Large-scale animal model study uncovers altered brain pH and lactate levels as a transdiagnostic endophenotype of neuropsychiatric disorders involving cognitive impairment.

Increased levels of lactate, an end-product of glycolysis, have been proposed as a potential surrogate marker for metabolic changes during neuronal excitation. These changes in lactate levels can result in decreased brain pH, which has been implicated in patients with various neuropsychiatric disorders. We previously demonstrated that such alterations are commonly observed in five mouse models of schizophrenia, bipolar disorder, and autism, suggesting a shared endophenotype among these disorders rather than mere artifacts due to medications or agonal state. However, there is still limited research on this phenomenon in animal models, leaving its generality across other disease animal models uncertain. Moreover, the association between changes in brain lactate levels and specific behavioral abnormalities remains unclear. To address these gaps, the International Brain pH Project Consortium investigated brain pH and lactate levels in 109 strains/conditions of 2294 animals with genetic and other experimental manipulations relevant to neuropsychiatric disorders. Systematic analysis revealed that decreased brain pH and increased lactate levels were common features observed in multiple models of depression, epilepsy, Alzheimer's disease, and some additional schizophrenia models. While certain autism models also exhibited decreased pH and increased lactate levels, others showed the opposite pattern, potentially reflecting subpopulations within the autism spectrum. Furthermore, utilizing large-scale behavioral test battery, a multivariate cross-validated prediction analysis demonstrated that poor working memory performance was predominantly associated with increased brain lactate levels. Importantly, this association was confirmed in an independent cohort of animal models. Collectively, these findings suggest that altered brain pH and lactate levels, which could be attributed to dysregulated excitation/inhibition balance, may serve as transdiagnostic endophenotypes of debilitating neuropsychiatric disorders characterized by cognitive impairment, irrespective of their beneficial or detrimental nature.

MR diagnosis of SCC arising within ovarian cystic teratomas: analysis of mural nodule characteristics.

PURPOSE: This study aims to evaluate and identify magnetic resonance (MR) findings of mural nodules to detect squamous cell carcinoma arising from ovarian mature cystic teratoma (SCC-MCT). METHODS: This retrospective study examined 135 patients (SCC-MCTs, n = 12; and benign MCTs, n = 123) with confirmed diagnoses across five different institutions between January 2010 and June 2022. Preoperative MR images for each patient were independently assessed by two experienced radiologists and analyzed following previously reported findings (PRFs): age, tumor size, presence of mural nodules, size of mural nodule, and the angle between mural nodule and cyst wall (acute or obtuse). Furthermore, this study evaluated four mural nodule features-diffusion restriction, fat intensity, Palm tree appearance, and calcification-and the presence of transmural extension. RESULTS: There were significant differences between the SCC-MCT and benign MCT groups in terms of all PRFs and all mural nodule findings (p < 0.01). Among the PRFs, "tumor size" demonstrated the highest diagnostic performance, with a sensitivity of 83.3% and a specificity of 88.6%. A combination of the aforementioned four mural nodule findings showed a sensitivity and specificity of 83.3% and 97.6%, respectively, for the diagnosis of SCC-MCT. Regarding diagnosis based on a combination of four mural nodule findings, the specificity was significantly higher than the diagnosis based on tumor size (p = 0.021). Based on these mural nodule findings, three SCC-MCT patients without transmural invasion could be diagnosed. CONCLUSION: Mural nodule MR findings had a higher diagnostic performance than PRFs for SCC-MCT and can potentially allow early detection of SCC-MCTs.

Perspectives of Japanese elders and their healthcare providers on use of wearable technology to monitor their health at home: A qualitative exploration.

BACKGROUND: With 24 million Japanese elderly aging at home, the challenges of managing chronic conditions are significant. As many Japanese elders manage multiple chronic conditions, investigating the usefulness of wearable health devices for this population is warranted. AIM: The purpose of this qualitative study, using grounded theory, was to explore the perspectives of Japanese elders, their caretakers, and their healthcare providers on the use of technology and wearable devices to monitor health conditions and keep Japanese elders safe at home. METHODS: In conducting this study, a community advisory board was first established to guide the research design; six focus groups and two one-on-one interviews were conducted, with a total of 21 participants. RESULTS: Four major themes emerged from the analysis: 1) Current Status of Health Issues Experienced by Japanese Elders and Ways of Being Monitored; 2) Current Use of Monitoring Technology and Curiosity about Use of the Latest Digital Technology to Keep Elderly Healthy at Home; 3) Perceived Advantages of Wearing Sensor Technology; and 4) Perceived Disadvantages of Wearing Technology. Many of the elderly participants were interested in using monitoring devices at home, particularly if not complicated. Healthcare workers found monitoring technologies particularly useful during the isolation of the COVID-19 pandemic. Elderly participants felt cost and technical issues could be barriers to using monitoring devices. CONCLUSION: While there are challenges to utilizing monitoring devices, the potential to aid the aging population of Japan justifies further investigation into the effectiveness of these devices. This study was not registered with a research trial registry.

[Relationship between work engagement and organizational justice among hospital nurses].

Objective　This study aimed to clarify the relationship between organizational justice and work engagement among nurses.Methods　Japanese nurses working in a medium-sized hospital in the Tokyo metropolitan area were surveyed using a self-administered questionnaire. We conducted a stepwise multiple regression analysis with scores from the Japanese version of the Utrecht Work Engagement Scale (UWES-J) as the dependent variable and scores from the Japanese version of the Organizational Justice Scale (OJS-J), age, sex, position, employment status, shift work, self-efficacy, social support, work control, and work quantitative load as the independent variables. Additionally, a stepwise multiple regression analysis was conducted for each OJS-J subscale score.Results　The questionnaire was distributed to 270 nurses, of whom 219 (83.0% response rate) provided valid responses. With the UWES-J as the dependent variable, Model 1 adjusted only for age and sex; Model 2 adjusted for position, employment status, shift work, and self-efficacy score; and Model 3 adjusted for the social support, work control, and work quantitative load scores. Model 2 and Model 3 showed a significant association to the positive direction between UWES-J and OJS-J (Model 3: ß=0.202, P<0.01, R2=0.363). Furthermore, when the same analysis was conducted for each OJS-J subscale score, a significant association was found between procedural justice scores and the UWES-J (Model 3: ß=0.165, P<0.05, R2=0.383). Neither model found a significant difference between distributional equity scores and information equity scores.Conclusion　The results of this study examining the relationship between work engagement and organizational justice among hospital nurses showed that work engagement was associated with organizational justice, especially procedural justice. These results suggest that maintaining and improving organizational justice is important for improving nurses' work engagement.

Transient Astrocytic Gq Signaling Underlies Remote Memory Enhancement.

Astrocytes elicit transient Ca2+ elevations induced by G protein-coupled receptors (GPCRs), yet their role in vivo remains unknown. To address this, transgenic mice with astrocytic expression of the optogenetic Gq-type GPCR, Optoα1AR, were established, in which transient Ca2+ elevations similar to those in wild type mice were induced by brief blue light illumination. Activation of cortical astrocytes resulted in an adenosine A1 receptor-dependent inhibition of neuronal activity. Moreover, sensory stimulation with astrocytic activation induced long-term depression of sensory evoked response. At the behavioral level, repeated astrocytic activation in the anterior cortex gradually affected novel open field exploratory behavior, and remote memory was enhanced in a novel object recognition task. These effects were blocked by A1 receptor antagonism. Together, we demonstrate that GPCR-triggered Ca2+ elevation in cortical astrocytes has causal impacts on neuronal activity and behavior.

Global knockdown of glutamate decarboxylase 67 elicits emotional abnormality in mice.

Reduced expression of glutamate decarboxylase 67 (GAD67), encoded by the Gad1 gene, is a consistent finding in postmortem brains of patients with several psychiatric disorders, including schizophrenia, bipolar disorder and major depressive disorder. The dysfunction of GAD67 in the brain is implicated in the pathophysiology of these psychiatric disorders; however, the neurobiological consequences of GAD67 dysfunction in mature brains are not fully understood because the homozygous Gad1 knockout is lethal in newborn mice. We hypothesized that the tetracycline-controlled gene expression/suppression system could be applied to develop global GAD67 knockdown mice that would survive into adulthood. In addition, GAD67 knockdown mice would provide new insights into the neurobiological impact of GAD67 dysfunction. Here, we developed Gad1tTA/STOP-tetO biallelic knock-in mice using Gad1STOP-tetO and Gad1tTA knock-in mice, and compared them with Gad1+/+ mice. The expression level of GAD67 protein in brains of Gad1tTA/STOP-tetO mice treated with doxycycline (Dox) was decreased by approximately 90%. The GABA content was also decreased in the brains of Dox-treated Gad1tTA/STOP-tetO mice. In the open-field test, Dox-treated Gad1tTA/STOP-tetO mice exhibited hyper-locomotor activity and decreased duration spent in the center region. In addition, acoustic startle responses were impaired in Dox-treated Gad1tTA/STOP-tetO mice. These results suggest that global reduction in GAD67 elicits emotional abnormalities in mice. These GAD67 knockdown mice will be useful for elucidating the neurobiological mechanisms of emotional abnormalities, such as anxiety symptoms associated with psychiatric disorders.

Neural substrate of a cognitive intervention program using Go game: a positron emission tomography study.

BACKGROUND: Influence of cognitive intervention programs on brain activity has not been enough explored. AIMS: The aims of the present study were to clarify changes in brain activity from a cognitive intervention program utilizing the board game "Go" and to examine the relationship between brain activity and the acquisition of Go skills. METHODS: Eighteen community-dwelling older adults were randomly assigned either to an intervention group (IG), in which members attended 12 Go lessons either in groups or individually using tablet computers, or a control group (CG), in which members attended health education lectures unrelated to Go. Fluorine-18 fluorodeoxyglucose (18F-FDG) positron emission tomography (PET), cognitive assessments, and Go tests were performed before and after the intervention. RESULTS: The results showed different patterns of regional FDG uptake in both groups: regional cerebral glucose metabolism was significantly increased in the left middle temporal gyrus (MTG) and bilateral putamen (p < 0.01; cluster level) in the IG, and in the left superior frontal gyrus in the CG, (p < 0.01; cluster level). Furthermore, Go test scores were significantly improved in the IG (p < 0.05), and a significant association was observed between changes in Go test scores and glucose metabolism in the left MTG (p < 0.05). CONCLUSIONS AND DISCUSSION: This study indicates that a cognitive intervention program using Go may enhance brain activity. Further studies with larger populations and longer observation periods are needed to clarify the neural mechanisms underlying our Go intervention program.

Quality of Life in Patients with Low-Risk Papillary Thyroid Microcarcinoma: Active Surveillance Versus Immediate Surgery.

OBJECTIVE: This study aimed to compare the quality of life (QoL) and psychological issues of patients with papillary thyroid microcarcinoma (PMC) who were under active surveillance (AS) and those who underwent immediate surgery (OP). METHODS: This was a cross-sectional study conducted on 347 patients with low-risk PMC who were under AS (n = 298) or who underwent OP (n = 49). They were asked to complete two questionnaires (thyroid cancer-specific health-related QoL [THYCA-QoL] and the Hospital Anxiety and Depression Scale [HADS]). The results between the AS and OP groups were compared. RESULTS: The mean ages of patients in the AS and OP groups were 58.6±12.5 and 58.4±13.1 years (P =.94), respectively, and the male ratios were 34/298 (11%) and 2/49 (4.1%) (P =.14), respectively. The median follow-up periods from diagnosis in the AS and OP groups were 56.5 months (interquartile range [IQR], 32 to 88 months) and 84 months (IQR, 64 to 130 months) (P<.001), respectively. In the THYCA-QoL questionnaire, the OP group had more complaints about "voice" (P<.001), "psychological" (P =.025), "problems with scar" (P<.001), and "gained weight" (P =.047) than the AS group. Other scales of the THYCA-QoL were comparable in the two groups. In the HADS questionnaire, the AS group had significantly better anxiety (P =.020), depression (P =.027), and total scores (P =.014) than the OP group. CONCLUSION: PMC patients in the OP group had more complaints and were more anxious and depressed than the AS group. These findings suggest that AS is a reasonable alternative to surgery for patients with low-risk PMC from the point of view of QoL and psychology. ABBREVIATIONS: AS = active surveillance; CI = confidence interval; HADS = Hospital Anxiety and Depression Scale; LT4 = levothyroxine; OP = immediate surgery; PMC = papillary microcarcinoma; PTC = papillary thyroid carcinoma; QoL = quality of life; STAI = State-Trait Anxiety Inventory; THYCA-QoL = thyroid cancer-specific health-related quality of life; TSH = thyrotropin.

Metabolic Network Topology of Alzheimer's Disease and Dementia with Lewy Bodies Generated Using Fluorodeoxyglucose Positron Emission Tomography.

BACKGROUND: Alzheimer's disease (AD) and dementia with Lewy bodies (DLB) are often misdiagnosed with each other because of similar symptoms including progressive memory loss. The metabolic network topology that describes inter-regional metabolic connections can be generated using fluorodeoxyglucose positron emission tomography (FDG-PET) data with the graph-theoretical method. We hypothesized that different metabolic connectivity underlies the symptoms of AD patients, DLB patients, and cognitively normal (CN) individuals. OBJECTIVE: This study aimed to generate metabolic connectivity using FDG-PET data and assess the network topology to differentiate AD patients, DLB patients, and CN individuals. METHODS: This study included 45 AD patients, 18 DLB patients, and 142 CN controls. We analyzed FDG-PET data using the graph-theoretical method and generated the network topology in AD patients, DLB patients, and CN individuals. We statistically assessed the topology with global and nodal parameters. RESULTS: The whole metabolic network was preserved in CN; however, diffusely decreased connection was found in AD and partially but more deeply decreased connection was observed in DLB. The metabolic topology revealed that the right posterior cingulate and the left transverse temporal gyrus were significantly different between AD and DLB. CONCLUSION: The present findings indicate that metabolic connectivity decreased in both AD and DLB, compared with CN. DLB was characterized restricted but deeper stereotyped network disruption compared with AD. The right posterior cingulate and the left transverse temporal gyrus are significant regions in the metabolic connectivity for differentiating AD from DLB.

Graves' disease and mental disorders.

Mental disorders merge highly with thyroid diseases. Because of its regulatory effects on serotonin and noradrenalin, T3 has been linked closely to depression and anxiety. It has known that in many cases, the mental symptoms persist even after normalization of thyroid function by treatment. Psychosocial factors including stress have been associated with mental symptoms even after thyroid function normalization in Graves' disease and a combination of mental disorders have been related to the exacerbation of hyperthyroidism. These findings suggest that psychosomatic approaches based on the bio-psycho-social medical model are important for the treatment of mental disorders associated with Graves' disease.

Effects of Brief Cognitive Behavioral Therapy for Insomnia on Improving Depression Among Community-Dwelling Older Adults: A Randomized Controlled Comparative Study.

BACKGROUND: Cognitive behavioral therapy for insomnia (CBT-I) has been shown to improve depressive symptoms in older adults with comorbid insomnia and depression. However, it remains unclear whether brief CBT-I is effective for improving depressive symptoms in community-dwelling older adults with insomnia symptoms of varying severity. AIM: This study sought to examine the effectiveness of a brief CBT-I intervention delivered by public health nurses to improve depressive symptoms among older adults recruited from a community setting. METHODS: This randomized controlled study compared sleep status and depression at baseline and a 3-month follow-up using a wait-list control design. Depression was evaluated using the Geriatric Depression Scale short form (GDS-SF). RESULTS: The GDS-SF scores in the CBT-I group improved over time (p < .01), with an effect size (Cohen's d) of 0.34 (95% CI [0.16, 0.58]). The results demonstrated the effectiveness of a brief CBT-I intervention for depression, although the effect size was small. LINKING EVIDENCE TO ACTION: A brief CBT-I intervention consisting of sleep hygiene education, stimulus control, sleep restriction, cognitive restructuring, and relaxation is effective for improving depressive symptoms among older adults in the community.

[Effects of Brief Cognitive Behavioral Therapy for insomnia on sleep and usage of hypnotics among community-dwelling older adults: Randomized controlled trial].

Objectives　Chronic insomnia is common in late adulthood. A non-pharmacological approach should take priority in the treatment of insomnia for the elderly. Many studies have shown the efficacy of Cognitive Behavioral Therapy for Insomnia (CBT-I) for elderly diagnosed with insomnia. However the effect of CBT-I on mild insomnia among older adults in community settings has not been ascertained. We conducted a randomized controlled trial to evaluate the effectiveness of a brief CBT-I delivered by nurses, which is feasible in community settings, to improve sleep quality and decrease the dose of hypnotics use for older adults.Methods　Participants aged 60 years and over were enrolled in this study. The participants in the intervention group were administrated the brief CBT-I consisting of a group session (60 min) and an individual session (30 min). The primary outcomes were the score differences in the Pittsburgh Sleep Quality Index (PSQI) and Insomnia Severity Index (ISI). The secondary outcomes were the change in the proportion of people diagnosed with insomnia and the dose of hypnotics used. The follow-up period was 3 months.Results　The score on PSQI in the intervention group (n=41) significantly decreased compared to the control group (n=38). The effect size (Cohen's d) was 0.56 (95% Confidence interval [CI], 0.07 to 1.05). The score on ISI also decreased significantly and Cohen's d was 0.77 (95%CI, 0.27 to 1.26). According to subgroup analysis, Number Needed to Treat (NNT) for improvement of insomnia was 2.8 (95%CI, 1.5-17.2) and NNT for decreasing of dose of hypnotics use was 2.8 (95%CI, 1.5-45.1).Conclusion　The present results have demonstrated that the brief CBT-I significantly improved subjective evaluation of sleep quality and insomnia symptoms among the elderly. In addition, the brief CBT-I decreased the usage of hypnotics. Further studies are needed in terms of the procedure and the effects of brief CBT-I for older adults living in a community.

Red fluorescent protein-based cAMP indicator applicable to optogenetics and in vivo imaging.

cAMP is a common second messenger that is involved in various physiological processes. To expand the colour palette of available cAMP indicators, we developed a red cAMP indicator named "Pink Flamindo" (Pink Fluorescent cAMP indicator). The fluorescence intensity of Pink Flamindo increases 4.2-fold in the presence of a saturating dose of cAMP, with excitation and emission peaks at 567 nm and 590 nm, respectively. Live-cell imaging revealed that Pink Flamindo is effective for monitoring the spatio-temporal dynamics of intracellular cAMP generated by photoactivated adenylyl cyclase in response to blue light, and in dual-colour imaging studies using a green Ca2+ indicator (G-GECO). Furthermore, we successfully monitored the elevation of cAMP levels in vivo in cerebral cortical astrocytes by two-photon imaging. We propose that Pink Flamindo will facilitate future in vivo, optogenetic studies of cell signalling and cAMP dynamics.

Rearing-environment-dependent hippocampal local field potential differences in wild-type and inositol trisphosphate receptor type 2 knockout mice.

KEY POINTS: Mice reared in an enriched environment are demonstrated to have larger hippocampal gamma oscillations than those reared in isolation, thereby confirming previous observations in rats. To test whether astrocytic Ca2+ surges are involved in this experience-dependent LFP pattern modulation, we used inositol trisphosphate receptor type 2 (IP3 R2)-knockout (KO) mice, in which IP3 /Ca2+ signalling in astrocytes is largely diminished. We found that this experience-dependent gamma power alteration persists in the KO mice. Interestingly, hippocampal ripple events, the synchronized events critical for memory consolidation, are reduced in magnitude and frequency by both isolated rearing and IP3 R2 deficiency. ABSTRACT: Rearing in an enriched environment (ENR) is known to enhance cognitive and memory abilities in rodents, whereas social isolation (ISO) induces depression-like behaviour. The hippocampus has been documented to undergo morphological and functional changes depending on these rearing environments. For example, rearing condition during juvenility alters CA1 stratum radiatum gamma oscillation power in rats. In the present study, hippocampal CA1 local field potentials (LFP) were recorded from bilateral CA1 in urethane-anaesthetized mice that were reared in either an ENR or ISO condition. Similar to previous findings in rats, gamma oscillation power during theta states was higher in the ENR group. Ripple events that occur during non-theta periods in the CA1 stratum pyramidale also had longer intervals in ISO mice. Because astrocytic Ca2+ elevations play a key role in synaptic plasticity, we next tested whether these changes in LFP are also expressed in inositol trisphosphate receptor type 2 (IP3 R2)-knockout (KO) mice, in which astrocytic Ca2+ elevations are largely diminished. We found that the gamma power was also higher in IP3 R2-KO-ENR mice compared to IP3 R2-KO-ISO mice, suggesting that the rearing-environment-dependent gamma power alteration does not necessarily require the astrocytic IP3 /Ca2+ pathway. By contrast, ripple events showed genotype-dependent changes, as well as rearing condition-dependent changes: ISO housing and IP3 R2 deficiency both lead to longer inter-ripple intervals. Moreover, we found that ripple magnitude in the right CA1 tended to be smaller in IP3 R2-KO. Because IP3 R2-KO mice have been reported to have depression phenotypes, our results suggest that ripple events and the mood of animals may be broadly correlated.

Glucose Hypometabolism in Developmental Venous Anomaly Without Apparent Parenchymal Damage.

Two cases of F-FDG PET in developmental venous anomaly (DVA) with visual impairment were examined. Plain MRI could not determine the cause of visual symptoms; a contrast-enhanced CT scan showed the existence of DVA without apparent parenchymal damage due to infarction or hemorrhage. F-FDG PET revealed that the hypometabolic area extended to the visual tract, thus explaining the association between the visual impairment and DVA. F-FDG PET is therefore a useful tool for the evaluation of symptomatic DVA.

Mammalian-Specific Central Myelin Protein Opalin Is Redundant for Normal Myelination: Structural and Behavioral Assessments.

Opalin, a central nervous system-specific myelin protein phylogenetically unique to mammals, has been suggested to play a role in mammalian-specific myelin. To elucidate the role of Opalin in mammalian myelin, we disrupted the Opalin gene in mice and analyzed the impacts on myelination and behavior. Opalin-knockout (Opalin-/-) mice were born at a Mendelian ratio and had a normal body shape and weight. Interestingly, Opalin-/- mice had no obvious abnormalities in major myelin protein compositions, expression of oligodendrocyte lineage markers, or domain organization of myelinated axons compared with WT mice (Opalin+/+) mice. Electron microscopic observation of the optic nerves did not reveal obvious differences between Opalin+/+ and Opalin-/- mice in terms of fine structures of paranodal loops, transverse bands, and multi-lamellae of myelinated axons. Moreover, sensory reflex, circadian rhythm, and locomotor activity in the home cage, as well as depression-like behavior, in the Opalin-/- mice were indistinguishable from the Opalin+/+ mice. Nevertheless, a subtle but significant impact on exploratory activity became apparent in Opalin-/- mice exposed to a novel environment. These results suggest that Opalin is not critical for central nervous system myelination or basic sensory and motor activities under conventional breeding conditions, although it might be required for fine-tuning of exploratory behavior.

Netrin-G1 regulates fear-like and anxiety-like behaviors in dissociable neural circuits.

In vertebrate mammals, distributed neural circuits in the brain are involved in emotion-related behavior. Netrin-G1 is a glycosyl-phosphatidylinositol-anchored synaptic adhesion molecule whose deficiency results in impaired fear-like and anxiety-like behaviors under specific circumstances. To understand the cell type and circuit specificity of these responses, we generated netrin-G1 conditional knockout mice with loss of expression in cortical excitatory neurons, inhibitory neurons, or thalamic neurons. Genetic deletion of netrin-G1 in cortical excitatory neurons resulted in altered anxiety-like behavior, but intact fear-like behavior, whereas loss of netrin-G1 in inhibitory neurons resulted in attenuated fear-like behavior, but intact anxiety-like behavior. These data indicate a remarkable double dissociation of fear-like and anxiety-like behaviors involving netrin-G1 in excitatory and inhibitory neurons, respectively. Our findings support a crucial role for netrin-G1 in dissociable neural circuits for the modulation of emotion-related behaviors, and provide genetic models for investigating the mechanisms underlying the dissociation. The results also suggest the involvement of glycosyl-phosphatidylinositol-anchored synaptic adhesion molecules in the development and pathogenesis of emotion-related behavior.