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Frequency-domain near-infrared (NIR) diffuse spectral tomography with a mode-locked Ti:sapphire laser is presented, providing tunable multiwavelength quantitative spectroscopy with maximal power for thick tissue imaging. The system was developed to show that intrinsically high stability can be achieved with many wavelengths in the NIR range, using a mode-locked signal of 80 MHz with heterodyned lock-in detection. The effect of cumulative noise from multiple wavelengths of data on the reconstruction process was studied, and it was shown that inclusion of more wavelengths can reduce skew in the noise distribution. This normalization of the data variance then minimizes errors in estimation of chromophore concentrations. Simulations and tissue phantom experiments were used to quantify this improvement in image accuracy for recovery of tissue hemoglobin and oxygen saturation. OCIS codes: 170.3890, 170.6510, 300.6360.

The measurement sensitivities of absorbing and fluorescing objects in tissue are compared to determine conditions for which fluorescence data are favorable over those derived from absorption. A simulated human breast volume was used to model the relative perturbation in boundary data caused by a deeply embedded anomaly containing elevated concentrations of theoretical exogenous contrast agents with absorption properties resembling lutetium texaphyrin (LuTex) and Indocyanine Green (ICG). Synthetic data were used to produce quantum yield values representing the transition between conditions favorable to fluorescence versus absorption imaging. The parameters explored include tumor-to-background contrast, background drug concentration, and excitation light filtering efficiency. Drug concentration in the background was the primary factor that determined which contrast mechanism provided the more sensitive measurements. Specifically, fluorescence measurements are favorable if background drug concentrations are below 135-200 nM for LuTex and 25-50 nM for ICG, while absorption measurements are more sensitive above these ranges. OCIS codes: 170.3660, 170.6280, 170.6960, 170.7050.

Applying localized external displacement to the breast surface can change the interstitial fluid pressure such that regional transient microvascular changes occur in oxygenation and vascular volume. Imaging these dynamic responses over time, while different pressures are applied, could provide selective temporal contrast for cancer relative to the surrounding normal breast. In order to investigate this possibility in normal breast tissue, a near-infrared spectral tomography system was developed that can simultaneously acquire data at three wavelengths with a 15 s time resolution per scan. The system was tested first with heterogeneous blood phantoms. Changes in regional blood concentrations were found to be linearly related to recovered mean hemoglobin concentration ([Hb.sub.T]) values ([R.sup.2] = 0.9). In a series of volunteer breast imaging exams, data from 17 asymptomatic subjects were acquired under increasing and decreasing breast compression. Calculations show that a 10 mm displacement applied to the breast results in surface pressures in the range of 0-55 kPa depending on breast density. The recovered human data indicate that [Hb.sub.T] was reduced under compression and the normalized change was significantly correlated to the applied pressure with a p value of 0.005. The maximum [Hb.sub.T] decreases in breast tissue were associated with body mass index (BMI), which is a surrogate indicator of breast density. No statistically valid correlations were found between the applied pressure and the changes in tissue oxygen saturation ([S.sub.t][O.sub.2]) or water percentage ([H.sub.2]O) across the range of BMI values studied. OCIS codes: 110.0110, 170.0170, 120.0120.

Subsurface tomography with diffuse light has been investigated with a noncontact approach to characterize the performance of absorption and fluorescence imaging. Using both simulations and experiments, the reconstruction of local subsurface heterogeneity is demonstrated, but the recovery of target size and fluorophore concentration is not linear when changes in depth occur, whereas the mean position of the object for experimental fluorescent and absorber targets is accurate to within 0.5 and 1.45 mm when located within the first 10 mm below the surface. Improvements in the linearity of the response with depth appear to remain challenging and may ultimately limit the approach to detection rather than characterization applications. However, increases in tissue curvature and/or the addition of prior information are expected to improve the linearity of the response. The potential for this type of imaging technique to serve as a surgical guide is highlighted. OCIS codes: 170.0170, 170.3890, 170.5270, 170.6960, 170.4580, 100.3010.

A novel magnetic-resonance-coupled broadband near-infrared (NIR) tomography system for small animal brain studies is described. Several features of the image formation approach are new in NIR tomography and represent major advances in the path to recovering high-resolution hemoglobin and oxygen saturation images of tissue. The NIR data were broadband and continuous wave and were used along with a second-derivative-based estimation of the path length from water absorption. The path length estimation from water was then used along with the attenuation spectrum to recover absorption and reduced scattering coefficient images at multiple wavelengths and then to recover images of total hemoglobin and oxygen saturation. Going beyond these basics of NIR tomography, software has been developed to allow inclusion of structures derived from MR imaging (MRI) for the external and internal tissue boundaries, thereby improving the accuracy and spatial resolution of the properties in each tissue type. The system has been validated in both tissue-simulating phantoms, with 10% accuracy observed, and in a rat cranium imaging experiment. The latter experiment used variation in inspired oxygen (Fi[O.sub.2]) to vary the observed hemoglobin and oxygen saturation images. Quantitative agreement was observed between the changes in deoxyhemoglobin values derived from NIR and the changes predicted with blood-oxygen-level-dependent (BOLD) MRI. This system represents the initial stage in what will likely be a larger role for NIR tomography, coupled to MRI, and illustrates that the technological challenges of using continuous-wave broadband data and inclusion of a priori structural information can be met with careful phantom studies.

Near infrared (NIR) optical tomography is an imaging technique in which internal images of optical properties are reconstructed with the boundary measurements of light propagation through the medium. Recent advances in instrumentation and theory have led to the use of this method for the detection and characterization of tumors within the female breast tissue. Most image reconstruction approaches have used the diffusion approximation and have assumed that the refractive index of the breast is constant, with a bulk value of approximately 1.4. We have applied a previously reported modified diffusion approximation, in which the refractive index for different tissues can be modeled. The model was used to generate NIR data from a realistic breast geometry containing- a localized anomaly. Using this simulated data, we have reconstructed optical images, both with and without correct knowledge of the refractive-index distribution to show that the modified diffusion approximation can accurately recover the anomaly given a priori knowledge of refractive index. But using a reconstruction algorithm without the use of correct a priori information regarding the refractive-index distribution is shown as recovering the anomaly but with a degraded quality, depending on the degree of refractive index mismatch. The results suggest that provided the refractive index of breast tissue is approximately 1.3-1.4, their exclusion will have minimal effect on the reconstructed images. OCIS codes: 170.3010, 170.3830, 170.6960.

A multispectral direct chromophore and scattering reconstruction technique has been implemented for near-infrared frequency-domain tomography in recovering images of total hemoglobin, oxygen saturation, water, and scatter parameters. The method applies the spectral constraint of the chromophores and scattering spectra directly in the reconstruction algorithm, thereby reducing the parameter space of the inversion process. This new method was validated by use of simulated and experimental data, and results show better robustness and stability in the presence of higher levels of noise. The method suppresses artifacts, especially those significant in water and scatter power images, and reduces cross talk between chromophore and scatter parameters. Variation in scattering was followed by this spectral approach successfully in experimental data from 90-mm-diameter cylindrical phantoms, and results show linear variation in scatter amplitude and reduced scattering coefficient ([[micro].sub.s]'), with total hemoglobin, oxygen saturation, and water remaining constant and quantitatively accurate. Similar experiments were carried out for varying oxygen saturation and total hemoglobin. Accurate quantification was obtained with a mean error of 7.7% for oxygen saturation and 6.2% for total hemoglobin, with minimal cross talk between different parameters. OCIS codes: 170.3010, 170.6960

The contrast-to-noise ratio (CNR) was used to determine the detectability of objects within reconstructed images from diffuse near-infrared tomography. It was concluded that there was a maximal value of CNR near the location of an object within the image and that the size of the true region could be estimated from the CNR. Experimental and simulation studies led to the conclusion that objects can be automatically detected with CNR analysis and that our current system has a spatial resolution limit near 4 mm and a contrast resolution limit near 1.4. A new linear convolution method of CNR calculation was developed for automated region of interest (ROI) detection. OCIS codes: 170.6960, 170.7050, 110.2960, 110.3000, 110.6960, 170.3830.

Near-infrared (NIR) optical tomography can provide estimates of the internal distribution of optical absorption and transport scattering from boundary measurements of light propagation within biological tissue. Although this is a truly three-dimensional (3D) imaging problem, most research to date has concentrated on two-dimensional modeling and image reconstruction. More recently, 3D imaging algorithms are demonstrating better estimation of the light propagation within the imaging region and are providing the basis of more accurate image reconstruction algorithms. As 3D methods emerge, it will become increasingly important to evaluate their resolution, contrast, and localization of optical property heterogeneity. We present a concise study of 3D reconstructed resolution of a small, low-contrast, absorbing and scattering anomaly as it is placed in different locations within a cylindrical phantom. The object is an 8-mm-diameter cylinder, which represents a typical small target that needs to be resolved in NIR mammographic imaging. The best resolution and contrast is observed when the object is located near the periphery of the imaging region (12-22 mm from the edge) and is also positioned within the multiple measurement planes, with the most accurate results seen for the scatter image when the anomaly is at 17 mm from the edge. Furthermore, the accuracy of quantitative imaging is increased to almost 100% of the target values when a priori information regarding the internal structure of imaging domain is utilized. OCIS codes: 170.3010, 110.6880.

Three-dimensional (3D), multiwavelength near-infrared tomography has the potential to provide new physiological information about biological tissue function and pathological transformation. Fast and reliable measurements of multiwavelength data from multiple planes over a region of interest, together with adequate model-based nonlinear image reconstruction, form the major components of successful estimation of internal optical properties of the region. These images can then be used to examine the concentration of chromophores such as hemoglobin, deoxyhemoglobin, water, and lipids that in turn can serve to identify and characterize abnormalities located deep within the domain. We introduce and discuss a 3D modeling method and image reconstruction algorithm that is currently in place. Reconstructed images of optical properties are presented from simulated data, measured phantoms, and clinical data acquired from a breast cancer patient. It is shown that, with a relatively fast 3D inversion algorithm, useful images of optical absorption and scatter can be calculated with good separation and localization in all cases. It is also shown that, by use of the calculated optical absorption over a range of wavelengths, the oxygen saturation distribution of a tissue under investigation can be deduced from oxygenated and deoxygenated hemoglobin maps. With this method the reconstructed tumor from the breast cancer patient was found to have a higher oxy-deoxy hemoglobin concentration and also a higher oxygen saturation level than the background, indicating a ductal carcinoma that corresponds well to histology findings. OCIS codes: 170.3010, 110.6880, 170.3830, 170.6960.

Near-infrared (NIR) spectroscopic diffuse tomography has been used to map the hemoglobin concentration and the hemoglobin oxygen saturation quantitatively in tissuelike phantoms and to determine average values in vivo. A series of phantom calibrations were performed to achieve quantitatively accurate images of the absorption and the reduced scattering coefficients at multiple optical wavelengths. A least-squares fit was applied to absorption-coefficient images at multiple NIR wavelengths to obtain hemoglobin images of the concentration and the hemoglobin oxygen saturation. Objects of varying hemoglobin concentration and oxygen saturation within highly scattering media were localized and imaged to within 15% of their actual values. The average hemoglobin concentration and oxygen saturation of breast tissue was measured in vivo for two women volunteers. The potential application for the diagnosis of breast tumors is discussed.

We demonstrate a new design for a fiber-optic bundle to measure fluorescence signals from tissue. In this design, the intensity of the signal is not significantly affected by the medium's absorption and scattering coefficients and hence depends only on the fluorophore's properties. Monte Carlo simulations of light scattering were used for designing and verifying the results obtained. The fiber-optic bundle was tested on tissue-simulating phantoms and compared with a standard nonimaging fiber-optic bundle. The new bundle was composed of 30 individual 100-[[micro]meter] fibers. Fibers on the end of the bundle that touch the tissue surface were separated from one another by approximately I mm. This design permits integration of the signal over several locations while maintaining localized sampling from regions smaller than the average mean free scattering path of the tissue. The bundle was tested by measurement of the fluorescence signals from tissue-simulating solutions containing fluorescent compounds. These studies demonstrate that the new bundle reduces the effect of the intrinsic absorption in the medium, permitting detection of fluorescence that is linearly proportional to the fluorophore concentration.

A dosimetric system has been developed to measure the spatially resolved light dose absorbed by a photosensitizer in a tissue-simulating medium. These gelatin-based dosimeters had macroscopic optical scattering and absorption properties that are typical for homogeneous tissue and contained the photosensitizer benzoporphyrin derivative monoacid (BPD-MA). A reporter molecule, 2[prime]7[prime]-dichlorofluorescin diacetate (DCF-DA), served as an actinometer, which could be photosensitized by BPD-MA to generate a highly fluorescent photoproduct. The relative photosensitizing efficiencies of high-intensity pulsed and cw laser light were compared in these tissue-simulating dosimeters. These measurements demonstrate an increase in penetration for pulsed light as compared with cw light in the dosimeters. A numerical simulation of the light propagation based on optical diffusion theory was used along with the energy levels of the photosensitizer molecule to examine the mechanisms involved in the absorbed dose. The increased penetration of high-intensity pulsed light was due to a transient decrease in the absorption of the photosensitizer, resulting from saturation of the photosensitizer optical transitions. This study provides the first direct comparison of the photodynamic dose absorbed by a photosensitizer using both high-intensity pulsed and cw laser light in a tissue-simulating medium. These measurements demonstrate that a small increase in depth of treatment is possible with pulsed laser light as compared with cw laser light simply on the basis of the unique photochemistry of the photosensitizer. However, this effect still needs to be examined carefully in tumor tissue, where other biological or chemical effects may become significant. Key words: Photodynamic therapy, photosensitizer, benzoporphyrin derivative, tissue optical property, tissue phantom.

In general it is not possible to write an analytic expression for the fluorescence signal generated by a fluorophore distributed in a scattering medium such as tissue. However, by assuming that the scattering properties of the tissue are the same at the excitation and emission wavelengths, we have derived a simple relation between the fluorescence and the scatter signals. Along with diffusion theory, this was used to write expressions for the fluorescence signal detected at the tissue surface in both the time and the frequency domains. Experiments using the fluorophore aluminum chlorosulfonated phthalocyanine in tissue-simulating materials confirmed the accuracy of the model. Applications to in vivo spectroscopy are discussed.

In this study experimental measurements are used to determine that the observed absorbance of opaque microstructures in optically diffuse media correlates with the total surface area rather than the attenuation as calculated in a nonscattering environment. The data suggest that it may be possible to use remote measurements of optical diffuse transmission to quantify surface areas of microcapillaries that are highly absorbing or larger blood vessels that can have high intrinsic attenuation because of hematocrit alone. Results obtained in a transmission geometry are insensitive to the position of the microstructure along the line between source and detector, whereas those collected in a remission geometry are highly sensitive to the depth at which the structure is located. These types of measurement involving microscopic structures embedded in diffuse media have potential application in quantifying blood vessel surface areas that contain contrast agents or other microparticles within tissue. OCIS codes: 110.7050, 170.3880, 170.7050, 170.5280, 170.4580, 290.2200.

Imaging of tissue with near-infrared spectral tomography is emerging as a practicable method to map hemoglobin concentrations within tissue. However, the accurate recovery of images by using modeling methods requires a good match between experiments and the model prediction of light transport in tissue. We illustrate the potential for a match between (i) three-dimensional (3-D) frequency-domain diffusion theory, (ii) two-dimensional diffusion theory, (iii) Monte Carlo simulations, and (iv) experimental data from tissue-simulating phantoms. Robin-type boundary conditions are imposed in the 3-D model, which can be implemented with a scalar coupling coefficient relating the flux through the surface to the diffuse fluence rate at the same location. A comparison of 3-D mesh geometries for breast imaging indicates that relative measurements are sufficiently similar when calculated on either cylindrical or female breast shapes, suggesting that accurate reconstruction may be achieved with the simpler cylindrical mesh. Simulation studies directly assess the effects from objects extending out of the image plane, with results suggesting that spherically shaped objects reconstruct at lower contrast when their diameters are less than 15-20 mm. The algorithm presented here illustrates that a 3-D forward diffusion model can be used with circular tomographic measurements to reconstruct two-dimensional images of the interior absorption coefficient. [C] 2001 Optical Society of America OCIS codes: 170.5280, 170.5270, 170.3830, 170.3010, 110.6880, 110.7050.

Diffuse tomography with near-infrared light has biomedical application for imaging hemoglobin, water, lipids, cytochromes, or exogenous contrast agents and is being investigated for breast cancer diagnosis. A Newton-Raphson inversion algorithm is used for image reconstruction of tissue optical absorption and transport scattering coefficients from frequency-domain measurements of modulated phase shift and light intensity. A variant of Tikhonov regularization is examined in which radial variation is allowed in the value of the regularization parameter. This method minimizes high-frequency noise in the reconstructed image near the source-detector locations and can produce constant image resolution and contrast across the image field. OCIS codes: 110.6960, 110.7050, 170.6960, 170.7050.