Novel High-Frequency Modulation Techniques for Transcranial Magnetic Stimulation: A Feasibility Study for a Transition to a Next Generation of Non-Invasive Neurostimulators

Transcranial magnetic stimulation (TMS) has been a promising non-invasive neuromodulation technique for nearly 40 years. Research has led to FDA-approved treatments for neurological and psychiatric disorders like major depressive disorder (MDD), obsessive-compulsive disorder (OCD), migraines, smoking cessation, and anxious depression. Current investigations also target conditions such as post-traumatic stress disorder (PTSD), traumatic brain injury (TBI), epilepsy, and Parkinson’s disease (PD), which require precise, small-region stimulation. Despite its potential, TMS has limitations, including large coils with low focality, demanding hardware, and loud, uncomfortable stimulation pulses. High-frequency electromagnetic energy, traditionally thought ineffective for neurostimulation due to poor axonal membrane response, is increasingly gaining attention among researchers. This study introduces two novel high-frequency modulated TMS methods supported by both computational modeling and proof-of-concept experiments: Temporal Interference TMS (TI-TMS) and Amplitude-Modulated TMS (AM-TMS), evaluated along with mathematical assessments of the electrophysiological response of axons to the pulse’s envelope. A custom-built neurostimulator operating at 25.5 kHz with size-reduced, high-permeability cored coils were used, with validations through simulations, bench measurements, and animal experimentation. Results showed effective stimulation of the motor cortex in adult rats, evidenced by motor-evoked potentials (MEPs). These methods yielded significant electromagnetic gains, lowering power requirements over 680-fold, and enabling smaller, more efficient coil designs. AM-TMS and TI-TMS produced significantly focal E-fields compared to conventional, standard-frequency TMS, minimizing unintended stimulation. Click-sound levels of pulses were decreased to 45 dB, comparable to background noise. These findings show potential for TI-TMS and AM-TMS to enhance precision, safety, and efficacy of TMS treatments.