Transcranial static magnetic field stimulation (tSMS) can induce functional recovery in patients with subacute stroke

In non-invasive brain stimulation (NIBS) for stroke rehabilitation, decreasing excitability in the contralesional motor cortex is one of the major strategies to facilitate the brain reorganization after stroke. Previous studies demonstrated that downregulation of excitability in the contralesional M1 with low-frequency repetitive transcranial magnetic stimulation (rTMS) or cathodal transcranial direct current stimulation (tDCS) improved motor function in the paretic hand of stroke patients. The bilateral hemispheres inhibit each other through transcallosal fibers (IHI, interhemispheric inhibition). After stroke, increased IHI from disinhibited undamaged hemisphere impair functional recovery in damaged hemisphere [[1]Murase N. Duque J. Mazzocchio R. Cohen L.G. Influence of interhemispheric interactions on motor function in chronic stroke.Ann Neurol. 2004; 55: 400-409Crossref PubMed Scopus (1118) Google Scholar]. Suppression of the hyperexcitability of undamaged hemisphere by NIBS can promote recovery in damaged hemisphere. Transcranial static magnetic field stimulation (tSMS) is a newly developed NIBS technique, which can temporarily suppress brain functions using a strong and compact permanent magnet [2Oliviero A. Mordillo‐Mateos L. Arias P. Panyavin I. Foffani G. Aguilar J. Transcranial static magnetic field stimulation of the human motor cortex.J Physiol. 2011; 589: 4949-4958Crossref PubMed Scopus (111) Google Scholar, 3Nojima I. Koganemaru S. Fukuyama H. Mima T. Static magnetic field can transiently alter the human intracortical inhibitory system.Clin Neurophysiol. 2015; 126: 2314-2319Crossref PubMed Google Scholar, 4Shibata S. Watanabe T. Yukawa Y. Minakuchi M. Shimomura R. Ichimura S. et al.Effects of transcranial static magnetic stimulation over the primary motor cortex on local and network spontaneous electroencephalogram oscillations.Sci Rep. 2021; 11: 1-7Crossref PubMed Scopus (8) Google Scholar, 5Shibata S. Watanabe T. Matsumoto T. Yunoki K. Horinouchi T. Kirimoto H. et al.Triple tSMS system (“SHIN jiba”) for non-invasive deep brain stimulation: a validation study in healthy subjects.J NeuroEng Rehabil. 2022; 19: 1-7Crossref PubMed Scopus (1) Google Scholar]. The advantages of tSMS over rTMS and tDCS include no provocation of seizures or tingling sensations, and lack of the need for expensive devices and high operational skill. We hypothesize that a possible target for tSMS is the contralesional (undamaged) motor cortex in patients with stroke. Actually our previous study on healthy people demonstrated that tSMS over the motor cortex can facilitate the excitability in the contralateral motor cortex [[6]Takamatsu Y. Koganemaru S. Watanabe T. Shibata S. Yukawa Y. Minakuchi M. et al.Transcranial static magnetic stimulation over the motor cortex can facilitate the contralateral cortical excitability in human.Sci Rep. 2021; : 11PubMed Google Scholar]. We report the results of a prospective, sham stimulation-controlled, cross-over, double-blind study assessing the effects of the modulation of the contralesional motor cortex by tSMS in twenty consecutive patients with subacute stroke (time since stroke <6 months) who presented to our hospital for neurorehabilitation. Participants received one session of 20-min tSMS (real or sham) over the representational area for the first dorsal interosseous (FDI) muscle during 60-min conventional occupational therapy (OT) for 10 consecutive days (one session a day). Participants who underwent real tSMS as first treatment were switched to sham stimulation, and vice versa. The order of these different treatments was randomized. A two-day wash-out was carried out to prevent carryover effects from the first treatment (Fig. 1(a)). All participants underwent a clinical assessment before the first treatment, between the first and second treatments, and after the second treatment. The primary outcome was quantitative evaluation of manual dexterity (modified 10-s tests) [[7]Hatanaka T. Koyama T. Kanematsu M. Takahashi N. Matsumoto K. Domen K. A new evaluation method for upper extremity dexterity of patients with hemiparesis after stroke: the 10-second tests.Int J Rehabil Res. 2007; 30: 243-247Crossref PubMed Scopus (12) Google Scholar]. In the modified 10-s tests, participants performed four types of hand-finger movements (grip and release, individual finger movement, hand pronation and supination, and finger tapping) as many times as possible within 10 s. The score of the modified 10-s tests was defined as the sum of all repeated movements. MEP of the FDI on both the unaffected and affected sides was also assessed before the first treatment, between the first and second treatments, and after the second treatment. Changes of the measures from before to after the treatment were compared between real and sham tSMS. They were analyzed with the Wilcoxon signed-rank test. Data are presented as median (interquartile range). The results were considered significant at p < 0.05. Details of the experimental methods, results, and discussion are described in Supplementary Data. Real tSMS showed a significantly larger increase in modified 10-s tests than sham tSMS {9.5 (2–15.5) in real tSMS and 4.5 (3–7.25) in sham tSMS, p = 0.008} (Fig. 1(b)). Real tSMS showed a significant decrease in MEP on the unaffected side compared to sham tSMS {0.80 (0.71–0.95) in real tSMS and 1.05 (0.91–1.28) in sham tSMS, p = 0.019} (Fig. 1(c)). In MEP on the affected side real tSMS showed a significantly larger increase than sham tSMS {1.80 (1.15–2.77) in real tSMS and 0.89 (0.50–1.04) in sham tSMS, p = 0.026} (Fig. 1(d)). We found that tSMS applied to the contralesional M1 in combination with OT significantly improved manual dexterity. The functional recovery was possibly due to the improvement of the corticospinal tract (CST) from the ipsilesional M1 resulted from the inhibition of IHI from the contralesional M1. We also confirmed the safety of tSMS in the stroke rehabilitation. This is the first study demonstrating the efficacy and safety of tSMS in the stroke rehabilitation. Since Oliviero et al. first reported that tSMS can reduce the excitability of the M1 in healthy humans [[2]Oliviero A. Mordillo‐Mateos L. Arias P. Panyavin I. Foffani G. Aguilar J. Transcranial static magnetic field stimulation of the human motor cortex.J Physiol. 2011; 589: 4949-4958Crossref PubMed Scopus (111) Google Scholar], this novel NIBS technique has been shown to inhibit the cortical functions below the magnet in various brain regions and to modulate the behavior of healthy humans. Recent studies showed tSMS can modulate the cortical functions on the contralateral side to the magnet via brain networks [[6]Takamatsu Y. Koganemaru S. Watanabe T. Shibata S. Yukawa Y. Minakuchi M. et al.Transcranial static magnetic stimulation over the motor cortex can facilitate the contralateral cortical excitability in human.Sci Rep. 2021; : 11PubMed Google Scholar,[8]Shibata S. Watanabe T. Yukawa Y. Minakuchi M. Shimomura R. Mima T. Effect of transcranial static magnetic stimulation on intracortical excitability in the contralateral primary motor cortex.Neurosci Lett. 2020; 723134871Crossref PubMed Scopus (10) Google Scholar]. Although the mechanisms of tSMS still remain unclear, the functional change of ion channels via diamagnetic anisotropy [[9]Rosen A.D. Mechanism of action of moderate-intensity static magnetic fields on biological systems.Cell Biochem Biophys. 2003; 39: 163-173Crossref PubMed Scopus (281) Google Scholar] and magnetic pressure [[10]Hernando A. Galvez F. García M.A. Soto-León V. Alonso-Bonilla C. Aguilar J. et al.Effects of moderate static magnetic field on neural systems is a non-invasive mechanical stimulation of the brain possible theoretically?.Front Neurosci. 2020; 14: 419Crossref PubMed Scopus (8) Google Scholar] could be involved at the cellular level. Electrophysiologically brain oscillations were reported to be modulated by tSMS [[4]Shibata S. Watanabe T. Yukawa Y. Minakuchi M. Shimomura R. Ichimura S. et al.Effects of transcranial static magnetic stimulation over the primary motor cortex on local and network spontaneous electroencephalogram oscillations.Sci Rep. 2021; 11: 1-7Crossref PubMed Scopus (8) Google Scholar]. These evidences suggest that tSMS can become a promising tool for neurorehabilitation. Downregulation of excitability in the contralesional M1 can be a strategy for improving motor function in stroke patients, possibly through modulation of inappropriate IHI. Our MEP findings showed both downregulation of the contralesional M1 and upregulation of the lesional M1. This suggested that tSMS over the contralesional M1 mitigated abnormally hyperexcited IHI from the contralesional M1 to the lesional M1 by reducing the excitability in the contralesional M1. This leads to the improvement of the CST from the ipsilesional M1. Since tSMS does not directly induce electric currents unlike rTMS and tDCS, it is not associated with risk of seizures or uncomfortable skin sensations. All the patients completed the scheduled intervention without any side effects in this study. In addition, tSMS requires only placing a simple permanent magnet on the head. Considering these advantages (safety, low-cost, and easy-to-use) of tSMS, tSMS can be applied to more patients with stroke than rTMS or tDCS. TSMS applied to the contralesional M1 in combination with OT was effective in increasing the excitability of the ipsilesional M1 through modulation of inappropriate IHI, and improving manual dexterity in patients with subacute stroke. Since tSMS is superior to conventional NIBS techniques in safety, low-cost, and easy-to-use, tSMS can become a promising tool for neurorehabilitation. This study was supported by Grants-in-Aid for Scientific Research (KAKENHI) [grant number 19H01091 (T.M.), 20K21770 (S.K.), 21H03308 (S.K.), 21K17671 (S.S.), and 22H04788 (T.M.)] from the Japan Society for the Promotion of Science.