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The assessment of myocardial fiber disarray is of major interest for the study of the progression of myocardial disease. However, time-resolved imaging of the myocardial structure remains unavailable in clinical practice. In this study, we introduce 3D Backscatter Tensor Imaging (3D-BTI), an entirely novel ultrasound-based imaging technique that can map the myocardial fibers orientation and its dynamics with a temporal resolution of 10 ms during a single cardiac cycle, non-invasively and in vivo in entire volumes. 3D-BTI is based on ultrafast volumetric ultrasound acquisitions, which are used to quantify the spatial coherence of backscattered echoes at each point of the volume. The capability of 3D-BTI to map the fibers orientation was evaluated in vitro in 5 myocardial samples. The helicoidal transmural variation of fiber angles was in good agreement with the one obtained by histological analysis. 3D-BTI was then performed to map the fiber orientation dynamics in vivo in the beating heart of an open-chest sheep at a volume rate of 90 volumes/s. Finally, the clinical feasibility of 3D-BTI was shown on a healthy volunteer. These initial results indicate that 3D-BTI could become a fully non-invasive technique to assess myocardial disarray at the bedside of patients.

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.

Imaging the brain vasculature can be critical for cerebral perfusion monitoring in the context of neurocritical care. Although ultrasensitive Doppler (UD) can provide good sensitivity to cerebral blood volume (CBV) in a large field of view, it remains difficult to perform through the skull. In this work, we investigate how a minimally invasive burr hole, performed for intracranial pressure (ICP) monitoring, could be used to map the entire brain vascular tree. We explored the use of a small motorized phased array probe with a non-implantable preclinical prototype in pigs. The scan duration (18 min) and coverage (62 $\pm$ 12 % of the brain) obtained allowed global CBV variations detection (relative in brain Dopplerdecrease =-3[-4-+16]% \& Dopplerincrease. = +1[-3-+15]%, n = 6 \& 5) and stroke detection (relative in core Dopplerstroke. =-25%, n = 1). This technology could one day be miniaturized to be implanted for brain perfusion monitoring in neurocritical care.

Imaging the human brain vasculature with high spatial and temporal resolution remains challenging in the clinic today. Transcranial ultrasound is scarcely used for cerebrovascular imaging, due to low sensitivity and strong phase aberrations induced by the skull bone that only enable major brain vessel imaging, even with ultrasound contrast agent injection (microbubbles). Here, we propose an adaptive aberration correction technique for skull bone aberrations based on the backscattered signals coming from intravenously injected microbubbles. Our aberration correction technique was implemented to image brain vasculature in adult humans through temporal and occipital bone windows. For each patient, an effective speed of sound, as well as a phase aberration profile, were determined in several isoplanatic patches spread across the image. This information was then used in the beamforming process. It improved image quality both for ultrafast Doppler imaging and Ultrasound Localization Microscopy (ULM), especially in cases of thick bone windows. For ultrafast Doppler images, the contrast was increased by 4dB on average, and for ULM, the number of detected microbubble tracks was increased by 38%. This technique is thus promising for better diagnosis and follow-up of brain pathologies such as aneurysms or stroke and could make transcranial ultrasound imaging possible even in particularly difficult-to-image patients.

Angiogenesis, the formation of new vessels, is one of the key mechanisms in tumor development and an appealing target for therapy. Non-invasive, high-resolution, high sensitivity, quantitative 3D imaging techniques are required to correctly depict tumor heterogeneous vasculature over time. Ultrafast Doppler was recently introduced and provides an unprecedented combination of resolution, penetration depth and sensitivity without requiring any contrast agents. The technique was further extended to 3D with Ultrafast Doppler Tomography (UFD-T). In this work, UFD-T was applied to the monitoring of tumor angiogenesis in vivo providing structural and functional information at different stages of development. UFD-T volume renderings showed that our murine model's vasculature stems from pre-existing vessels and sprouts to perfuse the whole volume as the tumor grows until a critical size is reached. Then, as the network becomes insufficient, the tumor core is no longer irrigated because the vasculature is mainly concentrated in the periphery. In addition to spatial distribution and growth patterns, UFD-T allowed a quantitative analysis of vessel size and length, revealing that the diameter-distribution of vessels remained relatively constant throughout tumor growth. The network is dominated by small vessels at all stages of tumor development with more than 74% of the vessels less than 200 $\mu$m in diameter. This study also showed that cumulative vessel length is more closely related to tumor radius than volume, indicating that the vascularization becomes insufficient when a critical mass is reached. UFD-T was also compared with dynamic contrast-enhanced ultrasound (DCE-US) and shown to provide complementary information regarding the link between structure and perfusion. In conclusion, UFD-T is capable of an in vivo quantitative assessment of the development of tumor vasculature (vessels with blood speed >1mm/s (sensitivity limit) assessed with a resolution limit of 80 $\mu$m) in 3D. The technique has very interesting potential as a tool for treatment monitoring, response assessment and treatment planning for optimal drug efficiency.

A shift of paradigm is currently underway in biomedical ultrasound thanks to plane and diverging waves for ultrafast imaging. One remaining challenge consists in the correction of phase and amplitude aberrations induced during propagation through complex layers. Unlike conventional line-per-line imaging, ultrafast ultrasound provides for each transmission, backscattering information from the whole imaged area. Here, we take benefit from this feature and propose an efficient approach to perform fast aberration correction based on the Singular Value Decomposition of an ultrafast compound matrix built from backscattered data for several plane wave transmissions. First, we explain the physical signification of SVD and associated singular vectors within the ultrafast matrix formalism. We theoretically demonstrate that the spatial and angular variables separation, rendered by SVD on ultrafast data, provides an elegant and straightforward way to optimize angular coherence of backscattered data. In heterogeneous media with an aberrating phase screen approximation, we demonstrate that the first spatial and angular singular vectors retrieve on one side the non-aberrated image, and on the other, the phase and amplitude of the aberration law. In vitro results prove the efficiency of the image correction, but also the accuracy of the aberrator determination. Based on spatial and angular coherence, we introduce a complete methodology for adaptive beamforming of ultrafast data, performed on successive isoplanatism patches undergoing SVD beamforming. The simplicity of this method paves the way to real-time adaptive ultrafast ultrasound imaging and provides a theoretical framework for future quantitative ultrasound applications.

We present a new approach for spatiotemporal focusing through complex scattering media by wave front shaping. Using a nonlinear feedback signal to shape the incident pulsed wave front, we show that the limit of a spatiotemporal matched filter can be achieved, i.e., the wave amplitude at the intended time and focus position is maximized for a given input energy. It is exactly what is also achieved with time-reversal. Demonstrated with ultrasound experiments, our method is generally applicable to all types of waves.