Faculty Profiles - IWAMOTO, Kunihiro

Cross-Disorder Analysis of Genic and Regulatory Copy Number Variations in Bipolar Disorder, Schizophrenia, and Autism Spectrum Disorder. Reviewed International journal

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, Norio Ozaki

Biological psychiatry Vol. 92 ( 5 ) page： 362 - 374 2022.9

Language：English Publishing type：Research paper (scientific journal)

BACKGROUND: 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). METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

DOI： 10.1016/j.biopsych.2022.04.003

ドライビングシミュレーターによる健常者の運転技能と視線特性との関係性 Reviewed

田中陽子, 宮田聖子, 岩本邦弘, 山本真江里, 三浦健一郎, 橋本亮太, 尾崎紀夫

日本安全運転医療学会誌 Vol. 2 ( 1 ) page： 46 - 53 2022.8

Language：Japanese Publishing type：Research paper (scientific journal) Publisher：日本安全運転医療学会

道路交通法により体調不良時の自動車運転は禁止されているが,患者に運転の可否を指導する上での医学的なエビデンスは乏しく,適切な指導のもと患者が自動車社会で生活するためには,運転技能に関わる医学的知見を蓄積することが求められる.運転技能に必須である視覚,認知機能,運動機能の中でも,とりわけ視覚情報は運転中に得られる情報の90%にも及び,視覚を支える視線を促えることが運転技能を予測する上で有用な可能性がある.そこで,本研究では,視線の基本的特性と運転技能との関連にっいて検討を行うため,同一被験者にて運転と視線計測を行った健常者36名を対象に運転と視線の関連にっいて解折した.運転課題は車線維持課題(横揺れの指標),急ブレーキ課題(反応時間の指標)を実施し,視線課題では,フリービューイング課題,固視課題,パシュート課題を実施した.運転の指標と視線の指標との相関解析により,横揺れの指標はフリービュ一イング課題におけるフィクセーション,サッケード関連指標,視線移動の総距離,およびパシュート課題におけるサッケード,垂直方向の視線移動に関する指標と有意な相関を示した.また,反応時間の指標はパシュート課題におけるサッケー一ドおよび垂直方向の視線移動の指標と有意な相関を示した.以上より,視線解析におけるサッケードや視線移動距離といった指標は,運転技能を予測できる可能性が示された.(著者抄録)

Polysomnographic characteristics and predictors of positional obstructive sleep apnea in Japanese elderly Reviewed International journal

Miyata Seiko, Otake Hironao, Fujishiro Hiroshige, Iwamoto Kunihiro, Noda Akiko, Sone Michihiko, Ozaki Norio

SLEEP AND BIOLOGICAL RHYTHMS Vol. 20 ( 3 ) page： 403 - 411 2022.7

Driving performance of euthymic outpatients with bipolar disorder undergoing real-world pharmacotherapy. Reviewed International journal

Akiko Yamaguchi, Kunihiro Iwamoto, Masahiko Ando, Kiyoshi Fujita, Motonori Yokoyama, Tsuyoshi Akiyama, Yoshio Igarashi, Norio Ozaki

Psychiatry and clinical neurosciences Vol. 76 ( 5 ) page： 172 - 178 2022.5

Authorship：Lead author,　Corresponding author Language：English Publishing type：Research paper (scientific journal)

OBJECTIVE: Medications for the treatment of bipolar disorder (BD) could affect patients' cognitive function. Patients with BD present with neurocognitive impairment even in a remission state. Little research is available on the daily functioning, especially driving performance, of stable outpatients with BD under pharmacological treatment. METHODS: In total, 58 euthymic outpatients with BD undergoing real-world pharmacotherapy and 80 sex- and age-matched healthy controls (HCs) were enrolled. Three driving tasks using a driving simulator-road-tracking, car-following, and harsh-braking-and three cognitive tasks-Continuous Performance Test, Wisconsin Card Sorting Test, and Trail-Making Test-were evaluated. Symptom assessment scales-Young Mania Rating Scale, Structured Interview Guide for the Hamilton Depression Rating Scale, Beck Depression Inventory-II, Social Adaptation Self-evaluation Scale, and Stanford Sleepiness Scale-were also completed. RESULTS: Car-following and road-tracking performance were significantly impaired in patients with BD compared with HCs after adjusting for demographic variables, but these performances generally overlapped. Broad neurocognitive functions were significantly lower in the patients with BD compared to HCs, but car-following performance was significantly negatively correlated with sustained attention only. Although most patients received multiple medications rather than monotherapy, no relationship between prescriptions and driving performance was found. CONCLUSION: Euthymic patients with BD under steady-state pharmacotherapy had impaired driving performance compared with HCs, but the overlapping distributions of driving performance suggested that driving performance is not always deteriorated in patients with BD. Therefore, attentional function may be a useful clinical feature for judging driving aptitude in patients with BD. This article is protected by copyright. All rights reserved.

DOI： 10.1111/pcn.13332

Atezolizumab, an immune checkpoint inhibitor, caused precedent depressive symptoms related to limbic encephalitis. Reviewed International journal

Shuhei Wada, Kunihiro Iwamoto, Norio Ozaki

Psychiatry and clinical neurosciences Vol. 76 ( 4 ) page： 125 - 126 2022.4

Residual effects of zopiclone on driving performance using a standardized driving simulator among healthy volunteers. Reviewed International journal

Kunihiro Iwamoto, Mari Iwata, Daiji Kambe, Yumiko Imadera, Naoki Tachibana, Yu Kajiyama, Masahiko Ando, Norio Ozaki

Psychopharmacology Vol. 239 ( 3 ) page： 841 - 850 2022.3

Authorship：Lead author,　Corresponding author Language：English Publishing type：Research paper (scientific journal)

RATIONALE: The effects of hypnotics on automobile driving have been attracting increasing attention. However, few driving simulators (DSs) have been confirmed to have acceptable reliability and validity for assessing the next-day residual effects of zopiclone as a positive control on driving performance. OBJECTIVE: To investigate whether a new DS could permit detection of the next-day residual effects of zopiclone on driving performance. METHODS: In this double-blind, randomized, placebo-controlled crossover trial, 28 healthy males received zopiclone 7.5 mg at bedtime on days 1 and 8 and placebo on the other days over a period of 16 days. The participants took part in three driving tasks-road-tracking, car-following, and harsh-braking-using a DS on days 2 and 9 at 9-h post-dosing. Scores on the Karolinska Sleepiness Scale and Profile of Mood States-Second Edition were then assessed, as was the serum concentration of zopiclone. RESULTS: The estimated differences in the standard deviation of lateral position (cm) in the road-tracking task between the zopiclone and placebo groups on days 2 and 9 were 3.75 cm (90% confidence interval (CI): 1.71-5.79) and 4.07 cm (90% CI: 2.02-6.11), respectively. The estimated differences in the distance coefficient of variation in the car-following task and in the brake reaction time in the harsh-braking task between the zopiclone and placebo groups on day 2 were 4.31 (90% CI: 1.94-6.69) and 24.6 ms (90% CI: 12.7-36.4), respectively. CONCLUSIONS: The DS used in this study has sufficient sensitivity to detect the next-day residual effects of zopiclone on driving performance.

DOI： 10.1007/s00213-022-06075-y

A Study of Factors Causing Sleep State Misperception in Patients with Depression. Reviewed International journal

Keita Kawai, Kunihiro Iwamoto, Seiko Miyata, Ippei Okada, Motoo Ando, Hiroshige Fujishiro, Akiko Noda, Norio Ozaki

Nature and science of sleep Vol. 14 page： 1273 - 1283 2022

Authorship：Corresponding author Language：English Publishing type：Research paper (scientific journal)

Purpose: Sleep state misperception, which is the discrepancy between subjective and objective sleep, is often observed in patients with depression. This phenomenon may delay the remission of depression. Previous studies have focused on the total sleep time (TST) misperception, with many of these studies using actigraphy. Thus, our study investigated depressed patients with the exploratory aim of clarifying factors associated with the sleep state misperception including the wake after sleep onset (WASO) misperception, with their objective sleep additionally evaluated by polysomnography (PSG). Patients and Methods: We conducted a cross-sectional study. Before undergoing overnight PSG monitoring, 40 patients with depression completed questionnaires that included the Beck Depression Inventory (BDI), Epworth sleepiness scale, Temperament and Character Inventory, and the Pittsburgh sleep quality index. Patients were also asked to estimate their subjective sleep duration after they woke up in the morning. Based on this data, we calculated the misperception using the following formula: subjective sleep duration minus objective sleep duration. We compared each factor between negative and positive misperception groups and the multiple regression analysis was performed for TST and WASO misperception, respectively. Results: Although sleep architectures, age, severity of depression and obstructive sleep apnea (OSA) exhibited differences in underestimating or overestimating the WASO, only sex differences were associated with underestimating or overestimating their total sleep time (TST). Moreover, BDI, the severity of OSA, sleep architectures (N1% and N2%), and benzodiazepine (BZD) use were significantly correlated with WASO misperception, whereas only OSA severity was significantly correlated with TST misperception. A subsequent multiple regression analysis demonstrated the BDI was independently correlated with the WASO misperception (β=0.341, p=0.049). Conclusion: In clinical practice, interventions especially for OSA, and the reduction of depressive symptoms are an important method for improving patient sleep perception. Moreover, current results suggest that BZD prescriptions should be avoided as well.

DOI： 10.2147/NSS.S366774

FLUID study: study protocol for an open-label, single-centre pilot study to investigate the efFect of Lemborexant on sleep management in Japanese sUbjects aged 50 years and older with Insomnia Disorder. Reviewed International journal

Ippei Okada, Kunihiro Iwamoto, Seiko Miyata, Akihiro Fujimoto, Masaki Tanaka, Manabu Amano, Nao Matsuyama, Toshiaki Taoka, Shinji Naganawa, Norio Ozaki

BMJ open Vol. 11 ( 11 ) page： e054885 2021.11

Authorship：Corresponding author Language：English Publishing type：Research paper (scientific journal)

INTRODUCTION: Bidirectional associations have been reported between sleep disturbance and both cognitive impairment, including Alzheimer's disease and amyloid beta-peptide (Aβ) accumulation. These relationships can be explained by the glymphatic system, which acts as a garbage drainage system in the brain. As interstitial fluid dynamics are suggested to increase during sleep, clearance of Aβ can be influenced by sleep disturbance or deprivation. We hypothesised that using lemborexant, an orexin receptor antagonist, to improve sleep quality would also improve the function of the glymphatic system. We plan to examine the effect of lemborexant on sleep quality and the glymphatic system among patients with insomnia disorder. METHODS AND ANALYSIS: This pilot study is designed as an open-label, single-arm, single-centre trial. Thirty patients aged 50 years and over with insomnia will be recruited. The participants will take lemborexant (5 mg) at bedtime for 12 weeks and undergo a home-based sleep study at baseline and weeks 4 and 12, as well as MRI examinations to evaluate the glymphatic system at baseline and week 12. The primary outcome will be changes in objective sleep parameters as evaluated using a sleep monitoring system. The secondary outcomes will be changes in subjective sleep parameters. The relationships between changes in sleep parameters and the glymphatic system will be evaluated using diffusion tensor image analysis along the perivascular space, which is called the ALPS-index. Sleep parameters and the ALPS-index will be analysed using a paired t-test or Pearson's correlation coefficient. ETHICS AND DISSEMINATION: The study protocol was approved by Nagoya University Certified Review Board. The findings from this research will be published in peer-reviewed journals and be presented at local, national and international conferences. TRIAL REGISTRATION NUMBER: jRCTs041210024.

DOI： 10.1136/bmjopen-2021-054885