Ultra-high frequency repetitive TMS at subthreshold intensity induces suprathreshold motor response via temporal summation

Abstract

Objective. The transcranial magnetic stimulation (TMS) coil induces an electric field that diminishes rapidly upon entering the brain. This presents a challenge in achieving focal stimulation of a deep brain structure. Neuronal elements, including axons, dendrites, and cell bodies, exhibit specific time constants. When exposed to repetitive TMS pulses at a high frequency, there is a cumulative effect on neuronal membrane potentials, resulting in temporal summation. This study aims to determine whether TMS pulse train at high-frequency and subthreshold intensity could induce a suprathreshold response. Approach. As a proof of concept, we developed a TMS machine in-house that could consistently output pulses up to 250 Hz, and performed experiments on 22 awake rats to test whether temporal summation was detectable under pulse trains at 100, 166, or 250 Hz. Main results. Results revealed that TMS pulses at 55% maximum stimulator output (MSO, peak dI/dt = 68.5 A/s at 100% MSO, pulse width = 48 s) did not induce motor responses with either single pulses or pulse trains. Similarly, a single TMS pulse at 65% MSO failed to evoke a motor response in rats; however, a train of TMS pulses at frequencies of 166 and 250 Hz, but not at 100 Hz, successfully triggered motor responses and MEP signals, suggesting a temporal summation effect dependent on both pulse intensities and pulse train frequencies. Significance. We propose that the temporal summation effect can be leveraged to design the next-generation focal TMS system: by sequentially driving multiple coils at high-frequency and subthreshold intensity, areas with the most significant overlapping E-fields undergo maximal temporal summation effects, resulting in a suprathreshold response.