研究者詳細 - 満倉　靖恵

論文 - 満倉　靖恵

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Exploring factors associated with inflammation in stressed workers: a cross-sectional study.

Akihiro Koreki, Hisateru Tachimori, Anna Kubota, Yoshiaki Kanamori, Manae Uchibori, Shiyori Usune, Akira Ninomiya, Akihiro Fujimoto, Kanako Inabe, Ryutaro Shirahama, Yasue Mitsukura, Hiroaki Miyata, Masaru Mimura, Mitsuhiro Sado.

BMC Public Health （SPRINGER NATURE） 25 （ 3937 ） 2025年11月

研究論文（学術雑誌）

Abstract
Background
Chronic occupational stress leads to physical and mental illnesses, highlighting the importance of
effective stress management in modern societies. Recently, chronic stress-induced systemic low-grade inflammation has garnered increasing attention for its stress response and crucial pathological role in the development of both physical and mental illnesses. In this context, elevated salivary interleukin-6 (sIL-6) levels have been developed as measurable and non-invasive stress indicators. However, the factors associated with sIL-6 in stressed office workers,
including the symptomatic manifestations of stress responses, have not been extensively investigated. Since direct measurement of inflammation is costly in routine stress management, identifying symptoms that reliably reflect inflammation could facilitate the development of more effective, inflammation-based stress management strategies.
Methods
In this cross-sectional study, stressed office workers were recruited through a screening process using
a Brief Job Stress Questionnaire. Saliva samples were collected to measure sIL-6 levels, and participants completed questionnaires addressing their occupational environment, symptomatic manifestations, and lifestyle. After excluding one participant owing to a medical history that could potentially affect sIL-6 levels, 128 stressed office workers were included in the analysis.
Results
Our model-based analysis for symptomatic manifestation demonstrated that elevated sIL-6 was significantly
associated with greater feelings of fatigue as well as relatively higher vigor. A separate model-based analysis for stressors revealed a significant association with higher qualitative job overload. Data-driven analyses further supported the finding that elevated sIL-6 was significantly associated with fatigue.
Conclusions
Our findings suggest that the feeling of fatigue may reflect chronic stress-induced systemic low-grade
inflammation in the body, highlighting the importance of self-monitoring fatigue for early intervention. Inflammation based stress management holds promise in preventing both mental and physical illnesses in stressed office workers.

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Development of Benefit-Effect Assessment Method for Improving Social Acceptance of Urban Air Mobility

Susumu Hara; Satoshi Kusano; Yasue Mitsukura; Hiroko Kamide; Yasuo Sasaki

American Institute of Aeronautics and Astoronautics （ American Institute of Aeronautics and Astoronautics） 2025年08月

n recent years, urban air mobility (UAM) technologies have been studied worldwide. However, social acceptance of UAMs and drones remains underexplored. Without adequate research, the anticipated “aerial industrial revolution” from drone use and flying vehicles may face social issues. To address this, the authors’ group proposed a social acceptance evaluation method combining subjective questionnaires with objective stress evaluations using a Kansei Analyzer based on a simple electroencephalograph and confirmed the effectiveness of this method. Related studies have assessed subjective stress from drone noise, but stress varies by the applications of the UAMs and stakeholders. It is critical to assess the stress people perceive from noise for each application and each stakeholder. This study evaluates sensitivity indices, including stress, for UAM uses, focusing on people uninvolved with UAMs, who face the greatest disadvantages. We conduct statistical tests for changes in cognitive sensitivities and physiological stress that is affected by the instruction in benefits of the UAM applications, focusing on residents uninvolved with UAMs, who face the greatest disadvantages. The study concludes with a summary of the benefit-effect assessment results.

Major Depressive Disorder, Bipolar Disorder and Schizophrenia in Patients with Prurigo Nodularis: a Multicenter Retrospective Cohort Study derived from TriNetX research network

Hui-Chin Chang; Tsung-Hsuan Hung; Shao-Wei Lo; Yasue Mitsukura; Shiu-Jau Chen; Shuo-Yan Gau

Journal of American Academy of Dermatology （Journal of American Academy of Dermatology） 2025年08月

Prurigo nodularis (PN) is a chronic, pruritic skin disease characterized by hyperkeratotic nodules and severe itch. Previous studies have described high rates of psychiatric comorbidities such as depression and anxiety in PN patients, but longitudinal evidence evaluating risk of severe mental illnesses remains scarce. Understanding whether PN contributes to new-onset psychiatric disorders is essential for clarifying its systemic impact and guiding interdisciplinary care.
We conducted a retrospective cohort study using the TriNetX (Global Collaborative Network), a widely used global electronic health record database for evaluating health outcomes.
As a conclusion, PN is associated with increased risks of MDD, BD, and schizophrenia. These findings support a broader view of PN as a systemic disease with neuropsychiatric implications.

Violet light could improve sleep quality and blood glucose levels in healthy individuals: A pilot study

Kato T., Mitsukura Y.

Plos One 20 （ 8 August ） e0314346 2025年08月

Light is perceived through the retina, the light-sensing tissue layer of the eye, and can directly influence the brain. Light exposure triggers various biological responses that improve sleep quality and stabilize mood. Recently, violet light, exhibiting a unique wavelength of 360–400 nm, has garnered significant attention due to its perception through a specific receptor, marking a novel research area. Herein, we used “violet light glasses” that directly emit violet light into the human eye and investigated their effects on healthy humans in real-life settings. This study demonstrated that two hours of violet light exposure in the morning enhanced sleep quality in approximately 20% of the healthy participants and was also associated with improved blood glucose levels. Although this was a pilot study due to its small sample size, our findings indicate that violet light could potentially promote health benefits in humans.

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Remote alpha/beta measurement system with support vector machine algorithm

Yuki Morishita; Hiroko Nakamura Miyamura; Yuki Sato; Jun Matsubara; Brian Sumali; Yasue Mitsukura

Nuclear Instruments and Methods in Physics Research Section A: Accelerators, Spectrometers, Detectors and Associated Equipment Volume 1076 （elsevier） 1076 2025年07月

Decommissioning nuclear reactor sites presents challenges due to the presence of various radionuclides, including alpha emitters (e.g., Pu, Am, Cm) and beta emitters (e.g., 137Cs, 90Sr–90Y), which pose significant internal exposure risks to workers. Traditional measurement methods require multiple instruments and are time-consuming, particularly in high gamma-ray environments. To address these issues, we developed a remote alpha and beta discrimination measurement system that integrates a stilbene scintillator detector with a silicon photomultiplier, enabling simultaneous detection of both alpha and beta particles. This study further incorporates machine learning techniques, specifically Support Vector Machines (SVM), for automatic discrimination, eliminating the need for user-defined thresholds and ensuring consistent operational conditions. The system was tested with known radiation sources, demonstrating over 96 % classification accuracy for alpha and beta particles. Measurements conducted in motion effectively identified contamination sources, confirming the system's capability for real-time analysis. This innovative approach enhances radiation safety and efficiency in nuclear decommissioning operations, making it particularly beneficial in environments where human access is limited.

A Novel Approach for Pulse Signals Extraction and Heart Rate Estimation With Hilbert Space Orthogonalization Using Event-Based Camera

Hayato Nakamura; Gengtao Lin; Yasue Mitsukura.

IEEE Access （IEEE） 13 112340 - 112353 2025年06月

This paper presents a novel signal processing pipeline for estimating pulse signals, onset peaks, and heart rate using an event-based camera (EVS). EVS capture changes in brightness as a series of events, including both spatially induced events triggered by motion artifacts and temporally induced events caused by changes in skin luminance. When reconstructing pulse signals, spatially induced ON- and OFF-events within the region of interest (ROI) often occur simultaneously, canceling each other out and compromising signal stability. Additionally, biases between ON- and OFF-events can cause peak inversions under certain conditions, further destabilizing the signal. The proposed method addresses these challenges and temporal characteristics of EVS by defining event streams in a Hilbert space and applying Gram-Schmidt orthogonalization to isolate the temporally induced event stream. This enables robust estimation of pulse signals, heart rate through frequency analysis, and onset peak detection. To our knowledge, this is the first study that applies orthogonalization in Hilbert space to improve the signal processing of event-based pulse waves. The performance of the proposed approach is evaluated by comparing the extracted parameters with ground truth photoplethysmography (PPG) signals under three different lighting conditions. In the setup combining a green LED and a green optical filter, the method achieves a mean absolute error (MAE) of 1.13 BPM, a root mean square error (RMSE) of 1.69 BPM, and a peak detection accuracy of 92.72%. These results demonstrate the effectiveness of the proposed event-based method and highlight the potential of EVS for non-contact heart rate monitoring.

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Advancing non-human primate welfare: An automated facial recognition system for unrestrained cynomolgus monkeys

Yosuke Numata; Brian Sumali; Ken’ichiro Hayashida; Hideshi Tsusaki; Yasue Mitsukura

PLoS ONE 20(4) （Public Library of Science ） 20 （ 4 ） e0319897 2025年04月

Cynomolgus monkeys (Macaca fascicularis) are vital in biomedical research, particularly for drug development and studying neurological diseases. However, accurately identifying individuals in group housing environments remains a significant challenge. This paper presents a near real-time facial recognition system tailored for cynomolgus monkeys, utilizing a fine-tuned Detectron2 model for face detection, followed by eigenface-based classification with Support Vector Machine (SVM) and radial basis function (RBF) kernel. The system achieved an accuracy of 97.65% in 10-fold cross-validation and identified individuals in under 1 minute under ideal conditions. This method eliminates the need for invasive identification techniques, potentially reducing stress and improving animal welfare, and has the potential to reduce the need for individualized housing or specialized enclosures. Additionally, as the system reduces the time and labor required for identifying monkeys, it might benefit research facilities with high turnover rates. This method could improve identification in non-human primate research while minimizing stress associated with traditional techniques.

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The roles of intrinsically disordered proteins in neurodegeneration

Kagistia Hana Utami; Satoru Morimoto; Yasue Mitsukura; Hideyuki Okano

Biochimica et Biophysica Acta (BBA) （elsevier） 1869 （ 4 ） 2025年04月

Neurodegenerative diseases such as Amyotrophic Lateral Sclerosis, Alzheimer's disease, Parkinson's disease, and Huntington's disease share a common pathological hallmark: the accumulation of misfolded proteins, particularly involving intrinsically disordered proteins (IDPs) like TDP-43, FUS, Tau, α-synuclein, and Huntingtin. These proteins undergo pathological aggregation, forming toxic inclusions that disrupt cellular function. The dysregulation of proteostasis mechanisms, including the ubiquitin-proteasome system (UPS), ubiquitin-independent proteasome system (UIPS), autophagy, and molecular chaperones, exacerbates these proteinopathies by failing to clear misfolded proteins effectively. Emerging therapeutic strategies aim to restore proteostasis through proteasome activators, autophagy enhancers, and chaperone-based interventions to prevent the toxic accumulation of IDPs. Additionally, understanding liquid-liquid phase separation (LLPS) and its role in stress granule dynamics offers novel insights into how aberrant phase transitions contribute to neurodegeneration. By targeting the molecular pathways involved in IDP aggregation and proteostasis regulation, and better understanding the specificity of each component, research in this area will pave the way for innovative therapeutic approaches to combat these neurodegenerative diseases. This review discusses the molecular mechanisms underpinning IDP pathology, highlights recent advancements in drug discovery, and explores the potential of targeting proteostasis machinery to develop effective therapies.

Disruption in Autonomic Nervous Activity Is Associated With Central and Peripheral-Level in Dry Eye With Unstable Tear Film

Minako Kaido; Reiko Arita; Yasue Mitsukura; Brian Sumali; Kazuo Tsubota

Investigative Ophthalmology & Visual Science （ARVO） 66 （ 2 ） 69 2025年02月

Purpose: To measure autonomic nerve activity (ANA) in several eye conditions and verify whether ANA modulation is regulated by peripheral or central control in short tear film break-up time dry eye (sBUTDE).

Methods: This study included 23 eyes of 23 patients with sBUTDE (mean age 55.2 ± 16.1 years; range 21–88 years) and 24 eyes of 24 age-matched non-dry eye (DE) controls. An ANA measurement, personality questionnaire, and Ocular Surface Disease Index were administered. ANA was continuously measured for 10 minutes under three conditions: eyes closed, eyes open, and eyes open under ocular surface anesthesia.

Results: The low-frequency (LF)/high-frequency (HF) ratio (LF/HF) with eyes closed was significantly higher in the sBUTDE group than in the control group (P < 0.05). In the sBUTDE group, HF increased and LF/HF decreased with eye opening compared with those in the control group; HF with eyes open decreased with ocular surface anesthesia and reached the same level as that in the control group. Among patients where HF decreased or LF/HF increased with eye opening, 57.1% or 64.3% showed a tendency to return to the ANA state with eyes closed by ocular surface anesthesia, respectively. Factors associated with DE symptoms included break-up time, HF with eyes open, and “openness” (P < 0.05).

Conclusions: ANA modulation can be caused by peripheral, central, or mixed abnormalities in sBUTDE. Furthermore, personality traits may play a role in symptom induction. Understanding the pathogenesis of sBUTDE may aid in the treatment of cases that are refractory to conventional treatments.

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Feature of autonomic nerve activity during different eye conditions in dry eye with unstable tear film

Minako Kaido; Reiko Arita; Yasue Mitsukura; Brian Sumali; Kazuo Tsubota

Investigative Ophthalmology & Visual Science （Investigative Ophthalmology & Visual Science） Vol. 65 （ Issue 7 ） 2955 2024年06月

Purpose : Neurological abnormality has been suggested to be involved in the pathogenesis of dry eye (DE) disease. We previously reported that autonomic nerve activity (ANA) may be a key for the symptom manifestation in short break up time of tear film (BUT) DE (sBUTDE), which exhibits severe symptoms even with little epithelial damage (Kaido et al. Invest Ophthalmol Vis Sci. 2023). In this study, we investigated whether the cause of ANA modulation is peripheral or central.

Methods : This prospective, cross-sectional, comparative clinical study included 23 eyes of 23 patients with sBUTDE (mean age: 55.2 ±16.1 years), who were receiving conventional treatments, and 16 eyes of 16 non-DE controls (mean age: 55.4 ± 16.5 years). An ANA measurement and the Japanese version of the Ocular Surface Disease Index (J-OSDI) were administered. ANA was continuously measured for 10 min. under each of three conditions: eyes closed, eyes open, and eyes open under ocular surface anesthesia. The parameters were component of low-frequency (LF) reflecting cardiac sympathetic and parasympathetic nerve activity, high-frequency (HF) reflecting parasympathetic nerve activity alone, ration of LF over HF (LF/HF), component coefficient of variation (ccv) of LF (ccvLF), and ccvHF.

Results : In sBUTDEs, HF and ccvHF were higher when the eyes are open than when the eyes are closed; LF/HF was higher when the eyes are closed than when the eyes are open, whereas non-DEs showed the opposite response. The difference values of HF, ccvHF, and LF/HF between the eyes closed and open were greater in sBUTDE than in non-DE. There were no significant changes in all parameters between the open eyes with and without anesthesia in both groups. In addition, the multiple regression analysis to determine the factors affecting J-OSDI scores with ANA parameters as independent variables showed that HF under eyes open was significantly associated with the J-OSDI scores.

Conclusions : The symptom manifestation in sBUTDE may be explained by abnormalities in ANA, and the fact that blockade of peripheral stimulation does not change ANA may suggest central involvement of ANA.

Electroencephalogram-detected stress levels in the frontal lobe region of patients with dry eye

Minako Kaido, Reiko Arita, Yasue Mitsukura, Kazuo Tsubota

The Ocular Surface （ELSEVIER） Vol. 32 139 - 144 2024年04月

Purpose
To evaluate stress levels extracted from prefrontal electroencephalogram (EEG) signals and investigate their relationship with dry eye symptoms.

Methods
This prospective, cross-sectional, comparative study included 25 eyes of 25 patients with aqueous tear-deficient dry eye (low Schirmer group), 25 eyes of 25 patients with short tear breakup time dry eye (short breakup time group), and 24 eyes of 24 individuals without dry eye. An EEG test, the Japanese version of the Ocular Surface Disease Index (OSDI), and a stress questionnaire were administered. EEG-detected stress levels were assessed under three conditions: eyes closed, eyes open, and eyes open under ocular surface anesthesia.

Results
Stress levels were significantly lower when the eyes were closed than when they were open in all groups (all P < 0.05). Stress levels during eyes open under ocular surface anesthesia were significantly lower than those during eyes open without anesthesia only in the low Schirmer group; no differences were found between the short breakup time and control groups. OSDI scores were associated with EEG-detected stress levels (P = 0.06) and vital staining score (P < 0.05) in the low Schirmer group; they were not associated with EEG-detected stress (P > 0.05), but with subjective stress questionnaire scores and breakup time values in the short breakup time group (P < 0.05).

Conclusions
In the low Schirmer group, peripheral nerve stimulation caused by ocular surface damage induced stress reactions in the frontal lobe, resulting in dry eye symptoms. Conversely, in the short breakup time group, the stress response in the frontal lobe was not related to symptom development.

Unraveling the Influence of Age, IQ, Education, and Negative Symptoms on Neurocognitive Performance in Schizophrenia: Conditional Inference Tree Analysis

Xenia M. Hart, Yasue Mitsukura, Robert Bies, Hiroyuki Uchida

Pharmacopsychiatry （Thieme） 2024年03月

Introduction The complex nature of neurocognitive impairment in schizophrenia has been discussed in light of the mixed effects of antipsychotic drugs, psychotic symptoms, dopamine D2 receptor blockade, and intelligence quotient (IQ). These factors have not been thoroughly examined before.

Methods This study conducted a comprehensive re-analysis of the CATIE data using machine learning techniques, in particular Conditional Inference Tree (CTREE) analysis, to investigate associations between neurocognitive functions and moderating factors such as estimated trough dopamine D2 receptor blockade with risperidone, olanzapine, or ziprasidone, Positive and Negative Syndrome Scale (PANSS), and baseline IQ in 573 patients with schizophrenia.

Results The study reveals that IQ, age, and education consistently emerge as significant predictors across all neurocognitive domains. Furthermore, higher severity of PANSS-negative symptoms was associated with lower cognitive performance scores in several domains. CTREE analysis, in combination with a genetic algorithm approach, has been identified as particularly insightful for illustrating complex interactions between variables. Lower neurocognitive function was associated with factors such as age>52 years, IQ<94/95,<12/13 education years, and more pronounced negative symptoms (score<26).

Conclusions These findings emphasize the multifaceted nature of neurocognitive functioning in patients with schizophrenia, with the PANSS-negative score being an important predictor. This gives rise to a role in addressing negative symptoms as a therapeutic objective for enhancing cognitive impairments in these patients. Further research must examine nonlinear relationships among various moderating factors identified in this work, especially the role of D2 occupancy.

Development of Novel Automatic Real-Time Face Recognition System for Cynomolgus Monkeys

Yosuke Numata, Brian Sumali, Kenichiro Hayashida, Hideshi Tsusaki, Masato Yasui, Yasue Mitsukura

Journal of Pharmacological Sciences Vol 154 （ Issue 2 ） 2024年02月

Many glaucoma treatments focus on lowering intraocular pressure (IOP), with novel drugs continuing to be developed. One widely used model involves raising IOP by applying a laser to the trabecular iris angle (TIA) of cynomolgus monkeys to damage the trabecular meshwork. This model, however, presents challenges such as varying IOP values, potential trabecular meshwork damage, and risk of animal distress. This study investigated whether animals with naturally high IOP (>25 mmHg) could be used to effectively evaluate IOP-lowering drugs, thereby possibly replacing laser-induced models. Relationships between TIA size, IOP, and pupil diameter were also examined. Three representative IOP-lowering drugs (latanoprost, timolol, ripasudil) were administered, followed by multiple IOP measurements and assessment of corneal thickness, TIA, and pupil diameter via anterior segment optical coherence tomography (AS-OCT). There was a positive correlation was noted between IOP and corneal thickness before instillation, and a negative correlation between IOP and TIA before instillation. Our findings suggest animals with naturally high IOP could be beneficial for glaucoma research and development as a viable replacement for the laser-induced model and that measuring TIA using AS-OCT along with IOP yields a more detailed evaluation.

Evaluation of a new portable corneal topography system for self-measurement using smartphones: a pilot study

Hidenaga Kobashi, Kazuo Tsubota, Shunsuke Aoki, Masaaki Kobayashi, Brian Sumali, Yasue Mitsukura

Graefe's Archive for Clinical and Experimental Ophthalmology （Springer） Vol. 262 2199 - 2207 2024年02月

Purpose
Herein, we propose the use of the “KeraVio Ring”, which is a portable, selfie-based, smartphone-attached corneal topography system that is based on the Placido ring videokeratoscope. The goal of this study was to evaluate and compare corneal parameters between KeraVio Ring and conventional corneal tomography images.

Methods
We designed the KeraVio Ring as a device comprising 3D-printed LED rings for generating Placido rings that can be attached to a smartphone. Two LED rings are attached to a cone-shaped device, and both corneas are illuminated. Selfies were taken using the KeraVio Ring attached to the smartphone without assistance from any of the examiners. Captured Placido rings on the cornea were analysed by intelligent software to calculate corneal parameters. Patients with normal, keratoconus, or LASIK-treated eyes were included. Anterior segment optical coherence tomography (AS-OCT) was also performed for each subject.

Results
We found highly significant correlations between the steepest and flattest keratometry, corneal astigmatism, and vector components obtained with the KeraVio Ring and AS-OCT. In subjects with normal, keratoconus, and LASIK-treated eyes, the mean difference in corneal astigmatism between the two devices was -0.8 ± 1.4 diopters (D) (95% limits of agreement (LoA), -3.6 to 2.0), -1.8 ± 3.7 D (95% LoA, -9.1 to 5.5), and -1.5 ± 1.3 D (95% LoA, -4.0 to 1.1), respectively.

Conclusions
The experimental results showed that the corneal parameters obtained by the KeraVio Ring were correlated with those obtained with AS-OCT. The KeraVio Ring has the potential to address an unmet need by providing a tool for portable selfie-based corneal topography.

カニクイザルにおける睾丸サイズと疼痛閾値の周期的変化

森大輝*, 満倉靖恵, 沼田洋輔, 林田健一郎

第97回日本薬理学会年会（第97回日本薬理学会年会） 2023年12月

Cynomolgus monkeys, like humans, are continuous breeders and while the female sexual cycle has been extensively studied, little is known about male sexual cycles, such as periodic changes in the testicle size. Although testosterone, the primary male hormone secreted by the testicles, has been demonstrated to increase pain thresholds in humans and animals, whether testicle size affects pain thresholds is unknown. In the present study, we measured the testicle size in 7 matured male cynomolgus monkeys (6-8 years old) once a week for 23 weeks and observed that there were periodic changes in testicle size, with an average interval between peak points of 36.5 days. We also examined pain thresholds in these animals by measuring paw withdrawal temperatures (PWTs) in the dorsal hind paws once a week for 22 weeks. Similar to the testicles, PWTs underwent periodic changes with an average interval between peak points of 27.6 days. Although their cycles were not synchronized, the mean values of testicle size and PWTs showed a significant correlation (P = 0.019). These results demonstrate the presence of male sexual cycle and indicate the relationship between testicle size and pain thresholds in cynomolgus monkeys, providing new insights into research not only in primates, but also in other continuous breeders, including humans.

Dexamethasone induces sleep disturbance in a dose-dependent manner in mice

Tomonobu Kato*, Gento Okawa, Kenji F. Tanaka, Yasue Mitsukura

PLOS ONE （PLOS ONE） Vol. 18 （ No. 2 ） e0296028 2023年12月

Synthetic corticosteroids, the most well-known anti-inflammatory drugs globally, are effective against inflammatory diseases despite their adverse effects that decrease a patient’s quality of life (QOL). One of these effects is sleep disturbance, which causes other health issues and further diminishes the QOL. However, the acute effects of steroid drugs on sleep-wake issues are not fully understood and must be clarified in detail using experimental animals. Therefore, this study examines the dose-dependent effect of dexamethasone (DXM), one of the strongest steroid drugs, on the sleep-wake architecture of mice. We conducted acute DXM administration at multiple doses and 24-hour EEG/EMG recordings. Our results revealed that DXM increased the time spent in arousal and decreased that of NREM sleep, even at very low doses. These results imply that steroid-induced sleep disturbance must be addressed at any dosage.

Autonomic Nerve Activity Features According to Dry Eye Type

Minako Kaido, Reiko Arita, Yasue Mitsukura, and Kazuo Tsubota

Investigative Ophthalmology & Visual Science （Investigative Ophthalmology & Visual Science） Vol. 64 （ No. 7 ） pp. 19 2023年06月

Purpose: The purpose of this study was to investigate the association between autonomic nerve activity and symptom intensity according to the type of dry eye (DE).

Methods: This prospective, cross-sectional, comparative study included 25 eyes of 25 patients with short tear break-up time DE (sBUTDE; mean age = 57.4 ± 11.4 years, range = 30–74 years) and 24 eyes of 24 patients with aqueous tear-deficient DE (ADDE; mean age = 62.3 ± 10.7 years, range = 29–76 years) were studied. Autonomic nerve activity was examined, and the Japanese version of the Ocular Surface Disease Index (J-OSDI) and a stress check questionnaire were administered. Autonomic nerve activity was continuously measured for 10 minutes. The parameters were low-frequency (LF) and high-frequency (HF) components of heart rate variability, reflecting cardiac sympathetic and parasympathetic nerve activity, and parasympathetic nerve activity alone, respectively; and the coefficient of variation of R wave-to-R wave (RR) interval (cvRR), component coefficient of variation of LF (ccvLF), and component coefficient of variation of HF (ccvHF), reflecting fluctuation of RR interval, LF, and HF, respectively.

Results: Higher J-OSDI scores were associated with higher HF, ccvHF, and subjective stress in sBUTDE, showing a significant correlation (r = 0.53, P < 0.01; r = 0.55, P = 0.01; and r = −0.66, P = 0.01); no correlations were observed between the J-OSDI score and autonomic parameters and stress in ADDE.

Conclusions: DE symptoms were significantly associated with the magnitude and fluctuation of parasympathetic activity in sBUTDE. Thus, among the autonomic parameters, parasympathetic activity is involved in the development of symptoms in sBUTDE, whereas the involvement of the autonomic nervous system may be minimal in ADDE.

Violet Light Therapy for Improving Sleep Quality: a Pilot Study

Yasue Mitsukura, Brian Sumali, Motoshi Hayano, Kazuo Tsubota

Investigative Ophthalmology & Visual Science （Investigative Ophthalmology & Visual Science） Vol. 64 （ Issue 8 ） 2023年06月

Purpose : Violet light (VL) is a part of natural sunlight with shorter wavelength than blue light and recently found to be beneficial for various parts of human health. However, the connection between VL and sleep is yet to be explored. This pilot study aims to elucidate the connection between VL and sleep quality with the hope to verify the potential effectiveness of VL therapy on sleep disorders.

Methods : Two experiments with similar protocol were conducted. The participant was instructed to arrive before 9AM with minimal exposure to sunlight. Then, they were instructed to perform a regular deskwork for three hours, from 09:10 until 12:10. During the night, their sleep was measured using apple watch. For the first experiment, the participants were 6 university students (M/F ratio 1:1) with experiment duration of 5 days (3 Intervention, 2 Control). For the second experiment, a university student (female) performed the experiment for 2x28 days, one as control period and the other 28 days as intervention period. The main measures of this study are body temperature (only for experiment 1) and sleep stages.

Results : For experiment 1, the body temperature differences show that the body temperature is higher before sleep compared to the sleep during the intervention periods as opposed to increasing temperature during control period. REM/NREM stages are also closer to ideal during the intervention periods, although there was no statistical significance. Statistical significance between sleep stages was found in the experiment 2, with higher N1, N3 and lower WK, REM ratio during intervention periods.

Conclusions : In this study, the relation between VL therapy and sleep quality was analyzed. Although potential improvement to sleep quality can be seen from both short-term and long-term experiment, there is also a concern of significantly lower REM percentage during long-term experiment.

Keratoconus detection using smartphone selfie

Hidenaga Kobashi, Kazuo Tsubota, Shunsuke Aoki, Brian Sumali, Yasue Mitsukura

Investigative Ophthalmology & Visual Science （Investigative Ophthalmology & Visual Science） Vol. 64 （ Issue 8 ） 2023年06月

Purpose : Smartphone is easy tool for patients and ophthalmologists to communicate the data access. We propose “Hikaru ring”, a portable, low-cost, and easily measurable keratoconus detection device which is based on smartphone selfie camera images.

Methods : We designed the Hikaru ring as a gadget comprising of a 3D-printed placido’s rings of LED light combined with the smartphone. Two circle LEDs (12-cm and 6-cm) were attached with cone-shaped gadget and both corneas were irradiated at a distance of 15 cm and 19 cm, respectively. Selfie photographs were taken using the ring attached smartphone in normal and keratoconus subjects. Captured mire images of the reflection of the placido’s rings on the cornea were analyzed by an intelligent Windows software based on the corneal parameters. Anterior segment optical coherence tomography was also performed in each subject.

Results : In a clinical study, we successfully identified the diagnosis of keratoconus based on eccentricity and steepest keratometry in smartphone selfie style. We found significant correlation of corneal astigmatism and steepest keratometry between Hikaru ring and standard tomography (r = 0.533, p < 0.001 and r = 0.656, p < 0.001).

Conclusions : Preliminary experimental results show that the proposed method could detect keratoconus. Our novel placido’s rings attached with smartphone is useful for the screening under remote medicine.

Violet light modulates the central nervous system to regulate memory and mood

Motoshi Hayano; Pooja Gusain; Sarah Robertson; Yasue Mitsukura; Kazuo Tsubota

Investigative Ophthalmology & Visual Science （Investigative Ophthalmology & Visual Science） Vol. 64 （ Issue 8 ） 5475 2023年06月

Purpose : The photostimulation of the external environment serves as a visual signal, as well as a non-visual signal through the protein opsin. In mammals, the non-visual photoreceptor opsin5 (also known as OPN5 or neuropsin) is expressed in the retinal ganglion cells RGCs) and hypothalamus. Violet light with a wavelength of 360-400 nm activates OPN5 and regulates the circadian cycle, thermogenesis, and myopia. However, the function of violet light and OPN5 in brain function is unknown.

Methods : We exposed aged mice to violet light and observed the effects on memory through contextual fear conditioning and the Barnes maze. In addition, we observed he effects on mood through a social defeat stress (SDS) model and a subsequent social interaction test. We analyzed neural activity and oligodendrogenesis in the SDS model through immunostaining for c-fos and MBP, and examined the projection pathway from OPN5-positive retinal ganglion cells to the brain using WGA and Opn5cre; Ai14 mice.

Results : Our results showed that violet light, as an external stimulus, regulates memory and mood function in the brain. Violet light improves memory function in aged mice and simultaneously increases the expression of oligodendrocyte-related genes such as MBP and MAG in the hippocampus. In addition, violet light improves depressive-like behaviors in the social defeat stress model in an OPN5-dependent manner and increases neural activity and oligodendrogenesis in the prefrontal cortex and nucleus accumbens. The neural network analysis using WGA and Opn5cre; Ai14 mice indicates that the signal received by OPN5-positive retinal ganglion cells is transmitted to the habenula brain region.

Conclusions : Our findings revealed a novel function for violet light in regulating cognitive function and mood behavior. The well-conserved OPN5 may be a non-visual photoreceptor for sensing the light environment and maintaining brain function throughout the lifespan. Although OPN5-RGCs project to the MHb, the central mechanism sensing VL needs to be further investigated. The role of violet light via OPN5 in underpinning myelination and oligodendrocyte function in influencing cognition and mood behavior opens an interesting new avenue for research and the development of novel therapeutic treatments for neurodegeneration and neuropsychiatry disorders.

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