Kullervo Hynynen

University of Toronto, Toronto, Ontario, Canada

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Publications (579)1316.69 Total impact

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    Robert M. Staruch · Kullervo Hynynen · Rajiv Chopra ·
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    ABSTRACT: Purpose: The aim of this study was to determine whether localised drug release using thermosensitive liposomal doxorubicin (TLD) and mild hyperthermia produced by a clinical magnetic resonance high intensity focused ultrasound (MR-HIFU) system improves anti-tumour efficacy over TLD alone in rabbit Vx2 tumours. Materials and methods: Rabbits bearing one Vx2 thigh tumour (n = 6 per group) were administered TLD (1.67 mg/kg) either with or without MR-HIFU mild hyperthermia (20 min, 42.0 °C). Tumour progression was measured using contrast-enhanced T1-weighted MR imaging. Toxicity was evaluated by changes in body weight, blood counts, and blood chemistry. Tumour volume, body weight, and blood data were acquired weekly for the first month and biweekly thereafter. Results: Rabbits treated with TLD plus MR-HIFU mild hyperthermia had target region temperatures with spatial-median, temporal-mean of 41.4° ± 0.6 °C; 10th and 90th percentile temperatures were 40.2 and 42.7 °C. All six rabbits that received TLD alone had rapid tumour progression and reached the tumour size end point (maximum dimension >6 cm) within 24 days. Four of six rabbits treated with TLD plus MR-HIFU mild hyperthermia survived to the study end point of 60 days; one reached tumour size end point, one had hyperthermia-related toxicity, all had at least a transient decrease in tumour volume. Weekly body weight, complete blood counts, and blood chemistry did not reveal additional evidence of drug or hyperthermia-related toxicity. Conclusions: Rabbit Vx2 tumours treated with a single infusion of TLD during MR-HIFU mild hyperthermia had reduced tumour growth vs. tumours treated with TLD alone. These findings are an important step toward clinical translation of localised drug delivery using MR-HIFU and TLD.
    International Journal of Hyperthermia 01/2015; 31(2). DOI:10.3109/02656736.2014.992483 · 2.65 Impact Factor
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    ABSTRACT: Assess the accuracy, precision, and sources of error using a preclinical MR-guided focused ultrasound system. A preclinical focused ultrasound system, described previously [Chopra et al., Med. Phys. 36(5), 1867-1874 (2009)], was tested on a benchtop and with 3T GE, 3T Philips, and 7T Bruker MR scanners for spatial targeting accuracy and precision. Randomly distributed water-filled holes drilled into a polystyrene plate were imaged using MRI and targeted using treatment planning software. The ultrasound focus of a 72 mm, f-number 0.8, 1.16 MHz transducer was aimed at the target locations, and 1-2 s continuous-wave sonications were performed on clear polystyrene plates to create localized spots of melted plastic. The distance between target and observed locations was measured and analyzed. Retrospective analysis of targeting accuracy was performed on preclinical data obtained from other experiments at their institution using the same system. The results suggest that the sources of targeting error under MR guidance can be roughly separated into three components-normally distributed random error; constant shift from inaccuracy in detection of the initial ultrasound focus; and angular misalignment between MR and focused ultrasound (FUS) coordinates. The lower bound on the targeting error was estimated to be 0.25 ± 0.13 mm, while the maximum observed targeting error did not exceed 2 mm. Measures required to reduce errors and improve targeting were developed to reduce the registration and misalignment errors such that maximum error was reduced to 0.36 ± 0.14 mm. Retrospective in vivo analysis indicated that the error was 1.02 ± 0.43 mm, including error extrinsic to the system. The FUS system, as described, is capable of precise and accurate sonications. The largest source of error-misregistration of the coordinate systems of the scanner and ultrasound system-was addressed which reduced the error to 0.36 ± 0.14 mm, sufficient for many preclinical applications.
    Medical Physics 01/2015; 42(1):430. DOI:10.1118/1.4903950 · 2.64 Impact Factor
  • Nazanin Hosseinkhah · David E Goertz · Kullervo Hynynen ·
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    ABSTRACT: Focused ultrasound with microbubbles is an emerging technique for blood brain barrier (BBB) opening. Here, a comprehensive theoretical model of a bubble-fluid-vessel system has been developed which accounts for the bubble's non-spherical oscillations inside a microvessel, and its resulting acoustic emissions. Numerical simulations of unbound and confined encapsulated bubbles were performed to evaluate the effect of the vessel wall on acoustic emissions and vessel wall stresses. Using a Marmottant shell model, the normalized second harmonic to fundamental emissions first decreased as a function of pressure (>50 kPa) until reaching a minima ("transition point") at which point they increased. The transition point of unbound compared to confined bubble populations occurred at different pressures and was associated with an accompanying increase in shear and circumferential wall stresses. As the wall stresses depend on the bubble to vessel wall distance, the stresses were evaluated for bubbles with their wall at a constant distance to a flat wall. As a result, the wall stresses were bubble size and frequency dependent and the peak stress values induced by bubbles larger than resonance remained constant versus frequency at a constant mechanical index.
    IEEE transactions on bio-medical engineering 12/2014; 62(5). DOI:10.1109/TBME.2014.2385651 · 2.35 Impact Factor
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    ABSTRACT: Background/introduction 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. Methods A Philips Sonalleve MRgHIFU device is being used to thermally ablate OO in pediatric patients. MR provides excellent soft tissue contrast, which enhances the interface between bone and surrounding soft tissues as well as the highly vascularized core of the OO, known as the nidus. The nidus is the primary target of thermal OO treatments since destroying it will prevent regrowth of this painful lesion. Ten patients will be recruited and complete age-appropriate and validated surveys (Pediatric Ouch, and PedsQLTM) to determine how lesion/bone pain and medication usage affects health-related quality of life (HRQL) metrics, such as physical, emotional, social, and school functioning. A planning MRI will be used to ensure lesion accessibility/patient eligibility and MR thermometry will measure temperature in the target and surrounding tissue to ensure patient safety. As thermal bone ablation is painful, patients will be under general anesthesia for the treatment. Follow-up on days 2, 7, 14, 30, 90 and 180 following treatment will record pain, HRQL, and drug usage. Clinical visits on days 30, 90 and 180 will comprise a physical examination and a diagnostic MRI of the OO. Contrast enhanced MRI will indicate non-perfused tissues corresponding to the ablated tissue volume, which should be fully resolved by day 180. Results and conclusions One patient with a 1cm OO on the left femoral head is currently enrolled in the study and was treated with MRgHIFU using seven 4mm treatment cells (Fig 1). Individual treatments were 12s in duration with a power of 40-60W. Temperatures >55°C were measured at the bone surface and a thermal dose of 240EM@43°C was achieved (Fig 2). A small region of non-perfused tissue was observed in contrast enhanced MRI corresponding to the thermal dose margins (Fig 3). One week after treatment the patient is pain free, off medication, and is consistently sleeping throughout the night. Study assessment of pain, HRQL and medication will follow. It is expected that MRgHIFU will be effective for reducing pain and medication usage, leading to an improvement in HRQL. Figure 1. Planned treatment cells to cover the volume of the osteoid osteoma. A total of seven 4mm treatment cells, arranged in a circular cluster, covered the extent of the 1cm lesion. Figure 2. Representative thermal map from one of the treatment sonications. A 50W exposure produced a maximum temperature above 55°C at the bone surface. A small region (approximately 1 x 4 mm) adjacent to the osteoid osteoma reached sufficient temperatures to achieve a thermal dose of 240EM@43°C, causing necrosis. Figure 3. Gadolinium enhanced T1-w image of the osteoid osteoma and treatment area following thermal ablation. A small region of non-perfused tissue is visible at the bone surface, adjacent to the osteoid osteoma lesion that is approximately the same extent as the thermal dose contour. Acknowledgements (Funding) We acknowledge project funding from the Focused Ultrasound Foundation and the Hospital for Sick Children Innovation Fund. This clinical study is not industry sponsored but we do receive technical support from Philips Healthcare and collaborate with Philips on preclinical focused ultrasound projects.
    FUS Symposium 2014, Washington, DC, USA; 10/2014
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    ABSTRACT: Microbubble-mediated opening of the blood–brain barrier (BBB) using ultrasound is a targeted technique that provides a transient time window during which circulating therapeutics that are normally restricted to the vasculature can pass into the brain. This effect has been associated with increases in cavitation activity of the circulating microbubbles, and our group has previously described a method to actively control treatments in pre-clinical rodent models based on acoustic emissions recorded by a single transducer. Recently, we have developed a clinical-scale receiver array capable of detecting bubble activity through ex vivo human skullcaps starting at pressure levels below the threshold for BBB opening. The use of this array to spatially map cavitation activity in the brain during ultrasound therapy will be discussed, including considerations for compensating for the distorting effects of the skull bone. Additionally, results from pre-clinical investigations examining safety and therapeutic potential will be presented, and receiver design considerations for both pre-clinical and clinical scale systems will be discussed.
    The Journal of the Acoustical Society of America 10/2014; 136(4):2300-2300. DOI:10.1121/1.4900320 · 1.50 Impact Factor
  • R Liu · T J Huynh · Y Huang · D Ramsay · K Hynynen · R I Aviv ·
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    ABSTRACT: Background: Contrast extravasation (CE) in spontaneous intracerebral hemorrhage (ICH), coined the spot sign, predicts hematoma expansion (HE) and poor clinical outcome. The dynamic relationship between CE and the mode of ICH growth are poorly understood. We characterized the in vivo pattern and rate of HE using a novel animal model of acute ICH. Methods: Basal ganglia ICH was created in 14 Yorkshire swine utilizing a novel MRI integrated model, permitting real-time CE observation using dynamic contrast-enhanced (DCE) MRI. Computerized planimetry measured CE volume at each time point. Spatial vector analysis along three orthogonal axes determined distance vectors. Maximizing and minimizing the coefficient of determination defined the temporal phases of growth and stability, respectively. CE rate was calculated using a Patlak model. Results: Asymmetric growth and variable rates of expansion characterized HE defining three distinct growth phases and patterns. A primary growth phase (duration 160 s; IQR 50-130) demonstrated rapid linear growth (0.04 mm/s IQR 0.01-0.10) accounting for 85 ± 15 % of total HE. The stationary phase demonstrated stability (duration 145 s; IQR 0-655). A secondary growth phase (duration 300; 130-600 s) accounted for 23 ± 8 % of total HE. In the primary and secondary growth phase, asymmetric growth occurred in the anterior-posterior (AP) planes (0.056 mm/s; p = 0.026 and 0.0112 mm/s; p = 0.03). Monophasic 2 (14 %), biphasic 4 (35 %) (primary followed by secondary growth), and triphasic 8 (56 %) patterns (primary, stationary, and secondary growth phase) were observed. Conclusions: A novel model of ICH provides real-time study of the dynamics and rate of CE. This data facilitates the understanding of pattern and rate of ICH formation.
    Neurocritical Care 09/2014; 22(2). DOI:10.1007/s12028-014-0071-z · 2.44 Impact Factor
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    Tam Nhan · Alison Burgess · Lothar Lilge · Kullervo Hynynen ·
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    ABSTRACT: Doxorubicin (Dox) is a well-established chemotherapeutic agent, however it has limited efficacy in treating brain malignancies due to the presence of the blood-brain barrier (BBB). Recent preclinical studies have demonstrated that focused ultrasound induced BBB disruption (BBBD) enables efficient delivery of Dox to the brain. For future treatment planning of BBBD-based drug delivery, it is crucial to establish a mathematical framework to predict the effect of transient BBB permeability enhancement on the spatiotemporal distribution of Dox at the targeted area. The constructed model considers Dox concentrations within three compartments (plasma, extracellular, intracellular) that are governed by various transport processes (e.g. diffusion in interstitial space, exchange across vessel wall, clearance by cerebral spinal fluid, uptake by brain cells). By examining several clinical treatment aspects (e.g. sonication scheme, permeability enhancement, injection mode), our simulation results support the experimental findings of optimal interval delay between two consecutive sonications and therapeutically-sufficient intracellular concentration with respect to transfer constant Ktrans range of 0.01–0.03 min−1. Finally, the model suggests that infusion over a short duration (20–60 min) should be employed along with single-sonication or multiple-sonication at 10 min interval to ensure maximum delivery to the intracellular compartment while attaining minimal cardiotoxicity via suppressing peak plasma concentration.
    Physics in Medicine and Biology 09/2014; 59(20):5987. DOI:10.1088/0031-9155/59/20/5987 · 2.76 Impact Factor
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    ABSTRACT: Purpose: To validate whether repeated magnetic resonance (MR) imaging-guided focused ultrasound treatments targeted to the hippocampus, a brain structure relevant for Alzheimer disease ( AD Alzheimer disease ), could modulate pathologic abnormalities, plasticity, and behavior in a mouse model. Materials and methods: All animal procedures were approved by the Animal Care Committee and are in accordance with the Canadian Council on Animal Care. Seven-month-old transgenic (TgCRND8) (Tg) mice and their nontransgenic (non-Tg) littermates were entered in the study. Mice were treated weekly with MR imaging-guided focused ultrasound in the bilateral hippocampus (1.68 MHz, 10-msec bursts, 1-Hz burst repetition frequency, 120-second total duration). After 1 month, spatial memory was tested in the Y maze with the novel arm prior to sacrifice and immunohistochemical analysis. The data were compared by using unpaired t tests and analysis of variance with Tukey post hoc analysis. Results: Untreated Tg mice spent 61% less time than untreated non-Tg mice exploring the novel arm of the Y maze because of spatial memory impairments (P < .05). Following MR imaging-guided focused ultrasound, Tg mice spent 99% more time exploring the novel arm, performing as well as their non-Tg littermates. Changes in behavior were correlated with a reduction of the number and size of amyloid plaques in the MR imaging-guided focused ultrasound-treated animals (P < .01). Further, after MR imaging-guided focused ultrasound treatment, there was a 250% increase in the number of newborn neurons in the hippocampus (P < .01). The newborn neurons had longer dendrites and more arborization after MR imaging-guided focused ultrasound, as well (P < .01). Conclusion: Repeated MR imaging-guided focused ultrasound treatments led to spatial memory improvement in a Tg mouse model of AD Alzheimer disease . The behavior changes may be mediated by decreased amyloid pathologic abnormalities and increased neuronal plasticity.
    Radiology 09/2014; 273(3):140245. DOI:10.1148/radiol.14140245 · 6.87 Impact Factor
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    G T Clement · R L King · S Maruvada · K Hynynen ·
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    ABSTRACT: The feasibility of using an acoustic camera as a thermal imaging device for focused ultrasound surgery is investigated. The present study compares thermocouple measurements with time-sequenced acoustic camera images of tissue samples after applying high intensity focused ultrasound. Images are acquired using the Acoustocam (Imperium, Inc, Maryland) acoustic camera system. This apparatus replaces the lens, aperture, and sensors of an optical CCD camera with acoustic counterparts. The camera’s image plane consists of a PVDF (polyvinylidene difluoride) piezoelectric divided into 128 X 128 pixel elements. The setup is operated in transmission mode, with a tissue sample placed between the camera and a 10 MHz illuminating transducer. Sections of fresh porcine liver and thigh muscle are placed in a bag containing degassed 0.9% saline and imaged. A high intensity CW ultrasound signal is then focused inside the tissue using a 2 MHz transducer. Images before, during, and after this sonication are examined. Time-dependent variations in image intensities are observed near the high-intensity focus. Additionally, permanent images are produced if the tissue is coagulated. Preliminary results indicate the camera may have application in guidance for ultrasound surgery in soft tissue such as the breast, where transmission can be applied.
  • Daniel Pajek · Alison Burgess · Yuexi Huang · Kullervo Hynynen ·
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    ABSTRACT: The purpose of this study was to evaluate use of intravascular perfluorocarbon droplets to reduce the sonication power required to achieve clot lysis with high-intensity focused ultrasound. High-intensity focused ultrasound with droplets was initially applied to blood clots in an in vitro flow apparatus, and inertial cavitation thresholds were determined. An embolic model for ischemic stroke was used to illustrate the feasibility of this technique in vivo. Recanalization with intravascular droplets was achieved in vivo at 24 ± 5% of the sonication power without droplets. Recanalization occurred in 71% of rabbits that received 1-ms pulsed sonications during continuous intravascular droplet infusion (p = 0.041 vs controls). Preliminary experiments indicated that damage was confined to the ultrasonic focus, suggesting that tolerable treatments would be possible with a more tightly focused hemispheric array that allows the whole focus to be placed inside of the main arteries in the human brain.
    Ultrasound in Medicine & Biology 09/2014; 40(9). DOI:10.1016/j.ultrasmedbio.2014.03.026 · 2.21 Impact Factor
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    ABSTRACT: Background The most commonly used animal models of spinal cord injury (SCI) involve surgical exposure of the dorsal spinal cord followed by transection, contusion or compression. This high level of invasiveness often requires significant post-operative care and can limit post-operative imaging, as the surgical incision site can interfere with coil placement for magnetic resonance imaging (MRI) during the acute phase of SCI. While these models are considered to be similar to human SCI, they do not occur in a closed vertebral system as do the majority of human injuries. New Method Here we describe a novel, non-surgical model of SCI in the rat using MR-guided Focused Ultrasound (FUS) in combination with intravenous injection of microbubbles, applied to the cervical spinal cord. Results The injury was well-tolerated and resulted in cervical spinal cord damage in 60% of the animals. The area of Gd-enhancement immediately post-FUS, and area of signal abnormality at 24 hours, were correlated with the degree of injury. The extent of injury was easily visualized with T2-weighted MRI and was confirmed using histology. Comparison with Existing Method(s) Pathology was similar to that seen in other rat models of direct spinal cord contusion and compression. Unlike these methods, FUS is non-surgical, and has lower mortality than seen in other models of cervical SCI. Conclusions We developed a novel model of SCI which was non-surgical, well-tolerated, localized, and replicated the pathology seen in other models of SCI.
    Journal of Neuroscience Methods 09/2014; 235. DOI:10.1016/j.jneumeth.2014.06.018 · 2.05 Impact Factor
  • Alison Burgess · Tam Nhan · Clare Moffatt · A.L. Klibanov · Kullervo Hynynen ·
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    ABSTRACT: Transcranial focused ultrasound (FUS) can cause temporary, localized increases in blood-brain barrier (BBB) permeability for effective drug delivery to the brain. In pre-clinical models of Alzheimer's disease, FUS has successfully been used to deliver therapeutic agents and endogenous therapeutic molecules to the brain leading to plaque reduction and improved behavior. However, prior to moving to clinic, questions regarding how the compromised vasculature in Alzheimer's disease responds to FUS need to be addressed. Here, we used two-photon microscopy to study changes in FUS-mediated BBB permeability in transgenic (TgCRND8) mice and their non-transgenic littermates. A custom-built ultrasound transducer was attached to the skull, covering a cranial window. Methoxy-X04 was used to visualize amyloid deposits in vivo. Fluorescent intravascular dyes were used to identify leakage from the vasculature after the application of FUS. Dye leakage occurred in both transgenic and non-transgenic mice at similar acoustic pressures but exhibited different leakage kinetics. Calculation of the permeability constant demonstrated that the vasculature in the transgenic mice was much less permeable after FUS than the non-transgenic littermates. Further analysis demonstrated that the change in vessel diameter following FUS was lessened in amyloid coated vessels. These data suggest that changes in vessel diameter may be directly related to permeability and the presence of amyloid plaque may reduce the permeability of a vessel after FUS. This study indicates that the FUS parameters used for the delivery of therapeutic agents to the brain may need to be adjusted for application in Alzheimer's disease.
    Journal of Controlled Release 08/2014; 192. DOI:10.1016/j.jconrel.2014.07.051 · 7.71 Impact Factor
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  • Mathew Carias · Kullervo Hynynen ·
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    ABSTRACT: The purpose of this study was to develop steerable MR-compatible ultrasound catheters suitable for minimally invasive MRI-guided cardiac ablation therapies. MRI-compatible ultrasound steerable catheters were developed and tested for their overall tissue heating performance and safety. Ultrasound transducers were mounted on a monodirectional deflectable catheter tip that was made to be MRI-compatible. Catheter safety was assessed on the potential to form hot spots at the distal end of the catheter throughout fast spin echo and thermometry scans. Heating experiments were performed on phantoms and ex vivo porcine cardiac samples. During catheter safety experiments, a maximum temperature increase of 11.35 ± 0.83°C was evident after a 12-min, 40-s fast spin echo scan with a whole body specific absorption rate (SAR) of 1.9 W/kg and 1.07 ± 0.22°C during thermometry scans (flip angle = 90°; scan time = 12 min, 41 s; whole body SAR = 0.34 W/kg). Temperature elevations induced by the sonication were shown to be on the order of 38.1 ± 5.2°C for phantom experiments and 49.3 ± 9.7°C for ex vivo cardiac samples. Steerable ultrasound catheters have the potential to be safely placed in an MR system with little concern of catheter self-heating and driven to heat surrounding structures to cause ablations. In addition, these catheters have the added benefit of a deflectable tip that allows the treatment of multiple targets from within the bore of the MR scanner. Magn Reson Med, 2013. © 2013 Wiley Periodicals, Inc.
    Magnetic Resonance in Medicine 08/2014; 72(2). DOI:10.1002/mrm.24945 · 3.57 Impact Factor
  • Nicholas Ellens · Kullervo Hynynen ·
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    ABSTRACT: Purpose: Assess the feasibility of using large-aperture, flat ultrasonic transducer arrays with 6500 small elements operating at 500 kHz without the use of any mechanical components for the thermal coagulation of uterine fibroids. This study examines the benefits and detriments of using a frequency that is significantly lower than that used in clinical systems (1-1.5 MHz). Methods: Ultrasound simulations were performed using the anatomies of five fibroid patients derived from 3D MRI. Using electronic steering solely, the ultrasound focus from a flat, 6500-element phased array was translated around the volume of the fibroids in various patterns to assess the feasibility of completing full treatments from fixed physical locations. Successive temperature maps were generated by numerically solving the bioheat equation. Using a thermal dose model, the bioeffects of these simulations were quantified and analyzed. Results: The simulations indicate that such an array could be used to perform fibroid treatments to 18 EM(43) at an average rate of 90 ± 20 cm(3)/h without physically moving the transducer array. On average, the maximum near-field thermal dose for each patient was below 4 EM(43). Fibroid tissue could be treated as close as 40 mm to the spine without reaching temperatures expected to cause pain or damage. Conclusions: Fibroids were successfully targeted and treated from a single transducer position to acceptable extents and without causing damage in the near- or far-field. Compared to clinical systems, treatment rates were good. The proposed treatment paradigm is a promising alternative to existing systems and warrants further investigation.
    Medical Physics 07/2014; 41(7):072902. DOI:10.1118/1.4883777 · 2.64 Impact Factor
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    ABSTRACT: The ability to focus acoustic energy through the intact skull on to targets millimeters in size represents an important milestone in the development of neurotherapeutics. Magnetic resonance-guided focused ultrasound (MRgFUS) is a novel, noninvasive method, which-under real-time imaging and thermographic guidance-can be used to generate focal intracranial thermal ablative lesions and disrupt the blood-brain barrier. An established treatment for bone metastases, uterine fibroids, and breast lesions, MRgFUS has now been proposed as an alternative to open neurosurgical procedures for a wide variety of indications. Studies investigating intracranial MRgFUS range from small animal preclinical experiments to large, late-phase randomized trials that span the clinical spectrum from movement disorders, to vascular, oncologic, and psychiatric applications. We review the principles of MRgFUS and its use for brain-based disorders, and outline future directions for this promising technology.
    Journal of the American Society for Experimental NeuroTherapeutics 05/2014; 11(3). DOI:10.1007/s13311-014-0281-2 · 5.05 Impact Factor
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    R I Aviv · T Huynh · Y Huang · D Ramsay · P Van Slyke · D Dumont · P Asmah · R Alkins · R Liu · K Hynynen ·
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    ABSTRACT: The "spot sign" or contrast extravasation is strongly associated with hematoma formation and growth. An animal model of contrast extravasation is important to test existing and novel therapeutic interventions to inform present and future clinical studies. The purpose of this study was to create an animal model of contrast extravasation in acute intracerebral hemorrhage. Twenty-eight hemispheres of Yorkshire male swine were insonated with an MR imaging-guided focused sonography system following lipid microsphere infusion and mean arterial pressure elevation. The rate of contrast leakage was quantified by using dynamic contrast-enhanced MR imaging and was classified as contrast extravasation or postcontrast leakage by using postcontrast T1. Hematoma volume was measured on gradient recalled-echo MR imaging performed 2 hours postprocedure. Following this procedure, sacrificed brain was subjected to histopathologic examination. Power level, burst length, and blood pressure elevation were correlated with leakage rate, hematoma size, and vessel abnormality extent. Median (intracerebral hemorrhage) contrast extravasation leakage was higher than postcontrast leakage (11.3; 6.3-23.2 versus 2.4; 1.1-3.1 mL/min/100 g; P < .001). Increasing burst length, gradient recalled-echo hematoma (ρ = 0.54; 95% CI, 0.2-0.8; P = .007), and permeability were correlated (ρ = 0.55; 95% CI, 0.1-0.8; P = .02). Median permeability (P = .02), gradient recalled-echo hematoma (P = .02), and dynamic contrast-enhanced volumes (P = .02) were greater at 1000 ms than at 10 ms. Within each burst-length subgroup, incremental contrast leakage was seen with mean arterial pressure elevation (ρ = 0.2-0.8). We describe a novel MR imaging-integrated real-time swine intracerebral hemorrhage model of acute hematoma growth and contrast extravasation.
    American Journal of Neuroradiology 04/2014; 35(9). DOI:10.3174/ajnr.A3939 · 3.59 Impact Factor
  • Y. Huang · N. Ellens · C. Mougenot · G. Czarnota · K. Hynynen ·
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    ABSTRACT: OBJECTIVE Magnetic resonance guided focused ultrasound (MRgFUS) has shown promising results in the palliative treatment of bone metastases. Despite its clinical effectiveness, temperature monitoring by MR thermometry proved challenging due to motion artifacts and non-uniform heating at the bone-muscle interface. In this study, ex vivo experiment and computer simulation were performed to optimize the treatment/imaging protocol; patient data from a clinical trial were processed retrospectively to investigate algorithms for minimizing motion artifacts. METHODS FUS heating on the femur bone of ex vivo porcine thighs were performed on a clinical MRgFUS system (Philips Sonalleve, Finland). The FUS array was 12 cm in diameter, f number of 1, operating at 1.2 MHz under a 3T MR scanner (Achieva, Philips). The focus was either placed at or behind the bone surface with 4 mm cells, or at the surface with 12 mm cells. Image resolution of MR thermometry was either 2.5x2.5x7.0 mm, or higher at 1.5x1.5x5.3 mm. Incident angle at the bone interface was 0 or 30 degrees. Computer simulations of flat and circular bone interface were performed with similar parameters as in the ex vivo study. MR thermometry data from a clinical trial were re-processed to minimize motion artifacts by subtracting only matched pairs of images. RESULTS Both ex vivo experiments and simulation showed more uniform heating with 12 mm cell focusing at the bone surface than 4 mm cell focusing behind the bone at similar energy levels, especially at 30 degree incident angle. Higher image resolution of MR thermometry visualized heating with better accuracy. By subtracting only matched pairs of images, transient motion artifacts were avoided in some cases and temperature information were restored. CONCLUSIONS In palliative treatment of bone metastases, ablation targets are the nerves in the periosteum at the bone surface. Therefore, focusing and steering at the bone surface with low to medium power levels provides more uniform and controllable heating than focusing behind the bone with high power levels. Motion in this application is often transitory due to pain reaction, therefore subtracting only matched pairs, or using a multi-baseline approach, may minimize motion artifacts in MR thermometry.
    ISTU 2014, Las Vegas, NV, USA; 04/2014
  • M.A. OReilly · Ryan M Jones · Kullervo Hynynen ·
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    ABSTRACT: There is an increasing interest in bubble-mediated focused ultrasound (FUS) interventions in the brain. However, current technology lacks the ability to spatially monitor the interaction of the microbubbles with the applied acoustic field, something which is critical for safe clinical translation of these treatments. Passive acoustic mapping could offer a means for spatially monitoring microbubble emissions that relate to bubble activity and associated bioeffects. In this study, a hemispherical receiver array was integrated within an existing transcranial therapy array to create a device capable of both delivering therapy and monitoring the process via passive imaging of bubble clouds. A 128-element receiver array was constructed and characterized for varying bubble concentrations and source spacings. Initial in vivo feasibility testing was performed. The system was found to be capable of monitoring bubble emissions down to single bubble events through an ex vivo human skull. The lateral resolution of the system was found to be between 1.25 and 2 mm and the axial resolution between 2 and 3.5 mm, comparable to the resolution of MRI-based temperature monitoring during thermal FUS treatments in the brain. The results of initial in vivo experiments show that bubble activity can be mapped starting at pressure levels below the threshold for blood–brain barrier disruption. This study presents a feasible solution for imaging bubble activity during cavitation-mediated FUS treatments in the brain.
    IEEE Transactions on Biomedical Engineering 04/2014; 61(4):1285-1294. DOI:10.1109/TBME.2014.2300838 · 2.35 Impact Factor
  • Ryan M Jones · Meaghan A O'Reilly · Kullervo Hynynen ·
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    ABSTRACT: Traditionally, the use of ultrasound (US) in the brain has been limited by the skull bone, which presents unique challenges for both transcranial therapy and imaging due to its attenuating and aberrating effects, which become more prevalent at higher US frequencies. On transmit, these skull-induced aberrations can be overcome through the use of large-aperture phased array transducers with appropriate driving frequencies, combined with computed tomography (CT)-based bone morphology and numerical models to derive element driving signals which minimize the distortions. Recently, we have demonstrated in silico that an analogous approach can be performed during beamforming on receive, to allow for passive acoustic imaging over a large region within the skull cavity [Jones et al., Phys. Med. Biol. 58, 4981-5005 (2013)]. We will present preliminary results obtained from applying this technique experimentally with a hemispherical (30 cm diam.) sparse receiver array (128 piezo-ceramic elements, 2.5 mm diam., and 612 kHz center frequency) to image acoustic sources through an ex vivo human skullcap. Images produced using non-invasive CT-based skull corrections will be compared with those obtained through an invasive hydrophone-based correction approach, and with images formed without skull-specific corrections. This technique has promising applications in both cavitation-mediated transcranial focused ultrasound therapies, by providing a method for treatment monitoring and control, as well as in ultrasound angiographic imaging of the brain.
    The Journal of the Acoustical Society of America 04/2014; 135(4):2208. DOI:10.1121/1.4877211 · 1.50 Impact Factor

Publication Stats

18k Citations
1,316.69 Total Impact Points


  • 2006-2015
    • University of Toronto
      • Department of Medical Biophysics
      Toronto, Ontario, Canada
    • University of Illinois, Urbana-Champaign
      Urbana, Illinois, United States
  • 1995-2014
    • Harvard Medical School
      • Department of Radiology
      Boston, Massachusetts, United States
  • 2006-2012
    • Sunnybrook Health Sciences Centre
      • Department of Physical Sciences
      Toronto, Ontario, Canada
  • 2010-2011
    • University of Eastern Finland
      • Department of Physics and Mathematics
      Kuopio, Northern Savo, Finland
  • 1990-2010
    • The University of Arizona
      • • Department of Radiation Oncology
      • • Department of Radiology
      Tucson, Arizona, United States
    • Oak Ridge National Laboratory
      Oak Ridge, Florida, United States
  • 2004-2008
    • University of Kuopio
      • Department of Applied Physics
      Kuopio, Northern Savo, Finland
  • 2007
    • Dana-Farber Cancer Institute
      • Department of Radiation Oncology
      Boston, Massachusetts, United States
  • 1994-2007
    • Brigham and Women's Hospital
      • Department of Radiology
      Boston, Massachusetts, United States
  • 2000-2002
    • Boston University
      • Department of Mechanical Engineering
      Boston, Massachusetts, United States
  • 1998-2002
    • Harvard University
      Cambridge, Massachusetts, United States
  • 1995-2002
    • Massachusetts Institute of Technology
      • Division of Health Sciences and Technology
      Cambridge, Massachusetts, United States
  • 1996
    • Indiana University-Purdue University School of Medicine
      Indianapolis, Indiana, United States
  • 1988-1992
    • Arizona Research Center
      Phoenix, Arizona, United States
    • O’Hehir University
      Phoenix, Arizona, United States