In vivoadaptive focusing for clinical contrast-enhanced transcranial ultrasound imaging in human.

Objective. Imaging the human brain vasculature with high spatial and temporal resolution remains challenging in the clinic today. Transcranial ultrasound is still scarcely used for cerebrovascular imaging, due to low sensitivity and strong phase aberrations induced by the skull bone that only enable the proximal part major brain vessel imaging, even with ultrasound contrast agent injection (microbubbles).Approach. 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 human adults through temporal and occipital bone windows. For each subject, 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.Main results. This aberration correction method reduced the number of artefacts, such as ghost vessels, in the images. It improved image quality both for ultrafast Doppler imaging and ultrasound localization microscopy (ULM), especially in patients with thick bone windows. For ultrafast Doppler images, the contrast was increased by 4 dB on average, and for ULM, the number of detected microbubble tracks was increased by 38%.Significance. This technique is thus promising for better diagnosis and follow-up of brain pathologies such as aneurysms, arterial stenoses, arterial occlusions, microvascular disease and stroke and could make transcranial ultrasound imaging possible even in particularly difficult-to-image human adults.

Performance benchmarking of microbubble-localization algorithms for ultrasound localization microscopy.

Ultrafast ultrasound localization microscopy can be used to detect the subwavelength acoustic scattering of intravenously injected microbubbles to obtain haemodynamic maps of the vasculature of animals and humans. The quality of the haemodynamic maps depends on signal-to-noise ratios and on the algorithms used for the localization of the microbubbles and the rendering of their trajectories. Here we report the results of benchmarking of the performance of seven microbubble-localization algorithms. We used metrics for localization errors, localization success rates, processing times and a measure of the reprojection of the localization of the microbubbles on the original beamformed grid. We combined eleven metrics into an overall score and tested the algorithms in three simulated microcirculation datasets, and in angiography datasets of the brain of a live rat after craniotomy, an excised rat kidney and a mammary tumour in a live mouse. The algorithms, metrics and datasets, which we have made openly available at https://github.com/AChavignon/PALA and https://doi.org/10.5281/zenodo.4343435 , will facilitate the identification or generation of optimal microbubble-localization algorithms for specific applications.

3D Transcranial Ultrasound Localization Microscopy in the Rat Brain With a Multiplexed Matrix Probe.

OBJECTIVE: Ultrasound Localization Microscopy (ULM) provides images of the microcirculation in-depth in living tissue. However, its implementation in two-dimension is limited by the elevation projection and tedious plane-by-plane acquisition. Volumetric ULM alleviates these issues and can map the vasculature of entire organs in one acquisition with isotropic resolution. However, its optimal implementation requires many independent acquisition channels, leading to complex custom hardware. METHODS: In this article, we implemented volumetric ultrasound imaging with a multiplexed 32 × 32 probe driven by a single commercial ultrasound scanner. We propose and compare three different sub-aperture multiplexing combinations for localization microscopy in silico and in vitro with a flow of microbubbles in a canal. Finally, we evaluate the approach for micro-angiography of the rat brain. The "light" combination allows a higher maximal volume rate than the "full" combination while maintaining the field of view and resolution. RESULTS: In the rat brain, 100,000 volumes were acquired within 7 min with a dedicated ultrasound sequence and revealed vessels down to 31 µm in diameter with flows from 4.3 mm/s to 28.4 mm/s. CONCLUSION: This work demonstrates the ability to perform a complete angiography with unprecedented resolution in the living rat's brain with a simple and light setup through the intact skull. SIGNIFICANCE: We foresee that it might contribute to democratize 3D ULM for both preclinical and clinical studies.

Transcranial ultrafast ultrasound localization microscopy of brain vasculature in patients.

Changes in cerebral blood flow are associated with stroke, aneurysms, vascular cognitive impairment, neurodegenerative diseases and other pathologies. Brain angiograms, typically performed via computed tomography or magnetic resonance imaging, are limited to millimetre-scale resolution and are insensitive to blood-flow dynamics. Here we show that ultrafast ultrasound localization microscopy of intravenously injected microbubbles enables transcranial imaging of deep vasculature in the adult human brain at microscopic resolution and the quantification of haemodynamic parameters. Adaptive speckle tracking to correct for micrometric brain-motion artefacts and ultrasonic-wave aberrations induced during transcranial propagation allowed us to map the vascular network of tangled arteries to functionally characterize blood-flow dynamics at a resolution of up to 25 µm and to detect blood vortices in a small deep-seated aneurysm in a patient. Ultrafast ultrasound localization microscopy may facilitate the understanding of brain haemodynamics and of how vascular abnormalities in the brain are related to neurological pathologies.

The Advent of Biomolecular Ultrasound Imaging.

Ultrasound imaging is one of the most widely used modalities in clinical practice, revealing human prenatal development but also arterial function in the adult brain. Ultrasound waves travel deep within soft biological tissues and provide information about the motion and mechanical properties of internal organs. A drawback of ultrasound imaging is its limited ability to detect molecular targets due to a lack of cell-type specific acoustic contrast. To date, this limitation has been addressed by targeting synthetic ultrasound contrast agents to molecular targets. This molecular ultrasound imaging approach has proved to be successful but is restricted to the vascular space. Here, we introduce the nascent field of biomolecular ultrasound imaging, a molecular imaging approach that relies on genetically encoded acoustic biomolecules to interface ultrasound waves with cellular processes. We review ultrasound imaging applications bridging wave physics and chemical engineering with potential for deep brain imaging.

Early Ultrafast Ultrasound Imaging of Cerebral Perfusion correlates with Ischemic Stroke outcomes and responses to treatment in Mice.

In the field of ischemic cerebral injury, precise characterization of neurovascular hemodynamic is required to select candidates for reperfusion treatments. It is thus admitted that advanced imaging-based approaches would be able to better diagnose and prognose those patients and would contribute to better clinical care. Current imaging modalities like MRI allow a precise diagnostic of cerebral injury but suffer from limited availability and transportability. The recently developed ultrafast ultrasound could be a powerful tool to perform emergency imaging and long term follow-up of cerebral perfusion, which could, in combination with MRI, improve imaging solutions for neuroradiologists. Methods: In this study, in a model of in situ thromboembolic stroke in mice, we compared a control group of non-treated mice (N=10) with a group receiving the gold standard pharmacological stroke therapy (N=9). We combined the established tool of magnetic resonance imaging (7T MRI) with two innovative ultrafast ultrasound methods, ultrafast Doppler and Ultrasound Localization Microscopy, to image the cerebral blood volumes at early and late times after stroke onset and compare with the formation of ischemic lesions.Results: Our study shows that ultrafast ultrasound can be used through the mouse skull to monitor cerebral perfusion during ischemic stroke. In our data, the monitoring of the reperfusion following thrombolytic within the first 2 h post stroke onset matches ischemic lesions measured 24 h. Moreover, similar results can be made with Ultrasound Localization Microscopy which could make it applicable to human patients in the future. Conclusion: We thus provide the proof of concept that in a mouse model of thromboembolic stroke with an intact skull, early ultrafast ultrasound can be indicative of responses to treatment and cerebral tissue fates following stroke. It brings new tools to study ischemic stroke in preclinical models and is the first step prior translation to the clinical settings.

Ultrafast 3D Ultrasound Localization Microscopy Using a 32 × 32 Matrix Array.

Ultrasound localization microscopy can map blood vessels with a resolution much smaller than the wavelength by localizing microbubbles. The current implementations of the technique are limited to 2-D planes or small fields of view in 3-D. These suffer from minute-long acquisitions, out-of-plane microbubbles, and tissue motion. In this paper, we exploit the recent development of 4D ultrafast ultrasound imaging to insonify an isotropic volume up to 20 000 times per second and perform localization microscopy in the three dimensions. Specifically, a 32 ×32 elements, 9-MHz matrix-array probe connected to a 1024-channel programmable ultrasound scanner was used to achieve sub-wavelength volumetric imaging of both the structure and vector flow of a complex 3D structure (a main canal branching out into two side canals). To cope with the large volumes and the need to localize the bubbles in the three dimensions, novel algorithms were developed based on deconvolution of the beamformed microbubble signal. For tracking, individual particles were paired following a Munkres assignment method, and velocimetry was done following a Lagrangian approach. ULM was able to clearly represent the 3-D shape of the structure with a sharp delineation of canal edges (as small as [Formula: see text]) and separate them with a spacing as low as [Formula: see text]. The compounded volume rate of 500 Hz was sufficient to describe velocities in 2.5-150-mm/s range and to reduce the maximum acquisition time to 12 s. This paper demonstrates the feasibility of in vitro 3-D ultrafast ultrasound localization microscopy and opens up the way toward in vivo volumetric ULM.

Microvascular flow dictates the compromise between spatial resolution and acquisition time in Ultrasound Localization Microscopy.

Medical ultrasound is a widely used diagnostic imaging technique for tissues and blood vessels. However, its spatial resolution is limited to a sub-millimeter scale. Ultrasound Localization Microscopy was recently introduced to overcome this limit and relies on subwavelength localization and tracking of microbubbles injected in the blood circulation. Yet, as microbubbles follow blood flow, long acquisition time are required to detect them in the smallest vessels, leading to long reconstruction of the microvasculature. The objective of this work is to understand how blood flow limits acquisition time. We studied the reconstruction of a coronal slice of a rat's brain during a continuous microbubble injection close to clinical concentrations. After acquiring 192000 frames over 4 minutes, we find that the biggest vessels can be reconstructed in seconds but that it would take tens of minutes to map the entire capillary network. Moreover, the appropriate characterization of flow profiles based on microbubble velocity within vessels is bound by even more stringent temporal limitations. As we use simple blood flow models to characterize its impact on reconstruction time, we foresee that these results and methods can be adapted to determine adequate microbubble injections and acquisition times in clinical and preclinical practice.

Ultrasound Localization Microscopy and Super-Resolution: A State of the Art.

Because it drives the compromise between resolution and penetration, the diffraction limit has long represented an unreachable summit to conquer in ultrasound imaging. Within a few years after the introduction of optical localization microscopy, we proposed its acoustic alter ego that exploits the micrometric localization of microbubble contrast agents to reconstruct the finest vessels in the body in-depth. Various groups now working on the subject are optimizing the localization precision, microbubble separation, acquisition time, tracking, and velocimetry to improve the capacity of ultrasound localization microscopy (ULM) to detect and distinguish vessels much smaller than the wavelength. It has since been used in vivo in the brain, the kidney, and tumors. In the clinic, ULM is bound to improve drastically our vision of the microvasculature, which could revolutionize the diagnosis of cancer, arteriosclerosis, stroke, and diabetes.