Multi-frequency harmonic arrays: initial experience with a novel transducer concept for nonlinear contrast imaging

We investigate high frequency nonlinear scattering and imaging of a contrast agent comprised of submicron bubbles. Agent characterization experiments conducted at 20 and 30 MHz transmit frequencies with a broadband PVDF transducer confirm the production of substantial amounts of energy in the subharmonic and second harmonic regions. Nonlinear contrast imaging with intravascular ultrasound (IVUS) is then explored with a prototype mechanically scanned system. Pulse-inversion techniques were employed with a 20 MHz transmit frequency (F20) for second harmonic imaging (H40), and with a 40 MHz transmit frequency (F40) for subharmonic imaging (SH20). H40 was found to produce improvements in contrast-to-tissue signal ratios (CTR) for low transmit amplitudes ( 15 MHz) nonlinear contrast imaging and suggest the potential application of these techniques in IVUS.

Breast cancer is the most frequent type of cancer among women, and accounts for 25% of all cancers across both sexes. There are various markers of malignancy. The angiogenic process that fuels the growth of tumors is one of the potential early indicators for differentiating between malignant and benign tumors. Recently, the use of microbubble based contrast agents in combination with ultrasound imaging has allowed for the development of contrast agent specific imaging modes that provide visualization of tumor neovascularity. This thesis evaluates the feasibility of using contrast-enhanced ultrasound imaging to generate quantifiable parameters of vascularity in breast lesions in a clinical population. This work is divided into two parts, the pre-clinical and clinical work. The pre-clinical work consisted of developing and implementing three-dimensional (3D) harmonic (HI) and subharmonic (SHI) imaging modes on a commercial ultrasound scanner. The ability to visualize and quantify blood perfusion using these modes is investigated in an in vivo canine model. The clinical study involved imaging women (n=237) identified with breast lesions using 3D HI and 3D SHI. The ultrasound contrast agent (UCA) used for this study was Definity (Lantheus Medical Imaging, N Billerica, MA). All lesions were biopsied after imaging and pathology was used as the reference standard. Time-intensity curves were generated based on UCA flow within the lesions and were used to evaluate vascular heterogeneity and develop parametric maps of blood perfusion and area under the curve. In terms of pre-clinical work, both 3D HI and 3D SHI were able to provide visualization of flow and, thus generate estimates of perfusion. However, 3D SHI provided near complete tissue suppression and improved visualization of UCA flow compared to 3D HI. Microsphere perfusion data (reference standard) showed an average perfusion of 9.30 ± 6.60 and 5.15 ± 3.42 mL/min/g pre and post ligation, respectively. The reference standard showed significant correlation with overall 3D HI perfusion estimates (r=0.38; P=0.007), but correlated better with 3D SHI (r=0.62; P<0.001). For the clinical study, biopsies resulted in 164 (75%) benign and 55 (25%) malignant lesions. Benign lesions primarily consisted of fibroadenomas (31%) while invasive ductal carcinomas (76%) made up the majority of malignant cases. For contrast-enhanced ultrasound, 3D SHI showed UCA flow in 83 (58 benign and 25 malignant) lesions while 3D HI only detected flow in 8 (5 benign and 3 malignant) lesions. Vascularity was observed with PDI in 95 lesions (69 benign and 26 malignant). Comparison of UCA flow parameters between malignant and benign lesions resulted in significantly longer transit times for invasive ductal carcinomas compared to fibroadenomas (28.97±3.21 vs. 20.95±2.22 seconds, p=0.0398). Overall, malignant lesions had a longer transit time compared to benign lesions, but this was not a statistically significant finding. Analysis of vascular heterogeneity using 3D SHI time-intensity curve volumes showed a significant difference in vascularity between central and peripheral sections (1.83±0.16 vs. 1.15±0.09, p=0.0003) for the benign cases, whereas malignant lesions showed no significant difference (1.72±0.33 vs. 1.26±0.21, p=0.23), indicative of more vascular coverage. Parametric maps of PER and AUC were able to highlight the variations in the vascularity for individual pixels in the lesion volume. It was observed that for malignant cases, specifically for IDC's the vascularity was dispersed throughout the lesion volume with feeding vessels being present around the lesion. Benign cases exhibited a more structured vasculature, usually with a single large vessel within the lesion volume. "Heat-maps" of the varying levels of PER and AUC across the lesion were generated in order visualize the localized variations in the behavior of vascularity. Malignant lesions had a significantly (p=0.032) higher number of perfused pixels/slice within the lesion volume compared to benign lesions. For specific lesion types, IDC's were significantly higher perfused (p=0.048) compared to the fibroadenomas. This thesis presents findings that show contrast-enhanced ultrasound imaging of breast lesions is feasible, specifically using a new contrast imaging mode; subharmonic imaging and capable of providing supplementary information to mammography for characterization of lesions.

A high resolution approach for nonlinear sub-harmonic imaging

Pancreatic cancer is associated with poor clinical outcomes primarily due to the advanced stage at the time of diagnosis. Endoscopic harmonic ultrasound imaging (HI) is being used to characterize pancreatic masses. Alternatively, transabdominal subharmonic imaging (SHI) may limit invasiveness and better suppress nonlinear tissue echoes. In both approaches, time-intensity curve (TIC) analysis can be performed to quantify blood flow dynamics. The purpose of this study was to compare TICs from both HI and SHI ultrasound of pancreatic masses. Patients underwent both endoscopic HI and SHI prior to an endoscopic biopsy of a pancreatic mass. SHI (transmitting/receiving at 2.5/1.25 MHz) was performed on a modified Logiq 9 system with a 4C probe (GE Healthcare, Milwaukee, WI), while endoscopic HI ultrasound (transmitting/receiving at 4.7/9.4 MHz) was performed with a radial endoscope (GF-UTC180; Olympus, Tokyo, Japan) and a ProSound SSD α-10 scanner (Hitachi-Aloka, Tokyo, Japan). TIC analysis was performed on a pixel by pixel basis to generate parametric images of peak intensity, time to peak, perfusion, and area under the curve and compared by modality to pathology. To date, TIC processing has been completed on 10 cases that were not compromised by excessive motion. No significant differences were observed between imaging modes for time to peak, perfusion, or area under the curve (p>0.11), while peak intensity was different (p=0.01) most likely due to scanner-specific properties such as transmit power, etc. When grouped by pathology (adenocarcinoma vs. other masses), neither modality showed significant differences in any TIC parameter, with peak intensity being the closest to demonstrating differences (p= 0.06). While the feasibility of parametric imaging of pancreatic masses has been demonstrated, future efforts with increased sample size and motion correction are likely needed to better elucidate any differences in blood flow TIC parameters between benign and malignant pancreatic lesions.

Is there a role for intravenous transpulmonary contrast imaging in pediatric stress echocardiography?

Ultrasonic characterization of the nonlinear properties of contrast microbubbles

The current excitation strategy for harmonic and subharmonic imaging (HI and SHI) uses short sine-bursts. However, alternate pulsing strategies may be useful for enhancing nonlinear emissions from ultrasound contrast agents. The goal of this study was to corroborate the hypothesis that chirp-coded excitation can improve the performance of high-frequency HI and SHI. A secondary goal was to understand the mechanisms that govern the response of ultrasound contrast agents to chirp-coded and sine-burst excitation schemes. Numerical simulations and acoustic measurements were conducted to evaluate the response of a commercial contrast agent (Targestar-P(®)) to chirp-coded and sine-burst excitation (10 MHz frequency, peak pressures 290 kPa). The results of the acoustic measurements revealed an improvement in signal-to-noise ratio by 4 to 14 dB, and a two- to threefold reduction in the subharmonic threshold with chirp-coded excitation. Simulations conducted with the Marmottant model suggest that an increase in expansion-dominated radial excursion of microbubbles was the mechanism responsible for the stronger nonlinear response. Additionally, chirp-coded excitation detected the nonlinear response for a wider range of agent concentrations than sine-bursts. Therefore, chirp-coded excitation could be a viable approach for enhancing the performance of HI and SHI.

901–49 Second Harmonic Imaging of Echocardiographic Contrast Agents: Unique Features and Promising Characteristics

Microbubble, nonlinear-contrast agents are used in nonlinear ultrasound imaging to increase the contrast between these agents and the surrounding tissue. Similar approaches were developed in Russia in the 1980s for bubble measurements at sea. Two methods can enhance nonlinear imaging. (1) Sum-frequency nonlinear imaging has several advantages over second harmonic imaging due to the absence of nonlinear distortion in electronic circuits and emitters. This method allows one to use significantly less ultrasound amplitude than in the method of second harmonic imaging. This method was used for bubble detection in sea sediments. (2) The nonlinear difference frequency Doppler effect is based on moving bubbles that are insonified by two acoustic beams of different frequencies directed from different directions. Difference-frequency scattering provides significant enhancement of the Doppler frequency shift. This method was tested in laboratory conditions. Nonlinear scattering by microbubbles could also lead to remote, direct blood-pressure measurements. This method could be based on measurements of microbubble resonance frequencies by using nonlinear scattering. The resonance frequency depends on the ambient pressure; nonlinear scattering provides high-resolution measurements of the resonance frequencies and avoids the influence of scattered signals reflected by different inhomogeneities in the human body. [Work was supported by Stevens.]

Histotripsy is a noninvasive focused ultrasound therapy that liquifies tissue via bubble activity. Conventional ultrasound imaging is used in current clinical practice to monitor histotripsy. Developing surrogate imaging metrics for successful treatment outcomes remains an unmet clinical need. The goal of this work was twofold. First, we investigated whether histotripsy bubble clouds detected with nonlinear imaging (chirp-coded subharmonic imaging with and without Volterra filtering) could be used to assess the ablation zone in vitro. Second, we evaluated the feasibility of improving bubble cloud contrast with this approach in ex vivo porcine kidney. Histotripsy bubble clouds were generated in red blood cell-doped agarose phantoms and imaged with a curvilinear ultrasound probe. The ablation zone was assessed based on images collected with a digital camera. The relationship between the bubble cloud area and the ablation area was assessed using receiver operating characteristic (ROC) analysis, F1 score, accuracy, and Matthews correlation coefficient. Histotripsy bubble clouds were also generated in ex vivo porcine tissue and the ability to improve bubble cloud contrast to tissue was evaluated. Implementing chirp-coded subharmonic imaging with the third-order Volterra filter enhanced contrast-to-tissue ratio (CTR) by up to $40.06~\pm ~0.70$ dB relative to standard imaging in vitro. Furthermore, subharmonic imaging combined with Volterra filtering estimated bubble cloud areas that best matched the ablation zone area based on the analysis metrics. Furthermore, ex vivo studies showed CTR improvement of up to $26.95~\pm ~6.49$ dB. Taken together, these findings advance image guidance and monitoring approaches for histotripsy.

Tissue Harmonic Imaging (THI) is an invaluable tool in clinical ultrasound owing to its enhanced contrast resolution and reduced reverberation clutter in comparison to fundamental mode imaging. However, harmonic content separation based on high pass filtering suffers from potential contrast degradation or lower axial resolution due to spectral leakage. Whereas nonlinear multi-pulse harmonic imaging schemes, such as amplitude modulation and pulse inversion, suffer from a reduced framerate and comparatively higher motion artifacts due to the necessity of at least two pulse echo acquisitions. To address this problem, we propose a deep-learning-based single-shot harmonic imaging technique capable of generating comparable image quality to pulse amplitude modulation methods, yet at a higher framerate and with fewer motion artifacts. Specifically, an asymmetric convolutional encoder-decoder structure is designed to estimate the combination of the echoes resulting from the half-amplitude transmissions using the echo produced from the full amplitude transmission as input. The echoes were acquired with the checkerboard amplitude modulation technique for training. The model was evaluated across various targets and samples to illustrate generalizability as well as the possibility and impact of transfer learning. Furthermore, for possible interpretability of the network, we investigate if the latent space of the encoder holds information on the nonlinearity parameter of the medium. We demonstrate the ability of the proposed approach to generate harmonic images with a single firing that are comparable to those from a multi-pulse acquisition.

Ultrasound (US) harmonic imaging has shown advantages in better spatial resolution and contrast compared to classic fundamental imaging, but it suffers from more attenuation due to the increased frequency. To achieve more penetration, high dynamic range (DR) front-end electronics is required to receive the weak harmonic components. Typical US front-ends use a variable gain amplifier (VGA) to compensate part of the required DR, in order to avoid using a highly sensitive analog-to-digital converter (ADC). However, in harmonic imaging, the received signal amplitude is dominated by the fundamental component, thus the VGA is less efficient for these small harmonics. An analog front-end filter can be used before the VGA to mitigate this issue but this has an impact on spatial resolution by changing the dominant frequency component and spatial pulse length of the received signal. In this work, a combined acoustic-and-electronic model is made to understand the impact of the use of an analog front-end filter in US harmonic imaging applications in terms of imaging resolution, contrast, and hardware requirements.

A novel drug reservoir termed an "Acoustically Sensitive Microcapsule" (ASM) was designed and sensitized using ultrasound contrast agents (UCAs) for the long-term goal of facilitating localized treatment of breast cancer. In this thesis, two objectives were met. First, an opto-acoustic interrogation system coupled with a microfluidic device was developed for visualizing the role of UCAs within ASMs in the drug-release process. The displacement of UCAs under continuous wave ultrasound (fc = 2.25 MHz, for 4 s) was 3.5 µm and pulsed wave (fc = 2.25 MHz, for 30 s) was 333 µm. It was concluded that by altering the acoustic pressure, center frequency, pulse repetition frequency, and duty cycle of the ultrasound, the UCAs could be manipulated. Second, ultrasound-imaging signatures were extracted from ASMs to help in differentiation of ASMs from surrounding tissue. During harmonic imaging with diagnostic ultrasound, ASMs generated second and third harmonic components that were 7 dB and 3 dB greater than the tissue- mimicking media. Sub-harmonic imaging offered 4 dB spectral amplitude increases for ASMs at sub-harmonic peaks. Phase Inversion and Signal Subtraction imaging techniques effectively suppressed the tissue echoes by 80% and improved the ASM to tissue contrast ratio. B-Mode and Power Doppler showed only marginal contrast. In conclusion, these imaging schemes could help successfully differentiate ASMs from surrounding tissue during an in vivo drug delivery process.

Nonlinear Pulse Compression in Pulse-Inversion Fundamental Imaging

Transmit Aperture Processing for Nonlinear Contrast Agent Imaging