Kullervo Hynynen

University of Toronto, Toronto, Ontario, Canada

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Publications (360)851.64 Total impact

  • Alison Burgess · Kullervo Hynynen
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    ABSTRACT: Introduction: The presence of the blood-brain barrier (BBB) is a significant impediment to the delivery of therapeutic agents to the brain for treatment of brain diseases. Focused ultrasound (FUS) has been developed as a noninvasive method for transiently increasing the permeability of the BBB to promote drug delivery to targeted regions of the brain. Areas covered: The present review briefly compares the methods used to promote drug delivery to the brain and describes the benefits and limitations of FUS technology. We summarize the experimental data which shows that FUS, combined with intravascular microbubbles, increases therapeutic agent delivery into the brain leading to significant reductions in pathology in preclinical models of disease. The potential for translation of this technology to the clinic is also discussed. Expert opinion: The introduction of magnetic resonance imaging guidance and intravascular administration of microbubbles to FUS treatments permits the consistent, transient and targeted opening of the BBB. The development of feedback systems and real-time monitoring techniques improve the safety of BBB opening. Successful clinical translation of FUS has the potential to revolutionize the treatment of brain disease resulting in effective, less-invasive treatments without the need for expensive drug development.
    Expert Opinion on Drug Delivery 03/2014; 11(5). DOI:10.1517/17425247.2014.897693 · 4.12 Impact Factor
  • Aki Pulkkinen · Beat Werner · Ernst Martin · Kullervo Hynynen
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    ABSTRACT: A computational model utilizing grid and finite difference methods were developed to simulate focused ultrasound functional neurosurgery interventions. The model couples the propagation of ultrasound in fluids (soft tissues) and solids (skull) with acoustic and visco-elastic wave equations. The computational model was applied to simulate clinical focused ultrasound functional neurosurgery treatments performed in patients suffering from therapy resistant chronic neuropathic pain. Datasets of five patients were used to derive the treatment geometry. Eight sonications performed in the treatments were then simulated with the developed model. Computations were performed by driving the simulated phased array ultrasound transducer with the acoustic parameters used in the treatments. Resulting focal temperatures and size of the thermal foci were compared quantitatively, in addition to qualitative inspection of the simulated pressure and temperature fields. This study found that the computational model and the simulation parameters predicted an average of 24 ± 13% lower focal temperature elevations than observed in the treatments. The size of the simulated thermal focus was found to be 40 ± 13% smaller in the anterior-posterior direction and 22 ± 14% smaller in the inferior-superior direction than in the treatments. The location of the simulated thermal focus was off from the prescribed target by 0.3 ± 0.1 mm, while the peak focal temperature elevation observed in the measurements was off by 1.6 ± 0.6 mm. Although the results of the simulations suggest that there could be some inaccuracies in either the tissue parameters used, or in the simulation methods, the simulations were able to predict the focal spot locations and temperature elevations adequately for initial treatment planning performed to assess, for example, the feasibility of sonication. The accuracy of the simulations could be improved if more precise ultrasound tissue properties (especially of the skull bone) could be obtained.
    Physics in Medicine and Biology 03/2014; 59(7):1679-1700. DOI:10.1088/0031-9155/59/7/1679 · 2.92 Impact Factor
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    ABSTRACT: Transcranial focused ultrasound (FUS) and microbubble contrast agent, applied at parameters known to transiently increase blood-brain barrier permeability, were tested for the potential to stimulate hippocampal neurogenesis. In adult mice, FUS treatment significantly increased the number of proliferating cells and newborn neurons in the dentate gyrus of the dorsal hippocampus. This provides evidence that FUS with microbubbles can stimulate hippocampal neurogenesis, a process involved in learning and memory and affected in neurological disorders, such as Alzheimer's disease.
    Brain Stimulation 03/2014; 7(2):304-7. DOI:10.1016/j.brs.2013.12.012 · 5.43 Impact Factor
  • Jarkko J Leskinen · Anu Olkku · Anitta Mahonen · Kullervo Hynynen
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    ABSTRACT: There is a growing interest to use ultrasound to stimulate cellular material in vitro conditions for the treatment of musculoskeletal disorders. However, the beneficial effect resulting from ultrasound exposure is not accurately specified. Many in vitro ultrasound setups are very vulnerable to temperature elevation due to sound absorption, sound reflections, and inadequate heat transfer. The objective of this study is to show that temperature variations capable of modifying biological results may exist in common in vitro exposure system. Human osteoblastic MG-63 cells plated on a 24-well cell plate were treated with pulsed ultrasound in 37 °C water bath (10 min, frequency = 1.035 MHz, burst length = 200 μs, pulse repetition frequency = 1 kHz, duty cycle = 0.2, temporal-average acoustic power = 2 W, and peak pressure = 670-730 kPa) and the activation of heat-dependent canonical Wnt cell signaling was measured. The ultrasound-induced temperature rise was measured with thermocouples and infrared imaging. Chamber-to-chamber comparison showed substantial temperature variation (41.6 °C versus 49.1 °C) among the different chambers. The chamber walls were the most susceptible to heating. The variations in the chamber temperatures correlated to variations in the cell signaling levels (1.3-fold versus 11.5-fold increase). These observations underline the need for system-specific temperature measurements during in vitro exposures.
    IEEE transactions on bio-medical engineering 03/2014; 61(3):920-7. DOI:10.1109/TBME.2013.2292546 · 2.23 Impact Factor
  • Meaghan A. O'Reilly · Ryan M. Jones · Kullervo Hynynen
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    ABSTRACT: Ultrasound imaging can be performed through narrow acoustic windows in the skull in order to minimize skull distortions. Alternatively, passive imaging using a larger aperture array can be used, which affords better resolution at the low frequencies that best penetrate the skull bone. However, to ensure image quality, it is necessary to correct for the distorting effects of the skull. In this study we examine a method to correct the distortions caused by a human skull using passive imaging of single microbubbles. The method is compared with images produced without phase correction, and those produced using a gold-standard invasive phase correction method. Using the non-invasive technique, the -6dB volume was found to vary by less than 22% from the invasive phase correction technique. By comparison, the -6dB volume when no correction was used was almost 300% larger than using the invasive correction technique. The bubblebased method introduced a positional error in the resulting image, which was most prevalent in the axial direction (on the order of 1 mm). The corrected image was biased by the location of the bubble used to calculate the correction terms. In the future, this method might be improved by using multiple bubbles to correct different regions of the image.
    Proceedings of SPIE - The International Society for Optical Engineering 02/2014; DOI:10.1117/12.2043832 · 0.20 Impact Factor
  • Source
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    ABSTRACT: Imaging has become a cornerstone for medical diagnosis and the guidance of patient management. A new field called image-guided drug delivery (IGDD) now combines the vast potential of the radiological sciences with the delivery of treatment and promises to fulfill the vision of personalized medicine. Whether imaging is used to deliver focused energy to drug-laden particles for enhanced, local drug release around tumors, or it is invoked in the context of nanoparticle-based agents to quantify distinctive biomarkers that could risk stratify patients for improved targeted drug delivery efficiency, the overarching goal of IGDD is to use imaging to maximize effective therapy in diseased tissues and to minimize systemic drug exposure in order to reduce toxicities. Over the last several years, innumerable reports and reviews covering the gamut of IGDD technologies have been published, but inadequate attention has been directed toward identifying and addressing the barriers limiting clinical translation. In this consensus opinion, the opportunities and challenges impacting the clinical realization of IGDD-based personalized medicine were discussed as a panel and recommendations were proffered to accelerate the field forward. WIREs Nanomed Nanobiotechnol 2014, 6:1-14. doi: 10.1002/wnan.1247 Conflict of interest: The authors have declared no conflicts of interest for this article. For further resources related to this article, please visit the WIREs website.
    Wiley Interdisciplinary Reviews Nanomedicine and Nanobiotechnology 01/2014; 6(1):1-14. DOI:10.1002/wnan.1247 · 4.24 Impact Factor
  • Source
    Brain Stimulation 01/2014; · 5.43 Impact Factor
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    ABSTRACT: Spectral mapping of nanoparticles with surface enhanced Raman scattering (SERS) capability in the near-infrared range is an emerging molecular imaging technique. We used magnetic resonance image-guided transcranial focused ultrasound (TcMRgFUS) to reversibly disrupt the blood-brain barrier (BBB) adjacent to brain tumor margins in rats. Glioma cells were found to internalize SERS capable nanoparticles of 50nm or 120nm physical diameter. Surface coating with anti-epidermal growth factor receptor antibody or non-specific human immunoglobulin G, resulted in enhanced cell uptake of nanoparticles in-vitro compared to nanoparticles with methyl terminated 12-unit polyethylene glycol surface. BBB disruption permitted the delivery of SERS capable spherical 50 or 120nm gold nanoparticles to the tumor margins. Thus, nanoparticles with SERS imaging capability can be delivered across the BBB non-invasively using TcMRgFUS and have the potential to be used as optical tracking agents at the invasive front of malignant brain tumors.
    Nanomedicine: nanotechnology, biology, and medicine 12/2013; 10(5). DOI:10.1016/j.nano.2013.12.006 · 5.98 Impact Factor
  • Daniel Pajek · Kullervo Hynynen
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    ABSTRACT: Purpose: Transcranial focused ultrasound is an emerging therapeutic modality that can be used to perform noninvasive neurosurgical procedures. The current clinical transcranial phased array operates at 650 kHz, however the development of a higher frequency array would enable more precision, while reducing the risk of standing waves. However, the smaller wavelength and the skull's increased distortion at this frequency are problematic. It would require an order of magnitude more elements to create such an array. Random sparse arrays enable steering of a therapeutic array with fewer elements. However, the tradeoffs inherent in the use of sparsity in a transcranial phased array have not been systematically investigated and so the objective of this simulation study is to investigate the effect of sparsity on transcranial arrays at a frequency of 1.5 MHz that provides small focal spots for precise exposure control.Methods: Transcranial sonication simulations were conducted using a multilayer Rayleigh-Sommerfeld propagation model. Element size and element population were varied and the phased array's ability to steer was assessed.Results: The focal pressures decreased proportionally as elements were removed. However, off-focus hotspots were generated if a high degree of steering was attempted with very sparse arrays. A phased array consisting of 1588 elements 3 mm in size, a 10% population, was appropriate for steering up to 4 cm in all directions. However, a higher element population would be required if near-skull sonication is desired.Conclusions: This study demonstrated that the development of a sparse, hemispherical array at 1.5 MHz could enable more precision in therapies that utilize lower intensity sonications.
    Medical Physics 12/2013; 40(12):122901. DOI:10.1118/1.4829510 · 3.01 Impact Factor
  • Meaghan A O'Reilly · Ryan M Jones · Kullervo Hynynen
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    ABSTRACT: Bubble-mediated ultrasound therapies in the brain, such as targeted disruption of the blood-brain barrier (BBB) or cavitation-enhanced stroke treatments, are being increasingly investigated due to their potential to revolutionize the treatment of brain disorders. Due to the fact that they are non-thermal in nature, these therapies must be monitored by acoustic means to ensure efficacy and safety. A sparse, 128-element hemispherical receiver array (612 kHz) was integrated within a 306 kHz therapy array. The receiver arrangement was optimized through numerical simulations. The array was characterized on the benchtop to map the activity of bubbles in a tube phantom through an ex vivo human skullcap. In vivo the array was used to map bubble activity in small animal models during microbubble-mediated BBB disruption. The array was investigated as well for diagnostic purposes, imaging transcranial structures filled with very dilute concentrations of microbubbles. A spiral tube phantom with tube diameter of 255 [micro sign]m was imaged, using a non-invasive phase correction technique, through an ex vivo human skullcap by mapping the activity from single bubbles. Applying super-resolution techniques, an image of the spiral phantom was produced that was comparable to an image obtained in a small-specimen micro CT.
    The Journal of the Acoustical Society of America 11/2013; 134(5):3975. DOI:10.1121/1.4830483 · 1.56 Impact Factor
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    ABSTRACT: Focused ultrasound has been shown to be the only method that allows noninvasive thermal coagulation of tissues and recently this potential has been explored for noninvasive image-guided drug delivery. In this presentation, the advances in ultrasound phased array technology for well controlled energy delivery will be discussed. In addition, some of the recent preclinical results for the treatments of brain tumors, stroke, and Alzheimer's disease will be reviewed. As conclusion, the advances in the image-guided focused ultrasound for the treatment of disease has been rapid and the future potential appears very promising.
    The Journal of the Acoustical Society of America 11/2013; 134(5):4088. DOI:10.1121/1.4830932 · 1.56 Impact Factor
  • Meaghan A O'Reilly · Kullervo Hynynen
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    ABSTRACT: Purpose: High-resolution vascular imaging has not been achieved in the brain due to limitations of current clinical imaging modalities. The authors present a method for transcranial ultrasound imaging of single micrometer-size bubbles within a tube phantom.Methods: Emissions from single bubbles within a tube phantom were mapped through an ex vivo human skull using a sparse hemispherical receiver array and a passive beamforming algorithm. Noninvasive phase and amplitude correction techniques were applied to compensate for the aberrating effects of the skull bone. The positions of the individual bubbles were estimated beyond the diffraction limit of ultrasound to produce a super-resolution image of the tube phantom, which was compared with microcomputed tomography (micro-CT).Results: The resulting super-resolution ultrasound image is comparable to results obtained via the micro-CT for small tissue specimen imaging.Conclusions: This method provides superior resolution to deep-tissue contrast ultrasound and has the potential to be extended to provide complete vascular network imaging in the brain.
    Medical Physics 11/2013; 40(11):110701. DOI:10.1118/1.4823762 · 3.01 Impact Factor
  • Ryan Alkins · Yuexi Huang · Dan Pajek · Kullervo Hynynen
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    ABSTRACT: Transcranial focused ultrasound is increasingly being investigated as a minimally invasive treatment for a range of intracranial pathologies. At higher peak rarefaction pressures than those used for thermal ablation, focused ultrasound can initiate inertial cavitation and create holes in the brain by fractionation of the tissue elements. We investigated the technical feasibility of using MRI-guided focused ultrasound to perform a third ventriculostomy as a possible noninvasive alternative to endoscopic third ventriculostomy for hydrocephalus. A craniectomy was performed in male pigs weighing 13-19 kg to expose the supratentorial brain, leaving the dura mater intact. Seven pigs were treated through the craniectomy, while 2 pigs were treated through ex vivo human skulls placed in the beam path. Registration and targeting was done using T2-weighted MRI sequences. For transcranial treatments a CT scan was used to correct the beam from aberrations due to the skull and maintain a small, high-intensity focus. Sonications were performed at both 650 kHz and 230 kHz at a range of intensities, and the in situ pressures were estimated both from simulations and experimental data to establish a threshold for tissue fractionation in the brain. In craniectomized animals at 650 kHz, a peak pressure 3 22.7 MPa for 1 second was needed to reliably create a ventriculostomy. Transcranially at this frequency the ExAblate 4000 was unable to generate the required intensity to fractionate tissue, although cavitation was initiated. At 230 kHz, ventriculostomy was successful through the skull with a peak pressure of 8.8 MPa. This is the first study to suggest that it is possible to perform a completely noninvasive third ventriculostomy using ultrasound. This may pave the way for future studies and eventually provide an alternative, non-invasive means for the creation of CSF communications in the brain, including perforation of the septum pellucidum or intraventricular membranes.
    Journal of Neurosurgery 09/2013; 119(6). DOI:10.3171/2013.8.JNS13969 · 3.15 Impact Factor
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    ABSTRACT: Reversible and localized blood-brain barrier disruption (BBBD) using focused ultrasound (FUS) in combination with intravascularly administered microbubbles (MBs) has been established as a non-invasive method for drug delivery to the brain. Using two-photon fluorescence microscopy (2PFM), we imaged the cerebral vasculature during BBBD and observed the extravasation of fluorescent dye in real-time in vivo. We measured the enhanced permeability upon BBBD for both 10kDa and 70kDa dextran conjugated Texas Red (TR) at the acoustic pressure range of 0.2-0.8 MPa and found permeability constants of TR10kDa and TR70kDa vary from 0.0006 to 0.0359 min(-1) and 0.0003 to 0.0231 min(-1), respectively. For both substances, a linear regression was applied on the permeability constant against the acoustic pressure and the slope from best-fit was found to be 0.039±0.005 min(-1)/MPa and 0.018±0.005 min(-1)/MPa, respectively. In addition, the pressure threshold for successfully induced BBBD was confirmed to be 0.4-0.6 MPa. Finally, we identified two types of leakage kinetics (fast and slow) that exhibit distinct permeability constants and temporal disruption onsets, as well as demonstrated their correlations with the applied acoustic pressure and vessel diameter. Direct assessment of vascular permeability and insights on its dependency on acoustic pressure, vessel size and leakage kinetics are important for treatment strategies of BBBD-based drug delivery.
    Journal of Controlled Release 09/2013; 172(1). DOI:10.1016/j.jconrel.2013.08.029 · 7.26 Impact Factor
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    ABSTRACT: While it is well established that ultrasound stimulated microbubbles (USMBs) can potentiate blood clot lysis, the mechanisms are not well understood. Here we examine the interaction between USMBs and fibrin clots, which are comprised of fibrin networks that maintain the mechanical integrity of blood clots. High speed camera observations demonstrated that USMBs can penetrate fibrin clots. Two-photon microscopy revealed that penetrating bubbles can leave behind patent “tunnels” along their paths and that fluid can be transported into the clots. Finally, it is observed that primary radiation forces associated with USMBs can induce local deformation and macroscopic translation of clot boundaries.
    Applied Physics Letters 07/2013; 103(5). DOI:10.1063/1.4816750 · 3.52 Impact Factor
  • Tam Nhan · Alison Burgess · Kullervo Hynynen
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    ABSTRACT: Focused ultrasound (FUS) and microbubbles have been used effectively for transient, noninvasive blood¿ brain barrier disruption (BBBD). The use of two-photon microscopy (2PM) imaging of BBBD can provide valuable insights into the associated cellular mechanisms and fundamental biological effects. Coupling a thin ring-shaped transducer to a coverslip offers a robust solution for simultaneous dorsal application of FUS for BBBD and in vivo 2PM imaging of the cerebral microvasculature under treatment conditions. Two modes of vibration (thickness and height) from the transducer configuration were investigated for BBBD in an animal model. With the transducer operating in the thickness mode at 1.2 MHz frequency, shallow and localized BBBD near the cortical surface of animal brain was detected via 2PM and confirmed by Evans blue (EB) extravasation. Acoustic pressures ranging from 0.2 to 0.8 MPa were tested and the probability for successful BBBD was identified. Two distinct types of disruption characterized by different leakage kinetics were observed and appeared to be dependent on acoustic pressure.
    IEEE Transactions on Ultrasonics Ferroelectrics and Frequency Control 07/2013; 60(7):1376-1385. DOI:10.1109/TUFFC.2013.2710 · 1.50 Impact Factor
  • Ryan M Jones · Meaghan A O'Reilly · Kullervo Hynynen
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    ABSTRACT: The feasibility of transcranial passive acoustic mapping with hemispherical sparse arrays (30 cm diameter, 16 to 1372 elements, 2.48 mm receiver diameter) using CT-based aberration corrections was investigated via numerical simulations. A multi-layered ray acoustic transcranial ultrasound propagation model based on CT-derived skull morphology was developed. By incorporating skull-specific aberration corrections into a conventional passive beamforming algorithm (Norton and Won 2000 IEEE Trans. Geosci. Remote Sens. 38 1337-43), simulated acoustic source fields representing the emissions from acoustically-stimulated microbubbles were spatially mapped through three digitized human skulls, with the transskull reconstructions closely matching the water-path control images. Image quality was quantified based on main lobe beamwidths, peak sidelobe ratio, and image signal-to-noise ratio. The effects on the resulting image quality of the source's emission frequency and location within the skull cavity, the array sparsity and element configuration, the receiver element sensitivity, and the specific skull morphology were all investigated. The system's resolution capabilities were also estimated for various degrees of array sparsity. Passive imaging of acoustic sources through an intact skull was shown possible with sparse hemispherical imaging arrays. This technique may be useful for the monitoring and control of transcranial focused ultrasound (FUS) treatments, particularly non-thermal, cavitation-mediated applications such as FUS-induced blood-brain barrier disruption or sonothrombolysis, for which no real-time monitoring techniques currently exist.
    Physics in Medicine and Biology 06/2013; 58(14):4981-5005. DOI:10.1088/0031-9155/58/14/4981 · 2.92 Impact Factor
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    ABSTRACT: Considerable effort is being directed towards investigating the use of ultrasound (US) stimulated microbubbles (MB) to promote the uptake of anticancer agents in tumors. In this study we propose and investigate a new method for combining therapeutic ultrasound with anticancer agents, which is to induce antivascular effects and combine these with an antiangiogenic treatment strategy, in this case metronomic chemotherapy. This is effectively a vascular targeting rather than a drug delivery approach. Experiments were conducted on MDA-MB-231 breast cancer tumors implanted in athymic mice. Metronomic cyclophosphamide (MCTX) was employed as an antiangiogenic therapy and was administered through the drinking water. Ultrasound stimulated microbubble treatments (USMB) were conducted at 1 MHz employing short bursts (0.00024 duty cycle) at 1.6MPa in combination with the commercial microbubble agent Definity. USMB treatments were performed on a weekly basis for 4 weeks and MCTX was administered for 10 weeks. The USMB induced an acute reduction of blood flow as confirmed with US contrast imaging and DiOC(7) perfusion staining. Longitudinal experiments demonstrated that significant growth inhibition occurred in MCTX-only and USMB-only treatment groups relative to control tumors. The combined USMB and MCTX treatment group showed significant growth inhibition and survival prolongation relative to the USMB-only (p<0.01) and MCTX-only treatment groups (p<0.01). These results indicate the feasibility of a new approach to combining therapeutic ultrasound with an anticancer agent. © 2012 Wiley Periodicals, Inc.
    International Journal of Cancer 06/2013; 132(12). DOI:10.1002/ijc.27977 · 5.01 Impact Factor
  • Yuexi Huang · Natalia I Vykhodtseva · Kullervo Hynynen
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    ABSTRACT: Low-intensity focused ultrasound was applied with microbubbles (Definity, Lantheus Medical Imaging, North Billerica, MA, USA; 0.02 mL/kg) to produce brain lesions in 50 rats at 558 kHz. Burst sonications (burst length: 10 ms; pulse repetition frequency: 1 Hz; total exposure: 5 min; acoustic power: 0.47-1.3 W) generated ischemic or hemorrhagic lesions at the focal volume revealed by both magnetic resonance imaging and histology. Shorter burst time (2 ms) or shorter sonication time (1 min) reduced the probability of lesion production. Longer pulses (200 ms, 500 ms and continuous wave) caused significant near-field damage. Using microbubbles with focused ultrasound significantly reduced acoustic power levels and, therefore, avoided skull heating issues and potentially can extend the treatable volume of transcranial focused ultrasound to brain tissues close to the skull.
    Ultrasound in medicine & biology 06/2013; 39(8). DOI:10.1016/j.ultrasmedbio.2013.03.006 · 2.10 Impact Factor
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    ABSTRACT: Noninvasive, targeted drug delivery to the brain can be achieved using transcranial focused ultrasound (FUS), which transiently increases the permeability of the blood-brain barrier (BBB) for localized delivery of therapeutics from the blood to the brain. Previously, we have demonstrated that FUS can deliver intravenously-administered antibodies to the brain of a mouse model of Alzheimer's disease (AD) and rapidly reduce plaques composed of amyloid-ß peptides (Aß). Here, we investigated two potential effects of transcranial FUS itself that could contribute to a reduction of plaque pathology, namely the delivery of endogenous antibodies to the brain and the activation of glial cells. We demonstrate that transcranial FUS application leads to a significant reduction in plaque burden four days after a single treatment in the TgCRND8 mouse model of AD and that endogenous antibodies are found bound to Aß plaques. Immunohistochemical and western blot analyses showed an increase in endogenous immunoglobulins within the FUS-targeted cortex. Subsequently, microglia and astrocytes in FUS-treated cortical regions show signs of activation through increases in protein expression and changes in glial size, without changes in glial cell numbers. Enhanced activation of glia correlated with increased internalization of Aβ in microglia and astrocytes. Together these data demonstrate that FUS improved bioavailability of endogenous antibodies and a temporal activation of glial cells, providing evidence towards antibody- and glia-dependent mechanisms of FUS-mediated plaque reduction.
    Experimental Neurology 05/2013; 248. DOI:10.1016/j.expneurol.2013.05.008 · 4.62 Impact Factor

Publication Stats

10k Citations
851.64 Total Impact Points


  • 2006–2015
    • University of Toronto
      • • Department of Medical Biophysics
      • • Department of Electrical and Computer Engineering
      Toronto, Ontario, Canada
    • University of Illinois, Urbana-Champaign
      Urbana, Illinois, United States
  • 2006–2014
    • 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
  • 1995–2011
    • Harvard Medical School
      • Department of Radiology
      Boston, Massachusetts, United States
  • 2002–2007
    • Harvard University
      Cambridge, Massachusetts, United States
    • Dana-Farber Cancer Institute
      • Department of Radiation Oncology
      Boston, MA, United States
  • 1994–2007
    • Brigham and Women's Hospital
      • • Department of Radiology
      • • Department of Medicine
      Boston, Massachusetts, United States
    • The University of Arizona
      Tucson, Arizona, United States
  • 2005–2006
    • University of Kuopio
      • Department of Applied Physics
      Kuopio, Eastern Finland Province, Finland
  • 2003
    • Foundation for Biomedical Research and Innovation
      Kōbe, Hyōgo, Japan
  • 1996–2002
    • Massachusetts Institute of Technology
      • Division of Health Sciences and Technology
      Cambridge, Massachusetts, United States