Recommendations for the Safe Application of Temporal Interference Stimulation in the Human Brain Part II: Biophysics, Dosimetry, and Safety Recommendations.

Temporal interference stimulation (TIS) is a new form of transcranial electrical stimulation (tES) that has been proposed as a method for targeted, noninvasive stimulation of deep brain structures. While TIS holds promise for a variety of clinical and nonclinical applications, little data is yet available regarding its effects in humans and its mechanisms of action. To inform the design and safe conduct of experiments involving TIS, researchers require quantitative guidance regarding safe exposure limits and other safety considerations. To this end, we undertook a two-part effort to determine frequency-dependent thresholds for applied currents below which TIS is unlikely to pose risk to humans in terms of heating or unwanted stimulation. In Part II of this effort, described here, we draw on a previously compiled list (see Part I) of adverse effects (AEs) reported for transcranial direct/alternating current stimulation (tDCS/ACS), deep brain stimulation (DBS), and TIS to determine biophysics-informed exposure metrics for assessing safety. Using an in silico approach, we conduct multiphysics simulations of various tACS, DBS, and TIS exposure scenarios in an anatomically detailed head and brain model. By matching the stimulation in terms of the identified exposure metrics, we infer frequency-dependent TIS parameters that produce exposure conditions equivalent to those known to be safe for tACS and DBS. Based on the results of our simulations and existing knowledge regarding tES and DBS safety, we propose frequency-dependent thresholds below which TIS voltages and currents are unlikely to pose a risk to humans. Safety-related data from ongoing and future human studies are required to verify and refine the thresholds proposed here.