Magnetic Resonance-Guided Focused Ultrasound : Current Status and Future Perspectives in Thermal Ablation and Blood-Brain Barrier Opening

Abstract

Magnetic resonance-guided focused ultrasound (MRgFUS) is an emerging new technology with considerable potential to treat various neurological diseases. With refinement of ultrasound transducer technology and integration with magnetic resonance imaging guidance, transcranial sonication of precise cerebral targets has become a therapeutic option. Intensity is a key determinant of ultrasound effects. High-intensity focused ultrasound can produce targeted lesions via thermal ablation of tissue. MRgFUS-mediated stereotactic ablation is non-invasive, incision-free, and confers immediate therapeutic effects. Since the US Food and Drug Administration approval of MRgFUS in 2016 for unilateral thalamotomy in medication-refractory essential tremor, studies on novel indications such as Parkinson's disease, psychiatric disease, and brain tumors are underway. MRgFUS is also used in the context of blood-brain barrier (BBB) opening at low intensities, in combination with intravenously-administered microbubbles. Preclinical studies show that MRgFUS-mediated BBB opening safely enhances the delivery of targeted chemotherapeutic agents to the brain and improves tumor control as well as survival. In addition, BBB opening has been shown to activate the innate immune system in animal models of Alzheimer's disease. Amyloid plaque clearance and promotion of neurogenesis in these studies suggest that MRgFUS-mediated BBB opening may be a new paradigm for neurodegenerative disease treatment in the future. Here, we review the current status of preclinical and clinical trials of MRgFUS-mediated thermal ablation and BBB opening, described their mechanisms of action, and discuss future prospects.

Keywords: Alzheimer disease; Blood-brain barrier; Essential tremor; High-intensity focused ultrasound ablation.

Fig. 1.

Schematic depicting proposed pulsed LIFU neuromodulation mechanism. A : Resting state of neuron without ultrasound. B : Depolarized state with ultrasound. The mechanical force of ultrasound wave changes neuronal lipid bilayers tension. Voltage-gated ion channels, including Na+ , Ca2+, and K+ channels, with mechanosensitive properties, open in response to pulsed LIFU, which leads to depolarization and generation of action potentials, eventually stimulating neurons. Here, Na+ channels are depicted as an example. LIFU : low-intensity focused ultrasound.

Fig. 2.

Schematic illustration of transient BBB opening. MRgFUS in conjunction with microbubbles leads to open the BBB by separating the endothelial tight junction, allowing enhanced delivery of therapeutic agents. BBB : blood-brain barrier, MRgFUS : magnetic resonance-guided focused ultrasound.

Fig. 3.

A : Schematic illustration of stable cavitation. As the acoustic wave propagates longitudinally, it alternates between compression and expansion, with changing acoustic pressures along the sinusoidal curve. When microbubbles are subjected to pressures below the inertial cavitation threshold, they contract during compression and expand during rarefaction, resulting in stable oscillation. B : With ultrasonic pressure above the inertial cavitation threshold, microbubbles initially oscillate but eventually implode at rarefaction pressure.