A systematic assessment of safety, tolerability and blinding effectiveness of kilohertz transcranial magnetic perturbation (kTMP)

Abstract

Objective. Non-invasive brain stimulation (NIBS) techniques are increasingly used to modulate brain activity in basic and translational research. Kilohertz transcranial magnetic perturbation (kTMP) is a recently developed NIBS approach that uses magnetic induction to generate subthreshold electric fields in the brain. kTMP has been shown to modulate cortical excitability while producing no perceptible sensation at the stimulation site. However, its safety and tolerability have not yet been systematically evaluated—a gap this study aims to address. Approach. We conducted sham-controlled experiments, within-subject comparisons, and patient feasibility studies with kTMP, entailing 433 sessions across 143 individuals. Participants rated annoyance, muscle activation, and pain on a 0–10 scale after each session. With primary motor cortex (M1) as the target, we compared active stimulation (∼8 V m−1 cortical field) to sham (0 V m−1) in healthy adults and chronic stroke patients. In healthy adults, we compared active vs. sham stimulation applied to dorsolateral prefrontal cortex, superior temporal gyrus, and cerebellum. Additional datasets examined tolerability across active kTMP parameters and multi-session feasibility in stroke patients. Safety monitoring included continuous observation for abnormal motor activity and EMG recording in initial experiments. Main results. No device-related adverse reactions occurred across 433 sessions. EMG monitoring revealed no artifacts, and no participants exhibited involuntary muscle contractions or signs of abnormal cortical excitation. kTMP was well tolerated, with mean ratings for active and sham stimulation remaining below 1.5 (where ‘2’ indicates just-noticeable sensation). Permutation tests showed no significant active–sham differences and bootstrapped 95% confidence intervals consistently fell within the ±1 equivalence margin. When auditory masking was used, participants could not distinguish active from sham stimulation. Significance. kTMP achieves cortical E-fields an order of magnitude higher than conventional subthreshold tES while maintaining robust safety margins and tolerability indistinguishable from sham, supporting its use for rigorous double-blind studies and translational settings. Trial Registration: ClinicalTrials.gov Identifier: NCT06317194.