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

Acoustic biomolecules enhance hemodynamic functional ultrasound imaging of neural activity

Hemodynamic functional ultrasound imaging (fUS) of neural activity provides a unique combination of spatial coverage, spatiotemporal resolution and compatibility with freely moving animals. However, deep and transcranial monitoring of brain activity and the imaging of dynamics in slow-flowing blood vessels remains challenging. To enhance fUS capabilities, we introduce biomolecular hemodynamic enhancers based on gas vesicles (GVs), genetically encodable ultrasound contrast agents derived from buoyant photosynthetic microorganisms. We show that intravenously infused GVs enhance ultrafast Doppler ultrasound contrast and visually-evoked hemodynamic contrast in transcranial fUS of the mouse brain. This hemodynamic contrast enhancement is smoother than that provided by conventional microbubbles, allowing GVs to more reliably amplify neuroimaging signals

Towards ultrasound full-waveform inversion in medical imaging

Ultrasound imaging is a front-line clinical modality with a wide range of applications. However, there are limitations to conventional methods for some medical imaging problems, including the imaging of the intact brain. The goal of this thesis is to explore and build on recent technological advances in ultrasonics and related areas such as geophysics, including the ultrasound data parallel acquisition hardware, advanced computational techniques for field modelling and for inverse problem solving. With the significant increase in the computational power now available, a particular focus will be put on exploring the potential of full-waveform inversion (FWI), a high-resolution image reconstruction technique which has shown significant success in seismic exploration, for medical imaging applications. In this thesis a range of technologies and systems have been developed in order to improve ultrasound imaging by taking advantage of these recent advances. In the first part of this thesis the application of dual frequency ultrasound for contrast enhanced imaging of neurovasculature in the mouse brain is investigated. Here we demonstrated a significant improvement in the contrast-to-tissue ratio that could be achieved by using a multi-probe, dual frequency imaging system when compared to a conventional approach using a single high frequency probe. However, without a sufficiently accurate calibration method to determine the positioning of these probes the image resolution was found to be significantly reduced. To mitigate the impact of these positioning errors, a second study was carried out to develop a sophisticated dual probe ultrasound tomography acquisition system with a robust methodology for the calibration of transducer positions. This led to a greater focus on the development of ultrasound tomography applications in medical imaging using FWI. A 2.5D brain phantom was designed that consisted of a soft tissue brain model surrounded by a hard skull mimicking material to simulate a transcranial imaging problem. This was used to demonstrate for the first time, as far as we are aware, the experimental feasibility of imaging the brain through skull using FWI. Furthermore, to address the lack of broadband sensors available for medical FWI reconstruction applications, a deep learning neural network was proposed for the bandwidth extension of observed narrowband data. A demonstration of this proposed technique was then carried out by improving the FWI image reconstruction of experimentally acquired breast phantom imaging data. Finally, the FWI imaging method was expanded for3D neuroimaging applications and an in silico feasibility of reconstructing the mouse brain with commercial transducers is demonstrated.Open Acces

Intensity distribution segmentation in ultrafast Doppler combined with scanning laser confocal microscopy for assessing vascular changes associated with ageing in murine hippocampi

Acknowledgements This work was mainly funded by the Agencia Nacional de Investigación e Innovación (ANII), grant FCE_1_2019_1_155539. Te authors also thank the support of PEDECIBA, CSIC-UdelaR and the Institut Franco—Uruguayen de Physique (IFUP), LIA-CNRS-UdelaR. J.P.D., C.N., N.R., A.K. and J.Br. thank SNI-ANII. M.A.F. thanks the support of ANII through POS_NAC_M_2020_1_164127 scholarship. M.M. thanks the support of ANII through POS_FCE_2020_1_1009181 scholarship. N.R. thanks the support of CSIC I+D group grant CSIC2018—FID 13—Grupo ID 722.Peer reviewedPublisher PD

Piezoelectric Photoacoustic System for Fluid Flow Monitoring

The aim of this study is to investigate the feasibility of using a laboratory assembled piezoelectric based photoacoustic (PA) system for noncontact monitoring fluid flow. This is to overcome the drawbacks of some existing fluid flow detection systems, which include expensive equipment and their maintenance cost, limited sensitivity and specificity in detecting signals from restricted regions or at low flow velocity. The produced PA signal waves detected by a piezoelectric transducer used in this study was processed to determine the required phase value (Ф), which value was found to correlate linearly with fluid flow status. The fluid pressure difference of 1.16 pascals (Pa) and 11.90 Pa applied to the developed mock circulatory system was observed to produce changes in phase value with mean ± standard deviation (SD) ΔФ of 0.79 ± 0.07 rad and 2.17 ± 0.07 rad, respectively, suggesting a linear response of the developed system with changes in circulation system. This trend was supported with the relatively low absolute difference of 0.07 ± 0.01 rad in the predicted values as compared to that of the ground truth. This work concluded that the capabilities and simplicity of the proposed PA system renders it feasible for cost effective, non-destructive assessment of fluid flow in future studies

Functional Ultrasound (fUS) During Awake Brain Surgery: The Clinical Potential of Intra-Operative Functional and Vascular Brain Mapping

Background and Purpose: Oncological neurosurgery relies heavily on making continuous, intra-operative tumor-brain delineations based on image-guidance. Limitations of currently available imaging techniques call for the development of real-time image-guided resection tools, which allow for reliable functional and anatomical information in an intra-operative setting. Functional ultrasound (fUS), is a new mobile neuro-imaging tool with unprecedented spatiotemporal resolution, which allows for the detection of small changes in blood dynamics that reflect changes in metabolic activity of activated neurons through neurovascular coupling. We have applied fUS during conventional awake brain surgery to determine its clinical potential for both intra-operative functional and vascular brain mapping, with the ultimate aim of achieving maximum safe tumor resection. Methods: During awake brain surgery, fUS was used to image tumor vasculature and task-evoked brain activation with electrocortical stimulation mapping (ESM) as a gold standard. For functional imaging, patients were presented with motor, language or visual tasks, while the probe was placed over (ESM-defined) functional brain areas. For tumor vascular imaging, tumor tissue (pre-resection) and tumor resection cavity (post-resection) were imaged by moving the hand-held probe along a continuous trajectory over the regions of interest. Results: A total of 10 patients were included, with predominantly intra-parenchymal frontal and temporal lobe tumors of both low and higher histopathological grades. fUS was able to detect (ESM-defined) functional areas deep inside the brain for a range of functional tasks including language processing. Brain tissue could be imaged at a spatial and temporal resolution of 300 μm and 1.5–2.0 ms respectively, revealing real-time tumor-specific, and healthy vascular characteristics. Conclusion: The current study presents the potential of applying fUS during awake brain surgery. We i