Focused Ultrasound

Among the most desirable replacements for invasive surgery is the use of focused ultrasound beams to coagulate or destroy tissue. Because ultrasound penetrates well through soft tissues and can be focused on distant spots that measure mere millimetres, the energy absorption elevates tissue temperature with such sharp thermal gradients that the boundaries of the treated tissue are clearly demarcated, and there is no damage to the overlying or surrounding tissues. Similar, well-controlled, noninvasive deep focusing cannot be achieved by any other heating method.

This power is now clinically available in the U.S. after a magnetic resonance imaging-guided and monitored focused ultrasound system (ExAblate 2000 from InSightec, based in Haifa, Israel) was approved in 2004 by the Food and Drug Administration for the noninvasive surgery of uterine fibroids. This device was a product of the research of Dr. Kullervo Hynynen in his laboratory at Brigham and Women’s Hospital and Harvard Medical School prior to his recruitment to Sunnybrook Research Institute in 2006.

Although diagnostic ultrasound-guided focused ultrasound devices are used for different tumours in China and Japan, and in Europe for prostate cancer, they are limited by the lack of monitoring of the induced thermal exposure. Traditional surgery is often combined with chemotherapy and/or radiation therapy to reduce the number of surviving cancer cells. Likewise, the effectiveness of ultrasound surgery could also be maximized by combining it with these other therapies. Our aim in this project is to develop novel treatments that will explore the ability to potentiate therapeutic effects through the use of ultrasound exposure with microbubbles or other agents that can be locally activated. Specific goals are as follows:

• to perform fundamental studies of targeted therapy with ultrasound
• to develop methods for targeted local molecular therapy
• to evaluate ultrasound-activated agents
• to develop targeted liver therapeutics.

Our goal is to develop a new imaging guidance and monitoring technique using ultrasound local harmonic motion (LHM) for thermal surgery. Local harmonic motion is induced by radiating the tissues with an amplitude modulated single-frequency ultrasound beam. Upon exposure, the tissues oscillate at the modulation frequency of the beam and, as the treatment progresses, the amplitude of the oscillation decreases. A separate ultrasound beam tracks the actual movement of the tissues in the focal zone. This technique could make monitoring of minimally invasive thermal and ultrasound therapies much less expensive than the current use of magnetic resonance imaging.

We have validated LHM in simulation (Heikkilä and Hynynen 2010) and in early in vivo testing (Curiel et al. 2009) in which LHM corresponded with magnetic resonance imaging displacement tracking (Huang et al. 2009). We are continuing to investigate the following:

• LHM performance in different types of tissues and near tissue-bone interfaces
• LHM with phased-array transducers through simulations.

Selected Publications:

1. Curiel L, Chopra R, and Hynynen K, “In vivo monitoring of focused ultrasound surgery using local harmonic motion,” Ultrasound Med Biol. 2009 Jan;35(1):65-78. Epub 2008 Sep 21.
2. Curiel L, Huang Y, Vykhodtseva N, and Hynynen K, “Focused ultrasound treatment of VX2 tumors controlled by local harmonic motion,” Phys Med Biol. 2009 Jun 7;54(11):3405-19. Epub 2009 May 13.
3. Huang Y, Curiel L, Kukic A, Plewes D, Chopra R, and Hynynen K, “MR acoustic radiation force imaging: in vivo comparison to ultrasound motion tracking,” Med Phys. 2009 Jun;36(6):2016-20.
4. Heikkilä J, Curiel L, and Hynynen K, “Local Harmonic Motion Monitoring of Focused Ultrasound Surgery-A Simulation Model,” IEEE Trans Biomed Eng. 2010 Jan;57(1):185-93. Epub 2009 Oct 9.

The widespread use of prostate-specific antigen screening and biopsy to detect prostate cancer has resulted in an increasing number of men being diagnosed with low-grade localized prostate cancer. This presents a dilemma for both patients and clinicians owing to the significant complications associated with conventional therapies. A minimally invasive therapy for localized prostate cancer that is capable of treating targeted volumes within the gland could be an important option for this growing population of men.

We are developing magnetic resonance (MR)-guided transurethral ultrasound therapy, in which a rotating applicator delivers high-intensity ultrasound energy to the prostate to generate a targeted region of thermal damage in the gland. Magnetic resonance imaging is used to measure the spatial temperature distribution in the prostate and surrounding tissues noninvasively during treatment. Accurate measurement of the temperature distribution during energy delivery can be used to produce a precisely shaped heating pattern in the prostate gland.

We have built a unique system for MR-guided transurethral prostate thermal therapy that incorporates real-time active temperature feedback to generate precise volumes of tissue coagulation. In addition we have developed MR-compatible transurethral ultrasound heating applicators. The capability to perform targeted heating in the prostate gland has been evaluated numerically using realistic patient geometries, and experimentally in a tissue-mimicking gel material and in a canine model. We are developing a system for clinical evaluation in patients.

Selected Publications:

1. Siddiqui K, Chopra R, Vedula S, Sugar L, Haider M, Boyes A, Musquera M, Bronskill M, Klotz L., “MRI-guided Transurethral Ultrasound Therapy of the Prostate Gland Using Real-time Thermal Mapping: Initial Studies,” Urology. 2010 Dec;76(6):1506-11. Epub 2010 Aug 14. 

The delivery of large molecular agents into the central nervous system via the blood supply is often impossible because the blood-brain barrier (BBB) protects brain tissue from foreign molecules. A technique that allows these agents to reach the brain tissue would open the door to new methods for the diagnosis and monitoring of brain disorders that currently cannot be performed. Such a technique would also result in a new research tool to investigate brain function and disorders in animal models using molecular imaging.

Laboratory experiments have shown that focused ultrasound beams can be used to open the BBB noninvasively in a highly localized tissue volume deep in the brain. We have demonstrated that highly focused ultrasound beams can be accurately delivered through an intact human skull with a phased array transducer, thus eliminating the most significant barrier for using focused ultrasound in the brain.

Our goal is to develop a device that opens the BBB for molecular imaging agents by delivering focused ultrasound through the intact skull to open the BBB at very low ultrasound power levels. Successful implementation of this method would make many new molecular imaging approaches possible in the brain.

Our goal is to develop and evaluate the benefits of simultaneous multimodality ultrasound and magnetic resonance (MR) imaging. These two modalities are routinely used independently and compared to each other through image registration techniques, a task that can be difficult in the presence of significant organ deformation or patient motion.

We believe that an integrated MR and ultrasound system capable of simultaneous imaging can provide diagnostic information superior to that achievable by both modalities sequentially.

There are three stages of research:

• To develop a prototype ultrasound and MR imaging system, and to evaluate the advantages of simultaneous ultrasound and MR imaging in phantoms and preclinical models. Methods to align the two imaging modalities spatially and temporally will be developed, and the impact on signal-to-noise of imaging simultaneously will be evaluated.
• To investigate the potential for ultrasound imaging to track the motion of an object, and to trigger MR imaging based on this information for improved motion compensation in MR imaging.
• To explore the feasibility of performing simultaneous contrast-enhanced imaging with MR and ultrasound imaging. A custom apparatus capable of imaging small preclinical models and phantoms will be constructed, and investigations will be conducted in both of these systems. These experiments will be performed in phantoms and in vivo in a preclinical model.

The outcomes of this project will be the development of a combined ultrasound and MR imaging system, and a thorough evaluation of the spatial and temporal resolution of this technology. The feasibility of using this multimodality system for novel clinical applications such as adaptive MR imaging and multimodality contrast enhanced imaging will also be evaluated.

Our goal is to deliver transcranial therapeutic ultrasound exposures noninvasively with an optimized phased array system. Experiments have shown that focused ultrasound beams can propagate through intact skull to destroy deep tissues, close blood vessels, activate drugs, open the blood-brain barrier and perhaps increase cell membrane permeability to molecules. This system could treat brain disorders such as tumours, functional problems and vascular malfunctions without difficult and invasive surgeries.

To accomplish this we plan to do the following:

• investigate the sonication parameters that produce different physiologic or histologic end points in the brain through in vivo rabbit and rat glioma studies
• theoretically and experimentally optimize the phased array design and the energy delivery
• improve our theoretical treatment planning programs by taking into account all of the available information from modern imaging systems and to test and improve these models in experiments with ex vivo human skulls
• integrate a complete phased-array system, planning software and sonication parameters into the animal experiments and perform tests in preparation for human studies.

Thrombolytic therapy is the most effective way to treat acute ischemic stroke. Currently, the standard practice is to administer the thrombolytic drug tissue plasminogen activator (tPA) to stroke patients. However, tPA is only safe to administer within 4.5 hours of stroke onset; even then, the drug has serious potential side effects. These limitations necessitate the development of an alternative treatment for ischemic stroke.

We are investigating the use of high-intensity focused ultrasound (HIFU) to break up the clot and serve as a standalone therapy for ischemic stroke. We aim:

• to determine optimal sonication parameters to re-establish blood flow in an occluded blood vessel in the brain
• to establish the time period for which HIFU is effective
• to assess the impact of HIFU on long-term neurological damage.

Selected Publications

1. Hitchcock KE, Holland CK. 2010. Ultrasound assisted thrombolysis for stroke therapy: better thrombus break up with bubbles. Stroke. In press
2. Wright C., Hynynen K. and Goertz D. An in vitro and in vivo investigation of high intensity focused ultrasound thrombolysis. Ultrasound Med Biol. Submitted
3. Saver JL., Albers GW., Dunn B., Johnston KC., Fisher M. 2009. Stroke therapy academic industry roundtable (STAIR) recommendations for extended window acute stroke therapy trials. Stroke. 40: 2594-2600.

Engineering and technology development

• Designing and building circuit boards
• Design of a verification system for multichannel phased array
• Miniaturisation of high-intensity focused ultrasound amplifier electronics using gallium nitride technology

Experimental work

• Focused ultrasound hyperthermia using acoustic lenses for heating large tissue volumes: a simulation study
• Activation of nanodroplets for drug delivery

Programming

• Skull segmentation for real-time monitoring of acoustic emissions during transcranial focused ultrasound therapy and stroke therapy
• Graphics processing unit-based beamforming for real-time microbubble mapping during focused ultrasound therapy
• Develop and test the accuracy of a photogrammetry-based image registration pipeline
• Develop graphical user interface for bench top equipment tests

Biology

• Effects of focused ultrasound on glial cell activation in a model of Alzheimer’s disease
• Effects of focused ultrasound on beta-amyloid plaques in Alzheimer’s disease
• Studying the effects of focused ultrasound on neuromodulation using microscopy

We’re looking for healthy participants to test the fit and comfort of a revolutionary new, non-invasive medical device. 

Principal investigator (PI): Dr. Kullervo Hynynen

Study title: Focused Ultrasound Conformal Array Helmet Fit Testing on Healthy Human Adults

Research Summary

The Weston Family Focused Ultrasound Initiative at Sunnybrook seeks to revolutionize the treatment of brain disorders such as Alzheimer’s disease in a non-invasive way. Based on a model of personalization and portability, new patient-specific therapeutic headsets are being developed which are intended to make affordable, repeatable and reliable treatments a reality for thousands of people.

The purpose of this trial is to test the comfort and fit of these non-invasive devices, so that the manufacturing parameters can be finalized. Periodic participation may be requested up to a three-year period.

Participation in this research project will include:

• A screening/consenting in-person interview
• A 30-60-minute MRI scan to design a custom helmet to fit you
• An initial fit test up to 60 minutes to test if the helmet fits you
• Two follow-up visits for an extended fit test to evaluate wearing the helmet for a duration of 2-3.5 hours, with optional MRI imaging
• Two short follow-up phone interviews after each extended fit test
• Additional tests may be requested as the design improves

A small monetary gift and a souvenir will be offered to participants who complete the study.

Eligibility

Inclusion Criteria:

• Participants who are healthy adults between the ages of 18-70
• Participants who have short hair or no hair
• Participants who are able and willing to undergo MRI scans
• Participants who are able and willing to comply with study protocols and provide informed consent

Exclusion Criteria:

• Participants who have an acute or chronic disease
• Participants who are pregnant
• Participants who are unable to give informed consent and comply with study procedures

If you’re interested in participating in this study or would like more information, please call 416-480-6100 ext. 689412 or email FUS.trial@sri.utoronto.ca