Faculty Bibliography

The field of ophthalmic imaging has grown substantially over the last years. Massive improvements in image processing and computer hardware have allowed the emergence of multiple imaging techniques of the eye that can transform patient care. The purpose of this review is to describe the most recent advances in eye imaging and explain how new technologies and imaging methods can be utilized in a clinical setting. The introduction of optical coherence tomography (OCT) was a revolution in eye imaging and has since become the standard of care for a plethora of conditions. Its most recent iterations, OCT angiography, and visible light OCT, as well as imaging modalities, such as fluorescent lifetime imaging ophthalmoscopy, would allow a more thorough evaluation of patients and provide additional information on disease processes. Toward that goal, the application of adaptive optics (AO) and full-field scanning to a variety of eye imaging techniques has further allowed the histologic study of single cells in the retina and anterior segment. Toward the goal of remote eye care and more accessible eye imaging, methods such as handheld OCT devices and imaging through smartphones, have emerged. Finally, incorporating artificial intelligence (AI) in eye images has the potential to become a new milestone for eye imaging while also contributing in social aspects of eye care.

Intracranial pressure (ICP) has been proposed to play an important role in the sensitivity to intraocular pressure (IOP) and susceptibility to glaucoma. However, the in vivo effects of simultaneous, controlled, acute variations in ICP and IOP have not been directly measured. We quantified the deformations of the anterior lamina cribrosa (ALC) and scleral canal at Bruch's membrane opening (BMO) under acute elevation of IOP and/or ICP. Four eyes of three adult monkeys were imaged in vivo with OCT under four pressure conditions: IOP and ICP either at baseline or elevated. The BMO and ALC were reconstructed from manual delineations. From these, we determined canal area at the BMO (BMO area), BMO aspect ratio and planarity, and ALC median depth relative to the BMO plane. To better account for the pressure effects on the imaging, we also measured ALC visibility as a percent of the BMO area. Further, ALC depths were analyzed only in regions where the ALC was visible in all pressure conditions. Bootstrap sampling was used to obtain mean estimates and confidence intervals, which were then used to test for significant effects of IOP and ICP, independently and in interaction. Response to pressure manipulation was highly individualized between eyes, with significant changes detected in a majority of the parameters. Significant interactions between ICP and IOP occurred in all measures, except ALC visibility. On average, ICP elevation expanded BMO area by 0.17mm²â€¯at baseline IOP, and contracted BMO area by 0.02 mm²â€¯at high IOP. ICP elevation decreased ALC depth by 10μm at baseline IOP, but increased depth by 7 μm at high IOP. ALC visibility decreased as ICP increased, both at baseline (-10%) and high IOP (-17%). IOP elevation expanded BMO area by 0.04 mm²â€¯at baseline ICP, and contracted BMO area by 0.09 mm²â€¯at high ICP. On average, IOP elevation caused the ALC to displace 3.3 μm anteriorly at baseline ICP, and 22 μm posteriorly at high ICP. ALC visibility improved as IOP increased, both at baseline (5%) and high ICP (8%). In summary, changing IOP or ICP significantly deformed both the scleral canal and the lamina of the monkey ONH, regardless of the other pressure level. There were significant interactions between the effects of IOP and those of ICP on LC depth, BMO area, aspect ratio and planarity. On most eyes, elevating both pressures by the same amount did not cancel out the effects. Altogether our results show that ICP affects sensitivity to IOP, and thus that it can potentially also affect susceptibility to glaucoma.

The goal of this study was to quantify the association between sensory integration abilities relevant for standing balance and disease stage in glaucoma. The disease stage was assessed using both functional (visual field deficit) and structural (retinal nerve fiber layer thickness) deficits in the better and worse eye. Balance was assessed using an adapted version of the well-established Sensory Organization Test (SOT). Eleven subjects diagnosed with mild to moderate glaucoma stood for 3 min in 6 sensory challenging postural conditions. Balance was assessed using sway magnitude and sway speed computed based on center-of-pressure data. Mixed linear regression analyses were used to investigate the associations between glaucoma severity and balance measures. Findings revealed that the visual field deficit severity in the better eye was associated with increased standing sway speed. This finding was confirmed in eyes open and closed conditions. Balance was not affected by the extent of the visual field deficit in the worse eye. Similarly, structural damage in either eye was not associated with the balance measures. In summary, this study found that postural control performance was associated with visual field deficit severity. The fact that this was found during eyes closed as well suggests that reduced postural control in glaucoma is not entirely attributed to impaired peripheral visual inputs. A larger study is needed to further investigate potential interactions between visual changes and central processing changes contributing to reduced balance function and increased incidence of falls in adults with glaucoma.

Early detection and monitoring are critical to the diagnosis and management of glaucoma, a progressive optic neuropathy that causes irreversible blindness. Optical coherence tomography (OCT) has become a commonly utilized imaging modality that aids in the detection and monitoring of structural glaucomatous damage. Since its inception in 1991, OCT has progressed through multiple iterations, from time-domain OCT, to spectral-domain OCT, to swept-source OCT, all of which have progressively improved the resolution and speed of scans. Even newer technological advancements and OCT applications, such as adaptive optics, visible-light OCT, and OCT-angiography, have enriched the use of OCT in the evaluation of glaucoma. This article reviews current commercial and state-of-the-art OCT technologies and analytic techniques in the context of their utility for glaucoma diagnosis and management, as well as promising future directions.

Purpose:To characterize the visual pathway integrity of five glaucoma animal models using diffusion tensor imaging (DTI). Methods:Two experimentally induced and three genetically determined models of glaucoma were evaluated. For inducible models, chronic IOP elevation was achieved via intracameral injection of microbeads or laser photocoagulation of the trabecular meshwork in adult rodent eyes. For genetic models, the DBA/2J mouse model of pigmentary glaucoma, the LTBP2 mutant feline model of congenital glaucoma, and the transgenic TBK1 mouse model of normotensive glaucoma were compared with their respective genetically matched healthy controls. DTI parameters, including fractional anisotropy, axial diffusivity, and radial diffusivity, were evaluated along the optic nerve and optic tract. Results:Significantly elevated IOP relative to controls was observed in each animal model except for the transgenic TBK1 mice. Significantly lower fractional anisotropy and higher radial diffusivity were observed along the visual pathways of the microbead- and laser-induced rodent models, the DBA/2J mice, and the LTBP2-mutant cats compared with their respective healthy controls. The DBA/2J mice also exhibited lower axial diffusivity, which was not observed in the other models examined. No apparent DTI change was observed in the transgenic TBK1 mice compared with controls. Conclusions:Chronic IOP elevation was accompanied by decreased fractional anisotropy and increased radial diffusivity along the optic nerve or optic tract, suggestive of disrupted microstructural integrity in both inducible and genetic glaucoma animal models. The effects on axial diffusivity differed between models, indicating that this DTI metric may represent different aspects of pathological changes over time and with severity.

Purpose : Falls risk increases with glaucoma. Gait impairments occur in people with glaucoma; however, they do not fully explain why greater visual field loss results in higher fall rates (Mihailovic 2020). Harmonic ratios, which are derived based on the frequency analysis of trunk acceleration signals, quantify step-to-step gait symmetry and have been associated with falls risk in older adults (Bellanca 2013). Harmonic ratios have not been examined in glaucoma. This pilot study tested the hypothesis that gait symmetry will be reduced with worse visual field loss in glaucoma, particularly under sensory challenging conditions and increased attention demands. Methods : Ten adults with glaucoma (6F/4M, 67+/-8 years), instrumented with motion capture markers (Vicon Motion Systems Ltd, UK) and accelerometers (Delsys Inc., MA), were asked to walk in 8 conditions with varying floor (hard floor, carpet), light (well-lit, dim) and concurrent information processing (IP) task conditions (no task, auditory IP choice reaction time task). Glaucoma severity was determined using the visual field mean deviation (VF MD) assessed by automated Humphrey perimetry (Zeiss, CA). The VF MD measured in the better/worse eye and averaged across the 10 participants was equal to -2.9+/-3.8 / -7.5+/-6.7 dB, respectively. The analyses used mixed linear models with the fixed effects including VF MD either in the better eye or worse eye, floor/light condition, IP condition and the first order interaction of these factors. Subject was added as a random effect. The dependent gait measure was the anteroposterior (AP) harmonic ratio (Bellanca 2013). Statistical significance was set at 0.05. Results : Visual field MD in the better eye was associated with the AP harmonic ratio (F(1,8)=11.9, p=0.009), i.e. step-to-step gait symmetry in the anteroposterior direction was reduced with worse visual field loss in the better eye. In addition, the main effect of floor/light condition was associated with the AP harmonic ratio (F(3,58)=8.4, p<0.0001). Post-hoc analyses found this effect was driven by a change in floor condition. All other effects included in the analyses did not reach statistical significance (p>0.1). Conclusions : Gait symmetry is reduced in glaucoma and thus may be an important metric. Further research is needed to determine if reduced gait symmetry is associated with increased falls risk in this population

Purpose : Rhesus macaques are a common animal model in ophthalmology because of the high similarity of their eyes and visual pathway to human. The characterization of optic nerve head (ONH) and peripapillary region in monkeys reported so far mostly involved a manual process which is laborious and subjected to operator errors. It is also usually generated from a cohort of similar age group. In this cross-sectional observational study, we deploy automated and manual segmentations to evaluate the OCT retinal nerve fiber layer (RNFL) thickness, ONH and lamina cribrosa (LC) microstructure parameters in a cohort of free roaming macaques. Methods : In-vivo ONH spectral-domain OCT scans (Leica, Chicago, IL) were obtained by a single experienced operator after excluding eyes with any retinal pathologies. The margins of the optic disc were drawn manually and the resultant scans were analyzed using an automated segmentation software of our own design. The LC microstructure parameters were obtained through a previously described segmentation algorithm. The other parameters of ONH, namely the cup-to-disc (C/D) ratio and minimum rim width (MRW) were assessed manually. Wilcoxon rank sum test was used to test the association of LC parameters, C/D ratio and MRW with age, while the rest of the parameters were analyzed using mixed effects model accounting for age, sex and intra-subject correlation. Results : 29 eyes from 19 monkeys (11 females, 8 males) with age ranging from 4.2 to 23.8 years were analyzed. Males were overall bigger and significantly heavier than females in our cohort (Table 1). Superior RNFL was thicker in male and is the only RNFL parameter that was associated with age or sex in this healthy cohort. No significant association was detected for any of the ONH parameters with age or sex. LC was more visible and thicker in male with higher beam to pore ratio and connective tissue fraction than in female. Conclusions : The characterization of normal macaque eyes from a cohort of free roaming animals is useful as a standard reference to assess pathological changes in future experimental studies

Purpose : To assess the repeatability of estimates of mean deviation (MD) and visual field index (VFI) obtained from an automated deep-learning approach that analysed raw OCT volumes. Methods : OCT scans were acquired from both eyes of 138 healthy, 743 glaucoma suspects and 941 glaucoma patients (Cirrus HD-OCT scanner, 200x200 ONH Cubes, Zeiss, Dublin CA). The scans were acquired at multiple visits, with two or more scans acquired at each visit. Scans with signal strength < 7 were discarded, giving us a total of 19,208 OCT scans. A subset of 5207 eyes (total of 10,414 scans) had repeat scans of that met the inclusion criteria. 24-2 Humphrey visual field (VF) tests were administered at each visit. A single convolutional neural network was trained to estimate the MD and VFI (dual outputs) from downsampled OCT volumes (50x50x128 voxels). The network consisted of 5 convolutional layers, followed by a global average pooling layer and dual outputs to enable the simultaneous estimation of MD and VFI. A mean squared error loss was used to train the network using an Adam optimiser over a total of 200 epochs. A 10-fold cross-validation scheme was used, where the dataset was divided into 10 non-overlapping folds (~182 subjects per fold) - trained on 8-folds, validated on one and tested on one. Each subject was limited to a unique fold. The performance of the method was assessed by computing the median error and interquartile range. The repeatability was assessed using a set of 5207 OCT scans that had repeats available. Results : The median absolute error (Q1, Q3) for the estimates of MD and VFI were 1.66 (0.79, 2.99) dB and 3.01 (1.48, 6.63) %, respectively. In the reproducibility test, the Pearson's correlation coefficient was 0.91 (CI: [0.91, 0.92]) and 0.91 (CI: [0.90, 0.92]), for MD and VFI, respectively. The median absolute difference between the repeated estimates for MD and VFI were 0.53 (0.21, 0.51) dB and 1.17 (0.45, 1.14)%, respectively. Conclusions : The deep-learning based approach for estimating visual field test parameters shows repeatability better than expected test-to-test variability

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 : 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