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.

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.

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.

Treatment Planning Strategies for Interstitial Ultrasound Ablation of Prostate Cancer.

PURPOSE: To develop patient-specific 3D models using Finite-Difference Time-Domain (FDTD) simulations and pre-treatment planning tools for the selective thermal ablation of prostate cancer with interstitial ultrasound. This involves the integration with a FDA 510(k) cleared catheter-based ultrasound interstitial applicators and delivery system. METHODS: A 3D generalized "prostate" model was developed to generate temperature and thermal dose profiles for different applicator operating parameters and anticipated perfusion ranges. A priori planning, based upon these pre-calculated lethal thermal dose and iso-temperature clouds, was devised for iterative device selection and positioning. Full 3D patient-specific anatomic modeling of actual placement of single or multiple applicators to conformally ablate target regions can be applied, with optional integrated pilot-point temperature-based feedback control and urethral/rectum cooling. These numerical models were verified against previously reported ex-vivo experimental results obtained in soft tissues. RESULTS: For generic prostate tissue, 360 treatment schemes were simulated based on the number of transducers (1-4), applied power (8-20 W/cm2), heating time (5, 7.5, 10 min), and blood perfusion (0, 2.5, 5 kg/m3/s) using forward treatment modelling. Selectable ablation zones ranged from 0.8-3.0 cm and 0.8-5.3 cm in radial and axial directions, respectively. 3D patient-specific thermal treatment modeling for 12 Cases of T2/T3 prostate disease demonstrate applicability of workflow and technique for focal, quadrant and hemi-gland ablation. A temperature threshold (e.g., Tthres = 52 °C) at the treatment margin, emulating placement of invasive temperature sensing, can be applied for pilot-point feedback control to improve conformality of thermal ablation. Also, binary power control (e.g., Treg = 45 °C) can be applied which will regulate the applied power level to maintain the surrounding temperature to a safe limit or maximum threshold until the set heating time. CONCLUSIONS: Prostate-specific simulations of interstitial ultrasound applicators were used to generate a library of thermal-dose distributions to visually optimize and set applicator positioning and directivity during a priori treatment planning pre-procedure. Anatomic 3D forward treatment planning in patient-specific models, along with optional temperature-based feedback control, demonstrated single and multi-applicator implant strategies to effectively ablate focal disease while affording protection of normal tissues.

Deep Brain Ultrasound Ablation Thermal Dose Modeling with in Vivo Experimental Validation.

Intracorporeal needle-based therapeutic ultrasound (NBTU) is a minimally invasive option for intervening in malignant brain tumors, commonly used in thermal ablation procedures. This technique is suitable for both primary and metastatic cancers, utilizing a high-frequency alternating electric field (up to 10 MHz) to excite a piezoelectric transducer. The resulting rapid deformation of the transducer produces an acoustic wave that propagates through tissue, leading to localized high-temperature heating at the target tumor site and inducing rapid cell death. To optimize the design of NBTU transducers for thermal dose delivery during treatment, numerical modeling of the acoustic pressure field generated by the deforming piezoelectric transducer is frequently employed. The bioheat transfer process generated by the input pressure field is used to track the thermal propagation of the applicator over time. Magnetic resonance thermal imaging (MRTI) can be used to experimentally validate these models. Validation results using MRTI demonstrated the feasibility of this model, showing a consistent thermal propagation pattern. However, a thermal damage isodose map is more advantageous for evaluating therapeutic efficacy. To achieve a more accurate simulation based on the actual brain tissue environment, a new finite element method (FEM) simulation with enhanced damage evaluation capabilities was conducted. The results showed that the highest temperature and ablated volume differed between experimental and simulation results by 2.1884°C (3.71%) and 0.0631 cm3 (5.74%), respectively. The lowest Pearson correlation coefficient (PCC) for peak temperature was 0.7117, and the lowest Dice coefficient for the ablated area was 0.7021, indicating a good agreement in accuracy between simulation and experiment.

Characterization of ultrasound elevation beamwidth artifacts for prostate brachytherapy needle insertion.

PURPOSE: Ultrasound elevation beamwidth leads to image artifacts and uncertainties in localizing objects (such as a surgical needle) in ultrasound images. The authors examined the clinical significance of errors caused by elevation beamwidth artifacts and imaging parameters in needle insertion procedures. METHODS: Beveled prostate brachytherapy needles were inserted through all holes of a grid template under real-time transrectal ultrasound (TRUS) guidance. The needle tip position as indicated by the TRUS image was compared to their observed physical location. A new device was developed to measure the ultrasound elevation beamwidth. RESULTS: Imaging parameters of the TRUS scanner have direct impact on the localization error ranging from 0.5 up to 4 mm. The smallest localization error was observed laterally close to the center of the grid template and axially within the beam's focal zone. Largest localization error occurs laterally around both sides of the grid template and axially within the beam's far field. The authors also found that the localization errors vary with both lateral and elevation offsets. CONCLUSIONS: The authors found properly adjusting the TRUS imaging settings to lower the ultrasound gain and power effectively minimized the appearance of elevation beamwidth artifacts and in turn reduced the localization errors of the needle tip.

Automated intraoperative calibration for prostate cancer brachytherapy.

PURPOSE: Prostate cancer brachytherapy relies on an accurate spatial registration between the implant needles and the TRUS image, called "calibration". The authors propose a new device and a fast, automatic method to calibrate the brachytherapy system in the operating room, with instant error feedback. METHODS: A device was CAD-designed and precision-engineered, which mechanically couples a calibration phantom with an exact replica of the standard brachytherapy template. From real-time TRUS images acquired from the calibration device and processed by the calibration system, the coordinate transformation between the brachytherapy template and the TRUS images was computed automatically. The system instantly generated a report of the target reconstruction accuracy based on the current calibration outcome. RESULTS: Four types of validation tests were conducted. First, 50 independent, real-time calibration trials yielded an average of 0.57 ± 0.13 mm line reconstruction error (LRE) relative to ground truth. Second, the averaged LRE was 0.37 ± 0.25 mm relative to ground truth in tests with six different commercial TRUS scanners operating at similar imaging settings. Furthermore, testing with five different commercial stepper systems yielded an average of 0.29 ± 0.16 mm LRE relative to ground truth. Finally, the system achieved an average of 0.56 ± 0.27 mm target registration error (TRE) relative to ground truth in needle insertion tests through the template in a water tank. CONCLUSIONS: The proposed automatic, intraoperative calibration system for prostate cancer brachytherapy has achieved high accuracy, precision, and robustness.

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.

An Integrated Robotic System for MRI-Guided Neuroablation: Preclinical Evaluation.

OBJECTIVE: Treatment of brain tumors requires high precision in order to ensure sufficient treatment while minimizing damage to surrounding healthy tissue. Ablation of such tumors using needle-based therapeutic ultrasound (NBTU) under real-time magnetic resonance imaging (MRI) can fulfill this need. However, the constrained space and strong magnetic field in the MRI bore restricts patient access limiting precise placement of the NBTU ablation tool. A surgical robot compatible with use inside the bore of an MRI scanner can alleviate these challenges. METHODS: We present preclinical trials of a robotic system for NBTU ablation of brain tumors under real-time MRI guidance. The system comprises of an updated robotic manipulator and corresponding control electronics, the NBTU ablation system and applications for planning, navigation and monitoring of the system. RESULTS: The robotic system had a mean translational and rotational accuracy of 1.39  ± 0.64 mm and 1.27 [Formula: see text] in gelatin phantoms and 3.13  ± 1.41 mm and 5.58 [Formula: see text] in 10 porcine trials while causing a maximum reduction in signal to noise ratio (SNR) of 10.3%. CONCLUSION: The integrated robotic system can place NBTU ablator at a desired target location in porcine brain and monitor the ablation in realtime via magnetic resonance thermal imaging (MRTI). SIGNIFICANCE: Further optimization of this system could result in a clinically viable system for use in human trials for various diagnostic or therapeutic neurosurgical interventions.

System Integration and Preliminary Clinical Evaluation of a Robotic System for MRI-Guided Transperineal Prostate Biopsy.

This paper presents the development, preclinical evaluation, and preliminary clinical study of a robotic system for targeted transperineal prostate biopsy under direct interventional magnetic resonance imaging (MRI) guidance. The clinically integrated robotic system is developed based on a modular design approach, comprised of surgical navigation application, robot control software, MRI robot controller hardware, and robotic needle placement manipulator. The system provides enabling technologies for MRI-guided procedures. It can be easily transported and setup for supporting the clinical workflow of interventional procedures, and the system is readily extensible and reconfigurable to other clinical applications. Preclinical evaluation of the system is performed with phantom studies in a 3 Tesla MRI scanner, rehearsing the proposed clinical workflow, and demonstrating an in-plane targeting error of 1.5mm. The robotic system has been approved by the institutional review board (IRB) for clinical trials. A preliminary clinical study is conducted with the patient consent, demonstrating the targeting errors at two biopsy target sites to be 4.0mm and 3.7mm, which is sufficient to target a clinically significant tumor foci. First-in-human trials to evaluate the system's effectiveness and accuracy for MR image-guide prostate biopsy are underway.

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.

Evaluation of robot-assisted MRI-guided prostate biopsy: needle path analysis during clinical trials.

While the interaction between a needle and the surrounding tissue is known to cause a significant targeting error in prostate biopsy leading to false-negative results, few studies have demonstrated how it impacts in the actual procedure. We performed a pilot study on robot-assisted MRI-guided prostate biopsy with an emphasis on the in-depth analysis of the needle-tissue interaction in vivo. The data were acquired during in-bore transperineal prostate biopsies in patients using a 4 degrees-of-freedom (DoF) MRI-compatible robot. The anatomical structures in the pelvic area and the needle path were reconstructed from MR images, and quantitatively analyzed. We analyzed each structure individually and also proposed a mathematical model to investigate the influence of those structures in the targeting error using the mixed-model regression. The median targeting error in 188 insertions (27 patients) was 6.3 mm. Both the individual anatomical structure analysis and the mixed-model analysis showed that the deviation resulted from the contact between the needle and the skin as the main source of error. On contrary, needle bending inside the tissue (expressed as needle curvature) did not vary among insertions with targeting errors above and below the average. The analysis indicated that insertions crossing the bulbospongiosus presented a targeting error lower than the average. The mixed-model analysis demonstrated that the distance between the needle guide and the patient skin, the deviation at the entry point, and the path length inside the pelvic diaphragm had a statistically significant contribution to the targeting error (p < 0.05). Our results indicate that the errors associated with the elastic contact between the needle and the skin were more prominent than the needle bending along the insertion. Our findings will help to improve the preoperative planning of transperineal prostate biopsies.

PLUS: open-source toolkit for ultrasound-guided intervention systems.

A variety of advanced image analysis methods have been under the development for ultrasound-guided interventions. Unfortunately, the transition from an image analysis algorithm to clinical feasibility trials as part of an intervention system requires integration of many components, such as imaging and tracking devices, data processing algorithms, and visualization software. The objective of our paper is to provide a freely available open-source software platform-PLUS: Public software Library for Ultrasound-to facilitate rapid prototyping of ultrasound-guided intervention systems for translational clinical research. PLUS provides a variety of methods for interventional tool pose and ultrasound image acquisition from a wide range of tracking and imaging devices, spatial and temporal calibration, volume reconstruction, simulated image generation, and recording and live streaming of the acquired data. This paper introduces PLUS, explains its functionality and architecture, and presents typical uses and performance in ultrasound-guided intervention systems. PLUS fulfills the essential requirements for the development of ultrasound-guided intervention systems and it aspires to become a widely used translational research prototyping platform. PLUS is freely available as open source software under BSD license and can be downloaded from http://www.plustoolkit.org.

Ultrasound-guided characterization of interstitial ablated tissue using RF time series: feasibility study.

This paper presents the results of a feasibility study to demonstrate the application of ultrasound RF time series imaging to accurately differentiate ablated and nonablated tissue. For 12 ex vivo and two in situ tissue samples, RF ultrasound signals are acquired prior to, and following, high-intensity ultrasound ablation. Spatial and temporal features of these signals are used to characterize ablated and nonablated tissue in a supervised-learning framework. In cross-validation evaluation, a subset of four features extracted from RF time series produce a classification accuracy of 84.5%, an area under ROC curve of 0.91 for ex vivo data, and an accuracy of 85% for in situ data. Ultrasound RF time series is a promising approach for characterizing ablated tissue.

Effects of ultrasound section-thickness on brachytherapy needle tip localization error.

PURPOSE: Ultrasound section-thickness is the out-of-plane beamwidth causing major roles in creating image artifacts normally appearing around the anechoic areas. These artifacts can introduce errors in localizing the needle tips during any ultrasound-guided procedure. To study how section-thickness and imaging parameters can affect observing and localizing needle tips, we have conducted a typical calibration setup experiment. METHOD: Multiple needles were inserted orthogonal to the axial image plane, at various distances from the transducer. The experiment was conducted on a brachytherapy stepper for a curvilinear transrectal-ultrasound probe. RESULT: Experiments demonstrated that the imaging parameters have direct impacts on observing needle tips at different axial locations. They suggest specific settings to minimize the imaging artifacts. CONCLUSION: The ultrasound section-thickness and side lobes could result in misjudgment of needle insertion depth in an ultrasound-guided procedure. A beam profile could assist in considering the likelihood of position errors, when the effects of side lobes are minimized.