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Applications of focused ultrasound in the brain: from thermoablation to drug delivery

Abstract

Focused ultrasound (FUS) is a disruptive medical technology, and its implementation in the clinic represents the culmination of decades of research. Lying at the convergence of physics, engineering, imaging, biology and neuroscience, FUS offers the ability to non-invasively and precisely intervene in key circuits that drive common and challenging brain conditions. The actions of FUS in the brain take many forms, ranging from transient blood–brain barrier opening and neuromodulation to permanent thermoablation. Over the past 5 years, we have seen a dramatic expansion of indications for and experience with FUS in humans, with a resultant exponential increase in academic and public interest in the technology. Applications now span the clinical spectrum in neurological and psychiatric diseases, with insights still emerging from preclinical models and human trials. In this Review, we provide a comprehensive overview of therapeutic ultrasound and its current and emerging indications in the brain. We examine the potential impact of FUS on the landscape of brain therapies as well as the challenges facing further advancement and broader adoption of this promising minimally invasive therapeutic alternative.

Key points

  • Recent advances have led to a surge of interest in focused ultrasound (FUS) as a non-invasive, potentially disruptive tool for the most intractable neurological conditions.

  • Magnetic resonance-guided FUS thermoablation has been approved for the treatment of essential tremor and tremor-dominant Parkinson disease and is being investigated in psychiatric applications as well as in chronic pain and epilepsy.

  • Transient opening of the blood–brain barrier for drug delivery is a burgeoning field, with early human studies demonstrating a favourable safety profile as well as versatility across and scalability within a range of clinical indications.

  • Future studies will investigate the delivery of established pharmaceuticals and novel therapies in combination with FUS blood–brain barrier opening.

  • Emerging applications are also harnessing the myriad of ways in which FUS can interact with the CNS, including immune modulation and neuromodulation.

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Fig. 1: The FUS literature.
Fig. 2: Current therapeutic ultrasound devices for brain applications.
Fig. 3: Biological effects of FUS.
Fig. 4: Intracranial applications of FUS in humans.
Fig. 5: The global landscape of human focused ultrasound clinical trials.

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Acknowledgements

We acknowledge Hang Yu Lin for her artistic contribution to the figures in this article. N. L. acknowledges and is grateful for the generous philanthropic gifts to the Sunnybrook Foundation, Sunnybrook Research Institute and the Harquail Centre for Neuromodulation as well as the support of the Focused Ultrasound Foundation.

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Contributions

Y.M. researched data for the article. Y.M. and N.L. wrote the article. All authors made substantial contributions to discussions of the content and reviewed and/or edited the manuscript before submission.

Corresponding author

Correspondence to Nir Lipsman.

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Competing interests

K.H. is an inventor on intellectual property owned by Brigham and Women’s Hospital in Boston, MA, USA, and Sunnybrook Research Institute in Toronto, Canada, related to intracranial focused ultrasound technology. N.L. has received an honorarium from the Focused Ultrasound Foundation, a not-for-profit funding agency, for serving on an expert steering committee on focused ultrasound in Alzheimer disease. Y.M. declares no competing interests.

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Glossary

Blood–brain barrier

(BBB). A structural and functional border along the capillaries in the brain that tightly regulates paracellular and transcellular transport.

Craniectomy

A surgical procedure in which a piece of the skull is removed and the overlying skin flap is replaced to create a window for ultrasound propagation.

Sonication

The active delivery of ultrasound. Currently, each typical sonication lasts ~0.5 min for thermoablation and ~1 min for blood–brain barrier (BBB) opening. A rest period allows scalp cooling in thermoablation and systemic clearance of microbubbles in BBB opening.

Cavitation

The change of a liquid to a gas state when subjected to reduced pressures and/or interactions of ultrasound with gas bubbles.

Treatment envelopes

The spatial extent of the brain regions where the desired biological effect (for example, thermoablation) can be successfully achieved with FUS.

Beta frequency

Sustained beta frequency oscillations (12.5–30 Hz) in the cortex and subthalamic nucleus are a characteristic of Parkinson disease and related motor impairments.

P-glycoprotein

A member of the ATP-binding cassette transporter B subfamily that pumps a wide range of foreign substances out of cells and is important in multidrug resistance.

Stereotactic frame

A stereotactic frame is fixed to the head to provide a reference for precise targeting. Common examples include the Leksell (polar coordinate) and Cosman–Roberts–Wells (Cartesian coordinate) frames.

Common Terminology Criteria for Adverse Events

The Common Terminology Criteria for Adverse Events allows the standardized classification of adverse events with condition-specific severity designations. Generally, grade 1 denotes a mild adverse event and grade 5 denotes death.

Optogenetics

A neuromodulation technology that uses specific wavelengths of light to excite or inhibit neurons through light-sensitive ion channels, which can be introduced through viral transfection.

Skull density ratio

(SDR). The ratio of cancellous to cortical bone density in the skull.

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Meng, Y., Hynynen, K. & Lipsman, N. Applications of focused ultrasound in the brain: from thermoablation to drug delivery. Nat Rev Neurol 17, 7–22 (2021). https://doi.org/10.1038/s41582-020-00418-z

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