A High-Precision Timing Method and Digital Interface for Closed-Loop TMS

Abstract Objective Current transcranial magnetic stimulation (TMS) protocols exhibit high inter-subject variability in treatment outcomes, highlighting the need for personalized, brain-state-dependent closed-loop stimulation protocols. To enable such protocols, we aim to provide robust, precisely timed external control of TMS, with stimulation timed relative to feedback signals such as the electroencephalogram (EEG). Approach Commercial TMS devices typically rely on trigger signals for precise external pulse timing, while adjusting stimulation parameters, such as intensity, is better handled via serial digital communication, which supports robust error detection and feedback. However, combining these communication methods is inherently complex and prone to timing issues, such as race conditions. Furthermore, trigger signals lack capabilities essential for real-time systems, such as preventing late pulse delivery. We present a method for precise and accurate pulse timing, implemented through a digital interface that uses exclusively serial digital messaging, eliminating the need for trigger signals. This interface enables external control of pulse timing, intensity, and other parameters. The TMS device maintains its own internal clock and delivers pulses at pre-scheduled times, decoupling timing precision from the control device. Additionally, we propose a method for synchronizing such time-tracking TMS devices with commercial EEG systems, enabling precisely timed EEG–TMS. Main results Using these methods, our custom TMS device delivered pulses precisely aligned to the EEG signal, with timing errors consistently below 0.3 ms. These errors were constrained by the experimental setup, including the sampling rate of our EEG device and the signal-to-noise ratio affecting pulse detection. Significance Our timing method achieves sub-millisecond precision in brain-state-dependent closed-loop EEG–TMS, providing a foundation for robust TMS timing that supports adaptive, personalized stimulation protocols. The digital control interface, co-designed with our TMS device, integrates pulse timing and parameters, setting a precedent for future advancements in computer-controlled TMS. Competing Interest Statement J.O.N. and R.J.I. are inventors on patents and patent applications related to mTMS technology. The authors declare no other competing interests.