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Image-guided small animal radiation research platforms allow more precise radiation treatment. Commercially available small animal X-ray irradiators are often equipped with a CT/cone-beam CT (CBCT) component for target guidance. Besides having poor soft-tissue contrast, CBCT unfortunately cannot provide molecular information due to its low sensitivity. Hence, there are extensive efforts to incorporate a molecular imaging component besides CBCT on these radiation therapy platforms. As an extension of these efforts, here we present a theranostic fluorescence tomography/CBCT-guided irradiator platform that provides both anatomical and molecular guidance, which can overcome the limitations of stand-alone CBCT. The performance of our hybrid system is validated using both tissue-like phantoms and mice ex vivo. Both studies show that fluorescence tomography can provide much more accurate quantitative results when CBCT-derived structural information is used to constrain the inverse problem. The error in the recovered fluorescence absorbance reduces nearly 10-fold for all cases, from approximately 60% down to 6%. This is very significant since high quantitative accuracy in molecular information is crucial to the correct assessment of the changes in tumor microenvironment related to radiation therapy.

Hypofractionated stereotactic body radiotherapy treatments (SBRT) have demonstrated impressive results for the treatment of a variety of solid tumors. The role of tumor supporting vasculature damage in treatment outcome for SBRT has been intensely debated and studied. Fast, non-invasive, longitudinal assessments of tumor vasculature would allow for thorough investigations of vascular changes correlated with SBRT treatment response. In this paper, we present a novel theranostic system which incorporates a fluorescence molecular imager into a commercial, preclinical, microCT-guided, irradiator and was designed to quantify tumor vascular response (TVR) to targeted radiotherapy. This system overcomes the limitations of single-timepoint imaging modalities by longitudinally assessing spatiotemporal differences in intravenously-injected ICG kinetics in tumors before and after high-dose radiation. Changes in ICG kinetics were rapidly quantified by principle component (PC) analysis before and two days after 10 Gy targeted tumor irradiation. A classifier algorithm based on PC data clustering identified pixels with TVR. Results show that two days after treatment, a significant delay in ICG clearance as measured by exponential decay (40.5± 16.1% P = 0.0405 Paired t-test n = 4) was observed. Changes in the mean normalized first and second PC feature pixel values (PC1 & PC2) were found (P = 0.0559, 0.0432 paired t-test), suggesting PC based analysis accurately detects changes in ICG kinetics. The PC based classification algorithm yielded spatially-resolved TVR maps. Our first-of-its-kind theranostic system, allowing automated assessment of TVR to SBRT, will be used to better understand the role of tumor perfusion in metastasis and local control.

In preclinical research, fluorescence molecular tomography (FMT) is the most sensitive imaging modality to interrogate whole-body and provide 3D distribution of fluorescent contract agents. Despite its superior sensitivity, its mediocre spatial-resolution has been the main barrier to its clinical translation. This limitation is mainly due to the high scattering of optical photons in biological tissue together with the limited boundary measurements that lead to an undetermined and ill-posed inverse problem. To overcome the limitations of FMT, we previously introduced a novel method termed, Temperature Modulated Fluorescence Tomography (TMFT). TMFT utilizes thermos-sensitive fluorescent agents (ThermoDots) as a key component and localizes them with high-intensity focused ultrasound (HIFU). Scanning the focused HIFU beam having a diameter Ø = 1.3 mm across the tissue while monitoring the variation in the measured fluorescence signals reveals the position of the ThermoDots with high spatial accuracy. We have formerly built a prototype TMFT system that uses optical fibers for detection. In this paper, we present an upgraded version using a CCD camera-based detection that enables non-contact imaging. In this version, the animal under investigation is placed on an ultrasound transparent membrane, which eliminates the need for its immersion in optical matching fluids that were required by the fiber-based system. This CCD-based system will pave the way for convenient and wide-spread use of TMFT in preclinical research. Its performance validation on phantom studies demonstrates that high spatial-resolution (∼1.3 mm) and quantitative accuracy in recovered fluorophore concentration (

We propose the proof-of-concept of a novel method for wide-field spectrally resolved near-infrared fluorescence (NIRF) imaging using a wavelength-swept laser. The performance of our method is evaluated on a biotissue-like phantom bearing two inclusions, one filled with indocyanine green (ICG) dissolved in distilled water and the second one in dimethyl sulfoxide (DMSO). A near-infrared wavelength-swept laser covering wavelengths around the peak absorption of ICG was used. The difference in the absorption spectra of these two ICG solutions gives rise to an additional spectral contrast. The distinction between the emitted fluorescence light from the two different solutions is performed using a principal component analysis (PCA)-based method. Results show that the two different ICG solutions were successfully resolved using this approach. This technique can be a powerful method to simultaneously spatio-spectrally image multiple near-infrared fluorescence agents.

Multiwavelength photo-magnetic imaging (PMI) is a novel combination of diffuse optics and magnetic resonance imaging, to the best of our knowledge, that yields tissue chromophore concentration maps with high resolution and quantitative accuracy. Here, we present the first experimental results, to the best of our knowledge, obtained using a spectrally constrained PMI image reconstruction method, where chromophore concentration maps are directly recovered, unlike the conventional two-step approach that requires an intermediate step of reconstructing wavelength-dependent absorption coefficient maps. The imposition of the prior spectral information into the PMI inverse problem improves the reconstructed image quality and allows recovery of highly quantitative concentration maps, which are crucial for effective cancer detection and characterization. The obtained results demonstrate the higher performance of the direct reconstruction method. Indeed, the reconstructed concentration maps are not only of higher quality but also obtained approximately 2 times faster than the conventional method.

Background and objectives In photothermal therapy, cancerous tissue is treated by the heat generated from absorbed light energy. For effective photothermal therapy, the parameters affecting the induced temperature should be determined before the treatment by modeling the increase in temperature via numerical simulations. However, accurate simulations can only be achieved when utilizing the accurate optical, thermal, and physiological properties of the treated tissue. Here, we propose a multi-wavelength photo-magnetic imaging (PMI) technique that provides quantitative and spatially resolved tissue optical absorption maps at any wavelength within the near-infrared (NIR) window to assist accurate photothermal therapy planning. Study design/materials and methods The study was conducted using our recently developed multi-wavelength PMI system, which operates at four laser wavelengths (760, 808, 860, and 980 nm). An agar tissue-simulating phantom containing water, lipid, and ink was illuminated using these wavelengths, and the slight internal laser-induced temperature rise was measured using magnetic resonance thermometry (MRT). The phantom optical absorption was recovered at the used wavelengths using our dedicated PMI image reconstruction algorithm. These absorption maps were then used to resolve the concentration of the tissue chromophores, and thus deduce its optical absorption spectrum in the NIR region based on the Beer-Lambert law. Results The optical absorption of the phantom was successfully recovered at the used four wavelengths with an average error of ~1.9%. The recovered absorption coefficient was then used to simulate temperature variations inside the phantom. A comparison between the modeled temperature maps and the MRT measured ones showed that these maps are in a good agreement with an average pseudo R2 statistic of 0.992. These absorption values were used to successfully recover the concentration of the used chromophores. Finally, these concentrations are used to accurately calculate the total absorption spectrum of the phantom in the NIR spectral window with an average error as low as ~2.3%. Conclusions Multi-wavelength PMI demonstrated a great ability to assess the distribution of tissue chromophores, thus providing its total absorption at any wavelength within the NIR spectral range. Therefore, applications of photothermal therapy applied at NIR wavelengths can benefit from the absorption spectrum recovered by PMI to determine important parameters such as laser power as well as the laser exposure time needed to attain a specific increase in temperature prior to treatment. Lasers Surg. Med. 00:00-00, 2020. © 2020 Wiley Periodicals LLC.

Tomographically recovering chromophore concentrations usually requires the intermediate step of reconstructing absorption maps at different wavelengths first. Here, we present a method that allows to obtain these concentrations directly from measured magnetic resonance temperature maps.

Photo-Magnetic Imaging (PMI) is a novel multimodality imaging technique that provides optical absorption maps with high-resolution and quantitative accuracy. Here, we present the preliminary experimental validation results obtained using our new multi-wavelength PMI system.

It has been reported that acoustic waves are generated when a high-energy pulsed proton beam is deposited in a small volume within tissue. One possible application of proton-induced acoustics is to get real-time feedback for intra-treatment adjustments by monitoring such acoustic waves. A high spatial resolution in ultrasound imaging may reduce proton range uncertainty. Thus, it is crucial to understand the dependence of the acoustic waves on the proton beam characteristics. In this manuscript, firstly, an analytic solution for the proton-induced acoustic wave is presented to reveal the dependence of the signal on the beam parameters; then it is combined with an analytic approximation of the Bragg curve. The influence of the beam energy, pulse duration and beam diameter variation on the acoustic waveform are investigated. Further analysis is performed regarding the Fourier decomposition of the proton-acoustic signals. Our results show that the smaller spill time of the proton beam upsurges the amplitude of the acoustic wave for a constant number of protons, which is hence beneficial for dose monitoring. The increase in the energy of each individual proton in the beam leads to the spatial broadening of the Bragg curve, which also yields acoustic waves of greater amplitude. The pulse duration and the beam width of the proton beam do not affect the central frequency of the acoustic wave, but they change the amplitude of the spectral components.

Background Bone metastases are common and devastating to cancer patients. Existing treatments do not specifically target the disease sites and are therefore ineffective and systemically toxic. Here we present a new strategy to treat bone metastasis by targeting both the cancer cells (“the seed”), and their surrounding niche (“the soil”), using stem cells engineered to home to the bone metastatic niche and to maximise local delivery of multiple therapeutic factors. Methods We used mesenchymal stem cells engineered using mRNA to simultaneously express P-selectin glycoprotein ligand-1 (PSGL-1)/Sialyl-Lewis X (SLEX) (homing factors), and modified versions of cytosine deaminase (CD) and osteoprotegerin (OPG) (therapeutic factors) to target and treat breast cancer bone metastases in two mouse models, a xenograft intratibial model and a syngeneic model of spontaneous bone metastasis. Findings We first confirmed that MSC engineered using mRNA produced functional proteins (PSGL-1/SLEX, CD and OPG) using various in vitro assays. We then demonstrated that mRNA-engineered MSC exhibit enhanced homing to the bone metastatic niche likely through interactions between PSGL-1/SLEX and P-selectin expressed on tumour vasculature. In both the xenograft intratibial model and syngeneic model of spontaneous bone metastasis, engineered MSC can effectively kill tumour cells and preserve bone integrity. The engineered MSC also exhibited minimal toxicity in vivo, compared to its non-targeted chemotherapy counterpart (5-fluorouracil). Interpretation Our combinatorial targeting of both the cancer cells and the niche represents a simple, safe and effective way to treat metastatic bone diseases, otherwise difficult to manage with existing strategies. It can also be applied to other cell types (e.g., T cells) and cargos (e.g., genome editing components) to treat a broad range of cancer and other complex diseases. Fund National Institutes of Health, National Cancer Institute of the National Institutes of Health, Department of Defense, California Institute of Regenerative Medicine, National Science Foundation, Baylx Inc., and Fondation ARC pour la recherche sur le cancer.

High scattering in biological tissues severely degrades the spatial resolution of optical fluorescence imaging in thick tissue. As one of the most sensitive in vivo molecular imaging modalities, Fluorescence Tomography plays an essential role in preclinical studies. To overcome the limitations of FT, we introduced a novel method termed, temperature modulated fluorescence tomography (TMFT). TMFT is based on two key elements: 1) temperature sensitive fluorescent agent (ThermoDots) and 2) high intensity focused ultrasound (HIFU). TMFT localizes the position of the fluorescent ThermoDots by scanning a HIFU beam across the tissue while monitoring the variation in the measured fluorescence signals. Actually, a binary mask is built by monitoring the sudden jumps in the fluorescence signal corresponding to the HIFU scan over a position containing ThermoDots. This binary map is used as functional a priori during the FT image reconstruction process. TMFT not only allowed us to resolve ThermoDots with high spatial resolution (~1.3 mm), deep in tissue (~ 60 mm) but with high quantitative accuracy as well (< 3% error). In this paper, we present the latest prototype of TMFT. Here, the fluorescence signals are acquired using a CCD camera, which increases the sensitivity of the system compared to the previous fiber-based system.

Although diffuse optical tomography (DOT) is able to obtain valuable functional information, its routine use in clinic is hampered by its poor spatial resolution and quantitative accuracy. Previously, our team introduced Photo-Magnetic Imaging (PMI) to overcome the limitation of DOT. PMI is a hybrid modality that synergistically utilizes optics and Magnetic Resonance Imaging (MRI). While illuminating the imaged medium by near-infrared laser, the induced internal temperature increase is measured using Magnetic Resonance Thermometry (MRT). Using these MRT maps, optical absorption maps at the laser's wavelength can be recovered using the dedicated PMI image reconstruction algorithm. In this paper, we present the result of the first validation simulation study of multi-wavelength PMI that utilizes five different laser wavelengths ranging between 760 and 980 nm. Using the high resolution wavelength specific absorption maps, PMI successfully recovered the concentration of three dyes, used as chromophore in the composition of our phantom, with high spatial resolution and quantitative accuracy. By providing functional information at high resolution, multi-wavelength PMI will be a valuable tool for monitoring tissue physiology, cancer detection and monitoring.

Molecular imaging is becoming essential for precision targeted radiation therapy, yet progress is hindered from a lack of integrated imaging and treatment systems. We report the development of a prototype positron emission tomography (PET) scanner integrated into a commercial cone beam computed tomography (CBCT) based small animal irradiation system for molecular-image-guided, targeted external beam radiation therapy. The PET component consists of two rotating Hamamatsu time-of-flight PET modules positioned with a bore diameter of 101.6 mm and a radial field-of-view of 53.1 mm. The measured energy resolution after linearity correction at 511 KeV was 12.9% and the timing resolution was 283.6 ps. The measured spatial resolutions at the field-of-view center and 5 mm off the radial center were 2.6 mm x 2.6 mm x 1.6 mm and 2.6 mm x 2.6 mm x 2.7 mm respectively. 18F-Fluorodeoxyglucose-based PET imaging of a NEMA NU 4-2008 phantom resolved cylindrical volumes with diameters as small as 3 mm. To validate the system in-vivo, we performed 64Cu-DOTA-M5A PET and computed tomography (CT) imaging of carcinoembryonic antigen (CEA)-positive colorectal cancer in athymic nude mice and compared the results with a commercially available Siemens Inveon PET/CT system. The prototype PET system performed comparably to the Siemens system for identifying the location, size, and shape of tumors. Regions of heterogeneous 64Cu-DOTA-M5A uptake were observed. Using 64Cu-DOTA-M5A PET and CT images, a Monte Carlo-based radiation treatment plan was created to escalate the dose to the 64Cu-DOTA-M5A-based, highly active, biological target volume while largely sparing the normal tissue. Results demonstrate the feasibility of molecular-image-guided treatment plans using the prototype theranostic system.

Photothermal therapy (PIT) is a minimally invasive alternative to conventional surgery and can provide faster recovery times as well as reduction in complication rates. Successfully targeting of gold nanoparticles to the tumor increases its light absorption leading to more important temperature rise in the tumor than surrounding tissue. Hence, it is possible to heat tumor with a minimal damage to the surrounding tissue only if the appropriate laser parameters are employed. In this study, our purpose is to develop a simulation tool capable of determining temperature rise and duration in the tissue for therapy planning. This simulation tool is based on a new analytical approach which models laser-induced temperature in a two-layered medium mimicking concentric tumor and its surrounding healthy tissue. First, the diffusion equation is used to model the light propagation in tissue and then a comprehensive solution is derived by obtaining a special Greens' function. Next, the Pennes' bioheat equation is analytically solved for a source term defined as the product of local optical absorption and the solution of the diffusion equation. Our approach is validated by comparing the spatiotemporal temperature distribution obtained by our method, finite element method, and experimental studies, respectively. The obtained results are in very good agreement with an average R-squared of 0.953. This analytical approach can provide a suitable and fast platform for modeling laser-induced temperature distribution for thermal therapy applications. (C) 2020 Elsevier Ltd. All rights reserved.

Photo-magnetic imaging (PMI) is an emerging optical imaging modality that showed great performance on providing absorption maps with high resolution and quantitative accuracy. As a multi-modality technology, PMI warms up the imaged object using a near infrared laser while temperature variation is measured using magnetic resonance imaging. By probing tissue at multiple wavelengths, concentration of the main tissue chromophores such as oxy-and deoxy-hemoglobin, lipid, and water are obtained then used to derive functional parameters such as total hemoglobin concentration and relative oxygen saturation. In this paper, we present a multi-wavelength PMI system that was custom-built to host five different laser wavelengths. After recovering the high-resolution absorption maps, a least-squared minimization process was used to resolve the different chromophore concentration. The performance of the system was experimentally tested on a phantom with two different dyes. Their concentrations were successfully assessed with high spatial resolution and average accuracy of nearly 80%. (C) 2020 Optical Society of America under the terms of the OSA Open Access Publishing Agreement

The dynamic response behavior of red blood cells holds the key to understanding red blood cell related diseases. In this regard, an understanding of the physiological functions of erythrocytes is significant before focusing on red blood cell aggregation in the microcirculatory system. In this work, we present a theoretical model for a photoacoustic signal that results when deformed red blood cells pass through a microfluidic channel. Using a Green’s function approach, the photoacoustic pressure wave is obtained analytically by solving a combined Navier-Stokes and photoacoustic equation system. The photoacoustic wave expression includes determinant parameters for the cell deformability such as plasma viscosity, density, and red blood cell aggregation, as well as involving laser parameters such as beamwidth, pulse duration, and repetition rate. The effects of aggregation on blood rheology are also investigated. The results presented by this study show good agreements with the experimental ones in the literature. The comprehensive analytical solution of the extended photoacoustic transport model including a modified Morse type potential function sheds light on the dynamics of aggregate formation and demonstrates that the profile of a photoacoustic pressure wave has the potential for detecting and characterizing red blood cell aggregation.

In this study, we develop an analytical based simulation method to determine laser parameters such as laser power and its duration for laser induced thermal ablation. This method utilizes two important physical approaches to model i) the light propagation and ii) the change in temperature due to the laser absorption in turbid media. First, the photon density is obtained analytically from the solution of the diffusion equation by deriving a special Greens’ function. Next, the Pennes bio-heat equation is solved analytically for a source term consisting of the product of the photon density and the optical absorption coefficient. Our approach is validated with the results obtained by Finite Element Method (FEM) and experimental results acquired from the gold-nanoparticle embedded phantom.

Photo-Magnetic Imaging (PMI) is a novel diffuse optical imaging technique that yields high resolution optical absorption images. It is based on the measurement of the temperature increase of a given medium after its illumination with a near-infrared laser using Magnetic Resonance Thermometry (MRT). In this paper, we present the first multi-wavelengths PMI system able to provide oxy- and deoxyhemoglobin concentration maps with high spatial and quantitative accuracy.

In this work, we introduce an analytical method to solve the diffusion equation in a cylindrical geometry. This method is based on an integral approach to derive the Green's function for specific boundary conditions. Using our approach, we obtain comprehensive analytical solutions with the Robin boundary condition for diffuse optical imaging in both two and three dimensions. The solutions are expressed in terms of the optical properties of tissue and the amplitude and position of the light source. Our method not only works well inside the tissue but provides very accurate results near the tissue boundaries as well. The results obtained by our method are first compared with those obtained by a conventional analytical method then validated using numerical simulations. Our new analytical method allows not only implementation of any boundary condition for a specific problem but also fast simulation of light propagation making it very suitable for iterative image reconstruction algorithms.

We present the feasibility of structured-light-based diffuse optical tomography (DOT) to quantify the breast density with an extensive simulation study. This study is performed on multiple numerical breast phantoms built from magnetic resonance imaging (MRI) images. These phantoms represent realistic tissue morphologies and are given typical breast optical properties. First, synthetic data are simulated at five wavelengths using our structured-light-based DOT forward problem. Afterwards, the inverse problem is solved to obtain the absorption images and subsequently the chromophore concentration maps. Parameters, such as segmented volumes and mean concentrations, are extracted from these maps and used in a regression model to estimate the percent breast densities. These estimations are correlated with the true values from MRI, r = 0.97, showing that our new technique is promising in measuring breast density.

We recently introduced a new high-resolution diffuse optical imaging technique termed photo-magnetic imaging (PMI), which utilizes magnetic resonance thermometry (MRT) to monitor the 3D temperature distribution induced in a medium illuminated with a near-infrared light. The spatiotemporal temperature distribution due to light absorption can be accurately estimated using a combined photon propagation and heat diffusion model. High-resolution optical absorption images are then obtained by iteratively minimizing the error between the measured and modeled temperature distributions. We have previously demonstrated the feasibility of PMI with experimental studies using tissue simulating agarose phantoms. In this Letter, we present the preliminary ex vivo PMI results obtained with a chicken breast sample. Similarly to the results obtained on phantoms, the reconstructed images reveal that PMI can quantitatively resolve an inclusion with a 3 mm diameter embedded deep in a biological tissue sample with only 10% error. These encouraging results demonstrate the high performance of PMI in ex vivo biological tissue and its potential for in vivo imaging. (C) 2017 Optical Society of America.

Previously, we demonstrated that temperature-modulated fluorescence tomography (TM-FT) could provide fluorescence images with high quantitative accuracy and the spatial resolution of focused ultrasound. TM-FT is based on scanning the focused ultrasound across the medium to activate temperature-reversible fluorescent nanoprobes (ThermoDots). This technique can resolve small fluorescent targets located several centimeters deep in turbid media with millimeter resolution. Our past studies with this multimodality technique used agar phantoms, which could not represent the true heterogeneous nature of the acoustic and optical properties of biological tissue. In this work, we report the results of the first TM-FT study performed on ex vivo chicken breast tissue. In order to improve the spatial resolution of this technique, diffuse optical tomography is also used to better estimate the optical property maps of the tissue, which is utilized as functional a priori for the TM-FT reconstruction algorithm. These ex vivo results show that TM-FT can accurately recover the concentration and position of a 1.5 mm×5 mm inclusion filled with ThermoDots. Since the inclusion is embedded 2cm deep in the chicken breast sample, these results demonstrate the great potential of TM-FT for future in vivo small animal imaging.

Fluorescence diffuse optical tomography (FDOT) has been widely used for in vivo small animal studies and the illposed problem in reconstruction can be eased by utilizing structural a priori obtained from an anatomic imaging modality. In this study, a multispectral fluorescence tomography (FT) is used, which has shown the ability to detect subtle shifts in the ICG absorption spectrum in our previous study. The imaging system is in trans-illumination mode with a swept-wavelength laser and a CCD on a rotation gantry and the structural image from the X-ray computed tomography is used to guide and constrain the FT reconstruction algorithm. In this work, a phantom with two inclusions filled with different fluorophores is utilized to evaluate whether the spectral information obtained using sweptwavelength laser can distinguish these two inclusions. The images are captured from 8 different views with three different wavelengths.

Recognizing motivationally salient information is critical to guiding behaviour. The amygdala and hippocampus are thought to support this operation, but the circuit-level mechanism of this interaction is unclear. We used direct recordings in the amygdala and hippocampus from human epilepsy patients to examine oscillatory activity during processing of fearful faces compared with neutral landscapes. We report high gamma (70–180 Hz) activation for fearful faces with earlier stimulus evoked onset in the amygdala compared with the hippocampus. Attending to fearful faces compared with neutral landscape stimuli enhances low-frequency coupling between the amygdala and the hippocampus. The interaction between the amygdala and hippocampus is largely unidirectional, with theta/alpha oscillations in the amygdala modulating hippocampal gamma activity. Granger prediction, phase slope index and phase lag analysis corroborate this directional coupling. These results demonstrate that processing emotionally salient events in humans engages an amygdala-hippocampal network, with the amygdala influencing hippocampal dynamics during fear processing., Amygdala and hippocampus are involved in processing motivationally salient stimuli but the precise circuit dynamics of the interaction is not understood. Here the authors show that in response to fearful faces in humans, theta/alpha oscillations in the amygdala modulate hippocampal activity dynamics.

In this study, we present a fast analytical approach for laser induced temperature increase in biological tissue. The whole problem consists of two main steps. These steps are the light propagation and heat transfer in tissue. We first obtain a detailed analytical solution for the diffusion equation based on an integral approach for specific boundary conditions. Secondly, we also solve the Pennes' bio-heat transfer equation analytically using the separation of variables technique and obtain the temperature induced by optical absorption of tissue. Here, heat source term consists of the local absorption and photon density, which will be determined from the diffusion equation. We find a very comprehensive solution for the diffusion equation by using an integral method for the Robin boundary condition. In other words, we obtain a particular Green's function in a different way. Next, we use this solution as a source term in the Pennes’ bio-heat equation by utilizing the heat convection boundary condition. It is important to note that these boundary conditions are good approximations for imaging of biological tissue. As a result, we obtain spatio-temporal temperature distribution inside the medium. First, our approach is validated by a numerical approach using a Finite Element Method (FEM). Next, we also validate our method by performing phantom and tissue experiments. Experimental data corresponding to spatio-temporal temperature distribution are recorded using magnetic resonance thermometry. The analytical results obtained by our method are in a very good agreement with ones obtained by the FEM and experiment.

Near-infrared fluorescence imaging (NIRF) is a powerful wide-field optical imaging tool that has a potential to visualize molecular-specific exogenous fluorescence agents, such as FDA approved Indocyanine Green (ICG), in thick tissue. Indeed, ICG is sensitive to biochemical environment such that it can be used to detect micro- or macroscopic environmental changes in tissue by solvatochromic shift that is defined by the dependence of absorption and emission spectra with the solvent polarity. For example, dimethyl sulfoxide (DMSO) is a very powerful drug carrier that can penetrate biological barriers such as the skin, the membranes, and the blood-brain-barrier. In presence of DMSO, ICG in tissue shows the excitation blue shift. However, NIRF imaging of microenvironment dependent changes of ICG has been challenging for the following reasons. First, the Stoke’s shift of ICG is too small to separate the excitation and emission spectra easily. Second, the solvatochromic shift of ICG is too small to be detected by conventional NIRF techniques. Last but not least, the multiple scattering in tissue degrades not only the spatial information but also the spectral contents by the red-shift. We developed a wavelength-swept laser-based NIRF system that can resolve the excitation shift of ICG in tissue such that DMSO can be indirectly visualized. We plan to conduct an in-vivo lymph-node drug-delivery study in a mouse model to show feasibility of the indirect imaging of the drug-carrier with the wavelength-swept-laser based NIRF system.

The strong scattering and absorption of light in biological tissue makes it challenging to model the propagation of light, especially in deep tissue. This is especially true in fluorescent tomography, which aims to recover the internal fluorescence source distribution from the measured light intensities on the surface of the tissue. The inherently ill-posed and underdetermined nature of the inverse problem along with strong tissue scattering makes Fluorescence Tomography (FT) extremely challenging. Previously, multispectral detection fluorescent tomography (FT) has been shown to improve the image quality of FT by incorporating the spectral filtering of biological tissue to provide depth information to overcome the inherent absorption and scattering limitations. We investigate whether multi-wavelength fluorescent tomography can be used to distinguish the signals from multiple fluorophores with overlapping fluorescence spectrums using a unique near-infrared (NIR) swept laser. In this work, a small feasibility study was performed to see whether multi-wavelength FT can be used to detect subtle shifts in the absorption spectrum due to differences in fluorophore microenvironment.

Optical imaging has long been hindered by the high absorption and scattering of light in biological tissue. This makes it difficult to probe beyond a few millimeters beneath the surface without sacrificing image resolution and quantitative accuracy. Strong scattering and the inherent nature of the inverse problem makes fluorescence diffuse optical tomography (FT) extremely challenging. To this end, multi-modality techniques that combine anatomical imaging with the functional optical information have been used to improve the resolution and accuracy of FT. Previously, we have reported on the feasibility of a new imaging method, "Thermal Outlining using Focused Ultrasound" (TOFU), which combines the sensitivity of FT with the resolution of focused ultrasound using temperature reversible fluorescent probes. In this method, the position of the temperature reversible fluorescent probes is localized by an increase in fluorescent signal when the hot spot of the focused ultrasound beam is scanned over the medium. This a priori information is then utilized to guide and constrain conventional reconstruction algorithm to recover the position and concentration of the probes more accurately. The small size of the focal spot (~1.4 mm) up to a depth of 6 cm, allows imaging the distribution of these temperature sensitive agents with not only high spatial resolution but also high quantitative accuracy in deep tissue. In this work, the performance of the system will be evaluated using simulation and phantoms to investigate the dependence that size of the fluorescent distribution has on the TOFU system performance.

Breast density is an independent risk factor for breast cancer, where women with denser breasts are more likely to develop cancer. By identifying women at higher risk, healthcare providers can suggest screening at a younger age to effectively diagnose and treat breast cancer in its earlier stages. Clinical risk assessment models currently do not incorporate breast density, despite its strong correlation with breast cancer. Current methods to measure breast density rely on mammography and MRI, both of which may be difficult to use as a routine risk assessment tool. We propose to use diffuse optical tomography with structured-light to measure the dense, fibroglandular (FGT) tissue volume, which has a different chromophore signature than the surrounding adipose tissue. To test the ability of this technique, we performed simulations by creating numerical breast phantoms from segmented breast MR images. We looked at two different cases, one with a centralized FGT distribution and one with a dispersed distribution. As expected, the water and lipid volumes segmented at half-maximum were overestimated for the dispersed case. However, it was noticed that the recovered water and lipid concentrations were lower and higher, respectively, than the centralized case. This information may provide insight into the morphological distribution of the FGT and can be a correction in estimating the breast density.

We introduce a new Photo-Magnetic Imaging image reconstruction algorithm that uses analytical methods to solve both its forward and inverse problem, making it 33 times faster than a single iteration of our previous FEM-based algorithm.

Laser induced thermal ablation is a minimally invasive alternative to conventional surgery and can provide faster recovery times as well as reduction in complication rates. In this study, our purpose is to develop a simulation tool for therapy planning to determine important laser parameters that govern the magnitude of temperature rise and its duration in the tissue. This tool is based on the use of a new analytical approach to model laser induced temperature in turbid media. First, the diffusion equation is used for the light propagation and a comprehensive solution is derived analytically by obtaining a special Greens’ function. Next, the heat equation is also solved analytically for a source term given by the product of the solution of the diffusion equation and the local optical absorption. The results obtained with our theoretical model are successfully validated using experimental data.

In this work, we present a new analytical approach to model continuous wave laser induced temperature in highly homogeneous turbid media. First, the diffusion equation is used to model light transport and a comprehensive solution is derived analytically by obtaining a special Greens' function. Next, the time-dependent bio-heat equation is used to describe the induced heat increase and propagation within the medium. The bio-heat equation is solved analytically utilizing the separation of variables technique. Our theoretical model is successfully validated using numerical simulations and experimental studies with agarose phantoms and ex-vivo chicken breast samples. The encouraging results show that our method can be implemented as a simulation tool to determine important laser parameters that govern the magnitude of temperature rise within homogenous biological tissue or organs. (c) 2015 Optical Society of America

Fluorescence tomography (FT) is a promising molecular imaging technique that can spatially resolve both fluorophore concentration and lifetime parameters. However, recovered fluorophore parameters highly depend on the size and depth of the object due to the ill-posedness of the FT inverse problem. Structural a priori information from another high spatial resolution imaging modality has been demonstrated to significantly improve FT reconstruction accuracy. In this study, we have constructed a combined magnetic resonance imaging (MRI) and FT system for small animal imaging. A photo-multiplier tube (PMT) is used as the detector to acquire frequency domain FT measurements. This is the first MR-compatible time-resolved FT system that can reconstruct both fluorescence concentration and lifetime maps simultaneously. The performance of the hybrid system is evaluated with phantom studies. Two different fluorophores, Indocyanine Green (ICG) and 3-3′ Diethylthiatricarbocyanine Iodide (DTTCI), which have similar excitation and emission spectra but different lifetimes, are utilized. The fluorescence concentration and lifetime maps are both reconstructed with and without the structural a priori information obtained from MRI for comparison. We show that the hybrid system can accurately recover both fluorescence intensity and lifetime within 10% error for two 4.2 mm-diameter cylindrical objects embedded in a 38 mm-diameter cylindrical phantom when MRI structural a priori information is utilized.

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.