Safety Review and Perspectives of Transcranial Focused Ultrasound Brain Stimulation.

Authors: Lee W, Weisholtz DS, Strangman GE, Yoo SS

Ultrasound is an important theragnostic modality in modern medicine. Technical advancement of both acoustic focusing and transcranial delivery have enabled administration of ultrasound waves to localized brain areas with few millimeters of spatial specificity and penetration depth sufficient to reach the thalamus. Transcranial focused ultrasound (tFUS) given at a low acoustic intensity has been shown to increase or suppress the excitability of region-specific brain areas. The neuromodulatory effects can outlast the sonication, suggesting the possibility of inducing neural plasticity needed for neurorehabilitation. Increasing numbers of studies have shown the efficacy and excellent safety profile of the technique, yet comparisons among the safety-related parameters have not been compiled. This review aims to provide safety information and perspectives of tFUS brain stimulation. First, the acoustic parameters most relevant to thermal/mechanical tissue damage are discussed along with regulated parameters for existing ultrasound therapies/diagnostic imaging. Subsequently, the parameters used in studies of large animals, non-human primates, and humans are surveyed and summarized in terms of the acoustic intensity and the mechanical index. The pulse-mode operation and the use of low ultrasound frequency for tFUS-mediated brain stimulation warrant the establishment of new safety guidelines/recommendations for the use of the technique among healthy volunteers, with additional cautionary requirements for its clinical translation.

Introduction

Purpose Transcranial ultrasound stimulation

Study Objective To review and summarize safety information and perspectives on transcranial focused ultrasound (tFUS) brain stimulation, including acoustic parameters and the need for new safety guidelines.

Disease model Healthy

Targeted brain region(s) Thalamus

Outcomes and Safety

Summary of Outcomes Low‑intensity transcranial focused ultrasound (tFUS) can increase or suppress region‑specific brain excitability with lasting neuromodulatory effects (minutes to >1 hour) and no adverse effects reported in large animals, non‑human primates, or humans. Successful parameters reported included in situ I_SPTA up to ~5.8 W/cm2 (visual) and ~4.4 W/cm2 (somatosensory) in humans, higher in animals (25.8 W/cm2 in non‑human primate visual cortex; 13.8 W/cm2 in sheep LGN), use of pulsed short sonications (e.g., ~200 ms bursts with ≥1 s intervals), low frequencies (e.g., ~250 kHz) and mechanical index limits near or below MI=1.9 (Pr ≲0.95 MPa at 250 kHz).

Duration of biological effect more than 1 hour

Safety-related matter No adverse effects have been reported in large animals, non-human primates, or healthy humans (e.g., in situ I_SPTA up to 25.8 W/cm^2 in primates and 13.8 W/cm^2 in large animals used without observable behavioral or histological anomalies). However, the authors call for new safety guidelines and caution regarding use in patients with brain damage, calcification, or implanted devices and recommend thermal and cavitation monitoring.

Brain Region

Ultrasound Parameters

FUS Mode pulsed

Focal Characteristics Focal depth: few millimeters; Focal length: None; Aperture size: None

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