Boosting transducer matrix sensitivity for 3D large field ultrasound localization microscopy using a multi-lens diffracting layer: a simulation study

Mapping blood microflows of the whole brain is crucial for early diagnosis of cerebral diseases. Ultrasound localization microscopy (ULM) was recently applied to map and quantify blood microflows in 2D in the brain of adult patients down to the micron scale. Whole brain 3D clinical ULM remains challenging due to the transcranial energy loss which significantly reduces the imaging sensitivity. Large aperture probes with a large surface can increase both resolution and sensitivity. However, a large active surface implies thousands of acoustic elements, with limited clinical translation. In this study, we investigate via simulations a new high-sensitive 3D imaging approach based on large diverging elements, combined with an adapted beamforming with corrected delay laws, to increase sensitivity. First, pressure fields from single elements with different sizes and shapes were simulated. High directivity was measured for curved element while maintaining high transmit pressure. Matrix arrays of 256 elements with a dimension of 10x10 cm with small ( $\lambda$ /2), large (4 $\lambda$ ), and curved elements (4 $\lambda$ ) were compared through point spread functions analysis. A large synthetic microvessel phantom filled with 100 microbubbles per frame was imaged using the matrix arrays in a transcranial configuration. 93% of the bubbles were detected with the proposed approach demonstrating that the multi-lens diffracting layer has a strong potential to enable 3D ULM over a large field of view through the bones

Imagerie échographique ultrarapide du cœur et des artères chez l’homme : Vers l’imagerie ultrarapide 3D et l’imagerie du tenseur de rétrodiffusion ultrasonore

In this thesis, we investigated various aspects of ultrafast ultrasound imaging of the cardiovascular system. First, we quantified the arterial stiffness with shear wave imaging and its dependence with stress, anisotropy and blood pressure. Thanks to experiments on an ex vivo horse artery and on in vivo rat arteries we measured the dependence with arterial pressure and arterial stiffness and were able to propose a method that quantifies non-invasively, the non-linear elastic parameter of arteries. In a second part, we have developed non-invasive ultrafast imaging of the human heart with coherent compounding of diverging waves. With this tool, we were able to visualize natural waves and to image shear waves in vivo in the human heart with increased sensitivity. In a third part, we have developed an original method to map the tissue microstructure that relies on the anisotropy of the spatial coherence of backscattered ultrasound from plane wave coherent compounding. With this method, we have successfully detected fiber directions ex vivo in anisotropic soft tissues such as the heart. Finally, we developed 3D ultrafast ultrasound imaging in real time, using a 2D matrix array probe with 1024 elements and a customized, programmable, 1024 channel ultrasound system. We successfully measured in 3D flow in vivo in the heart and the carotid artery, the propagation of pulse wave and shear wave in vivo and ex vivo respectively. The study of spatial coherence of backscattered field with the 2D matrix array enabled the mapping of the fibers in biological anisotropic soft tissues in entire 3D volumes.Dans cette thèse, nous nous sommes intéressés aux applications cardiovasculaires de l’imagerie échographique ultrarapide.Nous avons d’abord étudié les propriétés élastiques des parois artérielles par imagerie ultrarapide et palpation à distance et proposé une méthode pour mesurer de manière non-invasive les paramètres non-linéaires des artères chez l’homme en cours d’évaluation clinique. Nous avons ensuite développé l’imagerie ultrarapide non-invasive du cœur humain grâce à la sommation cohérente d’ondes divergentes émises par un transducteur ultrasonore d’imagerie transthoracique. Nous avons pu visualiser les ondes naturelles du cœur et imager les ondes de cisaillement in vivo dans un cœur humain, dans le but de cartographier l’activité électrique et l’élasticité du cœur respectivement.Dans une troisième partie, nous avons développé une méthode originale qui repose sur le critère de Van-Cittert Zernike et l’étude de la cohérence spatiale du champ rétrodiffusé en sommation cohérente d’onde plane, qui a permis d’imager l’orientation des fibres dans les tissus biologiques anisotropes et notamment dans le cœur. Enfin nous avons développé l’imagerie ultrarapide en 3D temps réel, en utilisant une sonde matricielle de 1024 éléments et un prototype d’échographe ultrarapide. Il nous a été possible de visualiser, les flux doppler du cœur et de la carotide ainsi que la propagation de l’onde de pouls et de l’onde de cisaillement, en imagerie ultrarapide 3D. L’étude de la cohérence spatiale du champ rétrodiffusé avec la sonde matricielle a finalement permis de cartographier en 3D la direction des fibres dans les tissus biologiques anisotropes

Supersonic shear wave imaging to assess arterial anisotropy: ex-vivo testing of the horse aorta

Supersonic shear wave imaging (SSI) has recently emerged as a reliable technique for soft tissue characterization in bulk tissues (e. g. in the context of breast and liver cancer diagnostics). Another promising application of SSI is arterial stiffness assessment, though challenged by complex shear wave (SW) propagation phenomena in this thin-walled setting such as guided waves, dispersion, reflection and refraction on the arterial walls. Therefore, we investigated the sensitivity of SSI to (i) stretch-induced stiffening and (ii) the arterial fiber organization in a simpler ex-vivo arterial setup based on equine aortic tissue, where the SW propagation is deprived of dispersion and guided-wave effects. For this purpose, we conducted simultaneous dynamic mechanical testing of the tissue along with SSI measurements. The probe was rotated around its axis relative to the tissue to investigate whether SSI is able to determine the dominant collagen fiber direction in the tissue. The cyclic behavior of the SW velocities as a response to the dynamic mechanical testing demonstrated the ability of SSI to detect stretch-induced stiffening, though mainly in the circumferential direction. Furthermore, SW velocities were lower when the probe was positioned away from the circumferential direction of the tissue, which could be explained due to the uni-axial testing, the arterial anisotropy and the progressive recruitment of collagen fibers in the circumferential direction. The elasticity modulus assessed from the SSI measurements and the mechanical testing demonstrated the feasibility of SSI to detect the increase in E-modulus as expected from the measured stress-strain curve (factor 2.1 versus 2.3 increase for SSI and mechanical testing respectively). Future work will include performing histology on the investigated tissue to confirm these findings and clarify the link between SSI measurements and the actual fiber orientation

In vivo whole brain microvascular imaging in mice using transcranial 3D Ultrasound Localization Microscopy

Background Non-invasive high-resolution imaging of the cerebral vascular anatomy and function is key for the study of intracranial aneurysms, stenosis, arteriovenous malformations, and stroke, but also neurological pathologies, such as degenerative diseases. Direct visualization of the microvascular networks in the whole brain remains however challenging in vivo. Methods In this work, we performed 3D ultrafast ultrasound localization microscopy (ULM) using a 2D ultrasound matrix array and mapped the whole-brain microvasculature and flow at microscopic resolution in C57Bl6 mice in vivo. Findings We demonstrated that the mouse brain vasculature can be imaged directly through the intact skull at a spatial resolution of 20 µm and over the whole brain depth and at high temporal resolution (750 volumes.s À1). Individual microbubbles were tracked to estimate the flow velocities that ranged from 2 mm.s À1 in arterioles and venules up to 100 mm.s À1 in large vessels. The vascular maps were registered automatically with the Allen atlas in order to extract quantitative vascular parameters such as local flow rates and velocities in regions of interest. Interpretation We show the potential of 3D ULM to provide new insights into whole-brain vascular flow in mice models at unprecedented vascular scale for an in vivo technique. This technology is highly translational and has the potential to become a major tool for the clinical investigation of the cerebral microcirculation

Supersonic shear wave imaging to assess arterial nonlinear behavior and anisotropy: proof of principle via ex vivo testing of the horse aorta

Supersonic shear wave imaging (SSI) is a noninvasive, ultrasound-based technique to quantify the mechanical properties of bulk tissues by measuring the propagation speed of shear waves (SW) induced in the tissue with an ultrasound transducer. The technique has been successfully validated in liver and breast (tumor) diagnostics and is potentially useful for the assessment of the stiffness of arteries. However, SW propagation in arteries is subjected to different wave phenomena potentially affecting the measurement accuracy. Therefore, we assessed SSI in a less complex ex vivo setup, that is, a thick-walled and rectangular slab of an excised equine aorta. Dynamic uniaxial mechanical testing was performed during the SSI measurements, to dispose of a reference material assessment. An ultrasound probe was fixed in an angle position controller with respect to the tissue to investigate the effect of arterial anisotropy on SSI results. Results indicated that SSI was able to pick up stretch-induced stiffening of the aorta. SW velocities were significantly higher along the specimen’s circumferential direction than in the axial direction, consistent with the circumferential orientation of collagen fibers. Hence, we established a first step in studying SW propagation in anisotropic tissues to gain more insight into the feasibility of SSI-based measurements in arteries

Assessment of coronary microcirculation alterations in a porcine model of no-reflow using ultrasound localization microscopy: a proof of concept studyResearch in context

Summary: Background: Coronary microvascular obstruction also known as no-reflow phenomenon is a major issue during myocardial infarction that bears important prognostic implications. Alterations of the microvascular network remains however challenging to assess as there is no imaging modality in the clinics that can image directly the coronary microvascular vessels. Ultrasound Localization Microscopy (ULM) imaging was recently introduced to map microvascular flows at high spatial resolution (∼10 μm). In this study, we developed an approach to image alterations of the microvascular coronary flow in ex vivo perfused swine hearts. Methods: A porcine model of myocardial ischemia-reperfusion was used to obtain microvascular coronary alterations and no-reflow. Four female hearts with myocardial infarction in addition to 6 controls were explanted and placed immediately in a dedicated preservation and perfusion box manufactured for ultrasound imaging. Microbubbles (MB) were injected into the vasculature to perform Ultrasound Localization Microscopy (ULM) imaging and a linear ultrasound probe mounted on a motorized device was used to scan the heart on multiple slices. The coronary microvascular anatomy and flow velocity was reconstructed using dedicated ULM algorithms and analyzed quantitatively. Findings: We were able to image the coronary microcirculation of ex vivo swine hearts at a resolution of tens of microns and measure flow velocities ranging from 10 mm/s in arterioles up to more than 200 mm/s in epicardial arteries. Under different aortic perfusion pressures, we measured in large arteries of a subset of control hearts an increase of flow velocity from 31 ± 11 mm/s at 87 mmHg to 47 ± 17 mm/s at 132 mmHg (N = 3 hearts, P < 0.05). This increase was compared with a control measurement with a flowmeter in the aorta. We also compared 6 control hearts to 4 hearts in which no-reflow was induced by the occlusion and reperfusion of a coronary artery. Using average MB velocity and average density of MB per unit of surface as two ULM quantitative markers of perfusion, we were able to detect areas of coronary no-reflow in good agreement with a control anatomical pathology analysis of the cardiac tissue. In the no-reflow zone, we measured an average perfusion of 204 ± 305 MB/mm2 compared to 3182 ± 1302 MB/mm2 in the surrounding re-perfused area. Interpretation: We demonstrated this approach can directly image and quantify coronary microvascular obstruction and no-reflow on large mammal perfused hearts. This is a first step for noninvasive, quantitative and affordable assessment of the coronary microcirculation function and particularly coronary microvascular anatomy in the infarcted heart. This approach has the potential to be extended to other clinical situations characterized by microvascular dysfunction. Funding: This study was supported by the French National Research Agency (ANR) under ANR-21-CE19-0002 grant agreement

Coronary Flow Assessment Using 3-Dimensional Ultrafast Ultrasound Localization Microscopy

International audienceObjectivesThe purpose of this study was to demonstrate 3-dimensional (3D) coronary ultrasound localization microscopy (CorULM) of the whole heart beyond the acoustic diffraction limit (1000 images/s).BackgroundDirect assessment of the coronary microcirculation has long been hampered by the limited spatial and temporal resolutions of cardiac imaging modalities.MethodsCorULM was performed in isolated beating rat hearts (N = 6) with ultrasound contrast agents (Sonovue, Bracco), using an ultrasonic matrix transducer connected to a high channel–count ultrafast electronics. We assessed the 3D coronary microvascular anatomy, flow velocity, and flow rate of beating hearts under normal conditions, during vasodilator adenosine infusion, and during coronary occlusion. The coronary vasculature was compared with micro-computed tomography performed on the fixed heart. In vivo transthoracic CorULM was eventually assessed on anaesthetized rats (N = 3).ResultsCorULM enables the 3D visualization of the coronary vasculature in beating hearts at a scale down to microvascular structures (<20 μm resolution). Absolute flow velocity estimates range from 10 mm/s in tiny arterioles up to more than 300 mm/s in large arteries. Fitting to a power law, the flow rate–radius relationship provides an exponent of 2.61 (r2 = 0.96; P < 0.001), which is consistent with theoretical predictions and experimental validations of scaling laws in vascular trees. A 2-fold increase of the microvascular coronary flow rate is found in response to adenosine, which is in good agreement with the overall perfusion flow rate measured in the aorta (control measurement) that increased from 8.80 ± 1.03 mL/min to 16.54 ± 2.35 mL/min (P < 0.001). The feasibility of CorULM was demonstrated in vivo for N = 3 rats.ConclusionCorULM provides unprecedented insights into the anatomy and function of coronary arteries at the microvasculature level in beating hearts. This new technology is highly translational and has the potential to become a major tool for the clinical investigation of the coronary microcirculation