Repetitive transcranial magnetic stimulation during a spatial memory task leads to a decrease in brain metabolic activity

Highlights

• Transcranial magnetic stimulation leads to a slight spatial learning facilitation in healthy rats.

• Transcranial magnetic stimulation generates greater location persistence.

• Transcranial magnetic stimulation provokes an efficient use of brain metabolism.

Abstract

Repetitive transcranial magnetic stimulation (rTMS) is a non-invasive neuromodulation technique that is able to generate causal-based interferences between brain networks and cognitive or behavioral responses. It has been used to improve cognition in several disease models. However, although its exploration in healthy animals is essential to attribute its pure effect in learning and memory processes, studies in this regard are scarce. We aimed to evaluate whether rTMS leads to memory facilitation in healthy rats, and to explore the brain-related oxidative metabolism. We stimulated healthy Wistar rats with a high-frequency (100 Hz) and low-intensity (0.33 T) protocol during three consecutive days and evaluated the effect on the performance of an allocentric spatial reference learning and memory task. Following the last day of learning, we assessed oxidative brain metabolism through quantitative cytochrome c oxidase (CCO) histochemistry. The results showed that rTMS did not improve spatial memory in healthy rats, but the behavioral outcome was accompanied by a CCO reduction in the prefrontal, retrosplenial, parietal, and rhinal cortices, as well as in the striatum, amygdala, septum, mammillary bodies, and the hippocampus, reflecting a lower metabolic activity. In conclusion, rTMS induces a highly efficient use of brain regions associated with spatial memory.

Introduction

Transcranial magnetic stimulation (TMS) is a non-invasive method that uses an induction coil to deliver electromagnetic fields through the scalp (Barker et al., 1985, Burke et al., 2019). TMS can be used both as a diagnostic (Val-Laillet et al., 2015, Voitenkov et al., 2019) and a neurophysiological tool (Borghetti et al., 2008, Meng et al., 2020). Moreover, a particular protocol of stimulation known as repetitive TMS (rTMS) can modulate brain function and the resulting effects can last beyond the stimulation period, and can be used for therapeutic applications (Lefaucheur et al., 2020, Leon-Sarmiento et al., 2015, Nardone et al., 2020, Zorzo et al., 2019a).

The clinical effects of rTMS have been largely explored. However, there is not enough research focused on the impact of rTMS on cognitive function (Patel et al., 2020). When addressed, it will usually refer to a deficit resulting from a certain disease or a reflection of brain injury (Begemann et al., 2020, Cantone et al., 2014, Doeltgen et al., 2015, Kim et al., 2019, Yin et al., 2020). Applying rTMS may cause cognitive changes, given that it induces either long-term potentiation or long-term depression-like plasticity mechanisms closely related to cognitive activity (Luber and Lisanby, 2014, Patel et al., 2020, Yeh and Rose, 2019). In this regard, studying the effect of rTMS on cognitive function is important both in healthy and clinical populations (Lefaucheur et al., 2020, Patel et al., 2020). It has been shown that rTMS can improve various cognitive domains in healthy subjects, including executive function, working memory, and episodic memory (Innoceti et al., 2010, Malkani and Zee, 2020, Patel et al., 2020) Furthermore, addressing healthy subjects can help achieve a better customization of rTMS protocols that aim to improve cognition (Akilan et al., 2020). It can also contribute to understanding the basic mechanisms of cognitive function and their modulation (Luber and Lisanby, 2014, Malkani and Zee, 2020), as well as the cellular and molecular related mechanisms better (Cirillo et al., 2017, Tremblay et al., 2020, Tuñez Fiñana and Pascual-Leone, 2014). Thus, conducting research with healthy subjects becomes essential.

Memory function, and particularly, the spatial cognition component, is commonly explored in rodents using the Morris Water Maze (MWM) task (Morris, 1984). This task makes it possible to assess the allocentric component of spatial navigation, i.e., the use of visual distal cues to establish a cognitive mapping that enables orientation in the surrounding environment (Epstein et al., 2017). Although the rTMS effect on spatial memory has been examined in various disease models (Chen et al., 2019, Hong et al., 2020, Yang et al., 2019), there are only two studies that aim to decipher the electromagnetic induction impact on spatial memory function in normal rats (Li et al., 2007, Shang et al., 2016).

Our objective in this study was to determine whether rTMS can generate spatial cognition changes in healthy rats, and to explore the underlying brain oxidative metabolic activity. To do this, we stimulated Wistar rats during three consecutive days with a high-frequency (100 Hz) and low-intensity (0.33 T) rTMS protocol. It was concomitant with the first three days of the MWM spatial training, which lasted five days and relied on the allocentric strategy to solve the task. Afterwards, brain-related function was assessed through a quantitative cytochrome c oxidase (CCO) histochemistry. CCO is a mitochondrial enzyme that catalyzes oxygen consumption during cellular respiration, and is actively involved in ATP production (Gonzalez-Lima and Cada, 1994, Wong-Riley, 1989). CCO quantification reveals changes in the brain metabolic capacity of healthy rats which are related to spatial memory processes (Méndez-López et al., 2013, Zorzo et al., 2020) and stimulation therapies (Arias et al., 2016, Pernia et al., 2020, Zorzo et al., 2019b).