Automated inter-device 3D OCT image registration using deep learning and retinal layer segmentation.

Optical coherence tomography (OCT) is the most widely used imaging modality in ophthalmology. There are multiple variations of OCT imaging capable of producing complementary information. Thus, registering these complementary volumes is desirable in order to combine their information. In this work, we propose a novel automated pipeline to register OCT images produced by different devices. This pipeline is based on two steps: a multi-modal 2D en-face registration based on deep learning, and a Z-axis (axial axis) registration based on the retinal layer segmentation. We evaluate our method using data from a Heidelberg Spectralis and an experimental PS-OCT device. The empirical results demonstrated high-quality registrations, with mean errors of approximately 46 µm for the 2D registration and 9.59 µm for the Z-axis registration. These registrations may help in multiple clinical applications such as the validation of layer segmentations among others.

Characteristics of Henle's fiber layer in healthy and glaucoma eyes assessed by polarization-sensitive optical coherence tomography.

Using conventional optical coherence tomography (OCT), it is difficult to image Henle fibers (HF) due to their low backscattering potential. However, fibrous structures exhibit form birefringence, which can be exploited to visualize the presence of HF by polarization-sensitive (PS) OCT. We found a slight asymmetry in the retardation pattern of HF in the fovea region that can be associated with the asymmetric decrease of cone density with eccentricity from the fovea. We introduce a new measure based on a PS-OCT assessment of optic axis orientation to estimate the presence of HF at various eccentricities from the fovea in a large cohort of 150 healthy subjects. By comparing a healthy age-matched sub-group (N = 87) to a cohort of 64 early-stage glaucoma patients, we found no significant difference in HF extension but a slightly decreased retardation at about 2° to 7.5° eccentricity from the fovea in the glaucoma patients. This potentially indicates that glaucoma affects this neuronal tissue at an early state.

Phase retardation and corneal sublayer thickness repeatability using ultrahigh-resolution polarization-sensitive OCT.

PURPOSE: To assess phase retardation and corneal sublayer thickness repeatability using ultrahigh-resolution polarization-sensitive optical coherence tomography (PS-OCT). SETTING: Narayana Nethralaya Eye Hospital, Bangalore. DESIGN: Observational. METHODS: In this study, all eyes were imaged using a custom-built ultrahigh-resolution PS-OCT and high-resolution hybrid OCT (MS-39). The repeatability of phase retardation en face maps and corneal sublayer thickness profiles was evaluated. The reflectivity and phase retardation were calculated from the 2 orthogonal polarization channels to generate en face maps of phase retardation and corneal sublayer thicknesses. 3 consecutive measurements of all participants were acquired for each eye. For each measurement, the participant was asked to sit back and was realigned again. The repeatability was assessed using the intraclass correlation coefficient (ICC). RESULTS: The study included 20 healthy eyes of 20 participants. The phase retardation en face maps showed preferential arrangement of collagen fibrils with least retardation in the apex and maximum retardation in the periphery. The phase retardation showed excellent repeatability (ICC >0.95) in all zones. The Bowman layer and stromal layer thicknesses were measured with excellent repeatability (ICC >0.93 and >0.99, respectively). Significant differences ( P < .05) in stromal layer thickness were observed between MS-39 and PS-OCT. The repeatability of epithelial thickness measurements was better with PS-OCT than MS-39. CONCLUSIONS: The combinational assessment of corneal birefringence and sublayer thicknesses shows the advanced potential of ultrahigh-resolution PS-OCT in routine clinical practice over current OCT devices.

Quantitative assessment of depolarization by the retinal pigment epithelium in healthy and glaucoma subjects measured over a large field of view.

We present measurements of depolarization introduced by the retinal pigment epithelium (RPE) over a 45° field of view using polarization sensitive optical coherence tomography. A detailed spatial distribution analysis of depolarization caused by the RPE is presented in a total of 153 subjects including both healthy and diseased eyes. Age and sex related differences in the depolarizing character of the RPE are investigated.

Birefringent Properties of the Peripapillary Retinal Nerve Fiber Layer in Healthy and Glaucoma Subjects Analyzed by Polarization-Sensitive OCT.

Purpose: To study the circumpapillary retinal nerve fiber layer (RNFL) birefringence (BIR) of early glaucoma and age-matched healthy eyes using polarization-sensitive optical coherence tomography (PS-OCT). Methods: In this prospective cross-sectional study, we compared virtual circular PS-OCT B-scans with a diameter of 3.5 mm centered on the optic disc (OD) acquired with a PS-OCT prototype (860 nm center wavelength). Early glaucoma was defined by the glaucomatous appearance of the OD and a pathologic visual field test with a mean deviation (MD) better than -6 dB. The main outcome parameters were BIR, RNFL-thickness (RNFL-T), and phase retardation (RET). The BIR value at each virtual A-scan position was the quotient of the RET measured at the inner segment/outer segment junction divided by the RNFL-T. Results: The dataset comprised 49 early glaucoma patients (mean ± standard deviation [SD]: 64 ± 10 years) and 49 healthy control subjects (61 ± 9 years). Glaucomatous eyes showed a statistically significant lower BIR globally (mean ± SD: 0.108 ± 0.008°/µm vs. 0.112 ± 0.009°/µm, P = 0.033), superiorly (0.116 ± 0.017°/µm vs. 0.126 ± 0.013°/µm, P = 0.0001), and inferiorly (0.112 ± 0.011°/µm vs. 0.121 ± 0.011°/µm, P < 0.0001), and increased BIR in the temporal quadrant (0.088 ± 0.015°/µm vs. 0.078 ± 0.014°/µm, P = 0.0001) compared to healthy eyes. Conclusions: We report a reduced BIR of the RNFL in early perimetric glaucoma, which can be interpreted as a sign of loss or change of intracellular microtubules and may contribute to a better understanding of early disease development. Prospective longitudinal studies are needed to determine whether BIR is altered in pre-perimetric human glaucoma before RNFL-T decline.

Automatic retinal nerve fiber bundle tracing based on large field of view polarization sensitive OCT data.

A technique to accurately estimate trajectories of retinal nerve fiber bundles (RNFB) in a large field of view (FOV) image covering 45° is described. The method utilizes stitched projections of polarization-sensitive optical coherence tomography (PS-OCT) data, as well as a mathematical model of average RNFB trajectories as prior. The fully automatic process was applied to data recorded in healthy subjects and glaucoma patients and automatically detected individual RNFB trajectories are compared to manual traces.

Farewell editorial.

Biomedical Optics Express Editor-in-Chief Christoph K. Hitzenberger and Deputy Editor Adam Gibson share some final remarks as they prepare to end their editorial terms on 31 December 2021.

Mapping of corneal birefringence in thin and asymmetric keratoconus corneas with ultrahigh-resolution polarization-sensitive OCT.

PURPOSE: To evaluate phase retardation (PR) across healthy eyes and eyes with thin corneas (<500 µm) and with asymmetric and bilateral keratoconus (KC). SETTING: Narayana Nethralaya Eye Hospital, Bangalore, India. DESIGN: Observational cross-sectional. METHODS: There were 4 eye groups: healthy eyes (Group 1; n = 10 eyes), eyes with thin corneas and no clinical disease (Group 2; n = 10 eyes), eyes with asymmetric KC (Group 3; n = 5 eyes), and eyes with clinical KC (Group 4; n = 15 eyes). All eyes were imaged with polarization-sensitive optical coherence tomography (PS-OCT), MS-39, and Corvis-ST. Using PS-OCT, PR was analyzed in annular regions. The anterior (A-E) and Bowman (E-B) wavefront aberrations, epithelial Zernike indices (EZI), total corneal thickness, Corvis biomechanical index (CBI), total biomechanical index (TBI), and Belin-Ambrósio overall deviation index (BAD-D) were analyzed. RESULTS: Only CBI, TBI, BAD-D, A-E and E-B aberrations, EZI, and total corneal thickness distributions of Groups 1 (n =10), 2 (n =10), and 3 (n =5) were similar ( P > .05) but not CCT ( P < .05). PR distributions clearly showed that the eyes in Groups 1, 2, and 3 had a normal corneal birefringence unlike Group 4 (n = 10) eyes ( P < .05). The PR map was similar to the preferred orientations of collagen fibers seen in X-ray diffraction ex vivo studies of corneal stroma. CONCLUSIONS: PR distributions may eliminate the uncertainty associated with the stromal status of thin and asymmetric KC corneas. Group 2 and 3 eyes appeared as healthy because of normal corneal birefringence at the time of imaging, but a longitudinal follow-up of these eyes with PS-OCT may assist in early detection of onset of disease.

Baseline predictors for subretinal fibrosis in neovascular age-related macular degeneration.

To find baseline predictors for subretinal fibrosis (SF) in neovascular age-related macular degeneration (nAMD). Forty-five eyes of 45 participants with treatment-naïve nAMD were consecutively enrolled and treated according to a standardized treat-and-extend protocol. Spectral-domain optical coherence tomography (OCT), color fundus photography and fluorescein angiography as well as novel imaging modalities polarization-sensitive OCT and OCT angiography (OCTA) were performed to detect SF after 1 year and find baseline predictors for SF development. Baseline OCTA scans were evaluated for quantitative features such as lesion area, vessel area, vessel junctions, vessel length, vessel endpoints and mean lacunarity. Additionally, the type of macular neovascularization, the presence of subretinal fluid, intraretinal fluid (IRF), subretinal hyperreflective material (SHRM), retinal hemorrhage as well as best-corrected visual acuity (BCVA) were evaluated. After 12 months 8 eyes (18%) developed SF. Eyes with SF had worse baseline BCVA (p = .001) and a higher prevalence of IRF (p = .014) and SHRM at baseline (p = .017). There was no significant difference in any of the evaluated quantitative OCTA parameters (p > .05) between eyes with and without SF. There were no quantitative baseline microvascular predictors for SF in our study. Low baseline BCVA, the presence of IRF and SHRM, however, are easily identifiable baseline parameters indicating increased risk.

Temporal phase evolution OCT for measurement of tissue deformation in the human retina in-vivo.

We demonstrate the use of temporal phase evolution (TPE-) OCT methods to evaluate retinal tissue deformation in-vivo over time periods of several seconds. A custom built spectral domain (SD)-OCT system with an integrated retinal tracker, ensuring stable imaging with sub-speckle precision, was used for imaging. TPE-OCT measures and images phase differences between an initial reference B-scan and each of the subsequent B-scans of the evaluated temporal sequence. In order to demonstrate the precision and repeatability of the measurements, retinal nerve fiber (RNF) tissue deformations induced by retinal vessels pulsating with the heartbeat were analyzed in several healthy subjects. We show TPE maps (M-scans of phase evolution as a function of position along B-scan trace vs. time) of wrapped phase data and corresponding deformation maps in selected regions of the RNF layer (RNFL) over the course of several cardiac cycles. A reproducible phase pattern is seen at each heartbeat cycle for all imaged volunteers. RNF tissue deformations near arteries and veins up to ∼ 1.6 µm were obtained with an average precision for a single pixel of about 30 nm. Differences of motion induced by arteries and veins are also investigated.

Retinal adaptive optics imaging with a pyramid wavefront sensor.

The pyramid wavefront sensor (P-WFS) has replaced the Shack-Hartmann (SH-) WFS as the sensor of choice for high-performance adaptive optics (AO) systems in astronomy. Many advantages of the P-WFS, such as its adjustable pupil sampling and superior sensitivity, are potentially of great benefit for AO-supported imaging in ophthalmology as well. However, so far no high quality ophthalmic AO imaging was achieved using this novel sensor. Usually, a P-WFS requires modulation and high precision optics that lead to high complexity and costs of the sensor. These factors limit the competitiveness of the P-WFS with respect to other WFS devices for AO correction in visual science. Here, we present a cost-effective realization of AO correction with a non-modulated P-WFS based on standard components and apply this technique to human retinal in vivo imaging using optical coherence tomography (OCT). P-WFS based high quality AO imaging was successfully performed in 5 healthy subjects and smallest retinal cells such as central foveal cone photoreceptors are visualized. The robustness and versatility of the sensor is demonstrated in the model eye under various conditions and in vivo by high-resolution imaging of other structures in the retina using standard and extended fields of view. As a quality benchmark, the performance of conventional SH-WFS based AO was used and successfully met. This work may trigger a paradigm shift with respect to the wavefront sensor of choice for AO in ophthalmic imaging.

Identification and quantification of fibrotic areas in the human retina using polarization-sensitive OCT.

Subretinal fibrosis is one of the most prevalent causes of blindness in the elderly population, but a true gold standard to objectively diagnose fibrosis is still lacking. Since fibrotic tissue is birefringent, it can be detected by polarization-sensitive optical coherence tomography (PS-OCT). We present a new algorithm to automatically detect, segment, and quantify fibrotic lesions within 3D data sets recorded by PS-OCT. The algorithm first compensates for the birefringence of anterior ocular tissues and then uses the uniformity of the birefringent optic axis as an indicator to identify fibrotic tissue, which is then segmented and quantified. The algorithm was applied to 3D volumes recorded in 57 eyes of 57 patients with neovascular age-related macular degeneration using a spectral domain PS-OCT system. The results of fibrosis detection were compared to the clinical diagnosis based on color fundus photography (CFP), and the precision of fibrotic area measurement was assessed by three repeated measurements in a sub-set of 15 eyes. The average standard deviation of the fibrotic area obtained in eyes with a lesion area > 0.7 mm2 was 15%. Fibrosis detection by CFP and PS-OCT agreed in 48 cases, discrepancies were only observed in cases of lesion area < 0.7 mm2. These remaining discrepancies are discussed, and a new method to treat ambiguous cases is presented.

Early Identification of Retinal Neuropathy in Subclinical Diabetic Eyes by Reduced Birefringence of the Peripapillary Retinal Nerve Fiber Layer.

Purpose: To study birefringence of the peripapillary retinal nerve fiber layer (RNFL) of diabetic eyes with no clinical signs of diabetic retinopathy (DR) or mild to moderate DR stages using spectral-domain polarization-sensitive (PS) optical coherence tomography (OCT). Methods: In this observational pilot study, circular PS-OCT scans centered on the optic nerve head were recorded in prospectively recruited diabetic and age-matched healthy eyes. From averaged circumpapillary intensity and retardation tomograms plots of RNFL birefringence were obtained by a linear fit of retardation versus depth within the RNFL tissue for each A-scan position and mean birefringence values for RNFL calculated. Spectral-domain OCT imaging (Heidelberg Engineering) was performed to assess peripapillary RNFL thickness and macular ganglion cell complex (GCC). Results: Out of 70 eyes of 43 diabetic patients (mean ± SD age: 50.86 ± 15.71) 36 showed no signs of DR, 17 mild and 17 moderate nonproliferative DR with no diabetic macular edema. Thirty-four eyes of 34 healthy subjects (53.21 ± 13.88 years) served as controls. Compared with healthy controls (0.143° ± 0.014°/µm) mean total birefringence of peripapillary RNFL was significantly reduced in subclinical diabetic eyes (0.131° ± 0.014°/µm; P = 0.0033), as well as in mild to moderate DR stages (0.125° ± 0.018°/µm, P < 0.0001) with borderline statistically significant differences between diabetic patients (P = 0.0049). Mean birefringence values were significantly lower in inferior compared with superior RNFL sectors (P < 0.0001) of diabetic eyes with no such difference detected in the healthy control group. Conclusions: We identified evidence of early neuroretinal alteration in diabetic eyes through reduced peripapillary RNFL birefringence assessed by PS-OCT occurring before appearance of clinical microvascular lesions or GCC alterations.

Analysis of retinal nerve fiber layer birefringence in patients with glaucoma and diabetic retinopathy by polarization sensitive OCT.

The retinal nerve fiber layer (RNFL) is a fibrous tissue that shows form birefringence. This optical tissue property is related to the microstructure of the nerve fiber axons that carry electrical signals from the retina to the brain. Ocular diseases that are known to cause neurologic changes, like glaucoma or diabetic retinopathy (DR), might alter the birefringence of the RNFL, which could be used for diagnostic purposes. In this pilot study, we used a state-of-the-art polarization sensitive optical coherence tomography (PS-OCT) system with an integrated retinal tracker to analyze the RNFL birefringence in patients with glaucoma, DR, and in age-matched healthy controls. We recorded 3D PS-OCT raster scans of the optic nerve head area and high-quality averaged circumpapillary PS-OCT scans, from which RNFL thickness, retardation and birefringence were derived. The precision of birefringence measurements was 0.005°/µm. As compared to healthy controls, glaucoma patients showed a slightly reduced birefringence (0.129 vs. 0.135°/µm), although not statistically significant. The DR patients, however, showed a stronger reduction of RNFL birefringence (0.103 vs. 0.135°/µm) which was highly significant. This result might open new avenues into early diagnosis of DR and related neurologic changes.

Visualizing human photoreceptor and retinal pigment epithelium cell mosaics in a single volume scan over an extended field of view with adaptive optics optical coherence tomography.

Using adaptive optics optical coherence tomography, human photoreceptors and retinal pigment epithelium (RPE) cells are typically visualized on a small field of view of ∼1° to 2°. In addition, volume averaging is required for visualizing the RPE cell mosaic. To increase the imaging area, we introduce a lens based spectral domain AO-OCT system that shows low aberrations within an extended imaging area of 4°×4° while maintaining a high (theoretical) transverse resolution (at >7 mm pupil diameter) in the order of 2 µm. A new concept for wavefront sensing is introduced that uses light mainly originating from the RPE layer and yields images of the RPE cell mosaic in a single volume acquisition. The capability of the instrument for in vivo imaging is demonstrated by visualizing various cell structures within the posterior retinal layers over an extended field of view.

Optical Coherence Tomography Findings in the Retinas of SOD1 Knockout Mice.

Purpose: The retinal phenotype of popular mouse models mimicking ophthalmic diseases, such as the superoxide dismutase 1 (SOD1) knockout (KO) mouse model, has mainly been assessed by ex vivo histology and in vivo fundus photography. We used multifunctional optical coherence tomography (OCT) to characterize the retinas of SOD1 KO mice in vivo. Methods: The custom-made ophthalmoscope featured a combination of conventional OCT, polarization-sensitive OCT, and OCT angiography. Seven SOD1 KO mice and nine age-matched controls were imaged between 6 and 17 months of age. A postprocessing framework was used to analyze total and outer retinal thickness changes. Drusenlike lesions were segmented, and their sizes and the number of lesions were assessed quantitatively. Their appearance in the conventional reflectivity images, as well as in the corresponding polarization-sensitive images, was characterized qualitatively. Results: Drusenlike lesions increased in size and number with age for SOD1 KO mice. Exploiting the multiple contrast channels, the appearance of the lesions was found to resemble pseudodrusen observed in eyes of patients suffering from dry age-related macular degeneration. The total and outer retinal thicknesses were lower on average after 11 months and 7 months in SOD1 KO mice compared with age-matched controls. Neovascularizations were found in one out of seven KO animals. Conclusions: OCT imaging proved beneficial for a detailed in vivo characterization of the pathological changes in SOD1 KO mice. Translational Relevance: Phenotyping of animal models using modern imaging concepts can be conducted with more precision and might also ease the translation of conclusions between clinical and preclinical research.

Analysis of longitudinal sections of retinal vessels using Doppler OCT.

We present a new method for imaging retinal vessels that provides both structural and hemodynamic information. Our technique is based on a single beam OCT system with an integrated retinal tracker that enables recording of arbitrary scan patterns. We record longitudinal sections along the traces of retinal vessels. The tracker function enables the acquisition of multiple longitudinal sections along the same trace to provide high-quality averaged OCT scans as well as temporal changes of flow dynamics. The vessel walls are clearly identified as narrow, bright lines from which the vessel diameter can be retrieved as a function of position along the vessel. Furthermore, the Doppler angle can be obtained at each position along the vessel trace, enabling measurement of absolute blood flow by Doppler OCT analysis. The method is demonstrated in flow phantoms and in-vivo on retinal vessel bifurcations in healthy volunteers. In 7 of 9 imaged bifurcations, measured in- and outflow deviate by less than 11%, demonstrating the consistency of the method.

Relationship between morphological and vascular alterations in geographic atrophy using a multimodal imaging approach.

PURPOSE: To assess geographic atrophy (GA) using a multimodal imaging approach, focusing on alterations at the level of the retinal pigment epithelium (RPE) and the choriocapillaris (CC) layers, by lesion demarcation, and assessment of morphological alterations within the atrophic area and in the transition zone. METHODS: Fifty-seven eyes of 34 patients with atrophic age-related macular degeneration (AMD) were included in this prospective, observational, cross-sectional study. Multimodal imaging using wide-field polarization-sensitive optical coherence tomography (PS-OCT), optical coherence tomography angiography (OCT-A) and fundus autofluorescence (FAF) was performed. The images were overlaid and used to analyse and compare alterations in the retina and the CC. RESULTS: Mean atrophic lesion size was 8.15 mm2 (range: 2.23-17.23 mm2 ). In 52 of 57 eyes (91%), OCT-A displayed focal hypodense areas at the CC level in the transition zone of GA, as well as increased focal depolarizing material (e.g. melanin-containing structures) showed in PS-OCT en face depolarizing material maps. These regions of increased depolarizing material at the transition zone corresponded to the hypodense areas on OCT-A scans. All 57 eyes presented with abnormal FAF patterns at the transition zone. All 57 eyes showed distinct alterations of CC flow pattern architecture. Six eyes (11%) demonstrated reduced and three eyes (5%) a complete loss of CC flow pattern architecture across the entire area of GA, while 48 of 57 eyes (84%) presented with irregular mixed patterns of different focal alterations of CC flow architecture within the area of GA. Reduced CC patterns exceeding GA lesion margins into the transitional zone were found in all eyes. CONCLUSIONS: Optical coherence tomography angiography images revealed different degrees of flow impairment within the atrophic lesion area and its transition zone. Alterations in RPE morphology and tissue integrity resulting in accumulation of depolarizing material, such as melanin, could result in misinterpretation of OCT-A imaging in areas in the shadow of depolarizing material. These changes seem to be partially independent from autofluorescence altering processes.

10th Anniversary of Biomedical Optics Express: editorial.

Editor-in-Chief Christoph Hitzenberger looks back on the successful first decade of publishing Biomedical Optics Express.

Generating large field of view en-face projection images from intra-acquisition motion compensated volumetric optical coherence tomography data.

A technique to generate large field of view projection maps of arbitrary optical coherence tomography (OCT) data is described. The technique is divided into two stages - an image acquisition stage that features a simple to use fast and robust retinal tracker to get motion free retinal OCT volume scans - and a stitching stage where OCT data from different retinal locations is first registered against a reference image using a custom pyramid-based approach and finally stitched together into one seamless large field of view (FOV) image. The method is applied to data recorded with a polarization sensitive OCT instrument in healthy subjects and glaucoma patients. The tracking and stitching accuracies are quantified, and finally, large FOV images of retinal nerve fiber layer retardation that contain the arcuate nerve fiber bundles from the optic nerve head to the raphe are demonstrated.