Shot-noise limited optical hybrid based on fused fiber couplers.

We describe a fiber-based coherent receiver topology which utilizes intrinsic phase shifts from fiber couplers to enable instantaneous quadrature projection with shot-noise limited signal-to-noise ratio (SNR). Fused 3 × 3 fiber couplers generate three phase-shifted signals simultaneously that can be combined with quadrature projection methods to detect magnitude and phase unambiguously. We present a novel, to the best of our knowledge, differential detection topology which utilizes a combination of 3 × 3 and 2 × 2 couplers to enable quadrature projection with fully differential detection. We present a mathematical analysis of this 3 × 3 differential detection topology, extended methods for signal calibration, and SNR analysis. We characterize the SNR advantage of this approach and demonstrate a sample application illustrating simultaneous magnitude and phase imaging of a chrome-on-glass test chart.

Spiral scanning improves subject fixation in widefield retinal imaging.

Point scanning retinal imaging modalities, including confocal scanning light ophthalmoscopy (cSLO) and optical coherence tomography, suffer from fixational motion artifacts. Fixation targets, though effective at reducing eye motion, are infeasible in some applications (e.g., handheld devices) due to their bulk and complexity. Here, we report on a cSLO device that scans the retina in a spiral pattern under pseudo-visible illumination, thus collecting image data while simultaneously projecting, into the subject's vision, the image of a bullseye, which acts as a virtual fixation target. An imaging study of 14 young adult volunteers was conducted to compare the fixational performance of this technique to that of raster scanning, with and without a discrete inline fixation target. Image registration was used to quantify subject eye motion; a strip-wise registration method was used for raster scans, and a novel, to the best of our knowledge, ring-based method was used for spiral scans. Results indicate a statistically significant reduction in eye motion by the use of spiral scanning as compared to raster scanning without a fixation target.

Line-scan phase-resolved synthetic wavelength LiDAR using an off-axis holographic approach.

We demonstrate a novel, to our knowledge, approach for phase-resolved coherent 3D surface imaging that utilizes synthetic wavelength phase-based ranging and line-scan off-axis holography. Our proof-of-concept system employs an akinetic tunable laser to perform fast wavelength switching and a galvanometer mirror for slow-axis mechanical scanning. Quantitative depth measurements of an anodized aluminum plate and 3D-printed depth calibration targets and a printed circuit board are demonstrated. Analyses of both shot-noise limited system performance and speckle noise are also presented. The proof-of-concept system achieves micron-scale depth precision with a FOV of 12.8 mm × 34 mm and a 50 ms image acquisition time.

Robotic Optical Coherence Tomography Retinal Imaging for Emergency Department Patients: A Pilot Study for Emergency Physicians' Diagnostic Performance.

STUDY OBJECTIVE: To evaluate the diagnostic performance of emergency physicians' interpretation of robotically acquired retinal optical coherence tomography images for detecting posterior eye abnormalities in patients seen in the emergency department (ED). METHODS: Adult patients presenting to Duke University Hospital emergency department from November 2020 through October 2021 with acute visual changes, headache, or focal neurologic deficit(s) who received an ophthalmology consultation were enrolled in this pilot study. Emergency physicians provided standard clinical care, including direct ophthalmoscopy, at their discretion. Retinal optical coherence tomography images of these patients were obtained with a robotic, semi-autonomous optical coherence tomography system. We compared the detection of abnormalities in optical coherence tomography images by emergency physicians with a reference standard, a combination of ophthalmology consultation diagnosis and retina specialist optical coherence tomography review. RESULTS: Nine emergency physicians reviewed the optical coherence tomography images of 72 eyes from 38 patients. Based on the reference standard, 33 (46%) eyes were normal, 16 (22%) had at least 1 urgent/emergency abnormality, and the remaining 23 (32%) had at least 1 nonurgent abnormality. Emergency physicians' optical coherence tomography interpretation had 69% (95% confidence interval [CI], 49% to 89%) sensitivity for any abnormality, 100% (95% CI, 79% to 100%) sensitivity for urgent/emergency abnormalities, 48% (95% CI, 28% to 68%) sensitivity for nonurgent abnormalities, and 64% (95% CI, 44% to 84%) overall specificity. In contrast, emergency physicians providing standard clinical care did not detect any abnormality with direct ophthalmoscopy. CONCLUSION: Robotic, semi-autonomous optical coherence tomography enabled ocular imaging of emergency department patients with a broad range of posterior eye abnormalities. In addition, emergency provider optical coherence tomography interpretation was more sensitive than direct ophthalmoscopy for any abnormalities, urgent/emergency abnormalities, and nonurgent abnormalities in this pilot study with a small sample of patients and emergency physicians.

QUANTITATIVE TOPOGRAPHIC CURVATURE MAPS OF THE POSTERIOR EYE UTILIZING OPTICAL COHERENCE TOMOGRAPHY.

PURPOSE: Deformations of the retina such as staphylomas in myopia or scleral flattening in high intracranial pressure can be challenging to quantify with en face imaging. We describe an optical coherence tomography-based method for the generation of quantitative posterior eye topography maps in normal and pathologic eyes. METHODS: Using "whole eye" optical coherence tomography, we corrected for subjects' optical distortions to generate spatially accurate posterior eye optical coherence tomography volumes and created local curvature (KM, mm-1) topography maps for each consented subject. We imaged nine subjects, three normal, two with myopic degeneration, and four with papilledema including one that was imaged longitudinally. RESULTS: Normal subjects mean temporal KM was 0.0923 mm-1, nasal KM was 0.0927 mm-1, and KM local variability was 0.0162 mm-1. In myopic degeneration, subjects KM local variability was higher at 0.0836 mm-1. In papilledema subjects nasal KM was flatter compared with temporal KM (0.0709 vs. 0.0885 mm-1). Mean intrasession KM repeatability for all subjects was 0.0036 mm-1. CONCLUSION: We have developed an optical coherence tomography based method for quantitative posterior eye topography that offers the ability to analyze local curvature with micron scale resolution and offers the potential to help clinicians and researchers characterize subtle, local retinal deformations earlier in patients and follow their development over time.

Spectroscopic optical coherence refraction tomography.

In optical coherence tomography (OCT), the axial resolution is often superior to the lateral resolution, which is sacrificed for long imaging depths. To address this anisotropy, we previously developed optical coherence refraction tomography (OCRT), which uses images from multiple angles to computationally reconstruct an image with isotropic resolution, given by the OCT axial resolution. On the other hand, spectroscopic OCT (SOCT), an extension of OCT, trades axial resolution for spectral resolution and hence often has superior lateral resolution. Here, we present spectroscopic OCRT (SOCRT), which uses SOCT images from multiple angles to reconstruct a spectroscopic image with isotropic spatial resolution limited by the OCT lateral resolution. We experimentally show that SOCRT can estimate bead size based on Mie theory at simultaneously high spectral and isotropic spatial resolution. We also applied SOCRT to a biological sample, achieving axial resolution enhancement limited by the lateral resolution.

Multimodal handheld adaptive optics scanning laser ophthalmoscope.

Non-confocal adaptive optics scanning laser ophthalmoscopy (AOSLO) has enhanced the study of human retinal photoreceptors by providing complementary information to standard confocal AOSLO images. Previously we developed the first confocal handheld AOSLO (HAOSLO) capable of in vivo cone photoreceptor imaging in supine and non-cooperative patients. Here, we introduce the first multimodal (M-)HAOSLO for confocal and non-confocal split-detection (SD) imaging to allow for more comprehensive patient data collection. Aside from its unprecedented miniature size and weight, M-HAOSLO is also the first system to perform sensorless wavefront-corrected SD imaging of cone photoreceptors.

Optical Coherence Tomography-Guided Robotic Ophthalmic Microsurgery via Reinforcement Learning from Demonstration.

Ophthalmic microsurgery is technically difficult because the scale of required surgical tool manipulations challenge the limits of the surgeon's visual acuity, sensory perception, and physical dexterity. Intraoperative optical coherence tomography (OCT) imaging with micrometer-scale resolution is increasingly being used to monitor and provide enhanced real-time visualization of ophthalmic surgical maneuvers, but surgeons still face physical limitations when manipulating instruments inside the eye. Autonomously controlled robots are one avenue for overcoming these physical limitations. We demonstrate the feasibility of using learning from demonstration and reinforcement learning with an industrial robot to perform OCT-guided corneal needle insertions in an ex vivo model of deep anterior lamellar keratoplasty (DALK) surgery. Our reinforcement learning agent trained on ex vivo human corneas, then outperformed surgical fellows in reaching a target needle insertion depth in mock corneal surgery trials. This work shows the combination of learning from demonstration and reinforcement learning is a viable option for performing OCT guided robotic ophthalmic surgery.

Three-dimensional pattern of extraretinal neovascular development in retinopathy of prematurity.

BACKGROUND: The application of three-dimensional (3D) visualization techniques to evaluate the earliest visible onset of abnormal retinal vascular development in preterm infants with retinopathy of prematurity (ROP), using bedside non-contact optical coherence tomography (OCT) imaging to characterize morphology and sequential structural changes of abnormal extraretinal neovascularization. METHODS: Thirty-one preterm infants undergoing routine ROP screening with written informed consent for research imaging were enrolled in this prospective observational study. We imaged the macula and temporal periphery of preterm infants using a handheld OCT system (Envisu 2300 or handheld swept-source research system). The scans obtained were segmented and, using enhanced ray casting, were converted to 3D volumes to which color filter was applied. RESULTS: Using colorized 3D visualization, we defined extraretinal neovascular structures as buds, bridging networks, and placoid lesions. We could longitudinally follow progression and regression of extraretinal neovascularization in stage 3 ROP after treatment in one infant over 12 weeks and document the appearance of early buds, and formation of florid neovascularization. From stages 2 to 3 ROP, we observed progression from sessile buds to a complex plaque that corresponded to stage 3 ROP on clinical examination. We demonstrated regression of neovascular complexes to small pre-retinal tufts after treatment with anti-VEGF. CONCLUSIONS: The extension of OCT processing to include surface flattening and colorization that further improved structural analysis rendered better understanding of extraretinal tissue. Our ability to image similar areas in the same infant over multiple visits enabled us to study the evolution of these structural components and follow pathological vascular events longitudinally in development and regression after treatment. These methods can be applied to further study which are likely contribute to our understanding of the pathophysiology of neovascularization in ROP.

VISUALIZATION FROM INTRAOPERATIVE SWEPT-SOURCE MICROSCOPE-INTEGRATED OPTICAL COHERENCE TOMOGRAPHY IN VITRECTOMY FOR COMPLICATIONS OF PROLIFERATIVE DIABETIC RETINOPATHY.

PURPOSE: To evaluate the use of live volumetric (4D) intraoperative swept-source microscope-integrated optical coherence tomography in vitrectomy for proliferative diabetic retinopathy complications. METHODS: In this prospective study, we analyzed a subgroup of patients with proliferative diabetic retinopathy complications who required vitrectomy and who were imaged by the research swept-source microscope-integrated optical coherence tomography system. In near real time, images were displayed in stereo heads-up display facilitating intraoperative surgeon feedback. Postoperative review included scoring image quality, identifying different diabetic retinopathy-associated pathologies and reviewing the intraoperatively documented surgeon feedback. RESULTS: Twenty eyes were included. Indications for vitrectomy were tractional retinal detachment (16 eyes), combined tractional-rhegmatogenous retinal detachment (2 eyes), and vitreous hemorrhage (2 eyes). Useful, good-quality 2D (B-scans) and 4D images were obtained in 16/20 eyes (80%). In these eyes, multiple diabetic retinopathy complications could be imaged. Swept-source microscope-integrated optical coherence tomography provided surgical guidance, e.g., in identifying dissection planes under fibrovascular membranes, and in determining residual membranes and traction that would benefit from additional peeling. In 4/20 eyes (20%), acceptable images were captured, but they were not useful due to high tractional retinal detachment elevation which was challenging for imaging. CONCLUSION: Swept-source microscope-integrated optical coherence tomography can provide important guidance during surgery for proliferative diabetic retinopathy complications through intraoperative identification of different complications and facilitation of intraoperative decision making.

Enhanced visualization of peripheral retinal vasculature with wavefront sensorless adaptive optics optical coherence tomography angiography in diabetic patients.

Optical coherence tomography angiography (OCTA) is a promising technique for non-invasive visualization of vessel networks in the human eye. We debut a system capable of acquiring wide field-of-view (>70°) OCT angiograms without mosaicking. Additionally, we report on enhancing the visualization of peripheral microvasculature using wavefront sensorless adaptive optics (WSAO). We employed a fast WSAO algorithm that enabled wavefront correction in <2 s by iterating the mirror shape at the speed of OCT B-scans rather than volumes. Also, we contrasted ∼7° field-of-view OCTA angiograms acquired in the periphery with and without WSAO correction. On average, WSAO improved the sharpness of microvasculature by 65% in healthy eyes and 38% in diseased eyes. Preliminary observations demonstrated that the location of 7° images could be identified directly from the wide field-of-view angiogram. A pilot study on a normal subject and patients with diabetic retinopathy showed the impact of utilizing WSAO for OCTA when visualizing peripheral vasculature pathologies.

Long working distance OCT with a compact 2f retinal scanning configuration for pediatric imaging.

Young and/or autistic children cannot be imaged with tabletop or handheld optical coherence tomography (OCT) because of their lack of attention and fear of large objects close to their face. We demonstrate a prototype retinal swept-source OCT system with a long working distance (from the last optical element to the subject's eye) to facilitate pediatric imaging. To reduce the number of optical elements and axial length compared to the traditional 4f telescope, we employ a compact 2f retinal scanning configuration and achieve a working distance of 350 mm with a 16° OCT field of view. We test our prototype system on pediatric and adult subjects.

Method for single illumination source combined optical coherence tomography and fluorescence imaging of fluorescently labeled ocular structures in transgenic mice.

In vivo imaging permits longitudinal study of ocular disease processes in the same animal over time. Two different in vivo optical imaging modalities - optical coherence tomography (OCT) and fluorescence - provide important structural and cellular data respectively about disease processes. In this Methods in Eye Research article, we describe and demonstrate the combination of these two modalities producing a truly simultaneous OCT and fluorescence imaging system for imaging of fluorescently labeled animal models. This system uses only a single light source to illuminate both modalities, and both share the same field of view. This allows simultaneous acquisition of OCT and fluorescence images, and the benefits of both techniques are realized without incurring increased costs in variability, light exposure, time, and post-processing effort as would occur when the modalities are used separately. We then utilized this system to demonstrate multi-modal imaging in a progression of samples exhibiting both fluorescence and OCT scattering beginning with resolution targets, ex vivo thy1-YFP labeled neurons in mouse eyes, and finally an in vivo longitudinal time course of GFP labeled myeloid cells in a mouse model of ocular allergy.

Optical coherence tomography accurately measures corneal power change from laser refractive surgery.

PURPOSE: To determine the ability of motion-corrected optical coherence tomography (OCT) to measure the corneal refractive power change due to LASIK. DESIGN: Evaluation of a diagnostic test or technology in a cohort. SUBJECTS: A total of 70 eyes from 37 subjects undergoing LASIK were measured preoperatively. A total of 39 eyes from 22 subjects were measured postoperatively and completed the study. METHODS: Consecutive patients undergoing LASIK at the Duke Eye Center who consented to participate were imaged with Placido-ring topography, Scheimpflug photography, and OCT on the day of their surgery. Patients were then reimaged with the same imaging systems at the postoperative month 3 visit. Change in preoperative to postoperative corneal refractive power as measured by each of the imaging modalities was compared with the preoperative to postoperative change in manifest refraction (MRx) using the t test with generalized estimating equations. MAIN OUTCOME MEASURES: Corneal refractive power change due to LASIK as measured by Placido-ring topography, Scheimpflug photography, and OCT compared with the MRx change vertexed to the corneal plane. The change in MRx should correspond to the change in the corneal refractive power from LASIK and was considered the reference measurement. RESULTS: In 22 individuals (39 eyes) returning after LASIK, we found no significant difference between the clinically measured pre- to post-LASIK change in MRx and both Scheimpflug photography (P = 0.714) and OCT (P = 0.216). In contrast, keratometry values from Placido-ring topography were found to be significantly different from the measured refractive change (P < 0.001). In addition, of the 3 imaging modalities, OCT recorded the smallest mean absolute difference from the reference measurement with the least amount of variability. CONCLUSIONS: Motion-corrected OCT more accurately measures the change in corneal refractive power due to laser refractive surgery than other currently available clinical devices. By offering accurate corneal refractive power measurements in normal and surgically modified subjects, OCT offers a compelling alternative to current clinical devices for determining corneal refractive power.

Spatial frequency-domain multiplexed microscopy for simultaneous, single-camera, one-shot, fluorescent, and quantitative-phase imaging.

Multimodal imaging is a crucial tool when imaging biological phenomena that cannot be comprehensively captured by a single modality. Here, we introduce a theoretical framework for spatial-frequency-multiplexed microscopy via off-axis interference as a novel wide-field imaging technique that enables true simultaneous multimodal and multichannel wide-field imaging. We experimentally demonstrate this technique for single-camera, simultaneous two-channel fluorescence and one-channel quantitative-phase imaging for fluorescent microspheres and fixed cells stained for F-actin and nuclear fluorescence.

INTRAOPERATIVE SPECTRAL DOMAIN OPTICAL COHERENCE TOMOGRAPHY IMAGING AFTER INTERNAL LIMITING MEMBRANE PEELING IN IDIOPATHIC EPIRETINAL MEMBRANE WITH CONNECTING STRANDS.

PURPOSE: To report the intraoperative optical coherence tomography findings in idiopathic epiretinal membrane (ERM) with connecting strands and to describe the postoperative outcomes. METHODS: A retrospective, case series study within a prospective observational intraoperative optical coherence tomography imaging study was performed. Epiretinal membranes with connecting strands were characterized on preoperative spectral domain optical coherence tomography images and assessed against corresponding intraoperative (after internal limiting membrane [ILM] peeling) and postoperative spectral domain optical coherence tomography images. RESULTS: Eleven locations of the connecting strands in 7 eyes were studied. The connecting strands had visible connections from the inner retinal surface to the ERM in all locations, and the reflectivity was moderate in 8 locations and high in 3 locations. After ERM and ILM peeling, disconnected strands were identified in all of the intraoperative optical coherence tomography images. The reflectivity of the remaining intraoperative strands was higher than that of the preoperative lesions and appeared as "finger-like" and branching projections. The remaining disconnected lesions were contiguous with the inner retinal layers. Postoperatively, the intraoperative lesions disappeared completely in all locations, and recurrent formation of ERM was not identified in any eyes. CONCLUSION: In ERM eyes with connecting strands, intraoperative spectral domain optical coherence tomography imaging showed moderately to highly reflective sub-ILM finger-like lesions that persist immediately after membrane and ILM peeling. Postoperatively, the hyperreflective lesions disappeared spontaneously without localized nerve fiber layer loss. The sub-ILM connecting strands may represent glial retinal attachments.

Quantitative classification of eyes with and without intermediate age-related macular degeneration using optical coherence tomography.

OBJECTIVE: To define quantitative indicators for the presence of intermediate age-related macular degeneration (AMD) via spectral-domain optical coherence tomography (SD-OCT) imaging of older adults. DESIGN: Evaluation of diagnostic test and technology. PARTICIPANTS AND CONTROLS: One eye from 115 elderly subjects without AMD and 269 subjects with intermediate AMD from the Age-Related Eye Disease Study 2 (AREDS2) Ancillary SD-OCT Study. METHODS: We semiautomatically delineated the retinal pigment epithelium (RPE) and RPE drusen complex (RPEDC, the axial distance from the apex of the drusen and RPE layer to Bruch's membrane) and total retina (TR, the axial distance between the inner limiting and Bruch's membranes) boundaries. We registered and averaged the thickness maps from control subjects to generate a map of "normal" non-AMD thickness. We considered RPEDC thicknesses larger or smaller than 3 standard deviations from the mean as abnormal, indicating drusen or geographic atrophy (GA), respectively. We measured TR volumes, RPEDC volumes, and abnormal RPEDC thickening and thinning volumes for each subject. By using different combinations of these 4 disease indicators, we designed 5 automated classifiers for the presence of AMD on the basis of the generalized linear model regression framework. We trained and evaluated the performance of these classifiers using the leave-one-out method. MAIN OUTCOME MEASURES: The range and topographic distribution of the RPEDC and TR thicknesses in a 5-mm diameter cylinder centered at the fovea. RESULTS: The most efficient method for separating AMD and control eyes required all 4 disease indicators. The area under the curve (AUC) of the receiver operating characteristic (ROC) for this classifier was >0.99. Overall neurosensory retinal thickening in eyes with AMD versus control eyes in our study contrasts with previous smaller studies. CONCLUSIONS: We identified and validated efficient biometrics to distinguish AMD from normal eyes by analyzing the topographic distribution of normal and abnormal RPEDC thicknesses across a large atlas of eyes. We created an online atlas to share the 38 400 SD-OCT images in this study, their corresponding segmentations, and quantitative measurements.

Structured illumination diffraction phase microscopy for broadband, subdiffraction resolution, quantitative phase imaging.

Structured illumination microscopy (SIM) is an established technique that allows subdiffraction resolution imaging by heterodyning high sample frequencies into the system's passband via structured illumination. However, until now, SIM has been typically used to achieve subdiffraction resolution for intensity-based imaging. Here, we present a novel optical setup that uses structured illumination with a broadband light source to obtain noise-reduced, subdiffraction resolution, quantitative phase imaging (QPM) of cells. We compare this with a previous work for subdiffraction QPM imaging via SIM that used a laser source, and was thus still corrupted by coherent noise.

Compressed wavefront sensing.

We report on an algorithm for fast wavefront sensing that incorporates sparse representation for the first time in practice. The partial derivatives of optical wavefronts were sampled sparsely with a Shack-Hartman wavefront sensor (SHWFS) by randomly subsampling the original SHWFS data to as little as 5%. Reconstruction was performed by a sparse representation algorithm that utilized the Zernike basis. We name this method sparse Zernike (SPARZER). Experiments on real and simulated data attest to the accuracy of the proposed techniques as compared to traditional sampling and reconstruction methods. We have made the corresponding dataset and software freely available online. Compressed wavefront sensing offers the potential to increase the speed of wavefront acquisition and to defray the cost of SHWFS devices.

Coherence revival multiplexed, buffered swept source optical coherence tomography: 400 kHz imaging with a 100 kHz source.

The effective speed of a swept source optical coherence tomography (SSOCT) imaging system was quadrupled using efficient sweep buffering along with coherence revival and spatial multiplexing. A polarizing beam splitter and fold mirror assembly were used to create a dual spot sample arm with a common objective designed for near-diffraction-limited retinal imaging. Using coherence revival, a variable optical delay line allowed for separate locations within a sample to be simultaneously imaged and frequency encoded by carefully controlling the optical path length of each sample path. This method can be used to efficiently quadruple the imaging speed of any SSOCT system employing a low duty-cycle laser that exhibits coherence revival. The system was used to image the retina of healthy human volunteers.