Invasive brain interventions often result in complications and long recovery times. In addition, the delivery of therapeutic agents via the blood supply is often impossible because the Blood-Brain Barrier (BBB) protects the brain tissue from foreign molecules. Laboratory experiments and first clinical trials have shown that focused ultrasound (FUS) beams can be used for noninvasive interventions. However, the utilization of FUS in the brain has been seriously limited by the difficulty of delivering ultrasound through the skull bone. The hypothesis of this grant has been that transcranial therapeutic ultrasound exposures can be delivered noninvasively through an intact skull. This hypothesis has now been validated in three clinical studies that demonstrate that brain tissue can be noninvasively coagulated in the central part of the brain. During the current grant period, we furthered our initial research and developed methods to enhance FUS interaction with tissue using microbubbles, thus making whole brain sonications feasible. We have further studied the impact of ultrasound exposures on brain tissue and demonstrated chemotherapy delivery across the BBB. We, and others, have used animal tumor models to demonstrate that chemotherapy treatment significantly increases animal survival when combined with FUS induced BBB disruption. We have also developed computer simulation programs, control technology and treatment methods that will improve the delivery of ultrasound energy. Our study plan is to extend our current research and further explore the feasibility of using intravascular microbubbles to enhance the trans-skull sonications. Our goals are: First, to use our prototype phased array ultrasound system with passive acoustic monitoring to provide acoustic signal feedback, and thus localize and control bubble- enhanced treatments. Second, to utilize our computer models to develop more precise focusing, using higher and multiple frequency sonications, such that the focal volume size is reduced. This will provide better control and allow nonuniform brain tissue to be adequately exposed. Third, to construct and test the new arrays designed using the computer simulations. Fourth, to perform in vivo two-photon microscopy and behavior studies to increase our understanding of ultrasound induced BBB disruption effects on delicate brain regions. Finally, to further test the effectiveness of the ultrasound-induced BBB disruption for the delivery of chemotherapeutic agents and natural killer cells for the treatment o malignant brain tumors, and the delivery of siRNA for the treatment of Huntington's disease. Our vision is that successful trans-skull delivery of FUS could have a major impact on the treatment of many brain disorders. If successful, this research will have a major impact on patient care.

Public Health Relevance

This research develops a system that uses many high frequency sound beams for completely noninvasive brain surgery that can be performed in an out-patient setting with eventually large reduction in cost and recovery time. The system is guided by magnetic resonance imaging (MRI) and thus provides high targeting accuracy. The method may be used to target drugs to specific brain locations in the future.

Agency
National Institute of Health (NIH)
Institute
National Institute of Biomedical Imaging and Bioengineering (NIBIB)
Type
Research Project (R01)
Project #
2R01EB003268-16
Application #
8371757
Study Section
Special Emphasis Panel (NOIT)
Program Officer
Lopez, Hector
Project Start
1998-02-01
Project End
2013-05-31
Budget Start
2012-08-01
Budget End
2013-05-31
Support Year
16
Fiscal Year
2012
Total Cost
$529,471
Indirect Cost
$29,689
Name
Sunnybrook & Women's Coll Health Sciences Center
Department
Type
DUNS #
200466345
City
Toronto
State
ON
Country
Canada
Zip Code
M4 3-M5
Burgess, Alison; Hynynen, Kullervo (2014) Drug delivery across the blood-brain barrier using focused ultrasound. Expert Opin Drug Deliv 11:711-21
Pulkkinen, Aki; Werner, Beat; Martin, Ernst et al. (2014) Numerical simulations of clinical focused ultrasound functional neurosurgery. Phys Med Biol 59:1679-700
Jolesz, Ferenc A; McDannold, Nathan J (2014) Magnetic resonance-guided focused ultrasound: a new technology for clinical neurosciences. Neurol Clin 32:253-69
O'Reilly, Meaghan A; Jones, Ryan M; Hynynen, Kullervo (2014) Three-dimensional transcranial ultrasound imaging of microbubble clouds using a sparse hemispherical array. IEEE Trans Biomed Eng 61:1285-94
Scarcelli, Tiffany; Jordão, Jessica F; O'Reilly, Meaghan A et al. (2014) Stimulation of hippocampal neurogenesis by transcranial focused ultrasound and microbubbles in adult mice. Brain Stimul 7:304-7
Pajek, Daniel; Burgess, Alison; Huang, Yuexi et al. (2014) High-intensity focused ultrasound sonothrombolysis: the use of perfluorocarbon droplets to achieve clot lysis at reduced acoustic power. Ultrasound Med Biol 40:2151-61
Aryal, Muna; Vykhodtseva, Natalia; Zhang, Yong-Zhi et al. (2013) Multiple treatments with liposomal doxorubicin and ultrasound-induced disruption of blood-tumor and blood-brain barriers improve outcomes in a rat glioma model. J Control Release 169:103-11
Huang, Yuexi; Vykhodtseva, Natalia I; Hynynen, Kullervo (2013) Creating brain lesions with low-intensity focused ultrasound with microbubbles: a rat study at half a megahertz. Ultrasound Med Biol 39:1420-8
Alkins, Ryan; Burgess, Alison; Ganguly, Milan et al. (2013) Focused ultrasound delivers targeted immune cells to metastatic brain tumors. Cancer Res 73:1892-9
Jordao, Jessica F; Thevenot, Emmanuel; Markham-Coultes, Kelly et al. (2013) Amyloid-* plaque reduction, endogenous antibody delivery and glial activation by brain-targeted, transcranial focused ultrasound. Exp Neurol 248:16-29

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