Biology subjects

Wollstein, G.

Publications and source records attributed to Wollstein, G..

9 recordsLinked to original sources

bioRxiv2025

Stimulus-driven cerebrospinal fluid dynamics is impaired in glaucoma patients

Cerebrospinal fluid (CSF) dynamics, driven by sensory stimulation-induced neuronal activity, is crucial for maintaining homeostasis and clearing metabolic waste. However, it remains unclear whether such CSF flow is impaired in age-related neurodegenerative diseases of the visual system. This study addresses this gap by examining CSF flow during visual stimulation in glaucoma patients and healthy older adults using functional magnetic resonance imaging. The findings reveal that in glaucoma, CSF inflow becomes decoupled from visually evoked blood-oxygenation-level-dependent (BOLD) response. Furthermore, stimulus-locked CSF patterns, characterized by decreases following stimulus onset and increases after offset, diminish as glaucoma severity worsens. Mediation analysis suggests that this flattened CSF pattern is driven by a flatter BOLD slope, resulting in a shallower CSF trough and a reduced rebound. These findings unveil a novel pathophysiological mechanism underlying disrupted stimulation-driven CSF dynamics in glaucoma and highlight potential in vivo biomarkers for monitoring CSF in the glaucomatous brain.

neuroscience↗

bioRxiv2023

In vivo Modulation of Intraocular and Intracranial Pressures Causes Nonlinear and Non-monotonic Deformations of the Lamina Cribrosa and Scleral Canal

PurposeTo evaluate changes in monkey optic nerve head (ONH) morphology under acutely controlled intraocular pressure (IOP) and intracranial pressure (ICP). MethodsSeven ONHs from six monkeys were imaged via optical coherence tomography while IOP and ICP were maintained at one of 16 conditions. These conditions were defined by 4 levels for each pressure: low, baseline, high and very high. Images were processed to determine scleral canal area, aspect ratio, and planarity and anterior lamina cribrosa (ALC) shape index and curvature. Linear mixed effect models were utilized to investigate the effects of IOP, ICP and their interactions on ONH morphological features. The IOP-ICP interaction model was compared with one based on translaminar pressure difference (TLPD). ResultsWe observed complex, eye-specific, non-linear patterns of ONH morphological changes with changes in IOP and ICP. For all ONH morphological features, linear mixed effects models demonstrated significant interactions between IOP and ICP that were unaccounted for by TLPD. Interactions indicate that the effects of IOP and ICP depend on the other pressure. The IOP-ICP interaction model was a higher quality predictor of ONH features than a TLPD model. ConclusionsIn vivo modulation of IOP and ICP causes nonlinear and non-monotonic changes in monkey ONH morphology that depend on both pressures and is not accounted for by a simplistic TLPD. These results support and extend prior findings. Translational Relevance: A better understanding of ICPs influence on the effects of IOP can help inform the highly variable presentations of glaucoma and effective treatment strategies.

bioengineering↗

bioRxiv2023

Efficient estimation of breakpoints in piecewise-linear mixed-effects models for longitudinal ophthalmic studies

PurposeBroken stick analysis is a widely used approach for detecting unknown breakpoints where association between measurements is non-linear. We propose LIMBARE, an advanced linear mixed-effects breakpoint analysis with robust estimation, especially designed for longitudinal ophthalmic studies. LIMBARE accommodates repeated measurements from both eyes and overtime, and effectively address the presence of outliers. MethodsThe model setup of LIMBARE and computing algorithm for point and confidence interval estimates of the breakpoint was introduced. The performance of LIMBARE and other competing methods was assessed via comprehensive simulation studies and application to a longitudinal ophthalmic study with 216 eyes (145 subjects) followed for an average of 3.7{+/-}1.3 years to examine the longitudinal association between structural and functional measurements. ResultsIn simulation studies, LIMBARE showed the smallest bias and mean squared error (MSE) for estimating the breakpoint, with empirical coverage probability of corresponding CI estimate closest to the nominal level for scenarios with and without outlier data points. In the application to the longitudinal ophthalmic study, LIMBARE detected two breakpoints between visual field mean deviation (MD) and retinal nerve fiber layer thickness (RNFL) and one breakpoint between MD and cup to disc ratio (CDR), while the cross-sectional analysis approach only detected one and none, respectively. ConclusionsLIMBARE enhances breakpoint estimation accuracy in longitudinal ophthalmic studies, while cross-sectional analysis approach is not recommended for future studies. Translational RelevanceOur proposed method and companion software R package provides a valuable computational tool for advancing longitudinal ophthalmology research and exploring the association relationships between ophthalmic variables.

bioinformatics↗

bioRxiv2022

GABA decrease is associated with degraded neural specificity in the visual cortex of glaucoma patients

Glaucoma is an age-related neurodegenerative disease of the visual system, affecting both the eye and the brain. Yet its underlying metabolic mechanisms and neurobehavioral relevance remain largely unclear. Here, using proton magnetic resonance spectroscopy and functional magnetic resonance imaging, we investigated the GABAergic and glutamatergic systems in the visual cortex of glaucoma patients, as well as neural specificity, which is shaped by GABA and glutamate signals and underlies efficient sensory and cognitive functions. Our study showed that among the older adults, both GABA and glutamate levels decrease with increasing glaucoma severity regardless of age. Further, the reduction of GABA but not glutamate predicted the neural specificity. This association was independent of the impairments on the retina structure and age. Our results suggest that glaucoma-specific decline of GABA undermines neural specificity in the visual cortex and that targeting GABA could improve the neural specificity in glaucoma.

neuroscience↗

bioRxiv2022

Comparing acute IOP-induced lamina cribrosa deformations pre-mortem and post-mortem

PurposeLamina cribrosa (LC) deformations caused by elevated intraocular pressure (IOP) are believed to contribute to glaucomatous neuropathy and have therefore been extensively studied, in many conditions from in-vivo to ex-vivo. We compare acute IOP-induced global and local LC deformations immediately before (pre-mortem) and after (post-mortem) sacrifice by exsanguination. MethodsThe optic nerve heads of three healthy monkeys 12-15 years old were imaged with spectral-domain optical coherence tomography under controlled IOP pre-mortem and post-mortem. Volume scans were acquired at baseline IOP (8-10 mmHg) and at 15, 30, and 40 mmHg IOP. A digital volume correlation technique was used to determine the IOP-induced 3D LC deformations (strains) in regions visible pre-mortem and post-mortem. ResultsBoth conditions exhibited similar nonlinear relationships between IOP increases and LC deformations. Median effective and shear strains were, on average over all eyes and pressures, smaller post-mortem than pre-mortem, by 14% and 11%, respectively (Ps < 0.001). Locally, however, the differences in LC deformation between conditions were variable. Some regions were subjected pre-mortem to triple the strains observed post-mortem, and others suffered smaller deformations pre-mortem than post-mortem. ConclusionsIncreasing IOP acutely caused nonlinear LC deformations with an overall smaller effect post-mortem than pre-mortem. Locally, deformations pre-mortem and post-mortem were sometimes substantially different. We suggest that the differences may be due to weakened mechanical support from the unpressurized central retinal vessels post-mortem. Translational RelevanceAdditional to the important pre-mortem information, comparison with post-mortem provides a unique context essential to understand the translational relevance of all post-mortem biomechanics literature. PrecisThe authors compared in monkeys acute IOP-induced deformations of the lamina cribrosa pre-mortem and post-mortem. Deformation trends were similar pre-mortem and post-mortem, but deformations pre-mortem were generally smaller than those post-mortem, with substantial local variations. The differences are likely due to loss of vessel support post-mortem.

bioengineering↗

bioRxiv2022

Age-related differences in ocular features of a naturalistic free-ranging population of rhesus macaques

PurposeRhesus macaques (Macaca mulatta) are the premier nonhuman primate model for studying human health and disease. We aimed to investigate if age was associated with ocular features of clinical relevance in a large cohort of free-ranging rhesus macaques from Cayo Santiago, Puerto Rico. MethodsWe evaluated 120 rhesus macaques (73 males, 47 females) aged from 0 to 29 years old (mean{+/-}SD: 12.6{+/-}6.4) from September to December, 2021. The ophthalmic evaluation included IOP assessment, corneal pachymetry, anterior segment biomicroscopy, A-Scan biometry, automated refraction, and fundus photography after pupil dilation. The effects of age on the outcome variables were investigated through multilevel mixed-effects models adjusted for sex and weight. ResultsOn average, IOP, pachymetry, axial length, and automated refraction spherical equivalent were 15.47{+/-}2.47 mmHg, 474.43{+/-}32.21 m, 19.49{+/-}1.24 mm, and 0.30{+/-}1.70 D, respectively. Age was significantly associated with pachymetry (Coef.= -1.20; 95%CI: -2.27 to -0.14; p=0.026), axial length (Coef.= 0.03; 95%CI: 0.01 to 0.05; p=0.002), and spherical equivalent (Coef.= -0.12; 95%CI: -0.22 to -0.02; p=0.015). No association was detected between age and IOP. The prevalence of cataracts in either eye was 10.83% (95% CI: 6.34 - 17.89%) and was significantly associated with age (OR= 1.20; 95%CI: 1.06 - 1.36; p=0.004). Retinal drusen in either eye was observed in 15.00% (95% CI: 9.60 - 22.68%) of the animals, which was also significantly associated with age (OR=1.14; 95%CI: 1.02 - 1.27; p=0.020). ConclusionsRhesus macaques exhibit age-related ocular associations similar to those observed in human aging, including decreased corneal thickness, increased axial length, myopic shift, and higher occurrence of cataract and retinal drusen.

systems biology↗

bioRxiv2021

Adaptive spectroscopic visible-light optical coherence tomography for human retinal oximetry

Alterations in the retinal oxygen saturation (sO2) and oxygen consumption are associated with nearly all blinding diseases. A technology that can accurately measure retinal sO2 has the potential to improve ophthalmology care significantly. Recently, visible-light optical coherence tomography (vis-OCT) showed great promise for noninvasive, depth-resolved measurement of retinal sO2 as well as ultra-high resolution anatomical imaging. We discovered that spectral contaminants (SC), if not correctly removed, could lead to incorrect vis-OCT sO2 measurements. There are two main types of SCs associated with vis-OCT systems and eye conditions, respectively. Their negative influence on sO2 accuracy is amplified in human eyes due to stringent laser power requirements, eye motions, and varying eye anatomies. We developed an adaptive spectroscopic vis-OCT (Ads-vis-OCT) method to iteratively remove both types of SCs. We validated Ads-vis-OCT in ex vivo bovine blood samples against a blood-gas analyzer. We further validated Ads-vis-OCT in 125 unique retinal vessels from 18 healthy subjects against pulse-oximeter readings, setting the stage for clinical adoption of vis-OCT.

bioengineering↗

bioRxiv2021

In Vivo Sublayer Analysis Of Human Retinal Inner Plexiform Layer Obtained By Visible-Light Optical Coherence Tomography

PurposeGrowing evidence suggests, in glaucoma, the dendritic degeneration of subpopulation of the retinal ganglion cells (RGCs) may precede RGCs soma death. Since different RGCs synapse in different IPL sublayers, visualization of the lamellar structure of the IPL could enable both clinical and fundamental advances in glaucoma understanding and management. In this pilot study, we investigated whether visible-light optical coherence tomography (vis-OCT) could detect the difference in the inner plexiform layer (IPL) sublayers thicknesses between small cohorts of healthy and glaucomatous subjects. MethodWe investigated vis-OCT retinal images from nine healthy and five glaucomatous subjects. 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. Raster speckle-reduction scans (3 by 3 by 1.2 mm^3: horizontal; vertical; axial directions with 8192x8x1024 samplings, respectively) of the superior macular were acquired. IPL sublayers were then manually segmented using averaged A-line profiles. ResultsThe mean ages of glaucoma and healthy subjects are 59.6 +/- 13.4 and 45.4 +/- 14.4 years (p =0.02, Wilcoxon rank-sum test), respectively. The visual field mean deviation (MD) are -26.4 to -7.7 dB in glaucoma patient and -1.6 to 1.1 dB in healthy subjects (p =0.002). The mean circumpapillary retinal nerve fiber layer (RNFL) thicknesses are 59.6 +/- 9.1 m in glaucoma and 99.2 +/- 16.2 m in healthy subjects (p=0.004). Median coefficients of variation (CVs) of intra-session 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 entire IPL thicknesses are 36.2 +/- 1.5 m in glaucomatous and 40.1 +/- 1.7 micrometer in healthy eyes (p=0.003, Mixed-effects model). We found that the middle sublayer thickness was responsible for the majority of the difference (14.2 +/- 1.8 m in glaucomatous and 17.5 +/- 1.4 in healthy eyes, p<0.01). ConclusionsIPL 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. Visualization of the IPL sublayers may enable the investigation of lamella-specific changes in the IPL in glaucoma and may help elucidate the response of different types of RGCs to the disease.

bioengineering↗

bioRxiv2020

Interplay between intraocular and intracranial pressure effects on the optic nerve head in vivo

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 Bruchs membrane opening (BMO) under acute elevation of IOP and/or ICP. Four eyes of three 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 0.17mm2 at baseline IOP, and contracted BMO area by 0.02 mm2 at high IOP. ICP elevation decreased ALC depth by 10m at baseline IOP, but increased depth by 7 m 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 mm2 at baseline ICP, and contracted BMO area by 0.09 mm2 at high ICP. On average, IOP elevation caused the ALC to displace 3.3 m anteriorly at baseline ICP, and 22 m 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. Research Highlights- In vivo ONH deformations caused by acute, controlled, simultaneous changes in IOP and/or ICP can be directly visualized and measured in the monkey eye using OCT. - Acute changes of either IOP or ICP significantly deformed both the scleral canal and the lamina cribrosa, regardless of the other pressure level. - Pressures interacted, meaning that the effects of one pressure depended significantly on the level of the other pressure. - Elevating both pressures did not cancel out the effects of one of them being elevated. - Our results show that ICP affects sensitivity to IOP, and thus that it can potentially also affect susceptibility to glaucoma.

bioengineering↗