Targeted Neuronal Injury for the Non-Invasive Disconnection of Brain Circuitry

Wilson Wang; Yanrong Zhang; Matthew J. Anzivino; Edward H. Bertram; James Woznak; Alexander Klibanov; Erik Dumont; Max Wintermark; Kevin S. Lee

doi:10.3791/61271

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Method Article

Targeted Neuronal Injury for the Non-Invasive Disconnection of Brain Circuitry

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DOI:

10.3791/61271

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September 27th, 2020

Wilson Wang^*¹ , Yanrong Zhang^*² , Matthew J. Anzivino¹ , Edward H. Bertram³ , James Woznak¹^,⁴ , Alexander Klibanov⁵ , Erik Dumont⁶ , Max Wintermark^*² , Kevin S. Lee^*¹^,⁷^,⁸

¹Department of Neuroscience, University of Virginia, ²Department of Radiology, Stanford University, ³Department of Neurology, University of Virginia, ⁴Global Internship Program, Focused Ultrasound Foundation, ⁵Department of Medicine, University of Virginia, ⁶Image Guided Therapy, ⁷Department of Neurosurgery, University of Virginia, ⁸Center for Brain, Immunology, and Glia, University of Virginia

^* These authors contributed equally

Summary

The goal of the protocol is to provide a method for producing non-invasive neuronal lesions in the brain. The method utilizes Magnetic Resonance-guided Focused Ultrasound (MRgFUS) to open the Blood Brain Barrier in a transient and focal manner, in order to deliver a circulating neurotoxin to the brain parenchyma.

Abstract

Surgical intervention can be quite effective for treating certain types of medically intractable neurological diseases. This approach is particularly useful for disorders in which identifiable neuronal circuitry plays a key role, such as epilepsy and movement disorders. Currently available surgical modalities, while effective, generally involve an invasive surgical procedure, which can result in surgical injury to non-target tissues. Consequently, it would be of value to expand the range of surgical approaches to include a technique that is both non-invasive and neurotoxic.

Here, a method is presented for producing focal, neuronal lesions in the brain in a non-invasive manner. This approach utilizes low-intensity focused ultrasound together with intravenous microbubbles to transiently and focally open the Blood Brain Barrier (BBB). The period of transient BBB opening is then exploited to focally deliver a systemically administered neurotoxin to a targeted brain area. The neurotoxin quinolinic acid (QA) is normally BBB-impermeable, and is well-tolerated when administered intraperitoneally or intravenously. However, when QA gains direct access to brain tissue, it is toxic to the neurons. This method has been used in rats and mice to target specific brain regions. Immediately after MRgFUS, successful opening of the BBB is confirmed using contrast enhanced T1-weighted imaging. After the procedure, T2 imaging shows injury restricted to the targeted area of the brain and the loss of neurons in the targeted area can be confirmed post-mortem utilizing histological techniques. Notably, animals injected with saline rather than QA do demonstrate opening of the BBB, but dot not exhibit injury or neuronal loss. This method, termed Precise Intracerebral Non-invasive Guided surgery (PING) could provide a non-invasive approach for treating neurological disorders associated with disturbances in neural circuitry.

Introduction

The purpose of this method is to provide a means for producing non-invasive neuronal lesions in a targeted region of the brain. The rationale for developing such an approach is to disconnect neuronal circuitry contributing to neurological disorders. For instance, surgery can be quite effective in treating certain medically intractable neurological disorders, such as drug resistant epilepsy (DRE)¹. However, each of the available surgical modalities possess limitations in terms of producing undesirable collateral damage to the brain. Traditional resective surgery can be highly invasive with the risk of bleeding, infection, blood clots, stroke, se....