Quadri-Pulse Theta Burst Stimulation using Ultra-High Frequency Bursts - A New Protocol to Induce Changes in Cortico-Spinal Excitability in Human Motor Cortex.

Patterned transcranial magnetic stimulation (TMS) such as theta burst stimulation (TBS) or quadri-pulse stimulation (QPS) can induce changes in cortico-spinal excitability, commonly referred to as long-term potentiation (LTP)-like and long-term depression (LTD)-like effects in human motor cortex (M1). Here, we aimed to test the plasticity-inducing capabilities of a novel protocol that merged TBS and QPS. 360 bursts of quadri-pulse TBS (qTBS) were continuously given to M1 at 90% of active motor threshold (1440 full-sine pulses). In a first experiment, stimulation frequency of each burst was set to 666 Hz to mimic the rhythmicity of the descending cortico-spinal volleys that are elicited by TMS (i.e., I-wave periodicity). In a second experiment, burst frequency was set to 200 Hz to maximize postsynaptic Ca2+ influx using a temporal pattern unrelated to I-wave periodicity. The second phase of sinusoidal TMS pulses elicited either a posterior-anterior (PA) or anterior-posterior (AP) directed current in M1. Motor evoked potentials (MEPs) were recorded before and after qTBS to probe changes in cortico-spinal excitability. PA-qTBS at 666 Hz caused a decrease in PA-MEP amplitudes, whereas AP-qTBS at 666 Hz induced an increase in mean AP-MEP amplitudes. At a burst frequency of 200 Hz, PA-qTBS and AP-qTBS produced an increase in cortico-spinal excitability outlasting for at least 60 minutes in PA- and AP-MEP amplitudes, respectively. Continuous qTBS at 666 Hz or 200 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

Experimental procedures, timeline of experiments and number of participants for each experiment.

<p>We performed two sets of experiments. In experiment 1, the interstimulus interval (ISI) of each pulse was set to 1.5 ms (666 Hz) to test I-wave frequency dependent patterns of qTBS. In experiment 2, the ISI was set to 5 ms and consequently suggested to be outside I-wave periodicity. In all experiments, the current flow in the brain was reversed from PA to AP. MEP: motor evoked potential, RMT: resting motor threshold, AMT: active motor threshold.</p

Results of MEP data after qTBS.

<p>(A) Timecourse of MEP amplitudes after qTBS at ISI of 1.5 ms in AP and PA direction. Flipping the current flow in M1-HAND led to bi-directional changes in synaptic plasticity with a significant increase of cortico-spinal excitability in AP direction and a significant decrease in PA direction. (B) MEP amplitudes of one representative subject before and after (POST4) qTBS 1.5 ms in AP and PA direction. Shown are averages of 20 MEP trials in each case. (C) Timecourse of MEP amplitudes after qTBS at ISI of 5 ms in AP and PA direction. In both current directions (i.e. AP and PA), MEP amplitudes significantly increased after qTBS. (D) MEP amplitudes of one representative subject before and after (POST4) qTBS at ISI of 5 ms in AP and PA direction. Shown are mean amplitudes of averages of 20 MEP trials in each case. Asterisks indicate significant differences between pre and post measurements (<i>p</i><0.05, paired <i>t</i>-test). Error bars indicate the standard error of the mean (S.E.M.). qTBS: quadri-pulse theta burst stimulation; PA: posterior-anterior; AP: anterior-posterior; ISI: interstimulus interval; MEP: motor evoked potential.</p

Schematic drawing of qTBS pulse sequence and of current waveforms.

<p>(A) The conditioning protocol of qTBS comprises 360 trains of TMS pulses. Each train consists of four biphasic magnetic pulses (i.e. quadri-pulse stimulation; QPS) delivered at interstimulus intervals of 1.5 ms and 5 ms resulting in a total of 1440 stimuli. Trains were repeated every 200 ms. (B) Each stimulus had a biphasic current waveform with 160 μs pulse duration. To reverse current direction from PA to AP and vice versa, a cable was connected to the coil changing the polarity of the induced current, hereby flipping the direction of the induced current in the M1-HAND. We refer to PA stimulation when the initially induced current in M1-HAND had a posterior-to-anterior direction and, conversely, AP stimulation refers to stimulation producing an anterior-to-posterior current flow in M1-HAND. For clarity, current direction always refers to the direction of current induced in M1-HAND by the second component of the induced current covering the second and third quarter of the biphasic cycle. ISI: interstimulus interval, IBI: interburst interval.</p