Resources
The North American Neuro-Ophthalmology Society (NANOS)
· Patient Brochure
· DrusenLP
· NOVEL- AAO- NANOS Clinical Collection: “Optic Disc Drusen”
American Academy of Ophthalmology (AAO)
· Optic disc drusen
· Diagnostic uncertainty due to optic disc drusen
· Buried optic disc drusen
Eyewiki
Publications
Optic Disc Drusen Papers
We are pleased to highlight 4 recent publications on optic disc drusen.
1. Yan Y, Ludwig CA, Liao YJ: Multimodal Imaging Features of Optic Disc Drusen. American journal of ophthalmology 2021, 225:18-26.
Highlights from this paper: This is a large study of 786 patients with optic disc drusen and analysis of their ophthalmic imaging features.
How to read this paper: The PDF version of the complete paper is free to download here
2. Yan Y, Liao YJ: Updates on ophthalmic imaging features of optic disc drusen, papilledema, and optic disc edema. Current opinion in neurology 2021, 34(1):108-115.
Highlights from this paper: This is a review of on optic disc drusen and other optic nerve diseases that mimick this condition. There are useful tables and figures highlighting the key features of optic nerve head swelling.
How to read this paper: The PDF version of the complete paper is free to download here
3. Yan Y, Zhou X, Chu Z et al: Vision Loss in Optic Disc Drusen Correlates With Increased Macular Vessel Diameter and Flux and Reduced Peripapillary Vascular Density. American journal of ophthalmology 2020, 218:214-224.
Highlights from this paper: Optic disc drusen is the most common risk factor associated with loss of blood supply to the anterior optic nerve. This is the first large study analyzing vascular changes in optic disc drusen. Analysis of optical coherence tomography angiography allows future prediction of who is more likely to develop vision loss in optic disc drusen
How to read this paper: The PDF version of the complete paper is free to download here
4. Sangeethabalasri Pugazhendhi S, Yan Y, Liao YJ. Multimodal Ophthalmic Imaging of Nonarteritic Anterior Ischemic Optic Neuropathy With and Without Optic Disc Drusen. J Neuroophthalmol. 2021 Apr 14. doi: 10.1097/WNO.0000000000001242. PMID: 33870937. Online ahead of print.
Highlights from this paper: This case series compares detailed ophthalmic imaging features of young onset anterior ischemic optic neuropathy in a patient with optic disc drusen compared with another patient with older onset anterior ischemic optic neuropathy not associated with optic disc drusen.
How to read this paper: This paper is currently only accessible to those with subscription to Journal of Neuro-Ophthalmology. Please email Brianna at bdenyven@stanford.edu to get a copy of the PDF.
Ophthalmology Faculty

Publications
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Pseudopapilledema Related to Staphylomatous Optic Nerve Elevation in a Child.
Journal of child neurology
Silverman, A., Beres, S.
2025: 8830738251328423
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View details for DOI 10.1177/08830738251328423
View details for PubMedID 40455010
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Agreement and Accuracy of Papilledema and Pseudopapilledema Classification Among Pediatric Neuro-Ophthalmologists Using Optic Disc Photographs.
Journal of neuro-ophthalmology : the official journal of the North American Neuro-Ophthalmology Society
Phillips, M. J., Reid, M. W., Gaier, E. D., Gise, R. A., Heidary, G., Beres, S. J., Pineles, S. L., Borchert, M. S., Chang, M. Y.
2025
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Abstract
Serial fundus photography is commonly used to differentiate between papilledema and pseudopapilledema, but there are limited data on the interrater reliability and accuracy of interpreting these images in children. The purpose of this study was to evaluate the agreement and accuracy of pediatric neuro-ophthalmologists in classifying fundus photographs of children with papilledema and pseudopapilledema.For this cross-sectional study, 3 masked experts (pediatric neuro-ophthalmologists) classified a multicenter image collection from children with a clinical diagnosis of either papilledema or pseudopapilledema, which was determined based on the results of history, examination, ancillary ophthalmic imaging, neuroimaging, and/or lumbar puncture. Fleiss kappa (κ) was calculated to assess interrater agreement; accuracy, sensitivity, and specificity were calculated to determine expert performance. Subgroup analyses according to papilledema grade and expert certainty were performed.Six hundred fifty-nine photographs from 171 children were included. The full data set, papilledema, and pseudopapilledema κ values were 0.36 (0.32-0.42), 0.40 (0.32-0.49), and 0.28 (0.22-0.34), respectively. Accuracy, sensitivity, and specificity ranged from 58.9% to 63.9%, 54.3% to 76.0%, and 56.1% to 62.6%, respectively, among the 3 experts. Grade 1 papilledema was associated with inaccurate agreement (misinterpretation as pseudopapilledema by all 3 experts) in 31.8% and disagreement in 59.0% of cases. Higher grades of papilledema were associated with higher rates of accurate agreement. All experts achieved high sensitivity in classifying photographs of moderate-to-high-grade papilledema (85%-94%).Overall agreement was low among pediatric neuro-ophthalmologists when classifying fundus photographs of children with papilledema and pseudopapilledema. When interpreting low-grade papilledema images, inaccurate agreement and disagreement were more likely than accurate agreement among experts. Our study highlights the limitations of interpreting fundus photographs of children with papilledema and pseudopapilledema in isolation, stressing the importance of obtaining a complete neuro-ophthalmologic history and examination, as well as other ancillary ophthalmic imaging, to guide decision making regarding systemic workup.
View details for DOI 10.1097/WNO.0000000000002316
View details for PubMedID 40378038
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A zebrafish model of crim1 loss of function has small and misshapen lenses with dysregulated clic4 and fgf1b expression.
Frontiers in cell and developmental biology
Le, T., Htun, S., Pandey, M. K., Sun, Y., Magnusen, A. F., Ullah, E., Lauzon, J., Beres, S., Lee, C., Guan, B., Hufnagel, R. B., Brooks, B. P., Baranzini, S. E., Slavotinek, A.
2025; 13: 1522094
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Abstract
Heterozygous deletions predicting haploinsufficiency for the Cysteine Rich Motor Neuron 1 (CRIM1) gene have been identified in two families with macrophthalmia, colobomatous, with microcornea (MACOM), an autosomal dominant trait. Crim1 encodes a type I transmembrane protein that is expressed at the cell membrane of lens epithelial and fiber cells at the stage of lens pit formation. Decreased Crim1 expression in the mouse reduced the number of lens epithelial cells and caused defective adhesion between lens epithelial cells and between the epithelial and fiber cells.We present three patients with heterozygous deletions and truncating variants predicted to result in haploinsufficiency for CRIM1 as further evidence for the role of this gene in eye defects, including retinal coloboma, optic pallor, and glaucoma. We used Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)/Cas9 to make a stable Danio rerio model of crim1 deficiency, generating zebrafish that were homozygous for a 2 basepair deletion, c.339_340delCT p.Leu112Leufs*, in crim1.Homozygous, crim1 -/- larvae demonstrated smaller eyes and small and misshapen lenses compared to controls, but we did not observe colobomas. Bulk RNA-Seq using dissected eyes from crim1 -/- larvae and controls at 72 h post fertilization showed significant downregulation of crim1 and chloride intracellular channel 4 (clic4) and upregulation of fibroblast growth factor 1b (fgf1b) and complement component 1, q subcomponent (c1q), amongst other dysregulated genes.Our work strengthens the association between haploinsufficiency for CRIM1 and eye defects and characterizes a stable model of crim1 loss of function for future research.
View details for DOI 10.3389/fcell.2025.1522094
View details for PubMedID 40114969
View details for PubMedCentralID PMC11922885

Publications
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Risk factors for development of anti-adalimumab antibodies in non-infectious uveitis.
Heliyon
Bromeo, A. J., Karaca, I., Ghoraba, H. H., Lyu, X., Than, N. T., Ongpalakorn, P., Shin, Y. U., Uludag, G., Tran, A. N., Thng, Z. X., Do, D. V., Or, C. M., Nguyen, Q. D.
2024; 10 (9): e29313
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Abstract
Purpose: To evaluate risk factors associated with development of anti-adalimumab antibodies (AAA) in patients with non-infectious uveitis treated with adalimumab.Methods: A retrospective, cross-sectional, case-control study was done evaluating patients with non-infectious uveitis treated with adalimumab for at least 12 months and have undergone testing for AAA levels. Demographics, clinical characteristics, grading of ocular inflammation, and previous and concomitant immunomodulatory therapy were assessed. Univariate and multivariate analysis were done to estimate odds ratio (OR) with 95% confidence intervals for the various risk factors.Results: A total of 31 patients were included in the analysis, in which 12 patients who tested positive (Group 1) were matched with 19 patients who tested negative for AAA (Group 2). The groups differed significantly in terms of sex (female) (91.7% vs 52.6%, p=0.046), presence of systemic disease (91.7% vs 42.1%, p=0.008), and presence of anterior chamber inflammation at baseline (100% vs 63.2%, p=0.026). A history of interruption in anti-TNF therapy prior to starting or restarting adalimumab was found to have an increased odds for development of AAA (OR 16.89 [2.92, 107.11], p=0.008), as well as flare-ups (reactivation of disease) during adalimumab therapy (OR 6.77 [1.80, 61.80], p=0.027). Weekly dosing of adalimumab was shown to decrease odds of AAA development (OR 0.34 [0.02, 0.70], p=0.040), while concomitant anti-metabolite therapy was not shown to be a statistically significant protective factor (OR 2.22 [0.50, 9.96], p=0.148).Conclusions: History of interruption in anti-TNF therapy and flare during adalimumab were associated with development of AAA, while weekly dosing of adalimumab was protective against AAA. Identification of those with higher risk of developing AAA may guide in clinical decision making to optimize management for these patients.
View details for DOI 10.1016/j.heliyon.2024.e29313
View details for PubMedID 38694084
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Importance of Baseline Fluorescein Angiography for Patients Presenting to Tertiary Uveitis Clinic.
American journal of ophthalmology
Karaca, I., Bromeo, A., Ghoraba, H., Lyu, X., Thng, Z. X., Yasar, C., Akhavanrezayat, A., Yavari, N., Kirimli, G. U., Than, N. T., Shin, Y., Gupta, A. S., Khatri, A., Mohammadi, S. S., Hung, J. H., Or, C., Do, D. V., Nguyen, Q. D.
2024
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Abstract
To ascertain whether the use of ultra-wide-field fluorescein angiography (UWFFA) at baseline visit alters the assessment of disease activity and localization, as well as the management of patients presenting to a tertiary uveitis clinic.Retrospective comparison of diagnostic approaches.Baseline visits of 158 patients who presented to the Uveitis Clinic at the Byers Eye Institute at Stanford between 2017 and 2022 were evaluated by three uveitis-trained ophthalmologists (I.K., A.B., and H.G.). Each eye had undergone clinical examination along with ultra-wide-field fundus photography (UWFFP) (Optos Plc, Dunfermline, Scotland, UK), spectral-domain optical coherence tomography (SD-OCT, Spectralis Heidelberg, Heidelberg Engineering, Heidelberg, Germany) and UWFFA (Optos Plc, Dunfermline, Scotland, UK) at the baseline visit. Investigators were asked to successively determine disease activity, localization of disease (anterior, posterior or both), and management decisions based on clinical examination and UWFFP and SD-OCT (Set 1) and Set 1 plus UWFFA (Set 2). The primary outcome was the percentage of eyes whose management changed based on the availability of UWFFA, compared with Set 1.The mean age of the patients was 46.9±22.4 (range, 7-96) and 91 (57.6%) were female. With Set 1 alone, 138 (55.2%) eyes were found to have active disease; localization was anterior in 58 (42.0%) eyes, posterior in 53 (38.4%) eyes and anterior + posterior in 27 (19.6%) eyes. With Set 2, 169 eyes of 107 patients had active anterior, posterior or pan-uveitis. In comparison with Set 1, assessment with Set 2 identified additional 31 (18.3%) eyes with active disease (p=0.006), and additional 31 (18.3%) eyes having disease in both anterior + posterior segments (p<0.001). Regarding the primary outcome, management was changed in 68 (27.4%) eyes in Set 2, compared to Set 1.Baseline UWFFA may alter assessment of disease activity, localization, and management decisions compared to clinical examination with only UWFFP and SD-OCT for eyes with uveitis. Thus, UWFFA may be considered as an essential tool in the evaluation of uveitis patients at the baseline visit.
View details for DOI 10.1016/j.ajo.2024.04.016
View details for PubMedID 38701875
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Aqueous humour interleukin-6 and vision outcomes with anti-vascular endothelial growth factor therapy.
Eye (London, England)
Sepah, Y. J., Do, D. V., Mesquida, M., Day, B. M., Blotner, S., Afridi, R., Halim, M. S., Hong, K., Wakshull, E., Fauser, S., Stoilov, I., Dong Nguyen, Q.
2024
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Abstract
This analysis evaluated aqueous humour (AH) interleukin (IL)-6 concentrations and the association between AH IL-6 and visual outcomes in patients with neovascular age-related macular degeneration (nAMD) or diabetic macular oedema (DMO) receiving anti-vascular endothelial growth factor (VEGF) monotherapy.Post hoc analysis of the multicentre, double-masked, randomised HARBOR (NCT00891735) and READ-3 (NCT01077401) trials. HARBOR enrolled treatment-naïve nAMD patients. READ-3 enrolled treatment-naïve/previously treated DMO patients. HARBOR patients received ranibizumab 0.5 or 2.0 mg monthly or as needed; AH samples were collected at month 2, after two previous intravitreal injections. READ-3 patients received ranibizumab 0.5 or 2.0 mg as needed; AH samples were collected at baseline and months 3, 6, 9, and 12.association between AH IL-6 concentrations and month 24 best-corrected visual acuity (BCVA).In both trials (HARBOR, N = 36; READ-3, N = 137), patients with higher AH IL-6 concentrations had worse visual outcomes. HARBOR patients with low AH IL-6 concentrations at month 2 had a mean (95% CI) BCVA change at month 24 of +2.9 (-2.6, 8.3) letters, whereas patients with high AH concentrations had a mean (95% CI) BCVA change of -9.0 (-22.7, 4.7) letters. READ-3 patients with low AH concentrations at baseline had a mean (95% CI) BCVA change at month 12 of +9.3 (7.4, 11.3) letters, whereas patients with high AH concentrations had a mean (95% CI) BCVA change of +5.6 (2.2, 9.1) letters.Higher IL-6 AH concentrations may predict suboptimal visual responses to anti-VEGF monotherapy in patients with nAMD/DMO.
View details for DOI 10.1038/s41433-024-03015-2
View details for PubMedID 38622330
View details for PubMedCentralID 4176007

Publications
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Enhanced genotype-phenotype analysis using multimodal adaptive optics and 3D protein structure in Bietti Crystalline Dystrophy.
American journal of ophthalmology case reports
Kumar, A., Sun, Y. J., Rasmussen, D. K., Hargrave, A., Phillips, C., Vu, J. T., Costa, M. G., Leung, L. B., Yu, C., Dubra, A., Mahajan, V. B.
2025; 38: 102312
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Abstract
Deep phenotyping of genetic retinal disease using multimodal adaptive optics ophthalmoscopy and protein structure variant analysis.In a patient with extensive atrophy of the retinal pigment epithelium and yellow deposits in the retina, genetic testing identified two CYP4V2 variants: c.802-8_810delinsGC and c.1169G > A, p.Arg390His. AI-generated protein structures indicated loss of CYP4V2 function. Reflectance confocal and multiple-scattering Adaptive Optics Scanning Light Ophthalmoscopy (AOSLO) captured crystalline deposits throughout the retina as well as previously unreported cyst-like structures that were mainly independent from the crystalline deposits. Sequential AOSLO imaging was conducted and revealed anatomical and morphological changes in the cysts and surrounding cellular structures.Cyst-like changes may represent a new BCD degenerative feature. Characterizing retinal genetic disease variants with protein structural modeling and phenotyping with AOSLO represents an advanced approach for clinical diagnosis and may serve as a biomarker of disease progression.
View details for DOI 10.1016/j.ajoc.2025.102312
View details for PubMedID 40236510
View details for PubMedCentralID PMC11997262
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Quantification of optical lensing by cellular structures in the living human eye.
Biomedical optics express
Bedggood, P., Ding, Y., Dierickx, D., Dubra, A., Metha, A.
2025; 16 (2): 473-498
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Abstract
Cells and other microscopic phase objects can be visualized in the living retina, non-invasively, using non-confocal light detection schemes in adaptive optics scanning light ophthalmoscopes (AOSLOs). There is not yet widespread agreement regarding the origin of image contrast, nor the best way to render multichannel images. Here, we present data to support the interpretation that variations in the intensity of non-confocal images approximate a direct linear mapping of the prismatic deflection of the scanned beam. We advance a simple geometric framework in which local 2D image gradients are used to estimate the spherocylindrical refractive power for each element of the tissue. This framework combines all available information from the non-confocal image channels simultaneously, reducing noise and directional bias. We show that image derivatives can be computed with a scalable, separable gradient operator that minimizes directional errors; this further mitigates noise and directional bias as compared with previous filtering approaches. Strategies to render the output of split-detector gradient operations have been recently described for the visualization of immune cells, blood flow, and photoreceptors; our framework encompasses these methods as rendering astigmatic refractive power. In addition to astigmatic power, we advocate the use of the mean spherical equivalent power, which appears to minimize artifacts even for highly directional micro-structures such as immune cell processes. We highlight examples of positive, negative, and astigmatic power that match expectations according to the known refractive indices and geometries of the relevant structures (for example, a blood vessel filled with plasma acts as a negatively powered cylindrical lens). The examples highlight the benefits of the proposed scheme for the visualization of diverse phase objects including rod and cone inner segments, immune cells near the inner limiting membrane, flowing blood cells, the intravascular cell-free layer, and anatomical details of the vessel wall.
View details for DOI 10.1364/BOE.547734
View details for PubMedID 39958845
View details for PubMedCentralID PMC11828430
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Quantification of optical lensing by cellular structures in the living human eye
BIOMEDICAL OPTICS EXPRESS
Bedggood, P., Ding, Y., Dierickx, D., Dubra, A., Metha, A.
2025; 16 (2): 473-498
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View details for DOI 10.1364/BOE.547734
View details for Web of Science ID 001406239600005

Publications
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Phase I NT-501 Ciliary Neurotrophic Factor Implant Trial for Primary Open-Angle Glaucoma: Safety, Neuroprotection, and Neuroenhancement.
Ophthalmology science
Goldberg, J. L., Beykin, G., Satterfield, K. R., Nunez, M., Lam, B. L., Albini, T. A.
2023; 3 (3): 100298
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Abstract
Purpose: To assess the safety and efficacy of a ciliary neurotrophic factor (CNTF) intraocular implant on neuroprotection and neuroenhancement in glaucoma.Design: Open-label, prospective, phase I clinical trial.Participants: A total of 11 participants were diagnosed with primary open-angle glaucoma (POAG). One eye of each patient was assigned as the study (implant) eye.Methods: The study eye was implanted with a high-dose CNTF-secreting NT-501 implant, whereas the other eye served as a control. All patients were followed up for 18 months. Analysis was limited to descriptive statistics.Main Outcome Measures: Primary outcome was safety through 18 months after implantation assessed by serial eye examinations, structural and functional testing, and adverse events (AEs) recording. Parameters measured included visual acuity (VA), Humphrey visual field (HVF), pattern electroretinogram, scanning laser polarimetry with variable corneal compensation (GDx VCC), and OCT. These parameters were also used for secondary analysis of efficacy outcome.Results: All NT-501 implants were well tolerated with no serious AEs associated with the implant. The majority of AEs were related to the implant placement procedure and were resolved by 12 weeks after surgery. Foreign-body sensation was the most commonly reported AE and was self-limited to the postoperative period. The most common implant-related AE was pupil miosis; no patients underwent explant. Visual acuity and contrast sensitivity decreased more in fellow eyes than in study eyes (VA,-5.82 vs.-0.82 letters; and contrast sensitivity,-1.82 vs.-0.37 letters, for fellow vs. study eyes, respectively). The median HVF visual field index and mean deviation measurements worsened (decreased) in fellow eyes (-13.0%,-3.9 dB) and improved (increased) in study eyes (2.7%, 1.2 dB). Implanted eyes showed an increase in retinal nerve fiber layer thickness measured by OCT and by GDx VCC (OCT, 2.66 mum vs. 10.16 mum; and GDx VCC, 1.58mumvs. 8.36mum in fellow vs. study eyes, respectively).Conclusions: The NT-501 CNTF implant was safe and well tolerated in eyes with POAG. Eyes with the implant demonstrated both structural and functional improvements suggesting biological activity, supporting the premise for a randomized phase II clinical trial of single and dual NT-501 CNTF implants in patients with POAG, which is now underway.Financial Disclosures: Proprietary or commercial disclosure may be found after the references.
View details for DOI 10.1016/j.xops.2023.100298
View details for PubMedID 37197702
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Cellular and subcellular optogenetic approaches towards neuroprotection and vision restoration.
Progress in retinal and eye research
Wood, E. H., Kreymerman, A., Kowal, T., Buickians, D., Sun, Y., Muscat, S., Mercola, M., Moshfeghi, D. M., Goldberg, J. L.
2022: 101153
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Abstract
Optogenetics is defined as the combination of genetic and optical methods to induce or inhibit well-defined events in isolated cells, tissues, or animals. While optogenetics within ophthalmology has been primarily applied towards treating inherited retinal disease, there are a myriad of other applications that hold great promise for a variety of eye diseases including cellular regeneration, modulation of mitochondria and metabolism, regulation of intraocular pressure, and pain control. Supported by primary data from the authors' work with in vitro and in vivo applications, we introduce a novel approach to metabolic regulation, Opsins to Restore Cellular ATP (ORCA). We review the fundamental constructs for ophthalmic optogenetics, present current therapeutic approaches and clinical trials, and discuss the future of subcellular and signaling pathway applications for neuroprotection and vision restoration.
View details for DOI 10.1016/j.preteyeres.2022.101153
View details for PubMedID 36503723
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Longitudinal in vivo Ca2+ imaging reveals dynamic activity changes of diseased retinal ganglion cells at the single-cell level.
Proceedings of the National Academy of Sciences of the United States of America
Li, L., Feng, X., Fang, F., Miller, D. A., Zhang, S., Zhuang, P., Huang, H., Liu, P., Liu, J., Sredar, N., Liu, L., Sun, Y., Duan, X., Goldberg, J. L., Zhang, H. F., Hu, Y.
2022; 119 (48): e2206829119
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Abstract
Retinal ganglion cells (RGCs) are heterogeneous projection neurons that convey distinct visual features from the retina to brain. Here, we present a high-throughput in vivo RGC activity assay in response to light stimulation using noninvasive Ca2+ imaging of thousands of RGCs simultaneously in living mice. Population and single-cell analyses of longitudinal RGC Ca2+ imaging reveal distinct functional responses of RGCs and unprecedented individual RGC activity conversions during traumatic and glaucomatous degeneration. This study establishes a foundation for future in vivo RGC function classifications and longitudinal activity evaluations using more advanced imaging techniques and visual stimuli under normal, disease, and neural repair conditions. These analyses can be performed at both the population and single-cell levels using temporal and spatial information, which will be invaluable for understanding RGC pathophysiology and identifying functional biomarkers for diverse optic neuropathies.
View details for DOI 10.1073/pnas.2206829119
View details for PubMedID 36409915

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Optineurin-facilitated axonal mitochondria delivery promotes neuroprotection and axon regeneration.
Nature communications
Liu, D., Webber, H. C., Bian, F., Xu, Y., Prakash, M., Feng, X., Yang, M., Yang, H., You, I. J., Li, L., Liu, L., Liu, P., Huang, H., Chang, C. Y., Liu, L., Shah, S. H., La Torre, A., Welsbie, D. S., Sun, Y., Duan, X., Goldberg, J. L., Braun, M., Lansky, Z., Hu, Y.
2025; 16 (1): 1789
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Abstract
Optineurin (OPTN) mutations are linked to amyotrophic lateral sclerosis (ALS) and normal tension glaucoma (NTG), but a relevant animal model is lacking, and the molecular mechanisms underlying neurodegeneration are unknown. We find that OPTN C-terminus truncation (OPTN∆C) causes late-onset neurodegeneration of retinal ganglion cells (RGCs), optic nerve (ON), and spinal cord motor neurons, preceded by a decrease of axonal mitochondria in mice. We discover that OPTN directly interacts with both microtubules and the mitochondrial transport complex TRAK1/KIF5B, stabilizing them for proper anterograde axonal mitochondrial transport, in a C-terminus dependent manner. Furthermore, overexpressing OPTN/TRAK1/KIF5B prevents not only OPTN truncation-induced, but also ocular hypertension-induced neurodegeneration, and promotes robust ON regeneration. Therefore, in addition to generating animal models for NTG and ALS, our results establish OPTN as a facilitator of the microtubule-dependent mitochondrial transport necessary for adequate axonal mitochondria delivery, and its loss as the likely molecular mechanism of neurodegeneration.
View details for DOI 10.1038/s41467-025-57135-8
View details for PubMedID 39979261
View details for PubMedCentralID 3714538
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RGC-specific ATF4 and/or CHOP deletion rescues glaucomatous neurodegeneration and visual function.
Molecular therapy. Nucleic acids
Fang, F., Liu, P., Huang, H., Feng, X., Li, L., Sun, Y., Kaufman, R. J., Hu, Y.
2023; 33: 286-295
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Abstract
Endoplasmic reticulum (ER) stress has been linked with various acute and chronic neurodegenerative diseases. We previously found that optic nerve (ON) injury and diseases induce neuronal ER stress in retinal ganglion cells (RGCs). We further demonstrated that germline deletion of CHOP preserves the structure and function of both RGC somata and axons in mouse glaucoma models. Here we report that RGC-specific deletion of CHOP and/or its upstream regulator ATF4 synergistically promotes RGC and ON survival and preserves visual function in mouse ON crush and silicone oil-induced ocular hypertension (SOHU) glaucoma models. Consistently, topical application of the ATF4/CHOP chemical inhibitor ISRIB or RGC-specific CRISPR-mediated knockdown of the ATF4 downstream effector Gadd45a also delivers significant neuroprotection in the SOHU glaucoma model. These studies suggest that blocking the neuronal intrinsic ATF4/CHOP axis of ER stress is a promising neuroprotection strategy for neurodegeneration.
View details for DOI 10.1016/j.omtn.2023.07.015
View details for PubMedID 37547290
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Osteopontin drives retinal ganglion cell resiliency in glaucomatous optic neuropathy.
Cell reports
Zhao, M., Toma, K., Kinde, B., Li, L., Patel, A. K., Wu, K. Y., Lum, M. R., Tan, C., Hooper, J. E., Kriegstein, A. R., La Torre, A., Liao, Y. J., Welsbie, D. S., Hu, Y., Han, Y., Duan, X.
2023; 42 (9): 113038
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Abstract
Chronic neurodegeneration and acute injuries lead to neuron losses via diverse processes. We compared retinal ganglion cell (RGC) responses between chronic glaucomatous conditions and the acute injury model. Among major RGC subclasses, αRGCs and intrinsically photosensitive RGCs (ipRGCs) preferentially survive glaucomatous conditions, similar to findings in the retina subject to axotomy. Focusing on an αRGC intrinsic factor, Osteopontin (secreted phosphoprotein 1 [Spp1]), we found an ectopic neuronal expression of Osteopontin (Spp1) in other RGCs subject to glaucomatous conditions. This contrasted with the Spp1 downregulation subject to axotomy. αRGC-specific Spp1 elimination led to significant αRGC loss, diminishing their resiliency. Spp1 overexpression led to robust neuroprotection of susceptible RGC subclasses under glaucomatous conditions. In contrast, Spp1 overexpression did not significantly protect RGCs subject to axotomy. Additionally, SPP1 marked adult human RGC subsets with large somata and SPP1 expression in the aqueous humor correlated with glaucoma severity. Our study reveals Spp1's role in mediating neuronal resiliency in glaucoma.
View details for DOI 10.1016/j.celrep.2023.113038
View details for PubMedID 37624696

Publications
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High Altitude as a Risk Factor for the Development of Nonarteritic Anterior Ischemic Optic Neuropathy.
Journal of neuro-ophthalmology : the official journal of the North American Neuro-Ophthalmology Society
Liu, Y. A., Mesentier-Louro, L. A., Shariati, M. A., Moss, H. E., Beres, S. J., Liao, Y. J.
2022
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Abstract
Episodic high-altitude exposure leads to optic disc edema and retinopathy. It is uncertain whether high-altitude exposure is a risk factor for nonarteritic anterior ischemic optic neuropathy (NAION).We performed a single-center, retrospective, cross-sectional case study of 5 patients with high-altitude-associated NAION (HA-NAION) from April 2014 to April 2019. Main study parameters included known vascular risk factors for NAION, evolution of visual acuity, visual field, optic disc, and macula measurements.We studied 5 eyes of 5 patients with HA-NAION that occurred at 7,000-9,000 ft above sea level, 28 patients with classic NAION that developed at sea level (normal altitude NAION or NA-NAION), and 40 controls. All 5 patients with HA-NAION had clinically confirmed NAION by a neuro-ophthalmologist within 3-21 days of onset and comprehensive follow-up evaluations (average follow-up of 23 months). Other than high-altitude exposure, 4 of 5 patients had undiagnosed obstructive sleep apnea (OSA, apnea-hypopnea index 5.4-22.2) and 1 had systemic vascular risk factors. All patients had disc-at-risk in the contralateral eye. The best-corrected distance visual acuity was 20/20 to 20/70 (median logMAR 0) at presentation and 20/70 to counting finger (median logMAR 0) at ≥6 months. Automated static perimetry revealed average mean deviation of -18.6 dB at presentation and -22.1 dB at ≥6 months. The average retinal nerve fiber layer was 244 µm (80-348 µm) at onset and 59 µm (55-80 µm) at ≥6 months. The average ganglion cell complex thickness was 50 µm (43-54 µm) at onset and 52 µm (50-55 µm) at ≥6 months. The patients with OSA were started on home continuous positive airway pressure treatment. Visual outcomes were similar in patients with HA-NAION and NA-NAION. - After addressing all NAION risk factors, no new events occurred in the HA-NAION group within 2-8 years with or without repeat high-altitude exposure.NAION can occur under high-altitude conditions. HA-NAION is associated with relatively younger age at onset, disc-at-risk, and OSA. These patients exhibit a relatively progressive course of vision loss after initial onset and severe thinning of optic nerves on optical coherence tomography. Treatment for OSA is recommended, especially with repeated high-altitude exposure.
View details for DOI 10.1097/WNO.0000000000001629
View details for PubMedID 36166787
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Immunoprofiling of Nonarteritic Anterior Ischemic Optic Neuropathy.
Translational vision science & technology
Mesentier-Louro, L. A., Stell, L., Yan, Y., Montague, A. A., de Jesus Perez, V., Liao, Y. J.
2021; 10 (8): 17
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Purpose: Nonarteritic anterior ischemic optic neuropathy (NAION) is a common acute optic neuropathy in those older than 50 years. There is no blood diagnostic test or efficient treatment for NAION. We investigated the suitability of blood inflammatory proteins as biomarkers and therapeutic targets of NAION.Methods: We conducted an exploratory, cross-sectional case-control study including 18 patients with NAION (n = 5 acute, and n = 13 chronic) and 9 controls. NAION was confirmed by clinical examination and optical coherence tomography. Subjects underwent peripheral blood collection; plasma was isolated within 2 hours and analyzed using a 76-plex array of cytokines, chemokines, and growth factors.Results: In acute NAION, there was increased peripapillary retinal thickness on optical coherence tomography consistent with optic disc edema. Plasma profiling revealed dramatic changes in inflammatory proteins in NAION. Statistical analysis generated a list of 20 top-ranked molecules in NAION, with 15% overlap in acute and chronic NAION. Principal component analysis, hierarchical clustering, and Spearman correlation generally segregated controls, acute and chronic NAION, with some overlap. Longitudinal data from one patient demonstrated an evolving inflammatory pattern from acute to chronic NAION. In acute NAION, Eotaxin-3, MCP-2, TPO, and TRAIL were the top biomarker candidates. In chronic NAION, IL-1alpha and CXCL10 emerged as the strongest therapeutic targets.Conclusions: Post-NAION inflammation occurs in both acute and chronic NAION. Statistical analysis of plasma profile changes generated a list of 20 potential biomarker and therapeutic targets of NAION.Translational Relevance: We identified blood molecular targets to improve NAION diagnosis and treatment.
View details for DOI 10.1167/tvst.10.8.17
View details for PubMedID 34264294
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Multimodal Imaging Features of Optic Disc Drusen.
American journal of ophthalmology
Yan, Y., Ludwig, C. A., Liao, Y. J.
2021
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PURPOSE: Identify key en face multimodal imaging features of optic disc drusen (ODD).DESIGN: Retrospective cross-sectional study.METHODS: .SETTING: Single academic center.PATIENT OR STUDY POPULATION: 786 patients (age 10-82 years) with diagnostic codes for ODD or the term "optic disc drusen" in clinical notes extracted using natural language processing.INTERVENTION OR OBSERVATION PROCEDURES: Color fundus image, green-light and blue-light fundus autofluorescence (FAF), near-infrared reflectance (NIR), and enhanced-depth imaging optical coherence tomography (EDI-OCT).MAIN OUTCOME MEASURES: Ophthalmic imaging characteristics and sensitivity of en face imaging compared with EDI-OCT.RESULTS: 38 (61 eyes) of 786 patients had high-quality EDI-OCT and en face multimodal imaging. Green-light FAF had the highest sensitivity (96.8%) and showed homogeneously hyperautofluorescence while blue-light FAF differentiated superficial and deep ODD by the heterogeneous brightness of FAF. Blue-light FAF (93.5%) and NIR (91.8%) were also sensitive and provided important features including the location, size, and depth of ODD and morphology of the optic disc and ODD-associated features such as horizontal hyperreflective lines and peripapillary hyperreflective ovoid mass-like structures (PHOMS), respectively. Color fundus imaging had the lowest sensitivity (82%). There was good inter-rater reliability for all en face imaging modalities (P < .0001 for all).CONCLUSIONS: Green-light FAF had the highest sensitivity in diagnosis of ODD, while blue-light FAF and NIR provided more information regarding the severity, location, depth, and size of ODD. In eyes that are negative on green-light FAF, EDI-OCT can be performed and provides the highest-resolution characterization of the entire optic disc to rule out ODD.
View details for DOI 10.1016/j.ajo.2020.12.023
View details for PubMedID 33485838

Publications
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Reversal of injury-associated retinal ganglion cell gene expression by a phosphodiesterase anchoring disruptor peptide.
Experimental eye research
Zhu, Y., Nair, R. V., Xia, X., Nahmou, M., Li, X., Yan, W., Li, J., Tanasa, B., Goldberg, J. L., Kapiloff, M. S.
2024; 246: 110017
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Loss of retinal ganglion cells (RGCs) is central to the pathogenesis of optic neuropathies such as glaucoma. Increased RGC cAMP signaling is neuroprotective. We have shown that displacement of the cAMP-specific phosphodiesterase PDE4D3 from an RGC perinuclear compartment by expression of the modified PDE4D3 N-terminal peptide 4D3(E) increases perinuclear cAMP and protein kinase A activity in cultured neurons and in vivo RGC survival after optic nerve crush (ONC) injury. To explore mechanisms by which PDE4D3 displacement promotes neuroprotection, in this study mice intravitreally injected with an adeno-associated virus to express an mCherry-tagged 4D3(E) peptide were subjected to ONC injury and analyzed by single cell RNA-sequencing (scRNA-seq). 4D3(E)-mCherry expression was associated with an attenuation of injury-induced changes in gene expression, thereby supporting the hypothesis that enhanced perinuclear PKA signaling promotes neuroprotective RGC gene expression.
View details for DOI 10.1016/j.exer.2024.110017
View details for PubMedID 39097072
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Protein phosphatase 2A anchoring disruptor gene therapy for familial dilated cardiomyopathy.
Molecular therapy. Methods & clinical development
Li, X., Li, J., Samuelsson, A. M., Thakur, H., Kapiloff, M. S.
2024; 32 (2): 101233
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Familial dilated cardiomyopathy is a prevalent cause of heart failure that results from the mutation of genes encoding proteins of diverse function. Despite modern therapy, dilated cardiomyopathy typically has a poor outcome and is the leading cause of cardiac transplantation. The phosphatase PP2A at cardiomyocyte perinuclear mAKAPβ signalosomes promotes pathological eccentric cardiac remodeling, as is characteristic of dilated cardiomyopathy. Displacement of PP2A from mAKAPβ, inhibiting PP2A function in that intracellular compartment, can be achieved by expression of a mAKAPβ-derived PP2A binding domain-derived peptide. To test whether PP2A anchoring disruption would be effective at preventing dilated cardiomyopathy-associated cardiac dysfunction, the adeno-associated virus gene therapy vector AAV9sc.PBD was devised to express the disrupting peptide in cardiomyocytes in vivo. Proof-of-concept is now provided that AAV9sc.PBD improves the cardiac structure and function of a cardiomyopathy mouse model involving transgenic expression of a mutant α-tropomyosin E54K Tpm1 allele, while AAV9sc.PBD has no effect on normal non-transgenic mice. At the cellular level, AAV9sc.PBD restores cardiomyocyte morphology and gene expression in the mutant Tpm1 mouse. As the mechanism of AAV9sc.PBD action suggests potential efficacy in dilated cardiomyopathy regardless of the underlying etiology, these data support the further testing of AAV9sc.PBD as a broad-based treatment for dilated cardiomyopathy.
View details for DOI 10.1016/j.omtm.2024.101233
View details for PubMedID 38572067
View details for PubMedCentralID PMC10988123
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Ca<SUP>2+</SUP> /calmodulin-dependent protein kinase II enhances retinal ganglion cell survival but suppresses axon regeneration after optic nerve injury
Xia, X., Shi, C., Tsien, C., Sun, C. B., Xie, L., Luo, Z., Bian, M., Russano, K., Thakur, H., Benowitz, L., Goldberg, J., Kapiloff, M.
ASSOC RESEARCH VISION OPHTHALMOLOGY INC. 2024
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View details for Web of Science ID 001313316200208

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Enhanced genotype-phenotype analysis using multimodal adaptive optics and 3D protein structure in Bietti Crystalline Dystrophy.
American journal of ophthalmology case reports
Kumar, A., Sun, Y. J., Rasmussen, D. K., Hargrave, A., Phillips, C., Vu, J. T., Costa, M. G., Leung, L. B., Yu, C., Dubra, A., Mahajan, V. B.
2025; 38: 102312
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Deep phenotyping of genetic retinal disease using multimodal adaptive optics ophthalmoscopy and protein structure variant analysis.In a patient with extensive atrophy of the retinal pigment epithelium and yellow deposits in the retina, genetic testing identified two CYP4V2 variants: c.802-8_810delinsGC and c.1169G > A, p.Arg390His. AI-generated protein structures indicated loss of CYP4V2 function. Reflectance confocal and multiple-scattering Adaptive Optics Scanning Light Ophthalmoscopy (AOSLO) captured crystalline deposits throughout the retina as well as previously unreported cyst-like structures that were mainly independent from the crystalline deposits. Sequential AOSLO imaging was conducted and revealed anatomical and morphological changes in the cysts and surrounding cellular structures.Cyst-like changes may represent a new BCD degenerative feature. Characterizing retinal genetic disease variants with protein structural modeling and phenotyping with AOSLO represents an advanced approach for clinical diagnosis and may serve as a biomarker of disease progression.
View details for DOI 10.1016/j.ajoc.2025.102312
View details for PubMedID 40236510
View details for PubMedCentralID PMC11997262
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N-terminomics and proteomics analysis of Calpain-2 reveal key proteolytic processing of metabolic and cell adhesion proteins.
Protein science : a publication of the Protein Society
Kapilan, A., Bulluss, M., Ziegler, A. R., Dabaja, M., Derakhshani, A., Anowai, A., Armstrong, V., Campden, R., Young, D., Sun, Y. J., Scott, N. E., Edgington-Mitchell, L. E., Mahajan, V. B., Dufour, A.
2025; 34 (5): e70144
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Aberrant levels of the cysteine protease Calpain-2 have been linked to neurodegeneration, inflammation, and cancer, yet our understanding of this protease and its substrates remains limited. Systematic studies to identify Calpain-2 substrates have been largely confined to peptide libraries or in vitro studies, which fail to represent physiological cellular conditions and physiologically relevant substrates. To identify existing and novel Calpain-2 substrates, we used a genetic approach to knockout Calpain-2 in the THP-1 human monocyte-like cells, followed by proteomic and N-terminomic/TAILS mass spectrometry approaches to identify Calpain-2 substrates. We identified 51 substrates that may be cleaved directly by Calpain-2 or indirectly by downstream proteases. The direct cleavage of selected substrates by Calpain-2 was confirmed using in vitro assays. Finally, metabolomics analysis identified a role for Calpain-2 in the regulation of pyrimidine and glutathione metabolism. Our unbiased and quantitative mass spectrometry analytical pipeline provides new evidence on the physiological functions of Calpain-2 and its newly identified substrates in THP-1 cells.
View details for DOI 10.1002/pro.70144
View details for PubMedID 40277457
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Artificial intelligence's contribution to biomedical literature search: revolutionizing or complicating?
PLOS digital health
Yip, R., Sun, Y. J., Bassuk, A. G., Mahajan, V. B.
2025; 4 (5): e0000849
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There is a growing number of articles about conversational AI (i.e., ChatGPT) for generating scientific literature reviews and summaries. Yet, comparative evidence lags its wide adoption by many clinicians and researchers. We explored ChatGPT's utility for literature search from an end-user perspective through the lens of clinicians and biomedical researchers. We quantitatively compared basic versions of ChatGPT's utility against conventional search methods such as Google and PubMed. We further tested whether ChatGPT user-support tools (i.e., plugins, web-browsing function, prompt-engineering, and custom-GPTs) could improve its response across four common and practical literature search scenarios: (1) high-interest topics with an abundance of information, (2) niche topics with limited information, (3) scientific hypothesis generation, and (4) for newly emerging clinical practices questions. Our results demonstrated that basic ChatGPT functions had limitations in consistency, accuracy, and relevancy. User-support tools showed improvements, but the limitations persisted. Interestingly, each literature search scenario posed different challenges: an abundance of secondary information sources in high interest topics, and uncompelling literatures for new/niche topics. This study tested practical examples highlighting both the potential and the pitfalls of integrating conversational AI into literature search processes, and underscores the necessity for rigorous comparative assessments of AI tools in scientific research.
View details for DOI 10.1371/journal.pdig.0000849
View details for PubMedID 40354425

Publications
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PARKINSONISM AND RELATED DISORDERS 134 (2025) 107742 OUTCOMES FOLLOWING INITIATION OF AMANTADINE DR/ER (GOCOVRI) IN PATIENTS WITH PARKINSON DISEASE-EVALUATION OF THE AAN AXON REGISTRY DATABASE
Grall, M., Crouse, N., Formella, A. E., Zwick, E., Moss, H.
ELSEVIER SCI LTD. 2025
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View details for Web of Science ID 001488156300090
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Venous Sinus Stenting Outcomes in Patients with Papilledema from Secondary Causes of Elevated Intracranial Pressure
NEURO-OPHTHALMOLOGY
Swaminathan, V. B., Oyemade, K. A., Xu, T. T., Cutsforth-Gregory, J. K., Lanzino, G., Moss, H. E., Dodd, R. L., Bhatti, M., Brinjikji, W., Tajfirouz, D. A., Chodnicki, K. D., Chen, J. J.
2025
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View details for DOI 10.1080/01658107.2025.2495303
View details for Web of Science ID 001477892800001
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Inpatient Implementation of Portable Ocular Fundus Photography Among Neurology Residents.
The Neurohospitalist
Schwartz, N. U., Silverman, A., Beres, S., Moss, H. E., Kvam, K., Galetta, K.
2025: 19418744251317260
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Background: Nonmydriatic ocular fundus photography has been studied with demonstrated benefit in the evaluation of emergency department neurological complaints, particularly in triaging headache and focal neurological deficits. Likewise, portable fundus camera usage may be practical for inpatients with neurological complaints, although feasibility has not been studied in a neurology teaching service. Purpose: The objective of this study is to determine if a portable, nonmydriatic fundus camera could be integrated into routine clinical care by neurology inpatient housestaff at a tertiary medical center. Research Design: Housestaff were asked to obtain fundus photographs for patients with specific indications for fundoscopy. Study Sample: During a 1-month pilot period, housestaff were successfully able to upload images from 21 patients, which were reviewed by a neuro-ophthalmology attending, with input from on-call ophthalmology if desired. Results: Surveys of housestaff before (n = 13) and after (n = 12) implementation demonstrated increased confidence in camera operation and in ocular structure identification, description, and interpretation. Thematic analysis on qualitative feedback suggested benefits in clinical (improving fundus visualization, aiding in triage, sharing images with offsite staff), health systems (reducing length of stay, reducing ophthalmology consultations, reduced unnecessary testing), and educational domains (facilitating group discussions of images, sharing photographs with patients). Conclusions: Overall, inpatient portable fundus photography was shown to be feasible and effective for rapid fundus visualization for neurological inpatients, enhancing the ability to share, document, and compare examinations among neurology housestaff. Further work is needed to confirm clinical and educational benefits of portable fundus photography usage by neurology residents, as suggested by this healthcare quality improvement pilot study.
View details for DOI 10.1177/19418744251317260
View details for PubMedID 39895825
View details for PubMedCentralID PMC11780609

Publications
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In situ UNIversal Orthogonal Network (UNION) bioink deposition for direct delivery of corneal stromal stem cells to corneal wounds.
Bioactive materials
Brunel, L. G., Cai, B., Hull, S. M., Han, U., Wungcharoen, T., Fernandes-Cunha, G. M., Seo, Y. A., Johansson, P. K., Heilshorn, S. C., Myung, D.
2025; 48: 414-430
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The scarcity of human donor corneal graft tissue worldwide available for corneal transplantation necessitates the development of alternative therapeutic strategies for treating patients with corneal blindness. Corneal stromal stem cells (CSSCs) have the potential to address this global shortage by allowing a single donor cornea to treat multiple patients. To directly deliver CSSCs to corneal defects within an engineered biomatrix, we developed a UNIversal Orthogonal Network (UNION) collagen bioink that crosslinks in situ with a bioorthogonal, covalent chemistry. This cell-gel therapy is optically transparent, stable against contraction forces exerted by CSSCs, and permissive to the efficient growth of corneal epithelial cells. Furthermore, CSSCs remain viable within the UNION collagen gel precursor solution under standard storage and transportation conditions. This approach promoted corneal transparency and re-epithelialization in a rabbit anterior lamellar keratoplasty model, indicating that the UNION collagen bioink serves effectively as an in situ-forming, suture-free therapy for delivering CSSCs to corneal wounds.
View details for DOI 10.1016/j.bioactmat.2025.02.009
View details for PubMedID 40083774
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Refillable Intraocular Drug-Eluting Implant.
ACS applied materials & interfaces
Kim, H., Kang, N. W., Wise, R., Feliz, A., Myung, D., DeBoer, C.
2025
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The increasing incidence of ophthalmic diseases has led the need for multiple dosage regimens, which can cause patient discomfort and noncompliance due to the frequency of medication administration. Still, ophthalmic drug delivery methods, such as eye drops and intravitreal injection, pose challenges, such as poor bioavailability, short half-life, and patient compliance. In this study, we introduce a novel refillable intracapsular drug-eluting reservoir for the long-term management of ocular diseases. This device, made of medical-grade silicone and stainless steel, has features to contour the lens capsule to facilitate microincisional implantation. Rheological and mechanical analyses of the silicone revealed the optimized conditions for the device construction and its application compliance for ocular intracapsular implantation. Furthermore, in vitro release studies exhibit controlled drug release, the kinetics of which were along with Fickian diffusion, while ex vivo implantation testing shows that the device can be easily delivered and placed at the time of cataract surgery. Taken altogether, the developed implant holds significant potential for improving therapeutic outcomes while offering a practical surgical application and compliance of patients.
View details for DOI 10.1021/acsami.5c03985
View details for PubMedID 40331902
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Targeted Interventions Lead to Quality Improvement in Year 2 of an Artificial Intelligence-Based Diabetic Retinopathy Detection Program in Northern California.
Retina (Philadelphia, Pa.)
Chen, K. M., Zhao, C. S., Knapp, A., Dow, E., Phadke, A., Tan, M., Desai, K., Or, C., Mahajan, V., Do, D. V., Mruthyunjaya, P., Leng, T., Myung, D.
2025
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This study evaluates the second-year outcomes of an AI-based diabetic retinopathy (DR) detection program (Stanford Teleophthalmology Autonomous Testing and Universal Screening (STATUS)) implemented in primary care and endocrinology clinics in Northern California. We focused on assessing improvements following implementation of an intervention-based framework to increase AI system gradability and patient encounters.A retrospective analysis was conducted involving diabetic patients aged 18 years and older with no prior DR diagnosis or examination in the past year. These patients presented for routine DR screening in primary care or endocrinology clinics. In its second year, the STATUS program expanded to additional sites and introduced an intervention-based framework, including targeted training protocols, to enhance screening accuracy and efficiency. Our study measured AI system gradability and tracked patient encounters over Year 2.The AI system's gradability increased from 62.3% in Year 1 to 71.2% in Year 2, comparable to non-mydriatic gradability rates observed in clinical trials. Patient encounters increased by 21.9%, indicating expanded reach and improved accessibility. Interventions, including enhanced training protocols and camera utilization reports, effectively improved screening efficiency.The second-year outcomes of the STATUS AI-based DR screening program demonstrate significant improvements in image gradability by the AI system as well as in patient encounter numbers. These findings highlight the potential of interventional methods to continually improve the outcomes of AI-based screening programs and offer a scalable solution to the growing burden of diabetic retinopathy. The success of STATUS supports further integration and expansion of AI-based screening in clinical practice for early detection and management of DR, improving patient outcomes.
View details for DOI 10.1097/IAE.0000000000004499
View details for PubMedID 40334205

Publications
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Effects of Two Different Doses of Ranibizumab on Diabetic Retinopathy Severity
Ophthalmology Retina
Sadiq, M. A., Hassan, M., Soliman, M. K., Afridi, R., Do, D. V., Nguyen, Q. D., Sepah, Y. J.
2017; 1 (6): 566-567
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View details for DOI 10.1016/j.oret.2017.03.002

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Repeated measures analysis for steady-state evoked potentials.
Computers in biology and medicine
Norouzpour, A., Roberts, T. L.
2025; 191: 110117
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Brain response to repetitive stimuli generates steady-state evoked potentials (ssEP) that vary depending on the experimental conditions. To analyze these responses, Fourier measurements extracted from ssEP data require statistical techniques to differentiate neural responses across various experimental conditions within the same participant(s). In this study, we introduce new statistical methods to compare multiple dependent clusters of discrete Fourier measurements corresponding to multiple experimental conditions.We present two statistics: 1) The first statistic is derived from repeated measures analysis of variance (ANOVA) for complex numbers, used to compare multiple dependent circular clusters of Fourier estimates under the assumption of equal variance across the clusters. 2) The second statistic is employed when either the assumption of circularity within the clusters or the assumption of equal variance across the clusters is violated. In this case, we derive the statistic from the rank-sum Friedman test to compare multiple related clusters of complex numbers.We demonstrated the validity of the statistics using simulated and empirical ssEP data. Our methods offer robust statistical tools that maintain a constant Type-I error of 0.05 in all conditions, including equal or unequal variance-covariance matrix of the real and imaginary components of Fourier estimates across the circular and elliptical clusters, even in the presence of outliers in the dataset. Furthermore, our statistics demonstrate a lower Type-II error compared to repeated measures multivariate analysis of variance (rmMANOVA).The statistical methods enable us to compare multiple dependent clusters of Fourier estimates corresponding to multiple experimental conditions within the same participant(s), whether or not the variance is equal across the circular or elliptical clusters, even with outliers in the dataset.
View details for DOI 10.1016/j.compbiomed.2025.110117
View details for PubMedID 40198991
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Scoping review: Intervention for ocular motor disorders in children and adults with mild traumatic brain injury.
Optometry and vision science : official publication of the American Academy of Optometry
Chen, A. M., Salzano, A. D., Burgher, A. P., Greenspan, L. D., Yap, T. P., Theis, J., Liu, S. H., Scheiman, M., Roberts, T. L.
2025
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Abstract
Intervention strategies for post-mild traumatic brain injury (mTBI) ocular motor disorders vary across disciplines and include watchful waiting, vestibular rehabilitation, vision rehabilitation/vision therapy, and optical intervention. However, evidence supporting their effectiveness is limited, highlighting the need for high-quality randomized controlled trials with standardized testing, diagnostic criteria, and reassessment of ocular motor function after intervention.Ocular motor disorders occur frequently after mTBI.This study aimed to conduct a scoping review of interventions for mTBI-related ocular motor disorders in children and adults.The following electronic bibliographic databases were searched: PubMed, Embase, PEDro, OVID, Clinical Key, Google Scholar, and REHABDATA.Intervention studies published in English between 2003 and 2024 involving mTBI participants who had an ocular motor assessment prior to intervention were included in this study.Preferred Reporting Items for Systematic reviews and Meta-Analyses extension for Scoping Reviews guidelines were followed for reporting. Study population, intervention, and outcomes were extracted and synthesized in tabular and graphical formats.Sixty-seven eligible studies were included, with only three (4%) judged as low risk of bias. Intervention strategies included watchful waiting (n = 31, 46%), vestibular rehabilitation (n = 13, 19%), vision rehabilitation/vision therapy (n = 10, 15%), optical intervention (n = 4, 6%), and alternative interventions or multifaceted interventions (n = 9, 14%). Among the studies providing statistically supported results, improvements in one or more ocular motor outcome domains were reported in nearly 80% of the studies on watchful waiting (19/24) and 100% of the studies on vestibular rehabilitation (4/4), vision rehabilitation/vision therapy (7/7), or optical intervention (1/1).Although post-mTBI ocular motor deficits improved with watchful waiting strategy, vestibular rehabilitation, vision rehabilitation/vision therapy, and optical interventions, most studies had significant risk of bias. This review emphasizes the necessity for high-quality randomized controlled trials with standardized testing protocols and diagnostic criteria and reassessment of ocular motor functions after intervention to evaluate the effectiveness of these interventions in different age groups and recovery stages.
View details for DOI 10.1097/OPX.0000000000002237
View details for PubMedID 39951336
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Accommodative and Vergence Responses to a Moving Stimulus in Concussion.
Investigative ophthalmology & visual science
Haensel, J. X., Marusic, S., Slinger, K. E., Wu, C. H., Vyas, N., Ameyaw Baah, C. A., Hu, A., Leonen, J., Lew, C. Y., Srinivasan, G., Norouzpour, A., Jenewein, E., Meiyeppen, S., Scheiman, M., Raghuram, A., Roberts, T. L.
2024; 65 (12): 45
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Concussed adolescents often report visual symptoms, especially for moving targets, but the mechanisms resulting in oculomotor deficits remain unclear. We objectively measured accommodative and vergence responses to a moving target in concussed adolescents and controls.Thirty-two symptomatic concussed participants (mean age, 14.4 ± 2.6 years; mean days since concussion, 107 days; range, 36-273 days) and 32 healthy controls (mean age, 12.7 ± 2.1 years) viewed a movie binocularly (closed-loop) and monocularly (vergence open-loop), as well as a Difference of Gaussians (DoG) target binocularly (accommodation open-loop). The movie or DoG target sinusoidally moved toward and away from participants at a 0.1-hertz (Hz) frequency at four separate stimulus amplitudes (1.50 diopters [D], 1.00 D, 0.50 D, 0.25 D) around a 2.50-D midpoint. Accommodation and vergence were continuously measured at 50 Hz using the PowerRef 3. Fourier analysis was used to assess the response amplitudes at the 0.1-Hz frequency. A 2 × 3 analysis of variance with the factors group (concussed, control) and viewing condition (binocular, monocular, DoG) was conducted on response amplitudes.Across groups, accommodative and vergence responses were significantly higher in binocular than monocular conditions (P < 0.001), but not DoG conditions. Compared to controls, concussed participants had significantly reduced monocular accommodative responses (P < 0.012; e.g., at 1.50 D, controls = 1.09 ± 0.47 D and concussed = 0.80 ± 0.36 D, P = 0.011). No group differences were observed for vergence responses in any viewing condition.Accommodative and vergence responses to the moving target were largely driven by disparity cues for both groups, with only minimal improvements in the presence of additional blur cues. Concussed participants showed reduced accommodative responses to a 0.1-Hz stimulus in monocular conditions, indicating mild accommodative deficits in the absence of disparity cues.
View details for DOI 10.1167/iovs.65.12.45
View details for PubMedID 39475939

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Effect of Brimonidine on Retinal Ganglion Cell Function by in vivo Calcium Imaging of Optic Nerve Crush in Mice.
Experimental eye research
Li, T., Kowal, T. J., Zhao, J., Li, L., Wang, Q., Ning, K., Lo, C. H., Liu, Z., Shen, Y., Yu, J., Jin, H., Sun, Y.
2025: 110355
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Brimonidine has shown neuroprotective effects in animal studies, but clinical trials failed to demonstrate effective endpoints. Here, we used a newly developed in vivo calcium imaging method to measure RGC function of brimonidine in mice optic nerve crush (ONC) models. To transduce RGCs in vivo, wild-type C57Bl/6j mice were treated with intravitreal AAV2-mSncg-jGCaMP7s, a live-cell Ca2+ tracer. RGCs are defined as 10 subtypes according to different responses to UV light. Mice were treated with topical brimonidine or placebo three times daily for two weeks after ONC. The calcium signals of live-cell RGCs were measured with the Heidelberg cSLO system. Ganglion cell complex (GCC) thickness and IOP were examined at different timepoints after treatment. RGCs were counted after RBPMS immunostaining. Live calcium imaging showed ONC significantly decreased RGC number at 14 days post-ONC compared to controls. The topical brimonidine administration changed calcium signal responses of RGC to UV light in ONC mice. It showed brimonidine partly prevented the decrease of survival ON-RGCs percent after ONC. Single RGC analysis showed a lower conversion percent of ON-RGCs to OFF-RGCs with brimonidine administration after ONC. However, no significant differences in RGC survival, IOP or GCC thickness were noted between eyes treated with brimonidine or placebo. In the acute ONC mice model, in vivo calcium imaging revealed that brimonidine maintained the Ca2+ activation of ON-RGCs to UV stimulation, inhibiting the conversion of survival ON-RGCs to OFF-RGCs. This indicates that ON-RGCs may be more resilient to acute optic nerve injury based on the calcium imaging method.
View details for DOI 10.1016/j.exer.2025.110355
View details for PubMedID 40127747
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Class I PI3Ks activate stretch-induced autophagy in trabecular meshwork cells.
Cellular and molecular life sciences : CMLS
Shim, M. S., Sim, E. J., Betsch, K., Desikan, V., Su, C. C., Pastor-Valverde, D., Sun, Y., Liton, P. B.
2025; 82 (1): 82
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Abstract
Elevated intraocular pressure (IOP) is the primary risk factor for glaucoma, a leading cause of irreversible blindness worldwide. IOP homeostasis is maintained through a balance between aqueous humor production and its drainage through the trabecular meshwork (TM)/Schlemm's Canal (SC) outflow pathway. Prior studies by our laboratory reported a key role of mechanical forces and primary cilia (PC)-dependent stretch-induced autophagy in IOP homeostasis. However, the precise mechanism regulating this process remains elusive. In this study, we investigated the upstream signaling pathway orchestrating autophagy activation during cyclic mechanical stretch (CMS) in primary cultured human TM cells, using biochemical and cell biological analyses. Our results indicate that TM cells express catalytic subunits of class IA PI3Ks (PIK3CA, B, and D), and that inhibition of class IA isoforms, but not class II and III, significantly prevent CMS-induced autophagy. Importantly, PIK3CA was found to localize in the PC. Furthermore, we identified a coordinated action of Class IA PI3Ks along INPP4A/B, a 4' inositol phosphatase, responsible for the formation of PI(3,4)P2 and PI(3)P and stretch-induced autophagy in TM cells. These findings contribute to a deeper understanding of the molecular mechanisms underlying IOP homeostasis.
View details for DOI 10.1007/s00018-025-05615-x
View details for PubMedID 39985671
View details for PubMedCentralID PMC11846827
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Optineurin-facilitated axonal mitochondria delivery promotes neuroprotection and axon regeneration.
Nature communications
Liu, D., Webber, H. C., Bian, F., Xu, Y., Prakash, M., Feng, X., Yang, M., Yang, H., You, I. J., Li, L., Liu, L., Liu, P., Huang, H., Chang, C. Y., Liu, L., Shah, S. H., La Torre, A., Welsbie, D. S., Sun, Y., Duan, X., Goldberg, J. L., Braun, M., Lansky, Z., Hu, Y.
2025; 16 (1): 1789
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Optineurin (OPTN) mutations are linked to amyotrophic lateral sclerosis (ALS) and normal tension glaucoma (NTG), but a relevant animal model is lacking, and the molecular mechanisms underlying neurodegeneration are unknown. We find that OPTN C-terminus truncation (OPTN∆C) causes late-onset neurodegeneration of retinal ganglion cells (RGCs), optic nerve (ON), and spinal cord motor neurons, preceded by a decrease of axonal mitochondria in mice. We discover that OPTN directly interacts with both microtubules and the mitochondrial transport complex TRAK1/KIF5B, stabilizing them for proper anterograde axonal mitochondrial transport, in a C-terminus dependent manner. Furthermore, overexpressing OPTN/TRAK1/KIF5B prevents not only OPTN truncation-induced, but also ocular hypertension-induced neurodegeneration, and promotes robust ON regeneration. Therefore, in addition to generating animal models for NTG and ALS, our results establish OPTN as a facilitator of the microtubule-dependent mitochondrial transport necessary for adequate axonal mitochondria delivery, and its loss as the likely molecular mechanism of neurodegeneration.
View details for DOI 10.1038/s41467-025-57135-8
View details for PubMedID 39979261
View details for PubMedCentralID 3714538

Publications
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Navigating the path to corneal healing success and challenges: a comprehensive overview.
Eye (London, England)
Shadmani, A., Wu, A. Y.
2025
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The cornea serves to protect the eye from external insults and refracts light to the retina. Maintaining ocular homeostasis requires constant epithelial renewal and an efficient healing process following injury. Corneal wound healing is a dynamic process involving several key cell populations and molecular pathways. Immediately after a large corneal epithelial injury involving limbal stem cells, conjunctival epithelial cells migrate toward the center of the wound guided by the newly formed electrical field (EF). Proliferation and transdifferentiation play a critical role in corneal epithelial regeneration. Corneal nerve endings migrate through the EF, connect with the migrating epithelial cells, and provide them with multiple growth factors. Finally, the migrated epithelial cells undergo differentiation, which is also regulated by corneal nerve endings. All these processes require energy and effective cellular cross-talk between different cell lines and extracellular matrix molecules. We provide an overview of the roles and interactions between corneal wound regeneration components that may help develop fascinating new targeted therapeutic strategies to enhance corneal wound healing with less injury-related corneal opacity and neovascularization.
View details for DOI 10.1038/s41433-025-03619-2
View details for PubMedID 39939391
View details for PubMedCentralID 7697722
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Association of ocular adverse events with varenicline solution use: a population-based study.
Expert opinion on drug safety
Lakhani, M., Kwan, A. T., Nguyen, A. X., Popovic, M. M., McIntyre, R. S., Wu, A. Y.
2025: 1-9
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Abstract
Approved by the FDA in 2021, varenicline solution is the first nasal spray specifically designed to enhance basal tear film production for treating dry eye disease (DED). However, there is a lack of data comprehensively comparing its safety profile to conventional DED therapies. Herein, we assess whether ocular adverse events (AEs) are disproportionately reported with the real-world use of varenicline solution.This observational, population-based pharmacovigilance study analyzed the Food and Drug Administration Adverse Event Reporting System (FAERS) data (inception-April 2024) using reporting odds ratio (ROR), with significance defined as a 95% CI lower bound > 1.0. Nasal saline and systane were the controls.A total of 1,125 AE reports were associated with varenicline solution. No disproportionate reporting of specific ocular AEs was observed when comparing varenicline solution with nasal saline. However, when compared with systane, varenicline solution showed higher odds of lacrimation (ROR = 2.18, 95%CI = 1.46-3.26, p < 0.0001), visual impairment (ROR = 2.27, 95%CI = 1.24-4.16, p = 0.0085), and photophobia (ROR = 7.50, 95%CI = 3.68-15.27, p < 0.0001).Although a direct causal relationship for higher RORs cannot be established for varenicline solution compared to systane, our findings provide evidence for potential risk signals and highlight the crucial role of post-marketing pharmacovigilance in monitoring long-term safety.
View details for DOI 10.1080/14740338.2025.2460454
View details for PubMedID 39921610
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Endoplasmic reticulum protein TXNDC5 modulates thyroid eye disease TGF-β1-induced myofibroblast transdifferentiation.
BMJ open ophthalmology
Chiu, H. I., Wu, S. B., Wu, A. Y., Tsai, C. C.
2024; 9 (1)
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Abstract
There remain limited therapies to treat thyroid eye disease (TED) orbital fibrosis, highlighting the urgency to develop novel targets. Transforming growth factor-β1 (TGF-β1)-induced myofibroblast transdifferentiation from orbital fibroblasts are important pathogenetic factor of TED. Endoplasmic reticulum (ER) stress may play a role in TED pathogenesis since it has been linked to liver, kidney, heart and lung fibrotic remodelling. We would evaluate the role of thioredoxin domain containing 5 (TXNDC5), a fibroblast-enriched ER protein, in TGF-β1-induced myofibroblast transdifferentiation from TED orbital fibroblasts.Orbital fibroblasts from patients with TED were treated with TGF-β1 to investigate ER stress-relative gene expression especially for TXNDC5. To determine if TXNDC5 is involved in TGF-β1-induced fibrosis, we transfected TED orbital fibroblasts by lentivirus with a small hairpin RNA of pLKO-TXNDC5 gene (shTXNDC5) to knockdown TXNDC5 protein expression levels. After transfection of shTXNDC5 in TED orbital fibroblast followed by TGF-β1 treatment, we analysed TGF-β1-induced fibrosis protein expression.We measured increased TXNDC5 gene and protein expression in primary TED orbital fibroblasts. TXNDC5 protein levels were increased in TED orbital fibroblasts under TGF-β1 stimulation (2.5, 5, 10 and 20 ng/mL). Moreover, TXNDC5 knockdown of attenuated TGFβ1 (5 ng/mL)-induced myofibroblast transdifferentiation and extracellular matrix protein upregulation whereas increasing TXNDC5 expression by a recombinant protein of TXNDC5 (rhTXNDC5) addition increased alpha smooth muscle actin, fibronectin and connective tissue growth factor protein expression.In conclusion, targeting TXNDC5 may be a novel therapeutic approach against TGF-β1-induced myofibroblast transdifferentiation in TED orbital fibroblasts.
View details for DOI 10.1136/bmjophth-2024-001693
View details for PubMedID 39721966
Other Stanford Faculty

Publications
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Gain, not concomitant changes in spatial receptive field properties, improves task performance in a neural network attention model.
eLife
Fox, K. J., Birman, D., Gardner, J. L.
2023; 12
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Abstract
Attention allows us to focus sensory processing on behaviorally relevant aspects of the visual world. One potential mechanism of attention is a change in the gain of sensory responses. However, changing gain at early stages could have multiple downstream consequences for visual processing. Which, if any, of these effects can account for the benefits of attention for detection and discrimination? Using a model of primate visual cortex we document how a Gaussian-shaped gain modulation results in changes to spatial tuning properties. Forcing the model to use only these changes failed to produce any benefit in task performance. Instead, we found that gain alone was both necessary and sufficient to explain category detection and discrimination during attention. Our results show how gain can give rise to changes in receptive fields which are not necessary for enhancing task performance.
View details for DOI 10.7554/eLife.78392
View details for PubMedID 37184221
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Texture-like representation of objects in human visual cortex.
Proceedings of the National Academy of Sciences of the United States of America
Jagadeesh, A. V., Gardner, J. L.
2022; 119 (17): e2115302119
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SignificanceHumans are exquisitely sensitive to the spatial arrangement of visual features in objects and scenes, but not in visual textures. Category-selective regions in the visual cortex are widely believed to underlie object perception, suggesting such regions should distinguish natural images of objects from synthesized images containing similar visual features in scrambled arrangements. Contrarily, we demonstrate that representations in category-selective cortex do not discriminate natural images from feature-matched scrambles but can discriminate images of different categories, suggesting a texture-like encoding. We find similar insensitivity to feature arrangement in Imagenet-trained deep convolutional neural networks. This suggests the need to reconceptualize the role of category-selective cortex as representing a basis set of complex texture-like features, useful for a myriad of behaviors.
View details for DOI 10.1073/pnas.2115302119
View details for PubMedID 35439063
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Population Models, Not Analyses, of Human Neuroscience Measurements.
Annual review of vision science
Gardner, J. L., Merriam, E. P.
2021
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Abstract
Selectivity for many basic properties of visual stimuli, such as orientation, is thought to be organized at the scale of cortical columns, making it difficult or impossible to measure directly with noninvasive human neuroscience measurement. However, computational analyses of neuroimaging data have shown that selectivity for orientation can be recovered by considering the pattern of response across a region of cortex. This suggests that computational analyses can reveal representation encoded at a finer spatial scale than is implied by the spatial resolution limits of measurement techniques. This potentially opens up the possibility to study a much wider range of neural phenomena that are otherwise inaccessible through noninvasive measurement. However, as we review in this article, a large body of evidence suggests an alternative hypothesis to this superresolution account: that orientation information is available at the spatial scale of cortical maps and thus easily measurable at the spatial resolution of standard techniques. In fact, a population model shows that this orientation information need not even come from single-unit selectivity for orientation tuning, but instead can result from population selectivity for spatial frequency. Thus, a categorical error of interpretation can result whereby orientation selectivity can be confused with spatial frequency selectivity. This is similarly problematic for the interpretation of results from numerous studies of more complex representations and cognitive functions that have built upon the computational techniques used to reveal stimulus orientation. We suggest in this review that these interpretational ambiguities can be avoided by treating computational analyses as models of the neural processes that give rise to measurement. Building upon the modeling tradition in vision science using considerations of whether population models meet a set of core criteria is important for creating the foundation for a cumulative and replicable approach to making valid inferences from human neuroscience measurements. Expected final online publication date for the Annual Review of Vision Science, Volume 7 is September 2021. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.
View details for DOI 10.1146/annurev-vision-093019-111124
View details for PubMedID 34283926

Publications
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TDP-43 represses cryptic exon inclusion in the FTD-ALS gene UNC13A.
Nature
Ma, X. R., Prudencio, M., Koike, Y., Vatsavayai, S. C., Kim, G., Harbinski, F., Briner, A., Rodriguez, C. M., Guo, C., Akiyama, T., Schmidt, H. B., Cummings, B. B., Wyatt, D. W., Kurylo, K., Miller, G., Mekhoubad, S., Sallee, N., Mekonnen, G., Ganser, L., Rubien, J. D., Jansen-West, K., Cook, C. N., Pickles, S., Oskarsson, B., Graff-Radford, N. R., Boeve, B. F., Knopman, D. S., Petersen, R. C., Dickson, D. W., Shorter, J., Myong, S., Green, E. M., Seeley, W. W., Petrucelli, L., Gitler, A. D.
2022
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Abstract
A hallmark pathological feature of the neurodegenerative diseases amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) is the depletion of RNA-binding protein TDP-43 from the nucleus of neurons in the brain and spinal cord1. A major function of TDP-43 is as a repressor of cryptic exon inclusion during RNA splicing2-4. Single nucleotide polymorphisms in UNC13A are among the strongest hits associated with FTD and ALS in human genome-wide association studies5,6, but how those variants increase risk for disease is unknown. Here we show that TDP-43 represses a cryptic exon-splicing event in UNC13A. Loss of TDP-43 from the nucleus in human brain, neuronal cell lines and motor neurons derived from induced pluripotent stem cells resulted in the inclusion of a cryptic exon in UNC13A mRNA and reduced UNC13A protein expression. The top variants associated with FTD or ALS risk in humans are located in the intron harbouring the cryptic exon, and we show that they increase UNC13A cryptic exon splicing in the face of TDP-43 dysfunction. Together, our data provide a direct functional link between one of the strongest genetic risk factors for FTD and ALS (UNC13A genetic variants), and loss of TDP-43 function.
View details for DOI 10.1038/s41586-022-04424-7
View details for PubMedID 35197626
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A prion-like protein regulator of seed germination undergoes hydration-dependent phase separation.
Cell
Dorone, Y., Boeynaems, S., Flores, E., Jin, B., Hateley, S., Bossi, F., Lazarus, E., Pennington, J. G., Michiels, E., De Decker, M., Vints, K., Baatsen, P., Bassel, G. W., Otegui, M. S., Holehouse, A. S., Exposito-Alonso, M., Sukenik, S., Gitler, A. D., Rhee, S. Y.
2021
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Abstract
Many organisms evolved strategies to survive desiccation. Plant seeds protect dehydrated embryos from various stressors and can lay dormant for millennia. Hydration is the key trigger to initiate germination, but the mechanism by which seeds sense water remains unresolved. We identified an uncharacterized Arabidopsis thaliana prion-like protein we named FLOE1, which phase separates upon hydration and allows the embryo to sense water stress. We demonstrate that biophysical states of FLOE1 condensates modulate its biological function invivo in suppressing seed germination under unfavorable environments. We find intragenic, intraspecific, and interspecific natural variation in FLOE1 expression and phase separation and show that intragenic variation is associated with adaptive germination strategies in natural populations. This combination of molecular, organismal, and ecological studies uncovers FLOE1 as a tunable environmental sensor with direct implications for the design of drought-resistant crops, in the face of climate change.
View details for DOI 10.1016/j.cell.2021.06.009
View details for PubMedID 34233164
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Single-cell transcriptomic analysis of the adult mouse spinal cord reveals molecular diversity of autonomic and skeletal motor neurons.
Nature neuroscience
Blum, J. A., Klemm, S., Shadrach, J. L., Guttenplan, K. A., Nakayama, L., Kathiria, A., Hoang, P. T., Gautier, O., Kaltschmidt, J. A., Greenleaf, W. J., Gitler, A. D.
2021
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Abstract
The spinal cord is a fascinating structure that is responsible for coordinating movement in vertebrates. Spinal motor neurons control muscle activity by transmitting signals from the spinal cord to diverse peripheral targets. In this study, we profiled 43,890 single-nucleus transcriptomes from the adult mouse spinal cord using fluorescence-activated nuclei sorting to enrich for motor neuron nuclei. We identified 16 sympathetic motor neuron clusters, which are distinguishable by spatial localization and expression of neuromodulatory signaling genes. We found surprising skeletal motor neuron heterogeneity in the adult spinal cord, including transcriptional differences that correlate with electrophysiologically and spatially distinct motor pools. We also provide evidence for a novel transcriptional subpopulation of skeletal motor neuron (gamma*). Collectively, these data provide a single-cell transcriptional atlas ( http://spinalcordatlas.org ) for investigating the organizing molecular logic of adult motor neuron diversity, as well as the cellular and molecular basis of motor neuron function in health and disease.
View details for DOI 10.1038/s41593-020-00795-0
View details for PubMedID 33589834

Publications
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Postsynaptic neuronal activity promotes regeneration of retinal axons.
Cell reports
Varadarajan, S. G., Wang, F., Dhande, O. S., Le, P., Duan, X., Huberman, A. D.
2023; 42 (5): 112476
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Abstract
The wiring of visual circuits requires that retinal neurons functionally connect to specific brain targets, a process that involves activity-dependent signaling between retinal axons and their postsynaptic targets. Vision loss in various ophthalmological and neurological diseases is caused by damage to the connections from the eye to the brain. How postsynaptic brain targets influence retinal ganglion cell (RGC) axon regeneration and functional reconnection with the brain targets remains poorly understood. Here, we established a paradigm in which the enhancement of neural activity in the distal optic pathway, where the postsynaptic visual target neurons reside, promotes RGC axon regeneration and target reinnervation and leads to the rescue of optomotor function. Furthermore, selective activation of retinorecipient neuron subsets is sufficient to promote RGC axon regeneration. Our findings reveal a key role for postsynaptic neuronal activity in the repair of neural circuits and highlight the potential to restore damaged sensory inputs via proper brain stimulation.
View details for DOI 10.1016/j.celrep.2023.112476
View details for PubMedID 37141093
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Brief structured respiration practices enhance mood and reduce physiological arousal.
Cell reports. Medicine
Balban, M. Y., Neri, E., Kogon, M. M., Weed, L., Nouriani, B., Jo, B., Holl, G., Zeitzer, J. M., Spiegel, D., Huberman, A. D.
2023: 100895
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Abstract
Controlled breathwork practices have emerged as potential tools for stress management and well-being. Here, we report a remote, randomized, controlled study (NCT05304000) of three different daily 5-min breathwork exercises compared with an equivalent period of mindfulness meditation over 1 month. The breathing conditions are (1) cyclic sighing, which emphasizes prolonged exhalations; (2) box breathing, which is equal duration of inhalations, breath retentions, and exhalations; and (3) cyclic hyperventilation with retention, with longer inhalations and shorter exhalations. The primary endpoints are improvement in mood and anxiety as well as reduced physiological arousal (respiratory rate, heart rate, and heart rate variability). Using a mixed-effects model, we show that breathwork, especially the exhale-focused cyclic sighing, produces greater improvement in mood (p < 0.05) and reduction in respiratory rate (p < 0.05) compared with mindfulness meditation. Daily 5-min cyclic sighing has promise as an effective stress management exercise.
View details for DOI 10.1016/j.xcrm.2022.100895
View details for PubMedID 36630953
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Characterization of non-alpha retinal ganglion cell injury responses reveals a possible block to restoring ipRGC function.
Experimental neurology
Hunyara, J. L., Foshe, S., Varadarajan, S. G., Gribble, K. D., Huberman, A. D., Kolodkin, A. L.
2022: 114176
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Abstract
Visual impairment caused by retinal ganglion cell (RGC) axon damage or degeneration affects millions of individuals throughout the world. While some progress has been made in promoting long-distance RGC axon regrowth following injury, it remains unclear whether RGC axons can properly reconnect with their central targets to restore visual function. Additionally, the regenerative capacity of many RGC subtypes remains unknown in part due to a lack of available genetic tools. Here, we use a new mouse line that labels On direction-selective RGCs (oDSGCs) and characterize the survival and regenerative potential of these cells following optic nerve crush (ONC). In parallel, we use a previously characterized mouse line to answer these same questions for M1 intrinsically photosensitive RGCs (ipRGCs). We find that both M1 ipRGCs and oDSGCs are resilient to injury but do not display long-distance axon regrowth following Lin28a overexpression. Unexpectedly, we found that M1 ipRGC, but not oDSGC, intraretinal axons exhibit ectopic branching and are misaligned near the optic disc between one- and three-weeks following injury. Additionally, we observe that numerous ectopic presynaptic specializations associate with misguided ipRGC intraretinal axons. Taken together, these results reveal insights into the injury response of M1 ipRGCs and oDSGCs, providing a foundation for future efforts seeking to restore visual system function following injury.
View details for DOI 10.1016/j.expneurol.2022.114176
View details for PubMedID 35870522

Publications
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Effect of bilirubin on visuocortical development in preterm infants.
Journal of perinatology : official journal of the California Perinatal Association
Good, W. V., Wong, R. J., Norcia, A. M., Hou, C., Cellucci, J., McGovern, M. Q., Wong-Kee-You, A., Acevedo Munares, G., Richburg, D., Loveridge-Easther, C., Lee, J. S., DeJesus, L., Slagle, T., Stevenson, D. K., Bhutani, V. K.
2025
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Abstract
To determine if visuocortical development in premature infants with high bilirubin levels is more adversely affected than that in full-term infants.57 preterm infants were managed using institutional guidelines for hyperbilirubinemia. At 12-months corrected age, Vernier acuity, contrast sensitivity, and grating acuity measured using the sweep visual evoked potential (sVEP) were correlated to total serum/plasma bilirubin (TSB) levels in the first week of life.As TSB levels increased, Vernier acuity worsened in infants <34 weeks' gestation compared with those >34 to <37 weeks' gestation (p < 0.001). Contrast sensitivity varied as a function of TSB levels (Spearman correlation 0.63, p < 0.001). Grating acuity was unaffected.Vernier acuity in preterm infants <34 weeks' gestation is more vulnerable to the effects of bilirubin, suggesting that the extrastriate visual cortex is primarily affected by bilirubin. Therefore, guidelines for management of hyperbilirubinemia in preterm infants (<34 weeks' gestation) should be revised.
View details for DOI 10.1038/s41372-025-02213-4
View details for PubMedID 39910190
View details for PubMedCentralID 4197714
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Late development of sensory thresholds for horizontal relative disparity in human visual cortex in the face of precocial development of thresholds for absolute disparity.
The Journal of neuroscience : the official journal of the Society for Neuroscience
Norcia, A. M., Kaestner, M., Chen, Y. D., Clement, C. S.
2025
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Abstract
Immaturities exist at multiple levels of the developing human visual pathway, starting with immaturities in photon efficiency and spatial sampling in the retina and on through immaturities in early and later stages of cortical processing. Here we use Steady-State Visual Evoked Potentials (SSVEPs) and controlled visual stimuli to determine the degree to which sensitivity to horizontal retinal disparity is limited by the visibility of the monocular half-images, the ability to encode absolute disparity or the ability to encode relative disparity. Responses were recorded from male and female human participants at average ages of 5.3 +/- 1.6 months, 4.7 +/- 1.3 years, and 25.3 +/ -6 years. Horizontal disparity sensitivity was measured using planar stereograms that modulated absolute disparity and in stereograms portraying disparity gratings that additionally contained relative disparity. Disparity thresholds for absolute disparity changed little over development, but those for relative disparity changed by a factor of ∼10. SSVEPs were also recorded in response to contrast and blur modulation of dynamic random dot patterns to measure sensitivity to the spatio-temporal content of the monocular half-images. Equating subjective contrast and blur levels between infants, children and adults based on these measurements did not equate disparity sensitivity. The protracted developmental sequence for horizontal relative disparity coding shown in our measurements is not simply inherited from immaturities in encoding absolute disparity or retinal image contrast, but rather reflects immaturities in the computations needed to represent relative disparity that likely involve extra-striate cortical areas where relative disparity is first extracted.Significance Statement The lateral separation of the eyes creates horizontal image disparities that provide the primary cue for depth. These disparities reflect the distance of a point from the plane of fixation (absolute disparities) or depth relationships between two or more points in the image (relative disparity). By recording SSVEPs driven by disparity modulation and stimuli that contain only absolute disparity versus those that also contain relative disparity, we find that sensitivity to absolute disparity develops to near adult levels within the first 6 months of life, but that relative disparity develops beyond 5 years of age. These developmental changes are dissociable from changes in the visibility of the half-images and reflect specific immaturities in disparity processing.
View details for DOI 10.1523/JNEUROSCI.0216-24.2024
View details for PubMedID 39794129
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The emergence of visual category representations in infants' brains.
eLife
Yan, X., Tung, S. S., Fascendini, B., Chen, Y. D., Norcia, A. M., Grill-Spector, K.
2024; 13
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Abstract
Organizing the continuous stream of visual input into categories like places or faces is important for everyday function and social interactions. However, it is unknown when neural representations of these and other visual categories emerge. Here, we used steady-state evoked potential electroencephalography to measure cortical responses in infants at 3-4 months, 4-6 months, 6-8 months, and 12-15 months, when they viewed controlled, gray-level images of faces, limbs, corridors, characters, and cars. We found that distinct responses to these categories emerge at different ages. Reliable brain responses to faces emerge first, at 4-6 months, followed by limbs and places around 6-8 months. Between 6 and 15 months response patterns become more distinct, such that a classifier can decode what an infant is looking at from their brain responses. These findings have important implications for assessing typical and atypical cortical development as they not only suggest that category representations are learned, but also that representations of categories that may have innate substrates emerge at different times during infancy.
View details for DOI 10.7554/eLife.100260
View details for PubMedID 39714017
View details for PubMedCentralID PMC11666245
1. Brolucizumab: Evolution through Preclinical and Clinical Studies and the Implications for the Management of Neovascular Age-Related Macular Degeneration.
Nguyen QD, Das A, Do DV, Dugel PU, Gomes A, Holz FG, Koh A, Pan CK, Sepah YJ, Patel N, MacLeod H, Maurer P.
Ophthalmology. 2020 Jul;127(7):963-976. doi: 10.1016/j.ophtha.2019.12.031. Epub 2020 Jan 17.
PMID: 32107066
2. Retinal arterial occlusive vasculitis following intravitreal brolucizumab administration.
Haug SJ, Hien DL, Uludag G, Ngoc TTT, Lajevardi S, Halim MS, Sepah YJ, Do DV, Khanani AM.Am J Ophthalmol Case Rep. 2020 Mar 31;18:100680. doi: 10.1016/j.ajoc.2020.100680. eCollection 2020 Jun.
PMID: 32258827
3. Interleukin-6 inhibition in the management of non-infectious uveitis and beyond.
Karkhur S, Hasanreisoglu M, Vigil E, Halim MS, Hassan M, Plaza C, Nguyen NV, Afridi R, Tran AT, Do DV, Sepah YJ, Nguyen QD.J Ophthalmic Inflamm Infect. 2019 Sep 16;9(1):17. doi: 10.1186/s12348-019-0182-y.
PMID: 31523783

Publications
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ISETHDR: A Physics-Based Synthetic Radiance Dataset for High Dynamic Range Driving Scenes
IEEE SENSORS JOURNAL
Liu, Z., Shah, D., Wandell, B. A.
2025; 25 (9): 15261-15269
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View details for DOI 10.1109/JSEN.2025.3550455
View details for Web of Science ID 001480473900005
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Deriving the cone fundamentals: a subspace intersection method.
Proceedings. Biological sciences
Wandell, B. A., Goossens, T., Brainard, D. H.
2024; 291 (2030): 20240347
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Two ideas, proposed by Thomas Young and James Clerk Maxwell, form the foundations of colour science: (i) three types of retinal receptors encode light under daytime conditions, and (ii) colour matching experiments establish the critical spectral properties of this encoding. Experimental quantification of these ideas is used in international colour standards. However, for many years, the field did not reach consensus on the spectral properties of the biological substrate of colour matching: the spectral sensitivity of the cone fundamentals. By combining auxiliary data (thresholds, inert pigment analyses), complex calculations, and colour matching from genetically analysed dichromats, the human cone fundamentals have now been standardized. Here, we describe a new computational method to estimate the cone fundamentals using only colour matching from the three types of dichromatic observers. We show that it is not necessary to include data from trichromatic observers in the analysis or to know the primary lights used in the matching experiments. Remarkably, it is even possible to estimate the fundamentals by combining data from experiments using different, unknown primaries. We then suggest how the new method may be applied to colour management in modern image systems.
View details for DOI 10.1098/rspb.2024.0347
View details for PubMedID 39226931
View details for PubMedCentralID PMC11371420
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Measuring brain beats: Cardiac-aligned fast functional magnetic resonance imaging signals.
Human brain mapping
Hermes, D., Wu, H., Kerr, A. B., Wandell, B. A.
2022
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Abstract
Blood and cerebrospinal fluid (CSF) pulse and flow throughout the brain, driven by the cardiac cycle. These fluid dynamics, which are essential to healthy brain function, are characterized by several noninvasive magnetic resonance imaging (MRI) methods. Recent developments in fast MRI, specifically simultaneous multislice acquisition methods, provide a new opportunity to rapidly and broadly assess cardiac-driven flow, including CSF spaces, surface vessels and parenchymal vessels. We use these techniques to assess blood and CSF flow dynamics in brief (3.5min) scans on a conventional 3T MRI scanner in five subjects. Cardiac pulses are measured with a photoplethysmography (PPG) on the index finger, along with functional MRI (fMRI) signals in the brain. We, retrospectively, align the fMRI signals to the heartbeat. Highly reliable cardiac-gated fMRI temporal signals are observed in CSF and blood on the timescale of one heartbeat (test-retest reliability within subjects R2 >50%). In blood vessels, a local minimum is observed following systole. In CSF spaces, the ventricles and subarachnoid spaces have a local maximum following systole instead. Slower resting-state scans with slice timing, retrospectively, aligned to the cardiac pulse, reveal similar cardiac-gated responses. The cardiac-gated measurements estimate the amplitude and phase of fMRI pulsations in the CSF relative to those in the arteries, an estimate of the local intracranial impedance. Cardiac aligned fMRI signals can provide new insights about fluid dynamics or diagnostics for diseases where these dynamics are important.
View details for DOI 10.1002/hbm.26128
View details for PubMedID 36308417