Faculty Bibliography

Purpose : Lamina cribrosa (LC) deformation is hypothesized to be a major cause of glaucoma. The LC undergoes different forms of stress both anteriorly from intraocular pressure (IOP), as well as posteriorly and circumferentially from subarachnoid cerebrospinal fluid pressure (CSFP) and the sclera. The purpose of this study was to determine possible in vivo changes in the path of the lamina pores under different IOP settings while maintaining fixed CSFP. Methods : Spectral-domain OCT scans (Leica, Chicago, IL) of the optic nerve head (ONH) were acquired in vivo under different pressure settings from healthy rhesus monkeys. IOP was controlled using a gravity-based perfusion system through a needle inserted into the anterior chamber. CSFP was maintained at the baseline opening pressure via gravitybased perfusion system through cannulation of the brain's lateral ventricle (range 8- 12mmHg). Scans were acquired at baseline IOP (15mmHg), high (30 mmHg) and very high IOP (40-50 mmHg) and registered in 3D. Pores from shared regions were automatically segmented using a previously described segmentation algorithm. The path of each pore was tracked based on the calculated geometric centroid of each pore. The tortuosity of each pore path was defined as the total actual distance of the centroid path divided by the minimal distance between the first (most anterior) and last (most posterior) pore centroids. Results : 7 eyes from 6 healthy adult Rhesus macaque were analyzed. The mean value of the pore path tortuosity varies between eyes at baseline IOP levels (range: 1.16-1.68; Table). Two main overall patterns of pore path tortuosity were detected in response to increased IOP at fixed CSFP: 4 eyes became more tortuous (M2, M5, M8, M11); in the rest of the eyes (M6 OD, M6 OS, M10) the pore paths remained either unchanged or showed a variable response. No statistically significant change (p > 0.05) was observed in this small sample in either the subject-specific analysis or the analysis of the pooled combined values of the pore path tortuosity. Conclusions : Baseline pore tortuosity as well as the response of the pores to acute IOP increase varies between eyes. Further investigation is warranted to determine if these differences are associated with glaucoma susceptibility

Purpose : Schlemm canal (SC) is characterized by high local variations in morphology. Previously, we reported characteristics of SC using SC area measurements by optical coherence tomography (OCT) in healthy eyes. Herein, we examine the interobserver variability of SC height, width, and area in glaucomatous and healthy eyes. Methods : The anterior segment of six eyes from three subjects (1 female, 2 male) were imaged using OCT (Cirrus HD-OCT, Zeiss, Dublin, California, USA). A 4x4mm volumetric image of the limbus (depth of 2mm) was acquired with the Anterior Segment Cube scan protocol, comprised of 128 horizontal B-scans composed of 512 A-scans. SC was positioned to the side of the image to maximize visualization of aqueous humor vessel crossings. Scans were processed to maximize visualization of SC; image volumes were averaged (3x3x3 kernel) and contrast was enhanced with the local histogram algorithm using Fiji (version 2.10/1.53c). A cross-sectional B-scan and the two B-scans +/-5 frames were identified as three reference frames, based on best visualized SC location (Fig. 1). Three independent observers performed manual segmentation to measure SC width, height, and cross-sectional area for these three reference frames per volume. Width was defined as the longest measure of SC and height as perpendicular to the line used for width measurement. The observers performed these measurements on 15 volumes for a total of 45 analyzed frames each. The coefficient of variation was calculated based on standard deviations estimated using hierarchical multi-level random-effects models. Interobserver variability was quantified with a two-way ANOVA to calculate the intraclass correlation coefficient (ICC). Results : Participants had a mean age of 72.0 +/- 7.47 years (range: 66 to 82) and consisted of one healthy subject and two with primary open angle glaucoma. Measurement means and variation are presented in Table 1. The ICCs for interobserver variability are excellent for width measurements and low to moderate for height and area (Table 2) Conclusions : Excellent ICC for interobserver variability of SC width suggests it is suitable for use in clinical trials

Purpose : The lamina cribrosa (LC) is considered to play an important role in the pathogenesis of glaucoma. In this study, we investigate the shape variation (SV) of the LC pores as a potential biomarker for quantifying the morphological irregularity in vivo. Methods : 36 healthy and 14 glaucomatous (GL) eyes (total: 39 subjects) underwent a comprehensive ophthalmic examination and scanning of the optic nerve head with sweptsource OCT (Table 1). Images were converted to isotropic and pores were segmented using ImageJ. SV was defined as the mean-squared error of the pore pattern with respect to a solid circle (Figure 1(a)) with SV of a circle marked as zero, and higher SV value with increasing shape irregularity. SV of each pore was automatically calculated by a MATLAB code. The overall SV value was generated as the average of SV in the stack of individual slices. Age effect on SV was examined in all healthy eyes and a subset of 14 eyes was selected for age-matched comparison with the glaucomatous eyes (Table 1). Results : No significant correlation was detected between SV and age (p=0.145; Spearman correlation) in all healthy subjects. Examining the effect of depth on the difference between SV of glaucomatous and healthy eyes, the posterior third of the LC had significantly lower than other sections (p=0.007; Figure 1(b)). SV in glaucoma eyes was significantly higher than in the healthy group (p=0.008; Figure 1(c)). Conclusions : We demonstrated morphological differences in pore shape variation between healthy and glaucoma eyes that is mostly affecting the anterior 2/3 of the LC. Further studies are warranted to assess the use of SV as a structural biomarker in glaucoma

Purpose : Intraocular pressure (IOP) is currently the only modifiable risk factor for glaucoma, yet glaucoma can continue to progress despite controlled IOP. Thus, development of glaucoma neurotherapeutics remains an unmet need. Scutellarin is a flavonoid that exhibits a number of neuroprotective effects on the brain and the eye. Here, we investigated the neurobehavioral effects of oral scutellarin treatment in a novel experimental model of chronic glaucoma. Methods : Ten adult C57BL/6J mice (Group 1) were unilaterally injected with an optically clear hydrogel into the anterior chamber to obstruct aqueous outflow and induce chronic IOP elevation. Eight other mice (Group 2) received a unilateral intracameral injection of phosphate-buffered saline only. Another eight mice (Group 3) with hydrogel-induced unilateral chronic IOP elevation also received daily oral gavage of 300 mg/kg scutellarin from 1 week before to 2 weeks after hydrogel injection. Tonometry, optical coherence tomography, and optokinetic visuobehavioral testing were performed longitudinally to monitor the IOP, total retinal thickness, visual acuity, and contrast threshold of bilateral eyes in all three groups. Results : Intracameral hydrogel injection resulted in unilateral chronic IOP elevation with no significant IOP difference between scutellarin treatment and untreated groups (Figure site uses cookies. By continuing to use our website, you are agreeing to 1). With scutellarin treatment, the hydrogel-injected eyes showed less retinal thinning and reduced visual behavioral deficits when compared to the untreated, hydrogel-injected eyes (Figure 2). No significant difference in retinal thickness or optokinetic measures was found in the non-injected eyes over time or between all groups. Conclusions : Oral scutellarin treatment appeared to preserve retinal structure and visual function in experimental glaucoma induced by chronic IOP elevation. Scutellarin may be a possible candidate as a novel neurotherapeutic agent for glaucoma treatment

Purpose : Mutations in optineurin (OPTN) are associated with familial normal tension glaucoma and other neurodegenerative diseases. It remains unclear how OPTN loss or mutation alters visual function during aging. Here, we used transgenic mouse models and in vivo assessments to test the hypothesis that OPTN dysfunction contributes to progressive visual impairment through a toxic gain of function mechanism. Methods : Mice with C57BL/6 background were used (Fig 1): wildtype (WT; n=19), homozygous OPTN knock-out (mOPTN-KO; n=13), hemizygous mouse E50K OPTN knock-in (mE50K-het; n=8), homozygous mouse E50K OPTN knock-in (mE50K homoz; n=10), and human E50K OPTN bacterial artificial chromosome overexpression (hE50K BAC; n=6) (PMID: 31076632, 25818176). Intraocular pressure (IOP), total retinal thickness (TRT), visual acuity (VA), and contrast sensitivity (CS) were measured at 6, 12, and 18 months of age in the same mice using the TonoLab rebound tonometer, Bioptigen spectral-domain optical te uses cookies. By continuing to use our website, you are agreeing to coherence tomography imaging, and OptoMotry optokinetic virtual reality system respectively. Left and right eye data were averaged and analyzed using ANOVAs followed by posthoc tests between genotype and age groups, as well as linear regressions for VA versus contrast threshold (CT). Results : Our longitudinal study of the same mice during the aging process showed that IOP remained normal between 10-15 mmHg (Fig 2A). Small to no difference in TRT over time or compared to WT was observed (Fig 2B). mE50K-homoz, mE50K-het, and hE50K BAC mice exhibited greater age-dependent decline in VA and CT than WT or mOPTN-KO mice (Fig 2C, 2D, 2E). In contrast, mOPTN-KO mice showed preservation of VA and CT over time compared to WT. Consistently, mice with one copy of E50K OPTN (mE50K het) experienced less deterioration of VA and CT compared to mice with two copies (mE50K homoz) or mild overexpression (hE50K BAC). Conclusions : Depsite limited IOP and TRT changes between age and genotype groups, E50K OPTN was associated with differential age-dependent visual impairment (greater for CS than VA). Surprisingly, OPTN deficiency preserved visual function such that CS in knockout mice was better than WT mice. Our results suggest visual loss associated with E50K OPTN is due to a toxic gain of function mechanism, and that suppression of OPTN might constitute a therapeutic strategy for glaucomatous neurodegeneration

Purpose : Prevalence and severity of glaucoma varies between ethnicities. It has been previously shown that ocular vessel density (VD) varies among healthy subjects of different ethnicities. To further elucidate the potential role of VD in glaucoma we examined ocular VD in Caucasian, African American (AA), and Latin at similar stages of glaucoma severity. Methods : 150 glaucoma eyes of which 46 eyes (30 subjects) were Caucasian, 71 eyes (43 subjects) African American, and 33 eyes (19 subjects) Latin were included in the analysis. Comorbidities known to affect the systemic or local micro-or macro-vasculature and medications that are known to modify vessel diameter were excluded. Disease severity distribution was similar across ethnicity groups. All eyes had comprehensive ophthalmic examination, Cirrus HD-OCT (Zeiss, Dublin, CA) and OCT angiography (OCTA; Angioplex, Zeiss) qualified scans of the macula and optic nerve head regions (200x200 OCT cube scans and 3x3mm / 6x6mm OCTA scans). VD as provided by the device's native software in the inner vascular plexus was used for the analysis. Statistical analysis was performed using mixed-effects models accounting for ethnicity, age, axial length, visual field mean deviation (MD), OCT signal strength (SS), disc area and intra-subject correlation. Tukeyadjusted p-values for pairwise ethnicity comparisons were obtained.Results : No significant difference was detected in age and MD among ethnicities (Table 1). Caucasian subjects had the longest AL and thinnest RNFL, and Latin subjects had the largest disc area and cup-to-disc ratio (CDR; Table 1). No significant differences were detected among ethnicities in ONH VD in any of the scan types and regions. In the macula, Caucasians had significantly higher VD in the center of both scan sizes in comparison with both AA and Latin (Table 2). Caucasian eyes also had significantly higher VD in the full 3x3 scan in comparison with AA eyes. There were no significant differences in the rest of the macular VD measurements among the 3 groups. Conclusions : Macular VD in glaucoma subjects varies among ethnicities and might play a role in the varying disease behavior among ethnicities. Differences in foveal avascular zone size might explain our findings but further investigation is warranted

Purpose : Dampened cerebrovascular reactivity (CVR) impairs blood delivery to brain regions. Multiple studies have suggested a role of the basal forebrain (BF) in glaucoma (PMID: 31242454; ARVO 2020: 4336). However, CVR changes in BF with glaucoma severity have yet to be explored. Recently, relative CVR (rCVR) mapping was introduced using resting-state functional MRI (rsfMRI) without gas challenges. Here, we investigate rCVR changes in the visual cortex and basal forebrain with glaucoma severity. Methods : Normal (n=22), early-stage (n=18), and advanced-stage (n=19) glaucoma patients underwent anatomical MRI and rsfMRI. The optic nerve and optic chiasm volumes were measured using ImageJ. rCVR maps and regional rCVR values were generated and extracted with MriCloud online tool. Age, optical coherence tomography measurements, and Humphrey visual field perimetry were obtained from clinical records. Results are presented as mean+/-SEM. One-way ANOVA followed by post-hoc Bonferroni's multiple comparisons test, and trend analysis were applied. Results : Demographics, clinical ophthalmic assessments, and volumetric MRI assessments illustrated the characteristics of the anterior visual pathways in the normal control, earlystage glaucoma and advance-stage glaucoma groups (Fig. 1). The averaged rCVR map from normal controls is consistent with previous studies (PMID: 27888058, 32278094) (Fig. 2). Advanced-stage glaucoma patients [1.03+/-0.03 relative unit (r.u.); p<0.05] have significantly lower rCVR in the visual cortex compared to normal controls (1.20+/-0.06 r.u.; early-stage: 1.09+/-0.05 r.u.), and exhibit a decreasing trend in more severe disease. These corroborate with a previous Doppler ultrasound study (PMID: 23816432). Interestingly, rCVR in BF has an increasing trend with severity. No significant rCVR change was observed in the somatosensory cortex. Conclusions : Visual cortical rCVR decreases with glaucoma severity, while rCVR in the basal forebrain increases with severity. Our results verify visual cortical CVR reduction in glaucoma patients and further solidify that the basal forebrain plays a role in glaucoma

Purpose : Current Optical Coherence Tomography (OCT) denoising techniques mainly focus on denoising 2-dimensional (2D) B-scans, especially for deep learning (DL) methods, which assume spatial integrity among neighboring samplings. However, OCT signal is essentially one dimensional (1D), and eye movements during scanning often violate the assumption. The purpose of this study was to see if 1D denoising is a feasible approach for clinical OCT imaging. Methods : 3D SD-OCT data within 6x6x2mm volumes centered on optic nerve head were obtained from 121 eyes (79 patients). Clean reference scans were constructed by registering and averaging 6 OCT scans obtained on the same day using ANTs software. As shown in Figure 1, we used a 5-layer U-shape net (UNet) for both 2D denoiser (Figure 1.(a)) and 1D denoiser (Figure1.(b)). In addition, both 2D and 1D approaches are combined by using the 2D denoised B-scan as a mask to selectively remove high signal peaks in the 1D denoised B-scan (Figure 1.(c)). Peak signal-to-noise ratio (PSNR) and contrast-to-noise ratio (CNR) were calculated to compare the performance. Results : Subjectively, the 2D denoiser generated smoother edges but tended to oversmooth textual information within the retinal layers, while the 1D denoiser preserved more textual information but caused more jittering at retinal edges due to the lack of structural information from neighboring A-scans. Quantitatively, the 1D denoiser showed similar PSNR to the 2D denoiser, while outperforming in CNR (PSNR: 31.20 (1D) V.S. 31.20 dB (2D), p=0.963; CNR: 4.23 (1D) V.S. 3.90 dB (2D), p<0.001, paired t-test, Table 1). The combined denoiser further improved CNR (4.39 (combined) V.S. 3.90 dB (2D), p<0.001). Combining 1D and 2D denoisers, the denoised B-scan showed more continuous edges compared to the 1D denoiser and did not lose the texture information compared to the 2D denoiser (Figure 2). Conclusions : Quantitatively, 1D denoiser performance is as good as 2D denoiser or even better. A combination of 1D and 2D approaches may provide well-balanced image enhancement in clinical applications

Purpose : The uncertainty quantification of segmentation results is critical for understanding the reliability of the segmentation model. The purpose of this study is to investigate the effect of deep learning-based segmentation with uncertainty measurement in the relationship between RNFL thickness and visual field mean deviation (MD) Methods : Optical coherence tomography (OCT) scans were acquired from both eyes on 634 glaucoma patients, 404 glaucoma suspects, and 49 healthy controls using commercial OCT device (Cirrus HD-OCT, 200x200 Optic Disc Cubes; Zeiss, Dublin, CA). All subjects had visual field (VF) tests at each visit (Humphrey VF, SITA 24-2 test; Zeiss). A segmentation model was trained using Bayesian deep learning for voxel-wise segmentation of RNFL layer in OCT volume and compute the voxel-wise uncertainty of the segmentation output. The higher uncertainty denotes the unreliability of the segmentation and vice versa and it allows the determination of erroneous segmentation at test time. Uncertainty-guided global mean of the RNLF thickness (RNFL-Umean) was then computed by discarding the voxels with erroneous segmentation labels with higher uncertainty during the thickness computation. Also, the global mean of the RNLF thickness (RNFLmean;) was computed without taking uncertainty into account. Pearson correlation coefficient between RNFLU and MD was computed and compared with the Pearson correlation coefficient between RNFLmean;and MD. Results : The proposed RNFL-Umean;gave stronger correlation with MD than RNFLmean;The Pearson correlation coefficients were (0.67 (RNFL-Umean;) vs 0.63 (RNFL mean;; p<0.001) for glaucoma subjects, (0.56 vs 0.53 ;p=0.01) for glaucoma suspects and (0.08 vs 0.01; p=0.21) for normal subjects. Conclusions : The proposed uncertainty-guided computation of RNFL thickness showed improved correlation with the visual field MD. This demonstrates that segmentation uncertainty can be used to reduce the effect of inaccurate segmentation in computing the RNFL thickness. This also shows that uncertainty-guided computation of RNFL thickness is a better predictor of visual function than the normal RNFL thickness computed without using uncertainty