Non-Invasive, Focal Disconnection of Brain Circuitry Using Magnetic Resonance-Guided Low-Intensity Focused Ultrasound to Deliver a Neurotoxin.
Disturbances in the function of neuronal circuitry contribute to most neurologic disorders. As knowledge of the brain's connectome continues to improve, a more refined understanding of the role of specific circuits in pathologic states will also evolve. Tools capable of manipulating identified circuits in a targeted and restricted manner will be essential not only to expand our understanding of the functional roles of such circuits, but also to therapeutically disconnect critical pathways contributing to neurologic disease. This study took advantage of the ability of low-intensity focused ultrasound (FUS) to transiently disrupt the blood-brain barrier (BBB) to deliver a neurotoxin with poor BBB permeability (quinolinic acid [QA]) in a guided manner to a target region in the brain parenchyma. Ten male Sprague-Dawley rats were divided into two groups receiving the following treatments: (i) magnetic resonance-guided FUS + microbubbles + saline (n = 5), or (ii) magnetic resonance-guided FUS + microbubbles + QA (n = 5). Systemic administration of QA was well tolerated. However, when QA and microbubbles were systemically administered in conjunction with magnetic resonance-guided FUS, the BBB was disrupted and primary neurons were destroyed in the targeted subregion of the hippocampus in all QA-treated animals. Administration of vehicle (saline) together with microbubbles and FUS also disrupted the BBB but did not produce neuronal injury. These findings indicate the feasibility of non-invasively destroying a targeted region of the brain parenchyma using low-intensity FUS together with systemic administration of microbubbles and a neurotoxin. This approach could be of therapeutic value in various disorders in which disturbances of neural circuitry contribute to neurologic disease.
Department of Ultrasound, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China; Department of Radiology, Neuroradiology Division, University of Virginia, Charlottesville, Virginia, USA.
Yanrong
Y
Zhang
Department of Anesthesiology, Sun Yat-Sen University Cancer Center, Guangzhou, China; Department of Anesthesiology, University of Virginia, Charlottesville, Virginia, USA.
Hongying
H
Tan
Department of Neurology, University of Virginia, Charlottesville, Virginia, USA.
Edward H
EH
Bertram
Department of Radiation Oncology, University of Virginia, Charlottesville, Virginia, USA; ESPCI ParisTech, PSL Research University, Institut Langevin, Paris, France; CNRS, Institut Langevin, Paris, France; INSERM, Institut Langevin, Paris, France.
Jean-François
JF
Aubry
Department of Pathology, University of Virginia, Charlottesville, Virginia, USA.
Maria-Beatriz
MB
Lopes
Department of Radiology, University of Virginia, Charlottesville, Virginia, USA.
Jack
J
Roy
Image Guided Therapy, Pessac, France.
Erik
E
Dumont
Department of Ultrasound, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.
Mingxing
M
Xie
Department of Anesthesiology, University of Virginia, Charlottesville, Virginia, USA.
Zhiyi
Z
Zuo
Cardiovascular Division, Department of Medicine, University of Virginia, Charlottesville, Virginia, USA.
Alexander L
AL
Klibanov
Departments of Neuroscience and Neurosurgery, and Center for Brain Immunology and Glia, University of Virginia, Charlottesville, Virginia, USA. Electronic address: ksl3h@virginia.edu.
Kevin S
KS
Lee
Department of Radiology, Neuroradiology Division, University of Virginia, Charlottesville, Virginia, USA; Department of Radiology, Neuroradiology Section, Stanford University, Palo Alto, California, USA. Electronic address: Max.Wintermark@gmail.com.
Max
M
Wintermark
D000818:Animals; D001812:Blood-Brain Barrier / Q000378:metabolism*; D001921:Brain; D016503:Drug Delivery Systems; D053783:Magnetic Resonance Imaging, Interventional; D008297:Male; D045423:Microbubbles; D023421:Models, Animal; D009498:Neurotoxins / Q000008:administration & dosage*; D017378:Quinolinic Acid / Q000008:administration & dosage*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012965:Sodium Chloride / Q000008:administration & dosage; D000069453:Ultrasonic Waves
D009498:Neurotoxins; D012965:Sodium Chloride; D017378:Quinolinic Acid
Blood–brain barrier; Epilepsy; Hippocampus; Magnetic resonance-guided focused ultrasound; Quinolinic acid; Transcranial drug delivery