Deep spectral learning for label-free optical imaging oximetry with uncertainty quantification

Measurement of blood oxygen saturation (sO2) by optical imaging oximetry provides invaluable insight into local tissue functions and metabolism. Despite different embodiments and modalities, all label-free optical-imaging oximetry techniques utilize the same principle of sO2-dependent spectral contrast from haemoglobin. Traditional approaches for quantifying sO2 often rely on analytical models that are fitted by the spectral measurements. These approaches in practice suffer from uncertainties due to biological variability, tissue geometry, light scattering, systemic spectral bias, and variations in the experimental conditions. Here, we propose a new data-driven approach, termed deep spectral learning (DSL), to achieve oximetry that is highly robust to experimental variations and, more importantly, able to provide uncertainty quantification for each sO2 prediction. To demonstrate the robustness and generalizability of DSL, we analyse data from two visible light optical coherence tomography (vis-OCT) setups across two separate in vivo experiments on rat retinas. Predictions made by DSL are highly adaptive to experimental variabilities as well as the depth-dependent backscattering spectra. Two neural-network-based models are tested and compared with the traditional least-squares fitting (LSF) method. The DSL-predicted sO2 shows significantly lower mean-square errors than those of the LSF. For the first time, we have demonstrated en face maps of retinal oximetry along with a pixel-wise confidence assessment. Our DSL overcomes several limitations of traditional approaches and provides a more flexible, robust, and reliable deep learning approach for in vivo non-invasive label-free optical oximetry.R01 CA224911 - NCI NIH HHS; R01 CA232015 - NCI NIH HHS; R01 NS108464 - NINDS NIH HHS; R21 EY029412 - NEI NIH HHSAccepted manuscrip

Quantitative optical imaging platform for studying neurovascular hemodynamics during ischemic stroke

The measurement of cerebral hemodynamics is vital for the study of physiological and pathophysiological conditions in the brain. Preclinical research examining the mechanisms, outcomes, and efficacies of interventions during ischemic stroke require quantitative imaging technologies. This dissertation presents the development of an optical imaging platform capable of chronic in vivo monitoring of cortical hemodynamics during ischemic stroke and the subsequent recovery. The system combines two different imaging techniques, laser speckle contrast imaging (LSCI) and oxygen-dependent quenching of phosphorescence, to measure cerebral blood flow (CBF) and dissolved oxygen tension (pO2) within cortical vasculature. Phosphorescence signal localization is achieved through the use of a spatial light modulator to selectively pattern excitation light in order to overcome the traditional limitations of the imaging modality. The spatial light modulator is also utilized to perform artery-targeted photothrombosis for the induction of highly-localized, reproducible infarcts as an extension of the photothrombotic model of ischemic stroke. The LSCI hardware implements the multi-exposure speckle imaging (MESI) technique for robust estimates of CBF that facilitate day-to-day and between-subject comparisons. The integration of an awake imaging system eliminates the confounding effects of anesthesia upon cerebral hemodynamics. The capabilities of the complete optical imaging platform are demonstrated by monitoring the acute hemodynamic response during targeted photothrombosis and the chronic recovery of the resulting ischemic infarctBiomedical Engineerin

Optical Imaging Of Tissue Physiology With Exogenous Contrast Agents

This thesis describes experiments and analyses which push the frontier per what one can learn from optically emitting exogenous contrast agents in living tissue. The first set of experiments concurrently measured cerebral blood flow and bothintravascular- and extravascular-tissue oxygen concentration in a rat brain during functional activation; the new instrumentation needed to collect this information used contrast agent phosphorescence lifetime to determine oxygen concentration and speckle contrast imaging to probe blood flow. The concurrent measurement of multiple physiological parameters with high temporal resolution (∼7 Hz) provided a unique opportunity to observe the interconnected dynamics of oxygen exchange, blood flow, and cerebral oxygen metabolism. The experiments showed that initial metabolic changes trigger a blood flow response; comprehensive theoretical modeling of the data exposed potential weaknesses of the well-known and often-used two-compartment oxygen diffusion model, and the experiments as a whole introduced a new tool for characterization of oxygen metabolism and neurovascular coupling in the brain. The second set of experiments developed instrumentation and a simple theoretical methodology for imaging fluorescent targets in turbid media such as tissue. This approach used the ideas of spatial frequency domain fluorescence diffuse optical tomography (SFD-FDOT). The new reconstruction algorithm modified the more complex SFD-FDOT reconstruction method to rapidly acquire the depth of fluorescent target(s) and then estimate the transverse margins of the fluorescent target(s). Tissue phantom experiments demonstrated the instrumentation and algorithm, and assessed limitations. The new methodology could be useful for image guidance during tumor resection surgery, and could also provide rapid and useful constraining information for more comprehensive fluorescent tomography

What are the major susceptibility factors for glaucoma progression?

Elevated intraocular pressure (IOP) is a major risk factor for open angle glaucoma (OAG) and medical IOP reduction is the standard treatment, yet no randomised placebo-controlled study of medical IOP reduction has been undertaken previously. In the present thesis, the methodology, baseline characteristics and results from the United Kingdom Glaucoma Treatment Study (UKGTS), the first randomised, double-masked, placebo-controlled, multicentre treatment trial for OAG, are presented. Survival analysis shows a statistically significant difference in the time from baseline to the event of confirmed visual field progression in the medical treatment (latanoprost) group, as compared to placebo, over 24 months. The role of average IOP during follow-up, as a risk factor for progression, is evaluated. Median IOP, as measured by Goldmann Applanation Tonometry (GAT), Dynamic Contour Tonometry and the Ocular Response Analyzer, is significantly, but weakly, correlated with visual field progression. Corneal compensated IOP (IOPcc) is the best predictor of progression across all the UKGTS sites. While the addition of central corneal thickness (CCT) slightly improves the GAT IOP prediction model, CCT on its own is not a significant predictor of progression in the UKGTS. The role of mitochondrial dysfunction and oxidative stress as risk factors for glaucoma progression is investigated within an exploratory study. Experiments conducted on the lymphocytes of healthy subjects and patients, contrast individuals at the extremes of IOP susceptibility: rapidly progressing patients with Normal Tension Glaucoma (NTG) and non-progressing patients with Ocular Hypertension (OHT). The experimental data presented show, for the first time, that OHT patients may have more efficient mitochondria at a systemic level, when compared to age-similar NTG subjects and nonglaucomatous controls. Overall, OHT lymphocytes produce higher levels of ATP (Complex I and Complexes II/III), have higher mitochondrial membrane potential, enhanced capacity to deal with exogenous oxidative stress insults, higher serum levels of urate, a potent antioxidant, and are more capable of taking up and buffering cytosolic calcium, as compared to NTG and control lymphocytes. Lymphocytes from NTG patients, when compared to the OHT and control groups, show lower ATP synthesis from Complex IV, lower aconitase activity, lower serum levels of vitamin C, and enhanced antioxidant defence (SOD2). In conclusion, this study implicates the role of a) systemic oxidative damage and complex IV-linked mitochondrial defects in the pathogenesis of NTG and b) efficient systemic mitochondria in resistance to glaucomatous optic neuropathy development and progression, particularly in the context of OHT

The Retina in Health and Disease

Vision is the most important sense in higher mammals. The retina is the first step in visual processing and the window to the brain. It is not surprising that problems arising in the retina lead to moderate to severe visual impairments. We offer here a collection of reviews as well as original papers dealing with various aspects of retinal function as well as dysfunction. New approaches in retinal research are described, such as the expression and localization of the endocannabinoid system in the normal retina and the role of cannabinoid receptors that could offer new avenues of research in the development of potential treatments for retinal diseases. Moreover, new insights are offered in advancing knowledge towards the prevention and cure of visual pathologies, mainly AMD, RP, and diabetic retinopathy

Orbital transfer vehicle launch operations study: Automated technology knowledge base, volume 4

A simplified retrieval strategy for compiling automation-related bibliographies from NASA/RECON is presented. Two subsets of NASA Thesaurus subject terms were extracted: a primary list, which is used to obtain an initial set of citations; and a secondary list, which is used to limit or further specify a large initial set of citations. These subject term lists are presented in Appendix A as the Automated Technology Knowledge Base (ATKB) Thesaurus