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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Correction to: Risdiplam in Patients Previously Treated with Other Therapies for Spinal Muscular Atrophy: An Interim Analysis from the JEWELFISH Study.
Neurology and therapy
Chiriboga, C. A., Bruno, C., Duong, T., Fischer, D., Mercuri, E., Kirschner, J., Kostera-Pruszczyk, A., Jaber, B., Gorni, K., Kletzl, H., Carruthers, I., Martin, C., Warren, F., Scalco, R. S., Wagner, K. R., Muntoni, F., JEWELFISH Study Group, Deconinck, N., Balikova, I., Joniau, I., Tahon, V., Wittevrongel, S., Goemans, N., Cassiman, C., Prove, L., Vancampenhout, L., van den Hauwe, M., Van Impe, A., Cances, C., Soler, V., De La Morandais, L. M., Vovan, D., Cintas, P., Auriol, F., Mus, M., Alphonsa, G., Bellio, V., Gil Mato, O., Flamein, F., Evrard, C., Ziouche, A., Bouacha-Allou, I., Debruyne, P., Derlyn, G., Defoort, S., Leroy, F., Danjoux, L., Desguerre, I., Bremond-Gignac, D., Rateuax, M., Deladriere, E., Vuillerot, C., Veillerot, Q., Sibille-Dabadi, B., Barriere, A., Tinat, M., Saidi, M., Fontaine, S., De Montferrand, C., Le-Goff, L., Portefaix, A., Louvier, U. W., Duval, P., Caradec, P., Touati, S., Herranz, A. Z., Kirschner, J., Bollig, J., Molnar, F., Vogt, S., Pechmann, A., Schorling, D., Wider, S., Kolbel, H., Schara, U., Braun, F., Gangfuss, A., Hagenacker, T., Eckstein, A., Dekowski, D., Oeverhaus, M., Stoehr, M., Andres, B., Smuda, K., Bertini, E., D'Amico, A., Petroni, S., Valente, P., Bonetti, A. M., Carlesi, A., Mizzoni, I., Bruno, C., Pedemonte, M., Brolatti, N., Priolo, E., Rao, G., Sposetti, L., Morando, S., Comi, G., Osnaghi, S., Minorini, V., Abbati, F., Fassini, F., Foa, M., Lopopolo, M. A., Magri, F., Govoni, A., Meneri, M., Parente, V., Mercuri, E., Antonaci, L., Pera, M. C., Pane, M., Amorelli, G. M., Barresi, C., D'Amico, G., Orazi, L., Coratti, G., De Sanctis, R., Vita, G., Sframeli, M., Vita, G. L., Aragona, P., Inferrera, L., Postorino, E. I., Montanini, D., Di Bella, V., Donato, C., Cala, E., Van der Pol, L., Aalbers, J., de Boer, J., Imhof, S., Cooijmans, P., Ruyten, T., Van Der Woude, D., Kostera-Pruszczyk, A., Klimaszewska, B., Romanczak, D., Gierlak-Wojcicka, Z., Kepa, M., Sikorski, A., Sobieraj, M., Lusakowska, A., Kierdaszuk, B., Czeczko, K., Fischer, D., Henzi, B., Gugleta, K., Kusnyerik, A., Siems, P., Akos, S., Frei, N., Seppi, C., Haschke, C. W., Guglieri, M., Straub, V., Bell, R., Nassar, M., Page, S., Clarke, M. P., Regan, A., Mayhew, A., Lofra, R. M., Parasuraman, D., Bruschi, S., Ghauri, A., Castle, A., Naqvi, S., Patt, N., Scoto, M., Trucco, F., Henderson, R. H., Kukadia, R., Moore, W., Milev, E., Rye, C., Selby, V., Wolfe, A., Darras, B., Baglieri, A. M., Fulton, A., Lucken, C., Maczek, E., Pasternak, A., Chiriboga, C. A., Kane, S., Bautista, M. E., Frommer, E., Pensec, N., Salazar, R., Yochai, C., Rodrigues-Torres, R., Chawla, M., Day, J., Beres, S., Gee, R., Young, S. D., Finkel, R., Nazario, A. N., Fasiuddin, A., Wells, J. A., Wilson, J., Berry, D., Rizzo, V., Duke, J., Monduy, M., Collado, J.
2023
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View details for DOI 10.1007/s40120-023-00503-7
View details for PubMedID 37395990
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Isolated Sixth Nerve Palsies in a Child With Familial Hemophagocytic Lymphohistiocytosis Type 2.
Journal of neuro-ophthalmology : the official journal of the North American Neuro-Ophthalmology Society
Chiang, H. H., Fernandez-Pol, S., Bae, G. H., Rieger, K. E., Dahmoush, H. M., Beres, S. J.
2023; 43 (1): 137-140
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Abstract
A previously healthy 2-year-old boy presented with a left sixth cranial nerve palsy. There was a family history of multiple sclerosis and optic neuritis. Neuroimaging showed multiple foci of T2/FLAIR hyperintense signal abnormality in both cerebral hemispheres and in the brainstem. The initial diagnosis was suspicious for demyelinating disease. However, there was no clinical improvement after a course of corticosteroids, and there was no change in his follow-up MRI. He later developed bilateral sixth nerve palsies, with esotropia addressed with bilateral medial rectus botulinum toxin injections. A brain biopsy was planned. However, his 3-month-old sister was separately admitted for fever and pancytopenia. She had markedly elevated ferritin, D-dimer, triglycerides, sIL-2R, CXCL9, and IL-18 and low fibrinogen. Her bone marrow biopsy showed hemophagocytosis. Genetic testing of both siblings revealed biallelic mutations in the PRF1 locus. The final diagnosis of familial hemophagocytic lymphohistiocytosis Type 2 was made. Both siblings underwent chemotherapy. The boy's sixth nerve palsies and MRI abnormalities resolved. Both siblings then went on to undergo bone marrow transplant.
View details for DOI 10.1097/WNO.0000000000001807
View details for PubMedID 36790062
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Risdiplam in Patients Previously Treated with Other Therapies for Spinal Muscular Atrophy: An Interim Analysis from the JEWELFISH Study.
Neurology and therapy
Chiriboga, C. A., Bruno, C., Duong, T., Fischer, D., Mercuri, E., Kirschner, J., Kostera-Pruszczyk, A., Jaber, B., Gorni, K., Kletzl, H., Carruthers, I., Martin, C., Warren, F., Scalco, R. S., Wagner, K. R., Muntoni, F.
2023
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Abstract
Risdiplam is a survival of motor neuron 2 (SMN2) splicing modifier for the treatment of patients with spinal muscular atrophy (SMA). The JEWELFISH study (NCT03032172) was designed to assess the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of risdiplam in previously treated pediatric and adult patients with types 1-3 SMA. Here, an analysis was performed after all patients had received at least 1 year of treatment with risdiplam.Patients with a confirmed diagnosis of 5q-autosomal recessive SMA between the ages of 6 months and 60 years were eligible for enrollment. Patients were previously enrolled in the MOONFISH study (NCT02240355) with splicing modifier RG7800 or treated with olesoxime, nusinersen, or onasemnogene abeparvovec. The primary objectives of the JEWELFISH study were to evaluate the safety and tolerability of risdiplam and investigate the PK after 2 years of treatment.A total of 174 patients enrolled: MOONFISH study (n = 13), olesoxime (n = 71 patients), nusinersen (n = 76), onasemnogene abeparvovec (n = 14). Most patients (78%) had three SMN2 copies. The median age and weight of patients at enrollment was 14.0 years (1-60 years) and 39.1 kg (9.2-108.9 kg), respectively. About 63% of patients aged 2-60 years had a baseline total score of less than 10 on the Hammersmith Functional Motor Scale-Expanded and 83% had scoliosis. The most common adverse event (AE) was upper respiratory tract infection and pyrexia (30 patients each; 17%). Pneumonia (four patients; 2%) was the most frequently reported serious AE (SAE). The rates of AEs and SAEs per 100 patient-years were lower in the second 6-month period compared with the first. An increase in SMN protein was observed in blood after risdiplam treatment and was comparable across all ages and body weight quartiles.The safety and PD of risdiplam in patients who were previously treated were consistent with those of treatment-naïve patients.
View details for DOI 10.1007/s40120-023-00444-1
View details for PubMedID 36780114
Publications
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Higher-Order Assessment of OCT in Diabetic Macular Edema from the VISTA Study: Ellipsoid Zone Dynamics and the Retinal Fluid Index.
Ophthalmology. Retina
Ehlers, J. P., Uchida, A., Hu, M., Figueiredo, N., Kaiser, P. K., Heier, J. S., Brown, D. M., Boyer, D. S., Do, D. V., Gibson, A., Saroj, N., Srivastava, S. K.
2019
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Abstract
PURPOSE: To investigate retinal fluid features and ellipsoid zone (EZ) integrity dynamics on spectral-domain OCT (SD-OCT) in eyes with diabetic macular edema (DME) treated with intravitreal aflibercept injection (IAI) in the VISTA-DME study.DESIGN: A post hoc subanalysis of a phase III, prospective clinical trial.PARTICIPANTS: Eyes received either IAI 2 mg every 4 weeks (2q4) or every 8 weeks after 5 initial monthly doses (2q8).METHODS: All eyes from the VISTA Phase III study in the IAI groups imaged with the Cirrus HD-OCT system (Zeiss, Oberkochen, Germany) were included. The OCT macular cube datasets were evaluated using a novel software platform to generate retinal layer and fluid boundary lines that were manually corrected for assessment of change in EZ parameters and volumetric fluid parameters from baseline. The retinal fluid index (i.e., proportion of the retinal volume consisting of cystic fluid) was also calculated at each time point.MAIN OUTCOME MEASURES: The feasibility of volumetric assessment of higher-order OCT-based retinal parameters and its correlation with best-corrected visual acuity (BCVA).RESULTS: Overall, 106 eyes of 106 patients were included. Specifically, 52 eyes of 52 patients were included in the IAI 2q4 arm, and 54 eyes of 54 patients were included in the IAI 2q8 arm. Ellipsoid zone integrity metrics significantly improved from baseline to week 100, including central macular mean EZ to retinal pigment epithelium (RPE) thickness (2q4: 26.6 mum to 31.6 mum, P < 0.001; 2q8: 25.2 mum to 31.4 mum, P < 0.001). At week 100, central macular intraretinal fluid volume was reduced by >65% (P < 0.001) and central macular subretinal fluid volume was reduced by >99% in both arms (P < 0.001). Central macular retinal fluid index (RFI) significantly improved in both arms (2q4: 17.9% to 7.2%, P < 0.001; 2q8: 19.8% to 4.2%, P < 0.001). Central macular mean EZ-RPE thickness (i.e., a surrogate for photoreceptor outer segment length) and central RFI were independently correlated with BCVA at multiple follow-up visits.CONCLUSIONS: Intravitreal aflibercept injection resulted in significant improvement in EZ integrity and quantitative fluid metrics in both 2q4 and 2q8 arms and correlated with visual function.
View details for DOI 10.1016/j.oret.2019.06.010
View details for PubMedID 31473172
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Traumatic chorioretinitis sclopetaria: Risk factors, management, and prognosis.
American journal of ophthalmology case reports
Ludwig, C. A., Shields, R. A., Do, D. V., Moshfeghi, D. M., Mahajan, V. B.
2019; 14: 39–46
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Abstract
Purpose: To describe new cases of sclopetaria and evaluate the risk factors, management, and visual prognosis of all reported cases in the literature.Observations: We performed a retrospective, observational case series. This study included six cases (median age 23, interquartile range 33) of sclopetaria. Additionally, literature searches were conducted in the PubMed and Cochrane Library databases to uncover risk factors associated with all published cases of sclopetaria. Main outcome measure was best corrected visual acuity (BCVA) worse than 20/20. Sixty-seven cases (71 eyes) of sclopetaria have been reported, of which 59 cases (61 eyes) met inclusion criteria in this study. Most were young (median age 19.5 years) men (51/59, 88.1%). Thirty-seven eyes were observed while 24 underwent immediate surgery including six pars plana vitrectomies and three scleral buckles. Compared to initial presentation, BCVA improved in 31/48 (64.6%) eyes, remained stable in 12/48 eyes (25.0%), and worsened in 5/48 eyes (10.4%). Ten patients (16.4%) achieved a final BCVA of 20/20 with median follow up time of seven months. In a multivariate model, location of sclopetaria in the macula, temporal retina, or immediate orbital foreign body removal predicted poor final BCVA with an area under receiver operating characteristic curve of 0.767.Conclusions and importance: Traumatic chorioretinitis sclopetaria is rare, but reports have increased dramatically over the past two decades. While pars plana vitrectomy may be required for the management of retinal detachments and non-clearing vitreous hemorrhage, close observation is appropriate in most cases. Visual prognosis is poor with most patients attaining 20/200 vision or worse.
View details for PubMedID 30834355
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Alendronate induced chorioretinitis: The importance of meticulous assessments.
American journal of ophthalmology case reports
Hassan, M., Maleki, A., Ying, Q., Nguyen, N., Halim, M. S., Sepah, Y. J., Do, D. V., Nguyen, Q. D.
2019; 14: 21–25
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Abstract
Purpose: To report a case of presumed bilateral chorioretinitis secondary to alendronate therapy.Observations: A 71-year-old female presented to the clinic in July 2017 with six months history of difficulty in reading along with floaters in both eyes which were more severe in the right eye. Past medical and surgical history revealed a history of hypertension, gout, hyperthyroidism, osteoporosis, and humerus fracture. She was started on alendronate three months before developing ocular symptoms. On ocular examination, best corrected visual acuity was 20/30 in the right and 20/25 in the left eye. Slit-lamp examination demonstrated normal anterior chamber examination in both eyes. Dilated fundus examination revealed geographic chorioretinal lesions around the optic nerve head in both eyes, more extensively in the right eye; and superior and temporal to the macula in the right eye. Past ocular records in February 2015 did not reveal any such findings. Fundus autofluorescence demonstrated hyper-autofluorescence in the peripapillary lesions in both eyes. The lesion adjacent to the macula in right eye displayed mixed hyper and hypo-autofluorescence. Fluorescein angiography showed combined hyper- and hypo-fluorescence compatible with window defect, staining and blockage. However, no leakage was appreciated in the macula, peripapillary, and peripheral lesions in both eyes. Optical coherence tomography scan showed septate hyporeflective intraretinal spaces in the right eye.Conclusion and importance: The index report underscore the importance of considering alendronate as an etiologic cause of chorioretinitis, especially in subjects with atypical lesions developing after alendronate therapy. We, therefore, recommend discontinuation of this medication in subjects who develop chorioretinitis after employing this medication.
View details for PubMedID 30809598
Publications
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Robust real-time estimation of non-uniform angular velocity and sub-pixel jitter in images captured with resonant scanners
OPTICS EXPRESS
Ayubi, G. A., Dubra, A.
2023; 31 (26): 44199-44211
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Abstract
Images captured with resonant scanners are affected by angular velocity fluctuations that result in image distortion and by poor synchronization between scanning and light detection that creates jitter between image rows. We previously demonstrated that both problems can be mitigated in post-processing by recording the scanner orientation in synchrony with the image capture, followed by data resampling [Opt. Express30, 112 (2022)10.1364/OE.446162]. Here we introduce more robust algorithms for estimation of both angular velocity fluctuation and jitter in the presence of random and deterministic noise. We also show linearization of the scanner oscillation model to reduce calculation times by two orders of magnitude, reaching 65,000 jitter estimations per second when using 2,800 samples per image row, and 500,000 when using only 500 samples, easily supporting real-time generation of jitter-corrected images.
View details for DOI 10.1364/OE.512233
View details for Web of Science ID 001155832000005
View details for PubMedID 38178497
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Structural and Functional Changes in Non-Paraneoplastic Autoimmune Retinopathy.
Diagnostics (Basel, Switzerland)
Akhavanrezayat, A., Khatri, A., Onghanseng, N. G., Halim, M. S., Or, C., Sredar, N., Razeen, M., Hasanreisoglu, M., Regenold, J., Thng, Z. X., Mohammadi, S. S., Jain, T., Yavari, N., Bazojoo, V., Gupta, A. S., Mobasserian, A., Yasar, C., Than, N. T., Uludag Kirimli, G., Karaca, I., Shin, Y., Yoo, W., Ghoraba, H., Do, D. V., Dubra, A., Nguyen, Q. D.
2023; 13 (21)
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Abstract
BACKGROUND: To describe longitudinal changes in patients with non-paraneoplastic autoimmune retinopathy (npAIR) by utilizing different diagnostic modalities/tests.METHODS: The index study is a retrospective longitudinal review of sixteen eyes of eight patients from a tertiary care eye hospital diagnosed with npAIR. Multiple diagnostic modalities such as wide-angle fundus photography (WAFP), WA fundus autofluorescence (WAFAF), spectral-domain optical coherence tomography (SD-OCT), Goldmann visual field (GVF) perimetry, microperimetry (MP), electrophysiologic testing, and adaptive optics scanning laser ophthalmoscopy (AOSLO) were reviewed and analyzed.RESULTS: At the baseline visits, anomalies were detected by multimodal diagnostic tests on all patients. Subjects were followed up for a median duration of 11.5 [3.0-18.7] months. Structural changes at the baseline were detected in 14 of 16 (87.5%) eyes on WAFP and WAFAF and 13 of 16 (81.2%) eyes on SD-OCT. Eight of the ten (80%) eyes that underwent AOSLO imaging depicted structural changes. Functional changes were detected in 14 of 16 (87.5%) eyes on GVF, 15 of 16 (93.7%) eyes on MP, and 11 of 16 (68.7%) eyes on full-field electroretinogram (ff-ERG). Multifocal electroretinogram (mf-ERG) and visual evoked potential (VEP) tests were performed in 14 eyes, of which 12 (85.7%) and 14 (100%) of the eyes demonstrated functional abnormalities, respectively, at baseline. Compared to all the other structural diagnostic tools, AOSLO had a better ability to demonstrate deterioration in retinal microstructures occurring at follow-ups. Functional deterioration at follow-up was detected on GVF in 8 of 10 (80%) eyes, mf-ERG in 4 of 8 (50%) eyes, and MP in 7 of 16 (43.7%) eyes. The ff-ERG and VEP were stable in the majority of cases at follow-up.CONCLUSIONS: The utilization of multimodal imaging/tests in the diagnosing and monitoring of npAIR patients can aid in identifying anomalous changes over time. Analysis of both the anatomical and functional aspects by these devices can be supportive of detecting the changes early in such patients. AOSLO shows promise as it enables the capture of high-resolution images demonstrating quantifiable changes to retinal microstructure.
View details for DOI 10.3390/diagnostics13213376
View details for PubMedID 37958272
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Invited Session V: The eye as a window to systemic and neurodegenerative health: Seeking Answers through a keyhole: Harnessing the Synergy of Dynamic OCT/OCT Angiography and Adaptive Optics SLO for Retinal Assessment of Systemic Disease.
Journal of vision
Rosen, R., Otero-Marquez, O., Migacz, J., Zhou, D., Pinhas, A., Castanos, M., Ahsanuddin, S., Rickford, K., Murillo, B., Zhou, R., Spellman, L., Sredar, N., Gillette, P., Weitz, R., Glassberg, J., Dubra, A., Chui, T.
2023; 23 (11): 30
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Abstract
The retina is our only non-invasive access to microworld of the body's capillaries and cellular activities. Leveraging the multimodal synergy of combining dynamic methods of OCT/OCTA, with Adaptive Optics SLO, clinicians have new opportunities to better appreciate some of the complexities of human disease. Serial OCTA imaging can reveal inconsistencies in retinal perfusion not appreciated on single images and can be used to measure activity status of sickle cell microvasculopathy. This approach facilitates earlier detection and immediate assessment of disease burden. AOSLO imaging provides cellular level resolution for confirmation of these OCTA events. En face OCT reflectance images which accompany OCTA studies offer a glimpse of the macrophage-like cellular activity above the retinal surface which responds to systemically instigated vascular events below. The complementary use of AOSLO to characterize morphology of these cells provides clues to their activation status and potential role in tissue maintenance and repair. Features of clinical OCT/OCTA interpreted by AOSLO imaging have the potential to become useful clinical biomarkers of disease activity and response to treatment.
View details for DOI 10.1167/jov.23.11.30
View details for PubMedID 37733548
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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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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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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
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Silicone Oil-Induced Ocular Hypertension Glaucoma Model (SOHU) in Rodent and Nonhuman Primate.
Methods in molecular biology (Clifton, N.J.)
Fang, F., Zhang, J., Hu, Y.
2023; 2708: 57-69
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In this chapter, we describe a clinically relevant inducible and reversible ocular hypertension glaucoma model, which mimics the secondary glaucoma that can be a postoperative complication when silicone oil (SO) is used as a tamponade agent in human vitreoretinal surgery. First, we detail the procedures for generating SO-induced ocular hypertension (SOHU) in mouse and describe the two variations of this model that simulate common but distinct glaucoma types. We also describe separately the related procedures for measuring IOP and removing SO to return IOP to normal. Lastly, we describe the extension of the SOHU model in nonhuman primate (NHP), which recapitulates the severe neurodegeneration of acute human glaucoma but with unique dynamic changes of IOP due to the tolerance of the NHP ciliary body. The SOHU glaucoma model is, therefore, suitable for assessing experimental therapies for neuroprotection and regeneration, with or without treatment to lower IOP (SO removal), and consequently for translating relevant findings into novel and effective clinical treatments for glaucoma and other neurodegenerations. This model is straightforward, does not require special equipment or repetitive procedures, closely simulates clinical situations, and may be applicable to diverse animal species although minor modifications may be required.
View details for DOI 10.1007/978-1-0716-3409-7_7
View details for PubMedID 37558960
View details for PubMedCentralID 5584058
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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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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
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A molecular switch for neuroprotective astrocyte reactivity.
Nature
Cameron, E. G., Nahmou, M., Toth, A. B., Heo, L., Tanasa, B., Dalal, R., Yan, W., Nallagatla, P., Xia, X., Hay, S., Knasel, C., Stiles, T. L., Douglas, C., Atkins, M., Sun, C., Ashouri, M., Bian, M., Chang, K. C., Russano, K., Shah, S., Woodworth, M. B., Galvao, J., Nair, R. V., Kapiloff, M. S., Goldberg, J. L.
2023
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The intrinsic mechanisms that regulate neurotoxic versus neuroprotective astrocyte phenotypes and their effects on central nervous system (CNS) degeneration and repair remain poorly understood. Here, we show injured white matter astrocytes differentiate into two distinct C3-positive and C3-negative reactive populations, previously simplified as neurotoxic (A1) and neuroprotective (A2)1,2, which can be further subdivided into unique subpopulations defined by proliferation and differential gene expression signatures. We find the balance of neurotoxic versus neuroprotective astrocytes is regulated by discrete pools of compartmented cAMP derived from soluble adenylyl cyclase (sAC) and show proliferating neuroprotective astrocytes inhibit microglial activation and downstream neurotoxic astrocyte differentiation to promote retinal ganglion cell (RGC) survival. Finally, we report a new, therapeutically tractable viral vector to specifically target optic nerve head astrocytes and show elevating nuclear or depleting cytoplasmic cAMP in reactive astrocytes inhibits deleterious microglial/macrophage cell activation and promotes RGC survival after optic nerve injury. Thus, soluble adenylyl cyclase and compartmented, nuclear- and cytoplasmic-localized cAMP in reactive astrocytes act as a molecular switch for neuroprotective astrocyte reactivity that can be targeted to inhibit microglial activation and neurotoxic astrocyte differentiation to therapeutic effect. These data expand upon and define new reactive astrocyte subtypes and represent a novel step toward the development of gliotherapeutics for the treatment of glaucoma and other optic neuropathies.
View details for DOI 10.1038/s41586-023-06935-3
View details for PubMedID 38086421
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Differential expression of PIEZO1 and PIEZO2 mechanosensitive channels in ocular tissues implicates diverse functional roles.
Experimental eye research
Zhu, Y., Garcia-Sanchez, J., Dalal, R., Sun, Y., Kapiloff, M. S., Goldberg, J. L., Liu, W. W.
2023: 109675
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PIEZO1 and PIEZO2 are mechanosensitive ion channels that regulate many important physiological processes including vascular blood flow, touch, and proprioception. As the eye is subject to mechanical stress and is highly perfused, these channels may play important roles in ocular function and intraocular pressure regulation. PIEZO channel expression in the eye has not been well defined, in part due to difficulties in validating available antibodies against PIEZO1 and PIEZO2 in ocular tissues. It is also unclear if PIEZO1 and PIEZO2 are differentially expressed. To address these questions, we used single-molecule fluorescence in situ hybridization (smFISH) together with transgenic reporter mice expressing PIEZO fusion proteins under the control of their endogenous promoters to compare the expression and localization of PIEZO1 and PIEZO2 in mouse ocular tissues relevant to glaucoma. We detected both PIEZO1 and PIEZO2 expression in the trabecular meshwork, ciliary body, and in the ganglion cell layer (GCL) of the retina. Piezo1 mRNA was more abundantly expressed than Piezo2 mRNA in these ocular tissues. Piezo1 but not Piezo2 mRNA was detected in the inner nuclear layer and outer nuclear layer of the retina. Our results suggest that PIEZO1 and PIEZO2 are differentially expressed and may have distinct roles as mechanosensors in glaucoma-relevant ocular tissues.
View details for DOI 10.1016/j.exer.2023.109675
View details for PubMedID 37820892
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Dock10 Regulates Cardiac Function under Neurohormonal Stress
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
Segal, L., Etzion, S., Elyagon, S., Shahar, M., Klapper-Goldstein, H., Levitas, A., Kapiloff, M. S., Parvari, R., Etzion, Y.
2022; 23 (17)
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Dedicator of cytokinesis 10 (Dock10) is a guanine nucleotide exchange factor for Cdc42 and Rac1 that regulates the JNK (c-Jun N-terminal kinase) and p38 MAPK (mitogen-activated protein kinase) signaling cascades. In this study, we characterized the roles of Dock10 in the myocardium. In vitro: we ablated Dock10 in neonatal mouse floxed Dock10 cardiomyocytes (NMCMs) and cardiofibroblasts (NMCFs) by transduction with an adenovirus expressing Cre-recombinase. In vivo, we studied mice in which the Dock10 gene was constitutively and globally deleted (Dock10 KO) and mice with cardiac myocyte-specific Dock10 KO (Dock10 CKO) at baseline and in response to two weeks of Angiotensin II (Ang II) infusion. In vitro, Dock10 ablation differentially inhibited the α-adrenergic stimulation of p38 and JNK in NMCM and NMCF, respectively. In vivo, the stimulation of both signaling pathways was markedly attenuated in the heart. The Dock10 KO mice had normal body weight and cardiac size. However, echocardiography revealed mildly reduced systolic function, and IonOptix recordings demonstrated reduced contractility and elevated diastolic calcium levels in isolated cardiomyocytes. Remarkably, Dock10 KO, but not Dock10 CKO, exaggerated the pathological response to Ang II infusion. These data suggest that Dock10 regulates cardiac stress-related signaling. Although Dock10 can regulate MAPK signaling in both cardiomyocytes and cardiofibroblasts, the inhibition of pathological cardiac remodeling is not apparently due to the Dock10 signaling in the cardiomyocyte.
View details for DOI 10.3390/ijms23179616
View details for Web of Science ID 000851094300001
View details for PubMedID 36077014
View details for PubMedCentralID PMC9455810
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Macular dystrophy in Kabuki syndrome due to de novo KMT2D variants: refining the phenotype with multimodal imaging and follow-up over 10 years: insight into pathophysiology.
Graefe's archive for clinical and experimental ophthalmology = Albrecht von Graefes Archiv fur klinische und experimentelle Ophthalmologie
Vaclavik, V., Navarro, A., Jacot-Guillarmod, A., Bottani, A., Sun, Y. J., Franco, J. A., Mahajan, V. B., Smirnov, V., Bouvet-Drumare, I.
2024
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BACKGROUND: Kabuki Syndrome is a rare and genetically heterogenous condition with both ophthalmic and systemic complications and typical facial features. We detail the macular phenotype in two unrelated patients with Kabuki syndrome due to de novo nonsense variants in KMT2D, one novel. A follow-up of 10 years is reported. Pathogenicity of both de novo nonsense variants is analyzed.METHODS: Four eyes of two young patients were studied by full clinical examination, kinetic perimetry, short wavelength autofluorescence, full field (ff) ERGs, and spectral-domain optical coherence tomography (SD-OCT). One patient had adaptive optic (AO) imaging. Whole exome sequencing was performed in both patients.RESULTS: Both patients had de novo nonsense variants in KMTD2. One patient had c.14843C>G; p. (Ser4948ter) novel variant and the second c.11119C>T; p. (Arg3707ter). Both had a stable Snellen visual acuity of 0.2-0.3. The retinal multimodal imaging demonstrated abnormalities at the fovea in both eyes: hyperreflectivity to blue light and a well-delimited gap-disruption of ellipsoid and interdigitation layer on OCT. The dark area on AO imaging is presumed to be absent for, or with structural change to photoreceptors. The ff ERGs and kinetic visual fields were normal. The foveal findings remained stable over several years.CONCLUSION: Kabuki syndrome-related maculopathy is a distinct loss of photoreceptors at the fovea as shown by multimodal imaging including, for the first time, AO imaging. This report adds to the literature of only one case with maculopathy with two additional macular dystrophies in patients with Kabuki syndrome. Although underestimated, these cases further raise awareness of the potential impact of retinal manifestations of Kabuki syndrome not only among ophthalmologists but also other healthcare professionals involved in the care of patients with this multisystem disorder.
View details for DOI 10.1007/s00417-023-06345-1
View details for PubMedID 38206414
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Liquid Biopsy Proteomics in Ophthalmology.
Journal of proteome research
Wolf, J., Franco, J. A., Yip, R., Dabaja, M. Z., Velez, G., Liu, F., Bassuk, A. G., Mruthyunjaya, P., Dufour, A., Mahajan, V. B.
2024
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Minimally invasive liquid biopsies from the eye capture locally enriched fluids that contain thousands of proteins from highly specialized ocular cell types, presenting a promising alternative to solid tissue biopsies. The advantages of liquid biopsies include sampling the eye without causing irreversible functional damage, potentially better reflecting tissue heterogeneity, collecting samples in an outpatient setting, monitoring therapeutic response with sequential sampling, and even allowing examination of disease mechanisms at the cell level in living humans, an approach that we refer to as TEMPO (Tracing Expression of Multiple Protein Origins). Liquid biopsy proteomics has the potential to transform molecular diagnostics and prognostics and to assess disease mechanisms and personalized therapeutic strategies in individual patients. This review addresses opportunities, challenges, and future directions of high-resolution liquid biopsy proteomics in ophthalmology, with particular emphasis on the large-scale collection of high-quality samples, cutting edge proteomics technology, and artificial intelligence-supported data analysis.
View details for DOI 10.1021/acs.jproteome.3c00756
View details for PubMedID 38171013
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AI-Human Hybrid Workflow Enhances Teleophthalmology for the Detection of Diabetic Retinopathy.
Ophthalmology science
Dow, E. R., Khan, N. C., Chen, K. M., Mishra, K., Perera, C., Narala, R., Basina, M., Dang, J., Kim, M., Levine, M., Phadke, A., Tan, M., Weng, K., Do, D. V., Moshfeghi, D. M., Mahajan, V. B., Mruthyunjaya, P., Leng, T., Myung, D.
2023; 3 (4): 100330
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Detection of diabetic retinopathy (DR) outside of specialized eye care settings is an important means of access to vision-preserving health maintenance. Remote interpretation of fundus photographs acquired in a primary care or other nonophthalmic setting in a store-and-forward manner is a predominant paradigm of teleophthalmology screening programs. Artificial intelligence (AI)-based image interpretation offers an alternative means of DR detection. IDx-DR (Digital Diagnostics Inc) is a Food and Drug Administration-authorized autonomous testing device for DR. We evaluated the diagnostic performance of IDx-DR compared with human-based teleophthalmology over 2 and a half years. Additionally, we evaluated an AI-human hybrid workflow that combines AI-system evaluation with human expert-based assessment for referable cases.Prospective cohort study and retrospective analysis.Diabetic patients ≥ 18 years old without a prior DR diagnosis or DR examination in the past year presenting for routine DR screening in a primary care clinic.Macula-centered and optic nerve-centered fundus photographs were evaluated by an AI algorithm followed by consensus-based overreading by retina specialists at the Stanford Ophthalmic Reading Center. Detection of more-than-mild diabetic retinopathy (MTMDR) was compared with in-person examination by a retina specialist.Sensitivity, specificity, accuracy, positive predictive value, and gradability achieved by the AI algorithm and retina specialists.The AI algorithm had higher sensitivity (95.5% sensitivity; 95% confidence interval [CI], 86.7%-100%) but lower specificity (60.3% specificity; 95% CI, 47.7%-72.9%) for detection of MTMDR compared with remote image interpretation by retina specialists (69.5% sensitivity; 95% CI, 50.7%-88.3%; 96.9% specificity; 95% CI, 93.5%-100%). Gradability of encounters was also lower for the AI algorithm (62.5%) compared with retina specialists (93.1%). A 2-step AI-human hybrid workflow in which the AI algorithm initially rendered an assessment followed by overread by a retina specialist of MTMDR-positive encounters resulted in a sensitivity of 95.5% (95% CI, 86.7%-100%) and a specificity of 98.2% (95% CI, 94.6%-100%). Similarly, a 2-step overread by retina specialists of AI-ungradable encounters improved gradability from 63.5% to 95.6% of encounters.Implementation of an AI-human hybrid teleophthalmology workflow may both decrease reliance on human specialist effort and improve diagnostic accuracy.Proprietary or commercial disclosure may be found after the references.
View details for DOI 10.1016/j.xops.2023.100330
View details for PubMedID 37449051
View details for PubMedCentralID PMC10336195
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Functional Visual Disorder Is Primarily a Psychiatric Condition.
Journal of neuro-ophthalmology : the official journal of the North American Neuro-Ophthalmology Society
Trobe, J. D., Moss, H. E., Lee, A. G., Van Stavern, G. P.
2024
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View details for DOI 10.1097/WNO.0000000000002121
View details for PubMedID 38526629
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Multi-registry analysis of patients with multiple sclerosis and neuromyelitis optica to improve capture of demographic data and compare visual outcomes.
Multiple sclerosis and related disorders
Moss, H. E., Wiener, L., Rizy, C., Baxi, S., Kocher, M., Torres, A. Z., Mbagwu, M.
2024; 84: 105499
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IMPORTANCE: The American Academy of Neurology Axon Registry provides real-world data for patients with multiple sclerosis and neuro-myelitis optica. However, some data are incomplete (e.g. demographics) and some relevant outcomes are not systematically captured in neurology documentation (e.g. visual acuity). The American Academy of Ophthalmology IRIS Registry (Intelligent Research in Sight) contains demographic and visual function data that may complement Axon Registry-derived data to enhance understanding of real-world visual outcomes in neurological disease.OBJECTIVE: To combine Axon Registry and IRIS Registry data to reduce missingness of demographic information and characterize visual outcomes in patients with multiple sclerosis and neuro-myelitis optica.DESIGN: Cross-sectional study.SETTING: Outpatient neurology and ophthalmology clinical practices.PARTICIPANTS: Patients participating in both registries between January 1, 2014 through December 10, 2021 were included if they had repeat ICD-9/10 codes for with multiple sclerosis or neuro-myelitis optica in the Axon registry.EXPOSURE: Diagnosis (multiple sclerosis or neuro-myelitis optica).MAIN OUTCOME AND MEASURE: Age, sex, race and ethnicity were assessed in the individual registries and classified as conflicting, missing, or not missing in the combined data set. The IRIS Registry contributed visual acuity data.RESULTS: Among 60,316 patients with multiple sclerosis and 1,068 patients with neuro-myelitis optica in the Axon Registry, 14,085 and 252 had temporal overlap in the IRIS Registry. Combining data reduced missing or conflicting data for race and ethnicity by 15-19 % (absolute reduction, all p ≤ 0.0005), but not age (p = 1.0) or gender (p = 0.08). 10,907 patients with MS and 142 with NMO had visual acuity data in the IRIS Registry. Visual acuity averaged between eyes was worse in patients with NMO after adjusting for age and gender (0.17 logMAR, 95 %CI 0.12,0.21, p < 0.0005).CONCLUSION AND RELEVANCE: Using data from two registries reduced missing data for race and ethnicity and enabled examination of outcomes captured in the IRIS Registry for conditions that are diagnosed more frequently in the Axon Registry, demonstrating the utility of a multi-registry analysis.
View details for DOI 10.1016/j.msard.2024.105499
View details for PubMedID 38387161
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Which OCT Measure of the Optic Nerve Head Improves Fastest? Towards Optimizing Early Detection of Resolving Papilledema in Children.
Translational vision science & technology
Majmudar, T. V., Moss, H. E., Avery, R. A.
2024; 13 (1): 12
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Optical coherence tomography (OCT) has been used to monitor papilledema. This study aims to determine which OCT-derived measures of the optic nerve head (ONH) detect resolving papilledema in children faster than standard OCT measures.Children (≤18 years of age) with papilledema who completed optic nerve SD-OCT pretreatment and had evidence of treatment response on one or more follow-up OCTs within 4 months were included. Standard (mean circumpapillary retinal nerve fiber layer [cpRNFL] thickness), device-derived (per-quadrant cpRNFL) and custom (ONH height, maximum Bruch's membrane displacement [BMD], ONH volume [ONHV], and BMD volume) OCT measures were calculated. Per-eye generalized estimating equations (GEEs) modelled changes in device-derived and custom measures as a function of mean cpRNFL to identify those measures that resolved faster during early (0-2 months) follow-up. Mean cpRNFL coefficients of greater than 1 indicated faster resolving papilledema.We included 52 eyes of 29 children (mean age, 12.8 years; 72.4% female). In analysis of early follow-up visits (38 eyes from 22 children), nasal cpRNFL and maximum BMD in each quadrant resolved faster than mean cpRNFL (GEE coefficients range, 1.14-3.37). Inferior cpRNFL, superior, nasal, and inferior ONH heights and ONHV resolved slower than mean cpRNFL (GEE coefficients range, 0.67-0.87).Nasal cpRNFL is a promising device-derived OCT measure for the early detection of resolving papilledema in children compared with mean cpRNFL. Maximum BMD, a custom measure, also shows promise, but its calculation has not yet been incorporated into commercial OCT devices.This study guides the optimal use of OCT in capturing resolving papilledema in children.
View details for DOI 10.1167/tvst.13.1.12
View details for PubMedID 38224329
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Electrospun Nanofiber Membrane for Cultured Corneal Endothelial Cell Transplantation.
Bioengineering (Basel, Switzerland)
Song, E., Chen, K. M., Margolis, M. S., Wungcharoen, T., Koh, W., Myung, D.
2024; 11 (1)
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The corneal endothelium, comprising densely packed corneal endothelial cells (CECs) adhering to Descemet's membrane (DM), plays a critical role in maintaining corneal transparency by regulating water and ion movement. CECs have limited regenerative capacity within the body, and globally, there is a shortage of donor corneas to replace damaged corneal endothelia. The development of a carrier for cultured CECs may address this worldwide clinical need. In this study we successfully manufactured a gelatin nanofiber membrane (gelNF membrane) using electrospinning, followed by crosslinking with glutaraldehyde (GA). The fabricated gelNF membrane exhibited approximately 80% transparency compared with glass and maintained a thickness of 20 m. The gelNF membrane demonstrated desirable permeability and degradability for a Descemet's membrane analog. Importantly, CECs cultured on the gelNF membrane at high densities showed no cytotoxic effects, and the expression of key CEC functional biomarkers was verified. To assess the potential of this gelNF membrane as a carrier for cultured CEC transplantation, we used it to conduct Descemet's membrane endothelial keratoplasty (DMEK) on rabbit eyes. The outcomes suggest this gelNF membrane holds promise as a suitable carrier for cultured CEC transplantation, offering advantages in terms of transparency, permeability, and sufficient mechanical properties required for successful transplantation.
View details for DOI 10.3390/bioengineering11010054
View details for PubMedID 38247931
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Embedded 3d Bioprinting of Collagen Inks into Microgel Baths to control hydrogel Microstructure and Cell Spreading.
Advanced healthcare materials
Brunel, L. G., Christakopoulos, F., Kilian, D., Cai, B., Hull, S. M., Myung, D., Heilshorn, S. C.
2023: e2303325
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Microextrusion-based 3D bioprinting into support baths has emerged as a promising technique to pattern soft biomaterials into complex, macroscopic structures. We hypothesized that interactions between inks and support baths, which are often composed of granular microgels, could be modulated to control the microscopic structure within these macroscopic-printed constructs. Using printed collagen bioinks crosslinked either through physical self-assembly or bioorthogonal covalent chemistry, we demonstrate that microscopic porosity is introduced into collagen inks printed into microgel support baths but not bulk gel support baths. The overall porosity is governed by the ratio between the ink's shear viscosity and the microgel support bath's zero-shear viscosity. By adjusting the flow rate during extrusion, the ink's shear viscosity was modulated, thus controlling the extent of microscopic porosity independent of the ink composition. For covalently crosslinked collagen, printing into support baths comprised of gelatin microgels (15-50 µm) resulted in large pores (∼40 µm) that allowed human corneal mesenchymal stromal cells to readily spread, while control samples of cast collagen or collagen printed in non-granular support baths did not allow cell spreading. Taken together, these data demonstrate a new method to impart controlled microscale porosity into 3D printed hydrogels using granular microgel support baths. This article is protected by copyright. All rights reserved.
View details for DOI 10.1002/adhm.202303325
View details for PubMedID 38134346
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AI-Human Hybrid Workflow Enhances Teleophthalmology for the Detection of Diabetic Retinopathy.
Ophthalmology science
Dow, E. R., Khan, N. C., Chen, K. M., Mishra, K., Perera, C., Narala, R., Basina, M., Dang, J., Kim, M., Levine, M., Phadke, A., Tan, M., Weng, K., Do, D. V., Moshfeghi, D. M., Mahajan, V. B., Mruthyunjaya, P., Leng, T., Myung, D.
2023; 3 (4): 100330
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Abstract
Detection of diabetic retinopathy (DR) outside of specialized eye care settings is an important means of access to vision-preserving health maintenance. Remote interpretation of fundus photographs acquired in a primary care or other nonophthalmic setting in a store-and-forward manner is a predominant paradigm of teleophthalmology screening programs. Artificial intelligence (AI)-based image interpretation offers an alternative means of DR detection. IDx-DR (Digital Diagnostics Inc) is a Food and Drug Administration-authorized autonomous testing device for DR. We evaluated the diagnostic performance of IDx-DR compared with human-based teleophthalmology over 2 and a half years. Additionally, we evaluated an AI-human hybrid workflow that combines AI-system evaluation with human expert-based assessment for referable cases.Prospective cohort study and retrospective analysis.Diabetic patients ≥ 18 years old without a prior DR diagnosis or DR examination in the past year presenting for routine DR screening in a primary care clinic.Macula-centered and optic nerve-centered fundus photographs were evaluated by an AI algorithm followed by consensus-based overreading by retina specialists at the Stanford Ophthalmic Reading Center. Detection of more-than-mild diabetic retinopathy (MTMDR) was compared with in-person examination by a retina specialist.Sensitivity, specificity, accuracy, positive predictive value, and gradability achieved by the AI algorithm and retina specialists.The AI algorithm had higher sensitivity (95.5% sensitivity; 95% confidence interval [CI], 86.7%-100%) but lower specificity (60.3% specificity; 95% CI, 47.7%-72.9%) for detection of MTMDR compared with remote image interpretation by retina specialists (69.5% sensitivity; 95% CI, 50.7%-88.3%; 96.9% specificity; 95% CI, 93.5%-100%). Gradability of encounters was also lower for the AI algorithm (62.5%) compared with retina specialists (93.1%). A 2-step AI-human hybrid workflow in which the AI algorithm initially rendered an assessment followed by overread by a retina specialist of MTMDR-positive encounters resulted in a sensitivity of 95.5% (95% CI, 86.7%-100%) and a specificity of 98.2% (95% CI, 94.6%-100%). Similarly, a 2-step overread by retina specialists of AI-ungradable encounters improved gradability from 63.5% to 95.6% of encounters.Implementation of an AI-human hybrid teleophthalmology workflow may both decrease reliance on human specialist effort and improve diagnostic accuracy.Proprietary or commercial disclosure may be found after the references.
View details for DOI 10.1016/j.xops.2023.100330
View details for PubMedID 37449051
View details for PubMedCentralID PMC10336195
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
Publications
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<i>Fcirc</i> statistic for steady-state evoked potentials; a generalized version of<i> T2circ</i> statistic
BIOMEDICAL SIGNAL PROCESSING AND CONTROL
Norouzpour, A., Roberts, T. L.
2024; 87
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View details for DOI 10.1016/j.bspc.2023.105549
View details for Web of Science ID 001092748300001
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Ocular motor disorders in children and adults with mTBI: a scoping review protocol.
BMJ open
Theis, J., Chen, A. M., Burgher, A. P., Greenspan, L. D., Morgenstern, A., Salzano, A. D., Yap, T. P., Scheiman, M., Roberts, T. L.
2023; 13 (10): e073656
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Abstract
Ocular motor function is susceptible to neurological injury because it requires a large portion of brain circuitry including every lobe of the brain, brainstem, thalamus, basal ganglia, cerebellum, cranial nerves and visual tracts. While reports of a high frequency of ocular motor dysfunctions after mild traumatic brain injury (mTBI) span multidisciplinary journals, there is no scoping review of the signs, diagnostic assessments and criteria, and appropriate management of ocular motor disorders post-mTBI. Post-mTBI ocular motor dysfunction has been reported to respond to active treatment. The objective of this scoping review is to map the available evidence on the diagnostic assessment and treatment modalities currently used in the management of mTBI-related ocular motor disorders in children and adults. This scoping review also aims to identify gaps in the current literature and provide suggestions for future research.This review will include populations with reported concussion and/or mTBI without restrictions on age, race, sex or time since injury. The review will evaluate the reported symptoms related to ocular motor dysfunction, types of assessments and diagnostic criteria used, reported treatments, and the level of evidence supporting the reported treatments. This review will exclude literature on brain injury of non-traumatic aetiology and moderate/severe traumatic brain injury. Ocular motor dysfunction after mTBI appears in journals across multiple disciplines. Thus, multiple databases will be evaluated including Pubmed, Embase, PEDro, OVID, Clinical Key, Google Scholar and REHABDATA. Literature will be searched from inception to present day. Evidence sources will include experimental study designs including randomised controlled trials, non-randomised controlled trials and interrupted time-series. Additionally, analytical observational studies including prospective and retrospective cohort studies, case series, cross-sectional studies and clinical practice guidelines will be considered for inclusion. Data will be extracted on clinical presentation, frequency, assessment, diagnostic criteria management strategies and outcomes of concussion and mTBI-related ocular motor disorders.This scoping review will use data from existing publications and does not require ethical approval by an institutional review board. Results will be disseminated through publication in a peer-reviewed scientific journal and presented at relevant conferences and as part of future workshops with professionals involved with diagnosis and management of patients with mTBI.
View details for DOI 10.1136/bmjopen-2023-073656
View details for PubMedID 37857540
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Low-Dose 0.01% Atropine Eye Drops vs Placebo for Myopia Control: A Randomized Clinical Trial.
JAMA ophthalmology
Repka, M. X., Weise, K. K., Chandler, D. L., Wu, R., Melia, B. M., Manny, R. E., Kehler, L. A., Jordan, C. O., Raghuram, A., Summers, A. I., Lee, K. A., Petersen, D. B., Erzurum, S. A., Pang, Y., Lenhart, P. D., Ticho, B. H., Beck, R. W., Kraker, R. T., Holmes, J. M., Cotter, S. A., Pediatric Eye Disease Investigator Group, Alexopoulous, D. D., Allen, M., Anderson, H. A., Austin, D. S., Black, S. C., Boyle, N. M., Casey, G. A., Chandler, M. A., Chinn, R., Clausius, D. A., Colon, B. J., Conner, C. L., Curtis, L. T., Dinani, Z., Donahue, Q., Dubois, M., Evans, P. L., Fimbel, B. P., Fowler, M. K., Golden, R. P., Harper, B. G., Henderson, R. J., Ho, D., Hoepner, J. E., Hopkins, K. B., Jenks, A. S., Kaplon, J. D., Khan, S., Koutnik, C. A., Kuo, A. F., Lee, J., Martinez, M. M., Marusic, S. M., McGregor, M. L., McMurtrey, J. R., Miller, K. B., Mokka, P. L., Montejo, J., Morrell, B. A., Nylin, E., Odom, K. C., Ortiz, G., Parra, S. A., Perkins, K. J., Plum, L. W., Redenbo, E. F., Robinson, J. L., Stutz, K. M., Sutherland, D. R., Teodorescu, M. X., Torgensen, L. L., Toro, D. O., Turner, P. B., Weil, N. C., Wiecek, E. K., Wilkins, C. S., Woodard, V. C., Woodruff, K. M., Yin, H., Yumang, M. L., Yamada, T., Ekdawi, N. S., Leske, D. A., Wallace, D. K., Christian, M. L., Glaser, S. R., Birch, E. E., Chen, A. M., Christiansen, S. P., Enyedi, L. B., Everett, D. F., Freedman, S. F., Good, W. V., Jenewein, E. C., London, R., Manh, V. M., Morrison, D. G., Pineles, S. L., Ralay Ranaivo, H., Roberts, T. L., Ruark, S. T., Schweinler, B. R., Silver, J. L., Suh, D. W., Verderber, L. C., Diener-West, M., Baker, J. D., Davis, B., Higgins, R. D., Poff, S. W., Saunders, R. A., Tychsen, L.
2023
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Abstract
Importance: Controlling myopia progression is of interest worldwide. Low-dose atropine eye drops have slowed progression in children in East Asia.Objective: To compare atropine, 0.01%, eye drops with placebo for slowing myopia progression in US children.Design, Setting, and Participants: This was a randomized placebo-controlled, double-masked, clinical trial conducted from June 2018 to September 2022. Children aged 5 to 12 years were recruited from 12 community- and institution-based practices in the US. Participating children had low to moderate bilateral myopia (-1.00 diopters [D] to -6.00 D spherical equivalent refractive error [SER]).Intervention: Eligible children were randomly assigned 2:1 to 1 eye drop of atropine, 0.01%, nightly or 1 drop of placebo. Treatment was for 24 months followed by 6 months of observation.Main Outcome Measures: Automated cycloplegic refraction was performed by masked examiners. The primary outcome was change in SER (mean of both eyes) from baseline to 24 months (receiving treatment); other outcomes included change in SER from baseline to 30 months (not receiving treatment) and change in axial length at both time points. Differences were calculated as atropine minus placebo.Results: A total of 187 children (mean [SD] age, 10.1 [1.8] years; age range, 5.1-12.9 years; 101 female [54%]; 34 Black [18%], 20 East Asian [11%], 30 Hispanic or Latino [16%], 11 multiracial [6%], 6 West/South Asian [3%], 86 White [46%]) were included in the study. A total of 125 children (67%) received atropine, 0.01%, and 62 children (33%) received placebo. Follow-up was completed at 24 months by 119 of 125 children (95%) in the atropine group and 58 of 62 children (94%) in the placebo group. At 30 months, follow-up was completed by 118 of 125 children (94%) in the atropine group and 57 of 62 children (92%) in the placebo group. At the 24-month primary outcome visit, the adjusted mean (95% CI) change in SER from baseline was -0.82 (-0.96 to -0.68) D and -0.80 (-0.98 to -0.62) D in the atropine and placebo groups, respectively (adjusted difference=-0.02 D; 95% CI, -0.19 to +0.15 D; P=.83). At 30 months (6 months not receiving treatment), the adjusted difference in mean SER change from baseline was -0.04 D (95% CI, -0.25 to +0.17 D). Adjusted mean (95% CI) changes in axial length from baseline to 24 months were 0.44 (0.39-0.50) mm and 0.45 (0.37-0.52) mm in the atropine and placebo groups, respectively (adjusted difference = -0.002 mm; 95% CI, -0.106 to 0.102 mm). Adjusted difference in mean axial elongation from baseline to 30 months was +0.009 mm (95% CI, -0.115 to 0.134 mm).Conclusions and Relevance: In this randomized clinical trial of school-aged children in the US with low to moderate myopia, atropine, 0.01%, eye drops administered nightly when compared with placebo did not slow myopia progression or axial elongation. These results do not support use of atropine, 0.01%, eye drops to slow myopia progression or axial elongation in US children.Trial Registration: ClinicalTrials.gov Identifier: NCT03334253.
View details for DOI 10.1001/jamaophthalmol.2023.2855
View details for PubMedID 37440213
Publications
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Crosstalk between the mTOR pathway and primary cilia in human diseases.
Current topics in developmental biology
Prosseda, P. P., Dannewitz Prosseda, S., Tran, M., Liton, P. B., Sun, Y.
2023; 155: 1-37
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Abstract
Autophagy is a fundamental catabolic process whereby excessive or damaged cytoplasmic components are degraded through lysosomes to maintain cellular homeostasis. Studies of mTOR signaling have revealed that mTOR controls biomass generation and metabolism by modulating key cellular processes, including protein synthesis and autophagy. Primary cilia, the assembly of which depends on kinesin molecular motors, serve as sensory organelles and signaling platforms. Given these pathways' central role in maintaining cellular and physiological homeostasis, a connection between mTOR and primary cilia signaling is starting to emerge in a variety of diseases. In this review, we highlight recent advances in our understanding of the complex crosstalk between the mTOR pathway and cilia and discuss its function in the context of related diseases.
View details for DOI 10.1016/bs.ctdb.2023.09.004
View details for PubMedID 38043949
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Differential expression of PIEZO1 and PIEZO2 mechanosensitive channels in ocular tissues implicates diverse functional roles.
Experimental eye research
Zhu, Y., Garcia-Sanchez, J., Dalal, R., Sun, Y., Kapiloff, M. S., Goldberg, J. L., Liu, W. W.
2023: 109675
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Abstract
PIEZO1 and PIEZO2 are mechanosensitive ion channels that regulate many important physiological processes including vascular blood flow, touch, and proprioception. As the eye is subject to mechanical stress and is highly perfused, these channels may play important roles in ocular function and intraocular pressure regulation. PIEZO channel expression in the eye has not been well defined, in part due to difficulties in validating available antibodies against PIEZO1 and PIEZO2 in ocular tissues. It is also unclear if PIEZO1 and PIEZO2 are differentially expressed. To address these questions, we used single-molecule fluorescence in situ hybridization (smFISH) together with transgenic reporter mice expressing PIEZO fusion proteins under the control of their endogenous promoters to compare the expression and localization of PIEZO1 and PIEZO2 in mouse ocular tissues relevant to glaucoma. We detected both PIEZO1 and PIEZO2 expression in the trabecular meshwork, ciliary body, and in the ganglion cell layer (GCL) of the retina. Piezo1 mRNA was more abundantly expressed than Piezo2 mRNA in these ocular tissues. Piezo1 but not Piezo2 mRNA was detected in the inner nuclear layer and outer nuclear layer of the retina. Our results suggest that PIEZO1 and PIEZO2 are differentially expressed and may have distinct roles as mechanosensors in glaucoma-relevant ocular tissues.
View details for DOI 10.1016/j.exer.2023.109675
View details for PubMedID 37820892
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Unleashing the potential of CRISPR multiplexing: Harnessing Cas12 and Cas13 for precise gene modulation in eye diseases.
Vision research
Bigini, F., Lee, S. H., Sun, Y. J., Sun, Y., Mahajan, V. B.
2023; 213: 108317
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Abstract
Gene therapy is a flourishing field with the potential to revolutionize the treatment of genetic diseases. The emergence of CRISPR-Cas9 has significantly advanced targeted and efficient genome editing. Although CRISPR-Cas9 has demonstrated promising potential applications in various genetic disorders, it faces limitations in simultaneously targeting multiple genes. Novel CRISPR systems, such as Cas12 and Cas13, have been developed to overcome these challenges, enabling multiplexing and providing unique advantages. Cas13, in particular, targets mRNA instead of genomic DNA, permitting precise gene expression control and mitigating off-target effects. This review investigates the potential of Cas12 and Cas13 in ocular gene therapy applications, such as suppression of inflammation and cell death. In addition, the capabilities of Cas12 and Cas13 are explored in addressing potential targets related with disease mechanisms such as aberrant isoforms, mitochondrial genes, cis-regulatory sequences, modifier genes, and long non-coding RNAs. Anatomical accessibility and relative immune privilege of the eye provide an ideal organ system for evaluating these novel techniques' efficacy and safety. By targeting multiple genes concurrently, CRISPR-Cas12 and Cas13 systems hold promise for treating a range of ocular disorders, including glaucoma, retinal dystrophies, and age-related macular degeneration. Nonetheless, additional refinement is required to ascertain the safety and efficacy of these approaches in ocular disease treatments. Thus, the development of Cas12 and Cas13 systems marks a significant advancement in gene therapy, offering the potential to devise effective treatments for ocular disorders.
View details for DOI 10.1016/j.visres.2023.108317
View details for PubMedID 37722240
Publications
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An organism-wide atlas of hormonal signaling based on the mouse lemur single-cell transcriptome.
Nature communications
Liu, S., Ezran, C., Wang, M. F., Li, Z., Awayan, K., Long, J. Z., De Vlaminck, I., Wang, S., Epelbaum, J., Kuo, C. S., Terrien, J., Krasnow, M. A., Ferrell, J. E.
2024; 15 (1): 2188
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Abstract
Hormones mediate long-range cell communication and play vital roles in physiology, metabolism, and health. Traditionally, endocrinologists have focused on one hormone or organ system at a time. Yet, hormone signaling by its very nature connects cells of different organs and involves crosstalk of different hormones. Here, we leverage the organism-wide single cell transcriptional atlas of a non-human primate, the mouse lemur (Microcebus murinus), to systematically map source and target cells for 84 classes of hormones. This work uncovers previously-uncharacterized sites of hormone regulation, and shows that the hormonal signaling network is densely connected, decentralized, and rich in feedback loops. Evolutionary comparisons of hormonal genes and their expression patterns show that mouse lemur better models human hormonal signaling than mouse, at both the genomic and transcriptomic levels, and reveal primate-specific rewiring of hormone-producing/target cells. This work complements the scale and resolution of classical endocrine studies and sheds light on primate hormone regulation.
View details for DOI 10.1038/s41467-024-46070-9
View details for PubMedID 38467625
View details for PubMedCentralID 1540572
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Functional Oculofacial Abstracts.
Ophthalmic plastic and reconstructive surgery
Ali, M. J., Bernardini, F. P., Savar, A., Wu, A. Y., Tawfik, H. A.
2024; 40 (2): 233-234
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View details for DOI 10.1097/IOP.0000000000002612
View details for PubMedID 38427839
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Research productivity and gender of research award recipients in international ophthalmology societies.
BMJ open ophthalmology
Nguyen, A. X., Venkatesh, D. S., Biyani, A., Ratan, S., Youn, G. M., Wu, A. Y.
2024; 9 (1)
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Abstract
The purpose of this study is to assess the research productivity and gender of award recipients of ophthalmology research awards in international societies.This is a retrospective, observational study. The study population included award recipients of research awards from 36 ophthalmologic societies (listed on the International Council of Ophthalmology database) in 99 years (1922-2021). A gender-specific pronoun and a photograph of each award recipient were extracted from professional websites to assign their gender. Research productivity levels were retrieved from the Elsevier Scopus author database. The main outcome measures were gender distribution of award recipients per year, mean h-index per year, mean m-quotient per year, mean h-index by society, and mean m-quotient by society.Out of 2506 recipients for 122 awards, 1897 (75.7%) were men and 609 (24.3%) were women. The proportion of woman recipients increased from 0% in 1922 to 41.0% in 2021. Compared with 2000-2010 (19.8%, 109 of 550), women received a greater proportion of awards (48.4%, 459 of 949) in the last decade, from 2011 to 2021. Furthermore, men more often had greater h-index scores and m-quotient scores.Women received awards (24.3%) at a lower rate than men (75.7%) while also exhibiting lower productivity, supporting the existence of a gender disparity. Our study found that women are under-represented in research awards, and further investigation into award selection processes and gender membership data is recommended.
View details for DOI 10.1136/bmjophth-2023-001323
View details for PubMedID 38417914
View details for PubMedCentralID PMC10900313
Other Stanford Faculty
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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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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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Abstract
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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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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Corrigendum to "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.
2023; 359: 114256
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View details for DOI 10.1016/j.expneurol.2022.114256
View details for PubMedID 36457222
Publications
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Poster Session I: Noninvasive neuromodulation of subcortical visual pathways with transcranial focused ultrasound.
Journal of vision
Ash, R., Mohammadjavadi, M., Butts Pauly, K., Norcia, A.
2023; 23 (15): 23
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Abstract
Transcranial ultrasound stimulation (TUS) is an emerging tool to noninvasively modulate neural activity in deep brain areas. In preparation for our first in-human TUS studies, we targeted TUS to the lateral geniculate nucleus (visual thalamus) in a large mammal (sheep). Full-field light flash stimuli were presented with or without concomitant TUS in randomly interleaved trials. Similar to what has previously observed by Fry et al (Nature 1959) in cats, EEG visual-evoked potentials (VEPs) were reversibly suppressed by TUS to the LGN. No changes in VEPs were observed in sheep who received sham-TUS to a control site in the basal ganglia, ruling out potential transducer auditory-somatosensory confounds. Magnetic resonance acoustic radiation force imaging (MR-ARFI), a technique to measure the ultrasound focus in situ, showed a focal volume of microscopic displacement at the expected target. Excitingly, MR-ARFI predicted the suppressive effect on VEPs in individual subjects, suggesting that MR-ARFI can be used to confirm TUS targeting and estimate neurophysiological impact. We are now translating this paradigm into human, targeting TUS to the LGN while participants perform a contrast detection task with EEG recording of steady-state VEPs. MR-ARFI will be measured to evaluate targeting and estimate TUS dosage in each participant. This work provides the foundation for a dissection of the roles of different subcortical nuclei in different aspects of human vision.
View details for DOI 10.1167/jov.23.15.23
View details for PubMedID 38109625
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Mouse visual cortex as a limited resource system that self-learns an ecologically-general representation.
PLoS computational biology
Nayebi, A., Kong, N. C., Zhuang, C., Gardner, J. L., Norcia, A. M., Yamins, D. L.
2023; 19 (10): e1011506
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Abstract
Studies of the mouse visual system have revealed a variety of visual brain areas that are thought to support a multitude of behavioral capacities, ranging from stimulus-reward associations, to goal-directed navigation, and object-centric discriminations. However, an overall understanding of the mouse's visual cortex, and how it supports a range of behaviors, remains unknown. Here, we take a computational approach to help address these questions, providing a high-fidelity quantitative model of mouse visual cortex and identifying key structural and functional principles underlying that model's success. Structurally, we find that a comparatively shallow network structure with a low-resolution input is optimal for modeling mouse visual cortex. Our main finding is functional-that models trained with task-agnostic, self-supervised objective functions based on the concept of contrastive embeddings are much better matches to mouse cortex, than models trained on supervised objectives or alternative self-supervised methods. This result is very much unlike in primates where prior work showed that the two were roughly equivalent, naturally leading us to ask the question of why these self-supervised objectives are better matches than supervised ones in mouse. To this end, we show that the self-supervised, contrastive objective builds a general-purpose visual representation that enables the system to achieve better transfer on out-of-distribution visual scene understanding and reward-based navigation tasks. Our results suggest that mouse visual cortex is a low-resolution, shallow network that makes best use of the mouse's limited resources to create a light-weight, general-purpose visual system-in contrast to the deep, high-resolution, and more categorization-dominated visual system of primates.
View details for DOI 10.1371/journal.pcbi.1011506
View details for PubMedID 37782673
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Stability of steady-state visual evoked potential contrast response functions.
Psychophysiology
Ash, R. T., Nix, K. C., Norcia, A. M.
2023: e14412
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Abstract
Repetitive sensory stimulation has been shown to induce neuroplasticity in sensory cortical circuits, at least under certain conditions. We measured the plasticity-inducing effect of repetitive contrast-reversal-sweep steady-state visual-evoked potential (ssVEP) stimuli, hoping to employ the ssVEP's high signal-to-noise electrophysiological readout in the study of human visual cortical neuroplasticity. Steady-state VEP contrast-sweep responses were measured daily for 4 days (four 20-trial blocks per day, 20 participants). No significant neuroplastic changes in response amplitude were observed either across blocks or across days. Furthermore, response amplitudes were stable within-participant, with measured across-block and across-day coefficients of variation (CV = SD/mean) of 15-20 ± 2% and 22-25 ± 2%, respectively. Steady-state VEP response phase was also highly stable, suggesting that temporal processing delays in the visual system vary by at most 2-3 ms across blocks and days. While we fail to replicate visual stimulation-dependent cortical plasticity, we show that contrast-sweep steady-state VEPs provide a stable human neurophysiological measure well suited for repeated-measures longitudinal studies.
View details for DOI 10.1111/psyp.14412
View details for PubMedID 37614220
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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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
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Validation of Physics-Based Image Systems Simulation With 3-D Scenes
IEEE SENSORS JOURNAL
Lyu, Z., Goossens, T., Wandell, B., Farrell, J.
2022; 22 (20): 19400-19410
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View details for DOI 10.1109/JSEN.2022.3199699
View details for Web of Science ID 000870341900036
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Visual encoding: Principles and software.
Progress in brain research
Wandell, B. A., Brainard, D. H., Cottaris, N. P.
2022; 273 (1): 199-229
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Abstract
For more than two centuries scientists and engineers have worked to understand and model how the eye encodes electromagnetic radiation (light). We now understand the principles of how light is transmitted through the optics of the eye and encoded by retinal photoreceptors and light-sensitive neurons. In recent years, new instrumentation has enabled scientists to measure the specific parameters of the optics and photoreceptor encoding. We implemented the principles and parameter estimates that characterize the human eye in an open-source software toolbox. This chapter describes the principles behind these tools and illustrates how to use them to compute the initial visual encoding.
View details for DOI 10.1016/bs.pbr.2022.04.006
View details for PubMedID 35940717