125 results on '"Hitoshi Kuwabara"'
Search Results
2. Interaction of genetic liability for attention deficit hyperactivity disorder (ADHD) and perinatal inflammation contributes to ADHD symptoms in children
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Nagahide Takahashi, Tomoko Nishimura, Taeko Harada, Akemi Okumura, Toshiki Iwabuchi, Md Shafiur Rahman, Hitoshi Kuwabara, Shu Takagai, Noriyoshi Usui, Manabu Makinodan, Hideo Matsuzaki, Norio Ozaki, Hiroaki Itoh, Yoko Nomura, Jeffrey H. Newcorn, and Kenji J. Tsuchiya
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Attention deficit hyperactivity disorder ,Inflammation ,Cytokine ,Cord blood ,Polygenic risk score ,Neurosciences. Biological psychiatry. Neuropsychiatry ,RC321-571 - Abstract
Objective: Genetic and environmental factors contribute to the development of Attention Deficit/Hyperactivity Disorder (ADHD). Perinatal inflammation is one of the promising environmental risk factors for ADHD, but the relationship between the genetic risk for ADHD and perinatal inflammation requires further examination. Methods: A possible gene-environmental interaction between perinatal inflammation and ADHD polygenic risk score (ADHD-PRS) on ADHD symptoms was investigated in children aged 8–9 from the Hamamatsu Birth Cohort for Mothers and Children (N = 531). Perinatal inflammation was evaluated by the level of concentration of three cytokines assayed in umbilical cord blood. The genetic risk for ADHD was assessed by calculating ADHD-PRS for each individual using a previously collected genome-wide association study of ADHD. Results: Perinatal inflammation (β [SE], 0.263 [0.017]; P
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- 2023
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3. Unique Morphometric Features of the Cerebellum and Cerebellocerebral Structural Correlation Between Autism Spectrum Disorder and Schizophrenia
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Chie Morimoto, Yuko Nakamura, Hitoshi Kuwabara, Osamu Abe, Kiyoto Kasai, Hidenori Yamasue, and Shinsuke Koike
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Autism spectrum disorder ,Cerebellocerebral structure ,Cerebellum ,MRI ,Schizophrenia ,Structural neuroimage ,Psychiatry ,RC435-571 - Abstract
Background: Although cerebellar morphological involvement has been increasingly recognized in autism spectrum disorder (ASD) and schizophrenia (SZ), the extent to which there are morphological differences between them has not been definitively quantified. Furthermore, although previous studies have demonstrated increased anatomical cerebellocerebral correlations in both conditions, differences between their associations have not been well characterized. Methods: We compared cerebellar volume between males with ASD (n = 31), males with SZ (n = 28), and typically developing males (n = 49). A total of 31 cerebellar subregions were investigated with the cerebellum segmented into their constituent lobules, in gray matter (GM) and white matter (WM) separately. Additionally, structural correlations with the contralateral cerebrum were analyzed for each cerebellar lobule. Results: We found significantly larger WM volume in the bilateral lobules VI and Crus I in the ASD group than in other groups. While WM or GM volumes of these right lobules had positive associations with ASD symptoms, there was a negative association between GM volume of the right Crus I and SZ symptoms. We further observed, in the ASD group specifically, significant correlations between WM of the right lobule VI and WM of the left frontal pole (r = 0.67) and between GM of the right lobule VI and the left caudate (r = 0.60). Conclusions: Our findings support evidence that cerebellar morphology is involved in ASD and SZ with different mechanisms. Furthermore, this study showed that these biological differences require consideration when determining diagnostic criteria and treatment for these disorders.
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- 2021
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4. Oxytocin-induced increase in N,N-dimethylglycine and time course of changes in oxytocin efficacy for autism social core symptoms
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Yasuhiko Kato, Hitoshi Kuwabara, Takashi Okada, Toshio Munesue, Seico Benner, Miho Kuroda, Masaki Kojima, Walid Yassin, Yosuke Eriguchi, Yosuke Kameno, Chihiro Murayama, Tomoko Nishimura, Kenji Tsuchiya, Kiyoto Kasai, Norio Ozaki, Hirotaka Kosaka, and Hidenori Yamasue
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Asperger ,Autism ,Clinical trial ,Developmental disorders ,Facial expression ,Metabolomics ,Neurology. Diseases of the nervous system ,RC346-429 - Abstract
Abstract 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 FDR = 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 FDR = 0.006, r = − 0.485, N = 43) and deteriorations between 2 and 4 weeks (P FDR = 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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- 2021
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5. Trajectories of Adaptive Behaviors During Childhood in Females and Males in the General Population
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Tomoko Nishimura, Takeo Kato, Akemi Okumura, Taeko Harada, Toshiki Iwabuchi, Md. Shafiur Rahman, Tomoya Hirota, Michio Takahashi, Masaki Adachi, Hitoshi Kuwabara, Shu Takagai, Yoko Nomura, Nagahide Takahashi, Atsushi Senju, and Kenji J. Tsuchiya
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trajectory ,adaptive behavior ,sex differences ,neurodevelopmental traits ,childhood ,autism spectrum disorder ,Psychiatry ,RC435-571 - Abstract
Little is known about the trajectory patterns and sex differences in adaptive behaviors in the general population. We examined the trajectory classes of adaptive behaviors using a representative sample and examined whether the class structure and trajectory patterns differed between females and males. We further explored sex differences in neurodevelopmental traits in each latent class. Participants (n = 994) were children in the Hamamatsu Birth Cohort for Mothers and Children (HBC Study)—a prospective birth cohort study. Adaptive behaviors in each domain of communication, daily living skills, and socialization were evaluated at five time points when participants were 2.7, 3.5, 4.5, 6, and 9 years old using the Vineland Adaptive Behavior Scales–Second Edition. Parallel process multigroup latent class growth analysis extracted sex-specific trajectory classes. Neurodevelopmental traits of children at age 9, autistic traits, attention deficit hyperactivity disorder (ADHD) traits, and cognitive ability were examined for females and males in each identified class. A 4-class model demonstrated the best fit. Moreover, a 4-class model that allowed for differences in class probabilities and means of growth parameters between females and males provided a better fit than a model assuming no sex differences. In the communication domain, females scored higher than their male counterparts in all four classes. In the daily living skills and socialization domains, the two higher adaptive classes (Class 1: females, 18.6%; males, 17.8%; Class 2: females, 48.8%; males, 49.8%) had similar trajectories for males and females, whereas in the two lower adaptive behavior classes (Class 3: females, 27.5%; males, 29.4%; Class 4: females, 5.1%; males, 3.0%), females had higher adaptive scores than their male counterparts. In Class 4, females were more likely to have autistic and ADHD traits exceeding the cutoffs, while males were more likely to have below-average IQ. Different trajectories in females and males suggest that adaptive skills may require adjustment based on the sex of the child, when standardizing scores, in order to achieve better early detection of skill impairment.
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- 2022
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6. Associations Among Maternal Metabolic Conditions, Cord Serum Leptin Levels, and Autistic Symptoms in Children
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Toshiki Iwabuchi, Nagahide Takahashi, Tomoko Nishimura, Md Shafiur Rahman, Taeko Harada, Akemi Okumura, Hitoshi Kuwabara, Shu Takagai, Yoko Nomura, Hideo Matsuzaki, Norio Ozaki, and Kenji J. Tsuchiya
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autism spectrum disorder ,maternal metabolic conditions ,overweight ,diabetes mellitus ,hypertensive disorders of pregnancy ,leptin ,Psychiatry ,RC435-571 - Abstract
IntroductionAccumulating evidence has shown that maternal metabolic conditions, such as pre-pregnancy overweight, diabetes mellitus, and hypertensive disorders of pregnancy (HDP) are potential risk factors of autism spectrum disorder (ASD). However, it remains unclear how these maternal conditions lead to neurodevelopmental outcomes in the offspring, including autistic symptoms. Leptin, an adipokine that has pro-inflammatory effects and affects fetal neurodevelopment, is a candidate mediator of the association between maternal metabolic factors and an increased risk of ASD. However, whether prenatal exposure to leptin mediates the association between maternal metabolic conditions and autistic symptoms in children has not been investigated yet.MethodsThis study investigated the associations between mothers' metabolic conditions (pre-pregnancy overweight, diabetes mellitus during or before pregnancy, and HDP), leptin concentrations in umbilical cord serum, and autistic symptoms among 762 children from an ongoing cohort study, using generalized structural equation modeling. We used the Social Responsive Scale, Second Edition (SRS-2) at 8–9 years old to calculate total T-scores. Additionally, we used the T-scores for two subdomains: Social Communication and Interaction (SCI) and Restricted Interests and Repetitive Behavior (RRB).ResultsUmbilical cord leptin levels were associated with pre-pregnancy overweight [coefficient = 1.297, 95% confidence interval (CI) 1.081–1.556, p = 0.005] and diabetes mellitus (coefficient = 1.574, 95% CI 1.206–2.055, p = 0.001). Furthermore, leptin levels were significantly associated with SRS-2 total T-scores (coefficient = 1.002, 95% CI 1.000–1.004, p = 0.023), SCI scores (coefficient = 1.002, 95% CI 1.000–1.004, p = 0.020), and RRB scores (coefficient = 1.001, 95% CI 1.000–1.003, p = 0.044) in children. Associations between maternal metabolic factors and autistic symptoms were not significant.DiscussionThe present study uncovered an association between cord leptin levels and autistic symptoms in children, while maternal metabolic conditions did not have an evident direct influence on the outcome. These results imply that prenatal pro-inflammatory environments affected by maternal metabolic conditions may contribute to the development of autistic symptoms in children. The findings warrant further investigation into the role of leptin in the development of autistic symptoms.
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- 2022
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7. Preliminary efficacy of cognitive-behavioral therapy on emotion regulation in adults with autism spectrum disorder: A pilot randomized waitlist-controlled study.
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Miho Kuroda, Yuki Kawakubo, Yoko Kamio, Hidenori Yamasue, Toshiaki Kono, Maiko Nonaka, Natsumi Matsuda, Muneko Kataoka, Akio Wakabayashi, Kazuhito Yokoyama, Yukiko Kano, and Hitoshi Kuwabara
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Medicine ,Science - Abstract
Previous studies have demonstrated the clinical utility of cognitive-behavioral therapy in improving emotion regulation in children on the autism spectrum. However, no studies have elucidated the clinical utility of cognitive-behavioral therapy in improving emotion regulation in autistic adults. The aim of the present pilot study was to explore the preliminary clinical utility of a group-based cognitive-behavioral therapy program designed to address emotion regulation skills in autistic adults. We conducted a clinical trial based on a previously reported protocol; 31 participants were randomly allocated to the intervention group and 29 to the waitlist control group. The intervention group underwent an 8-week program of cognitive-behavioral therapy sessions. Two participants from the intervention group withdrew from the study, leaving 29 participants (93.5%) in the group. Compared with the waitlist group, the cognitive-behavioral therapy group exhibited significantly greater pre-to-post (Week 0-8) intervention score improvements on the attitude scale of the autism spectrum disorder knowledge and attitude quiz (t = 2.21, p = 0.03, d = 0.59) and the difficulty describing feelings scale of the 20-item Toronto Alexithymia Scale (t = -2.07, p = 0.04, d = -0.57) in addition to pre-to-follow-up (Week 0-16) score improvements on the emotion-oriented scale of the Coping Inventory for Stressful Situations (t = -2.14, p = 0.04, d = -0.59). Our study thus provides preliminary evidence of the efficacy of the group-based cognitive-behavioral therapy program on emotion regulation in autistic adults, thereby supporting further evaluation of the effectiveness of the cognitive-behavioral therapy program in the context of a larger randomized clinical trial. However, the modest and inconsistent effects underscore the importance of continued efforts to improve the cognitive-behavioral therapy program beyond current standards.
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- 2022
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8. Cognitive-behavioral family therapy as psychoeducation for adolescents with high-functioning autism spectrum disorders: Aware and Care for my Autistic Traits (ACAT) program study protocol for a pragmatic multisite randomized controlled trial
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Fumiyo Oshima, Mandy William, Noriko Takahashi, Aki Tsuchiyagaito, Hitoshi Kuwabara, Akihiro Shiina, Mikuko Seto, Minako Hongo, Yui Iwama, Yoshiyuki Hirano, Chihiro Sutoh, Kayoko Taguchi, Tokiko Yoshida, Yohei Kawasaki, Yoshihito Ozawa, Jiro Masuya, Noriyuki Sato, Shizuka Nakamura, Masaru Kuno, Jumpei Takahashi, Toshiyuki Ohtani, Daisuke Matsuzawa, Naoko Inada, Miho Kuroda, Mika Ando, Arinobu Hori, Akiko Nakagawa, and Eiji Shimizu
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High-functioning autism spectrum disorder ,Randomized controlled trial ,Cognitive-behavioral family therapy ,Psychoeducation ,Medicine (General) ,R5-920 - Abstract
Abstract Background One aim of an autism spectrum disorder (ASD) diagnosis is to obtain special support for the disorder, though this does not guarantee practical support. We developed a psychoeducational program using cognitive-behavioral therapy (CBT) and Aware and Care for my Autistic Traits (ACAT) for Japanese adolescents with high-functioning ASD and their parents. Methods This multisite study is a randomized controlled trial. In total, 24 participants will be assigned to the ACAT group and 24 to the treatment-as-usual (TAU) group. The ACAT group will receive a weekly 100-min session for 6 weeks, regular medical care, and one follow-up session. In this ongoing clinical trial, we will compare the scores of the measures recorded in the pre- and post-intervention stages between the ACAT and TAU groups. A total of 41 patients out of a target of 48 have participated in the trial to date. The primary outcome measure is the Autism Knowledge Questionnaire. Secondary outcome measures include Barriers to Access to Care Evaluation 3rd Edition, the Strengths and Difficulties Questionnaire, the Vineland Adaptive Behavior Scales second edition, the Parenting Resilience Elements Questionnaire, the General Health Questionnaire 12, and the Depression Self-Rating Scale for Children assessments, as well as an electroencephalographic recording. Discussion It is expected that participants in the ACAT group will significantly increase their self-understanding and awareness of ASD symptoms compared to those in the TAU group. Additionally, the ACAT group is expected to exhibit improved social adaptation and mental health if children and parents are able to better understand the ASD characteristics through sessions. This intervention will contribute to the establishment of an effective evidence-based treatment strategy for adolescents with ASD. Trial registration UMIN Register 000029851 . Registered on January 06, 2018
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- 2020
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9. Sensitivity to gene dosage and gene expression affects genes with copy number variants observed among neuropsychiatric diseases
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Maria Yamasaki, Takashi Makino, Seik-Soon Khor, Hiromi Toyoda, Taku Miyagawa, Xiaoxi Liu, Hitoshi Kuwabara, Yukiko Kano, Takafumi Shimada, Toshiro Sugiyama, Hisami Nishida, Nagisa Sugaya, Mamoru Tochigi, Takeshi Otowa, Yuji Okazaki, Hisanobu Kaiya, Yoshiya Kawamura, Akinori Miyashita, Ryozo Kuwano, Kiyoto Kasai, Hisashi Tanii, Tsukasa Sasaki, Makoto Honda, and Katsushi Tokunaga
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Copy number variants ,Ohnolog ,Two-round whole-genome duplication ,Gene dosage sensitivity ,Gene expression sensitivity ,Neuropsychiatric diseases ,Internal medicine ,RC31-1245 ,Genetics ,QH426-470 - Abstract
Abstract Background Copy number variants (CNVs) have been reported to be associated with diseases, traits, and evolution. However, it is hard to determine which gene should have priority as a target for further functional experiments if a CNV is rare or a singleton. In this study, we attempted to overcome this issue by using two approaches: by assessing the influences of gene dosage sensitivity and gene expression sensitivity. Dosage sensitive genes derived from two-round whole-genome duplication in previous studies. In addition, we proposed a cross-sectional omics approach that utilizes open data from GTEx to assess the effect of whole-genome CNVs on gene expression. Methods Affymetrix Genome-Wide SNP Array 6.0 was used to detect CNVs by PennCNV and CNV Workshop. After quality controls for population stratification, family relationship and CNV detection, 287 patients with narcolepsy, 133 patients with essential hypersomnia, 380 patients with panic disorders, 164 patients with autism, 784 patients with Alzheimer disease and 1280 healthy individuals remained for the enrichment analysis. Results Overall, significant enrichment of dosage sensitive genes was found across patients with narcolepsy, panic disorders and autism. Particularly, significant enrichment of dosage-sensitive genes in duplications was observed across all diseases except for Alzheimer disease. For deletions, less or no enrichment of dosage-sensitive genes with deletions was seen in the patients when compared to the healthy individuals. Interestingly, significant enrichments of genes with expression sensitivity in brain were observed in patients with panic disorder and autism. While duplications presented a higher burden, deletions did not cause significant differences when compared to the healthy individuals. When we assess the effect of sensitivity to genome dosage and gene expression at the same time, the highest ratio of enrichment was observed in the group including dosage-sensitive genes and genes with expression sensitivity only in brain. In addition, shared CNV regions among the five neuropsychiatric diseases were also investigated. Conclusions This study contributed the evidence that dosage-sensitive genes are associated with CNVs among neuropsychiatric diseases. In addition, we utilized open data from GTEx to assess the effect of whole-genome CNVs on gene expression. We also investigated shared CNV region among neuropsychiatric diseases.
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- 2020
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10. Association Between Genetic Risks for Obesity and Working Memory in Children
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Nagahide Takahashi, Tomoko Nishimura, Taeko Harada, Akemi Okumura, Toshiki Iwabuchi, Md. Shafiur Rahman, Hitoshi Kuwabara, Shu Takagai, Yoko Nomura, Nori Takei, and Kenji J. Tsuchiya
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polygenic risk score ,obesity ,cognition ,GWAS ,child development ,Neurosciences. Biological psychiatry. Neuropsychiatry ,RC321-571 - Abstract
Introduction: Obesity is highly heritable, and recent evidence demonstrates that obesity is associated with cognitive deficits, specifically working memory. However, the relationship between genetic risks for obesity and working memory is not clear. In addition, whether the effect of these genetic risks on working memory in children is mediated by increased body mass index (BMI) has not been elucidated.Methods: In order to test whether the polygenic risk score (PRS) for obesity in adulthood (adulthood-BMI-PRS) is associated with working memory at 8 years of age, and whether the effect is mediated by childhood BMI, in children from the general population, participants in the Hamamatsu Birth Cohort for Mothers and Children (HBC) study in Hamamatsu, Japan, underwent testing for association of adulthood-BMI-PRS with working memory. HBC data collection began in December 2007 and is ongoing. Adulthood-BMI-PRS values were generated using summary data from the recent genome-wide association study (GWAS) undertaken in Japan, and the significance of thresholds was calculated for each outcome. Outcomes measured included the working memory index (WMI) of Weschler Intelligence Scale-4 (WISC-IV) scores and the BMI at 8 years of age. Gene-set enrichment analysis was conducted to clarify the molecular basis common to adulthood-BMI and childhood-WMI. Mediation analysis was performed to assess whether childhood-BMI of children mediated the association between adulthood-BMI-PRS and working memory.Results: A total of 734 participants (377 males, 357 females) were analyzed. Adulthood-BMI-PRS was associated with lower childhood-WMI (β[SE], −1.807 [0.668]; p = 0.010, corrected) of WISC-IV. Gene-set enrichment analyses found that regulation of neurotrophin Trk receptor signaling (β[SE], −2.020 [6.39]; p = 0.002, corrected), negative regulation of GTPase activity (β[SE], 2.001 [0.630]; p = 0.002, corrected), and regulation of gene expression epigenetic (β[SE], −2.119 [0.664]; p = 0.002, corrected) were enriched in BMI in adulthood and WMI in childhood. Mediation analysis showed that there is no mediation effect of childhood-BMI between the adulthood-BMI-PRS and working memory deficits in children.Conclusion: Adulthood-BMI-PRS was associated with working memory among children in the general population. These genetic risks were not mediated by the childhood-BMI itself and were directly associated with working memory deficits.
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- 2021
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11. A 2-year longitudinal follow-up of quantitative assessment neck tics in Tourette's syndrome.
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Yosuke Eriguchi, Xiaoxue Gu, Naoto Aoki, Maiko Nonaka, Ryunosuke Goto, Hitoshi Kuwabara, Yukiko Kano, and Kiyoto Kasai
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Medicine ,Science - Abstract
BackgroundNeck motor tics in Tourette's syndrome can cause severe neck complications. Although addressed in a few longitudinal studies, the clinical course of Tourette's syndrome has not been quantitatively assessed. We had previously developed a method for quantifying the angular movements of neck tics using a compact gyroscope. Here, we present a follow-up study aimed at elucidating the clinical course of neck tics at both the group and individual levels.MethodsEleven patients with Tourette's syndrome from our previous study participated in the present study, and their neck tics were recorded during a 5-min observation period. The severity of neck symptoms was assessed using the Yale Global Tic Severity Scale. The peak angular velocities and accelerations, tic counts, and severity scores in our previous study (baseline) and the present study (2-year follow-up) were compared at the group and individual levels. The individual level consistency between baseline and follow-up were calculated using intra-class correlation coefficients (ICCs, one-way random, single measure).ResultsAt the group level, no significant change was observed between baseline and follow-up. At the individual level, angular velocity (ICC 0.73) and YGTSS scores (ICC 0.75) had substantial consistency over the two time points, and angular acceleration (ICC 0.59) and tic counts (ICC 0.69) had moderate consistency.ConclusionsThe intensity and frequency of neck tics did not change over time. Therefore, quantification of angular neck motor tics will aid in identifying patients with neck tics at high risk for severe neck complications.
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- 2021
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12. Comparative Analyses of Copy-Number Variation in Autism Spectrum Disorder and Schizophrenia Reveal Etiological Overlap and Biological Insights
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Itaru Kushima, Branko Aleksic, Masahiro Nakatochi, Teppei Shimamura, Takashi Okada, Yota Uno, Mako Morikawa, Kanako Ishizuka, Tomoko Shiino, Hiroki Kimura, Yuko Arioka, Akira Yoshimi, Yuto Takasaki, Yanjie Yu, Yukako Nakamura, Maeri Yamamoto, Tetsuya Iidaka, Shuji Iritani, Toshiya Inada, Nanayo Ogawa, Emiko Shishido, Youta Torii, Naoko Kawano, Yutaka Omura, Toru Yoshikawa, Tokio Uchiyama, Toshimichi Yamamoto, Masashi Ikeda, Ryota Hashimoto, Hidenaga Yamamori, Yuka Yasuda, Toshiyuki Someya, Yuichiro Watanabe, Jun Egawa, Ayako Nunokawa, Masanari Itokawa, Makoto Arai, Mitsuhiro Miyashita, Akiko Kobori, Michio Suzuki, Tsutomu Takahashi, Masahide Usami, Masaki Kodaira, Kyota Watanabe, Tsukasa Sasaki, Hitoshi Kuwabara, Mamoru Tochigi, Fumichika Nishimura, Hidenori Yamasue, Yosuke Eriguchi, Seico Benner, Masaki Kojima, Walid Yassin, Toshio Munesue, Shigeru Yokoyama, Ryo Kimura, Yasuko Funabiki, Hirotaka Kosaka, Makoto Ishitobi, Tetsuro Ohmori, Shusuke Numata, Takeo Yoshikawa, Tomoko Toyota, Kazuhiro Yamakawa, Toshimitsu Suzuki, Yushi Inoue, Kentaro Nakaoka, Yu-ichi Goto, Masumi Inagaki, Naoki Hashimoto, Ichiro Kusumi, Shuraku Son, Toshiya Murai, Tempei Ikegame, Naohiro Okada, Kiyoto Kasai, Shohko Kunimoto, Daisuke Mori, Nakao Iwata, and Norio Ozaki
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Biology (General) ,QH301-705.5 - Abstract
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
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- 2018
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13. A small number of abnormal brain connections predicts adult autism spectrum disorder
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Noriaki Yahata, Jun Morimoto, Ryuichiro Hashimoto, Giuseppe Lisi, Kazuhisa Shibata, Yuki Kawakubo, Hitoshi Kuwabara, Miho Kuroda, Takashi Yamada, Fukuda Megumi, Hiroshi Imamizu, José E. Náñez Sr, Hidehiko Takahashi, Yasumasa Okamoto, Kiyoto Kasai, Nobumasa Kato, Yuka Sasaki, Takeo Watanabe, and Mitsuo Kawato
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Science - Abstract
Autism spectrum disorder (ASD) is manifested by subtle but significant changes in the brain. Here, Yahata and colleagues devise a novel machine learning algorithm and develop a reliable ASD classifier based on brain functional connectivity, with which they quantitatively measure neuroimaging dimensions between ASD and other mental disorders.
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- 2016
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14. Computer-analyzed facial expression as a surrogate marker for autism spectrum social core symptoms.
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Keiho Owada, Masaki Kojima, Walid Yassin, Miho Kuroda, Yuki Kawakubo, Hitoshi Kuwabara, Yukiko Kano, and Hidenori Yamasue
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Medicine ,Science - Abstract
To develop novel interventions for autism spectrum disorder (ASD) core symptoms, valid, reliable, and sensitive longitudinal outcome measures are required for detecting symptom change over time. Here, we tested whether a computerized analysis of quantitative facial expression measures could act as a marker for core ASD social symptoms. Facial expression intensity values during a semi-structured socially interactive situation extracted from the Autism Diagnostic Observation Schedule (ADOS) were quantified by dedicated software in 18 high-functioning adult males with ASD. Controls were 17 age-, gender-, parental socioeconomic background-, and intellectual level-matched typically developing (TD) individuals. Statistical analyses determined whether values representing the strength and variability of each facial expression element differed significantly between the ASD and TD groups and whether they correlated with ADOS reciprocal social interaction scores. Compared with the TD controls, facial expressions in the ASD group appeared more "Neutral" (d = 1.02, P = 0.005, PFDR < 0.05) with less variation in Neutral expression (d = 1.08, P = 0.003, PFDR < 0.05). Their expressions were also less "Happy" (d = -0.78, P = 0.038, PFDR > 0.05) with lower variability in Happy expression (d = 1.10, P = 0.003, PFDR < 0.05). Moreover, the stronger Neutral facial expressions in the ASD participants were positively correlated with poorer ADOS reciprocal social interaction scores (ρ = 0.48, P = 0.042). These findings indicate that our method for quantitatively measuring reduced facial expressivity during social interactions can be a promising marker for core ASD social symptoms.
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- 2018
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15. Prefrontal activation during inhibitory control measured by near-infrared spectroscopy for differentiating between autism spectrum disorders and attention deficit hyperactivity disorder in adults
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Ayaka Ishii-Takahashi, Ryu Takizawa, Yukika Nishimura, Yuki Kawakubo, Hitoshi Kuwabara, Junko Matsubayashi, Kasumi Hamada, Shiho Okuhata, Noriaki Yahata, Takashi Igarashi, Shingo Kawasaki, Hidenori Yamasue, Nobumasa Kato, Kiyoto Kasai, and Yukiko Kano
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Autism spectrum disorders ,Attention deficit hyperactivity disorder ,Near-infrared spectroscopy ,Inhibitory control ,Stop signal task ,Computer applications to medicine. Medical informatics ,R858-859.7 ,Neurology. Diseases of the nervous system ,RC346-429 - Abstract
The differential diagnosis of autism spectrum disorders (ASDs) and attention deficit hyperactivity disorder (ADHD) based solely on symptomatic and behavioral assessments can be difficult, even for experts. Thus, the development of a neuroimaging marker that differentiates ASDs from ADHD would be an important contribution to this field. We assessed the differences in prefrontal activation between adults with ASDs and ADHD using an entirely non-invasive and portable neuroimaging tool, near-infrared spectroscopy. This study included 21 drug-naïve adults with ASDs, 19 drug-naïve adults with ADHD, and 21 healthy subjects matched for age, sex, and IQ. Oxygenated hemoglobin concentration changes in the prefrontal cortex were assessed during a stop signal task and a verbal fluency task. During the stop signal task, compared to the control group, the ASDs group exhibited lower activation in a broad prefrontal area, whereas the ADHD group showed underactivation of the right premotor area, right presupplementary motor area, and bilateral dorsolateral prefrontal cortices. Significant differences were observed in the left ventrolateral prefrontal cortex between the ASDs and ADHD groups during the stop signal task. The leave-one-out cross-validation method using mean oxygenated hemoglobin changes yielded a classification accuracy of 81.4% during inhibitory control. These results were task specific, as the brain activation pattern observed during the verbal fluency task did not differentiate the ASDs and ADHD groups significantly. This study therefore provides evidence of a difference in left ventrolateral prefrontal activation during inhibitory control between adults with ASDs and ADHD. Thus, near-infrared spectroscopy may be useful as an auxiliary tool for the differential diagnosis of such developmental disorders.
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- 2014
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16. Altered metabolites in the plasma of autism spectrum disorder: a capillary electrophoresis time-of-flight mass spectroscopy study.
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Hitoshi Kuwabara, Hidenori Yamasue, Shinsuke Koike, Hideyuki Inoue, Yuki Kawakubo, Miho Kuroda, Yosuke Takano, Norichika Iwashiro, Tatsunobu Natsubori, Yuta Aoki, Yukiko Kano, and Kiyoto Kasai
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Medicine ,Science - Abstract
Clinical diagnosis and severity of autism spectrum disorders (ASD) are determined by trained clinicians based on clinical evaluations of observed behaviors. As such, this approach is inevitably dependent on the expertise and subjective assessment of those administering the clinical evaluations. There is a need to identify objective biological markers associated with diagnosis or clinical severity of the disorder. To identify novel candidate metabolites as potential biomarkers for ASD, the current study applied capillary electrophoresis time-of-flight mass spectroscopy (CE-TOFMS) for high-throughput profiling of metabolite levels in the plasma of 25 psychotropic-naïve adult males with high-functioning ASD and 28 age-matched typically-developed control subjects. Ten ASD participants and ten age-matched controls were assigned in the first exploration set, while 15 ASD participants and 18 controls were included in the second replication set. By CE-TOFMS analysis, a total of 143 metabolites were detected in the plasma of the first set. Of these, 17 metabolites showed significantly different relative areas between the ASD participants and the controls (p
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- 2013
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17. Diminished medial prefrontal activity behind autistic social judgments of incongruent information.
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Takamitsu Watanabe, Noriaki Yahata, Osamu Abe, Hitoshi Kuwabara, Hideyuki Inoue, Yosuke Takano, Norichika Iwashiro, Tatsunobu Natsubori, Yuta Aoki, Hidemasa Takao, Hiroki Sasaki, Wataru Gonoi, Mizuho Murakami, Masaki Katsura, Akira Kunimatsu, Yuki Kawakubo, Hideo Matsuzaki, Kenji J Tsuchiya, Nobumasa Kato, Yukiko Kano, Yasushi Miyashita, Kiyoto Kasai, and Hidenori Yamasue
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Medicine ,Science - Abstract
Individuals with autism spectrum disorders (ASD) tend to make inadequate social judgments, particularly when the nonverbal and verbal emotional expressions of other people are incongruent. Although previous behavioral studies have suggested that ASD individuals have difficulty in using nonverbal cues when presented with incongruent verbal-nonverbal information, the neural mechanisms underlying this symptom of ASD remain unclear. In the present functional magnetic resonance imaging study, we compared brain activity in 15 non-medicated adult males with high-functioning ASD to that of 17 age-, parental-background-, socioeconomic-, and intelligence-quotient-matched typically-developed (TD) male participants. Brain activity was measured while each participant made friend or foe judgments of realistic movies in which professional actors spoke with conflicting nonverbal facial expressions and voice prosody. We found that the ASD group made significantly less judgments primarily based on the nonverbal information than the TD group, and they exhibited significantly less brain activity in the right inferior frontal gyrus, bilateral anterior insula, anterior cingulate cortex/ventral medial prefrontal cortex (ACC/vmPFC), and dorsal medial prefrontal cortex (dmPFC) than the TD group. Among these five regions, the ACC/vmPFC and dmPFC were most involved in nonverbal-information-biased judgments in the TD group. Furthermore, the degree of decrease of the brain activity in these two brain regions predicted the severity of autistic communication deficits. The findings indicate that diminished activity in the ACC/vmPFC and dmPFC underlies the impaired abilities of individuals with ASD to use nonverbal content when making judgments regarding other people based on incongruent social information.
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- 2012
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18. Developmental changes of prefrontal activation in humans: a near-infrared spectroscopy study of preschool children and adults.
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Yuki Kawakubo, Toshiaki Kono, Ryu Takizawa, Hitoshi Kuwabara, Ayaka Ishii-Takahashi, and Kiyoto Kasai
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Medicine ,Science - Abstract
Previous morphological studies indicated that development of the human prefrontal cortex (PFC) appears to continue into late adolescence. Although functional brain imaging studies have sought to determine the time course of functional development of the PFC, it is unclear whether the developmental change occurs after adolescence to adulthood and when it achieves a peak because of the narrow or discontinuous range in the participant's age. Moreover, previous functional studies have not focused on the anterior frontal region, that is, the frontopolar regions (BA9/10). Thus, the present study investigated the developmental change in frontopolar PFC activation associated with letter fluency task by using near-infrared spectroscopy (NIRS), in subjects from preschool children to adults. We analyzed the relative concentration of hemoglobin (ΔHb) in the prefrontal cortex measured during the activation task in 48 typically-developing children and adolescents and 22 healthy adults. Consistent with prior morphological studies, we found developmental change with age in the children/adolescents. Moreover, the average Δoxy-Hb in adult males was significantly larger than that in child/adolescent males, but was not true for females. These data suggested that functional development of the PFC continues into late adolescence. Although the developmental change of the frontopolar PFC was independent of gender from childhood to adolescence, in adulthood a gender difference was shown.
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- 2011
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19. Impaired prefrontal hemodynamic maturation in autism and unaffected siblings.
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Yuki Kawakubo, Hitoshi Kuwabara, Kei-Ichiro Watanabe, Michiko Minowa, Toshikazu Someya, Iwao Minowa, Toshiaki Kono, Hisami Nishida, Toshiro Sugiyama, Nobumasa Kato, and Kiyoto Kasai
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Medicine ,Science - Abstract
BACKGROUND: Dysfunctions of the prefrontal cortex have been previously reported in individuals with autism spectrum disorders (ASD). Previous studies reported that first-degree relatives of individuals with ASD show atypical brain activity during tasks associated with social function. However, developmental changes in prefrontal dysfunction in ASD and genetic influences on the phenomena remain unclear. In the present study, we investigated the change in hemoglobin concentration in the prefrontal cortex as measured with near-infrared spectroscopy, in children and adults with ASD during the letter fluency test. Moreover, to clarify the genetic influences on developmental changes in the prefrontal dysfunction in ASD, unaffected siblings of the ASD participants were also assessed. METHODOLOGY/PRINCIPAL FINDINGS: Study participants included 27 individuals with high-functioning ASD, age- and IQ-matched 24 healthy non-affected siblings, and 27 unrelated healthy controls aged 5 to 39 years. The relative concentration of hemoglobin ([Hb]) in the prefrontal cortex was measured during the letter fluency task. For children, neither the [oxy-Hb] change during the task nor task performances differed significantly among three groups. For adults, the [oxy-Hb] increases during the task were significantly smaller in the bilateral prefrontal cortex in ASD than those in control subjects, although task performances were similar. In the adult siblings the [oxy-Hb] change was intermediate between those in controls and ASDs. CONCLUSION/SIGNIFICANCE: Although indirectly due to a cross-sectional design, the results of this study indicate altered age-related change of prefrontal activity during executive processing in ASD. This is a first near-infrared spectroscopy study that implies alteration in the age-related changes of prefrontal activity in ASD and genetic influences on the phenomena.
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- 2009
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20. Lower Availability of Mitochondrial Complex I in Anterior Cingulate Cortex in Autism: A Positron Emission Tomography Study
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Yasuhiko Kato, Masamichi Yokokura, Toshiki Iwabuchi, Chihiro Murayama, Taeko Harada, Takafumi Goto, Taishi Tamayama, Yosuke Kameno, Tomoyasu Wakuda, Hitoshi Kuwabara, Seico Benner, Atsushi Senju, Hideo Tsukada, Sadahiko Nishizawa, Yasuomi Ouchi, and Hidenori Yamasue
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Psychiatry and Mental health - Abstract
Mitochondrial dysfunction has been implicated in the pathophysiology of autism spectrum disorder (ASD) in previous studies of postmortem brain or peripheral samples. The authors investigated whether and where mitochondrial dysfunction occurs in the living brains of individuals with ASD and to identify the clinical correlates of detected mitochondrial dysfunction.This case-control study used positron emission tomography (PET) with 2-Among the brain regions in which mitochondrial dysfunction has been reported in postmortem studies of autistic brains, participants with ASD had significantly decreased [This study provides direct evidence to link in vivo brain mitochondrial dysfunction with ASD pathophysiology and its communicational deficits. The findings support the possibility that mitochondrial electron transport chain complex I is a novel therapeutic target for ASD core symptoms.
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- 2023
21. Changes in child behavioral problems and maternal attachment towards children with attention‐deficit/hyperactivity disorder following behavioral parent training: A pilot study
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Ayaka Ishii‐Takahashi, Yuki Kawakubo, Junko Hamada, Naomi Nakajima, Takuya Kawahara, Akiko Hirose, Rio Yamaguchi, Hitoshi Kuwabara, Takashi Okada, and Yukiko Kano
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Psychiatry and Mental health ,Neurology ,General Neuroscience ,Neurology (clinical) ,General Medicine - Published
- 2023
22. Extrastriatal dopamine D2/3 receptor binding, functional connectivity, and autism socio-communicational deficits: a PET and fMRI study
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Chihiro Murayama, Toshiki Iwabuchi, Yasuhiko Kato, Masamichi Yokokura, Taeko Harada, Takafumi Goto, Taishi Tamayama, Yosuke Kameno, Tomoyasu Wakuda, Hitoshi Kuwabara, Atsushi Senju, Sadahiko Nishizawa, Yasuomi Ouchi, and Hidenori Yamasue
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Male ,Brain Mapping ,Autism Spectrum Disorder ,Communication ,Dopamine ,Brain ,Magnetic Resonance Imaging ,Cellular and Molecular Neuroscience ,Psychiatry and Mental health ,Positron-Emission Tomography ,Neural Pathways ,Humans ,Autistic Disorder ,Molecular Biology - Abstract
The social motivation hypothesis of autism proposes that social communication symptoms in autism spectrum disorder (ASD) stem from atypical social attention and reward networks, where dopamine acts as a crucial mediator. However, despite evidence indicating that individuals with ASD show atypical activation in extrastriatal regions while processing reward and social stimuli, no previous studies have measured extrastriatal dopamine D2/3 receptor (D2/3R) availability in ASD. Here, we investigated extrastriatal D2/3R availability in individuals with ASD and its association with ASD social communication symptoms using positron emission tomography (PET). Moreover, we employed a whole-brain multivariate pattern analysis of resting-state functional magnetic resonance imaging (fMRI) to identify regions where functional connectivity atypically correlates with D2/3R availability depending on ASD diagnosis. Twenty-two psychotropic-free males with ASD and 24 age- and intelligence quotient-matched typically developing males underwent [11C]FLB457 PET, fMRI, and clinical symptom assessment. Participants with ASD showed lower D2/3R availability throughout the D2/3R-rich extrastriatal regions of the dopaminergic pathways. Among these, the posterior region of the thalamus, which primarily comprises the pulvinar, displayed the largest effect size for the lower D2/3R availability, which correlated with a higher score on the Social Affect domain of the Autism Diagnostic Observation Schedule-2 in participants with ASD. Moreover, lower D2/3R availability was correlated with lower functional connectivity of the thalamus-superior temporal sulcus and cerebellum-medial occipital cortex, specifically in individuals with ASD. The current findings provide novel molecular evidence for the social motivation theory of autism and offer a novel therapeutic target.
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- 2022
23. Children with special health care needs and mothers' anxiety/depression: Findings from the <scp>Tokyo Teen Cohort</scp> study
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Atsushi Nishida, Syudo Yamasaki, Akiko Kanehara, Seiichiro Jinde, Shuntaro Ando, Mariko Hiraiwa-Hasegawa, Takashi Igarashi, Namiko Kaji, Kiyoto Kasai, Hitoshi Kuwabara, Yoshihiro Satomura, and Yukiko Kano
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Adult ,Male ,Mediation (statistics) ,Adolescent ,Anxiety depression ,Population ,Children with special health care needs ,Mothers ,Anxiety ,Cohort Studies ,Social support ,Humans ,Medicine ,Child ,Tokyo ,education ,Depression (differential diagnoses) ,education.field_of_study ,Depression ,business.industry ,General Neuroscience ,General Medicine ,Disabled Children ,Psychiatry and Mental health ,Cross-Sectional Studies ,Neurology ,Female ,Neurology (clinical) ,medicine.symptom ,business ,Cohort study ,Clinical psychology - Abstract
Aim Children with special health care needs (CSHCN) are those who require more care for their physical, developmental, or emotional differences than their typically developing peers. Among a wide range of burdens that caregivers of CSHCN experience, the mental burden of caregivers is still not well investigated. This study aimed at examining the relationship between caring for CSHCN and mothers' anxiety/depression. Methods This study used data from the Tokyo Early Adolescence Survey, a population-based cross-sectional survey. Using screening questionnaires, we evaluated the prevalence of CSHCN and identified their primary caregivers. Focusing on mothers as caregivers, we analyzed the relationship between having CSHCN and mothers' anxiety/depression, and between the severity of children's condition and mothers' anxiety/depression. We further determined what mediates these relationships using path analyses. Results Among 4003 participants, we identified 502 CSHCN (12.5%), and 93% of responding caregivers were mothers. We found that mothers with CSHCN were significantly more anxious/depressed than those without CSHCN, which was closely related to the severity of children's condition. The mediation effect of social support on the relation between CSHCN and mothers' anxiety/depression was statistically significant. Conclusion Mothers of CSHCN were more anxious/depressed than other mothers in this study. Social support was indicated to have a significant mediating effect on the relationship between CSHCN and mothers' anxiety/depression. Our results suggest that considering ways to offer social support may effectively relieve the mental stress experienced by mothers of CSHCN. This article is protected by copyright. All rights reserved.
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- 2021
24. Unique Morphometric Features of the Cerebellum and Cerebellocerebral Structural Correlation Between Autism Spectrum Disorder and Schizophrenia
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Yuko Nakamura, Chie Morimoto, Osamu Abe, Shinsuke Koike, Kiyoto Kasai, Hidenori Yamasue, and Hitoshi Kuwabara
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Psychiatry ,Cerebellum ,Cerebrum ,business.industry ,RC435-571 ,General Medicine ,Negative association ,Anatomy ,medicine.disease ,White matter ,medicine.anatomical_structure ,Schizophrenia ,Structural correlation ,Autism spectrum disorder ,mental disorders ,medicine ,Left frontal pole ,Structural neuroimage ,business ,Cerebellocerebral structure ,MRI - Abstract
Background Although cerebellar morphological involvement has been increasingly recognized in autism spectrum disorder (ASD) and schizophrenia (SZ), the extent to which there are morphological differences between them has not been definitively quantified. Furthermore, although previous studies have demonstrated increased anatomical cerebellocerebral correlations in both conditions, differences between their associations have not been well characterized. Methods We compared cerebellar volume between males with ASD (n = 31), males with SZ (n = 28), and typically developing males (n = 49). A total of 31 cerebellar subregions were investigated with the cerebellum segmented into their constituent lobules, in gray matter (GM) and white matter (WM) separately. Additionally, structural correlations with the contralateral cerebrum were analyzed for each cerebellar lobule. Results We found significantly larger WM volume in the bilateral lobules VI and Crus I in the ASD group than in other groups. While WM or GM volumes of these right lobules had positive associations with ASD symptoms, there was a negative association between GM volume of the right Crus I and SZ symptoms. We further observed, in the ASD group specifically, significant correlations between WM of the right lobule VI and WM of the left frontal pole (r = 0.67) and between GM of the right lobule VI and the left caudate (r = 0.60). Conclusions Our findings support evidence that cerebellar morphology is involved in ASD and SZ with different mechanisms. Furthermore, this study showed that these biological differences require consideration when determining diagnostic criteria and treatment for these disorders.
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- 2021
25. Genetic influences on prefrontal activation during a verbal fluency task in adults: A twin study based on multichannel near-infrared spectroscopy.
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Eisuke Sakakibara, Ryu Takizawa, Yukika Nishimura, Shingo Kawasaki, Yoshihiro Satomura, Akihide Kinoshita, Shinsuke Koike, Kohei Marumo, Masaru Kinou, Mamoru Tochigi, Nao Nishida, Katsushi Tokunaga, Satoshi Eguchi, Syudo Yamasaki, Tatsunobu Natsubori, Norichika Iwashiro, Hideyuki Inoue, Yosuke Takano, Kunio Takei, Motomu Suga, Hidenori Yamasue, Junko Matsubayashi, Kenji Kohata, Chie Shimojo, Shiho Okuhata, Toshiaki Kono, Hitoshi Kuwabara, Ayaka Ishii-Takahashi, Yuki Kawakubo, and Kiyoto Kasai
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- 2014
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26. Application of a Machine Learning Algorithm for Structural Brain Images in Chronic Schizophrenia to Earlier Clinical Stages of Psychosis and Autism Spectrum Disorder: A Multiprotocol Imaging Dataset Study
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Yinghan Zhu, Hironori Nakatani, Walid Yassin, Norihide Maikusa, Naohiro Okada, Akira Kunimatsu, Osamu Abe, Hitoshi Kuwabara, Hidenori Yamasue, Kiyoto Kasai, Kazuo Okanoya, and Shinsuke Koike
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Machine Learning ,Psychiatry and Mental health ,Psychotic Disorders ,Autism Spectrum Disorder ,Schizophrenia ,Brain ,Humans ,Magnetic Resonance Imaging - Abstract
Background and Hypothesis Machine learning approaches using structural magnetic resonance imaging (MRI) can be informative for disease classification; however, their applicability to earlier clinical stages of psychosis and other disease spectra is unknown. We evaluated whether a model differentiating patients with chronic schizophrenia (ChSZ) from healthy controls (HCs) could be applied to earlier clinical stages such as first-episode psychosis (FEP), ultra-high risk for psychosis (UHR), and autism spectrum disorders (ASDs). Study Design Total 359 T1-weighted MRI scans, including 154 individuals with schizophrenia spectrum (UHR, n = 37; FEP, n = 24; and ChSZ, n = 93), 64 with ASD, and 141 HCs, were obtained using three acquisition protocols. Of these, data regarding ChSZ (n = 75) and HC (n = 101) from two protocols were used to build a classifier (training dataset). The remainder was used to evaluate the classifier (test, independent confirmatory, and independent group datasets). Scanner and protocol effects were diminished using ComBat. Study Results The accuracy of the classifier for the test and independent confirmatory datasets were 75% and 76%, respectively. The bilateral pallidum and inferior frontal gyrus pars triangularis strongly contributed to classifying ChSZ. Schizophrenia spectrum individuals were more likely to be classified as ChSZ compared to ASD (classification rate to ChSZ: UHR, 41%; FEP, 54%; ChSZ, 70%; ASD, 19%; HC, 21%). Conclusion We built a classifier from multiple protocol structural brain images applicable to independent samples from different clinical stages and spectra. The predictive information of the classifier could be useful for applying neuroimaging techniques to clinical differential diagnosis and predicting disease onset earlier.
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- 2022
27. Cognitive-behavioral family therapy as psychoeducation for adolescents with high-functioning autism spectrum disorders: Aware and Care for my Autistic Traits (ACAT) program study protocol for a pragmatic multisite randomized controlled trial
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Mandy William, Jumpei Takahashi, Akiko Nakagawa, Yoshiyuki Hirano, Mikuko Seto, Mika Ando, Toshiyuki Ohtani, Minako Hongo, Yohei Kawasaki, Shizuka Nakamura, Yui Iwama, Noriyuki Sato, Jiro Masuya, Naoko Inada, Miho Kuroda, Eiji Shimizu, Aki Tsuchiyagaito, Akihiro Shiina, Kayoko Taguchi, Tokiko Yoshida, Fumiyo Oshima, Noriko Takahashi, Masaru Kuno, Yoshihito Ozawa, Hitoshi Kuwabara, Arinobu Hori, Chihiro Sutoh, and Daisuke Matsuzawa
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High-functioning autism spectrum disorder ,Adolescent ,Autism Spectrum Disorder ,medicine.medical_treatment ,Medicine (miscellaneous) ,Cognitive-behavioral family therapy ,law.invention ,03 medical and health sciences ,Study Protocol ,0302 clinical medicine ,Cognition ,Randomized controlled trial ,law ,mental disorders ,medicine ,Psychoeducation ,Humans ,0501 psychology and cognitive sciences ,Pharmacology (medical) ,Autistic Disorder ,Child ,Randomized Controlled Trials as Topic ,lcsh:R5-920 ,Cognitive Behavioral Therapy ,business.industry ,05 social sciences ,Strengths and Difficulties Questionnaire ,medicine.disease ,Vineland Adaptive Behavior Scale ,High-functioning autism ,Treatment Outcome ,Autism spectrum disorder ,Autism ,Family Therapy ,General Health Questionnaire ,business ,lcsh:Medicine (General) ,030217 neurology & neurosurgery ,050104 developmental & child psychology ,Clinical psychology - Abstract
Background One aim of an autism spectrum disorder (ASD) diagnosis is to obtain special support for the disorder, though this does not guarantee practical support. We developed a psychoeducational program using cognitive-behavioral therapy (CBT) and Aware and Care for my Autistic Traits (ACAT) for Japanese adolescents with high-functioning ASD and their parents. Methods This multisite study is a randomized controlled trial. In total, 24 participants will be assigned to the ACAT group and 24 to the treatment-as-usual (TAU) group. The ACAT group will receive a weekly 100-min session for 6 weeks, regular medical care, and one follow-up session. In this ongoing clinical trial, we will compare the scores of the measures recorded in the pre- and post-intervention stages between the ACAT and TAU groups. A total of 41 patients out of a target of 48 have participated in the trial to date. The primary outcome measure is the Autism Knowledge Questionnaire. Secondary outcome measures include Barriers to Access to Care Evaluation 3rd Edition, the Strengths and Difficulties Questionnaire, the Vineland Adaptive Behavior Scales second edition, the Parenting Resilience Elements Questionnaire, the General Health Questionnaire 12, and the Depression Self-Rating Scale for Children assessments, as well as an electroencephalographic recording. Discussion It is expected that participants in the ACAT group will significantly increase their self-understanding and awareness of ASD symptoms compared to those in the TAU group. Additionally, the ACAT group is expected to exhibit improved social adaptation and mental health if children and parents are able to better understand the ASD characteristics through sessions. This intervention will contribute to the establishment of an effective evidence-based treatment strategy for adolescents with ASD. Trial registration UMIN Register 000029851. Registered on January 06, 2018
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- 2020
28. Machine-learning classification using neuroimaging data in schizophrenia, autism, ultra-high risk and first-episode psychosis
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Keiho Owada, Wataru Gonoi, Walid Yassin, Norichika Iwashiro, Masaki Kojima, Tatsunobu Natsubori, Shinsuke Koike, Osamu Abe, Hironori Nakatani, Kiyoto Kasai, Yukiko Kano, Yuta Aoki, Hidemasa Takao, Hidenori Yamasue, Hitoshi Kuwabara, and Yinghan Zhu
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medicine.medical_specialty ,Psychosis ,Autism Spectrum Disorder ,Neuroimaging ,Audiology ,Predictive markers ,Article ,lcsh:RC321-571 ,Machine Learning ,Prognostic markers ,Cellular and Molecular Neuroscience ,Feature (machine learning) ,medicine ,Humans ,Autistic Disorder ,lcsh:Neurosciences. Biological psychiatry. Neuropsychiatry ,Biological Psychiatry ,business.industry ,Reproducibility of Results ,Diagnostic markers ,Autism spectrum disorders ,medicine.disease ,Support vector machine ,Psychiatry and Mental health ,Statistical classification ,Psychotic Disorders ,Autism spectrum disorder ,Schizophrenia ,Autism ,business - Abstract
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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- 2020
29. Polygenic risk score analysis revealed shared genetic background in attention deficit hyperactivity disorder and narcolepsy
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Toshiki Iwabuchi, Akemi Okumura, Nagahide Takahashi, Shu Takagai, Jeffrey H. Newcorn, Hitoshi Kuwabara, Kenji J. Tsuchiya, Taeko Harada, Tomoko Nishimura, Yoko Nomura, Damee Choi, and Nori Takei
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0301 basic medicine ,Excessive daytime sleepiness ,Article ,lcsh:RC321-571 ,03 medical and health sciences ,Cellular and Molecular Neuroscience ,0302 clinical medicine ,Neurodevelopmental disorder ,Risk Factors ,mental disorders ,medicine ,Humans ,ADHD ,Attention deficit hyperactivity disorder ,Clinical genetics ,Child ,lcsh:Neurosciences. Biological psychiatry. Neuropsychiatry ,Biological Psychiatry ,Narcolepsy ,Genetic association ,Mechanism (biology) ,business.industry ,Dopaminergic ,medicine.disease ,Psychiatry and Mental health ,030104 developmental biology ,Attention Deficit Disorder with Hyperactivity ,Polygenic risk score ,medicine.symptom ,business ,Genetic Background ,030217 neurology & neurosurgery ,Genome-Wide Association Study ,Clinical psychology - Abstract
Attention deficit hyperactive disorder (ADHD) is a highly heritable neurodevelopmental disorder, and excessive daytime sleepiness is frequently observed in ADHD patients. Excessive daytime sleepiness is also a core symptom of narcolepsy and essential hypersomnia (EHS), which are also heritable conditions. Psychostimulants are effective for the symptomatic control of ADHD (primary recommended intervention) and the two sleep disorders (frequent off-label use). However, the common biological mechanism for these disorders has not been well understood. Using a previously collected genome-wide association study of narcolepsy and EHS, we calculated polygenic risk scores (PRS) for each individual. We investigated a possible genetic association between ADHD and narcolepsy traits in the Hamamatsu Birth Cohort for mothers and children (HBC study) (n = 876). Gene-set enrichment analyses were used to identify common pathways underlying these disorders. Narcolepsy PRS were significantly associated with ADHD traits both in the hyperactivity domain (e.g., P-value threshold P = 0.002) and inattention domain (e.g., P-value threshold P = 0.004). However, EHS PRS was not significantly associated with either domain of ADHD traits. Gene-set enrichment analyses revealed that pathways related to dopaminergic signaling, immune systems, iron metabolism, and glial cell function involved in both ADHD and narcolepsy. Findings indicate that ADHD and narcolepsy are genetically related, and there are possible common underlying biological mechanisms for this relationship. Future studies replicating these findings would be warranted to elucidate the genetic vulnerability for daytime sleepiness in individuals with ADHD.
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- 2020
30. Prediction of Welding Deformation of Automotive Components Using Large-scale Thermal Elastic Plastic Analysis
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Hitoshi Kuwabara, Taro Uchimura, Hiroaki Kanetake, Shintaro Maeda, Kazuki Ikushima, Masakazu Shibahara, and Atsushi Kawahara
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Materials science ,Scale (ratio) ,Mechanics of Materials ,business.industry ,Welding deformation ,Mechanical Engineering ,Thermal ,Metals and Alloys ,Automotive industry ,Mechanical engineering ,business ,Surfaces, Coatings and Films ,Elastic plastic - Published
- 2020
31. Trajectories of Adaptive Behaviors During Childhood in Females and Males in the General Population
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Tomoko Nishimura, Takeo Kato, Akemi Okumura, Taeko Harada, Toshiki Iwabuchi, Md. Shafiur Rahman, Tomoya Hirota, Michio Takahashi, Masaki Adachi, Hitoshi Kuwabara, Shu Takagai, Yoko Nomura, Nagahide Takahashi, Atsushi Senju, and Kenji J. Tsuchiya
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Psychiatry and Mental health - Abstract
Little is known about the trajectory patterns and sex differences in adaptive behaviors in the general population. We examined the trajectory classes of adaptive behaviors using a representative sample and examined whether the class structure and trajectory patterns differed between females and males. We further explored sex differences in neurodevelopmental traits in each latent class. Participants (n = 994) were children in the Hamamatsu Birth Cohort for Mothers and Children (HBC Study)—a prospective birth cohort study. Adaptive behaviors in each domain of communication, daily living skills, and socialization were evaluated at five time points when participants were 2.7, 3.5, 4.5, 6, and 9 years old using the Vineland Adaptive Behavior Scales–Second Edition. Parallel process multigroup latent class growth analysis extracted sex-specific trajectory classes. Neurodevelopmental traits of children at age 9, autistic traits, attention deficit hyperactivity disorder (ADHD) traits, and cognitive ability were examined for females and males in each identified class. A 4-class model demonstrated the best fit. Moreover, a 4-class model that allowed for differences in class probabilities and means of growth parameters between females and males provided a better fit than a model assuming no sex differences. In the communication domain, females scored higher than their male counterparts in all four classes. In the daily living skills and socialization domains, the two higher adaptive classes (Class 1: females, 18.6%; males, 17.8%; Class 2: females, 48.8%; males, 49.8%) had similar trajectories for males and females, whereas in the two lower adaptive behavior classes (Class 3: females, 27.5%; males, 29.4%; Class 4: females, 5.1%; males, 3.0%), females had higher adaptive scores than their male counterparts. In Class 4, females were more likely to have autistic and ADHD traits exceeding the cutoffs, while males were more likely to have below-average IQ. Different trajectories in females and males suggest that adaptive skills may require adjustment based on the sex of the child, when standardizing scores, in order to achieve better early detection of skill impairment.
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- 2021
32. Associations Among Maternal Metabolic Conditions, Cord Serum Leptin Levels, and Autistic Symptoms in Children
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Toshiki Iwabuchi, Nagahide Takahashi, Tomoko Nishimura, Md Shafiur Rahman, Taeko Harada, Akemi Okumura, Hitoshi Kuwabara, Shu Takagai, Yoko Nomura, Hideo Matsuzaki, Norio Ozaki, and Kenji J. Tsuchiya
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Psychiatry ,Psychiatry and Mental health ,diabetes mellitus ,hypertensive disorders of pregnancy ,RC435-571 ,overweight ,autism spectrum disorder ,maternal metabolic conditions ,leptin - Abstract
IntroductionAccumulating evidence has shown that maternal metabolic conditions, such as pre-pregnancy overweight, diabetes mellitus, and hypertensive disorders of pregnancy (HDP) are potential risk factors of autism spectrum disorder (ASD). However, it remains unclear how these maternal conditions lead to neurodevelopmental outcomes in the offspring, including autistic symptoms. Leptin, an adipokine that has pro-inflammatory effects and affects fetal neurodevelopment, is a candidate mediator of the association between maternal metabolic factors and an increased risk of ASD. However, whether prenatal exposure to leptin mediates the association between maternal metabolic conditions and autistic symptoms in children has not been investigated yet.MethodsThis study investigated the associations between mothers' metabolic conditions (pre-pregnancy overweight, diabetes mellitus during or before pregnancy, and HDP), leptin concentrations in umbilical cord serum, and autistic symptoms among 762 children from an ongoing cohort study, using generalized structural equation modeling. We used the Social Responsive Scale, Second Edition (SRS-2) at 8–9 years old to calculate total T-scores. Additionally, we used the T-scores for two subdomains: Social Communication and Interaction (SCI) and Restricted Interests and Repetitive Behavior (RRB).ResultsUmbilical cord leptin levels were associated with pre-pregnancy overweight [coefficient = 1.297, 95% confidence interval (CI) 1.081–1.556, p = 0.005] and diabetes mellitus (coefficient = 1.574, 95% CI 1.206–2.055, p = 0.001). Furthermore, leptin levels were significantly associated with SRS-2 total T-scores (coefficient = 1.002, 95% CI 1.000–1.004, p = 0.023), SCI scores (coefficient = 1.002, 95% CI 1.000–1.004, p = 0.020), and RRB scores (coefficient = 1.001, 95% CI 1.000–1.003, p = 0.044) in children. Associations between maternal metabolic factors and autistic symptoms were not significant.DiscussionThe present study uncovered an association between cord leptin levels and autistic symptoms in children, while maternal metabolic conditions did not have an evident direct influence on the outcome. These results imply that prenatal pro-inflammatory environments affected by maternal metabolic conditions may contribute to the development of autistic symptoms in children. The findings warrant further investigation into the role of leptin in the development of autistic symptoms.
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- 2021
33. Cross-Disorder Analysis of Genic and Regulatory Copy Number Variations in Bipolar Disorder, Schizophrenia, and Autism Spectrum Disorder
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Itaru Kushima, Masahiro Nakatochi, Branko Aleksic, Takashi Okada, Hiroki Kimura, Hidekazu Kato, Mako Morikawa, Toshiya Inada, Kanako Ishizuka, Youta Torii, Yukako Nakamura, Satoshi Tanaka, Miho Imaeda, Nagahide Takahashi, Maeri Yamamoto, Kunihiro Iwamoto, Yoshihiro Nawa, Nanayo Ogawa, Shuji Iritani, Yu Hayashi, Tzuyao Lo, Gantsooj Otgonbayar, Sho Furuta, Nakao Iwata, Masashi Ikeda, Takeo Saito, Kohei Ninomiya, Tomo Okochi, Ryota Hashimoto, Hidenaga Yamamori, Yuka Yasuda, Michiko Fujimoto, Kenichiro Miura, Masanari Itokawa, Makoto Arai, Mitsuhiro Miyashita, Kazuya Toriumi, Kazutaka Ohi, Toshiki Shioiri, Kiyoyuki Kitaichi, Toshiyuki Someya, Yuichiro Watanabe, Jun Egawa, Tsutomu Takahashi, Michio Suzuki, Tsukasa Sasaki, Mamoru Tochigi, Fumichika Nishimura, Hidenori Yamasue, Hitoshi Kuwabara, Tomoyasu Wakuda, Takahiro A. Kato, Shigenobu Kanba, Hideki Horikawa, Masahide Usami, Masaki Kodaira, Kyota Watanabe, Takeo Yoshikawa, Tomoko Toyota, Shigeru Yokoyama, Toshio Munesue, Ryo Kimura, Yasuko Funabiki, Hirotaka Kosaka, Minyoung Jung, Kiyoto Kasai, Tempei Ikegame, Seiichiro Jinde, Shusuke Numata, Makoto Kinoshita, Tadafumi Kato, Chihiro Kakiuchi, Kazuhiro Yamakawa, Toshimitsu Suzuki, Naoki Hashimoto, Shuhei Ishikawa, Bun Yamagata, Shintaro Nio, Toshiya Murai, Shuraku Son, Yasuto Kunii, Hirooki Yabe, Masumi Inagaki, Yu-ichi Goto, Yuto Okumura, Tomoya Ito, Yuko Arioka, Daisuke Mori, and Norio Ozaki
- Subjects
Bipolar Disorder ,DNA Copy Number Variations ,Autism Spectrum Disorder ,Schizophrenia ,Humans ,Genetic Predisposition to Disease ,Biological Psychiatry ,Chromatin ,Genome-Wide Association Study - Abstract
We aimed to determine the similarities and differences in the roles of genic and regulatory copy number variations (CNVs) in bipolar disorder (BD), schizophrenia (SCZ), and autism spectrum disorder (ASD).Based on high-resolution CNV data from 8708 Japanese samples, we performed to our knowledge the largest cross-disorder analysis of genic and regulatory CNVs in BD, SCZ, and ASD.In genic CNVs, we found an increased burden of smaller (100 kb) exonic deletions in BD, which contrasted with the highest burden of larger (500 kb) exonic CNVs in SCZ/ASD. Pathogenic CNVs linked to neurodevelopmental disorders were significantly associated with the risk for each disorder, but BD and SCZ/ASD differed in terms of the effect size (smaller in BD) and subtype distribution of CNVs linked to neurodevelopmental disorders. We identified 3 synaptic genes (DLG2, PCDH15, and ASTN2) as risk factors for BD. Whereas gene set analysis showed that BD-associated pathways were restricted to chromatin biology, SCZ and ASD involved more extensive and similar pathways. Nevertheless, a correlation analysis of gene set results indicated weak but significant pathway similarities between BD and SCZ or ASD (r = 0.25-0.31). In SCZ and ASD, but not BD, CNVs were significantly enriched in enhancers and promoters in brain tissue.BD and SCZ/ASD differ in terms of CNV burden, characteristics of CNVs linked to neurodevelopmental disorders, and regulatory CNVs. On the other hand, they have shared molecular mechanisms, including chromatin biology. The BD risk genes identified here could provide insight into the pathogenesis of BD.
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- 2021
34. Individual psychotherapy using psychological first aid for frontline nurses at high risk of psychological distress during the <scp>COVID</scp> ‐19 pandemic
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Daisuke Asai, Noriyuki Enomoto, Hidenori Yamasue, Hitoshi Kuwabara, Atsuko Hanada, Yumi Naito, and Yosuke Kameno
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Adult ,Sleep Wake Disorders ,2019-20 coronavirus outbreak ,medicine.medical_specialty ,Coronavirus disease 2019 (COVID-19) ,Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) ,Clinical Neurology ,MEDLINE ,Appetite ,Nursing Staff, Hospital ,Psychological Distress ,Psychological first aid ,Occupational Stress ,Pandemic ,medicine ,First Aid ,Humans ,Longitudinal Studies ,Psychiatry ,Retrospective Studies ,business.industry ,General Neuroscience ,COVID-19 ,Psychological distress ,General Medicine ,Psychotherapy ,Alcoholism ,Psychiatry and Mental health ,Treatment Outcome ,Neurology ,Neurology (clinical) ,business - Published
- 2020
35. Paternal age contribution to brain white matter aberrations in autism spectrum disorder
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Norichika Iwashiro, Hidenori Yamasue, Osamu Abe, Hitoshi Kuwabara, Hidemasa Takao, Wataru Gonoi, Kiyoto Kasai, Walid Yassin, Keiho Owada, Yuta Aoki, Masaki Kojima, Yukiko Kano, and Tatsunobu Natsubori
- Subjects
Adult ,Male ,medicine.medical_specialty ,Autism Spectrum Disorder ,Uncinate fasciculus ,Audiology ,behavioral disciplines and activities ,Paternal Age ,White matter ,Young Adult ,03 medical and health sciences ,0302 clinical medicine ,Fractional anisotropy ,Fasciculus ,Humans ,Medicine ,Cingulum (brain) ,biology ,business.industry ,General Neuroscience ,General Medicine ,medicine.disease ,biology.organism_classification ,White Matter ,030227 psychiatry ,Psychiatry and Mental health ,Diffusion Tensor Imaging ,medicine.anatomical_structure ,Neurology ,Autism spectrum disorder ,FMRIB Software Library ,Neurology (clinical) ,business ,030217 neurology & neurosurgery ,Maternal Age ,Diffusion MRI - Abstract
AIM Although advanced parental age holds an increased risk for autism spectrum disorder (ASD), its role as a potential risk factor for an atypical white matter development underlying the pathophysiology of ASD has not yet been investigated. The current study was aimed to detect white matter disparities in ASD, and further investigate the relationship of paternal and maternal age at birth with such disparities. METHODS Thirty-nine adult males with high-functioning ASD and 37 typically developing (TD) males were analyzed in the study. The FMRIB Software Library and tract-based spatial statistics were utilized to process and analyze the diffusion tensor imaging data. RESULTS Subjects with ASD exhibited significantly higher mean diffusivity (MD) and radial diffusivity (RD) in white matter fibers, including the association (inferior fronto-occipital fasciculus, right inferior longitudinal fasciculus, superior longitudinal fasciculi, uncinate fasciculus, and cingulum), commissural (forceps minor), and projection tracts (anterior thalamic radiation and right corticospinal tract) compared to TD subjects (Padjusted
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- 2019
36. Quantitative facial expression analysis revealed the efficacy and time course of oxytocin in autism
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Seico Benner, Walid Yassin, Yota Uno, Haruhiro Higashida, Takashi Okada, Nanayo Ogawa, Kaori Matsumoto, Toshio Munesue, Yuko Yoshimura, Toru Fujioka, Teruko Yuhi, Naoko Kawano, Yuko Okamoto, Hirotaka Kosaka, Yosuke Eriguchi, Yuko Arioka, Masaki Kojima, Miho Kuroda, Yuki Kawakubo, Maeri Yamamoto, Yukiko Kano, Keiho Owada, Yukari Uemura, Norio Ozaki, Itaru Kushima, Daisuke Mori, Kiyoto Kasai, Hidenori Yamasue, and Hitoshi Kuwabara
- Subjects
Adult ,Male ,0301 basic medicine ,Oncology ,medicine.medical_specialty ,Time Factors ,Adolescent ,Autism Spectrum Disorder ,Oxytocin ,Confirmatory trial ,Autism Diagnostic Observation Schedule ,Young Adult ,03 medical and health sciences ,0302 clinical medicine ,Double-Blind Method ,Internal medicine ,medicine ,Pervasive developmental disorder ,Humans ,Interpersonal Relations ,Administration, Intranasal ,Facial expression ,Cross-Over Studies ,business.industry ,Middle Aged ,medicine.disease ,Facial Expression ,030104 developmental biology ,Autism spectrum disorder ,Asperger syndrome ,Autism ,Neurology (clinical) ,business ,030217 neurology & neurosurgery ,Neurotypical - Abstract
Discrepancies in efficacy between single-dose and repeated administration of oxytocin for autism spectrum disorder have led researchers to hypothesize that time-course changes in efficacy are induced by repeated administrations of the peptide hormone. However, repeatable, objective, and quantitative measurement of autism spectrum disorder’s core symptoms are lacking, making it difficult to examine potential time-course changes in efficacy. We tested this hypothesis using repeatable, objective, and quantitative measurement of the core symptoms of autism spectrum disorder. We examined videos recorded during semi-structured social interaction administered as the primary outcome in single-site exploratory (n = 18, crossover within-subjects design) and multisite confirmatory (n = 106, parallel-group design), double-blind, placebo-controlled 6-week trials of repeated intranasal administrations of oxytocin (48 IU/day) in adult males with autism spectrum disorder. The main outcomes were statistical representative values of objectively quantified facial expression intensity in a repeatable part of the Autism Diagnostic Observation Schedule: the maximum probability (i.e. mode) and the natural logarithm of mode on the probability density function of neutral facial expression and the natural logarithm of mode on the probability density function of happy expression. Our recent study revealed that increases in these indices characterize autistic facial expression, compared with neurotypical individuals. The current results revealed that oxytocin consistently and significantly decreased the increased natural logarithm of mode on the probability density function of neutral facial expression compared with placebo in exploratory (effect-size, −0.57; 95% CI, −1.27 to 0.13; P = 0.023) and confirmatory trials (−0.41; −0.62 to −0.20; P < 0.001). A significant interaction between time-course (at baseline, 2, 4, 6, and 8 weeks) and the efficacy of oxytocin on the natural logarithm of mode on the probability density function of neutral facial expression was found in confirmatory trial (P < 0.001). Post hoc analyses revealed maximum efficacy at 2 weeks (P < 0.001, Cohen’s d = −0.78; 95% CI, −1.21 to −0.35) and deterioration of efficacy at 4 weeks (P = 0.042, Cohen’s d = −0.46; 95% CI, −0.90 to −0.01) and 6 weeks (P = 0.10, Cohen’s d = −0.35; 95% CI, −0.77 to 0.08), while efficacy was preserved at 2 weeks post-treatment (i.e. 8 weeks) (P < 0.001, Cohen’s d = −1.24; 95% CI, −1.71 to −0.78). Quantitative facial expression analyses successfully verified the positive effects of repeated oxytocin on autistic individuals’ facial expressions and demonstrated a time-course change in efficacy. The current findings support further development of an optimized regimen of oxytocin treatment.
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- 2019
37. Effect of a novel nasal oxytocin spray with enhanced bioavailability on autism: a randomized trial
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Hidenori Yamasue, Masaki Kojima, Hitoshi Kuwabara, Miho Kuroda, Kaori Matsumoto, Chieko Kanai, Naoko Inada, Keiho Owada, Keiko Ochi, Nobutaka Ono, Seico Benner, Tomoyasu Wakuda, Yosuke Kameno, Jun Inoue, Taeko Harada, Kenji Tsuchiya, Kazuo Umemura, Aya Yamauchi, Nanayo Ogawa, Itaru Kushima, Norio Ozaki, Satoshi Suyama, Takuya Saito, Yukari Uemura, Junko Hamada, Yukiko Kano, Nami Honda, Saya Kikuchi, Moe Seto, Hiroaki Tomita, Noriko Miyoshi, Megumi Matsumoto, Yuko Kawaguchi, Koji Kanai, Manabu Ikeda, Itta Nakamura, Shuichi Isomura, Yoji Hirano, Toshiaki Onitsuka, Hirotaka Kosaka, and Takashi Okada
- Subjects
Male ,Autism Spectrum Disorder ,Biological Availability ,Nasal Sprays ,Oxytocin ,Treatment Outcome ,Double-Blind Method ,Animals ,Humans ,Female ,Neurology (clinical) ,Rabbits ,Autistic Disorder ,Administration, Intranasal - Abstract
Although intranasal oxytocin is expected to be a novel therapy for the core symptoms of autism spectrum disorder, which has currently no approved medication, the efficacy of repeated administrations was inconsistent, suggesting that the optimal dose for a single administration of oxytocin is not optimal for repeated administration. The current double-blind, placebo-controlled, multicentre, crossover trial (ClinicalTrials.gov Identifier: NCT03466671) was aimed to test the effect of TTA-121, a new formulation of intranasal oxytocin spray with an enhanced bioavailability (3.6 times higher than Syntocinon® spray, as assessed by area under the concentration–time curve in rabbit brains), which enabled us to test a wide range of multiple doses, on autism spectrum disorder core symptoms and to determine the dose–response relationship. Four-week administrations of TTA-121, at low dose once per day (3 U/day), low dose twice per day (6 U/day), high dose once per day (10 U/day), or high dose twice per day (20 U/day), and 4-week placebo were administered in a crossover manner. The primary outcome was the mean difference in the reciprocity score (range: 0–14, higher values represent worse outcomes) on the Autism Diagnostic Observation Schedule between the baseline and end point of each administration period. This trial with two administration periods and eight groups was conducted at seven university hospitals in Japan, enrolling adult males with high-functioning autism spectrum disorder. Enrolment began from June 2018 and ended December 2019. Follow-up ended March 2020. Of 109 males with high-functioning autism spectrum disorder who were randomized, 103 completed the trial. The smallest P-value, judged as the dose–response relationship, was the contrast with the peak at TTA-121 6 U/day, with inverted U-shape for both the full analysis set (P = 0.182) and per protocol set (P = 0.073). The Autism Diagnostic Observation Schedule reciprocity score, the primary outcome, was reduced in the TTA-121 6 U/day administration period compared with the placebo (full analysis set: P = 0.118, mean difference = −0.5; 95% CI: −1.1 to 0.1; per protocol set: P = 0.012, mean difference = −0.8; 95% CI: −1.3 to −0.2). The per protocol set was the analysis target population, consisting of all full analysis set participants except those who deviated from the protocol. Most dropouts from the full analysis set to the per protocol set occurred because of poor adherence to the test drug (9 of 12 in the first period and 8 of 15 in the second period). None of the secondary clinical and behavioural outcomes were significantly improved with the TTA-121 compared with the placebo in the full analysis set. A novel intranasal spray of oxytocin with enhanced bioavailability enabled us to test a wide range of multiple doses, revealing an inverted U-shape dose–response curve, with the peak at a dose that was lower than expected from previous studies. The efficacy of TTA-121 shown in the current exploratory study should be verified in a future large-scale, parallel-group trial.
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- 2021
38. A loss-of-function variant in SUV39H2 identified in autism-spectrum disorder causes altered H3K9 trimethylation and dysregulation of protocadherin β-cluster genes in the developing brain
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Toshihiro Endo, Motoko Maekawa, Kam Y. J. Zhang, Manabu Toyoshima, Kazuhiko Nakamura, Shabeesh Balan, Hideo Matsuzaki, Akiko Watanabe, Tetsuo Ohnishi, Takeo Yoshikawa, Takeshi Otowa, Kaoru Kotoshiba, Masatsugu Tsujii, Maren Kirstin Schuhmacher, Hitoshi Kuwabara, Mikiko Fukuda, Tomoko Toyota, Yoichi Shinkai, Yasuko Hisano, Atsuko Shirai, Ayumi Yamada, Mamoru Tochigi, Hisako Ohba, Kalarickal V. Dileep, Tsukasa Sasaki, Albert Jeltsch, Sara Weirich, and Yoshimi Iwayama
- Subjects
Genetics ,Histone methyltransferase activity ,Protocadherin ,Brain ,Promoter ,Histone-Lysine N-Methyltransferase ,Biology ,Protocadherins ,Histones ,Cellular and Molecular Neuroscience ,Psychiatry and Mental health ,Histone H3 ,Mice ,Histone methyltransferase ,Animals ,Autistic Disorder ,Molecular Biology ,Gene ,Loss function ,SUV39H1 - Abstract
Recent evidence has documented the potential roles of histone-modifying enzymes in autism-spectrum disorder (ASD). Aberrant histone H3 lysine 9 (H3K9) dimethylation resulting from genetic variants in histone methyltransferases is known for neurodevelopmental and behavioral anomalies. However, a systematic examination of H3K9 methylation dynamics in ASD is lacking. Here we resequenced nine genes for histone methyltransferases and demethylases involved in H3K9 methylation in individuals with ASD and healthy controls using targeted next-generation sequencing. We identified a novel rare variant (A211S) in the SUV39H2, which was predicted to be deleterious. The variant showed strongly reduced histone methyltransferase activity in vitro. In silico analysis showed that the variant destabilizes the hydrophobic core and allosterically affects the enzyme activity. The Suv39h2-KO mice displayed hyperactivity and reduced behavioral flexibility in learning the tasks that required complex behavioral adaptation, which is relevant for ASD. The Suv39h2 deficit evoked an elevated expression of a subset of protocadherin β (Pcdhb) cluster genes in the embryonic brain, which is attributable to the loss of H3K9 trimethylation (me3) at the gene promoters. Reduced H3K9me3 persisted in the cerebellum of Suv39h2-deficient mice to an adult stage. Congruently, reduced expression of SUV39H1 and SUV39H2 in the postmortem brain samples of ASD individuals was observed, underscoring the role of H3K9me3 deficiency in ASD etiology. The present study provides direct evidence for the role of SUV39H2 in ASD and suggests a molecular cascade of SUV39H2 dysfunction leading to H3K9me3 deficiency followed by an untimely, elevated expression of Pcdhb cluster genes during early neurodevelopment.
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- 2021
39. Oxytocin-induced increase in N,N-dimethylglycine and time course of changes in oxytocin efficacy for autism social core symptoms
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Hirotaka Kosaka, Toshio Munesue, Yasuhiko Kato, Chihiro Murayama, Kenji J. Tsuchiya, Tomoko Nishimura, Hidenori Yamasue, Yosuke Eriguchi, Hitoshi Kuwabara, Miho Kuroda, Seico Benner, Takashi Okada, Kiyoto Kasai, Walid Yassin, Norio Ozaki, Masaki Kojima, and Yosuke Kameno
- Subjects
Oncology ,Male ,Autism ,Oxytocin ,lcsh:RC346-429 ,law.invention ,0302 clinical medicine ,Randomized controlled trial ,law ,Medicine ,Asperger ,0303 health sciences ,Developmental disorders ,Middle Aged ,Clinical trial ,Psychiatry and Mental health ,Treatment Outcome ,Autism spectrum disorder ,medicine.drug ,Adult ,medicine.medical_specialty ,Facial expression ,Adolescent ,Plasticity ,Neuropeptide ,Placebo ,Confirmatory trial ,03 medical and health sciences ,Young Adult ,Developmental Neuroscience ,Double-Blind Method ,Internal medicine ,Humans ,Metabolomics ,Autistic Disorder ,Social Behavior ,Molecular Biology ,lcsh:Neurology. Diseases of the nervous system ,Administration, Intranasal ,030304 developmental biology ,business.industry ,Research ,Sarcosine ,medicine.disease ,N,N-Dimethylglycine ,business ,030217 neurology & neurosurgery ,Developmental Biology - Abstract
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 (PFDR = 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 (PFDR = 0.006, r = − 0.485, N = 43) and deteriorations between 2 and 4 weeks (PFDR = 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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- 2020
40. Oxytocin-Induced Increase in N,N-dimethylglycine and Time-Course of Changes in Oxytocin Efficacy for Autism Social Core Symptoms
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Yasuhiko Kato, Hitoshi Kuwabara, Takashi Okada, Toshio Munesue, Seico Benner, Miho Kuroda, Masaki Kojima, Walid Yassin, Yosuke Eriguchi, Yosuke Kameno, Chihiro Murayama, Kiyoto Kasai, Norio Ozaki, Hirotaka Kosaka, and Hidenori Yamasue
- Abstract
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 (PFDR=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 (PFDR=0.006, r=-0.485, N=43) and deteriorations between 2 and 4 weeks (PFDR=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 multicenter, parallel group, placebo-controlled, double blind, confirmatory trial of intranasal oxytocin in participants with autism spectrum disorders. (The date registered: 30th Oct 2020; UMIN Clinical Trials Registry: https://upload.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000017703) (UMIN000015264)
- Published
- 2020
41. Distinct Genetic Profiles in Postpartum Depression With Different Trajectory of Illness
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Yoko Nomura, Nagahide Takahashi, Taeko Harada, Tomoko Nishimura, Nori Takei, Hitoshi Kuwabara, Shu Takagai, Hanae Tainaka, Kenji J. Tsuchiya, Akemi Okumura, Toshiki Iwabuchi, and Damee Choi
- Subjects
Postpartum depression ,business.industry ,Trajectory ,Medicine ,business ,medicine.disease ,Clinical psychology - Abstract
BackgroundPostpartum depression (PPD) is a common and highly heritabledisorder in the postnatal period of new mothers. The development of PPD is shown to affectneurodevelopment in children and recent evidence suggests thatthe trajectory of PPDisalso associated with children’s neurodevelopment and mental conditions. Thus, early identification and intervention for individuals at high risk of PPD are urgently needed.Additionally, it is not clear whether genetic factors affect thetrajectory of PPD. Therefore, using a polygenic risk score (PRS) approach, we investigated if PRS for depression (Depression-PRS) and bipolar disorder (Bipolar-PRS) are associated with the development and clinical course of PPD.Methods Usingrecent large genome-wide association studies(GWAS) of depression and bipolar disorder as discovery cohorts, we calculatedDepression-PRS and Bipolar-PRS in each individual. Then, we investigated the possible association between Depression-PRS and Bipolar-PRS with the development andtrajectory of PPD insubjects from the Hamamatsu Birth Cohort for mothers and children (n = 136). Depressive symptoms were assessed using the Edinburgh Postpartum Depression Scale. Gene-set enrichment analyses were used to identify pathways underlying these conditions. ResultsDepression-PRS was significantly higher in subjects with PPD than in those without PPD(t = -3.283, P = 0.002)and logistic analysis showed that Depression-PRS significantly increases therisk of developing PPD(OR [SE] = 2.274 [0.585], P = 0.002). Furthermore, Depression-PRS was positively associated with continuity of PPD (β [SE]=1.621 [0.672]; P = 0.032).Gene-set enrichment analyses revealed that pathways such as“response to hormone”(β[SE] -2.285[1.002], P < 0.001) and “epigenetic regulation”(β[SE] 2.831 [1.317], P < 0.001) were involved in the continuity of PPD. ConclusionThese preliminary findings indicate that the genetic component plays an important role not only in the development but also inthe continuity of PPD. A polygenic risk score approach could be useful to identify subjects at risk for PPD, especially for persistent PPD,who needcareful monitoring and intervention after delivery.
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- 2020
42. Sensitivity to gene dosage and gene expression affects genes with copy number variants observed among neuropsychiatric diseases
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Xiaoxi Liu, Hitoshi Kuwabara, Yuji Okazaki, Katsushi Tokunaga, Maria Yamasaki, Seik-Soon Khor, Takafumi Shimada, Ryozo Kuwano, Akinori Miyashita, Taku Miyagawa, Makoto Honda, Mamoru Tochigi, Hisashi Tanii, Tsukasa Sasaki, Hiromi Toyoda, Nagisa Sugaya, Hisanobu Kaiya, Takashi Makino, Yukiko Kano, Toshiro Sugiyama, Hisami Nishida, Takeshi Otowa, Kiyoto Kasai, and Yoshiya Kawamura
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Genetic Markers ,lcsh:Internal medicine ,lcsh:QH426-470 ,DNA Copy Number Variations ,Gene dosage sensitivity ,Gene Dosage ,Neuropsychological Tests ,Biology ,Gene dosage ,mental disorders ,Gene duplication ,Genetics ,medicine ,Humans ,Copy-number variation ,lcsh:RC31-1245 ,Neuropsychiatric diseases ,Gene ,Genetics (clinical) ,Copy number variants ,Genome, Human ,Mental Disorders ,medicine.disease ,Human genetics ,lcsh:Genetics ,Cross-Sectional Studies ,Phenotype ,Gene Expression Regulation ,Case-Control Studies ,Two-round whole-genome duplication ,Autism ,Ohnolog ,Gene expression sensitivity ,DNA microarray ,Genome-Wide Association Study ,Research Article ,SNP array - Abstract
Background Copy number variants (CNVs) have been reported to be associated with diseases, traits, and evolution. However, it is hard to determine which gene should have priority as a target for further functional experiments if a CNV is rare or a singleton. In this study, we attempted to overcome this issue by using two approaches: by assessing the influences of gene dosage sensitivity and gene expression sensitivity. Dosage sensitive genes derived from two-round whole-genome duplication in previous studies. In addition, we proposed a cross-sectional omics approach that utilizes open data from GTEx to assess the effect of whole-genome CNVs on gene expression. Methods Affymetrix Genome-Wide SNP Array 6.0 was used to detect CNVs by PennCNV and CNV Workshop. After quality controls for population stratification, family relationship and CNV detection, 287 patients with narcolepsy, 133 patients with essential hypersomnia, 380 patients with panic disorders, 164 patients with autism, 784 patients with Alzheimer disease and 1280 healthy individuals remained for the enrichment analysis. Results Overall, significant enrichment of dosage sensitive genes was found across patients with narcolepsy, panic disorders and autism. Particularly, significant enrichment of dosage-sensitive genes in duplications was observed across all diseases except for Alzheimer disease. For deletions, less or no enrichment of dosage-sensitive genes with deletions was seen in the patients when compared to the healthy individuals. Interestingly, significant enrichments of genes with expression sensitivity in brain were observed in patients with panic disorder and autism. While duplications presented a higher burden, deletions did not cause significant differences when compared to the healthy individuals. When we assess the effect of sensitivity to genome dosage and gene expression at the same time, the highest ratio of enrichment was observed in the group including dosage-sensitive genes and genes with expression sensitivity only in brain. In addition, shared CNV regions among the five neuropsychiatric diseases were also investigated. Conclusions This study contributed the evidence that dosage-sensitive genes are associated with CNVs among neuropsychiatric diseases. In addition, we utilized open data from GTEx to assess the effect of whole-genome CNVs on gene expression. We also investigated shared CNV region among neuropsychiatric diseases.
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- 2020
43. Association of Genetic Risks With Autism Spectrum Disorder and Early Neurodevelopmental Delays Among Children Without Intellectual Disability
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Nagahide Takahashi, Akemi Okumura, Kenji J. Tsuchiya, Hitoshi Kuwabara, Yoko Nomura, Toshiki Iwabuchi, Damee Choi, Nori Takei, Taeko Harada, Tomoko Nishimura, and Shu Takagai
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Male ,Autism Spectrum Disorder ,Developmental Disabilities ,Gross motor skill ,Population ,behavioral disciplines and activities ,Polymorphism, Single Nucleotide ,Risk Assessment ,Autism Diagnostic Observation Schedule ,Cohort Studies ,mental disorders ,Intellectual disability ,medicine ,Humans ,Genetic Predisposition to Disease ,Association (psychology) ,education ,Child ,education.field_of_study ,business.industry ,Gestational age ,Infant ,General Medicine ,medicine.disease ,Autism spectrum disorder ,Female ,business ,Clinical psychology ,Cohort study ,Genome-Wide Association Study - Abstract
Autism spectrum disorder (ASD) is highly heritable, and modest contributions of common genetic variants to ASD have been reported. However, the association of genetic risks derived from common risk variants with ASD traits in children from the general population is not clear, and the association of these genetic risks with neurodevelopment in infants has not been well understood.To test whether a polygenic risk score (PRS) for ASD is associated with neurodevelopmental progress at age 18 months and ASD traits at age 6 years among children from the general population.In this cohort study, 876 children in the Hamamatsu Birth Cohort for Mothers and Children in Hamamatsu, Japan, underwent testing for the association of an ASD PRS with neurodevelopmental progress and ASD traits. Data collection began in December 2007 and is ongoing. Data analysis was conducted from April to December 2019.Summary data from the largest genome-wide association study were used to generate ASD PRSs, and significance of thresholds was calculated for each outcome. The Autism Diagnostic Observation Schedule 2 was used to measure ASD traits at age 6 years, and the Mullen Scales of Early Learning was used to measure neurodevelopmental progress at age 18 months.Of 876 participants (mean [SD] gestational age at birth, 38.9 [1.6] weeks; 438 [50.0%] boys; 868 [99.1%] Japanese), 734 were analyzed. The ASD PRS was associated with ASD traits (R2 = 0.024; β, 0.71; SE, 0.24; P = .03). The association of ASD PRS with infant neurodevelopment was most pronounced in gross motor (R2 = 0.015; β, -1.25; SE, 0.39; P = .01) and receptive language (R2 = 0.014; β, -1.19; SE, 0.39; P = .02) scores on the Mullen Scales of Early Learning. Gene set enrichment analyses found that several pathways, such as cell maturation (R2 = 0.057; β, -5.28; SE, 1.40; P .001) and adenylyl cyclase activity and cyclic adenosine monophosphate concentration (R2 = 0.064; β, -5.30; SE 1.30; P .001), were associated with ASD traits. Gene sets associated with inflammation were commonly enriched with ASD traits and gross motor skills (eg, chemokine motif ligand 2 production: R2 = 0.051; β, -6.04; SE, 1.75; P = .001; regulation of monocyte differentiation: R2 = 0.052; β, -6.63; SE, 1.90; P = .001; and B-cell differentiation: R2 = 0.051; β, 7.37; SE, 2.15; P = .001); glutamatergic signaling-associated gene sets were commonly enriched with ASD traits and receptive language skills (eg, regulation of glutamate secretion: R2 = 0.052; β, -5.82; SE, 1.68; P = .001; ionotropic glutamate receptor signaling pathway: R2 = 0.047; β, 3.54; SE, 1.09; P = .001; and negative regulation of glutamate secretion: R2 = 0.045; β, -5.38; SE, 1.74; P = .002).In this study, the ASD PRS was associated with ASD traits among children from the general population. Genetic risks for ASD might be associated with delays in some neurodevelopmental domains, such as gross motor and receptive language skills.
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- 2020
44. Neurochemical evidence for differential effects of acute and repeated oxytocin administration
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Seico Benner, Takamitsu Watanabe, Hidemasa Takao, Nozomi Endo, Yuta Aoki, Kiyoto Kasai, Akira Kunimatsu, Osamu Abe, Masaki Kakeyama, Miho Kuroda, Hidenori Yamasue, Haruhiko Bito, Hitoshi Kuwabara, and Yuki Kawakubo
- Subjects
Male ,0301 basic medicine ,medicine.medical_specialty ,Autism Spectrum Disorder ,medicine.medical_treatment ,Intraperitoneal injection ,Oxytocin ,Placebo ,Mice ,03 medical and health sciences ,Cellular and Molecular Neuroscience ,Glutamatergic ,0302 clinical medicine ,Neurochemical ,Double-Blind Method ,Internal medicine ,medicine ,Animals ,Humans ,Molecular Biology ,Saline ,Administration, Intranasal ,business.industry ,Magnetic Resonance Imaging ,Crossover study ,Mice, Inbred C57BL ,Psychiatry and Mental health ,030104 developmental biology ,Endocrinology ,Nasal administration ,business ,hormones, hormone substitutes, and hormone antagonists ,030217 neurology & neurosurgery ,medicine.drug - Abstract
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.
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- 2018
45. Comparative Analyses of Copy-Number Variation in Autism Spectrum Disorder and Schizophrenia Reveal Etiological Overlap and Biological Insights
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Ryota Hashimoto, Toshiya Inada, Shuraku Son, Youta Torii, Tomoko Toyota, Yutaka Omura, Jun Egawa, Hirotaka Kosaka, Toshio Munesue, Yuto Takasaki, Masaki Kojima, Toshiya Murai, Yuichiro Watanabe, Masahide Usami, Takeo Yoshikawa, Naoko Kawano, Tokio Uchiyama, Masashi Ikeda, Yuka Yasuda, Mitsuhiro Miyashita, Daisuke Mori, Fumichika Nishimura, Toshimichi Yamamoto, Yota Uno, Kentaro Nakaoka, Ichiro Kusumi, Kyota Watanabe, Masahiro Nakatochi, Hiroki Kimura, Yasuko Funabiki, Makoto Ishitobi, Masanari Itokawa, Walid Yassin, Tsutomu Takahashi, Itaru Kushima, Yushi Inoue, Kazuhiro Yamakawa, Masaki Kodaira, Masumi Inagaki, Kiyoto Kasai, Mako Morikawa, Kanako Ishizuka, Yosuke Eriguchi, Nakao Iwata, Takashi Okada, Yukako Nakamura, Nanayo Ogawa, Yu-ichi Goto, Akiko Kobori, Tetsuro Ohmori, Naohiro Okada, Shohko Kunimoto, Maeri Yamamoto, Yuko Arioka, Hidenori Yamasue, Branko Aleksic, Makoto Arai, Shigeru Yokoyama, Hitoshi Kuwabara, Toshimitsu Suzuki, Ayako Nunokawa, Yanjie Yu, Shuji Iritani, Tomoko Shiino, Hidenaga Yamamori, Norio Ozaki, Naoki Hashimoto, Michio Suzuki, Tempei Ikegame, Ryo Kimura, Teppei Shimamura, Shusuke Numata, Tetsuya Iidaka, Emiko Shishido, Tsukasa Sasaki, Seico Benner, Toshiyuki Someya, Mamoru Tochigi, Toru Yoshikawa, and Akira Yoshimi
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Adult ,Male ,0301 basic medicine ,Adolescent ,DNA Copy Number Variations ,Genotype ,Bioinformatics analysis ,Autism Spectrum Disorder ,Biology ,General Biochemistry, Genetics and Molecular Biology ,Young Adult ,03 medical and health sciences ,0302 clinical medicine ,mental disorders ,Intellectual disability ,medicine ,Gene set analysis ,Humans ,Genetic Predisposition to Disease ,Copy-number variation ,Child ,lcsh:QH301-705.5 ,Genetics ,Middle Aged ,Japanese population ,medicine.disease ,Oxidative Stress ,030104 developmental biology ,lcsh:Biology (General) ,Autism spectrum disorder ,Schizophrenia ,Etiology ,Female ,030217 neurology & neurosurgery ,Genome-Wide Association Study - Abstract
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
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- 2018
46. Effect of intranasal oxytocin on the core social symptoms of autism spectrum disorder: a randomized clinical trial
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Masaki Kojima, Yukiko Kano, Itaru Kushima, Yosuke Eriguchi, Toru Fujioka, Maeri Yamamoto, Toshio Munesue, Naoko Kawano, Walid Yassin, Takashi Okada, Nanayo Ogawa, Norio Ozaki, Seico Benner, Hidenori Yamasue, Daisuke Mori, Kaori Matsumoto, Hitoshi Kuwabara, Yuko Arioka, Haruhiro Higashida, Keiho Owada, Yukari Uemura, Kiyoto Kasai, Teruko Yuhi, Yuki Kawakubo, Miho Kuroda, Yota Uno, Yuko Yoshimura, Yuko Okamoto, and Hirotaka Kosaka
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Adult ,Male ,0301 basic medicine ,medicine.medical_specialty ,Adolescent ,Autism Spectrum Disorder ,Oxytocin ,Placebo ,Autism Diagnostic Observation Schedule ,law.invention ,Young Adult ,03 medical and health sciences ,Cellular and Molecular Neuroscience ,0302 clinical medicine ,Double-Blind Method ,Japan ,Randomized controlled trial ,law ,Internal medicine ,Clinical endpoint ,Humans ,Medicine ,Adverse effect ,Molecular Biology ,Administration, Intranasal ,business.industry ,Middle Aged ,medicine.disease ,Psychiatry and Mental health ,030104 developmental biology ,Gynecomastia ,Autism spectrum disorder ,business ,030217 neurology & neurosurgery ,medicine.drug - Abstract
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
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- 2018
47. Neuroanatomical Correlates of Advanced Paternal and Maternal Age at Birth in Autism Spectrum Disorder
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Osamu Abe, Wataru Gonoi, Kiyoto Kasai, Hidenori Yamasue, Yuta Aoki, Hitoshi Kuwabara, Hidemasa Takao, Walid Yassin, Masaki Kojima, Keiho Owada, Yukiko Kano, Norichika Iwashiro, and Tatsunobu Natsubori
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Adult ,Male ,medicine.medical_specialty ,Autism Spectrum Disorder ,Cognitive Neuroscience ,Precuneus ,Neuroimaging ,Audiology ,Paternal Age ,050105 experimental psychology ,Young Adult ,03 medical and health sciences ,Cellular and Molecular Neuroscience ,0302 clinical medicine ,Image Interpretation, Computer-Assisted ,mental disorders ,medicine ,Humans ,0501 psychology and cognitive sciences ,Cerebral Cortex ,business.industry ,05 social sciences ,Paternal age ,medicine.disease ,Magnetic Resonance Imaging ,medicine.anatomical_structure ,Autism spectrum disorder ,Posterior cingulate ,Autism ,business ,030217 neurology & neurosurgery ,Maternal Age - Abstract
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.
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- 2018
48. Trends in psychological distress and alcoholism after The Great East Japan Earthquake of 2011
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Yukiko Kano, Kiyoto Kasai, Hitoshi Kuwabara, Shuntaro Ando, Akiko Kanehara, Satoshi Usami, and Tsuyoshi Araki
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Longitudinal study ,medicine.medical_specialty ,Health (social science) ,Population ,Psychological distress ,Affect (psychology) ,Article ,03 medical and health sciences ,0302 clinical medicine ,medicine ,Risk factor ,lcsh:Social sciences (General) ,Natural disaster ,education ,Psychiatry ,education.field_of_study ,Health Policy ,lcsh:Public aspects of medicine ,Public Health, Environmental and Occupational Health ,lcsh:RA1-1270 ,Mental illness ,medicine.disease ,Mental health ,CAGE questionnaire ,030227 psychiatry ,Alcoholism ,lcsh:H1-99 ,Psychology ,030217 neurology & neurosurgery - Abstract
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.
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- 2016
49. Optically Stimulated Luminescence Analysis Method for High Dose Rate Using an Optical Fiber Type Dosimeter
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Hitoshi Kuwabara, Takahiro Tadokoro, Ishizawa Koji, Katsunori Ueno, Yoshinori Takahashi, and Tominaga Kazuo
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Nuclear and High Energy Physics ,Materials science ,Dosimeter ,Optically stimulated luminescence ,010308 nuclear & particles physics ,Gamma ray ,Analytical chemistry ,Order (ring theory) ,Type (model theory) ,01 natural sciences ,030218 nuclear medicine & medical imaging ,03 medical and health sciences ,0302 clinical medicine ,Nuclear Energy and Engineering ,0103 physical sciences ,Irradiation ,Electrical and Electronic Engineering ,Luminescence ,Intensity (heat transfer) - Abstract
The investigation of air dose rates at locations in the Fukushima Dai-ichi Nuclear Power Station is necessary for safe removal of the molten nuclear fuel. The target performance for the investigation is to analyze a dose rate in the range of $10 ^{-3}~ \mathrm {Gy}/\mathrm {h}$ to $10 ^{2}~\mathrm {Gy}/\mathrm {h}$ with a measurement precision of ±4.0% full scale (F.S.) at a measurement interval of 60 s. In order to achieve this target, the authors proposed an optically stimulated luminescence (OSL) analysis method using prompt OSL for a wide dynamic range of dose rates; the OSL is generated using BaFBr:Eu with a fast decay time constant. The luminescence intensity by prompt OSL was formulated by the electron concentration of the trapping state during gamma ray and stimulation light irradiations. The prototype OSL monitor using BaFBr:Eu was manufactured for investigation of prompt OSL and evaluation of the measurement precision. The time dependence of the luminescence intensity by prompt OSL was analyzed by irradiating the OSL sensor in a 60Co irradiation facility. The measured dose rates were obtained in a prompt mode and an accumulating mode with a precision of ±3.3% F.S. for the dose rate range of $9.5\, \times 10 ^{-4}~\mathrm {Gy}/\mathrm {h}$ to $1.2\,\times 10 ^{2} ~\mathrm {Gy}/\mathrm {h}$ .
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- 2016
50. A small number of abnormal brain connections predicts adult autism spectrum disorder
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Yuka Sasaki, Miho Kuroda, Giuseppe Lisi, Yasumasa Okamoto, Hiroshi Imamizu, Nobumasa Kato, Yuki Kawakubo, José E. Náñez, Kazuhisa Shibata, Noriaki Yahata, Kiyoto Kasai, Hitoshi Kuwabara, Takashi Yamada, Mitsuo Kawato, Takeo Watanabe, Ryuichiro Hashimoto, Jun Morimoto, Hidehiko Takahashi, and Fukuda Megumi
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0301 basic medicine ,Adult ,Male ,Adolescent ,genetic structures ,Autism Spectrum Disorder ,Science ,Models, Neurological ,General Physics and Astronomy ,behavioral disciplines and activities ,General Biochemistry, Genetics and Molecular Biology ,Article ,03 medical and health sciences ,Young Adult ,0302 clinical medicine ,Neuroimaging ,Neural Pathways ,mental disorders ,medicine ,Humans ,Multidisciplinary ,Small number ,Brain ,General Chemistry ,medicine.disease ,Prognosis ,030104 developmental biology ,Autism spectrum disorder ,Cohort ,Major depressive disorder ,Female ,Abnormality ,Nerve Net ,Psychology ,Neuroscience ,030217 neurology & neurosurgery ,Algorithms - Abstract
Although autism spectrum disorder (ASD) is a serious lifelong condition, its underlying neural mechanism remains unclear. Recently, neuroimaging-based classifiers for ASD and typically developed (TD) individuals were developed to identify the abnormality of functional connections (FCs). Due to over-fitting and interferential effects of varying measurement conditions and demographic distributions, no classifiers have been strictly validated for independent cohorts. Here we overcome these difficulties by developing a novel machine-learning algorithm that identifies a small number of FCs that separates ASD versus TD. The classifier achieves high accuracy for a Japanese discovery cohort and demonstrates a remarkable degree of generalization for two independent validation cohorts in the USA and Japan. The developed ASD classifier does not distinguish individuals with major depressive disorder and attention-deficit hyperactivity disorder from their controls but moderately distinguishes patients with schizophrenia from their controls. The results leave open the viable possibility of exploring neuroimaging-based dimensions quantifying the multiple-disorder spectrum., Autism spectrum disorder (ASD) is manifested by subtle but significant changes in the brain. Here, Yahata and colleagues devise a novel machine learning algorithm and develop a reliable ASD classifier based on brain functional connectivity, with which they quantitatively measure neuroimaging dimensions between ASD and other mental disorders.
- Published
- 2016
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