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. 2023 Jul 16;13(1):11477.
doi: 10.1038/s41598-023-38531-w.

Backscattering amplitude in ultrasound localization microscopy

Noemi Renaudin  1 , Sophie Pezet  1 , Nathalie Ialy-Radio  1 , Charlie Demene  1 , Mickael Tanter  2
Affiliations

Backscattering amplitude in ultrasound localization microscopy

Noemi Renaudin et al. Sci Rep. .

Abstract

In the last decade, Ultrafast ultrasound localisation microscopy has taken non-invasive deep vascular imaging down to the microscopic level. By imaging diluted suspensions of circulating microbubbles in the blood stream at kHz frame rate and localizing the center of their individual point spread function with a sub-resolution precision, it enabled to break the unvanquished trade-off between depth of imaging and resolution by microscopically mapping the microbubbles flux and velocities deep into tissue. However, ULM also suffers limitations. Many small vessels are not visible in the ULM images due to the noise level in areas dimly explored by the microbubbles. Moreover, as the vast majority of studies are performed using 2D imaging, quantification is limited to in-plane velocity or flux measurements which hinders the accurate velocity determination and quantification. Here we show that the backscattering amplitude of each individual microbubble can also be exploited to produce backscattering images of the vascularization with a higher sensitivity compared to conventional ULM images. By providing valuable information about the relative distance of the microbubble to the 2D imaging plane in the out-of-plane direction, backscattering ULM images introduces a physically relevant 3D rendering perception in the vascular maps. It also retrieves the missing information about the out-of-plane motion of microbubbles and provides a way to improve 3D flow and velocity quantification using 2D ULM. These results pave the way to improved visualization and quantification for 2D and 3D ULM.

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Conflict of interest statement

M.T. is a co-founder and shareholder of the Iconeus company, which commercializes ultrasound neuroimaging scanners. M.T. is a co-inventor of the patent WO2012080614A1 filed on 2010-12-16 and licenced to Iconeus company. All other authors declare no competing interests.

Figures

Figure 1
Figure 1
ULM Backscattering imaging offers better vessel delineation than MB count ULM. (A) Left: MB count ULM map of blood vessels in a rat brain coronal plane. Right: Corresponding normalized backscattering amplitude ULM map. (C) Zoom in the thalamus corresponding to the blue box in (A): MB count (left) and backscattering (right) maps in dB. The image log-dynamic is set by the noise level determined in areas surrounded by a white dash line. (C) Same analysis as in (B) for another thalamus area in a second animal. Green arrows depicts better small vessel delineation in backscattering imaging.
Figure 2
Figure 2
MB backscattering and ultrasound beam geometry. (A) Schematic of an ultrasound beam produced by a linear array transducer and of a microbubble (MB) flowing through a blood vessel orthogonal to the imaging plane. ti: time point i. The red curves show the simulated normalized ultrasound intensity along the Z dimension (averaged along X and Y) (right) and y dimension (z = 5 mm, averaged along X) (bottom). (B) BMode images of the microbubble at t1 and t2. (C) Variation of the backscattered ultrasound intensity and consequently of the amplitude on the BMode image as a function of Y for a fixed (x0, z0) position. The red curve show the simulated normalized ultrasound intensity along the Y dimension (z = 5 mm, averaged along X).
Figure 3
Figure 3
MB backscattering offers 3D information – illustrations. (A) Backscattering imaging ULM map of vessels in the rat thalamus crossing the ultrasound beam in the out of plane direction. The backscattering amplitude is low where the vessels are near the beam edges (blue arrows) and maximal when it is at the centre of the beam (green arrows). (B) Normalized backscattering amplitude as a function of time of one MB travelling in the blood vessel whose trajectory is shown on (A) as a red line. (C) Backscattering imaging ULM map of blood vessels in the rat cortex. (D) Histograms of the backscattering amplitude of all MB trajectories detected in three blood vessels pointed at by the blue, green and red arrows on (C). (E) ULM MB count map of a zoom in a rat cortex with downward flow in red and upward flow in blue (respectively arteriolar and venous flow). (F) Histogram of the backscattering amplitude of all the MB flowing through the white segment shown on (E), and related MB trajectories (top right). (G) Venous and arteriolar MB from (F) are separated based on flow direction and the histograms from their backscattering amplitude are displayed in blue and red respectively. Related MB trajectories with flow speed are displayed (top right).
Figure 4
Figure 4
2D ULM backscattering imaging and 3D sub-resolution localization. (A) 2D ULM backscattering imaging of 5 coronal planes in the rat thalamus spaced by 100 µm from each other in the elevation (Y) direction. (B) Backscattering amplitude of pixel M (red cross in (A)) for the 5 planes. The blue curves is a gaussian fit on the 5 points. y0 depicts the sub-resolution localisation of the maximum, i.e. the y-position of the vessel. (C) Violet curve: experimental gaussian fitting width parameter averaged per depth (mean + /–SEM). Red curve : beam width obtained by simulation. (D–F) Sub-resolution maps of the location (y0) in the Y (out-of-plane) direction based on a gaussian fit (width parameter = w). (D) No constraint on w. (E) Constrained width parameter w(z) obtained from experiment results (violet curve in C). (F) Constrained width parameter w(z) obtained from transducer beam simulation (red curve in C).
Figure 5
Figure 5
Backscattering imaging and speed vector correction. (A–D) Schematic of the speed vector correction: (A) Vx and Vy are estimated thanks to 2D ULM while Vy is estimated thanks to ULM backscattering imaging (B) Arrows depict selected vessels for (D). (C) Blood vessel angle θ toward imaging plane is determined using knowledge of the local beam width w(z) and width at half maximum dS of backscattering amplitude function along the vessel. The schematic explains the geometry. (D) Comparison between angle estimation using one plane and multiple planes backscattering information. (E) Speed estimation in classical 2D ULM. (F) Speed estimation correction with ULM backscattering imaging using a single plane. (G) For comparison, speed estimation correction using ULM backscattering imaging information in multiple planes, as done in Fig. 4.
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