[Paper Review] ITRUSST Consensus on Biophysical Safety for Transcranial Ultrasound Stimulation

Jean‐François Aubry, David Attali+16 more|arXiv (Cornell University)|Nov 9, 2023

Ultrasound and Hyperthermia Applications36 citations

TL;DR

ITRUSST establishes consensus non-significant risk thresholds for transcranial ultrasound stimulation, detailing mechanical and thermal safety limits.

ABSTRACT

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 (MItc) 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.

Motivation & Objective

• Define levels of nonsignificant biophysical risk for transcranial ultrasound stimulation (TUS) in individuals without contraindications.
• Summarize mechanical and thermal safety criteria drawn from literature and biomedical device regulations.
• Provide guidance to inform regulators and ethics reviews without replacing official standards.

Proposed method

• Review literature relevant to TUS biophysical safety and existing biomedical device regulations.
• Propose explicit nonsignificant risk levels for mechanical effects (MI and MItc ≤ 1.9).
• Propose explicit nonsignificant risk levels for thermal effects including temperature rise, absolute temperature, thermal dose (CEM43), and thermal index (TI).
• Clarify that these levels are consensus expert opinion and not safety limits or regulatory standards.
• Discuss limitations, future developments, and how the consensus should inform, but not replace, ethical evaluation.

Experimental results

Research questions

• RQ1 What constitute acceptable nonsignificant risk thresholds for mechanical effects of transcranial ultrasound stimulation?
• RQ2 What constitute acceptable nonsignificant risk thresholds for thermal effects of transcranial ultrasound stimulation?
• RQ3 How should these consensus thresholds interface with regulatory standards and ethical assessments?

Key findings

• Mechanical risk: nonsignificant if mechanical index (MI) or transcranial MI (MItc) ≤ 1.9.
• Thermal risk: nonsignificant if any of the following holds: peak temperature rise ≤ 2°C (baseline 37°C), or peak absolute temperature ≤ 39°C, or thermal dose (CEM43) thresholds (brain 2, bone 16, skin 21), or TI within exposure-time-specific values.
• Consensus is based on literature and biomedical device regulations and is not a substitute for official standards.
• Statement that levels are for nonsignificant risk and require further data to establish significant-risk thresholds.
• Acknowledgment of limitations and need for future data and developments.