Feasibility of Harmonic Motion Imaging Using a Single Transducer: In Vivo Imaging of Breast Cancer in a Mouse Model and Human Subjects

Abstract

Harmonic motion imaging (HMI) interrogates the mechanical properties of tissues by simultaneously generating and tracking harmonic oscillation using focused ultrasound and imaging transducers, respectively. Instead of using two transducers, the objective of this work is to develop a single transducer HMI (ST-HMI) to both generate and track harmonic motion at "on-axis" to the force for facilitating data acquisition. In ST-HMI, the amplitude-modulated force was generated by modulating excitation pulse duration and tracking of motion was performed by transmitting tracking pulses interleaved between excitation pulses. The feasibility of ST-HMI was performed by imaging two elastic phantoms with three inclusions (N = 6) and comparing it with acoustic radiation force impulse (ARFI) imaging, in vivo longitudinal monitoring of 4T1, orthotropic breast cancer mice (N = 4), and patients (N = 3) with breast masses in vivo. Six inclusions with Young's moduli of 8, 10, 15, 20, 40, and 60 kPa were embedded in a 5 kPa background. The ST-HMI-derived peak-to-peak displacement (P2PD) successfully detected all inclusions with [Formula: see text] of the linear regression between the P2PD ratio of background to inclusion versus Young's moduli ratio of inclusion to background. The contrasts of 10 and 15 kPa inclusions were higher in ST-HMI than ARFI-derived images. In the mouse study, the median P2PD ratio of tumor to non-cancerous tissues was 3.0, 5.1, 6.1, and 7.7 at 1, 2, 3, and 4 weeks post-injection of the tumor cells, respectively. In the clinical study, ST-HMI detected breast masses including fibroadenoma, pseudo angiomatous stromal hyperplasia, and invasive ductal carcinoma with a P2PD ratio of 1.37, 1.61, and 1.78, respectively. These results indicate that ST-HMI can assess the mechanical properties of tissues via generation and tracking of harmonic motion "on-axis" to the ARF. This study is the first step towards translating ST-HMI in clinics.

Figures

Fig 1:

Data processing steps employed to generate ST-HMI-derived peak-2-peak displacement (P2PD) image. DAS = Dealy-and-sum; NCC = Normalized cross-correlation;

Fig 2:

ST-HMI pulse sequence with the duration of excitation (red) and tracking (blue and green) pulse for 220-Hz oscillation frequency, 0.2 ms offset, and 8 excitation pulses per cycle. Y-axis contains a break to accommodate the difference in excitation and tracking pulse duration. The duration of excitation pulses is variable to generate amplitude-modulated force whereas the duration of tracking pulses is fixed. Displacement was estimated with respect to the reference tracking pulse (green).

Fig 3:

(a) Focused excitation and tracking beams electronically translated across lateral field to generate a 2-D image in ST-HMI. (b) One RF-line consists of reference, excitation, and tracking pulses with several cycles of 220 Hz oscillation.

Fig. 4:

ST-HMI derived (a) displacement profiles (b) differential displacement between successive time points (c) magnitude spectrum of fast Fourier transform (FFT) of the differential displacement profiles (d) filtered displacement profiles in 15 kPa inclusion (blue) and 5 kPa background (red). Green circles represent cutoff values for the bandpass filter. ST-HMI oscillation frequency was 220 Hz with 0.2 ms offset and 8 excitation pulses per cycle.

Fig 5:

(a) Bmode ultrasound image and (b) ST-HMI derived peak-to-peak displacement (P2PD) image of a 15 kPa inclusion embedded in a 5 kPa background. (c) Axial distance versus median P2PD over a lateral distance of [−10 −8.2] and [7.9 9.7] mm. (d) Normalized P2PD of the same inclusion. Magenta contour represents the inclusion boundary derived from the B-mode ultrasound image. Arrowhead in the B-mode image indicates slightly hypoechoic regions in the inclusion’s boundary.

Fig 6:

ST-HMI derived normalized peak-to-peak displacement (left column) and ARFI-derived normalized peak displacement (right column) images of homogenous background (BKD, 1st row) and 8 kPa (2nd row), 10 kPa (3rd row) and 15 kPa (4th row) inclusions. Magenta contour represents the inclusion boundary derived from the B-mode ultrasound image.

Fig 7:

(a) ST-HMI derived normalized peak-to-peak displacement (P2PD) images of 8, 10, 14, 15, 20, 40, and 60 kPa inclusions embedded in a 5-kPa background of two commercial phantoms. Magenta contour represents the inclusion boundary derived from the B-mode ultrasound image. Circular and rectangular contours in the background (black) and inclusion (white) represent the region of interest for the calculation of image quality metrics and the comparison of the P2PD ratio versus the Young’s moduli ratio, respectively.

Fig. 8:

(a) Contrast (red/magenta, left y-axis) and CNR (blue/cyan, right y-axis) of ARFI and ST-HMI-derived images versus Young’s moduli ratio of inclusion (INC) to background (BKD). The ARFI imaging was performed only on 8, 10, and 15 kPa inclusions. The contrast was not statistically different between ARFI verus ST-HMI images of 8 kPa inclusion but was statistically different between ARFI verus ST-HMI images of 10 and 15 kPa inclusions (signed ranksum, p2 value. The numerator and denominator are interchanged in the abscissa and ordinate’s ratio as the Young’s modulus and P2PD/PD are inversely related. Data are plotted as median ± 0.5* interquartile range over 6 repeated acquisitions.

Fig 9:

ST-HMI derived normalized peak-to-peak displacement images of 15 kPa (top row) and 60 kPa (bottom row) inclusions embedded in a 5 kPa background for oscillation frequency of 60 Hz (1st column), 100 Hz (2nd column),180 Hz (3rd column), 260 Hz (4th column), 300 Hz (5th column), and 420 Hz (6th column). Magenta contour represents the inclusion boundary derived from the B-mode ultrasound image.

Fig 10:

(a) Contrast and (b) CNR of the ST-HMI derived peak-to-peak displacement images of 15 kPa (blue) and 60 kPa (red) inclusions as a function of oscillation frequency. Data are plotted as median ± 0.5*interquartile range over 6 repeated acquisitions. The Kruskal–Wallis test suggested that contrast and CNR were statistically different across frequencies for both inclusions. For clarity, median contrast and CNR at frequencies that were statistically different (sign ranksum) from the highest median contrast (180 Hz for both inclusions) and CNR (300 and 260 Hz for 15 and 60 kPa inclusions) are shown. Blue and red asterisk (*) represent statistical significance for 15 and 60 kPa inclusions, respectively.

Fig. 11:

Contrast (top row) and CNR (bottom row) of the ST-HMI derived peak-to-peak displacement images of 15 kPa (blue) and 60 kPa (red) inclusions versus HMI excitation duty cycle (left column), oscillation cycle number (center column), and excitation pulse offset (right column). Data are plotted as median ± 0.5*interquartile range over 6 repeated acquisitions. For clarity, the asterisk is only shown when Kruskal–Wallis test suggests a statistical difference and median contrast and CNR were statistically different from the highest median contrast and CNR.

Fig 12:

The normalized peak-to-peak displacement image overlaid on the B-mode ultrasound image of an orthotropic, 4T1 mouse tumor at 1, 2, 3, and 4-weeks post-injection of cancer cells. Magenta, black and white contours represent tumor boundary, the region of interest (ROI) in the non-cancerous tissues, and ROI in the tumor, respectively.

Fig 13:

Peak-to-peak (P2PD) displacement ratio of the healthy tissue (BKD) to the tumor (red, left y-axis) and tumor diameter (blue, right y-axis) as a function of time after tumor cell injection. Data are plotted as median ± 05*inter-quartile range over 4 mice. The Kruskal–Wallis test suggests both P2PD ratio and diameter were statistically different across time points. Asterisk (*) represents statistically significant P2PD ratios and diameters between two imaging time points.

Fig. 14:

Normalized peak-to-peak displacements (P2PD) image overlaid on the B-mode ultrasound image of patients with Fibroadenoma, pseudo angiomatous stromal hyperplasia, and invasive ductal carcinoma with respective median P2PD ratio of non-cancerous tissue over tumor at the bottom. Magenta, black and white contours represent tumor boundary, region of interest (ROI) in the non-cancerous tissue, and ROI in the tumor, respectively.