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Abstract Memory retrieval can become difficult over time, but it is important to note that memories that appear to be forgotten might still be stored in the brain, as shown by their occasional spontaneous retrieval. Histamine in the central nervous system is a promising target for facilitating the recovery of memory retrieval. Our previous study demonstrated that histamine H3 receptor (H3R) inverse agonists/antagonists, activating histamine synthesis and release, enhance activity in the perirhinal cortex and help in retrieving forgotten long-term object recognition memories. However, it is unclear whether enhancing histaminergic activity alone is enough for the recovery of memory retrieval, considering that H3Rs are also located in other neuron types and affect the release of multiple neurotransmitters. In this study, we employed a chemogenetic method to determine whether specifically activating histamine neurons in the tuberomammillary nucleus facilitates memory retrieval. In the novel object recognition test, control mice did not show a preference for objects based on memory 1 week after training, but chemogenetic activation of histamine neurons before testing improved memory retrieval. This selective activation did not affect the locomotor activity or anxiety-related behavior. Administering an H2R antagonist directly into the perirhinal cortex inhibited the recovery of memory retrieval induced by the activation of histamine neurons. Furthermore, we utilized the Barnes maze test to investigate whether chemogenetic activation of histamine neurons influences the retrieval of forgotten spatial memories. Control mice explored all the holes in the maze equally 1 week after training, whereas mice with chemogenetically activated histamine neurons spent more time around the target hole. These findings indicate that chemogenetic activation of histamine neurons in the tuberomammillary nucleus can promote retrieval of seemingly forgotten object recognition and spatial memories.

Abstract Selecting an appropriate behaviour is critical for survival in conflict scenarios, wherein animals face both appetitive and aversive stimuli. Behavioural selection consists of multiple processes: (1) animals remain quiet in a safe place to avoid aversive stimuli (suspension), (2) once they decide to take risks to approach appetitive stimuli, they assess the risks (risk assessment), and (3) they act to reach the reward. However, most studies have not addressed these distinct behavioural processes separately. Here, we developed a new experimental paradigm called the three-compartment conflict task to quantitatively evaluate conflict processes. Our apparatus consisted of start, flat, and grid compartments. Mice needed to explore the grid compartment, where they might receive foot shocks while trying to obtain sucrose. Applying foot shocks increased sucrose acquisition latency in subsequent trials, reflecting elevated conflict levels throughout trials. The time spent in the start compartment and the number of retreats were determined to measure the conflict levels in suspension and risk assessment, respectively. Foot shocks increased these parameters, whereas diazepam decreased them. Our new paradigm is valuable for quantitatively evaluating distinct behavioural processes and contributes to developing effective treatments for psychiatric disorders associated with maladaptive behaviours in conflict scenarios.

Abstract Histamine is a neurotransmitter that modulates neuronal activity and regulates various brain functions. Histamine H3 receptor (H3R) antagonists/inverse agonists enhance its release in most brain regions, including the cerebral cortex, which improves learning and memory and exerts an antiepileptic effect. However, the mechanism underlying the effect of H3R antagonists/inverse agonists on cortical neuronal activity in vivo remains unclear. Here, we show the mechanism by which pitolisant, an H3R antagonist/inverse agonist, influenced perirhinal cortex (PRh) activity in individual neuron and neuronal population levels. We monitored neuronal activity in the PRh of freely moving mice using in vivo Ca2+ imaging through a miniaturized one-photon microscope. Pitolisant increased the activity of some PRh neurons while decreasing the activity of others without affecting the mean neuronal activity across neurons. Moreover, it increases neuron pairs with synchronous activity in excitatory-responsive neuronal populations. Furthermore, machine learning analysis revealed that pitolisant altered the neuronal population activity. The changes in the population activity were dependent on the neurons that were excited and inhibited by pitolisant treatment. These findings indicate that pitolisant influences the activity of a subset of PRh neurons by increasing the synchronous activity and modifying the population activity.

Abstract Background Glyphosate and its salt formulations are nonselective herbicides that have been extensively used worldwide, both for residential and agricultural purposes. The possible carcinogenicity and teratogenicity of glyphosate remain to be elucidated. We developed a sensitive and high-throughput analytical method for urinary glyphosate using liquid chromatography-tandem mass spectrometry with the aim of contributing to glyphosate exposure assessment in epidemiological studies. Methods After urine dilution (creatinine matching dilution to 0.05 g creatinine/L), glyphosate was extracted using two types of solid phase extraction columns (SCX and NH2) with automated sample preparation instruments. The eluate was dried and dissolved in the mobile phase, followed by liquid chromatography-tandem mass spectrometry analysis. The optimized method was applied to urine samples obtained from 54 Japanese adults and children. Results The results from the validation study demonstrated good recoveries (91.0-99.6%), within- and between-run precisions (< 15%), low detection limits (0.1 μg/L), and lower limit of quantification (0.3 μg/L). The detection frequency and median concentration of the urinary glyphosate in Japanese subjects were 59% and 0.25 μg/L (0.34 μg/g creatinine). Conclusions Our reliable determination method was successful in measuring urinary glyphosate concentration. Moreover, this is the first biomonitoring report of urinary glyphosate levels in the Japanese general population.

Abstract Information from direct experience and observation of others is integrated in the brain to enable appropriate responses to environmental stimuli. Fear memory can be acquired by observing a conspecific’s distress. However, it remains unclear how prior fear observation affects self-experienced fear learning. In this study, we tested whether prior observation of a conspecific receiving contextual fear conditioning affects subsequent self-experienced fear conditioning and how neuronal ensembles represent the integration of the observation and self-experience. Test mice observed demonstrator mice experiencing fear conditioning on day 1 and directly experienced fear conditioning on day 2. Contextual fear memory was tested on day 3. The prior observation of fear conditioning promoted subsequent self-experienced fear conditioning in a hippocampus-dependent manner. We visualized hippocampal neurons that were activated during the observation and self-experience of fear conditioning and found that self-experienced fear conditioning preferentially activated dorsal CA1 neurons that were activated during the observation. When mice observed and directly experienced fear conditioning in different contexts, preferential reactivation was not observed in the CA1, and fear memory was not enhanced. These findings indicate that dorsal CA1 neuronal ensembles that were activated during both the observation and self-experience of fear learning are implicated in the integration of observation and self-experience for strengthening fear memory.

Abstract Aims Thermoregulatory responses in homeothermic animals, including humans, are classified into involuntary autonomous and voluntary behavioral thermoregulatory responses. Although behavioral thermoregulatory responses are probably driven by positive (pleasant) and/or negative (unpleasant) emotions, the neuronal mechanisms underlying the induction of negative emotions by hot and cold environments remain poorly understood. The bed nucleus of the stria terminalis is a brain region implicated in stress responses and negative emotions, such as fear, anxiety, and aversion. Various stimuli that cause negative emotions, such as immobilization stress, fox odor, gastric distension, and inflammatory pain, increase noradrenaline release in the rat bed nucleus of the stria terminalis, especially in the ventral bed nucleus of the stria terminalis. It has been reported that the negative emotional component of pain is mediated by noradrenergic neurotransmission in the ventral bed nucleus of the stria terminalis. However, the role of intra‐ventral bed nucleus of the stria terminalis noradrenergic neurotransmission in the induction of negative emotion by exposure to hot and cold environments remains to be elucidated. For the first step to address this issue, the effects of hot and cold environments on noradrenaline release in the ventral bed nucleus of the stria terminalis were examined. Methods In vivo microdialysis analyses in unanesthetized, freely moving male Sprague‐Dawley rats were performed to examine hot and cold environments‐induced noradrenaline release in the ventral bed nucleus of the stria terminalis. Results Exposure to hot (38°C) and cold (8°C) environments significantly increased noradrenaline release in the ventral bed nucleus of the stria terminalis. Conclusions The results suggest that exposure to hot and cold environments enhances noradrenergic neurotransmission in the ventral bed nucleus of the stria terminalis, which may induce negative emotion, and thereby drive avoidance behaviors, that is, escape from hot and cold environments.

Background/Aims: We investigated writing abilities in patients with the amnestic type of mild cognitive impairment (aMCI) and mild Alzheimer's disease (AD). To examine the earliest changes in writing function, we used writing tests for both words and sentences with different types of Japanese characters (Hiragana, Katakana, and Kanji). Methods: A total of 25 aMCI patients, 38 AD patients, and 22 healthy controls performed writing to dictation for Kana and Kanji words, copied Kanji words, and wrote in response to a picture story task. Analysis of variance was used to test the subject group effects on the scores in the above writing tasks. Results: For the written Kanji words, the mild AD group performed worse than the aMCI group and the controls, but there was no difference between the aMCI group and the controls. For the picture story writing task, the mild AD and aMCI groups performed worse than the controls, but the difference between the AD and the aMCI groups was not significant. Conclusions: The mild AD group showed defects in writing Kanji characters, and the aMCI group showed impairments in narrative writing. Our study suggests that narrative writing, which demands complex integration of multiple cognitive functions, can be used to detect the subtle writing deficits in aMCI patients.

Prevention of relapses is a major challenge in treating anxiety disorders. Fear reinstatement can cause relapse in spite of successful fear reduction through extinction-based exposure therapy. By utilising a contextual fear-conditioning task in mice, we found that reinstatement was accompanied by decreased c-Fos expression in the infralimbic cortex (IL) with reduction of synaptic input and enhanced c-Fos expression in the medial subdivision of the central nucleus of the amygdala (CeM). Moreover, we found that IL dopamine plays a key role in reinstatement. A reinstatement-inducing reminder shock induced c-Fos expression in the IL-projecting dopaminergic neurons in the ventral tegmental area, and the blocking of IL D1 signalling prevented reduction of synaptic input, CeM c-Fos expression, and fear reinstatement. These findings demonstrate that a dopamine-dependent inactivation of extinction circuits underlies fear reinstatement and may explain the comorbidity of substance use disorders and anxiety disorders.

The aim of this study was to understand the survival and differentiation of neural stem/progenitor cells (NSPCs) cultured on chitosan matrices in vivo in a complete transection model of spinal cord injury. NSPCs were isolated from the subependyma of lateral ventricles of adult GFP transgenic rat forebrains. The GFP-positive neurospheres were seeded onto the inner lumen of chitosan tubes to generate multicellular sheets ex vivo. These bioengineered neurosphere tubes were implanted into a completely transected spinal cord and assessed after 5 weeks for survival and differentiation. The in vivo study showed excellent survival of NSPCs, as well as differentiation into astrocytes and oligodendrocytes. Importantly, host neurons were identified in the tissue bridge that formed within the chitosan tubes and bridged the transected cord stumps. The excellent in vivo survival of the NSPCs coupled with their differentiation and maintenance of host neurons in the regenerated tissue bridge demonstrates the promise of the chitosan tubes for stem cell delivery and tissue regeneration.

An ignition device that can induce a cool flame around a hydrocarbon droplet and simultaneously detect the ignition occurrence was developed for microgravity experiments of cool-flame spread along a fuel droplet array. The ignition system circuit was designed based on the principle of a hot wire anemometer to ignite droplet without inducing hot-flame ignition. The ignition wire senses the heat generated by the cool flame and decreases the output power. Thus, one can detect the cool-flame ignition by measuring the current passing through the ignition wire. As a result of the preliminary experiments at normal gravity, the cool-flame ignition of a fuel droplet was successfully induced, and, from the histories of current passing through the ignition wire, the cool-flame ignition, the two-stage ignition (cool flame to hot flame transition), and pure evaporation were distinguished respectively. The cool-flame ignition delay time for various droplet diameters and fuels was also measured. It was found that the tendency of the cool-flame ignition delay time to the initial droplet diameter and fuel type is the same as that of the hot-flame ignition delay time in high temperature environments. [ABSTRACT FROM AUTHOR]

The simulation for liquid phase sintering has been newly developed by Monte Carlo method. The basic three mechanisms in liquid phase sintering, namely (1) liquid wetting on solid surface, (2) rearrangement of solid particle by capillary force of liquid, (3) growth of solid particles by solution-reprecipitation through liquid phase (Ostwald ripening), have been introduced in the simulation. The liquid wetting on a solid plane or solid particle surface progressed more easily as decreasing the energy between solid and liquid (γSL). The introduction of rearrangement into the simulation brought the result that relative density increased with decreasing γSL and pores remained. The introduction of Ostwald ripening in addition to liquid wetting and rearrangement produced the result that relative density increased on the whole and the effect of γSL became clear. The simulation including Ostwald ripening was able to demonstrate clearly and continuously the influence of γSL on growth and contiguity of solid particles. [ABSTRACT FROM AUTHOR]

Evaporation of a single n-decane droplet at high pressures and high temperature has been studied experimentally under normal and microgravity conditions. Ambient pressure was set at 0.10 and 0.50 MPa. Ambient temperature was fixed at 773 K. At normal gravity, initial droplet diameter was varied from 0.4 to 0.80 mm. To examine unsteadiness of droplet evaporation, instantaneous droplet evaporation rate coefficient was measured. The effect of natural convection on instantaneous droplet evaporation rate coefficient was evaluated as a function of the Grashof number. The unsteadiness of droplet evaporation appears in entire period of evaporation lifetime. The effect of natural convection on instantaneous droplet evaporation rate coefficient changes during evaporation and its dependence on Grashof number in the range where the effect of natural convection was regarded as quasi-steady was expressed as the empirical equations. [ABSTRACT FROM AUTHOR]

A microgravity experiment is going to be held in 2022 by using sounding rocket to clarify a cool flame dynamics of multiple n-decane droplets such as ignition delay time, ignition location, cool flame propagation, and so on. To predict the cool flame dynamics near ignition limit, 2D axisymmetric unsteady numerical calculation was carried out. A single droplet, droplet pairs whose inter-droplet distances are 8 mm and 16 mm, and droplet array with inter-droplet distance of 8 mm are simulated. Ambient temperature, pressure, and initial droplet diameter are 550 K, 1.0 atm, and 1.0 mm respectively. To acquire the mixture reactivity for the identification of the cool flame ignition start point, 0D reaction calculation is also carried out. It is found that the highly reactive mixture distributes in the outside of the droplets where temperature is high and mixture fraction is low. Temperature rise caused by the cool flame generation starts from the outside of the droplet pair, and the cool flame surrounds the droplet pair with small inter-droplet distance. In the case of the droplet array, the cool flame is generated at the outside of the array. As tracing the highly reactive mixture region, it propagates inward with average propagation velocity of 7.3 cm/s, and the cool flame propagation velocity accelerated just before burned out. [ABSTRACT FROM AUTHOR]

Case: We report a patient with hypereosinophilia-associated massive osteolytic lesion of the sacrum who was admitted to our hospital. Genetic analysis revealed that atypical eosinophilic cells were positive for FIP1-like-1-platelet-derived growth factor receptor-alpha (FIP1L1-PDGFRA) fusion gene. Treatment was initiated with oral administration of imatinib mesylate. The patient responded rapidly to this medication with a marked reduction in eosinophilia both from the peripheral blood and FIP1L1-PDGFRA fusion gene in the bone marrow within 2 weeks, followed by gradual osteosclerotic repair of the sacrum. Conclusions: This case study found that the drug imatinib proved very effective in the treatment of this rare condition. [ABSTRACT FROM AUTHOR]

Fuel droplet array combustion experiments of a fuel droplet array were performed at microgravity to investigate the mechanism of fuel droplet group combustion. The purpose of this research is to understand the dependence of flame spread speed on droplet spacing and initial droplet diameter. Ten fuel droplets were generated using a thin glass needle and suspended at the crossing points with SiC fibers of 7.5 and 14 µm in diameter, respectively. Sequential backlit-images of the droplet suspension fibers and the droplets were taken at the time of flame spread. n-Decane was employed as the fuel. The effect of initial droplet diameter on the normalized flame spread speed were examined with varying droplet spacing. In the case of 3.75 in nondimensional droplet spacing showed that the normalized flame spread speed increased less than 0.48mm in initial droplet diameter and remained constant above 0.48 mm. In the case of short flame spread induction times, which is the time for a flame to travel between two droplets, the normalized flame spread speed increased as the initial droplet diameter increased. The reason for this believed to the flame spread induction time is dominated by the premixed- flame propagation time. [ABSTRACT FROM AUTHOR]

Sensory stimuli not only activate specific populations of cortical neurons but can also silence other populations. However, it remains unclear whether neuronal silencing per se leads to memory formation and behavioral expression. Here we show that mice can report optogenetic inactivation of auditory neuron ensembles by exhibiting fear responses or seeking a reward. Mice receiving pairings of footshock and silencing of a neuronal ensemble exhibited a fear response selectively to the subsequent silencing of the same ensemble. The valence of the neuronal silencing was preserved for at least 30 d and was susceptible to extinction training. When we silenced an ensemble in one side of auditory cortex for conditioning, silencing of an ensemble in another side induced no fear response. We also found that mice can find a reward based on the presence or absence of the silencing. Neuronal silencing was stored as working memory. Taken together, we propose that neuronal silencing without explicit activation in the cerebral cortex is enough to elicit a cognitive behavior. [ABSTRACT FROM AUTHOR]

Synaptic plasticity is a cellular mechanism putatively underlying learning and memory. However, it is unclear whether learning induces synaptic modification globally or only in a subset of neurons in associated brain regions. In this study, we genetically identified neurons activated during contextual fear learning and separately recorded synaptic efficacy from recruited and nonrecruited neurons in the mouse basolateral amygdala (BLA). We found that the fear learning induces presynaptic potentiation, which was reflected by an increase in the miniature EPSC frequency and by a decrease in the paired-pulse ratio. Changes occurred only in the cortical synapses targeting the BLA neurons that were recruited into the fear memory trace. Furthermore, we found that fear learning reorganizes the neuronal ensemble responsive to the conditioning context in conjunction with the synaptic plasticity. In particular, the neuronal activity during learning was associated with the neuronal recruitment into the context-responsive ensemble. These findings suggest that synaptic plasticity in a subset of BLA neurons contributes to fear memory expression through ensemble reorganization. [ABSTRACT FROM AUTHOR]

The “Group Combustion” experiment is planned as the first combustion experiment in the KIBO on the ISS. Flame spread characteristics of n-decane droplet clouds and linear array will be investigated in detail. The experiment will employ the Multi-purpose Small Payload Rack (MSPR), the Chamber for Combustion Experiment (CCE), and the Group Combustion Experiment Module (GCEM) as experimental apparatus. At present, development of the GCEM has been on-going in parallel to detail planning of the experiment operation onboard the KIBO. In this paper, current status on preparation of the experiment will be introduced. [ABSTRACT FROM AUTHOR]

As a fundamental study on the droplet-interaction effect in the fuel-spray ignition, spontaneous ignition of an n-decane droplet pair in hot air was experimentally studied in normal gravity and microgravity. Two suspended droplets initially at room temperature were brought into a hot furnace filled with air and ignited spontaneously. In the previous studies, cool-flame and hot-flame ignition delays were evaluated thorough thermocouple measurement, and their dependence on inter-droplet distance was discussed thorough the development of temperature and fuel-concentration distribution around a droplet pair. However, two-dimensional observation of cool-flame and hot-flame behavior was not possible with thermocouple measurement. In the present study, interferometry was applied in order to detect cool flame, which emits almost no visible light. Density field around a droplet pair was qualitatively observed with a high-speed camera, and the locations of cool-flame and hot-flame appearance were evaluated. Pressure was 0.3 MPa, and ambient temperature was between 560 and 680 K. The ambient conditions are in the range where two-stage ignition occurs. Initial droplet diameter was either 0.8 mm or 1 mm. In normal gravity, cool flame always appeared on the lower side of the droplet pair, and hot flame appeared on the upper side in most cases, which is obviously the effect of buoyancy. In microgravity, cool flame appeared on the outer side of the pair, and hot flame appeared on the inner side of the pair, which corresponds with the discussion in the previous studies. [ABSTRACT FROM AUTHOR]

The present study reports the beneficial effects of an anti-mouse interleukin-6 (IL-6) receptor antibody (MR16-1) on neuropathic pain in mice with spinal cord injury (SCI). Following laminectomy, contusion SCI models were produced using an Infinite Horizon (IH)-impactor. MR16-1 was continuously injected for 14 days using Alzet osmotic pumps. A mouse IL-6 ELISA kit was then used to analyze IL-6 levels in the spinal cord tissue between 12 and 72 h after injury. Motor and sensory functions were evaluated each week using the Basso Mouse Scale (BMS), plantar von Frey and thermal threshold tests. Histological examinations were performed 42 days after SCI. Between 24 and 72 h after SCI, the expression levels of IL-6 were significantly decreased in the MR16-1 treated group. Six weeks after surgery, the BMS score of the MR16-1-treated group indicated significant recovery of neurological functions. MR16-1-treated mice in the SCI group exhibited lower paw withdrawal thresholds in the plantar von Frey and thermal tests, which were used to evaluate allodynia. MR16-1 treatment significantly increased the area of Luxol fast blue-stained tissue, representing spared myelin sheaths. These results indicate that the continuous inhibition of IL-6 signaling by MR16-1 between the early and sub-acute phases following SCI leads to neurological recovery and the suppression of hyperalgesia and allodynia. Overall, our data suggest that the inhibition of severe inflammation may be a promising neuroprotective approach to limit secondary injury following SCI and that an anti-IL-6 receptor antibody may have clinical potential for the treatment of SCI. [ABSTRACT FROM AUTHOR]

Vagus nerve stimulation (VNS) is an approved treatment for epilepsy and depression and has cognition-enhancing effects in patients with Alzheimer's disease. The hippocampus is widely recognized to be related to epilepsy, depression, and Alzheimer's disease. One possible mechanism of VNS involves its effect on the hippocampus; i.e. it increases the release of noradrenaline in the hippocampus. However, the effect of VNS on synaptic transmission in the hippocampus is unknown. To determine whether VNS modulates neurotransmission in the hippocampus, we examined the effects of VNS on perforant path (PP)-CA3 synaptic transmission electrophysiologically in anaesthetized rats. VNS induces a persistent enhancement of PP-CA3 field excitatory post-synaptic potentials (fEPSPs). Arc, an immediate early gene, was used to identify active brain regions after VNS. The locus coeruleus (LC), which contains the perikarya of noradrenergic projections, harboured more Arc-positive cells, as measured by in-situ hybridization, after 10-min VNS. In addition, electrical lesions of LC neurons or intraventricular administration of the β-adrenergic receptor antagonist timolol prevented the enhancement of PP-CA3 responses by VNS. In conclusion, the protracted increase in PP-CA3 synaptic transmission that is induced by VNS entails activation of the LC and β-adrenergic receptors. Our novel findings suggest that information from the periphery modulates synaptic transmission in the CA3 region of the hippocampus. [ABSTRACT FROM AUTHOR]

The article presents a study which explores how chronic pain–induced neuronal plasticity in the bed nucleus of the stria terminalis causes maladaptive anxiety . It mentions the use of a mouse model of neuropathic pain, and demonstrated neuronal plasticity in the bed nucleus of the stria terminalis (BNST), which plays a critical role in chronic pain–induced maladaptive anxiety.

Abstract Background  The joint gap is set rectangular at 90° flexion during total knee arthroplasty (TKA). However, the condition of the joint gap in deep knee flexion is obscure. Methods  The method for obtaining a posteroanterior view radiograph of the knee at 90° flexion (the epicondylar view) was modified, and a method to obtain an anteroposterior view radiograph at 120° flexion (deep flexion view) was established. With this method, subjects lie on the radiography table with their thighs placed on a device so their lower legs hang down in neutral rotation with a 1.5-kg weight attached to the ankle. The joint gap angle and medial and lateral joint space widths were measured on epicondylar view and deep flexion view radiographs in 20 normal male subjects, 20 normal female subjects, and 20 subjects after TKA. Results  The joint gap was almost rectangular at two flexion angles in normal subjects. In the implanted knees, the gap angle was 1.4° varus ± 3.3° (mean ± standard deviation), and no significant difference was found between medial and lateral joint space widths at 90° flexion. In contrast, the gap angle was 2.5° varus ± 2.5° and the lateral joint space width was significantly wider than the medial joint space width at 120° flexion (P P Conclusions  The joint gap was trapezoidal with a wider lateral side at 120° flexion even though it was almost rectangular at 90° flexion after TKA. [ABSTRACT FROM AUTHOR]

Aim: Yokukansan (YKS), a traditional herbal medicine, has been used to treat behavioral and psychological symptoms of dementia (BPSD). The present study is the first double-blind, randomized, placebo-controlled trial to determine the efficacy and safety of YKS for the treatment of BPSD in Alzheimer's disease (AD)., Methods: A total of 22 sites consisting of clinics, hospitals and nursing homes participated. A total of 145 patients with AD were randomized. Active YKS (7.5 g/day) and placebo were supplied to 75 and 70 participants, respectively. The primary outcome measure was the 4-week change in total score of the Neuropsychiatric Inventory Brief Questionnaire Form (NPI-Q), an instrument that evaluates BPSD. Secondary outcome measures included 12-week changes in NPI-Q scores, changes in NPI-Q subcategory scores and total scores of the Mini-Mental-State Examination., Results: Four-week changes in NPI-Q total scores did not differ significantly between the treatment and placebo groups. There were also no significant differences between groups in 12-week changes in total NPI-Q scores, NPI-Q subcategory scores or total Mini-Mental-State Examination scores. However, a subgroup with fewer than 20 points on the Mini-Mental-State Examination at baseline showed a greater decrease in "agitation/aggression" score in the YKS group than in the placebo group (P = 0.007). No serious adverse effects were observed during the study., Conclusions: Our data did not reach statistical significance regarding the efficacy of YKS against BPSD; however, YKS improves some symptoms including "agitation/aggression" and "hallucinations" with low frequencies of adverse events. Geriatr Gerontol Int 2017; 17: 211-218., (© 2015 Japan Geriatrics Society.)