In this phase I study, it was feasible and safe to thermally trigger drug release over oncologically relevant volumes by using extracorporeally applied US-guided focused ultrasound, with treatment plans based on patient-specific modelling. Purpose To demonstrate the feasibility and safety of using focused ultrasound planning models to determine the treatment parameters needed to deliver volumetric mild hyperthermia for targeted drug delivery without real-time thermometry. Materials and Methods This study was part of the Targeted Doxorubicin, or TARDOX, phase I prospective trial of focused ultrasound–mediated, hyperthermia-triggered drug delivery to solid liver tumors (ClinicalTrials.gov identifier NCT02181075). Ten participants (age range, 49–68 years; average age, 60 years; four women) were treated from March 2015 to March 2017 by using a clinically approved focused ultrasound system to release doxorubicin from lyso-thermosensitive liposomes. Ultrasonic heating of target tumors (treated volume: 11–73 cm3 [mean ± standard deviation, 50 cm3 ± 26]) was monitored in six participants by using a minimally invasive temperature sensor; four participants were treated without real-time thermometry. For all participants, CT images were used with a pa...

Sources of nonlinear acoustic emissions, particularly those associated with cavitation activity, play a key role in the safety and efficacy of current and emerging therapeutic ultrasound applications, such as oncological drug delivery, blood-brain barrier opening, and histotripsy. Passive acoustic mapping (PAM) is the first technique to enable real-time and non-invasive imaging of cavitation activity during therapeutic ultrasound exposure, through the recording and passive beamforming of broadband acoustic emissions using an array of ultrasound detectors. Initial limitations in PAM spatial resolution led to the adoption of optimal data-adaptive beamforming algorithms, such as the robust capon beamformer (RCB), that provide improved interference suppression and calibration error mitigation compared to non-adaptive beamformers. However, such approaches are restricted by the assumption that the recorded signals have a Gaussian distribution. To overcome this limitation and further improve the source resolvability of PAM, we propose a new beamforming approach termed robust beamforming by linear programming (RLPB). Along with the variance, this optimization-based method uses higher-order-statistics of the recorded signals, making no prior assumption on the statistical distribution of the acoustic signals. The RLPB is found via numerical simulations to improve resolvability over time exposure acoustics and RCB. In vitro experimentation yielded improved resolvability with respect to the source-to-array distance on the order of 22% axially and 13% transversely relative to RCB, whilst successfully accounting for array calibration errors. The improved resolution and decreased dependence on accurate calibration of RLPB is expected to facilitate the clinical translation of PAM for diagnostic, including super-resolution, and therapeutic ultrasound applications.

It is currently thought that all fishes detect acoustic particle motion, and it is therefore critical to measure this vector quantity when studying hearing, acoustic behavior, and noise impacts. Proper measurement of particle motion in any of its forms (acceleration, velocity, or displacement) is subject to a range of errors whose magnitude depends on the sound source(s) of interest and the environments in which they are observed. Particle motion measurement principles and errors have primarily been addressed in the literature for free field plane waves. However, such fields are rarely encountered in bioacoustic studies, and experiments or calculations made based on plane wave assumptions can lead to substantially erroneous measurement results and flawed study conclusions. This paper presents a unified treatment of underwater acoustic particle motion measurement by reviewing acoustic field attributes of commonly encountered source/environment scenarios, quantifying measurement error sources, and concluding with guidelines and recommendations for bioacoustic studies.

Over the last decade, a variety of noninvasive techniques has been developed to monitor therapeutic ultrasound procedures in support of safety or efficacy assessments. One class of methods employs diagnostic ultrasound arrays to sense acoustic emissions, thereby providing a means to passively detect, localize and quantify the strength of nonlinear sources, including cavitation. Real array element diffraction patterns may differ substantially from those presumed in existing beamforming algorithms. However, diffraction compensation has received limited treatment in passive and active imaging, and measured diffraction data has yet to be used for array response correction. The objectives of this work were to identify differences between ideal and real element diffraction patterns, and to quantify the impact of diffraction correction on cavitation mapping beamformer performance. These objectives were addressed by performing calibration measurements on a diagnostic linear array, using the results to calculate diffraction correction terms, and applying the corrections to cavitation emission data collected from soft tissue phantom experiments. Measured diffraction patterns were found to differ significantly from those of ideal element forms, particularly at higher frequencies and shorter distances from the array. Diffraction compensation of array data resulted in cavitation energy estimates elevated by as much as a factor of five, accompanied by the elimination of a substantial bias between two established beamforming algorithms. These results illustrate the importance of using measured array responses to validate analytical field models and to minimize observation biases in imaging applications where quantitative analyses are critical for assessment of therapeutic safety and efficacy.

Several active and passive techniques have been developed to detect, localize and quantify cavitation activity during therapeutic ultrasound procedures. Much of the prior cavitation monitoring research has been conducted using lossless in vitro systems or small animal models in which path attenuation effects were minimal. However, the performance of these techniques may be substantially degraded by attenuation between the internal therapeutic target and the external monitoring system. As a further step towards clinical application of passive acoustic mapping (PAM), this paper presents methods for attenuation estimation and compensation based on broadband cavitation data measured with a linear ultrasound array. Soft tissue phantom experiment results are used to illustrate: 1) the impact of realistic attenuation on PAM images, 2) the possibility of estimating attenuation from cavitation data, 3) cavitation source energy estimation following attenuation compensation, and 4) the impact of sound speed uncertainty on PAM-related processing. Cavitation-based estimates of attenuation were within 1.5-6.2 % of the values found from conventional through-transmission measurements. Tissue phantom attenuation reduced the PAM energy estimate by an order of magnitude, but array data compensation using the cavitation-based attenuation spectrum enabled recovery of the PAM energy estimate to within 2.9-5.9% of the values computed in the absence of the phantom. Sound speed uncertainties were found to modestly impact attenuation-compensated PAM energies, inducing errors no larger than 28% for a 40 m/s path-averaged speed error. Together, the results indicate the potential to significantly enhance the quantitative capabilities of PAM for ensuring therapeutic safety and efficacy.

Passive acoustic mapping (PAM) techniques have been developed for the purposes of detecting, localizing and quantifying cavitation activity during therapeutic ultrasound procedures. Implementation with conventional diagnostic ultrasound arrays has allowed planar mapping of bubble acoustic emissions to be overlaid with B-mode anatomical images, with a variety of beamforming approaches providing enhanced resolution at the cost of extended computation times. However, no passive signal processing techniques implemented to date have overcome the fundamental physical limitation of the conventional diagnostic array aperture that results in point spread functions with axial/lateral beamwidth ratios of nearly an order of magnitude. To mitigate this problem, the use of a pair of orthogonally oriented diagnostic arrays was recently proposed, with potential benefits arising from the substantially expanded range of observation angles. This paper presents experiments and simulations intended to demonstrate the performance and limitations of the dual-array system concept. The key finding of this study is that source pair resolution of better than 1 mm is now possible in both dimensions of the imaging plane using a pair of 7.5 MHz center frequency conventional arrays at a distance of 7.6 cm. With an eye toward accelerating computations for real time applications, channel count reductions of up to a factor of eight induce negligible performance losses. Modest sensitivities to sound speed and relative array position uncertainties were identified, but if these can be kept on the order of 1% and 1 mm, respectively, then the proposed methods offer the potential for a step improvement in cavitation monitoring capability.