December 2023
Volume 64, Issue 15
Open Access
Glaucoma  |   December 2023
Displacement of the Lamina Cribrosa With Acute Intraocular Pressure Increase in Brain-Dead Organ Donors
Author Affiliations & Notes
  • Christopher A. Girkin
    Department of Ophthalmology, University of Alabama at Birmingham/Callahan Eye Hospital, Birmingham, Alabama, United States
  • Mary A. Garner
    Department of Neuroscience, University of Alabama at Birmingham School of Medicine, Birmingham, Alabama, United States
  • Stuart K. Gardiner
    Devers Eye Institute, Legacy Health, Portland, Oregon, United States
  • Mark E. Clark
    Department of Ophthalmology, University of Alabama at Birmingham/Callahan Eye Hospital, Birmingham, Alabama, United States
  • Meredith Hubbard
    Legacy of Hope, Birmingham, Alabama, United States
  • Udayakumar Karuppanan
    Department of Ophthalmology, University of Alabama at Birmingham/Callahan Eye Hospital, Birmingham, Alabama, United States
  • Gianfranco Bianco
    Department of Ophthalmology, University of Alabama at Birmingham/Callahan Eye Hospital, Birmingham, Alabama, United States
  • Luigi Bruno
    Department of Mechanical, Energy and Management Engineering, University of Calabria, Rende, Italy
  • Massimo A. Fazio
    Department of Ophthalmology, University of Alabama at Birmingham/Callahan Eye Hospital, Birmingham, Alabama, United States
  • Correspondence: Massimo A. Fazio, Department of Ophthalmology and Visual Sciences, University of Alabama at Birmingham, 1720 University Blvd., CEH 609, Birmingham, AL 35294, USA; massimofazio@uabmc.edu
Investigative Ophthalmology & Visual Science December 2023, Vol.64, 19. doi:https://doi.org/10.1167/iovs.64.15.19
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      Christopher A. Girkin, Mary A. Garner, Stuart K. Gardiner, Mark E. Clark, Meredith Hubbard, Udayakumar Karuppanan, Gianfranco Bianco, Luigi Bruno, Massimo A. Fazio; Displacement of the Lamina Cribrosa With Acute Intraocular Pressure Increase in Brain-Dead Organ Donors. Invest. Ophthalmol. Vis. Sci. 2023;64(15):19. https://doi.org/10.1167/iovs.64.15.19.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Purpose: To examine deformations of the optic nerve head (ONH) deep tissues in response to acute elevation of intraocular pressure (IOP).

Methods: Research-consented brain-dead organ donors underwent imaging by spectral domain optical coherence tomography (OCT). OCT imaging was repeated while the eye was sequentially maintained at manometric pressures of 10, 30, and 50 mm Hg. Radial scans of the ONH were automatically segmented by deep learning and quantified in three dimensions by a custom algorithm. Change in lamina cribrosa (LC) depth and choroidal thickness was correlated with IOP and age by linear mixed-effect models. LC depth was computed against commonly utilized reference planes.

Results: Twenty-six eyes from 20 brain-dead organ donors (age range, 22–62 years; median age, 43 years) were imaged and quantified. LC depth measured against a reference plane based on Bruch's membrane (BM), BM opening, and an anterior sclera canal opening plane showed both a reduction and an increase in LC depth with IOP elevation. LC depth universally increased in depth when measured against a sclera reference plane. Choroidal (−0.5222 µm/mm Hg, P < 0.001) and retinal nerve fiber layer thickness (−0.0717 µm/mm Hg, P < 0.001) significantly thinned with increasing IOP. The magnitude of LC depth change with IOP was significantly smaller with increasing age (P < 0.03 for all reference planes).

Conclusions: LC depth changes with IOP reduce with age and are significantly affected by the reference plane of choice, which highlights a need for standardizing LC metrics to properly follow progressive remodeling of the loadbearing tissues of the ONH by OCT imaging and for the definition of a reference database.

The optic nerve head (ONH) is the primary site of injury common to glaucomatous optic neuropathies where retinal ganglion cell axons traverse the large pressure gradient across the lamina cribrosa.1 The pressure gradients produce mechanical strains that can directly damage these axons, reduce ONH perfusion, and activate cellular processes involved in inflammation, mitophagy, and remodeling.2 Spectral domain optical coherence tomography (OCT) allows for the in vivo quantification of the morphology of these deeper loadbearing tissues (i.e., the lamina cribrosa [LC] and the peripapillary sclera [ppScl]) distinct from the overlying neurovascular tissues they support.3 Several clinical studies using OCT have attempted to estimate the mechanical properties of the loadbearing tissues of the optic nerve head while increasing intraocular pressure (IOP) in vivo in order to develop mechanistic predictors of the development and progression of glaucoma.46 
These prior imaging studies altered IOP acutely by ophthalmodynamometric compression,49 the application of tight-fitting goggles,10 applying negative pressure through goggles,1113 and with the dark room14 and water drinking tests.15 Acute changes in the LC position have also been evaluated following surgical and medical reductions in IOP.5,1618 These studies have demonstrated that the LC appears to move both anteriorly and posteriorly in response to changes in IOP. It has been suggested that scleral rigidity may modulate this effect in eyes with less rigid sclera where scleral canal expansion may pull the LC anteriorly19,20; however, these studies have major limitations such as being based on numerical models lacking empirical validation. There is currently no methodology to apply a precise IOP load and directly measure IOP at the time of acute elevation. Moreover, the compressive4,21 or stretching11,22 methods to acutely elevate IOP may impact corneal curvature and hence induce optical distortions in the follow-up scans. Lastly, most of the studies to date employed a reference plane based on Bruch's membrane opening (BMO) position,46 which is also impacted by changes in IOP due to the high compressibility of the choroidal tissue and its thinning with age.23,24 The purpose of this study is to determine the impact of manometrically controlled IOP elevation and of the chosen reference plane on the morphometry of the LC and choroid in the living human eye. 
Methods
In this study, we induced controlled mechanical deformations to the ONH by inducing acute IOP elevation in the living human eyes of research-consented brain-dead organ donors seen in the Donor Recovery Center of the Legacy of Hope organ recover program in Birmingham, Alabama (formerly known as “The Alabama Organ Center”). The Living Eye Project is a collaboration with the authors’ laboratories, Advancing Sight Network (formerly Alabama Eye Bank) and Legacy of Hope. This program enables examination, imaging, electrophysiology, and IOP manipulation to be performed in research-consented brain-dead organ donors in vivo, hereinafter referred to as “living donors,” while the tissues can be rapidly made available for ex vivo experiments. The study was approved by the institutional review board as nonhuman subjects research and by the research oversight committee for the Legacy of Hope organ procurement center. 
Screening Criteria
The enrollment process has been previously described.25,26 Briefly, all donors are screened and the next of kin interviewed by a certified tissue procurement technician to obtain the medical and ophthalmic history of donors consented for organ and tissue transplant and research. Consented donors’ charts are reviewed, and the research team discusses inclusion of the eye for research with Advancing Sight Network to determine tissue availability and, when needed, with the medical examiner to ensure ocular tissues are not required for forensic needs. Following these approvals, all the eyes were directly examined by a specialist in glaucoma and neuro-ophthalmology (CAG). The exam included examination of the anterior segment and ocular fundus examination by binocular indirect ophthalmoscopy. Donors were excluded with (1) any history of significant ocular trauma, surgery, or eye disease other than cataracts or cataract surgery; (2) any systematic disorders known to affect the retina and/or ONH; (3) any significant abnormalities or agonal effects of the ONH or retina (i.e., retinal ischemia, papilledema) detected on funduscopic examination; (4) significant swelling or abnormalities of the ocular adnexa; or (5) low blood pressure. One or both of the eyes were selected for testing based on discussion with the organ procurement team prioritizing the needs of the procurement process. Living donors that passed this screening underwent baseline OCT and OCT angiography (OCTA) imaging, and patients with any OCT/A signs for disc edema or other macular or optic nerve pathology were excluded from further testing. 
IOP Control
IOP was manometrically controlled by anterior chamber cannulation and by adjusting the height of a phosphate-buffered saline solution bottle relative to the living donor's eye height, which was precisely set with the assistance of a self-leveling cross-line laser (Bosch GmbH, Gerlingen, Germany). The eye was cannulated with a 25-gauge anterior chamber maintainer (Anodyne Surgical, Inc, O'Fallon, MO, USA) through a 1-mm keratome incision in the peripheral cornea. IOP was measured by a digital manometer (XP2i, Crystal Engineering; San Luis Obispo, CA, USA) in line with the infusion into the anterior chamber to monitor inflow pressure. Starting from a baseline of 10 mm Hg, IOP was incrementally set at 30 and 50 mm Hg, with OCT imaging performed at baseline and following each incremental increase. The cornea was lubricated with balanced salt solution, and a rigid gas-permeable contact lens was fitted on the cornea to prevent evaporation, enhance OCT image quality, and avoid magnification changes during the follow-up imaging. IOP was set and kept constant for 2 minutes before acquisition of the baseline OCT scan and maintained at the same pressure throughout the OCT scan. Following each IOP elevation step, IOP was maintained constant for 2 minutes before capturing and throughout the follow-up OCT scans. 
Imaging
OCT imaging was performed with second-generation spectral domain OCT/A equipped with research software (Spectralis OCT2; Heidelberg Engineering Inc., Heidelberg, Germany) and modified to mount the imaging head on a custom counterweighted support arm that allows for six-axis fine manipulation (Spectralis Flex Module; Heidelberg Engineering Inc.). With the organ donor in a supine position, baseline and follow-up high-resolution 15° radial scans of the ONH were performed. These consisted of 24 B-scans made up of 768 A-scans with 25 to 30 images averaged/B-scan. The axial scaling factor was 3.87 µm for all the eyes, and the lateral scaling factor was 5.36 µm, on average. 
Quantification of the ONH Morphology
A custom nonstochastic automated three-dimensional (3D) quantification method of the ONH morphology was used to automatically parametrize the ONH layers of interest. A detailed description of the parametrization approach is described in Fazio et al.25 The 3D coordinates of that delimiting the surfaces for each layer (Fig. 1) were computed by a commercial deep learning autosegmentation software (Reflectivity; Abyss Processing, Pte Ltd, Singapore) instead of being manually delineated. Estimated parameters to characterize the change in ONH morphology with IOP were LC depth against a BMO reference plane (LC depth–BMO), LC depth against a Bruch's membrane (BM) reference plane (LC depth–BM), LC depth against an anterior sclera (AS) canal opening (ASCO) reference plane (LC depth–ASCO), and LC depth against a sclera (Scl) reference plane (LC depth–Scl) (Fig. 1). The reference planes for BMO and ASCO were computed by linear interpolation of the BMO and ASCO points, respectively. The BM and Scl reference planes were computed by linear fitting of the BM and AS points belonging to a 250-µm-wide anulus radially distant 1750 µm from the ONH center defined by the BMO points centroid. 
Figure 1.
 
(a) Highlights of the major retinal layer delineated by a commercial deep learning software (Reflectivity; Abyss) and of the parametrization of the four reference planes used for computing laminar depth: BMO, BM, ASCO, and sclera reference plane. The BMO points are marked in green; the ASCO points are marked in yellow; ALCS points are marked in red. Delineation points of the internal limiting membrane (blue), retinal nerve fiber layer (RNFL; cyan), ganglion cell layer (GCL; magenta), and posterior lamina surface (dark red) are shown for illustration purposes only. (b) Graphical representation of the 3D spatial distribution of the BM points (green), sclera anterior surface points (yellow), ALCS points (red), and volume of interest used to compute central LC depth, which was defined as the intersection of the ALCS, the given reference plane, and a 350-µm-wide cylinder oriented normally to the reference plane of choice.
Figure 1.
 
(a) Highlights of the major retinal layer delineated by a commercial deep learning software (Reflectivity; Abyss) and of the parametrization of the four reference planes used for computing laminar depth: BMO, BM, ASCO, and sclera reference plane. The BMO points are marked in green; the ASCO points are marked in yellow; ALCS points are marked in red. Delineation points of the internal limiting membrane (blue), retinal nerve fiber layer (RNFL; cyan), ganglion cell layer (GCL; magenta), and posterior lamina surface (dark red) are shown for illustration purposes only. (b) Graphical representation of the 3D spatial distribution of the BM points (green), sclera anterior surface points (yellow), ALCS points (red), and volume of interest used to compute central LC depth, which was defined as the intersection of the ALCS, the given reference plane, and a 350-µm-wide cylinder oriented normally to the reference plane of choice.
Definition of LC Depth
LC depth was computed as the 3D average distance between the anterior LC surface (ALCS) and any of the four reference planes (BMO, BM, ASCO, and Scl). The median BMO radius was 1.5 mm. The central portion of the lamina was set as one-fourth of the BMO radius (or 350 µm). We also performed an analysis using the entire visible ALCS, which provided similar results (Supplementary Table S2). Averaging occurred within a central volume defined by the geometrical 3D intersection with the ALCS of a 350-µm radially wide cylinder oriented normally to each reference plane of choice. Graphical representation of the volume of interest used for computing LC depth is depicted in Figure 1b. 
Definition of LC Displacement
Change in laminar depth of each follow-up scan (30 and 50 mm Hg) against their baseline depth (10 mm Hg scan) was used as the metric for directional displacement of the LC. A positive relative change was counted as a posterior displacement of the lamina. A negative relative change was counted as an anterior displacement of the LC. 
Definition of Choroidal Thickness
Choroidal thickness was computed as the 3D average distance between a subset of points belonging to the BM and AS falling in a 250-µm-wide anulus radially distant 1750 µm from the ONH center. Graphical representation of the volume of interest used for computing the BM and AS subset point is depicted in Figure 1b. 
Definition of Retinal Nerve Fiber Layer Thickness Thickness
Similarly to the computation of choroidal thickness, retinal nerve fiber layer thickness (RNFL) thickness was computed as the 3D average distance between a subset of points belonging to the internal limiting membrane (ILM) (Fig. 1a, blue-colored profile) and anterior ganglion cell layer boundary (Fig. 1a, magenta-colored profile) falling in a 250-µm-wide anulus radially distant 1750 µm from the ONH center. 
Statistical Analysis
Linear mixed-effects models were used to assess the effect of acute IOP elevation on the relative change in position of the LC, choroidal, and RNFL thickness while accounting for the correlation between eyes from the same donor (R software with the NLME package; R Foundation for Statistical Computing, Vienna, Austria). Relative positive change in depth was defined as the posterior movement per mm Hg change in IOP compared to baseline (10 mm Hg). The number of eyes in which the LC was displaced anteriorly versus posteriorly was calculated and compared between reference planes using McNemar's test. To highlight a possible nonlinear response of the ONH morphologic parameters, linear regression was separately fitted over the IOP subranges of 10 to 30 mm Hg and 30 to 50 mm Hg. 
Results
In accordance with the stated inclusion criteria, 26 eyes from 20 living organ donors were included in the study. Age ranged from 22 to 62 years with median age of 43 years. LC depth as it changed with IOP largely varied depending on the reference plane against which it was computed. Donor characteristics on cause of death are summarized in Supplementary Table S1
Directional Displacement of Laminar Depth as It Varies With Reference Plane
When computed against BMO points the LC of 11 eyes displaced anteriorly and 15 eyes posteriorly, as reported in the contingency matrix (Table 1) and shown in Figure 2a. LC displaced primarily posteriorly (Figs. 2b, 2c) when computed against a BM and ASCO reference plane (Table 1). LC universally displaced posteriorly when computed against a sclera reference plane (Table 1Fig. 2d). Pairwise McNemar's tests comparing reference planes in terms of the frequency of anterior versus posterior displacement are shown in Table 1. The test was significantly different for the BMO versus ASCO directional displacement counts (P = 0.0082). The test was consistently significantly different for the counts against the sclera reference plane (BMO versus Scl, P = 0.0009; BM versus Scl, P = 0.02535; ASCO versus Scl, P = 0.0455). Using a sclera reference plane significantly reduced the number of eyes exhibiting anterior displacement, resulting in a more consistent direction of displacement between eyes. 
Table 1.
 
Contingency Matrix of the Directional Displacement of the LC With Acute IOP Increase When Computed Against the Four Reference Planes: (a) BMO, (b) BM, (c) ASCO, and (d) Scl
Table 1.
 
Contingency Matrix of the Directional Displacement of the LC With Acute IOP Increase When Computed Against the Four Reference Planes: (a) BMO, (b) BM, (c) ASCO, and (d) Scl
Figure 2.
 
Changes in morphologic parameters with IOP. (a–d) Change in the anterior lamina cribrosa surface depth (ALCSD) with a manometrically controlled 40 mm Hg increase in IOP when measured against four reference planes of interest: (a) BMO, (b) BM, (c) ASCO, and (d) Scl. The change in ALCSD computed against a BMO reference plane showed the most variability of ALCS either displacing anteriorly or posteriorly across eyes. Change in ALCSD computed against a Scl reference plane rather showed that LC uniquely displaced posteriorly with increasing IOP. (e, f) Changes in choroidal (e) and RNFL thickness (f) with 40 mm Hg of IOP increase; choroid and RNFL thickness decreased in response to IOP elevation for most of the eyes. Note that IOP is reported as relative change from baseline (10 mm Hg).
Figure 2.
 
Changes in morphologic parameters with IOP. (a–d) Change in the anterior lamina cribrosa surface depth (ALCSD) with a manometrically controlled 40 mm Hg increase in IOP when measured against four reference planes of interest: (a) BMO, (b) BM, (c) ASCO, and (d) Scl. The change in ALCSD computed against a BMO reference plane showed the most variability of ALCS either displacing anteriorly or posteriorly across eyes. Change in ALCSD computed against a Scl reference plane rather showed that LC uniquely displaced posteriorly with increasing IOP. (e, f) Changes in choroidal (e) and RNFL thickness (f) with 40 mm Hg of IOP increase; choroid and RNFL thickness decreased in response to IOP elevation for most of the eyes. Note that IOP is reported as relative change from baseline (10 mm Hg).
ONH Changes With Acute IOP Elevation
Laminar depth displacement (relative change from baseline metrics), choroidal and RNFL thickness changes with IOP, and the interaction of IOP with age across the range of IOP are reported in Table 2 and shown in Figure 2. For all the reference planes against which ALCS depth was computed, estimates of the mean coefficient for the IOP was positive and significant (Table 2), indicating that, on average, ALCS depth consistently moved posteriorly with IOP increase. In all subjects, choroidal thickness was significantly and consistently (Fig. 2e) reduced with elevation in IOP (−0.5218 µm/mm Hg, P < 0.0001; Table 2). Similar to the choroid, RNFL thickness was significantly and consistently (Fig. 2f) reduced with elevation in IOP (0.07168 µm/mm Hg, P < 0.0001; Table 2). 
Table 2.
 
Estimates of the Relative Change From Baseline (10 mm Hg) Metrics of the ALCS Depth, Choroidal Thickness, and RNFL Thickness to an Acute Increase of IOP
Table 2.
 
Estimates of the Relative Change From Baseline (10 mm Hg) Metrics of the ALCS Depth, Choroidal Thickness, and RNFL Thickness to an Acute Increase of IOP
Nonlinear Response of the ONH Response to IOP Elevation
Laminar depth displacement (relative change from baseline metrics), choroidal and RNFL thickness changes with IOP, and the interaction of IOP with age for IOP elevation from 10 to 30 mm Hg and from 30 to 50 mm Hg are reported separately in Table 2 and illustrated in Figure 3. Graphically, greater laminar displacement was noticeable when the IOP was elevated from 10 to 30 mm Hg than from 30 to 50 mm Hg In contrast, the RNFL and choroid exhibited similar thinning rates for the stepwise regression of the 10 to 30 mm Hg and 30 to 50 mm Hg changes in IOP (Fig. 3; blue regressive lines, plots e and f) and for the overall IOP change from 10 to 50 mm Hg (Fig. 3; red regressive line, plots e and f). 
Figure 3.
 
Linear and stepwise morphologic changes with IOP. (a–d) Change in the ALCSD with stepwise (10–30 and 30–50 mm Hg; blue regressive lines) and overall (10–50 mm Hg; red lines) change in IOP against the four reference planes of interest. Graphically, it is noticeable that the ALCSD exhibited greater change when IOP was elevated from 10 to 30 mm Hg than from 30 to 50 mm Hg. (e, d) The decrease in choroidal (e) and RNFL thickness (f) was similar for the stepwise (10–30 and 30–50 mm Hg; blue) and overall change in IOP (10–50 mm Hg; red). Note that IOP is reported as relative change from baseline (10 mm Hg).
Figure 3.
 
Linear and stepwise morphologic changes with IOP. (a–d) Change in the ALCSD with stepwise (10–30 and 30–50 mm Hg; blue regressive lines) and overall (10–50 mm Hg; red lines) change in IOP against the four reference planes of interest. Graphically, it is noticeable that the ALCSD exhibited greater change when IOP was elevated from 10 to 30 mm Hg than from 30 to 50 mm Hg. (e, d) The decrease in choroidal (e) and RNFL thickness (f) was similar for the stepwise (10–30 and 30–50 mm Hg; blue) and overall change in IOP (10–50 mm Hg; red). Note that IOP is reported as relative change from baseline (10 mm Hg).
Figure 4.
 
Scatterplots of the association with age and change in morphologic parameters following elevation from 10 to 30 mm Hg (ΔIOP = 20, red) and from 10 to 50 mm Hg (ΔIOP = 40, blue). The association with age and ALCSD with a manometrically controlled increase in IOP when measured against four reference planes of interest: (a) BMO, (b) BM, (c) ASCO, and (d) Scl. The ALCSD exhibited less deformation in older donors when IOP was elevated from 10 to 30 mm Hg and similarly from 10 to 50 mm Hg. The decrease in choroidal (e) and RNFL thickness (f) did not vary significantly with age.
Figure 4.
 
Scatterplots of the association with age and change in morphologic parameters following elevation from 10 to 30 mm Hg (ΔIOP = 20, red) and from 10 to 50 mm Hg (ΔIOP = 40, blue). The association with age and ALCSD with a manometrically controlled increase in IOP when measured against four reference planes of interest: (a) BMO, (b) BM, (c) ASCO, and (d) Scl. The ALCSD exhibited less deformation in older donors when IOP was elevated from 10 to 30 mm Hg and similarly from 10 to 50 mm Hg. The decrease in choroidal (e) and RNFL thickness (f) did not vary significantly with age.
Interaction With Age
For all the reference planes against which ALCS depth was computed, estimates of the mean coefficient for the IOP and age interaction were negative, indicating that there was less IOP-induced posterior displacement of the LC with increasing age (Fig. 4). Statistical significance for the interaction term was P = 0.0137 for LC computed against a BMO reference plane, P = 0.0272 for LC computed against a BM reference plane, P = 0.0064 for LC computed against an ASCO reference plane, and P = 0.0025 for LC computed against a sclera reference plane. 
Goodness of fit of the sclera reference plane model was the highest among all other reference plane models, as evincible in Table 2 by comparing marginal and conditional R2s for all models. 
There was no significant association between RNFL (P = 0.1628) or choroidal thickness (P = 0.5517) with age (Table 2 and Fig. 4). 
Discussion
The current study demonstrates a consistent change in ONH morphology seen with increasing IOP in the living eyes of organ donors under direct manometric measurement and control of IOP. These changes included compression of the choroid and consistent deepening of the LC depending on what reference plane was used. We also found a significant association with aging and the mechanical behavior of the LC with less posterior deformation of the LC seen with aging. 
This could be due to age-related stiffening of the ocular coat or of the LC itself, resulting in less compliance in response to IOP elevation with age. 
To our knowledge, this is the first study to evaluate optic nerve compliance in brain-dead organ donors and provides findings that contradict results seen in prior studies that noninvasively examine acute and chronic LC deformation in human eyes using noninvasive methods to alter IOP acutely in living patients.49 When measured from the BMO or BM-based reference plane, LC depth mostly displaced posteriorly with a few subjects deviating anteriorly. However, LC depth measurements made using these reference planes also include changes in the choroid, a highly compressible and mostly vascular tissue. Thus, apparent shallowing of the LC based on these reference planes may be driven by the significant choroidal compression seen in these eyes. The effect of choroidal thickness on BMO position is in agreement with our prior studies using in vivo OCT imaging in human eyes that first demonstrated this relationship,27 which was confirmed in a large multicenter study.28 
The impact of the choroid is further noted when using scleral-based reference planes, which reduced or eliminated anterior deformation of the LC with increasing IOP in the cohort when using either extrapolated ASCO-based or peripheral scleral-based reference planes. Using the ASCO-based approaches, three eyes showed possible slight anterior deformation of the LC, while with the peripheral scleral reference plane, all eyes showed posterior deformation. While it is unclear why there are differences in these scleral approaches, the ASCO points are measured at the anterior scleral canal boundary defined by extrapolation from the pericentral scleral plane, and thus these measurements are made based on the orientation of the tissues of the scleral flange and not a direct measurement of the ASCO. ASCO is not a reliably visible structure on OCT and is impossible to pinpoint in many locations. Nasally, there is shadowing, and temporally, it is less clear where the sclera terminates as the scleral rim slopes into the scleral canal. In contrast, the scleral reference plane is based on a directly observed structure. Even in eyes with thick choroid, the choroidal–scleral interface remains quite visible, especially after light attenuation compensation and with the deep learning segmentation as the features defining this interface are sharply contrasting in texture. Also, a scleral surface is mostly perpendicular to the scanning beam, which increases visibility of the structure. Moreover, the thin scleral flange tissue can also clearly deform posteriorly in some eyes with acute IOP elevation (see Supplementary Video S1), which could also mask deepening of the LC. The peripheral scleral reference plane is based farther out from the ONH where the sclera is thicker, more rigid, more perpendicular to the scanning beam, and likely less prone to deformation in response to IOP. 
To our knowledge, the current study was the first of its kind to examine the impact of manometrically controlled IOP elevation in living eyes. While the disparity between the current findings in the organ donor eye and prior efforts in living subjects is not clear, it is important to note that the prior noninvasive approaches do not afford tight control of the elevation in IOP and cannot measure IOP at the time imaging is performed. 
Several cross-sectional OCT studies in human subjects have evaluated laminar surface depth and found associations with aging2932 and advancing glaucoma severity,29,33,34 have been histologically validated,25 and have shown significant differences between diseased, ocular hypertensive and normal eyes.35,36 Longitudinally, these metrics have been shown to change with progressive glaucoma31,37,38 and to be associated with visual field and retinal nerve fiber layer progression.37,39 Moreover, LC surface changes have been shown to precede RNFL loss in the chronically elevated IOP nonhuman primate model.40,41 Anterior and posterior remodeling of the LC has been demonstrated across all of these studies regardless of reference plane used. These chronic changes reflect remodeling of these tissues, which is important in defining pathologic and age-related remodeling. In contrast, acute changes in ONH morphology in response to acute IOP elevation reflect the material properties and morphology of these tissues.42 There is a significant variation in measurement planes used across these studies, which makes interpretation more challenging. 
The in vivo mechanical compliance of the loadbearing connective tissues of the ONH have been measured as lamina deformations based on depth and curvature changes using manual and automated methods or by utilizing digital volume correlation (DVC)16,43,44 to estimate the measurement of LC strain. DVC estimates of LC strain along with shifts in LC surface position have been estimated following acute changes in IOP after suture lysis posttrabeculectomy45 and with ophthalmodynamometric compression (ODM).49 Short-term responses have also been evaluated following surgical46 or medical IOP lowering,47,48 but these changes may incorporate more chronic remodeling responses as well. ODM measurements of IOP elevation in human subjects are the most similar to the current study, which focuses on changes in LC surface position following manometric IOP elevation. Our findings contrast with a current hypothesis regarding the impact of scleral rigidity on the direction of LC deformation19,20 and inform the use of these metrics that have been and are currently employed in longitudinal studies. 
One difficulty with comparing these results with in vivo human studies is the variation in the time of measurements across studies. Agoumi et al.6 performed imaging at approximately 2 minutes after compressive IOP elevation, while Fazio et al.4 obtained images at 1 and 5 minutes. Chuangsuwanich et al.9 measured pressure 2 to 3 minutes following IOP elevation. Beotra et al.8 and Gizzi et al.5 did not mention a specific time, just that it was immediately after elevation. In the clinical setting, as mentioned by Agoumi et al.,6 there is some variability in the timing these images are obtained. In the organ center setting under manometric control, these measurements can be performed at more precise intervals. 
Comparing the magnitude of depth changes across studies that reported laminar deformation is also made more difficult by the various approaches used. Agoumi et al.6 used a BMO-based reference plane in normal and glaucoma subjects using an applied force of 30 to 40 Pa, attempting an increase of approximately 10 mm Hg, and found that the LC surface displaced posteriorly an average of 0.15 microns/mm Hg. Fazio et al.4 used a similar approach in normal subjects and found a posterior deflection of 0.23 microns/mm Hg in the overall group but found directional differences based across racial groups. Beotra et al.8 found the LC posteriorly displaced an average of 0.17 microns/mm Hg with an applied force estimated to achieve an IOP elevation in their normal group from a mean of 17 mm Hg to a pressure of 38 mm Hg and –0.13 microns/mm Hg of posterior deflection when raised from baseline to an estimated mean of 46 mm Hg. The current study, using the same reference plane, showed a larger magnitude of change (–0.38 microns/mm Hg) when manometric pressures were elevated from 10 to 30 mm Hg and less change when pressure was elevated from 30 to 50 mm Hg (–0.18 microns/mm Hg). This nonlinear response of these tissues to IOP elevation is similar to what was demonstrated by Beotra et al.8 
Moreover, these compression-based approaches to acutely alter IOP could potentially deform the cornea, which might interfere with imaging by inducing magnification errors that would be indistinguishable from IOP-induced deformations. Several key differences exist between the current approach and prior studies elevating IOP in living subjects. First, we imaged all subjects with a hard contact lens to minimize loss of image quality due to corneal tear evaporation. Since the manometric approach does not require focal deformation of the globe to increase IOP, as used in living subjects, possible changes in corneal curvature should not induce magnification artifacts. Also, the presence of a hard contact lens during imaging further reduced any influence of optical magnifications. Additionally, IOP is directly measured concurrently with imaging, which is not possible in clinical subjects. Lastly, it is possible that there was an impact of the lack of voluntary subject motion in the organ donor. 
The scleral mechanical response to IOP is known to be nonlinear.24 Our result confirms this expected nonlinear response in that most of the LC deformation occurs as the eye is elevated from 10 to 30 mm Hg, with less change at higher pressures (Table 2Fig. 3). In contrast, the nonloadbearing tissues of the ONH exhibit a similar magnitude of change across this IOP range. However, proper characterization of the nonlinear model would require collection of more than three datapoints. The small time window available for imaging the brain-dead organ donors is a significant impediment to developing a more accurate characterization of the nonlinear morphologic changes with IOP. 
The age range for the tested organ donors in the current study was lower than that of the living subjects. However, the studies performed in living subjects suggested that there was greater anterior deformation in younger patients, so this could not explain the universally posterior deformations seen with a scleral reference plane. These prior observations led to the development of the hypothesis that increased scleral rigidity with aging results in greater posterior deformation of the LC and may contribute to the higher risk for developing glaucoma with advancing age.49,50 The findings of the current study, evaluated under invasive control and precise measurements, do not show this bidirectional deformation in the LC. In contrast, the current study shows that the magnitude of LC increase in depth in response to acute IOP decreases with aging. These findings call into question the theory that increased scleral rigidity with age may induce greater LC posterior deformation and suggests that there is an age-related stiffening of the LC tissues. 
These findings support work in human cadaveric eyes and tissue culture models51 that strain-related stiffening in the LC leads to increasing fibrosis with aging and disease, which in turn leads to greater pathologic fibrotic response. Increased mechanical rigidity with age and glaucoma has been widely experimentally validated with various techniques in the sclera.5260 
There are several limitations to this study. As mentioned, previously, the age range is relatively narrow due to the available study population (range, 20–66 years; median, 43 years). Thus, aging effects may not have been fully explored. In addition, research in the organ donor setting must be done in a way that does not interfere with the donor process, does not result in prolonged experimentation, and is respectful to the family and donor. These experiments are conducted in an intensive care setting and are necessarily limited in duration and scope.6164 Thus, there is a limited testing window afforded in the organ donor setting that does not allow for prolonged imaging under the current protocols. The longer-term impact of IOP elevation on ocular structures cannot be ascertained. Lastly, low prevalence conditions such as glaucoma are not able to be studied beyond a few cases. Thus, this approach can only examine impacts of common factors (i.e., demographic variation) or acute exposures. While the opportunity to carefully control pressure and for in vivo examination in the same eye that is available for ex vivo experimentation is promising, it is only complementary to human clinical studies and animal and tissue culture models that afford longitudinal evaluation of exposures. 
Lastly, an additional important consideration is that it is possible the cause of death may have impacted the perfusion, morphology, or mechanical behavior of the retina or optic nerve. To minimize this impact, we carefully screened all donors included in this study with funduscopic examination, OCT, and OCTA and excluded any agonal abnormality of the retina or optic nerve, including any retinal hemorrhages or infarctions, as well as any sign of optic disc edema on OCT or fundoscopic exam. Moreover, we did not include any subjects with a low or unstable blood pressure or subjects that showed any overt perfusion defects on OCTA. 
While this is a limitation of research in this setting, it is also common to all research involving postmortem human tissue, which is limited to examination of cadaveric tissues and the available medical record if any. The ability to directly examine the eye in vivo to determine normality is a significant advantage, and future work evaluating the electroretinogram (ERG) and OCTA response in organ donors would clarify if there are subclinical signs of abnormalities in brain-dead organ donor eyes. 
Despite these limitations, this approach affords the opportunity to define the impact of the tissue effects of IOP elevation in vivo in the living eye of organ donors, paving the way to correlate these in vivo structural changes with cellular and molecular responses of the optic nerve evaluated ex vivo. 
In summary, this study has demonstrated that the mechanical response of the LC to acute elevations in IOP was consistent in direction across individuals, showing consistent posterior deformation of the LC and RNFL and choroidal compression. While the direction of laminar deformation may differ in this model from that seen in in vivo studies, it does not mean that scleral rigidity is not a significant factor in defining the mechanical behavior of the ONH, as animal and computational models clearly indicate there are significant associations,19,20 just that the manner of interaction may be different than anticipated. We have performed scleral inflation studies on most of these eyes and will be able to more directly define this relationship in the future. Further research correlating the responses of ex vivo mechanical testing of the ocular coat could clarify any association between the rigidity of the sclera and the variation in deformation of the LC seen with elevation in IOP. 
Acknowledgments
Disclosure: C.A. Girkin, National Eye Institute (F), Research to Prevent Blindness (F), EyeSight Foundation of Alabama (F), Heidelberg Engineering GmbH (F), Topcon Medical Inc. (F), Iridex (C); M.A. Garner, None; S.K. Gardiner, None; M.E. Clark, None; M. Hubbard, None; U. Karuppanan, None; G. Bianco, None; L. Bruno, None; M.A. Fazio, National Eye Institute (F), Research to Prevent Blindness (F), EyeSight Foundation of Alabama (F), Heidelberg Engineering GmbH (F), Topcon Healthcare Inc. (F), Wolfram Research (R) 
References
Quigley H, Addicks E, Green W, Maumenee A. Optic nerve damage in human glaucoma: II. The site of injury and susceptibility to damage. Arch Ophthalmol. 1981; 99: 635–649. [CrossRef] [PubMed]
Burgoyne CF, Downs JC. Premise and prediction—how optic nerve head biomechanics underlies the susceptibility and clinical behavior of the aged optic nerve head. J Glaucoma. 2008; 17: 318–328. [CrossRef] [PubMed]
Sigal IA, Wang B, Strouthidis NG, Akagi T, Girard MJA. Recent advances in OCT imaging of the lamina cribrosa. Br J Ophthalmol. 2014; 98: ii34–ii39. [CrossRef] [PubMed]
Fazio MA, Johnstone JK, Smith B, Wang L, Girkin CA. Displacement of the lamina cribrosa in response to acute intraocular pressure elevation in normal individuals of African and European Descent. Invest Ophthalmol Vis Sci. 2016; 57: 3331–3339. [CrossRef] [PubMed]
Gizzi C, Cellini M, Campos EC. In vivo assessment of changes in corneal hysteresis and lamina cribrosa position during acute intraocular pressure elevation in eyes with markedly asymmetrical glaucoma. Clin Ophthalmol. 2018; 12: 481–492. [CrossRef] [PubMed]
Agoumi Y, Sharpe GP, Hutchison DM, Nicolela MT, Artes PH, Chauhan BC. Laminar and prelaminar tissue displacement during intraocular pressure elevation in glaucoma patients and healthy controls. Ophthalmology. 2011; 118: 52–59. [CrossRef] [PubMed]
Braeu FA, Chuangsuwanich T, Tun TA, et al. AI-based clinical assessment of optic nerve head robustness superseding biomechanical testing. Br J Ophthalmol. 2023: bjo-2022-322374, doi:10.1136/bjo-2022-322374. Epub ahead of print.
Beotra MR, Wang X, Tun TA, et al. In vivo three-dimensional lamina cribrosa strains in healthy, ocular hypertensive, and glaucoma eyes following acute intraocular pressure elevation. Invest Ophthalmol Vis Sci. 2018; 59: 260–272. [CrossRef] [PubMed]
Chuangsuwanich T, Tun TA, Braeu FA, et al. Differing associations between optic nerve head strains and visual field loss in patients with normal- and high-tension glaucoma. Ophthalmology. 2023; 130: 99–110. [CrossRef] [PubMed]
Paula AP, Paula JS, Silva MJ, Rocha EM, De Moraes CG, Rodrigues ML. Effects of swimming goggles wearing on intraocular pressure, ocular perfusion pressure, and ocular pulse amplitude. J Glaucoma. 2016; 25: 860–864. [CrossRef] [PubMed]
Kamalipour A, Moghimi S, Inpirom VR, Mahmoudinezhad G, Weinreb RN. Multipressure dial goggle effects on circumpapillary structure and microvasculature in glaucoma patients. Ophthalmol Glaucoma. 2022; 5: 572–580. [CrossRef] [PubMed]
Shafer B, Ferguson TJ, Chu N, Brambilla E, Yoo P. The effect of periocular negative pressure application on intraocular and retrobulbar pressure in human cadaver eyes. Ophthalmol Ther. 2022; 11: 365–376. [CrossRef] [PubMed]
Sun MT, Beykin G, Lee WS, et al. Structural and metabolic imaging after short-term use of the balance goggles system in glaucoma patients: a pilot study. J Glaucoma. 2022; 31: 634–638. [CrossRef] [PubMed]
Jiang R, Xu L, Liu X, Chen JD, Jonas JB, Wang YX. Optic nerve head changes after short-term intraocular pressure elevation in acute primary angle-closure suspects. Ophthalmology. 2015; 122: 730–737. [CrossRef] [PubMed]
Soydan A, Ulas F, Kaymaz A, Toprak G, Uyar E, Celebi S. Investigation of the short-term effects of water drinking test on the eye using optical coherence tomography angiography in young healthy male subjects. Cutan Ocul Toxicol. 2022; 41: 291–295. [CrossRef] [PubMed]
Girard MJ, Beotra MR, Chin KS, et al. In vivo 3-dimensional strain mapping of the optic nerve head following intraocular pressure lowering by trabeculectomy. Ophthalmology. 2016; 123: 1190–1200. [CrossRef] [PubMed]
Lanzagorta-Aresti A, Perez-Lopez M, Palacios-Pozo E, Davo-Cabrera J. Relationship between corneal hysteresis and lamina cribrosa displacement after medical reduction of intraocular pressure. Br J Ophthalmol. 2017; 101: 290–294. [PubMed]
Lee EJ, Kim TW, Weinreb RN, Kim H. Reversal of lamina cribrosa displacement after intraocular pressure reduction in open-angle glaucoma. Ophthalmology. 2013; 120: 553–559. [CrossRef] [PubMed]
Sigal IA, Flanagan JG, Ethier CR. Factors influencing optic nerve head biomechanics. Invest Ophthalmol Vis Sci. 2005; 46: 4189–4199. [CrossRef] [PubMed]
Sigal IA, Yang H, Roberts MD, Burgoyne CF, Downs JC. IOP-induced lamina cribrosa displacement and scleral canal expansion: an analysis of factor interactions using parameterized eye-specific models. Invest Ophthalmol Vis Sci. 2011; 52: 1896–1907. [CrossRef] [PubMed]
Sharma S, Tun TA, Baskaran M, et al. Effect of acute intraocular pressure elevation on the minimum rim width in normal, ocular hypertensive and glaucoma eyes. Br J Ophthalmol. 2018; 102: 131–135. [CrossRef] [PubMed]
Fazio MA, Bianco G, Karuppanan U, Hubbard M, Bruno L, Girkin CA. The effect of negative pressure on IOP in the living human eye. medRxiv. 2022. 2022.2006.2027.22276880, doi:10.1101/2022.06.27.22276880.
Johnstone J, Fazio M, Rojananuangnit K, et al. Variation of the axial location of Bruch's membrane opening with age, choroidal thickness, and race. Invest Ophthalmol Vis Sci. 2014; 55: 2004–2009. [CrossRef] [PubMed]
Eilaghi A, Flanagan JG, Tertinegg I, Simmons CA, Wayne Brodland G, Ross Ethier C. Biaxial mechanical testing of human sclera. J Biomech. 2010; 43: 1696–1701. [CrossRef] [PubMed]
Fazio MA, Gardiner SK, Bruno L, et al. Histologic validation of optical coherence tomography-based three-dimensional morphometric measurements of the human optic nerve head: methodology and preliminary results. Exp Eye Res. 2021; 205: 108475. [CrossRef] [PubMed]
Fazio MA, Clark ME, Bruno L, Girkin CA. In vivo optic nerve head mechanical response to intraocular and cerebrospinal fluid pressure: imaging protocol and quantification method. Sci Rep. 2018; 8: 12639. [CrossRef] [PubMed]
Johnstone J, Fazio M, Rojananuangnit K, et al. Variation of the axial location of Bruch's membrane opening with age, choroidal thickness, and race. Invest Ophthalmol Vis Sci. 2014; 55: 2004–2009. [CrossRef] [PubMed]
Luo H, Yang H, Gardiner SK, et al. Factors influencing central lamina cribrosa depth: a multicenter study. Invest Ophthalmol Vis Sci. 2018; 59: 2357–2370. [CrossRef] [PubMed]
Lee KM, Kim TW, Weinreb RN, Lee EJ, Girard MJ, Mari JM. Anterior lamina cribrosa insertion in primary open-angle glaucoma patients and healthy subjects. PLoS One. 2014; 9: e114935. [CrossRef] [PubMed]
Park SC, Brumm J, Furlanetto RL, et al. Lamina cribrosa depth in different stages of glaucoma. Invest Ophthalmol Vis Sci. 2015; 56: 2059–2064. [CrossRef] [PubMed]
Wu Z, Xu G, Weinreb RN, Yu M, Leung CK. Optic nerve head deformation in glaucoma: a prospective analysis of optic nerve head surface and lamina cribrosa surface displacement. Ophthalmology. 2015; 122(7): 1317–1329. [CrossRef] [PubMed]
Rhodes LA, Huisingh C, Johnstone J, et al. Variation of laminar depth in normal eyes with age and race. Invest Ophthalmol Vis Sci. 2014; 55: 8123–8133. [CrossRef] [PubMed]
Girkin CA, Fazio MA, Bowd C, et al. Racial differences in the association of anterior lamina cribrosa surface depth and glaucoma severity in the African Descent and Glaucoma Evaluation Study (ADAGES). Invest Ophthalmol Vis Sci. 2019; 60: 4496–4502. [CrossRef] [PubMed]
Ren R, Yang H, Gardiner SK, et al. Anterior lamina cribrosa surface depth, age, and visual field sensitivity in the Portland Progression Project. Invest Ophthalmol Vis Sci. 2014; 55: 1531–1539. [CrossRef] [PubMed]
Lee SH, Kim TW, Lee EJ, Girard MJ, Mari JM. Diagnostic power of lamina cribrosa depth and curvature in glaucoma. Invest Ophthalmol Vis Sci. 2017; 58: 755–762. [CrossRef] [PubMed]
Kim JA, Kim TW, Lee EJ, Girard MJA, Mari JM. Comparison of lamina cribrosa morphology in eyes with ocular hypertension and normal-tension glaucoma. Invest Ophthalmol Vis Sci. 2020; 61: 4. [CrossRef]
Kim JA, Kim TW, Weinreb RN, Lee EJ, Girard MJA, Mari JM. Lamina cribrosa morphology predicts progressive retinal nerve fiber layer loss in eyes with suspected glaucoma. Sci Rep. 2018; 8: 738. [CrossRef] [PubMed]
Girkin CA, Belghith A, Bowd C, et al. Racial differences in the rate of change in anterior lamina cribrosa surface depth in the African Descent and Glaucoma Evaluation Study. Invest Ophthalmol Vis Sci. 2021; 62: 12. [CrossRef] [PubMed]
Wu Z, Lin C, Crowther M, Mak H, Yu M, Leung CK. Impact of rates of change of lamina cribrosa and optic nerve head surface depths on visual field progression in glaucoma. Invest Ophthalmol Vis Sci. 2017; 58: 1825–1833. [CrossRef] [PubMed]
Strouthidis NG, Fortune B, Yang H, Sigal IA, Burgoyne CF. Longitudinal change detected by spectral domain optical coherence tomography in the optic nerve head and peripapillary retina in experimental glaucoma. Invest Ophthalmol Vis Sci. 2011; 52: 1206–1219. [CrossRef] [PubMed]
Fortune B, Reynaud J, Wang L, Burgoyne CF. Does optic nerve head surface topography change prior to loss of retinal nerve fiber layer thickness: a test of the site of injury hypothesis in experimental glaucoma. PLoS ONE. 2013; 8: e77831. [CrossRef] [PubMed]
Burgoyne CF. A biomechanical paradigm for axonal insult within the optic nerve head in aging and glaucoma. Exp Eye Res. 2011; 93: 120–132. [CrossRef] [PubMed]
Midgett DE, Quigley HA, Nguyen TD. In vivo characterization of the deformation of the human optic nerve head using optical coherence tomography and digital volume correlation. Acta Biomater. 2019; 96: 385–399. [CrossRef] [PubMed]
Fazio MA, Clark ME, Bruno L, Girkin CA. In vivo optic nerve head mechanical response to intraocular and cerebrospinal fluid pressure: imaging protocol and quantification method. Sci Rep. 2018; 8: 12639. [CrossRef] [PubMed]
Czerpak CA, Kashaf MS, Zimmerman BK, Quigley HA, Nguyen TD. The strain response to intraocular pressure decrease in the lamina cribrosa of patients with glaucoma. Ophthalmol Glaucoma. 2023; 6: 11–22. [CrossRef] [PubMed]
Lee SH, Lee EJ, Kim JM, Girard MJA, Mari JM, Kim TW. Lamina cribrosa moves anteriorly after trabeculectomy in myopic eyes. Invest Ophthalmol Vis Sci. 2020; 61: 36. [CrossRef]
Kim JA, Lee SH, Son DH, et al. Morphologic changes in the lamina cribrosa upon intraocular pressure lowering in patients with normal tension glaucoma. Invest Ophthalmol Vis Sci. 2022; 63: 23. [CrossRef]
Hannay V, Czerpak CA, Quigley HA, Nguyen TD. A noninvasive clinical method to measure in vivo mechanical strains of the lamina cribrosa by optical coherence tomography. medRxiv. [Preprint]. 2023: 2023.08.14.23294082, doi:10.1101/2023.08.14.23294082.
Sigal IA, Flanagan JG, Ethier CR. Factors influencing optic nerve head biomechanics. Invest Ophthalmol Vis Sci. 2005; 46: 4189–4199. [CrossRef] [PubMed]
Fazio MA, Grytz R, Morris JS, et al. Age-related changes in human peripapillary scleral strain. Biomech Model Mechanobiol. 2013; 13: 551–563. [CrossRef] [PubMed]
Hopkins AA, Murphy R, Irnaten M, Wallace DM, Quill B, O'Brien C. The role of lamina cribrosa tissue stiffness and fibrosis as fundamental biomechanical drivers of pathological glaucoma cupping. Am J Physiol Cell Physiol. 2020; 319: C611–C623. [CrossRef] [PubMed]
Bruno L, Bianco G, Fazio MA. A multi-camera speckle interferometer for dynamic full-field 3D displacement measurement: validation and inflation testing of a human eye sclera. Opt Lasers Eng. 2018; 107: 91–101. [CrossRef]
Grytz R, Fazio MA, Girard MJ, et al. Material properties of the posterior human sclera. J Mech Behav Biomed Mater. 2014; 29: 602–617. [CrossRef] [PubMed]
Fazio MA, Grytz R, Morris JS, et al. Age-related changes in human peripapillary scleral strain. Biomech Model Mechanobiol. 2014; 13: 551–563. [CrossRef] [PubMed]
Fazio MA, Grytz R, Morris JS, Bruno L, Girkin CA, Downs JC. Human scleral structural stiffness increases more rapidly with age in donors of African descent compared to donors of European descent. Invest Ophthalmol Vis Sci. 2014; 55: 7189–7198. [CrossRef] [PubMed]
Grytz R, Fazio MA, Girard MJ, et al. Loss of elasticity in the aging human sclera. Invest Ophthalmol Vis Sci. 2012; 53: 2800–2800.
Coudrillier B, Pijanka JK, Jefferys JL, et al. Glaucoma-related changes in the mechanical properties and collagen micro-architecture of the human sclera. PLoS One. 2015; 10: e0131396. [CrossRef] [PubMed]
Campbell IC, Coudrillier B, Ross Ethier C. Biomechanics of the posterior eye: a critical role in health and disease. J Biomech Eng. 2014; 136: 021005–021019. [CrossRef] [PubMed]
Coudrillier B, Tian J, Alexander S, Myers KM, Quigley HA, Nguyen TD. Biomechanics of the human posterior sclera: age- and glaucoma-related changes measured using inflation testing. Invest Ophthalmol Vis Sci. 2012; 53: 1714–1728. [CrossRef] [PubMed]
Girard MJ, Suh JK, Bottlang M, Burgoyne CF, Downs JC. Scleral biomechanics in the aging monkey eye. Invest Ophthalmol Vis Sci. 2009; 50: 5226–5237. [CrossRef] [PubMed]
DeVita MA, Wicclair M, Swanson D, et al. Research involving the newly dead: an institutional response. Crit Care Med. 2003; 31: S385–S390. [CrossRef] [PubMed]
Guterman L. Crossing the line? Medical research on brain-dead people raises ethical questions. Chron High Educ. 2003; 49: A13–A15. [PubMed]
Wicclair MR, DeVita M. Oversight of research involving the dead. Kennedy Inst Ethics J. 2004; 14: 143–164. [CrossRef] [PubMed]
Wicclair MR. Informed consent and research involving the newly dead. Kennedy Inst Ethics J. 2002; 12: 351–372. [CrossRef] [PubMed]
Figure 1.
 
(a) Highlights of the major retinal layer delineated by a commercial deep learning software (Reflectivity; Abyss) and of the parametrization of the four reference planes used for computing laminar depth: BMO, BM, ASCO, and sclera reference plane. The BMO points are marked in green; the ASCO points are marked in yellow; ALCS points are marked in red. Delineation points of the internal limiting membrane (blue), retinal nerve fiber layer (RNFL; cyan), ganglion cell layer (GCL; magenta), and posterior lamina surface (dark red) are shown for illustration purposes only. (b) Graphical representation of the 3D spatial distribution of the BM points (green), sclera anterior surface points (yellow), ALCS points (red), and volume of interest used to compute central LC depth, which was defined as the intersection of the ALCS, the given reference plane, and a 350-µm-wide cylinder oriented normally to the reference plane of choice.
Figure 1.
 
(a) Highlights of the major retinal layer delineated by a commercial deep learning software (Reflectivity; Abyss) and of the parametrization of the four reference planes used for computing laminar depth: BMO, BM, ASCO, and sclera reference plane. The BMO points are marked in green; the ASCO points are marked in yellow; ALCS points are marked in red. Delineation points of the internal limiting membrane (blue), retinal nerve fiber layer (RNFL; cyan), ganglion cell layer (GCL; magenta), and posterior lamina surface (dark red) are shown for illustration purposes only. (b) Graphical representation of the 3D spatial distribution of the BM points (green), sclera anterior surface points (yellow), ALCS points (red), and volume of interest used to compute central LC depth, which was defined as the intersection of the ALCS, the given reference plane, and a 350-µm-wide cylinder oriented normally to the reference plane of choice.
Figure 2.
 
Changes in morphologic parameters with IOP. (a–d) Change in the anterior lamina cribrosa surface depth (ALCSD) with a manometrically controlled 40 mm Hg increase in IOP when measured against four reference planes of interest: (a) BMO, (b) BM, (c) ASCO, and (d) Scl. The change in ALCSD computed against a BMO reference plane showed the most variability of ALCS either displacing anteriorly or posteriorly across eyes. Change in ALCSD computed against a Scl reference plane rather showed that LC uniquely displaced posteriorly with increasing IOP. (e, f) Changes in choroidal (e) and RNFL thickness (f) with 40 mm Hg of IOP increase; choroid and RNFL thickness decreased in response to IOP elevation for most of the eyes. Note that IOP is reported as relative change from baseline (10 mm Hg).
Figure 2.
 
Changes in morphologic parameters with IOP. (a–d) Change in the anterior lamina cribrosa surface depth (ALCSD) with a manometrically controlled 40 mm Hg increase in IOP when measured against four reference planes of interest: (a) BMO, (b) BM, (c) ASCO, and (d) Scl. The change in ALCSD computed against a BMO reference plane showed the most variability of ALCS either displacing anteriorly or posteriorly across eyes. Change in ALCSD computed against a Scl reference plane rather showed that LC uniquely displaced posteriorly with increasing IOP. (e, f) Changes in choroidal (e) and RNFL thickness (f) with 40 mm Hg of IOP increase; choroid and RNFL thickness decreased in response to IOP elevation for most of the eyes. Note that IOP is reported as relative change from baseline (10 mm Hg).
Figure 3.
 
Linear and stepwise morphologic changes with IOP. (a–d) Change in the ALCSD with stepwise (10–30 and 30–50 mm Hg; blue regressive lines) and overall (10–50 mm Hg; red lines) change in IOP against the four reference planes of interest. Graphically, it is noticeable that the ALCSD exhibited greater change when IOP was elevated from 10 to 30 mm Hg than from 30 to 50 mm Hg. (e, d) The decrease in choroidal (e) and RNFL thickness (f) was similar for the stepwise (10–30 and 30–50 mm Hg; blue) and overall change in IOP (10–50 mm Hg; red). Note that IOP is reported as relative change from baseline (10 mm Hg).
Figure 3.
 
Linear and stepwise morphologic changes with IOP. (a–d) Change in the ALCSD with stepwise (10–30 and 30–50 mm Hg; blue regressive lines) and overall (10–50 mm Hg; red lines) change in IOP against the four reference planes of interest. Graphically, it is noticeable that the ALCSD exhibited greater change when IOP was elevated from 10 to 30 mm Hg than from 30 to 50 mm Hg. (e, d) The decrease in choroidal (e) and RNFL thickness (f) was similar for the stepwise (10–30 and 30–50 mm Hg; blue) and overall change in IOP (10–50 mm Hg; red). Note that IOP is reported as relative change from baseline (10 mm Hg).
Figure 4.
 
Scatterplots of the association with age and change in morphologic parameters following elevation from 10 to 30 mm Hg (ΔIOP = 20, red) and from 10 to 50 mm Hg (ΔIOP = 40, blue). The association with age and ALCSD with a manometrically controlled increase in IOP when measured against four reference planes of interest: (a) BMO, (b) BM, (c) ASCO, and (d) Scl. The ALCSD exhibited less deformation in older donors when IOP was elevated from 10 to 30 mm Hg and similarly from 10 to 50 mm Hg. The decrease in choroidal (e) and RNFL thickness (f) did not vary significantly with age.
Figure 4.
 
Scatterplots of the association with age and change in morphologic parameters following elevation from 10 to 30 mm Hg (ΔIOP = 20, red) and from 10 to 50 mm Hg (ΔIOP = 40, blue). The association with age and ALCSD with a manometrically controlled increase in IOP when measured against four reference planes of interest: (a) BMO, (b) BM, (c) ASCO, and (d) Scl. The ALCSD exhibited less deformation in older donors when IOP was elevated from 10 to 30 mm Hg and similarly from 10 to 50 mm Hg. The decrease in choroidal (e) and RNFL thickness (f) did not vary significantly with age.
Table 1.
 
Contingency Matrix of the Directional Displacement of the LC With Acute IOP Increase When Computed Against the Four Reference Planes: (a) BMO, (b) BM, (c) ASCO, and (d) Scl
Table 1.
 
Contingency Matrix of the Directional Displacement of the LC With Acute IOP Increase When Computed Against the Four Reference Planes: (a) BMO, (b) BM, (c) ASCO, and (d) Scl
Table 2.
 
Estimates of the Relative Change From Baseline (10 mm Hg) Metrics of the ALCS Depth, Choroidal Thickness, and RNFL Thickness to an Acute Increase of IOP
Table 2.
 
Estimates of the Relative Change From Baseline (10 mm Hg) Metrics of the ALCS Depth, Choroidal Thickness, and RNFL Thickness to an Acute Increase of IOP
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