Influence of Systematic Errors in Reference States on Image Quality and on Stability of Derived Information for dc Optical Imaging.

Optical measurements of tissue can be performed in discrete, time-averaged, and time-varying data collection modes. This information can be evaluated to yield estimates of either absolute optical coefficient values or some relative change in these values compared with a defined state. In the case of time-varying data, additional analysis can be applied to define various dynamic features. Here we have explored the accuracy with which such information can be recovered from dense scattering media using linear perturbation theory, as a function of the accuracy of the reference medium that serves as the initial guess. Within the framework of diffusion theory and a first-order solution, we have observed the following inequality regarding the sensitivity of computed measures to inaccuracy in the reference medium: Absolute measures ? relative measures > dynamic measures. In fact, the fidelity of derived dynamic measures was striking; we observed that accurate measures of dynamic behavior could be defined even if the quality of the image data from which these measures were derived was comparatively modest. In other studies we identified inaccuracy in the estimates of the reference detector values, and not to corresponding errors in the image operators, as the primary factor responsible for instability of absolute measures. The significance of these findings for practical imaging studies of tissue is discussed.

Optical tomographic imaging of dynamic features of dense-scattering media.

Methods used in optical tomography have thus far proven to produce images of complex target media (e.g., tissue) having, at best, relatively modest spatial resolution. This presents a challenge in differentiating artifact from true features. Further complicating such efforts is the expectation that the optical properties of tissue for any individual are largely unknown and are likely to be quite variable due to the occurrence of natural vascular rhythms whose amplitudes are sensitive to a host of autonomic stimuli that are easily induced. We recognize, however, that rather than frustrating efforts to validate the accuracy of image features, the time-varying properties of the vasculature can be exploited to aid in such efforts, owing to the known structure-dependent frequency response of the vasculature and to the fact that hemoglobin is a principal contrast feature of the vasculature at near-infrared wavelengths. To accomplish this, it is necessary to generate a time series of image data. In this report we have tested the hypothesis that through analysis of time-series data, independent contrast features can be derived that serve to validate, at least qualitatively, the accuracy of imaging data, in effect establishing a self-referencing scheme. A significant finding is the observation that analysis of such data can produce high-contrast images that reveal features that are mainly obscured in individual image frames or in time-averaged image data. Given the central role of hemoglobin in tissue function, this finding suggests that a wealth of new features associated with vascular dynamics can be identified from the analysis of time-series image data.

Instrumentation and calibration protocol for imaging dynamic features in dense-scattering media by optical tomography.

Instrumentation is described that is suitable for acquiring multisource, multidetector, time-series optical data at high sampling rates (up to 150 Hz) from tissues having arbitrary geometries. The design rationale, calibration protocol, and measured performance features are given for both a currently used, CCD-camera-based instrument and a new silicon-photodiode-based system under construction. Also shown are representative images that we reconstructed from data acquired in laboratory studies using the described CCD-based instrument.

Clinical characteristics of sudden death victims in heritable (chromosome 1p1-1q1) conduction and myocardial disease.

OBJECTIVES: The purpose of this study was to identify the clinical characteristics of family members at risk of sudden death. BACKGROUND: The significance of sudden death in heritable cardiac disorders with delayed expression is incompletely understood. Additional insights come from a four-decade experience of seven generations of a family of German origin with autosomal dominant (chromosome 1p1-1q1) cardiac conduction and myocardial disease. METHODS AND RESULTS: A total of 38 family members (20 males; 18 females) were identified with sudden death. Twenty-eight family members (mean age 48+/-8 years) from earlier generations had no pacemaker at the time of sudden death. In this group, 15 subjects were asymptomatic prior to sudden death. Ten family members with sudden death, from later generations, had chronically implanted pacemakers for high grade atrioventricular block. This group was older (mean age 57+/-2 years), with decreased functional status (New York Heart Association class II to IV), enlarged left atria, dilated left ventricles with reduced systolic function and documented ventricular fibrillation in three members. Twenty-eight family members with sudden death were descendants of sib lineages 2 or 6; 21 family members with sudden death were offspring of a parent who also suffered sudden death. CONCLUSION: Sudden death is an important late outcome in heritable (chromosome 1p1-1q1) cardiac conduction and myocardial disease. Pacemaker therapy is important for the treatment of symptomatic bradycardia, but it does not prevent sudden death. Family members who are beyond the third decade of life with reduced functional capacity, left ventricular dysfunction, pacemakers and who are the offspring of a parent with sudden death appear to be at greatest risk

Nonlinear effects of localized absorption perturbations on the light distribution in a turbid medium.

A theoretical model of photon propagation in a scattering medium is presented, from which algebraic formulas for the detector-reading perturbations (delta R) produced by one or two localized perturbations in the macroscopic absorption cross section (delta mu a) are derived. Examination of these shows that when delta mu a is titrated from very small to large magnitudes in one voxel, the curve traced by the corresponding delta R values is a rectangular hyperbola. Furthermore, while delta Rinfinity identical to lim delta mu a-->infinity delta R is dependent on the location of the detector with respect to the source and the voxel, the ratio delta R/ delta Rinfinity is independent of the detector location. We also find that when delta mu a is varied in two voxels simultaneously, the quantity delta R (delta mu a,1 [symbol: see text] delta mu a,2) is a bilinear rational function of the delta mu aS. These results apply not only in the case of steady-state illumination and detection but to time-harmonic measurements as well. The validity of the theoretical formulas is demonstrated by applying them to the results of selected numerical diffusion computations. Potential applications of the derived expressions to image-reconstruction problems are discussed.

Improved Reconstruction Algorithm for Luminescence Optical Tomography when Background Lumiphore is Present.

We examine the impact of background lumiphore on image quality in luminescence optical tomography. A modification of a previously described algorithm [J. Chang, H. L. Graber, and R. L. Barbour, J. Opt. Soc. Am. A 14, 288-299 (1997); J. Chang, H. L. Graber, and R. L. Barbour, IEEE Trans. Biomed. Eng. 44, 810-822 (1997)] that estimates the background luminescence directly from the detector readings is developed. Numerical simulations were performed to calculate the diffusion-regime limiting form of forward-problem solutions for a specific test medium. We performed image reconstructions with and without white noise added to the detector readings, using both the original and the improved versions of the algorithm. The results indicate that the original version produces unsatisfactory reconstructions when background lumiphore is present, whereas the improved algorithm yields qualitatively better images, especially for small target-to-background luminescence yield ratios.

Dependence of image quality on image operator and noise for optical diffusion tomography.

By applying linear perturbation theory to the radiation transport equation, the inverse problem of optical diffusion tomography can be reduced to a set of linear equations, Wµ=R, where W is the weight function, µ are the cross-section perturbations to be imaged, and R is the detector readings perturbations. We have studied the dependence of image quality on added systematic error and/or random noise in W and R. Tomographic data were collected from cylindrical phantoms, with and without added inclusions, using Monte Carlo methods. Image reconstruction was accomplished using a constrained conjugate gradient descent method. Results show that accurate images containing few artifacts are obtained when W is derived from a reference state whose optical thickness matches that of the unknown test medium. Comparable image quality was also obtained for unmatched W, but the location of the target becomes more inaccurate as the mismatch increases. Results of the noise study show that image quality is much more sensitive to noise in W than in R, and the impact of noise increases with the number of iterations. Images reconstructed after pure noise was substituted for R consistently contain large peaks clustered about the cylinder axis, which was an initially unexpected structure. In other words, random input produces a nonrandom output. This finding suggests that algorithms sensitive to the evolution of this feature could be developed to suppress noise effects. © 1998 Society of Photo-Optical Instrumentation Engineers.

Imaging of fluorescence in highly scattering media.

Two one-speed radiation transport equations coupled by a dynamic equation for the distribution of fluorophore electronic states are used to model the migration of excitation photons and emitted fluorescence photons. The conditions for producing appreciable levels of fluorophore in the excited state are studied, with the conclusion that minimal saturation occurs under the conditions applicable to tissue imaging. This simplifies the derivation of the frequency response and of the imaging operator for a time-harmonic excitation source. Several factors known to influence the fluorescence response-the concentration, mean lifetime and quantum yield of the fluorophore, and the modulation frequency of the excitatory source-are examined. Optimal sensitivity conditions are obtained by analyzing the fluorescence source strength as a function of the mean lifetime and modulation frequency. The dependence of demodulation of the fluorescent signal on the above factors is also examined. In complementary studies, transport-theory-based operators for imaging fluorophore distributions in a highly scattering medium are derived. Experimental data were collected by irradiating a cylindrical phantom containing one or two fluorophore-filled balloons with continuous wave laser light. The reconstruction results show that qualitatively and quantitatively good images can be obtained, with embedded objects accurately located and the fluorophore concentration correctly determined.

Iterative total least-squares image reconstruction algorithm for optical tomography by the conjugate gradient method.

We present an iterative total least-squares algorithm for computing images of the interior structure of highly scattering media by using the conjugate gradient method. For imaging the dense scattering media in optical tomography, a perturbation approach has been described previously [Y. Wang et al., Proc. SPIE 1641, 58 (1992); R. L. Barbour et al., in Medical Optical Tomography: Functional Imaging and Monitoring (Society of Photo-Optical Instrumentation Engineers, Bellingham, Wash., 1993), pp. 87-120], which solves a perturbation equation of the form W delta x = delta I. In order to solve this equation, least-squares or regularized least-squares solvers have been used in the past to determine best fits to the measurement data delta I while assuming that the operator matrix W is accurate. In practice, errors also occur in the operator matrix. Here we propose an iterative total least-squares (ITLS) method that minimizes the errors in both weights and detector readings. Theoretically, the total least-squares (TLS) solution is given by the singular vector of the matrix [W/ delta I] associated with the smallest singular value. The proposed ITLS method obtains this solution by using a conjugate gradient method that is particularly suitable for very large matrices. Simulation results have shown that the TLS method can yield a significantly more accurate result than the least-squares method.

Optical imaging of anatomical maps derived from magnetic resonance images using time-independent optical sources.

We present a model suitable for computing images of absorption cross sections of thick tissue structures illuminated at near infrared (NIR) wavelengths from tomographic projection data. Image reconstruction is accomplished by solving a system of linear equations derived from transport theory. Reconstruction results using different algebraic solvers are shown for anatomical maps of the breast, derived from magnetic resonance imaging data, containing two simulated pathologies, in which case qualitatively good reconstructions were obtained. Evaluation of magnetic resonance (MR) data to optimize NIR optical tomographic imaging methods and to assess the feasibility of a combined MR-optical measurement scheme is discussed.

Luminescence optical tomography of dense scattering media.

Using a set of coupled radiation transport equations, we derive image operators for luminescence optical tomography with which it is possible to reconstruct concentration and mean lifetime distribution from information obtained from dc and time-harmonic optical sources. Weight functions and detector readings were computed from analytic solutions of the diffusion equation and from numerical solutions of the transport equation by Monte Carlo methods. Detector readings were also obtained from experiments on vessels containing a balloon filled with dye embedded in an Intralipid suspension with dye in the background. Image reconstructions were performed by the conjugate gradient descent method and the simultaneous algebraic reconstruction technique with a positivity constraint. A concentration correction was developed in which the reconstructed concentration information is used in the mean-lifetime reconstruction. The results show that the target can be accurately located in both the simulated and the experimental cases, but quantitative inaccuracies are present. Observed errors include a shadowing effect in regions that have the lowest weight within the inclusion. Application of the concentration correction can significantly improve computational efficiency and reduce error in the mean-lifetime reconstructions.

Regularized progressive expansion algorithm for recovery of scattering media from time-resolved data.

Reconstructions of the absorption cross sections of dense scattering media from time-resolved data are presented. A progressive expansion (PE) algorithm, similar to a layer-stripping, is developed to circumvent the underdeterminedness of the inverse problem. An overlapping scheme, which used detector readings from several consecutive time intervals, is introduced to reduce the propagation of reconstruction errors that occur at shallower depths. To reduce the sensitivity of the PE algorithm to noise a regularized progressive expansion (RPE) algorithm is proposed, which incorporates regularization techniques into the PE algorithm. The PE and the RPE algorithms are applied to the problem of image reconstruction from time-resolved data. The test media were isotropically scattering slabs containing one or two compact absorbers at different depths below the surface. The data were corrupted by additive white Gaussian noise with various strengths. The reconstruction results show that the PE and the RPE algorithms, when they are combined by proper overlapping, can effectively overcome the underdeterminedness of the inverse problem. The RPE algorithm yields reconstructions that are more accurate and more stable under the same noise level.

Sensitivity studies for imaging a spherical object embedded in a spherically symmetric, two-layer turbid medium with photon-density waves.

We present analytic expressions for the amplitude and phase of photon-density waves in strongly scattering, spherically symmetric, two-layer media containing a spherical object. This layered structure is a crude model of multilayered tissues whose absorption and scattering coefficients lie within a range reported in the literature for most tissue types. The embedded object simulates a pathology, such as a tumor. The normal-mode-series method is employed to solve the inhomogeneous Helmholtz equation in spherical coordinates, with suitable boundary conditions. By comparing the total field at points in the outer layer at a fixed distance from the origin when the object is present and when it is absent, we evaluate the potential sensitivity of an optical imaging system to inhomogeneities in absorption and scattering. For four types of background media with different absorption and scattering properties, we determine the modulation frequency that achieves an optimal compromise between signal-detection reliability and sensitivity to the presence of an object, the minimum detectable object radius, and the smallest detectable change in the absorption and scattering coefficients for a fixed object size. Our results indicate that (l) enhanced sensitivity to the object is achieved when the outer layer is more absorbing or scattering than the inner layer; (2) sensitivity to the object increases with the modulation frequency, except when the outer layer is the more absorbing; (3) amplitude measurements are proportionally more sensitive to a change in absorption, phase measurements are proportionally more sensitive to a change in scattering, and phase measurements exhibit a much greater capacity for distinguishing an absorption perturbation from a scattering perturbation.

Recovery of optical cross-section perturbations in dense-scattering media by transport-theory-based imaging operators and steady-state simulated data.

We present a useful strategy for imaging perturbations of the macroscopic absorption cross section of dense-scattering media using steady-state light sources. A perturbation model based on transport theory is derived, and the inverse problem is simplified to a system of linear equations, WΔµ = ΔR, where W is the weight matrix, Δµ is a vector of the unknown perturbations, and ΔR is the vector of detector readings. Monte Carlo simulations compute the photon flux across the surfaces of phantoms containing simple or complex inhomogeneities. Calculation of the weight matrix is also based on the results of Monte Carlo simulations. Three reconstruction algorithms-conjugate gradient descent, projection onto convex sets, and the simultaneous algebraic reconstruction technique, with or without imposed positivity constraints-are used for image reconstruction. A rescaling technique that improves the conditioning of the weight matrix is also developed. Results show that the analysis of time-independent data by a perturbation model is capable of resolving the internal structure of a dense-scattering medium. Imposition of positivity constraints improves image quality at the cost of a reduced convergence rate. Use of the rescaling technique increases the initial rate of convergence, resulting in accurate images in a smaller number of iterations.

A gene defect that causes conduction system disease and dilated cardiomyopathy maps to chromosome 1p1-1q1.

Longitudinal evaluation of a seven generation kindred with an inherited conduction system defect and dilated cardiomyopathy demonstrated autosomal dominant transmission of a progressive disorder that both perturbs atrioventricular conduction and depresses cardiac contractility. To elucidate the molecular genetic basis for this disorder, a genome-wide linkage analysis was performed. Polymorphic loci near the centromere of chromosome 1 demonstrated linkage to the disease locus (maximum multipoint lod score = 13.2 in the interval between D1S305 and D1S176). Based on the disease phenotype and map location we speculate that gap junction protein connexin 40 is a candidate for mutations that result in conduction system disease and dilated cardiomyopathy.

Evolution of a hereditary cardiac conduction and muscle disorder: a study involving a family with six generations affected.

This study describes six generations of a family with autosomal dominant cardiac conduction system and myocardial disease with recognizable clinical stages. A 20 year follow-up of nine family members, a medical questionnaire of 196, electrocardiographic screening of 91, noninvasive testing of 20, and catheterization with endomyocardial biopsy of six are the basis of this report. The clinical stages are as follows: Stage I occurs in the second and third decades of life and is characterized by an absence of symptoms, normal heart size, sinus bradycardia, and premature atrial contractions. Stage II is marked by first-degree atrioventricular block in the third and fourth decades. Stage III occurs in the fourth and fifth decades and is accompanied by chest pain, fatigue, lightheadedness, and advanced atrioventricular block followed by the development of atrial fibrillation or flutter. Stage IV, in the fifth and sixth decades of life, is characterized by congestive heart failure and recurrent ventricular arrhythmias. Light microscopy of right ventricular endomyocardial biopsy specimens from patients in stage II revealed very mild fibrosis; electron microscopy of the specimens demonstrated mild dilatation of tubules, mitochondrial swelling, and minimal myofibrillar loss. Biopsy specimens from patients with stage III disease were similar to those from patients with stage II disease except for an increase of myofibrillar loss. The stage IV specimens had diffuse fibrosis and more severe tubular dilatation, mitochondrial cristolysis, and myofibrillar loss. At autopsy in the proband, the atrial changes were more severe than the ventricular and were especially marked in the sinoatrial and atrial myocardium. Early recognition of the disease and use of pacemakers and antiarrhythmic agents have proved beneficial for affected family members. Thorough family studies of patients with conduction system disease and/or dilated cardiomyopathy are necessary to better understand the hereditary basis and natural course of this category of disease.

Calcification of the mitral annulus: etiology, clinical associations, complications and therapy.

This report reviews the clinical features of 80 patients with roentgenographically proved mitral annular calcification. The mean age of the group was 73 years, and there was a 2.5 to 1 female to male ratio. Evaluation for underlying cardiovascular disease revealed six patients with severe calcific valvular aortic stenosis; five patients with hypertrophic cardiomyopathy, 11 with mitral prolapse and 33 with significant arterial hypertension (blood pressure greater or equal to 150/96 mm Hg). Eighty-five per cent of the group (68 of 80 patients) had an underlying cardiac disorder associated with either chronically increased left ventricular systolic pressure or abnormal leaflet motion. Other cardiovascular abnormalities occurring as complications secondary to the mitral ring calcification included subacute bacterial endocarditis (three cases), arterial emboli (five episodes) and high grade atrioventricular block (16 cases). Twelve patients had severe mitral regurgitation; successful mitral valve replacement was carried out in four patients (all with myxomatous mitral tissue). Evidence of diffuse conduction system disease, not limited to the area of the cardiac fibrous skeleton, was found frequently (44 patients). Nine patients had sinus node dysfunction and 35 patients had electrocardiographic evidence of distal intraventricular (fascicular) block. Twenty-one patients eventually required pacemakers for management of symptomatic bradyarrhythmias. Atrial fibrillation was present in 23 patients. In this review it was found that calcification of the mitral annulus is frequently associated with or induces serious cardiovascular disease. Since some of these disorders may be modified by appropriate therapy, calcification of the mitral annulus should no longer be ignored as a benign marker of the elderly heart.