Methodological considerations of priming repetitive transcranial magnetic stimulation protocols in clinical populations

Abstract

To the editor: Repetitive transcranial magnetic stimulation (rTMS) is a neuroplasticity-enhancing technique that modifies brain responsiveness to various therapeutic modalities in clinical psychiatric and neurological applications.1 Furthermore, its effect can be attributed to long-term potentiation (LTP) or long-term depression (LTD)-like neuroplasticity. However, responsiveness to rTMS is largely variable in healthy and pathological brains2 and is mediated by complex biological mechanisms. Metaplasticity refers to a higher-order plasticity mechanism in which the direction and magnitude of synaptic plasticity are modified by prior neuronal activity and is believed to be a significant factor leading to the response variability of rTMS.3 According to its mechanism of action, the threshold for induction of LTP and LTD is dynamically adjusted to the level of prior neuronal activity: a low level of prior neuronal activity slides down the threshold to preferentially induce LTP. By contrast, a high level slides up the threshold to preferentially induce LTD.4 The induction of metaplasticity has been demonstrated in the human cortex using rTMS. Successively applying two identical rTMS protocols may lead to the reversal of the aftereffect of the protocol owing to the saturation of LTP/LTD and homeostatic regulation via metaplasticity. By contrast, pairing two non-identical stimulation protocols appears to induce additive neuroplastic effects through therapeutically beneficial metaplasticity induction.4 Therefore, researchers have used priming protocols to stabilise and increase the aftereffects of the subsequent conditioning session (figure 1A). A total of two kinds of priming protocols for inducing therapeutically beneficial metaplasticity, ‘preceding excitation enhances subsequent inhibition’ and ‘preceding inhibition amplifies subsequent excitation’, have been tested with conventional high-frequency/low-frequency rTMS as well as intermittent/continuous theta burst stimulation (iTBS/cTBS) in the M1 of healthy individuals, measured using motor-evoked potential (MEP).5 Figure 1 (A) Design of priming rTMS protocol and its underlying sliding threshold model: a low level of neuronal …