Machine Learning Algorithm Detection of Confluent B-Lines.

OBJECTIVE: B-lines are a ring-down artifact of lung ultrasound that arise with increased alveolar water in conditions such as pulmonary edema and infectious pneumonitis. Confluent B-line presence may signify a different level of pathology compared with single B-lines. Existing algorithms aimed at B-line counting do not distinguish between single and confluent B-lines. The objective of this study was to test a machine learning algorithm for confluent B-line identification. METHODS: This study used a subset of 416 clips from 157 subjects, previously acquired in a prospective study enrolling adults with shortness of breath at two academic medical centers, using a hand-held tablet and a 14-zone protocol. After exclusions, random sampling generated a total of 416 clips (146 curvilinear, 150 sector and 120 linear) for review. A group of five experts in point-of-care ultrasound blindly evaluated the clips for presence/absence of confluent B-lines. Ground truth was defined as majority agreement among the experts and used for comparison with the algorithm. RESULTS: Confluent B-lines were present in 206 of 416 clips (49.5%). Sensitivity and specificity of confluent B-line detection by algorithm compared with expert determination were 83% (95% confidence interval [CI]: 0.77-0.88) and 92% (95% CI: 0.88-0.96). Sensitivity and specificity did not statistically differ between transducers. Agreement between algorithm and expert for confluent B-lines measured by unweighted κ was 0.75 (95% CI: 0.69-0.81) for the overall set. CONCLUSION: The confluent B-line detection algorithm had high sensitivity and specificity for detection of confluent B-lines in lung ultrasound point-of-care clips, compared with expert determination.

What happens to brain outside the thermal ablation zones? An assessment of needle-based therapeutic ultrasound in survival swine.

BACKGROUND: In stereotactic radiosurgery, isodose lines must be considered to determine how surrounding tissue is affected. In thermal ablative therapy, such as laser interstitial thermal therapy (LITT), transcranial MR-guided focused ultrasound (tcMRgFUS), and needle-based therapeutic ultrasound (NBTU), how the surrounding area is affected has not been well studied. OBJECTIVE: We aimed to quantify the transition zone surrounding the ablation core created by magnetic resonance-guided robotically-assisted (MRgRA) delivery of NBTU using multi-slice volumetric 2-D magnetic resonance thermal imaging (MRTI) and subsequent characterization of the resultant tissue damage using histopathologic analysis. METHODS: Four swine underwent MRgRA NBTU using varying duration and wattage for treatment delivery. Serial MRI images were obtained, and the most representative were overlaid with isodose lines and compared to brain tissue acquired postmortem which underwent histopathologic analysis. These results were also compared to predicted volumes using a finite element analysis model. Contralateral brain tissue was used for control data. RESULTS: Intraoperative MRTI thermal isodose contours were characterized and comprehensively mapped to post-operative MRI images and qualitatively compared with histological tissue sections postmortem. NBTU 360° ablations induced smaller lesion volumes (33.19 mm3; 120 s, 3 W; 30.05 mm3, 180 s, 4 W) versus 180° ablations (77.20 mm3, 120 s, 3 W; 109.29 mm3; 180 s; 4 W). MRTI/MRI overlay demonstrated the lesion within the proximal isodose lines. The ablation-zone was characterized by dense macrophage infiltration and glial/neuronal loss as demonstrated by glial fibrillary acidic protein (GFAP) and neurofilament (NF) absence and avid CD163 staining. The transition-zone between lesion and normal brain demonstrated decreased macrophage infiltration and measured ∼345 microns (n - 3). We did not detect overt hemorrhages or signs of edema in the adjacent spared tissue. CONCLUSION: We successfully performed MRgRA NBTU ablation in swine and demonstrated minimal histologic changes extended past the ablation-zone. The lesion was characterized by macrophage infiltration and glial/neuronal loss which decreased through the transition-zone.

Low Intensity Focused Ultrasound Increases Duration of Anti-Nociceptive Responses in Female Common Peroneal Nerve Injury Rats.

OBJECTIVE: Chronic pain affects 7%-10% of Americans, occurs more frequently and severely in females, and available treatments have been shown to have less efficacy in female patients. Preclinical models addressing sex-specific treatment differences in the treatment of chronic pain have been limited. Here we examine the sex-specific effects of low intensity focused ultrasound (liFUS) in a modified sciatic nerve injury (SNI) model. MATERIALS AND METHODS: A modified SNI performed by ligating the common peroneal nerve (CPN) was used to measure sensory, behavioral pain responses, and nerve conduction studies in female and male rats, following liFUS of the L5 dorsal root ganglion. RESULTS: Using the same dose of liFUS in females and males of the same weight, CPN latency immediately after treatment was increased for 50 min in females compared to 25 min in males (p < 0.001). Improvements in mechanical pain thresholds after liFUS lasted significantly longer in females (seven days; p < 0.05) compared to males (three days; p < 0.05). In females, there was a significant improvement in depression-like behavior as a result of liFUS (N = 5; p < 0.01); however, because males never developed depression-like behavior there was no change after liFUS treatment. CONCLUSIONS: Neuromodulation with liFUS has a greater effect in female rats on CPN latency, mechanical allodynia duration, and depression-like behavior. In order to customize neuromodulatory techniques for different patient phenotypes, it is essential to understand how they may alter sex-specific pathophysiologies.

Predicting ablation zones with multislice volumetric 2-D magnetic resonance thermal imaging.

BACKGROUND: High-intensity focused ultrasound (HIFU) serves as a noninvasive stereotactic system for the ablation of brain metastases; however, treatments are limited to simple geometries and energy delivery is limited by the high acoustic attenuation of the calvarium. Minimally-invasive magnetic resonance-guided robotically-assisted (MRgRA) needle-based therapeutic ultrasound (NBTU) using multislice volumetric 2-D magnetic resonance thermal imaging (MRTI) overcomes these limitations and has potential to produce less collateral tissue damage than current methods. OBJECTIVE: To correlate multislice volumetric 2-D MRTI volumes with histologically confirmed regions of tissue damage in MRgRA NBTU. METHODS: Seven swine underwent a total of 8 frontal MRgRA NBTU lesions. MRTI ablation volumes were compared to histologic tissue damage on brain sections stained with 2,3,5-triphenyltetrazolium chloride (TTC). Bland-Altman analyses and correlation trends were used to compare MRTI and TTC ablation volumes. RESULTS: Data from the initial and third swine's ablations were excluded due to sub-optimal tissue staining. For the remaining ablations (n = 6), the limits of agreement between the MRTI and histologic volumes ranged from -0.149 cm3 to 0.252 cm3 with a mean difference of 0.052 ± 0.042 cm3 (11.1%). There was a high correlation between the MRTI and histology volumes (r2 = 0.831) with a strong linear relationship (r = 0.868). CONCLUSION: We used a volumetric MRTI technique to accurately track thermal changes during MRgRA NBTU in preparation for human trials. Improved volumetric coverage with MRTI enhanced our delivery of therapy and has far-reaching implications for focused ultrasound in the broader clinical setting.

Effects of external low intensity focused ultrasound on inflammatory markers in neuropathic pain.

BACKGROUND: Changes in inflammatory cytokine levels contribute to the induction and maintenance of neuropathic pain. We have shown that external low intensity focused ultrasound (liFUS) reduces allodynia in a common peroneal nerve injury (CPNI). Here, we investigate an underlying mechanism of action for this treatment and measure the effect of liFUS on inflammatory markers. METHODS: Male rats were divided into four groups: CPNI/liFUS, CPNI/shamliFUS, shamCPNI/liFUS, and shamCPNI/shamliFUS. Mechanical nociceptive thresholds were measured using Von Frey filaments (VFF) to confirm the absence/presence of allodynia at baseline, after CPNI, and after liFUS. Commercial microarray and ELISA assays were used to assess cytokine expression in the treated L5 dorsal root ganglion (DRG) and dorsal horn (DH) tissue 24 and 72 h after liFUS. RESULTS: VFF thresholds were significantly reduced following CPNI in both groups that received the injury (p < 0.001). After liFUS, only the CPNI/liFUS cohort showed a significant increase in mechanical thresholds (p < 0.001). CPNI significantly increased TNFa, IL6, CNTF, IL1b (p < 0.05 for all) levels in the DRG and DH, compared to baseline, consistent with previous work in sciatic nerve injury. LiFUS in CPNI rats resulted in a decrease in these cytokines in DRG 72 h post-therapy (TNFa, IL6, CNTF and IL1b, p < 0.001). In the DH, IL1b, CNTF, and TNFa (p < 0.05 for all) decreased 72 h after liFUS. CONCLUSION: We have demonstrated that liFUS modifies inflammatory cytokines in both DRG and DH in CPNI rats. These data provide evidence that liFUS, reverses the allodynic phenotype, in part, by altering inflammatory cytokine pathways.

Pilot study on the effects of low intensity focused ultrasound in a swine model of neuropathic pain.

OBJECTIVE: The authors' laboratory has previously demonstrated beneficial effects of noninvasive low intensity focused ultrasound (liFUS), targeted at the dorsal root ganglion (DRG), for reducing allodynia in rodent neuropathic pain models. However, in rats the DRG is 5 mm below the skin when approached laterally, while in humans the DRG is typically 5-8 cm deep. Here, using a modified liFUS probe, the authors demonstrated the feasibility of using external liFUS for modulation of antinociceptive responses in neuropathic swine. METHODS: Two cohorts of swine underwent a common peroneal nerve injury (CPNI) to induce neuropathic pain. In the first cohort, pigs (14 kg) were iteratively tested to determine treatment parameters. liFUS penetration to the L5 DRG was verified by using a thermocouple to monitor tissue temperature changes and by measuring nerve conduction velocity (NCV) at the corresponding common peroneal nerve (CPN). Pain behaviors were monitored before and after treatment. DRG was evaluated for tissue damage postmortem. Based on data from the first cohort, a treatment algorithm was developed, parameter predictions were verified, and neuropathic pain was significantly modified in a second cohort of larger swine (20 kg). RESULTS: The authors performed a dose-response curve analysis in 14-kg CPNI swine. Specifically, after confirming that the liFUS probe could reach 5 cm in ex vivo tissue experiments, the authors tested liFUS in 14-kg CPNI swine. The mean ± SEM DRG depth was 3.79 ± 0.09 cm in this initial cohort. The parameters were determined and then extrapolated to larger animals (20 kg), and predictions were verified. Tissue temperature elevations at the treatment site did not exceed 2°C, and the expected increases in the CPN NCV were observed. liFUS treatment eliminated pain guarding in all animals for the duration of follow-up (up to 1 month) and improved allodynia for 5 days postprocedure. No evidence of histological damage was seen using Fluoro-Jade and H&E staining. CONCLUSIONS: The results demonstrate that a 5-cm depth can be reached with external liFUS and alters pain behavior and allodynia in a large-animal model of neuropathic pain.

Artificial Intelligence-enabled, Real-time Intraoperative Ultrasound Imaging of Neural Structures Within the Psoas: Validation in a Porcine Spine Model.

STUDY DESIGN: Experimental in-vivo animal study. OBJECTIVE: The aim of this study was to evaluate an Artificial Intelligence (AI)-enabled ultrasound imaging system's ability to detect, segment, classify, and display neural and other structures during trans-psoas spine surgery. SUMMARY OF BACKGROUND DATA: Current methodologies for intraoperatively localizing and visualizing neural structures within the psoas are limited and can impact the safety of lateral lumbar interbody fusion (LLIF). Ultrasound technology, enhanced with AI-derived neural detection algorithms, could prove useful for this task. METHODS: The study was conducted using an in vivo porcine model (50 subjects). Image processing and machine learning algorithms were developed to detect neural and other anatomic structures within and adjacent to the psoas muscle while using an ultrasound imaging system during lateral lumbar spine surgery (SonoVision,™ Tissue Differentiation Intelligence, USA). The imaging system's ability to detect and classify the anatomic structures was assessed with subsequent tissue dissection. Dice coefficients were calculated to quantify the performance of the image segmentation. RESULTS: The AI-trained ultrasound system detected, segmented, classified, and displayed nerve, psoas muscle, and vertebral body surface with high sensitivity and specificity. The mean Dice coefficient score for each tissue type was >80%, indicating that the detected region and ground truth were >80% similar to each other. The mean specificity of nerve detection was 92%; for bone and muscle, it was >95%. The accuracy of nerve detection was >95%. CONCLUSION: This study demonstrates that a combination of AI-derived image processing and machine learning algorithms can be developed to enable real-time ultrasonic detection, segmentation, classification, and display of critical anatomic structures, including neural tissue, during spine surgery. AI-enhanced ultrasound imaging can provide a visual map of important anatomy in and adjacent to the psoas, thereby providing the surgeon with critical information intended to increase the safety of LLIF surgery.Level of Evidence: N/A.

Effects of external low intensity focused ultrasound on electrophysiological changes in vivo in a rodent model of common peroneal nerve injury.

Non-invasive treatment methods for neuropathic pain are lacking. We assess how modulatory low intensity focused ultrasound (liFUS) at the L5 dorsal root ganglion (DRG) affects behavioral responses and sensory nerve action potentials (SNAPs) in a common peroneal nerve injury (CPNI) model. Rats were assessed for mechanical and thermal responses using Von Frey filaments (VFF) and the hot plate test (HPT) following CPNI surgery. Testing was repeated 24 h after liFUS treatment. Significant increases in mechanical and thermal sensory thresholds were seen post-liFUS treatment, indicating a reduction in sensitivity to pain (p < 0.0001, p = 0.02, respectively). Animals who received CPNI surgery had significant increases in SNAP latencies compared to sham CPNI surgery animals (p = 0.0003) before liFUS treatment. LiFUS induced significant reductions in SNAP latency in both CPNI liFUS and sham CPNI liFUS cohorts, for up to 35 min post treatment. No changes were seen in SNAP amplitude and there was no evidence of neuronal degeneration 24 h after liFUS treatment, showing that liFUS did not damage the tissue being modulated. This is the first in vivo study of the impact of liFUS on peripheral nerve electrophysiology in a model of chronic pain. This study demonstrates the effects of liFUS on peripheral nerve electrophysiology in vivo. We found that external liFUS treatment results in transient decreased latency in common peroneal nerve (CPN) sensory nerve action potentials (SNAPs) with no change in signal amplitude.

Low Intensity Focused Ultrasound Modulation of Vincristine Induced Neuropathy.

Previously, we showed internal low intensity focused ultrasound (liFUS) improves nociceptive thresholds in rats with vincristine-induced neuropathy (VIN) for 48-h post-treatment. Here, we perform more rigorous behavioral testing with the internal device and introduce external liFUS treatment. Behavioral testing confirmed VIN (Von Frey fibers, VFF; hot plate, HPT; locomotion, OFT). This was followed by internal or external liFUS treatment (2.5 W or 8 W, for 3 min, respectively) to the left L5 dorsal root ganglia (DRG). A thermocouple placed at the DRG documented temperature changes during treatment, to confirm the modulatory nature of our treatment. Behavioral testing was performed pre-liFUS, and for five consecutive days post-liFUS. Groups included: (1) VIN/liFUS, (2) saline/liFUS, (3) VIN/sham liFUS, and (4) saline/sham liFUS. Significant improvements in mechanical (VFF) and thermal (HPT) nociceptive thresholds were seen in the VIN/liFUS group following both internal and external treatment. Hematoxylin and Eosin, and Fluorojade staining showed no histological damage to the DRG. Internal liFUS treatment produced a mean temperature rise of 3.21 ±â€¯0.30 °C, whereas external liFUS resulted in a mean temperature rise of 1.78 °C ±â€¯0.21 °C. We demonstrate that, in a VIN rat model, external liFUS treatment of the L5 DRG significantly reduces nociceptive sensitivity thresholds without causing tissue damage.

Robotic Assisted MRI-Guided Interventional Interstitial MR-Guided Focused Ultrasound Ablation in a Swine Model.

BACKGROUND: Ablative lesions are current treatments for epilepsy and brain tumors. Interstitial magnetic resonance (MR) guided focused ultrasound (iMRgFUS) may be an alternate ablation technique which limits thermal tissue charring as compared to laser therapy (LITT) and can produce larger ablation patterns nearer the surface than transcranial MR guided focused ultrasound (tcMRgFUS). OBJECTIVE: To describe our experience with interstitial focused ultrasound (iFUS) ablations in swine, using MR-guided robotically assisted (MRgRA) delivery. METHODS: In an initial 3 animals, we optimized the workflow of the robot in the MR suite and made modifications to the robotic arm to allow range of motion. Then, 6 farm pigs (4 acute, 2 survival) underwent 7 iMRgFUS ablations using MRgRA. We altered dosing to explore differences between thermal dosing in brain as compared to other tissues. Imaging was compared to gross examination. RESULTS: Our work culminated in adjustments to the MRgRA, iMRgFUS probes, and dosing, culminating in 2 survival surgeries; swine had ablations with no neurological sequelae at 2 wk postprocedure. Immediately following iMRgFUS therapy, diffusion-weighted imaging, and T1 weighted MR were accurate reflections of the ablation volume. T2 and fluid-attenuated inversion-recovery (FLAIR) images were accurate reflections of ablation volume 1-wk postprocedure. CONCLUSION: We successfully performed MRgRA iFUS ablation in swine and found intraoperative and postoperative imaging to correlate with histological examination. These data are useful to validate our system and to guide imaging follow-up for thermal ablation lesions in brain tissue from our therapy, tcMRgFUS, and LITT.

The use of focused ultrasound for the treatment of cutaneous allodynia associated with chronic migraine.

Chronic migraines (CM) are the third most common disease and are refractory to medical treatment in 15% of patients. Currently, temporary relief is achieved with steroid blocks or pulsed radiofrequency ablation, which have short-term benefits. Our project aims to develop a non-invasive treatment for medically refractory chronic migraine, which does not require a permanent implant. This project investigates the safety and effectiveness of pulsed focused ultrasound (FUS) in a validated rodent headache model of cutaneous allodynia associated with chronic migraine (CM) as compared to sumatriptan and ablative lesioning. We demonstrate a significant reduction in mechanical thresholds as measured through Von Frey filaments in CM in the forepaw and periorbital region (p < 0.001). Sumatriptan and pulsed FUS both significantly improve thresholds at day 3 after treatment in the periorbital region. Ablative lesioning has no effect. This study provides initial evidence that FUS may provide an important therapeutic option for patients suffering from CM.

A minimally invasive catheter-based ultrasound technology for therapeutic interventions in brain: initial preclinical studies.

OBJECTIVE Minimally invasive procedures may allow surgeons to avoid conventional open surgical procedures for certain neurological disorders. This paper describes the iterative process for development of a catheter-based ultrasound thermal therapy applicator. METHODS Using an ultrasound applicator with an array of longitudinally stacked and angularly sectored tubular transducers within a catheter, the authors conducted experimental studies in porcine liver, in vivo and ex vivo, in order to characterize the device performance and lesion patterns. In addition, they applied the technique in a rodent model of Parkinson's disease to investigate the feasibility of its application in brain. RESULTS Thermal lesions with multiple shapes and sizes were readily achieved in porcine liver. The feasibility of catheter-based focused ultrasound in the treatment of brain conditions was demonstrated in a rodent model of Parkinson's disease. CONCLUSIONS The authors show proof of principle of a catheter-based ultrasound system that can create lesions with concurrent thermode-based measurements.

Magnetic resonance-guided interstitial high-intensity focused ultrasound for brain tumor ablation.

Currently, treatment of brain tumors is limited to resection, chemotherapy, and radiotherapy. Thermal ablation has been recently explored. High-intensity focused ultrasound (HIFU) is being explored as an alternative. Specifically, the authors propose delivering HIFU internally to the tumor with an MRI-guided robotic assistant (MRgRA). The advantage of the authors' interstitial device over external MRI-guided HIFU (MRgHIFU) is that it allows for conformal, precise ablation and concurrent tissue sampling. The authors describe their workflow for MRgRA HIFU delivery.

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.

Trimodal Therapy: Combining Hyperthermia with Repurposed Bexarotene and Ultrasound for Treating Liver Cancer.

Repurposing of existing cancer drugs to overcome their physical limitations, such as insolubility, represents an attractive strategy to achieve enhanced therapeutic efficacy and broaden the range of clinical applications. Such an approach also promises to offer substantial cost savings in drug development efforts. Here we repurposed FDA-approved topical agent bexarotene (Targretin), currently in limited use for cutaneous manifestations of T-cell lymphomas, and re-engineer it for use in solid tumor applications by forming self-assembling nanobubbles. Physico-chemical characterization studies of the novel prodrug nanobubbles demonstrated their stability, enhanced target cell internalization capability, and highly controlled release profile in response to application of focused ultrasound energy. Using an in vitro model of hepatocellular carcinoma and an in vivo large animal model of liver ablation, we demonstrate the effectiveness of bexarotene prodrug nanobubbles when used in conjunction with catheter-based ultrasound, thereby highlighting the therapeutic promise of this trimodal approach.

Quantitative Ultrasound Comparison of MAT and 4T1 Mammary Tumors in Mice and Rats Across Multiple Imaging Systems.

OBJECTIVES: Quantitative ultrasound estimates such as the frequency-dependent backscatter coefficient (BSC) have the potential to enhance noninvasive tissue characterization and to identify tumors better than traditional B-mode imaging. Thus, investigating system independence of BSC estimates from multiple imaging platforms is important for assessing their capabilities to detect tissue differences. METHODS: Mouse and rat mammary tumor models, 4T1 and MAT, respectively, were used in a comparative experiment using 3 imaging systems (Siemens, Ultrasonix, and VisualSonics) with 5 different transducers covering a range of ultrasonic frequencies. RESULTS: Functional analysis of variance of the MAT and 4T1 BSC-versus-frequency curves revealed statistically significant differences between the two tumor types. Variations also were found among results from different transducers, attributable to frequency range effects. At 3 to 8 MHz, tumor BSC functions using different systems showed no differences between tumor type, but at 10 to 20 MHz, there were differences between 4T1 and MAT tumors. Fitting an average spline model to the combined BSC estimates (3-22 MHz) demonstrated that the BSC differences between tumors increased with increasing frequency, with the greatest separation above 15 MHz. Confining the analysis to larger tumors resulted in better discrimination over a wider bandwidth. CONCLUSIONS: Confining the comparison to higher ultrasonic frequencies or larger tumor sizes allowed for separation of BSC-versus-frequency curves from 4T1 and MAT tumors. These constraints ensure that a greater fraction of the backscattered signals originated from within the tumor, thus demonstrating that statistically significant tumor differences were detected.

Enhancing cell kill in vitro from hyperthermia through pre-sensitizing with ultrasound-stimulated microbubbles.

Ultrasound-stimulated microbubbles (MBs) were demonstrated to enhance cell kill from hyperthermia. Definity MBs were injected into wells containing 4T1 cells in culture media and scanned with 1-MHz ultrasound, an exposure duration of 30 s and a negative pressure of 0.5 or 1.3 MPa. Some cell samples were placed in a water bath heated to 42 °C for 5 min. Cell death was quantified. When combining MBs, ultrasound at 1.3 MPa and hyperthermia, more than 58.8% ± 7.21% of cells were nonviable. When exposed to hyperthermia alone or exposure to MBs and ultrasound but no hyperthermia, cell death was less than 10.1% ± 6.96% and 30.1% ± 10.8%, respectively.

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.

Exploring potential mechanisms responsible for observed changes of ultrasonic backscattered energy with temperature variations.

PURPOSE: Previous studies have provided the observation that the ultrasonic backscattered energy from a tissue region will change due to a change of temperature. The mechanism responsible for the changes in backscattered energy (CBE) with temperature has been hypothesized to be from the changes in scattering properties of local aqueous and lipid scatterers. An alternative mechanism is hypothesized here to be capable of producing similar CBE curves, i.e., changes in speckle resulting from changes in summation of scattered wavelets. METHODS: Both simulations and experiments were conducted with a 5.5 MHz, 128-element linear array and synthetic and physical phantoms containing randomly spaced scatterers. The speckle pattern resulting from summation of scattered wavelets was changed in simulations and experiments by directly increasing the background sound speed from 1520 to 1540 m/s, and changing the temperature from 37 °C to 48 °C, respectively. Shifts in the backscattered signal were compensated using 2D cross-correlation techniques. RESULTS: Excellent agreement between simulations and experiments was observed, with each pixel in the CBE images on average undergoing either a monotonic increase (up to 3.2 dB) or a monotonic decrease (down to -1.9 dB) with increasing sound speed or temperature. Similar CBE curves were also produced by shifting the image plane in the elevational and axial directions even after correcting for apparent motion. CONCLUSIONS: CBE curves were produced by changing the sound speed or temperature in tissue mimicking phantoms or by shifting the image plane in the elevational and axial directions and the production of these CBE curves did not require the presence of lipid and aqueous scatterers.