Contrast harmonic imaging

The behavior of ultrasound contrast agents depends highly on the acoustic pressure of the insonified ultrasound wave. For low pressure the expansion and compression is linear to the pressure, for medium acoustic pressure nonlinear behavior starts to occur and for high pressures, but still in the diagnostic range transient scattering can be noticed, resulting in an enhanced scattering followed by a disappearance of the bubble. The nonlinear and transient regime can be utilized for imaging of the contrast agent in or nearby tissue. The magnitude of the nonlinear signal from the contrast has to compete with the nonlinear component of the ultrasound wave, which is generated during propagation. It is shown that contrast is superior to tissue when using low frequencies and imaging the third or fourth harmonic of the transmitted frequency.     

Ultrasonic Lamb wave diffraction tomography.

Ultrasonic guided waves, Lamb waves, allow large sections of aircraft structures to be rapidly inspected. Unlike conventional ultrasonic C-scan imaging that requires access to the whole inspected area, tomographic algorithms work with data collected over the perimeter. Because the velocity of Lamb waves depends on thickness the travel times of the fundamental modes can be converted into a thickness map of inspected region. Lamb waves cannot penetrate through holes and other strongly scattering defects and the assumption of straight wave paths, essential for many tomographic algorithms, fails. Diffraction tomography is a way to incorporate scattering effects into tomographic algorithms in order to improve image quality and resolution. This work describes the iterative reconstruction procedure developed for Lamb wave tomography and allowing for ray bending correction for imaging of moderately scattering objects.     

Cell viability and MRI performance of highly efficient polyol-coated magnetic nanoparticles

This work aimed at determining conditions that would allow us to control the size of the NPs and create a system with characteristics apt for biomedical applications. We describe a comprehensive study on the synthesis and physical characterization of two highly sensitive sets of triethylene glycol (TREG) and polyethylene glycol (PEG)-coated superparamagnetic iron oxide nanoparticles (SPIONs) to be evaluated for use as magnetic resonance (MR) contrast agents. The ferrofluids demonstrated excellent colloidal stability in deionized water at pH 7.0 as indicated by dynamic light scattering (DLS) data. The magnetic relaxivities, r ₂, were measured on a 1.5 T clinical MRI instrument. Values in the range from 205 to 257 mM^?1 s^?1 were obtained, varying proportionally to the SPIONs’ sizes and coating nature. Further in vitro cell viability tests and in vivo biodistribution analyses of the intravenously administered nanoparticles showed that the prepared systems have good biocompatibility and migrate to several organs, mainly the meninges, spleen, and liver. Based on these results, our findings demonstrated the potential utility of these nanosystems as clinical contrast agents for MR imaging.     

Optical tomography using the time-independent equation of radiative transfer—Part 2: inverse model

Optical tomography is a novel imaging modality that is employed to reconstruct cross-sectional images of the optical properties of highly scattering media given measurements performed on the surface of the medium. Recent advances in this field have mainly been driven by biomedical applications in which near-infrared light is used for transillumination and reflectance measurements of highly scattering biological tissues. Many of the reconstruction algorithms currently utilized for optical tomography make use of model-based iterative image reconstruction (MOBIIR) schemes. The imaging problem is formulated as an optimization problem, in which an objective function is minimized. In the simplest case the objective function is a normalized-squared error between measured and predicted data. The predicted data are obtained by using a forward model that describes light propagation in the scattering medium given a certain distribution of optical properties.In part I of this two-part study, we presented a forward model that is based on the time-independent equation of radiative transfer. Using experimental data we showed that this transport-theory-based forward model can accurately predict light propagation in highly scattering media that contain void-like inclusions. In part II we focus on the details of our image reconstruction scheme (inverse model). A crucial component of this scheme involves the efficient and accurate determination of the gradient of the objective function with respect to all optical properties. This calculation is performed using an adjoint differentiation algorithm that allows for fast calculation of this gradient. Having calculated this gradient, we minimize the objective function with a gradient-based optimization method, which results in the reconstruction of the spatial distribution of scattering and absorption coefficients inside the medium. In addition to presenting the mathematical and numerical background of our code, we present reconstruction results based on experimentally obtained data from highly scattering media that contain void-like regions. These types of media play an important role in optical tomographic imaging of the human brain and joints.     

Optical and optoacoustic measurements of the absorption properties of spherical gold nanoparticles within a highly scattering medium

In the present paper the requirements for optical parameter characterization of absorbing materials located within a highly scattering medium has been addressed. The measurement scheme incorporates the optoacoustic technique where a single acoustic transducer is used to detect ultrasonic transients generated from laser irradiation. The absorbing medium is based on different concentrations of spherical gold nanoparticles (SGNP’s), these are currently being considered as non-toxic targeted optical contrast agents for both medical imaging and cancer therapeutics. In this paper we present results which demonstrate the two main advantages the optoacoustic technique has over other measurement schemes. These are the possibility to obtain information on the position and dimensions of absorbing bodies using a time of flight analysis (TOF) and secondly, the higher sensitivity of the optoacoustics compared to optical transmission techniques. The former advantage is of particular interest for imaging applications and the latter for detection and characterization of absorbing materials surrounded by high levels of high scattering mediums. We present for the first time the characterization of SGNP within a highly scattering medium. To further demonstrate the feasibility of the optoacoustic technique, the scattering coefficient of the surrounding medium has also been characterized.     

基于压缩感知的动态散射成像

利用基于压缩感知的成像系统可以透过静态的散射介质获得高质量的重建图像. 但是当散射介质动态变化时, 因为采样所得的测量值受到散射介质衰减系数非线性变化的影响, 重建图像质量会大大下降. 针对上述情况, 本文提出基于压缩感知成像系统的测量值线性拉伸算法, 该算法能够对所得到的非线性测量值进行分析, 根据测量值大小的不同将测量值划分成数个区域并计算补偿系数, 从而根据补偿系数进行测量值线性拉伸变换, 使测量值线性化. 最后再对变换后的测量值进行压缩感知重建计算. 通过理论分析、计算机仿真和实验证明了所提算法能够有效地应对动态的散射介质, 提高基于压缩感知成像系统在透过动态散射介质时的图像重建质量.     

浑浊介质中图像对比度与成像方式的关系

浑浊介质中图像对比度的物理增强方法一直是研究热点, 目前学者们提出的距离选通成像、偏振差分成像和偏振距离选通成像均能提高图像的对比度, 但提高效果与成像距离的关系尚不明确. 本文分别利用以上三种成像方式及普通强度成像对处于不同浓度浑浊介质中的目标进行成像, 研究了图像强度和对比度随成像距离的变化情况. 结果表明: 从滤除的散射光强来看, 偏振距离选通成像最优, 而偏振差分成像在成像距离较远时优于距离选通成像; 三种成像方式滤除的散射光强值趋于稳定的阈值距离各不相同; 对比度改变相同量时, 偏振距离选通成像对应成像距离的变化量最大, 偏振差分成像次之, 强度成像最小, 且均与散射系数成反比. 本文对浑浊介质成像效果及机理的分析, 对进一步提高浑浊介质中目标的分辨及识别具有重要意义.     

Testing methodologies for the nonlinear analysis of causal relationships in neurovascular coupling

We investigated the use and implementation of a nonlinear methodology for establishing which changes in neurophysiological signals cause changes in the blood oxygenation level-dependent (BOLD) contrast measured in functional magnetic resonance imaging. Unlike previous analytical approaches, which used linear correlation to establish covariations between neural activity and BOLD, we propose a directed information-theoretic measure, the transfer entropy, which can elucidate even highly nonlinear causal relationships between neural activity and BOLD signal. In this study we investigated the practicality of such an analysis given the limited data samples that can be collected experimentally due to the low temporal resolution of BOLD signals. We implemented several algorithms for the estimation of transfer entropy and we tested their effectiveness using simulated local field potentials (LFPs) and BOLD data constructed to match the main statistical properties of real LFP and BOLD signals measured simultaneously in monkey primary visual cortex. We found that using the advanced methods of entropy estimation implemented and described here, a transfer entropy analysis of neurovascular coupling based on experimentally attainable data sets is feasible.     

Neutron dark-field tomography

We report how a grating interferometer yields neutron dark-field scatter images for tomographic investigations. The image contrast is based on ultrasmall-angle scattering. It provides otherwise inaccessible spatially resolved information about the distribution of micrometer and submicrometer sized structural formations. Three complementary sets of tomographic data corresponding to attenuation, differential phase, and small-angle scattering can be obtained from one measurement. The method is compatible with conventional imaging and provides significantly higher efficiency than existing techniques.     

All-optical anatomical co-registration for molecular imaging of small animals using dynamic contrast

Optical molecular imaging in small animals harnesses the power of highly specific and biocompatible contrast agents for drug development and disease research1-7. However, the widespread adoption of in vivo optical imaging has been inhibited by its inability to clearly resolve and identify targeted internal organs. Optical tomography8-11 and combined X-ray and micro-computed tomography (micro-CT)12 approaches developed to address this problem are generally expensive, complex or incapable of true anatomical co-registration. Here, we present a remarkably simple all-optical method that can generate co-registered anatomical maps of a mouse's internal organs, while also acquiring in vivo molecular imaging data. The technique uses a time series of images acquired after injection of an inert dye. Differences in the dye's in vivo biodistribution dynamics allow precise delineation and identification of major organs. Such co-registered anatomical maps permit longitudinal organ identification irrespective of repositioning or weight gain, thereby promising greatly improved accuracy and versatility for studies of orthotopic disease, diagnostics and therapies.     

Using Copula distributions to support more accurate imaging-based diagnostic classifiers for neuropsychiatric disorders

Many investigators have tried to apply machine learning techniques to magnetic resonance images (MRIs) of the brain in order to diagnose neuropsychiatric disorders. Usually the number of brain imaging measures (such as measures of cortical thickness and measures of local surface morphology) derived from the MRIs (i.e., their dimensionality) has been large (e.g. > 10) relative to the number of participants who provide the MRI data (< 100). Sparse data in a high dimensional space increase the variability of the classification rules that machine learning algorithms generate, thereby limiting the validity, reproducibility, and generalizability of those classifiers. The accuracy and stability of the classifiers can improve significantly if the multivariate distributions of the imaging measures can be estimated accurately. To accurately estimate the multivariate distributions using sparse data, we propose to estimate first the univariate distributions of imaging data and then combine them using a Copula to generate more accurate estimates of their multivariate distributions. We then sample the estimated Copula distributions to generate dense sets of imaging measures and use those measures to train classifiers. We hypothesize that the dense sets of brain imaging measures will generate classifiers that are stable to variations in brain imaging measures, thereby improving the reproducibility, validity, and generalizability of diagnostic classification algorithms in imaging datasets from clinical populations. In our experiments, we used both computer-generated and real-world brain imaging datasets to assess the accuracy of multivariate Copula distributions in estimating the corresponding multivariate distributions of real-world imaging data. Our experiments showed that diagnostic classifiers generated using imaging measures sampled from the Copula were significantly more accurate and more reproducible than were the classifiers generated using either the real-world imaging measures or their multivariate Gaussian distributions. Thus, our findings demonstrate that estimated multivariate Copula distributions can generate dense sets of brain imaging measures that can in turn be used to train classifiers, and those classifiers are significantly more accurate and more reproducible than are those generated using real-world imaging measures alone.     

Single-shot grating-based x-ray differential phase contrast imaging with a modified analyzer grating

X-ray grating interferometer has attracted widely attention in the past years due to its capability in achieving x-ray phase contrast imaging with low brilliance source. However, the widely used phase stepping information extraction method reduces system stability and prolongs data acquisition time by several times compared with conventional x-ray absorptionbased imaging. The mechanical stepping can be avoided by using a staggered grating, but at the cost of low vertical spatial resolution. In this paper, employing a modified staggered grating and the angular signal radiography, we proposed a single-shot grating-based x-ray differential phase contrast imaging with decent vertical spatial resolution. The theoretical framework was deduced and proved by numerical experiments. Absorption, phase, and scattering computed tomography can be performed without phase stepping. Therefore, we believe this fast and highly stable imaging method with decent resolution would be widely applied in x-ray grating-based phase contrast imaging.     

Transillumination Laser Computed Tomography System with Fiber-Optic-Based Coherent Detection Imaging Method - High Spatial-Resolution and Quantitative Tomographic Imaging of Highly Scattering Objects -

We recently proposed and developed a novel transillumination laser computed tomography (CT) imaging system using a fiber-optic method based on coherent detection imaging (CDI) for biomedical use. Use of optical fibers enables portability and robustness against environmental changes in a room, such as variable temperature, air-flow shifts, and unexpected vibrations. In addition, motion-artifact-free images can be obtained because measurements can be performed with the object fixed. In the present paper, we experimentally investigate in detail the fundamental imaging properties of the system, which has a spatial resolution of 500 μm, a dynamic range of approximately 120 dB, and a minimum-detectable-optical power of 10⁻¹⁴W as a result of the excellent properties of the heterodyne detection. Based on experimental observations, the proposed system can reconstruct tomographic images of highly scattering objects in the transillumination mode, similar to X-ray CT, at sub-millimeter spatial resolution and with quantitativeness. Finally, we demonstrate with experiments using a physical phantom that the imaging system possesses high resolution and quantitative imaging abilities for highly scattering objects.     

Optimal design of gold nanoshells for optical imaging and photothermal therapy

Gold nanoshells are of great interest in optical imaging based on their light scattering properties and photothermal therapy due to their light absorption properties. Strong light scattering is essential for optical imaging, while effective photothermal therapy requires high light absorption. In this article, the optimal core radii and shell thicknesses of silica–gold and hollow gold nanoshells, possessing maximal light scattering and absorption at wavelengths between 700 and 1100 nm, are obtained using the Mie theory of a coated sphere. The results show that large-sized gold nanoshells of high aspect ratios (the aspect ratio is defined as the ratio of core radius to shell thickness) are the efficient contrast agents for optical imaging, while smaller gold nanoshells of high aspect ratios are the ideal therapeutic agents for photothermal therapy. From the comparison of the numerical results for silica–gold and hollow gold nanoshells, the latter are seen to offer a little superior light scattering and absorption at smaller particle size. Fitting expressions for the optimal core radii and shell thicknesses are also obtained, which can provide design guidelines for experimentalists to optimize the synthetic process of gold nanoshells.     

Gold nanoshell bioconjugates for molecular imaging in living cells

Advances in scattering-based optical imaging technologies offer a new approach to noninvasive point-of-care detection, diagnosis, and monitoring of cancer. Emerging photonics technologies provide a cost-effective means to image tissue in vivo with high resolution in real time. Advancing the clinical potential of these imaging strategies requires the development of optical contrast agents targeted to specific molecular signatures of disease. We describe the use of a novel class of contrast agents based on nanoshell bioconjugates for molecular imaging in living cells. Nanoshells offer significant advantages over conventional imaging probes including continuous and broad wavelength tunability, far greater scattering and absorption coefficients, increased chemical stability, and improved biocompatibility. We show that nanoshell bioconjugates can be used to effectively target and image human epidermal growth factor receptor 2 (HER2), a clinically relevant biomarker, in live human breast carcinoma cells.     

Polymeric contrast agent with targeting potential

The Arg-Gly-Asp (RGD) peptide sequence was conjugated to poly (lactid acid), (PLA), microcapsules. These hollow, biodegradable PLGA microcapsules were developed in our laboratory for use as ultrasound contrast agents. By modifying the surface of the agent with a targeting ligand, it can be targeted to a specific address within the body. This application is ideal for both targeted imaging and/or targeted drug delivery. Integrins are membrane-spanning proteins in cells that play a vital role in cell attachment and many other processes. The RGD peptide sequence targets integrins expressed during angiogenesis, alphavbeta3 and alphavbeta5. The integrins specific to angiogenesis are more active during cancer and can be used as receptors for the RGD-conjugated contrast agents. Although the generic RGD sequence is not specific to only alphavbeta3 and alphavbeta5 integrins, it is an excellent candidate for proof of concepts studies such as described here. Preliminary in vitro results indicate that the modified capsules remain highly echogenic (maximum enhancement of 20 dB in vitro) and adhere specifically to a breast cancer cell line MDA-MB-231 in static experiments. However, no adherence is seen with either unmodified capsules (negative control), or when cells that have been pre-saturated with RGD ligand are contacted with modified capsules (positive control). Specific targeting of ultrasound contrast agents could lead the way to imaging as a method for discrimination of malignant from benign.     

High-contrast mapping of basal cell carcinomas

Because of low optical contrast in the visible spectral range, accurate detection of basal cell carcinomas (BCC) remains a challenging problem. In this letter, we experimentally demonstrate that reflectance confocal imaging in the vicinity of 1300 nm can be used for the detection of BCC without exogenous contrast agents. We present high-contrast reflectance confocal images of thick fresh skin tissues with clearly delineated cancer and discuss possible reasons for causing decreased scattering of BCC. Comparison with histopathology confirms that tumors scatter less and exhibit lower pixel values in the images, as compared to benign skin structures. The results demonstrate the feasibility of real-time noninvasive detection of BCC using intrinsic differences in scattering between tumors and normal skin.     

Optical detection of indocyanine green encapsulated biocompatible poly (lactic-co-glycolic) acid nanoparticles with photothermal optical coherence tomography

We describe a functional imaging paradigm that uses photothermal optical coherence tomography (PT-OCT) to detect indocyanine green (ICG)-encapsulated biocompatible poly(lactic-co-glycolic) acid (PLGA) nanoparticles embedded in highly scattering tissue phantoms with high resolution and sensitivity. The ICG-loaded PLGA nanoparticles were fabricated using a modified emulsification solvent diffusion method. With a 20 kHz axial scan rate, PT-OCT based on spectral-domain interferometric configuration at 1310 nm was used to detect phase changes induced by a 808 nm photothermal excitation of ICG-encapsulated PLGA nanoparticles. An algorithm based on Fourier transform analysis of differential phase of the spectral interferogram was developed for detecting the depth resolved localized photothermal signal. Excellent contrast difference was observed with PT-OCT between phantoms containing different concentrations of ICG-encapsulated PLGA nanoparticles. This technique has the potential to provide simultaneous structural and molecular-targeted imaging with excellent signal-to-noise for various clinical applications.     

“Molecular” MR imaging at high fields

Magnetic resonance imaging (MRI) and spectroscopy (MRS) have contributed considerably to clinical radiology, and a variety of MR techniques have been developed to evaluate pathological processes as well as normal tissue biology at the cellular and molecular level. However, in comparison to nuclear imaging, MRI has relatively poor sensitivity for detecting true molecular changes or for detecting the presence of targeted contrast agents, though these remain under active development. In recent years very high field (7 T and above) MRI systems have been developed for human studies and these provide new opportunities and technical challenges for molecular imaging. We identify 5 types of intrinsic contrast mechanisms that do not require the use of exogenous agents but which can provide molecular and cellular information. We can derive information on tissue composition by (i) imaging different nuclei, especially sodium (ii) exploiting chemical shift differences as in MRS (iii) exploiting specific relaxation mechanisms (iv) exploiting tissue differences in the exchange rates of molecular species such as amides or hydroxyls and (v) differences in susceptibility. The increased signal strength at higher fields enables higher resolution images to be acquired, along with increased sensitivity to detecting subtle effects caused by molecular changes in tissues.     

Engineered microsphere contrast agents for optical coherence tomography

Contrast agents are utilized in virtually every imaging modality to enhance diagnostic capabilities. We introduce a novel class of optical contrast agent, namely, encapsulating microspheres, that are based not on fluorescence but on scattering nanoparticles within the shell or core. The agents are suitable for reflection- or scattering-based techniques such as optical coherence tomography, light microscopy, and reflectance confocal microscopy. We characterize the optical properties of gold-, melanin-, and carbon-shelled contrast agents and demonstrate enhancement of optical coherence tomography imaging after intravenous injection of such an agent into a mouse.