Research Achievements - Original paper -
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A rare genetic variant in the cleavage site of prepro-orexin is associated with idiopathic hypersomnia.
Taku Miyagawa, Susumu Tanaka, Mihoko Shimada, Noriaki Sakai, Kotomi Tanida, Nozomu Kotorii, Tatayu Kotorii, Yu Ariyoshi, Yuji Hashizume, Kimihiro Ogi, Hiroshi Hiejima, Takashi Kanbayashi, Aya Imanishi, Azusa Ikegami, Yuichi Kamei, Akiko Hida, Yamato Wada, Masayuki Miyamoto, Masanori Takami, Hideaki Kondo, Yoshiyuki Tamura, Yukari Taniyama, Naoto Omata, Tomoyuki Mizuno, Shunpei Moriya, Hirokazu Furuya, Mitsuhiro Kato, Kayoko Kato, Jun Ishigooka, Kazuhito Tsuruta, Shigeru Chiba, Naoto Yamada, Masako Okawa, Koichi Hirata, Kenji Kuroda, Kazuhiko Kume, Naohisa Uchimura, Masaaki Kitada, Tohru Kodama, Yuichi Inoue, Seiji Nishino, Kazuo Mishima, Katsushi Tokunaga, Makoto Honda
NPJ genomic medicine 7 ( 1 ) 29 - 29 2022.04 [Refereed]
Research paper (journal) Domestic Co-author
Idiopathic hypersomnia (IH) is a rare, heterogeneous sleep disorder characterized by excessive daytime sleepiness. In contrast to narcolepsy type 1, which is a well-defined type of central disorders of hypersomnolence, the etiology of IH is poorly understood. No susceptibility loci associated with IH have been clearly identified, despite the tendency for familial aggregation of IH. We performed a variation screening of the prepro-orexin/hypocretin and orexin receptors genes and an association study for IH in a Japanese population, with replication (598 patients and 9826 controls). We identified a rare missense variant (g.42184347T>C; p.Lys68Arg; rs537376938) in the cleavage site of prepro-orexin that was associated with IH (minor allele frequency of 1.67% in cases versus 0.32% in controls, P = 2.7 × 10-8, odds ratio = 5.36). Two forms of orexin (orexin-A and -B) are generated from cleavage of one precursor peptide, prepro-orexin. The difference in cleavage efficiency between wild-type (Gly-Lys-Arg; GKR) and mutant (Gly-Arg-Arg; GRR) peptides was examined by assays using proprotein convertase subtilisin/kexin (PCSK) type 1 and PCSK type 2. In both PCSK1 and PCSK2 assays, the cleavage efficiency of the mutant peptide was lower than that of the wild-type peptide. We also confirmed that the prepro-orexin peptides themselves transmitted less signaling through orexin receptors than mature orexin-A and orexin-B peptides. These results indicate that a subgroup of IH is associated with decreased orexin signaling, which is believed to be a hallmark of narcolepsy type 1.
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Inoue Takeshi, Shimada Satoshi, Kasuga Akiko, Shiihashi Ayako, Kitajima Tasuku, Matsushima Naho, Arakawa Akari, Oto Yuji, Otani Ryoko, Mishima Kazuo, Sakuta Ryoichi
NO TO HATTATSU ( The Japanese Society of Child Neurology ) 54 ( 2 ) 135 - 137 2022.03 [Refereed]
Research paper (journal) Domestic Co-author
<p> This pilot study examined the effects of bright light therapy (BLT) on children with circadian rhythm sleep-wake disorder associated with school refusal. Study participants were 12 children (age : 13-15 years). They were randomly divided into two groups based on the therapy they underwent for 3 weeks : inpatient therapy alone (IT) and IT plus BLT (plus BLT) groups. Two participants dropped out of the study. The wake-up time regressed/relapsed 2 weeks after discharge in the IT group (5 patients) but was maintained in the plus BLT group (5 patients). Moreover, the plus BLT group showed significantly lower insomnia severity questionnaire scores. These results suggest that BLT is effective for children.</p>
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Development and acceptability of a decision aid for chronic insomnia considering discontinuation of benzodiazepine hypnotics.
Aoki, Yumi ; Takaesu, Yoshikazu ; Suzuki, Masahiro; Okajima, Isa ; Takeshima, Masahiro ; Shimura, Akiyoshi ; Utsumi, Tomohiro ; Kotorii, Nozomu ; Yamashita, Hidehisa ; Kuriyama, Kenichi ; Watanabe, Norio ; Mishima, Kazuo
Neuropsychopharmacol Rep. 2022.03 [Refereed]
Research paper (journal) Domestic Co-author
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Diabetes and anxiety were associated with insomnia among Japanese male truck drivers.
Yuta Sugano, Takashi Miyachi, Tomoka Ando, Toyoto Iwata, Toshikazu Yamanouchi, Kazuo Mishima, Kyoko Nomura
Sleep medicine 90 102 - 108 2022.02 [Refereed]
Research paper (journal) Domestic Co-author
OBJECTIVE/BACKGROUND: Insomnia among truck drivers may contribute to traffic accidents. We previously reported that truck drivers had adverse lifestyle habits, including smoking and drinking alcohol, in addition to enforced sedentarism making them more vulnerable to lifestyle-related diseases. This study aimed to investigate the association between insomnia and diabetes, as well as the effect of anxiety related to driving tasks on this association. PATIENTS/METHODS: A total of 755 male truck drivers under 65 years of age who belonged to Akita prefecture Truck Association in Japan were investigated. Insomnia and State-Trait Anxiety Inventory (STAI) score were assessed using a self-administered questionnaire in 2020. Insomnia was defined in accordance with International classification of sleep disorders-third edition. Diabetes was defined as a fasting blood glucose level of ≥126 mg/dL and/or use of anti-diabetic drugs using data obtained from health checkups in 2018. RESULTS: The proportions of truck drivers with insomnia and diabetes were 13.9% and 9.7%, respectively, which were higher than those in the general working population in Japan. After adjusting for age, smoking, drinking, daily hours of driving and sleep, and hypertension, the STAI score (odds ratio [OR] for the highest quartile vs. the lowest: 3.88, 95% confidence interval [CI]: 1.84-8.18) and diabetes (OR: 2.49, 95% CI: 1.11-5.60) were found to be associated with insomnia. A statistical interaction with STAI scores was not observed between diabetes and insomnia. CONCLUSIONS: The present study demonstrated that diabetes and anxiety are independently and significantly associated with insomnia in male Japanese truck drivers.
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Genome-wide association study of idiopathic hypersomnia in a Japanese population
Kotomi Tanida, Mihoko Shimada, Seik-Soon Khor, Hiromi Toyoda, Kayoko Kato, Nozomu Kotorii, Tatayu Kotorii, Yu Ariyoshi, Takao Kato, Hiroshi Hiejima, Motohiro Ozone, Naohisa Uchimura, Azusa Ikegami, Kazuhiko Kume, Takashi Kanbayashi, Aya Imanishi, Yuichi Kamei, Akiko Hida, Yamato Wada, Kenji Kuroda, Masayuki Miyamoto, Koichi Hirata, Masanori Takami, Naoto Yamada, Masako Okawa, Naoto Omata, Hideaki Kondo, Tohru Kodama, Yuichi Inoue, Kazuo Mishima, Makoto Honda, Katsushi Tokunaga, Taku Miyagawa
SLEEP AND BIOLOGICAL RHYTHMS ( SPRINGER JAPAN KK ) 20 ( 1 ) 137 - 148 2022.01 [Refereed]
Research paper (journal) Domestic Co-author
Idiopathic hypersomnia (IH) is a rare sleep disorder characterized by excessive daytime sleepiness, great difficulty upon awakening, and prolonged sleep time. In contrast to narcolepsy type 1, which is a well-recognized hypersomnia, the etiology of IH remains poorly understood. No susceptibility loci for IH have been identified, although familial aggregations have been observed among patients with IH. Narcolepsy type 1 is strongly associated with human leukocyte antigen (HLA)-DQB1*06:02; however, no significant associations between IH and HLA alleles have been reported. To identify genetic variants that affect susceptibility to IH, we performed a genome-wide association study (GWAS) and two replication studies involving a total of 414 Japanese patients with IH and 6587 healthy Japanese individuals. A meta-analysis of the three studies found no single-nucleotide polymorphisms (SNPs) that reached the genome-wide significance level. However, we identified several candidate SNPs for IH. For instance, a common genetic variant (rs2250870) within an intron of PDE9A was suggestively associated with IH. rs2250870 was significantly associated with expression levels of PDE9A in not only whole blood but also brain tissues. The leading SNP in the PDE9A region was the same in associations with both IH and PDE9A expression. PDE9A is a potential target in the treatment of several brain diseases, such as depression, schizophrenia, and Alzheimer's disease. It will be necessary to examine whether PDE9A inhibitors that have demonstrated effects on neurophysiologic and cognitive function can contribute to the development of new treatments for IH, as higher expression levels of PDE9A were observed with regard to the risk allele of rs2250870. The present study constitutes the first GWAS of genetic variants associated with IH. A larger replication study will be required to confirm these associations.
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Sleep Apnea Syndrome (SAS) Clinical Practice Guidelines 2020.
Tsuneto Akashiba, Yuichi Inoue, Naohisa Uchimura, Motoharu Ohi, Takatoshi Kasai, Fusae Kawana, Shigeru Sakurai, Misa Takegami, Rho Tachikawa, Takeshi Tanigawa, Shintaro Chiba, Kazuo Chin, Satoru Tsuiki, Morio Tonogi, Hiroshi Nakamura, Takeo Nakayama, Koji Narui, Tomoko Yagi, Motoo Yamauchi, Yoshihiro Yamashiro, Masahiro Yoshida, Toru Oga, Yasuhiro Tomita, Satoshi Hamada, Kimihiko Murase, Hiroyuki Mori, Hiroo Wada, Makoto Uchiyama, Hiromasa Ogawa, Kazumichi Sato, Seiichi Nakata, Kazuo Mishima, Shin-Ichi Momomura
Respiratory investigation 60 ( 1 ) 3 - 32 2022.01 [Refereed]
Research paper (journal) Domestic Co-author
The prevalence of sleep disordered breathing (SDB) is reportedly very high. Among SDBs, the incidence of obstructive sleep apnea (OSA) is higher than previously believed, with patients having moderate-to-severe OSA accounting for approximately 20% of adult males and 10% of postmenopausal women not only in Western countries but also in Eastern countries, including Japan. Since 1998, when health insurance coverage became available, the number of patients using continuous positive airway pressure (CPAP) therapy for sleep apnea has increased sharply, with the number of patients about to exceed 500,000 in Japan. Although the "Guidelines for Diagnosis and Treatment of Sleep Apnea Syndrome (SAS) in Adults" was published in 2005, a new guideline was prepared in order to indicate the standard medical care based on the latest trends, as supervised by and in cooperation with the Japanese Respiratory Society and the "Survey and Research on Refractory Respiratory Diseases and Pulmonary Hypertension" Group, of Ministry of Health, Labor and Welfare and other related academic societies, including the Japanese Society of Sleep Research, in addition to referring to the previous guidelines. Because sleep apnea is an interdisciplinary field covering many areas, this guideline was prepared including 36 clinical questions (CQs). In the English version, therapies and managements for SAS, which were written from CQ16 to 36, were shown. The Japanese version was published in July 2020 and permitted as well as published as one of the Medical Information Network Distribution Service (Minds) clinical practice guidelines in Japan in July 2021.
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Associations Between the 2011 Great East Japan Earthquake and Tsunami and the Sleep and Mental Health of Japanese People: A 3-Wave Repeated Survey.
Yu Itoh, Masahiro Takeshima, Yoshitaka Kaneita, Naohisa Uchimura, Yuichi Inoue, Makoto Honda, Wataru Yamadera, Norio Watanabe, Shingo Kitamura, Isa Okajima, Naoko Ayabe, Kyoko Nomura, Kazuo Mishima
Nature and science of sleep 14 61 - 73 2022.01 [Refereed]
Research paper (journal) Domestic Co-author
PURPOSE: Large-scale natural disasters have an enormous physical and mental impact, immediately after they occur, on people living near the central disaster areas. It is known that, in the early stages, a seismic disaster triggers high rates of symptoms for insomnia, depression, and anxiety. However, little information is available about their medium- to long-term clinical outcomes. In this study, we conducted a repeated cross-sectional nationwide questionnaire survey to clarify changes in the prevalence of insomnia and its background factors after the Great East Japan Earthquake, a huge earthquake with a moment magnitude of 9.0 that occurred on March 11, 2011. METHODS: We conducted a repeated cross-sectional survey in November 2009 (pre-earthquake, 1224 participants), July 2011 (4 months post-earthquake, 1259 participants), and August 2012 (18 months post-earthquake, 1289 participants) using stratified random sampling from 157 Japanese sites. RESULTS: Compared to 2009, the prevalence of insomnia statistically increased nationwide immediately post-disaster (11.7% vs 21.2%; p < 0.001) but significantly decreased in 2012 compared to immediately after the earthquake (10.6% vs 21.2%; p < 0.001). In 2011, insomnia was most frequent in the central disaster area. Multivariable logistic regression models demonstrated the association between the following factors and increased risk of insomnia: being a woman (odds ratio [OR] 1.48, 95% confidence interval [CI]: 1.00-2.19), being employed in 2009 (OR 1.74, 95% CI: 1.15-2.62), and being of younger age group (20-64 years) in 2011 (OR 1.64, 95% CI: 1.12-2.42) and 2012 (OR 2.50 95% CI: 1.47-4.23). Post-earthquake, the prevalence of insomnia symptoms in men increased, while the gender difference decreased and was no longer statistically significant. Additionally, insomnia was associated with psychological distress (scores ≥5 on the Kessler Psychological Distress Scale) in 2011 and 2012. CONCLUSION: This study demonstrated that the prevalence of insomnia was significantly higher after the earthquake. Moreover, individuals with insomnia were more likely to experience psychological distress after the earthquake that continued until 2012.
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Training types associated with knowledge and experience in public health workers.
Zui Narita, Yoshio Yamanouchi, Kazuo Mishima, Yoko Kamio, Naoko Ayabe, Ryoko Kakei, Yoshiharu Kim
Archives of public health = Archives belges de sante publique 80 ( 1 ) 44 - 44 2022.01 [Refereed]
Research paper (journal) Domestic Co-author
BACKGROUND: Training non-specialist workers in mental healthcare improves knowledge, attitude, confidence, and recognition of mental illnesses. However, still little information is available on which type of mental health training is important in the improvement of these capacities. METHODS: We studied web-based survey data of 495 public health workers to examine training types associated with knowledge and experience in supporting individuals with mental illness. Multivariable logistic regression analysis was conducted to evaluate the association between a lack of knowledge and experience (outcome) and mental health training (exposure). We fitted three regression models. Model 1 evaluated unadjusted associations. Model 2 adjusted for age and sex. Model 3 adjusted for age, sex, years of experience, mental health full-time worker status, and community population. Bias-corrected and accelerated bootstrap confidence intervals (CIs) were used. RESULTS: For all training types, the association between a lack of knowledge and experience and mental health training attenuated as the model developed. In Model 3, a lack of knowledge and experience was significantly associated with training in specific illness (OR, 0.54; 95% CI, 0.32-0.93) and screening and assessment (OR, 0.63; 95% CI, 0.39-0.99). Non-significant results were produced for training in counseling, psychosocial support, collaborative work, and law and regulation in Model 3. CONCLUSIONS: We believe that the present study provides meaningful information that training in specific illness and screening and assessment may lead to knowledge and experience of public health workers. Further studies should employ a longitudinal design and validated measurements.
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Nomura K.
Environmental Health and Preventive Medicine ( Environmental Health and Preventive Medicine ) 26 ( 1 ) 2021.12 [Refereed]
Research paper (journal) Domestic Co-author
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Daytime nap and nighttime breastfeeding are associated with toddlers’ nighttime sleep
Nakagawa M.
Scientific Reports ( Scientific Reports ) 11 ( 1 ) 2021.12 [Refereed]
Research paper (journal) Domestic Co-author
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Development and acceptability of a decision aid for chronic insomnia considering discontinuation of benzodiazepine hypnotics.
Yumi Aoki, Yoshikazu Takaesu, Masahiro Suzuki, Isa Okajima, Masahiro Takeshima, Akiyoshi Shimura, Tomohiro Utsumi, Nozomu Kotorii, Hidehisa Yamashita, Kenichi Kuriyama, Norio Watanabe, Kazuo Mishima
Neuropsychopharmacology reports 42 ( 1 ) 10 - 20 2021.11 [Refereed]
Research paper (journal) Domestic Co-author
AIM: To describe the development and acceptability of a decision aid (DA) for chronic insomnia considering discontinuation of benzodiazepine (BZD) and benzodiazepine receptor agonist (BZRA) hypnotics, and if discontinuing, tapering with or without cognitive behavioral therapy for insomnia (CBT-I). METHODS: We reviewed relevant literature describing chronic insomnia to identify options. We used the results of the systematic review and meta-analysis conducted previously to determine the related outcomes of two options: discontinuation of BZD/BZRA hypnotics by gradual tapering alone and discontinuation of BZD/BZRA hypnotics by gradual tapering with CBT-I. We then developed a prototype of DA following the International Patient Decision Aid Standards. A mixed methods survey was conducted to assess the acceptability among patients and healthcare providers. RESULTS: The prototype consisted of a description of insomnia, options of continuing or discontinuing BZD/BRZA hypnotics (if discontinuing, the options of tapering hypnotics with or without CBT-I), pros and cons of each option, and a value clarification exercise. Patients (n = 24) reported that the DA had acceptable language (79%), adequate information (71%), and well-balanced presentation (91%). Healthcare providers (n = 20) also provided favorable feedback. CONCLUSION: We developed a DA for chronic insomnia considering discontinuation of BZD/BRZA hypnotics, which was acceptable for stakeholders. The developed DA was designed to support patients and healthcare providers to make a decision about whether to discontinue BZD/BRZA hypnotics.
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Aripiprazole as a new treatment for the prolonged nocturnal sleep of patient with idiopathic hypersomnia.
Aya Imanishi, Yuki Omori, Hideaki Ishido, Yohei Sagawa, GoEun Han, Kazuo Mishima, Takashi Kanbayashi, Hideaki Kondo
Psychiatry and clinical neurosciences 75 ( 10 ) 320 - 322 2021.10 [Refereed]
Research paper (journal) Domestic Co-author
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Pregabalin withdrawal in patients without psychiatric disorders taking a regular dose of pregabalin: A case series and literature review.
Hayahito Ishikawa, Masahiro Takeshima, Hiroyasu Ishikawa, Naoko Ayabe, Hidenobu Ohta, Kazuo Mishima
Neuropsychopharmacology reports 41 ( 3 ) 434 - 439 2021.09 [Refereed]
Research paper (journal) Domestic Co-author
Pregabalin is a drug that can cause psychiatric symptoms via pregabalin withdrawal. Prior reports on pregabalin withdrawal have mainly focused on cases with pregabalin dependence or abuse, and little attention has been paid to patients who are prescribed regular doses of pregabalin. Herein, we report three cases of pregabalin withdrawal in patients without psychiatric disorders, taking regular doses of pregabalin, who developed psychiatric symptoms such as insomnia and anxiety after abrupt discontinuation of pregabalin. In addition, we conducted a systematic review of six case reports (previous studies) of pregabalin withdrawal under regular doses of pregabalin. Among the six cases, three patients had no comorbid mental or substance use disorders, the dose of pregabalin ranged from 150 to 600 mg/d, and the duration of pregabalin use ranged from a few weeks to many years. Of these six cases of pregabalin withdrawal, five had psychopathological symptoms, three had vegetative symptoms, and three had neurologic and physical complications. We concluded that since pregabalin withdrawal can occur even with regular doses and short-term use, clinicians must carefully reduce pregabalin doses when reducing or discontinuing treatment, paying close attention to withdrawal symptoms. Our case series sheds light on the scant evidence from previous research on physical dependence in patients who are taking regular doses of pregabalin. Furthermore, our cases were also valuable in demonstrating that pregabalin withdrawal can occur even after a relatively short period of 2 months.
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Sleep maturation influences cognitive development of preterm toddlers.
Akiko Ando, Hidenobu Ohta, Yuko Yoshimura, Machiko Nakagawa, Yoko Asaka, Takayo Nakazawa, Yusuke Mitani, Yoshihisa Oishi, Masato Mizushima, Hiroyuki Adachi, Yosuke Kaneshi, Keita Morioka, Rinshu Shimabukuro, Michio Hirata, Takashi Ikeda, Rika Fukutomi, Kyoko Kobayashi, Miwa Ozawa, Masahiro Takeshima, Atsushi Manabe, Tsutomu Takahashi, Kazuo Mishima, Isao Kusakawa, Hitoshi Yoda, Mitsuru Kikuchi, Kazutoshi Cho
Scientific reports 11 ( 1 ) 15921 - 15921 2021.08 [Refereed]
Research paper (journal) Domestic Co-author
Our recent study on full-term toddlers demonstrated that daytime nap properties affect the distribution ratio between nap and nighttime sleep duration in total sleep time but does not affect the overall total amount of daily sleep time. However, there is still no clear scientific consensus as to whether the ratio between naps and nighttime sleep or just daily total sleep duration itself is more important for healthy child development. In the current study, to gain an answer to this question, we examined the relationship between the sleep properties and the cognitive development of toddlers born prematurely using actigraphy and the Kyoto scale of psychological development (KSPD) test. 101 premature toddlers of approximately 1.5 years of age were recruited for the study. Actigraphy units were attached to their waist with an adjustable elastic belt for 7 consecutive days and a child sleep diary was completed by their parents. In the study, we found no significant correlation between either nap or nighttime sleep duration and cognitive development of the preterm toddlers. In contrast, we found that stable daily wake time was significantly associated with better cognitive development, suggesting that sleep regulation may contribute to the brain maturation of preterm toddlers.
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Attention-deficit/hyperactivity disorder symptoms and sleep problems in preschool children: the role of autistic traits
Andrew Stickley, Aya Shirama, Shingo Kitamura, Yoko Kamio, Hidetoshi Takahashi, Aya Saito, Hideyuki Haraguchi, Hirokazu Kumazaki, Kazuo Mishima, Tomiki Sumiyoshi
Sleep Medicine ( Elsevier BV ) 83 214 - 221 2021.07 [Refereed]
Research paper (journal) Domestic Co-author
BACKGROUND: Sleep problems are elevated in children with attention-deficit/hyperactivity disorder (ADHD). However, until now there has been comparatively little research on the role of autistic traits in this association. The current study examined the association between ADHD symptoms and sleep problems in Japanese preschool children and whether autistic traits might also be important for this relationship. METHODS: Data were analyzed from 1053 children (average age 64.14 months, range 58-71; 50.3% male) that were drawn from the Tama Children's Survey (TCS). Parent-reported information was obtained on ADHD symptoms using the Strengths and Difficulties Questionnaire (SDQ) and autistic traits with the Social Responsiveness Scale Second Edition (SRS-2). Parents also provided information on three different categories of sleep problems experienced by their children - parasomnias, sleep disordered breathing and awakening/daytime problems. Ordinal logistic regression analysis was used to examine the associations. RESULTS: In analyses adjusted for sociodemographic factors, the mother's mental health and child's emotional problems, compared to children with no ADHD symptoms or autistic traits, children with only ADHD symptoms had significantly increased odds for only one of 11 individual sleep problems - waking in a negative mood. In contrast, children with comorbid ADHD symptoms and autistic traits had elevated odds for five sleep problems with odds ratios ranging from 2.10 (takes time to become alert in the morning) to 3.46 (excessive body movement while sleeping). CONCLUSIONS: Sleep problems may be especially elevated in children with comorbid ADHD symptoms and autistic traits.
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Association between sleep habits/disorders and emotional/behavioral problems among Japanese children.
Masahiro Takeshima, Hidenobu Ohta, Tomoko Hosoya, Masakazu Okada, Yukako Iida, Aiko Moriwaki, Hidetoshi Takahashi, Yoko Kamio, Kazuo Mishima
Scientific reports ( NATURE RESEARCH ) 11 ( 1 ) 11438 - 11438 2021.06 [Refereed]
Research paper (journal) Domestic Co-author
Actual sleep status and the association between sleep habits/disorders and emotional/behavioral problems among children in the development stage have not been fully clarified. A questionnaire survey was conducted on the sleep habits/disorders (Brief Child Sleep Questionnaire; BCSQ) and emotional/behavioral problems (Strengths and Difficulties Questionnaire; SDQ) of 87,548 children enrolled in ordinary classes in nine grade levels from the first grade of elementary school to the third grade of junior high school from December 2009 to April 2010. As school grade increased, children's bedtimes were delayed and sleep duration was reduced by 2.0 h over the nine grade levels. Based on the BCSQ, 18.3% of children were judged to have some type of sleep disorder, and about 30% to 40% of children had sleep symptoms at bedtime, during sleep, and at wake time. Multiple regression analysis showed that emotional and behavioral problems were associated with presence of any sleep symptom, longer sleep latency, and longer awake time after sleep onset, whereas total sleep time was not. Sleep symptoms at wake time were most strongly associated with emotional and behavioral problems. Status of sleep habits/disorders should be considered when interpreting emotional/behavioral problems in school-age children.
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Development and validation of the Benzodiazepine Hypnotics Withdrawal Symptom Scale (BHWSS) based on item response theory.
Hajime Narisawa, Yuichi Inoue, Mina Kobayashi, Isa Okajima, Takashi Kikuchi, Tatsuo Kagimura, Kentaro Matsui, Ken Inada, Kazuo Mishima
Psychiatry research 300 113900 - 113900 2021.06 [Refereed]
Research paper (journal) Domestic Co-author
This study aimed to refine and validate the Benzodiazepine Hypnotics Withdrawal Symptom Scale (BHWSS). The 12-item prototype version of the BHWSS was administered to a sample of 346 patients with chronic insomnia (161 males and 185 females, mean age: 52.8 ± 16.6 years) who had been taking hypnotics (benzodiazepines [BZDs] or BZD receptor agonists) for at least 3 months. The item information curve indicated that two of the 12 BHWSS items should be excluded. As a result of analyzing the 10-item version of the BHWSS (revised-BHWSS), the contribution rate in the case of the factor 1 was 0.49, Cronbach's α was 0.90, and the reliability coefficient ω was 0.91. An analysis of the item information curve for the revised-BHWSS indicated that the information amount per item increased from 3.90 for the original 12-item BHWSS to 4.37 for the 10-item revised-BHWSS. The receiver operating characteristic curve indicated that 6.5 points on the revised-BHWSS was the most appropriate cutoff for estimating moderate or severe withdrawal symptoms using the Benzodiazepine Dependence Self-Report Questionnaire as a reference. These results suggest that the 10-item revised-BHWSS has sufficient reliability and validity for evaluating the severity of withdrawal symptoms after discontinuing BZDs.
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The Role of the Thalamus in the Neurological Mechanism of Subjective Sleepiness: An fMRI Study
Yuki Motomura, Shingo Kitamura, Kyoko Nakazaki, Kentaro Oba, Ruri Katsunuma, Yuri Terasawa, Akiko Hida, Yoshiya Moriguchi, Kazuo Mishima
Nature and Science of Sleep ( Informa UK Limited ) Volume 13 899 - 921 2021.06 [Refereed]
Research paper (journal) Domestic Co-author
Purpose: The thalamus, the region that forms the attentional network and transmits external sensory signals to the entire brain, is important for sleepiness. Herein, we examined the relationship between activity in the thalamus-seed brain network and subjective sleepiness. Materials and Methods: Fifteen healthy male participants underwent an experiment comprising a baseline evaluation and two successive interventions, a 9-day sleep extension followed by 1-night total sleep deprivation. Pre- and post-intervention tests included the Karolinska sleepiness scale and neuroimaging for arterial spin labeling and functional connectivity. We examined the association between subjective sleepiness and the functional magnetic resonance imaging indices. Results: The functional connectivity between the left or right thalamus and various brain regions displayed a significant negative association with subjective sleepiness, and the functional connectivity between the left and right thalamus displayed a significant positive association with subjective sleepiness. The graph theory analysis indicated that the number of positive functional connectivity related to the thalamus showed a strong negative association with subjective sleepiness, and conversely, the number of negative functional connectivity showed a positive association with subjective sleepiness. Arterial spin labeling analysis indicated that the blood flow in both the left and right thalami was significantly negatively associated with subjective sleepiness. Functional connectivity between the anterior cingulate cortex and salience network areas of the left insular cortex, and that between the anterior and posterior cingulate cortices showed a strong positive and negative association with subjective sleepiness, respectively. Conclusion: Subjective sleepiness and the thalamic-cortical network dynamics are strongly related, indicating the application of graph theory to study sleepiness and consciousness. These results also demonstrate that resting functional connectivity largely reflects the "state" of the subject, suggesting that the control of sleep and conscious states is essential when using functional magnetic resonance imaging indices as biomarkers.
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Melatonin Treatment and Adequate Sleep Hygiene Interventions in Children with Autism Spectrum Disorder: A Randomized Controlled Trial.
Masaharu Hayashi, Kazuo Mishima, Michio Fukumizu, Hiroyuki Takahashi, Yuko Ishikawa, Izumi Hamada, Hideyuki Sugioka, Osamu Yotsuya, Yushiro Yamashita
Journal of autism and developmental disorders 52 ( 6 ) 2784 - 2793 2021.06 [Refereed]
Research paper (journal) Domestic Co-author
Robust clinical evidence has not been available for melatonin, a drug commonly administered for treating sleep problems of children with autism spectrum disorder (ASD). In a phase 3 randomized, placebo-controlled clinical trial, we administered 1-mg melatonin (n = 65), 4-mg melatonin (n = 65), or placebo (n = 66) to196 children with ASD once daily before bedtime under adequate sleep hygiene interventions. The primary outcome was sleep onset latency (SOL) assessed with the electronic sleep diary. SOL shortened significantly in the 1- and 4-mg melatonin groups compared to the placebo group (- 22.0, - 28.0, and - 5.0 min, respectively; p < 0.0001 each). This therapeutic regimen of melatonin is a reasonable clinical approach to cope with ASD-emergent difficulties in children with ASD.
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Parthenogenetic mosaicism: generation via second polar body retention and unmasking of a likely causative PER2 variant for hypersomnia.
Yohei Masunaga, Masayo Kagami, Fumiko Kato, Takeshi Usui, Takako Yonemoto, Kazuo Mishima, Maki Fukami, Kazushi Aoto, Hirotomo Saitsu, Tsutomu Ogata
Clinical epigenetics 13 ( 1 ) 73 - 73 2021.04 [Refereed]
Research paper (journal) Domestic Co-author
BACKGROUND: Parthenogenetic mosaicism is an extremely rare condition identified only in five subjects to date. The previous studies indicate that this condition is mediated by parthenogenetic activation and is free from a specific phenotype ascribed to unmaking of a maternally inherited recessive variant in the parthenogenetic cell lineage. RESULTS: We examined a 28-year-old Japanese 46,XX female with Silver-Russell syndrome and idiopathic hypersomnia. The results revealed (1) predominance of maternally derived alleles for all the differentially methylated regions examined; (2) no disease-related copy-number variant; (3) two types of regions for all chromosomes, i.e., four BAF (B-allele frequency) band regions with single major microsatellite peaks of maternal origin and single minor microsatellite peaks of non-maternal (paternal) origin, and six BAF band regions with single major microsatellite peaks of maternal origin and two minor microsatellite peaks of maternal and non-maternal (paternal) origin; (4) an unmasked extremely rare PER2 variant (c.1403G>A:p.(Arg468Gln)) with high predicted pathogenicity; (5) mildly affected local structure with altered hydrogen bonds of the p.Arg468Gln-PER2 protein; and (6) nucleus-dominant subcellular distribution of the p.Arg468Gln-PER2 protein. CONCLUSIONS: The above findings imply that the second polar body retention occurred around fertilization, resulting in the generation of the parthenogenetic cell lineage by endoreplication of a female pronucleus and the normal cell lineage by fusion of male and female pronuclei, and that the homozygous PER2 variant in the parthenogenetic cells is the likely causative factor for idiopathic hypersomnia.