Safety of transcranial focused ultrasound stimulation: A systematic review of the state of knowledge from both human and animal studies

Abstract

Background: Low-intensity transcranial focused ultrasound stimulation (TFUS) holds great promise as a highly focal technique for transcranial stimulation even for deep brain areas. Yet, knowledge about the safety of this novel technique is still limited. Objective: To systematically review safety related aspects of TFUS. The review covers the mechanisms-ofaction by which TFUS may cause adverse effects and the available data on the possible occurrence of such effects in animal and human studies. Methods: Initial screening used key term searches in PubMed and bioRxiv, and a review of the literature lists of relevant papers. We included only studies where safety assessment was performed, and this results in 33 studies, both in humans and animals. Results: Adverse effects of TFUS were very rare. At high stimulation intensity and/or rate, TFUS may cause haemorrhage, cell death or damage, and unintentional blood-brain barrier (BBB) opening. TFUS may also unintentionally affect long-term neural activity and behaviour. A variety of methods was used mainly in rodents to evaluate these adverse effects, including tissue staining, magnetic resonance imaging, temperature measurements and monitoring of neural activity and behaviour. In 30 studies, adverse effects were absent, even though at least one Food and Drug Administration (FDA) safety index was frequently exceeded. Two studies reported microhaemorrhages after long or relatively intense stimulation above safety limits. Another study reported BBB opening and neuronal damage in a control condition, which intentionally and substantially exceeded the safety limits. Conclusion: Most studies point towards a favourable safety profile of TFUS. Further investigations are warranted to establish a solid safety framework for the therapeutic window of TFUS to reliably avoid adverse effects while ensuring neural effectiveness. The comparability across studies should be improved by a more standardized reporting of TFUS parameters.

Systematic examination of low-intensity ultrasound parameters on human motor cortex excitability and behavior

“…Low-intensity transcranial ultrasound (TUS) is a promising noninvasive brain stimulation technique actively being studied for its ability to reversibly modulate mammalian brain activity (Fomenko et al, 2018;Naor et al, 2016;Tyler et al, 2008). By focusing the propagation of acoustic wave through the skull, a higher degree of spatial specificity and deep targeting can be achieved over other noninvasive stimulation methods such as transcranial magnetic stimulation (TMS) and transcranial direct-current stimulation (Fomenko and Lozano, 2019;Pasquinelli et al, 2019).…”

Sono-optogenetics facilitated by a circulation-delivered rechargeable light source for minimally invasive optogenetics

“…Third, the FUS stimuli in our in vivo experiments were measured to have a spatial peak pulsed average intensity (ISPPA) of 10 W/cm 2 at the ultrasound focus in the brain tissue ( SI Appendix , Fig. S9), significantly lower than the safety limit of FUS in mice (43) and the threshold required to provide nonspecific neural stimulation at 1.5 MHz (44). We estimate that with our protocol, the pressure produced by FUS in the brain tissue was able to produce “band tilting” of 0.96 V, sufficient to release the trapped electrons at a depth of 0.5 V to the conduction band for mechanoluminescence emission (35).…”

Neuromodulation Management of Chronic Neuropathic Pain in the Central Nervous System

“…Although it has been very rare to elicit adverse neural effects by administering tFUS through a survey of 33 studies in human and animal models [243] and through a recent review of 54 studies by Blackmore et al, [144] the in vivo guidance and feedback would still be highly needed to ensure the safety of tFUS for translational application. Despite the fact that researchers have been exploring ultrasound parametric space aggressively and propose for a new set of ultrasound safety guideline for neuromodulation purpose, the prevailing standard is still the FDA's ultrasound energy thresholds for diagnostic ultrasound equipment, that is, the derated acoustic output at the global maximum is required not to exceed "Pre-amendments acoustic output exposure levels".…”