Published papers

Myopia has become a major public health concern, particularly across much of Asia. It has been shown in multiple studies that outdoor activity has a protective effect on myopia. Recent reports have shown that short-wavelength visible violet light is the component of sunlight that appears to play an important role in preventing myopia progression in mice, chicks, and humans. The mechanism underlying this effect has not been understood. Here, we show that violet light prevents lens defocus–induced myopia in mice. This violet light effect was dependent on both time of day and retinal expression of the violet light sensitive atypical opsin, neuropsin (OPN5). These findings identify Opn5-expressing retinal ganglion cells as crucial for emmetropization in mice and suggest a strategy for myopia prevention in humans.

Abstract Life has evolved under continuous exposure to solar light, and the emergence of the eye during the Cambrian period is thought to have accelerated biological diversification. Beyond vision, light acts as a biological regulator of metabolism and tissue organization. To elucidate ocular disease mechanisms and develop new therapies, we have investigated how light is sensed by the eye and coupled to physiological and pathological responses. This review reexamines the eye as a photoreceptive organ and summarizes recent advances showing how light input governs retinal metabolism, refractive development, and visual restoration. First, we describe how retinal light reception is linked to oxygen-dependent metabolic control. As one of the most oxygen-demanding tissues, the retina relies on hypoxia-inducible factor (HIF) signaling to coordinate angiogenesis, mitochondrial metabolism, fibrosis, and neuronal survival. Beyond pathological neovascularization, disrupted light-metabolic coupling contributes to neurodegeneration and subretinal scarring. Screening of natural compounds identified HIF regulators with therapeutic efficacy, and optical approaches were developed to detect hypoxia-induced intraocular cytokines noninvasively. Second, we show that environmental light regulates ocular growth in ways beyond image formation. Violet light activates nonvisual photoreception via OPN5-expressing retinal ganglion cells, engaging an OPN5-EGR1 pathway that preserves choroidal thickness and suppresses axial elongation through coordinated retina-brain-choroid-sclera interactions. Third, we demonstrate that light itself becomes therapeutic through optogenetic visual restoration. Chimeric rhodopsins confer high-sensitivity light responsiveness to surviving inner retinal neurons and have recently entered first-in-human clinical evaluation for advanced retinitis pigmentosa. These findings establish photobiology as a unifying framework for translational ophthalmology.

Abstract The non-perfusion area (NPA) of the retina is an important indicator in the visual prognosis of patients with retinal vein occlusion (RVO). However, the current evaluation method of NPA, fluorescein angiography (FA), is invasive and burdensome. In this study, we examined the use of deep learning models for detecting NPA in color fundus images, bypassing the need for FA, and we also investigated the utility of synthetic FA generated from color fundus images. The models were evaluated using the Dice score and Monte Carlo dropout uncertainty. We retrospectively collected 403 sets of color fundus and FA images from 319 RVO patients. We trained three deep learning models on FA, color fundus images, and synthetic FA. As a result, though the FA model achieved the highest score, the other two models also performed comparably. We found no statistical significance in median Dice scores between the models. However, the color fundus model showed significantly higher uncertainty than the other models (p < 0.05). In conclusion, deep learning models can detect NPAs from color fundus images with reasonable accuracy, though with somewhat less prediction stability. Synthetic FA stabilizes the prediction and reduces misleading uncertainty estimates by enhancing image quality.

The choroid, a vascularized tissue situated between the retina and the sclera, plays a crucial role in maintaining ocular homeostasis. Despite its significance, research on choroidal abnormalities and the establishment of effective in vitro models have been limited. In this study, we developed an in vitro choroid model through the co-culture of human induced pluripotent stem cells (hiPSC)-derived endothelial cells (ECs) and mouse choroidal fibroblasts (msCFs) with hiPSC-derived retinal pigment epithelial (RPE) cells via a permeable membrane. This model, inclusive of ECs, CFs, and RPE cells, exhibited similarities with in vivo choroidal vessels, as confirmed through immunohistochemistry of extracellular matrix markers and vascular-related markers, as well as choroid angiogenesis sprouting assay analysis. The effectiveness of our in vitro model was demonstrated in assessing vascular changes induced by drugs targeting vasoregulation. Our model offers a valuable tool for gaining insights into the pathological mechanisms underlying choroid development and the progression of choroidal vascular diseases.

Background: Optogenetic tools have been extensively investigated in basic and clinical research to restore vision in advanced retinal degeneration. Although microbial ion channel opsins, mammalian G protein-coupled receptor opsins, and chimeric opsins combining domains from different molecules have been reported, how these domain combinations affect opsin function and retinal responses remains poorly understood. Methods:We engineered a chimeric GtACR2 (chGtACR2) containing bovine rhodopsin cytoplasmic loops and delivered it to the retinas of rd1 mice. light-induced responses of GtACR2 and chGtACR2 in the cell line and retinas were compared by patch-clump and multielectrode array, respectively. Visual acuity and contrast sensitivity of chGtACR2-treated mice were examined by optomotor response test. Endogenous ion channels involved in the chGtACR2-induced light responses were tested by pharmacological blockade. Findings: Although patch-clamp recordings confirmed that chGtACR2 functioned as a light-gated chloride channel that induced membrane hyperpolarization, multielectrode array recordings revealed chGtACR2-induced ON-like responses in retinal ganglion cells across the tested stimulus intensities, with increases in the number of responsive units and their firing rates. Visual acuity and contrast sensitivity were improved in vivo. Hyperpolarization-activated cyclic nucleotide-gated (HCN) channel activity contributed to these ON-like responses. Interpretation:These findings suggest that endogenous HCN channel activity can influence retinal responses to an introduced optogenetic tool and highlight the potential of modifying cytoplasmic domains to alter the functional properties of microbial opsins. Funding: AMED-CRST (JP22gm1510007), JSPS KAKENHI (JP25K12842, JP26H00468, and JP24K12796), and SPRING(JPMJSP2123).

Objective/purpose: To investigate the spatial heterogeneity of early postoperative retinal remodeling following pars plana vitrectomy (PPV) for epiretinal membrane (ERM) using layer-by-layer ultra-widefield optical coherence tomography (UWF-OCT) to evaluate both the central and peripheral retina. Design: Retrospective observational study. Subjective, participants, and/or controls: Thirty eyes of 30 patients who underwent PPV for ERM. Methods, intervention, or testing: We acquired swept-source UWF-OCT images preoperatively and at 1 month postoperatively. Using automated segmentation, the analysis area was divided into a central 5-mm diameter region and 8 peripheral sectors extending to an 18-mm diameter. We quantified regional changes in total retinal thickness, the thickness of 5 segmented retinal layers, retinal vessel density, and choroidal thickness across the central and peripheral subfields. Results: The mean age was 68.0 ± 8.0 years, and 29 of 30 eyes (96.7%) underwent combined phacovitrectomy. Visual acuity improved from 0.19 ± 0.19 to 0.05 ± 0.12 logarithm of the minimum angle of resolution at 1 month (P < 0.001). Central total retinal thickness decreased significantly (P < 0.001), primarily because of thinning of the retinal nerve fiber layer, ganglion cell layer–inner plexiform layer, and inner nuclear layer–outer plexiform layer. In contrast, total retinal thickness increased significantly in 4 of the 8 peripheral sectors (L2, L6, L7, and L8; P < 0.0056), and the inner segment/outer segment junction–retinal pigment epithelium compartment thickened significantly across all 8 peripheral sectors. The overall time-by-region interaction for retinal vessel density was not significant (P = 0.105), although an isolated increase in L4 met the Bonferroni-adjusted threshold (P = 0.005). No significant postoperative changes were detected in choroidal thickness in any region. Conclusions: Early after epiretinal membrane surgery, retinal remodeling appears spatially heterogeneous, with central inner retinal thinning and peripheral thickening of the inner segment/outer segment junction–retinal pigment epithelium compartment. Layer-specific ultra-widefield optical coherence tomography may complement macular metrics in postoperative structural assessment. The biological basis and functional relevance of these peripheral changes require confirmation in larger longitudinal studies.

Purpose: To demonstrate the novel use of a 31-gauge needle for flanged intrascleral intraocular lens (IOL) fixation using the double-needle technique. Methods: Flanged intrascleral IOL fixation was performed using the ZELOSTAT 31G (ASTI, Shizuoka, Japan) needle in a 73-year-old male with right IOL subluxation. Results: The IOL was successfully fixated with smooth intraoperative handling, excellent postoperative outcomes, no complications, and minimal refractive error. Conclusion: The 31-gauge needle has a larger inner diameter compared to the conventional 30-gauge thin-wall needle, which may facilitate intrascleral IOL fixation procedures.

Abstract Background Retinal pigment epithelial and outer retinal atrophy (RORA) and complete RORA (cRORA) are major determinants of long-term vision in neovascular age-related macular degeneration (nAMD), but their development across subtypes is poorly defined, especially in Asian populations, in whom pachychoroid-driven disease is common. We compared long-term visual outcomes and atrophy burden between the conventional and novel nAMD classifications. Methods One hundred twenty eyes of 120 treatment-naïve patients with nAMD followed at least six years were classified by conventional (typical nAMD [tAMD], polypoidal choroidal vasculopathy [PCV], retinal angiomatous proliferation [RAP]) and novel (drusen type, pachychoroid type, mixed type, other type) schemes. All eyes received three loading anti-VEGF injections followed by a pro re nata regimen. RORA within the central 1 mm was graded on optical coherence tomography; lesions ≥ 250 μm were defined as cRORA. Visual acuity (VA) retention, atrophy prevalence, and VA around atrophy onset were assessed. Results Mean age was 78.0 ± 9.2 years and overall VA retention was 71%. VA retention did not differ among conventional subtypes, but under the novel classification was significantly lower in the drusen type and higher in the pachychoroid type ( P  < 0.01). VA declined significantly after both RORA and cRORA onset (both P  < 0.001). Final RORA/cRORA prevalence was 44.4%/29.6% in tAMD, 50.0%/28.3% in PCV, 83.3%/50.0% in RAP and 76.9%/61.5% in the drusen type, in which cRORA was highest ( P  < 0.05). Conclusions The novel classification distinguished long-term visual outcomes that the conventional classification did not: the drusen type showed the poorest VA retention and highest cRORA prevalence, whereas the pachychoroid type fared best.

PURPOSE. To evaluate the therapeutic potential of nicotinamide mononucleotide (NMN) for modulating the neurovascular inflammatory microenvironment and blunting tissue remodeling in neovascular age-related macular degeneration (nAMD). METHODS. A laser-induced choroidal neovascularization (CNV) model was established in C57BL/6J mice, and CNV lesion size was quantified on RPE/choroid flat mounts. Immunostaining evaluated myeloid cell accumulation and fibrosis-associated remodeling. Quantitative RT-PCR and Western blotting assessed inflammatory/angiogenic gene expression and signaling activation in the retina and RPE/choroid. In vitro, lipopolysaccharide (LPS)–stimulated bEnd.3 and primary mouse RPE cells and TGF-β–stimulated THP-1–derived macrophage cells were used to model inflammatory and profibrotic responses. RESULTS. NMN treatment significantly reduced CNV size in the laser-induced CNV model. This was accompanied by decreased myeloid cell accumulation within CNV lesions. NMN attenuated inflammatory and angiogenesis-related gene expression in the RPE/choroid and neural retina and reduced downstream signaling activation. In vitro, NMN suppressed LPS-induced inflammatory and proangiogenic responses in primary RPE cells and bEnd.3 endothelial cells and inhibited NF-κB activation. NMN further attenuated tissue remodeling, as shown by reduced collagen I–positive area under prolonged and delayed dosing regimens, together with decreased F4/80-positive area and α–smooth muscle actin–positive area within CNV lesions. In TGF-β–induced THP-1–derived macrophage cells, NMN suppressed profibrotic responses. CONCLUSIONS. Our findings indicate that NMN reduces inflammatory signaling and alleviates the inflammatory microenvironment in CNV, accompanied by decreased angiogenesis-related gene expression and fibrosis-related remodeling. By attenuating inflammatory activation and tissue remodeling processes, NMN warrants further evaluation as an adjunctive approach to limit CNV progression and late-stage tissue remodeling in nAMD.

Retinitis pigmentosa (RP) is a group of inherited retinal diseases that are caused by genetic defects that lead to progressive photoreceptor loss and eventual blindness. Early diagnosis would be helpful for effective management of the disease; however, many patients stay unaware of early symptoms. Meanwhile, fundus images are widely obtained during routine medical checkups but are underused for detecting RP. This study explores the effectiveness of finetuning deep learning models, pre-trained for general visual tasks, to identify RP from color fundus images. The dataset comprised 321 color fundus images from 201 Japanese subjects at Keio University Hospital, including 200 images from 107 patients with retinitis pigmentosa and 121 images from 94 non-retinitis pigmentosa subjects. Multiple images were available for some subjects. Using transfer learning, pretrained convolutional neural network models -VGG16, Resnet50, and InceptionV3- were finetuned to detect RP. As a result, Inception V3 achieved the best accuracy of 96.97%, which matches the average diagnostic accuracy of ophthalmologists. Gradient-weighted Class Activation Mapping (Grad-CAM) suggested that the model attended to clinically relevant fundus regions, including the peripheral retina and posterior pole, which may reflect features such as peripheral degenerative changes and retinal vascular attenuation. These findings support the potential interpretability of the finetuned model and suggest that deep learning may assist ophthalmologists in RP screening as a supportive tool.

Purpose: Although Japan has an established welfare system for individuals with visual impairments, medical-welfare coordination remains limited. To address this gap, the Low Vision Care Hub (LVCH) was established within a university hospital. We evaluated the impact of LVCH on visitor satisfaction before and after consultation Study design: A single-center, one-group pre–post study Methods: Individuals with self-reported functional vision difficulties who visited LVCH between July 1 and December 20, 2024 were included. Consultation was provided based on seven domains of low vision care outlined by the Japan Society for Low-Vision Research and Rehabilitation. Satisfaction was measured on a custom 6-point ordinal scale (0–5) pre/post consultation. Changes in satisfaction scores were analyzed using the Wilcoxon signed-rank test. Multivariable logistic regression adjusted for potential confounders Results: Ninety-three participants were included. Satisfaction scores significantly increased after consultation (p <.001) and improvements were consistent across sex, age groups, and visual impairment classification using the International Council of Ophthalmology (ICO) criteria (all p <.001). Notably, participants not meeting the ICO-defined low vision criteria also improved (p <.001). On multivariable logistic regression, only older age (≥ 60 years) remained significantly associated with a markedly improved satisfaction score (OR = 2.98, 95% CI 1.10–8.05, p =.03) Conclusion: Consultations provided at LVCH significantly improved visitor satisfaction, including those who did not meet the ICO low vision criteria. Consultation may be particularly effective in individuals aged over 60 years. Overall, early-stage intervention through structured consultation may benefit individuals with functional vision difficulties

Pathogenic variants in small nuclear RNA (snRNA) genes have recently emerged as a major cause of Mendelian disorders, particularly neurodevelopmental disorders, yet they remain difficult to detect in routine diagnostics because conventional whole-exome sequencing (WES) does not capture snRNA loci. Here, we reanalyzed whole-genome sequencing (WGS) data from 1,578 unsolved probands and identified pathogenic variants in multiple snRNA genes, including RNU4-2, RNU2-2, RNU5B-1, and RNU4ATAC, accounting for 1.2% (19 patients) of previously unsolved cases. We then developed an snRNA-extended WES approach by incorporating capture probes targeting 50 snRNA genes into a standard exome design. Benchmarking demonstrated robust, uniform coverage across all targeted snRNA loci without increasing sequencing depth. Applying this approach to patient samples reliably detected disease-causing snRNA variants previously identified by WGS. Our results establish snRNA-extended WES as a cost-effective and scalable strategy to improve diagnostic yield and bridge the gap between recent gene discoveries and clinical genomic practice.

The myopia epidemic is a major public health concern, yet the underlying causes and mechanisms of myopia progression remain unclear. Recent studies have reported an association between myopia progression and higher order aberrations (HOAs). However, to our knowledge, no research has reported the relationship between HOAs and environmental factors, which are well-established contributors to myopia progression. In this prospective study, we investigated this association across the COVID-19 pandemic. Children aged 6 to 12 years from one elementary school in Tokyo were enrolled. Non-cycloplegic refraction and ocular biometry were measured. Investigations were carried out every summer from 2018 to 2021. We adopted ocular spherical aberration (SA), third- and fourth-order aberrations (S3 and S4), and total HOAs (THOA) (calculated as the root mean squares from the third- to sixth-order Zernike coefficients) evaluated with a natural pupillary diameter. We analyzed 357 students during 2018 to 2019 (pre-pandemic period), 217 during 2019 to 2020 (pandemic period), and 285 during 2020 to 2021 (post-pandemic period). The time spent outdoors decreased significantly from 100.5 min/day in 2018 to 66.2 min/day in 2020 (p < 0.001). The time spent on near work including digital device usage initially decreased and then increased during the observation period. The time spent on smartphones was correlated inversely with the changes in S3, S4, and THOA in the pre-pandemic period. During the pandemic, the time spent on computers was correlated positively with the changes in the SA, S3, S4, and THOA. In the post-pandemic period, the time spent on reading and studying was correlated positively with the changes in THOA. Remarkably, the outdoor time was not a significant variable during any period. In conclusion, lifestyle factors changed dramatically throughout the pandemic and, particularly near work, may have been associated with the HOAs in children.

While choroidal macrophages regulate homeostasis in macular degeneration, their role in myopia is unclear. In this study, depleting choroidal macrophages via clodronate liposome injections induced myopia. To further dissect their function, introducing polarized classically activated (M1) or alternatively activated (M2) macrophages into a myopia model revealed that both the presence and polarization of choroidal macrophages affect myopia progression. Further exploration in normal mice showed that choroidal M1 macrophages polarization triggered choroidal thinning and promoted myopia progression, whereas M2 macrophages polarization enhanced choroidal thickening and suppressed myopia development. These opposite effects of M1 and M2 macrophages on choroidal thickness and myopia progression appeared to be related to their differential regulation of inflammatory responses and oxidative stress. Taken together, these results support a role for choroidal macrophages and their polarization states in myopia onset and progression, suggesting potential therapeutic strategies for controlling the development and progression of myopia.

As the prevalence of myopia, or near-sightedness, continues to rise globally, it becomes imperative to determine the mechanisms driving myopia so that appropriate interventions to mitigate it can be developed. Light appears to be critical for normal ocular development, and over the past several decades research has explored the connection between light exposure and myopia development. This review explores the growing field of photobiomodulation, or the use of light to modulate biological processes, to prevent myopia development. To complete this review, relevant texts published from January 1990 to December 2025 were retrieved from the PubMed database using a combination of search terms covering myopia and ocular development, light exposure conditions related to myopia, myopia development in relation to circadian and diurnal regulation, nonvisual opsins and myopia, and light-induced ocular damage. Through this review, we see that photobiomodulation offers a potential intervention to control myopia progression, but the mechanisms behind light’s influence on ocular development remain complex and incompletely understood. This review aims to summarize what is currently known to serve as a basis for future research and to delineate important findings.

Purpose To report a rare case of a full-thickness macular hole (FTMH) that underwent spontaneous closure on two separate occasions following vitrectomy and intraocular lens (IOL) scleral fixation. Observations A 58-year-old man, who had undergone IOL scleral fixation and vitrectomy for a dislocated IOL, developed an FTMH (minimum diameter: 21 μm) in the left eye approximately one year post-surgery. While awaiting surgical intervention, the macular hole closed spontaneously two months after its discovery. Two years and nine months later, the FTMH recurred (minimum diameter: 180 μm) and closed spontaneously again within four weeks. Optical coherence tomography (OCT) confirmed the presence of epiretinal proliferation (EP) at the macular surface during both occurrences. Conclusions and Importance Small-diameter FTMHs that form after vitrectomy, particularly those with associated EP, may have the potential for spontaneous closure. This case indicates that short-term observation may be a reasonable management option for select cases of small post-vitrectomy macular holes before proceeding with further surgery.

Purpose: To investigate time-dependent structural and functional retinal alterations in a mouse model of prolonged lens-induced myopia. Methods: Myopia was induced in male C57BL/6J mice by fitting −30 D lenses on both eyes starting at postnatal week 3. Mice were assigned to either a long-term induction group (3–9 weeks of age) or a short-term induction group (3–6 weeks of age). Separate groups fitted with 0 D lenses served as controls. Ocular parameters, including refraction, axial length, choroidal thickness, and retinal thickness were measured at weeks 3, 6, and 9 using an infrared photorefractor and spectral-domain optical coherence tomography. Retinal function was assessed by dark-adapted electroretinography at week 9 for the long-term group and at week 6 for the short-term group. Statistical analyses included two-way repeated-measures ANOVA followed by Bonferroni’s post hoc test for comparisons across groups and time points, and two-tailed unpaired t-test or one-way ANOVA with Fisher’s LSD post hoc test for group comparisons at individual time points. Results: After 6 weeks of myopia induction, the long-term myopia group exhibited significant reduction in refraction, axial length elongation, and choroidal thickness thinning. Inner retinal thickness was markedly reduced, and electroretinography revealed attenuated amplitudes and delayed implicit times of the oscillatory potentials. Conclusion: Prolonged lens-induced myopia in mice induces time-dependent structural and functional retinal alterations, particularly in the inner layers. This model underscores the significance of early retinal monitoring under long-term myopic conditions and serves as a platform for investigating retinal vulnerability and developing preservation strategies over time.

This study evaluated the association between systolic blood pressure (SBP) and diabetic retinopathy (DR) across different glycemic levels in a Japanese population. We analyzed data from 1,049 residents aged ≥ 40 years with diabetes who underwent ophthalmic screening in Chikusei City. Participants were stratified into four groups by glycated hemoglobin (HbA1c) level (< 7% or ≥ 7%) and SBP (< 140 or ≥ 140 mmHg). Logistic regression was used to examine associations between SBP and prevalent DR within HbA1c strata. DR was present in 136 participants (13.0%), including 82 (7.8%) with mild-to-moderate nonproliferative DR (NPDR) and 54 (5.1%) with severe NPDR or proliferative DR (PDR). Among participants with lower HbA1c levels, higher SBP was significantly associated with greater odds of DR (odds ratio, 2.21; 95% confidence interval, 1.16–4.23). A similar association was observed among those with mild-to-moderate NPDR, but not among participants with higher HbA1c levels. SBP was not significantly associated with severe NPDR or PDR in any group. These findings suggest that elevated SBP may contribute to the development of early-stage DR even in individuals with well-controlled blood glucose levels, underscoring the importance of blood pressure management in DR prevention strategies.