Faculty Bibliography

Purpose : Glaucoma is a widespread neurodegenerative disease affecting the retinal ganglion cells, optic nerve, distal visual pathways and beyond. Recent studies suggest that cerebrospinal fluid (CSF) plays a role in clearing wastes from the brain and that CSF dynamics may be altered in neurodegenerative diseases. Since CSF dynamics can be facilitated by the global brain activity, in the present study, we investigated how the dynamics of CSF and its coupling with global brain activity may be altered in glaucoma using functional magnetic resonance imaging (fMRI). Methods : 19 early glaucoma patients (62.3+/-1.7 yrs) (mean+/-SEM), 19 advanced glaucoma patients (64.7+/-2.4 yrs), and 19 healthy subjects (59+/-2.4 yrs) underwent anatomical MRI and resting-state fMRI with eyes closed. Age did not differ across groups (P=0.188). We extracted the CSF signal time profiles from the fourth ventricle (Fig. 1A) and the global brain activity [blood-oxygenation-level-dependent signal time profiles] from the entire gray matter (Fig. 1B). Following previous literature (Han F, et al. PLOS Biol 2021;19), the coupling between the CSF signals and the global brain activity (CSF-BOLD coupling) was examined via cross correlation at the 4s time lag, where more negative values indicate stronger coupling. We also associated these correlations with the volumes of the anterior visual pathway in anatomical MRI. Results : A significant group difference was observed in the power (i.e., strength) of the low frequency (0.01-0.03Hz) in the CSF signals (P=0.013; Fig.1C). Specifically, early glaucoma patients showed significantly greater power than advanced glaucoma patients (Bonferroni P=0.010). The power of the global brain activity showed similar trends but did not reach significance (P=0.390; Fig.1D). The CSF-BOLD coupling at the 4s lag differed significantly across groups (P=0.007; Fig. 1E). Early glaucoma patients had significantly stronger coupling than advanced glaucoma patients (Bonferroni P=0.025) and healthy controls (Bonferroni P=0.013). Further, CSF-BOLD coupling was correlated with the volumes of optic nerve (right: R=-0.342, P=0.009; left: R=-0.344, P=0.009, Fig. 2D,E) and optic chiasm (R=0.264, P=0.047, Fig. 2F). Conclusions : Our observations of the altered CSF dynamics and CSF-BOLD coupling provide physiological evidence to support the recent hypothesis of widespread brain involvements in the early stage of glaucoma

Purpose : Previously we described the longitudinal glaucoma relationship between structure and function using a broken stick analysis approach to identify the location where the rate of change accelerates or decelerates. In that analysis we used each measurement point as an independent point, aggregated all eyes from all visits, and treated longitudinal data as cross-sectional. Using improved statistical methodology, we accounted for repeated measurements and the use of data from both eyes in the longitudinal model. The purpose of this study is to identify the locations of tipping points and rates of change before and after them in structural and functional measurements. Methods : Subjects with comprehensive ophthalmic examination and 5 or more visits with qualified visual fields (VF; Humphrey Field Analyzer; Zeiss, Dublin, CA) and OCT (Cirrus HD-OCT; Zeiss) with ONH and macular scans were enrolled. Segmented mixed models that account for repeated measurements were utilized to estimate the tipping points and the difference-in-slope. The number of tipping points was determined by identifying the optimal model using Bayesian information criterion. Results : 216 eyes (164 open angle glaucoma, 45 glaucoma suspect, and 7 healthy eyes) of 145 subjects were analyzed (Table). Retinal nerve fiber layer (RNFL), and ganglion cell inner retinal layer (GCIPL) decreases and cup to disc ratio (CDR) increases since early stages of the disease were measured (Figure). Unlike previous cross-sectional reports, visual field mean deviation (MD) also decreases along with structural parameters since early stages of the disease. RNFL thinning stalls beyond MD<-15.63dB (Figure A) while GCIPL keeps decreasing (B), and CDR slowly increases (C) throughout the functional damage range. Direct comparison between the structural parameters shows that RNFL thinning decelerates in advanced disease compared to both GCIPL and CDR and GCIPL thinning decelerates compared to CDR. Conclusions : Structural and functional measurements (RNFL, GCIPL, CDR and MD) are useful to evaluate glaucoma change from early stages of the disease. As glaucoma progresses and RNFL reaches its minimal measurable level GCIPL, CDR and MD remain useful to evaluate the disease. The clinical routine for following subjects with glaucoma should account for the ability to measure relevant parameters at various stages of disease

Purpose:The lamina cribrosa (LC) is a leading target for initial glaucomatous damage. We investigated the in vivo microstructural deformation within the LC volume in response to acute IOP modulation while maintaining fixed intracranial pressure (ICP). Methods:In vivo optic nerve head (ONH) spectral-domain optical coherence tomography (OCT) scans (Leica, Chicago, IL, USA) were obtained from eight eyes of healthy adult rhesus macaques (7 animals; ages = 7.9-14.4 years) in different IOP settings and fixed ICP (8-12 mm Hg). IOP and ICP were controlled by cannulation of the anterior chamber and the lateral ventricle of the brain, respectively, connected to a gravity-controlled reservoir. ONH images were acquired at baseline IOP, 30 mm Hg (H1-IOP), and 40 to 50 mm Hg (H2-IOP). Scans were registered in 3D, and LC microstructure measurements were obtained from shared regions and depths. Results:Only half of the eyes exhibited LC beam-to-pore ratio (BPR) and microstructure deformations. The maximal BPR change location within the LC volume varied between eyes. BPR deformer eyes had a significantly higher baseline connective tissue volume fraction (CTVF) and lower pore aspect ratio (P = 0.03 and P = 0.04, respectively) compared to BPR non-deformer. In all eyes, the magnitude of BPR changes in the anterior surface was significantly different (either larger or smaller) from the maximal change within the LC (H1-IOP: P = 0.02 and H2-IOP: P = 0.004). Conclusions:The LC deforms unevenly throughout its depth in response to IOP modulation at fixed ICP. Therefore, analysis of merely the anterior LC surface microstructure will not fully capture the microstructure deformations within the LC. BPR deformer eyes have higher CTVF than BPR non-deformer eyes.

Purpose/UNASSIGNED:The lamina cribrosa (LC) has an important role in the pathophysiology of ocular diseases. The purpose of this study is to characterize in vivo, noninvasively, and in 3D the structure of the LC in healthy non-human primates (NHPs). Methods/UNASSIGNED:Spectral-domain optical coherence tomography (OCT; Leica, Chicago, IL) scans of the optic nerve head (ONH) were obtained from healthy adult rhesus macaques monkeys. Using a previously reported semi-automated segmentation algorithm, microstructure measurements were assessed in central and peripheral regions of an equal area, in quadrants and depth-wise. Linear mixed-effects models were used to compare parameters among regions, adjusting for visibility, age, analyzable depth, graded scan quality, disc area, and the correlation between eyes. Spearmen's rank correlation coefficients were calculated for assessing the association between the lamina's parameters. Results/UNASSIGNED:Sixteen eyes of 10 animals (7 males and 3 females; 9 OD, 7 OS) were analyzed with a mean age of 10.5 ± 2.1 years. The mean analyzable depth was 175 ± 37 µm, with average LC visibility of 25.4 ± 13.0% and average disc area of 2.67 ± 0.45mm2. Within this volume, an average of 74.9 ± 39.0 pores per eye were analyzed. The central region showed statistically significantly thicker beams than the periphery. The quadrant-based analysis showed significant differences between the superior and inferior quadrants. The anterior LC had smaller beams and pores than both middle and posterior lamina. Conclusions/UNASSIGNED:Our study provides in vivo microstructure details of NHP's LC to be used as the foundation for future studies. We demonstrated mostly small but statistically significant regional variations in LC microstructure that should be considered when comparing LC measurements.

Purpose/UNASSIGNED:Vivid Vision Perimetry (VVP; Vivid Vision, Inc) is a novel method for performing in-office and home-based visual field assessment using a virtual reality platform and oculokinetic perimetry. Here we examine the reproducibility of VVP Swift and compare results with conventional standard automated perimetry (SAP) and spectral-domain (SD) OCT. Design/UNASSIGNED:Cross-sectional study. Participants/UNASSIGNED:Fourteen eyes of 7 patients with open-angle glaucoma (OAG) (average age, 64.6 years; 29% women) and 10 eyes of 5 patients with suspected glaucoma (average age, 61.8 years; 40% women) were enrolled. Methods/UNASSIGNED:Patients with OAG and suspected glaucoma were enrolled prospectively and underwent 2 VVP Swift examinations. Results were compared with 1 conventional SAP examination (Humphrey Visual Field [HVF]; Zeiss) and 1 SD OCT examination. Main Outcome Measures/UNASSIGNED:Mean sensitivity (in decibels) obtained for each eye in 2 VVP Swift test sessions and a conventional SAP examination, thickness of the retinal nerve fiber layer (RNFL) and ganglion cell complex (GCC) for the SD OCT examination, and mean test durations of the VVP Swift and SAP examinations. Results/UNASSIGNED:< 0.001), respectively. Conclusions/UNASSIGNED:Our results demonstrated that the VVP Swift test can generate reproducible results and is comparable with conventional SAP. This suggests that the device can be used by clinicians to assess visual function in glaucoma.

Purpose/UNASSIGNED:Growing evidence suggests that dendrite retraction or degeneration in a subpopulation of the retinal ganglion cells (RGCs) may precede detectable soma abnormalities and RGC death in glaucoma. Visualization of the lamellar structure of the inner plexiform layer (IPL) could advance clinical management and fundamental understanding of glaucoma. We investigated whether visible-light optical coherence tomography (vis-OCT) could detect the difference in the IPL sublayer thicknesses between small cohorts of healthy and glaucomatous subjects. Method/UNASSIGNED:We imaged nine healthy and five glaucomatous subjects with vis-OCT. Four of the healthy subjects were scanned three times each in two separate visits, and five healthy and five glaucoma subjects were scanned three times during a single visit. IPL sublayers were manually segmented using averaged A-line profiles. Results/UNASSIGNED:The mean ages of glaucoma and healthy subjects are 59.6 ± 13.4 and 45.4 ± 14.4 years (P = 0.02.) The visual field mean deviations (MDs) are -26.4 to -7.7 dB in glaucoma patients and -1.6 to 1.1 dB in healthy subjects (P = 0.002). Median coefficients of variation (CVs) of intrasession repeatability for the entire IPL and three sublayers are 3.1%, 5.6%, 6.9%, and 5.6% in healthy subjects and 1.8%, 6.0%, 7.7%, and 6.2% in glaucoma patients, respectively. The mean IPL thicknesses are 36.2 ± 1.5 µm in glaucomatous and 40.1 ± 1.7 µm in healthy eyes (P = 0.003). Conclusions/UNASSIGNED:IPL sublayer analysis revealed that the middle sublayer could be responsible for the majority of IPL thinning in glaucoma. Vis-OCT quantified IPL sublayers with good repeatability in both glaucoma and healthy subjects.

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.