symptoms and environmental factors from childhood to early adolescence using a structural equation model (SEM).

Methods: The analyses were based on Tokyo TEEN Cohort (TTC) data collected between October 2012 and March 2016. We obtained self-reported psychological symptoms and environmental factors from both parents and children (at their ages of 10 and 12). Participants were 3,171 children aged 10 [girls = 1,487 (46.9%), mean age, SD = 10.2, 0.28] and subsequently 12 (N = 3,007, follow-up rate 94.8%, mean age, SD = 12.2, 0.31) from three municipalities in Tokyo area.

Results: The best-fit symptom models included four unique factors and general psychopathology as the common factor. Combining the good fit bifactor model and the SEM, positive relationships between symptoms and environmental factors at the same waves and some bi-directional relationships were found. Especially, general psychopathology at age 10 was associated with bullying at age 12 and parental depressive symptoms at age 10 with general psychopathology at age 12. However, some negative relationships such as bullying/bullied involvement and later psychological symptoms were also seen.

Conclusion: By using the newly introduced methodology, our results were partly consistent with previous literature. Further studies are needed to validate this methodology and accelerate the findings regarding the emergence of psychological symptoms and the impact of environmental factors from childhood to early adolescence.
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http://dx.doi.org/10.3389/fpsyt.2020.574182DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7495193PMC
September 2020

Relationship between white matter microstructure and work hours.

Neurosci Lett 2021 01 18;740:135428. Epub 2020 Oct 18.

Department of Pathology of Mental Diseases, National Institute of Mental Health, National Center of Neurology and Psychiatry, 4-1-1 Ogawahigashi, Kodaira, Tokyo 187-8553, Japan; Osaka University, 1-1 Yamadaoka, Suita, Osaka 565-0871, Japan. Electronic address:

Human social activities are realized by a synergy of neuronal activity over various regions of the brain, which is supported by their connectivity. In the present study, we examined associations between social activities, represented by work hours, and brain connectivity as quantified using diffusion tensor imaging (DTI). In 483 healthy participants, DTI analysis was performed using 3 T magnetic resonance imaging, and work hours were calculated, considering hours of paid employment (the "Work for Pay" category), hours of housework (the "Work at Home" category), and hours of school-related study (the "Student" category). The correlations between each class of work time and DTI indices were analyzed. The mean diffusivity (MD) values of the anterior limb of the internal capsule (ALIC) and the superior fronto-occipital fasciculus (SFO) were negatively correlated with total work hours (ALIC: r = -0.192, p =  2.3 × 10; SFO: r = -0.161, p =  3.8 × 10). We also found that the MD values of the ALIC and the SFO were correlated with work hours in the Work for Pay category (ALIC: r = -0.211, p =  3.2 × 10; SFO: r = -0.163, p =  3.4 × 10) but not with those in the Work at Home category or the Student category. These results suggest that social activity is associated with the white matter microstructure of the ALIC and the SFO. The main difference between "Work for Pay" and the other two social activities appears to be the type of motivation-for example, external versus internal. Therefore, the white matter microstructure of the ALIC and SFO may be related to externally motivated social activities.
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http://dx.doi.org/10.1016/j.neulet.2020.135428DOI Listing
January 2021

Translatability of Scalp EEG Recordings of Duration-Deviant Mismatch Negativity Between Macaques and Humans: A Pilot Study.

Front Psychiatry 2020 26;11:874. Epub 2020 Aug 26.

Department of Integrative Physiology, Graduate School of Medical, University of Yamanashi, Yamanashi, Japan.

Mismatch negativity (MMN) is a negative deflection of the auditory event-related potential (ERP) elicited by an abrupt change in a sound presented repeatedly. In patients with schizophrenia, MMN is consistently reduced, which makes it a promising biomarker. A non-human primate (NHP) model of MMN based on scalp electroencephalogram (EEG) recordings can provide a useful translational tool, given the high structural homology of the prefrontal and auditory cortices between NHPs, such as macaques, and humans. However, in previous MMN studies, the NHP models used did not allow for comparison with humans because of differences in task settings. Moreover, duration-deviant MMN (dMMN), whose reduction is larger than that in the frequency-deviant MMN (fMMN) in patients with schizophrenia, has never been demonstrated in NHP models. In this study, we determined whether dMMN can be observed in macaque scalp EEG recordings. EEGs were recorded from frontal electrodes (Fz) in two Japanese macaques. Consistent with clinical settings, auditory stimuli consisted of two pure tones, a standard and a deviant tone, in an oddball paradigm. The deviant and standard tones differed in duration (50 and 100 ms for the standard and deviant tones, respectively). A robust dMMN with a latency of around 200 ms, comparable to that in humans, was observed in both monkeys. A comparison with fMMN showed that the dMMN latency was the longer of the two. By bridging the gap between basic and clinical research, our results will contribute to the development of innovative therapeutic strategies for schizophrenia.
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http://dx.doi.org/10.3389/fpsyt.2020.00874DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7479845PMC
August 2020

Long and short sleep duration and psychotic symptoms in adolescents: Findings from a cross-sectional survey of 15 786 Japanese students.

Psychiatry Res 2020 11 30;293:113440. Epub 2020 Aug 30.

Research Center for Social Science & Medicine, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan.

Sleep problems during adolescence affect current and subsequent mental health and are associated with experiences of psychotic symptoms. Recent studies have suggested that short sleep duration increases the risk of experiencing psychotic symptoms in the general adolescent population; however, whether long sleep duration is associated with an increased risk of psychotic symptoms in adolescence remains unclear. The present study aimed to examine the relationships between long sleep duration, short sleep duration, and the risk of experiencing psychotic symptoms in adolescence. Cross-sectional survey data from 15,786 junior and senior high school students (12- to 15-year-olds and 15- to 18-year-olds, respectively) in Japan were collected and analyzed using logistic regression analysis after controlling for covariates, including depressive symptoms. Long sleep duration was associated with a 1.6- to 2.8-fold increased risk of psychotic symptoms in male but not in female adolescents. Short sleep duration was also related with a 1.6- to 2.9-fold increased risk of experiencing psychotic symptoms, except for 15- to 18-year-old female adolescents. The present study suggested that adolescents with long and short sleep duration should be assessed for their risk of experiencing psychotic symptoms regardless of concurrent depressive symptoms.
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http://dx.doi.org/10.1016/j.psychres.2020.113440DOI Listing
November 2020

Rotational plane-wise analysis of angular movement of neck motor tics in Tourette's syndrome.

Prog Neuropsychopharmacol Biol Psychiatry 2021 Jun 3;108:110092. Epub 2020 Sep 3.

Department of Neuropsychiatry, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.

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.
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http://dx.doi.org/10.1016/j.pnpbp.2020.110092DOI Listing
June 2021

Association between the superior longitudinal fasciculus and perceptual organization and working memory: A diffusion tensor imaging study.

Neurosci Lett 2020 11 2;738:135349. Epub 2020 Sep 2.

Department of Psychiatry, Osaka University Graduate School of Medicine, Osaka, Japan; Department of Pathology of Mental Diseases, National Institute of Mental Health, National Center of Neurology and Psychiatry, Tokyo, Japan; Molecular Research Center for Children's Mental Development, United Graduate School of Child Development, Osaka University, Osaka, Japan.

The superior longitudinal fasciculus (SLF) is a white matter structure that has long bidirectional projections among the prefrontal, temporal, occipital, and parietal cortices and extends over a wide area in a human brain. Recently, anatomical details of the SLF have been clarified using a diffusion tensor imaging (DTI) template of subjects from the Human Connectome Project. However, the neurobehavioral functions of the SLF have not been fully elucidated. It is speculated that the SLF contributes to a broad cognitive domain including visuospatial nonverbal cognitive ability and verbal memory ability because of its anatomical location; however, previous findings in imaging studies are inconsistent. Showing the contribution of the SLF to cognitive function may be important for improving our understanding of the functional role of white matter structures in the human brain. This study aimed to identify the relationship between DTI indices of the SLF and the Verbal Comprehension, Perceptual Organization, Working Memory and Processing Speed Indices of the Wechsler Adult Intelligence Scale-Third Edition using regression analysis, accounting for the effects of age, sex and scanner type in 583 healthy volunteers. We showed significant correlations between the fractional anisotropy of the left SLF and the Perceptual Organization Index (β = 0.21, p =  4.5×10) and Working Memory Index (β = 0.19, p =  4.0×10). These findings may have implications for the rehabilitation of cognitive function in patients with neurological disorders.
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http://dx.doi.org/10.1016/j.neulet.2020.135349DOI Listing
November 2020

Mismatch Negativity Predicts Remission and Neurocognitive Function in Individuals at Ultra-High Risk for Psychosis.

Front Psychiatry 2020 3;11:770. Epub 2020 Aug 3.

Department of Neuropsychiatry, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.

Background: In the early intervention in psychosis, ultra-high risk (UHR) criteria have been used to identify individuals who are prone to develop psychosis. Although the transition rate to psychosis in individuals at UHR is 10% to 30% within several years, some individuals at UHR present with poor prognoses even without transition occurring. Therefore, it is important to identify biomarkers for predicting the prognosis of individuals at UHR, regardless of transition. We investigated whether mismatch negativity (MMN) in response to both duration deviant stimuli (dMMN) and frequency deviant stimuli (fMMN) could predict prognosis, including remission and neurocognitive function in individuals at UHR.

Materials And Methods: Individuals at UHR (n = 24) and healthy controls (HC; n = 18) participated in this study. In an auditory oddball paradigm, both dMMN and fMMN were measured at baseline. Remission and neurocognitive function after > 180 days were examined in the UHR group. Remission from UHR was defined as functional and symptomatic improvement using the Global Assessment of Functioning (GAF) score and Scale of Prodromal Symptoms (SOPS) positive subscales. Neurocognitive function was measured using the Brief Assessment of Cognition in Schizophrenia (BACS). We examined differences in MMN amplitude at baseline between those who achieved remission (remitters) and those who did not (non-remitters). Multiple regression analyses were performed to identify predictors for functioning, positive symptoms, and neurocognitive function.

Results: Compared with the HC group, the UHR group had a significantly attenuated dMMN amplitude ( = 0.003). In the UHR group, GAF scores significantly improved during the follow-up period (mean value 47.1 to 55.5, = 0.004). The dMMN amplitude at baseline was significantly larger in the remitter (n = 6) than in the non-remitter group (n = 18) ( = 0.039). The total SOPS positive subscale scores and fMMN amplitude at baseline could predict BACS attention subscore at the follow-up point (SOPS positive subscales, = 0.030; fMMN, = 0.041).

Conclusion: Our findings indicate that dMMN and fMMN predicted remission and neurocognitive function, respectively, in individuals at UHR, which suggests that there are both promising biomarker candidates for predicting prognosis in individuals at UHR.
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http://dx.doi.org/10.3389/fpsyt.2020.00770DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7416637PMC
August 2020

Machine-learning classification using neuroimaging data in schizophrenia, autism, ultra-high risk and first-episode psychosis.

Transl Psychiatry 2020 08 17;10(1):278. Epub 2020 Aug 17.

Center for Evolutionary Cognitive Sciences, Graduate School of Arts and Sciences, The University of Tokyo, Tokyo, 153-8902, Japan.

Neuropsychiatric disorders are diagnosed based on behavioral criteria, which makes the diagnosis challenging. Objective biomarkers such as neuroimaging are needed, and when coupled with machine learning, can assist the diagnostic decision and increase its reliability. Sixty-four schizophrenia, 36 autism spectrum disorder (ASD), and 106 typically developing individuals were analyzed. FreeSurfer was used to obtain the data from the participant's brain scans. Six classifiers were utilized to classify the subjects. Subsequently, 26 ultra-high risk for psychosis (UHR) and 17 first-episode psychosis (FEP) subjects were run through the trained classifiers. Lastly, the classifiers' output of the patient groups was correlated with their clinical severity. All six classifiers performed relatively well to distinguish the subject groups, especially support vector machine (SVM) and Logistic regression (LR). Cortical thickness and subcortical volume feature groups were most useful for the classification. LR and SVM were highly consistent with clinical indices of ASD. When UHR and FEP groups were run with the trained classifiers, majority of the cases were classified as schizophrenia, none as ASD. Overall, SVM and LR were the best performing classifiers. Cortical thickness and subcortical volume were most useful for the classification, compared to surface area. LR, SVM, and DT's output were clinically informative. The trained classifiers were able to help predict the diagnostic category of both UHR and FEP Individuals.
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http://dx.doi.org/10.1038/s41398-020-00965-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7429957PMC
August 2020