ITRUSST Consensus on Biophysical Safety for Transcranial Ultrasound Stimulation.

Transcranial ultrasound stimulation (TUS) is an emerging technology for non-invasive brain stimulation. The International Transcranial Ultrasonic Stimulation Safety and Standards consortium (ITRUSST) has established consensus on considerations for nonsignificant biophysical risk of TUS, drawing upon the literature and established regulations for biomedical devices. Here, we assume the application of TUS to individuals without contraindications, compromised thermoregulation, vascular vulnerabilities, or administered ultrasound contrast agents. In this context, we present a concise yet comprehensive set of levels for nonsignificant risks of TUS application. For mechanical effects, it is non-significant risk if the mechanical index (MI) or the mechanical index for transcranial application (MI_tc) does not exceed 1.9. For thermal effects, it is non-significant risk if any of the following three levels are met: the peak temperature rise does not exceed 2°C or the peak absolute temperature does not exceed 39°C, assuming a baseline temperature of 37°C, the thermal dose does not exceed 2 CEM43 in brain tissue, 16 CEM43 in bone tissue, and 21 CEM43 in skin tissue, or specific values of the thermal index (TI) for a given exposure time. This report reflects a consensus expert opinion and can inform, but not replace, regulatory guidelines or official international standards. Similarly, this consensus can inform, but not replace, ethical evaluation, which weighs the total burden, risks, and benefits of the proposed action. The stated levels are not safety limits per se, and further data is needed to establish the threshold for significant risk. We review literature relevant to our considerations and discuss limitations and future developments of our approach.