National Center of Neurology and Psychiatry
Recent publications
Background Training non-specialist workers in mental healthcare improves knowledge, attitude, confidence, and recognition of mental illnesses. However, still little information is available on which type of mental health training is important in the improvement of these capacities. Methods We studied web-based survey data of 495 public health workers to examine training types associated with knowledge and experience in supporting individuals with mental illness. Multivariable logistic regression analysis was conducted to evaluate the association between a lack of knowledge and experience (outcome) and mental health training (exposure). We fitted three regression models. Model 1 evaluated unadjusted associations. Model 2 adjusted for age and sex. Model 3 adjusted for age, sex, years of experience, mental health full-time worker status, and community population. Bias-corrected and accelerated bootstrap confidence intervals (CIs) were used. Results For all training types, the association between a lack of knowledge and experience and mental health training attenuated as the model developed. In Model 3, a lack of knowledge and experience was significantly associated with training in specific illness (OR, 0.54; 95% CI, 0.32–0.93) and screening and assessment (OR, 0.63; 95% CI, 0.39–0.99). Non-significant results were produced for training in counseling, psychosocial support, collaborative work, and law and regulation in Model 3. Conclusions We believe that the present study provides meaningful information that training in specific illness and screening and assessment may lead to knowledge and experience of public health workers. Further studies should employ a longitudinal design and validated measurements.
Autism spectrum disorder (ASD) is a neurodevelopmental condition characterized by specific social symptoms, restricted interests, stereotyped repetitive behaviors, and delayed language development. The 3q29 microdeletion (3q29del), a recurrent copy number variant, confers a high risk for ASD and schizophrenia, and serves as an important pathological model for investigating the molecular pathogenesis of a large number of neurodevelopmental and psychiatric conditions. Recently, mouse models carrying a deletion of the chromosomal region corresponding to the human 3q29 region (Df/+ mice) were generated and demonstrated neurodevelopmental and psychiatric conditions associated behavioral abnormalities, pointing to the relevance of Df/+ mice as a model for these conditions with high construct and face validity. Currently, the molecular pathogenesis of these behavioral phenotypes in Df/+ mice remains unclear. The oxytocin (OXT) system plays a central role in social behavior across species and has a potential role in ASD. In this study, to elucidate the molecular mechanisms behind impaired social behavior in Df/+ mice, we investigated the possible involvement of OXT signaling in impaired social behavior in Df/+ mice. We demonstrated that OXT administration restored the impaired social behavior in Df/+ mice. We also demonstrated that the number of OXT-positive cells in the paraventricular nucleus (PVN) was significantly lower in Df/+ mice than in wild-type (WT) littermates. Consistent with this, the level of OXT peptide in the cerebral cortex of Df/+ mice was lower than in WT littermates. Our study may provide important insights into the molecular pathophysiological basis of neurodevelopmental and psychiatric conditions, including ASD.
Background The transient receptor potential cation channel subfamily V member 2 (TRPV2) is a stretch-sensitive calcium channel. TRPV2 overexpression in the sarcolemma of skeletal and cardiac myocytes causes calcium influx into the cytoplasm, which triggers myocyte degeneration. In animal models of cardiomyopathy and muscular dystrophy (MD), TRPV2 inhibition was effective against heart failure and motor function. Our previous pilot study showed that tranilast, a TRPV2 inhibitor, reduced brain natriuretic peptide (BNP) levels in two MD patients with advanced heart failure. Thus, this single-arm, open-label, multicenter study aimed to evaluate the safety and efficacy of tranilast for heart failure. Methods The study enrolled MD patients with advanced heart failure whose serum BNP levels were > 100 pg/mL despite receiving standard cardioprotective therapy. Tranilast was administered orally at 100 mg, thrice daily. The primary endpoint was the change in log (BNP) (Δlog [BNP]) at 6 months from baseline. The null hypothesis was determined based on a previous multicenter study of carvedilol results in a mean population Δlog (BNP) of 0.18. TRPV2 expression on peripheral blood mononuclear cell surface, cardiac events, total mortality, left ventricular fractional shortening, human atrial natriuretic peptide, cardiac troponin T, and creatine kinase, and pinch strength were also assessed. Results Because of the poor general condition of many patients, only 18 of 34 patients were included and 13 patients could be treated according to the protocol throughout the 6-month period. However, there were no serious adverse events related to tranilast except diarrhea, a known adverse effect, and the drug was administered safely. TRPV2 expression on the mononuclear cell surface was elevated at baseline and reduced after treatment. Cardiac biomarkers such as BNP, human atrial natriuretic peptide, and fractional shortening remained stable, suggesting a protective effect against the progression of heart failure. In the per protocol set group, Δlog [BNP] was − 0.2 and significantly lower than that in the null hypothesis. Conclusions Tranilast is safe and effective in inhibiting TRPV2 expression, even in MD patients with advanced heart failure. Further trials are needed to evaluate the efficacy of tranilast in preventing myocardial damage, heart failure, motor impairment, and respiratory failure. Clinical trial registration The study was registered in the UMIN Clinical Trials Registry (UMIN-CTR: UMIN000031965, URL: ) [March 30, 2018] and the Japan Registry of Clinical Trials (jRCT, registration number: jRCTs031180038, URL: ) [November 12, 2021]. Patient registration was started in December 19, 2018.
The magnetic resonance imaging (MRI)-less non-standard pipeline for amyloid positron emission tomography (PET) published by Bourgeat et al., in 2018 calculates Centiloid scale values that are highly consistent with those computed using the standard pipeline. The purpose of this study was to demonstrate that the non-standard pipeline can compute Centiloid scale values in high agreement with the standard pipeline when using different datasets of amyloid PET tracers in our local computer environment. PET images of ¹¹C-Pittsburgh compound B (¹¹C-PiB), ¹⁸F-florbetapir, ¹⁸F-flutemetamol, ¹⁸F-florbetaben, and ¹⁸F-NAV4694 from the calibration dataset were processed using both the standard and non-standard pipelines, and the computed cortical standardized uptake value ratio (SUVr) value was converted to the Centiloid scale value using the method described by Klunk et al., in 2015. The conversion equations from the SUVr to Centiloid scale values for each tracer were obtained during this process. Using these equations, we compared the Centiloid scale values obtained using the standard and non-standard pipelines using the validation datasets of each tracer from the Japanese Alzheimer’s Disease Neuroimaging Initiative (J-ADNI), Alzheimer’s Disease Neuroimaging Initiative (ADNI), and Australian Imaging Biomarkers and Lifestyle (AIBL). In the calibration datasets, there was high agreement (R² > 0.97) and slight bias between the Centiloid scale values calculated by the non-standard and standard pipelines for all tracers. Despite relatively little NAV4694 data in the validation datasets, there was high agreement between the Centiloid scale values calculated using the non-standard and standard pipelines for all tracers. The bias for florbetaben and NAV4694 using the non-standard pipeline was 1.6% underestimation and 3.3% overestimation, respectively; these values were smaller than those reported by Bourgeat et al. Analysis of outliers also suggested that the non-standard pipeline might be vulnerable to anatomical anomalies. Given the slight variance of the Centiloid scale in young controls, flutemetamol and NAV4694 might be suitable tracers for the non-standard pipelines. This study demonstrates the replicability of the non-standard pipelines across computing environments, datasets, scanners, and tracers. When MRI is not available, the non-standard pipeline may provide information to aid in visual assessment of amyloid PET.
The Nausea and Vomiting of Pregnancy Quality of Life (NVP QOL) Questionnaire is a self‐report measure of health‐related QOL for nausea and vomiting during pregnancy. This study determines the best fitting factor structure for the NVP QOL Questionnaire and explores its measurement invariance in terms of observation time and parity. A test–retest study of pregnant women was conducted at Gestational Weeks (GWs) 10–13 (T1: N = 381) and 1 week later (T2: n = 128) at one hospital and five clinics with the NVP QOL and the Pregnancy‐Unique Quantification of Emesis and Nausea (PUQE). Exploratory and confirmatory factor analyses were performed to compare different factor structure models and evaluate measurement invariance of the best fitting model between two time points and between primiparas and multiparas. Concurrent validity of the NVP QOL was clarified by correlations with the PUQE, Sheehan Disability Scale, and other scales. The one‐factor model had the best fit. This factor structure model was acceptable up to the factor invariance level for two time points and up to the factor mean level for primiparas versus multiparas. Correlations between NVP QOL, PUQE, and Sheehan Disability Scale scores were strong. Women with higher NVP QOL scores were more likely to lose weight, have lower daily fluid intake, have reduced fluid and food intake since pregnancy began, and receive outpatient or inpatient treatment. The one‐factor structure and measurement invariance of the NVP QOL at different times and parities were demonstrated, suggesting that the NVP QOL can be used to evaluate primiparas and multiparas in a longitudinal study.
The aim of this study is to examine the long‐term impact of early menarche with adult depression, and to assess whether this association was explained by childhood traumatic experience and socioeconomic condition in early adulthood. The data were derived from World Mental Health Survey Japan Second, a cross‐sectional survey conducted among Japanese community residents between 2013 and 2015. We used the data of female respondents aged 20–75 years (N = 1171). Hazard ratio (HR) of the onset of major depression up to 40 years was calculated for an early‐menarche group and a non‐early‐menarche group, respectively. Kaplan–Meier curve and log–rank statistics were used to examine the difference in failure. Cox proportional hazard models were administered for the association of major depression with early‐menarche and early‐life psychosocial factors. Risk for major depressive disorders were three to four times higher in an early‐menarche group, and the differences in survival functions were significant (p < 0.001). HR of early menarche was 2.79 (95% CI = 1.29–6.02), and was slightly changed when childhood traumatic experience and socioeconomic conditions in young adulthood were added in the model (HR = 2.88, 95% CI = 1.30–6.38; HR = 3.19, 95% CI = 1.41–7.21). Early menarche was significantly associated with increased risk for depression by the age of 40 years. Childhood trauma and socioeconomic hardship in early adulthood did not account for the association. Both physical and psychosocial risk factors in early life need to be addressed for preventing women's depression. Women who had menarche at an earlier age were at higher risk for depression up to the age of 40 years. This association was independent of psychosocial stressors in early life, such as childhood trauma and socioeconomic hardship in early adulthood. Biological factors that affect the central nervous system during early puberty may be a potential mediator between early menarche and adult depression
Some studies have examined the relationship between premenstrual syndrome (PMS) and antenatal depression. However, retrospective designs were used to obtain the PMS experiences. Different from such earlier research, this study aims to investigate the association between PMS before pregnancy and antenatal depression with a prospective design. This is a secondary analysis of a randomized controlled trial (RCT) conducted among pregnant women. Premenstrual symptoms before pregnancy of the participants were obtained prospectively via a period tracking app. At the baseline of the RCT, 5073 women participated. Of those, 3004 had one or more symptom records related to menstruation 1 year before pregnancy. The outcome, antenatal depression, was assessed using the Edinburgh Postnatal Depression Scale (EPDS) at the RCT baseline, and the cut‐off value was set at 11. For covariates, age, education, planned pregnancy, and the number of children were also measured at the same time. Multiple logistic regression analyses were employed to estimate the odds ratio (OR) of having antenatal depression, adjusting for the covariates. A total of 366 individuals who had three or more cycles of menstrual‐related symptom records were included in the analyses, and of those 52 were applicable to PMS before pregnancy. There was no significant association between PMS and antenatal depression (adjusted OR = 1.28, P = 0.61). The present study was the first study to utilize a prospective design to obtain premenstrual symptoms. Future research should consider using a validated and objective measure of PMS diagnosis and a larger sample.
The human vesicular monoamine transporter 1 (VMAT1) harbors unique substitutions (Asn136Thr/Ile) that affect monoamine uptake into synaptic vesicles. These substitutions are absent in all known mammals, suggesting their contributions to distinct aspects of human behavior modulated by monoaminergic transmission, such as emotion and cognition. To directly test the impact of these human-specific mutations, we introduced the humanized residues into mouse Vmat1 via CRISPR/Cas9-mediated genome editing and examined changes at the behavioral, neurophysiological, and molecular levels. Behavioral tests revealed reduced anxiety-related traits of Vmat1Ile mice, consistent with human studies, and electrophysiological recordings showed altered oscillatory activity in the amygdala under anxiogenic conditions. Transcriptome analyses further identified changes in gene expressions in the amygdala involved in neurodevelopment and emotional regulation, which may corroborate the observed phenotypes. This knock-in mouse model hence provides compelling evidence that the mutations affecting monoaminergic signaling and amygdala circuits have contributed to the evolution of human socio-emotional behaviors.
Glutamate is a pivotal excitatory neurotransmitter in mammalian brains, but excessive glutamate causes numerous neural disorders. Almost all extracellular glutamate is retrieved by the glial transporter, Excitatory Amino Acid Transporter 2 (EAAT2), belonging to the SLC1A family. However, in some cancers, EAAT2 expression is enhanced and causes resistance to therapies by metabolic disturbance. Despite its crucial roles, the detailed structural information about EAAT2 has not been available. Here, we report cryo-EM structures of human EAAT2 in substrate-free and selective inhibitor WAY213613-bound states at 3.2 Å and 2.8 Å, respectively. EAAT2 forms a trimer, with each protomer consisting of transport and scaffold domains. Along with a glutamate-binding site, the transport domain possesses a cavity that could be disrupted during the transport cycle. WAY213613 occupies both the glutamate-binding site and cavity of EAAT2 to interfere with its alternating access, where the sensitivity is defined by the inner environment of the cavity. We provide the characterization of the molecular features of EAAT2 and its selective inhibition mechanism that may facilitate structure-based drug design for EAAT2. EAAT2 is an amino acid transporter implicated in glutamate homeostasis in brain and therapy resistance of cancer cells. Here, the authors report cryo-EM structures and reveal inhibitory mechanisms via selective inhibitor WAY213613.
Anti-mitochondrial antibody (AMA)-associated myopathies represent a homogeneous disease entity with severe arrhythmia and slowly progressive proximal muscle weakness with lordotic posture, irrespective of the presence of primary biliary cholangitis (PBC). We herein report a case of myositis associated with PBC without AMAs. A 48-year-old woman presented with clinical features very similar to AMA-associated myositis, despite negative AMAs. PBC, ascertained by a liver biopsy performed based on mildly elevated liver enzymes, and the efficacy of steroid therapy on muscle weakness confirmed the diagnosis of immune-mediated myositis. When AMAs are negative, a liver biopsy is indispensable for diagnosing treatable PBC-associated myositis.
Impact of venous thromboembolism in Japanese colorectal cancer patients has not been elucidated. This pre-specified sub-analysis of the Cancer-VTE Registry aimed to report venous thromboembolism and event data after 1 year of follow-up in 2477 patients with colorectal cancer and investigate risk factors of venous thromboembolism. Of 2477 patients, 158 (6.4%) had venous thromboembolism in venous thromboembolism screening at enrollment. Asymptomatic distal deep vein thrombosis accounted for 123/158 (77.8%) of venous thromboembolism cases. During the follow-up period, symptomatic, incidental events requiring treatment and composite venous thromboembolism incidences were 0.3%, 0.8%, and 1.0%, respectively. The incidence of bleeding events, cerebral infarction/transient ischemic attack/systemic embolic event, and all-cause death were 1.0%, 0.3%, and 4.8%, respectively. These results were consistent with the main study results. In multivariable analysis, venous thromboembolism at baseline was a risk factor of composite venous thromboembolism during the follow-up period. Japanese patients with colorectal cancer and advancing cancer stage before treatment had more frequent venous thromboembolism complications at baseline, higher incidence of venous thromboembolism events during cancer treatment, and higher mortality.
Thermoregulation is an important aspect of human homeostasis, and high temperatures pose serious stresses for the body. Malignant hyperthermia (MH) is a life-threatening disorder in which body temperature can rise to a lethal level. Here we employ an optically controlled local heat-pulse method to manipulate the temperature in cells with a precision of less than 1 °C and find that the mutants of ryanodine receptor type 1 (RyR1), a key Ca ²⁺ release channel underlying MH, are heat hypersensitive compared with the wild type (WT). We show that the local heat pulses induce an intracellular Ca ²⁺ burst in human embryonic kidney 293 cells overexpressing WT RyR1 and some RyR1 mutants related to MH. Fluorescence Ca ²⁺ imaging using the endoplasmic reticulum–targeted fluorescent probes demonstrates that the Ca ²⁺ burst originates from heat-induced Ca ²⁺ release (HICR) through RyR1-mutant channels because of the channels’ heat hypersensitivity. Furthermore, the variation in the heat hypersensitivity of four RyR1 mutants highlights the complexity of MH. HICR likewise occurs in skeletal muscles of MH model mice. We propose that HICR contributes an additional positive feedback to accelerate thermogenesis in patients with MH.
Dystonin (DST), which encodes cytoskeletal linker proteins, expresses three tissue-selective isoforms: neural DST-a, muscular DST-b, and epithelial DST-e. DST mutations cause different disorders, including hereditary sensory and autonomic neuropathy 6 (HSAN-VI) and epidermolysis bullosa simplex; however, etiology of the muscle phenotype in DST-related diseases has been unclear. Because DST-b contains all of the DST-a-encoding exons, known HSAN-VI mutations could affect both DST-a and DST-b isoforms. To investigate the specific function of DST-b in striated muscles, we generated a Dst-b-specific mutant mouse model harboring a nonsense mutation. Dst-b mutant mice exhibited late-onset protein aggregate myopathy and cardiomyopathy without neuropathy. We observed desmin aggregation, focal myofibrillar dissolution, and mitochondrial accumulation in striated muscles, which are common characteristics of myofibrillar myopathy. We also found nuclear inclusions containing p62, ubiquitin, and SUMO proteins with nuclear envelope invaginations as a unique pathological hallmark in Dst-b mutation-induced cardiomyopathy. RNA-sequencing analysis revealed changes in expression of genes responsible for cardiovascular functions. In silico analysis identified DST-b alleles with nonsense mutations in populations worldwide, suggesting that some unidentified hereditary myopathy and cardiomyopathy are caused by DST-b mutations. Here, we demonstrate that the Dst-b isoform is essential for long-term maintenance of striated muscles.
Purpose of review: This review summarizes and comments on current knowledge in dermatomyositis. Recent findings: The 2018 European Neuromuscular Centre classification of dermatomyositis has been challenging by the discovery of clinicopathological features associated with dermatomyositis-specific antibody (DMSA) that were not incorporated in the original criteria. These features include but may not be limited to the presence of perifascicular necrosis in anti-Mi-2 dermatomyositis; presence of diffuse nonperifascicular sarcoplasmic myxovirus resistance protein A expression in anti-MDA5 dermatomyositis; and dermatomyositis sine dermatitis in anti-NXP-2 dermatomyositis. Variations and subclassifications within the same DMSA subtypes are observed: anti-MDA5 dermatomyositis is clinically subcategorized into good, intermediate, and poor prognostic subgroups; concurrent anti-CCAR1 and anti-TIF1-γ positivity identify anti-TIF1-γ-positive patient with a lower risk for cancer-associated myositis. Owing to distinct IFN1-signaling pathway activation in dermatomyositis, JAK-STAT inhibitor - the pathway-targeted therapy, have been studied with promising results in refractory dermatomyositis and some new-onset dermatomyositis. In addition, the potential serum biomarkers for IFN1 pathway activation are being investigated for their performance in monitoring the disease activity and the efficacy of the treatment. Summary: DMSA, evidence of prominent IFN1 pathway activation, and risk/severity-associated biomarkers would likely play major roles in future dermatomyositis classification, disease monitoring, and treatment decision.
Background: Social cognitive impairments adversely affect social functioning (e.g., employment status) in patients with schizophrenia. Although pharmacological interventions have been suggested to provide some benefits on social cognition, little information is available on the comparative efficacy of pharmacotherapy. Thus, the aim of this planned systematic review and network meta-analysis is to perform a quantitative comparison of the effects of various psychotropic drugs, including supplements, on social cognition disturbances of schizophrenia. Methods: The literature search will be carried out using the PubMed, Embase, Cochrane Central Register of Controlled Trials, PsycINFO,, and International Clinical Trials Registry Platform databases from inception onward. Randomized controlled trials that examined the efficacy of drugs in social cognitive disturbances will be included, based on the most recent studies and the broader literature than previously searched. This protocol defines a priori the methods that will be used for study selection, data collection, quality assessment, and statistical syntheses. Discussion: The findings this work are expected to help promote the development of better therapeutics of social cognitive impairments in schizophrenia and related psychiatric conditions. Systematic Review Registration: [], identifier [CRD42021293224].
Aim The aim of this pilot study is to evaluate a Japanese version of brief Cognitive Behavioral Therapy for Insomnia (CBT-I) and contribute to primary care which leads to prevention of a lifestyle-related disease or a psychiatric disorder. Method A single-arm study in nine patients with chronic insomnia who were under the pharmacotherapy was executed. The Insomnia Severity Index (ISI), the Athens Insomnia Scale (AIS), and the European Quality of Life 5 Items (EQ-5D) were assessed at the beginning of intervention, at the end of intervention, and after 12 weeks. Findings There were no patient dropouts nor adverse events. The average change in ISI score was −7.33 (95% CI: −10.31 to −4.36) at post-treatment and −6.11 (95% CI: −8.20 to −4.03) at the 12-week follow-up point (Cohen’s d = 2.25). The AIS score improved as well, and the EQ-5D score improved after 12 weeks. The safety and efficacy of the brief CBT-I were suggested.
Dopamine dysfunction has been associated with depression. However, results of recent neuroimaging studies on dopamine transporter (DAT), which reflect the function of the dopaminergic system, are inconclusive. The aim of this study was to apply texture analysis, a novel method to extract information about the textural properties of images (e.g., coarseness), to single-photon emission computed tomography (SPECT) imaging in depression. We performed SPECT using 123I-ioflupane to measure DAT binding in 150 patients with major depressive disorder (N = 112) and bipolar disorder (N = 38). The texture features of DAT binding in subregions of the striatum were calculated. We evaluated the relationship between the texture feature values (coarseness, contrast, and busyness) and severity of depression, and then examined the effects of medication and diagnosis on such relationship. Furthermore, using the data from 40 healthy subjects, we examined the effects of age and sex on the texture feature values. The degree of busyness of the limbic region in the left striatum linked to the severity of depression (p = 0.0025). The post-hoc analysis revealed that this texture feature value was significantly higher in both the severe and non-severe depression groups than in the remission group (p = 0.001 and p = 0.028, respectively). This finding remained consistent after considering the effect of medication. The effects of age and sex in healthy individuals were not evident in this texture feature value. Our findings imply that the application of texture analysis to DAT-SPECT may provide a state-marker of depression.
Mitochondrial disorders are a group of clinically and genetically heterogeneous multisystem disorders and peripheral neuropathy is frequently described in the context of mutations in mitochondrial-related nuclear genes. This study aimed to identify the causative mutations in mitochondrial-related nuclear genes in suspected hereditary peripheral neuropathy patients. We enrolled a large Japanese cohort of clinically suspected hereditary peripheral neuropathy patients who were mutation negative in the prescreening of the known Charcot–Marie–Tooth disease-causing genes. We performed whole-exome sequencing on 247 patients with autosomal recessive or sporadic inheritance for further analysis of 167 mitochondrial-related nuclear genes. We detected novel bi-allelic likely pathogenic/pathogenic variants in four patients, from four mitochondrial-related nuclear genes: pyruvate dehydrogenase beta-polypeptide ( PDHB ), mitochondrial poly(A) polymerase ( MTPAP ), hydroxyacyl-CoA dehydrogenase/3-ketoacyl-CoA thiolase/enoyl-CoA hydratase, beta subunit ( HADHB ), and succinate-CoA ligase ADP-forming beta subunit ( SUCLA2 ). All these patients showed sensory and motor axonal polyneuropathy, combined with central nervous system or multisystem involvements. The pathological analysis of skeletal muscles revealed mild neurogenic changes without significant mitochondrial abnormalities. Targeted screening of mitochondria-related nuclear genes should be considered for patients with complex hereditary axonal polyneuropathy, accompanied by central nervous system dysfunctions, or with unexplainable multisystem disorders.
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294 members
Ichizo Nishino
  • Department of Neuromuscular Research
Noritaka Ichinohe
  • Department of Ultrastructural Research
Masaki Iwasaki
  • Department of Neurosurgery
Yuma Yokoi
  • Translational Medical Center
Eiji Nakagawa
  • Department of Child Neurology
4-1-1 Ogawahigashi-cho, 187-8502, Kodaira, Tōkyō, Japan