Stroke occurs in more than 12 million people worldwide every year, and its incidence is steadily increasing owing to various factors, including population aging (1). Approximately 80% of stroke survivors have motor disorders that affect their daily lives (2). Furthermore, 60–70% of the patients with stroke experience upper extremity motor function damage during hospitalization, and approximately half (33% of all strokes) of them are classified as having severe paralysis. Additionally, 50–70% of stroke survivors suffer paralysis of upper extremity motor function 2–4 years after stroke (3).

Various treatments have been attempted to restore upper limb motor function after stroke, with upper limb rehabilitation treatment, including various physical training approaches (work therapy, muscle strengthening, etc.), currently being applied as a standard treatment for upper limb motor function recovery after stroke (4). These upper-limb rehabilitation treatments induce continuous cortical reconstruction in both hemispheres and promote adaptation to cortical maps, resulting in neuroplasticity after stroke, which benefits functional recovery with longer repetition or intervention periods. However, the extent of recovery of damaged brain tissue and its function using this method is limited. Therefore, many patients have limitations in function due to the aftereffects of stroke, which leads to an increase in social costs (4, 5).

Recently, several non-invasive neuroregulatory intervention studies have reported maximizing functional recovery after stroke in upper limb rehabilitation (5); several studies have reported that repetitive transcranial magnetic stimulation (rTMS) with rehabilitation training such as occupational therapy increases functional recovery (4). Chang et al. (6) investigated the effects of high-frequency rTMS (10 Hz) on the affected hemisphere’s primary motor cortex by comparing it with sham rTMS in patients with subacute stroke who underwent motor training. The results revealed that the group that received the real rTMS showed greater recovery in the sequential finger motor task, indicating the positive impact of rTMS on motor function improvement (6). Di Lazzaro et al. (7) conducted a study comparing the effects of inhibitory theta burst stimulation (iTBS) and sham TBS administered prior to physical therapy in patients with chronic stroke. The results revealed that the iTBS group showed significantly higher scores on the Jebsen-Taylor Test at 3 months post treatment, compared with the sham group (7). rTMS is a treatment method that repetitively stimulates the cerebral nerve area by inducing current to the cerebral cortex, by forming a magnetic field similar to that of Magnetic Resonance Imaging (MRI) in the cerebral cortex. It is a non-invasive and safe method that is widely used not only for patients with stroke but also for neurostimulation in patients with depression, Parkinson’s disease, Huntington’s disease, and cerebral palsy (5).

Representative rTMS protocols include high-frequency rTMS, which is mainly implemented in the ipsilesional primary motor cortex, and low-frequency rTMS, which is mainly implemented in the contralesional M1 (8). Low-frequency rTMS over the contralesional primary motor cortex (M1) has been used to suppress excessive inhibition of ipsilesional M1. That is, it is applied as an attempt to reduce interhemispheric inhibition (IHI) (9). Low frequency rTMS has less impact on motor behavior and reduces risk of seizures in healthy cortical spine systems (8, 10). Therefore, most studies on motor recovery after stroke have applied low-frequency rTMS over the contralesional M1 region.

Research on the effectiveness of rTMS remains controversial. Hsu et al. (11) performed a meta-analysis of 34 existing studies in 2012 and confirmed the significant effects of rTMS on upper limb motor function recovery in patients with stroke. In contrast, Graef et al. (4) investigated the effects of rTMS combined with upper limb training vs. sham rTMS combined with upper limb training on upper limb recovery after stroke in 2016 and concluded that there were no significant differences between groups. Harvey et al. (12) reported a clinical study comparing the effects of rTMS and sham rTMS on the functional recovery of the upper extremities of stroke patients in 2018, and found no difference between the rTMS and sham rTMS groups. Therefore, it is unclear whether rTMS affects the recovery of upper limb function in patients with stroke. Harvey et al. (12) suggested that no significant effect was confirmed because the effect of rTMS may vary depending on the location or severity of the stroke. Graef et al. (4) suggested that the heterogeneity of occupational therapy between studies was the reason why a significant effect of rTMS was not confirmed in the meta-analysis.

Kim et al. (13) conducted a randomized controlled trial to determine the efficacy of low-frequency rTMS on the contralateral M1 combined with occupational therapy in patients with stroke. Although the study did not show a significant difference between the rTMS and sham groups, subgroup analysis based on cortical involvement revealed that low frequency rTMS on contralesional M1 led to improvements in the Brunnstrom stage of hand function in the group without cortical involvement. This result led us to hypothesize that the type and location of stroke may affect the efficacy of rTMS warranting further investigation.

Therefore, a multicenter randomized controlled trial has been designed to confirm the effectiveness of low-frequency rTMS over the contralesional M1 in patients with subcortical and brainstem ischemic stroke.

This study was designed as a multi-center, double-blind, randomized sham-controlled trial that aims to confirm the efficacy of low-frequency contralesional rTMS in the recovery of upper limb motor function in patients with subcortical or brainstem ischemic stroke. To ensure the rigor of the investigation, the participants will be stratified into two subgroups based on their initial severity. Moreover, the amount of OT and PT will be the same in the intervention and control groups during the intervention period, and the amount of total therapy will be recorded throughout the trial. By controlling and recording the potential cofounders of the motor recovery after stroke, the study results are anticipated to report high-quality evidence on the effectiveness of rTMS on motor recovery after stroke.

In this study, among various rTMS protocols, low frequency rTMS over the contralesional M1 will be applied in attempts to normalize imbalance of IHI by suppressing the over-inhibition of contralesional M1 toward ipsilesional M1 (9). In previous studies, low-frequency rTMS was often chosen over high-frequency rTMS because of the low risk of seizures in the healthy corticospinal system and its minimal effect on motor behavior (8, 10). However, previous results regarding the efficacy of low-frequency rTMS over the contralesional M1 for motor recovery in patients with acute and subacute stroke remain inconsistent. Khedr et al. (24) reported that low-frequency rTMS is more advantageous in recovering upper extremity function after stroke compared to high-frequency rTMS. Dafotakis et al. (29) also reported the possible beneficial effects of low-frequency rTMS on hand function recovery in patients with acute and subacute subcortical stroke. In contrast, other studies have reported no significant beneficial effects of low-frequency rTMS compared with sham rTMS (30, 31). In a meta-analysis, Hsu et al. (11) confirmed the effect of low-frequency rTMS on the recovery of upper extremity function in patients with stroke and reiterated the notion that post-stroke hemisphere competition is altered and that this imbalance can be resolved by reducing the cortical excitability of unaffected hemispheres through low-frequency rTMS.

Recently, it has been reported that the location of stroke lesions is a key factor in the efficacy of rTMS in upper limb motor recovery. Kim et al. (13) confirmed that the recovery of the upper extremities was significant only in patients without cortical invasion. Ameli et al. demonstrated that high-frequency rTMS on the ipsilesional M1 was effective only in patients with subcortical stroke and not in patients with additional cortical stroke (32). Nowak et al. (33) conducted cross-over investigation in patients with subacute subcortical stroke and found that application of rTMS to the contralesional M1 improved the kinematics of finger and grasp movements in the affected hand. Based on these findings, the target population of this trial was narrowed down to patients with subacute subcortical or brainstem ischemic stroke. Previous studies have explained possible reasons for the better effects of rTMS in patients with stroke without cortical involvement. First, the expected increase in cortical activity in the ipsilesional M1 through rTMS is inefficient in propagating to other nodes of the motor network for motor recovery, as there is a structural or functional disconnection in stroke that invades the cortex (32, 34). Second, in the cortical brainstem, GABAergic intracortical inhibition is greater, and concurrent downregulation of GABA receptors in both hemispheres has been identified, which may be associated with the reduced effects of rTMS (13).

We also stratified the participants into two subgroups based on the initial UE-FMA score because it has been reported that rTMS can be less effective in patients with stroke with severe upper extremity paralysis. Ludemann-Podubeck et al. (35) insisted that when a larger part of the M1 or its corticospinal projections is involved in stroke, causing a more profound clinical hand motor deficit, the contralesional dorsal premotor cortex may have a positive influence on motor recovery. Therefore, low-frequency rTMS of the contralesional M1 may not help to restore functionality (35). Two other studies referred to the same mechanism and explained the correlation between the degree of paralysis and the effect of rTMS (36, 37). Based on these results, we excluded patients with stroke with extremely severe upper extremities paralysis (UE-FMA score of 15 or less and those with a wrist score of less than 1 and a hand score of less than 1) and stratified into two subgroups (UE-FMA score of 28 or higher and UE-FMA score below 28) to ensure that the initial severity in both the intervention group and control group is evenly distributed.

In this clinical trial, the change in the number of BBT at 4 weeks after EOT compared with that at baseline has been set as the primary efficacy evaluation variable. The BBT has been used in various rehabilitation studies since 1994, when its reliability and validity were verified as measures of hand function in the elderly (38); it is often used as a clinical variable to confirm hand function status and total agility of the upper limb, especially in patients with stroke (3). Accordingly, BBT has also been used as an effectiveness evaluation variable in various studies to evaluate the recovery of upper limb motor function using rTMS in patients with stroke (3, 5, 13, 18). The UE-FMA is more useful in assessing abnormalities of movement, whereas the BBT is more suitable for evaluating activity limitations (39). However, with UE-FMA, it is difficult to confirm the response to the treatment of patients with stroke with mild upper limb hemiplegia due to the ceiling effect. Therefore, in this study, the primary outcome measurement has been chosen as the change in the BBT.

This study has a few limitations. First, in the control group, a sham coil will not be used for sham rTMS. Instead, the real coil will be positioned perpendicular to the scalp with an intensity of 100% of the patient’s RMT, and the frequency and position will be the same as those in the intervention group. Although the electrical field induced by this sham stimulation method is lower and less focal than that of real stimulation (40), we cannot rule out the possibility that this low electric field strength may influence the modulation of cortical neurons. However, it has been reported that the intensity of sham stimulation is significantly weaker than that of real stimulation, suggesting a low likelihood of producing similar physiological effects as actual stimulation (41). To ensure the blindedness of the participants during intervention, the position of the coil will be placed and removed by the researcher to ensure that the participants cannot see the position of the coil throughout the intervention. Moreover, as all the participants in this study are patients with first-time stroke, there is little possibility that they could guess the group assigned to them because they may not have encountered rTMS equipment before. Second, in this study, a navigation system will not be used to determine the motor hotspots, which requires a separate MRI sequence for treatment and is difficult to apply in real clinical settings. We will use the Motor Evoked Potentials (MEP) of the First Dorsal interossei (FDI) muscle to determine motor hotspots because it has been reported that the method of finding the rTMS motor hotspot by MEP of the FDI muscle may be more effective than navigated rTMS (42).

This study is expected to provide evidence of the efficacy of upper limb motor function recovery using contralesional low-frequency rTMS in patients with subcortical and brainstem ischemic stroke.

The studies involving humans were approved by institutional review boards of Seoul National University Bundang Hospital and Chungnam National University Hospital. The studies were conducted in accordance with the local legislation and institutional requirements. Written informed consent for participation in this study was provided by the participants’ legal guardians/next of kin.

MKS, SJ, WKC, W-SK, and N-JP conceived and coordinated the study. H-MC, SC, MKS, SJ, WKC, W-SK, and N-JP designed the study. WKC and N-JP administered the project. H-MC drafted the manuscript. All authors participated in reviewing and editing the manuscript. All authors contributed to the article and approved the submitted version.

This work is supported by the Research Fund of Remed (Seongnam-si, Republic of Korea). Remed has no role in the design and conduct of the study; collection, management, analysis and interpretation of the data. The research team has full autonomy in all aspects of the study.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.