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Abstract Background The approval of lecanemab, an anti-amyloid therapy for Alzheimer’s disease (AD), necessitates addressing healthcare preparedness for disease-modifying treatment (DMT) to ensure appropriate, safe, and sustainable drug administration. Understanding public perceptions on this matter is crucial. We aimed to assess discrepancies and similarities in the perceptions of Japanese trial-ready cohort study (‘J-TRC webstudy’) participants and clinical specialists in the fields of dementia treatment and radiology, concerning affairs related to challenges in DMT preparedness. Methods This was a cross-sectional prospective observational study conducted in November–December 2023. The J-TRC webstudy participants were invited to participate in an online survey using Google Forms, and clinical specialists were invited to complete a mail-based survey. Main questionnaire items had been designed to be common in both surveys, and their responses were analyzed for participant attributes, interests, attitudes, expectations, and concerns about DMTs without specifying lecanemab. Results Responses were obtained from n = 2,050 J-TRC webstudy participants and n = 1,518 clinical specialists. Compared to specialists, more J-TRC respondents perceived the eligible proportion for DMT as smaller (59.1% versus 30.7%), perceived the eligible severity for DMT as more limited (58.0% versus 24.5%), and perceived the efficacy of DMT as slightly more encouraging (29.3% versus 34.8%). In terms of treatment prioritization, both J-TRC respondents and specialist respondents exhibited similar levels of acceptance for prioritizing patients to treat: e.g., approximately two-thirds endorsed patient prioritization under hypothetical resource constraints or other reasons. A medical rationale emerged as the most compelling reason for acceptance of patient prioritization across the surveys. In contrast, the need to address vulnerable populations was the reason that led to the least acceptance of prioritization, followed by economic considerations. Conclusions Our findings offer valuable insights into the discrepancies in knowledge and perception between patients and healthcare providers. This could enhance the delivery of patient information in clinical settings and inform the discussion surrounding patient prioritization strategies.

Introduction: Although the prevalence of Alzheimer’s disease (AD) is higher in older people compared to younger people, dementia has also been documented in younger adults. Although early-onset dementia and late-onset dementia had been considered a single disease in pathological investigations, many studies revealed differences in cognitive and neuroimaging changes between them. We evaluated differences in cognitive and neuroimaging changes among the following groups: individuals with early-onset AD (EOAD), late-onset AD (LOAD), early-onset mild cognitive impairment (EOMCI), or late-onset MCI (LOMCI), and healthy controls (HCs). Methods: Patients underwent both a 1.5 Tesla magnetic resonance imaging scan and the Mini-Mental State Examination (MMSE). Differences in regional gray matter volumes and MMSE subscales were investigated among the five diagnostic groups. Results: Compared to the EOAD group, the LOAD group had significantly higher scores on orientation in place. Compared to the LOMCI patients, the EOMCI patients achieved significantly higher recall scores. The LOAD and LOMC groups showed significant volume reductions in bilateral medial temporal regions compared to the HCs. The EOAD and EOMCI groups did not show significant atrophy of the medial temporal region compared to the HC group. Conclusions: The hippocampal volume and memory were preserved in the patients with EOMCI or EOAD compared to those with LOMCI or LOAD. These findings may indicate that the distinct and differing patterns of neuropsychological changes between EOAD and LOAD are also common in MCI, which is intermediate between normal cognition and AD.

Abstract Machine learning can be used to define subtypes of psychiatric conditions based on shared biological foundations of mental disorders. Here we analyzed cross-sectional brain images from 4,222 individuals with schizophrenia and 7038 healthy subjects pooled across 41 international cohorts from the ENIGMA, non-ENIGMA cohorts and public datasets. Using the Subtype and Stage Inference (SuStaIn) algorithm, we identify two distinct neurostructural subgroups by mapping the spatial and temporal ‘trajectory’ of gray matter change in schizophrenia. Subgroup 1 was characterized by an early cortical-predominant loss with enlarged striatum, whereas subgroup 2 displayed an early subcortical-predominant loss in the hippocampus, striatum and other subcortical regions. We confirmed the reproducibility of the two neurostructural subtypes across various sample sites, including Europe, North America and East Asia. This imaging-based taxonomy holds the potential to identify individuals with shared neurobiological attributes, thereby suggesting the viability of redefining existing disorder constructs based on biological factors.

Abstract Establishing a brain biomarker for schizophrenia is strongly desirable not only to support diagnosis by psychiatrists but also to help track the progressive changes in the brain over the course of the illness. A brain morphological signature of schizophrenia was reported in a recent study and is defined by clusters of brain regions with reduced volume in schizophrenia patients compared to healthy individuals. This signature was proven to be effective at differentiating patients with schizophrenia from healthy individuals, suggesting that it is a good candidate brain biomarker of schizophrenia. However, the longitudinal characteristics of this signature have remained unclear. In this study, we examined whether these changes occurred over time and whether they were associated with clinical outcomes. We found a significant change in the brain morphological signature in schizophrenia patients with more brain volume loss than the natural, age‐related reduction in healthy individuals, suggesting that this change can capture a progressive morphological change in the brain. We further found a significant association between changes in the brain morphological signature and changes in the full‐scale intelligence quotient (IQ). The patients with IQ improvement showed preserved brain morphological signatures, whereas the patients without IQ improvement showed progressive changes in the brain morphological signature, suggesting a link between potential recovery of intellectual abilities and the speed of brain pathology progression. We conclude that the brain morphological signature is a brain biomarker that can be used to evaluate progressive changes in the brain that are associated with cognitive impairment due to schizophrenia.

Abstract Introduction The number of smartphone apps for brain training is increasing, and the number of people who are working on brain training is also increasing. However, researchers disagree about the effectiveness of brain training. Methods Therefore, in this study, we conducted an intervention test with the participation of 70 healthy middle‐aged men and women and measured the effect of smartphone apps on lifestyle improvement using brain healthcare quotient calculated from brain imaging data. Results As a result, in the intervention group, significant improvements were seen in fractional anisotropy (FA) of the whole brain, corpus callosum, internal capsule, corona radiata, posterior thalamic radiation, external capsule, and superior longitudinal fasciculus. Additionally, in the intervention group, these FA increments correlated with improvements in cognitive function as measured by the trail‐making test and vigor as measured by the Profile of Mood States 2nd Edition. Conclusion The results of this study suggest that improving lifestyle habits through smartphone apps can improve brain health and cognitive and emotional performance of healthy middle‐aged adults. This is consistent with previous research that suggests that FA integrity in the limbic‐thalamo‐cortical pathway influences cognitive function and emotion regulation.

Abstract Dementia with Lewy bodies (DLB) and Alzheimer's disease (AD), the two most common neurodegenerative dementias, both exhibit altered emotional processing. However, how vocal emotional expressions alter in and differ between DLB and AD remains uninvestigated. We collected voice data during story reading from 152 older adults comprising DLB, AD, and cognitively unimpaired (CU) groups and compared their emotional prosody in terms of valence and arousal dimensions. Compared with matched AD and CU participants, DLB patients showed reduced overall emotional expressiveness, as well as lower valence (more negative) and lower arousal (calmer), the extent of which was associated with cognitive impairment and insular atrophy. Classification models using vocal features discriminated DLB from AD and CU with an AUC of 0.83 and 0.78, respectively. Our findings may aid in discriminating DLB patients from AD and CU individuals, serving as a surrogate marker for clinical and neuropathological changes in DLB. Highlights DLB showed distinctive reduction in vocal expression of emotions. Cognitive impairment was associated with reduced vocal emotional expression in DLB. Insular atrophy was associated with reduced vocal emotional expression in DLB. Emotional expression measures successfully differentiated DLB from AD or controls.

BackgroundAlzheimer’s disease (AD) and Lewy body disease (LBD), the two most common causes of neurodegenerative dementia with similar clinical manifestations, both show impaired visual attention and altered eye movements. However, prior studies have used structured tasks or restricted stimuli, limiting the insights into how eye movements alter and differ between AD and LBD in daily life.ObjectiveWe aimed to comprehensively characterize eye movements of AD and LBD patients on naturalistic complex scenes with broad categories of objects, which would provide a context closer to real-world free viewing, and to identify disease-specific patterns of altered eye movements.MethodsWe collected spontaneous viewing behaviors to 200 naturalistic complex scenes from patients with AD or LBD at the prodromal or dementia stage, as well as matched control participants. We then investigated eye movement patterns using a computational visual attention model with high-level image features of object properties and semantic information.ResultsCompared with matched controls, we identified two disease-specific altered patterns of eye movements: diminished visual exploration, which differentially correlates with cognitive impairment in AD and with motor impairment in LBD; and reduced gaze allocation to objects, attributed to a weaker attention bias toward high-level image features in AD and attributed to a greater image-center bias in LBD.ConclusionOur findings may help differentiate AD and LBD patients and comprehend their real-world visual behaviors to mitigate the widespread impact of impaired visual attention on daily activities.

Research into the health benefits of scents is on the rise. However, little is known about the effects of continuous inhalation, such as wearing scents on clothing, on brain structure. Therefore, in this study, an intervention study was conducted on a total of 50 healthy female people, 28 in the intervention group and 22 in the control group, asking them to wear a designated rose scent on their clothes for a month. The effect of continuous inhalation of essential oil on the gray matter of the brain was measured by calculating changes in brain images of participants taken before and after the intervention using Magnetic Resonance Imaging (MRI). The results showed that the intervention increased the gray matter volume (GMV) of the whole brain and posterior cingulate cortex (PCC) subregion. On the other hand, the GMV of the amygdala and orbitofrontal cortex (OFC) did not change. This study is the first to show that continuous scent inhalation changes brain structure.

In addressing the challenge of assessing healthy brain aging across diverse interventions, this study introduces the use of MRI-derived Brain Healthcare Quotients (BHQ) for comprehensive evaluation. We analyzed BHQ changes in 319 participants aged 24–69, who were allocated into dietary (collagen peptide, euglena, matcha, isohumulone, xanthophyll) and physical activity (hand massage with lavender oil, handwriting, office stretching, pink lens, clinical art) groups, alongside a control group, over a month. These interventions were specifically chosen to test the efficacy of varying health strategies on brain health, measured through BHQ indices: GM-BHQ for gray matter volume, and FA-BHQ for white matter integrity. Notably, significant improvements in FA-BHQ were observed in the collagen peptide group, with marginal increases in the hand massage and office stretching groups. These findings highlight BHQ’s potential as a sensitive tool for detecting brain health changes, offering evidence that low-intensity, easily implemented interventions can have beneficial effects on brain health. Moreover, BHQ allows for the systematic evaluation of such interventions using standard statistical approaches, suggesting its value in future brain healthcare research.

Abstract To disseminate, educate, and validate psychiatric clinical practice guidelines, the Effectiveness of Guidelines for Dissemination and Education in Psychiatric Treatment (EGUIDE) project was launched in 2016. In this study, we investigated whether the web‐based courses offered by this project would be as effective as the face‐to‐face courses. We analyzed and compared survey answers about overall participant satisfaction with the course and answers regarding clinical knowledge of schizophrenia and major depressive disorder between 170 participants who took the web‐based courses in 2020 and 689 participants who took the face‐to‐face courses from 2016 to 2019. The web‐based course participants completed the survey questions about satisfaction with the web‐based courses. The web‐based courses were conducted using a combination of web services to make it as similar as possible to the face‐to‐face courses. The degree of satisfaction assessed by the general evaluation of the web‐based courses was higher than what was expected from the face‐to‐face courses. The degree of satisfaction was similar for the courses on schizophrenia and major depressive disorder. In addition, there were no significant differences in overall satisfaction and clinical knowledge between web‐based and face‐to‐face courses. In conclusion, the web‐based courses on clinical practice guidelines provided by the EGUIDE project were rated as more satisfying than the face‐to‐face course that the participants expected to take and no differences in the effectiveness of either course. The results suggest that, after the COVID‐19 pandemic, it would be possible to disseminate this educational material more widely by adopting web‐based courses additionally face‐to‐face courses.

Abstract Background Supporting parents with severe and persistent mental illness (SPMI) requires knowledge, skills, and a positive attitude toward parenthood. We developed a Japanese e-learning program for public health nurses (PHNs) to enable them to support parents with SPMI and their family members. This study aimed to evaluate the effectiveness of the program in improving the knowledge, skills, attitudes, and self-efficacy of PHNs in supporting them. Methods A three-hour video-based e-learning program was developed. A randomized controlled trial was conducted with 176 PHNs responsible for maternal and child health in Japan. The outcome measures included the Sense of Coping Difficulty/Possibility Scale, skills to support people with SPMI, and achievement of program goals. Outcome data were collected at three time points during the study: baseline (T1), post-intervention (T2), and one month after T2 (T3) using self-administered electronic questionnaires. Outcome measures were assessed by comparing the two groups at the endpoint (T3) using t-tests and ANOVA. Effectiveness over time was assessed using a mixed model for repeated measures, with group and time interactions as fixed effects. Results The study participants were randomly allocated to two groups:89 in the intervention group, and 87 in the control group. The total score and the scores in the two subscales of the Sense of Coping Difficulty/Possibility Scale in the intervention group at T3 were significantly higher than those in the control group, as shown by the t-test and ANOVA (all p

BackgroundIt remains unclear how fear of COVID-19 and resilience are related to psychological distress based on occupations among healthcare workers (HCWs) in hospitals treating patients with COVID-19. We conducted a survey on the mental health of HCWs during the COVID-19 pandemic to determine the relationship between factors such as fear of COVID-19 and resilience as well as mental distress in each occupation of HCWs.MethodsWe conducted a web-based survey among HCWs at seven hospitals treating COVID-19 patients in Japan from December 24, 2020 to March 31, 2021. A total of 634 participants were analyzed, and information regarding their socio-demographic characteristics and employment status was collected. Several psychometric measures were used, including the Kessler’s Psychological Distress Scale (K6), the fear of COVID-19 Scale (FCV-19S), and the Resilience Scale (RS14). Factors related to psychological distress were identified by logistic regression analysis. The association between job title and psychological scales was examined by one-way ANOVA, and t-tests were conducted to examine the association between the FCV-19S and hospital initiatives.ResultsIt was found that nurses and clerical workers were associated with psychological distress without considering FCV-19S or RS14; in a model that included FCV-19S, FCV-19S was associated with psychological distress, but job title was not; when RS14 was considered, resilience was protective. In terms of occupation, FCV-19S was lower among physicians and higher among nurses and clerical workers, while RS14 was higher among physicians and lower among other occupations. Having access to in-hospital consultation regarding infection control as well as to psychological and emotional support was associated with lower FCV-19S.ConclusionBased on our findings, we can conclude that the level of mental distress differed by occupation and the differences in the fear of COVID-19 and resilience were important factors. In order to provide mental healthcare for HCWs during a pandemic, it is important to create consultation services that enable employees to discuss their concerns. In addition, it is important to take steps to strengthen the resilience of HCWs in preparation for future disasters.

Abstract The Effectiveness of Guidelines for Dissemination and Education in psychiatric treatment (EGUIDE) project, which is a nationwide dissemination and implementation program for clinical practice guidelines (CPGs) in the field of psychiatry, is currently ongoing. In the current study, a subjective assessment of the participants in the EGUIDE programs was assessed using a questionnaire. Then, the relationships between the subjective assessment, the characteristics of the participants, and the clinical knowledge of the CPGs were evaluated. More than 90% of the participants gave a high rating for the components of content, recommendation, knowledge, skill, and adherence, but not for the component of confidence. A positive correlation was found between years of professional experience and the score of confidence. These results suggest that it may be necessary to apply the knowledge and skills of CPGs obtained in the education programs into practice to increase confidence in the proper use of psychiatric therapies based on CPGs.

A growing amount of research is being conducted on cultural intelligence (CQ), which is the ability to adjust and adapt successfully to a variety of surroundings. CQ is a vital quality for people in diversified societies, as are seen today. However, it is still unclear how an individual can develop or strengthen CQ because previous studies have shown that variables such as foreign experience and personality are not exclusively sufficient as CQ antecedents. If CQ can be treated health-scientifically, as the CQ developers argue, diet and exercise that are effective in keeping the body and brain healthy may also correlate with CQ. It is of great significance to clarify the relationship between lifestyle and CQ by applying recent previous research showing the relationship between CQ and both the brain and intelligence, as well as between lifestyle and both the brain and intelligence. Using data derived from 142 Japanese businesspersons, the results of structural equation modeling indicate that lifestyles (dietary balance and walking frequency) are significantly associated with CQ after controlling for personalities (curiosity and grit) and international experiences (length of studying and working abroad), which have been used as predictors of CQ in previous studies. Furthermore, the moderation test showed that the effect of dietary balance on increasing CQ is greater for people with less overseas experience, indicating that dietary balance compensates for lack of overseas experience in the effect of maintaining the level of CQ. These suggest the effectiveness of a health-scientific approach to the influencing factors of CQ. This study is the first to show that CQ is influenced by lifestyle such as walking and dieting, in addition to personality and overseas experience, and will contribute to the future development of health science and cross-cultural research.

Abstract As the population ages, the realization of a long and happy life is becoming an increasingly important issue in many societies. Therefore, it is important to clarify how happiness and the brain change with aging. In this study, which was conducted with 417 healthy adults in Japan, the analysis showed that fractional anisotropy (FA) correlated with happiness, especially in the internal capsule, corona radiata, posterior thalamic radiation, cingulum, and superior longitudinal fasciculus. According to previous neuroscience studies, these regions are involved in emotional regulation. In psychological studies, emotional regulation has been associated with improvement in happiness. Therefore, this study is the first to show that FA mediates the relationship between age and subjective happiness in a way that bridges these different fields.

BackgroundThe rising number of patients with dementia has become a serious social problem worldwide. To help detect dementia at an early stage, many studies have been conducted to detect signs of cognitive decline by prosodic and acoustic features. However, many of these methods are not suitable for everyday use as they focus on cognitive function or conversational speech during the examinations. In contrast, conversational humanoid robots are expected to be used in the care of older people to help reduce the work of care and monitoring through interaction. ObjectiveThis study focuses on early detection of mild cognitive impairment (MCI) through conversations between patients and humanoid robots without a specific examination, such as neuropsychological examination. MethodsThis was an exploratory study involving patients with MCI and cognitively normal (CN) older people. We collected the conversation data during neuropsychological examination (Mini-Mental State Examination [MMSE]) and everyday conversation between a humanoid robot and 94 participants (n=47, 50%, patients with MCI and n=47, 50%, CN older people). We extracted 17 types of prosodic and acoustic features, such as the duration of response time and jitter, from these conversations. We conducted a statistical significance test for each feature to clarify the speech features that are useful when classifying people into CN people and patients with MCI. Furthermore, we conducted an automatic classification experiment using a support vector machine (SVM) to verify whether it is possible to automatically classify these 2 groups by the features identified in the statistical significance test. ResultsWe obtained significant differences in 5 (29%) of 17 types of features obtained from the MMSE conversational speech. The duration of response time, the duration of silent periods, and the proportion of silent periods showed a significant difference (P

Abstract Aim Suicide prevention for depressive patients is an important clinical issue in psychiatry. However, not all depressive patients plan or attempt suicide. In this study, we investigated the differences of functional brain networks between a high‐risk group and a low‐risk group for suicide by comparing resting‐state functional connectivity (rsFC). Methods The subjects were 29 patients with major depressive disorder, nine of whom had attempted suicide. The suicidal ideation of all subjects was assessed with the Columbia‐Suicide Severity Rating Scale, then the subjects were divided into two groups based on the most severe suicidal ideation (MSI) in their lifetime. We compared rsFC between the two groups. Results Of the 29 subjects, 16 were in the severe MSI group. We found that the severe MSI group members had significantly smaller rsFC in two networks: one comprised the right dorsolateral prefrontal cortex and the default‐mode network, and the other comprised the left rostrolateral prefrontal cortex and the striatum, amygdala, and hippocampus. These regions are reported to be associated with rumination, retrieval suppression, and delay discounting (DD). Conclusion Our results suggest that functional networks related to rumination, retrieval suppression, and DD might be impaired in depressive patients with severe suicidal ideation. It might be beneficial for psychiatrists to assess these characteristics in terms of suicide prevention for depressive patients.

Abstract Aim Risk factors for attempted suicide have been widely studied. However, there is limited evidence on predictive factors for suicide reattempts. We aimed to identify these in suicide attempters admitted to emergency departments. Methods This is the second analysis from a randomized controlled multicenter trial, ACTION‐J. Patient characteristics were extracted from baseline demographic data and clinical data of participants. Predictive factors for a recurrent suicide attempt in each gender were examined using Cox proportional hazards regression analysis. Dependent variables were months from trial entry to the first reattempt. Independent variables were characteristics regarded as potential predictive factors. Results The study included 914 adults (400 men and 514 women). A visit to a psychiatrist within a month of the suicide attempt was significantly associated with reattempts in men (hazard ratio [HR] 2.49, 95% confidence interval [CI] 1.21–5.25). Substance‐related disorders (HR 3.65, 95% CI 1.16–7.9.60), drinking alcohol less than once per month (HR 0.42, 95% CI 0.17–0.88), previous suicide attempts (HR 2.28, 95% CI 1.40–3.87), and taking a drug overdose for the first suicide attempt (HR 1.82, 95% CI 1.14–3.01) were significantly associated with reattempts in women. Conclusion Our data highlight the importance of visits to a psychiatrist a short time before the first suicide attempt in men and substance‐related disorder, previous suicide attempts, and drug overdose in the first suicide attempt in women as predictive factors for future suicide reattempts.

BackgroundWith the aging of populations worldwide, early detection of cognitive impairments has become a research and clinical priority, particularly to enable preventive intervention for dementia. Automated analysis of the drawing process has been studied as a promising means for lightweight, self-administered cognitive assessment. However, this approach has not been sufficiently tested for its applicability across populations. ObjectiveThe aim of this study was to evaluate the applicability of automated analysis of the drawing process for estimating global cognition in community-dwelling older adults across populations in different nations. MethodsWe collected drawing data with a digital tablet, along with Montreal Cognitive Assessment (MoCA) scores for assessment of global cognition, from 92 community-dwelling older adults in the United States and Japan. We automatically extracted 6 drawing features that characterize the drawing process in terms of the drawing speed, pauses between drawings, pen pressure, and pen inclinations. We then investigated the association between the drawing features and MoCA scores through correlation and machine learning–based regression analyses. ResultsWe found that, with low MoCA scores, there tended to be higher variability in the drawing speed, a higher pause:drawing duration ratio, and lower variability in the pen’s horizontal inclination in both the US and Japan data sets. A machine learning model that used drawing features to estimate MoCA scores demonstrated its capability to generalize from the US dataset to the Japan dataset (R2=0.35; permutation test, P

Background Clinical practice guidelines for schizophrenia and major depressive disorder have been published. However, these have not had sufficient penetration in clinical settings. We developed the Effectiveness of Guidelines for Dissemination and Education in Psychiatric Treatment (EGUIDE) project as a dissemination and education programme for psychiatrists. Aims The aim of this study is to assess the effectiveness of the EGUIDE project on the subjective clinical behaviour of psychiatrists in accordance with clinical practice guidelines before and 1 and 2 years after participation in the programmes. Method A total of 607 psychiatrists participated in this study during October 2016 and March 2019. They attended both 1-day educational programmes based on the clinical practice guidelines for schizophrenia and major depressive disorder, and answered web questionnaires about their clinical behaviours before and 1 and 2 years after attending the programmes. We evaluated the changes in clinical behaviours in accordance with the clinical practice guidelines between before and 2 years after the programme. Results All of the scores for clinical behaviours in accordance with clinical practice guidelines were significantly improved after 1 and 2 years compared with before attending the programmes. There were no significant changes in any of the scores between 1 and 2 years after attending. Conclusions All clinical behaviours in accordance with clinical practice guidelines improved after attending the EGUIDE programme, and were maintained for at least 2 years. The EGUIDE project could contribute to improved guideline-based clinical behaviour among psychiatrists.

Abstract Background Guideline for Pharmacological Therapy for Schizophrenia was published by the Japanese Society of Neuropsychopharmacology in 2015. “Effectiveness of Guidelines for Dissemination and Education in psychiatric treatment (EGUIDE)” project aimed to standardize medical practice using quality indicators (QIs) as indices to evaluate the quality of medical practice. In this study, we have reported the quality indicator values of prescription before the beginning of the guideline lectures in the EGUIDE project to ascertain the baseline status of treating patients with schizophrenia. Methods A cross‐sectional, retrospective case record survey was conducted, involving 1164 patients with schizophrenia at the time of discharge. We checked all types and dosage of psychotropic drugs. Results Forty‐three percent of patients had antipsychotic polypharmacy, and substantial concomitant medication was observed (antidepressants; 8%, mood stabilizers: 37%, anxiolytics or hypnotics: 68%). Conclusions In the results obtained in this study, we plant to report changes in the effectiveness of education in the EGUIDE project near the future.

Abstract Aim Matrix metalloproteinase‐9 (MMP‐9) has been shown to modulate synaptic plasticity and may contribute to the pathophysiology of schizophrenia. This study investigated the peripheral levels of MMP‐9 and its association with cognitive functions in patients with schizophrenia to see the possible involvement of MMP‐9 in pathophysiology of schizophrenia, especially in cognitive decline. Methods We measured the plasma levels of MMP‐9 in 257 healthy controls and 249 patients with schizophrenia, including antipsychotic drug–free patients. We also explored the possible association between plasma MMP‐9 levels and cognitive performance in healthy controls and patients with schizophrenia using the Wechsler Adult Intelligence Scale, Third Edition (WAIS‐ III), the Wechsler Memory Scale‐Revised (WMS‐R), and the Rey Auditory Verbal Learning Test (AVLT). Results We found that the plasma levels of MMP‐9 were significantly higher in patients with schizophrenia, including antipsychotic drug–free patients, than in healthy controls. We found a significant negative association between plasma MMP‐9 levels and cognitive performance in controls and patients with schizophrenia. Conclusion Together, these convergent data suggest a possible biological mechanism for schizophrenia, whereby increased MMP‐9 levels are associated with cognitive impairment.

ObjectiveTuberous sclerosis complex (TSC) is a genetic disease that arises from TSC1 or TSC2 abnormalities and induces the overactivation of the mammalian/mechanistic target of rapamycin pathways. The neurological symptoms of TSC include epilepsy and tuberous sclerosis complex-associated neuropsychiatric disorders (TAND). Although TAND affects TSC patients' quality of life, the specific region in the brain associated with TAND remains unknown. We examined the association between white matter microstructural abnormalities and TAND, using diffusion tensor imaging (DTI).MethodsA total of 19 subjects with TSC and 24 age-matched control subjects were enrolled. Tract-based spatial statistics (TBSS) were performed to assess group differences in fractional anisotropy (FA) between the TSC and control groups. Atlas-based association analysis was performed to reveal TAND-related white matter in subjects with TSC. Multiple linear regression was performed to evaluate the association between TAND and the DTI parameters; FA and mean diffusivity in seven target regions and projection fibers.ResultsThe TBSS showed significantly reduced FA in the right hemisphere and particularly in the inferior frontal occipital fasciculus (IFOF), inferior longitudinal fasciculus (ILF), superior longitudinal fasciculus (SLF), uncinate fasciculus (UF), and genu of corpus callosum (CC) in the TSC group relative to the control group. In the association analysis, intellectual disability was widely associated with all target regions. In contrast, behavioral problems and autistic features were associated with the limbic system white matter and anterior limb of the internal capsule (ALIC) and CC.ConclusionThe disruption of white matter integrity may induce underconnectivity between cortical and subcortical regions. These findings suggest that TANDs are not the result of an abnormality in a specific brain region, but rather caused by connectivity dysfunction as a network disorder. This study indicates that abnormal white matter connectivity including the limbic system is relevant to TAND. The analysis of brain and behavior relationship is a feasible approach to reveal TAND related white matter and neural networks. TAND should be carefully assessed and treated at an early stage.

Background. Dark chocolate has attracted attention for its potential for cognitive improvement. Though some reports indicate that dark chocolate is good for cognitive function, others raise doubts. This inconsistency in past results reflecting the relationship between dark chocolate and cognitive function indicates the potential existence of factors that mediate between dark chocolate intake and cognitive function. Methods. With the hypothesis that fatigue may be one such mediating factor, we performed a four-week randomized control study to seek a link between dark chocolate consumption, cognitive function, fatigue, and the brain in middle-aged adults. Results. We found that dark chocolate reduced mental and physical fatigue, and a path analysis revealed that it enhanced vitality, executive function, memory, and gray matter volume both directly and indirectly. Fatigue reduction was also associated with an improvement in physical function, which had a positive impact on emotional functioning, relief of bodily pain, and social functioning. Conclusions. Our results suggest that dark chocolate may help reduce fatigue in individuals, leading to improvements in brain health and various cognitive functions as well as in quality of life.

BackgroundWith the spread of COVID-19, the deterioration of public mental health has become a major global and social problem. ObjectiveThe purpose of this study was to elucidate the relationship between the 3 mental health problems associated with COVID-19, that is, perceived stress, severe mental distress, and anxiety symptoms, and the various demographic factors, including occupation. MethodsA nationwide web-based questionnaire survey was conducted in Japan from August 4 to 31, 2020. In addition to sociodemographic data, the degrees of perceived stress, severe mental distress, and anxiety symptoms associated with COVID-19 were measured. After performing a descriptive statistical analysis, factors related to stress, severe mental distress, and anxiety symptoms were analyzed using logistic regression analysis. ResultsA total of 8203 respondents submitted survey responses, among whom 34.9% (2861/8203) felt intense stress associated with COVID-19, 17.1% (1403/8203) were depressed, and 13.5% (1110/8203) had severe anxiety symptoms. The logistic regression analysis showed that each of the 3 mental health problems were prevalent in females, nonbinary gender, people in their 50s, 60s and older, respondents who visited psychiatrists, and those currently in psychiatric care. Severe mental distress and anxiety symptoms were associated with the number of effective lifestyle coping strategies during the lockdown period. Severe mental distress was only prevalent in teenagers and respondents in their 20s, as students tended to develop stress and severe mental distress. With regard to occupation, working in nursing care and welfare, education and research, and medical and health sectors was associated with stress; however, working in these occupations was not associated with severe mental distress and anxiety symptoms. Unemployment was associated with severe mental distress and anxiety symptoms. All 3 mental health problems were prevalent in part-time workers and those working in entertainment and arts sectors. ConclusionsGender, age, occupation, history of psychiatric visits, and stress coping mechanisms were associated with mental health during the COVID-19 pandemic, but their associations with stress, severe mental distress, and anxiety symptoms differed. In addition, the actual state of mental health varied according to the respondents’ occupation. It is necessary to consider the impact of the COVID-19 pandemic on mental health not only at the individual level but also at the occupational level.

Health-monitoring technologies for automatically detecting the early signs of Alzheimer's disease (AD) have become increasingly important. Speech responses to neuropsychological tasks have been used for quantifying changes resulting from AD and differentiating AD and mild cognitive impairment (MCI) from cognitively normal (CN). However, whether and how other types of speech tasks with less burden on older adults could be used for detecting early signs of AD remains unexplored. In this study, we developed a tablet-based application and compared speech responses to daily life questions with those to neuropsychological tasks in terms of differentiating MCI from CN. We found that in daily life questions, around 80% of speech features showing significant differences between CN and MCI overlapped those showing significant differences in both our study and other studies using neuropsychological tasks, but the number of significantly different features as well as their effect sizes from life questions decreased compared with those from neuropsychological tasks. On the other hand, the results of classification models for detecting MCI by using the speech features showed that daily life questions could achieve high accuracy, i.e., 86.4%, comparable to neuropsychological tasks by using eight questions against all five neuropsychological tasks. Our results indicate that, while daily life questions may elicit weaker but statistically discernable differences in speech responses resulting from MCI than neuropsychological tasks, combining them could be useful for detecting MCI with comparable performance to using neuropsychological tasks, which could help develop health-monitoring technologies for early detection of AD in a less burdensome manner.

Assessing fear and anxiety regarding COVID-19 viral infection is essential for investigating mental health during this epidemic. We have developed and validated a Japanese-language version of The Fear of COVID-19 Scale (FCV-19S) based on a large, nationwide residential sample (n = 6,750) recruited through news and social media responding to an online version of the questionnaire. Data was collected from August 4-25, 2020. Results correlated with K6, GAD-7 and IES-R psychological scales, and T-tests and analysis of variance identified associated factors. All indices indicated the two-factor model emotional fear reactions and symptomatic expressions of fear a better fit for our data than a single-factor model in Confirmatory Factor Analysis (χ2 = 164.16, p

Aim. We investigated the relationship between cognitive function and olfactory and physical functions in middle-aged persons with and without type 2 diabetes (T2D) to examine the potential of olfactory and physical functions as biomarkers for early cognitive impairment. Methods. Enrolled were 70 T2D patients (age 40 to

As the population ages worldwide, the prevalence of cognitive disorders including mild cognitive impairment (MCI) is increasing. MCI appears in 10–20% of adults aged 65 years and older and is generally referred to as an intermediate stage between normal cognitive aging and dementia. To develop timely prevention and early treatment strategies by identifying biological factors, we investigated the relationship between dietary consumption of fish, brain structure, and MCI in cognitively normal subjects. The brain structure was assessed using neuroimaging-derived measures including the “gray-matter brain healthcare quotient (GM-BHQ)” and “fractional-anisotropy brain healthcare quotient (FA-BHQ),” which are approved as the international standard (H.861.1) by the International Telecommunication Union Telecommunication Standardization Sector. Dietary consumption of fish was calculated using the brief self-administered diet history questionnaire (BDHQ), and MCI was assessed using the Memory Performance Index (MPI) of MCI screening method (MCI Screen). This study showed that fish intake was positively associated with both FA-BHQ and MPI, and FA-BHQ was more strongly associated with MPI than fish intake. Our findings are in line with those in previous studies, but our study further indicates that the condition of the whole brain integrity measured by the FA-BHQ may mediate the relationship between fish intake and MCI prevention in healthy people. In other words, FA-BHQ may be used to identify people at high risk of MCI to provide the appropriate intervention.

Background: The effect of duration of illness and antipsychotic medication on the volumes of subcortical structures in schizophrenia is inconsistent among previous reports. We implemented a large sample analysis utilizing clinical data from 11 institutions in a previous meta-analysis. Methods: Imaging and clinical data of 778 schizophrenia subjects were taken from a prospective meta-analysis conducted by the COCORO consortium in Japan. The effect of duration of illness and daily dose and type of antipsychotics were assessed using the linear mixed effect model where the volumes of subcortical structures computed by FreeSurfer were used as a dependent variable and age, sex, duration of illness, daily dose of antipsychotics and intracranial volume were used as independent variables, and the type of protocol was incorporated as a random effect for intercept. The statistical significance of fixed-effect of dependent variable was assessed. Results: Daily dose of antipsychotics was positively associated with left globus pallidus volume and negatively associated with right hippocampus. It was also positively associated with laterality index of globus pallidus. Duration of illness was positively associated with bilateral globus pallidus volumes. Type of antipsychotics did not have any effect on the subcortical volumes. Discussion: A large sample size, uniform data collection methodology and robust statistical analysis are strengths of the current study. This result suggests that we need special attention to discuss about relationship between subcortical regional brain volumes and pathophysiology of schizophrenia because regional brain volumes may be affected by antipsychotic medication. Keywords: Schizophrenia, MRI, Globus pallidus, Hippocampus, Antipsychotic, Duration of illness

Cognitive impairments are a core feature in schizophrenia patients (SCZ) and are also observed in first-degree relatives (FR) of SCZ. However, substantial variability in the impairments exists within and among SCZ, FR and healthy controls (HC). A cluster-analytic approach can group individuals based on profiles of traits and create more homogeneous groupings than predefined categories. Here, we investigated differences in the Brief Assessment of Cognition in Schizophrenia (BACS) neuropsychological battery (six subscales) among SCZ, unaffected FR and HC. To identify three homogeneous and meaningful cognitive groups regardless of categorical diagnoses (SCZ, FR and HC), cognitive clustering was performed, and differences in the BACS subscales among the cognitive cluster groups were investigated. Finally, the effects of diagnosis and cognition on brain volumes were examined. As expected, there were significant differences in the five BACS subscales among the diagnostic groups. The cluster-analytic approach generated three meaningful subgroups: (i) neuropsychologically normal, (ii) intermediate impaired and (iii) widespread impaired. The cognitive subgroups were mainly affected by the clinical diagnosis, and significant differences in all BACS subscales among clusters were found. The effects of the diagnosis and cognitive clusters on brain volumes overlapped in the frontal, temporal and limbic regions. Frontal and temporal volumes were mainly affected by the diagnosis, whereas the anterior cingulate cortex (ACC) volumes were affected by the additive effects of diagnosis and cognition. Our findings demonstrate a cognitive continuum among SCZ, FR and HC and support the concept of cognitive impairment and the related ACC volumes as intermediate phenotypes in SCZ. Keywords: Schizophrenia, First-degree relative, Cognitive clustering, Brain volume, Anterior cingulate cortex

Background: Impaired cognitive flexibility has been implicated in the genetic basis of obsessive-compulsive disorder (OCD). Recent endophenotype studies of OCD showed neural inefficiency in the cognitive control network and interference by the limbic network of the cognitive control network. Exploring the relationship between the functional brain network and impaired cognitive flexibility may provide novel information about the neurobiological basis of OCD. Methods: We obtained resting-state functional magnetic resonance imaging (rsfMRI) scans and measured the cognitive flexibility of 37 medication-free OCD patients and 40 healthy control (HC) participants using the Wisconsin Card Sorting Test (WCST). We explored the difference between OCD and HC groups in the functional brain network related to impaired cognitive flexibility from the amygdala and dorsal striatal regions of interest (ROIs) by using a seed-based approach. Results: Significant differences between the OCD and HC groups were identified in the resting state functional network from the dorsal caudate. Increased functional connectivity from the dorsal caudate to the dorsal anterior cingulate cortex (dACC) and anterior insula (AI) was associated with poorer cognitive flexibility in the OCD group, but better cognitive flexibility in the HC group. Conclusions: These results provide evidence that the impaired cognitive flexibility of OCD may be associated with dysfunctions of the brain network from the dorsal caudate (DC) to important nodes of the salience network. Our results extend the neuropsychological model of OCD by showing intrinsically different associations between OCD and HC in functional network and cognitive flexibility. Keywords: Obsessive-compulsive disorder, Cognitive flexibility, Salience network, Dorsal caudate, Functional connectivity, Resting state functional MRI

Stress is associated with a greater risk for various health problems including reduced gray matter volume (GMV) and density in a number of brain regions. Previous studies show that neuroimaging could be a means to objectively evaluate stress. However, to date, no definite neuroimaging-derived measures are available to detect stress. In this research we used the gray-matter brain healthcare quotient (GM-BHQ), an MRI-based quotient for monitoring brain health based on GMV, as an objective scale to measure the association of stress with the whole brain. We recruited 63 healthy adults to acquire structural T1-weighted images and stress levels evaluated using three representative stress scales: the Profile of Mood States (POMS), Perceived Stress Scale (PSS) and Chalder Fatigue Scale (CFS). We found that the GM-BHQ was sensitive to fatigue and the interaction between fatigue and stress.

Background: Previously, we reported on vascular cognitive impairment (VCI) templates, consisting of patients with VCI associated with carotid stenosis (>60%) using a quantitative electroencephalographic (EEG) technique called neuronal activity topography (NAT). Here using the VCI templates, we investigated the hypothesis that internal carotid artery–intima-media thickness (ICA–IMT) is associated with EEG spectrum intensity (sNAT) and spectrum steepness (vNAT).Methods: A total of 221 community-dwelling elderly subjects were recruited. Four groups were classified according to quartiles of ICA–IMT as assessed by ultrasonography: control group A, normal (≤0.9 mm); group B, mild atherosclerosis (1−1.1 mm); group C, moderate atherosclerosis (1.2−1.8 mm); and group D, severe atherosclerosis (≥1.9 mm). EEG markers of power ratio index (PRI), and the binary likelihood of being in the VCI group vs. the that of being in control group A (sLx:VCI−A, vLx:VCI−A) were assessed, respectively. Differences in mean total scores for PRI, sLx:VCI−A, vLx:VCI−A, between control group A and the other groups were compared using Dunnett's test, respectively.Results: The mean total scores of the PRI were 3.25, 3.00, 2.77, and 2.26 for groups A, B, C, and D, respectively. There was a significant decrease in the PRI in group D compared with group A (P = 0.0066). The mean total scores of the sLx:VCI−A were −0.14, −0.11, −0.1, and −0.03 for groups A, B, C, and D, respectively. The sLx:VCI−A in group D was significantly higher compared to that in group A (P < 0.0001). The mean total scores of the vLx:VCI−A were −0.04,−0.01, 0.01, and 0.06 for group A, B, C, and D, respectively. The vLx:VCI−A in group D and group C was significantly higher compared to that in group A, respectively (P < 0.0001, P = 0.02).Conclusion: Community-dwelling elderly subjects in the increased carotid atherosclerosis of ICA–IMT (≥1.9 mm) were at greatest risk of an EEG change as assessed by NAT.

Neurological and psychiatric disorders are a burden on social and economic resources. Therefore, maintaining brain health and preventing these disorders are important. While the physiological functions of the brain are well studied, few studies have focused on keeping the brain healthy from a neuroscientific viewpoint. We propose a magnetic resonance imaging (MRI)-based quotient for monitoring brain health, the Brain Healthcare Quotient (BHQ), which is based on the volume of gray matter (GM) and the fractional anisotropy (FA) of white matter (WM). We recruited 144 healthy adults to acquire structural neuroimaging data, including T1-weighted images and diffusion tensor images, and data associated with both physical (BMI, blood pressure, and daily time use) and social (subjective socioeconomic status, subjective well-being, post-materialism and Epicureanism) factors. We confirmed that the BHQ was sensitive to an age-related decline in GM volume and WM integrity. Further analysis revealed that the BHQ was critically affected by both physical and social factors. We believe that our BHQ is a simple yet highly sensitive, valid measure for brain health research that will bridge the needs of the scientific community and society and help us lead better lives in which we stay healthy, active, and sharp.

BackgroundYWHAE is a possible susceptibility gene for schizophrenia that encodes 14-3-3epsilon, a Disrupted-in-Schizophrenia 1 (DISC1)-interacting molecule, but the effect of variation in its genotype on brain morphology remains largely unknown.MethodsIn this voxel-based morphometric magnetic resonance imaging study, we conducted whole-brain analyses regarding the effects of YWHAE single-nucleotide polymorphisms (SNPs) (rs28365859, rs11655548, and rs9393) and DISC1 SNP (rs821616) on gray matter volume in a Japanese sample of 72 schizophrenia patients and 86 healthy controls. On the basis of a previous animal study, we also examined the effect of rs28365859 genotype specifically on hippocampal volume.ResultsWhole-brain analyses showed no significant genotype effect of these SNPs on gray matter volume in all subjects, but we found significant genotype-by-diagnosis interaction for rs28365859 in the left insula and right putamen. The protective C allele carriers of rs28365859 had a significantly larger left insula than the G homozygotes only for schizophrenia patients, while the controls with G allele homozygosity had a significantly larger right putamen than the C allele carriers. The C allele carriers had a larger right hippocampus than the G allele homozygotes in schizophrenia patients, but not in healthy controls. No significant interaction was found between rs28365859 and DISC1 SNP on gray matter volume.ConclusionsThese different effects of the YWHAE (rs28365859) genotype on brain morphology in schizophrenia and healthy controls suggest that variation in its genotype might be, at least partly, related to the abnormal neurodevelopment, including in the limbic regions, reported in schizophrenia. Our results also suggest its specific role among YWHAE SNPs in the pathophysiology of schizophrenia.

BACKGROUND: The rs12807809 single-nucleotide polymorphism in NRGN is a genetic risk variant with genome-wide significance for schizophrenia. The frequency of the T allele of rs12807809 is higher in individuals with schizophrenia than in those without the disorder. Reduced immunoreactivity of NRGN, which is expressed exclusively in the brain, has been observed in Brodmann areas (BA) 9 and 32 of the prefrontal cortex in postmortem brains from patients with schizophrenia compared with those in controls. METHODS: Genotype effects of rs12807809 were investigated on gray matter (GM) and white matter (WM) volumes using magnetic resonance imaging (MRI) with a voxel-based morphometry (VBM) technique in a sample of 99 Japanese patients with schizophrenia and 263 healthy controls. RESULTS: Although significant genotype-diagnosis interaction either on GM or WM volume was not observed, there was a trend of genotype-diagnosis interaction on GM volume in the left anterior cingulate cortex (ACC). Thus, the effects of NRGN genotype on GM volume of patients with schizophrenia and healthy controls were separately investigated. In patients with schizophrenia, carriers of the risk T allele had a smaller GM volume in the left ACC (BA32) than did carriers of the non-risk C allele. Significant genotype effect on other regions of the GM or WM was not observed for either the patients or controls. CONCLUSIONS: Our findings suggest that the genome-wide associated genetic risk variant in the NRGN gene may be related to a small GM volume in the ACC in the left hemisphere in patients with schizophrenia.