Dose-Dependent Effects of Theta Burst rTMS on Cortical Excitability and Resting-State Connectivity of the Human Motor System

Abstract

Theta burst stimulation (TBS), a specific protocol of repetitive transcranial magnetic stimulation (rTMS), induces changes in cortical excitability that last beyond stimulation. TBS-induced aftereffects, however, vary between subjects, and the mechanisms underlying these aftereffects to date remain poorly understood. Therefore, the purpose of this study was to investigate whether increasing the number of pulses of intermittent TBS (iTBS) (1) increases cortical excitability as measured by motor-evoked potentials (MEPs) and (2) alters functional connectivity measured using resting-state fMRI, in a dose-dependent manner. Sixteen healthy, human subjects received three serially applied iTBS blocks of 600 pulses over the primary motor cortex (M1 stimulation) and the parieto-occipital vertex (sham stimulation) to test for dose-dependent iTBS effects on cortical excitability and functional connectivity (four sessions in total). iTBS over M1 increased MEP amplitudes compared with sham stimulation after each stimulation block. Although the increase in MEP amplitudes did not differ between the first and second block of M1 stimulation, we observed a significant increase after three blocks (1800 pulses). Furthermore, iTBS enhanced resting-state functional connectivity between the stimulated M1 and premotor regions in both hemispheres. Functional connectivity between M1 and ipsilateral dorsal premotor cortex further increased dose-dependently after 1800 pulses of iTBS over M1. However, no correlation between changes in MEP amplitudes and functional connectivity was detected. In summary, our data show that increasing the number of iTBS stimulation blocks results in dose-dependent effects at the local level (cortical excitability) as well as at a systems level (functional connectivity) with a dose-dependent enhancement of dorsal premotor cortex-M1 connectivity.

Multiple blocks of intermittent and continuous theta‐burst stimulation applied via transcranial magnetic stimulation differently affect sensory responses in rat barrel cortex

“…A recent human TMS study demonstrated that repetition of iTBS blocks caused a stronger increase in motor cortex excitability than a single iTBS block (Nettekoven et al . 2014). It can thus be suggested that repetition of stimulus trains with breaks of considerable length, as with iTBS, typical high-frequency rTMS (>4 Hz) and biomimetic high-frequency stimulation (BHFS; Rodger et al .…”

Interindividual variability in response to continuous theta-burst stimulation in healthy adults

“…Several factors have been suggested as potential contributors to the interindividual variability in response to TBS, including the activated intracortical networks (Hamada et al, 2013), functional connectivity in the motor system (Nettekoven et al, 2014, 2015), state-dependent factors (Suppa et al, 2016), and single-nucleotide polymorphisms (SNPs) that can influence neuroplasticity.…”

Inter-individual variability in cortical excitability and motor network connectivity following multiple blocks of rTMS

“…Moreover, we could recently show that increases in cortical excitability after iTBS are paralleled by increases in resting-state functional connectivity (rsFC) (Nettekoven et al, 2014). Both, increases at the local (MEPs) as well as at the systems level (rsFC) were found to be dose-dependent with an additional increase after three blocks of iTBS (3 × 600 pulses).…”

“…We, therefore, re-analyzed the entire data set of our previous study (Nettekoven et al, 2014) with respect to individual responsiveness at the MEP level as well as fMRI network level, a question that we did not address in the original publication. To assess changes in MEP size and rsFC, 16 healthy subjects received three blocks of iTBS applied over left M1 and a control stimulation over the vertex (Nettekoven et al, 2014).…”