Focused Ultrasound for Noninvasive, Focal Pharmacologic Neurointervention

Abstract

A long-standing goal of translational neuroscience is the ability to noninvasively deliver therapeutic agents to specific brain regions with high spatiotemporal resolution. Focused ultrasound (FUS) is an emerging technology that can noninvasively deliver energy up the order of 1 kW/cm² with millimeter and millisecond resolution to any point in the human brain with Food and Drug Administration-approved hardware. Although FUS is clinically utilized primarily for focal ablation in conditions such as essential tremor, recent breakthroughs have enabled the use of FUS for drug delivery at lower intensities (i.e., tens of watts per square centimeter) without ablation of the tissue. In this review, we present strategies for image-guided FUS-mediated pharmacologic neurointerventions. First, we discuss blood-brain barrier opening to deliver therapeutic agents of a variety of sizes to the central nervous system. We then describe the use of ultrasound-sensitive nanoparticles to noninvasively deliver small molecules to millimeter-sized structures including superficial cortical regions and deep gray matter regions within the brain without the need for blood-brain barrier opening. We also consider the safety and potential complications of these techniques, with attention to temporal acuity. Finally, we close with a discussion of different methods for mapping the ultrasound field within the brain and describe future avenues of research in ultrasound-targeted drug therapies.

Keywords: blood–brain barrier; drug delivery; focused ultrasound; nanotechnology; neurointervention; neuromodulation.

FIGURE 1

Focused ultrasound (FUS) for noninvasively delivering acoustic energy to the brain. (A) Schematic of FUS use. A transducer is coupled to the skin using a water bag and delivers ultrasound waves to a focus within the brain. (B) Simulation of energy deposited by a commercial MRI-guided FUS system (Exablate 4000, Insightec, Haifa, Israel) through the skull. Adapted from Vyas et al. (2016). Reprinted with permission from the American Association of Physicists in Medicine.

FIGURE 2

Reversible blood–brain barrier opening (BBBO) with focused ultrasound (FUS). (A) Sagittal autoradiography image of a rat following intravenous administration of radiolabeled histamine demonstrates the efficience of exclusion of certain agents from the central nervous system by the blood–brain barrier. Adapted from Pardridge et al. (1986). Reprinted with permission from The American College of Physicians. (B) Schematic of BBBO with FUS. Microbubbles (blue) are injected into the bloodstream and are activated by FUS. This causes the spaces between pericytes and astrocytes to open up, enabling delivery of the therapeutic agent (green) past the BBB. (C) T1-weighted gadolinium MR images for a patient before (left), immediately after (center), and 24 h after (right) FUS-mediated BBBO. Adapted from Lipsman et al. (2018). Reprinted under Creative Commons License.

FIGURE 3

Long-term cortical atrophy after repeated focused ultrasound (FUS)-mediated blood–brain barrier opening sessions. (A) Representative T2* images demonstrating long-term effects of 6 weekly BBBO sessions in cortical and deep structures of the brain (white dashed lines). (B) Quantification of distribution of T2* times at the targeted sites (solid lines) vs. the contralateral site (dashed lines). Adapted from Kovacs et al. (2018). Reprinted under Creative Commons License.

FIGURE 4

Ultrasonic drug uncaging for spatiotemporally precise neuromodulation. (A) Schematic of ultrasonic drug uncaging. Nanoparticles (blue) are administered intravenously, where they are selectively activated by focused ultrasound (FUS) (green). The activated nanoparticles then release their drug (yellow), and the freed drug then diffuses across an intact blood–brain barrier (BBB) into the brain parenchyma (pink). (B) Uncaging propofol in the visual cortex silences visually evoked potentials (VEPs), with intensity recovering seconds after ultrasound ceases. (C) Fluorodeoxyglucose-positron emission tomography demonstrates that the neuromodulation induced by propofol uncaging is spatially limited to the ultrasound focus (black oval). Adapted from Wang et al. (2018). Reprinted with permission from Elsevier.

FIGURE 5

(A) Experimental 128-element imaging array (5 MHz) integrated into the 230 kHz hemispherical transducer of an InSightec ExAblate 4000 MRgFUS system for three-dimensional cavitation imaging and skull localization (Crake et al., 2018). © Institute of Physics and Engineering in Medicine. Reproduced by permission of the Institute of Physics Publishing. All rights reserved. (B) Conventional ultrasound imaging array (5 MHz) integrated with a single-element therapy transducer (660 kHz) for two-dimensional cavitation imaging (Gateau et al., 2011). Reprinted with permission from the Institute of Electrical and Electronics Engineers. (C) (Top) Cavitation image overlaid with a B-mode image obtained during an ultrasound-mediated blood–brain barrier opening (BBBO) experiment (Burgess et al., 2018). (Bottom) © Institute of Physics and Engineering in Medicine. Reproduced by permission of the Institute of Physics Publishing. All rights reserved. (D) Example of magnetic resonance-acoustic radiation force imaging (MR-ARFI) displacement image in ex vivo porcine brain. The images indicate the focused ultrasound (FUS) energy distribution (de Bever et al., 2018). Reprinted with permission from John Wiley and Sons. (E) Displacement maps and temperature rise measured with a modified MR-ARFI sequence for increasing acoustic power (Kaye et al., 2013). Reprinted with permission from John Wiley and Sons.