Recommendations for the Safe Application of Temporal Interference Stimulation in the Human Brain Part I: Principles of Electrical Neuromodulation and Adverse Effects.

Temporal interference stimulation (TIS) is a new form of transcranial electrical stimulation (tES) that has been proposed as a method for targeted, non-invasive stimulation of deep brain structures. While TIS holds promise for a variety of clinical and non-clinical applications, little data is yet available regarding its effects in humans and its mechanisms of action. In order 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. Part I of this effort, described here, comprises a summary of the current knowledge pertaining to the safety of TIS and related techniques. Specifically, we provide: i) a broad overview of the electrophysiological impacts neurostimulation, ii) a review of the (bio-)physical principles underlying the mechanisms of action of transcranial alternating/direct stimulation (tACS/tDCS), deep brain stimulation (DBS), and TIS, and iii) a comprehensive survey of the adverse effects (AEs) associated with each technique as reported in the scientific literature and regulatory and clinical databases. In Part II, we perform an in silico study to determine field exposure metrics for tDCS/tACS and DBS under normal (safe) operating conditions and infer frequency-dependent current thresholds for TIS that result in equivalent levels of exposure.