Mehmet Burcin Unlu

Combined Diffuse Optical Tomography (DOT) and MRI System for Cancer Imaging in Small Animals

Recently, there has been a great amount of interest in developing multi-modality imaging techniques for oncologic research and clinical studies with the aim of obtaining complementary information and, thus, improving the detection and characterization of tumors. In this present work, the details of a combined MR-diffuse optical imaging system for dual-modality imaging of small animals are given. As a part of this effort, a multi-spectral frequency domain diffuse optical tomography system is integrated with an MRI system. Here, a network analyzer provides the rf modulation signal for the laser diodes and measures the amplitude and the phase of the detected signals. Photomultiplier tubes are utilized to measure low-level signals. The integration of this optical imaging system with the 4T MRI system is realized by incorporating a fiber adaptive interface inside the MR magnet. Coregistration is achieved by a special probe design utilizing fiducial markers. A finite element algorithm is used to solve the diffusion equation and an inverse solver based on this forward solver is implemented to calculate the absorption and scattering maps from the acquired data. The MR a priori information is used to guide the optical reconstruction algorithm. Phantom studies show that the absorption coefficient of a 7 mm inclusion in an irregular object located in 64 mm phantom is recovered with 11% error when MR a priori information is used. ENU induced tumor model is used to test the performance of the system in vivo.

Diffuse optical tomographic reconstruction using multifrequency data

We investigated the use of multifrequency diffuse optical tomography (MF-DOT) data for the reconstruction of the optical parameters. The experiments were performed in a 63 mm diameter cylindrical phantom containing a 15 mm diameter cylindrical object. Modulation frequencies ranging from 110 MHz to 280 MHz were used in the phantom experiments changing the contrast in absorption of the object with respect to the phantom while keeping the scattering value the same. The diffusion equation was solved using the finite element method. The sensitivity information from each frequency was combined to form a single Jacobian. The inverse problem was solved iteratively by minimizing the difference between the measurements and forward problem using single and multiple modulation frequency data. A multiparameter Tikhonov scheme was used for regularization. The phantom results show that the peak absorption coefficient in a region of interest was obtained with an error less then 5% using two-frequency reconstruction for absorption contrast values up to 2.2 times higher than background and 10% for the absorption contrast values larger than 2.2. The use of two-frequency data is sufficient to improve the quantitative accuracy compared with the single frequency reconstruction with appropriate selection of these frequencies.

Simultaneous in vivo dynamic magnetic resonance-diffuse optical tomography for small animal imaging

We present simultaneous measurement of enhancement kinetics of an optical and a magnetic resonance (MR) contrast agent in a small animal breast tumor model (R3230 ac) using a combined MR-diffuse optical tomographic (MR-DOT) imaging system. A mixture of a small molecular-weight MR contrast agent gadolinium-diethylene-triamine-pentaacetic acid (Gd-DTPA) and a large molecular-weight optical contrast agent indocyanine green (ICG) was administered intravenously for multimodal dynamic imaging. Coregistration of optical and MR images was accomplished using agar-water-based markers. Using T(2) and dynamic T(1) weighted MR images, we divided the entire tumor into two regions of interest (ROI): a viable and a nonviable region. The absorption enhancements in the ROIs were calculated. An enhancement of the ICG was observed in the viable region. On the contrary, there was a lower enhancement in the nonviable region.

A gantry-based tri-modality system for bioluminescence tomography

A gantry-based tri-modality system that combines bioluminescence (BLT), diffuse optical (DOT), and x-ray computed tomography (XCT) into the same setting is presented here. The purpose of this system is to perform bioluminescence tomography using a multi-modality imaging approach. As parts of this hybrid system, XCT and DOT provide anatomical information and background optical property maps. This structural and functional a priori information is used to guide and restrain bioluminescence reconstruction algorithm and ultimately improve the BLT results. The performance of the combined system is evaluated using multi-modality phantoms. In particular, a cylindrical heterogeneous multi-modality phantom that contains regions with higher optical absorption and x-ray attenuation is constructed. We showed that a 1.5 mm diameter bioluminescence inclusion can be localized accurately with the functional a priori information while its source strength can be recovered more accurately using both structural and the functional a priori information.

Dual-Contrast Dynamic MRI-DOT for Small Animal Imaging

In this paper we present first-of-its-kind spatially resolved enhancement kinetics of optical and magnetic resonance (MR) agents obtained by a combined MR and Diffuse Optical Tomography (MR-DOT) animal imaging system. A unique MR compatible fiber optic interface allows co-registration of MR and DOT data in space and time. High temporal resolution of the hybrid system permits acquisition of data in dynamic mode. Rats bearing a R3230 AC breast cancer tumor model are used for in vivo studies. Thirty-two optical and thirty MR images are acquired during a single imaging session that lasts nearly ten minutes. Both optical, indocyanine green (ICG), and MR contrast agents, gadolinium-DTPA (Gd-DTPA), are injected simultaneously after the acquisition of several baseline frames. Contrast enhancement time curves obtained by MR and DOT systems both indicate higher average enhancement in tumor regions, up to ten-fold for MRI and 3-fold for DOT, compared to close by non-tumor regions. This feasibility study is the first step towards clinical translation of this hybrid imaging platform. The ultimate aim is to use the enhancement kinetics of the optical agent ICG, which binds to plasma proteins, as complementary information to the kinetics of the MR agent Gd-DTPA, a small molecular agent that does not bind to plasma proteins, to better differentiate benign and malignant lesions.

A Simulation Study of the Variability of Indocyanine Green Kinetics and Using Structural a priori Information in Dynamic Contrast Enhanced Diffuse Optical Tomography (DCE-DOT)

We investigated (1) the variability of indocyanine green kinetics (ICG) between different cases in the existence of random noise, changing the size of the imaging region, the location and the size of the inclusion, (2) the use of structural a priori information to reduce the variability. We performed two-dimensional simulation studies for this purpose. In the simulations, we used a two-compartmental model to describe the ICG transport and obtained pharmacokinetic parameters. The transfer constant and the rate constant showed a wide variation, i.e. 60% and 95%, respectively, when random Gaussian noise with a standard deviation of 1% in amplitude and 0.4 degrees in phase was added to data. Moreover, recovered peak ICG concentration and time to reach the peak concentration was different within different cases. When structural a priori information was used in the reconstructions, the variations in the transfer and the rate constant were reduced to 29%, 15%, respectively. As a result, although the recovered peak concentration was still case dependent, the variability of the shape of the kinetic curve was reduced.

Dynamic contrast-enhanced diffuse optical tomography (DCE-DOT): experimental validation with a dynamic phantom

Dynamic contrast-enhanced diffuse optical tomography (DCE-DOT) can provide spatially resolved enhancement kinetics of an optical contrast agent. We undertook a systematic phantom study to evaluate the effects of the geometrical parameters such as the depth and size of the inclusion as well as the optical parameters of the background on the recovered enhancement kinetics of the most commonly used optical contrast agent, indocyanine green (ICG). For this purpose a computer-controlled dynamic phantom was constructed. An ICG-intralipid-water mixture was circulated through the inclusions while the DCE-DOT measurements were acquired with a temporal resolution of 16 s. The same dynamic study was repeated using inclusions of different sizes located at different depths. In addition to this, the effect of non-scattering regions was investigated by placing a second inclusion filled with water in the background. The phantom studies confirmed that although the peak enhancement varied substantially for each case, the recovered injection and dilution rates obtained from the percentage enhancement maps agreed within 15% independent of not only the depth and the size of the inclusion but also the presence of a non-scattering region in the background. Although no internal structural information was used in these phantom studies, it may be necessary to use it for small objects buried deep in tissue. However, the different contrast mechanisms of optical and other imaging modalities as well as imperfect co-registration between both modalities may lead to potential errors in the structural a priori. Therefore, the effect of erroneous selection of structural priors was investigated as the final step. Again, the injection and dilution rates obtained from the percentage enhancement maps were also immune to the systematic errors introduced by erroneous selection of the structural priors, e.g. choosing the diameter of the inclusion 20% smaller increased the peak enhancement 60% but changed the injection and dilution rates only less than 10%.

Simultaneous monitoring of multiple contrast agents using a hybrid MR-DOT system

Frequency domain diffuse optical tomography (DOT) is a recently emerging technique that uses arrays of sources and detectors to obtain spatially dependent optical parameters of tissue. Here, we describe the design of a hybrid MR-DOT system for dynamic imaging cancer. The combined system acquires both MR and optical data simultaneously. The performance of the system is tested with phantom and in-vivo studies. Gd-DTPA and ICG was used for this purpose and the enhancement kinetics of both agents are recorded using the hybrid system.

A multi-modality system for dynamic imaging of cancer

In the present work, the details of a combined MR-diffuse optical imaging system for dynamic contrast enhanced imaging of cancer are given. As a part of this effort, a multi-spectral diffuse optical tomography system was integrated with an MRI system. The integration of the optical imaging system with the 4T MRI system was realized by incorporating a fiber adaptive interface inside the MR magnet. Coregistration was achieved by a special probe design utilizing fiducial markers. A dynamic phantom was developed and used to test the performance of the system. Human and animal studies are currently being undertaken to assess the performance of the system in-vivo

A multimodal contrast agent for simultaneous magnetic resonance and optical imaging of small animal

Our goal is to assess the feasibility of a bi-functional contrast agent that is intravenously injected to an R3230 induced small animal breast tumor model. The MR/optical contrast agent was produced by GE Global Research, NY, and it was available in one size, Dp20. We used a combined frequency domain diffuse optical tomography (DOT) and a 4T magnetic resonance (MR) scanner to simultaneously measure the kinetics of the contrast agent in vivo. Both systems detected the signal change in the tumor and the non-tumor region. MR measurements served as a gold standard to validate the optical kinetics. We present both MR and DOT dynamic curves as well as the reconstructed optical absorption map.