Gut permeability and its clinical relevance in schizophrenia.

AIM: We aimed to examine the gut permeability in patients with schizophrenia and its relevance to schizophrenia symptoms, medication, cognitive functions, and blood immune markers. METHODS: We selected 22 patients with schizophrenia (mean age: 37.9 ± 10.5 years) comprising 9 men and 13 women. Furthermore, we included 86 healthy controls (mean age: 43.5 ± 11.0 years) comprising 41 men and 45 women. All participants were biologically unrelated and of Japanese descent. We used the Positive and Negative Syndrome Scale (PANSS) and Brief Assessment of Cognition in Schizophrenia (BACS) to measure the severity of schizophrenia symptoms and cognitive functions, respectively. The lactulose-mannitol loading test was used to measure the permeability of the small intestine. Furthermore, we used the lactulose to mannitol ratio (LMR) as an index of gut permeability. We measured the C-reactive protein and natural killer (NK) cell activity in the blood as highly sensitive immune markers. RESULTS: The patients had a significantly higher rate of "leaky gut" (defined as LMR ≥ 0.1) compared to the control group (22.7% vs. 5.8%, odds ratio: 4.8 [95% confidence interval, 1.2-18.3], Fisher's exact test, P = 0.03). There was no significant correlation between the LMR and PANSS scores or in the daily antipsychotic dose. In addition, the LMR was negatively correlated with the total Z-score of the BACS and NK cell activity in the patients. CONCLUSIONS: Our results suggest a higher rate of abnormally increased gut permeability in patients with schizophrenia than in controls. Moreover, gut permeability may be related to the cognitive and cellular immunity function of patients with schizophrenia.

Effect of Lacticaseibacillus paracasei Strain Shirota on Improvement in Depressive Symptoms, and Its Association with Abundance of Actinobacteria in Gut Microbiota.

We previously reported lower counts of lactobacilli and Bifidobacterium in the gut microbiota of patients with major depressive disorder (MDD), compared with healthy controls. This prompted us to investigate the possible efficacy of a probiotic strain, Lacticaseibacillus paracasei strain Shirota (LcS; basonym, Lactobacillus casei strain Shirota; daily intake of 8.0 × 1010 colony-forming units), in alleviating depressive symptoms. A single-arm trial was conducted on 18 eligible patients with MDD or bipolar disorder (BD) (14 females and 4 males; 15 MDD and 3 BD), assessing changes in psychiatric symptoms, the gut microbiota, and biological markers for intestinal permeability and inflammation, over a 12-week intervention period. Depression severity, evaluated by the Hamilton Depression Rating Scale, was significantly alleviated after LcS treatment. The intervention-associated reduction of depressive symptoms was associated with the gut microbiota, and more pronounced when Bifidobacterium and the Atopobium clusters of the Actinobacteria phylum were maintained at higher counts. No significant changes were observed in the intestinal permeability or inflammation markers. Although it was difficult to estimate the extent of the effect of LcS treatment alone, the results indicated that it was beneficial to alleviate depressive symptoms, partly through its association with abundance of Actinobacteria in the gut microbiota.

Altered polyunsaturated fatty acid levels in relation to proinflammatory cytokines, fatty acid desaturase genotype, and diet in bipolar disorder.

Inflammation and altered polyunsaturated fatty acid (PUFA) levels have been implicated in bipolar disorder (BD). A recent genome-wide association study identified a locus in the fatty acid desaturase (FADS) gene cluster conferring susceptibility to BD. In this study, we examined PUFA levels in patients with BD in relation to proinflammatory cytokines, FADS genotype, and dietary habits. We enrolled 83 patients with BD and 217 healthy controls who underwent plasma PUFA measurement. A subsample of 65 patients and 90 controls underwent plasma interleukin (IL)-6 and tumor necrosis factor alpha (TNFα) measurement, and three FADS single nucleotide polymorphisms (SNPs) were genotyped. Information on fish consumption was obtained by a self-reported diet history questionnaire. In comparing PUFA levels between patients and controls, significant differences were found for all 7 PUFAs tested. Specifically, n-3 eicosapentaenoic acid (EPA) level was decreased, and n-6 arachidonic acid level was increased in the patients (p < 0.0001 for both). Plasma IL-6 and TNFα levels were both significantly increased in the patients. Plasma EPA level was negatively correlated with IL-6 and TNFα levels. The FADS genotype, which was associated with increased n-6 PUFA levels, was also associated with marked elevation in TNFα levels. Less frequent fish intake was associated with low EPA and high IL-6 level. Taken together, our results provide strong evidence for altered plasma PUFA and proinflammatory cytokine levels in patients with BD. Furthermore, FADS genotype and fish consumption may contribute not only to altered PUFA levels but also to inflammation in BD.

Ventral striatum links motivational and motor networks during operant-conditioned movement in rats.

Voluntary actions require motives. It is already known that the medial prefrontal cortex (MPFC) assess the motivational values. However, it remains unclear how the motivational process gains access to the motor execution system in the brain. Here we present evidence that the ventral striatum (VS) plays a hub-like role in mediating motivational and motor processing in operant behavior. We used positron emission tomography (PET) to detect the neural activation areas associated with motivational action. Using obtained regions, partial correlation analysis was performed to examine how the motivational signals propagate to the motor system. The results revealed that VS activity propagated to both MPFC and primary motor cortex through the thalamus. Moreover, muscimol injection into the VS suppressed the motivational behavior, supporting the idea of representations of motivational signals in VS that trigger motivational behavior. These results suggest that the VS-thalamic pathway plays a pivotal role for both motivational processing through interactions with the MPFC and for motor processing through interactions with the motor BG circuits.

A Single Intraperitoneal Injection of Endotoxin Changes Glial Cells in Rats as Revealed by Positron Emission Tomography Using [11C]PK11195.

PURPOSE: Intracranial administration of lipopolysaccharide (LPS) is known to elicit a rapid innate immune response, activate glial cells in the brain, and induce depression-like behavior. However, no study has focused on the changes in glial cells induced by intraperitoneal injection of LPS in vivo. METHODS: Ten adult male Fischer F344 rats underwent [11C]PK11195 PET before and 2 days after intraperitoneal injection of LPS to evaluate the changes in glial cells. The difference in standardized uptake values (SUV) of [11C]PK11195 between before and after injection was determined. RESULTS: There was a cluster of brain regions that showed significant reductions in SUV. This cluster included the bilateral striata and bilateral frontal regions, especially the somatosensory areas. CONCLUSIONS: Changes in activity of glial cells induced by the intraperitoneal injection of LPS were detected in vivo by [11C]PK11195 PET. Intraperitoneal injection of LPS is known to induce depression, and further studies with [11C]PK11195 PET would clarify the relationships between neuroinflammation and depression.

Effects of L-theanine on anxiety-like behavior, cerebrospinal fluid amino acid profile, and hippocampal activity in Wistar Kyoto rats.

RATIONALE AND OBJECTIVES: The amino acid L-theanine (N-ethyl-L-glutamine) has historically been considered a relaxing agent. In the present study, we examined the effects of repeated L-theanine administration on behavior, levels of amino acids in the cerebrospinal fluid (CSF), and hippocampal activity in Wistar Kyoto (WKY) rats, an animal model of anxiety and depressive disorders. METHODS: Behavioral tests were performed after 7-10 days of L-theanine (0.4 mg kg-1 day-1) or saline administration, followed by CSF sampling for high-performance liquid chromatography (HPLC) analysis. An independent set of animals was subjected to [18F]fluorodeoxyglucose positron emission tomography (PET) scanning after the same dose of L-theanine or saline administration for 7 days. RESULTS: In the elevated plus maze test, the time spent in the open arms was significantly longer in the L-theanine group than in the saline group (P = 0.035). In addition, significantly lower CSF glutamate (P = 0.039) and higher methionine (P = 0.024) concentrations were observed in the L-theanine group than in the saline group. A significant increase in the standard uptake value ratio was observed in the hippocampus/cerebellum of the L-theanine group (P < 0.001). CONCLUSIONS: These results suggest that L-theanine enhances hippocampal activity and exerts anxiolytic effects, which may be mediated by changes in glutamate and methionine levels in the brain. Further study is required to more fully elucidate the mechanisms underlying the effects of L-theanine.

(-)-Linalool influence on the cerebral blood flow in healthy male volunteers revealed by three-dimensional pseudo-continuous arterial spin labeling.

BACKGROUND: Although aromatherapy is widely used, the pharmacology of the essential oils remains undiscovered. AIM: The present study assessed the effect of (-)-linalool, the main contained material of lavender, on the brain function. MATERIALS AND METHODS: Healthy male volunteers calculated the regional cerebral blood flow (CBF) before and after inhalation of (-)-linalool, and CBF changes were evaluated. RESULTS: There were significant CBF reductions in the right superior temporal gyrus to insula, anterior cingulate cortex after inhalation. CONCLUSIONS: The previous study detected the regulatory influence of (-)-linalool on the glutamatergic transmission. The effect of (-)-linalool on the ACC and insula would cause the sedative and anxiolytic activity.

Improving the workflow of nursing assistants at a general hospital in Japan.

Transferring non-specialised tasks from registered nurses to nursing assistants may help registered nurses focus on specialised tasks. Optimising the workflow of nursing assistants by making their tasks more efficient may improve problems associated with the shortage of registered nurses. The nursing assistants at our hospital were stressed about referring inpatients to outpatient specialty clinics. Therefore, we initiated a project to optimise the referral process and reduce the time spent by nursing assistants on this task, with the collaboration of physicians, registered nurses and administrative assistants. The Training for Effective & Efficient Action in Medical Service-Better Process (TEAMS-BP) method, which was developed by modifying the Japanese Training Within Industry-Job Method, was used for the optimisation process. TEAMS-BP teaches users how to break each task down into its individual components, to scrutinise the details, and then to develop new processes by eliminating, combining, rearranging and simplifying tasks. At baseline, each referral took 10 min and was performed 39 times over 10 days in six wards. The first TEAMS-BP cycle did not yield satisfactory results for the nursing assistants. In the second TEAMS-BP cycle, participants included inpatient and outpatient physicians, registered nurses and administrative assistants. As a result, we changed the referral process from paper to electronic records and streamlined referrals that were ordered by inpatient physicians to outpatient physicians. The use of this method saved the equivalent of 175 hours of nursing assistants' time per year at no additional cost. If we had been able to define the referral process as an interdisciplinary task and show the merits to each department from the beginning, we may have been able to form the interprofessional team in the first TEAMS-BP. Improving the efficiency of nursing assistants can allow other professionals to focus on their specialised tasks more effectively.

Development of a removable head fixation device for longitudinal behavioral and imaging studies in rats.

BACKGROUND: In some behavioral neuroscience studies, an attachment is surgically fixed onto the head of an awake animal to allow the animal to perform learning tasks repeatedly in the same position in a task-training system. A recently developed task-training system enables operant conditioning of head-fixed rats within only a few days, and this system has been rigorously applied to record learning-associated neural activity using electrophysiological techniques. However, the head attachment of this device is made of metal and thus is not suitable for simultaneous brain imaging studies with X-ray computed tomography (CT), magnetic resonance imaging (MRI) or positron emission tomography (PET). NEW METHOD: We developed a novel head fixation device with a removable attachment to position the rat head precisely in both imaging and training devices across different sessions. The device consisted of a removable attachment, a clamp and a stage, all of which were made of PET/MRI compatible acrylic resin. We tested the usefulness of the device with (18)F-fluorodeoxyglucose (FDG) PET and CT. RESULTS: The new device did not substantially affect (18)F-FDG PET images. Repositioning of the rat's head across sessions and experimenters was at a level of submillimeter accuracy. COMPARISON WITH EXISTING METHOD: The errors of radioactivity concentration of (18)F-FDG in the PET image were lower with the present attachment than with the conventional metal attachment. Repositioning accuracy was considerably improved compared with a visual inspection method. CONCLUSIONS: The developed fixation device is useful for longitudinal behavioral and brain imaging studies in rats.