Modeling of the hemodynamics in the feet of patients with peripheral artery disease.

To simulate the hemodynamic effects in the feet in response to a thigh cuff occlusion, we have developed a multi-compartmental model in which the circulatory system for the leg is represented by its electrical equivalents. Dynamic vascular optical tomographic imaging data previously obtained from 20 patients with peripheral artery disease (PAD) and 20 healthy subjects is used to test the model. Analyzing the clinical data with the support of the model yields diagnostic specificity and sensitivity in the 90-95% range, significantly higher than previously reported.

Non-contact dynamic diffuse optical tomography imaging system for evaluating lower extremity vasculature.

A novel multi-view non-contact dynamic diffuse optical tomographic imaging system for the clinical evaluation of vasculature in the lower extremities is presented. The system design and implementation are described in detail, including methods for simultaneously obtaining and reconstructing diffusely reflected and transmitted light using a system of mirrors and a single CCD camera. The system and its performance using numeric simulations and optical phantoms. Measurements of a healthy foot in vivo demonstrates the potential of the system in assessing perfusion within the foot.

Detection of Peripheral Arterial Disease Within the Foot Using Vascular Optical Tomographic Imaging: A Clinical Pilot Study.

OBJECTIVE: Vascular optical tomographic imaging (VOTI) is a novel imaging modality that is capable of detecting hemoglobin concentrations in tissue. VOTI is non-invasive, non-ionizing and does not require contrast injection. This technology was applied to the diagnosis of peripheral arterial disease (PAD) within lower extremities of diabetic patients with calcified arteries. This could be of substantial benefit as these patients suffer from comorbidities such as arterial incompressibility, which complicates diagnosis and monitoring. METHODS: Forty individuals (10 non-diabetic patients with PAD, 10 diabetic patients with PAD, and 20 healthy volunteers) were enrolled in a diagnostic pilot study using the VOTI system. The patients were imaged during at high pressure cuff occlusion. RESULTS: The VOTI system was capable of quantifying the blood volume changes within the foot during the thigh cuff occlusion and outputting diagnostic parameters, such as change in hemoglobin concentration, enabling the assessment of foot perfusion. This study resulted in a statistically significant difference between the healthy cohort and both the non-diabetic and the diabetic PAD cohorts (p = .006, p = .006). Receiver operating characteristic (ROC) curve analysis showed that PAD diagnosis could be made with over 80% sensitivity or specificity depending on the characteristic cutoff point. In addition, VOTI was capable of providing the locations of under-perfused regions within the foot and evaluating the severity of arterial disease, even within diabetic patients with calcified arteries, who are traditionally difficult to diagnose. CONCLUSION: VOTI can effectively diagnose PAD independently of arterial compressibility, making it very useful for assessing vascular disease in diabetic patients.

A wireless handheld probe with spectrally constrained evolution strategies for diffuse optical imaging of tissue.

We present a low-cost, portable, wireless diffuse optical imaging device. The handheld device is fast, portable, and can be applied to a wide range of both static and dynamic imaging applications including breast cancer, functional brain imaging, and peripheral artery disease. The continuous-wave probe has four near-infrared wavelengths and uses digital detection techniques to perform measurements at 2.3 Hz. Using a multispectral evolution algorithm for chromophore reconstruction, we can measure absolute oxygenated and deoxygenated hemoglobin concentration as well as scattering in tissue. Performance of the device is demonstrated using a series of liquid phantoms comprised of Intralipid(®), ink, and dye.

Digital lock-in algorithm for biomedical spectroscopy and imaging instruments with multiple modulated sources.

Digital lock-in detection provides spectroscopic and imaging instruments a means of measuring physical quantities with improved signal to noise ratios compared to analogue detection schemes. We introduce a digital lock-in detection algorithm for measuring the amplitude and phase of multiple amplitude modulated signals simultaneously by using particular modulation and sampling constraints and averaging filters. The technique exhibits exceptional reduction in both noise and inter-source distortion. It is shown that the digital lock-in technique can be performed as a simple matrix multiplication in order to reduce computation time. The digital lock-in algorithm is described and analyzed under certain sampling and modulation conditions. Results are shown for experimental data.

First clinical evaluation of sagittal laser optical tomography for detection of synovitis in arthritic finger joints.

OBJECTIVE: To identify classifiers in images obtained with sagittal laser optical tomography (SLOT) that can be used to distinguish between joints affected and not affected by synovitis. METHODS: 78 SLOT images of proximal interphalangeal joints II-IV from 13 patients with rheumatoid arthritis were compared with ultrasound (US) images and clinical examination (CE). SLOT images showing the spatial distribution of scattering and absorption coefficients within the joint cavity were generated. The means and standard errors for seven different classifiers (operator score and six quantitative measurements) were determined from SLOT images using CE and US as diagnostic references. For classifiers showing significant differences between affected and non-affected joints, sensitivities and specificities for various cut off parameters were obtained by receiver operating characteristic (ROC) analysis. RESULTS: For five classifiers used to characterise SLOT images the mean between affected and unaffected joints was statistically significant using US as diagnostic reference, but statistically significant for only one classifier with CE as reference. In general, high absorption and scattering coefficients in and around the joint cavity are indicative of synovitis. ROC analysis showed that the minimal absorption classifier yields the largest area under the curve (0.777; sensitivity and specificity 0.705 each) with US as diagnostic reference. CONCLUSION: Classifiers in SLOT images have been identified that show statistically significant differences between joints with and without synovitis. It is possible to classify a joint as inflamed with SLOT, without the need for a reference measurement. Furthermore, SLOT based diagnosis of synovitis agrees better with US diagnosis than CE.

Three-dimensional optical tomographic brain imaging in small animals, part 1: hypercapnia.

In this study, we explore the potential of diffuse optical tomography for brain oximetry. While several groups have already reported on the sensitivity of optical measurements to changes in oxyhemoglobin, deoxyhemoglobin, and blood volume, these studies were often limited to single source-detector geometries or topographic maps, where signals obtained from within the brain are projected onto 2-D surface maps. In this two-part study, we report on our efforts toward developing a volumetric optical imaging system that allows one to spatially resolve 3-D hemodynamic effects in rat brains. In part 1, we describe the instrumentation, optical probe design, and the model-based iterative image reconstruction algorithm employed in this work. Consideration of how a priori anatomical knowledge can be incorporated in the reconstruction process is presented. This system is then used to monitor global hemodynamic changes that occur in the brain under various degrees of hypercapnia. The physiologic cerebral response to hypercapnia is well known and therefore allows an initial performance assessment of the imaging system. As expected, we observe global changes in blood volume and oxygenation, which vary linearly as a function of the concentration of the inspired carbon dioxide. Furthermore, experiments are designed to determine the sensitivity of the reconstructions of only 1 mm to inaccurate probe positioning. We determine that shifts can significantly influence the reconstructions. In part 2 we focus on more local hemodynamic changes that occur during unilateral carotid occlusion performed at lower-than-normal systemic blood pressure. In this case, the occlusion leads to a predominantly monohemispherically localized effect, which is well described in the literature. Having explored the system with a well-characterized physiologic effect, we investigate and discuss the complex compensatory cerebrovascular hemodynamics that occur at normotensive blood pressure. Overall, these studies demonstrate the potential and limitations of our diffuse optical imager for visualizing global and focal hemodynamic phenomenon three dimensionally in the brains of small animals.

Three-dimensional optical tomographic brain imaging in small animals, part 2: unilateral carotid occlusion.

This is the second part of a two-part study that explores the feasibility of 3-D, volumetric brain imaging in small animals by optical tomographic techniques. In part 1, we demonstrated the ability to visualize global hemodynamic changes in the rat head in response to elevated levels of CO(2) using a continuous-wave instrument and model-based iterative image reconstruction (MOBIIR) algorithm. Now we focus on lateralized, monohemispherically localized hemodynamic effects generated by unilateral common carotid artery (CCA) occlusion. This illustrates the capability of our optical tomographic system to localize and distinguish hemodynamic responses in different parts of the brain. Unilateral carotid occlusions are performed in ten rodents under two experimental conditions. In the first set of experiments the normal systemic blood pressure is lowered to 50 mmHg, and on unilateral carotid occlusion, we observe an ipsilateral monohemispheric global decrease in blood volume and oxygenation. This finding is consistent with the known physiologic response to cerebral ischemia. In a second set of experiments designed to observe the spatial-temporal dynamics of CCA occlusion at normotensive blood pressure, more complex phenomena are observed. We find three different types of responses, which can be categorized as compensation, overcompensation, and noncompensation.

Near-infrared diffuse optical tomography.

Diffuse optical tomography (DOT) is emerging as a viable new biomedical imaging modality. Using near-infrared (NIR) light, this technique probes absorption as well as scattering properties of biological tissues. First commercial instruments are now available that allow users to obtain cross-sectional and volumetric views of various body parts. Currently, the main applications are brain, breast, limb, joint, and fluorescence/bioluminescence imaging. Although the spatial resolution is limited when compared with other imaging modalities, such as magnetic resonance imaging (MRI) or X-ray computerized tomography (CT), DOT provides access to a variety of physiological parameters that otherwise are not accessible, including sub-second imaging of hemodynamics and other fast-changing processes. Furthermore, DOT can be realized in compact, portable instrumentation that allows for bedside monitoring at relatively low cost. In this paper, we present an overview of current state-of-the -art technology, including hardware and image-reconstruction algorithms, and focus on applications in brain and joint imaging. In addition, we present recent results of work on optical tomographic imaging in small animals.

Diffuse optical tomography of highly heterogeneous media.

We investigate the performance of diffuse optical tomography to image highly heterogeneous media, such as breast tissue, as a function of background heterogeneity. To model the background heterogeneity, we have employed the functional information derived from Gadolinium-enhanced magnetic resonance images of the breast. We demonstrate that overall image quality and quantification accuracy worsens as the background heterogeneity increases. Furthermore we confirm the appearance of characteristic artifacts at the boundaries that scale with background heterogeneity. These artifacts are very similar to the ones seen in clinical examinations and can be misinterpreted as actual objects if not accounted for. To eliminate the artifacts and improve the overall image reconstruction, we apply a data-correction algorithm that yields superior reconstruction results and is virtually independent of the degree of the background heterogeneity.

Use of penalty terms in gradient-based iterative reconstruction schemes for optical tomography.

It is well known that the reconstruction problem in optical tomography is ill-posed. In other words, many different spatial distributions of optical properties inside the medium can lead to the same detector readings on the surface of the medium under consideration. Therefore, the choice of an appropriate method to overcome this problem is of crucial importance for any successful optical tomographic image reconstruction algorithm. In this work we approach the problem within a gradient-based iterative image reconstruction scheme. The image reconstruction is considered to be a minimization of an appropriately defined objective function. The objective function can be separated into a least-square-error term, which compares predicted and actual detector readings, and additional penalty terms that may contain a priori information about the system. For the efficient minimization of this objective function the gradient with respect to the spatial distribution of optical properties is calculated. Besides presenting the underlying concepts in our approach to overcome ill-posedness in optical tomography, we will show numerical results that demonstrate how prior knowledge, represented as penalty terms, can improve the reconstruction results.

Photon migration through fetal head in utero using continuous wave, near-infrared spectroscopy: development and evaluation of experimental and numerical models.

In this work experimental tissue phantoms and numerical models were developed to estimate photon migration through the fetal head in utero. The tissue phantoms incorporate a fetal head within an amniotic fluid sac surrounded by a maternal tissue layer. A continuous wave, dual-wavelength (lambda = 760 and 850 nm) spectrometer was employed to make near-infrared measurements on the tissue phantoms for various source-detector separations, fetal-head positions, and fetal-head optical properties. In addition, numerical simulations of photon propagation were performed with finite-difference algorithms that provide solutions to the equation of radiative transfer as well as the diffusion equation. The simulations were compared with measurements on tissue phantoms to determine the best numerical model to describe photon migration through the fetal head in utero. Evaluation of the results indicates that tissue phantoms in which the contact between fetal head and uterine wall is uniform best simulates the fetal head in utero for near-term pregnancies. Furthermore, we found that maximum sensitivity to the head can be achieved if the source of the probe is positioned directly above the fetal head. By optimizing the source-detector separation, the signal originating from photons that have traveled through the fetal head can drastically be increased.

Monte Carlo simulations of the diffuse backscattering mueller matrix for highly scattering media.

We have developed a Monte Carlo algorithm that computes all two-dimensional elements of the diffuse backscattering Mueller matrix for highly scattering media. Using the Stokes-Mueller formalism and scattering amplitudes calculated with Mie theory, we are able to consider polarization-dependent photon propagation in highly scattering media, including linearly and circularly polarized light. The numerically determined matrix elements are compared with experimental data for different particle sizes and show good agreement in both azimuthal and radial direction.

Iterative reconstruction scheme for optical tomography based on the equation of radiative transfer.

We report on the development of an iterative image reconstruction scheme for optical tomography that is based on the equation of radiative transfer. Unlike the commonly applied diffusion approximation, the equation of radiative transfer accurately describes the photon propagation in turbid media without any limiting assumptions regarding the optical properties. The reconstruction scheme consists of three major parts: (1) a forward model that predicts the detector readings based on solutions of the time-independent radiative transfer equation, (2) an objective function that provides a measure of the differences between the detected and the predicted data, and (3) an updating scheme that uses the gradient of the objective function to perform a line minimization to get new guesses of the optical properties. The gradient is obtained by employing an adjoint differentiation scheme, which makes use of the structure of the finite-difference discrete-ordinate formulation of the transport forward model. Based on the new guess of the optical properties a new forward calculation is performed to get new detector predictions. The reconstruction process is completed when the minimum of the objective function is found within a defined error. To illustrate the performance of the code we present initial reconstruction results based on simulated data.

Gradient-based iterative image reconstruction scheme for time-resolved optical tomography.

Currently available tomographic image reconstruction schemes for optical tomography (OT) are mostly based on the limiting assumptions of small perturbations and a priori knowledge of the optical properties of a reference medium. Furthermore, these algorithms usually require the inversion of large, full, ill-conditioned Jacobian matrixes. In this work a gradient-based iterative image reconstruction (GIIR) method is presented that promises to overcome current limitations. The code consists of three major parts: 1) A finite-difference, time-resolved, diffusion forward model is used to predict detector readings based on the spatial distribution of optical properties; 2) An objective function that describes the difference between predicted and measured data; 3) An updating method that uses the gradient of the objective function in a line minimization scheme to provide subsequent guesses of the spatial distribution of the optical properties for the forward model. The reconstruction of these properties is completed, once a minimum of this objective function is found. After a presentation of the mathematical background, two- and three-dimensional reconstruction of simple heterogeneous media as well as the clinically relevant example of ventricular bleeding in the brain are discussed. Numerical studies suggest that intraventricular hemorrhages can be detected using the GIIR technique, even in the presence of a heterogeneous background.

Comparison of finite-difference transport and diffusion calculations for photon migration in homogeneous and heterogeneous tissues.

We analyse the limits of the diffusion approximation to the time-independent equation of radiative transfer for homogeneous and heterogeneous biological media. Analytical calculations and finite-difference simulations based on diffusion theory are compared with discrete-ordinate, finite-difference transport calculations. The influence of the ratio of absorption and transport scattering coefficient (mu(a)/mu'(s)) on the accuracy of the diffusion approximation are quantified and different definitions for the diffusion coefficient, D, are discussed. We also address effects caused by void-like heterogeneities in which absorption and scattering are very small compared with the surrounding medium. Based on results for simple homogeneous and heterogeneous systems, we analyse diffusion and transport calculation of light propagation in the human brain. For these simulations we convert density maps obtained from magnetic resonance imaging (MRI) to optical-parameter maps (mu(a) and mu'(s)) of the brain. We show that diffusion theory fails to describe accurately light propagation in highly absorbing regions, such as haematoma, and void-like spaces, such as the ventricles and the subarachnoid space.

Evidence of intrinsic differences in the light scattering properties of tumorigenic and nontumorigenic cells.

BACKGROUND: The objective of this study was to determine whether there are intrinsic differences in the light scattering properties of tumorigenic and nontumorigenic cells from a multistep carcinogenesis model. METHODS: Wavelength-dependent and polarization-dependent light scattering properties of cell suspensions were measured. RESULTS: Statistically significant differences were found between the tumorigenic and nontumorigenic cells. CONCLUSIONS. Differences in the light scattering properties of tumorigenic and nontumorigenic cells are attributed to a change in the average size of the scattering centers on the order of a few ten of nanometers. This work is relevant to the development of noninvasive optical methods for cancer diagnosis.

Mechanisms of light scattering from biological cells relevant to noninvasive optical-tissue diagnostics.

We have studied the optical properties of mammalian cell suspensions to provide a mechanistic basis for interpreting the optical properties of tissues in vivo. Measurements of the wavelength dependence of the reduced scattering coefficient and measurements of the phase function demonstrated that there is a distribution of scatterer sizes. The volumes of the scatterers are equivalent to those of spheres with diameters in the range between ~0.4 and 2.0 mum. Measurements of isolated organelles indicate that mitochondria and other similarly sized organelles are responsible for scattering at large angles, whereas nuclei are responsible for small-angle scattering. Therefore optical diagnostics are expected to be sensitive to organelle morphology but not directly to the size and shape of the cells.

Influence of particle size and concentration on the diffuse backscattering of polarized light from tissue phantoms and biological cell suspensions.

We present experimental results that show the spatial variations of the diffuse-backscattered intensity when linearly polarized light is incident upon highly scattering media. Experiments on polystyrene-sphere and Intralipid suspensions demonstrate that the radial and azimuthal variations of the observed pattern depend on the concentration, size, and anisotropy factor g of the particles that constitute the scattering medium. Measurements performed on biological-cell suspensions show the potential of this method for cell characterization.

Influence of the scattering phase function on light transport measurements in turbid media performed with small source-detector separations.

Many methods of optical tissue diagnosis require that measurements be performed with small source-detector separations in a backscatter geometry. Monte Carlo simulations are used to demonstrate that for these situations light transport depends on the exact form of the angular scattering probability distribution, P(theta). Simulations performed with different forms of P(theta) with the same value of ?cos theta? result in the collection of significantly different fractions of the incident photons, particularly when small-numerical-aperture delivery and collection fibers are employed. More photons are collected for the distribution that has a higher probability of scattering events with theta > 125 degrees . For the clinically relevant optical parameters employed here, the differences in light collection are >60%.