Details of a Researcher - Mimura, Masaru

Papers - Mimura, Masaru

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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

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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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

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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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

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

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

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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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 2019.12

© 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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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 2019.12

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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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 ) 2019.12

© 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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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 ) 2019.12

© 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 2019.12

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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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 2019.12

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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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 ) 2019.12

© 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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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 2019.11

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 2019.11

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 2019.11

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 ) 2019.10

© 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 2019.10

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 2019.10

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 2019.10

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 2019.10

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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