研究者詳細 - 三村　将

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Increased blood COASY DNA methylation levels a potential biomarker for early pathology of Alzheimer’s disease

Kobayashi N., Shinagawa S., Niimura H., Kida H., Nagata T., Tagai K., Shimada K., Oka N., Shikimoto R., Noda Y., Nakajima S., Mimura M., Shigeta M., Kondo K.

Scientific Reports （Scientific Reports） 10 （ 1 ） 2020年12月

© 2020, The Author(s). Early diagnosis of dementia including Alzheimer’s disease (AD) is an urgent medical and welfare issue. However, to date, no simple biometrics have been available. We reported that blood DNA methylation levels of the COASY gene, which encodes coenzyme A synthase, were increased in individuals with AD and amnestic mild cognitive impairment (aMCI). The present study sought to replicate these findings with larger numbers of samples. Another objective was to clarify whether COASY methylation is associated with neurodegeneration through a comparison of AD, AD with cardiovascular disease (CVD), and vascular dementia (VaD). We measured blood COASY methylation levels in normal controls (NCs) (n = 200), and individuals with aMCI (n = 22), AD (n = 151), and VaD (n = 21). Compared with NCs, they were significantly higher in individuals with aMCI and AD. Further, they were significantly higher in AD patients without cardiovascular diseases compared to AD patients with them. These findings suggest that COASY methylation levels may be related to neurodegeneration in AD.

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Study design and baseline characteristics of a population-based prospective cohort study of dementia in Japan: the Japan Prospective Studies Collaboration for Aging and Dementia (JPSC-AD)

Ninomiya T., Nakaji S., Maeda T., Yamada M., Mimura M., Nakashima K., Mori T., Takebayashi M., Ohara T., Hata J., Kokubo Y., Uchida K., Taki Y., Kumagai S., Yonemoto K., Yoshida H., Muto K., Momozawa Y., Akiyama M., Kubo M., Ikeda M., Kanba S., Kiyohara Y., Ninomiya T., Shibata M., Yoshida D., Hirakawa Y., Honda T., Chen S., Hirabayashi N., Furuta Y., Mihara A., Nakazawa T., Ohara T., Ihara K., Murashita K., Sawada K., Jung S., Terayama Y., Yonezawa H., Takahashi J., Akasaka H., Noguchi-Shinohara M., Iwasa K., Sakai K., Hayashi K., Niimura H., Shikimoto R., Kida H., Eguchi Y., Fukada Y., Kowa H., Wada K., Kishi M., Yoshida T., Shimizu H., Tachibana A., Ueno S.i., Ishikawa T., Fukuhara R., Koyama A., Hashimoto M., Esaki M., Takano Y., Inoue Y.

Environmental Health and Preventive Medicine （Environmental Health and Preventive Medicine） 25 （ 1 ） 2020年12月

ISSN 1342078X

© 2020, The Author(s). Background: The burden of dementia is growing rapidly and has become a medical and social problem in Japan. Prospective cohort studies have been considered an effective methodology to clarify the risk factors and the etiology of dementia. We aimed to perform a large-scale dementia cohort study to elucidate environmental and genetic risk factors for dementia, as well as their interaction. Methods: The Japan Prospective Studies Collaboration for Aging and Dementia (JPSC-AD) is a multisite, population-based prospective cohort study of dementia, which was designed to enroll approximately 10,000 community-dwelling residents aged 65 years or older from 8 sites in Japan and to follow them up prospectively for at least 5 years. Baseline exposure data, including lifestyles, medical information, diets, physical activities, blood pressure, cognitive function, blood test, brain magnetic resonance imaging (MRI), and DNA samples, were collected with a pre-specified protocol and standardized measurement methods. The primary outcome was the development of dementia and its subtypes. The diagnosis of dementia was adjudicated by an endpoint adjudication committee using standard criteria and clinical information according to the Diagnostic and Statistical Manual of Mental Disorders, 3rd Revised Edition. For brain MRI, three-dimensional acquisition of T1-weighted images was performed. Individual participant data were pooled for data analyses. Results: The baseline survey was conducted from 2016 to 2018. The follow-up surveys are ongoing. A total of 11,410 individuals aged 65 years or older participated in the study. The mean age was 74.4 years, and 41.9% were male. The prevalence of dementia at baseline was 8.5% in overall participants. However, it was 16.4% among three sites where additional home visit and/or nursing home visit surveys were performed. Approximately two-thirds of dementia cases at baseline were Alzheimer’s disease. Conclusions: The prospective cohort data from the JPSC-AD will provide valuable insights regarding the risk factors and etiology of dementia as well as for the development of predictive models and diagnostic markers for the future onset of dementia. The findings of this study will improve our understanding of dementia and provide helpful information to establish effective preventive strategies for dementia in Japan.

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Primary functional brain connections associated with melancholic major depressive disorder and modulation by antidepressants

Ichikawa N., Lisi G., Yahata N., Okada G., Takamura M., Hashimoto R.i., Yamada T., Yamada M., Suhara T., Moriguchi S., Mimura M., Yoshihara Y., Takahashi H., Kasai K., Kato N., Yamawaki S., Seymour B., Kawato M., Morimoto J., Okamoto Y.

Scientific Reports （Scientific Reports） 10 （ 1 ） 2020年12月

© 2020, The Author(s). The limited efficacy of available antidepressant therapies may be due to how they affect the underlying brain network. The purpose of this study was to develop a melancholic MDD biomarker to identify critically important functional connections (FCs), and explore their association to treatments. Resting state fMRI data of 130 individuals (65 melancholic major depressive disorder (MDD) patients, 65 healthy controls) were included to build a melancholic MDD classifier, and 10 FCs were selected by our sparse machine learning algorithm. This biomarker generalized to a drug-free independent cohort of melancholic MDD, and did not generalize to other MDD subtypes or other psychiatric disorders. Moreover, we found that antidepressants had a heterogeneous effect on the identified FCs of 25 melancholic MDDs. In particular, it did impact the FC between left dorsolateral prefrontal cortex (DLPFC)/inferior frontal gyrus (IFG) and posterior cingulate cortex (PCC)/precuneus, ranked as the second ‘most important’ FC based on the biomarker weights, whilst other eight FCs were normalized. Given that left DLPFC has been proposed as an explicit target of depression treatments, this suggest that the limited efficacy of antidepressants might be compensated by combining therapies with targeted treatment as an optimized approach in the future.

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Optimal robot for intervention for individuals with autism spectrum disorders

Kumazaki H., Muramatsu T., Yoshikawa Y., Matsumoto Y., Ishiguro H., Kikuchi M., Sumiyoshi T., Mimura M.

Psychiatry and Clinical Neurosciences （Psychiatry and Clinical Neurosciences） 74 （ 11 ） 581 - 586 2020年11月

ISSN 13231316

© 2020 The Authors. Psychiatry and Clinical Neurosciences published by John Wiley & Sons Australia, Ltd on behalf of Japanese Society of Psychiatry and Neurology With recent rapid advances in technology, human-like robots have begun functioning in a variety of ways. As increasing anecdotal evidence suggests, robots may offer many unique opportunities for helping individuals with autism spectrum disorders (ASD). Individuals with ASD often achieve a higher degree of task engagement through the interaction with robots than through interactions with human trainees. The type and form of robots to be used for individuals with ASD have been meticulously considered. Simple robots and animal robots are acceptable because of their simplicity and the ease of interesting and engaging interactions. Android robots have the benefit of the potential of generalization into daily life to some extent. Considering the affinity between robots and users is important to draw out the potential capabilities of robotic intervention to the fullest extent. In the robotic condition, factors such as the appearance, biological motion, clothes, hairstyle, and disposition are important. Many factors of a user, such as age, sex, and IQ, may also affect the affinity of individuals with ASD toward a robot. The potential end-users of this technology may be unaware or unconvinced of the potential roles of robots in ASD interventions. If trainers have extensive experience in using robots, they can identify many potential roles of robots based on their experience. To date, only a few studies have been conducted in the field of robotics for providing assistance to individuals with ASD, and future studies are needed to realize an optimal robot for this purpose.

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Lower mortality from suicidal trauma among patients with a psychiatric diagnosis upon admission: Nationwide japanese retrospective cohort study

Ishida T., Kuwahara Y., Shibahashi K., Okura Y., Sugiyama K., Hamabe Y., Mimura M., Suzuki T., Uchida H.

Psychiatry Research （Psychiatry Research） 293 2020年11月

ISSN 01651781

© 2020 Suicide and self-harm are major public health issues. Few studies have compared mortality from suicidal trauma between patients with and without contact with psychiatric services. This study aimed to compare the in-hospital mortality of suicidal trauma between patients with and without a psychiatric diagnosis upon hospital admission. Data on 15- to 90-year-old patients with suicidal trauma between 2004 and 2015 was extracted from the Japan Trauma Data Bank. In-hospital mortality were compared between patients with and without a psychiatric diagnosis. A total of 9,803 patients were included. The median age was 42 years (interquartile range: 29–59), and 5,010 patients (51.1%) were male. The most frequent method of injury was falling from a height (53.4%), followed by stabbing (32.3%) and burns (6.2%). In total, 4,878 patients (49.8%) had a psychiatric diagnosis upon admission. The proportion of patients with a psychiatric diagnosis was significantly lower among males, teenagers, and older people. In-hospital mortality was significantly lower among patients with a psychiatric diagnosis than those without (10.9%vs18.7%). Contact with psychiatric services might be protective among people with suicidal trauma. However, the proportion of psychiatric service use was generally low. These findings show the importance of delivering appropriate psychiatric services to high-risk patients.

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A multi-center, randomized controlled trial by the Integrative Management in Japan for Epidemic Disease (IMJEDI study-RCT) on the use of Kampo medicine, kakkonto with shosaikotokakikyosekko, in mild-To-moderate COVID-19 patients for symptomatic relief and prevention of severe stage: A structured summary of a study protocol for a randomized controlled trial

Takayama S., Namiki T., Ito T., Arita R., Nakae H., Kobayashi S., Yoshino T., Ishigami T., Tanaka K., Kainuma M., Nochioka K., Takagi A., Mimura M., Yamaguchi T., Ishii T.

Trials （Trials） 21 （ 1 ） 2020年10月

© 2020 The Author(s). Objectives: We aimed to test our hypothesis that additional administration of traditional Japanese (Kampo) medicine, kakkonto (kakkon-To: KT) and shosaikotokakikyosekko (sho-saiko-To-ka-kikyo-sekko: SSKKS), is more effective in relieving symptoms and preventing the onset of severe infection in mild-To-moderate COVID-19 patients compared to those treated only with conventional treatment. Trial design: The study is designed as a multi-center, interventional, parallel-group, randomized (1:1 ratio), investigator-sponsored, two-Arm study. Participants: Patients and inpatients will be recruited from 8 Japanese academic and non-Academic hospitals. The inclusion and exclusion criteria are as follows: Inclusion criteria: 1. Diagnosed as positive for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) 2. Clinical stages of mild-To-moderate COVID-19 3. Symptomatic 4. ≥ 20 years of age 5. Male or female 6. Ability to communicate in Japanese 7. Outpatients and inpatients 8. Provided informed consent Exclusion criteria: 1. Difficulty in providing informed consent due to dementia, psychosis, or psychiatric symptoms 2. Allergic to Kampo or Western medicines used in this study 3. Pregnant and lactating 4. Unable to follow up 5. Participating in another clinical trial or interventional study 6. Hypokalemic or taking oral furosemide or steroids 7. Determined unsuitable for this study by the physician Intervention and comparator: Patients in the control group will receive conventional treatment with antipyretics, painkillers, or antitussives for symptoms that occurred after they contracted the SARS-CoV-2 infection. Patients in the Kampo group will receive 2.5 g of KT (TJ-1@TSUMURA and Co.) and 2.5 g of SSKKS (TJ-109@TSUMURA and Co.) 3 times a day, orally, for 14 days in addition to the conventional treatment as mentioned above. Main outcomes: The number of days till at least one of the symptoms (fever, cough, sputum, malaise, shortness of breath) improves in the first 14 days of treatment. To assess the cough, sputum, malaise, and shortness of breath, a numeric rating scale will be used to define improvement in terms of a 2-point decrease in the number of days from the start of treatment for at least 2 days. Fever will be defined as an improvement when the temperature is less than 37 °C. Randomization: Patients are randomized (1:1 ratio) to each group using the minimization method, with balancing of the arms with severity of disease stage and patient age (< 65, 65 to < 75, or ≥ 75 years). Computer-generated random numbers will be used for the minimization method. Blinding (masking): Open-label with no blinding Numbers to be randomized (sample size): The main research hypothesis of this study is that the combination of Kampo medicine and conventional treatment will significantly improve the patients' symptoms (fever, fatigue, cough, sputum, and shortness of breath) during the first 14 days of treatment as compared with conventional treatment alone. Concerning the analysis of the primary endpoint, the duration of time before improvement of at least one of the common cold-like symptoms (fever, malaise, cough, sputum, and shortness of breath) will be estimated using the Kaplan-Meier method, and the survival curves will be compared between groups using the log-rank test. Assuming this method of analysis and based on previous studies reporting the efficacy of Kampo medicine for COVID-19 and H1N1 influenza patients, the median survival time in the Kampo medicine group is estimated as 3 days; this time will be 1.5 times longer in the control group. Assuming a one-sided significance level of 5%, a power of 70%, and an allocation ratio of 1:1, the required sample size is calculated as 126 cases. To compensate for a loss in follow-up, we plan to include 150 cases in both groups (Kampo group = 75, control group = 75). Trial status: Protocol version 1.2 as of August 20, 2020 Recruitment start (expected): October 1, 2020 Recruitment finish (expected): October 31, 2023 Trial registration: Japan Registry of Clinical Trials (jRCT) jRCTs021200020. Registered on August 25, 2020 Full protocol: The full protocol is attached as an additional file and is accessible from the Trials website (Additional file 1). In the interest of expediting the dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol.

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Gap between patients with schizophrenia and their psychiatrists on the needs to psychopharmacological treatment: A cross-sectional study

Takahashi K., Yamazawa R., Suzuki T., Mimura M., Uchida H.

Neuropsychopharmacology Reports （Neuropsychopharmacology Reports） 40 （ 3 ） 232 - 238 2020年09月

© 2020 The Authors. Neuropsychopharmacology Reports published by John Wiley & Sons Australia, Ltd on behalf of the Japanese Society of NeuropsychoPharmacology. Aim: Psychopharmacological treatment is indispensable in patients with schizophrenia but data on needs, preferences, and complaints about their medications are limited. Moreover, there has been no study to assess the degree of awareness of their psychiatrists (gap in needs) regarding these issues. Methods: Ninety-seven Japanese patients with schizophrenia (ICD-10) were asked to fill in the questionnaire consisting of multiple-choice questions regarding (a) their needs and complaints about psychopharmacological treatment that they were receiving, and (b) their preference of dosage form, dosing frequency, and timing of dosing. Additionally, their psychiatrists in charge were asked to predict their patients’ response to the above questions. Results: Both the most frequently endorsed need and complaints about the current psychopharmacological treatment were “nothing in particular” (n = 14, 16.7% and n = 17, 20.2%); merely 23.1% and 15.4% of their psychiatrists correctly predicted these responses, respectively. “Once a day” (n = 56, 65.1%), “at bedtime” (n = 53, 61.6%), and “tablet” (n = 51, 59.3%) were the patients’ most favorite dosing frequency, timing, and dosage form, respectively; 59.8% (n = 49), 54.9% (n = 45), and 64.6% (n = 53) of their psychiatrists predicted them. Conclusions: These findings suggest that there is substantial room for improvement on the side of psychiatrists to capture their patients’ needs and complaints about psychopharmacological treatment.

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Prescription patterns of psychotropics in patients receiving synthetic glucocorticoids

Yatomi T., Uchida T., Takeuchi H., Kuramochi S., Yoshimura K., Mimura M., Uchida H.

Acta Psychiatrica Scandinavica （Acta Psychiatrica Scandinavica） 142 （ 3 ） 242 - 248 2020年09月

ISSN 0001690X

© 2020 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd Objective: Synthetic glucocorticoids cause various psychiatric symptoms. Prescription of psychotropic drugs could be considered to be a proxy for manifestation of psychiatric symptoms. The aim of this study was to investigate the prescriptions of psychotropics in outpatients receiving synthetic glucocorticoids. Methods: We used the claims sampling data during January 2015 from the National Database of Health Insurance Claims and Specific Health Checkups of Japan made by the Ministry of Health, Labor, and Welfare in Japan. We compared the prescription rates of psychotropics between outpatients receiving oral synthetic glucocorticoids and age- and sex-matched controls and the prescription rates of psychotropics among the eight dosage groups of synthetic glucocorticoids by chi-squared test, and chlorpromazine/imipramine/diazepam equivalent doses (or daily defined doses) of respective psychotropics among these groups using Welch's t-test. Results: Synthetic glucocorticoids were prescribed to 3.1% (n = 18 122) of 581 990 patients. The prescription rates of psychotropics were significantly higher among the synthetic glucocorticoid recipients than among the non-recipients: antipsychotics, 1.8% (n = 321) vs. 1.1% (n = 201) (P = 1.4 × 10−7); antidepressants, 4.0% (n = 724) vs. 2.0% (n = 359) (P = 8.7 × 10−30); anxiolytics/hypnotics, 16.7% (n = 3029) vs. 10.2% (n = 1841) (P = 2.7 × 10−75); and mood stabilizers, 1.3% (n = 238) vs. 0.7% (n = 120) (P = 3.6 × 10−10) respectively. There was no significant difference in the prescription rates of any psychotropic drugs, other than anxiolytics/hypnotics, among the eight synthetic glucocorticoid dosage groups. Conclusion: Prescriptions of oral synthetic glucocorticoids were found to be associated with the use of any of the types of psychotropic drugs, other than anxiolytics/hypnotics, although a causal relationship could not be confirmed due to the retrospective and cross-sectional nature of this study.

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Machine-learning approach to predict on-road driving ability in healthy older people

Yamamoto Y., Hirano J., Yoshitake H., Negishi K., Mimura M., Shino M., Yamagata B.

Psychiatry and Clinical Neurosciences （Psychiatry and Clinical Neurosciences） 74 （ 9 ） 488 - 495 2020年09月

ISSN 13231316

© 2020 The Authors Psychiatry and Clinical Neurosciences © 2020 Japanese Society of Psychiatry and Neurology Aim: In Japan, fatal traffic accidents due to older drivers are on the rise. Considering that approximately half the older drivers who have caused fatal accidents are cognitively normal healthy people, it has been required to detect older drivers who are cognitively normal but at high risk of having fatal traffic accidents. However, a standardized method for assessing the driving ability of older drivers has not yet been established. We thus aimed to identify a new sensing method for the evaluation of the on-road driving ability of healthy older people on the basis of vehicle behaviors. Methods: We enrolled 33 healthy older individuals aged over 65 years and utilized a machine-learning approach to dissociate unsafe drivers from safe drivers based on cognitive assessments and a functional visual acuity test. Results: The linear support vector machine classifier successfully dissociated unsafe drivers from safe drivers with accuracy of 84.8% (sensitivity of 66.7% and specificity of 95.2%). Five clinical parameters, namely age, the first trial of the Rey Auditory Verbal Learning Test immediate recall, the delayed recall of the Rey–Osterrieth Complex Figure Test, the result of the free-drawn Clock Drawing Test, and maximal visual acuity, were consistently selected as essential features for the best classification model. Conclusion: Our findings improve our understanding of clinical risk factors leading to unsafe driving and may provide insight into a new intervention that prevents fatal traffic accidents caused by healthy older people.

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Using speech recognition technology to investigate the association between timing-related speech features and depression severity

Yamamoto M., Takamiya A., Sawada K., Yoshimura M., Kitazawa M., Liang K.C., Fujita T., Mimura M., Kishimoto T.

PLoS ONE （PLoS ONE） 15 （ 9 September ） 2020年09月

© 2020 Yamamoto et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Background There are no reliable and validated objective biomarkers for the assessment of depression severity. We aimed to investigate the association between depression severity and timing-related speech features using speech recognition technology. Method Patients with major depressive disorder (MDD), those with bipolar disorder (BP), and healthy controls (HC) were asked to engage in a non-structured interview with research psychologists. Using automated speech recognition technology, we measured three timing-related speech features: speech rate, pause time, and response time. The severity of depression was assessed using the Hamilton Depression Rating Scale 17-item version (HAMD-17). We conducted the current study to answer the following questions: 1) Are there differences in speech features among MDD, BP, and HC? 2) Do speech features correlate with depression severity? 3) Do changes in speech features correlate with within-subject changes in depression severity? Results We collected 1058 data sets from 241 individuals for the study (97 MDD, 68 BP, and 76 HC). There were significant differences in speech features among groups; depressed patients showed slower speech rate, longer pause time, and longer response time than HC. All timing-related speech features showed significant associations with HAMD-17 total scores. Longitudinal changes in speech rate correlated with changes in HAMD-17 total scores. Conclusions Depressed individuals showed longer response time, longer pause time, and slower speech rate than healthy individuals, all of which were suggestive of psychomotor retardation. Our study suggests that speech features could be used as objective biomarkers for the assessment of depression severity.

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Resting-state isolated effective connectivity of the cingulate cortex as a neurophysiological biomarker in patients with severe treatment-resistant schizophrenia

Wada M., Nakajima S., Tarumi R., Masuda F., Miyazaki T., Tsugawa S., Ogyu K., Honda S., Matsushita K., Kikuchi Y., Fujii S., Blumberger D.M., Daskalakis Z.J., Mimura M., Noda Y.

Journal of Personalized Medicine （Journal of Personalized Medicine） 10 （ 3 ） 1 - 12 2020年09月

© 2020 by the authors. Licensee MDPI, Basel, Switzerland. Background: The neural basis of treatment-resistant schizophrenia (TRS) remains unclear. Previous neuroimaging studies suggest that aberrant connectivity between the anterior cingulate cortex (ACC) and default mode network (DMN) may play a key role in the pathophysiology of TRS. Thus, we aimed to examine the connectivity between the ACC and posterior cingulate cortex (PCC), a hub of the DMN, computing isolated effective coherence (iCoh), which represents causal effective connectivity. Methods: Resting-state electroencephalogram with 19 channels was acquired from seventeen patients with TRS and thirty patients with non-TRS (nTRS). The iCoh values between the PCC and ACC were calculated using sLORETA software. We conducted four-way analyses of variance (ANOVAs) for iCoh values with group as a between-subject factor and frequency, directionality, and laterality as within-subject factors and post-hoc independent t-tests. Results: The ANOVA and post-hoc t-tests for the iCoh ratio of directionality from PCC to ACC showed significant findings in delta (t45 = 7.659, p = 0.008) and theta (t45 = 8.066, p = 0.007) bands in the left side (TRS < nTRS). Conclusion: Left delta and theta PCC and ACC iCoh ratio may represent a neurophysiological basis of TRS. Given the preliminary nature of this study, these results warrant further study to confirm the importance of iCoh as a clinical indicator for treatment-resistance.

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The project for objective measures using computational psychiatry technology (PROMPT): Rationale, design, and methodology

Kishimoto T., Takamiya A., Liang K.c., Funaki K., Fujita T., Kitazawa M., Yoshimura M., Tazawa Y., Horigome T., Eguchi Y., Kikuchi T., Tomita M., Bun S., Murakami J., Sumali B., Warnita T., Kishi A., Yotsui M., Toyoshiba H., Mitsukura Y., Shinoda K., Sakakibara Y., Mimura M.

Contemporary Clinical Trials Communications （Contemporary Clinical Trials Communications） 19 2020年09月

ISSN 24518654

© 2020 The Authors Introduction: Depressive and neurocognitive disorders are debilitating conditions that account for the leading causes of years lived with disability worldwide. However, there are no biomarkers that are objective or easy-to-obtain in daily clinical practice, which leads to difficulties in assessing treatment response and developing new drugs. New technology allows quantification of features that clinicians perceive as reflective of disorder severity, such as facial expressions, phonic/speech information, body motion, daily activity, and sleep. Methods: Major depressive disorder, bipolar disorder, and major and minor neurocognitive disorders as well as healthy controls are recruited for the study. A psychiatrist/psychologist conducts conversational 10-min interviews with participants ≤10 times within up to five years of follow-up. Interviews are recorded using RGB and infrared cameras, and an array microphone. As an option, participants are asked to wear wrist-band type devices during the observational period. Various software is used to process the raw video, voice, infrared, and wearable device data. A machine learning approach is used to predict the presence of symptoms, severity, and the improvement/deterioration of symptoms. Discussion: The overall goal of this proposed study, the Project for Objective Measures Using Computational Psychiatry Technology (PROMPT), is to develop objective, noninvasive, and easy-to-use biomarkers for assessing the severity of depressive and neurocognitive disorders in the hopes of guiding decision-making in clinical settings as well as reducing the risk of clinical trial failure. Challenges may include the large variability of samples, which makes it difficult to extract the features that commonly reflect disorder severity. Trial Registration: UMIN000021396, University Hospital Medical Information Network (UMIN).

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Increasing light physical activity helps to maintain cognitive function among the community-dwelling oldest old population: a cross-sectional study using actigraph from the Arakawa 85+ study

Suzuki K., Niimura H., Kida H., Eguchi Y., Kitashima C., Takayama M., Mimura M.

Geriatrics and Gerontology International （Geriatrics and Gerontology International） 20 （ 8 ） 773 - 778 2020年08月

ISSN 14441586

© 2020 Japan Geriatrics Society Aim: To investigate the influence of replacing sedentary time with physical activity on cognitive function using an isotemporal substitution model in a population of community-dwelling oldest old. Methods: This cross-sectional study included residents of the Arakawa ward, Tokyo, who were part of a prospective cohort from the Arakawa 85+ study. We measured physical activity in 136 participants using a triaxial actigraph. Cognitive function was measured using the Addenbrooke's Cognitive Examination-III and participants were divided into a “cognitive decline group” (Addenbrooke's Cognitive Examination-III ≤88) and “cognitive maintain group” (Addenbrooke's Cognitive Examination-III ≥89). Physical activity was divided into three categories: sedentary behavior (≤1.5 metabolic equivalents), light physical activity (>1.5 to <3.0 metabolic equivalents), and moderate-to-vigorous physical activity (≥3 metabolic equivalents). Using an isotemporal substitution approach, we applied multiple logistic regression analysis to demonstrate the association between cognitive function and replacing 30 min/day of sedentary behavior with an equal period of light physical activity. Covariates included age, education and the Center for Epidemiologic Studies Depression Scale. Results: Our findings showed that in men, replacing 30 min of sedentary behavior per day with light physical activity was associated with a 1.47-fold increase in the odds of maintaining cognitive function. An association between physical activity and cognitive function was not observed in female participants. Conclusions: Our results indicate that substituting sedentary behavior with light physical activity could be helpful in maintaining cognitive function in community-dwelling oldest old men. These results highlight the importance of behavioral changes to promote cognition. Geriatr Gerontol Int 2020; 20: 773–778.

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Remote neuropsychological assessment of elderly Japanese population using the Alzheimer’s Disease Assessment Scale: A validation study

Yoshida K., Yamaoka Y., Eguchi Y., Sato D., Iiboshi K., Kishimoto M., Mimura M., Kishimoto T.

Journal of Telemedicine and Telecare （Journal of Telemedicine and Telecare） 26 （ 7-8 ） 482 - 487 2020年08月

ISSN 1357633X

© The Author(s) 2019. Introduction: Studies have demonstrated the high agreement of several remote neuropsychological tests using video teleconferencing (VTC) with face-to-face (FTF) tests. However, the reliability of the remotely administered Alzheimer’s Disease Assessment Scale cognitive subscale (ADAS-cog), one of the most commonly used neuropsychological tests to detect cognitive decline, has not been substantially elucidated, particularly in Japanese populations. Therefore, this study aimed to evaluate the reliability of the remotely administered ADAS-cog compared with FTF-administered ADAS-cog among elderly Japanese participants. Methods: Participants aged ≥60 years with and without cognitive impairment, i.e. those with mild cognitive impairment (MCI), those with dementia and healthy controls (HCs), were assessed with the ADAS-cog using VTC and FTF testing at an interval of >2 weeks and <3 months. The assessment order (VTC or FTF) was randomized by participants. Participants’ scores were compared among the entire sample, as well as subgroups, using intra-class correlation coefficients (ICCs) in a mixed-effects model. Results: A total of 73 participants were included in the study (36 men; age, 76.3 ± 7.6 years). The ICC for the ADAS-cog total score was high in the entire sample (0.86), whereas ICCs were moderate to high for the subgroups (MCI: 0.63, dementia: 0.80 and HC: 0.74). Discussion: The results indicate that a VTC-administered ADAS-cog could be an alternative for an FTF-administered ADAS-cog, although further replication studies with larger sample sizes and a wider range of cognitive functionalities are warranted.

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Dissociation in Pharmacokinetic Attenuation Between Central Dopamine D2 Receptor Occupancy and Peripheral Blood Concentration of Antipsychotics: A Systematic Review

Kurose S., Mimura Y., Uchida H., Takahata K., Kim E., Suzuki T., Mimura M., Takeuchi H.

The Journal of clinical psychiatry （The Journal of clinical psychiatry） 81 （ 5 ） 2020年07月

© Copyright 2020 Physicians Postgraduate Press, Inc. OBJECTIVE: The objective of this study was to examine the extent of possible dissociation in pharmacokinetic decay between central dopamine D₂ receptor occupancy with antipsychotics and their peripheral blood concentrations. DATA SOURCES: MEDLINE and Embase were searched using the following keywords: (positron emission tomography OR PET OR single-photon emission computed tomography OR SPECT) AND (dopamine OR D2) AND (receptor* OR occupanc*) AND antipsychotic*, with a limitation of English language (last search: December 14, 2019). STUDY SELECTION: The search identified 18 studies that met the following criteria: (1) including patients with schizophrenia spectrum disorders and/or healthy subjects, (2) using positron emission tomography or single-photon emission computed tomography, and (3) examining the time courses of D₂ occupancy with antipsychotics and their blood concentrations. DATA EXTRACTION: The ratios of D₂ occupancy reduction rate (%) from peak to blood concentration reduction rate (%) from peak (relative attenuation ratio) were calculated. RESULTS: Among the studies, oral risperidone, olanzapine, quetiapine, aripiprazole, ziprasidone, perospirone, haloperidol, sulpiride, and clozapine and long-acting injectable risperidone and haloperidol were included. Relative attenuation ratios were less than 1, indicating a slower central versus peripheral attenuation, across the time points for all antipsychotic types and doses with only a few exceptions. The ratio decreased in a dose-dependent as well as a peak D₂ occupancy-dependent fashion. It contrarily increased in a time-dependent manner. CONCLUSIONS: The findings indicate pharmacokinetic attenuation of antipsychotics was generally slower at the central versus the peripheral level and pose a critical challenge to the current dosing strategy that primarily relies on peripheral pharmacokinetics of antipsychotics.

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Alterations of Heartbeat Evoked Magnetic Fields Induced by Sounds of Disgust

Kato Y., Takei Y., Umeda S., Mimura M., Fukuda M.

Frontiers in Psychiatry （Frontiers in Psychiatry） 11 2020年07月

© Copyright © 2020 Kato, Takei, Umeda, Mimura and Fukuda. The majority of the models of emotional processing attribute subjective emotional feelings to physiological changes in the internal milieu, which are sensed by the interoceptive system. These physiological reactions evoked by emotional phenomena occur via the autonomic nervous system, and give rise to alterations in body-mind interactions that are characterized by heartbeat evoked magnetic fields (HEFs) involving brain regions associated with emotional perception. The current study used magnetoencephalography (MEG) to examine regional cortical activity and connectivity changes in HEFs provoked by the emotion of disgust. MEG results from 39 healthy subjects (22 female) revealed that passively listening to sounds of disgust elicited right insular cortical activity and enhancement of cortical connectivity between the right anterior ventral insular cortex and left ventromedial prefrontal cortex, demonstrated by phase lag indexes in the beta frequency range. Furthermore, inter-trial coherence significantly increased at 19 Hz and 23 Hz, and decreased at 14 Hz, which highlights the involvement of low beta oscillations in emotional processing. As these results were based on spontaneously triggered bioelectrical signals, more indigenous and induced signals were extracted with a block designed experiment. The insular cortices play an important role in emotional regulation and perception as the main cortical target for signals with interoceptive information, providing direct substrates of emotional feelings. The current results provide a novel insight into frequency properties of emotional processing, and suggest that emotional arousal evoked by listening to sounds of disgust partially impact the autonomic nervous system, altering HEFs via connectivity changes in the right anterior ventral insular cortex and left ventromedial prefrontal cortex.

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A validation study of the remotely administered Montreal cognitive assessment tool in the elderly Japanese population

Iiboshi K., Yoshida K., Yamaoka Y., Eguchi Y., Sato D., Kishimoto M., Funaki K., Mimura M., Kishimoto T.

Telemedicine and e-Health （Telemedicine and e-Health） 26 （ 7 ） 1 - 9 2020年07月

ISSN 15305627

© MARY ANN LIEBERT, INC. Background: In an aging society, neuropsychological testing using video teleconferencing (VTC) is increasingly important. Despite the potential benefit of a VTC-administered Montreal Cognitive Assessment Tool (MoCA) to detect cognitive decline, only a limited number of studies have investigated this tool's reliability. Therefore, we aimed to evaluate the reliability of VTC-administered MoCA compared with face-to-face (FTF)-administered MoCA among elderly Japanese participants. Moreover, we examined participants' satisfaction with VTC-administered MoCA. Methods: Participants ‡60 years of age with and without cognitive impairment (i.e., those with mild cognitive impairment [MCI], those with dementia, and healthy controls [HC]) were assessed with VTC- and FTF-administered MoCA at an interval of >2 weeks and <3 months. The order effect (VTC first vs. FTF first) and time effect (first vs. second testing session), as well as several covariates such as age and years of education were controlled. Intraclass correlation coefficients (ICCs) were calculated using a mixed-effects model to assess the agreement between the two (VTC- vs. FTF-administered) groups. Participants' satisfaction with VTC-administered MoCA was examined using a Likert scale asking seven questions. Results: We included 73 participants in the study (36 men; age, 76.3 - 7.5 years). The ICC for the MoCA total score was high in the entire sample (0.85), whereas ICCs were moderate to high for the subgroups (MCI: 0.82, dementia: 0.82, and HC: 0.53). Furthermore, we found good overall participant satisfaction with VTC-administered MoCA. Discussion: VTC-administered MoCA appears viable as an alternative to FTF-administered MoCA, although further replication studies with larger sample sizes are needed.

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Opposing Ventral Striatal Medium Spiny Neuron Activities Shaped by Striatal Parvalbumin-Expressing Interneurons during Goal-Directed Behaviors

Yoshida K., Tsutsui-Kimura I., Kono A., Yamanaka A., Kobayashi K., Watanabe M., Mimura M., Tanaka K.F.

Cell Reports （Cell Reports） 31 （ 13 ） 2020年06月

© 2020 The Authors Medium spiny neurons (MSNs) of mice show opposing activities upon the initiation of a food-seeking lever press task. Ventromedial striatal (VMS)-MSNs are inhibited but ventrolateral striatal (VLS)-MSNs are activated; these activities mediate action selection and action initiation, respectively. To understand what input shapes the opposing MSN activities, here, we monitor cortical input activities at the cell population level and artificially reverse them. We demonstrate that the ventral hippocampus (vHP) and the insular cortex (IC) are major inputs to the VMS and VLS, both projections show silencing at the trial start time, and the vHP-VMS and IC-VLS pathways form functionally coupled input-output units during the task. Of note, the upstream IC silencing is converted to the downstream VLS-MSN activation. We find biased localization of striatal parvalbumin-expressing interneurons (PV INs) and verify PV IN-dependent feedforward architecture in the VLS. Our results reveal a distinct mode of cortico-striatal signal conveyance via feedforward disinhibition in behaving animals.

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Pharmacological management of behavioral disturbances in patients with Alzheimer’s disease

Nagata T., Shinagawa S., Nakajima S., Noda Y., Mimura M.

Expert Opinion on Pharmacotherapy （Expert Opinion on Pharmacotherapy） 21 （ 9 ） 1093 - 1102 2020年06月

ISSN 14656566

© 2020, © 2020 Informa UK Limited, trading as Taylor & Francis Group. Neuropsychiatric symptoms (NPS) inevitably occur during the course of Alzheimer’s disease (AD) including psychosis, aggression, and depression. The effectiveness of pharmacological treatments for NPS has been limited because of their lack of efficacy, discontinuation due to undesirable adverse events, or poor adherence. In recent consensus guidelines, non-pharmacological treatments for NPS have been prioritized as first-line management strategies. Pharmacological treatments for severe NPS should be administrated as a second-line approach, and have been suggested to be started at a lower dosage followed by titration to a minimum effective dosage and for a limited time period. However, recent studies have shown that some patients receiving pharmacological treatments do not exhibit treatment efficacy in comparison with placebo. The concurrence of several sub-symptoms in NPS makes it difficult to target one symptom exclusively. Therefore, the current review focuses on a strategy for such refractory NPS in patients with AD. Recent randomized controlled trials have shown that the severity of NPS gradually reduces in a time-dependent manner regardless of active treatments. Therefore, clinicians should consider potential causes of NPS sub-symptoms from multifactorial aspects and select alternative treatments (e.g. neuromodulation or relocation into specialized care units) during the long-term disease course.

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White matter microstructural organizations in patients with severe treatment-resistant schizophrenia: A diffusion tensor imaging study

Ochi R., Noda Y., Tsuchimoto S., Tarumi R., Honda S., Matsushita K., Tsugawa S., Plitman E., Masuda F., Ogyu K., Wada M., Miyazaki T., Fujii S., Chakravarty M.M., Graff-Guerrero A., Uchida H., Mimura M., Nakajima S.

Progress in Neuro-Psychopharmacology and Biological Psychiatry （Progress in Neuro-Psychopharmacology and Biological Psychiatry） 100 2020年06月

ISSN 02785846

© 2020 Elsevier Inc. Previous diffusion tensor imaging (DTI) studies have reported white matter alterations in patients with schizophrenia. Notably, one third of this population does not respond to first-line antipsychotics and is thus referred to as treatment-resistant schizophrenia (TRS). Despite potentially distinct neural bases between TRS and non-TRS, few studies have compared white matter integrity between these groups. In order to reflect clinical picture of TRS, we enrolled TRS patients who had severe symptoms. According to the consensus criteria for TRS. TRS was defined by severe positive symptomatology despite optimal antipsychotic treatment. Fractional anisotropy (FA), an index of white matter integrity, was examined by DTI and analyzed with tract-based spatial statistics in 24 TRS patients (mean PANSS = 108.9), 28 non-TRS patients (mean PANSS = 50.0), and 27 healthy controls (HCs) for group comparison. Additionally, correlation analyses were conducted between FA values and symptomatology. The TRS group had lower FA values in multiple tracts (cerebral peduncle, corona radiata, corpus callosum, external and internal capsules, posterior thalamic radiation, sagittal stratum, superior longitudinal fasciculus, tapetum, and uncinate fasciculus) compared to the HC group as well as the non-TRS group (p <.05; family-wise error-corrected), while no differences were found between the non-TRS and HC groups. In the TRS group, FA values in most of the tracts (other than the left anterior limb of internal capsule, left cerebral peduncle, and right uncinate fasciculus) were negatively correlated with the Positive and Negative Syndrome Scale total scores, and negative and general symptom scores. No such relationships were found in the non-TRS group. The identified white matter integrity deficits may reflect the pathophysiology of TRS.

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Two-day assertive-case-management educational program for medical personnel to prevent suicide attempts: A multicenter pre–post observational study

Kawashima Y., Yonemoto N., Kawanishi C., Otsuka K., Mimura M., Otaka Y., Okamura K., Kinoshita T., Shirakawa O., Yoshimura R., Eto N., Hashimoto S., Tachikawa H., Furuno T., Sugimoto T., Ikeshita K., Inagaki M., Yamada M.

Psychiatry and Clinical Neurosciences （Psychiatry and Clinical Neurosciences） 74 （ 6 ） 362 - 370 2020年06月

ISSN 13231316

© 2020 The Authors Psychiatry and Clinical Neurosciences © 2020 Japanese Society of Psychiatry and Neurology Aim: Suicide attempters have a high risk of repeated suicide attempts and completed suicide. There is evidence that assertive case management can reduce the incidence of recurrent suicidal behavior among suicide attempters. This study evaluated the effect of an assertive-case-management training program. Methods: This multicenter, before-and-after study was conducted at 10 centers in Japan. Participants were 274 medical personnel. We used Japanese versions of the Attitudes to Suicide Prevention Scale, the Gatekeeper Self-Efficacy Scale, the Suicide Intervention Response Inventory (SIRI), and the Attitudes Toward Suicide Questionnaire. We evaluated the effects with one-sample t-tests, and examined prognosis factors with multivariable analysis. Results: There were significant improvements between pre-training and post-training in the Attitudes to Suicide Prevention Scale (mean: −3.07, 95% confidence interval [CI]: −3.57 to −2.57, P < 0.001), the Gatekeeper Self-Efficacy Scale (mean: 10.40, 95%CI: 9.48 to 11.32, P < 0.001), SIRI-1 (appropriate responses; mean: 1.15, 95%CI: 0.89 to 1.42, P < 0.001), and SIRI-2 (different to the expert responses; mean: −4.78, 95%CI: −6.18 to −3.38, P < 0.001). Significant improvements were found on all Attitudes Toward Suicide Questionnaire subscale scores, except Unjustified Behavior. The effect of training was influenced by experience of suicide-prevention training and experience of working with suicidal patients. Conclusion: The training program (which was developed to implement and disseminate evidence-based suicide-prevention measures) improved attitudes, self-efficacy, and skills for suicide prevention among medical personnel. Specialized suicide-prevention training and experience with suicidal patients are valuable for enhancing positive attitudes and self-efficacy; furthermore, age and clinical experience alone are insufficient for these purposes.

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Early improvements of individual symptoms as a predictor of treatment response to asenapine in patients with schizophrenia

Ogyu K., Noda Y., Yoshida K., Kurose S., Masuda F., Mimura Y., Nishida H., Plitman E., Tarumi R., Tsugawa S., Wada M., Miyazaki T., Uchida H., Graff-Guerrero A., Mimura M., Nakajima S.

Neuropsychopharmacology Reports （Neuropsychopharmacology Reports） 40 （ 2 ） 138 - 149 2020年06月

© 2020 The Authors. Neuropsychopharmacology Reports published by John Wiley & Sons Australia, Ltd on behalf of The Japanese Society of Neuropsycho Pharmacology Aim: It is well accepted that early improvement with antipsychotics predicts subsequent response in patients with schizophrenia. However, no study has examined the contribution of individual symptoms rather than overall symptom severity as the predictors. Thus, we aimed to detect individual symptoms whose improvements could predict subsequent response in patients with schizophrenia during treatment with asenapine and examine whether a prediction model with individual symptoms would be superior to a model using overall symptom severity. Methods: This study analyzed a dataset including 532 patients with schizophrenia enrolled in a 6-week double-blind, placebo-controlled, randomized trial of asenapine. Response to asenapine was defined as a ≥30% decrease in Positive and Negative Syndrome Scale (PANSS) total score from baseline to week 6. Stepwise logistic regression analyses were performed to investigate the associations among response and PANSS total/individual item score improvements at week 1 or week 2. Results: Response was associated with early improvement in the following PANSS items: disturbance of volition, active social avoidance, poor impulse control at week 1; and active social avoidance, poor attention, lack of judgment and insight at week 2. Prediction accuracy was almost compatible between the model with individual symptoms and the model with PANSS total score both at weeks 1 and 2 (Nagelkerke R2:.51,.42 and.55,.54, respectively). Conclusion: Early improvement in negative symptoms, poor attention and impulse control, and lack of insight, in particular predicted subsequent treatment response in patients with schizophrenia during treatment with asenapine as accurately as prediction based on overall symptom severity.

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Reliability of the glasgow antipsychotic side-effects scale for Clozapine Japanese version (GASS-C-J)

Kitagawa K., So R., Nomura N., Mizuno Y., Misawa F., Kodama M., Uchida H., Mimura M., Takeuchi H.

PLoS ONE （PLoS ONE） 15 （ 6 ） 2020年06月

Copyright: © 2020 Kitagawa et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. The purpose of this study was to develop the Glasgow Antipsychotic Side effects Scale for Clozapine Japanese version (GASS-C-J) and examine its reliability to assess clozapine-related side effects. We developed the GASS-C-J using forward and backward translation. Semantic equivalence of the GASS-C-J to the GASS-C was confirmed by the original author. We then administered the GASS-C-J twice to 109 patients on clozapine treatment at two psychiatric hospitals in Japan. We assessed the internal consistency and test-retest reliability of the GASS-C-J using Cronbach's alpha and weighted kappa coefficient, respectively. We also examined if discrepancies in each GASS-C-J item score between the first and second rating were correlated with items of the Brief Evaluation of Psychosis Symptom Domains (BE-PSD). The Cronbach's alpha coefficient of the GASS-C-J at the first and second rating was 0.78 (95% CI: 0.72 to 0.84) and 0.82 (95% CI: 0.76 to 0.88), respectively. The weighted kappa coefficient of individual and total GASS-C-J item scores ranged from 0.45 to 0.88. Some symptom domains were correlated with discrepancies in specific items of the GASS-C-J: psychotic symptoms and nausea/vomiting (rs = 0.27), thirst (rs = 0.31), and appetite/weight gain (rs = 0.27); disorganized thinking and urinary incontinence (rs = 0.26); depression/anxiety and myoclonus (rs = 0.25), hypersalivation (rs = -0.27), and blurred vision (rs = -0.22). These findings demonstrate that the GASS-C-J can be used in clinical and research settings as a reliable scale to assess clozapine-related side effects.

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Speech quality feature analysis for classification of depression and dementia patients

Sumali B., Mitsukura Y., Liang K.C., Yoshimura M., Kitazawa M., Takamiya A., Fujita T., Mimura M., Kishimoto T.

Sensors (Switzerland) （Sensors (Switzerland)） 20 （ 12 ） 1 - 17 2020年06月

ISSN 14248220

© MDPI AG. All rights reserved. Loss of cognitive ability is commonly associated with dementia, a broad category of progressive brain diseases. However, major depressive disorder may also cause temporary deterioration of one’s cognition known as pseudodementia. Differentiating a true dementia and pseudodementia is still difficult even for an experienced clinician and extensive and careful examinations must be performed. Although mental disorders such as depression and dementia have been studied, there is still no solution for shorter and undemanding pseudodementia screening. This study inspects the distribution and statistical characteristics from both dementia patient and depression patient, and compared them. It is found that some acoustic features were shared in both dementia and depression, albeit their correlation was reversed. Statistical significance was also found when comparing the features. Additionally, the possibility of utilizing machine learning for automatic pseudodementia screening was explored. The machine learning part includes feature selection using LASSO algorithm and support vector machine (SVM) with linear kernel as the predictive model with age-matched symptomatic depression patient and dementia patient as the database. High accuracy, sensitivity, and specificity was obtained in both training session and testing session. The resulting model was also tested against other datasets that were not included and still performs considerably well. These results imply that dementia and depression might be both detected and differentiated based on acoustic features alone. Automated screening is also possible based on the high accuracy of machine learning results.

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Pisa syndrome induced by switching of a choline-esterase inhibitor treatment from donepezil to galantamine: A case report

Mimura Y., Kurose S., Takata T., Tabuchi H., Mimura M., Funayama M.

BMC Neurology （BMC Neurology） 20 （ 1 ） 2020年05月

© 2020 The Author(s). Background: Pisa syndrome (PS) is characterized by an abnormally sustained posture, with flexion of the body and head to one side and slight rotation of the trunk. Although PS most commonly arises as an adverse effect of antipsychotic drugs, choline-esterase inhibitors (ChEIs) are also sometimes known to induce PS. Despite the fact that the precise mechanism remains unclear, cholinergic-dopaminergic imbalance has been considered as a possible pathophysiologic mechanism underlying the genesis of PS. Case presentation: We hereby report the case of a 60-year-old woman with Alzheimer's disease who presented with the signs of PS after her treatment was switched to galantamine, a type of ChEI, even though she had received donepezil, another type of ChEI, for 5 years without any complications. To the best of our knowledge, this is the first report of PS associated with treatment switch from one to another type of ChEI. Galantamine, but not other ChEIs, can enhance striatal dopamine release through allosteric modulation of the nicotinic acetylcholine receptor, and has weaker muscarinic effects than donepezil. Therefore, we propose two novel hypotheses to explain the development of PS, as follows; galantamine, which enhances dopamine release, can induce imbalance of dopamine levels in the striatum of patients with dementia, resulting in PS, and the weaker muscarinic effects of the drug could be one of the factors predisposing to the development of PS. Conclusion: The present case suggests that treatment with galantamine is associated with a higher risk of development of PS than that with other ChEIs, such as donepezil, despite the pharmacological profile of galantamine as a dopamine modulator. Also, this report provides novel insight into another plausible mechanism underlying the development of PS, besides cholinergic-dopaminergic imbalance, namely, dopamine imbalance in the striatum with muscarinic-nicotinic imbalance.

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Behavioral and electrophysiological evidence for a neuroprotective role of aquaporin-4 in the 5xFAD transgenic mice model

Abe Y., Ikegawa N., Yoshida K., Muramatsu K., Hattori S., Kawai K., Murakami M., Tanaka T., Goda W., Goto M., Yamamoto T., Hashimoto T., Yamada K., Shibata T., Misawa H., Mimura M., Tanaka K.F., Miyakawa T., Iwatsubo T., Hata J.I., Niikura T., Yasui M.

Acta Neuropathologica Communications （Acta Neuropathologica Communications） 8 （ 1 ） 2020年05月

© 2020 The Author(s). Aquaporin-4 (AQP4) has been suggested to be involved in the pathogenesis of neurodegenerative diseases including Alzheimer's disease (AD), which may be due to the modulation of neuroinflammation or the impairment of interstitial fluid bulk flow system in the central nervous system. Here, we show an age-dependent impairment of several behavioral outcomes in 5xFAD AQP4 null mice. Twenty-four-hour video recordings and computational analyses of their movement revealed that the nighttime motion of AQP4-deficient 5xFAD mice was progressively reduced between 20 and 36 weeks of age, with a sharp deterioration occurring between 30 and 32 weeks. This reduction in nighttime motion was accompanied by motor dysfunction and epileptiform neuronal activities, demonstrated by increased abnormal spikes by electroencephalography. In addition, all AQP4-deficient 5xFAD mice exhibited convulsions at least once during the period of the analysis. Interestingly, despite such obvious phenotypes, parenchymal amyloid β (Aβ) deposition, reactive astrocytosis, and activated microgliosis surrounding amyloid plaques were unchanged in the AQP4-deficient 5xFAD mice relative to 5xFAD mice. Taken together, our data indicate that AQP4 deficiency greatly accelerates an age-dependent deterioration of neuronal function in 5xFAD mice associated with epileptiform neuronal activity without significantly altering Aβ deposition or neuroinflammation in this mouse model. We therefore propose that there exists another pathophysiological phase in AD which follows amyloid plaque deposition and neuroinflammation and is sensitive to AQP4 deficiency.

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Life-Threatening Serotonin Syndrome Precipitated by Discontinuation of Serotonin-Dopamine Antagonist in the Presence of Serotonergic Agents: A Case Report

Ishida T., Uchida H., Kaneko S., Sugiyama K., Hamabe Y., Mimura M., Suzuki T.

Clinical Neuropharmacology （Clinical Neuropharmacology） 43 （ 3 ） 81 - 83 2020年05月

ISSN 03625664

© Wolters Kluwer Health, Inc. All rights reserved. Introduction Serotonin syndrome is caused by excessive activation of serotonin (5-hydroxytryptamine [5-HT]) neurotransmission. Although the discontinuation of antipsychotics with 5-HT2 receptor antagonistic characteristics could theoretically result in serotonin syndrome, there have been very few reports on the syndrome thus far. Case Presentation A 75-year-old woman with somatoform disorder was transferred to our emergency room because of pyrexia, unconsciousness, and myoclonus with hyperreflexia. She had been taking milnacipran and perospirone for 10 years and had started taking duloxetine 2 months before the event. Thereafter, she suffered diaphoresis, gait disturbance, and tremor. Her psychiatrist advised her to stop taking perospirone, because of suspicion of extrapyramidal symptoms, a day before admission. The clinical diagnosis of serotonin syndrome was made based on her symptoms while using serotonergic agents. Her symptoms were so severe that she was transferred to the intensive care unit, where supportive care was successful. Conclusions Discontinuation of antipsychotics that are 5-HT2 receptor antagonists may lead to serotonin syndrome in patients who take serotonergic agents. As extrapyramidal symptoms and serotonin toxicity share some clinical features, detailed drug history and physical examination are necessary for successful treatment.

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Mindfulness-based cognitive therapy for improving subjective well-being among healthy individuals: Protocol for a randomized controlled trial

Sado M., Kosugi T., Ninomiya A., Nagaoka M., Park S., Fujisawa D., Shirahase J., Mimura M.

JMIR Research Protocols （JMIR Research Protocols） 9 （ 5 ） 2020年05月

© 2020 Mitsuhiro Sado, Teppei Kosugi, Akira Ninomiya, Maki Nagaoka, Sunre Park, Daisuke Fujisawa, Joichiro Shirahase, Masaru Mimura. Background: Previous studies have indicated that higher subjective well-being works as a protective factor for health. Some studies have already shown the effects of mindfulness-based interventions on improving subjective well-being. However, these studies targeted specific populations rather than the general public. Furthermore, they assessed either life evaluation or affective aspects of subjective well-being rather than the concept as a whole, including the eudemonic aspect of well-being. Objective: This study aims to investigate the effectiveness and cost-effectiveness of mindfulness-based cognitive therapy (MBCT) for improving the wholistic aspects of subjective well-being in healthy individuals. Methods: This study was an 8-week, randomized, parallel-group, superiority trial with a 2-month follow-up. Healthy individuals aged 20-65 years with scores lower than 25 on the Satisfaction With Life Scale (SWLS) were eligible to participate and randomly allocated to the MBCT group or the wait-list control group. The intervention program was developed by modifying an MBCT program to improve the well-being of a nonclinical population. The primary outcome was the difference between the two groups in mean change scores from the baseline on the SWLS. The secondary outcomes included scores on the Flourishing Scale and the Scale of Positive and Negative Experience as well as the incremental cost-effectiveness ratio. Results: This study began recruiting participants in July 2018 and recruitment was completed at the end of September 2019. Data collection and dataset construction was completed by the end of March 2020. Conclusions: This study is unique in that it investigates MBCT's effects on the three different aspects of subjective well-being: Life evaluation, affect, and eudemonia. It is limited, as the specific effect attributable to MBCT cannot be detected because of the lack of an active control group.

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The utility of simple questions to evaluate cognitive impairment

Daté Y., Sugiyama D., Tabuchi H., Saito N., Konishi M., Eguchi Y., Momota Y., Yoshizaki T., Mashima K., Mimura M., Nakahara J., Ito D.

PLoS ONE （PLoS ONE） 15 （ 5 ） 2020年05月

© 2020 Daté et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Objectives As the population of patients with cognitive decline grows, physicians and caregivers need brief screening tools. Comprehensive neurocognitive batteries require special training and time for evaluation. We focused on accessibility and compared the diagnostic power of several easy questions. Design “Attended With” (AW) and “Head-Turning Sign” (HTS) factors and participants’ replies to following questions were recorded: “Do you feel that you have more difficulties in your daily life than you used to?”, [no consciousness (C-) or consciousness+ (C+)], “Could you tell me about your daily pleasures or pastimes?” [no pleasure (P-) or pleasure + (P+)], “What are notable current/recent news/topics?” [no news (N-) or news+ (N+)]. Setting This took place in our Memory Clinic between May 2016 and July 2019. Participants We enrolled 162 consecutive cases (44 cognitive normal (CN), 55 amnestic mild cognitive impairment (aMCI), and 48 Alzheimer’s disease (AD)). Measurements The sensitivity and specificity of each battery were calculated, and on account of those numbers, the population attributable risk percent % (PAR%) of (AW and HTS+), (C- and P-), (C- and N-), (P- and N-) as analysis of combination of questions, respectively, were calculated. Results AW had high sensitivity, 87.4, 95.8% (CN vs aMCI + AD, CN + aMCI vs AD) but the sensitivity of HTS was only 46.4, 57.7%, and HTS showed high specificity, 100.0, 71.8%. C- had high sensitivity, 80.6, 87.5%, whereas P- and N- had high specificity, both 83.9% in CN vs aMCI + AD, 88.1% and 75.9% in CN + aMCI vs AD, respectively. In combination analysis, the PAR% of (C- and N-) were as high as (AW and HTS+). Conclusions The combination of (C- and N-) is as powerful as (AW and HTS+) in screening AD. Our findings provide novel insights for screening utility of brief questions “Consciousness of Impairment” and “Recent News.”

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Neural correlates of delay discount alterations in addiction and psychiatric disorders: A systematic review of magnetic resonance imaging studies

Noda Y., Barr M.S., ElSalhy M., Masuda F., Tarumi R., Ogyu K., Wada M., Tsugawa S., Miyazaki T., Nakajima S., Mimura M.

Progress in Neuro-Psychopharmacology and Biological Psychiatry （Progress in Neuro-Psychopharmacology and Biological Psychiatry） 99 2020年04月

ISSN 02785846

© 2019 Elsevier Inc. Delay discounting (DD) represents decreased subjective value for delayed reward relative to the same reward at present. The concept of DD has been applied for pathophysiology of addiction and psychiatric disorders. However, the detailed neuroimaging correlates of DD underlying pathophysiology still remain unclear. Thus, we conducted a systematic review to investigate neural correlates of DD on magnetic resonance imaging studies among addiction and psychiatric disorders. Specific search terms were set on PubMed to identify relevant articles. Initial search identified 551 records and 31 studies met the inclusion criteria. The present review revealed that greater DD was correlated with increased activity in areas related to reward evaluation and prediction as well as decreased activity in areas related to cognitive control. Healthy controls showed smaller changes in activities of these areas associated with DD when compared to patient groups. As the neural basis related to DD, three neural networks have been proposed that are associated with the actions of short-term interests and long-term benefits. Among the three potential neural networks on DD, the first one included the ventromedial prefrontal cortex and ventral striatum and implicated in evaluating reward values, the second network included the anterior cingulate cortex and linked to cognitive control, and the third network included the middle temporal gyrus and was involved in predictions and affection. This review generated consistent findings on the neural basis of DD among patients with addiction and psychiatric disorders, which may represent the pathophysiology related to DD and impulsivity of mental illness.

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Widespread White Matter Aberrations Are Associated with Phonemic Verbal Fluency Impairment in Chronic Traumatic Brain Injury

Yamagata B., Ueda R., Tasato K., Aoki Y., Hotta S., Hirano J., Takamiya A., Nakaaki S., Tabuchi H., Mimura M.

Journal of Neurotrauma （Journal of Neurotrauma） 37 （ 7 ） 975 - 981 2020年04月

ISSN 08977151

© Copyright 2020, Mary Ann Liebert, Inc., publishers. Microstructural white matter (WM) disruption and resulting abnormal structural connectivity form a potential underlying pathology in traumatic brain injury (TBI). Herein, to determine the potential mechanism of cognitive deterioration in TBI, we examined the association of damage to specific WM tracts with cognitive function in TBI patients. We recruited 18 individuals with mild-to-moderate/severe TBI in the chronic phase and 17 age-matched controls. We determined the pattern of WM aberrations in TBI using tract-based spatial statistics (TBSS) and then examined the relationship between cognitive impairment and WM damage using the threshold-free cluster enhancement correction in TBSS. TBSS analysis showed that TBI patients exhibited WM aberrations in a wide range of brain regions. In the majority of these regions, lower fractional anisotropy (FA) largely overlapped with increased radial diffusivity, but not with axial diffusivity. Further, voxel-wise correction in TBSS demonstrated that higher FA values were associated with better performance in the phonemic verbal fluency task (VFT) in widespread WM regions, but not with the semantic VFT. Despite variation in the magnitude and location of brain injury between individual cases, chronic TBI patients exhibited widespread WM aberrations. We confirmed the findings of previous studies that WM integrity is lower across the spectrum of TBI severity in chronic subjects compared to controls. Further, phonemic VFT may be a more sensitive cognitive measure of executive dysfunction associated with WM aberrations in TBI compared with semantic VFT.

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Early improvements of individual symptoms with antipsychotics predict subsequent treatment response of neuropsychiatric symptoms in Alzheimer's disease: A re-analysis of the CATIE-AD study

Nagata T., Shinagawa S., Yoshida K., Noda Y., Shigeta M., Mimura M., Nakajima S.

Journal of Clinical Psychiatry （Journal of Clinical Psychiatry） 81 （ 2 ） 2020年04月

ISSN 01606689

© Copyright 2020 Physicians Postgraduate Press, Inc. Objective: The aim of the present study was to identify individual symptoms whose early improvements contributed to subsequent treatment response to antipsychotics for neuropsychiatric symptoms (NPSs) in patients with Alzheimer's disease (AD) using the dataset of the Clinical Antipsychotic Trials of Intervention Effectiveness-Alzheimer's Disease (CATIE-AD). Methods: The CATIE-AD study was conducted between April 2001 and November 2004 at 45 sites in the United States. Data for 421 patients with DSM-IV AD with NPSs treated with antipsychotics were analyzed in the present study. Treatment response was defined as a reduction of ≥ 9 points in the Neuropsychiatric Inventory (NPI) score or a reduction of ≥ 25% from baseline in Brief Psychiatric Rating Scale (BPRS) total score at week 8. Logistic regression analyses were performed to examine associations between response and clinical and demographic characteristics, including each total or individual symptom score reduction at week 2. Results: Reduction in NPI or BPRS total score at week 2 and several individual symptom score reductions (euphoria/elation, irritability, hallucinations, anxiety, agitation, apathy, disinhibition, and depression among NPI subitems; excitement, suspiciousness, disorientation, hostility, depressive mood, and emotional withdrawal among BPRS subitems) at week 2 were significantly associated with subsequent treatment response at week 8 (all P values < .05); Early non-improvements of irritability and suspiciousness were shown to be especially influential clinical markers in predicting subsequent treatment nonresponse. Furthermore, healthier condition at baseline was significantly associated with treatment response at week 8 (P < .05). Conclusions: Although further research to validate these preliminary findings is needed, focusing on early improvements of individual symptoms could help identify subsequent treatment responders to antipsychotics in AD patients with NPSs.

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Approach-oriented coping strategy level may be related to volume of the whole hippocampus in the elderly

Kida H., Nakajima S., Shikimoto R., Ochi R., Noda Y., Tsugawa S., Fujii S., Takayama M., Mimura M., Niimura H.

Psychiatry and Clinical Neurosciences （Psychiatry and Clinical Neurosciences） 74 （ 4 ） 270 - 276 2020年04月

ISSN 13231316

© 2020 The Authors. Psychiatry and Clinical Neurosciences © 2020 Japanese Society of Psychiatry and Neurology Aim: Stress-related disorders and severe stress exposure can cause atrophy of the whole hippocampus and its subfields. However, the impact of stress coping strategies on the hippocampus remains unclear. Therefore, we aimed to examine the relation between approach- and avoidance-oriented coping strategies and hippocampal volume in elderly persons. Methods: A total of 1045 elderly persons living in Arakawa-ward, Tokyo (mean ± SD age: 72.8 ± 5.2 years; 569 females [54.4%]) were included in the study and completed several questionnaires and face-to-face interviews and underwent magnetic resonance imaging. Approach- or avoidance-oriented coping strategies were assessed with the Stress and Coping Inventory, while cognitive function and depressive symptoms were assessed with the Mini-Mental State Examination and Geriatric Depression Scale, respectively. The volume of the whole hippocampus on T1-weighted images was delineated and calculated using FreeSurfer 6.0. Multiple regression analyses were performed to examine the relation between Stress and Coping Inventory scores and whole hippocampal volume. Results: Approach-oriented coping strategy scores were positively correlated with whole hippocampal volume. Furthermore, these relations remained significant after controlling for the influence of cognitive function and depressive symptoms on these volumetric variables. In contrast, avoidance-oriented coping strategy scores were not correlated with whole hippocampal volume. Conclusion: This study demonstrated that hippocampal volume may be associated with the approach-oriented coping strategy; therefore, this strategy may preserve hippocampal volume in the elderly.

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Factors associated with successful antipsychotic dose reduction in schizophrenia: a systematic review of prospective clinical trials and meta-analysis of randomized controlled trials

Tani H., Takasu S., Uchida H., Suzuki T., Mimura M., Takeuchi H.

Neuropsychopharmacology （Neuropsychopharmacology） 45 （ 5 ） 887 - 901 2020年04月

ISSN 0893133X

© 2019, The Author(s), under exclusive licence to American College of Neuropsychopharmacology. This systematic review and meta-analysis examined predictors of successful antipsychotic dose reduction in schizophrenia. Prospective clinical trials and randomized controlled trials (RCTs) investigating antipsychotic dose reduction in schizophrenia were selected for systematic review and meta-analysis, respectively. In total, 37 trials were identified. Only 8 studies focused on second-generation antipsychotics (SGAs); no studies investigated long-acting injectable SGAs. Of 24 studies evaluating relapse or symptom changes, 20 (83.3%) met the criteria for successful dose reduction. Factors associated with successful dose reduction were study duration < 1 year, age > 40 years, duration of illness > 10 years, and post-reduction chlorpromazine equivalent (CPZE) dose > 200 mg/day. Clinical deterioration was mostly re-stabilized by increasing the dose to the baseline level (N = 7/8, 87.5%). A meta-analysis of 18 RCTs revealed that relapse rate was significantly higher in the reduction group than the maintenance group (risk ratio [RR] = 1.96; 95% confidence interval [CI], 1.23–3.12), whereas neurocognition was significantly improved (standardized mean difference = 0.69; 95% CI, 0.25–1.12). A subgroup analysis indicated that only a post-reduction CPZE dose ≤ 200 mg/day was associated with an increased risk of relapse (RR = 2.79; 95% CI, 1.29–6.03). Thus, when reducing antipsychotic doses, clinicians should consider the long-term risk of relapse in younger patients with a relatively short illness duration and keep the final doses higher than CPZE 200 mg/day. Further studies, particularly those involving SGAs, are warranted to determine the optimal strategies for successful antipsychotic dose reduction in schizophrenia.

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Gut microbiota and majore depressive disorder: A systematic review and meta-analysis

Sanada K., Nakajima S., Kurokawa S., Barceló-Soler A., Ikuse D., Hirata A., Yoshizawa A., Tomizawa Y., Salas-Valero M., Noda Y., Mimura M., Iwanami A., Kishimoto T.

Journal of Affective Disorders （Journal of Affective Disorders） 266 1 - 13 2020年04月

ISSN 01650327

© 2020 Elsevier B.V. Background: Growing attention has been paid to the field of gut microbiota for mental disorders over the last decade. However, to our knowledge, no studies have conducted systematic reviews on the association between gut microbiota and major depressive disorder (MDD) in both interventional and non-interventional studies. Methods: We conducted a systematic review and meta-analysis of 16 studies (10 observational [701 participants] and six interventional trials [302 participants]) examining gut microbiota in patients with MDD. The primary outcome measures were differences in the profile of microbiota inthe observational studies, and symptom changes for depression between pre- and post-intervention with probiotics in the interventional trials. Results: In the observational studies, significant reductions in several taxa at the family and genus levels were observed in patients with MDD compared to non-depressed controls. In the interventional studies with probiotics, a significant improvement was found in depressive symptomatology compared to controls (SMD = .-1.62, 95% CI = .-2.73 to -0.51, p< 0.01). Limitations: Lack of consideration of the effects of diet and pharmacotherapy was a possible limitation. Conclusions: Our results indicate that several taxa at the family and genus levels, specifically family Prevotellaceae, genus Coprococcus,and Faecalibacterium, were decreased in MDD compared to non-depressed controls in observational studies, and depressive symptoms were improved compared to controls in interventional studies with probiotics. Due to the limited number of studies, further studies considering diet and pharmacotherapy are needed to explore the relationships between gut microbiota and MDD in humans.

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Evaluating the severity of depressive symptoms using upper body motion captured by RGB-depth sensors and machine learning in a clinical interview setting: A preliminary study

Horigome T., Sumali B., Kitazawa M., Yoshimura M., Liang K.c., Tazawa Y., Fujita T., Mimura M., Kishimoto T.

Comprehensive Psychiatry （Comprehensive Psychiatry） 98 2020年04月

ISSN 0010440X

© 2020 The Authors Background: Mood disorders have long been known to affect motor function. While methods to objectively assess such symptoms have been used in experiments, those same methods have not yet been applied in clinical practice because the methods are time-consuming, labor-intensive, or invasive. Methods: We videotaped the upper body of each subject using a Red-Green-Blue-Depth (RGB-D) sensor during a clinical interview setting. We then examined the relationship between depressive symptoms and body motion by comparing the head motion of patients with major depressive disorders (MDD) and bipolar disorders (BD) to the motion of healthy controls (HC). Furthermore, we attempted to predict the severity of depressive symptoms by using machine learning. Results: A total of 47 participants (HC, n = 16; MDD, n = 17; BD, n = 14) participated in the study, contributing to 144 data sets. It was found that patients with depression move significantly slower compared to HC in the 5th percentile and 50th percentile of motion speed. In addition, Hamilton Depression Rating Scale (HAMD)-17 scores correlated with 5th percentile, 50th percentile, and mean speed of motion. Moreover, using machine learning, the presence and/or severity of depressive symptoms based on HAMD-17 scores were distinguished by a kappa coefficient of 0.37 to 0.43. Limitations: Limitations include the small number of subjects, especially the number of severe cases and young people. Conclusions: The RGB-D sensor captured some differences in upper body motion between depressed patients and controls. If much larger samples are accumulated, machine learning may be useful in identifying objective measures for depression in the future.

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Levels of glutamatergic neurometabolites in patients with severe treatment-resistant schizophrenia: a proton magnetic resonance spectroscopy study

Tarumi R., Tsugawa S., Noda Y., Plitman E., Honda S., Matsushita K., Chavez S., Sawada K., Wada M., Matsui M., Fujii S., Miyazaki T., Chakravarty M.M., Uchida H., Remington G., Graff-Guerrero A., Mimura M., Nakajima S.

Neuropsychopharmacology （Neuropsychopharmacology） 45 （ 4 ） 632 - 640 2020年03月

ISSN 0893133X

© 2019, The Author(s), under exclusive licence to American College of Neuropsychopharmacology. Approximately 30% of patients with schizophrenia do not respond to antipsychotics and are thus considered to have treatment-resistant schizophrenia (TRS). To date, only four studies have examined glutamatergic neurometabolite levels using proton magnetic resonance spectroscopy (1H-MRS) in patients with TRS, collectively suggesting that glutamatergic dysfunction may be implicated in the pathophysiology of TRS. Notably, the TRS patient population in these studies had mild-to-moderate illness severity, which is not entirely reflective of what is observed in clinical practice. In this present work, we compared glutamate + glutamine (Glx) levels in the dorsal anterior cingulate cortex (dACC) and caudate among patients with TRS, patients with non-TRS, and healthy controls (HCs), using 3T 1H-MRS (PRESS, TE = 35 ms). TRS criteria were defined by severe positive symptoms (i.e., ≥5 on 2 Positive and Negative Syndrome Scale (PANSS)-positive symptom items or ≥4 on 3 PANSS-positive symptom items), despite standard antipsychotic treatment. A total of 95 participants were included (29 TRS patients [PANSS = 111.2 ± 20.4], 33 non-TRS patients [PANSS = 49.8 ± 13.7], and 33 HCs). dACC Glx levels were higher in the TRS group vs. HCs (group effect: F[2,75] = 4.74, p = 0.011; TRS vs. HCs: p = 0.012). No group differences were identified in the caudate. There were no associations between Glx levels and clinical severity in either patient group. Our results are suggestive of greater heterogeneity in TRS relative to non-TRS with respect to dACC Glx levels, necessitating further research to determine biological subtypes of TRS.

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Sleep stage detection using only heart rate

Mitsukura Y., Fukunaga K., Yasui M., Mimura M.

Health Informatics Journal （Health Informatics Journal） 26 （ 1 ） 376 - 387 2020年03月

ISSN 14604582

© The Author(s) 2019. Getting enough quality sleep plays a vital role in protecting our mental health, physical health, and quality of life. Sleep deprivation can make it difficult to concentrate on daily activities, and lower sleep quality is associated with hypertension, hyperglycemia, and hyperlipidemia. The amount of sleep we get is important, but in recent years, quality sleep has also been deemed significant. Polysomnography, which has been the gold standard in assessing sleep quality based on stages, requires that the subject be attached to electrodes, which can disrupt sleep. An easier method to objectively measure sleep is therefore needed. The aim of this study was to construct an easy and objective sleep stage monitoring method. A cross-sectional study for healthy subjects has been done in our research. A new easy model for monitoring the sleep stages is built on only heart rate calculated by the electrocardiogram. This enabled us to easily assess the sleep quality based on five stages. This experiment included a total of 50 subjects. The overall accuracy in determining the five sleep stages was 66.0 percent. Four stages for sleep are identified accurately compared with other conventional methods. Despite there are no five sleep stage separation method using only heart rate, our method achieved the five separation for sleep with a relatively good accuracy. This study represents a great contribution to the field of sleep science. Because sleep stages can be recognized by the heart rate alone, sleep can be noninvasively assessed with any heart rate meter. This method will make it easier to determine sleep stages and diagnose sleep disorders.

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Discrimination of prediction models between cold-heat and deficiency-excess patterns

Maeda-Minami A., Yoshino T., Katayama K., Horiba Y., Hikiami H., Shimada Y., Namiki T., Tahara E., Minamizawa K., Muramatsu S., Yamaguchi R., Imoto S., Miyano S., Mima H., Mimura M., Nakamura T., Watanabe K.

Complementary Therapies in Medicine （Complementary Therapies in Medicine） 49 2020年03月

ISSN 09652299

© 2020 Elsevier Ltd Objective: The purpose of this study was to extract important patient questionnaire items by creating random forest models for predicting pattern diagnosis considering an interaction between deficiency-excess and cold-heat patterns. Design: A multi-centre prospective observational study. Setting: Participants visiting six Kampo speciality clinics in Japan from 2012 to 2015. Main outcome measure: Deficiency–excess pattern diagnosis made by board-certified Kampo experts. Methods: We used 153 items as independent variables including, age, sex, body mass index, systolic and diastolic blood pressures, and 148 subjective symptoms recorded through a questionnaire. We sampled training data with an equal number of the different patterns from a 2 × 2 factorial combination of deficiency–excess and cold–heat patterns. We constructed the prediction models of deficiency–excess and cold–heat patterns using the random forest algorithm, extracted the top 10 essential items, and calculated the discriminant ratio using this prediction model. Results: BMI and blood pressure, and subjective symptoms of cold or heat sensations were the most important items in the prediction models of deficiency–excess pattern and of cold–heat patterns, respectively. The discriminant ratio was not inferior compared with the result ignoring the interaction between the diagnoses. Conclusions: We revised deficiency–excess and cold–heat pattern prediction models, based on balanced training sample data obtained from six Kampo speciality clinics in Japan. The revised important items for diagnosing a deficiency–excess pattern and cold–heat pattern were compatible with the definition in the 11th version of international classification of diseases.

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Neural and clinical changes of cognitive behavioural therapy versus talking control in patients with major depression: A study protocol for a randomised clinical trial

Katayama N., Nakagawa A., Abe T., Kurata C., Sasaki Y., Mitsuda D., Nakao S., Mizuno S., Ozawa M., Nakagawa Y., Ishikawa N., Umeda S., Terasawa Y., Tabuchi H., Kikuchi T., Mimura M.

BMJ Open （BMJ Open） 10 （ 2 ） 2020年02月

© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ. While major depression causes substantial distress and impairment for affected individuals and society, the effectiveness of cognitive behavioural therapy (CBT) in treating the condition has been established. However, the therapeutic mechanism underlying the efficacy of CBT remains unknown. This study aimed to describe a protocol for a randomised controlled trial that will measure the CBT-induced clinical and neural changes in patients with non-psychotic major depression. Methods and analysis The current study is a 16-week assessor-blinded, randomised, parallel-group trial with a 12-month follow-up as part of usual depression care at an outpatient clinic. Patients aged 20-69 years with major depressive disorder will be randomly assigned to receive either CBT in addition to their usual treatment or talking control in addition to their usual treatment for 16 weeks. The primary outcome is the functional changes in the brain areas that have been associated with future-oriented thinking at 16 weeks; secondary outcomes include changes in functional brain connectivity, severity and changes in the scores of objective and subjective clinical depression symptoms, proportion of responders and remitters and quality of life. The intention-to-treat analysis will be used. Ethics and dissemination All protocols and the informed consent form are compliant with the Ethics Guideline for Clinical Research (Japanese Ministry of Health, Labour and Welfare). Ethical Review Committees at the Keio University School of Medicine have approved the study protocol (version 3, 11 September 2017). We will disseminate research findings to scientific and general audiences through national and international conference presentations as well as lay summaries to the general public, including mental health consumer and publications in international peer-reviewed psychiatry and brain imaging journals. Trial registration number UMIN Clinical Trials Registry (UMIN000018155); Pre-results.

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Visualization of AMPA receptors in living human brain with positron emission tomography

Miyazaki T., Nakajima W., Hatano M., Shibata Y., Kuroki Y., Arisawa T., Serizawa A., Sano A., Kogami S., Yamanoue T., Kimura K., Hirata Y., Takada Y., Ishiwata Y., Sonoda M., Tokunaga M., Seki C., Nagai Y., Minamimoto T., Kawamura K., Zhang M.R., Ikegaya N., Iwasaki M., Kunii N., Kimura Y., Yamashita F., Taguri M., Tani H., Nagai N., Koizumi T., Nakajima S., Mimura M., Yuzaki M., Kato H., Higuchi M., Uchida H., Takahashi T.

Nature Medicine （Nature Medicine） 26 （ 2 ） 281 - 288 2020年02月

ISSN 10788956

© 2020, The Author(s), under exclusive licence to Springer Nature America, Inc. Although aberrations in the number and function of glutamate AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid) receptors are thought to underlie neuropsychiatric disorders, no methods are currently available for visualizing AMPA receptors in the living human brain. Here we developed a positron emission tomography (PET) tracer for AMPA receptors. A derivative of 4-[2-(phenylsulfonylamino)ethylthio]-2,6-difluoro-phenoxyacetamide radiolabeled with 11C ([11C]K-2) showed specific binding to AMPA receptors. Our clinical trial with healthy human participants confirmed reversible binding of [11C]K-2 in the brain according to Logan graphical analysis (UMIN000020975; study design: non-randomized, single arm; primary outcome: dynamics and distribution volumes of [11C]K-2 in the brain; secondary outcome: adverse events of [11C]K-2 during the 4–10 d following dosing; this trial met prespecified endpoints). In an exploratory clinical study including patients with epilepsy, we detected increased [11C]K-2 uptake in the epileptogenic focus of patients with mesial temporal lobe epilepsy, which was closely correlated with the local AMPA receptor protein distribution in surgical specimens from the same individuals (UMIN000025090; study design: non-randomized, single arm; primary outcome: correlation between [11C]K-2 uptake measured with PET before surgery and AMPA receptor protein density examined by biochemical study after surgery; secondary outcome: adverse events during the 7 d following PET scan; this trial met prespecified endpoints). Thus, [11C]K-2 is a potent PET tracer for AMPA receptors, potentially providing a tool to examine the involvement of AMPA receptors in neuropsychiatric disorders.

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Community transition at younger ages contributes to good cognitive function outcomes in long-term hospitalized patients with schizophrenia spectrum disorder: A 15-year follow-up study with group-based trajectory modeling

Kida H., Niimura H., Nemoto T., Ryu Y., Sakuma K., Mimura M., Mizuno M.

Psychiatry and Clinical Neurosciences （Psychiatry and Clinical Neurosciences） 74 （ 2 ） 105 - 111 2020年02月

ISSN 13231316

© 2019 The Authors. Psychiatry and Clinical Neurosciences © 2019 Japanese Society of Psychiatry and Neurology Aim: Cognitive dysfunction is a core symptom of schizophrenia spectrum disorder, but the reported long-term cognitive outcomes are heterogeneous. This study aimed to elucidate the long-term trajectories of patients with schizophrenia spectrum disorder who transitioned to community dwelling with integrated care, and to identify predictors of successful community reintegration. Methods: After the closure of a psychiatric hospital, 78 patients with schizophrenia spectrum disorder (mean age: 54.6 years) were transferred to the community. We assessed patients' cognitive function over 15 years with the Mini-Mental State Examination (MMSE) and analyzed the scores every 3 years. Forty-four patients completed all assessments. Results: The mean MMSE score at discharge was 25.8, which changed to 26.8 after 3 years and 25.3 after 6 years. After 12 and 15 years, it had decreased significantly to 23.3 and 23.0, respectively. Group-based trajectory modeling identified two groups of patients: a ‘poor-outcome’ group (63.4%), showing a decline in scores after maintaining post-discharge levels for several years, and a ‘good-outcome’ group (36.6%), maintaining post-discharge scores after showing improved scores. Conclusion: Considering the significant difference in age between the aforementioned groups (P = 0.040), we suggest that community transitions at younger ages contribute to better cognitive function and adaptation to community life. Even middle-aged and elderly patients with chronic schizophrenia spectrum disorder showed improved or maintained cognitive function at least 3 years after discharge, and the good-outcome group maintained cognitive function over 15 years. Improvements were dominated primarily by age at discharge, with cognitive function being maintained longer in patients in the good-outcome group.

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Effectiveness of mindfulness-based cognitive therapy in patients with anxiety disorders in secondary-care settings: A randomized controlled trial

Ninomiya A., Sado M., Park S., Fujisawa D., Kosugi T., Nakagawa A., Shirahase J., Mimura M.

Psychiatry and Clinical Neurosciences （Psychiatry and Clinical Neurosciences） 74 （ 2 ） 132 - 139 2020年02月

ISSN 13231316

© 2019 The Authors. Psychiatry and Clinical Neurosciences © 2019 Japanese Society of Psychiatry and Neurology Aim: The primary objective of this study was to examine the effectiveness of mindfulness-based cognitive therapy (MBCT) in secondary-care settings where the vast majority of the patients have already undergone pharmacotherapy but have not remitted. Methods: Eligible participants were aged between 20 and 75 years and met the criteria for panic disorder/agoraphobia or social anxiety disorder specified in the DSM-IV. They were randomly assigned to either the MBCT group (n = 20) or the wait-list control group (n = 20). The primary outcome was the difference in mean change scores between pre- and post-intervention assessments on the State–Trait Anxiety Inventory (STAI). The outcome was analyzed using an intent-to-treat approach and a mixed-effect model repeated measurement. Results: We observed significant differences in mean change scores for the STAI State Anxiety subscale (difference, −10.1; 95% confidence interval, −16.9 to −3.2; P < 0.005) and STAI Trait Anxiety subscale (difference, −11.7; 95% confidence interval, −17.0 to −6.4; P < 0.001) between the MBCT and control groups. Conclusion: MBCT is effective in patients with anxiety disorders in secondary-care settings where the vast majority of patients are treatment-resistant to pharmacotherapy.

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Feasibility of autism-focused public speech training using a simple virtual audience for autism spectrum disorder

Kumazaki H., Muramatsu T., Kobayashi K., Watanabe T., Terada K., Higashida H., Yuhi T., Mimura M., Kikuchi M.

Psychiatry and Clinical Neurosciences （Psychiatry and Clinical Neurosciences） 74 （ 2 ） 124 - 131 2020年02月

ISSN 13231316

© 2019 The Authors. Psychiatry and Clinical Neurosciences © 2019 Japanese Society of Psychiatry and Neurology Aim: Public speaking seems to be one of the most anxiety-provoking situations for individuals with autism spectrum disorder (ASD). However, there are few evidence-based interventions. We developed Autism-Focused Public Speech Training using Simple Virtual Audiences (APSV), which differs from a general virtual audience in terms of its simple facial expressions and emphasis on the importance of the eyes. The present study aimed to evaluate the feasibility of APSV as an educational method for individuals with ASD. Methods: Fifteen male individuals with ASD were randomly assigned to two groups: one group received APSV (n = 8), and the other group (n = 7) received independent study (IS). From Days 2 to 6, participants in the APSV and IS groups were encouraged to read and answer questions often asked in actual public speaking events. Participants in the APSV study group performed this activity in front of the APSV system, while those in the IS group performed in an empty room. Before and after the intervention (Days 1 and 7), the participants in the two groups had a mock public speaking experience in front of 10 people for approximately 10 min. Results: After the training sessions, the participants’ self-confidence had improved and salivary cortisol levels were significantly decreased in the APSV group as compared to those in the IS group. APSV improved self-confidence and decreased public speaking stress in individuals with ASD. Conclusion: APSV appears to be useful in improving self-confidence and decreasing public speaking stress in individuals with ASD.

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Evaluating depression with multimodal wristband-type wearable device: screening and assessing patient severity utilizing machine-learning

Tazawa Y., Liang K.c., Yoshimura M., Kitazawa M., Kaise Y., Takamiya A., Kishi A., Horigome T., Mitsukura Y., Mimura M., Kishimoto T.

Heliyon （Heliyon） 6 （ 2 ） 2020年02月

ISSN 24058440

© 2020 Objective: We aimed to develop a machine learning algorithm to screen for depression and assess severity based on data from wearable devices. Methods: We used a wearable device that calculates steps, energy expenditure, body movement, sleep time, heart rate, skin temperature, and ultraviolet light exposure. Depressed patients and healthy volunteers wore the device continuously for the study period. The modalities were compared hourly between patients and healthy volunteers. XGBoost was used to build machine learning models and 10-fold cross-validation was applied for the validation. Results: Forty-five depressed patients and 41 healthy controls participated, creating a combined 5,250 days' worth of data. Heart rate, steps, and sleep were significantly different between patients and healthy volunteers in some comparisons. Similar differences were also observed longitudinally when patients' symptoms improved. Based on seven days' data, the model identified symptomatic patients with 0.76 accuracy and predicted Hamilton Depression Rating Scale-17 scores with a 0.61 correlation coefficient. Skin temperature, sleep time-related features, and the correlation of those modalities were the most significant features in machine learning. Limitations: The small number of subjects who participated in this study may have weakened the statistical significance of the study. There are differences in the demographic data among groups although we performed a correction for multiple comparisons. Validation in independent datasets was not performed, although 10-fold cross validation with the internal data was conducted. Conclusion: The results indicated that utilizing wearable devices and machine learning may be useful in identifying depression as well as assessing severity.

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Relationship between polydipsia and antipsychotics: A systematic review of clinical studies and case reports

Kirino S., Sakuma M., Misawa F., Fujii Y., Uchida H., Mimura M., Takeuchi H.

Progress in Neuro-Psychopharmacology and Biological Psychiatry （Progress in Neuro-Psychopharmacology and Biological Psychiatry） 96 2020年01月

ISSN 02785846

© 2019 Elsevier Inc. Objective: This systematic review aimed to elucidate the relationship between polydipsia and antipsychotics. Methods: We systematically searched MEDLINE, Embase, and PsycINFO, and included clinical studies and case reports on polydipsia induced or improved by antipsychotics. Results: We identified 61 articles: 1 double-blind randomized controlled trial (RCT), 4 single-arm trials, 1 cross-sectional study, 3 case series, and 52 case reports. The double-blind RCT demonstrated no significant difference in improvement in polydipsia between olanzapine and haloperidol. Two single-arm trials showed that polydipsia improved during clozapine treatment, whereas the other 2 showed that risperidone did not improve polydipsia. The cross-sectional study showed the prevalence of hyponatremia with first-generation antipsychotics (FGAs: 26.1%) and second-generation antipsychotics (SGAs: 4.9%). Two case series reported that clozapine improved polydipsia; the other one indicated that patients with polydipsia who were treated with FGAs had schizophrenia (70.4%) and mental retardation (25.9%). Of 90 cases in the case reports, 67 (75.3%) were diagnosed with schizophrenia. Of 83 cases in which antipsychotic treatment started before the onset of polydipsia, 75 (90.3%) received FGAs, particularly haloperidol (n = 24, 28.9%), and 11 (13.3%) received risperidone. Among 40 cases in which polydipsia was improved following antipsychotic treatment, 36 (90.0%) received SGAs, primarily clozapine (n = 14, 35.0%). Conclusions: Although the causal relationship between polydipsia and antipsychotics remains unclear because of the paucity of high-quality studies, antipsychotics with high affinity to dopamine D2 receptors may be associated with an increased risk of polydipsia while clozapine may be effective for treating polydipsia.

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An Evaluation of Family-Based Treatment for OCD in Japan: A Pilot Randomized Controlled Trial

Kobayashi Y., Kanie A., Nakagawa A., Takebayashi Y., Shinmei I., Nakayama N., Yamaguchi K., Nakayama C., Hirabayashi N., Mimura M., Horikoshi M.

Frontiers in Psychiatry （Frontiers in Psychiatry） 10 2020年01月

© Copyright © 2020 Kobayashi, Kanie, Nakagawa, Takebayashi, Shinmei, Nakayama, Yamaguchi, Nakayama, Hirabayashi, Mimura and Horikoshi. Objective: Although family involvement in the treatment of obsessive-compulsive disorder (OCD) produces a reduction in OCD symptoms and has significant effects on global functioning, few studies have focused on family intervention as part of OCD treatment in Japan. This study aims to examine the feasibility and efficacy of the family-based exposure and response prevention (FERP) program for adult patients with OCD and their family members. Design: Randomized controlled pilot study. Methods: A total of 18 outpatients aged 18–65 years with a primary diagnosis of OCD and one family member of each patient were randomized to an intervention group or a control group (1:1). The intervention group received the FERP program, which consisted of 16 weekly face-to-face cognitive behavioral therapy (CBT) sessions, including eight joint sessions with family members, in addition to treatment-as-usual (TAU). The control group received TAU alone. The primary outcome was the alleviation of OCD symptoms, as measured by changes in the total Yale-Brown Obsessive Compulsive Scale (Y-BOCS) score from baseline to posttreatment. Analyses were provided on an intention-to-treat basis, and linear mixed models were used to test for significant group differences. Results: After 16 weeks, patients allocated to the FERP program showed improvement in OCD symptom severity, as measured by the total change score of the Y-BOCS (Hedges’ g = −1.58), as compared to the control group. Two patients (22.2%) in the FERP group reached remission, and five patients (55.6%) in the FERP group achieved treatment response. Clinical global improvement measured by the FAS-SR scores, K6 scores, and CGI-S scores was also observed (Hedges’ g = −1.35, −1.25, and −1.26, respectively) in the FERP group as compared to the control group. The dropout rate from the study was low (n = 2, 11.8%), and no adverse events were reported in the FERP group. Conclusion: Our results suggest that FERP may be an effective program for reducing patients’ OCD symptoms. Clinical Trial Registration: www.umin.ac.jp/ctr/, identifier UMIN000021763.

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Disclosure of Amyloid Status for Risk of Alzheimer Disease to Cognitively Normal Research Participants With Subjective Cognitive Decline: A Longitudinal Study

Wake T., Tabuchi H., Funaki K., Ito D., Yamagata B., Yoshizaki T., Nakahara T., Jinzaki M., Yoshimasu H., Tanahashi I., Shimazaki H., Mimura M.

American journal of Alzheimer's disease and other dementias （American journal of Alzheimer's disease and other dementias） 35 2020年01月

This study aimed to investigate the long-term impacts of disclosing amyloid status for a risk of Alzheimer disease (AD) to cognitively normal research participants with subjective cognitive decline (SCD), which represents an initial manifestation of AD. Forty-two participants were classified as the amyloid-positive (n = 10) or amyloid-negative (n = 32) groups. We assessed symptoms of anxiety, depression, and test-related distress at 6, 24, and 52 weeks after results disclosure. No difference was found over time in anxiety, depression, and test-related distress in either group. Although no significant differences were observed between groups in anxiety or depression, the amyloid-negative group had a significantly higher level of test-related distress than the amyloid-positive group at 52 weeks. Disclosing amyloid status to cognitively healthy research participants with SCD did not cause significant long-term psychological risks. However, a theoretical spectrum of subjective concern may exist about cognitive decline in amyloid-negative individuals.

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Factor structure of the Japanese version of the Quality of Life in Alzheimer's Disease Scale (QOL-AD)

Yamada T., Nakaaki S., Sato J., Sato H., Shikimoto R., Furukawa T.A., Mimura M., Akechi T.

Psychogeriatrics （Psychogeriatrics） 20 （ 1 ） 79 - 86 2020年01月

ISSN 13463500

© 2019 Japanese Psychogeriatric Society Background: The Quality of Life in Alzheimer's Disease Scale (QOL-AD) developed by Logsdon et al. in1999 is believed to be useful for evaluating responses from both patients and their caregivers. We previously confirmed both the reliability and the validity of the Japanese version of the QOL-AD. However, the factor structure of this scale should be confirmed because the QOL-AD covers multiple facets of dementia patients’ lives. Thus, we performed a factor analysis of the Japanese QOL-AD. Then, we examined the correlations between each of the identified QOL factor scores and the results of other scales. Methods: The Japanese version of the QOL-AD was given to 132 AD patients and 132 caregivers. Four other tests were also performed at the same time: the Mini-Mental State Examination, the Neuropsychiatric Inventory (NPI), the Hyogo Activities of Daily Living Scale (HADL), and the Short Memory Questionnaire. A factor analysis using Varimax rotation was used to examine the dimensions underlying the QOL-AD. In addition, we examined the Pearson correlations between each of the identified QOL factor scores and the results of the other four tests. Results: Factor analyses of both versions of the Japanese QOL-AD (both the patients’ and the caregivers’ responses) revealed three factors that were named ‘psychological wellbeing’, ‘human relationships’, and ‘physical and social environment’. The ‘psychological wellbeing’ factor was significantly correlated with the Mood factor of the NPI. The ‘human relationships’ factor was significantly correlated with the Psychosis factor of the NPI. The ‘physical and social environment’ factor was significantly correlated with the HADL. Conclusions: Both the patients’ and the caregivers’ responses to the Japanese version of the QOL-AD were composed of three factors: ‘psychological wellbeing’, ‘human relationships’, and ‘physical and social environment’. The present results support the multi-domain concept of QOL proposed by Lawton.

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Sociopsychological characteristics of late nonagenarians in Japan: the protocol of the Arakawa 95+ study

Niimura H., Eguchi Y., Kida H., Suzuki K., Takayama M., Mimura M.

Psychogeriatrics （Psychogeriatrics） 20 （ 1 ） 50 - 58 2020年01月

ISSN 13463500

© 2019 Japanese Psychogeriatric Society Aim: The aim of this study was to examine sociopsychological characteristics of the oldest old in Japan. We conducted a baseline survey of a community-based cohort of persons aged 95 or older. Methods: Participants were aged 95+ years and resided in Arakawa Ward in Tokyo on 1 January 2016. We mailed a questionnaire to these individuals to assess their physical, mental, and social status. Subsequently, if respondents agreed, we conducted in-home interviews and examined their physical and cognitive function. Also, we mailed non-respondents a simplified version of full questionnaire. Additionally, we examined the basic registered data of the study population and the status of their Long-term Care Insurance. Data at baseline and 1-year follow-up were compared. Results: With regard to Long-term Care Insurance, 423 residents aged 95+ years (78.0%) were on long-term care level, 35 (6.5%) were on support level, and 84 (15.5%) did not require support. At the 1-year follow-up, 275 (50.7%) had the same care level, 107 (19.7%) required a greater level of care, and 131 had died (annual death rate: 24.2%). Compared to the simplified questionnaire group (n = 128) and the full questionnaire-only group (n = 14), a higher proportion of respondents who had completed the full questionnaire and had in-home interviews (n = 26) were men, lived only with a spouse, had higher activities of daily living, and reported more positive feelings and well-being. Conclusions: In the late nonagenarian population, the annual death rate was high, and care needs increased rapidly. However, some persons maintained the same care level or even showed improvement and successful ageing.

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Antipsychotic treatment in the maintenance phase of schizophrenia: An updated systematic review of the guidelines and algorithms

Shimomura Y., Kikuchi Y., Suzuki T., Uchida H., Mimura M., Takeuchi H.

Schizophrenia Research （Schizophrenia Research） 215 8 - 16 2020年01月

ISSN 09209964

© 2019 Elsevier B.V. Background: We updated our previous systematic review regarding clinical guidelines and algorithms on antipsychotic treatment in the maintenance phase of schizophrenia (doi: 10.1016/j.schres.2011.11.021) to incorporate and synthesize more recent findings to guide clinical practice. Methods: We conducted a systematic literature search to identify clinical guidelines and algorithms describing antipsychotic treatment in the maintenance phase of schizophrenia using MEDLINE and Embase. We assessed overall quality of the guidelines/algorithms according to the AGREE II instrument and extracted information on treatment recommendations. Results: We identified 20 guidelines/algorithms from various regions, including 11 updated or newly launched ones after the previous systematic review in 2012. All of the guidelines/algorithms satisfied a certain level of quality. Where mentioned, endorsements were sorted into “recommended”, “partially recommended”, or “not recommended”. As for antipsychotic discontinuation strategy, a majority of guidelines/algorithms that mentioned this strategy did not recommend it for multiple-episode schizophrenia (N = 5/6). On the other hand, the guidelines/algorithms tended to shift from “not recommended” to “partially recommended” both for schizophrenia in general (N = 7/13, N = 7/8 for those published after 2013) and first-episode schizophrenia (N = 10/11, N = 7/7 for those published after 2013) regarding this strategy. All guidelines/algorithms (N = 9/9) converged to discourage antipsychotic intermittent/targeted strategy. Similar to antipsychotic discontinuation strategy, all of the updated or new guidelines/algorithms (N = 6/6) endorsed antipsychotic dose reduction/lower dose strategy. Conclusion: Recent clinical guidelines and algorithms on antipsychotic maintenance treatment in schizophrenia shifted more toward a possibility of antipsychotic discontinuation and dose reduction/lower dose strategies. Nonetheless, clinicians need to contemplate on the risk-benefit balance of these strategies for individual patients.

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Lower Proportion of Fatal Arrhythmia in Sudden Cardiac Arrest Among Patients With Severe Mental Illness Than Nonpsychiatric Patients

Ishida T., Sugiyama K., Tanabe T., Hamabe Y., Mimura M., Suzuki T., Uchida H.

Psychosomatics （Psychosomatics） 61 （ 1 ） 24 - 30 2020年01月

ISSN 00333182

© 2019 Academy of Consultation-Liaison Psychiatry Background: Sudden unexpected deaths occur more frequently among patients with severe mental illness (SMI), but direct evidence on the causes is still scarce. Objective: The objective of this study is to investigate initial rhythms and characteristics of out-of-hospital cardiac arrest among patients with SMI. Methods: We conducted a systematic chart review of adult patients who suffered from out-of-hospital cardiac arrest and transferred to Tokyo Metropolitan Bokutoh Hospital in Japan between January 2011 and December 2017. The initial rhythms, clinical characteristics, and outcomes were compared between patients with schizophrenia or mood disorders (i.e., SMI) and nonpsychiatric control patients. Values of interest were compared using Fisher's exact test or Mann-Whitney U-test, as appropriate. Multiple regression analysis was also conducted to investigate the effect of SMI on the initial rhythms. Results: A total of 2631 patients were included in this study. Of these, 157 patients had SMI. Fatal arrhythmias (i.e., ventricular fibrillation and ventricular tachycardia) were less frequently noted as the initial rhythms among patients with SMI than among controls (5.7% vs. 18.8%, adjusted odds ratio = 0.27, 95% confidence interval = 0.13–0.55, P < 0.001). Patients with SMI were significantly younger (median [range], 58 years [22–85] vs. 72 years [18–108], P < 0.001) and less frequently had comorbid physical illnesses than controls (the proportion of patients without comorbidities; 58.6% vs. 37.1%, P < 0.001). Survival and neurological function at discharge were not different between the 2 groups. Conclusion: Fatal arrhythmia may account for a relatively small portion in excess of sudden death among patients with SMI. Furthermore, appropriate medical checkups for the patients with SMI at earlier ages would be important to prevent sudden cardiac death.

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Quantitative Assessment of the Retina Using OCT and Associations with Cognitive Function

Ito Y., Sasaki M., Takahashi H., Nozaki S., Matsuguma S., Motomura K., Ui R., Shikimoto R., Kawasaki R., Yuki K., Sawada N., Mimura M., Tsubota K., Tsugane S.

Ophthalmology （Ophthalmology） 127 （ 1 ） 107 - 118 2020年01月

ISSN 01616420

© 2019 American Academy of Ophthalmology Purpose: To determine the association of retinal thickness with cognitive function in Japanese persons. Design: Cross-sectional, population-based survey. Participants: A total of 1293 Japanese persons aged 65 to 86 years who resided in the Saku area in the Japan Public Health Center–Based Prospective Study participated in the eye and mental health screening. Methods: Participants underwent comprehensive ophthalmic assessment, including fundus photography, measurement of intraocular pressure, and determination of refraction status. We assessed the thickness of the macular retinal nerve fiber layer (mRNFL), ganglion cell-inner plexiform layer (GC-IPL), and ganglion cell complex (GCC, which includes the retinal nerve fiber layer and GC-IPL), and the full thickness in the macula and peripapillary retinal nerve fiber layer (ppRNFL) using spectral-domain (SD) OCT. Cognitive tests consisted of the Mini-Mental State Examination, Wechsler Memory Scale Revised logical memory I/II subtest, clock drawing test, and Clinical Dementia Rating Scale. These were used to designate the participants in the following 3 groups: Normal, those with mild cognitive impairment (MCI), and those with dementia. Multivariable logistic regression models were used to analyze associations between retinal thickness and cognitive function after adjusting potential confounding factors. Main Outcome Measures: Association of retinal thickness with cognitive function. Results: Among the 1293 potential subjects, 114 were excluded for a diagnosis of depression, 64 were excluded for retinal disease, and 140 were excluded for scanning errors or suboptimal OCT images. The remaining 975 participants (mean age, 73.2 years) were included in this analysis. Significant differences were found in the 3 groups in all layers and GCC thickness, but not in ppRNFL thickness. After adjusting for age, sex, educational status, and refraction, full macular thickness and GCC thickness were inversely associated with the presence of dementia, but ppRNFL thickness was not. Furthermore, GC-IPL, GCC, and full macular thicknesses were all associated with the presence of dementia in the inferior sectors. Conclusions: Macular thickness was associated with the presence of dementia, but ppRNFL was not. Our results suggest that OCT measurements of the macula could be superior to those of the ppRNFL in assessing neurodegenerative changes and a potentially useful diagnostic biomarker of cognitive function.

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Predicting relapse with residual symptoms in schizophrenia: A secondary analysis of the PROACTIVE trial

Saito Y., Sakurai H., Kane J.M., Schooler N.R., Suzuki T., Mimura M., Uchida H.

Schizophrenia Research （Schizophrenia Research） 215 173 - 180 2020年01月

ISSN 09209964

© 2019 Elsevier B.V. Introduction: Little attention has been paid to the contribution of individual residual symptom to predict relapse in patients with schizophrenia receiving oral or long-acting injectable (LAI) antipsychotics. Method: We used the data from the Preventing Relapse on Oral Antipsychotics Compared to Injectables - Evaluating Efficacy (PROACTIVE) study, in which 305 outpatients with schizophrenia were randomly allocated to either biweekly LAI-risperidone (LAI-R) or daily oral second-generation antipsychotics (SGA) and assessed for up to 30 months. Baseline individual symptoms that could predict subsequent relapse were identified, using a Cox proportional hazards model. Moreover, among those who relapsed during the study (n = 73), individual symptoms were compared between baseline and biweekly ratings 8 to 2 weeks before relapse, using the linear mixed model. Results: A greater score in grandiosity at baseline was significantly associated with subsequent relapse (adjusted HR = 1.24, p = 0.006). When the two treatment groups were separately analyzed, more severe grandiosity (adjusted HR = 1.43, p = 0.003) and less severe hallucinatory behavior (adjusted HR = 0.70, p = 0.013) at baseline were significantly associated with relapse in the oral SGA group, but none was identified in the LAI-R group. Emotional withdrawal was significantly worse 8 and 2 weeks before relapse compared to the baseline (p = 0.032 and p = 0.043, respectively). Discussion: More severe grandiosity and less hallucination may have led to more frequent relapses in patients with schizophrenia receiving oral antipsychotics, which was not a case in those receiving LAI-R. The exploratory analysis indicates an increase in emotional withdrawal before relapse may be a useful marker for earlier interventions to possibly avert relapse.

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Drug attitude, insight, and patient’s knowledge about prescribed antipsychotics in schizophrenia: A cross-sectional survey

Nagai N., Tani H., Yoshida K., Gerretsen P., Suzuki T., Ikai-Tani S., Mimura M., Uchida H.

Neuropsychiatric Disease and Treatment （Neuropsychiatric Disease and Treatment） 16 781 - 787 2020年

ISSN 11766328

© 2020 Nagai et al. Introduction: While patients’ perspectives toward pharmacotherapy are expected to be directly influenced by their motivation and understanding of the treatment that they are currently receiving, no study has comprehensively investigated the impact of insight into illness and knowledge for the ongoing pharmacotherapy on the attitude towards drug treatment among patients with schizophrenia. Materials and Methods: One hundred forty-eight Japanese outpatients diagnosed with schizophrenia, according to the International Classification of Diseases 10th edition, were included (mean±SD age, 47.3±12.4 years; 90 men (60.8%)). Attitudes toward antipsychotic treatment and insight into illness were assessed with the Drug Attitude Inventory-10 (DAI-10) and the VAGUS, respectively. In addition, a multiple-choice questionnaire that was designed to examine patients’ knowledge about therapeutic effects, types, and implicated neurotransmitters of antipsychotic drugs they were receiving was utilized. Results: The mean±SD of DAI-10 score was 4.7±4.2. The multiple regression analysis found that lower Positive and Negative Syndrome Scale (PANSS) scores, higher VAGUS scores, and longer illness duration were significantly associated with higher DAI-10 scores (β=−0.226, P=0.009; β=0.250, P=0.008; β=0.203, P=0.034, respectively). There was a significant difference in the DAI-10 scores between the subjects who gave more accurate answers regarding the effects of their primary antipsychotic and those who did not (mean ±SD, 5.57±4.38 vs 4.13±4.04, P=0.043); however, this finding failed to survive the multiple regression analysis. Conclusion: Better insight into illness and treatment, lower illness severity, longer illness duration, and possibly greater knowledge about the therapeutic effects of medications may lead to better attitudes towards pharmacotherapy among patients with schizophrenia, which has an important implication for this typically chronic mental condition requiring long-term antipsychotic treatment to sustain stability.

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Does the Combination of the Cognitive Interventions Improve the Function of Daily Living and Save the Long-Term Care Cost? A Pilot Study of Effectiveness and Cost Saving Analysis of 'Learning Therapy' for People with Dementia

Sado M., Funaki K., Ninomiya A., Knapp M., Mimura M.

Journal of Alzheimer's Disease （Journal of Alzheimer's Disease） 74 （ 3 ） 775 - 784 2020年

ISSN 13872877

© 2020-IOS Press and the authors. All rights reserved. Background: Although the effects of various types of cognitive interventions have been evaluated, effectiveness and cost-saving effect of the combination of the different cognitive interventions is unknown. Objective: This study aimed to evaluate the feasibility of conducting a definitive trial to assess the effectiveness of combined cognitive intervention. Methods: A matched controlled trial of learning therapy (LT), a combination of cognitive training and stimulation, was conducted. The samples were recruited from the nursing homes. Inclusion criteria were as follows: age 65 years or older, clinical diagnosis of dementia, level of activities of daily living at II or above, Mini-Mental State Examination score between 10 and 26, receiving long-term-care services without history of LT, and provision of written consent. The primary outcomes were safety, validity of eligibility, retention rate, and effect on the functions of daily living represented by Criterion Time for Certification of Needed Long-Term-Care (CT for CNLTC) at 12 months. Cost-benefit analysis was also conducted to assess the cost saving effect of LT. Results: No serious adverse events were detected. The exclusion rate at the screening phase was 5% and the retention rate was 77% at 12 months. LT demonstrated statistically significant improvement in CT for CNLTC at 12 months (Δ=18.8, almost equivalent to 'one' degree of the care needed level) and saved the long-term-care cost by JPY 200,000 (USD 1,618). Conclusions: LT is effective for improving care recipients' level of care needed and has a cost saving effect. A randomized controlled trial is required to verify these findings. Clinical Trial Registration: This study was approved by the ethics committee at Keio University School of Medicine (ID: 20150061). This trial was registered at University hospital Medical Information Network Clinical Trial Registry (UMIN-CTR ID: UMIN000018223).

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Cross-cultural validation of the Cancer Stigma Scale in the general Japanese population

Takeuchi E., Fujisawa D., Miyawaki R., Yako-Suketomo H., Oka K., Mimura M., Takahashi M.

Palliative and Supportive Care （Palliative and Supportive Care） 2020年

ISSN 14789515

© 2020 The Author(s). Published by Cambridge University Press. Background: The stigma associated with cancer has negative impacts on cancer patients as well as the general public, who have a potential risk of cancer. To the best of our knowledge, a validated measure to assess cancer stigma among the general Japanese population does not exist. Method: We translated the Cancer Stigma Scale (CASS) - a 25-item self-administered scale to evaluate stigma related to cancer - into Japanese and examined its psychometric properties. The Japanese version of CASS (J-CASS) was validated among a sample of the general Japanese population through an online survey to validate its test-retest reliability, internal consistency, and concurrent validity. Results: A total of 319 responses were included in the analysis. An exploratory factor analysis eliminated two original items but showed a six-factor model (Awkwardness, Severity, Avoidance, Policy Opposition, Personal Responsibility, and Financial Discrimination), which was similar to the original scale. Cronbach's alpha for each factor was satisfactory, ranging from 0.81 to 0.91. The internal correlation coefficients were above 0.70, except for Policy Opposition. The total and subtotal scores of each factor of the J-CASS were significantly associated with respondents' age, gender, familiarity with cancer patients, and social desirability, demonstrating the scales' good concurrent validity. A substantial proportion of the participants selected "unsure"for some items of the scale, suggesting a further need for refining the scale. Significance of results. This study demonstrated that J-CASS is a reliable and valid measure for evaluating misconceptions and stigma toward cancer in the general Japanese population.

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Costs and resource use associated with community-dwelling patients with Alzheimer's disease in Japan: Baseline results from the prospective observational GERAS-J Study

Nakanishi M., Igarashi A., Ueda K., Brnabic A.J.M., Treuer T., Sato M., Kahle-Wrobleski K., Meguro K., Yamada M., Mimura M., Arai H.

Journal of Alzheimer's Disease （Journal of Alzheimer's Disease） 74 （ 1 ） 127 - 138 2020年

ISSN 13872877

© 2020 - IOS Press and the authors. All rights reserved. Background: As the Japanese population ages, caring for people with Alzheimer's disease (AD) dementia is becoming a major socioeconomic issue. Objective: To determine the contribution of patient and caregiver costs to total societal costs associated with AD dementia. Methods: Baseline data was used from the longitudinal, observational GERAS-J study. Using the Mini-Mental State Examination (MMSE) score, patients routinely visiting memory clinics were stratified into three groups based on AD severity. Health care resource utilizationwas recorded using the Resource Utilization in Dementia questionnaire. Total monthly societal costs were estimated using Japan-specific unit costs of services and products (patient direct health care use, patient social care use, and informal caregiving time). Uncertainty around mean costs was estimated using bootstrapping methods. Results: Overall, 553 community-dwelling patients withADdementia (28.3% mild[MMSE21-26], 37.8% moderate[MMSE 15-20], and 34.0% moderately severe/severe [MMSE < 14]) and their caregivers were enrolled. Patient characteristics were: mean age 80.3 years, 72.7% female, and 13.6% living alone. Caregiver characteristics were: mean age 62.1 years, 70.7% female, 78.8% living with patient, 49.0% child of patient, and 39.2% sole caregiver. Total monthly societal costs of AD dementia (Japanese yen) were: 158,454 (mild), 211,301 (moderate), and 294,224 (moderately severe/severe). Informal caregiving costs comprised over 50% of total costs. Conclusion: Baseline results of GERAS-J showed that total monthly societal costs associated with AD dementia increased with AD severity. Caregiver-related costs were the largest cost component. Interventions are needed to decrease informal costs and decrease caregiver burden.

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Virtual reality exposure therapy for social anxiety disorder: A systematic review and meta-analysis

Horigome T., Kurokawa S., Sawada K., Kudo S., Shiga K., Mimura M., Kishimoto T.

Psychological Medicine （Psychological Medicine） 2020年

ISSN 00332917

© 2020 The Author(s). Published by Cambridge University Press. Background Virtual reality exposure therapy (VRET) is currently being used to treat social anxiety disorder (SAD); however, VRET's magnitude of efficacy, duration of efficacy, and impact on treatment discontinuation are still unclear. Methods We conducted a meta-analysis of studies that investigated the efficacy of VRET for SAD. The search strategy and analysis method are registered at PROSPERO (#CRD42019121097). Inclusion criteria were: (1) studies that targeted patients with SAD or related phobias; (2) studies where VRET was conducted for at least three sessions; (3) studies that included at least 10 participants. The primary outcome was social anxiety evaluation score change. Hedges' g and its 95% confidence intervals were calculated using random-effect models. The secondary outcome was the risk ratio for treatment discontinuation. Results Twenty-two studies (n = 703) met the inclusion criteria and were analyzed. The efficacy of VRET for SAD was significant and continued over a long-term follow-up period: Hedges' g for effect size at post-intervention,-0.86 (-1.04 to-0.68); three months post-intervention,-1.03 (-1.35 to-0.72); 6 months post-intervention,-1.14 (-1.39 to-0.89); and 12 months post-intervention,-0.74 (-1.05 to-0.43). When compared to in vivo exposure, the efficacy of VRET was similar at post-intervention but became inferior at later follow-up points. Participant dropout rates showed no significant difference compared to in vivo exposure. Conclusion VRET is an acceptable treatment for SAD patients that has significant, long-lasting efficacy, although it is possible that during long-term follow-up, VRET efficacy lessens as compared to in vivo exposure.

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Electroconvulsive Therapy for Parkinson's Disease: A Systematic Review and Meta-Analysis

Takamiya A., Seki M., Kudo S., Yoshizaki T., Nakahara J., Mimura M., Kishimoto T.

Movement Disorders （Movement Disorders） 2020年

ISSN 08853185

© 2020 International Parkinson and Movement Disorder Society Background: Electroconvulsive therapy (ECT) is a well-established treatment for psychiatric disorders, including depression and psychosis. ECT has been reported to be effective in treating such psychiatric symptoms in patients with Parkinson's disease (PD) and has been also reported to be effective in treating motor symptoms. The aim of the study is to summarize previous clinical studies investigating the efficacy of ECT for symptoms in patients with PD. Methods: A systematic review and meta-analysis of any study designs assessing motor and/or non-motor symptoms in patients with PD before and after ECT. Co-primary outcomes were set as motor manifestations assessed using the Unified Parkinson's Disease Rating Scale or other rating scales, and non-motor symptoms included depression and psychosis. Secondary outcomes were wearing-off phenomenon and cognitive function. The impact of ECT on those symptoms was examined by comparing the severity of the symptoms before and after ECT using a random effect model and was expressed in standardized mean difference. Results: Of 1219 identified citations, 14 studies (n = 129; 1 randomized controlled study, 9 prospective observational studies, and 4 retrospective studies) were analyzed. The findings were as follows: ECT significantly improved motor manifestations in patients with PD, and the improvement was significant in the subpopulation without psychiatric symptoms; ECT significantly improved depression and psychosis; and ECT significantly relieved wearing-off phenomenon and did not worsen cognitive functioning. Conclusion: The current meta-analysis suggests the potential benefit of ECT on motor and non-motor symptoms in presumably complicated and difficult-to-treat subgroups. © 2020 International Parkinson and Movement Disorder Society.

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Thalamic and striato-pallidal volumes in schizophrenia patients and individuals at risk for psychosis: A multi-atlas segmentation study

Takahashi T., Tsugawa S., Nakajima S., Plitman E., Chakravarty M.M., Masuda F., Wada M., Kurose S., Ochi R., Matsushita K., Sasabayashi D., Nakamura M., Nishikawa Y., Takayanagi Y., Nishiyama S., Higuchi Y., Mizukami Y., Furuichi A., Kido M., Hashimoto R., Noguchi K., Fujii S., Mimura M., Noda Y., Suzuki M.

Schizophrenia Research （Schizophrenia Research） 2020年

ISSN 09209964

© 2020 Elsevier B.V. Despite previous neuroimaging studies demonstrating morphological abnormalities of the thalamus and other subcortical structures in patients with schizophrenia, the potential role of the thalamus and its subdivisions in the pathophysiology of this illness remains elusive. It is also unclear whether similar changes of these structures occur in individuals at high risk for psychosis. In this study, magnetic resonance imaging was employed with the Multiple Automatically Generated Templates (MAGeT) brain segmentation algorithm to determine volumes of the thalamic subdivisions, the striatum (caudate, putamen, and nucleus accumbens), and the globus pallidus in 62 patients with schizophrenia, 38 individuals with an at-risk mental state (ARMS) [4 of whom (10.5%) subsequently developed schizophrenia], and 61 healthy subjects. Cognitive function of the patients was assessed by using the Brief Assessment of Cognition in Schizophrenia (BACS) and the Schizophrenia Cognition Rating Scale (SCoRS). Thalamic volume (particularly the medial dorsal and ventral lateral nuclei) was smaller in the schizophrenia group than the ARMS and control groups, while there were no differences for the striatum and globus pallidus. In the schizophrenia group, the reduction of thalamic ventral lateral nucleus volume was significantly associated with lower BACS score. The pallidal volume was positively correlated with the dose of antipsychotic treatment in the schizophrenia group. These results suggest that patients with schizophrenia, but not those with ARMS, exhibit volume reduction in specific thalamic subdivisions, which may underlie core clinical features of this illness.

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Spatial inference without a cognitive map: the role of higher-order path integration

Bouchekioua Y., Blaisdell A.P., Kosaki Y., Tsutsui-Kimura I., Craddock P., Mimura M., Watanabe S.

Biological Reviews （Biological Reviews） 2020年

ISSN 14647931

© 2020 Cambridge Philosophical Society The cognitive map has been taken as the standard model for how agents infer the most efficient route to a goal location. Alternatively, path integration – maintaining a homing vector during navigation – constitutes a primitive and presumably less-flexible strategy than cognitive mapping because path integration relies primarily on vestibular stimuli and pace counting. The historical debate as to whether complex spatial navigation is ruled by associative learning or cognitive map mechanisms has been challenged by experimental difficulties in successfully neutralizing path integration. To our knowledge, there are only three studies that have succeeded in resolving this issue, all showing clear evidence of novel route taking, a behaviour outside the scope of traditional associative learning accounts. Nevertheless, there is no mechanistic explanation as to how animals perform novel route taking. We propose here a new model of spatial learning that combines path integration with higher-order associative learning, and demonstrate how it can account for novel route taking without a cognitive map, thus resolving this long-standing debate. We show how our higher-order path integration (HOPI) model can explain spatial inferences, such as novel detours and shortcuts. Our analysis suggests that a phylogenetically ancient, vector-based navigational strategy utilizing associative processes is powerful enough to support complex spatial inferences.

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Neuronal network mechanisms associated with depressive symptom improvement following electroconvulsive therapy

Takamiya A., Kishimoto T., Hirano J., Nishikata S., Sawada K., Kurokawa S., Yamagata B., Kikuchi T., Mimura M.

Psychological Medicine （Psychological Medicine） 2020年

ISSN 00332917

Copyright © The Author(s) 2020. Published by Cambridge University Press. BackgroundElectroconvulsive therapy (ECT) is the most effective antidepressant treatment for severe depression. Although recent structural magnetic resonance imaging (MRI) studies have consistently reported ECT-induced hippocampal volume increases, most studies did not find the association of the hippocampal volume changes with clinical improvement. To understand the underlying mechanisms of ECT action, we aimed to identify the longitudinal effects of ECT on hippocampal functional connectivity (FC) and their associations with clinical improvement.MethodsResting-state functional MRI was acquired before and after bilateral ECT in 27 depressed individuals. A priori hippocampal seed-based FC analysis and a data-driven multivoxel pattern analysis (MVPA) were conducted to investigate FC changes associated with clinical improvement. The statistical threshold was set at cluster-level false discovery rate-corrected p < 0.05.ResultsDepressive symptom improvement after ECT was positively associated with the change in the right hippocampus-ventromedial prefrontal cortex FC, and negatively associated with the right hippocampus-superior frontal gyrus FC. MVPA confirmed the results of hippocampal seed-based analyses and identified the following additional clusters associated with clinical improvement following ECT: the thalamus, the sensorimotor cortex, and the precuneus.ConclusionsECT-induced change in the right frontotemporal connectivity and thalamocortical connectivity, and changes in the nodes of the default mode network were associated with clinical improvement. Modulation of these networks may explain the underlying mechanisms by which ECT exert its potent and rapid antidepressant effect.

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Low carbohydrate diet and all cause and cause-specific mortality

Akter S., Mizoue T., Nanri A., Goto A., Noda M., Sawada N., Yamaji T., Iwasaki M., Inoue M., Tsugane S., Tsugane S., Sawada N., Iwasaki M., Ninue M., Yamaji T., Goto A., Shimazu T.T., Charvat H., Budhathoki S., Muto M., Suzuki H., Miamizono T., Kobayashi Y., Iriei M., Doi M., Katagiri M., Tagami T., Sou Y., Uehara M., Hakubo Y., Yamagishi , Noda M., Mizoue T., Kawauchi Y., Nakamura K., Takachi R., Ishihara J., Iso H., Sovue T., Sito I., Yasuda N., Mimura M., Sakata K.

Clinical Nutrition （Clinical Nutrition） 2020年

ISSN 02615614

© 2020 The Authors Background: Evidence is limited regarding the association between low-carbohydrate diet (LCD) score and mortality among Asians, a population that consumes a large amount of carbohydrates. Objective: The present study examined the association between low-carbohydrate diet (LCD) score (based on percentage of energy as carbohydrate, fat, and protein) and the risk of total and cause-specific mortality among Asians. Design: This study was a prospective cohort study in Japan with follow-up for a median of 16.9 years involving 43008 men and 50646 women aged 45–75 years. Association of LCD score, LCD score based on animal sources of protein and fat, and LCD score based on plant sources of protein and fat with risk of mortality was assessed using Cox proportional hazards model. Results: A U-shaped association was observed between LCD score and total mortality: the multivariable-adjusted hazard ratios (HRs) (95% CI) of total mortality for lowest through highest scores were 1.00, 0.95 (0.91, 1.01), 0.93 (0.88, 0.98), 0.93 (0.88, 0.98), and 1.01 (0.95, 1.07) (P-non-linearity <0.01). A similar association was found for mortality from cardiovascular disease (CVD) and heart disease. LCD score based on carbohydrate, animal protein, and animal fat also showed a U-shaped association for total mortality (P-non-linearity <0.01). In contrast, LCD score based on carbohydrate, plant protein, and plant fat was linearly associated with lower total (HR, 0.89; 95% CI: 0.83, 0.94 for highest versus lowest quintile), CVD [0.82 (0.73, 0.92)], heart disease [0.83 (0.71, 0.98)], and cerebrovascular disease [0.75 (0.62, 0.91) mortality. Conclusions: Both LCD with high animal protein and fat and high-carbohydrate diet with low animal protein and fat were associated with higher risk of mortality. Meanwhile, LCD high in plant-based sources of protein and fat was associated with a lower risk of total and CVD mortality.

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Excess tau PET ligand retention in elderly patients with major depressive disorder

Moriguchi S., Takahata K., Shimada H., Kubota M., Kitamura S., Kimura Y., Tagai K., Tarumi R., Tabuchi H., Meyer J.H., Mimura M., Kawamura K., Zhang M.R., Murayama S., Suhara T., Higuchi M.

Molecular Psychiatry （Molecular Psychiatry） 2020年

ISSN 13594184

© 2020, The Author(s), under exclusive licence to Springer Nature Limited. Depression is one of the common psychiatric disorders in old age. Major depressive disorder (MDD) has been identified as a risk factor or prodrome for neurodegenerative dementias, suggesting neuropathological overlaps and a continuum between MDD and neurodegenerative disorders. In this study, we examined tau and amyloid-β (Aβ) accumulations in the brains of MDD and healthy controls using positron emission tomography (PET) to explore pathological substrates of this illness. Twenty MDD and twenty age-matched, healthy controls were examined by PET with a tau radioligand, [11C]PBB3, and an Aβ radioligand, [11C]PiB. Radioligand retentions were quantified as a standardized uptake value ratio (SUVR). We also assessed clinical manifestations of the patients using the 17-item Hamilton Depression Scale, the Geriatric Depression Scale, and psychotic symptoms. Mean cortical [11C]PBB3 SUVRs in MDD patients were significantly higher than those of healthy controls. These values were higher in MDD patients with psychotic symptoms than in those without any. The present findings indicate that tau depositions may underlie MDD, and especially in patients with psychotic symptoms. PET detection of tau accumulations may provide mechanistic insights into neuronal dysfunctions in these cases and could serve as predictions of their clinical consequences.

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Acceptability of escitalopram versus duloxetine in outpatients with depression who did not respond to initial second-generation antidepressants: Study protocol for a randomized, parallel-group, non-inferiority trial

Yokoi Y., Nakagawa A., Yoshimura N., Furukawa T.A., Mimura M., Iwanami A., Abe T., Nakagome K.

Neuropsychopharmacology Reports （Neuropsychopharmacology Reports） 39 （ 4 ） 262 - 272 2019年12月

© 2019 The Authors. Neuropsychopharmacology Reports published by John Wiley & Sons Australia, Ltd on behalf of The Japanese Society of Neuropsycho Pharmacology. Aim: The purpose of this study is to compare acceptability of two second generation antidepressants for major depressive disorder patients who have not responded to the first antidepressant for current episode. We will investigate the treatment discontinuation rate and treatment adherence as well as incidence of adverse events in order to evaluate safety. Methods: This is a two-arm, three-phased randomized controlled trial in which independent assessors will be blinded while treating psychiatrists and patients remain unblinded to treatment allocation. Patients will be randomized to escitalopram or duloxetine in Step 1 (8 weeks), and when entering Step 2 (8 weeks), the drug will be switched to the other if the first one is not effective at the end of Step 1. The acceptability of the allocated drugs, improvements in depression from baseline, adverse events, and attrition rates will be recorded and assessed for up to 52 weeks, including the follow-up step. Results: It is going to be disseminated via our following reports or presentations. Conclusions: This study will provide valuable information for clinicians who encounter patients who failed to respond to their first treatment.

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Diet quality and depression risk in a Japanese population: the Japan Public Health Center (JPHC)-based Prospective Study

Okubo R., Matsuoka Y.J., Sawada N., Mimura M., Kurotani K., Nozaki S., Shikimoto R., Tsugane S.

Scientific Reports （Scientific Reports） 9 （ 1 ） 2019年12月

© 2019, The Author(s). The association of overall diet quality based on the Japanese Food Guide Spinning Top with risk of depression is not known. This prospective cohort study aimed to determine whether higher adherence to the Japanese food guide reduced the risk of depression. Of 12,219 residents enrolled at baseline, we extracted 1,112 participants who completed a 5-year follow-up (1995) and participated in a mental health screening (2014–2015). Diet quality was scored based on adherence to the Japanese food guide and the ratio of white to red meat according to the Alternative Healthy Index and ranged from 0 (worst) to 80 (best). We calculated odds ratios and 95% confidence intervals for current psychiatrist-diagnosed depression per quartile of total score and of eight component scores with the lowest quartile as reference. Mean age of the participants was 73 years and 59% were women. Total diet quality score was not significantly associated with risk of depression 20 years after the baseline assessment. Among the eight components on the diet quality score, there was a significantly reduced risk for the highest quartile of the white to red meat ratio score. In conclusion, our results do not indicate that higher adherence to the Japanese food guide prevents depression.

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Dementia trajectory for patients with logopenic variant primary progressive aphasia

Funayama M., Nakagawa Y., Nakajima A., Takata T., Mimura Y., Mimura M.

Neurological Sciences （Neurological Sciences） 40 （ 12 ） 2573 - 2579 2019年12月

ISSN 15901874

© 2019, Fondazione Società Italiana di Neurologia. Background: The timing of progression of logopenic variant primary progressive aphasia (lvPPA) to severe dementia has not been elucidated. To address this shortcoming, 10 patients with lvPPA were continuously followed. Methods: Patients were assessed with the annual rate of change in the Clinical Dementia Rating (CDR) sum of boxes and period from lvPPA onset to the onset of benchmark signs, including mild, moderate, or severe dementia, episodic memory deficits, topographical disorientation, difficulties with using controls for electronic appliances, and conceptual apraxia. When severe dementia was evident, we also investigated the incidence of severe cognitive and behavioral signs such as neologistic jargon, difficulties in recognizing family members, pica, and mirror sign. Results: The mean time for patients to reach a particular CDR was as follows: CDR of 1, 4.1 ± 1.3 years post-onset; CDR 2, 5.7 ± 1.6 years; CDR 3, 7.3 ± 1.6 years. The annual rate of change in the CDR sum of boxes was 3.4 ± 1.1, corresponding to 1.7 years for the CDR to increase by 1.0. Difficulties with using electronic controls began at 3.3 ± 1.6 years, episodic memory deficits at 4.0 ± 2.0 years, topographical disorientation at 5.2 ± 2.1 years, and conceptual apraxia at 5.5 ± 2.1 years. For patients who progressed to severe dementia, six could not recognize family members, five exhibited pica, three experienced mirror sign, and one developed neologistic jargon. Conclusions: Our results suggest that patients with lvPPA progress rapidly to dementia and develop conceptual apraxia, episodic memory deficits, visuospatial deficits, and semantic memory deficits.

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Enriched environment alleviates stress-induced dry-eye through the BDNF axis

Sano K., Kawashima M., Imada T., Suzuki T., Nakamura S., Mimura M., Tanaka K.F., Tsubota K.

Scientific Reports （Scientific Reports） 9 （ 1 ） 2019年12月

© 2019, The Author(s). The number of patients with dry eye disease (DED) is increasing, and DED has become an urgent public health problem. A comorbidity of mental disorders has been reported in DED patients. We hypothesized that physical and psychological stressors impair tear secretion. To examine the relationship between stress loading and decreased tear secretion, we established a stress-induced DED mouse model, which permitted us to address the underlying mechanism of pathogenesis and resilience. Enriched environment (EE) was an effective intervention to prevent and alleviate stress-induced decreased tear secretion. Because stress loading resulted in decreased brain-derived neurotrophic factor (BDNF) expression while EE resulted in increased expression, we focused on the role of BDNF in tear secretion. Using two distinct Bdnf gene knockdown mice, we evaluated whether BDNF was a deterministic factor in regulating tear secretion in healthy and stressed conditions. Bdnf knockdown mice showed decreased basal tear secretion and loss of stress tolerance by EE for tear secretion. These results suggest that BDNF expression is related to tear secretion and to the pathology of DED.

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Motor cortex excitability and inhibitory imbalance in autism spectrum disorder assessed with transcranial magnetic stimulation: a systematic review

Masuda F., Nakajima S., Miyazaki T., Yoshida K., Tsugawa S., Wada M., Ogyu K., Croarkin P., Blumberger D., Daskalakis Z., Mimura M., Noda Y.

Translational Psychiatry （Translational Psychiatry） 9 （ 1 ） 2019年12月

© 2019, The Author(s). Cortical excitation/inhibition (E/I) imbalances contribute to various clinical symptoms observed in autism spectrum disorder (ASD). However, the detailed pathophysiologic underpinning of E/I imbalance remains uncertain. Transcranial magnetic stimulation (TMS) motor-evoked potentials (MEP) are a non-invasive tool for examining cortical inhibition in ASD. Here, we conducted a systematic review on TMS neurophysiology in motor cortex (M1) such as MEPs and short-interval intracortical inhibition (SICI) between individuals with ASD and controls. Out of 538 initial records, we identified six articles. Five studies measured MEP, where four studies measured SICI. There were no differences in MEP amplitudes between the two groups, whereas SICI was likely to be reduced in individuals with ASD compared with controls. Notably, SICI largely reflects GABA(A) receptor-mediated function. Conversely, other magnetic resonance spectroscopy and postmortem methodologies assess GABA levels. The present review demonstrated that there may be neurophysiological deficits in GABA receptor-mediated function in ASD. In conclusion, reduced GABAergic function in the neural circuits could underlie the E/I imbalance in ASD, which may be related to the pathophysiology of clinical symptoms of ASD. Therefore, a novel treatment that targets the neural circuits related to GABA(A) receptor-mediated function in regions involved in the pathophysiology of ASD may be promising.

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Machine learning approach to identify a resting-state functional connectivity pattern serving as an endophenotype of autism spectrum disorder

Yamagata B., Itahashi T., Fujino J., Ohta H., Nakamura M., Kato N., Mimura M., Hashimoto R.i., Aoki Y.

Brain Imaging and Behavior （Brain Imaging and Behavior） 13 （ 6 ） 1689 - 1698 2019年12月

ISSN 19317557

© 2018, Springer Science+Business Media, LLC, part of Springer Nature. Endophenotype refers to a measurable and heritable component between genetics and diagnosis, and the same endophenotype is present in both individuals with a diagnosis and their unaffected siblings. Determination of the neural correlates of an endophenotype and diagnosis is important in autism spectrum disorder (ASD). However, prior studies enrolling individuals with ASD and their unaffected siblings have generally included only one group of typically developing (TD) subjects; they have not accounted for differences between TD siblings. Thus, they could not differentiate the neural correlates for endophenotype from the clinical diagnosis. In this context, we enrolled pairs of siblings with an ASD endophenotype (individuals with ASD and their unaffected siblings) and pairs of siblings without this endophenotype (pairs of TD siblings). Using resting-state functional MRI, we first aimed to identify an endophenotype pattern consisting of multiple functional connections (FCs) then examined the neural correlates of FCs for ASD diagnosis, controlling for differences between TD siblings. Sparse logistic regression successfully classified subjects as to the endophenotype (area under the curve = 0.78, classification accuracy = 75%). Then, a bootstrapping approach controlling for differences between TD siblings revealed that an FC between the right middle temporal gyrus and right anterior cingulate cortex was substantially different between individuals with ASD and their unaffected siblings, suggesting that this FC may be a neural correlate for the diagnosis, while the other FCs represent the endophenotype. The current findings suggest that an ASD endophenotype pattern exists in FCs, and a neural correlate for ASD diagnosis is dissociable from this endophenotype. (250 words).

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Factors Associated with Delirium following Electroconvulsive Therapy: A Systematic Review

Tsujii T., Uchida T., Suzuki T., Mimura M., Hirano J., Uchida H.

Journal of ECT （Journal of ECT） 35 （ 4 ） 279 - 287 2019年12月

ISSN 10950680

© 2019 Wolters Kluwer Health, Inc. All rights reserved. Objectives Delirium following electroconvulsive therapy (ECT) has been a clinical challenge, which, however, has not been investigated through a systematic literature review. The objective of this study was to systematically synthesize available evidence regarding factors associated with post-ECT delirium. Methods We conducted a systematic literature search for any type of original investigations that reported risk factors of post-ECT delirium, using PubMed. Results The literature search identified 43 relevant articles. One study found an association between catatonic feature and increased risk of postictal delirium. Five studies reported that the presence of cerebrovascular disease, Parkinson disease, or dementia was related to higher incidence of post-ECT delirium. Incidence of post-ECT course delirium was increased with bitemporal stimulation (3 studies). One study showed that ultrabrief pulse ECT reduced reorientation time following seizure compared with brief pulse ECT. High stimulus intensity resulted in more prolonged reorientation time after ECT than lower stimulus intensity (2 studies). Longer seizure length was significantly associated with post-ECT delirium in 1 study. Eight studies that examined postictal delirium in association with medications used, including lithium, did not show any consistent finding in their relationships. Four studies showed decreased incidence of postictal delirium in those receiving dexmedetomidine. Conclusions Limited evidence suggests that catatonic feature, cerebrovascular disease, Parkinson disease, dementia, bitemporal electrode placement, high stimulus intensity, or longer seizure length are associated with an increased risk of post-ECT delirium. Moreover, dexmedetomidine and ultrabrief pulse ECT seem to have preventive effects of post-ECT delirium.

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Concomitant use of alcohol and benzodiazepine hypnotics in psychiatric outpatients: A cross-sectional survey

Uchida T., Hirano J., Sakurai H., Suzuki T., Mimura M., Uchida H.

International Clinical Psychopharmacology （International Clinical Psychopharmacology） 34 （ 6 ） 291 - 297 2019年11月

ISSN 02681315

© 2019 The Author(s). Published by Wolters Kluwer Health, Inc. Concomitant use of benzodiazepines and alcohol appears prevalent in a clinical setting. The objectives of this study were as follows: (1) to investigate the prevalence of concomitant use of benzodiazepine hypnotics and alcohol in psychiatric outpatients, (2) to examine the clinical characteristics and factors associated with the concomitant use, and (3) to investigate the awareness of the psychiatrists-in-charge about the concomitant use. Outpatients with schizophrenia, depression, and insomnia who were receiving benzodiazepine hypnotics were asked to fill in a sleeping diary for seven consecutive days in which use of hypnotics and alcohol was also recorded. Clinical characteristics were assessed, and logistic analysis was performed to examine factors associated with the concomitant use. In addition, psychiatrists-in-charge were asked as to whether they thought their patients were concomitantly using them. The prevalence rate of the concomitant use was 39.8% (37/93). The CAGE score showed significant positive association with the concomitant use (odds ratio = 2.40, 95% confidence interval = 1.39-4.16, P = 0.002). Only in 32.4% of the concomitant users were suspected by their psychiatrists. The results suggest that concomitantly used benzodiazepine hypnotics and alcohol appears prevalent, and has been frequently overlooked by treating psychiatrists. The CAGE questionnaire may be helpful to screen such potentially hazardous users.

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Higher Dietary Non-enzymatic Antioxidant Capacity Is Associated with Decreased Risk of All-Cause and Cardiovascular Disease Mortality in Japanese Adults

Kashino I., Mizoue T., Serafini M., Akter S., Sawada N., Ishihara J., Kotemori A., Inoue M., Yamaji T., Goto A., Iwasaki M., Noda M., Tsugane S., Tsugane S., Sawada N., Iwasaki M., Inoue M., Yamaji T., Goto A., Shimazu T., Charvat H., Budhathoki S., Muto M., Suzuki H., Minamizono T., Kobayashi Y., Irei M., Doi M., Katagiri M., Tagami T., Sou Y., Uehara M., Kokubo Y., Yamagishi Y., Noda M., Kawaguchi Y., Nakamura K., Takachi R., Ishihara J., Iso H., Sobue T., Saito I., Yasuda N., Mimura M., Sakata K.

Journal of Nutrition （Journal of Nutrition） 149 （ 11 ） 1967 - 1976 2019年11月

ISSN 00223166

Copyright © American Society for Nutrition 2019. Background: Few studies have assessed associations of non-enzymatic antioxidant capacity (NEAC) in the overall diet with all-cause or specific mortality, and their results have been inconsistent. Objectives: The present study investigated the association between dietary NEAC and all-cause or cause-specific mortality. Methods: The study was a large-scale population-based prospective cohort study in Japan consisting of 42,520 men and 50,207 women aged 44-76 y, who had no history of cancer, stroke, ischemic heart disease, or chronic liver disease. We evaluated FFQ-based dietary NEAC with use of published databases in which the NEACs of individual foods were analyzed by ferric reducing antioxidant power (FRAP) and oxygen radical absorbance capacity (ORAC) assays. Dietary NEAC was calculated by multiplying the estimated NEAC with the consumed amount and summing up those values for all foods, and was categorized in quartiles. We identified death and cause of death with use of residential registry and death certificates. HRs and 95% Cls for death from the second survey, which was conducted from April 1995 to December 2014 were estimated with Cox proportional hazards regression analysis. Results: After 1,498,308 person-years of follow-up, 12,978 total deaths occurred. The multivariable-adjusted HRs (95% Cls) for all-cause mortality for the highest compared with the lowest quartile of FRAP and ORAC were 0.85 (0.80, 0.89) and 0.84 (0.79, 0.89), respectively. Dietary NEACs were inversely associated with mortality from cardiovascular disease (CVD), but not from cancer. The multivariable-adjusted HRs (95% Cls) for CVD for the highest compared with the lowest quartile of FRAP and ORAC were 0.83 (0.75, 0.92) and 0.79 (0.70, 0.89), respectively. Conclusions: Higher dietary NEACs from FRAP and ORAC were associated with lower risk of all-cause mortality and mortality from CVD in Japanese adults.

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Identification of glycyrrhizin metabolites in humans and of a potential biomarker of liquorice-induced pseudoaldosteronism: a multi-centre cross-sectional study

Takahashi K., Yoshino T., Maki Y., Ishiuchi K., Namiki T., Ogawa-Ochiai K., Minamizawa K., Makino T., Nakamura T., Mimura M., Watanabe K.

Archives of Toxicology （Archives of Toxicology） 93 （ 11 ） 3111 - 3119 2019年11月

ISSN 03405761

© 2019, Springer-Verlag GmbH Germany, part of Springer Nature. Liquorice [main ingredient, glycyrrhizin (GL)] is widely used as a food sweetener and herbal medicine. Occasionally, liquorice consumption causes pseudoaldosteronism as a side effect which causes oedema, hypokalaemia, and hypertension due to hyperactivity of mineral corticoid receptor. We aimed to detect GL metabolites in human blood and urine samples and to determine the pathological relationship between GL metabolites and pseudoaldosteronism. For this multi-centre, retrospective, cross-sectional study, we recruited patients who had visited Center for Kampo Medicine in Keio University Hospital, Department of Japanese Oriental (Kampo) Medicine in Chiba University Hospital, Clinic of Japanese Oriental (Kampo) Medicine in Kanazawa University Hospital, and Department of Oriental Medicine in Kameda Medical Center from November 2011 to July 2018. We collected laboratory data including concentration of serum potassium, plasma activity of renin and aldosterone, and residual blood and/or urine samples of participants who had experienced symptoms/signs of pseudoaldosteronism in the form of increase in blood pressure and occurrence or aggregation of oedema while taking liquorice-containing herbal preparations, and measured GL metabolites using a highly selective liquid chromatography tandem mass spectrometer system. We registered 97 participants (mean age 60 ± 15 years; male:female 14:83). 18β-glycyrrhetinic acid (GA) was detected in 67 serum samples (median 122 nM, range 5 nM–1.8 µM) and 18β-glycyrrhetyl-3-O-sulfate (compound 3) in 68 samples (median 239 nM, range 2 nM–4.2 µM). 3-Monoglucuronyl 18β-glycyrrhetinic acid, 22α-hydroxy-18β-glycyrrhetyl-3-O-sulfate-30-glucuronide, 22α-hydroxy-18β-glycyrrhetyl-3-O-sulfate, and GL itself were not or rarely detected. We could not find any correlation between blood pressure or peripheral oedema and serum concentration of GL metabolites. Sulfotransferase 2A1 catalysed the metabolic reaction of GA to compound 3, a major GL metabolite in human blood. High serum concentration of compound 3 was related to lower renin, aldosterone, and potassium levels, suggesting a pathological relationship between compound 3 and liquorice-induced pseudoaldosteronism. This is the first study to identify the association between a novel metabolite, compound 3, and the incidence of pseudoaldosteronism, highlighting it as a promising biomarker.

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Survey of the effects of internet usage on the happiness of Japanese university students

Kitazawa M., Yoshimura M., Hitokoto H., Sato-Fujimoto Y., Murata M., Negishi K., Mimura M., Tsubota K., Kishimoto T.

Health and Quality of Life Outcomes （Health and Quality of Life Outcomes） 17 （ 1 ） 2019年10月

© 2019 The Author(s). Background: Besides research on psychiatric diseases related to problematic Internet use (PIU), a growing number of studies focus on the impact of Internet on subjective well-being (SWB). However, in previous studies on the relationship between PIU and SWB, there is little data for Japanese people specifically, and there is a lack of consideration for differences in perception of happiness due to cultural differences. Therefore, we aimed to clarify how happiness is interdependent on PIU measures, with a focus on how the concept of happiness is interpreted among Japanese people, and specifically among Japanese university students. Methods: A paper-based survey was conducted with 1258 Japanese university students. Respondents were asked to fill out self-report scales regarding their happiness using the Interdependent Happiness Scale (IHS). The relationship between IHS and Internet use (Japanese version of the Internet addiction test, JIAT), use of social networking services, as well as social function and sleep quality (Pittsburgh Sleep Quality Index, PSQI) were sought using multiple regression analyses. Results: Based on multiple regression analyses, the following factors related positively to IHS: female gender and the number of Twitter followers. Conversely, the following factors related negatively to IHS: poor sleep, high- PIU, and the number of times the subject skipped a whole day of school. Conclusions: It was shown that there was a significant negative correlation between Japanese youths' happiness and PIU. Since epidemiological research on happiness that reflects the cultural background is still scarce, we believe future studies shall accumulate similar evidence in this regard.

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Clinical effectiveness of repetitive transcranial magnetic stimulation treatment in children and adolescents with neurodevelopmental disorders: A systematic review

Masuda F., Nakajima S., Miyazaki T., Tarumi R., Ogyu K., Wada M., Tsugawa S., Croarkin P.E., Mimura M., Noda Y.

Autism （Autism） 23 （ 7 ） 1614 - 1629 2019年10月

ISSN 13623613

© The Author(s) 2019. Neurodevelopmental disorders, including autism spectrum disorder, are common in children and adolescents, but treatment strategies remain limited. Although repetitive transcranial magnetic stimulation has been studied for neurodevelopmental disorders, there is no clear consensus on its therapeutic effects. This systematic review examined literature on repetitive transcranial magnetic stimulation for children and adolescents with neurodevelopmental disorders published up to 2018 using the PubMed database. The search identified 264 articles and 14 articles met eligibility criteria. Twelve of these studies used conventional repetitive transcranial magnetic stimulation and two studies used theta burst stimulation. No severe adverse effects were reported in these studies. In patients with autism spectrum disorder, low-frequency repetitive transcranial magnetic stimulation and intermittent theta burst stimulation applied to the dorsolateral prefrontal cortex may have therapeutic effects on social functioning and repetitive behaviors. In patients with attention deficit/hyperactivity disorder, low-frequency repetitive transcranial magnetic stimulation applied to the left dorsolateral prefrontal cortex and high-frequency repetitive transcranial magnetic stimulation applied to the right dorsolateral prefrontal cortex may target inattention, hyperactivity, and impulsivity. In patients with tic disorders, low-frequency repetitive transcranial magnetic stimulation applied to the bilateral supplementary motor area improved tic symptom severity. This systematic review suggests that repetitive transcranial magnetic stimulation may be a promising intervention for children and adolescents with neurodevelopmental disorders. The results warrant further large randomized controlled trials of repetitive transcranial magnetic stimulation in children with neurodevelopmental disorders.

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Glutathione levels and activities of glutathione metabolism enzymes in patients with schizophrenia: A systematic review and meta-analysis

Tsugawa S., Noda Y., Tarumi R., Mimura Y., Yoshida K., Iwata Y., Elsalhy M., Kuromiya M., Kurose S., Masuda F., Morita S., Ogyu K., Plitman E., Wada M., Miyazaki T., Graff-Guerrero A., Mimura M., Nakajima S.

Journal of Psychopharmacology （Journal of Psychopharmacology） 33 （ 10 ） 1199 - 1214 2019年10月

ISSN 02698811

© The Author(s) 2019. Background: Glutathione is among the important antioxidants to prevent oxidative stress. However, the relationships between abnormality in the glutathione system and pathophysiology of schizophrenia remain uncertain due to inconsistent findings on glutathione levels and/or glutathione-related enzyme activities in patients with schizophrenia. Methods: A systematic literature search was conducted using Embase, Medline, PsycINFO, and PubMed. Original studies, in which three metabolite levels (glutathione, glutathione disulfide, and total glutathione (glutathione+glutathione disulfide)) and five enzyme activities (glutathione peroxidase, glutathione reductase, glutamate-cysteine ligase, glutathione synthetase, and glutathione S-transferase) were measured with any techniques in both patients with schizophrenia and healthy controls, were included. Standardized mean differences were calculated to determine the group differences in the glutathione levels with a random-effects model. Results: We identified 41, 9, 15, 38, and seven studies which examined glutathione, glutathione disulfide, total glutathione, glutathione peroxidase, and glutathione reductase, respectively. Patients with schizophrenia had lower levels of both glutathione and total glutathione and decreased activity of glutathione peroxidase compared to controls. Glutathione levels were lower in unmedicated patients with schizophrenia than those in controls while glutathione levels did not differ between patients with first-episode psychosis and controls. Conclusions: Our findings suggested that there may be glutathione deficits and abnormalities in the glutathione redox cycle in patients with schizophrenia. However, given the small number of studies examined the entire glutathione system, further studies are needed to elucidate a better understanding of disrupted glutathione function in schizophrenia, which may pave the way for the development of novel therapeutic strategies in this disorder.

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App<sup>NL-G-F/NL-G-F</sup> mice overall do not show impaired motivation, but cored amyloid plaques in the striatum are inversely correlated with motivation

Hamaguchi T., Tsutsui-Kimura I., Mimura M., Saito T., Saido T.C., Tanaka K.F.

Neurochemistry International （Neurochemistry International） 129 2019年10月

ISSN 01970186

© 2019 Elsevier Ltd Apathy is clinically defined as lack of motivation. Apathy is a frequent symptom in patients with Alzheimer's disease (AD). It is unclear whether amyloid β (Aβ)pathology is associated with apathy. To address this question, we employed the AppNL-G-F/NL-G-F mouse, an Aβ deposition-bearing mouse without neurofibrillary tangles and neuronal cell death throughout the lifespan and used a progressive-ratio (PR)task to monitor instrumental motivation between the ages of 16 and 39 weeks. In the PR task, the number of lever presses to receive one reward increases and the number of active lever presses in the final trial a mouse completes represents a break point, which is an index of motivation. During the observation period, AppNL-G-F/NL-G-F mice overall did not show impaired motivation. However, AppNL-G-F/NL-G-F mice showed a dispersion of the break point at 39 weeks of age within the group. Therefore, we examined the association between the degree of the break point and Aβ pathology; the number of cored amyloid plaques in the striatum was inversely correlated with the degree of motivation. Furthermore, we measured the dopamine transporter (DAT)levels in the subcortical tissues including the striatum using western blot analysis and showed that AppNL-G-F/NL-G-F mice have lower DAT levels than do C57BL/6J mice. Although we could not directly determine the effect of core amyloid plaques on the DAT, the results of this study suggest a pathway through which cored amyloid plaques damage the DAT and cause impaired motivation. These results will draw attention to cored amyloid plaques and will aid researchers searching for new strategies that are effective for the prevention and treatment of impaired motivation.

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Circadian patterns of hallucinatory experiences in patients with schizophrenia: Potentials for chrono-pharmacology

Koizumi T., Suzuki T., Pillai N.S., Bies R.R., Takeuchi H., Yoshimura K., Mimura M., Uchida H.

Journal of Psychiatric Research （Journal of Psychiatric Research） 117 1 - 6 2019年10月

ISSN 00223956

© 2019 Elsevier Ltd The objective of this study was to investigate possible circadian pattern of psychotic symptoms in patients with schizophrenia, which could be reflected on the dosing schedule/regimen, i.e. chrono-pharmacology. Patients with schizophrenia (ICD-10) who reported having auditory hallucination, receiving monotherapy with risperidone, olanzapine or paliperidone for at least two weeks were included. The subjects were provided a diary and asked to record the time and duration of auditory hallucinations during the eight time periods (i.e. 00:00–03:00, 03:00–06:00, 06:00–09:00, 09:00–12:00, 12:00–15:00, 15:00–18:00, 18:00–21:00, and 21:00–24:00). In the diary, times of medication doses and sleep were also recorded. Time and degree of peak and trough dopamine D2 receptor blockade with antipsychotics were estimated from 2 sparsely collected plasma drug concentrations. The prevalence and duration of auditory hallucinations were statistically examined among the eight time periods, respectively. Forty-nine patients participated in this study (mean ± SD age, 50.7 ± 14.8 years; 36 men (73.5%); 34 inpatients (69.4%)). Auditory hallucinations occurred most frequently and lasted for the longest duration in the period of 18:00–21:00 (75.5% (37/49) and 1.37 ± 1.67 h). This happened despite the fact that the difference in D2 receptor occupancy between the peak and trough was less than 2%, indicating a stable drug delivery. Since the dopamine D2 receptor blockade by antipsychotics was stable, the nocturnal circadian pattern found in this study may reflect intrinsic dopaminergic fluctuation or generally quieter environments at night. These circadian patterns may be considered to devise individualized treatment approach in the context of “chrono-pharmacology” for patients with schizophrenia.

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Reproductive history and risk of cognitive impairment in Japanese women

Shimizu Y., Sawada N., Iwasaki M., Shikimoto R., Nozaki S., Mimura M., Tsugane S.

Maturitas （Maturitas） 128 22 - 28 2019年10月

ISSN 03785122

© 2019 Objective: While exposure to endogenous estrogen may be associated with better cognitive performance, it is still unclear whether it has an association with mild cognitive impairment (MCI) or dementia. The aim of this study was to clarify the effects of reproductive history, as a surrogate marker of exposure to endogenous estrogen, on the risk of cognitive impairment (MCI or dementia) in women. Study design: A total of 747 women aged 40–59 years in the Saku area (Nagano Prefecture) were followed as part of the Japan Public Health Center-based Prospective (JPHC) Study, which started in 1990. Participants had undergone a mental health examination in 2014–2015. Main outcome measures: We used multiple logistic regression to analyze the association between reproductive history, obtained at baseline and 10-year follow-up, with current cognitive impairment diagnosed by a trained psychiatrist, adjusting for various lifestyle factors. Results: Among 670 eligible women, current cognitive impairment was diagnosed in 227, 196 of whom had MCI and 31 dementia. A longer reproductive period had a significantly inverse association with cognitive impairment (P-trend = 0.032). In particular, women with a reproductive period ≥38 years compared with ≤33 years had a significantly lower risk of cognitive impairment (multivariable adjusted odds ratio=0.62, 95% confidence interval=0.40–0.96). Conclusions: A longer reproductive period was associated with a lower risk of cognitive impairment, which suggests that a longer exposure to endogenous estrogen may have a protective effect against cognitive impairment.

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Thalamic volume, resting-state activity, and their association with the efficacy of electroconvulsive therapy

Takamiya A., Kishimoto T., Liang K.c., Terasawa Y., Nishikata S., Tarumi R., Sawada K., Kurokawa S., Hirano J., Yamagata B., Mimura M.

Journal of Psychiatric Research （Journal of Psychiatric Research） 117 135 - 141 2019年10月

ISSN 00223956

© 2019 Electroconvulsive therapy (ECT) is the most effective antidepressant treatment. Biological predictors of clinical outcome to ECT are valuable. We aimed to examine multimodal magnetic resonance imaging (MRI) data that correlates to the efficacy of ECT. Structural and resting-state functional MRI data were acquired from 46 individuals (25 depressed individuals who received ECT, and 21 healthy controls). Whole-brain grey matter volume (GMV) and fractional amplitude of low frequency fluctuations (fALFF) were investigated to identify brain regions associated with post-ECT Hamilton Depression Rating Scale (HAM-D) total scores. GMV and fALFF values were compared with those in healthy controls using analysis of covariance (ANCOVA). Remission was defined by HAM-D ≤7. A multiple regression analysis revealed that pretreatment smaller GMV in the left thalamus was associated with worse response to ECT (i.e. higher post-ECT HAM-D). Pretreatment higher fALFF in the right anterior insula, and lower fALFF in the left thalamus and the cerebellum were associated with worse outcomes. The left thalamus was identified in both GMV and fALFF analyses. Nonremitters showed significantly smaller thalamic GMV compared to remitters and controls. We found that pretreatment thalamic volume and resting-state activity were associated with the efficacy of ECT. Our results highlight the importance of the thalamus as a possible biological predictor and its role in the underlying mechanisms of ECT action.

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Acute and long-term effects of electroconvulsive therapy on human dentate gyrus

Takamiya A., Plitman E., Chung J.K., Chakravarty M., Graff-Guerrero A., Mimura M., Kishimoto T.

Neuropsychopharmacology （Neuropsychopharmacology） 44 （ 10 ） 1805 - 1811 2019年09月

ISSN 0893133X

© 2019, American College of Neuropsychopharmacology. Electroconvulsive therapy (ECT) is the most effective treatment for severe depression, although the underlying mechanisms remain unclear. Animal studies have consistently shown that electroconvulsive stimulation induces neuroplastic changes in the dentate gyrus. To date, few studies have investigated the effect of ECT on human hippocampal subfields. In the current study, structural magnetic resonance imaging (MRI) was conducted in 25 patients with major depressive episodes at 3 time points: before ECT (TP1), after 1 week of the last ECT (TP2) and after 3 months of the last ECT (TP3). Twenty healthy controls were scanned twice with an interval similar to patients between TP1 and TP2. Volumetric analyses of the cornu ammonis (CA)4/dentate gyrus (DG) were performed using the MAGeT-Brain (Multiple Automatically Generated Templates) algorithm. Clinically remitted patients after ECT showed larger volume increases in the right CA4/DG than non-remitted patients. Volume increases in the right CA4/DG were negatively associated with age. Increased CA4/DG volumes after ECT returned to baseline levels after 3 months irrespective of clinical state. ECT-induced volume increase in the CA4/DG was associated with age and clinical remission. These findings are consistent with the neurotrophic processes seen in preclinical studies. Neuroplastic change in the CA4/DG might mediate some of the short-term antidepressant effects of ECT.

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Effectiveness and safety of long-term benzodiazepine use in anxiety disorders: A systematic review and meta-analysis

Shinfuku M., Kishimoto T., Uchida H., Suzuki T., Mimura M., Kikuchi T.

International Clinical Psychopharmacology （International Clinical Psychopharmacology） 34 （ 5 ） 211 - 221 2019年09月

ISSN 02681315

© 2019 Wolters Kluwer Health, Inc. Long-term benzodiazepines (BZDs) use is not endorsed in the treatment guidelines for anxiety disorders, but is prevalent in the real-world clinical settings. A systematic literature review was performed by using PubMed (last search: May 2019) to identify randomized controlled trials (RCTs) or maintenance studies following RCT that examined the effectiveness of BZDs in patients with anxiety disorders for a duration of 13 weeks or more. Meta-analyses were then conducted regarding changes in the Hamilton Anxiety Rating Scale (HAM-A) scores from baseline through endpoint, all-cause discontinuation, side effects, and the numbers of panic attacks at endpoint. Eight studies were identified (N = 1228). There were no significant differences in all outcomes between BZDs and antidepressants after the initial 8-week treatment. While no significant difference was noted in the HAM-A score changes between BZDs and placebo, BZDs resulted in a lower discontinuation rate and more frequent constipation and dry mouth than placebo. Our study indicates that for those who respond to an initial 8-week treatment, continuing BZDs is equivalent to antidepressants in efficacy and safety. However, the limited number of studies warranted further investigations of the long-term effectiveness and safety of BZDs.

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Attitudes Toward Electroconvulsive Therapy among Involuntary and Voluntary Patients

Takamiya A., Sawada K., Mimura M., Kishimoto T.

Journal of ECT （Journal of ECT） 35 （ 3 ） 165 - 169 2019年09月

ISSN 10950680

© Wolters Kluwer Health, Inc. All rights reserved. Objective We aimed to examine attitudes toward electroconvulsive therapy (ECT) among involuntary patients, voluntary patients, and their relatives. Methods Patients experiencing a major depressive episode and receiving ECT and their relatives were recruited for the survey. Patients and their relatives answered the self-rating questionnaires with a 7-point Likert scale. We explored differences in the survey results between involuntary and voluntary patients, as well as differences in the survey results between patients and their relatives. Results We recruited 97 participants (53 patients and 44 relatives) for the survey. Approximately 80% of the patients showed positive attitudes toward ECT. There were no statistically significant differences between involuntary (n = 23) and voluntary (n = 30) patients across multiple aspects of the ECT experience, including treatment satisfaction, positive or adverse effects of ECT, and treatment preference in the future. Relatives were more satisfied with the positive effects of ECT and with the information offered before ECT treatment than the patients themselves. Conclusions Approximately 80% of the patients showed overall satisfaction with ECT irrespective of consent status. Relatives were more satisfied with ECT than patients. Electroconvulsive therapy can be a lifesaving treatment for severely depressed patients, and the subjective experience of involuntary patients should be taken into consideration when discussing involuntary ECT treatment.

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Alteration in AMPA receptor subunit expression and receptor binding among patients with addictive disorders: A systematic review of human postmortem studies

Ueno F., Suzuki T., Nakajima S., Matsushita S., Mimura M., Miyazaki T., Takahashi T., Uchida H.

Neuropsychopharmacology Reports （Neuropsychopharmacology Reports） 39 （ 3 ） 148 - 155 2019年09月

© 2019 The Authors. Neuropsychopharmacology Reports published by John Wiley & Sons Australia, Ltd. Background and Objectives: Altered trafficking of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors has been reported in postmortem studies and suggested the involvement of AMPA receptors in the pathophysiology underpinning addictive disorders. However, these findings seemed mixed. Methods: A systematic literature search was conducted, using PubMed and Embase (last search, August 2018), to identify human postmortem studies that examined the expression of proteins and mRNA of AMPA receptor subunits in patients with addictive disorders in comparison with healthy controls. Results: Twelve (18 studies) out of 954 articles were identified to be relevant. Eight studies included alcohol use disorders, and four studies included heroin/cocaine abusers. The most frequently investigated regions were the hippocampus (three studies), amygdala (three studies), and putamen (three studies). In summary, two out of the three studies showed an increase in the expression of AMPA receptors in the hippocampus, while the other study found no change. Two studies to examine the amygdala demonstrated either a decreased or no change in receptor expression or binding. Concerning putamen, two studies showed no significant change whereas an overexpression of receptors was observed in the other. Conclusions and Scientific Significance: The hippocampus and amygdala may be pertinent to addictive disorders through their functions on learning and memory, whereas findings in other regions were inconsistent across the studies. Human postmortem studies are prone to degenerative changes after death. Moreover, only qualitative assessment was conducted because of the limited, heterogenous data. These limitations emphasize the need to investigate AMPA receptors in the living human brains.

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Impairment in judgement of the moral emotion guilt following orbitofrontal cortex damage

Funayama M., Koreki A., Muramatsu T., Mimura M., Kato M., Abe T.

Journal of Neuropsychology （Journal of Neuropsychology） 13 （ 3 ） 550 - 563 2019年09月

ISSN 17486645

© 2018 The British Psychological Society Although neuroimaging studies have provided evidence for an association between moral emotions and the orbitofrontal cortex, studies on patients with focal lesions using experimental probes of moral emotions are scarce. Here, we addressed this topic by presenting a moral emotion judgement task to patients with focal brain damage. Four judgement tasks in a simple pairwise choice paradigm were given to 72 patients with cerebrovascular disease. These tasks consisted of a perceptual line judgement task as a control task; the objects’ preference task as a basic preference judgement task; and two types of moral emotion judgement task, an anger task and a guilt task. A multiple linear regression analysis was performed on each set of task performance scores to take into account potential confounders. Performance on the guilt emotion judgement task negatively correlated with the orbitofrontal cortex damage, but not with the other variables. Results for the other judgement tasks did not reach statistical significance. The close association between orbitofrontal cortex damage and a decrease in guilt emotion judgement consistency might suggest that the orbitofrontal cortex plays a key role in the sense of guilt, a hallmark of morality.

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The P300 event-related potential in bipolar disorder: A systematic review and meta-analysis

Wada M., Kurose S., Miyazaki T., Nakajima S., Masuda F., Mimura Y., Nishida H., Ogyu K., Tsugawa S., Mashima Y., Plitman E., Chakravarty M.M., Mimura M., Noda Y.

Journal of Affective Disorders （Journal of Affective Disorders） 256 234 - 249 2019年09月

ISSN 01650327

© 2019 Background: Neurophysiology including P300, that is a typical index of event-related potential, may be potential biomarkers for bipolar disorder (BD) and it can be useful towards elucidating the pathophysiology of BD. However, previous findings from P300 studies were inconsistent due to the heterogeneity of research methods, which make it difficult to understand the neurobiological significance of them. The aim of this study is to conduct a meta-analysis on P300 in patients with BD. Method: A literature search was conducted using PubMed to identify studies that compared P300 event-related potential between patients with BD and healthy controls (HCs). We analyzed P300 indices such as amplitude and latency of P3a and P3b in auditory or visual paradigms. Further, moderator analyses were conducted to investigate the influence of patient characteristics (i.e. history of psychosis, diagnostic subcategories [BD-I/BD-II], and phase of illness [euthymic, manic, or depressive]) on P300 indices. Result: Out of 124 initial records, we included 30 articles (BD: N = 1331; HCs: N = 1818). Patients with BD showed reduced P3a and P3b amplitude in both paradigms and delayed P3b latency in auditory paradigms compared to HCs. There was no influence on the history of psychosis, diagnostic subcategories, or phase of illness on P300 indices. Limitation: The difference in medication use was difficult to control and it may affect the results. Conclusion: This meta-analysis provides evidence for P300 abnormalities in patients with BD compared to HCs. Our results suggest that P300 may be trait markers rather than state markers in this illness.

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Long-Acting Injectables Versus Oral Antipsychotics: A Retrospective Bidirectional Mirror-Image Study

Miura G., Misawa F., Kawade Y., Fujii Y., Mimura M., Kishimoto T.

Journal of Clinical Psychopharmacology （Journal of Clinical Psychopharmacology） 39 （ 5 ） 441 - 445 2019年09月

ISSN 02710749

© Wolters Kluwer Health, Inc. All rights reserved. Purpose Mirror-image studies, which compare equal periods of time before and after a new treatment is introduced, may reflect the real-world impact of that treatment. However, most mirror-image studies that have investigated the impact of long-acting injectable antipsychotics (LAIs) were unidirectional in design, for patients switching from oral antipsychotics (OAPs) to LAIs. Therefore, we conducted a bidirectional mirror-image study comparing LAIs and OAPs. Methods We included 126 schizophrenia or schizoaffective disorder patients' LAI treatment data from 3 psychiatric hospitals. Patients took OAPs for 6 months or more before initiating LAIs, or the reverse. We obtained data on the number of hospitalizations as a primary outcome, plus the total duration and mean duration of hospitalization as secondary outcomes during the 6 months of the patients' first treatment, and the 6 months after the patients started their second type of treatment. Results The results indicated that there was no significant difference in any outcomes between LAI and OAP treatment when going from LAIs to OAPs (n = 59). However, when patients started with OAPs and switched to LAIs (n = 67), they were hospitalized a significantly fewer number of times, and the duration of their stays was shorter in the LAI phase than in the OAP phase. When combined with bidirectional data, LAI superiority was still observed. Conclusions The findings endorse the relative effectiveness of LAIs over OAPs in the real world, although the inherent flaws of mirror-image studies such as expectation bias and having no parallel comparator should be considered.

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Brief Report: Olfactory Adaptation in Children with Autism Spectrum Disorders

Kumazaki H., Muramatsu T., Miyao M., Okada K.i., Mimura M., Kikuchi M.

Journal of Autism and Developmental Disorders （Journal of Autism and Developmental Disorders） 49 （ 8 ） 3462 - 3469 2019年08月

ISSN 01623257

© 2019, Springer Science+Business Media, LLC, part of Springer Nature. Olfactory adaptation is an important process that allows the individual to adjust to changes in the environment. This process has been proposed to be aberrant in individuals with autism spectrum disorders (ASD). However, few studies have examined olfactory adaptation in children with ASD. We examined olfactory adaptation in children with ASD and typically developing (TD) children using a pulse ejection system, which resolved problems associated with previous laboratory-based olfactory psychophysical studies. Nine children with ASD and nine TD children participated in this study and all participants completed the entire experiment. Using this system, we found that the TD group showed greater adaptation than the ASD group. Our results provide a better understanding of olfactory adaptation in children with ASD.

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Job interview training targeting nonverbal communication using an android robot for individuals with autism spectrum disorder

Kumazaki H., Muramatsu T., Yoshikawa Y., Corbett B.A., Matsumoto Y., Higashida H., Yuhi T., Ishiguro H., Mimura M., Kikuchi M.

Autism （Autism） 23 （ 6 ） 1586 - 1595 2019年08月

ISSN 13623613

© The Author(s) 2019. Job interviews are significant barriers for individuals with autism spectrum disorder because these individuals lack good nonverbal communication skills. We developed a job interview training program using an android robot. The job interview training program using an android robot consists the following three stages: (1) tele-operating an android robot and conversing with others through the android robot, (2) a face-to-face mock job interview with the android robot, and (3) feedback based on the mock job interview and nonverbal communication exercises using the android robot. The participants were randomly assigned to the following two groups: one group received a combined intervention with “interview guidance by teachers and job interview training program using an android robot” (n = 13), and the other group received an intervention with interview guidance by teachers alone (n = 16). Before and after the intervention, the participants in both groups underwent a mock job interview with a human interviewer, who provided outcome measurements of nonverbal communication, self-confidence, and salivary cortisol. After the training sessions, the participants who received the combined interview guidance by teachers and the job interview training program using an android robot intervention displayed improved nonverbal communication skills and self-confidence and had significantly lower levels of salivary cortisol than the participants who only received interview guidance by teachers. The job interview training program using an android robot improved various measures of job interview skills in individuals with autism spectrum disorder.

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Prediction of deficiency-excess pattern in Japanese Kampo medicine: Multi-centre data collection

Complementary Therapies in Medicine （Complementary Therapies in Medicine） 45 228 - 233 2019年08月

ISSN 09652299

© 2019 Elsevier Ltd Objective: The purpose of the present study was to compare important patient questionnaire items by creating a random forest model for predicting deficiency-excess pattern diagnosis in six Kampo specialty clinics. Design: A multi-centre prospective observational study. Setting: Participants who visited six Kampo specialty clinics in Japan from 2012 to 2015. Main outcome measure: Deficiency-excess pattern diagnosis made by board-certified Kampo experts. Methods: To predict the deficiency-excess pattern diagnosis by Kampo experts, we used 153 items as independent variables, namely, age, sex, body mass index, systolic and diastolic blood pressures, and 148 subjective symptoms recorded through a questionnaire. We extracted the 30 most important items in each clinic's random forest model and selected items that were common among the clinics. We integrated participating clinics’ data to construct a prediction model in the same manner. We calculated the discriminant ratio using this prediction model for the total six clinics’ data and each clinic's independent data. Results: Fifteen items were commonly listed in top 30 items in each random forest model. The discriminant ratio of the total six clinics’ data was 82.3%; moreover, with the exception of one clinic, the independent discriminant ratio of each clinic was approximately 80% each. Conclusions: We identified common important items in diagnosing a deficiency-excess pattern among six Japanese Kampo clinics. We constructed the integrated prediction model of deficiency-excess pattern.

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Resting-state hyperperfusion in the whole brain: A case of malignant catatonia that improved with electric convulsion therapy

Kurose S., Koreki A., Funayama M., Takahashi E., Kaji M., Ogyu K., Takasu S., Koizumi T., Suzuki H., Onaya M., Mimura M.

Schizophrenia Research （Schizophrenia Research） 210 287 - 288 2019年08月

ISSN 09209964

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Glutamatergic neurometabolite levels in major depressive disorder: a systematic review and meta-analysis of proton magnetic resonance spectroscopy studies

Moriguchi S., Takamiya A., Noda Y., Horita N., Wada M., Tsugawa S., Plitman E., Sano Y., Tarumi R., ElSalhy M., Katayama N., Ogyu K., Miyazaki T., Kishimoto T., Graff-Guerrero A., Meyer J.H., Blumberger D.M., Daskalakis Z.J., Mimura M., Nakajima S.

Molecular Psychiatry （Molecular Psychiatry） 24 （ 7 ） 952 - 964 2019年07月

ISSN 13594184

© 2018, The Author(s). Alterations in glutamatergic neurotransmission are implicated in the pathophysiology of depression, and the glutamatergic system represents a treatment target for depression. To summarize the nature of glutamatergic alterations in patients with depression, we conducted a meta-analysis of proton magnetic resonance (1H-MRS) spectroscopy studies examining levels of glutamate. We used the search terms: depress* AND (MRS OR “magnetic resonance spectroscopy”). The search was performed with MEDLINE, Embase, and PsycINFO. The inclusion criteria were 1H-MRS studies comparing levels of glutamate + glutamine (Glx), glutamate, or glutamine between patients with depression and healthy controls. Standardized mean differences (SMD) were calculated to assess group differences in the levels of glutamatergic neurometabolites. Forty-nine studies met the eligibility criteria, which included 1180 patients and 1066 healthy controls. There were significant decreases in Glx within the medial frontal cortex (SMD = −0.38; 95% CI, −0.69 to −0.07) in patients with depression compared with controls. Subanalyses revealed that there was a significant decrease in Glx in the medial frontal cortex in medicated patients with depression (SMD = −0.50; 95% CI, −0.80 to −0.20), but not in unmedicated patients (SMD = −0.27; 95% CI, −0.76 to 0.21) compared with controls. Overall, decreased levels of glutamatergic metabolites in the medial frontal cortex are linked with the pathophysiology of depression. These findings are in line with the hypothesis that depression may be associated with abnormal glutamatergic neurotransmission.

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Model-guided antipsychotic dose reduction in schizophrenia: A pilot, single-blind randomized controlled trial

Ozawa C., Bies R.R., Pillai N., Suzuki T., Mimura M., Uchida H.

Journal of Clinical Psychopharmacology （Journal of Clinical Psychopharmacology） 39 （ 4 ） 329 - 335 2019年07月

ISSN 02710749

© 2019 Wolters Kluwer Health, Inc. All rights reserved. Purpose/Background Patients with schizophrenia as well as their psychiatrists are hesitant to reduce the antipsychotic dose in fear of relapse. To overcome such dilemmas, we developed models to individually calculate an oral dose that corresponds to a given target dopamine D2 receptor occupancy. Methods/Procedures In this pilot, 52-week single-blind randomized controlled trial, 35 clinically stable patients with schizophrenia receiving either risperidone or olanzapine monotherapy were randomly assigned to dose reduction (n = 17) or dose maintenance group (n = 18). In the former group, baseline doses were reduced to the doses corresponding to 65% D2 occupancy (the lower end of therapeutic window) at trough that were calculated from randomly collected plasma concentrations using our models. Findings/Results In the dose reduction group, doses of risperidone and olanzapine were decreased from 4.2 ± 1.9 to 1.4 ± 0.4 and 12.8 ± 3.9 to 6.7 ± 1.8 mg/d, whereas the doses in the dose maintenance group were 4.3 ± 1.9 and 15.8 ± 4.6 mg/d, respectively. Twelve subjects (70.5%) and 13 subjects (72.2%) in the dose reduction and dose maintenance groups completed the study (P = 0.604), whereas 3 subjects (18.8%) and none dropped out because of clinical worsening in the dose reduction and dose maintenance groups, respectively. There were not significant differences in score changes in Positive and Negative Syndrome Scale between the 2 groups but in Positive subscale scores in the Clinical Global Impression-Schizophrenia (0.4 ± 0.7 in the dose reduction group vs -0.1 ± 0.7 in the dose maintenance group, P = 0.029). Implications/Conclusions Although our model-guided dose reduction strategy was found to be comparable with no-dose change in terms of dropout rates, safety issues have to be further examined.

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Can we predict amyloid deposition by objective cognition and regional cerebral blood flow in patients with subjective cognitive decline?

Funaki K., Nakajima S., Noda Y., Wake T., Ito D., Yamagata B., Yoshizaki T., Kameyama M., Nakahara T., Murakami K., Jinzaki M., Mimura M., Tabuchi H.

Psychogeriatrics （Psychogeriatrics） 19 （ 4 ） 325 - 332 2019年07月

ISSN 13463500

© 2019 Japanese Psychogeriatric Society Background: Subjective cognitive decline (SCD) may herald the first symptoms of Alzheimer's disease (AD) whereas individuals with beta-amyloid (Aβ) deposition are regarded as a high-risk group for AD. Recently, amyloid positron emission tomography (PET) studies have demonstrated clinical and cognitive feature differences between Aβ-positive and negative SCD, but details of their differences remain unclear. We aimed to investigate the relationships among Aβ deposition, clinical, and cognitive features in patients with SCD. Methods: Forty-two patients with SCD (22 women, 74.5 ± 4.7 years) were examined using fluorine-18 florbetaben PET and were divided into Aβ-positive (n = 10) and negative (n = 32) groups. We compared cognitive and psychological outcomes, and single photon emission computed tomography (SPECT) imaging data between the two groups. In addition, a linear regression analysis was performed to assess relationships between the severity of SCD and neuropsychological tests, affective scores, and demographic factors. Results: The rate of score changes from the immediate recall to delayed recall in the logical memory subtest of the Wechsler's Memory Scale Revised were different between the groups (P = 0.04). However, the binary logistic regression analysis showed no significant differences between the two. In addition, the severity of SCD was significantly strong in women (P = 0.002). Furthermore, within the Aβ-negative group, subjective memory loss correlated with word fluency category score (P = 0.023) and apathy scale (P = 0.037). Conclusions: No significant differences were observed between Aβ-positive and -negative SCD on any of the neuropsychological measures, clinical measures, or SPECT imaging. Further, the severity of SCD was not predicted by the symptoms of anxiety, depression, or neuropsychological examination.

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Does the rapid response of an antidepressant contribute to better cost-effectiveness? Comparison between mirtazapine and SSRIs for first-line treatment of depression in Japan

Sado M., Wada M., Ninomiya A., Nohara H., Kosugi T., Arai M., Endo R., Mimura M.

Psychiatry and Clinical Neurosciences （Psychiatry and Clinical Neurosciences） 73 （ 7 ） 400 - 408 2019年07月

ISSN 13231316

© 2019 The Authors. Psychiatry and Clinical Neurosciences © 2019 Japanese Society of Psychiatry and Neurology Aim: Previous studies indicate that mirtazapine is unique in its quick responsiveness compared to other antidepressants. Although some other studies have evaluated its cost-effectiveness, they have not considered its early stage remission rate. The aim of this study was to address this research gap by using precise clinical data to evaluate the cost-effectiveness of mirtazapine in Japan. Methods: We developed a Markov model to reflect the week-by-week transition probabilities. The Markov cycle was set as 1 week. While our clinical parameters were obtained largely from existing meta-analyses, cost data were derived from government reports. Cost-effectiveness was evaluated by incremental cost-effectiveness ratios (ICERs) per quality-adjusted life year estimated based on the probability sensitivity analyses. The ICERs were estimated at 2, 8, 26, and 52 weeks. Results: In severe depression, the ICERs ranged between JPY 872 153 and 1 772 723. The probability of mirtazapine being cost-effective ranged from 0.75 to 0.99 when the ICER threshold was JPY 5 000 000. In moderate depression, the ICERs ranged between JPY 2 356 499 and 4 770 145. The probability of mirtazapine being cost-effective ranged from 0.55 to 0.83 when the ICER threshold was JPY 5 000 000. Conclusion: When considering the early stage efficacy of mirtazapine, it appeared to be cost-effective compared to selective serotonin reuptake inhibitors, especially for severe depression and in the early stage treatment in the Japanese setting. However, our study has some limitations. First, mirtazapine is compared with batched selective serotonin reuptake inhibitors rather than individual ones. Second, we did not consider antidepressant combination therapy as treatment options.

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Cortical surface architecture endophenotype and correlates of clinical diagnosis of autism spectrum disorder

Yamagata B., Itahashi T., Fujino J., Ohta H., Takashio O., Nakamura M., Kato N., Mimura M., Hashimoto R.i., Aoki Y.Y.

Psychiatry and Clinical Neurosciences （Psychiatry and Clinical Neurosciences） 73 （ 7 ） 409 - 415 2019年07月

ISSN 13231316

© 2019 The Authors. Psychiatry and Clinical Neurosciences © 2019 Japanese Society of Psychiatry and Neurology Aim: Prior structural magnetic resonance imaging studies demonstrated atypical gray matter characteristics in siblings of individuals with autism spectrum disorder (ASD). However, they did not clarify which aspect of gray matter is related to the endophenotype (i.e., genetic vulnerability) of ASD. Further, because they did not enroll siblings of typically developing (TD) people, they may have underestimated the difference between individuals with ASD and their unaffected siblings. The current study aimed to address these gaps. Methods: We recruited 30 pairs of adult male siblings (15 pairs with an ASD endophenotype and 15 pairs without) and focused on four gray matter parameters: cortical volume and three surface-based parameters (cortical thickness, fractal dimension, and sulcal depth [SD]). First, we sought to identify a pattern of an ASD endophenotype, comparing the four parameters. Then, we compared individuals with ASD and their unaffected siblings in the cortical parameters to identify neural correlates for the clinical diagnosis accounting for the difference between TD siblings. Results: A sparse logistic regression with a leave-one-pair-out cross-validation showed the SD as having the highest accuracy for the identification of an ASD endophenotype (73.3%) compared with the other three parameters. A bootstrapping analysis accounting for the difference in the SD between TD siblings showed a significantly large difference between individuals with ASD and their unaffected siblings in six out of 68 regions of interest. Conclusion: This proof-of-concept study suggests that an ASD endophenotype emerges in the SD and that neural bases for ASD diagnosis can be discerned from the endophenotype when accounting for the difference between TD siblings.

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Actigraphy for evaluation of mood disorders: A systematic review and meta-analysis

Tazawa Y., Wada M., Mitsukura Y., Takamiya A., Kitazawa M., Yoshimura M., Mimura M., Kishimoto T.

Journal of Affective Disorders （Journal of Affective Disorders） 253 257 - 269 2019年06月

ISSN 01650327

© 2019 Background: Actigraphy has enabled consecutive observation of individual health conditions such as sleep or daily activity. This study aimed to examine the usefulness of actigraphy in evaluating depressive and/or bipolar disorder symptoms. Method: A systematic review and meta-analysis was conducted. We selected studies that used actigraphy to compare either patients vs. healthy controls, or pre- vs. post-treatment data from the same patient group. Common actigraphy measurements, namely daily activity and sleep-related data, were extracted and synthesized. Results: Thirty-eight studies (n = 3,758) were included in the analysis. Compared with healthy controls, depressive patients were less active (standardized mean difference; SMD=1.27, 95%CI=[0.97, 1.57], P<0.001) and had longer wake after sleep onset (SMD= − 0.729, 95%CI=[− 1.20, − 0.25], p = 0.003). Total sleep time (SMD= − 0.33, 95%CI=[− 0.55, − 0.11], P = 0.004), sleep latency (SMD= − 0.22, 95%CI=[− 0.42, − 0.02], P = 0.032), and wake after sleep onset (SMD= − 0.22, 95%CI=[− 0.39, − 0.04], P = 0.015) were longer in euthymic/remitted patients compared to healthy controls. In pre- and post-treatment comparisons, sleep latency (SMD=− 0.85, 95%CI=[− 1.53, − 0.17], P = 0.015), wake after sleep onset (SMD= − 0.65, 95%CI=[− 1.20, − 0.10], P = 0.022), and sleep efficiency (SMD=0.77, 95%CI=[0.29, 1.24], P = 0.002) showed significant improvement. Limitation: The sample sizes for each outcome were small. The type of actigraphy devices and patients’ illness severity differed across studies. It is possible that hospitalizations and medication influenced the outcomes. Conclusion: We found significant differences between healthy controls and mood disorders patients for some actigraphy-measured modalities. Specific measurement patterns characterizing each mood disorder/status were also found. Additional actigraphy data linked to severity and/or treatment could enhance the clinical utility of actigraphy.

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Brain functional alterations observed 4-weekly in major depressive disorder following antidepressant treatment

Yamagata B., Yamanaka K., Takei Y., Hotta S., Hirano J., Tabuchi H., Mimura M.

Journal of Affective Disorders （Journal of Affective Disorders） 252 25 - 31 2019年06月

ISSN 01650327

© 2019 Background: Major depressive disorder (MDD) is a heterogeneous condition. Identifying the brain responses to antidepressant treatment is of particular interest as these may represent potential neural networks related to treatment response, forming one aspect of the biological markers of MDD. Near-infrared spectroscopy (NIRS) is suitable for repeated measurements with short intervals because of its noninvasiveness, and can provide detailed time courses of functional alterations in prefrontal regions. Methods: We conducted a 12-week longitudinal study to explore prefrontal hemodynamic changes at 4-week intervals following sertraline treatment in 11 medication-naïve participants with MDD using 52-channel NIRS. Results: While all participants achieved remission after treatment, intra-class correlation coefficient of oxygenated hemoglobin [oxy-Hb] values throughout the 12-week observation was moderate at the spatially and temporally contiguous cluster located in the left inferior frontal and temporal gyri. There was a significant negative correlation between mean [oxy-Hb] values in the significant cluster at 4 weeks and changes in Hamilton Rating Scale for Depression total score from 4 to 8 weeks (r = −0.73, P = 0.011) and from 4 to 12 weeks (r = −0.63, P = 0.039). Limitations: Without healthy controls for comparison, we were unable to fully evaluate whether improvement of [oxy-Hb] activations after treatment in MDD reached normal levels or not. Conclusion: Our NIRS findings of detailed prefrontal hemodynamic alterations over short interval observations such as 4 weeks may have revealed potential trait marker for MDD and biological maker for predicting clinical response to sertraline treatment in MDD.

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Discrepancies between Nomenclature and Indications of Psychotropics

Minami F., Zohar J., Suzuki T., Koizumi T., Mimura M., Yagi G., Uchida H.

Pharmacopsychiatry （Pharmacopsychiatry） 52 （ 4 ） 175 - 179 2019年05月

ISSN 01763679

© Georg Thieme Verlag KG Stuttgart · New York. Introduction While the current nomenclature of psychotropic drugs is disease-based, their approved indications do not always match their classifications. Methods Information on approved indications of second-generation antipsychotics and newer antidepressants that are available in the United States (US), the United Kingdom (UK), France, Germany, and Japan were extracted from their packet inserts. Results A significant proportion of atypical antipsychotics were approved for psychiatric conditions other than psychotic disorders (i. e., bipolar disorder, major depressive disorder, and autistic disorder) as follows: 76.9% in the US, 66.7% in the UK, 66.7% in France, 60.0% in Germany, and 44.4% in Japan. Likewise, more than half of newer antidepressants had approved indications for psychiatric conditions other than depression (e. g., panic disorder, obsessive compulsive disorder, social anxiety disorder, general anxiety disorder, and post-traumatic stress disorder): 56.3% in the US, 69.2% in the UK, 69.2% in France, 50.0% in Germany, and 62.5% in Japan. Conclusions Our results raise concerns regarding generic terminologies of antipsychotics and antidepressants since the conventional indication-based nomenclature does not fit well with the official indication.

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Serotonin-mediated inhibition of ventral hippocampus is required for sustained goal-directed behavior

Yoshida K., Drew M., Mimura M., Tanaka K.

Nature Neuroscience （Nature Neuroscience） 22 （ 5 ） 770 - 777 2019年05月

ISSN 10976256

© 2019, The Author(s), under exclusive licence to Springer Nature America, Inc. The ability to sustain goal-directed action is essential for success in many domains, but little is known about the corresponding neural substrates. Using fiber photometry to monitor population neural activity, we demonstrate that engagement in sustained food- or punishment-motivated behavior is associated with suppression of ventral but not dorsal hippocampal activity. Using optogenetic stimulation, we demonstrate that this suppression is required for goal-directed behavior, whereas optogenetic suppression of the ventral hippocampus (vHP) enhances the ability to sustain goal-directed behavior. Suppression of vHP during sustained goal-directed behavior was accompanied by increased activity in median but not dorsal raphe, implicating serotonergic signaling through Htr3a as a mechanism of vHP suppression during successful goal-directed behavior. Sustainment of goal-directed action may require suppression of vHP because of the structure’s well-documented role in behavioral inhibition.

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Etiology of out-of-hospital cardiac arrest in psychiatric patients: Chart review

Ishida T., Miyazaki K., Yukawa T., Yamagishi T., Sugiyama K., Tanabe T., Hamabe Y., Mimura M., Suzuki T., Uchida H.

Psychiatry and Clinical Neurosciences （Psychiatry and Clinical Neurosciences） 73 （ 5 ） 243 - 247 2019年05月

ISSN 13231316

© 2018 The Authors. Psychiatry and Clinical Neurosciences © 2018 Japanese Society of Psychiatry and Neurology Aim: Although sudden cardiac deaths are more common in psychiatric patients than the general population, data on their causes are very limited. The aim of this study was to investigate initial rhythms and causes of out-of-hospital cardiac arrest (OHCA) in patients with psychiatric disorders. Methods: We conducted a systematic chart review of patients resuscitated after OHCA and hospitalized in the Tertiary Emergency Medical Center of Tokyo Metropolitan Bokutoh Hospital in Japan between January 2010 and December 2017. The initial rhythms and causes of OHCA were compared between psychiatric patients and non-psychiatric patients. Parameters of interest were compared using chi-squared test, Fisher's exact test, or the Mann–Whitney U-test, as appropriate. Results: A total of 49 psychiatric and 600 non-psychiatric patients were eligible for this study. Fatal but shockable arrhythmias (i.e. ventricular fibrillation and ventricular tachycardia) were less frequently observed as initial rhythms in patients with psychiatric disorders than the others (22.4% vs 49.7%, P < 0.001). Cardiac origin was less common as the cause of OHCA (26.5% vs 58.5%, P < 0.01), while airway obstruction and pulmonary embolism were more frequent in psychiatric versus non-psychiatric patients (24.5% vs 6.5%, P < 0.01; and 12.2% vs 1.5%, P < 0.01, respectively). The results were similar when psychiatric patients were compared with sex- and age-matched controls selected from the non-psychiatric patient group. Conclusion: Although fatal arrhythmias may be less common, non-cardiac causes such as pulmonary embolism and airway obstruction need to be treated with high clinical suspicion in an event of sudden cardiac arrest in psychiatric patients.

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Remarkable behavioural signs and progressive non-fluent aphasia in a patient with adult-onset leucoencephalopathy with axonal spheroids and pigmented glia

Funayama M., Sugihara M., Takata T., Mimura M., Ikeuchi T.

Psychogeriatrics （Psychogeriatrics） 19 （ 3 ） 282 - 285 2019年05月

ISSN 13463500

© 2018 Japanese Psychogeriatric Society Adult-onset leucoencephalopathy with axonal spheroids and pigmented glia (ALSP), also known as hereditary diffuse leucoencephalopathy with spheroids (HDLS), is a progressive neurocognitive disorder that predominantly affects the cerebral white matter, mainly the frontal subcortical areas and the corpus callosum. Patients with ALSP are clinically characterized by a gradual onset of cognitive and behavioural dysfunction and personality changes, followed by motor impairments such as gait disturbance and bradykinesia. Given the disease-related degenerative changes of the frontal white matter, it is no wonder that patients with ALSP present with behavioural symptoms and non-fluent aphasia, which are found in patients with frontotemporal lobar degeneration. However, behavioural symptoms and non-fluent aphasia in a patient with ALSP have rarely reported in detail. Here, we describe a patient with ALSP who initially presented with remarkable behavioural signs and non-fluent primary progressive aphasia, which resembled symptoms of frontotemporal lobar degeneration. The present case suggests that ALSP should be included in the differential diagnosis for frontotemporal lobar degeneration.

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Neuroimaging correlates of narcolepsy with cataplexy: A systematic review

Wada M., Mimura M., Noda Y., Takasu S., Plitman E., Honda M., Natsubori A., Ogyu K., Tarumi R., Graff-Guerrero A., Nakajima S.

Neuroscience Research （Neuroscience Research） 142 16 - 29 2019年05月

ISSN 01680102

© 2018 Elsevier B.V. and Japan Neuroscience Society Recent developments in neuroimaging techniques have advanced our understanding of biological mechanisms underpinning narcolepsy. We used MEDLINE to retrieve neuroimaging studies to compare patients with narcolepsy and healthy controls. Thirty-seven studies were identified and demonstrated several replicated abnormalities: (1) gray matter reductions in superior frontal, superior and inferior temporal, and middle occipital gyri, hypothalamus, amygdala, insula, hippocampus, cingulate cortex, thalamus, and nucleus accumbens, (2) decreased fractional anisotropy in white matter of fronto-orbital and cingulate area, (3) reduced brain metabolism or cerebral blood flow in middle and superior frontal, and cingulate cortex (4) increased activity in inferior frontal gyri, insula, amygdala, and nucleus accumbens, and (5) N-acetylaspartate/creatine-phosphocreatine level reduction in hypothalamus. In conclusion, all the replicated findings are still controversial due to the limitations such as heterogeneity or size of the samples and lack of multimodal imaging or follow-up. Thus, future neuroimaging studies should employ multimodal imaging methods in a large sample size of patients with narcolepsy and consider age, duration of disease, age at onset, severity, human leukocyte antigen type, cerebrospinal fluid hypocretin levels, and medication intake in order to elucidate possible neuroimaging characteristic of narcolepsy and identify therapeutic targets.

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A content analysis of multidimensional support needs regarding fertility among cancer patients: How can nonphysician health care providers support?

Takeuchi E., Shimizu M., Miyata K., Shimizu R., Matsunaga N., Moroi N., Fujisawa D., Mimura M., Kato M.

Journal of Adolescent and Young Adult Oncology （Journal of Adolescent and Young Adult Oncology） 8 （ 2 ） 205 - 211 2019年04月

ISSN 21565333

© Copyright 2019, Mary Ann Liebert, Inc., publishers 2019. Purpose: This study aimed to identify support needs among young cancer patients regarding fertility-related issues to describe multidimensional support provided by nonphysician health care providers. Methods: Participants were cancer patients and their families who contacted the Hotline for Cancer Treatment and Reproduction at National Cancer Center Hospital in Japan. Medical charts were analyzed through content analysis. Results: A total of 51 participants met the inclusion criteria, of which 32 cases (63%) involved patients themselves, 13 (25%) patients' family members, and 6 (12%) both patients and their families. About patients' demographic status, 40% of the patients were female and 28% were in their thirties. Gynecological and breast cancer patients were the majority, and 24 patients (47%) had not yet started cancer treatment. As a result of content analysis regarding support needs, 9 categories and 55 codes were extracted. The categories included information about risk of infertility, information about means to maintain reproductive function, referral to specialists, support for economic burden, support for worry about cancer progression, support for psychological distress upon facing the risk of infertility, support for communication with oncologists, support for family relationships, and decisional aid. Conclusions: This study suggests that nonphysician health care providers should acquire knowledge about fertility preservation and provide psychological support within their specialties.

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Brief Report: Evaluating the Utility of Varied Technological Agents to Elicit Social Attention from Children with Autism Spectrum Disorders

Kumazaki H., Warren Z., Swanson A., Yoshikawa Y., Matsumoto Y., Yoshimura Y., Shimaya J., Ishiguro H., Sarkar N., Wade J., Mimura M., Minabe Y., Kikuchi M.

Journal of Autism and Developmental Disorders （Journal of Autism and Developmental Disorders） 49 （ 4 ） 1700 - 1708 2019年04月

ISSN 01623257

© 2018, The Author(s). Technological agents could be effective tools to be used in interventions for enhancing social orienting for some young children with ASD. We examined response to social bids in preschool children with ASD and typical development (TD) at a very early age (i.e., around 3 years) using social prompts presented by technological agents of various forms and human comparisons. Children with ASD demonstrated less response overall to social bids compared to TD controls, across agents or human. They responded more often to a simple humanoid robot and the simple avatar compared to the human. These results support the potential utilization of specific robotic and technological agents for harnessing and potentially increasing motivation to socially-relevant behaviors in some young children with ASD.

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Brief Report: A Novel System to Evaluate Autism Spectrum Disorders Using Two Humanoid Robots

Kumazaki H., Muramatsu T., Yoshikawa Y., Yoshimura Y., Ikeda T., Hasegawa C., Saito D.N., Shimaya J., Ishiguro H., Mimura M., Kikuchi M.

Journal of Autism and Developmental Disorders （Journal of Autism and Developmental Disorders） 49 （ 4 ） 1709 - 1716 2019年04月

ISSN 01623257

© 2018, Springer Science+Business Media, LLC, part of Springer Nature. We investigated the feasibility of our novel evaluation system for use with children with autism spectrum disorders (ASD). We prepared the experimental setting with two humanoid robots in reference to the birthday party scene in the Autism Diagnostic Observational Schedule (ADOS). We assessed the relationship between social communication ability measured in the ADOS condition (i.e., with a human clinician) and in a robotic condition for children with ASD. There were significant correlations between the social communication scores in the gold-standard ADOS condition and the robotic condition for children with ASD. The current work provides support for a unique application of a robotic system (i.e., two robot-mediated interaction) to evaluate the severity of autistic traits for children with ASD.

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Glutamatergic Neurometabolite Levels in Patients With Ultra-Treatment-Resistant Schizophrenia: A Cross-Sectional 3T Proton Magnetic Resonance Spectroscopy Study

Iwata Y., Nakajima S., Plitman E., Caravaggio F., Kim J., Shah P., Mar W., Chavez S., De Luca V., Mimura M., Remington G., Gerretsen P., Graff-Guerrero A.

Biological Psychiatry （Biological Psychiatry） 85 （ 7 ） 596 - 605 2019年04月

ISSN 00063223

© 2018 Society of Biological Psychiatry Background: In terms of antipsychotic treatment response, patients with schizophrenia can be classified into three groups: 1) treatment resistant to both non-clozapine (non-CLZ) antipsychotics and CLZ (ultra-treatment-resistant schizophrenia [URS]), 2) treatment resistant to non-CLZ antipsychotics but CLZ-responsive schizophrenia [non-URS]), and 3) responsive to first-line antipsychotics (non-treatment-resistant schizophrenia). This study aimed to compare glutamatergic neurometabolite levels among these three patient groups and healthy control subjects using proton magnetic resonance spectroscopy. Methods: Glutamate and glutamate+glutamine levels were assessed in the caudate, the dorsal anterior cingulate cortex (dACC), and the dorsolateral prefrontal cortex using 3T proton magnetic resonance spectroscopy (point-resolved spectroscopy, echo time = 35 ms). Glutamatergic neurometabolite levels were compared between the groups. Results: A total of 100 participants were included, consisting of 26 patients with URS, 27 patients with non-URS, 21 patients with non-treatment-resistant schizophrenia, and 26 healthy control subjects. Group differences were detected in ACC glutamate+glutamine levels (F 3,96 = 2.93, p =.038); patients with URS showed higher dACC glutamate+glutamine levels than healthy control subjects (p =.038). There were no group differences in the caudate or dorsolateral prefrontal cortex. Conclusions: Taken together with previous studies that demonstrated higher ACC glutamate levels in patients with treatment-resistant schizophrenia, this study suggests that higher levels of ACC glutamatergic metabolites may be among the shared biological characteristics of treatment resistance to antipsychotics, including CLZ.

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Subiculum volumes associated with memory function in the oldest-old individuals aged 95 years and older

Eguchi Y., Noda Y., Nakajima S., Tsugawa S., Kida H., Plitman E., Graff-Guerrero A., Chakravarty M.M., Takayama M., Arai Y., Matsuda H., Mimura M., Niimura H.

Geriatrics and Gerontology International （Geriatrics and Gerontology International） 19 （ 4 ） 347 - 351 2019年04月

ISSN 14441586

© 2019 Japan Geriatrics Society Aim: Few cohort studies targeting the oldest-old individuals have been carried out. The subiculum in the hippocampus is thought to be related to memory function, and atrophy of this structure might result in the conversion from amnestic mild cognitive impairment to Alzheimer's disease. Thus, we sought to examine the relationship between subiculum volumes and memory function in individuals aged ≥95 years, using a novel cognitive examination called the Addenbrooke's Cognitive Examination III (ACE-III) and an advanced magnetic resonance imaging analytical method, Multiple Automatically Generated Templates Brain Segmentation Algorithm (MAGeTbrain), to measure hippocampal subfield volumes. Methods: A part of the cohort data of the Arakawa 95+ study for the oldest-old aged ≥95 years was used. A total of 10 individuals completed all of the examinations. The MAGeT brain was applied to estimate the subfield volumes of the hippocampus. Correlation analyses and multiple regression analyses were carried out to examine a relationship among ACE-III memory scores and the subfield volumes in the hippocampus, including the subiculum. Results: There was a significant relationship between ACE-III memory scores and subdivision volumes. Regression analyses showed that subiculum volumes were associated with ACE-III memory scores in the oldest-old individuals (β = 0.721, P = 0.019; F 1, 8 = 8.67, adjusted R 2 = 0.46). Conclusions: The subiculum might play a pivotal role in memory function in the oldest-old individuals aged ≥95 years. The present finding warrants further research including larger sample sizes. Geriatr Gerontol Int 2019; 19: 347–351.

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Predictive factors of the duration of sick leave due to mental disorders

Sakakibara S., Sado M., Ninomiya A., Arai M., Takahashi S., Ishihara C., Miura Y., Tabuchi H., Shirahase J., Mimura M.

International Journal of Mental Health Systems （International Journal of Mental Health Systems） 13 （ 1 ） 2019年03月

© 2019 The Author(s). Background: This study aimed to examine potential predictors of duration of sick leave due to mental disorders in Japan. Methods: A total of 207 employees at a manufacturing company in Japan with a past history of sick leave due to mental disorders participated in this study. Mental disorders were defined as those listed in the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV). All of the participants used the mental health program that the company provided. The predictive power of the variables was tested using a Cox proportional hazard analysis. The hazard ratios in the final model were used to identify the predictor variables of the duration of sick leave. We included socio-demographic (age, sex, tenure), clinical (diagnosis and number of previous sick leave), and work-related factors (employment rank) as possible predictors. Data on these variables were obtained through the psychiatrists and psychologists in the company's mental health program. Results: The results of the univariate analyses showed that the number of previous sick leave episodes, diagnosis and employee rank were significant predictors of the duration of sick leave due to mental disorders. A multivariate analysis indicated that age, number of previous sick leave and employee rank were statistically significant predictors of return to work. Conclusions: Diagnosis, number of previous sick leave episodes, and employee rank are predictors of the duration of sick leave due to mental disorders. This study's findings have implications in the development of effective interventions to prevent protracted sick leave.

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Impact of subjective vs. objective remission status on subjective cognitive impairments in depression

Sawada K., Yoshida K., Ozawa C., Mizuno Y., Rubinstein E.B., Suzuki T., Mimura M., Uchida H.

Journal of Affective Disorders （Journal of Affective Disorders） 246 99 - 104 2019年03月

ISSN 01650327

© 2018 Elsevier B.V. Objective: The impact of subjective vs. objective illness severity on subjective cognitive impairment in patients with depression has not been addressed. Methods: This study is a post-hoc analysis of our cross-sectional study in Japanese outpatients with depressive disorder (ICD-10) (Ozawa et al., 2017). The participants received assessments with the Japanese version of the Perceived Deficits Questionnaire (J-PDQ), Quick Inventory of Depressive Symptomatology (QIDS), and Montgomery–Asberg Depression Rating Scale (MADRS). First, multiple regression analysis was conducted to examine the effects of demographic and clinical characteristics, including illness severity and medications (e.g., antidepressants and benzodiazepines), on the PDQ total score. Next, we categorized the participants into 4 groups based on the presence/absence of subjective and objective symptom remission (i.e., QIDS total score of ≤5 and MADRS total score of ≤9, respectively), and compared the differences in PDQ total scores between the QIDS- and MADRS-remitted group and the QIDS-non-remitted but MADRS-remitted group. Results: 102 participants were included (45 men; mean ± SD age, 50.5 ± 14.7 years). Higher QIDS and MADRS total scores were significantly associated with a greater PDQ total score (both p's < 0.001), while other factors did not exhibit any associations. The QIDS-non-remitted but MADRS-remitted group showed a significantly higher PDQ total score than that of the QIDS- and MADRS-remitted group (median 10.0 [8.0–12.0] vs. 3.0 [range: 2.0–4.0], p < 0.001). Conclusions: These findings suggest that objective remission in the absence of subjective remission may not be adequate to improve subjective cognitive functioning.

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Comparison of emotional processing assessed with fear conditioning by interpersonal conflicts in patients with depression and schizophrenia

Tani H., Tada M., Maeda T., Konishi M., Umeda S., Terasawa Y., Mimura M., Takahashi T., Uchida H.

Psychiatry and Clinical Neurosciences （Psychiatry and Clinical Neurosciences） 73 （ 3 ） 116 - 125 2019年03月

ISSN 13231316

© 2018 The Authors. Psychiatry and Clinical Neurosciences © 2018 Japanese Society of Psychiatry and Neurology Aim: While emotional processing is implicated in various psychiatric illnesses, its differences among diagnoses are unclear. We compared associative learning of social values in patients with depression and schizophrenia by measuring skin conductance response to interpersonal stimuli. Methods: We included 20 female outpatients each with depression and schizophrenia. They underwent Pavlovian conditioning experiments in response to a classical aversive sound, and an interpersonal stimulus that was designed to cause aversive social conditioning with actors’ faces coupled with negative verbal messages. Multiple regression analysis was performed to examine the associations between the degree of conditioned response and the clinical characteristics of the participants. Results: Conditioned responses during the acquisition phase in both conditions were higher in depression compared to schizophrenia. Patients with depression successfully showed fear conditioning in both conditions, and they exhibited slower extinction in the interpersonal condition. The conditioned response during the extinction phase showed a positive association with Emotion Regulation Questionnaire Expressive Suppression score, and a negative association with the Emotion Regulation Questionnaire Cognitive Reappraisal score and the use of antidepressants. Patients with schizophrenia did not become conditioned in either of the conditions. The Positive and Negative Syndrome Scale Negative Syndrome score was negatively associated with the degree of conditioned response during the acquisition phase in the interpersonal condition. Conclusion: Female patients with schizophrenia, especially those who prominently demonstrated negative symptoms, suggested their intrinsic impairments in the associative learning of social context. Antidepressants and adaptive emotional regulation strategy may enhance the extinction learning of aversive social conditioning in depression.

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Electroconvulsive therapy modulates resting-state EEG oscillatory pattern and phase synchronization in nodes of the default mode network in patients with depressive disorder

Takamiya A., Hirano J., Yamagata B., Takei S., Kishimoto T., Mimura M.

Frontiers in Human Neuroscience （Frontiers in Human Neuroscience） 13 2019年02月

© 2019 Takamiya, Hirano, Yamagata, Takei, Kishimoto and Mimura. Introduction: Electroconvulsive therapy (ECT) has antidepressant effects, but it also has possible cognitive side effects. The effects of ECT on neuronal oscillatory pattern and phase synchronization, and the relationship between clinical response or cognitive change and electroencephalogram (EEG) measurements remain elusive. Methods: Individuals with unipolar depressive disorder receiving bilateral ECT were recruited. Five minutes of resting, eyes-closed, 19-lead EEG recordings were obtained before and after a course of ECT. Non-overlapping 60 artifact-free epocs of 2-s duration were used for the analyses. We used exact low resolution electromagnetic tomography (eLORETA) to compute the whole-brain three-dimensional intracortical distribution of current source density (CSD) and phase synchronization among 28 regions-of-interest (ROIs). Paired t-tests were used to identify cortical voxels and connectivities showing changes after ECT. Montgomery Asberg Depression Rating Scale (MADRS) and Mini-Mental State Examination (MMSE) were used to evaluate the severity of depression and the global cognitive function. Correlation analyses were conducted to identify the relationship between changes in the EEG measurements and changes in MADRS or MMSE. Results: Thirteen depressed patients (five females, mean age: 58.4 years old) were included. ECT increased theta CSD in the anterior cingulate cortex (ACC), and decreased beta CSD in the frontal pole (FP), and gamma CSD in the inferior parietal lobule (IPL). ECT increased theta phase synchronization between the posterior cingulate cortex (PCC) and the anterior frontal cortex, and decreased beta phase synchronization between the PCC and temporal regions. A decline in beta synchronization in the left hemisphere was associated with cognitive changes after ECT. Conclusion: ECT modulated resting-state EEG oscillatory patterns and phase synchronization in central nodes of the default mode network (DMN). Changes in beta synchronization in the left hemisphere might explain the ECT-related cognitive side effects.

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Placebo effects in adult and adolescent patients with schizophrenia: combined analysis of nine RCTs

Kubo K., Fleischhacker W.W., Suzuki T., Yasui-Furukori N., Mimura M., Uchida H.

Acta Psychiatrica Scandinavica （Acta Psychiatrica Scandinavica） 139 （ 2 ） 108 - 116 2019年02月

ISSN 0001690X

© 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd Objective: To examine characteristics of placebo responders and seek optimal criteria of early improvement with placebo for predicting subsequent placebo response in patients with schizophrenia. Method: Data of 672 patients with schizophrenia randomized to placebo in nine double-blind antipsychotic trials were analyzed. Multiple logistic regression analyses were conducted to examine associations between placebo response at week 6 (i.e., a ≥ 25% reduction in the Positive and Negative Syndrome Scale [PANSS] score) and gender, age, study locations, baseline PANSS total or Marder 5-Factor scores, and per cent PANSS score reduction at week 1. Predictive power of improvement at week 1 for subsequent response was investigated; sensitivity and specificity of incremental 5% cutoff points between 5% and 25% reduction in the PANSS total score at week 1 were calculated. Results: Per cent PANSS total score reduction at week 1 and lower PANSS Marder disorganized thought scores at baseline were significantly associated with subsequent placebo response. A 10% reduction in a per-protocol analysis or a 15% reduction in last-observation-carried-forward analysis in the PANSS total score at week 1 showed the highest predictive power. Conclusion: These findings are informative to identify potential placebo responders at the earliest opportunity for optimal trial design for schizophrenia.

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Suicide and microglia: Recent findings and future perspectives based on human studies

Suzuki H., Ohgidani M., Kuwano N., Chrétien F., Lorin de la Grandmaison G., Onaya M., Tominaga I., Setoyama D., Kang D., Mimura M., Kanba S., Kato T.A.

Frontiers in Cellular Neuroscience （Frontiers in Cellular Neuroscience） 13 1 - 10 2019年01月

ISSN 16625102

© 2019 Suzuki, Ohgidani, Kuwano, Chrétien, Lorin de la Grandmaison, Onaya, Tominaga, Setoyama, Kang, Mimura, Kanba and Kato. Suicide is one of the most disastrous outcomes for psychiatric disorders. Recent advances in biological psychiatry have suggested a positive relationship between some specific brain abnormalities and specific symptoms in psychiatric disorders whose organic bases were previously completely unknown. Microglia, immune cells in the brain, are regarded to play crucial roles in brain inflammation by releasing inflammatory mediators and are suggested to contribute to various psychiatric disorders such as depression and schizophrenia. Recently, activated microglia have been suggested to be one of the possible contributing cells to suicide and suicidal behaviors via various mechanisms especially including the tryptophan-kynurenine pathway. Animal model research focusing on psychiatric disorders has a long history, however, there are only limited animal models that can properly express psychiatric symptoms. In particular, to our knowledge, animal models of human suicidal behaviors have not been established. Suicide is believed to be limited to humans, therefore human subjects should be the targets of research despite various ethical and technical limitations. From this perspective, we introduce human biological studies focusing on suicide and microglia. We first present neuropathological studies using the human postmortem brain of suicide victims. Second, we show recent findings based on positron emission tomography (PET) imaging and peripheral blood biomarker analysis on living subjects with suicidal ideation and/or suicide-related behaviors especially focusing on the tryptophan-kynurenine pathway. Finally, we propose future perspectives and tasks to clarify the role of microglia in suicide using multi-dimensional analytical methods focusing on human subjects with suicidal ideation, suicide-related behaviors and suicide victims.

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Effectiveness of the prefrontal repetitive transcranial magnetic stimulation on cognitive profiles in depression, schizophrenia, and Alzheimer's disease: A systematic review

Iimori T., Nakajima S., Miyazaki T., Tarumi R., Ogyu K., Wada M., Tsugawa S., Masuda F., Daskalakis Z., Blumberger D., Mimura M., Noda Y.

Progress in Neuro-Psychopharmacology and Biological Psychiatry （Progress in Neuro-Psychopharmacology and Biological Psychiatry） 88 31 - 40 2019年01月

ISSN 02785846

© 2018 Elsevier Inc. Repetitive transcranial magnetic stimulation (rTMS) is an effective clinical intervention for various neuropsychiatric diseases. However, it is still unclear whether rTMS has an effect on cognitive functioning. In this review, we aimed to systematically evaluate the cognitive effects of rTMS in depression, schizophrenia, and Alzheimer's disease. We searched PubMed (1996–2018) under the set terms to review randomized controlled trials (RCT) to examine the effectiveness of rTMS administered to the dorsolateral prefrontal cortex (DLPFC) and evaluated cognitive functions in patients with depression, schizophrenia, and Alzheimer's disease. Two authors reviewed each article and came to consensus on the inclusion and exclusion criteria. All eligible studies were reviewed, duplicates were removed, and data were extracted individually. The search identified 579 articles, 31 of which met inclusion and exclusion criteria. Among them, 15 were conducted in patients with depression, 11 in patients with schizophrenia, and 5 in patients with Alzheimer's disease. Specifically, 6 studies demonstrated a significant improvement of executive function across these diseases. Further, no evidence for cognitive adverse effects was found in these included rTMS studies. Although the heterogeneity between studies in terms of cognitive measures applied, stimulation parameters, and participants limits the ability to generalize conclusions, this review demonstrated that prefrontal rTMS could exert pro-cognitive effects on executive function and attention in some patients with depression but inconsistent cognitive impacts in any of the examined domains especially in patients with schizophrenia and Alzheimer's disease. The results warrant further rTMS studies that include systematic assessment of cognition across various neuropsychiatric diseases.

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The association between midlife serum high-density lipoprotein and mild cognitive impairment and dementia after 19 years of follow-up

Svensson T., Sawada N., Mimura M., Nozaki S., Shikimoto R., Tsugane S.

Translational Psychiatry （Translational Psychiatry） 9 （ 1 ） 2019年01月

© 2019, The Author(s). A third of dementia cases could be attributable to modifiable risk-factors. Midlife high-density lipoprotein cholesterol (HDL-C) is a measure which could help identify individuals at reduced risk of developing age-related cognitive decline. The Japan Public Health Centre-based prospective (JPHC) Study is a large population-based cohort which started in 1990. This study included 1299 participants from Saku area in Nagano prefecture. Participants had HDL-C measured in 1995–1996, and underwent a mental health screening in 2014–2015. Of these, 1114 participants were included in MCI analyses, and 781 participants were included in dementia analyses. Logistic regression models were used to determine odds ratios (OR) and 95% confidence intervals (CI) for the association between HDL-C quartiles and MCI and dementia, respectively. For dementia analysis, quartiles 2–4 were collapsed due to low number of cases. Missing data was addressed through multiple imputations. There were 386 cases of MCI and 53 cases of dementia. Compared to the lowest HDL-C quartile, the highest HDL-C quartile was significantly inversely associated with MCI (OR = 0.47, 95% CI, 0.28–0.79) in the multivariable analysis. High HDL-C (quartiles 2–4) was inversely associated with dementia compared to low HDL-C (quartile 1) (OR = 0.37, 95% CI, 0.16–0.88). This study has found that high midlife HDL-C levels are inversely associated with both late-life MCI and dementia in a Japanese population.

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Early placebo improvement is a marker for subsequent placebo response in long-acting injectable antipsychotic trials for schizophrenia: Combined analysis of 4 RCTs

Kumagai F., Suzuki T., Fleischhacker W., Yasui-Furukori N., Mimura M., Uchida H.

Journal of Clinical Psychiatry （Journal of Clinical Psychiatry） 80 （ 1 ） 2019年01月

ISSN 01606689

© Copyright 2018 Physicians Postgraduate Press, Inc. Objective: Placebo effects remain largely unexplored in clinical trials of long-acting injectable (LAI) antipsychotics for schizophrenia. This study aims to characterize patients showing improvements after placebo injections and to search for criteria for the prediction of subsequent response based on the magnitude of score changes after the first week of treatment. Methods: Data from 450 patients with schizophrenia (DSM-IV) who received placebo injections in 4 double-blind randomized controlled trials evaluating efficacy of LAI paliperidone palmitate obtained through the Yale University Open Data Access (YODA) project were analyzed. These 4 studies were conducted from October 2003 to March 2008. Multiple logistic regression analyses were conducted to examine associations between placebo response and demographic and clinical characteristics. The predictive power of improvement at week 1 for response at week 9 was investigated; sensitivity and specificity of incremental 5% cutoff points between a 5% and 25% reduction in Positive and Negative Syndrome Scale (PANSS) total score at week 1 were calculated. Results: Percent reduction in the PANSS total score at week 1 and a lower PANSS G12 item score (ie, better in judgment and insight) at baseline were significantly associated with placebo response at week 9 (odds ratio [OR] = 1.063; 95% CI, 1.040-1.087, P < .001; and OR= 0.739; 95% CI, 0.553-0.986, P = .040, respectively, in the per-protocol analysis). Cutoffs of a 10% (accuracy = 0.724 in the per-protocol analysis) and 15% (accuracy = 0.722 in the last-observation-carried-forward analysis) reduction in the PANSS total score at week 1 showed the highest predictive power. Conclusions: The appreciation that longer-term response following placebo injections can be predicted by a 10%-15% PANSS total score reduction at week 1 could guide the design of future clinical trials of LAI antipsychotics in schizophrenia to identify and exclude potential placebo responders early during the course of the study.

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Regional brain volume reductions in major depressive disorder and bipolar disorder: An analysis by voxel-based morphometry

Niida R., Yamagata B., Matsuda H., Niida A., Uechi A., Kito S., Mimura M.

International Journal of Geriatric Psychiatry （International Journal of Geriatric Psychiatry） 34 （ 1 ） 186 - 192 2019年01月

ISSN 08856230

© 2018 John Wiley & Sons, Ltd. Objectives: The present study investigated the usefulness of evaluating the existence of volume reduction in brain regions using voxel-based morphometry (VBM) to dissociate major depressive disorder (MDD) from bipolar disorder (BD). Methods/Design: This study enrolled 92 individuals with MDD, 32 individuals with BD, and 43 healthy controls (HCs). We focused on gray matter volume (GMV) of the subgenual anterior cingulate cortex (sgACC), subcallosal area (SCA), and hippocampus. The degree of volume reduction in these brain regions was calculated as the z score, and the differences of z scores in these regions were investigated among the MDD, BD, and HC groups. We then performed a receiver operating characteristic curve analysis to dissociate the individuals with MDD and BD from the HCs based on the z scores in the GMV of these brain regions. Results: While there were no significant differences in the z scores of the hippocampus among the three groups, the z score of the sgACC was significantly higher in the MDD group than in the BD and HC groups, and the SCA z score was significantly higher in the MDD and BD groups than in the HC group. Conclusions: Our findings suggest that VBM evaluation of GMV reduction in the sgACC may be useful as an objective adjunctive tool to distinguish between MDD and BD.

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Dysconnectivity of the agency network in schizophrenia: A functional magnetic resonance imaging study

Koreki A., Maeda T., Okimura T., Terasawa Y., Kikuchi T., Umeda S., Nishikata S., Yagihashi T., Kasahara M., Nagai C., Moriyama Y., Den R., Watanabe T., Kikumoto H., Kato M., Mimura M.

Frontiers in Psychiatry （Frontiers in Psychiatry） 10 （ APR ） 2019年

Copyright © 2019 Koreki, Maeda, Okimura, Terasawa, Kikuchi, Umeda, Nishikata, Yagihashi, Kasahara, Nagai, Moriyama, Den, Watanabe, Kikumoto, Kato and Mimura. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. Background: Self-disturbances in schizophrenia have recently been explained by an abnormality in the sense of agency (SoA). The cerebral structures of SoA in healthy people are considered to mainly include the insula and inferior parietal lobule. In contrast, the functional lesion of aberrant SoA in schizophrenia is not yet fully understood. Considering the recent explanation of establishing SoA from the standpoint of associative learning, the “agency network” may include not only the insula and inferior parietal lobule but also the striatum. We hypothesized that aberrant SoA in schizophrenia is based on a deficit in the “agency network.” Methods: Functional magnetic resonance imaging data were acquired while patients with schizophrenia (n = 15) and matched controls (n = 15) performed our adaptation method of agency attribution task on a trial-by-trial basis to assess participants' explicit experience of the temporal causal relationship between an action and an external event with temporal biases. Analysis of functional connectivity was done using the right supramarginal gyrus and the right middle frontal gyrus as seed regions. Results: In healthy controls, analyses revealed increased activation of the right inferior parietal lobule (mainly the supramarginal gyrus), right insula, and right middle frontal gyrus as an activation of the agency condition. We defined activated Brodmann areas shown in the agency condition of healthy controls as the seed region for connectivity analysis. The connectivity analysis revealed lower connectivity between the head of the left caudate nucleus and right supramarginal gyrus in the patients compared to healthy controls. Conclusions: This dysconnectivity of the agency network in schizophrenia may lead to self-disturbance through deficits in associative learning of SoA. These findings may explain why pathological function of the striatum in schizophrenia leads to self-disturbance.

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Frontopolar cortex activation associated with pessimistic future-thinking in adults with major depressive disorder

Katayama N., Nakagawa A., Umeda S., Terasawa Y., Kurata C., Tabuchi H., Kikuchi T., Mimura M.

NeuroImage: Clinical （NeuroImage: Clinical） 23 2019年

© 2019 The Author(s) Background: Pessimistic thinking about the future is one of the cardinal symptoms of major depressive disorder (MDD) and is an important domain of cognitive functioning associated with hopelessness. Neuroimaging studies have shown that the frontopolar cortex (Brodmann area [BA] 10) is involved in thinking about the future and demonstrated that patients with MDD have dysfunctions in BA10. However, the relationship between pessimistic thinking about the future and brain activity is unclear. Hence, we aimed to compare brain activity during future-thinking between patients with MDD and healthy individuals. Methods: We assessed 23 patients with current MDD and 23 healthy individuals. Participants were instructed to imagine the future or to recall the past using the future-thinking paradigm with four distinct temporal conditions (distant future, near future, distant past, and near past) during functional MRI. Resting-state functional MRI was also performed to explore the functional connectivity of BA10. Results: Compared with healthy individuals, patients with MDD had greater negative thinking about the distant future and exhibited increased activation in the medial BA10 when imagining the distant future, following small-volume correction focusing on the frontopolar a priori region of interest (family-wise error correction p < 0.05). Increased positive functional correlation between the right BA10 seed region and the posterior cingulate cortex was also observed. Conclusion: Patients with MDD who show greater pessimistic thinking about the distant future demonstrate increased activation in the frontopolar cortex. These findings are consistent with the hypothesis that frontopolar cortical dysfunction plays a key role in the hopelessness that manifests in patients with MDD.

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Shortened Measurement Time of Functional Visual Acuity for Screening Visual Function

Hidaka Y., Masui S., Nishi Y., Ayaki M., Kaido M., Mimura M., Tsubota K., Negishi K.

Journal of Ophthalmology （Journal of Ophthalmology） 2019 2019年

ISSN 2090004X

© 2019 Yuki Hidaka et al. The functional visual acuity test which is the average of the visual acuities measured during a specific time frame (standard, 60 seconds) has been used recently to assess the visual function in various conditions. The availability of a shorter version of the functional visual acuity test promises to be patient friendly in that it is a simple screening test performed in a shorter period of time than the standard test. The results of measurements of the FVA test between the 30-second measurement time (short-version FVA test) and the standard 60-second measurement are compared, and the feasibility of the short-version FVA test instead of the standard FVA test is investigated. Twenty-eight healthy volunteers (25 men and 3 women) were enrolled in this prospective observational study. All subjects underwent measurement of the binocular distance-corrected visual acuity and the binocular distance-corrected FVA with the 60-second and 30-second measurement times. The interchangeability of the corrected-distance FVA, maximal VA, visual maintenance ratio, and average response time in the short-version and the standard FVA tests was evaluated using the Bland-Altman method, and the results showed agreements of the two tests except for the minimal VA. The short-version FVA test is equivalent to the standard method except for evaluating the visual acuity fluctuations and promises to be a simple visual screening test that can be performed in a shorter time.

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Role-play-based guidance for job interviews using an android robot for individuals with autism spectrum disorders

Kumazaki H., Muramatsu T., Yoshikawa Y., Matsumoto Y., Ishiguro H., Mimura M., Kikuchi M.

Frontiers in Psychiatry （Frontiers in Psychiatry） 10 （ APR ） 2019年

© 2019 Kumazaki, Muramatsu, Yoshikawa, Matsumoto, Ishiguro, Mimura and Kikuchi. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. Interventions for job interviews targeting the impaired theory of mind observed in individuals with autism spectrum disorders (ASD) are limited. We developed a role-play-based guidance system for job interviews using an android robot resembling a real person. Individuals with ASD worked in pairs and played dual roles in mock job interviews. Specifically, one participant acted as the interviewee, while the other participant operated the android robot and acted as the interviewer. Eight individuals with high-functioning ASD participated in this study. After the training sessions, participants learned to understand the point of view of the interviewer, which may contribute to increased recognition of the importance of gestures and the motivation to learn how to behave in a job interview. In addition, participants reported improved self-confidence. These results provide preliminary support for the efficacy of playing dual roles using android robots.

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Relationships between internet addiction and clinicodemographic and behavioral factors

ElSalhy M., Miyazaki T., Noda Y., Nakajima S., Nakayama H., Mihara S., Kitayuguchi T., Higuchi S., Muramatsu T., Mimura M.

Neuropsychiatric Disease and Treatment （Neuropsychiatric Disease and Treatment） 15 739 - 752 2019年

ISSN 11766328

© 2019 ElSalhy et al. Backgrounds and aims: While the Internet became an indispensable component of our contemporary life, public and academic attention is also gathered to its negative impact, namely Internet addiction (IA). Although clinicodemographic and behavioral factors are hypothetically implicated in the mechanism of IA, it still remains largely unknown how such factors are linked to IA severity. Thus, this study sought to examine relationships among IA severity and factors potentially associated with IA in Japanese students in different educational stages. Methods: We conducted a questionnaire-based survey, which included questions about types of online activities and clinicodemographic information, the IA test for IA severity, and the K6 scale for psychological distress in 3,224 students at elementary, junior, and senior high schools, and universities. A multiple regression analysis was performed to predict IA severity with clinicodemographic and behavioral factors. Results: IA severity was significantly positively related to the following factors: e-messaging, social networking services (SNS), games, holiday Internet usage, and K6 scores, while IA severity had negative correlation with using Internet for educational purposes, age of first exposure to the Internet, and sleep duration. Age was not related to IA severity among participants using both SNS and e-messaging. Conclusions: IA was linked to various online activities and the degree of psychological distress. This indicates the importance of comprehensive assessment of online behavior and psychological factors for further understanding of IA.

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PET-detectable tau pathology correlates with long-term neuropsychiatric outcomes in patients with traumatic brain injury

Takahata K., Kimura Y., Sahara N., Koga S., Shimada H., Ichise M., Saito F., Moriguchi S., Kitamura S., Kubota M., Umeda S., Niwa F., Mizushima J., Morimoto Y., Funayama M., Tabuchi H., Bieniek K.F., Kawamura K., Zhang M.R., Dickson D.W., Mimura M., Kato M., Suhara T., Higuchi M.

Brain （Brain） 142 （ 10 ） 3265 - 3279 2019年

ISSN 00068950

© The Author(s) (2019). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. Tau deposits is a core feature of neurodegenerative disorder following traumatic brain injury (TBI). Despite ample evidence from post-mortem studies demonstrating exposure to both mild-repetitive and severe TBIs are linked to tau depositions, associations of topology of tau lesions with late-onset psychiatric symptoms due to TBI have not been explored. To address this issue, we assessed tau deposits in long-term survivors of TBI by PET with 11C-PBB3, and evaluated those associations with late-life neuropsychiatric outcomes. PET data were acquired from 27 subjects in the chronic stage following mild-repetitive or severe TBI and 15 healthy control subjects. Among the TBI patients, 14 were diagnosed as having late-onset symptoms based on the criteria of traumatic encephalopathy syndrome. For quantification of tau burden in TBI brains, we calculated 11C-PBB3 binding capacity (cm3), which is a summed voxel value of binding potentials (BP*ND) multiplied by voxel volume. Main outcomes of the present study were differences in 11C-PBB3 binding capacity between groups, and the association of regional 11C-PBB3 binding capacity with neuropsychiatric symptoms. To confirm 11C-PBB3 binding to tau deposits in TBI brains, we conducted in vitro PBB3 fluorescence and phospho-tau antibody immunofluorescence labelling of brain sections of chronic traumatic encephalopathy obtained from the Brain Bank. Our results showed that patients with TBI had higher 11C-PBB3 binding capacities in the neocortical grey and white matter segments than healthy control subjects. Furthermore, TBI patients with traumatic encephalopathy syndrome showed higher 11C-PBB3 binding capacity in the white matter segment than those without traumatic encephalopathy syndrome, and regional assessments revealed that subgroup difference was also significant in the frontal white matter. 11C-PBB3 binding capacity in the white matter segment correlated with the severity of psychosis. In vitro assays demonstrated PBB3-positive tau inclusions at the depth of neocortical sulci, confirming 11C-PBB3 binding to tau lesions. In conclusion, increased 11C-PBB3 binding capacity is associated with late-onset neuropsychiatric symptoms following TBI, and a close correlation was found between psychosis and 11C-PBB3 binding capacity in the white matter.

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Kampo, A Japanese Traditional Medicinal System for Psychiatric Conditions: A Narrative Review

Tatsumi L., Suzuki T., Yamada K., Mimura M., Uchida H.

Pharmacopsychiatry （Pharmacopsychiatry） 52 （ 6 ） 251 - 260 2019年

ISSN 01763679

© 2019 Royal Society of Chemistry. All rights reserved. Introduction Kampo is a Japanese traditional medicinal system and is represented by unity of mind and body. It is originally based upon Chinese traditional medicine but has uniquely developed in Japan. Methods A narrative review on the use of Kampo for psychiatric conditions is provided. Results Kampo formula is a combination of several crude ingredients; most derive from natural plants and some from animals and minerals. These Kampo formulae are widely prescribed in almost all medical disciplines, including psychiatry, in Japan; they have been used for various psychiatric disorders such as dementia, schizophrenia spectrum disorders, mood disorders, anxiety disorders, and personality disorders. Kampo is a versatile traditional medicine with a variety of positive effects on mental states with relatively benign side effect profiles. Kampo formulae can be adjunctively combined with or substituted for the Western psychotropic drugs, which will provide more treatment options to patients with psychiatric conditions. Discussion This review summarizes the current knowledge on Kampo for psychiatric conditions, highlighting a paucity of data and a need for further good-quality evidence on these medications.

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In vitro modeling of the bipolar disorder and schizophrenia using patient-derived induced pluripotent stem cells with copy number variations of PCDH15 and RELN

Ishii T., Ishikawa M., Fujimori K., Maeda T., Kushima I., Arioka Y., Mori D., Nakatake Y., Yamagata B., Nio S., Kato T.A., Yang N., Wernig M., Kanba S., Mimura M., Ozaki N., Okano H.

eNeuro （eNeuro） 6 （ 5 ） 2019年

© 2019 Ishii et al. (Figure Presented) Bipolar disorder (BP) and schizophrenia (SCZ) are major psychiatric disorders, but the molecular mechanisms underlying the complicated pathologies of these disorders remain unclear. It is difficult to establish adequate in vitro models for pathological analysis because of the heterogeneity of these disorders. In the present study, to recapitulate the pathologies of these disorders in vitro, we established in vitro models by differentiating mature neurons from human induced pluripotent stem cells (hiPSCs) derived from BP and SCZ patient with contributive copy number variations, as follows: two BP patients with PCDH15 deletion and one SCZ patient with RELN deletion. Glutamatergic neurons and GABAergic neurons were induced from hiPSCs under optimized conditions. Both types of induced neurons from both hiPSCs exhibited similar phenotypes of MAP2 (microtubule-associated protein 2)-positive dendrite shortening and decreasing synapse numbers. Additionally, we analyzed isogenic PCDH15-or RELN-deleted cells. The dendrite and synapse phenotypes of isogenic neurons were partially similar to those of patient-derived neurons. These results suggest that the observed phenotypes are general phenotypes of psychiatric disorders, and our in vitro models using hiPSC-based technology may be suitable for analysis of the pathologies of psychiatric disorders.

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How the realism of robot is needed for individuals with autism spectrum disorders in an interview setting

Kumazaki H., Muramatsu T., Yoshikawa Y., Matsumoto Y., Miyao M., Ishiguro H., Mimura M., Minabe Y., Kikuchi M.

Frontiers in Psychiatry （Frontiers in Psychiatry） 10 （ JULY ） 2019年

Copyright © 2019 Kumazaki, Muramatsu, Yoshikawa, Matsumoto, Miyao, Ishiguro, Mimura, Minabe and Kikuchi. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. The preliminary efficacy of interview training using an android robot whose appearance and movements resemble those of an actual human for treating social and communication difficulties in individuals with autism spectrum disorders (ASD) has been demonstrated. Patient preferences regarding the appearance of robots are crucial for incentivizing them to undergo robot-assisted therapy. However, very little is known about how the realistic nature of an android robot is related to incentivizing individuals with ASD in an interview setting. In this study, individuals with ASD underwent an interview with a human interviewer and an android robot. Twenty-three individuals with ASD (age, 17-25 years) participated in this study. After the interview, the participants were evaluated in terms of their motivation to practice an interview with an android robot and their impression of the nature of the android robot in terms of humanness. As expected, subjects exhibited higher motivation to undergo interview training with an android robot than with a human interviewer. Higher motivation to undergo an interview with the android robot was negatively correlated with the participants' impressions of the extent to which the android robot exhibited humanness. This study brings us one step closer to understanding how such an android robot should be designed and implemented to provide sufficiently realistic interview training that can be of therapeutic value.

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Assessing cortical plasticity after spinal cord injury by using resting-state functional magnetic resonance imaging in awake adult mice

Matsubayashi K., Nagoshi N., Komaki Y., Kojima K., Shinozaki M., Tsuji O., Iwanami A., Ishihara R., Takata N., Matsumoto M., Mimura M., Okano H., Nakamura M.

Scientific Reports （Scientific Reports） 8 （ 1 ） 2018年12月

© 2018, The Author(s). Neural connectivity has recently been shown to be altered after spinal cord injury (SCI) not only in the spinal cord but also in the brain. However, to date, no studies have analyzed the functional alterations after SCI in various areas of the cerebral cortex over time. To examine the plasticity of the neural connectivity in the brain after SCI, we performed resting-state functional magnetic resonance imaging (rs-fMRI) in awake adult mice pre- and post-SCI. After a complete thoracic SCI, the functional connectivity between the primary motor (MOp) and primary sensory (SSp) areas was significantly decreased during the chronic phase. In contrast, the connectivity between the MOp and motivation area was increased. Thus, impairments in sensory and motor connections after SCI led to a time-dependent compensatory upregulation of “motor functional motivation”. Moreover, the functional connectivity between the SSp and pain-related areas, such as the caudoputamen (CP) and the anterior cingulate area (ACA), was strengthened during the chronic phase, thus suggesting that rs-fMRI can indicate the presence of neuropathic pain after SCI. Therefore, rs-fMRI is a useful tool for revealing the pathological changes that occur in the brain after SCI.

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Clinical characteristics of patients with schizophrenia who successfully discontinued antipsychotics: A literature review

Tani H., Suzuki T., Wolfgang Fleischhacker W., Tomita M., Mimura M., Uchida H.

Journal of Clinical Psychopharmacology （Journal of Clinical Psychopharmacology） 38 （ 6 ） 582 - 589 2018年12月

ISSN 02710749

© Wolters Kluwer Health, Inc. All rights reserved. Purpose/Background Although discontinuing antipsychotics clearly increases the risk of relapse in schizophrenia, some patients remain clinically well without continuous antipsychotic treatment. However, data on the characteristics of such patients are still scarce. Methods/Procedures A systematic literature review was conducted to identify predictive factors for successful antipsychotic discontinuation in schizophrenia using PubMed (last search; June 2018) with the following search terms: (antipsychotic∗ or neuroleptic) AND (withdraw∗ or cessat∗ or terminat∗ or discontinu∗) AND (schizophreni∗ or psychosis). The search was filtered with humans and English. Factors associated with a lower risk of relapse, when replicated in 2 or more studies with a follow-up period of 3 months or longer, were considered successful. Findings/Results Systematic literature search identified 37 relevant articles. Mean relapse rate after antipsychotic discontinuation was 38.3% (95% confidence interval = 16.0%-60.6%) per year. Factors associated with a lower risk of relapse were being maintained on a lower antipsychotic dose before discontinuation, older age, shorter duration of untreated psychosis, older age at the onset of illness, a lower severity of positive symptoms at baseline, better social functioning, and a lower number of previous relapses. Implications/Conclusions Although this literature review suggests some predictors for successful antipsychotic withdrawal in patients with schizophrenia, the very limited evidence base and unequivocally high relapse rates after discontinuation must remain a matter of serious debate for risk/benefit considerations.

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Visualization of myelinated fiber bundles orientation during brain slice preparation by reflection polarized light microscopy

Takata N., Kusayanagi K., Maruyama H., Eitai K., Abo M., Akiyama F., Tajima R., Inaba S., Tanaka K., Mimura M., Sanaka K.

Microscopy Research and Technique （Microscopy Research and Technique） 81 （ 12 ） 1366 - 1373 2018年12月

ISSN 1059910X

© 2018 Wiley Periodicals, Inc. Polarized light imaging (PLI) enables detecting the orientation of myelinated axon bundles in brain slices at microscopic resolution without histological staining. However, standard PLI requires labor-intensive procedures such as mounting brain cryosections on slide glasses. We developed an optical system that does not require a mounting procedure for PLI. Specifically, we developed an optical system to perform PLI in reflection mode (rPLI) instead of employing transmitted light as in standard PLI. We integrated this rPLI system with a conventional vibratome slicer whose cutting blade surface is a mirror. This combination allowed PLI measurements directly during the slicing procedure at room temperature. Thus, mounting procedure for PLI is not necessary. As a proof-of-concept experiment, a perfusion-fixed brain of a mouse was embedded in gelatin-containing agar and cut serially at 40~200 μm intervals. The slicing procedure was temporarily halted after each cut to capture the PLI images of the slice on the reflecting blade surface while the slice was still held up by the agar block. The orientation of the fiber bundle estimated with this method agreed with the results obtained from previous reports. Combination of a popular vibratome slicer and our rPLI system that uses versatile and inexpensive optical components would increase popularity of PLI and facilitates connectome studies at microscopic resolution. Research Highlights: Polarized light imaging (PLI) of brain slices was realized by using reflected light (rPLI) instead of transmitted light. The rPLI method allows detecting the myelinated fiber bundle orientation during slice preparation.

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Altered perception might be a symptom of anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis

Funayama M., Mizushima J., Takata T., Koreki A., Mimura M.

Neurocase （Neurocase） 24 （ 5-6 ） 255 - 258 2018年11月

ISSN 13554794

© 2019, © 2019 Informa UK Limited, trading as Taylor & Francis Group. Most patients with N-methyl-D-aspartate receptor (NMDAR) encephalitis initially present with psychiatric symptoms. Although a delayed diagnosis may lead to a poor outcome, psychiatric symptoms that could differentiate anti-NMDAR encephalitis from other psychoses have not been fully investigated. We evaluated two patients with anti-NMDAR encephalitis who were observed by psychiatrists from onset throughout the course of disease. Both patients exhibited disorientation, memory deficits, perceptual disturbances, hallucinations, and mood liability. Among those, altered perceptions were most prominent - in particular, altered time perceptions without disorganization syndrome. The information obtained for these patients may help clinicians differentiate anti-NMDAR encephalitis from other psychoses, e.g., schizophrenia.

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Utilization of Facial Image Analysis Technology for Blink Detection: A Validation Study

Kitazawa M., Yoshimura M., Liang K.C., Wada S., Mimura M., Tsubota K., Kishimoto T.

Eye & contact lens （Eye & contact lens） 44 S297 - S301 2018年11月

PURPOSE: The assessment of anterior eye diseases and the understanding of psychological functions of blinking can benefit greatly from a validated blinking detection technology. In this work, we proposed an algorithm based on facial recognition built on current video processing technologies to automatically filter and analyze blinking movements. We compared electrooculography (EOG), the gold standard of blinking measurement, with manual video tape recording counting (mVTRc) and our proposed automated video tape recording analysis (aVTRa) in both static and dynamic conditions to validate our aVTRa method. METHODS: We measured blinking in both static condition, where the subject was sitting still with chin fixed on the table, and dynamic condition, where the subject's face was not fixed and natural communication was taking place between the subject and interviewer. We defined concordance of blinks between measurement methods as having less than 50 ms difference between eyes opening and closing. RESULTS: The subjects consisted of seven healthy Japanese volunteers (3 male, four female) without significant eye disease with average age of 31.4±7.2. The concordance of EOG vs. aVTRa, EOG vs. mVTRc, and aVTRa vs. mVTRc (average±SD) were found to be 92.2±10.8%, 85.0±16.5%, and 99.6±1.0% in static conditions and 32.6±31.0%, 28.0±24.2%, and 98.5±2.7% in dynamic conditions, respectively. CONCLUSIONS: In static conditions, we have found a high blink concordance rate between the proposed aVTRa versus EOG, and confirmed the validity of aVTRa in both static and dynamic conditions.

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Detailed analysis of the Japanese version of the Rapid Dementia Screening Test using Arabic-hiragana conversion

Moriyama Y., Yoshino A., Muramatsu T., Mimura M.

Psychogeriatrics （Psychogeriatrics） 18 （ 6 ） 446 - 450 2018年11月

ISSN 13463500

© 2018 Japanese Psychogeriatric Society Aim: The number-transcoding task on the Japanese version of the Rapid Dementia Screening Test (RDST-J) requires conversion between Arabic and Chinese numerals (209 to 二百九, 4054 to 四千五十四, 六百八十一 to 681, 二千二十七 to 2027). In this task, questions and answers are written for Chinese-Arabic conversion. We reported that the RDST-J could distinguish subjects with Alzheimer's disease with a Clinical Dementia Rating Scale score of 0.5 from controls. In this study, we investigated the impact of changing the task to a hiragana-Arabic conversion. Methods: Participants consisted of 45 patients with a Clinical Dementia Rating Scale score of 0.5 and 52 normal controls. Results: The sensitivity and specificity of total scores ≥9 on the two RDST-J versions for discriminating subjects with a Clinical Dementia Rating Scale score of 0.5 from controls were 73.1% and 75.5%, respectively, on the original version, and 71.8% and 73.0%, respectively, on the revised version. Conclusions: The sensitivity and specificity of the revised version of the RDST-J was equivalent to those of the original version.

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Sleep disorders are a prevalent and serious comorbidity in dry eye

Ayaki M., Tsubota K., Kawashima M., Kishimoto T., Mimura M., Negishi K.

Investigative Ophthalmology and Visual Science （Investigative Ophthalmology and Visual Science） 59 （ 14 Special Issue ） DES143 - DES150 2018年11月

ISSN 01460404

© 2018 The Authors. PURPOSE. Sleep is an essential life habit and closely associated with lifespan, diabetes, hypertension, and mental health. Sleep disorders are a prominent, but overlooked problem in patients with dry eye disease (DED), characterized by a poor sleep index, short sleep duration, long sleep latency, and poor subjective sleep. DED and sleep disorders are more prevalent in women than men. Moreover, sleep quality in DED is worse than in other eye diseases, including glaucoma, retinal diseases, cataract, and allergic and chronic conjunctivitis. METHODS. We reviewed the literature for studies investigating sleep and health, eyes and sleep, and DED and sleep, in terms of systemic and eye health, especially in women. RESULTS. Two studies reported that approximately half of patients with DED suffer from poor sleep. The severity of mood disorders, including anxiety and depression, is correlated strongly with sleep disorders in DED, and the symptoms and signs of DED, especially pain, also are correlated with sleep quality. Sleep disorders are documented in primary Sjögren’s syndrome and an association with sleep apnea and depression is suggested. Primary Sjögren’s syndrome includes arthritis and other rheumatic disease causing pain and fatigue; however, how sicca contributes to sleep disorders is not known. CONCLUSIONS. Possible explanations for sleep disorders in DED may be depression, pain, and eye exposure at night. Reciprocal effects may be expected and consultation-liaison psychiatry is recommended for the management of sleep disorders in DED. Topical medication and lid heating also may be advantageous for sleep quality in DED.

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The estimated cost of dementia in Japan, the most aged society in the world

Sado M., Ninomiya A., Shikimoto R., Ikeda B., Baba T., Yoshimura K., Mimura M.

PLoS ONE （PLoS ONE） 13 （ 11 ） 2018年11月

© 2018 Sado et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Objective Dementia has become a global critical issue. It is estimated that the global cost of dementia was 818 billion USD in 2015. The situation in Japan, which is the most aged country in the world, should be critical. However, the societal cost of dementia in Japan has not yet been estimated. This study was designed to estimate cost of dementia from societal perspective. Design We estimated the cost from societal perspective with prevalence based approach. Setting, participants and measures Main data sources for the parameters to estimate the costs are the National Data Base, a nationwide representative individual-level database for healthcare utilization, the Survey of Long-Term Care Benefit Expenditures, a nationwide survey based on individual-level secondary data for formal long-term care utilization, and the results of an informal care time survey for informal care cost. We conducted the analyses with ‘probabilistic modeling’ using the parameters obtained to estimate the costs of dementia. We also projected future costs. Results The societal costs of dementia in Japan in 2014 were estimated at JPY 14.5 trillion (se 66.0 billion). Of these, the costs for healthcare, long-term care, and informal care are JPY 1.91 trillion (se 4.91 billion), JPY 6.44 trillion (se 63.2 billion), and JPY 6.16 trillion (se 12.5 billion) respectively. The cost per person with dementia appeared to be JPY5.95 million (se 27 thousand). The total costs would reach JPY 24.3 trillion by 2060, which is 1.6 times higher than that in 2014. Conclusions The societal cost of dementia in Japan appeared to be considerable. Interventions to mitigate this impact should be considered.

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The relationship of dry eye disease with depression and anxiety: A naturalistic observational study

Kitazawa M., Sakamoto C., Yoshimura M., Kawashima M., Inoue S., Mimura M., Tsubota K., Negishi K., Kishimoto T.

Translational Vision Science and Technology （Translational Vision Science and Technology） 7 （ 6 ） 2018年11月

© 2018 The Authors. Purpose: In recent years, the relationship between dry eye disease (DED) and psychiatric disorders has been gaining attention. The relationship between dry eye symptoms and psychiatric symptoms has been reported in multiple retrospective studies. However, in previous studies there have been limitations to these observations, such as a lack of close examination of either DED or mood symptoms. Methods: In this study, we evaluated the psychological state and social functionality of DED patients by administering validated psychiatric tests as well as ophthalmologic examinations twice during the course of DED treatment. Forty subjects (61.3 ± 18.1-years old) received the primary psychiatric assessments and 26 received the secondary psychiatric assessments. Results: In a cross-sectional examination, we found patients with depressive and/or anxiety symptoms had higher Dry Eye Related Quality of Life Score (DEQ) scores, whereas the objective symptoms of DED did not differ between groups. We also found a positive relationship between depression/anxiety scores and DED subjective symptoms. On the other hand, in longitudinal examination, we found psychiatric symptoms had no impact on subjective and objective DED symptoms throughout the course of DED symptoms. Conclusions: We found depression and anxiety were related to the subjective symptoms of DED but not the objective symptoms. Translational Relevance: It is important to pay attention to psychiatric symptoms in patients with DED and an investigation into appropriate treatment strategies for patients with DED in combination with psychiatric symptoms is needed in the future.

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Aberrant anterior thalamic radiation structure in bipolar disorder: A diffusion tensor tractography study

Niida R., Yamagata B., Niida A., Uechi A., Matsuda H., Mimura M.

Frontiers in Psychiatry （Frontiers in Psychiatry） 9 2018年10月

© 2018 Niida, Yamagata, Niida, Uechi, Matsuda and Mimura. Disrupted white matter (WM) integrity in the anterior thalamic radiation (ATR) has been identified in individuals with bipolar disorder (BD). We explored whether structural WM aberration in the ATR could be visually evaluated by diffusion tensor tractography (DTT). The study comprised 114 participants, including 57 patients with BD and 57 healthy controls (HCs). A poorly visualized ATR reflects an abnormal WM structure. We defined a poorly visualized ATR as one in which at least one ATR fiber bundle failed to reach to the boundary between gray and white matter. Poor ATR visualization occurred significantly more frequently in the left ATR of those with BD than in HCs (P = 0.042). Furthermore, we adjusted the fractional anisotropy (FA) value and when evaluation of a given ATR changed from good to poor, we defined that value as the optimal FA threshold. In the right ATR, we successfully classified BD and HCs with 71.1% accuracy (sensitivity = 89.5% and specificity = 52.6%) and an area under the curve of 0.76 using the optimal FA threshold of 0.28. The present results suggest that the optimal FA threshold can serve as a biological marker that distinguishes individuals with BD from HCs. Thus, visual evaluation of the ATR by DTT may prove to be a useful adjunctive diagnostic tool for BD in clinical practice.

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The effects of an educational program for non-physician health care providers regarding fertility preservation

Takeuchi E., Kato M., Miyata K., Suzuki N., Shimizu C., Okada H., Matsunaga N., Shimizu M., Moroi N., Fujisawa D., Mimura M., Miyoshi Y.

Supportive Care in Cancer （Supportive Care in Cancer） 26 （ 10 ） 3447 - 3452 2018年10月

ISSN 09414355

© 2018, Springer-Verlag GmbH Germany, part of Springer Nature. Purpose: The American Society of Clinical Oncology (ASCO) Clinical Practice guidelines recommend that physicians, nurses, social workers, and other health care providers should be prepared to discuss the risk of infertility with patients. We conducted an educational program for non-physician health care providers regarding fertility preservation and evaluated the effects of the educational program. Methods: The 4-h educational program consisted of lectures about infertility as a potential risk of cancer treatment, fertility preservation, and psychosocial support. Knowledge, confidence, institutional change, and self-practice were assessed pre-program, immediately post-program, and 6 months post-program. Results: Of 124 participants who joined the program, 74 completed and returned the follow-up survey 6 months after the program. Sixty-one percent of the participants were nurses, 27% were social workers, and 4% were psychologists. The scores for confidence and knowledge increased between pre- and immediate post-program periods (p < 0.01), and between pre- and 6-month post-program periods (p < 0.01). The knowledge score was 52, 76, and 71% at the 3 points respectively. The participants became more likely to disseminate fertility preservation counseling at their institutions (p < 0.01) and use informational resources (p < 0.01). Overall, self-practice and institutional support did not change. Conclusions: The study revealed that this educational program is applicable for non-physicians to learn about fertility preservation. The participants improved significantly in confidence and knowledge, but not in counseling skills.

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Feasibility study of mindfulness-based cognitive therapy for anxiety disorders in a Japanese setting Retrospectively registered at the University Hospital Medical Information Network on 1st August 2013 (ID UMIN000011347)

Sado M., Park S., Ninomiya A., Sato Y., Fujisawa D., Shirahase J., Mimura M.

BMC Research Notes （BMC Research Notes） 11 （ 1 ） 2018年09月

© 2018 The Author(s). Objective: Mindfulness-based cognitive therapy (MBCT) could be a treatment option for anxiety disorders. Although its effectiveness under conditions of low pharmacotherapy rates has been demonstrated, its effectiveness under condition of high pharmacotherapy rate is still unknown. The aim of the study was to evaluate effectiveness of MBCT under the context of high pharmacotherapy rates. Results: A single arm with pre-post comparison design was adopted. Those who had any diagnosis of anxiety disorders, between the ages of 20 and 74, were included. Participants attended 8 weekly 2-hour-long sessions followed by 2 monthly boosters. Evaluation was conducted at baseline, in the middle, at end of the intervention, and at follow-up. The State-Trait Anxiety Inventory (STAI)-state was set as the primary outcome. Pre-post analyses with mixed-effect models repeated measures were conducted. Fourteen patients were involved. The mean age was 45.0, and 71.4% were female. The mean change in the STAI-state at every point showed statistically significant improvement. The STAI-trait also showed improvement at a high significance level from the very early stages. The participants showed significant improvement at least one point in some other secondary outcomes. Trial registration Retrospectively registered at the University Hospital Medical Information Network on 1st August 2013 (ID: UMIN000011347)

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5-HT<inf>3</inf> antagonists decrease discounting rate without affecting sensitivity to reward magnitude in the delay discounting task in mice

Mori M., Tsutsui-Kimura I., Mimura M., Tanaka K.

Psychopharmacology （Psychopharmacology） 235 （ 9 ） 2619 - 2629 2018年09月

ISSN 00333158

© 2018, Springer-Verlag GmbH Germany, part of Springer Nature. Rationale: Impulsive choice has often been evaluated in rodents according to the proportion of choices for the delayed large magnitude reinforcer (%large choice) in a delay-discounting task (DDT). However, because %large choice is influenced by both sensitivity to reinforcer magnitude and sensitivity to delayed reinforcement (i.e., discounting rate), distinctively evaluating such discounting parameters represents a critical issue demanding methods to determine each parameter in rats. The serotonin (5-HT) system is well known to be involved in impulsive choice; nevertheless, only a few studies have distinguished discounting parameters and investigated how 5-HT modulators affect discounting rate. Objective: Here, we performed a discounting parameter analysis in mice and examined the effects of various 5-HT modulators on discounting rate. Methods: We set up DDTs with different delay schedules to determine which schedule could address delay-discounting rates in mice. We examined the effect of the following drugs on impulsive choice: a 5-HT reuptake inhibitor (paroxetine), a 5-HT1A receptor agonist (8-OH-DPAT), and two 5-HT3 receptor antagonists (granisetron and ondansetron). Results: Mice showed typical delay discounting at the shorter delay schedules (up to 4 s delay). The %large choice under shorter, but not longer, schedules followed an exponential function and allowed us to derive discounting rates. We selected a DDT with a 4-s delay schedule for further experiments. Granisetron and ondansetron, but not paroxetine or 8-OH-DPAT, decreased discounting rates without affecting sensitivity to reinforcer magnitude. Conclusion: We found that a method to calculate discounting rates in rats is also applicable to mouse models. We also provided evidence that 5-HT3 antagonism controls impulsive choice in mice.

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Web-based cognitive behavioral therapy blended with face-to-face sessions for major depression: Randomized controlled trial

Nakao S., Nakagawa A., Oguchi Y., Mitsuda D., Kato N., Nakagawa Y., Tamura N., Kudo Y., Abe T., Hiyama M., Iwashita S., Ono Y., Mimura M.

Journal of Medical Internet Research （Journal of Medical Internet Research） 20 （ 9 ） 2018年09月

© Shigetsugu Nakao, Atsuo Nakagawa, Yoshiyo Oguchi, Dai Mitsuda, Noriko Kato, Yuko Nakagawa, Noriko Tamura, Yuka Kudo, Takayuki Abe, Mitsunori Hiyama, Satoru Iwashita, Yutaka Ono, Masaru Mimura. Originally published in the Journal of Medical Internet Research (http://www.jmir.org), 21.09.2018. This is an open-access article distributed under the terms of the Creative Commons Attribution License. Background: Meta-analyses of several randomized controlled trials have shown that cognitive behavioral therapy (CBT) has comparable efficacy to antidepressant medication, but therapist availability and cost-effectiveness is a problem. Objective: This study aimed to evaluate the effectiveness of Web-based CBT blended with face-to-face sessions that reduce therapist time in patients with major depression who were unresponsive to antidepressant medications. Methods: A 12-week, assessor-masked, parallel-group, waiting- list controlled, randomized trial was conducted at 3 medical institutions in Tokyo. Outpatients aged 20-65 years with a primary diagnosis of major depression who were taking ≥1 antidepressant medications at an adequate dose for ≥6 weeks and had a 17-item GRID-Hamilton Depression Rating Scale (HAMD) score of ≥14 were randomly assigned (1:1) to blended CBT or waiting-list groups using a computer allocation system, stratified by the study site with the minimization method, to balance age and baseline GRID-HAMD score. The CBT intervention was given in a combined format, comprising a Web-based program and 12 45-minute face-to-face sessions. Thus, across 12 weeks, a participant could receive up to 540 minutes of contact with a therapist, which is approximately two-thirds of the therapist contact time provided in the conventional CBT protocol, which typically provides 16 50-minute sessions. The primary outcome was the alleviation of depressive symptoms, as measured by a change in the total GRID-HAMD score from baseline (at randomization) to posttreatment (at 12 weeks). Moreover, in an exploratory analysis, we investigated whether the expected positive effects of the intervention were sustained during follow-up, 3 months after the posttreatment assessment. Analyses were performed on an intention-to-treat basis, and the primary outcome was analyzed using a mixed-effects model for repeated measures. Results: We randomized 40 participants to either blended CBT (n=20) or waiting-list (n=20) groups. All patients completed the 12-week treatment protocol and were included in the intention-to-treat analyses. Participants in the blended CBT group had significantly alleviated depressive symptoms at week 12, as shown by greater least squares mean changes in the GRID-HAMD score, than those in the waiting list group (−8.9 points vs −3.0 points; mean between-group difference=−5.95; 95% CI −9.53 to −2.37; P<.001). The follow-up effects within the blended CBT group, as measured by the GRID-HAMD score, were sustained at the 3-month follow-up (week 24) and posttreatment (week 12): posttreatment, 9.4 (SD 5.2), versus follow-up, 7.2 (SD 5.7); P=.009. Conclusions: Although our findings warrant confirmation in larger and longer term studies with active controls, these suggest that a combined form of CBT is effective in reducing depressive symptoms in patients with major depression who are unresponsive to antidepressant medications.

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Optogenetic astrocyte activation evokes BOLD fMRI response with oxygen consumption without neuronal activity modulation

Takata N., Sugiura Y., Yoshida K., Koizumi M., Hiroshi N., Honda K., Yano R., Komaki Y., Matsui K., Suematsu M., Mimura M., Okano H., Tanaka K.F.

GLIA （GLIA） 66 （ 9 ） 2013 - 2023 2018年09月

ISSN 08941491

© 2018 Wiley Periodicals, Inc. Functional magnetic resonance imaging (fMRI) based on the blood oxygenation level-dependent (BOLD) signal has been used to infer sites of neuronal activation in the brain. A recent study demonstrated, however, unexpected BOLD signal generation without neuronal excitation, which led us to hypothesize the presence of another cellular source for BOLD signal generation. Collective assessment of optogenetic activation of astrocytes or neurons, fMRI in awake mice, electrophysiological measurements, and histochemical detection of neuronal activation, coherently suggested astrocytes as another cellular source. Unexpectedly, astrocyte-evoked BOLD signal accompanied oxygen consumption without modulation of neuronal activity. Imaging mass spectrometry of brain sections identified synthesis of acetyl-carnitine via oxidative glucose metabolism at the site of astrocyte-, but not neuron-evoked BOLD signal. Our data provide causal evidence that astrocytic activation alone is able to evoke BOLD signal response, which may lead to reconsideration of current interpretation of BOLD signal as a marker of neuronal activation.

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Neurometabolite levels in antipsychotic-naïve/free patients with schizophrenia: A systematic review and meta-analysis of <sup>1</sup> H-MRS studies

Iwata Y., Nakajima S., Plitman E., Mihashi Y., Caravaggio F., Chung J., Kim J., Gerretsen P., Mimura M., Remington G., Graff-Guerrero A.

Progress in Neuro-Psychopharmacology and Biological Psychiatry （Progress in Neuro-Psychopharmacology and Biological Psychiatry） 86 340 - 352 2018年08月

ISSN 02785846

© 2018 Elsevier Inc. Background: Studies using proton magnetic resonance spectroscopy ( 1 H-MRS) have reported altered neurometabolite levels in patients with schizophrenia. However, results are possibly confounded by the influence of antipsychotic (AP). Thus, this meta-analysis aimed to examine neurometabolite levels in AP-naïve/free patients with schizophrenia. Methods: A literature search was conducted using Embase, Medline, and PsycINFO to identify studies that compared neurometabolite levels in AP-naïve/free patients with schizophrenia to healthy controls (HCs). Eight neurometabolites (glutamate, glutamine, glutamate + glutamine, N-acetylaspartate [NAA], choline, creatine, myo-inositol, and γ-Aminobutyric acid [GABA]) and seven regions of interest (ROI; medial prefrontal cortex, dorsolateral prefrontal cortex, frontal white matter, occipital lobe, basal ganglia, hippocampus/medial temporal lobe, and thalamus) were examined. Results: Twenty-one studies (N = 1281) were included in the analysis. The results showed lower thalamic NAA levels (3 studies, n = 174, effect size = −0.56, P = 0.0005) in the patient group. No group differences were identified for other neurometabolites. Conclusions: Our findings suggest that impaired neuronal integrity in the thalamus may be a potential trait maker in the early stages of schizophrenia.

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Decision-making based on social conventional rules by elderly people

Komeda H., Eguchi Y., Kusumi T., Kato Y., Narumoto J., Mimura M.

Frontiers in Psychology （Frontiers in Psychology） 9 （ AUG ） 2018年08月

© 2018 Komeda, Eguchi, Kusumi, Kato, Narumoto and Mimura. Information used by older adults engaging in a social decision making task of judging a protagonist as a good or a bad person was investigated. Older (n = 100, 50 women, mean age = 63.6 years) and younger (n = 100, 50 women, mean age = 25.7 years) adults participated in a web-based survey. In Experiment 1, we assessed participants' rapid decision-making processes when making good or bad judgments after reading consecutive sentences without reviewing previously read sentences. The percentages of good judgments were analyzed. In Experiment 2, two protagonists engaging in a deliberate decision-making process were presented, and participants were asked to judge better and worse protagonists. The percentages of behavior-based judgments were analyzed. Results of Experiment 1 indicated that older adults judged protagonists as "good" more often than younger adults. Especially, older adults judged protagonists with good behavior as being "good." In Experiment 2, older adults made behavior-based judgments more than younger people. Additionally, older and younger adults used information on personalities of protagonists for making judgments in situations with bad outcomes, or incongruent. Moreover, multiple regression analysis suggested that people with more general trust engaged more, whereas people with more caution engaged less in making behavior-based judgments.

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Predictive factors associated with psychological distress of caregivers of people with dementia in Japan: A cross-sectional study

Shikimoto R., Sado M., Ninomiya A., Yoshimura K., Ikeda B., Baba T., Mimura M.

International Psychogeriatrics （International Psychogeriatrics） 30 （ 8 ） 1089 - 1098 2018年08月

ISSN 10416102

© 2017 International Psychogeriatric Association. Background: Caregivers of people with dementia are likely to have psychological distress that sometimes results in mental health problems, such as depression. The objective of this study was to examine some predictive factors that are thought to be associated with psychological distress of caregivers of people with dementia in Japan. Methods: Design: A cross-sectional study. Sample: As part of a study to estimate the cost of dementia in Japan, 1,437 people with dementia-caregiver dyads were enrolled in the current informal care time study. The measurements in the study included were the basic characteristics of the caregivers and the people with dementia, and the informal care time during a week.Analysis: Factors that predict caregivers' psychological distress, which was measured by Kessler's Psychological Distress scale (K6) score, were evaluated using univariate and multivariate regression analyses. Results: Approximately 69% of the caregivers recorded a K6 score higher than 4, while 18% scored higher than 12. According to the results of the logistic regression analysis (cut-off 4/5), the K6 score was associated with mental and comorbid diseases of people with dementia, informal care time, its lower number of caregivers, and the level of nursing care. According to the results of logistic regression analysis (cut-off 12/13), the K6 score was associated with mental symptoms and comorbid disease of people with dementia, sex of caregivers, informal care time, and its lower number of caregivers. Conclusion: Our findings indicated that the psychological distress of the caregivers is quite high and that informal care time and behavioral and psychological symptoms of dementia are associated with it. These results corroborate with previous findings.

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The effect of fecal microbiota transplantation on psychiatric symptoms among patients with irritable bowel syndrome, functional diarrhea and functional constipation: An open-label observational study

Kurokawa S., Kishimoto T., Mizuno S., Masaoka T., Naganuma M., Liang K., Kitazawa M., Nakashima M., Shindo C., Suda W., Hattori M., Kanai T., Mimura M.

Journal of Affective Disorders （Journal of Affective Disorders） 235 506 - 512 2018年08月

ISSN 01650327

© 2018 Elsevier B.V. Backgrounds: The intestinal microbiota is considered as a potential common underpinning pathophysiology of Functional Gastrointestinal Disorders (FGIDs) and psychiatric disorders such as depression and anxiety. Fecal Microbiota Transplantation (FMT) has been reported to have therapeutic effects on diseases related to dysbiosis, but few studies have evaluated its effect on psychiatric symptoms. Methods: We followed 17 patients with either Irritable Bowel Syndrome (IBS), Functional Diarrhea (FDr) or Functional Constipation (FC) who underwent FMT for the treatment of gastrointestinal symptoms and observation of psychiatric symptoms. Changes in Hamilton Rating Scale for Depression (HAM-D) and subscale of sleep-related items, Hamilton Rating Scale for Anxiety (HAM-A) and Quick Inventory for Depressive Symptoms (QIDS) between baseline and 4 weeks after FMT, and relationship with the intestinal microbiota were measured. Results: At baseline, 12 out of 17 patients were rated with HAM-D ≥ 8. Significant improvement in HAM-D total and sleep subscale score, HAM-A and QIDS were observed (p = 0.007, p = 0.007, p = 0.01, p = 0.007, respectively). Baseline Shannon index indicated that microbiota showed lower diversity in patients with HAM-D ≥ 8 compared to those of healthy donors and patients with HAM-D < 8. There was a significant correlation between baseline Shannon index and HAM-D score, and a correlation between Shannon index change and HAM-D improvement after FMT. Limitations: The small sample size with no control group. Conclusions: Our results suggest that depression and anxiety symptoms may be improved by FMT regardless of gastrointestinal symptom change in patients with IBS, FDr and FC, and the increase of microbiota diversity may help to improve patient's mood.

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Associations between problematic Internet use and psychiatric symptoms among university students in Japan

Kitazawa M., Yoshimura M., Murata M., Sato-Fujimoto Y., Hitokoto H., Mimura M., Tsubota K., Kishimoto T.

Psychiatry and Clinical Neurosciences （Psychiatry and Clinical Neurosciences） 72 （ 7 ） 531 - 539 2018年07月

ISSN 13231316

© 2018 The Author. Psychiatry and Clinical Neurosciences © 2018 Japanese Society of Psychiatry and Neurology Aim: Research on the adverse effects of Internet use has gained importance recently. However, there is currently insufficient data on Japanese young adults’ Internet use, so we conducted a survey targeting Japanese university students to research problematic Internet use (PIU). We also investigated the relationship between PIU and multiple psychiatric symptoms. Methods: A paper-based survey was conducted at five universities in Japan. Respondents were asked to fill out self-report scales regarding their Internet dependency using the Internet Addiction Test (IAT). Sleep quality, attention-deficit hyperactivity disorder (ADHD) tendency, depression, and anxiety symptom data were also collected based on respective self-reports. Results: There were 1336 responses and 1258 were included in the analysis. The mean IAT score (± SD) was 37.87 ± 12.59; and 38.2% of participants were classified as PIU, and 61.8% as non-PIU. The trend level for young women showed that they were more likely to be classified as PIU than young men (40.6% and 35.2% respectively, P = 0.05). Compared to the non-PIU group, the PIU group used the Internet longer (P < 0.001), had significantly lower sleep quality (P < 0.001), had stronger ADHD tendencies (P < 0.001), had higher Depression scores (P < 0.001), and had higher Trait-Anxiety scores (P < 0.001). Based on multiple logistic regression analyses, the factors that contributed to an increased risk of PIU were: being female (odds ratio [OR] = 1.52), being older (OR = 1.17), having poor sleep quality (OR = 1.52), having ADHD tendencies (OR = 2.70), having depression (OR = 2.24), and having anxiety tendencies (OR = 1.43). Conclusion: We found a high PIU prevalence among Japanese young adults. The factors that predicted PIU were: female sex, older age, poor sleep quality, ADHD tendencies, depression, and anxiety.

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Kynurenine pathway in depression: A systematic review and meta-analysis

Ogyu K., Kubo K., Noda Y., Iwata Y., Tsugawa S., Omura Y., Wada M., Tarumi R., Plitman E., Moriguchi S., Miyazaki T., Uchida H., Graff-Guerrero A., Mimura M., Nakajima S.

Neuroscience and Biobehavioral Reviews （Neuroscience and Biobehavioral Reviews） 90 16 - 25 2018年07月

ISSN 01497634

© 2018 Elsevier Ltd Abnormalities of the kynurenine (KYN) pathway may be implicated in the pathophysiology of depression. However, the relationships between depression and each metabolite of the KYN pathway remain uncertain. Therefore, we conducted a meta-analysis about the levels of the metabolites of KYN pathway between patients with depression and controls. Out of 899 initial records, we identified 22 articles to form the empirical basis. Seventeen, 10, and 18 studies examined levels of kynurenic acid (KYNA), quinolinic acid (QUIN), and KYN, respectively. KYNA and KYN levels were lower in patients with depression in comparison to controls, while QUIN levels did not differ between the two groups. Antidepressant-free patients showed decreased KYNA levels and increased QUIN levels compared with controls. Male ratios of the samples were negatively associated with study SMDs for KYNA. In conclusion, this meta-analysis revealed that patients with depression had decreased level of KYNA and KYN, whereas antidepressant-free patients showed increased level of QUIN. Nevertheless, given the heterogeneity among their sample characteristics, further research is clearly needed.

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Striatonigral direct pathway activation is sufficient to induce repetitive behaviors

Bouchekioua Y., Tsutsui-Kimura I., Sano H., Koizumi M., Tanaka K., Yoshida K., Kosaki Y., Watanabe S., Mimura M.

Neuroscience Research （Neuroscience Research） 132 53 - 57 2018年07月

ISSN 01680102

© 2017 Pharmacological intervention in the substantia nigra is known to induce repetitive behaviors in rodents, but a direct causal relationship between a specific neural circuit and repetitive behavior has not yet been established. Here we demonstrate that optogenetic activation of dopamine D1 receptor-expressing MSNs terminals in the substantia nigra pars reticulata resulted in sustained and chronic repetitive behaviors. These data show for the first time that activation of the striatonigral direct pathway is sufficient to generate motor stereotypies.

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Relationships between socio-clinico-demographic factors and global cognitive function in the oldest old living in the Tokyo Metropolitan area: Reanalysis of the Tokyo Oldest Old Survey on Total Health (TOOTH)

Eguchi Y., Tasato K., Nakajima S., Noda Y., Tsugawa S., Shinagawa S., Niimura H., Hirose N., Arai Y., Mimura M.

International Journal of Geriatric Psychiatry （International Journal of Geriatric Psychiatry） 33 （ 7 ） 926 - 933 2018年07月

ISSN 08856230

Copyright © 2018 John Wiley & Sons, Ltd. Background: Despite a steady increase in life expectancy, a few studies have investigated cross-sectional correlates and longitudinal predictors of cognitive function, a core domain of the successful aging, among socio-clinico-demographic factors in the oldest-old exclusively. Objectives: The aims of this study were to examine socio-clinico-demographic characteristics associated with global cognition and its changes in the oldest-old. Methods: We reanalyzed a dataset of cognitively preserved community-dwelling subjects aged 85 years and older in the Tokyo Oldest Old Survey on Total Health, a 6-year longitudinal observational study. This study consisted of (1) baseline cross-sectional analyses examining correlates of global cognition (n = 248) among socio-clinico-demographic factors and (2) longitudinal analyses examining baseline predictors for changes of global cognition in 3-year follow-up (n = 195). The Mini-Mental State Examination was used as a screening test to assess global cognition. Results: At baseline, higher weights were related to higher cognitive function in the oldest-old. The baseline predictors of global cognitive decline in 3-year follow-up were higher global cognition, shorter education period, and lower sociocultural activities and lower instrumental activity of daily living, in this order. Conclusions: The present study suggests that it is crucial to attain higher education during early life and avoid leanness or obesity, participate in sociocultural cognitive activities during late life, and maintain instrumental activity of daily living to preserve optimal cognitive function in the oldest-old, which will facilitate developing prevention strategies for cognitive decline and promoting successful aging in this increasing population.

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A practical BCG measuring system with bed sensors and algorithm for heartbeat detection

Nagura M., Mitsukura Y., Kishimoto T., Mimura M.

Proceedings - 2018 IEEE 15th International Workshop on Advanced Motion Control, AMC 2018 （Proceedings - 2018 IEEE 15th International Workshop on Advanced Motion Control, AMC 2018） 317 - 321 2018年06月

ISSN 9781538619469

© 2018 IEEE. Ballistocardiogram (BCG) is useful and informative signal result from the cardiac activity. In this paper, we present a practical BCG measurement system with bed sensors. Moreover, the simple algorithm to detect all individual heartbeats and estimate beat-to-beat interval lengths is presented. These are effective for all night continuous monitoring of cardiovascular system and enable us to detect sleep stage. Heart beats is detected by cross-correlation method. This method has three steps, preprocessing, typical wave form creation and cross-correlation calculation. Output of this process were validated with 10 subjects. As the results, the average 71.5% of the beat-to-beat intervals were detected. Moreover this study revealed that the individual difference is significant factor to detect heart beats precisely.

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Catatonic Stupor in Schizophrenic Disorders and Subsequent Medical Complications and Mortality

Funayama M., Takata T., Koreki A., Ogino S., Mimura M.

Psychosomatic Medicine （Psychosomatic Medicine） 80 （ 4 ） 370 - 376 2018年05月

ISSN 00333174

© 2018 The Author(s). Objective Although catatonia can occur secondary to a general medical condition, catatonia itself has been known to lead to various medical compolications. Although case reports on the association of catatonia with subsequent medical complications have been documented, no comprehensive large-scale study has been performed. To investigate specific medical complications after catatonia, we conducted a retrospective cohort study of specific medical complications of schizophrenia patients with catatonia. Methods The 1719 schizophrenia inpatients in our study were categorized into two groups: the catatonia group, i.e., those who exhibited catatonic stupor while they were hospitalized, and the noncatatonia group, i.e., those who never exhibited catatonic stupor. Differences between the two groups in the occurrence of subsequent medical complications were examined using linear and logistic regression analyses, and models were adjusted for potentially confounding factors. Results The catatonia group had an increased risk for mortality (odds ratio = 4.8, 95% confidence interval = 2.0-10.6, p <.01) and certain specific medical complications, i.e., pneumonia, urinary tract infection, sepsis, disseminated intravascular coagulation, rhabdomyolysis, dehydration, deep venous thrombosis, pulmonary embolism, urinary retention, decubitus, arrhythmia, renal failure, neuroleptic malignant syndrome, hypernatremia, and liver dysfunction (all p values <.01, except for deep venous thrombosis, p =.04 in the multiple linear regression analysis). Conclusions Catatonic stupor in schizophrenia substantially raises the risk for specific medical complications and mortality. Hyperactivity of the sympathetic nervous system, dehydration, and immobility, which are frequently involved in catatonia, might contribute to these specific medical complications. In catatonia, meticulous care for both mental and medical conditions should be taken to reduce the risk of adverse medical consequences.

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Prediction Model of Serum Lithium Concentrations

Yoshida K., Uchida H., Suzuki T., Watanabe M., Yoshino N., Houchi H., Mimura M., Fukuoka N.

Pharmacopsychiatry （Pharmacopsychiatry） 51 （ 3 ） 82 - 88 2018年05月

ISSN 01763679

© Georg Thieme Verlag KG Stuttgart.New York. Introduction Therapeutic drug monitoring is necessary for lithium, but clinical application of several prediction strategies is still limited because of insufficient predictive accuracy. We herein proposed a suitable model, using creatinine clearance (CLcr)-based lithium clearance (Li-CL). Methods Patients receiving lithium provided the following information: serum lithium and creatinine concentrations, time of blood draw, dosing regimen, concomitant medications, and demographics. Li-CL was calculated as a daily dose per trough concentration for each subject, and the mean of Li-CL/CLcr was used to estimate Li-CL for another 30 subjects. Serum lithium concentrations at the time of sampling were estimated by 1-compartment model with Li-CL, fixed distribution volume (0.79 L/kg), and absorption rate (1.5/hour) in the 30 subjects. Results One hundred thirty-one samples from 82 subjects (44 men; mean±standard deviation age: 51.4±16.0 years; body weight: 64.6±13.8 kg; serum creatinine: 0.78±0.20 mg/dL; dose of lithium: 680.2±289.1 mg/day) were used to develop the pharmacokinetic model. The mean±standard deviation (95% confidence interval) of absolute error was 0.13±0.09 (0.10-0.16) mEq/L. Discussion Serum concentrations of lithium can be predicted from oral dosage with high precision, using our prediction model.

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The psychological impact of disclosing amyloid status to Japanese elderly: A preliminary study on asymptomatic patients with subjective cognitive decline

Wake T., Tabuchi H., Funaki K., Ito D., Yamagata B., Yoshizaki T., Kameyama M., Nakahara T., Murakami K., Jinzaki M., Mimura M.

International Psychogeriatrics （International Psychogeriatrics） 30 （ 5 ） 635 - 639 2018年05月

ISSN 10416102

© 2018 International Psychogeriatric Association. In Japan, 4.6 million people are living with dementia and the number is expected to rise to 7 million by 2025. Amyloid-β (Aβ) positron emission tomography (PET) is used for cognitively normal Japanese people with or without subjective cognitive decline (SCD) for the purpose of clinical trials or diagnosis. Nevertheless, no empirical studies have been conducted on the safety of disclosing amyloid status to such populations. We conducted amyloid PET imaging on 42 participants (Aβ positive (n = 10) and negative (n = 32)). State anxiety and depression were measured at pre- and post-disclosure, and test-related distress at post-disclosure. Mean state anxiety and depression scores were below the cut-off through pre- and post-disclosure in the Aβ positive and negative groups. State anxiety and depression did not change over time and were not different between groups. Mean test-related distress scores were within normal limits at post-disclosure in both groups. No significant difference was found between groups. Disclosing Aβ positive results did not cause greater mood disturbance than negative results in a short period of time. The short-term psychological safety of disclosing Aβ PET results to asymptomatic Japanese adults with SCD was indicated.

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A Possible Role of Takotsubo Cardiomyopathy in Ventricular Fibrillation During Delirium Tremens: A Case Report and Literature Review

Ishida T., Uchida H., Miyazaki K., Yukawa T., Sugiyama K., Hamabe Y., Mimura M., Suzuki T.

Psychosomatics （Psychosomatics） 59 （ 3 ） 293 - 297 2018年05月

ISSN 00333182

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An estimation of heart rate variability from ballistocardiogram measured with bed leg sensors

Nagura M., Mitsukura Y., Kishimoto T., Mimura M.

Proceedings of the IEEE International Conference on Industrial Technology （Proceedings of the IEEE International Conference on Industrial Technology） 2018-February 2005 - 2009 2018年04月

ISSN 9781509059492

© 2018 IEEE. Ballistocardiogram (BCG) is the repetitive body movements related to cardiac cycle. All night continuous measuring of BCG by using bed sensors enable us to detect sleep stage. However conventional methods are seemed to have unreliability caused by position of lying down. In this paper, we propose a reliable method of all night continuous measuring of BCG. Heart rate variability (HRV) is estimated from BCG measured with new bed sensors by template-matching approach. This approach has three steps, pre-processing, template-creation and template matching. Output of this process were validated with 4 subjects. The mean beat-to-beat interval error was 9.8[ms] and on an average 87.1% of the beat-to-beat intervals were detected.

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Religiosity and psychological resilience in patients with schizophrenia and bipolar disorder: an international cross-sectional study

Mizuno Y., Hofer A., Frajo-Apor B., Wartelsteiner F., Kemmler G., Pardeller S., Suzuki T., Mimura M., Fleischhacker W.W., Uchida H.

Acta Psychiatrica Scandinavica （Acta Psychiatrica Scandinavica） 137 （ 4 ） 316 - 327 2018年04月

ISSN 0001690X

© 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd Objective: The impact of religious/spiritual activities on clinical outcomes in patients with serious mental illnesses remains controversial, which was addressed in this international cross-sectional study. Method: Three-hundred sixty-nine subjects were recruited from Austria (n = 189) and Japan (n = 180), consisting of 112 outpatients with paranoid schizophrenia, 120 with bipolar I disorder (DSM-IV), and 137 healthy controls. Religiosity was assessed in terms of attendance and importance of religious/spiritual activities, while resilience was assessed using the 25-item Resilience Scale. General linear models were used to test whether higher religiosity will be associated with higher resilience, higher social functioning, and lower psychopathology. The association between levels of spiritual well-being and resilience was also examined. Results: Attendance of religious services (F [4,365] = 0.827, P = 0.509) and importance of religion/spirituality (F [3,365] = 1.513, P = 0.211) did not show significant associations with resilience. Regarding clinical measures, a modest association between higher importance of religion/spirituality and residual manic symptoms was observed in bipolar patients (F [3,118] = 3.120, P = 0.029). In contrast to the findings regarding religiosity, spiritual well-being showed a strong positive correlation with resilience (r = 0.584, P < 0.001). Conclusion: The protective effect of religiosity in terms of resilience, social functioning, and psychopathology was not evident in our sample. Spiritual well-being appears more relevant to resilience than religiosity.

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Is it possible to implement community care based on mental health in Japan? A comparison between decade ago and present on Duration of Untreated Psychosis (DUP)

Suzuki K., Niimura H., Yamazawa R., Nemoto T., Murakami M., Mimura M., Mizuno M.

Asian Journal of Psychiatry （Asian Journal of Psychiatry） 33 88 - 92 2018年03月

ISSN 18762018

© 2018 Elsevier B.V. Introduction: In recent years, the early detection and treatment of the first episode of schizophrenia (FES) has attracted worldwide attention. In Japan, psychiatric care has changed to an open and accessible framework over the past decade. Therefore, the duration of untreated psychosis (DUP) is thought to have been shortened. The purposes of this study were to investigate whether recent DUP periods are shorter than they were 10 years ago and whether the DUP at present differs among psychiatric facilities. We investigated the recent DUP at a psychiatric hospital and its satellite clinic. Material and methods: We examined the differences in DUP, age, sex, referral pathway, living companions, social participation, and schooling history among 3 groups of FES patients: (i) a psychiatric hospital during 1999–2001 and (ii) during 2009–2011, and (iii) a psychiatric clinic during 2009–2011. Results: The average DUP was 14.3 (SD = 17.5) months for the psychiatric hospital during 1999–2001, 16.0 (SD = 18.7) months for the psychiatric hospital during 2009–2011, and 24.4 (SD = 30.0) months for the psychiatric clinic during 2009–2011. No significant differences were found in the DUP for each facility and during this decade. Also, the differences in the DUP could not be attributed to factors such as living companions or social participation. Discussion: Increases in the numbers of patients and psychiatric clinics have not led to the early detection of FES. To shorten the DUP in the future, closer cooperation among the medical field, the educational field, and the health and welfare will be needed.

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Can robotic systems promote self-disclosure in adolescents with autism spectrum disorder? A pilot study

Kumazaki H., Warren Z., Swanson A., Yoshikawa Y., Matsumoto Y., Takahashi H., Sarkar N., Ishiguro H., Mimura M., Minabe Y., Kikuchi M.

Frontiers in Psychiatry （Frontiers in Psychiatry） 9 （ FEB ） 2018年02月

© 2018 Kumazaki, Warren, Swanson, Yoshikawa, Matsumoto, Takahashi, Sarkar, Ishiguro, Mimura, Minabe and Kikuchi. Research suggests that many individuals with autism spectrum disorder (ASD) often demonstrate challenges providing appropriate levels of information during conversational interchanges. Considering the preference of individuals with ASD, and recent rapid technological advances, robotic systems may yield promise in promoting certain aspects of conversation and interaction such as self-disclosure of appropriate personal information. In the current work, we evaluated personal disclosures of events with specific emotional content across two differing robotic systems (android and simplistic humanoid) and human interactions. Nineteen participants were enrolled in this study: 11 (2 women and 9 men) adolescents with ASD and 8 (4 women and 4 men) adolescents with TD. Each participant completed a sequence of three interactions in a random order. Results indicated differences regarding comfort level and length of disclosures between adolescents with ASD and typically developing (TD) controls in relation to system interactions. Specifically, adolescents with ASD showed a preference for interacting with the robotic systems compared to TD controls and demonstrated lengthier disclosures when interacting with the visually simple humanoid robot compared to interacting with human interviewer. The findings suggest that robotic systems may be useful in eliciting and promoting aspects of social communication such as self-disclosure for some individuals with ASD.

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Exercise program improved subjective dry eye symptoms for office workers

Sano K., Kawashima M., Takechi S., Mimura M., Tsubota K.

Clinical Ophthalmology （Clinical Ophthalmology） 12 307 - 311 2018年02月

ISSN 11775467

© 2018 Sano et al. Introduction: We investigated the benefits of a cognitive behavior therapy-based exercise program to reduce the dry eye symptoms of office workers. Materials and methods: We recruited 11 office workers with dry eye symptoms, aged 31–64 years, who voluntarily participated in group health guidance at a manufacturing company. Participants learned about the role of physical activity and exercise in enhancing wellness and performed an exercise program at home 3 days per week for 10 weeks. We estimated the indexes of body composition, dry eye symptoms, and psychological distress using the Dry Eye-Related Quality of Life Score and the World Health Organization’s Subjective Well-Being Inventory questionnaires pre- and postintervention. Results: The 10-week exercise program and the questionnaires were completed by 48.1% (39 of 81) of the participants. Body composition did not change pre- and postintervention. However, the average of the Dry Eye-Related Quality of Life Score scores in participants with subjective dry eye significantly improved after the intervention. Moreover, the World Health Organization’s Subjective Well-Being Inventory positive well-being score tended to increase after the intervention. Conclusion: In this study, we showed that a 10-week exercise program improved subjective dry eye symptoms of healthy office workers. Our study suggests that a cognitive behavior therapy-based exercise program can play an important role in the treatment of patients with dry eye disease.

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Strengths use as a secret of happiness: Another dimension of visually impaired individuals’ psychological state

Matsuguma S., Kawashima M., Negishi K., Sano F., Mimura M., Tsubota K.

PLoS ONE （PLoS ONE） 13 （ 2 ） 2018年02月

© 2018 Matsuguma et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. It is well recognized that visual impairments (VI) worsen individuals’ mental condition. However, little is known about the positive aspects including subjective happiness, positive emotions, and strengths. Therefore, the purpose of this study was to investigate the positive aspects of persons with VI including their subjective happiness, positive emotions, and strengths use. Positive aspects of persons with VI were measured using the Subjective Happiness Scale (SHS), the Scale of Positive and Negative Experience-Balance (SPANE-B), and the Strengths Use Scale (SUS). A cross-sectional analysis was utilized to examine personal information in a Tokyo sample (N = 44). We used a simple regression analysis and found significant relationships between the SHS or SPANE-B and SUS; on the contrary, VI-related variables were not correlated with them. A multiple regression analysis confirmed that SUS was a significant factor associated with both the SHS and SPANE-B. Strengths use might be a possible protective factor from the negative effects of VI.

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Effect of electroconvulsive therapy on hippocampal and amygdala volumes: Systematic review and meta-analysis

Takamiya A., Chung J., Liang K., Graff-Guerrero A., Mimura M., Kishimoto T.

British Journal of Psychiatry （British Journal of Psychiatry） 212 （ 1 ） 19 - 26 2018年01月

ISSN 00071250

© 2018 The Royal College of Psychiatrists. Background Electroconvulsive therapy (ECT) is one of the most effective treatments for depression, although the underlying mechanisms remain unclear. Animal studies have shown that electroconvulsive shock induced neuroplastic changes in the hippocampus. Aims To summarise volumetric magnetic resonance imaging studies investigating the effects of ECT on limbic brain structures. Method A systematic review and meta-analysis was conducted to assess volumetric changes of each side of the hippocampus and amygdala before and after ECT. Standardised mean difference (SMD) was calculated. Results A total of 8 studies (n = 193) were selected for our analyses. Both right and left hippocampal and amygdala volumes increased after ECT. Meta-regression analyses revealed that age, percentage of those responding and percentage of those in remission were negatively associated with volume increases in the left hippocampus. Conclusions ECT increased brain volume in the limbic structures. The clinical relevance of volume increase needs further investigation.

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Effect of Education on Alzheimer's Disease-Related Neuroimaging Biomarkers in Healthy Controls, and Participants with Mild Cognitive Impairment and Alzheimer's Disease: A Cross-Sectional Study

Wada M., Noda Y., Shinagawa S., Chung J., Sawada K., Ogyu K., Tarumi R., Tsugawa S., Miyazaki T., Yamagata B., Graff-Guerrero A., Mimura M., Nakajima S.

Journal of Alzheimer's Disease （Journal of Alzheimer's Disease） 63 （ 2 ） 861 - 869 2018年

ISSN 13872877

© 2018 - IOS Press and the authors. All rights reserved. Background: Cognitive reserve is the acquired capacity reflecting a functional brain adaptability/flexibility in the context of aging. Educational attainment is thought to be among the most important factors that contribute to cognitive reserve. Objective: The aim of this study is to investigate the relationships among duration of education and Alzheimer's disease (AD) related neuroimaging biomarkers such as amyloid-β deposition, glucose metabolism, and brain volumes in each stage of AD. Methods: We reanalyzed a part of the datasets of the Alzheimer's Disease Neuroimaging Initiative. Participants were between 55 and 90 years of age and diagnosed as one of the following: healthy controls (HC), mild cognitive impairment (MCI), or AD. Multiple regression analyses were conducted to examine the relationships among duration of education and amyloid-β deposition (n=825), brain metabolism (n=1,304), and brain volumes (n=1,606) among three groups using data for 18 F-Florbetapir (AV-45) imaging, fludeoxyglucose (FDG) positron emission tomography, and T1-weighted magnetic resonance imaging. Results: Duration of education had no correlations with amyloid-β deposition or brain metabolism in any groups. However, duration of education was positively associated with the total brain volume only in participants with MCI. Conclusions: Our findings suggest that education may exert a protective effect on total brain volume in the MCI stage but not in HC or AD. Thus, education may play an important role in preventing the onset of dementia through brain reserve in MCI.

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Association between Neuropsychiatric Improvement and Neurocognitive Change in Alzheimer's Disease: Analysis of the CATIE-AD Study

Nagata T., Shinagawa S., Nakajima S., Mimura M., Shigeta M.

Journal of Alzheimer's disease : JAD （Journal of Alzheimer's disease : JAD） 66 （ 1 ） 139 - 148 2018年

BACKGROUND/OBJECTIVE: To assess associations between improvements in neuropsychiatric symptoms (NPS) and neurocognitive change in patients with Alzheimer's disease (AD) during treatment using the Clinical Antipsychotic Trials of Intervention Effectiveness-Alzheimer Disease (CATIE-AD) dataset. METHODS: AD outpatients with NPS who needed pharmacological treatment (n = 421) were followed up with antipsychotics, citalopram, or placebo for up to 36 weeks (mean±SD = 252±52 days). The study aim was to investigate associations between improvement in each NPS evaluating scale (by Clinical Global Impression of Change [CGI-C], Neuropsychiatric Inventory [NPI], or Brief Psychiatric Scale [BPRS]) at endpoint (week 36 or early termination [ET], n = 340) and neurocognitive change (change score in the Mini-Mental State Examination [MMSE] between endpoint and baseline during the treatment). Multiple logistic regression analyses were performed on the associations between each NPS improvement and neurocognitive change as well as socio-clinico-demographic variables of interest. RESULTS: At endpoint, NPS improvement rates were 76.1%, 70.8%, and 58.1% in CGI-C, NPI, and BPRS, respectively, while MMSE score change was -2.3±3.8. NPS improvement was significantly related to more severe psychotic symptoms at baseline and preserved levels of neurocognition (smaller MMSE score change) among several variables. CONCLUSIONS: Our findings suggested that neurocognitive preservation may be associated with attaining optimal benefits from any treatment against NPSs in a longitudinal treatment course of patients with AD.

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Approaches for assessing olfaction in children with autism spectrum disorder

Kumazaki H., Okamoto M., Kanzaki S., Okada K.i., Mimura M., Minabe Y., Kikuchi M.

Methods in Molecular Biology （Methods in Molecular Biology） 1820 221 - 228 2018年

ISSN 10643745

© Springer Science+Business Media, LLC, part of Springer Nature 2018. Olfactory traits in individuals with autism spectrum disorder (ASD) are considered the strongest predictors of social impairment. Compared to other sensory abnormalities, olfactory abnormalities in individuals with ASD are poorly understood. In this chapter, we provide an overview of the current assessment in individuals with ASD. Several confounding factors have to be considered when conducting research on olfaction in individuals with ASD. Qualitative measures of olfaction contain only limited information about the olfactory stimuli. In addition, little systematic information is available about individual’s actual uses of olfaction in daily life. Only a limited number of experimental studies have performed quantitative measurements of olfactory abnormalities in ASD. Therefore, clarifying the relationship between olfactory traits and the influence of real-life situations in a laboratory setting is very difficult. Some new methodologies for measuring olfactory traits are gradually becoming available. New methods that reveal important links between ASD and olfactory traits should be developed in the future.

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White matter endophenotypes and correlates for the clinical diagnosis of autism spectrum disorder

Yamagata B., Itahashi T., Nakamura M., Mimura M., Hashimoto R., Kato N., Aoki Y.

Social Cognitive and Affective Neuroscience （Social Cognitive and Affective Neuroscience） 13 （ 7 ） 765 - 773 2018年

ISSN 17495016

© The Author(s) (2018). Since prior diffusion tensor imaging (DTI) studies reported no significant differences in white matter organizations between individuals with autism spectrum disorder (ASD) and their unaffected siblings, the neural correlates for developing a clinical diagnosis among people with endophenotypes remain undetermined. We obtained DTI data from a total of 60 participants consisting of 30 people with endophenotypes and 30 people without. We first followed a conventional approach by comparing individuals with ASD and their unaffected siblings. Using region-of-interest approach, we then performed bootstrapping to examine whether the differences in white matter organizations between individuals with ASD and their unaffected siblings were substantially large, considering the distribution of differences between typically developing (TD) siblings. Conventional approaches revealed no significant differences in white matter organizations between individuals with ASD and their unaffected siblings. Bootstrapping revealed a significantly large difference in axial diffusivity in the left stria terminalis between individuals with ASD and their unaffected siblings after accounting for the distribution of differences in axial diffusivity among TD siblings (99.998 percentile). The results remained significant after controlling for multiple comparisons with Bonferroni method. We assumed that one aspect of this tract was associated with the development of a clinical diagnosis.

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Linked functional network abnormalities during intrinsic and extrinsic activity in schizophrenia as revealed by a data-fusion approach

Hashimoto R.i., Itahashi T., Okada R., Hasegawa S., Tani M., Kato N., Mimura M.

NeuroImage: Clinical （NeuroImage: Clinical） 17 69 - 79 2018年

© 2017 The Authors Abnormalities in functional brain networks in schizophrenia have been studied by examining intrinsic and extrinsic brain activity under various experimental paradigms. However, the identified patterns of abnormal functional connectivity (FC) vary depending on the adopted paradigms. Thus, it is unclear whether and how these patterns are inter-related. In order to assess relationships between abnormal patterns of FC during intrinsic activity and those during extrinsic activity, we adopted a data-fusion approach and applied partial least square (PLS) analyses to FC datasets from 25 patients with chronic schizophrenia and 25 age- and sex-matched normal controls. For the input to the PLS analyses, we generated a pair of FC maps during the resting state (REST) and the auditory deviance response (ADR) from each participant using the common seed region in the left middle temporal gyrus, which is a focus of activity associated with auditory verbal hallucinations (AVHs). PLS correlation (PLS-C) analysis revealed that patients with schizophrenia have significantly lower loadings of a component containing positive FCs in default-mode network regions during REST and a component containing positive FCs in the auditory and attention-related networks during ADR. Specifically, loadings of the REST component were significantly correlated with the severities of positive symptoms and AVH in patients with schizophrenia. The co-occurrence of such altered FC patterns during REST and ADR was replicated using PLS regression, wherein FC patterns during REST are modeled to predict patterns during ADR. These findings provide an integrative understanding of altered FCs during intrinsic and extrinsic activity underlying core schizophrenia symptoms.

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Protocol for a prospective multicentre registry cohort study on suicide attempters given the assertive case management intervention after admission to an emergency department in Japan: Post-ACTION-J Study (PACS)

Kawanishi C., Ishii T., Yonemoto N., Yamada M., Tachikawa H., Kishimoto T., Tsujii N., Hashimoto S., Kinoshita T., Mimura M., Okubo Y., Otsuka K., Yoshimura R.

BMJ Open （BMJ Open） 8 （ 9 ） 2018年

© Author(s) (or their employer(s)) 2018. Introduction Suicide attempt is the most important risk factor for later suicide. A randomised-controlled, multicentre trial of postsuicide attempt case management for the prevention of further suicide attempts in Japan, named ACTION-J, has established effective interventions for prevention of suicide reattempts. The ACTION-J assertive case management intervention programme was adopted by the Japanese Ministry of Health, Labour and Welfare in 2016, when medical fees were revised. This nationwide programme is provided to patients who attempt suicide and who are admitted to emergency departments in Japan. The aim of the present study is to examine the current implementation status of the ACTION-J programme. The present study also aims to clarify which patients' and hospitals' factors affect the implementation of the programme. Methods and analysis This is a prospective, multicentre, patient registry cohort study. Participants will be suicide attempters admitted to the emergency departments of medical facilities with both psychiatry and emergency departments. The assertive case management programme will be delivered to participants by a case manager for up to 24 weeks, based on psychiatric diagnoses, social risks and patient needs. The core feature of the programme is to encourage patients to participate in psychiatric treatment. The primary outcome will be the proportion of patients still participating in the case management intervention at 24 weeks after registration. The secondary outcomes will include measures of the fidelity of the case management intervention. The fidelity will be evaluated using a fidelity assessment manual developed by the study group. Ethics and dissemination This observational study has been approved by the ethics board of Sapporo Medical University. Enrolment began in October 2016 and will continue until December 2018. Dissemination plans include presentations at scientific conferences and scientific publications.

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