Daniel X. Hammer

Ultrahigh-speed multimodal adaptive optics system for microscopic structural and functional imaging of the human retina

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We describe the design and performance of a multimodal and multifunctional adaptive optics (AO) system that combines scanning laser ophthalmoscopy (SLO) and optical coherence tomography (OCT) for simultaneous retinal imaging at 13.4 Hz. The high-speed AO-OCT channel uses a 3.4 MHz Fourier-domain mode-locked (FDML) swept source. The system achieves exquisite resolution and sensitivity for pan-macular and transretinal visualization of retinal cells and structures while providing a functional assessment of the cone photoreceptors. The ultra-high speed also enables wide-field scans for clinical usability and angiography for vascular visualization. The FDA FDML-AO system is a powerful platform for studying various retinal and neurological diseases for vision science research, retina physiology investigation, and biomarker development

Deep learning-enabled volumetric cone photoreceptor segmentation in adaptive optics optical coherence tomography images of normal and diseased eyes

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Deep learning-enabled volumetric cone photoreceptor segmentation in adaptive optics optical coherence tomography images of normal and diseased eyes Objective quantification of photoreceptor cell morphology, such as cell diameter and outer segment length, is crucial for early, accurate, and sensitive diagnosis and prognosis of retinal neurodegenerative diseases. Adaptive optics optical coherence tomography (AO-OCT) provides three-dimensional (3-D) visualization of photoreceptor cells in the living human eye. The current gold standard for extracting cell morphology from AO-OCT images involves the tedious process of 2-D manual marking. To automate this process and extend to 3-D analysis of the volumetric data, we propose a comprehensive deep learning framework to segment individual cone cells in AO-OCT scans. Our automated method achieved human-level performance in assessing cone photoreceptors of healthy and diseased participants captured with three different AO-OCT systems representing two different types of point scanning OCT: spectral domain and swept source.

Weakly supervised individual ganglion cell segmentation from adaptive optics OCT images for glaucomatous damage assessment

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Cell-level quantitative features of retinal ganglion cells (GCs) are potentially important biomarkers for improved diagnosis and treatment monitoring of neurodegenerative diseases such as glaucoma, Parkinson’s disease, and Alzheimer’s disease. Yet, due to limited resolution, individual GCs cannot be visualized by commonly used ophthalmic imaging systems, including optical coherence tomography (OCT), and assessment is limited to gross layer thickness analysis. Adaptive optics OCT (AO-OCT) enables in vivo imaging of individual retinal GCs. We present an automated segmentation of GC layer (GCL) somas from AO-OCT volumes based on weakly supervised deep learning (named WeakGCSeg), which effectively utilizes weak annotations in the training process. Experimental results show that WeakGCSeg is on par with or superior to human experts and is superior to other state-of-the-art networks. The automated quantitative features of individual GCLs show an increase in structure–fun...

Dissecting the microvascular contributions to diffuse correlation spectroscopy measurements of cerebral hemodynamics using optical coherence tomography angiography

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Significance: Diffuse correlation spectroscopy (DCS) is an emerging noninvasive, diffuse optical modality that purportedly enables direct measurements of microvasculature blood flow. Functional optical coherence tomography angiography (OCT-A) can resolve blood flow in vessels as fine as capillaries and thus has the capability to validate key attributes of the DCS signal. Aim: To characterize activity in cortical vasculature within the spatial volume that is probed by DCS and to identify populations of blood vessels that are most representative of the DCS signals. Approach: We performed simultaneous measurements of somatosensory-evoked cerebral blood flow in mice in vivo using both DCS and OCT-A. Results: We resolved sensory-evoked blood flow in the somatosensory cortex with both modalities. Vessels with diameters smaller than 10 μ m featured higher peak flow rates during the initial poststimulus positive increase in flow, whereas larger vessels exhibited considerably larger magni...

Integrating adaptive optics-SLO and OCT for multimodal visualization of the human retinal pigment epithelial mosaic

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In vivo imaging of human retinal pigment epithelial (RPE) cells has been demonstrated through multiple adaptive optics (AO)-based modalities. However, whether consistent and complete information regarding the cellular structure of the RPE mosaic is obtained across these modalities remains uncertain due to limited comparisons performed in the same eye. Here, an imaging platform combining multimodal AO-scanning light ophthalmoscopy (AO-SLO) with AO-optical coherence tomography (AO-OCT) is developed to make a side-by-side comparison of the same RPE cells imaged across four modalities: AO-darkfield, AO-enhanced indocyanine green (AO-ICG), AO-infrared autofluorescence (AO-IRAF), and AO-OCT. Co-registered images were acquired in five subjects, including one patient with choroideremia. Multimodal imaging provided multiple perspectives of the RPE mosaic that were used to explore variations in RPE cell contrast in a subject-, location-, and even cell-dependent manner. Estimated cell-to-cell ...

Label-free adaptive optics imaging of human retinal macrophage distribution and dynamics

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Microglia are resident central nervous system macrophages and the first responders to neural injury. Until recently, microglia have been studied only in animal models with exogenous or transgenic labeling. While these studies provided a wealth of information on the delicate balance between neuroprotection and neurotoxicity within which these cells operate, extrapolation to human immune function has remained an open question. Here we examine key characteristics of retinal macrophage cells in live human eyes, both healthy and diseased, with the unique capabilities of our adaptive optics–optical coherence tomography approach and owing to their propitious location above the inner limiting membrane (ILM), allowing direct visualization of cells. Our findings indicate that human ILM macrophage cells may be distributed distinctly, age differently, and have different dynamic characteristics than microglia in other animals. For example, we observed a macular pattern that was sparse cent...

Direct laser writing of a titanium dioxide-laden retinal cone phantom for adaptive optics-optical coherence tomography

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The spatial resolution of adaptive optics-optical coherence tomography (AO-OCT) enables visualization of retinal components ( e.g ., photoreceptors), which can advance clinical diagnosis of ocular diseases. Currently, however, variability in AO-OCT system performance suggests a need for standardized physical models, or “phantoms”, that replicate the opto-structural properties of retinal components. Here we employ direct laser writing – a two-photon polymerization-based additive manufacturing technology – using a light scattering titanium (IV) dioxide nanoparticle-laden photomaterial to create novel retinal cone outer segment (OS) phantoms. Fabrication results demonstrate effective mimicry of cone OS diameter and spacing at four retinal eccentricities, while AO-OCT experiments demonstrate cone spacings >4 µ m can be resolved. These results suggest a promising methodology for biomimetic photoreceptor phantom development for AO-OCT. ( Read Full Arti...

Application of optical coherence tomography and optical path length method for monitoring corneal thickness and refractive index change during corneal cross-linking

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Corneal cross-linking (CXL) using UVA irradiation with a riboflavin photosensitizer has emerged as a new treatment paradigm for corneal ectatic disorders. The thickness threshold for protection of intraocular structures has often been challenged with ongoing developments, and corneal thinning becomes an important safety concern, especially for patients with thin corneas. In this study with an ex vivo bovine eye model, we monitored corneal thinning and corneal refractive index changes using optical coherence tomography (OCT) integrated with an adaptation of the optical path length method. CXL experiments were performed based on the standard protocol that includes removal of the corneal epithelium to facilitate diffusion of riboflavin into the stroma. The corneal stromal thickness and group refractive index were measured by a 1310 nm Fourier-domain OCT imaging system at three critical points of the procedure: immediately after epithelial removal, after 30 min riboflavin instillation, ...

Toward optical coherence tomography angiography-based biomarkers to assess the safety of peripheral nerve electrostimulation

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Objective: Peripheral nerves serve as a link between the central nervous system and its targets. Altering peripheral nerve activity through targeted electrical stimulation is being investigated as a therapy for modulating end organ function. To support rapid advancement in the field, novel approaches to predict and prevent nerve injury resulting from the electrical stimulation must be developed to overcome the limitations of traditional histological methods. The present study aims to develop an optical imaging-based approach for real-time assessment of peripheral nerve injury associated with electrical stimulation.
 
 Approach: We developed an optical coherence tomography angiography system and a 3-D printed stimulating nerve stabilizer to assess the real-time microvascular and blood flow changes associated with electrical stimulation of peripheral nerves. We then compared the microvascular changes with established nerve function analysis and immunohistochemistry to ...

3-D printed photoreceptor phantoms for evaluating lateral resolution of adaptive optics imaging systems

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With adaptive optics (AO), optical coherence tomography and scanning laser ophthalmoscopy imaging systems can resolve individual photoreceptor cells in living eyes, due to enhanced lateral spatial resolution. However, no standard test method exists for experimentally quantifying this parameter in ophthalmic AO imagers. Here, we present three-dimensional (3-D) printed phantoms, which enable the measurement of lateral resolution in an anatomically relevant manner. We used two-photon polymerization to fabricate two phantoms, which mimic the mosaic of cone photoreceptor outer segments at multiple retinal eccentricities. With these phantoms, we demonstrated that the resolution of two multimodal AO systems is similar to theoretical predictions, with some intriguing speckle effects. ( Read Full Article )

Optical coherence tomography angiography based biomarkers to assess the safety of peripheral nerve electrostimulation

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Peripheral nerves connect and relay information between the central nervous system and its target organs. Small arteries traverse the epineurium and are responsible for supplying blood to the axons and cells within the nerves. Constriction or damage to these vessels can reduce perfusion leading to ischemic insults. Peripheral nerve electrostimulation has been approved for the treatment of epilepsy, depression and migraines, and is also being studied for the treatment of rheumatoid arthritis, Crohn’s disease, polycystic ovary syndrome, and type II diabetes. While the safety and efficacy of currently approved medical devices is well established, next generation devices may require novel stimulation parameters that pose additional risks. Therefore it is important to develop new methods to assess stimulation-induced nerve injury. To that end, we have begun to explore optical imaging based biomarkers, including optical coherence tomography angiography (OCT-A) to quantify changes in...

Optic Nerve Head Measurements With Optical Coherence Tomography: A Phantom-Based Study Reveals Differences Among Clinical Devices

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Purpose : Optical coherence tomography (OCT) can monitor for glaucoma by measuring dimensions of the optic nerve head (ONH) cup and disc. Multiple clinical studies have shown that different OCT devices yield different estimates of retinal dimensions. We developed phantoms mimicking ONH morphology as a new way to compare ONH measurements from different clinical OCT devices. Methods : Three phantoms were fabricated to model the ONH: One normal and two with glaucomatous anatomies. Phantoms were scanned with Stratus, RTVue, and Cirrus clinical devices, and with a laboratory OCT system as a reference. We analyzed device-reported ONH measurements of cup-to-disc ratio (CDR) and cup volume and compared them with offline measurements done manually and with a custom software algorithm, respectively. Results : The mean absolute difference between clinical devices with device-reported measurements versus offline measurements was 0.082 vs. 0.013 for CDR and 0.044 mm 3 vs. 0.019 mm 3 for cup volu...

Feature of the Week 03/20/2016: Closed Loop Tracked Doppler OCT Based Heart Monitor for the Drosophila Melanogaster Larvae

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A fruit fly larva (top) was continuously tracked for continuous remote monitoring. A heartbeat trace of freely moving larva (bottom) was obtained by a low coherence interferometry based doppler sensing technique. This paper presents a novel instrument for biosciences, useful for studies of moving embryos. A dual sequential imaging/measurement channel is assembled via a closed-loop tracking architecture. The dual channel system can operate in two regimes: (i) single-point Doppler signal monitoring or (ii) fast 3-D swept source OCT imaging. The system is demonstrated for characterizing cardiac dynamics in Drosophila melanogaster larva. Closed loop tracking enables long term in vivo monitoring of the larvae heart without anesthetic or physical restraint. Such an instrument can be used to measure subtle variations in the cardiac behavior otherwise obscured by the larvae movements.  For more information see recent Article. CourtesyMantas Zurauskas from Oxford Uni...

IMAGING WITH MULTIMODAL ADAPTIVE-OPTICS OPTICAL COHERENCE TOMOGRAPHY IN MULTIPLE EVANESCENT WHITE DOT SYNDROME: THE STRUCTURE AND FUNCTIONAL RELATIONSHIP

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Purpose: To elucidate the location of pathological changes in multiple evanescent white dot syndrome (MEWDS) with the use of multimodal adaptive optics (AO) imaging . Methods: A 5-year observational case study of a 24-year-old female with recurrent MEWDS. Full examination included history, Snellen chart visual acuity, pupil assessment, intraocular pressures, slit lamp evaluation, dilated fundoscopic exam, imaging with Fourier-domain optical coherence tomography (FD-OCT), blue-light fundus autofluorescence (FAF), fundus photography, fluorescein angiography, and adaptive-optics optical coherence tomography . Results: Three distinct acute episodes of MEWDS occurred during the period of follow-up. Fourier-domain optical coherence tomography and adaptive-optics imaging showed disturbance in the photoreceptor outer segments (PR OS) in the posterior pole with each flare. The degree of disturbance at the photoreceptor level corresponded to size and extent of the visual field changes. All fi...

Image quality metrics for optical coherence angiography

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We characterized image quality in optical coherence angiography (OCA) en face planes of mouse cortical capillary network in terms of signal-to-noise ratio (SNR) and Weber contrast (Wc) through a novel mask-based segmentation method. The method was used to compare two adjacent B-scan processing algorithms, (1) average absolute difference (AAD) and (2) standard deviation (SD), while varying the number of lateral cross-sections acquired (also known as the gate length, N). AAD and SD are identical at N = 2 and exhibited similar image quality for N<10. However, AAD is relatively less susceptible to bulk tissue motion artifact than SD. SNR and Wcwere 15% and 35% higher for AAD from N = 25 to 100. In addition data sets were acquired with two objective lenses with different magnifications to quantify the effect of lateral resolution on fine capillary detection. The lower power objective yielded a significant mean broadening of 17% in Full Width Half Maximum (FWHM) diameter. The...

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