Closed-Loop Estimation of Individualized Inter-Stimulus Interval Window for Transient Neuromodulation via Paired Mechanical and Brain Stimulation

Mechanical stimulation-conditioned transcranial magnetic stimulation (Mstim-cTMS) is a neuromodulation technique that transiently enhances neural excitability through paired peripheral and cortical stimulation. Importantly, the temporal inter-stimulus interval (ISI) must fall within an individual’s specific ISI window (ISI-W) to induce neuromodulatory effects. Currently, ISI-W identification is inefficient, incrementally applying Mstim-cTMS within a wide search range. This paper aims to test a real-time, closed-loop framework that decreases the number of trials required to obtain individualized ISI-Ws by implementing a previously developed statistical regression algorithm. Each Mstim-cTMS trial consisted of peripheral mechanical stimulation using a precise, tapping robot paired with transcranial magnetic stimulation to the motor cortex. Neuromodulation was characterized by measuring resulting motor evoked potentials (MEPs). The closed-loop process estimated the effective ISI-W by iterating Mstim-cTMS at statistically determined ISIs based on the detected MEPs. The estimated ISI-Ws of two subjects had an average correlation coefficient of 0.84 with their reference windows obtained using the conventional search method. The estimation reduced the number of required Mstim-cTMS trials by an average of 93.8%. The results indicate the proposed method’s potential for decreasing Mstim-cTMS startup durations. Future rehabilitation and neurophysiological studies can benefit from efficiently updating ISI-Ws to account for long-term neural variability.