Safety Review and Perspectives of Transcranial Focused Ultrasound Brain Stimulation

Abstract

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.

Keywords: Acoustic Stimulation; Low Intensity Pulsed Ultrasound; Neuromodulators; Safety.

Fig. 1. Example of single-element tFUS transducer setup on a mannequin head. Left: a tFUS headgear for targeting deep brain areas (8 cm depth). Right: a tFUS headgear for targeting cortical areas (3 cm depth). Acoustic beam paths are illustrated in green. For the illustration of image-guidance for the tFUS targeting and numerical simulation of acoustic propagation, please refer to the previous article [11].

tFUS, transcranial focused ultrasound.

Fig. 2. Graphical illustration of the I_SPTA and MI (in log-scale) used in clinical practice involving ultrasound. The panels with blue dotted line indicate range of the parameters used in diagnostic ultrasound imaging (the magnified panel on the right side shown in linear-scale). The use-specific exceptions for cardiac (in orange), ophthalmic (in gray) and fetal imaging and ‘others’ (in pink) are also noted (‘others category’ includes abdominal, intraoperative, pediatric, small organs such as breast, thyroid, and testes).

I_SPTA, spatial-peak temporal-average intensity; MI, mechanical index; HIFU, high-intensity focused ultrasound.

Fig. 3. Graphical illustration of the I_SPTA and P_r used in the representative FUS-mediated brain stimulation studies. (a-c) are for large animal studies using ovine, (d-h) are for non-human primate studies, and (i-p) are for human studies.

I_SPTA, spatial-peak temporal-average intensity; P_r, peak negative pressure; FUS, focused ultrasound; MI, mechanical index.