Adam Waspe

High-Intensity Focused Ultrasound (HIFU) for Dissolution of Clots in a Rabbit Model of Embolic Stroke

It is estimated that only 2–6% of patients receive thrombolytic therapy for acute ischemic stroke suggesting that alternative therapies are necessary. In this study, we investigate the potential for high intensity focused ultrasound (HIFU) to initiate thrombolysis in an embolic model of stroke. Iron-loaded blood clots were injected into the middle cerebral artery (MCA) of New Zealand White rabbits, through the internal carotid artery and blockages were confirmed by angiography. MRI was used to localize the iron-loaded clot and target the HIFU beam for treatment. HIFU pulses (1.5 MHz, 1 ms bursts, 1 Hz pulse repetition frequency, 20 s duration) were applied to initiate thrombolysis. Repeat angiograms and histology were used to assess reperfusion and vessel damage. Using 275 W of acoustic power, there was no evidence of reperfusion in post-treatment angiograms of 3 rabbits tested. In a separate group of animals, 415 W of acoustic power was applied and reperfusion was observed in 2 of the 4 (50%) animals treated. In the last group of animals, acoustic power was further increased to 550 W, which led to the reperfusion in 5 of 7 (∼70%) animals tested. Histological analysis confirmed thatthe sonicated vessels remained intact after HIFU treatment. Hemorrhage was detected outside of the sonication site, likely due to the proximity of the target vessel with the base of the rabbit skull. These results demonstrate the feasibility of using HIFU, as a stand-alone method, to cause effective thrombolysis without immediate damage to the targeted vessels. HIFU, combined with imaging modalities used to identify and assess stroke patients, could dramatically reduce the time to achieve flow restoration in patients thereby significantly increasing the number of patients which benefit from thrombolysis treatments.

Focused-Ultrasound Disruption of the Blood-Brain Barrier Using Closely-Timed Short Pulses: Influence of Sonication Parameters and Injection Rate

Blood-brain barrier disruption (BBBD) shows promise for drug delivery in the brain; however, optimal parameters for disruption have yet to be firmly established. Previous work has shown that BBBD can be achieved using bursts comprised of microsecond-length pulses at 50% duty cycle to eliminate standing waves and variability. The capabilities and limitations of this sort of pulse sequence comprising short bursts were examined. Ultrasound-induced BBBD was performed in 28 rats using Definity contrast agent. The spacing between 3-μs pulses at 1.18 MHz was either 6 μs, 60 μs, 300 μs or 600 μs during a 10-ms pulse, or 1 s for a single-pulse burst. The rate of infusion of the microbubbles was also examined, as well as the burst pulse repetition frequency (PRF) under infusion conditions. A semi-log relationship between enhancement mean and the number of cycles in a burst was discovered, with a one-pulse burst (i.e., a 3-μs burst at 1 Hz) still capable of disrupting the BBB. No increased efficacy or safety benefit over bursts containing more cycles was found, however. Microbubble infusions showed no improvement in T1w enhancement, but did improve consistency. Increased burst PRF combined with infusion improved T1w enhancement but without statistical significance, whereas a decrease in burst PRF showed a statistically significant decrease in enhancement.

MatMRI and MatHIFU: software toolboxes for real-time monitoring and control of MR-guided HIFU

BackgroundThe availability of open and versatile software tools is a key feature to facilitate pre-clinical research for magnetic resonance imaging (MRI) and magnetic resonance-guided high-intensity focused ultrasound (MR-HIFU) and expedite clinical translation of diagnostic and therapeutic medical applications.In the present study, two customizable software tools that were developed at the Thunder Bay Regional Research Institute are presented for use with both MRI and MR-HIFU. Both tools operate in a MATLAB®; environment. The first tool is named MatMRI and enables real-time, dynamic acquisition of MR images with a Philips MRI scanner. The second tool is named MatHIFU and enables the execution and dynamic modification of user-defined treatment protocols with the Philips Sonalleve MR-HIFU therapy system to perform ultrasound exposures in MR-HIFU therapy applications.MethodsMatMRI requires four basic steps: initiate communication, subscribe to MRI data, query for new images, and unsubscribe. MatMRI can also pause/resume the imaging and perform real-time updates of the location and orientation of images. MatHIFU requires four basic steps: initiate communication, prepare treatment protocol, and execute treatment protocol. MatHIFU can monitor the state of execution and, if required, modify the protocol in real time.ResultsFour applications were developed to showcase the capabilities of MatMRI and MatHIFU to perform pre-clinical research. Firstly, MatMRI was integrated with an existing small animal MR-HIFU system (FUS Instruments, Toronto, Ontario, Canada) to provide real-time temperature measurements. Secondly, MatMRI was used to perform T2-based MR thermometry in the bone marrow. Thirdly, MatHIFU was used to automate acoustic hydrophone measurements on a per-element basis of the 256-element transducer of the Sonalleve system. Finally, MatMRI and MatHIFU were combined to produce and image a heating pattern that recreates the word ‘HIFU’ in a tissue-mimicking heating phantom.ConclusionsMatMRI and MatHIFU leverage existing MRI and MR-HIFU clinical platforms to facilitate pre-clinical research. MatMRI substantially simplifies the real-time acquisition and processing of MR data. MatHIFU facilitates the testing and characterization of new therapy applications using the Philips Sonalleve clinical MR-HIFU system. Under coordination with Philips Healthcare, both MatMRI and MatHIFU are intended to be freely available as open-source software packages to other research groups.

MRI-guided disruption of the blood-brain barrier using transcranial focused ultrasound in a rat model.

Focused ultrasound (FUS) disruption of the blood-brain barrier (BBB) is an increasingly investigated technique for circumventing the BBB(1-5). The BBB is a significant obstacle to pharmaceutical treatments of brain disorders as it limits the passage of molecules from the vasculature into the brain tissue to molecules less than approximately 500 Da in size(6). FUS induced BBB disruption (BBBD) is temporary and reversible(4) and has an advantage over chemical means of inducing BBBD by being highly localized. FUS induced BBBD provides a means for investigating the effects of a wide range of therapeutic agents on the brain, which would not otherwise be deliverable to the tissue in sufficient concentration. While a wide range of ultrasound parameters have proven successful at disrupting the BBB(2,5,7), there are several critical steps in the experimental procedure to ensure successful disruption with accurate targeting. This protocol outlines how to achieve MRI-guided FUS induced BBBD in a rat model, with a focus on the critical animal preparation and microbubble handling steps of the experiment.

Establishing a clinical service for the treatment of osteoid osteoma using magnetic resonance-guided focused ultrasound: overview and guidelines

Recent studies have demonstrated the effectiveness of magnetic resonance-guided focused ultrasound (MRgFUS) in the treatment of osteoid osteoma (OO), a painful, benign bone tumor. As MRgFUS is a noninvasive and radiation-free treatment, it stands to replace the current standard of care, percutaneous radiofrequency, or laser thermal ablation. Within an institution, creation of a clinical OO MRgFUS treatment program would not only provide cutting edge medical treatment at the current time but would also establish the foundation for an MRgFUS clinical service to introduce treatments currently under development into clinical practice in the future. The purpose of this document is to provide information to facilitate creation of a clinical service for MRgFUS treatment of OO by providing (1) recommendations for the multi-disciplinary management of patients and (2) guidelines regarding current best practices for MRgFUS treatment. This paper will discuss establishment of a multi-disciplinary clinic, patient accrual, inclusion/exclusion criteria, diagnosis, preoperative imaging, patient preparation, anesthesia, treatment planning, targeting and treatment execution, complication avoidance, and patient follow-up to assure safety and effectiveness.

A rapid magnetic resonance acoustic radiation force imaging sequence for ultrasonic refocusing.

Magnetic resonance guided acoustic radiation force imaging (MR-ARFI) is being used to correct for aberrations induced by tissue heterogeneities when using high intensity focusing ultrasound (HIFU). A compromise between published MR-ARFI adaptive solutions is proposed to achieve efficient refocusing of the ultrasound beam in under 10 min. In addition, an ARFI sequence based on an EPI gradient echo sequence was used to simultaneously monitor displacement and temperature with a large SNR and low distortion. This study was conducted inside an Achieva 3T clinical MRI using a Philips Sonalleve MR-HIFU system to emit a 1 ms pulsed sonication with duty cycle of 2.3% at 300 Wac inside a polymer phantom. Virtual elements defined by a Hadamard array with sonication patterns composed of 6 phase steps were used to characterize 64 groups of 4 elements to find the optimal phase of the 256 elements of the transducer. The 384 sonication patterns were acquired in 580 s to identify the set of phases that maximize the displacement at the focal point. Three aberrators (neonatal skull, 8 year old skull and a checkered pattern) were added to each sonication pattern to evaluate the performance of this refocusing algorithm (n  =  4). These aberrators reduced the relative intensities to 95.3%, 69.6% and 25.5% for the neonatal skull, 8 year old skull, and checkered pattern virtual aberrators respectively. Using a 10 min refocusing algorithm, relative intensities of 101.6%, 91.3% and 93.3% were obtained. Better relative intensities of 103.9%, 94.3% and 101% were achieved using a 25 min refocusing algorithm. An average temperature increase of 4.2 °C per refocusing test was induced for the 10 min refocusing algorithm, resulting in a negligible thermal dose of 2 EM. A rapid refocusing of the beam can be achieved while keeping thermal effects to a minimum.

Acoustic characterization of a neonate skull using a clinical MR-guided high intensity focused ultrasound system for pediatric neurological disorder treatment planning

Transcranial MR-guided Focused Ultrasound (TcMRgFUS) treatments are now clinically performed on adult patients for brain tumor or essential tremor therapies. However, no application has been proposed for children despite their thinner skull being less of an acoustic barrier and the presence of a fontanelle on neonates, which could constitute a natural acoustic window for the transmission of ultrasound waves. As there is minimal literature data on the attenuation and speed-of-sound of the skull in neonatal patients, the aim of this study was to perform the acoustic characterization of a neonate skull.

An MRI-compatible three-axis focused ultrasound system for performing drug delivery studies in small animal models

MRI-guided focused-ultrasound is a non-invasive technique that can enhance the delivery of therapeutic agents. The objective of this work was to develop a focused-ultrasound system for preclinical research in small animals that is capable of sonicating with high spatial precision within a closed-bore MRI. The system features a computer-controlled, non-magnetic, three-axis positioning system that uses piezoelectric actuators and linear optical encoders to position a focused-ultrasound transducer to targeted tissues under MRI guidance. The actuator and encoder signals are transmitted through low-pass-filtered connectors on a grounded RF-penetration panel to prevent artifacts during image acquisition. The transducer is attached to the positioning system by a rigid arm and is submerged within a closed water tank. The arm passes into the tank through flexible bellows to ensure that the system remains sealed. An RF coil acquires high-resolution images in the vicinity of the target tissue. An aperture on the water tank, centered about the RF coil, provides an access point for target sonication. Registration between ultrasound and MRI coordinates involves sonicating a temperature-sensitive phantom and measuring the centroid of the thermal focal zone in 3D with MR thermometry. Linear distances of 5 cm with a positioning resolution of 0.05 mm can be achieved for each axis. The system was operated successfully on MRI scanners from different vendors at both 1.5 and 3.0 T, and simultaneous motion and imaging was possible without any mutual interference or imaging artifacts. This system is used for high-throughput small-animal experiments to study the efficacy of ultrasound-enhanced drug delivery.

Magnetic resonance guided focused ultrasound for noninvasive pain therapy of osteoid osteoma in children.

Osteoid osteoma (OO), a small painful benign bone tumor, is the most common bone tumor in children. Pain is managed with nonsteroidal anti-inflammatory drugs but minimally invasive techniques, such as CT-guided laser ablation, have become a standard intervention. However, the potential for non-target injury is a concern as tissue temperature cannot be measured with CT and the laser induces temperatures >90°C for 10 minutes. It also includes risks from exposure to ionizing radiation, fracture, infection and transmitted thermal damage from the access needle. Magnetic resonance guided high intensity focused ultrasound (MRgHIFU) has been used successfully in small cohorts of adults with OO. The noninvasive nature of the energy means that procedures do not need to be conducted in a sterile environment since there is no mechanical penetration of the bone, reducing the chance of pathologic fracture and infection.

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

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.