RESUMEN
Dendrite pathology and synaptic loss result in neural circuit dysfunction, a common feature of neurodegenerative diseases. There is a lack of strategies that target dendritic and synaptic regeneration to promote neurorecovery. We show that daily human recombinant insulin eye drops stimulate retinal ganglion cell (RGC) dendrite and synapse regeneration during ocular hypertension, a risk factor to develop glaucoma. We demonstrate that the ribosomal protein p70S6 kinase (S6K) is essential for insulin-dependent dendritic regrowth. Furthermore, S6K phosphorylation of the stress-activated protein kinase-interacting protein 1 (SIN1), a link between the mammalian target of rapamycin complexes 1 and 2 (mTORC1/2), is required for insulin-induced dendritic regeneration. Using two-photon microscopy live retinal imaging, we show that insulin rescues single-RGC light-evoked calcium (Ca2+) dynamics. We further demonstrate that insulin enhances neuronal survival and retina-brain connectivity leading to improved optomotor reflex-elicited behaviors. Our data support that insulin is a compelling pro-regenerative strategy with potential clinical implications for the treatment and management of glaucoma.
Asunto(s)
Glaucoma , Insulina , Células Ganglionares de la Retina , Células Ganglionares de la Retina/metabolismo , Células Ganglionares de la Retina/efectos de los fármacos , Glaucoma/tratamiento farmacológico , Glaucoma/metabolismo , Glaucoma/patología , Insulina/metabolismo , Insulina/farmacología , Animales , Humanos , Ratones , Modelos Animales de Enfermedad , Dendritas/metabolismo , Dendritas/efectos de los fármacos , Sinapsis/metabolismo , Sinapsis/efectos de los fármacos , Calcio/metabolismoRESUMEN
Purpose: It has been hypothesized that compromised ocular circulation in glaucoma may be concomitant of systemic changes. The purpose of this study is to test whether systemic blood flow pulse waveform patterns differ between individuals with glaucoma (GL), glaucoma suspects (GLS), and normal healthy controls (HC). Methods: The study included 35 bilateral GL, 67 bilateral GLS, 29 individuals with unilateral GL who were considered GLS in the other eye, and 44 healthy controls. Systemic pulsatile blood pressure waveforms were recorded using a finger cuff. A continuous 200 Hz plethysmography recording is made to obtain a pulse waveform. Waveform parameters were extracted using custom software from an average of eight pulse cycles. These were compared between GL, GLS, and HC groups on a per-eye basis, using generalized estimating equation models to account for intereye correlations; and plotted against disease severity by visual field linearized mean deviation (MDlin) and retinal nerve fiber layer thickness (RNFLT). Results: Averaged blood pressure was significantly lower in the HC group (mean ± standard deviation 91.7 ±11.7 mm Hg) than the GLS (102.4 ± 13.9) or GL (102.8 ± 13.7) groups, with P < 0.0001 (generalized estimating equation regression). Waveform parameters representing vascular resistance were higher in both GLS and GL groups than the HC group; and were correlated with RNFLT and MDlin (P ≤ 0.05). Conclusions: The shape of the systemic pulsatile waveform differs in individuals with GL/GLS suspects, compared to HC eyes. Blood pressure changes more rapidly in individuals with GL, which suggests higher arterial stiffness.
Asunto(s)
Presión Sanguínea , Presión Intraocular , Hipertensión Ocular , Humanos , Masculino , Femenino , Persona de Mediana Edad , Presión Sanguínea/fisiología , Presión Intraocular/fisiología , Anciano , Hipertensión Ocular/fisiopatología , Campos Visuales/fisiología , Glaucoma/fisiopatología , Glaucoma/diagnóstico , Análisis de la Onda del Pulso , Frecuencia Cardíaca/fisiología , Adulto , Pletismografía , Fibras Nerviosas/patología , Células Ganglionares de la Retina/patologíaRESUMEN
PURPOSE: To compare the prevalence, location and magnitude of optic nerve head (ONH) OCT-detected, exposed neural canal (ENC), externally oblique choroidal border tissue (EOCBT) and exposed scleral flange (ESF) regions in 122 highly myopic (Hi-Myo) versus 362 nonhighly myopic healthy (Non-Hi-Myo-Healthy) eyes. DESIGN: Cross-sectional study. METHODS: After OCT radial B-scan, ONH imaging, Bruch's membrane opening (BMO), the anterior scleral canal opening (ASCO), and the scleral flange opening (SFO) were manually segmented in each B-scan and projected to BMO reference plane. The direction and magnitude of BMO/ASCO offset and BMO/SFO offset as well as the location and magnitude of ENC, EOCBT and ESF regions, perineural canal (pNC) retinal nerve fiber layer thickness (RNFLT) and pNC choroidal thickness (CT) were calculated within 30° sectors relative to the Foveal-BMO (FoBMO) axis. Hi-ESF eyes were defined to be those with an ESF region ≥100 µms in at least 1 sector. RESULTS: Hi-Myo eyes more frequently demonstrated Hi-ESF regions (87/122) than Non-Hi-myo-Healthy eyes (73/362) and contained significantly larger ENC, EOCBT, and ESF regions (P < .001) which were greatest in magnitude and prevalence within the inferior-temporal FoBMO sectors where Hi-Myo pNC-RNFLT and pNCCT were thinnest. BMO/ASCO offset and the BMO/SFO offset were both significantly increased (P < .001) in the Hi-Myo eyes, with the latter demonstrating a greater increase. CONCLUSIONS: ENC region tissue remodeling that includes the scleral flange is enhanced in Hi-Myo compared to Non-Hi-Myo-Healthy eyes. Longitudinal studies are necessary to determine whether the presence of an ENC region influences ONH susceptibility to aging and/or glaucoma.
Asunto(s)
Miopía , Disco Óptico , Humanos , Disco Óptico/anatomía & histología , Tomografía de Coherencia Óptica/métodos , Tubo Neural , Estudios Transversales , Miopía/diagnóstico , Lámina Basal de la Coroides/anatomía & histología , Presión IntraocularRESUMEN
PURPOSE: To determine the prevalence and magnitude of optical coherence tomography (OCT) exposed neural canal (ENC), externally oblique choroidal border tissue (EOCBT), and exposed scleral flange (ESF) regions in 362 non-highly myopic (spherical equivalent -6.00 to 5.75 diopters) eyes of 362 healthy subjects. DESIGN: Cross-sectional study. METHODS: After OCT optic nerve head (ONH) imaging, Bruch membrane opening (BMO), the anterior scleral canal opening (ASCO), and the scleral flange opening (SFO) were manually segmented. BMO, ASCO, and SFO points were projected to the BMO reference plane. The direction and magnitude of BMO/ASCO offset as well as the magnitude of ENC, EOCBT, and ESF was calculated within 30° sectors relative to the foveal-BMO axis. Hi-ESF eyes demonstrated an ESF ≥100 µm in at least 1 sector. Sectoral peri-neural canal choroidal thickness (pNC-CT) was measured and correlations between the magnitude of sectoral ESF and proportional pNC-CT were assessed. RESULTS: Seventy-three Hi-ESF (20.2%) and 289 non-Hi-ESF eyes (79.8%) were identified. BMO/ASCO offset as well as ENC, EOCBT, and ESF prevalence and magnitude were greatest inferior temporally where the pNC-CT was thinnest. Among Hi-ESF eyes, the magnitude of each ENC region correlated with the BMO/ASCO offset magnitude, and the sectors with the longest ESF correlated with the sectors with proportionally thinnest pNC-CT. CONCLUSIONS: ONH BMO/ASCO offset, either as a cause or result of ONH neural canal remodeling, corresponds with the sectoral location of maximum ESF and minimum pNC-CT in non-highly myopic eyes. Longitudinal studies to characterize the development and clinical implications of ENC Hi-ESF regions in non-highly myopic and highly myopic eyes are indicated.
Asunto(s)
Miopía , Disco Óptico , Humanos , Tomografía de Coherencia Óptica/métodos , Tubo Neural , Estudios Transversales , Miopía/diagnóstico , Lámina Basal de la Coroides , Presión IntraocularRESUMEN
Purpose: The Retinal Ganglion Cell (RGC) Repopulation, Stem Cell Transplantation, and Optic Nerve Regeneration (RReSTORe) consortium was founded in 2021 to help address the numerous scientific and clinical obstacles that impede development of vision-restorative treatments for patients with optic neuropathies. The goals of the RReSTORe consortium are: (1) to define and prioritize the most critical challenges and questions related to RGC regeneration; (2) to brainstorm innovative tools and experimental approaches to meet these challenges; and (3) to foster opportunities for collaborative scientific research among diverse investigators. Design and Participants: The RReSTORe consortium currently includes > 220 members spanning all career stages worldwide and is directed by an organizing committee comprised of 15 leading scientists and physician-scientists of diverse backgrounds. Methods: Herein, we describe the structure and organization of the RReSTORe consortium, its activities to date, and the perceived impact that the consortium has had on the field based on a survey of participants. Results: In addition to helping propel the field of regenerative medicine as applied to optic neuropathies, the RReSTORe consortium serves as a framework for developing large collaborative groups aimed at tackling audacious goals that may be expanded beyond ophthalmology and vision science. Conclusions: The development of innovative interventions capable of restoring vision for patients suffering from optic neuropathy would be transformative for the ophthalmology field, and may set the stage for functional restoration in other central nervous system disorders. By coordinating large-scale, international collaborations among scientists with diverse and complementary expertise, we are confident that the RReSTORe consortium will help to accelerate the field toward clinical translation. Financial Disclosures: Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.
RESUMEN
Early diagnosis and detection of disease progression are critical to successful therapeutic intervention in glaucoma, the leading cause of irreversible blindness worldwide. Optical coherence tomography (OCT) is a non-invasive imaging technique that allows objective quantification in vivo of key glaucomatous structural changes in the retina and the optic nerve head (ONH). Advances in OCT technology have increased the scan speed and enhanced image quality, contributing to early glaucoma diagnosis and monitoring, as well as the visualization of critically important structures deep within the ONH, such as the lamina cribrosa. OCT angiography (OCTA) is a dye-free technique for noninvasively assessing ocular microvasculature, including capillaries within each plexus serving the macula, peripapillary retina and ONH regions, as well as the deeper vessels of the choroid. This layer-specific assessment of the microvasculature has provided evidence that retinal and choroidal vascular impairments can occur during early stages of glaucoma, suggesting that OCTA-derived measurements could be used as biomarkers for enhancing detection of glaucoma and its progression, as well as to reveal novel insights about pathophysiology. Moreover, these innovations have demonstrated that damage to the macula, a critical region for the vision-related quality of life, can be observed in the early stages of glaucomatous eyes, leading to a paradigm shift in glaucoma monitoring. Other advances in software and hardware, such as artificial intelligence-based algorithms, adaptive optics, and visible-light OCT, may further benefit clinical management of glaucoma in the future. This article reviews the utility of OCT and OCTA for glaucoma diagnosis and disease progression detection, emphasizes the importance of detecting macula damage in glaucoma, and highlights the future perspective of OCT and OCTA. We conclude that the OCT and OCTA are essential glaucoma detection and monitoring tools, leading to clinical and economic benefits for patients and society.
RESUMEN
Retinal ganglion cells, the neurons that die in glaucoma, are endowed with a high metabolism requiring optimal provision of oxygen and nutrients to sustain their activity. The timely regulation of blood flow is, therefore, essential to supply firing neurons in active areas with the oxygen and glucose they need for energy. Many glaucoma patients suffer from vascular deficits including reduced blood flow, impaired autoregulation, neurovascular coupling dysfunction, and blood-retina/brain-barrier breakdown. These processes are tightly regulated by a community of cells known as the neurovascular unit comprising neurons, endothelial cells, pericytes, Müller cells, astrocytes, and microglia. In this review, the neurovascular unit takes center stage as we examine the ability of its members to regulate neurovascular interactions and how their function might be altered during glaucomatous stress. Pericytes receive special attention based on recent data demonstrating their key role in the regulation of neurovascular coupling in physiological and pathological conditions. Of particular interest is the discovery and characterization of tunneling nanotubes, thin actin-based conduits that connect distal pericytes, which play essential roles in the complex spatial and temporal distribution of blood within the retinal capillary network. We discuss cellular and molecular mechanisms of neurovascular interactions and their pathophysiological implications, while highlighting opportunities to develop strategies for vascular protection and regeneration to improve functional outcomes in glaucoma.
Asunto(s)
Células Endoteliales , Nanotubos , Humanos , Células Endoteliales/metabolismo , Encéfalo/irrigación sanguínea , Encéfalo/metabolismo , Oxígeno/metabolismoRESUMEN
Retinal ganglion cell (RGC) death in glaucoma and other optic neuropathies results in irreversible vision loss due to the mammalian central nervous system's limited regenerative capacity. RGC repopulation is a promising therapeutic approach to reverse vision loss from optic neuropathies if the newly introduced neurons can reestablish functional retinal and thalamic circuits. In theory, RGCs might be repopulated through the transplantation of stem cell-derived neurons or via the induction of endogenous transdifferentiation. The RGC Repopulation, Stem Cell Transplantation, and Optic Nerve Regeneration (RReSTORe) Consortium was established to address the challenges associated with the therapeutic repair of the visual pathway in optic neuropathy. In 2022, the RReSTORe Consortium initiated ongoing international collaborative discussions to advance the RGC repopulation field and has identified five critical areas of focus: (1) RGC development and differentiation, (2) Transplantation methods and models, (3) RGC survival, maturation, and host interactions, (4) Inner retinal wiring, and (5) Eye-to-brain connectivity. Here, we discuss the most pertinent questions and challenges that exist on the path to clinical translation and suggest experimental directions to propel this work going forward. Using these five subtopic discussion groups (SDGs) as a framework, we suggest multidisciplinary approaches to restore the diseased visual pathway by leveraging groundbreaking insights from developmental neuroscience, stem cell biology, molecular biology, optical imaging, animal models of optic neuropathy, immunology & immunotolerance, neuropathology & neuroprotection, materials science & biomedical engineering, and regenerative neuroscience. While significant hurdles remain, the RReSTORe Consortium's efforts provide a comprehensive roadmap for advancing the RGC repopulation field and hold potential for transformative progress in restoring vision in patients suffering from optic neuropathies.
Asunto(s)
Enfermedades del Nervio Óptico , Células Ganglionares de la Retina , Animales , Humanos , Retina , Encéfalo , Diferenciación Celular , MamíferosRESUMEN
Purpose: To compare parameters of electroretinogram (ERG) responses for their ability to detect functional loss in early stages of nonhuman primate (NHP) experimental glaucoma (EG), including photopic negative responses (PhNR) to a standard brief red flash on a blue background (R/B) and 200-ms-long R/B and white-on-white (W/W) flashes, to W/W flicker stimuli (5-50 Hz), and to a dark-adapted intensity series. Methods: Light-adapted ERGs were recorded in 12 anesthetized monkeys with unilateral EG. Amplitudes and implicit times of the a-wave, b-wave, and d-wave were measured, as well as amplitudes of PhNRs and oscillatory potentials for flash onset and offset. Flicker ERGs were measured using peak-trough and fundamental frequency analyses. Dark-adapted ERG parameters were modeled by Naka-Rushton relationships. Results: Only PhNR amplitudes were significantly reduced in EG eyes compared to fellow control (FC) eyes. The d-wave implicit time was delayed in EG versus FC eyes only for the W/W long flash, but in all eyes it was 10 to 20 ms slower for R/B versus the W/W condition. Flicker ERGs were <0.5 ms delayed in EG versus FC overall, but amplitudes were affected only at 5 Hz. The brief R/B PhNR amplitude had the highest sensitivity to detect EG and strongest correlation to parameters of structural damage. Conclusions: The PhNR to the standard brief R/B stimulus was best for detecting and following early-stage functional loss in NHP EG. Translational Relevance: These results suggest that there would be no benefit in using longer duration flashes to separate onset and offset responses for clinical management of glaucoma.
Asunto(s)
Glaucoma , Animales , Glaucoma/diagnóstico , OjoRESUMEN
PURPOSE: To report on the venous abnormalities of a patient with Sturge-Weber syndrome (SWS). METHOD: Case report. PATIENT: A 29-year-old woman with a history of SWS since infancy was referred for evaluation of possible diffuse choroidal hemangioma. Multimodal imaging, including ultra-widefield fluorescein, indocyanine green, and optical coherence tomography-angiography (OCTA) were performed. RESULTS: Dilated fundus examination was remarkable for increased cupping of the optic disc in the right eye, venous tortuosity, and marked dilation of the choroidal vessels. Ultra-widefield fluorescein angiography confirmed marked venous tortuosity and dilation, as well as anastomoses of the retinal veins ipsilateral to the port wine stain. Indocyanine green angiography revealed marked engorgement of the vortex veins and choroidal vasculature. OCTA revealed dilated vascular channels in the deep capillary plexus (DCP) that were directly anastomosing to the superficial capillary plexus, but not the intermediate capillary plexus. Engorgement of the ampullae of the DCP vortex system was also observed. The normal contralateral eye was used as comparison for all imaging studies. CONCLUSION: These findings support the notion of generalized venous hypertension state in adult eyes with SWS and corroborate prior evidence that the deep capillary plexus acts as a venous outflow system.
RESUMEN
Purpose: Tissue stiffening and alterations in retinal blood flow have both been suggested as causative mechanisms of glaucomatous damage. We tested the hypothesis that retinal blood vessels also stiffen, using laser speckle flowgraphy (LSFG) to characterize vascular resistance. Methods: In the longitudinal Portland Progression Project, 231 eyes of 124 subjects received LSFG scans of the optic nerve head (ONH) and automated perimetry every 6 months for six visits. Eyes were classified as either "glaucoma suspect" or "glaucoma" eyes based on the presence of functional loss on the first visit. Vascular resistance was quantified using the mean values of several instrument-defined parameterizations of the pulsatile waveform measured by LSFG, either in major vessels within the ONH (serving the retina) or in capillaries within ONH tissue, and age-adjusted using a separate group of 127 healthy eyes of 63 individuals. Parameters were compared against the severity and rate of change of functional loss using mean deviation (MD) over the six visits, within the two groups. Results: Among 118 "glaucoma suspect" eyes (average MD, -0.4 dB; rate, -0.45 dB/y), higher vascular resistance was related to faster functional loss, but not current severity of loss. Parameters measured in major vessels were stronger predictors of rate than parameters measured in tissue. Among 113 "glaucoma" eyes (average MD, -4.3 dB; rate, -0.53 dB/y), higher vascular resistance was related to more severe current loss but not rate of loss. Conclusions: Higher retinal vascular resistance and, by likely implication, stiffer retinal vessels were associated with more rapid functional loss in eyes without significant existing loss at baseline.
Asunto(s)
Glaucoma , Hipertensión Ocular , Disco Óptico , Rigidez Vascular , Humanos , Presión Intraocular , Tomografía de Coherencia Óptica , Disco Óptico/irrigación sanguínea , Glaucoma/diagnóstico , Vasos RetinianosRESUMEN
Neuronal repopulation achieved through transplantation or transdifferentiation from endogenous sources holds tremendous potential for restoring function in chronic neurodegenerative disease or acute injury. Key to the evaluation of neuronal engraftment is the definitive discrimination of new or donor neurons from preexisting cells within the host tissue. Recent work has identified mechanisms by which genetically encoded donor cell reporters can be transferred to host neurons through intercellular material transfer. In addition, labeling transplanted and endogenously transdifferentiated neurons through viral vector transduction can yield misexpression in host cells in some circumstances. These issues can confound the tracking and evaluation of repopulated neurons in regenerative experimental paradigms. Using the retina as an example, we discuss common reasons for artifactual labeling of endogenous host neurons with donor cell reporters and suggest strategies to prevent erroneous conclusions based on misidentification of cell origin.
RESUMEN
PURPOSE: To use optical coherence tomography (OCT) to characterize optic nerve head (ONH) peri-neural canal (pNC) scleral bowing (pNC-SB) and pNC choroidal thickness (pNC-CT) in 69 highly myopic and 138 healthy, age-matched, control eyes. DESIGN: Cross-sectional, case control study. METHODS: Within ONH radial B-scans, Bruch membrane (BM), BM opening (BMO), anterior scleral canal opening (ASCO), and pNC scleral surface were segmented. BMO and ASCO planes and centroids were determined. pNC-SB was characterized within 30° foveal-BMO (FoBMO) sectors by 2 parameters: pNC-SB-scleral slope (pNC-SB-SS), measured within 3 pNC segments (0-300, 300-700, and 700-1000 µm from the ASCO centroid); and pNC-SB-ASCO depth relative to a pNC scleral reference plane (pNC-SB-ASCOD). pNC-CT was calculated as the minimum distance between the scleral surface and BM at 3 pNC locations (300, 700, and 1100 µm from the ASCO). RESULTS: pNC-SB increased and pNC-CT decreased with axial length (P < .0133; P < .0001) and age (P < .0211; P < .0004) among all study eyes. pNC-SB was increased (P < .001) and pNC-CT was decreased (P < .0279) in the highly myopic compared to control eyes, and these differences were greatest in the inferior quadrant sectors (P < .0002). Sectoral pNC-SB was not related to sectoral pNC-CT in control eyes, but was inversely related to sectoral pNC-CT (P < .0001) in the highly myopic eyes. CONCLUSIONS: Our data suggest that pNC-SB is increased and pNC-CT is decreased in highly myopic eyes and that these phenomena are greatest in the inferior sectors. They support the hypothesis that sectors of maximum pNC-SB may predict sectors of greatest susceptibility to aging and glaucoma in future longitudinal studies of highly myopic eyes. NOTE: Publication of this article is sponsored by the American Ophthalmological Society.
Asunto(s)
Miopía , Disco Óptico , Humanos , Disco Óptico/anatomía & histología , Tomografía de Coherencia Óptica/métodos , Estudios Transversales , Tubo Neural , Estudios de Casos y Controles , Lámina Basal de la Coroides , Miopía/diagnósticoRESUMEN
PURPOSE: The relationships between intraocular pressure (IOP), ocular perfusion pressure (OPP), retinal perfusion, and retinal electrophysiologic responses have been explored experimentally across several animal models. These studies have demonstrated that elevated IOP reduces OPP, and when this reduction in OPP exceeds the autoregulatory capacity of the retina vasculature, retinal perfusion and electrophysiologic responses are reduced. This study aimed to evaluate these interactions for the first time in the living human eye. METHODS: Five eyes from three research-consented brain-dead organ donors underwent optical coherence tomography with angiographic (OCT/A; Spectralis, Heidelberg Engineering) and electroretinographic (ERG, Diagnosys LLC) measurements while IOP was manometrically-elevated stepwise to pressures of 10, 30 and 50 mmHg. Systemic blood pressure (BP) was monitored continuously during testing. Correlation analysis was applied to assess association between ERG and OPP changes. In a single eye, prolonged IOP elevation was induced with viscoelastic injection and serial ERG measurements were obtained. RESULTS: Reductions in inner retinal function defined by photopic ERG were observed with elevation in IOP and concomitant reduction in OPP. Reductions, especially in b-wave, and photopic negative response (PhNR) amplitudes and implicit times were significantly correlated with elevation in IOP and reduction in OPP. There were more appreciable changes in perfusion and functional responses in eyes tested while systemic blood pressure was lower. With prolonged IOP elevation, selective loss of the PhNR response was observed. CONCLUSIONS: In the living human eye, retinal perfusion and inner retinal function are acutely impacted by elevation of IOP, and this impact is related to systemic BP and OPP. This novel approach provides a viable model to study the autoregulatory responses to IOP elevation in the living human eye.
Asunto(s)
Glaucoma , Hipertensión Ocular , Animales , Humanos , Presión Intraocular , Retina , Tonometría Ocular , Electrorretinografía/métodosRESUMEN
Purpose: Glaucoma is associated with structural changes of the optic nerve head such as deformation, lamina cribosa defects, prelaminar schisis, and peripapillary retinal schisis. We describe optic nerve cavitations that were detected by routine spectral domain optical coherence tomography (OCT). Observations: OCT imaging showed cavitations in 5 eyes of 4 patients with an initial diagnosis of glaucoma or glaucoma suspect. The cavitations were seen as hyporeflective spaces that are sharply delineated from surrounding tissue. They were centered inferonasally, anterior to the lamina cribosa, and at least partially within the Bruch's membrane opening (BMO). They extended from 3 to 6 clock hours. Conclusion: AND IMPORTANCE: We describe a new OCT finding in patients with a diagnosis of glaucoma and glaucoma suspect. While previous reports describe cavitations in the choroid in patients with pathological myopia, our patients had minimal refractive error and the cavitations were located within the optic nerve. We will examine these patients over time to determine the impact of this finding on longitudinal changes in structure and function.
RESUMEN
In-vivo optic nerve head (ONH) biomechanics characterization is emerging as a promising way to study eye physiology and pathology. We propose a high-accuracy and high-efficiency digital volume correlation (DVC) method to characterize the in-vivo ONH deformation from optical coherence tomography (OCT) volumes. Using a combination of synthetic tests and analysis of OCTs from monkey ONHs subjected to acutely elevated intraocular pressure, we demonstrate that our proposed methodology overcame several challenges for conventional DVC methods: First, a pre-registration technique was used to remove large ONH rigid body motion in OCT volumes which could lead to analysis failure; second, a modified 3D inverse-compositional Gaussian Newton method was used to ensure sub-voxel accuracy of displacement calculations despite high noise and low image contrast of some OCT volumes; third, a tricubic B-spline interpolation method was applied to improve computational efficiency; fourth, a confidence parameter was introduced to guide the searching path in the displacement calculation; fifth, a confidence-weighted strain calculation method was applied to further improve the accuracy. The proposed DVC method had displacement errors smaller than 0.037 and 0.028 voxels with Gaussian and speckle noises, respectively. The strain errors in the three directions were less than 0.0045 and 0.0018 with Gaussian and speckle noises, respectively. Compared with the conventional DVC method, the proposed method reduced the errors of displacement and strain calculations by up to 70% under large body motions, with 75% lower computation time, while saving about 30% memory. Our study demonstrates the potential of the proposed technique to investigate ONH biomechanics. STATEMENT OF SIGNIFICANCE: The biomechanics of the optic nerve head (ONH) in the posterior pole of the globe play a central role in eye physiology and pathology. The application of digital volume correlation (DVC) to the analysis of optical coherence tomography (OCT) images of the ONH has emerged as a promising way to quantify ONH biomechanics. Conventional DVC methods, however, face several important challenges when analyzing OCT images of the ONH. We introduce a high-accuracy and high-efficiency DVC method to characterize in vivo ONH deformations from OCT volumes. We demonstrate the new method using synthetic tests and actual OCT data from monkey ONHs. The new method also has the potential to be used to study other tissues, as OCT applications continue to expand.
Asunto(s)
Disco Óptico , Fenómenos Biomecánicos , Biofisica , Presión Intraocular , Disco Óptico/diagnóstico por imagen , Disco Óptico/fisiología , Tomografía de Coherencia Óptica/métodosRESUMEN
Purpose: Glia and their communication via connexin 43 (Cx43) gap junctions are known to mediate neurovascular coupling, a process driven by metabolic demand. However, it is unclear whether Cx43 mediated glial communication intermediates classical autoregulation. Here we used viral transfection and a glial fibrillary acidic protein (GFAP) promoter to downregulate glial Cx43 to evaluate its role in retinal vascular autoregulation to ocular perfusion pressure (OPP) reduction. Methods: Adult rats were intravitreally injected with the viral active construct or a control. Three weeks after the injection, eyes were imaged using confocal scanning laser ophthalmoscopy before and during a period of OPP decrease induced by blood draw to lower blood pressure or by manometric IOP elevation. Vessel diameter responses to the OPP decrease were compared between Cx43-downregulated and control-injected eyes. The extent of Cx43 downregulation was evaluated by Western blot and immunohistochemistry. Results: In control eyes, the OPP decrease induced dilatation of arterioles, but not venules. In Cx43-downregulated eyes, Cx43 expression in whole retina was decreased by approximately 40%. In these eyes, the resting diameter of the venules increased significantly, but there was no effect on arterioles. In Cx43-downregulated eyes, vasoreactivity evoked by blood pressure lowering was significantly compromised in both arterioles (P = 0.005) and venules (P = 0.001). Cx43 downregulation did not affect the arteriole responses to IOP elevation, whereas the responses of the venules showed a significantly greater decrease in diameter (P < 0.001). Conclusions: The downregulation of retinal Cx43 in GFAP-expressing cells compromises vasoreactivity of both arterioles and venules in response to an OPP decrease achieved via blood pressure lowering or IOP elevation. The results also suggest that Cx43-mediated glial communication actively regulates resting venular diameter.
Asunto(s)
Presión Sanguínea/fisiología , Conexina 43/genética , Regulación de la Expresión Génica/fisiología , Proteína Ácida Fibrilar de la Glía/genética , Presión Intraocular/fisiología , Arteria Retiniana/fisiología , Vena Retiniana/fisiología , Animales , Western Blotting , Dependovirus/genética , Regulación hacia Abajo , Inmunohistoquímica , Masculino , Microscopía Confocal , Oftalmoscopía , Ratas , Ratas Endogámicas BN , Flujo Sanguíneo Regional , Retina/metabolismo , TransfecciónRESUMEN
PURPOSE: To compare the frequency of observing optic nerve head (ONH) prelaminar schisis by optical coherence tomography (OCT) in glaucoma and glaucoma suspect (GL/S) eyes vs healthy control (HC) eyes and to assess its association with other markers of glaucoma severity. METHODS: This cross-sectional study included 298 eyes of 150 GL/S patients and 88 eyes of 44 HCs. OCT scans were obtained, including 24 radial B-scans, each composed of 768 A-lines spanning 15°, centered on the ONH. Two reviewers masked to all other clinical, demographic, and ocular information independently graded the OCT scans for the presence of ONH prelaminar schisis on a 4-point scale of 0 (none) to 3 (severe). The probability of ONH schisis was compared between groups and against demographic and ocular factors, including structural and functional measures of glaucoma severity. RESULTS: The frequency and severity of ONH prelaminar schisis were greater in GL/S than in HC (P = .009). Among the GL/S group, 165 eyes (55.4%) had no visible schisis (Grade 0), 71 (23.8%) had Grade 1, 46 (15.4%) had Grade 2 and 16 (5.4%) had Grade 3 schisis. Among HC eyes, 59 (67.0%) had Grade 0, 24 (27.3%) had Grade 1, 5 (5.7%) had Grade 2, none had Grade 3. ONH schisis was more common in eyes with thinner MRW and a deeper cup. CONCLUSIONS: ONH prelaminar schisis may be a sign of glaucomatous deformation and reflect ongoing pathophysiological damage. ONH prelaminar schisis can impact OCT image segmentation and diagnostic parameters, resulting in substantial overestimation of the true rim tissue thickness and underestimation of cup depth.