High-intensity Focused Ultrasound Exposure Research Articles

Feasibility of real-time treatment feedback using novel filter for eliminating therapeutic ultrasound noise with high-speed ultrasonic imaging in ultrasound-guided high-intensity focused ultrasound treatment

In the conventional ultrasonic monitoring of high-intensity focused ultrasound (HIFU) treatment, a significant interval between HIFU shots is required when monitoring target tissue to avoid interference between HIFU noise and RF echo signals. In our previous study, a new filtering method to eliminate only HIFU noise while maintaining tissue signals intact was proposed, and it was shown that the thermal coagulation could be detected during simultaneous HIFU irradiation through off-line processing. In this study, the filtering method and a real-time coagulation detection algorithm were implemented in an ultrasound imaging system, whose use for sequential exposure with multiple foci was demonstrated similarly to a commercial HIFU ablation system. The coagulation was automatically detected by the proposed method during real-time simultaneous HIFU irradiation, and the HIFU exposure time was controlled according to the changes in the tissue. The results imply that ultrasonic monitoring with the filtering and detection methods is useful for true real-time detection of changes in the tissue due to thermal coagulation during HIFU exposure.

Monitoring of high-intensity focused ultrasound treatment by shear wave elastography induced by two-dimensional-array therapeutic transducer

Shear wave elastography (SWE) is expected to be a noninvasive monitoring method of high-intensity focused ultrasound (HIFU) treatment. However, conventional SWE techniques encounter difficulty in inducing shear waves with adequate displacements in deep tissue. To observe tissue coagulation at the HIFU focal depth via SWE, in this study, we propose using a two-dimensional-array therapeutic transducer for not only HIFU exposure but also creating shear sources. The results show that the reconstructed shear wave velocity maps detected the coagulated regions as the area of increased propagation velocity even in deep tissue. This suggests that “HIFU-push” shear elastography is a promising solution for the purpose of coagulation monitoring in deep tissue, because push beams irradiated by the HIFU transducer can naturally reach as deep as the tissue to be coagulated by the same transducer.

Improved highly accurate localized motion imaging for monitoring high-intensity focused ultrasound therapy

Visualizing an area subjected to high-intensity focused ultrasound (HIFU) therapy is necessary for controlling the amount of HIFU exposure. One of the promising monitoring methods is localized motion imaging (LMI), which estimates coagulation length by detecting the change in stiffness. In this study, we improved the accuracy of our previous LMI by dynamic cross-correlation window (DCCW) and maximum vibration amount (MVA) methods. The DCCW method was used to increase the accuracy of estimating vibration amplitude, and the MVA method was employed to increase signal–noise ratio of the decrease ratio at the coagulated area. The qualitative comparison of results indicated that the two proposed methods could suppress the effect of noise. Regarding the results of the quantitative comparison, coagulation length was estimated with higher accuracy by the improved LMI method, and the root-mean-square error (RMSE) was reduced from 2.51 to 1.69 mm.

Ultrasound-Guided Transesophageal High-Intensity Focused Ultrasound Cardiac Ablation in a Beating Heart: A Pilot Feasibility Study in Pigs

Catheter ablation for the treatment of arrhythmia is associated with significant complications and often-repeated procedures. Consequently, a less invasive and more efficient technique is required. Because high-intensity focused ultrasound (HIFU) enables the generation of precise thermal ablations in deep-seated tissues without harming the tissues in the propagation path, it has the potential to be used as a new ablation technique. A system capable of delivering HIFU into the heart by a transesophageal route using ultrasound (US) imaging guidance was developed and tested in vivo in six male pigs. HIFU exposures were performed on atria and ventricles. At the time of autopsy, visual inspection identified thermal lesions in the targeted areas in three of the animals. These lesions were confirmed by histologic analysis (mean size: 5.5 mm2 × 11 mm2). No esophageal thermal injury was observed. One animal presented with bradycardia due to an atrio-ventricular block, which provides real-time confirmation of an interaction between HIFU and the electrical circuits of the heart. Thus, US-guided HIFU has the potential to minimally invasively create myocardial lesions without an intra-cardiac device.

Detection of tissue coagulation by decorrelation of ultrasonic echo signals in cavitation-enhanced high-intensity focused ultrasound treatment.

BackgroundA noninvasive technique to monitor thermal lesion formation is necessary to ensure the accuracy and safety of high-intensity focused ultrasound (HIFU) treatment. The purpose of this study is to ultrasonically detect the tissue change due to thermal coagulation in the HIFU treatment enhanced by cavitation microbubbles.MethodsAn ultrasound imaging probe transmitted plane waves at a center frequency of 4.5 MHz. Ultrasonic radio-frequency (RF) echo signals during HIFU exposure at a frequency of 1.2 MHz were acquired. Cross-correlation coefficients were calculated between in-phase and quadrature (IQ) data of two B-mode images with an interval time of 50 and 500 ms for the estimation of the region of cavitation and coagulation, respectively. Pathological examination of the coagulated tissue was also performed to compare with the corresponding ultrasonically detected coagulation region.ResultsThe distribution of minimum hold cross-correlation coefficient between two sets of IQ data with 50-ms intervals was compared with a pulse inversion (PI) image. The regions with low cross-correlation coefficients approximately corresponded to those with high brightness in the PI image. The regions with low cross-correlation coefficients in 500-ms intervals showed a good agreement with those with significant change in histology.ConclusionsThe results show that the regions of coagulation and cavitation could be ultrasonically detected as those with low cross-correlation coefficients between RF frames with certain intervals. This method will contribute to improve the safety and accuracy of the HIFU treatment enhanced by cavitation microbubbles.

Spatial–temporal three-dimensional ultrasound plane-by-plane active cavitation mapping for high-intensity focused ultrasound in free field and pulsatile flow

Cavitation plays important roles in almost all high-intensity focused ultrasound (HIFU) applications. However, current two-dimensional (2D) cavitation mapping could only provide cavitation activity in one plane. This study proposed a three-dimensional (3D) ultrasound plane-by-plane active cavitation mapping (3D-UPACM) for HIFU in free field and pulsatile flow. The acquisition of channel-domain raw radio-frequency (RF) data in 3D space was performed by sequential plane-by-plane 2D ultrafast active cavitation mapping. Between two adjacent unit locations, there was a waiting time to make cavitation nuclei distribution of the liquid back to the original state. The 3D cavitation map equivalent to the one detected at one time and over the entire volume could be reconstructed by Marching Cube algorithm. Minimum variance (MV) adaptive beamforming was combined with coherence factor (CF) weighting (MVCF) or compressive sensing (CS) method (MVCS) to process the raw RF data for improved beamforming or more rapid data processing. The feasibility of 3D-UPACM was demonstrated in tap-water and a phantom vessel with pulsatile flow. The time interval between temporal evolutions of cavitation bubble cloud could be several microseconds. MVCF beamformer had a signal-to-noise ratio (SNR) at 14.17dB higher, lateral and axial resolution at 2.88times and 1.88times, respectively, which were compared with those of B-mode active cavitation mapping. MVCS beamformer had only 14.94% time penalty of that of MVCF beamformer. This 3D-UPACM technique employs the linear array of a current ultrasound diagnosis system rather than a 2D array transducer to decrease the cost of the instrument. Moreover, although the application is limited by the requirement for a gassy fluid medium or a constant supply of new cavitation nuclei that allows replenishment of nuclei between HIFU exposures, this technique may exhibit a useful tool in 3D cavitation mapping for HIFU with high speed, precision and resolution, especially in a laboratory environment where more careful analysis may be required under controlled conditions.

Quantitative Ultrasound for Monitoring High-Intensity Focused Ultrasound Treatment In Vivo.

The success of any minimally invasive treatment procedure can be enhanced significantly if combined with a robust noninvasive imaging modality that can monitor therapy in real time. Quantitative ultrasound (QUS) imaging has been widely investigated for monitoring various treatment responses such as chemotherapy, radiation, and thermal therapy. Previously, we demonstrated the feasibility of using spectral-based QUS parameters to monitor high-intensity focused ultrasound (HIFU) treatment of in situ tumors in euthanized rats [Ultrasonic Imaging 36(4), 239-255, 2014]. In the present study, we examined the use of spectral-based QUS parameters to monitor HIFU treatment of in vivo rat mammary adenocarcinoma tumors (MAT) where significant tissue motion was present. HIFU was applied to tumors in rats using a single-element transducer. During the off part of the HIFU duty cycle, ultrasound backscatter was recorded from the tumors using a linear array co-aligned with the HIFU focus. A total of 10 rats were treated with HIFU in this study with an additional sham-treated rat. Spectral parameters from the backscatter coefficient, i.e., effective scatterer diameter (ESD) and effective acoustic concentration (EAC), were estimated. The changes of each parameter during treatment were compared with a temperature profile recorded by a fine-needle thermocouple inserted into the tumor a few millimeters behind the focus of the HIFU transducer. The mean ESD changed from 121 ±6 to [Formula: see text], and the EAC changed from 33 ±2 to [Formula: see text] during HIFU exposure as the temperature increased on average from 38.7 ±1.0 (°)C to 64.2 ±2.7 (°)C. The changes in ESD and EAC were linearly correlated with the changes in tissue temperature during the treatment. When HIFU was turned off, the ESD increased from 81 ±8 to [Formula: see text] and the EAC dropped from 46 ±3 to 36±2 dB/cm(3) as the temperature decreased from 64.2 ±2.7 (°)C to 45 ±2.7 (°)C. QUS was demonstrated in vivo to track temperature elevations caused by HIFU exposure.

Acoustic Cavitation Enhances Focused Ultrasound Ablation with Phase-Shift Inorganic Perfluorohexane Nanoemulsions: An In Vitro Study Using a Clinical Device.

Purpose. To investigate whether acoustic cavitation could increase the evaporation of a phase-shift inorganic perfluorohexane (PFH) nanoemulsion and enhance high intensity focused ultrasound (HIFU) ablation. Materials and Methods. PFH was encapsulated by mesoporous silica nanocapsule (MSNC) to form a nanometer-sized droplet (MSNC-PFH). It was added to a tissue-mimicking phantom, whereas phosphate buffered saline (PBS) was added as a control (PBS-control). HIFU (P ac = 150 W, t = 5/10 s) exposures were performed in both phantoms with various duty cycles (DC). US images, temperature, and cavitation emissions were recorded during HIFU exposure. HIFU-induced lesions were measured and calculated. Results. Compared to PBS-control, MSNC-PFH nanoemulsion could significantly increase the volume of HIFU-induced lesion (P < 0.01). Peak temperatures were 78.16 ± 5.64°C at a DC of 100%, 70.17 ± 6.43°C at 10%, 53.17 ± 4.54°C at 5%, and 42.00 ± 5.55°C at 2%, respectively. Inertial cavitation was much stronger in the pulsed-HIFU than that in the continuous-wave HIFU exposure. Compared to 100%-DC exposure, the mean volume of lesion induced by 5 s exposure at 10%-DC was significantly larger, but smaller at 2%-DC. Conclusions. MSNC-PFH nanoemulsion can significantly enhance HIFU ablation. Appropriate pulsed-HIFU exposure could significantly increase the volume of lesion and reduce total US energy required for HIFU ablation.

Radio frequency ultrasound time series signal analysis to evaluate high-intensity focused ultrasound lesion formation status in tissue

High-intensity focused ultrasound (HIFU) is a novel treatment modality used by scientists and clinicians in the recent decades. This modality has had a great and significant success as a noninvasive surgery technique applicable in tissue ablation therapy and cancer treatment. In this study, radio frequency (RF) ultrasound signals were acquired and registered in three stages of before, during, and after HIFU exposures. Different features of RF time series signals including the sum of amplitude spectrum in the four quarters of the frequency range, the slope, and intercept of the best-fit line to the entire power spectrum and the Shannon entropy were utilized to distinguish between the HIFU-induced thermal lesion and the normal tissue. We also examined the RF data, frame by frame to identify exposure effects on the formation and characteristics of a HIFU thermal lesion at different time steps throughout the treatment. The results obtained showed that the spectrum frequency quarters and the slope and intercept of the best fit line to the entire power spectrum both increased two times during the HIFU exposures. The Shannon entropy, however, decreased after the exposures. In conclusion, different characteristics of RF time series signal possess promising features that can be used to characterize ablated and nonablated tissues and to distinguish them from each other in a quasi-quantitative fashion.

Image-Guided High Intensity Focused Ultrasound System for Large Animal Nerve Ablation Studies.

High intensity focused ultrasound (HIFU) is a form of thermal ablation technique, which can treat a variety of medical afflictions. One promising therapeutic use is the permanent destruction of nerves non-invasively in patients with severe spasticity or certain types of pain (e.g., phantom limb pain). To this end, HIFU requires ultrasound guidance, which allows the non-invasive, target-specific deposition of thermal energy to the targeted nerve, thereby blocking axonal conduction. In this paper, a composite system comprising both ultrasound-imaging and HIFU therapy was developed and used to induce localized non-invasive nerve blockage in an in vivo large animal study. Five pigs were used with the femoral nerve as the target. Calibrated needle thermocouples inserted at the target site were employed to monitor the target tissue temperature. The degree of nerve blockage was assessed by measuring compound action potential (CAP) signal with a clinical nerve electrophysiology system before and after HIFU exposures. An average CAP signal amplitude reduction of 49% of baseline with a standard deviation of 9% was observed after 20–30 min post exposure. These results demonstrate the feasibility of the proposed ultrasound-guided HIFU modality as a potential non-invasive nerve ablation method.

Harmonic motion imaging for abdominal tumor detection and high-intensity focused ultrasound ablation monitoring: an in vivo feasibility study in a transgenic mouse model of pancreatic cancer.

Harmonic motion imaging (HMI) is a radiationforce- based elasticity imaging technique that tracks oscillatory tissue displacements induced by sinusoidal ultrasonic radiation force to assess the resulting oscillatory displacement denoting the underlying tissue stiffness. The objective of this study was to evaluate the feasibility of HMI in pancreatic tumor detection and high-intensity focused ultrasound (HIFU) treatment monitoring. The HMI system consisted of a focused ultrasound transducer, which generated sinusoidal radiation force to induce oscillatory tissue motion at 50 Hz, and a diagnostic ultrasound transducer, which detected the axial tissue displacements based on acquired radio-frequency signals using a 1-D cross-correlation algorithm. For pancreatic tumor detection, HMI images were generated for pancreatic tumors in transgenic mice and normal pancreases in wild-type mice. The obtained HMI images showed a high contrast between normal and malignant pancreases with an average peak-to-peak HMI displacement ratio of 3.2. Histological analysis showed that no tissue damage was associated with HMI when it was used for the sole purpose of elasticity imaging. For pancreatic tumor ablation monitoring, the focused ultrasound transducer was operated at a higher acoustic power and longer pulse length than that used in tumor detection to simultaneously induce HIFU thermal ablation and oscillatory tissue displacements, allowing HMI monitoring without interrupting tumor ablation. HMI monitoring of HIFU ablation found significant decreases in the peak-to-peak HMI displacements before and after HIFU ablation with a reduction rate ranging from 15.8% to 57.0%. The formation of thermal lesions after HIFU exposure was confirmed by histological analysis. This study demonstrated the feasibility of HMI in abdominal tumor detection and HIFU ablation monitoring.

Real-time feedback control for high-intensity focused ultrasound system using localized motion imaging

High-intensity focused ultrasound (HIFU) is one of the noninvasive treatment for tumors. Visualizing the treated area inside the human body is necessary to control the HIFU exposure. Localized motion imaging (LMI) using ultrasound to induce and detect tissue deformation is one technique to detect a change in tissue stiffness caused by thermal coagulation. In experiments with porcine liver, LMI has shown to detect deformation with less than 20% accuracy. We have developed a prototype feedback control system using real-time LMI. In this system, coagulation size was measured every 1 s and controlled to correspond to a targeted size. The typical size error was reduced to 14% from 35%. LMI displacements in normal and coagulated tissues were sufficiently different to discriminate between coagulated areas and noncoagulated ones after HIFU sonication and to visualize treated areas after HIFU treatment.

Elimination of therapeutic ultrasound noise from pre-beamformed RF data in ultrasound imaging for ultrasound-guided high-intensity focused ultrasound treatment

In conventional ultrasonic monitoring of high-intensity focused ultrasound (HIFU) treatment, a significant interval between consecutive HIFU shots is set for monitoring target tissue to avoid the interference of HIFU noise with RF echo signals. Thus, it is difficult to detect changes in tissue on the order of milliseconds, which are required to dynamically control the HIFU exposure. In this study, a new filtering method to eliminate the HIFU noise in the RF signals before beamforming is proposed. The CW response was estimated from RF signals with no pulse response to the imaging exposure, and the estimated CW response was subtracted from the entire RF signal to selectively eliminate the HIFU noise for each channel of the array probe before dynamic focusing was applied. The HIFU noise was selectively eliminated by this method when it existed. The results imply that the proposed filtering method is useful for true real-time detection of changes in tissue due to thermal coagulation during HIFU exposure.

Influence of Temperature-Dependent Thermal Parameters on Temperature Elevation of Tissue Exposed to High-Intensity Focused Ultrasound: Numerical Simulation

High-intensity focused ultrasound (HIFU) has been used successfully as a non-invasive modality in treating solid tumors. The temperature rise HIFU irradiation causes in a tissue depends on the thermal properties of the tissue. This study was motivated by our observation that the thermal properties of a tissue vary significantly with temperature (Guntur SR, Lee KI, Paeng DG, Coleman AJ, Choi MJ. Ultrasound Med Biol 2013;39:1771–1784). This research investigated how significantly the alteration of tissue thermal parameters, in the ranges of values measured at 25°C–90°C, affects prediction of the temperature elevation of tissue under the same HIFU exposure. The numerical simulation was performed by coupling a non-linear Khokhlov–Zabolotskaya–Kuznetsov equation with a bio-heat transfer function. In the conventional method of prediction, the thermal parameters were set as constants measured at room temperature (25°C). This study compared the conventional prediction with those predicted with different thermal parameters measured at the various temperatures up to 90°C. The results indicated that the conventional method significantly overestimated the rise in focal temperature in the liver tissue exposed to a clinical HIFU field, compared with the prediction made using thermal parameters measured at temperatures that cause thermal denaturation. This finding suggests that temperature-dependent thermal parameters should be considered in predicting the temperature rise in a tissue to avoid use of an insufficient thermal dose in treatment planning for HIFU surgery.

Nanohybrid liposomal cerasomes with good physiological stability and rapid temperature responsiveness for high intensity focused ultrasound triggered local chemotherapy of cancer.

The high intensity focused ultrasound (HIFU) and thermosensitive cerasomes (HTSCs) were successfully assembled by employing cerasome-forming lipid (CFL) in combination with the component lipids of conventional low temperature sensitive liposomes (LTSLs) including 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC), 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[methoxy(polyethylene glycol)-2000] (DSPE-PEG-2000) and 1-stearoyl-2-hydroxy-sn-glycero-3-phosphocholine (MSPC). The HTSCs showed spherical shape with a mean diameter around 200 nm, exhibiting good biocompatibility. Both hydrophilic and lipophilic drugs can be efficiently encapsulated into HTSCs. In addition, the release rate of HTSCs could be conveniently adjusted by varying the molar ratios of CFL to DPPC. The drug loaded HTSCs showed much longer blood circulation time (half-life >8.50 ± 1.49 h) than conventional LTSLs (0.92 ± 0.17 h). An in vitro study demonstrated that the drug loaded HTSCs are highly stable at 37 °C and show a burst release at 42 °C, providing a capability to act synergistically against tumors. We found that the HTSCs with a proportion of 43.25% of CFL could release more than 90% hydrophilic drugs in 1 min at an elevated temperature of 42 °C generated by HIFU exposure. After intravenous injection of doxorubicin (DOX) loaded HTSCs at 5 mg DOX/kg, followed by double HIFU sonication, the tumor growth of the adenocarcinoma (MDA-MB-231) bearing mice could be significantly inhibited. Therefore, the drug loaded HTSCs combined with HIFU hold great potential for efficient local chemotherapy of cancer due to the ability to deliver high concentration of chemotherapy drugs directly to the tumor, achieve maximum therapeutic efficacy and minimal side effects, and avoid the damage to the healthy tissues caused by systemic administration of drugs.

High-Intensity Focused Ultrasound Attenuates Neural Responses of Sciatic Nerves Isolated from Normal or Neuropathic Rats

Patients with diabetic neuropathy often have neuropathic pain. The purpose of our work was to investigate the effects of high-intensity focused ultrasound (HIFU) on the conduction block of normal and neuropathic nerves for soothing pain. Adult male Sprague–Dawley rats were used, and diabetes was induced by streptozotocin injection. Diabetic neuropathy was evaluated with animal behavior tests. Sciatic nerves of both control and neuropathic rats were dissected from the starting point of the sciatic nerve to the point where the sural nerve ends near the ankle. The nerves were stored in Ringer's solution. The in vitro nerve was placed on a self-developed experimental platform for HIFU exposure. Stimulation and recording of the compound action potentials (CAPs) and sensory action potentials (SAPs) were performed. Control and neuropathic nerves exposed or not exposed to HIFU were submitted to histologic analysis. For the control and neuropathic nerves, suppression of CAPs and SAPs started 2 min post-HIFU treatment. Maximum suppression of SAPs was 34.4 ± 3.2% for the control rats and 11.6 ± 2.0% and 9.8 ± 3.0% for rats 4 wk post-injection and 8 wk post-injection, respectively. Time to full recovery was 25, 70 and 80 min, respectively. Histologic analysis revealed that the nerves in which CAPs and SAPs did not fully recover were damaged thermally or mechanically by HIFU. It is feasible to reversibly block nerves with appropriate HIFU treatment. Diabetic nerves were less suppressed by HIFU and were more vulnerable to permanent damage.

Modulation of the interstitial fluid pressure by high intensity focused ultrasound as a way to alter local fluid and solute movement: insights from a mathematical model

High intensity focused ultrasound (HIFU) operated in thermal mode has been reported to reduce interstitial fluid pressure and improve the penetration of large macromolecules and nanoparticles in tumor and normal tissue. Little is understood about how the interstitial fluid pressure and velocity as well as the interstitial macromolecule transport are affected by HIFU exposure. A mathematical model is presented here which sheds light on the initial biophysical changes brought about HIFU. Our continuum model treats tissue as an effective poro-elastic material that reacts to elevated temperatures with a rapid drop in interstitial elastic modulus. Using parameters from the literature, the model is extrapolated to derive information on the effect in tumors, and to predict its impact on the convective and diffusive transport of macromolecular drugs. The model is first solved using an analytical approximation with step-wise changes at each boundary, and then solved numerically starting from a Gaussian beam approximation of the ultrasound treatment. Our results indicate that HIFU causes a rapid drop in interstitial fluid pressure that may be exploited to facilitate convection of macromolecules from vasculature to the exposed region. However, following a short recovery period in which the interstitial fluid pressure is normalized, transport returns to normal and the advantages disappear over time. The results indicate that this effect is strongest for the delivery of large molecules and nanoparticles that are in the circulation at the time of treatment. The model may be easily applied to more complex situations involving effects on vascular permeability and diffusion.

Quantitative ultrasound imaging to monitor in vivo high-intensity ultrasound treatment

The success of any minimally invasive treatment procedure can be enhanced significantly if combined with a robust noninvasive quantitative imaging modality. Quantitative ultrasound (QUS) imaging has been widely investigated for monitoring various treatment responses such as chemotherapy and thermal therapy. Previously we have shown the feasibility of using spectral based quantitative ultrasound parameters to monitor high-intensity focused ultrasound (HIFU) treatment of in situ tumors [Ultrasonic Imaging, 2014]. In the present study we examined the use the various QUS parameters to monitor HIFU treatment of an in vivo mouse mammary adenocarcinoma model. Spectral parameters in terms of the backscatter coefficient, integrated backscattered energy, attenuation coefficient, and effective scatterer size and concentration were estimated from radiofrequency signals during the treatment. The characteristic of each parameter was compared to the temperature profile recorded by needle thermocouple inserted into the tumor a few millimeters away from the focal zone of the intersecting HIFU and the imaging transducer beams. The changes in the QUS parameters during the HIFU treatment followed similar trends observed in the temperature readings recorded from the thermocouple. These results suggest that QUS techniques have the potential to be used for non-invasive monitoring of HIFU exposure.

Prediction and suppression of HIFU-induced vessel rupture using passive cavitation detection in an ex vivo model.

BackgroundOcclusion of blood vessels using high-intensity focused ultrasound (HIFU) is a potential treatment for arteriovenous malformations and other neurovascular disorders. However, attempting HIFU-induced vessel occlusion can also cause vessel rupture, resulting in hemorrhage. Possible rupture mechanisms include mechanical effects of acoustic cavitation and heating of the vessel wall.MethodsHIFU exposures were performed on 18 ex vivo porcine femoral arteries with simultaneous passive cavitation detection. Vessels were insonified by a 3.3-MHz focused source with spatial-peak, temporal-peak focal intensity of 15,690–24,430 W/cm2 (peak negative-pressure range 10.92–12.52 MPa) and a 50% duty cycle for durations up to 5 min. Time-dependent acoustic emissions were recorded by an unfocused passive cavitation detector and quantified within low-frequency (10–30 kHz), broadband (0.3–1.1 MHz), and subharmonic (1.65 MHz) bands. Vessel rupture was detected by inline metering of saline flow, recorded throughout each treatment. Recorded emissions were grouped into ‘pre-rupture’ (0–10 s prior to measured point of vessel rupture) and ‘intact-vessel’ (>10 s prior to measured point of vessel rupture) emissions. Receiver operating characteristic curve analysis was used to assess the ability of emissions within each frequency band to predict vessel rupture.Based on these measurements associating acoustic emissions with vessel rupture, a real-time feedback control module was implemented to monitor acoustic emissions during HIFU treatment and adjust the ultrasound intensity, with the goal of maximizing acoustic power delivered to the vessel while avoiding rupture. This feedback control approach was tested on 10 paired HIFU exposures of porcine femoral and subclavian arteries, in which the focal intensity was stepwise increased from 9,117 W/cm2 spatial-peak temporal-peak (SPTP) to a maximum of 21,980 W/cm2, with power modulated based on the measured subharmonic emission amplitude. Time to rupture was compared between these feedback-controlled trials and paired controller-inactive trials using a paired Wilcoxon signed-rank test.ResultsSubharmonic emissions were found to be the most predictive of vessel rupture (areas under the receiver operating characteristic curve (AUROC) = 0.757, p < 10-16) compared to low-frequency (AUROC = 0.657, p < 10-11) and broadband (AUROC = 0.729, p < 10-16) emissions. An independent-sample t test comparing pre-rupture to intact-vessel emissions revealed a statistically significant difference between the two groups for broadband and subharmonic emissions (p < 10-3), but not for low-frequency emissions (p = 0.058).In a one-sided paired Wilcoxon signed-rank test, activation of the control module was shown to increase the time to vessel rupture (T- = 8, p = 0.0244, N = 10). In one-sided paired t tests, activation of the control module was shown to cause no significant difference in time-averaged focal intensity (t = 0.362, p = 0.363, N = 10), but was shown to cause delivery of significantly greater total acoustic energy (t = 2.037, p = 0.0361, N = 10).ConclusionsThese results suggest that acoustic cavitation plays an important role in HIFU-induced vessel rupture. In HIFU treatments for vessel occlusion, passive monitoring of acoustic emissions may be useful in avoiding hemorrhage due to vessel rupture, as shown in the rupture suppression experiments.

Quantitative Ultrasound Imaging for Monitoring In Situ High-Intensity Focused Ultrasound Exposure

Quantitative ultrasound (QUS) imaging is hypothesized to map temperature elevations induced in tissue with high spatial and temporal resolution. To test this hypothesis, QUS techniques were examined to monitor high-intensity focused ultrasound (HIFU) exposure of tissue. In situ experiments were conducted on mammary adenocarcinoma tumors grown in rats and lesions were formed using a HIFU system. A thermocouple was inserted into the tumor to provide estimates of temperature at one location. Backscattered time-domain waveforms from the tissue during exposure were recorded using a clinical ultrasonic imaging system. Backscatter coefficients were estimated using a reference phantom technique. Two parameters were estimated from the backscatter coefficient (effective scatterer diameter (ESD) and effective acoustic concentration (EAC). The changes in the average parameters in the regions corresponding to the HIFU focus over time were correlated to the temperature readings from the thermocouple. The changes in the EAC parameter were consistently correlated to temperature during both heating and cooling of the tumors. The changes in the ESD did not have a consistent trend with temperature. The mean ESD and EAC before exposure were 120 ± 16 μm and 32 ± 3 dB/cm3, respectively, and changed to 144 ± 9 μm and 51 ± 7 dB/cm3, respectively, just before the last HIFU pulse was delivered to the tissue. After the tissue cooled down to 37 °C, the mean ESD and EAC were 126 ± 8 μm and 35 ± 4 dB/cm3, respectively. Peak temperature in the range of 50-60 °C was recorded by a thermocouple placed just behind the tumor. These results suggest that QUS techniques have the potential to be used for non-invasive monitoring of HIFU exposure.