FV 5 Quadri-pulse theta burst stimulation using ultra-high frequency bursts at I-wave periodicity induces direction dependent bi-directional plasticity in human primary motor cortex

Abstract

Background/Question Long-term potentiation (LTP) and long-term depression (LTD) are forms of cortical plasticity and are considered to be synaptic processes underlying learning and memory. Patterned transcranial magnetic stimulation (TMS) such as theta burst stimulation (TBS) or quadri-pulse stimulation (QPS) can induce LTP-like and LTD-like effects in human primary motor cortex (M1), displayed by an increase or decrease in cortico-spinal excitability. Here, we aimed to test the plasticity-inducing capabilities of a novel protocol that merged TBS and QPS – so called quadri-pulse theta burst stimulation (qTBS) – at interstimulus intervals (ISI) that mimic I-wave periodicity (i.e. 1.5 ms/666 Hz) with an effective anterior-posterior (AP) and posterior-anterior (PA) current flow in the brain. Methods We investigated healthy volunteers (n = 12 per protocol) with 360 bursts of qTBS that was continuously given to M1 (i.e. 1440 full-sine pulses). QTBS consisted of repeated bursts of four biphasic TMS pulses (duration: 160 μ s) separated by ISI of 1.5 ms (666 Hz) and inter-burst intervals of 200 ms. (5 Hz). TMS was applied by a custom-made magnetic stimulator (IMETUM, Munich). Resting motor threshold (rMT), and motor evoked potential (MEP) amplitudes with stimulus intensities to target amplitudes of 1mv (SI1mV) were measured before (Pre) qTBS, directly after (Post1), after 15 min (Post2), after 30 min (Post3) and after 60 min (Post4). Results PA-qTBS at 666 Hz caused a decrease in mean MEP amplitudes, whereas AP-qTBS at 666 Hz induced an increase in mean MEP amplitudes outlasting for approximately 60 min. As expected, baseline data of rMT prior to qTBS differed significantly, with higher thresholds in AP direction. Discussion/Conclusion Continuous qTBS at 666 Hz can induce lasting changes in cortico-spinal excitability. Induced current direction in the brain appears to be relevant when qTBS targets I-wave periodicity, corroborating that high-fidelity spike timing mechanisms are critical for inducing bi-directional plasticity in human M1.