Critical role of glutamatergic and GABAergic neurotransmission in the central mechanisms of theta-burst stimulation

Abstract

Theta-burst stimulation (TBS) is a varied form of repetitive transcranial magnetic stimulation (rTMS) and has more rapid and powerful effects than rTMS. Experiments on the human motor cortex have demonstrated that intermittent TBS has facilitatory effects, whereas continuous TBS has inhibitory effects. Huang's simplified model provides a solid basis for elucidating such after-effects. However, evidence increasingly indicates that not all after-effects of TBS are as expected, and high variability among individuals has been observed. Studies have suggested that the GABAergic and glutamatergic neurotransmission play a vital role in the aforementioned after-effects, which might explain the interindividual differences in these after-effects. Herein, we reviewed the latest findings on TBS from animal and human experiments on glutamatergic and GABAergic neurotransmissions in response to TBS. Furthermore, an updated theoretical model integrating glutamatergic and GABAergic neurotransmissions is proposed.

Keywords: GABA; glutamate; mechanisms; repetitive transcranial magnetic stimulation; theta-burst stimulation.

Figure 1

(a) Standard pattern of intermittent and continuous theta‐burst stimulation (iTBS and cTBS, respectively). (b) After‐effects of iTBS and cTBS on motor‐evoked potential (MEP). According to a recent meta‐analysis, cTBS reduces MEP amplitudes lasting up to 60 min (a pooled standard mean difference [SMD] of −0.9, p < .00001), whereas iTBS increases MEP amplitudes lasting up to 30 min (SMD = 0.71, p < .00001) (Chung et al., 2016) * p < .00001

Figure 2

Schematic epidural recording of descending volleys through transcranial magnetic stimulation at a high stimulation intensity and the resultant small D wave, followed by the I‐1 wave and later I waves

Figure 3

Schematic depicting how the intermittent and continuous theta‐burst stimulation (iTBS and cTBS, respectively) protocols produce the expected facilitatory and inhibitory after‐effects on the hand region of the motor cortex, respectively. (a) Bursts from iTBS activate pathways contributing to later I waves (solid red circles), including apical and basal dendrites of layer‐2/3 neurons in the target regions (i.e., the main targets of corticocortical inputs), to induce long‐term potentiation. The rapidly induced activations may also lead to suppression of GABA interneurons (dotted red circles), potentially via a feedforward inhibitory pathway. The effects are summed to generate facilitatory after‐effects. (b) Continuous bursts from cTBS could cause prolonged Ca2+ increases, leading to long‐term depression of synaptic strength of the layer‐2/3 neurons in the targeted regions (dotted green circle). In turn, the continuous bursts might slowly increase the inhibitory activities of the GABAergic interneurons (solid green circles). Most importantly, cTBS mainly activates the I‐1 pathway (dashed green triangle). The contribution of the I‐1 wave is plotted separately from the later I waves for clarity. The overall effects from cTBS, therefore, cause inhibitory after‐effects [Color figure can be viewed at http://wileyonlinelibrary.com]