Biomechanical testing of ex vivo porcine tendons following high intensity focused ultrasound thermal ablation.

INTRODUCTION: Magnetic resonance-guided focused ultrasound (MRgFUS) has been demonstrated to be able to thermally ablate tendons with the aim to non-invasively disrupt tendon contractures in the clinical setting. However, the biomechanical changes of tendons permitting this disrupting is poorly understood. We aim to obtain a dose-dependent biomechanical response of tendons following magnetic resonance-guided focused ultrasound (MRgFUS) thermal ablation. METHODS: Ex vivo porcine tendons (n = 72) were embedded in an agar phantom and randomly assigned to 12 groups based on MRgFUS treatment. The treatment time was 10, 20, or 30s, and the applied acoustic power was 25, 50, 75, or 100W. Following each MRgFUS treatment, tendons underwent biomechanical tensile testing on an Instron machine, which calculated stress-strain curves during tendon elongation. Rupture rate, maximum treatment temperature, Young's modulus and ultimate strength were analyzed for each treatment energy. RESULTS: The study revealed a dose-dependent response, with tendons rupturing in over 50% of cases when energy delivery exceeded 1000J and 100% disruption at energy levels beyond 2000J. The achieved temperatures during MRgFUS were directly proportional to energy delivery. The highest recorded temperature was 56.8°C ± 9.34 (3000J), while the lowest recorded temperate was 18.6°C ± 0.6 (control). The Young's modulus was highest in the control group (47.3 MPa ± 6.5) and lowest in the 3000J group (13.2 MPa ± 5.9). There was no statistically significant difference in ultimate strength between treatment groups. CONCLUSION: This study establishes crucial thresholds for reliable and repeatable disruption of tendons, laying the groundwork for future in vivo optimization. The findings prompt further exploration of MRgFUS as a non-invasive modality for tendon disruption, offering hope for improved outcomes in patients with musculotendinous contractures.

Noninvasive release of tendons using MRI guided focused ultrasound: a hybrid therapy using long-pulse focused ultrasound followed by thermal ablation.

INTRODUCTION: Magnetic Resonance-guided Focused Ultrasound (MRgFUS) thermal ablation is an effective noninvasive ultrasonic therapy to disrupt in vivo porcine tendon but is prone to inducing skin burns. We evaluated the safety profile of a novel hybrid protocol that minimizes thermal spread by combining long-pulse focused ultrasound followed by thermal ablation. METHODS: In-vivo Achilles tendons (hybrid N = 15, thermal ablation alone N = 21) from 15 to 20 kg Yorkshire pigs were randomly assigned to 6 treatment groups in two studies. The first (N = 21) was ablation (600, 900, or 1200 J). The second (N = 15) was hybrid: pulsed FUS (13.5 MPa peak negative pressure) followed by ablation (600, 900, or 1200 J). Measurements of ankle range of motion, tendon temperature, thermal dose (240 CEM43), and assessment of skin burn were performed in both groups. RESULTS: Rupture was comparable between the two protocols: 1/5 (20%), 5/5 (100%) and 5/5 (100%) for hybrid protocol, compared to 2/7 (29%), 6/7 (86%) and 7/7 (100%) for the ablation-only protocol with energies of 600, 900, and 1200 J, respectively. The hybrid protocol produced lower maximum temperatures, smaller areas of thermal dose, fewer thermal injuries to the skin, and fewer full-thickness skin burns. The standard deviation for the area of thermal injury was also smaller for the hybrid protocol, suggesting greater predictability. CONCLUSION: This study demonstrated a hybrid MRgFUS protocol combining long-pulse FUS followed by thermal ablation to be noninferior and safer than an ablation-only protocol for extracorporeal in-vivo tendon rupture for future clinical application for noninvasive release of contracted tendon.

An augmented hybrid multibaseline and referenceless MR thermometry motion compensation algorithm for MRgHIFU hyperthermia.

PURPOSE: A hybrid principal component analysis and projection onto dipole fields (PCA-PDF) MR thermometry motion compensation algorithm was optimized with atlas image augmentation and validated. METHODS: Experiments were conducted on a 3T Philips MRI and Profound V1 Sonalleve high intensity focused ultrasound (high intensity focused ultrasound system. An MR-compatible robot was configured to induce motion on custom gelatin phantoms. Trials with periodic and sporadic motion were introduced on phantoms while hyperthermia was administered. The PCA-PDF algorithm was augmented with a predictive atlas to better compensate for larger sporadic motion. RESULTS: During periodic motion, the temperature SD in the thermometry was improved from 1 . 1 ± 0 . 1 $$ 1.1\pm 0.1 $$ to 0 . 5 ± 0 . 1 ∘ $$ 0.5\pm 0.{1}^{\circ } $$ C with both the original and augmented PCA-PDF application. For large sporadic motion, the augmented atlas improved the motion compensation from the original PCA-PDF correction from 8 . 8 ± 0 . 5 $$ 8.8\pm 0.5 $$ to 0 . 7 ± 0 . 1 ∘ $$ 0.7\pm 0.{1}^{\circ } $$ C. CONCLUSION: The PCA-PDF algorithm improved temperature accuracy to <1°C during periodic motion, but was not able to adequately address sporadic motion. By augmenting the PCA-PDF algorithm, temperature SD during large sporadic motion was also reduced to <1°C, greatly improving the original PCA-PDF algorithm.

Noninvasive magnetic resonance-guided focused ultrasound for tendon disruption: an in vivo Animal study.

PURPOSE: Surgical resection of the tendon is an effective treatment for severe contracture. Magnetic Resonance-guided Focused Ultrasound (MRgFUS) is a non-invasive ultrasonic therapy which produces a focal increase in temperature, subsequent tissue ablation and disruption. We evaluated MRgFUS as a clinically translatable treatment modality to non-invasively disrupt in vivo porcine tendons. MATERIAL AND METHODS: In vivo Achilles tendons (n = 28) from 15-20kg Yorkshire pigs (n = 16) were randomly assigned to 4 treatment groups of 600, 900, 1200 and 1500 J. Pretreatment range of motion (ROM) of the ankle joint was measured with the animal under general anesthesia. Following MRgFUS treatment, success of tendon rupture, ROM increase, temperature, thermal dosage, skin burn, and histology analyses were performed. RESULTS: Rupture success was found to be 29%, 86%, 100% and 100% for treatment energies of 600, 900, 1200 and 1500 J respectfully. ROM difference at 90° flexion showed a statistically significant change in ROM between 900 J and 1200 J from 16° to 27°. There was no statistical significance between other groups, but there was an increase in ROM as more energy was delivered in the treatment. For each of the respective treatment groups, the maximal temperatures were 58.4 °C, 63.3 °C, 67.6 °C, and 69.9 °C. The average areas of thermal dose measured were 24.3mm2, 53.2mm2, 77.8mm2 and 91.6mm2. The average areas of skin necrosis were 5.4mm2, 21.8mm2, 37.2mm2, and 91.4mm2. Histologic analysis confirmed tissue ablation and structural collagen fiber disruption. CONCLUSIONS: This study demonstrated that MRgFUS is able to disrupt porcine tendons in vivo without skin incisions.

An adaptive targeting algorithm for magnetic resonance-guided high-intensity focused ultrasound controlled hyperthermia.

BACKGROUND: Mild hyperthermia has been demonstrated to improve the efficacy of chemotherapy, radiation, and immunotherapy in various cancer types. One localized, non-invasive method of administering mild hyperthermia is magnetic resonance-guided high-intensity focused ultrasound (MRgHIFU). However, challenges for ultrasound such as beam deflection, refraction and coupling issues may result in a misalignment of the HIFU focus and the tumor during hyperthermia. Currently, the best option is to stop the treatment, wait for the tissue to cool, and redo the treatment planning before restarting the hyperthermia. This current workflow is both time-consuming and unreliable. PURPOSE: An adaptive targeting algorithm was developed for MRgHIFU controlled hyperthermia treatments for cancer therapeutics. This algorithm executes in real time while hyperthermia is being administered to ensure that the focus is within our target region. If a mistarget is detected, the HIFU system will electronically steer the focus of the HIFU beam to the correct target. The goal of this study was to quantify the accuracy and precision of the adaptive targeting algorithm's ability to correct a purposely misplanned hyperthermia treatment in real-time using a clinical MRgHIFU system. METHODS: A gelatin phantom with acoustic properties matched to the average speed of sound in human tissue was used to test the adaptive targeting algorithm's accuracy and precision. The target was purposely offset 10 mm away from the focus at the origin, in four orthogonal directions, allowing the algorithm to correct for this mistarget. In each direction, 10 data sets were collected for a total sample size of 40. Hyperthermia was administered with a target temperature set at 42°C. The adaptive targeting algorithm was run during the hyperthermia treatment and 20 thermometry images were collected after the beam steering occurred. The location of the focus was quantified by calculating the center of heating on the MR thermometry data. RESULTS: The average calculated trajectory passed to the HIFU system was 9.7 mm ± 0.4 mm where the target trajectory was 10 mm. The accuracy of the adaptive targeting algorithm after the beam steering correction was 0.9 mm and the precision was 1.6 mm. CONCLUSION: The adaptive targeting algorithm was implemented successfully and was able to correct the 10 mm mistargets with high accuracy and precision in gelatin phantoms. The results demonstrate the capability to correct the MRgHIFU focus location during controlled hyperthermia.

Magnetic Resonance-Guided High Intensity Focused Ultrasound Generated Hyperthermia: A Feasible Treatment Method in a Murine Rhabdomyosarcoma Model.

Magnetic resonance-guided high intensity focused ultrasound (MRgHIFU) is an established method for producing localized hyperthermia. Given the real-time imaging and acoustic energy modulation, this modality enables precise temperature control within a defined area. Many thermal applications are being explored with this noninvasive, nonionizing technology, such as hyperthermia generation, to release drugs from thermosensitive liposomal carriers. These drugs can include chemotherapies such as doxorubicin, for which targeted release is desired due to the dose-limiting systemic side effects, namely cardiotoxicity. Doxorubicin is a mainstay for treating a variety of malignant tumors and is commonly used in relapsed or recurrent rhabdomyosarcoma (RMS). RMS is the most common solid soft tissue extracranial tumor in children and young adults. Despite aggressive, multimodal therapy, RMS survival rates have remained the same for the past 30 years. To explore a solution for addressing this unmet need, an experimental protocol was developed to evaluate the release of thermosensitive liposomal doxorubicin (TLD) in an immunocompetent, syngeneic RMS mouse model using MRgHIFU as the source of hyperthermia for drug release.

Passive Directivity Detection Using Individual Biaxial Ultrasound Transducers.

Biaxial transducers are an emerging technology that can steer generated ultrasound waves using a single piezoceramic component. Simulations have also shown that biaxial transducers can passively estimate the direction of arrival (DOA) of sound waves when operating in the receive mode. This research seeks to experimentally verify biaxial directivity estimates and establish directivity as an independent parameter detected by biaxial transducers. Three cuboid ( 3.84×3.84×5.92 mm) biaxial piezoceramics with two pairs of orthogonal electrodes (one pair applied laterally and one pair applied in the polling direction) were manufactured and characterized. Each transducer was placed in a water tank where an independent hemispherical source was attached to a moveable arm and operated at 250 kHz. Terminal voltages were recorded for 81 source positions in a plane parallel to the transducer's front face and at a depth of approximately 9 cm. Collection was repeated three times per transducer to ensure reproducibility. In silico results were compared with the experimental results. Two derived metrics were then calculated using both the forward and lateral terminal voltages: the phase difference and amplitude ratio. Biaxial transducers demonstrate an ability to estimate the DOA of incident sound waves, independently of any time-of-flight (TOF) information. The phase difference and amplitude ratio complement each other to provide statistically significant and repeatable estimates over a range of 48° (from -24° to +24°). These results can be used to augment a variety of medical, geophysical, and industrial passive ultrasound imaging techniques.

A robotic MR-guided high-intensity focused ultrasound platform for intraventricular hemorrhage: assessment of clot lysis efficacy in a brain phantom.

OBJECTIVE: Intraventricular hemorrhage (IVH) is a neurovascular complication due to premature birth that results in blood clots forming within the ventricles. Magnetic resonance-guided high-intensity focused ultrasound (MRgHIFU) has been investigated as a noninvasive treatment to lyse clots. The authors designed and constructed a robotic MRgHIFU platform to treat the neonatal brain that facilitates ergonomic patient positioning. The clot lysis efficacy of the platform is quantified using a brain phantom and clinical MRI system. METHODS: A thermosensitive brain-mimicking phantom with ventricular cavities was developed to test the clot lysis efficacy of the robotic MRgHIFU platform. Whole porcine blood was clotted within the phantom's cavities. Using the MRgHIFU platform and a boiling histotripsy treatment procedure (500 W, 10-msec pulse duration, 1.0% duty cycle, and 40-second duration), the clots were lysed inside the phantom. The contents of the cavities were vacuum filtered, and the remaining mass of the solid clot particles was used to quantify the percentage of clot lysis. The interior of the phantom's cavities was inspected for any collateral damage during treatment. RESULTS: A total of 9 phantoms were sonicated, yielding an average (± SD) clot lysis of 97.0% ± 2.57%. Treatment resulted in substantial clot lysis within the brain-mimicking phantoms that were apparent on postsonication T2-weighted MR images. No apparent collateral damage was observed within the phantom after treatment. The results from the study showed the MRgHIFU platform was successful at lysing more than 90% of a blood clot at a statistically significant level. CONCLUSIONS: The robotic MRgHIFU platform was shown to lyse a large percentage of a blood clot with no observable collateral damage. These results demonstrate the platform's ability to induce clot lysis when targeting through simulated brain matter and show promise toward the final application in neonatal patients.

Preliminary Study of a Modular MR-Compatible Robot for Image-Guided Insertion of Multiple Needles.

Percutaneous needle-based interventions such as transperineal prostate brachytherapy require the accurate placement of multiple needles to treat cancerous lesions within the target organ. To guide needle placement, magnetic resonance imaging (MRI) offers excellent visualization of the target lesion without the need for ionizing radiation. To date, multi-needle insertion relies on a grid template, which limits the ability to steer individual needles. This work describes an MR-compatible robot designed for the sequential insertion of multiple non-parallel needles under MR guidance. The 6-DOF system is designed with an articulated arm to extend the reach of the robot. This strategy presents a novel approach enabling the robot to maneuver around existing needles while minimizing the footprint of the robot. Forward kinematics as well as optimization-based inverse kinematics are presented. The impact of the robot on image quality was tested for four sequences (T1w-TSE, T2w-TSE, THRIVE and EPI) on a 3T Philips Achieva system. Quantification of the signal-to-noise ratio showed a 46% signal loss in a gelatin phantom when the system was powered on but no further adverse effects when the robot was moving. Joint level testing showed a maximum error of 2.10 ± 0.72°s for revolute joints and 0.31 ± 0.60 mm for prismatic joints. The theoretical workspace spans the proposed clinical target surface of 10 x 10 cm. Lastly, the feasibility of multi-needle insertion was demonstrated with four needles inserted under real-time MR-guidance with no visible loss in image quality.

A robotic magnetic resonance-guided high-intensity focused ultrasound platform for neonatal neurosurgery: Assessment of targeting accuracy and precision in a brain phantom.

BACKGROUND: Intraventricular hemorrhage (IVH) is one of the most serious neurovascular complications resulting from premature birth. It can result in clotting of blood within the ventricles, which causes a buildup of cerebrospinal fluid that can lead to posthemorrhagic ventricular dilation and posthemorrhagic hydrocephalus. Currently, there are no direct treatments for these blood clots as the standard of care is invasive surgery to insert a shunt. Magnetic resonance-guided high-intensity focused ultrasound (MRgHIFU) has been investigated as a noninvasive treatment to lyse blood clots. However, current MRgHIFU systems are not suitable in the context of treating IVH in neonates. PURPOSE: We have developed a robotic MRgHIFU neurosurgical platform designed to treat the neonatal brain. This platform facilitates ergonomic patient positioning and directs treatment through their open anterior fontanelle while providing a larger treatment volume. The platform is based on an MR-compatible robot developed by our group. Further development of the platform has warranted investigation of its targeting ability to assess its feasibility in the neonatal brain. This study aimed to quantify the platform's targeting accuracy, precision, and repeatability using a brain phantom and clinical MRI system. METHODS: A thermosensitive brain-mimicking phantom was developed to test the platform's targeting accuracy. Rectangular grid patterns were created with HIFU thermal energy "lesions" in the phantoms by targeting specific coordinate points. The intended target locations were demarcated by inserting carbon fiber rods through a targeting assessment template. Coordinates for the intended and actual targets were derived from T2-weighted MRI scans, and the centroid distance between them was measured. Subsequently, the platform's targeting accuracy was quantified according to equations derived from ISO Standard 9283:1998. RESULTS: HIFU ablation resulted in distinct thermal lesions within the thermosensitive phantoms, which appeared as discrete hypointense regions in T2-weighted MR scans. A total of 127 target points were included in the data analysis, which yielded a targeting accuracy of 0.6 mm and targeting precision of 1.2 mm. CONCLUSIONS: The robotic MRgHIFU platform was shown to have a high degree of accuracy, precision, and repeatability. The results demonstrate the platform's functionality when targeting through simulated brain matter. These results serve as an initial verification of the platform targeting ability and showed promise toward the final application in a neonatal brain.

Turning down the heat: The case for mild hyperthermia and thermosensitive liposomes.

"A single disappointing study does not mean an end to the future of ThermoDox®", writes Michael Tardugno (CEO of Celsion Corporation), after announcing the termination of Celsion's second Phase III clinical trial. The OPTIMA trial, as it was known, evaluated their thermosensitive liposome (TSL) formulation of doxorubicin (ThermoDox®) in combination with radiofrequency ablation for the treatment of hepatocellular carcinoma (HCC). The purpose of this perspective is to review the case of ThermoDox and to address questions related to its clinical translation. Specifically, what has prevented the clinical translation of this once highly regarded breakthrough technology? Is this the end of TSLs? What can we learn from the challenges faced in the clinical development of this multi-modal therapy? As formulation scientists working in the field, we continue to believe that heat-triggered drug delivery platforms have tremendous potential as chemotherapy. Herein, we highlight potential limitations in the design of many of the Thermodox clinical trials, and we propose that despite these setbacks, TSLs have the potential to become an effective component of cancer therapy.

Prediction of persistent ventricular dilation by initial ventriculomegaly and clot volume in a porcine model.

OBJECTIVE: While intraventricular hemorrhage (IVH) is associated with posthemorrhagic ventricular dilation (PHVD), not all infants affected by high-grade IVH develop PHVD. The authors aimed to determine clot-associated predictors of PHVD in a porcine model by varying the amount and rate of direct intraventricular injection of whole autologous blood. METHODS: Seven 1-week-old piglets underwent craniectomy and injection of autologous blood into the right lateral ventricle. They survived for a maximum of 28 days. MRI was performed prior to injection, immediately postoperatively, and every 7 days thereafter. T1-weighted, T2-weighted, and susceptibility-weighted imaging (SWI) sequences were used to segment ventricular and clot volumes. Spearman correlations were used to determine the relationship between blood and clot volumes and ventricular volumes over time. RESULTS: The maximum ventricular volume was up to 12 times that of baseline. One animal developed acute hydrocephalus on day 4. All other animals survived until planned endpoints. The interaction between volume of blood injected and duration of injection was significantly associated with clot volume on the postoperative scan (p = 0.003) but not the amount of blood injected alone (p = 0.38). Initial postoperative and day 7 clot volumes, but not volume of blood injected, were correlated with maximum (p = 0.007 and 0.014) and terminal (p = 0.014 and 0.036) ventricular volumes. Initial postoperative ventricular volume was correlated with maximum and terminal ventricular volume (p = 0.007 and p = 0.014). CONCLUSIONS: Initial postoperative, maximum, and terminal ventricular dilations were associated with the amount of clot formed, rather than the amount of blood injected. This supports the hypothesis that PHVD is determined by clot burden rather than the presence of blood products and allows further testing of early clot lysis to minimize PHVD risk.

Peripheral Nerve Focused Ultrasound Lesioning-Visualization and Assessment Using Diffusion Weighted Imaging.

Objectives: Magnetic resonance-guided focused ultrasound (MRgFUS) is a non-invasive targeted tissue ablation technique that can be applied to the nervous system. Diffusion weighted imaging (DWI) can visualize and evaluate nervous system microstructure. Tractography algorithms can reconstruct fiber bundles which can be used for treatment navigation and diffusion tensor imaging (DTI) metrics permit the quantitative assessment of nerve microstructure in vivo. There is a need for imaging tools to aid in the visualization and quantitative assessment of treatment-related nerve changes in MRgFUS. We present a method of peripheral nerve tract reconstruction and use DTI metrics to evaluate the MRgFUS treatment effect. Materials and Methods: MRgFUS was applied bilaterally to the sciatic nerves in 6 piglets (12 nerves total). T1-weighted and diffusion images were acquired before and after treatment. Tensor-based and constrained spherical deconvolution (CSD) tractography algorithms were used to reconstruct the nerves. DTI metrics of fractional anisotropy (FA), and mean (MD), axial (AD), and radial diffusivities (RD) were measured to assess acute (<1-2 h) treatment effects. Temperature was measured in vivo via MR thermometry. Histological data was collected for lesion assessment. Results: The sciatic nerves were successfully reconstructed in all subjects. Tract disruption was observed after treatment using both CSD and tensor models. DTI metrics in the targeted nerve segments showed significantly decreased FA and increased MD, AD, and RD. Transducer output power was positively correlated with lesion volume and temperature and negatively correlated with MD, AD, and RD. No correlations were observed between FA and other measured parameters. Conclusions: DWI and tractography are effective tools for visualizing peripheral nerve segments for targeting in non-invasive surgical methods and for assessing the microstructural changes that occur following MRgFUS treatment.

Acute MR-Guided High-Intensity Focused Ultrasound Lesion Assessment Using Diffusion-Weighted Imaging and Histological Analysis.

Objectives: The application of magnetic resonance-guided focused ultrasound (MRgFUS) for the treatment of neurological conditions has been of increasing interest. Conventional MR imaging can provide structural information about the effect of MRgFUS, where differences in ablated tissue can be seen, but it lacks information about the status of the cellular environment or neural microstructure. We investigate in vivo acute changes in water diffusion and white matter tracts in the brain of a piglet model after MRgFUS treatment using diffusion-weighted imaging (DWI) with histological verification of treatment-related changes. Methods: MRgFUS was used to treat the anterior body of the fornix in four piglets. T1 and diffusion-weighted images were collected before and after treatment. Mean diffusion-weighted imaging (MDWI) images were generated to measure lesion volumes via signal intensity thresholds. Histological data were collected for volume comparison and assessment of treatment effect. DWI metric maps of fractional anisotropy (FA), apparent diffusion coefficient (ADC), axial diffusivity (AD), radial diffusivity (RD), and mean diffusivity (MD) were generated for quantitative assessment. Fornix-related fiber tracts were generated before and after treatment for qualitative assessment. Results: The volume of treated tissue measured via MDWI did not differ significantly from histological measurements, and both were significantly larger than the treatment cell volume. Diffusion metrics in the treatment region were significantly decreased following MRgFUS treatment, with the peak change seen at the lesion core and decreasing radially. Histological analysis confirmed an area of coagulative necrosis in the targeted region with sharp demarcation zone with surrounding brain. Tractography from the lesion core and the fornix revealed fiber disruptions following treatment. Conclusions: Diffusion maps and fiber tractography are an effective method for assessing lesion volumes and microstructural changes in vivo following MRgFUS treatment. This study demonstrates that DWI has the potential to advance MRgFUS by providing convenient in vivo microstructural lesion and fiber tractography assessment after treatment.

Acute ex vivo changes in brain white matter diffusion tensor metrics.

PURPOSE: Diffusion magnetic resonance imaging and tractography has an important role in the visualization of brain white matter and assessment of tissue microstructure. There is a lack of correspondence between diffusion metrics of live tissue, ex vivo tissue, and histological findings. The objective of this study is to elucidate this connection by determining the specific diffusion alterations between live and ex vivo brain tissue. This may have an important role in the incorporation of diffusion imaging in ex vivo studies as a complement to histological sectioning as well as investigations of novel neurosurgical techniques. METHODS: This study presents a method of high angular resolution diffusion imaging and tractography of intact and non-fixed ex vivo piglet brains. Most studies involving ex vivo brain specimens have been formalin-fixed or excised from their original biological environment, processes both of which are known to affect diffusion parameters. Thus, non-fixed ex vivo tissue is used. A region-of-interest based analysis of diffusion tensor metrics are compared to in vivo subjects in a selection of major white matter bundles in order to assess the translatability of ex vivo diffusion measurements. RESULTS: Tractography was successfully achieved in both in vivo and ex vivo groups. No significant differences were found in tract connectivity, average streamline length, or apparent fiber density. Significantly decreased diffusivity (mean, axial, and radial; p<0.0005) in the non-fixed ex vivo group and unaltered fractional anisotropy (p>0.059) between groups were observed. CONCLUSION: This study validates the extrapolation of non-fixed fractional anisotropy measurements to live tissue and the potential use of ex vivo tissue for methodological development.

Magnetic Resonance-guided High-intensity Focused Ultrasound (MRgHIFU) Virtual Treatment Planning for Abdominal Neuroblastoma Utilizing Retrospective Diagnostic 3D CT Images.

Magnetic resonance-guided high-intensity focused ultrasound (MRgHIFU) is a novel treatment for neuroblastoma using ultrasound-induced thermal ablation with real-time MR thermometry. It is unclear which patients would be amenable to MRgHIFU given the retroperitoneal location of many neuroblastomas within the smaller pediatric abdomen. In addition, planning relies on MR scans, which are not routine in the standard pediatric neuroblastoma workup. This study sought to demonstrate that neuroblastomas are targetable with MRgHIFU and available computed tomographic imaging could be utilized for MRgHIFU virtual treatment. Cross-sectional images of 88 pediatric abdominal neuroblastoma patients were retrospectively processed with custom software to be made compatible with the Sonalleve MRgHIFU platform. Targetability measured percent treatment to lesion volume, within adequate safety margins from critical structures. All images were successfully converted into treatment planning files. Median lesion size was 191±195 cm and depth was 29±17 mm. Up to 78 (85%) patients had targetable lesions with a median targetable volume of 15% and ranging up to 79%. Targetability was highest in superficial, right upper quadrant lesions >200 cm, but limited by proximity to bowel and ribs. This study demonstrates the capacity for MRgHIFU to potentially treat the majority of abdominal neuroblastomas and the feasibility of using computed tomographic images for MRgHIFU virtual treatment planning.

Noninvasive ablation of rabbit fetal and placental tissue targets in utero using magnetic resonance-guided high-intensity focused ultrasound.

OBJECTIVE: Magnetic resonance-guided high-intensity focused ultrasound (MRgHIFU) is a potential noninvasive therapy for fetal conditions. In utero MRgHIFU delivery and proton resonance frequency shift (PRFS) thermometry monitoring will control accuracy of HIFU ablation and confirm in situ tissue heating in a rabbit model. METHODS: High-resolution 3T MR images were acquired in late-gestation rabbits (approximately 30 days, n = 5). HIFU sonications, using magnetic resonance (MR) thermometry as a guide, were delivered to achieve necrosis in relevant fetal targets. Thermometry, posttreatment magnetic resonance imaging (MRI), and follow-up histology confirmed ablation. RESULTS: Placentas (n = 14) were treated with 127 ± 34 Wac; thermometry-indicated temperatures reached 67°C. Lungs (n = 8) were treated with 85 ± 15 Wac and reached 73°C, livers (n = 6) with 80 ± 15 Wac and reached 74°C, and kidneys (n = 5) with 100 Wac and reached 66°C. Histological changes showed focal areas of necrosis with circumferential hemorrhage and/or vasodilation, which transitioned abruptly to healthy tissue. CONCLUSION: MRgHIFU therapy can effectively target and thermally treat specific in utero organs in this acute fetal rabbit model. PRFS gives in situ temperature control of therapy on tissues. Conceivably, MRgHIFU therapy may be applicable to specific fetal organ anomalies clinically and has the potential to improve the overall fetal outcome over traditional invasive surgical procedures.

Motion compensation using principal component analysis and projection onto dipole fields for abdominal magnetic resonance thermometry.

PURPOSE: High intensity focused ultrasound (HIFU) has the potential to locally and non-invasively treat cancer with fewer side effects than alternative therapies. However, motion and tissue heterogeneity in the abdomen can compromise the HIFU focus and confound current thermometry methods. METHODS: The proposed thermometry method combines principal component analysis (PCA), as a multi-baseline technique, and projection onto dipole fields (PDF), as a near-referenceless method. PCA forgoes tracking tools by projecting incoming images onto a subspace spanning the motion history. PDF is subsequently used to synthesize the naturally feasible components of the residual phase using a magnetic dipole model. This leaves only the phase shifts that are induced by HIFU. RESULTS: With in vivo measurements, in porcine and human kidneys, the mean pixel-wise temperature SD was 0.86 ± 0.41°C in selected regions of interest (ROIs) across all data sets, without any user-interaction or supplementary tracking tools. This is an improvement over a benchmark hybrid method, which scored 1.36 ± 1.20°C on the same data. Uncorrected subtraction of the data yielded a score of 3.02 ± 2.87°C. CONCLUSION: The PCA-PDF hybrid method achieves superior artifact correction by exploiting the motion history and intrinsic magnetic susceptibility of the underlying tissue.

An MR-based quantitative intraventricular hemorrhage porcine model for MR-guided focused ultrasound thrombolysis.

PURPOSE: Intraventricular hemorrhage (IVH) affects approximately 50% of premature births where 50% further develop post-hemorrhagic ventricular dilation (PHVD). Patients face significant impact to long-term development if PHVD is not managed. Unfortunately, there is no accepted treatment to remove the thrombus caused by IVH. This paper describes an acute and chronic IVH model for use with magnetic resonance-guided focused ultrasound (MRgFUS) thrombolysis. METHODS: A total of 12 pigs (~ 1 month in age) were used in the model (eight acute and four chronic). A pre-operative brain MRI was obtained for ventricular targeting. 1.25 cm3/kg of autologous blood was injected through a burr hole lateral to the midline and anterior of the coronal suture at a rate of 0.6 cm3/min. A craniotomy was performed to simulate a "fontanelle". Post-operative MRI was used to calculate the clot volume. Chronic piglets were recovered, monitored daily with a neurological scoring system (NSS), and MRI scanned for 21 days. RESULTS: The clot injection was well tolerated. The average clot size was 3987 mm3 (median = 4330 mm, standard deviation = 739 mm3). Postmortem examination validated the presence of the clot. In the chronic animals, there was an increase in ventricular volume of 30%. Transient neurological impairment immediately followed clot injection and with onset of hydrocephalus in the chronic animals. CONCLUSIONS: This model establishes a measurable and targetable IVH clot in an MRI-based neonatal porcine model. The progressive post-hemorrhagic ventricular dilation in the chronic model is a potential alterable outcome from MRgFUS thrombolysis.

Simulating thermal effects of MR-guided focused ultrasound in cortical bone and its surrounding tissue.

PURPOSE: Magnetic resonance-guided focused ultrasound (MRgFUS) is emerging as a treatment alternative for osteoid osteoma and painful bone metastases. This study describes a new simulation platform that predicts the distribution of heat generated by MRgFUS when applied to bone tissue. METHODS: Calculation of the temperature distribution was performed using two mathematical models. The first determined the propagation and absorption of acoustic energy through each medium, and this was performed using a multilayered approximation of the Rayleigh integral method. The ultrasound energy distribution derived from these equations could then be converted to heat energy, and the second mathematical model would then use the heat generated to determine the final temperature distribution using a finite-difference time-domain application of Pennes' bio-heat transfer equation. Anatomical surface geometry was generated using a modified version of a mesh-based semiautomatic segmentation algorithm, and both the acoustic and thermodynamic models were calculated using a parallelized algorithm running on a graphics processing unit (GPU) to greatly accelerate computation time. A series of seven porcine experiments were performed to validate the model, comparing simulated temperatures to MR thermometry and assessing spatial, temporal, and maximum temperature accuracy in the soft tissue. RESULTS: The parallelized algorithm performed acoustic and thermodynamic calculations on grids of over 108 voxels in under 30 s for a simulated 20 s of heating and 40 s of cooling, with a maximum time per calculated voxel of less than 0.3 µs. Accuracy was assessed by comparing the soft tissue thermometry to the simulation in the soft tissue adjacent to bone using four metrics. The maximum temperature difference between the simulation and thermometry in a region of interest around the bone was measured to be 5.43 ± 3.51°C average absolute difference and a percentage difference of 16.7%. The difference in heating location resulted in a total root-mean-square error of 4.21 ± 1.43 mm. The total size of the ablated tissue calculated from the thermal dose approximation in the simulation was, on average, 67.6% smaller than measured from the thermometry. The cooldown was much faster in the simulation, where it decreased by 14.22 ± 4.10°C more than the thermometry in 40 s after sonication ended. CONCLUSIONS: The use of a Rayleigh-based acoustic model combined with a discretized bio-heat transfer model provided a rapid three-dimensional calculation of the temperature distribution through bone and soft tissue during MRgFUS application, and the parallelized GPU algorithm provided the computational speed that would be necessary for an intraoperative treatment planning software platform.