Motion Rejection and Spectral Unmixing for Accurate Estimation of In Vivo Oxygen Saturation Using Multispectral Optoacoustic Tomography.

Multispectral optoacoustic tomography (MSOT) uniquely enables spatial mapping in high resolution of oxygen saturation (SO2), with potential applications in studying pathological complications and therapy efficacy. MSOT offers seamless integration with ultrasonography, by using a common ultrasound (US) detector array. However, MSOT relies on multiple successive acquisitions of optoacoustic (OA) images at different optical wavelengths and the low frame rate of OA imaging makes the MSOT acquisition sensitive to body/respiratory motion. Moreover, the estimation of SO2 is highly sensitive to noise, and artifacts related to the respiratory motion of the animal were identified as the primary source of noise in MSOT. In this work, we propose a two-step image processing method for SO2 estimation in deep tissues. First, to mitigate motion artifacts, we propose a method of selection of OA images acquired only during the respiratory pause of the animal, using ultrafast ultrasound (US) images acquired immediately after each OA acquisition (US image acquisition duration of 1.4 ms and a total delay of 7 ms). We show that gating is more effective using US images than OA images at different optical wavelengths. Second, we propose a novel method that can estimate directly the SO2 value of a pixel and at the same time evaluate the amount of noise present in that pixel. Hence, the method can efficiently eliminate the pixels dominated by noise from the final SO2 map. Our postprocessing method is shown to outperform conventional methods for SO2 estimation, and the method was validated by in vivo oxygen challenge experiments.

Acute stress induces long-term metabolic, functional, and structural remodeling of the heart.

Takotsubo cardiomyopathy is a stress-induced cardiovascular disease with symptoms comparable to those of an acute coronary syndrome but without coronary obstruction. Takotsubo was initially considered spontaneously reversible, but epidemiological studies revealed significant long-term morbidity and mortality, the reason for which is unknown. Here, we show in a female rodent model that a single pharmacological challenge creates a stress-induced cardiomyopathy similar to Takotsubo. The acute response involves changes in blood and tissue biomarkers and in cardiac in vivo imaging acquired with ultrasound, magnetic resonance and positron emission tomography. Longitudinal follow up using in vivo imaging, histochemistry, protein and proteomics analyses evidences a continued metabolic reprogramming of the heart towards metabolic malfunction, eventually leading to irreversible damage in cardiac function and structure. The results combat the supposed reversibility of Takotsubo, point to dysregulation of glucose metabolic pathways as a main cause of long-term cardiac disease and support early therapeutic management of Takotsubo.

Machine Learning of Multi-Modal Tumor Imaging Reveals Trajectories of Response to Precision Treatment.

The standard assessment of response to cancer treatments is based on gross tumor characteristics, such as tumor size or glycolysis, which provide very indirect information about the effect of precision treatments on the pharmacological targets of tumors. Several advanced imaging modalities allow for the visualization of targeted tumor hallmarks. Descriptors extracted from these images can help establishing new classifications of precision treatment response. We propose a machine learning (ML) framework to analyze metabolic-anatomical-vascular imaging features from positron emission tomography, ultrafast Doppler, and computed tomography in a mouse model of paraganglioma undergoing anti-angiogenic treatment with sunitinib. Imaging features from the follow-up of sunitinib-treated (n = 8, imaged once-per-week/6-weeks) and sham-treated (n = 8, imaged once-per-week/3-weeks) mice groups were dimensionally reduced and analyzed with hierarchical clustering Analysis (HCA). The classes extracted from HCA were used with 10 ML classifiers to find a generalized tumor stage prediction model, which was validated with an independent dataset of sunitinib-treated mice. HCA provided three stages of treatment response that were validated using the best-performing ML classifier. The Gaussian naive Bayes classifier showed the best performance, with a training accuracy of 98.7 and an average area under curve of 100. Our results show that metabolic-anatomical-vascular markers allow defining treatment response trajectories that reflect the efficacy of an anti-angiogenic drug on the tumor target hallmark.

Dynamic contrast enhanced - MRI efficiency in detecting embolization-induced perfusion defects in a rabbit model of critical-limb-ischemia.

Critical limb ischemia (CLI) is a severe disease which affects about 2 million people in the US. Its prevalence is assessed at 800/100,000 population. However, no reliable tools are currently available to assess perfusion defects at the muscle tissue level. DCE-MRI is a technique that holds the potential to be effective in achieving this goal. However, preclinical studies performed with DCE-MRI have indicated low sensitivity assessing perfusion at resting state. To improve these previous results, in this work we propose new methodologies for data acquisition and analysis and we also revisit the biological model used for evaluation. Eleven rabbits underwent embolization of a lower limb. They were imaged at day 7 after embolization using DCE-MRI, performed on a 4.7 T small imaging device. Among them, n = 4 rabbits were used for MRI sequence optimization and n = 6 for data analysis after one exclusion. Normalized Areas under the curve (AUCn), and kinetic parameters such as Ktrans and Vd resulting from the Tofts-Kety modeling (KTM) were calculated on the embolized and contralateral limbs. Average and heterogeneity features, consisting on standard-deviation and quantiles, were calculated on muscle groups and whole limbs. The Wilcoxon and Fisher-tests were performed to compare embolized and contralateral regions of interests. The Wilcoxon test was also used to compare features of parametric maps. Quantiles of 5 and 95% in the contralateral side were used to define low and high outliers. A P-value <0.05 was considered statistically significant. Average features were inefficient to identify injured muscles, in agreement with the low sensitivity of the technique previously reported by the literature. However, these findings were dramatically improved by the use of additional heterogeneity features (97% of total accuracy for group muscles, P < 0.01 and 100% of total accuracy for the total limbs). The mapping analysis and automatic outlier detection quantification improvement was explained by the presence of local hyperemia that impair the average calculations. The analysis with KTM did not provide any additional information compared to AUCn. The DCE technique can be effective in detecting embolization-induced disorders of limb muscles in a CLI model when heterogeneity is taken into account in the data processing, even without vascular stimulation. The simultaneous presence of areas of ischemia and hyperemia appeared as a signature of the injured limbs. These areas seem to reflect the simultaneous presence of infarcted areas and viable peripheral areas, characterized by a vascular response that is visible in DCE.

Ultrafast Ultrasound Imaging for Super-Resolution Preclinical Cardiac PET.

PURPOSE: Physiological motion and partial volume effect (PVE) significantly degrade the quality of cardiac positron emission tomography (PET) images in the fast-beating hearts of rodents. Several Super-resolution (SR) techniques using a priori anatomical information have been proposed to correct motion and PVE in PET images. Ultrasound is ideally suited to capture real-time high-resolution cine images of rodent hearts. Here, we evaluated an ultrasound-based SR method using simultaneously acquired and co-registered PET-CT-Ultrafast Ultrasound Imaging (UUI) of the beating heart in closed-chest rodents. PROCEDURES: The method was tested with numerical and animal data (n = 2) acquired with the non-invasive hybrid imaging system PETRUS that acquires simultaneously PET, CT, and UUI. RESULTS: We showed that ultrasound-based SR drastically enhances the quality of PET images of the beating rodent heart. For the simulations, the deviations between expected and mean reconstructed values were 2 % after applying SR. For the experimental data, when using Ultrasound-based SR correction, contrast was improved by a factor of two, signal-to-noise ratio by 11 %, and spatial resolution by 56 % (~ 0.88 mm) with respect to static PET. As a consequence, the metabolic defect following an acute cardiac ischemia was delineated with much higher anatomical precision. CONCLUSIONS: Our results provided a proof-of-concept that image quality of cardiac PET in fast-beating rodent hearts can be significantly improved by ultrasound-based SR, a portable low-cost technique. Improved PET imaging of the rodent heart may allow new explorations of physiological and pathological situations related with cardiac metabolism.

Concurrent imaging of vascularization and metabolism in a mouse model of paraganglioma under anti-angiogenic treatment.

Rationale: Deregulation of metabolism and induction of vascularization are major hallmarks of cancer. Using a new multimodal preclinical imaging instrument, we explored a sequence of events leading to sunitinib-induced resistance in a murine model of paraganglioma (PGL) invalidated for the expression of succinate dehydrogenase subunit B (Sdhb-/-). Methods: Two groups of Sdhb-/- tumors bearing mice were treated with sunitinib (6 weeks) or vehicle (3 weeks). Concurrent Positron Emission Tomography (PET) with 2' -deoxy-2'-[18F]fluoro-D-glucose (FDG), Computed Tomography (CT) and Ultrafast Ultrasound Imaging (UUI) imaging sessions were performed once a week and ex vivo samples were analyzed by western blots and histology. Results: PET-CT-UUI enabled to detect a rapid growth of Sdhb-/- tumors with increased glycolysis and vascular development. Sunitinib treatment prevented tumor growth, vessel development and reduced FDG uptake at week 1 and 2 (W1-2). Thereafter, imaging revealed tumor escape from sunitinib treatment: FDG uptake in tumors increased at W3, followed by tumor growth and vessel development at W4-5. Perfused vessels were preferentially distributed in the hypermetabolic regions of the tumors and the perfused volume increased during escape from sunitinib treatment. Finally, initial changes in total lesion glycolysis and maximum vessel length at W1 were predictive of resistance to sunitinib. Conclusion: These results demonstrate an adaptive resistance of Sdhb-/- tumors to six weeks of sunitinib treatment. Early metabolic changes and delayed vessel architecture changes were detectable and predictable in vivo early during anti-angiogenic treatment. Simultaneous metabolic, anatomical and functional imaging can monitor precisely the effects of anti-angiogenic treatment of tumors.

Speed of sound ultrasound transmission tomography image reconstruction based on Bézier curves.

Speed of Sound (SoS) maps from ultrasound tomography (UST) provide valuable quantitative information for soft tissue characterization and identification of lesions, making this technique interesting for breast cancer detection. However, due to the complexity of the processes that characterize the interaction of ultrasonic waves with matter, classic and fast tomographic algorithms such as back-projection are not suitable. Consequently, the image reconstruction process in UST is generally slow compared to other more conventional medical tomography modalities. With the aim of facilitating the translation of this technique into real clinical practice, several reconstruction algorithms are being proposed to make image reconstruction in UST to be a fast and accurate process. The geometrical acoustic approximation is often used to reconstruct SoS with less computational burden in comparison with full-wave inversion methods. In this work, we propose a simple formulation to perform on-the-flight reconstruction for UST using geometrical acoustics with refraction correction based on quadratic Bézier polynomials. Here we demonstrate that the trajectories created with these polynomials are an accurate approximation to reproduce the refracted acoustic paths connecting the emitter and receiver transducers. The method is faster than typical acquisition times in UST. Thus, it can be considered a step towards real-time reconstructions, which may contribute to its future clinical translation.

Performance evaluation of the PET component of a hybrid PET/CT-ultrafast ultrasound imaging instrument.

We recently introduced a hybrid imaging instrument, PETRUS, based on a combination of positron emission tomography (PET) for molecular imaging, x-ray computed tomography (CT) for anatomical imaging, co-registration and attenuation correction, and ultrafast ultrasound imaging (UUI) for motion-correction, hemodynamic and biomechanical imaging. In order to ensure a precise co-registration of simultaneous PET-UUI acquisitions, ultrasound probes attached to an ultrafast ultrasound scanner are operated in the field of view (FOV) of a small animal PET/CT scanner using a remote-controlled micro-positioner. Here we explore the effect of the presence of ultrasound probes on PET image quality. We compare the performance of PET and image quality with and without the presence of probes in the PET field of view, both in vitro following the NEMA-NU-4-2008 standard protocol, and in vivo in small animals. Overall, deviations in the quality of images acquired with and without the ultrasound probes were under 10% and under 7% for the NEMA protocol and in vivo tests, respectively. Our results demonstrate the capability of the PETRUS device to acquire multimodal images in vivo without significant degradation of image quality.

Improving PET Quantification of Small Animal [68Ga]DOTA-Labeled PET/CT Studies by Using a CT-Based Positron Range Correction.

PURPOSE: Image quality of positron emission tomography (PET) tracers that emits high-energy positrons, such as Ga-68, Rb-82, or I-124, is significantly affected by positron range (PR) effects. PR effects are especially important in small animal PET studies, since they can limit spatial resolution and quantitative accuracy of the images. Since generators accessibility has made Ga-68 tracers wide available, the aim of this study is to show how the quantitative results of [68Ga]DOTA-labeled PET/X-ray computed tomography (CT) imaging of neuroendocrine tumors in mice can be improved using positron range correction (PRC). PROCEDURES: Eighteen scans in 12 mice were evaluated, with three different models of tumors: PC12, AR42J, and meningiomas. In addition, three different [68Ga]DOTA-labeled radiotracers were used to evaluate the PRC with different tracer distributions: [68Ga]DOTANOC, [68Ga]DOTATOC, and [68Ga]DOTATATE. Two PRC methods were evaluated: a tissue-dependent (TD-PRC) and a tissue-dependent spatially-variant correction (TDSV-PRC). Taking a region in the liver as reference, the tissue-to-liver ratio values for tumor tissue (TLRtumor), lung (TLRlung), and necrotic areas within the tumors (TLRnecrotic) and their respective relative variations (ΔTLR) were evaluated. RESULTS: All TLR values in the PRC images were significantly different (p < 0.05) than the ones from non-PRC images. The relative differences of the tumor TLR values, respect to the case with no PRC, were ΔTLRtumor 87 ± 41 % (TD-PRC) and 85 ± 46 % (TDSV-PRC). TLRlung decreased when applying PRC, being this effect more remarkable for the TDSV-PRC method, with relative differences respect to no PRC: ΔTLRlung = - 45 ± 24 (TD-PRC), - 55 ± 18 (TDSV-PRC). TLRnecrotic values also decreased when using PRC, with more noticeable differences for TD-PRC: ΔTLRnecrotic = - 52 ± 6 (TD-PRC), - 48 ± 8 (TDSV-PRC). CONCLUSION: The PRC methods proposed provide a significant quantitative improvement in [68Ga]DOTA-labeled PET/CT imaging of mice with neuroendocrine tumors, hence demonstrating that these techniques could also ameliorate the deleterious effect of the positron range in clinical PET imaging.

Simultaneous positron emission tomography and ultrafast ultrasound for hybrid molecular, anatomical and functional imaging.

Positron emission tomography-computed tomography (PET-CT) is the most sensitive molecular imaging modality, but it does not easily allow for rapid temporal acquisition. Ultrafast ultrasound imaging (UUI)-a recently introduced technology based on ultrasonic holography-leverages frame rates of up to several thousand images per second to quantitatively map, at high resolution, haemodynamic, biomechanical, electrophysiological and structural parameters. Here, we describe a pre-clinical scanner that registers PET-CT and UUI volumes acquired simultaneously and offers multiple combinations for imaging. We demonstrate that PET-CT-UUI allows for simultaneous images of the vasculature and metabolism during tumour growth in mice and rats, as well as for synchronized multi-modal cardiac cine-loops. Combined anatomical, functional and molecular imaging with PET-CT-UUI represents a high-performance and clinically translatable technology for biomedical research.

Tissue-Dependent and Spatially-Variant Positron Range Correction in 3D PET.

Positron range (PR) is a significant factor that limits PET image resolution, especially with some radionuclides currently used in clinical and preclinical studies such as (82)Rb, (124)I and (68)Ga. The use of an accurate model of the PR in the image reconstruction may minimize its impact on the image quality. Nevertheless, PR distributions are difficult to model, as they may be different at each voxel and direction, depending on the materials that the positron flies through. Several approximated methods have been proposed, considering only one or several propagating media without taking into account boundaries effects. In some regions, like lungs or trachea, these methods may not be accurate enough and yield artifacts. In this work, we present an efficient method to accurately incorporate spatially-variant PR corrections. The method is based on pre-computing voxel-dependent PR kernels using a CT or a manually segmented image, and a model of the dependence of the PR on each material derived from Monte Carlo simulations. The images are convoluted with these kernels in the forward-projection step of the iterative reconstruction algorithm. This implementation of the algorithm adds a modest overhead to the overall reconstruction time and it obtains artifact-free PR-corrected images, even when the activity is concentrated at tissue boundaries with extreme changes of density. We verified the method with the preclinical Argus PET/CT scanner, but it can be also applied to other scanners and improve the image quality in clinical PET studies using isotopes with large PR.

Measurement of the photoeffect cross section and the K-absorption edge energy of Dy, Ta, Pt and Au atoms using Bremsstrahlung / Medición de la sección eficaz de fotoefecto y de la energía del borde de absorción K de los átomos Dy, Ta, Pt y Au utilizando radiación de frenado

An experimental setup to determine the K-shell photoelectric cross-section of Dy, Ta, Pt and Au atoms was implemented at the Nuclear Analytical Laboratory (LAN) of the InSTEC. Bremsstrahlung photons, produced by - beta particles hitting a thin Ni converter, were used to irradiate the target under study. A HPGe detector, coupled to standard nuclear instrumentation, collected the incident and transmitted spectra. A sharp decrease in intensity at the K-shell binding energy was observed in the transmitted spectra. The photon beam divergence effects were corrected with a calibration curve calculated with Monte Carlo simulations (MCNPX 2.6). In order to establish accurately the cross section at the K-edge energy, the obtained data was processed by two methods: fitting the total cross section to a sigmoidal function, as well as the cross section branches around the K-edge to the empirical law . The Empirical Law method was introduced in this work to minimize the detector resolution effects. The results were compared with experimental and theoretical values showing the best agreement when the thinner targets were used. For the first time the photoeffect cross section at the K-edge energy for Pt is reported at first time.

Se determina la sección eficaz fotoeléctrica de la capa K de los átomos Dy, Ta, Pt y Au en un arreglo experimental desarrollado en el Laboratorio Analítico Nuclear del InSTEC. Los blancos bajo estudio se irradiaron con fotones de frenado producidos en un radiador de Ni por las partículas beta emitidas por una fuente de -. Los espectros incidentes y de transmisión se colectaron en un detector de germanio hiperpuro, acoplado a su instrumentación nuclear estándar. En los espectros de transmisión se observó un decrecimiento agudo de la intensidad correspondiente a la energía del borde K. Los efectos de interacciones múltiples del haz fotónico en las láminas blanco se corrigieron a través de una curva de calibración calculada mediante simulaciones Monte Carlo (MCNPX 2.6). Con vistas a garantizar la mejor precisión en la determinación de la sección eficaz para la energía del borde K, los datos obtenidos se ajustaron según dos comportamientos funcionales en esta región: una sigmoide y una ley empírica del tipo . Este último método se introdujo en el trabajo y permite minimizar los efectos resolutivos. Los resultados obtenidos se compararon con valores teóricos y experimentales, mostrando mayor concordancia cuando se emplean blancos finos. Se reporta, por primera vez, la sección eficaz de fotoefecto en el borde K del platino (Pt).