Dynamic assessment of the tear film muco-aqueous and lipid layers using a novel tear film imager (TFI).

PURPOSE: The objective of the study was to assess a new technology, the tear film imager (TFI), which can dynamically image the muco-aqueous and lipid layers. METHODS: Prospective pilot case series of individuals with and without dry eye (DE). Two sequential images were obtained with the TFI. Measurements were assessed for reproducibility and compared with clinically derived DE metrics. Individuals were grouped into DE categories based on signs of DE. RESULTS: 49 patients participated in the study with a mean age of 58.8 years (SD 15.9) and a female majority (69%). Reproducibility of the muco-aqueous layer thickness (MALT) was excellent (r=0.88). MALT measurements significantly correlated with the Schirmer score (r=0.31). Lipid break up time (LBUT) as measured by the TFI significantly correlated with the clinical measure of tear break up time (TBUT) (r=0.73). MALT and LBUT were significantly thinner and shorter, respectively, in the DE groups (mild-moderate and severe) compared with the control group. When comparing TFI parameters to clinically assessed signs, sensitivity of the device was 87% and specificity was 88%. CONCLUSION: The TFI is the first machine capable of reproducibly measuring muco-aqueous thickness in human subjects which correlates with Schirmer score. In parallel, it assesses other important aspects of tear film function which correlate with clinician assessed DE metrics.

Optical Detection of Ultrasound in Photoacoustic Imaging.

OBJECTIVE: Photoacoustic (PA) imaging emerges as a unique tool to study biological samples based on optical absorption contrast. In PA imaging, piezoelectric transducers are commonly used to detect laser-induced ultrasonic waves. However, they typically lack adequate broadband sensitivity at ultrasonic frequency higher than 100 MHz, whereas their bulky size and optically opaque nature cause technical difficulties in integrating PA imaging with conventional optical imaging modalities. To overcome these limitations, optical methods of ultrasound detection were developed and shown their unique applications in PA imaging. METHODS: We provide an overview of recent technological advances in optical methods of ultrasound detection and their applications in PA imaging. A general theoretical framework describing sensitivity, bandwidth, and angular responses of optical ultrasound detection is also introduced. RESULTS: Optical methods of ultrasound detection can provide improved detection angle and sensitivity over significantly extended bandwidth. In addition, its versatile variants also offer additional advantages, such as device miniaturization, optical transparency, mechanical flexibility, minimal electrical/mechanical crosstalk, and potential noncontact PA imaging. CONCLUSION: The optical ultrasound detection methods discussed in this review and their future evolution may play an important role in PA imaging for biomedical study and clinical diagnosis.

Parallel Solver for Diffuse Optical Tomography on Realistic Head Models With Scattering and Clear Regions.

Diffuse optical tomography is an imaging technique, based on evaluation of how light propagates within the human head to obtain the functional information about the brain. Precision in reconstructing such an optical properties map is highly affected by the accuracy of the light propagation model implemented, which needs to take into account the presence of clear and scattering tissues. We present a numerical solver based on the radiosity-diffusion model, integrating the anatomical information provided by a structural MRI. The solver is designed to run on parallel heterogeneous platforms based on multiple GPUs and CPUs. We demonstrate how the solver provides a 7 times speed-up over an isotropic-scattered parallel Monte Carlo engine based on a radiative transport equation for a domain composed of 2 million voxels, along with a significant improvement in accuracy. The speed-up greatly increases for larger domains, allowing us to compute the light distribution of a full human head ( ≈ 3 million voxels) in 116 s for the platform used.

Optical cone beam tomography of Cherenkov-mediated signals for fast 3D dosimetry of x-ray photon beams in water.

PURPOSE: To test the use of a three-dimensional (3D) optical cone beam computed tomography reconstruction algorithm, for estimation of the imparted 3D dose distribution from megavoltage photon beams in a water tank for quality assurance, by imaging the induced Cherenkov-excited fluorescence (CEF). METHODS: An intensified charge-coupled device coupled to a standard nontelecentric camera lens was used to tomographically acquire two-dimensional (2D) projection images of CEF from a complex multileaf collimator (MLC) shaped 6 MV linear accelerator x-ray photon beam operating at a dose rate of 600 MU/min. The resulting projections were used to reconstruct the 3D CEF light distribution, a potential surrogate of imparted dose, using a Feldkamp-Davis-Kress cone beam back reconstruction algorithm. Finally, the reconstructed light distributions were compared to the expected dose values from one-dimensional diode scans, 2D film measurements, and the 3D distribution generated from the clinical Varian ECLIPSE treatment planning system using a gamma index analysis. A Monte Carlo derived correction was applied to the Cherenkov reconstructions to account for beam hardening artifacts. RESULTS: 3D light volumes were successfully reconstructed over a 400 × 400 × 350 mm(3) volume at a resolution of 1 mm. The Cherenkov reconstructions showed agreement with all comparative methods and were also able to recover both inter- and intra-MLC leaf leakage. Based upon a 3%/3 mm criterion, the experimental Cherenkov light measurements showed an 83%-99% pass fraction depending on the chosen threshold dose. CONCLUSIONS: The results from this study demonstrate the use of optical cone beam computed tomography using CEF for the profiling of the imparted dose distribution from large area megavoltage photon beams in water.

Performance assessment of time-domain optical brain imagers, part 1: basic instrumental performance protocol.

Performance assessment of instruments devised for clinical applications is of key importance for validation and quality assurance. Two new protocols were developed and applied to facilitate the design and optimization of instruments for time-domain optical brain imaging within the European project nEUROPt. Here, we present the "Basic Instrumental Performance" protocol for direct measurement of relevant characteristics. Two tests are discussed in detail. First, the responsivity of the detection system is a measure of the overall efficiency to detect light emerging from tissue. For the related test, dedicated solid slab phantoms were developed and quantitatively spectrally characterized to provide sources of known radiance with nearly Lambertian angular characteristics. The responsivity of four time-domain optical brain imagers was found to be of the order of 0.1 m² sr. The relevance of the responsivity measure is demonstrated by simulations of diffuse reflectance as a function of source-detector separation and optical properties. Second, the temporal instrument response function (IRF) is a critically important factor in determining the performance of time-domain systems. Measurements of the IRF for various instruments were combined with simulations to illustrate the impact of the width and shape of the IRF on contrast for a deep absorption change mimicking brain activation.

Performance assessment of time-domain optical brain imagers, part 2: nEUROPt protocol.

The nEUROPt protocol is one of two new protocols developed within the European project nEUROPt to characterize the performances of time-domain systems for optical imaging of the brain. It was applied in joint measurement campaigns to compare the various instruments and to assess the impact of technical improvements. This protocol addresses the characteristic of optical brain imaging to detect, localize, and quantify absorption changes in the brain. It was implemented with two types of inhomogeneous liquid phantoms based on Intralipid and India ink with well-defined optical properties. First, small black inclusions were used to mimic localized changes of the absorption coefficient. The position of the inclusions was varied in depth and lateral direction to investigate contrast and spatial resolution. Second, two-layered liquid phantoms with variable absorption coefficients were employed to study the quantification of layer-wide changes and, in particular, to determine depth selectivity, i.e., the ratio of sensitivities for deep and superficial absorption changes. We introduce the tests of the nEUROPt protocol and present examples of results obtained with different instruments and methods of data analysis. This protocol could be a useful step toward performance tests for future standards in diffuse optical imaging.

On the feasibility of polyurethane based 3D dosimeters with optical CT for dosimetric verification of low energy photon brachytherapy seeds.

PURPOSE: To investigate the feasibility of and challenges yet to be addressed to measure dose from low energy (effective energy <50 keV) brachytherapy sources (Pd-103, Cs-131, and I-125) using polyurethane based 3D dosimeters with optical CT. METHODS: The authors' evaluation used the following sources: models 200 (Pd-103), CS-1 Rev2 (Cs-131), and 6711 (I-125). The authors used the Monte Carlo radiation transport code MCNP5, simulations with the ScanSim optical tomography simulation software, and experimental measurements with PRESAGE(®) dosimeters/optical CT to investigate the following: (1) the water equivalency of conventional (density = 1.065 g/cm(3)) and deformable (density = 1.02 g/cm(3)) formulations of polyurethane dosimeters, (2) the scatter conditions necessary to achieve accurate dosimetry for low energy photon seeds, (3) the change in photon energy spectrum within the dosimeter as a function of distance from the source in order to determine potential energy sensitivity effects, (4) the optimal delivered dose to balance optical transmission (per projection) with signal to noise ratio in the reconstructed dose distribution, and (5) the magnitude and characteristics of artifacts due to the presence of a channel in the dosimeter. Monte Carlo simulations were performed using both conventional and deformable dosimeter formulations. For verification, 2.8 Gy at 1 cm was delivered in 92 h using an I-125 source to a PRESAGE(®) dosimeter with conventional formulation and a central channel with 0.0425 cm radius for source placement. The dose distribution was reconstructed with 0.02 and 0.04 cm(3) voxel size using the Duke midsized optical CT scanner (DMOS). RESULTS: While the conventional formulation overattenuates dose from all three sources compared to water, the current deformable formulation has nearly water equivalent attenuation properties for Cs-131 and I-125, while underattenuating for Pd-103. The energy spectrum of each source is relatively stable within the first 5 cm especially for I-125. The inherent assumption of radial symmetry in the TG43 geometry leads to a linear increase in sample points within the 3D dosimeter as a function of distance away from the source, which partially offsets the decreasing signal. Simulations of dose reconstruction using optical CT showed the feasibility of reconstructing dose out to a radius of 10 cm without saturating projection images using an optimal dose and high dynamic range scanning; the simulations also predicted that reconstruction artifacts at the channel surface due to a small discrepancy in refractive index should be negligible. Agreement of the measured with calculated radial dose function for I-125 was within 5% between 0.3 and 2.5 cm from the source, and the median difference of measured from calculated anisotropy function was within 5% between 0.3 and 2.0 cm from the source. CONCLUSIONS: 3D dosimetry using polyurethane dosimeters with optical CT looks to be a promising application to verify dosimetric distributions surrounding low energy brachytherapy sources.

The effect of temporal impulse response on experimental reduction of photon scatter in time-resolved diffuse optical tomography.

New fast detector technology has driven significant renewed interest in time-resolved measurement of early photons in improving imaging resolution in diffuse optical tomography and fluorescence mediated tomography in recent years. In practice, selection of early photons results in significantly narrower instrument photon density sensitivity functions (PDSFs) than the continuous wave case, resulting in a better conditioned reconstruction problem. In this work, we studied the quantitative impact of the instrument temporal impulse response function (TIRF) on experimental PDSFs in tissue mimicking optical phantoms. We used a multimode fiber dispersion method to vary the system TIRF over a range of representative literature values. Substantial disagreement in PDSF width--by up to 40%--was observed between experimental measurements and Monte Carlo (MC) models of photon propagation over the range of TIRFs studied. On average, PDSFs were broadened by about 0.3 mm at the center plane of the 2 cm wide imaging chamber per 100 ps of the instrument TIRF at early times. Further, this broadening was comparable on both the source and detector sides. Results were confirmed by convolution of instrument TIRFs with MC simulations. These data also underscore the importance of correcting imaging PDSFs for the instrument TIRF when performing tomographic image reconstruction to ensure accurate data-model agreement.

Quantitative estimation of mechanical and optical properties from ultrasound assisted optical tomography data.

We demonstrate quantitative optical property and elastic property imaging from ultrasound assisted optical tomography data. The measurements, which are modulation depth M and phase ϕ of the speckle pattern, are shown to be sensitively dependent on these properties of the object in the insonified focal region of the ultrasound (US) transducer. We demonstrate that Young's modulus (E) can be recovered from the resonance observed in M versus ω (the US frequency) plots and optical absorption (µ(a)) and scattering (µ(s)) coefficients from the measured differential phase changes. All experimental observations are verified also using Monte Carlo simulations.

Early-photon fluorescence tomography of a heterogeneous mouse model with the telegraph equation.

In this study, we investigate the performance of early-photon fluorescence tomography based on a heterogeneous mouse model. The telegraph equation is used to accurately describe the propagation of light in tissues at short times. The optimal time gate for early photons is determined by singular value analysis at first. Then, fluorescent targets located in different organs of the mouse model are investigated. The simulation results demonstrate that the reconstructed tomographic images based on early photons yield improvement in spatial resolution and quantification than the quasi-CW measurements. Meanwhile, compared with the homogeneous model, the use of the heterogeneous model can improve the accuracy of fluorescence distribution and quantification in early-photon fluorescence tomography.

Signal detectability in diffusive media using phased arrays in conjunction with detector arrays.

We investigate Hotelling observer performance (i.e., signal detectability) of a phased array system for tasks of detecting small inhomogeneities and distinguishing adjacent abnormalities in uniform diffusive media. Unlike conventional phased array systems where a single detector is located on the interface between two sources, we consider a detector array, such as a CCD, on a phantom exit surface for calculating the Hotelling observer detectability. The signal detectability for adjacent small abnormalities (2 mm displacement) for the CCD-based phased array is related to the resolution of reconstructed images. Simulations show that acquiring high-dimensional data from a detector array in a phased array system dramatically improves the detectability for both tasks when compared to conventional single detector measurements, especially at low modulation frequencies. It is also observed in all studied cases that there exists the modulation frequency optimizing CCD-based phased array systems, where detectability for both tasks is consistently high. These results imply that the CCD-based phased array has the potential to achieve high resolution and signal detectability in tomographic diffusive imaging while operating at a very low modulation frequency. The effect of other configuration parameters, such as a detector pixel size, on the observer performance is also discussed.

Monte Carlo-based fluorescence molecular tomography reconstruction method accelerated by a cluster of graphic processing units.

High-speed fluorescence molecular tomography (FMT) reconstruction for 3-D heterogeneous media is still one of the most challenging problems in diffusive optical fluorescence imaging. In this paper, we propose a fast FMT reconstruction method that is based on Monte Carlo (MC) simulation and accelerated by a cluster of graphics processing units (GPUs). Based on the Message Passing Interface standard, we modified the MC code for fast FMT reconstruction, and different Green's functions representing the flux distribution in media are calculated simultaneously by different GPUs in the cluster. A load-balancing method was also developed to increase the computational efficiency. By applying the Fréchet derivative, a Jacobian matrix is formed to reconstruct the distribution of the fluorochromes using the calculated Green's functions. Phantom experiments have shown that only 10 min are required to get reconstruction results with a cluster of 6 GPUs, rather than 6 h with a cluster of multiple dual opteron CPU nodes. Because of the advantages of high accuracy and suitability for 3-D heterogeneity media with refractive-index-unmatched boundaries from the MC simulation, the GPU cluster-accelerated method provides a reliable approach to high-speed reconstruction for FMT imaging.

Optical simulation of monolithic scintillator detectors using GATE/GEANT4.

Much research is being conducted on position-sensitive scintillation detectors for medical imaging, particularly for emission tomography. Monte Carlo simulations play an essential role in many of these research activities. As the scintillation process, the transport of scintillation photons through the crystal(s), and the conversion of these photons into electronic signals each have a major influence on the detector performance; all of these processes may need to be incorporated in the model to obtain accurate results. In this work the optical and scintillation models of the GEANT4 simulation toolkit are validated by comparing simulations and measurements on monolithic scintillator detectors for high-resolution positron emission tomography (PET). We have furthermore made the GEANT4 optical models available within the user-friendly GATE simulation platform (as of version 3.0). It is shown how the necessary optical input parameters can be determined with sufficient accuracy. The results show that the optical physics models of GATE/GEANT4 enable accurate prediction of the spatial and energy resolution of monolithic scintillator PET detectors.

Time-gated perturbation Monte Carlo for whole body functional imaging in small animals.

This paper explores a time-resolved functional imaging method based on Monte Carlo model for whole-body functional imaging of small animals. To improve the spatial resolution and quantitative accuracy of the functional map, a Bayesian hierarchical method with a high resolution spatial prior is applied to guide the optical reconstructions. Simulated data using the proposed approach are employed on an anatomically accurate mouse model where the optical properties range and volume limitations of the diffusion equation model exist. We investigate the performances of using time-gated data type and spatial priors to quantitatively image the functional parameters of multiple organs. Accurate reconstructions of the two main functional parameters of the blood volume and the relative oxygenation are demonstrated by using our method. Moreover, nonlinear optode settings guided by anatomical prior is proved to be critical to imaging small organs such as the heart.

High throughput transmission optical projection tomography using low cost graphics processing unit.

We implement the use of a graphics processing unit (GPU) in order to achieve real time data processing for high-throughput transmission optical projection tomography imaging. By implementing the GPU we have obtained a 300 fold performance enhancement in comparison to a CPU workstation implementation. This enables to obtain on-the-fly reconstructions enabling for high throughput imaging.

An optimal permissible source region strategy for multispectral bioluminescence tomography.

Multispectral bioluminescence tomography (BLT) attracts increasing more attention in the area of small animal studies because multispectral data acquisition could help in the 3D location of bioluminescent sources. Generally, BLT problem is ill-posed and a priori information is indispensable to reconstruction bioluminescent source uniquely and quantitatively. In this paper, we propose a spectrally solved bioluminescence tomography algorithm with an optimal permissible source region strategy. Being the most different from earlier studies, an optimal permissible source region strategy which is automatically selected without human intervention is developed to reduce the ill-posedness of BLT and therefore improves the reconstruction quality. Furthermore, both numerical stability and computational efficiency benefit from the strategy. In the numerical experiments, a heterogeneous phantom is used to evaluate the proposed algorithm and the synthetic data is produced by Monte Carlo method for avoiding the inverse crime. The results demonstrate the feasibility and potential of our methodology for reconstructing the distribution of bioluminescent sources.

An electrically-activated dynamic tissue-equivalent phantom for assessment of diffuse optical imaging systems.

A novel design of solid dynamic phantom with tissue-like optical properties is presented, which contains variable regions of contrast which are activated electrically. Reversible changes in absorption are produced by localized heating of targets impregnated with thermochromic pigment. A portable, battery-operated prototype has been constructed, and its optical and temporal characteristics have been investigated. The phantom has been developed as a means of assessing the performance of diffuse optical imaging systems, such as those used to monitor haemodynamic changes in the brain and other tissues. Images of the phantom have been reconstructed using data acquired with a continuous wave optical topography system.

Comparison of simplified Monte Carlo simulation and diffusion approximation for the fluorescence signal from phantoms with typical mouse tissue optical properties.

A simplified approach is proposed to simulate the fluorescence signal from a fluorophore submerged inside a turbid medium using the Monte Carlo method. Based on the reversibility of photon propagation, the fluorescence signal can be obtained from a single Monte Carlo simulation of the excitation light. This is computationally less expensive and also allows for the direct use of well-validated nonfluorescence photon migration Monte Carlo codes. Fluorescence signals from a mouse tissuelike phantom were computed using both the simplified Monte Carlo simulation and the diffusion approximation. The relative difference of signal intensity was found to be at most 30% for a fluorophore placed in the medium at various depths and horizontally midway between a source-detector pair separated by 3 mm. The difference in time characteristics of the signal is also examined.

Numerical study on the validity of the diffusion approximation for computational optical biopsy.

Currently, we are developing a computational optical biopsy technology for molecular sensing. We use the diffusion equation to model photon propagation but have a concern about the accuracy of diffusion approximation when the optical sensor is close to a bioluminescent source. We derive formulas to describe photon fluence for point and ball sources and measurement formulas for an idealized optical biopsy probe. Then, we numerically compare the diffusion approximation and the radiative transport as implemented by Monte Carlo simulation in the cases of point and ball sources. Our simulation results show that the diffusion approximation can be accurately applied if mu's>>mu(a) even if the sensor is very close to the source (>1mm). Furthermore, an approximate formula is given to describe the measurement of a cut-end fiber probe for a ball source.

The effectiveness of the Heidelberg Retina Tomograph and laser diagnostic glaucoma scanning system (GDx) in detecting and monitoring glaucoma.

OBJECTIVES: To determine the potential of optic nerve head tomography [Heidelberg Retina Tomograph (HRT)] and scanning laser polarimetry (GDx) for identifying patients with glaucomatous visual field loss. DESIGN: Examinations were performed with the HRT, GDx and Humphrey Field Analyzer (HFA). Glaucoma was defined by the presence of a field defect. Patients within the cross-sectional groups underwent a single examination, whereas patients in the longitudinal groups were examined 6 monthly, for an average of 3.5 years. SETTING: Manchester Royal Eye Hospital, UK. PARTICIPANTS: Patients with primary open angle glaucoma (POAG) or who were at risk of developing glaucoma. INTERVENTIONS: The diagnostic accuracies of the HRT and GDx were compared; specificity was set at 95%. The rate of change was determined by linear regression. To estimate the clinical application of the instruments, the proportion of an unselected group of patients on whom the examinations could be performed was calculated. Additionally, the time taken to perform and process each examination was measured. MAIN OUTCOME MEASURES: The ability of the techniques to identify cases showing deterioration. The level of agreement and applicability of the techniques. Time taken to perform and process each examination. RESULTS: From the cross-sectional group, the maximum sensitivities of the HRT and GDx were 59% and 45%, respectively (at 95% specificity). From the two longitudinal cohorts, the level of agreement between the three instruments for identification of the development and deterioration of POAG was low. The applicability of the techniques was 80% (HRT), 88% (GDx) and 98% (HFA). The length of time to perform a full examination with each instrument was 12.3, 11.8 and 28.3 minutes, respectively. Agreement of HRT and GDx parameters between and within observers was largely good. CONCLUSIONS: There is poor agreement for detection of glaucoma between the HFA, HRT and GDx. The techniques are amenable to use in the clinical environment, but no single examination has sufficient diagnostic precision to be used in isolation; also, the imaging techniques were not universally applicable. Neither the HRT nor GDx should be viewed as a replacement for visual field examination. Further research is needed into why most patients within the longitudinal arms of the study showed very little deterioration and into determining aspects of the structure versus function relationship in glaucoma that may explain why any one technique fails to detect a proportion of cases.