Theta Burst Stimulation with Ultra-high Frequency Quadri-pulse Bursts Induces Metaplasticity in Human Primary Motor Cortex

Question: Changes in neuronal efficacy such as long-term potentiation (LTP) and long-term depression (LTD) are thought to reflect synaptic processes underlying learning and memory, and play a pivotal role in development and developmental disorders. Metaplasticity is a higher-order form of synaptic plasticity depending on the current synaptic state. Quadri-pulse-theta burst stimulation (qTBS) is a recently introduced short and patterned transcranial magnetic stimulation (TMS) protocol which is suited for non-invasive brain stimulation in children due to its short duration (app. 2 min). QTBS induced a lasting increase or decrease in neuronal excitability of human primary motor cortex (M1) probably corresponding to the model of LTP- and LTD-like plasticity. Here, we aimed to probe metaplastic interactions of a facilitating priming qTBS protocol on subsequent facilitating and inhibitory qTBS.

Material and Method: We investigated priming mechanisms of facilitating qTBS on subsequent facilitating qTBS (experiment 1) in 8 healthy volunteers and on subsequent inhibitory qTBS (experiment 2) in 10 healthy volunteers using a custom-made magnet stimulator (MSB, Munich). Facilitating qTBS consisted of 1440 full-sine pulses given continuously to M1 with bursts of four TMS pulses separated by inter-stimulus intervals (ISI) of 5 ms and inter-burst intervals of 200 ms. (qTBS5/200). Inhibitory qTBS (qTBS50/200) consisted of the same burst pattern but with ISI of 50 ms (200 Hz). Motor evoked potential (MEP) amplitudes with stimulus intensities to target amplitudes of 1mV were measured before priming qTBS5/200 (pre), directly after (post1), after 15 minutes (post2) and after 30 minutes (post3). Following post 3 measurements of the priming protocol, the second stimulation (qTBS5/200 or qTBS50/200) was applied and MEP were measured for 60 minutes (post 4 – post7).

Results: In both experiments, mean MEP amplitudes increased after the priming facilitatory qTBS5/200 protocol. After priming, neither a facilitatory qTBS5/200 protocol (Expt.1) nor an inhibitory qTBS50/200 protocol (Expt.2) were able to produce further changes in corticospinal excitability.

Discussion: Facilitating qTBS increased the threshold for both LTP- and LTD-like changes in human M1. This may point towards metaplastic mechanisms of facilitatory qTBS5/200 and inhibitory qTBS 50/200 following priming with qTBS5/200 which blocks following bidirectional plasticity. The finding may be of particular interest when applying the protocol in a pediatric clinical setting, for example to support motor rehabilitation in children with movement disorders.

Conclusion: Our findings support the assumption that changes in cortico-spinal excitability of qTBS protocols applied over M1 underlie metaplastic interactions.

No conflict of interest has been declared by the author(s).