Details of a Researcher - Mimura, Masaru

Papers - Mimura, Masaru

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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 2020.02

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 2020.02

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 2020.02

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 2020.02

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 ) 2020.02

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 2020.01

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 2020.01

© 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 2020.01

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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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 2020.01

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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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 2020.01

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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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 2020.01

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 2020.01

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 2020.01

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 2020.01

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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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

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

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

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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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

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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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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