Immediate and cumulative effects of high-frequency repetitive transcranial magnetic stimulation on cognition and neuronal excitability in mice

Highlights

• High-frequency rTMS had immediate effect of increasing neuronal excitability in mice.

• High-frequency rTMS had cumulative effect of increasing cognition and neuronal excitability in mice.

• The improvement of cognitive ability in mice might be related to the enhancement of granule cells’ neuronal excitability.

Abstract

This study primarily explored the potential effects of high-frequency (20 Hz) repetitive transcranial magnetic stimulation (rTMS) with different intervention protocols on cognition and neuronal excitability in mice. Mice were randomly divided into 4 groups: a control group that received sham stimulation, an rTMS in vitro group whose acute brain slices received high-frequency stimulation, an rTMS 1 d group that received high-frequency stimulation for only 1 d, and an rTMS 15 d group that received high-frequency stimulation for 15 d. The novel object recognition and step-down tests were used to assess cognitive ability. The patch-clamp technique was used to record the membrane potentials and neural discharges of dentate gyrus granule cells to evaluate neuronal excitability. Results revealed that cognition and neuronal excitability in the rTMS 15 d group were significantly increased than that in the control and rTMS 1 d groups. The neuronal excitability in the rTMS in vitro group was also significantly increased than that in the control and rTMS 1 d groups. No significant changes were observed between the control and rTMS 1 d groups. These results suggested that high-frequency rTMS applied to the acute brain slices of mice in vitro exerted an immediate effect on increasing neuronal excitability. Chronic high-frequency rTMS applied to the brain of mice in vivo exerted a cumulative effect in improving cognition and increasing neuronal excitability.

Introduction

Repetitive transcranial magnetic stimulation (rTMS) is a brain stimulation technique that is gaining interest as a therapeutic neural rehabilitative tool (Chail et al., 2018; Tan et al., 2013). rTMS is based on the principle of electromagnetic induction discovered by Faraday in 1831 (Lefaucheur, 2019; Müller-Dahlhaus and Vlachos, 2013) and the modern TMS device invented by Barker. rTMS is an indirect and noninvasive method used to induce excitability changes in the motor cortex through a wire coil generating a magnetic field that passes through the scalp (Klomjai et al., 2015). A previous report provided a clear definition of high and low frequency. ‘High-frequency’ rTMS is referred to stimulus rates greater than 1 Hz, whereas ‘low-frequency’ rTMS is referred to stimulus rates of 1 Hz or less (Rossi et al., 2009). rTMS modulates cognition and behaviour by an increase or decrease in neuronal excitability (Wang et al., 2015b) and its effect depends on several stimulation parameters, such as stimulation frequency, duration of the stimulation period, intensity, and so on (Miniussi and Rossini, 2011; Simonetta-Moreau, 2014).

Studies have confirmed that high-frequency rTMS improves cognitive performance in behavioural tests and in the excitability or plasticity of neurons, both in clinical application and in scientific research in animal models (Koch et al., 2018; Shang et al., 2016; Solé-Padullés et al., 2006; Wang et al., 2015a, 2013; Wölwer et al., 2014). Moreover, previous studies investigated the immediate and cumulative effects of rTMS. Banerjee et al. (2017) used a whole-cell patch-clamp technique in acute rat brain slices to investigate the effects of high-frequency (20 Hz) rTMS on the cortical neuron. The results demonstrated that rTMS could immediately affect neuronal activity and enhance neuronal responses. High-frequency rTMS (5 Hz) applied to normal Wistar rats for 14 d remarkably enhanced spatial learning/memory, reversal learning/memory, and synaptic plasticity (Shang et al., 2016). As a clinical and scientific research tool, rTMS has attracted increasing attention in cognitive neuroscience, but its underlying mechanisms are not clear.

The hippocampus is primarily involved in learning and memory (Holscher, 1999), and excitatory neurons in the mouse dentate gyrus (DG) are essential for memory formation and retrieval (Kheirbek et al., 2013; Pierson et al., 2015). A previous article reviewed evidence from studies employing colchicine-induced granule cell loss in the adult rat brain and irradiation-induced hypoplasia of neonatal DG on the performance of behavioural tasks. The conclusion suggested that the DG is critically involved in the tasks that required spatial orientation based on place (Xavier and Costa, 2009). Hippocampal neurons activated during encoding drive the recall of contextual fear memory, and activation of granule cells in the DG create an artificial memory and abolish natural recall (Stefanelli et al., 2016). Many studies have demonstrated the importance of DG for cognition. However, the effect of rTMS on the neuronal excitability of DG granule cells and its potential relationship with cognition have not been reported yet.

Considering the above results, we aimed to understand better the regulation mechanism of rTMS on cognition—to explore the potential relationship between cognition and neuronal excitability of DG granule cells, and to optimize rTMS protocols. Therefore, in this study, we explored the effects of high-frequency rTMS with different intervention protocols on cognition and neuronal excitability.