Advancements in repetitive transcranial magnetic Stimulation for ischemic stroke rehabilitation

Yongfang Li; Ji-Xian Wang; Guo-Yuan Yang

doi:10.4103/2773-2398.372307

REVIEW

Year : 2023 | Volume : 2 | Issue : 1 | Page : 13-20

Advancements in repetitive transcranial magnetic Stimulation for ischemic stroke rehabilitation

Yongfang Li¹, Ji-Xian Wang², Guo-Yuan Yang³
¹ Department of Rehabilitation Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine; Med-X Research Institute and School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, China
² Department of Rehabilitation Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
³ Med-X Research Institute and School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, China

Date of Submission	07-Jun-2022
Date of Decision	03-Jan-2023
Date of Acceptance	03-Jan-2023
Date of Web Publication	28-Mar-2023

Correspondence Address:
Guo-Yuan Yang
MD, PhD, Med-X Research Institute and School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai
China
Ji-Xian Wang
Department of Rehabilitation Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai
China

Source of Support: None, Conflict of Interest: None

DOI: 10.4103/2773-2398.372307

Abstract

Despite significant improvements in acute stroke management, numerous stroke patients continue to experience wide-ranging disabilities, posing a severe global healthcare problem. Effective neuro-rehabilitation is critical for reduction of disability and improvement of life quality after stroke. Rapid developments in several post-ischemic stroke rehabilitation techniques, including magnetic, ultrasonic, optogenetic and electronic modalities, have been achieved in recent years. Repetitive transcranial magnetic stimulation has shown promising therapeutic efficacy in ischemic stroke rehabilitation during the last two decades. This review provides a detailed summary of the development, safety and efficacy of transcranial magnetic stimulation devices, current experimental models and mechanisms of repetitive transcranial magnetic stimulation in the context of ischemic stroke rehabilitation.

Keywords: cellular mechanism; ischemia; rehabilitation; stroke; transcranial magnetic stimulation

How to cite this article:
Li Y, Wang JX, Yang GY. Advancements in repetitive transcranial magnetic Stimulation for ischemic stroke rehabilitation. Brain Netw Modulation 2023;2:13-20

How to cite this URL:
Li Y, Wang JX, Yang GY. Advancements in repetitive transcranial magnetic Stimulation for ischemic stroke rehabilitation. Brain Netw Modulation [serial online] 2023 [cited 2023 Dec 2];2:13-20. Available from: http://www.bnmjournal.com/text.asp?2023/2/1/13/372307

Introduction

Transcranial magnetic stimulation (TMS) is a non-invasive brain stimulation and neural regulation technique. It regulates cortical excitability in the stimulated and distant sites via electrical current generated by the rapid time-varying electromagnetic field, ultimately modulating neuroplasticity and brain function to achieve therapeutic effects (Rossi et al., 2009). Single-pulse TMS has been employed as a tool for neurophysiological experiments, especially for assessment of corticospinal function, since 1985 (Barker et al., 1985; Rossi et al., 2009). Subsequently, repetitive TMS (rTMS) gained increasing research interest in application evaluation of different diseases following the demonstration of its potential therapeutic effect on depression in 1995 (Fleischmann et al., 1995; Wassermann, 1998; Rossi et al., 2009). Over the past two decades, the applications of rTMS have been expanded to a range of fields including pain relief, mild cognitive impairments, movement disorders, ischemia stroke, Alzheimer’s disease, Parkinson’s disease, multiple sclerosis, consciousness disorders, tinnitus, substance abuse and addiction, schizophrenia and miscellaneous psychiatric conditions (Rossi et al., 2009; Lefaucheur et al., 2020).

Both TMS and transcranial direct current stimulation (tDCS) require close proximity to the scalp. However, compared with tDCS, the magnetic field of TMS can pass through the scalp and skull with almost no attenuation, does not stimulate the scalp and has better tolerance. Since the size and configuration of TMS coils can be specially designed, rTMS exhibits greater focality and spatial resolution than tDCS, potentially reaching areas of ~25 mm². Moreover, rTMS has a higher temporal resolution higher than tDCS and is easier for doctors and physiotherapists to handle in clinical settings. Based on these characteristics, rTMS provides a suitable tool for probing and stimulation of specific brain circuits (Priori et al., 2009). Overall, rTMS represents a promising therapeutic modality with low risk of severe side-effects and high safety (Lefaucheur et al., 2020; Camacho-Conde et al., 2022).

Ischemic stroke is an acute cerebrovascular disorder with high morbidity, disability and mortality rates associated with significant healthcare costs (GBD 2016 Stroke Collaborators, 2019; Hollist et al., 2021). The stroke patients often live with varying degrees of dysfunction in movement, speech, swallowing, sensation, cognition, balance, emotional control, and so on. The combination of physical therapy, occupational therapy, speech therapy and cognitive rehabilitation is routinely applied to help rehabilitate patients after stroke in clinical practice. Clinical studies and trials of novel rehabilitation therapies including rTMS, tDCS, ultrasound stimulation, deep brain stimulation, virtual reality, robot-assisted therapy and brain-computer interface are in progress to explore the potentials of their future clinical application in management of stroke (Chen et al., 2021; Pruvost-Robieux et al., 2021; Sehle et al., 2021; Singh et al., 2021; Guo et al., 2022). Considerable progress in the development of rTMS for stroke therapy, in particular, post-stroke patient rehabilitation, has been reported over the past two decades (Lefaucheur et al., 2020; Starosta et al., 2022).

In this review, we focus on current advancements in rTMS for stroke rehabilitation, including the development of latest TMS devices, experimental models and contributory mechanisms to the therapeutic effects of rTMS.

Development of Advanced Transcranial Magnetic Stimulation Devices

TMS device systems are relatively large and heavy due to the need of producing fairly rapid time-varying current and high voltage in the coils, which limit the portability of TMS. New TMS devices are designed by advancing hardware and software configurations, adding new complementary technologies based on the old ones (Rossi et al., 2021). With continual development, the TMS devices are getting progressively smaller in size, the pulsed electric field and stimulation focality are getting more controllable. Several TMS devices have been approved for treatment of depression and obsessive-compulsive disorder by the US Food and Drug Administration since 2008 (Gattinger et al., 2012; Paulus et al., 2013; Cohen et al., 2022). These articles may be consulted for more detailed information on TMS device development (Rossi et al., 2021; Zhong et al., 2021; Cohen et al., 2022). Although no TMS devices have been approved for ischemic stroke rehabilitation to date, the possibility of implementing TMS into routine ischemic stroke clinical rehabilitation is under investigation (Smith and Stinear, 2016). As a result of unremitting and ongoing research efforts, improvements in TMS devices and up-to-date treatment indications are continuously being achieved.

Safety of Repetitive Transcranial Magnetic Stimulation

The technical design, manufacturing process, usage and maintenance of TMS require optimization to ensure safety of both subjects and operators. Procedures to enhance the lifetime of the device should be considered, which include insulating high voltage, reducing the heating, friction and vibration of the coils, and generating reliable magnetic fields (Rossi et al., 2021; Zeng et al., 2022). Technical safety may be enhanced by improving the targeting accuracy, response detection sensitivity, efficiency of threshold and dose algorithms of the device (Marjenin et al., 2020; Rossi et al., 2021).

Both the therapeutic and side-effects of TMS mainly depend on the stimulating protocol and device quality. Control of the stimulation dose is the key to minimize side-effects while maximizing the therapeutic effect (Zhong et al., 2021). The most severe side-effect of TMS is seizures, with a recorded overall rate of 0.31 per 10,000 sessions and 0.71 per 1000 patients (Taylor et al., 2021). The intensity, number, patterns, frequency and waveforms of the pulse, distribution of E-field, and individual differences induce alterations in the seizure threshold. Operators should therefore pay attention to these parameters when conducting TMS (Rossi et al., 2021). The lowest parameters for TMS-induced seizures using conventional devices are a single train with 25 Hz frequency and 100% maximal stimulator output continuing for up to 10 seconds. Under optimal parameters of TMS, including the dose and intensity of stimulus, duration, frequency, pulse number and session paradigms, the occurrence of seizures is relatively low (Rossi et al., 2009, 2021).

Experimental Ischemic Models Used in Repetitive Transcranial Magnetic Stimulation Application Investigation

Research on rTMS in ischemic stroke has been performed using rodent and primate models or tissues and cells in vitro (Tang et al., 2017). For ischemic stroke rodent model, mice or rats were subjected to transient or permanent middle cerebral artery occlusion (Peng et al., 2019; Park et al., 2020; Deng et al., 2021), photothrombosis of the cortical area of interest (Zong et al., 2020a, b) or common carotid artery occlusion (Fujiki et al., 2003). For central post-stroke pain, a primate model of unilateral hemorrhage of ventral posterolateral nucleus of the thalamus was used and the effects of rTMS treatment on the ipsilesional primary motor cortex were examined (Kadono et al., 2021). For in vitro studies, hippocampal organotypic culture was incubated with artificial cerebral fluid under hypoxic conditions (Ogiue-Ikeda et al., 2005) or brain cells were exposed to oxygen-glucose deprivation (Hong et al., 2020; Li et al., 2020a).

The cellular and molecular mechanisms underlying efficacy of rTMS in ischemic stroke

Investigations on the cellular mechanisms underlying the therapeutic activity of rTMS in ischemic stroke mainly include: 1) neuronal pathways by which rTMS affects axonal membrane and action potentials and potential alterations in specific biological functions, architecture and neuroplasticity, and 2) whether brain cells other than neurons are affected and the associated pathways (Camacho-Conde et al., 2022; Starosta et al., 2022).

In neurons, rTMS and the induced electric field could activate voltage-dependent calcium channels (Luo et al., 2019; Xia et al., 2021), N-methyl-D-aspartate receptor (Tokay et al., 2014; Natale et al., 2021) and calmodulin-dependent protein kinase II (Xia et al., 2021), along with promoting changes in the release of dopamine, glutamate and gamma-aminobutyric acid (Kanno et al., 2004; Yue et al., 2009; Zhang et al., 2022). These alterations elicit Ca²+ influx, excitatory postsynaptic potential, inhibitory postsynaptic potential and activation of molecular pathways critical for plasticity, such as Akt/mammalian target of rapamycin, mitogen-activated protein kinase/extracellular signal-regulated protein kinase 1/2 and ribosomal protein S6 (Vlachos et al., 2012; Tan et al., 2013; Fujiki et al., 2020). These changes in the synaptic dendrites induce long-term potentiation or long-term depression (Yang et al., 1999), alteration of gene expression and structural remodeling of dendritic spines, further contributing to the plasticity of synapses, neurons and brain (Vlachos et al., 2012; Tokay et al., 2014; Lenz et al., 2015, 2016; Ikeda et al., 2018; Cambiaghi et al., 2021; Tang et al., 2021). For example, cumulative stimulation of rTMS enhanced dentate gyrus neuronal excitability in neonatal mice (Zhu et al., 2021). rTMS additionally upregulated genes associated with synaptic plasticity and downregulated genes associated with inflammation in ischemic rats (Hong et al., 2021, 2022). rTMS could drive structural synaptic plasticity in young and aged mice (Tang et al., 2021), which was related to the improvement of cognition. Moreover, rTMS promoted the secretion of glial cell-derived neurotrophic factor from dopaminergic neurons (Yang et al., 2021). In a rat photothrombotic stroke model, 5 days of exposure to theta-burst rTMS reduced synaptic loss and neuronal degeneration, concomitant with inhibition of the inflammatory response, preservation of mitochondrial membrane integrity and suppression of apoptosis (Zong et al., 2020b). In addition, rTMS pre-treatment induced ischemic tolerance and protected neurons against delayed death, which was associated with the protection of neuronal function and induction of a particular gene set (Fujiki et al., 2003; Ogiue-Ikeda et al., 2005).

High-frequency rTMS (HF-rTMS) was shown to promote neural stem cell (NSC) proliferation possibly via brain-derived neurotrophic factor/Akt signaling and inhibition of inflammation (Zhao et al., 2019; Luo et al., 2022a). rTMS also stimulated NSC migration via the stromal cell-derived factor 1α/C-X-C chemokine receptor 4 axis after ischemic stroke (Deng et al., 2021). Another earlier report suggests that rTMS enhances NSC differentiation into neurons via Ca²⁺ influx and MAPK signaling after hemorrhagic stroke (Cui et al., 2019). In addition, rMS enhanced miR-106b expression to promote NSC proliferation (Liu et al., 2018).

In astrocytes, rMS could promote astrocytic intracellular calcium release and alters glial fibrillary acidic protein and inflammatory gene expression in vitro (Clarke et al., 2017; Hong et al., 2020). In a rat chronic neuropathic pain model, 20 Hz rTMS suppressed proliferation of astrocytes and downregulated the expression of neuronal nitric oxide synthase, which could potentially contribute to its beneficial effects on neuropathic pain relief (Yang et al., 2018). In a rat photothrombosis stroke model, intermittent theta-burst stimulation (iTBS) beginning 3 hours after stroke for 6 days promoted hypoxia-inducible factor 1-alpha signaling, shifted astrocyte polarization to A2, and increased vascular endothelial growth factor (VEGF) and transforming growth factor beta expression levels, which may partially underlie its activities in reducing blood-brain barrier permeability, increasing angiogenesis, and preserving neuronal and synaptic structure integrity and neurofunction (Zong et al., 2020a). In a rat model of depression, 10 Hz rTMS induced an increase in the number of astrocytes, fibroblast growth factor 2 expression in astrocytes, and activation of the fibroblast growth factor 2/fibroblast growth factor receptor 2/extracellular signal-regulated protein kinase signaling pathway (Yan et al., 2022).

In microglia, long-term low-frequency rTMS (LF-rTMS) stimulation promoted their polarization to M2 phenotype without affecting the proliferation of microglia after ischemia in spontaneously hypertensive rats (Luo et al., 2022a). In a rat photothrombosis stroke model, rTMS also promoted microglia polarization from M1 to M2 phenotype along with decreased interleukin (IL)-1 beta, IL-6, and tumor necrosis factor-α expression (Zong et al., 2020b). Recent studies showed that this effect of TMS on microglia was partially due to inhibition of nuclear factor kappa B and signal transducer and activator of transcription 6 pathway (Luo et al., 2022a), and the toll-like receptor 4/nuclear factor kappa B/NOD-like receptor 3 signaling pathway (Luo et al., 2022b). In addition, iTBS application for 4 weeks suppressed microglia activation and enhanced IL-10 expression at demyelinated lesions in mice (Yang et al., 2020). Stimulation with 25 Hz rTMS for 8 weeks in rat spinal cord injury lesions reduced the expression of ionized calcium binding adapter molecule 1 by ~30% (Kim et al., 2013).

In oligodendrocytes (OLs), 14 consecutive days of iTBS exposure led to an increase in the number of promyelinating and myelinating OLs via promoting OL survival, but had no effect on OL precursor cell (OPC) proliferation or differentiation in normal mouse cortex (Cullen et al., 2019). In vitro, stimulation OPCs with 40 Hz low-field rMS for 5 consecutive days enhanced their differentiation into OLs via activation of transforming growth factor beta 1, Akt and extracellular signal-regulated protein kinase 1/2 pathways (Dolgova et al., 2021). In a mouse model of multiple sclerosis, LF-rTMS stimulation was also shown to promote the expression of myelin basic protein, myelin OL glycoprotein and transforming growth factor beta, finally improving cognitive function (Wang et al., 2021). However, the precise effects of rTMS on OLs and OPCs after stroke remain to be elaborated.

iTBS treatment for 6 days attenuated the apoptosis of both existing and newborn endothelial cells and increased platelet-derived growth factor receptor βexpression in brain microvasculature but had no obvious effect on endothelial cell proliferation at 6 and 22 days following stroke in a rat model of photothrombosis stroke (Zong et al., 2020a).

Recently, the effects of rTMS on the brain glymphatic drainage system have attracted considerable research interest. In a mouse model of Alzheimer’s disease, 14 consecutive days of rTMS exposure enhanced the glymphatic and meningeal lymphatic drainage efficiency of Aβwithout affecting lymphagenesis and further reduced microglia and astrocyte activation, with the improvement of neuronal activity (Lin et al., 2021). In normal wild-type mice, application of continuous theta burst stimulation (cTBS) induced an increase in the diameters of glymphatic and meningeal lymphatic vessels and expression of VEGF-C in the meninges, which were abolished upon inhibition of the VEGF-C/VEGF receptor 3 pathway (Li et al., 2020b). The cellular and molecular mechanisms of rTMS implicated in the treatment of ischemic stroke are summarized in [Figure 1].

Figure 1: The cellular and molecular mechanisms of rTMS in ischemic stroke.
Note: rTMS stimulation can act on different brain cells including neurons and other brain cells to promote post-ischemic rehabilitation. rTMS activated voltage-dependent calcium channels and CaMKII, altered neurotransmitter release and gene expression, finally contributed to LTP/LTD, increased neural activity, synaptic plasticity and survival, and decreased neural apoptosis. rTMS could activate BDNF/Akt, SDF-1α/CXCR4 pathway and increase miR-106 level to promote the proliferation, migration and differentiation of NSCs. For astrocytes, rTMS increased intracellular calcium level, VEGF, transforming growth factor beta and fibroblast growth factor 2 expression, inhibited astrocyte proliferation and promoted the A2 polarization. Similarly, rTMS reduced microglia activation but enhanced M2 polarization, decreased the expression of IL-1β, IL-6 and increased IL-10 expression, which was associated with the inhibition of NF-κB/STAT 6 and TLR4/NFκB/NLRP3 pathways. rTMS could promoted angiogenesis through enhance the survival of existing and newborn endothelial cells. However, the effects of rTMS on OLs/OPCs and brain gramphatic system have not yet been investigated in ischemic stroke. BDNF: Brain derived neurotrophic factor; CaMKII: calmodulin-dependent protein kinase II; ERK1/2: extracellular signal-regulated protein kinase 1/2; FGF 2: fibroblast growth factor 2; GDNF: glial cell-derived neurotrophic factor; IL: interleukin; LTD: long-term depression; LTP: long-term potentiation; MBP: myelin basic protein; MOG: myelin oligodendrocyte glycoprotein; NF-κB/STAT 6: nuclear factor kappa B and signal transducer and activator of transcription 6; nNOS: neuronal nitric oxide synthase; NSC: neural stem cell; OL: oligodendrocyte; OPC: oligodendrocyte precursor cell; PDFGR-β: platelet-derived growth factor receptor β; rTMS: repetitive transcranial magnetic stimulation; SDF-1α/CXCR4: stromal cell-derived factor 1α/C-X-C chemokine receptor 4; TLR4/NFκB/NLRP3: Toll-like receptor 4/nuclear factor kappa B/NOD-like receptor 3; TNF-α: tumor necrosis factor-α; VEGF: vascular endothelial growth factor. Created with BioRender.

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The neural circuit mechanisms of rTMS in ischemic stroke

After ischemic stroke, the ipsilateral excitability is reduced, while the contralateral hemisphere is relatively overexcited, in turn further inhibits the ipsilateral excitability (Gerges et al., 2022). This phenomenon, initially reported in 1996, is known as “interhemispheric inhibition” (Boroojerdi et al., 1996). The biphasic balance recovery model links balanced hemispheres and functional recovery with structural integrity after brain injury (Di Pino et al., 2014). The intermispheric inhibition model postulates that patients with less significant injury and greater neural structure integrity have better functional recovery. Currently, this concept is commonly accepted as a theoretical model for rTMS application in ischemic stroke with relatively sufficient structural reservation (Di Pino et al., 2014; Lefaucheur et al., 2020). Based on this theoretical model, application of LF-rTMS/cTBS to inhibit contralateral excitability or HF-rTMS/iTBS to enhance ipsilateral excitability could benefit functional recovery. For these patients, the more balanced excitability between the two hemispheres, the better for the brain functional recovery. Another theoretical model is the variation theory where activity in the ipsilateral brain networks is severely damaged, which usually needs to stimulate the contralateral hemisphere to compensate the functional loss of the ipsilateral hemisphere after ischemic stroke (Finger, 2010; Di Pino et al., 2014). For patients with severe injury and lower neural structure integrity, increased excitability of the contralateral hemisphere may be more conducive to functional recovery, which compensates the function of affected hemisphere. Based on this model, HF-rTMS/iTBS could be applied to increase contralateral excitability for functional recovery under conditions of severe structural damage.

The stimulatory effects and after-effects of rTMS in stroke patients are not limited to the target brain area but also affect the distant interconnected brain circuit and spinal networks (Liew et al., 2014; Klomjai et al., 2015; Charalambous et al., 2016). Moreover, the effects of rTMS depend on the stimulation patterns including frequency, duration and intensity, stimulation loci, lesion location (dominant hemisphere, cortex or subcortex) and stroke stage (Ameli et al., 2009; Lefaucheur et al., 2020; Starosta et al., 2022). The after-effects of rTMS could be sustained from 4 to 12 weeks after stroke treatment (Emara et al., 2010; Lefaucheur et al., 2020; Rossi et al., 2021). Neuroimaging and neurophysiological techniques, such as functional magnetic resonance imaging, single-photon emission computerized tomography, functional near-infrared spectroscopy and electroencephalography, could be effectively used to ascertain the activities of different neural circuits and networks (Liew et al., 2014; Caparelli et al., 2022; Li et al., 2022; Walia et al., 2022). However, our current understanding of the mechanisms by which rTMS affects the stimulated region and interconnected networks remains limited.

Excitatory stimulation patterns with HF-rTMS/iTBS initially increase the excitability of the affected primary motor cortex (M1) and subsequently enhance the activity of supplementary motor area, contralateral corticospinal tract, spinal interneurons and motor neurons, which are responsible for voluntary movement (Hsu et al., 2012; Hannah, 2020). Moreover, rTMS in the affected M1 modulates the connection efficiency between M1, basal ganglia and thalamus (Liew et al., 2014). In contrast, inhibitory LF-rTMS/cTBS to unaffected M1 balances abnormal tanscallosal inhibition and facilitates excitability of the affected M1 and supplementary motor area (Takeuchi et al., 2005; Grefkes et al., 2010; Lefaucheur et al., 2020). A meta-analysis of the effects of rTMS on motor functions in stroke patients showed that both excitatory stimulation of the affected primary motor cortex and inhibitory stimulation of the unaffected hemisphere enhance motor function outcomes of patients (Hsu et al., 2012). However, cTBS stimulation of the contralateral M1 in chronic subcortical stroke patients led to decreased ipsilateral M1 excitability and upper limb function (Ackerley et al., 2010). These inconsistent results highlight the complexity of the neural circuit response after rTMS stimulation, showing variations with stroke stage and location. The neural circuit mechanisms implicated in rTMS therapy for ischemic stroke are briefly summarized in [Figure 2].

Figure 2: The brief neural circuit mechanisms of rTMS in ischemic stroke.
Note: In intermispheric inhibition model where the structural reservation is relatively sufficient, using LF-rTMS and/or cTBS to inhibit the unaffected hemisphere, using HF-rTMS and/or iTBS to excite the affected hemisphere, could both increase the excitability of M1, SMA, corticospinal tract, basal ganglia and thalamus. In variation model where the functional structure is severely damaged, using HF-rTMS and/or iTBS to excite the affected hemisphere could facilitate the excitability of the affected M1 and SMA to alternatively activate the affected corticospinal tract. Therefore, choosing appropriate rTMS stimulation protocols according to the actual situation is critical to the functional recovery in post-stroke rehabilitation. cTBS: Continuous theta burst stimulation; HF-rTMS: high-frequency rTMS; iTBS: intermittent theta burst stimulation; LF-rTMS: low-frequency rTMS; M1: primary motor cortex; rTMS: repetitive transcranial magnetic stimulation; SMA: supplementary motor area. Created with BioRender.

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Conclusion

The safety guidelines for the application of TMS in research and clinical settings is continuously updated and advanced every 10 years proposed by the international consensus conference (Rossi et al., 2009, 2021). In October 2018, the Siena (Italy) consensus conference proposed updating of the 10 safety guidelines for application of TMS in research and clinical settings (Rossi et al., 2009, 2021). Although TMS is used in routine clinical rehabilitation, safety issues require careful consideration. The above conference focused on the safety of available TMS devices and pulse configurations, duties and responsibilities of device manufactures, novel scenarios of TMS applications (such as in the neuroimaging context or imaging-guided and robot-guided TMS), combined effects of TMS interleaved with tDCS, safety during paired associative stimulation interventions, and risks of TMS inducing therapeutic seizures. These revised operational guidelines should facilitate establishment of criteria for appropriate use of TMS in stroke rehabilitation. The ongoing investigation of the underlying mechanisms of rTMS has advanced our understanding of the therapeutic effects of rTMS in post-stroke rehabilitation. Our review summarizes the current underlying mechanisms of rTMS application in stroke rehabilitation. However, the specific parameters and protocols of rTMS and the advanced application of rTMS combined with other therapies are not addressed in this review. We believe the increasing and more specific mechanism studies of rTMS will promote the development of rTMS application in stroke rehabilitation.

Author contributions

YFL conceived and drafted the manuscript and figures. GYY conducted critical revision of this manuscript. JXW contributed the design, discussion, correction and proofread the manuscript. All authors reviewed and approved the final version of the manuscript.

Conflicts of interest

The authors declare that they have no competing interest.

Editor note: JXW, and GYY are Editorial Board members of Brain Network and Modulation. They were blinded from reviewing or making decisions on the manuscript. The article was subject to the journal’s standard procedures, with peer review handled independently of these Editorial Board members and their research groups.

Data availability statement

No additional data are available.

Open access statement

This is an open access journal, and articles are distributed under the terms of the Creative Commons AttributionNonCommercial-ShareAlike 4.0 License, which allows others to remix, tweak, and build upon the work non-commercially, as long as appropriate credit is given and the new creations are licensed under the identical terms.[87]

References

1.	Ackerley SJ, Stinear CM, Barber PA, Byblow WD (2010) Combining theta burst stimulation with training after subcortical stroke. Stroke 41:1568-1572.
2.	Ameli M, Grefkes C, Kemper F, Riegg FP, Rehme AK, Karbe H, Fink GR, Nowak DA (2009) Differential effects of high-frequency repetitive transcranial magnetic stimulation over ipsilesional primary motor cortex in cortical and subcortical middle cerebral artery stroke. Ann Neurol 66:298-309.
3.	Barker AT, Jalinous R, Freeston IL (1985) Non-invasive magnetic stimulation of human motor cortex. Lancet 1:1106-1107.
4.	Boroojerdi B, Diefenbach K, Ferbert A (1996) Transcallosal inhibition in cortical and subcortical cerebral vascular lesions. J Neurol Sci 144:160-170.
5.	Camacho-Conde JA, Gonzalez-Bermudez MDR, Carretero-Rey M, Khan ZU (2022) Brain stimulation: a therapeutic approach for the treatment of neurological disorders. CNS Neurosci Ther 28:5-18.
6.	Cambiaghi M, Cherchi L, Masin L, Infortuna C, Briski N, Caviasco C, Hazaveh S, Han Z, Buffelli M, Battaglia F (2021) High-frequency repetitive transcranial magnetic stimulation enhances layer II/III morphological dendritic plasticity in mouse primary motor cortex. Behav Brain Res 410:113352.
7.	Caparelli EC, Schleyer B, Zhai T, Gu H, Abulseoud OA, Yang Y (2022) High-frequency transcranial magnetic stimulation combined with functional magnetic resonance imaging reveals distinct activation patterns associated with different dorsolateral prefrontal cortex stimulation sites. Neuromodulation 25:633-643.
8.	Charalambous CC, Bowden MG, Adkins DL (2016) Motor cortex and motor cortical interhemispheric communication in walking after stroke: the roles of transcranial magnetic stimulation and animal models in our current and future understanding. Neurorehabil Neural Repair 30:94-102.
9.	Chen YH, Chen CL, Huang YZ, Chen HC, Chen CY, Wu CY, Lin KC (2021) Augmented efficacy of intermittent theta burst stimulation on the virtual reality-based cycling training for upper limb function in patients with stroke: a double-blinded, randomized controlled trial. J Neuroeng Rehabil 18:91.
10.	Clarke D, Penrose MA, Penstone T, Fuller-Carter PI, Hool LC, Harvey AR, Rodger J, Bates KA (2017) Frequency-specific effects of repetitive magnetic stimulation on primary astrocyte cultures. Restor Neurol Neurosci 35:557-569.
11.	Cohen SL, Bikson M, Badran BW, George MS (2022) A visual and narrative timeline of US FDA milestones for Transcranial Magnetic Stimulation (TMS) devices. Brain Stimul 15:73-75.
12.	Cui M, Ge H, Zeng H, Yan H, Zhang L, Feng H, Chen Y (2019) Repetitive transcranial magnetic stimulation promotes neural stem cell proliferation and differentiation after intracerebral hemorrhage in mice. Cell Transplant 28:568-584.
13.	Cullen CL, Senesi M, Tang AD, Clutterbuck MT, Auderset L, O'Rourke ME, Rodger J, Young KM (2019) Low-intensity transcranial magnetic stimulation promotes the survival and maturation of newborn oligodendrocytes in the adult mouse brain. Glia 67:1462-1477.
14.	Deng Y, Guo F, Han X, Huang X (2021) Repetitive transcranial magnetic stimulation increases neurological function and endogenous neural stem cell migration via the SDF-1α/CXCR4 axis after cerebral infarction in rats. Exp Ther Med 22:1037.
15.	Di Pino G, Pellegrino G, Assenza G, Capone F, Ferreri F, Formica D, Ranieri F, Tombini M, Ziemann U, Rothwell JC, Di Lazzaro V (2014) Modulation of brain plasticity in stroke: a novel model for neurorehabilitation. Nat Rev Neurol 10:597-608.
16.	Dolgova N, Wei Z, Spink B, Gui L, Hua Q, Truong D, Zhang Z, Zhang Y (2021) Low-field magnetic stimulation accelerates the differentiation of oligodendrocyte precursor cells via non-canonical TGF-βsignaling pathways. Mol Neurobiol 58:855-866.
17.	Emara TH, Moustafa RR, ElNahas NM, ElGanzoury AM, Abdo TA, Mohamed SA, ElEtribi MA (2010) Repetitive transcranial magnetic stimulation at 1Hz and 5Hz produces sustained improvement in motor function and disability after ischaemic stroke. Eur J Neurol 17:1203-1209.
18.	Finger S (2010) Chapter 51: recovery of function: redundancy and vicariation theories. Handb Clin Neurol 95:833-841.
19.	Fleischmann A, Prolov K, Abarbanel J, Belmaker RH (1995) The effect of transcranial magnetic stimulation of rat brain on behavioral models of depression. Brain Res 699:130-132.
20.	Fujiki M, Yee KM, Steward O (2020) Non-invasive high frequency repetitive transcranial magnetic stimulation (hfrTMS) robustly activates molecular pathways implicated in neuronal growth and synaptic plasticity in select populations of neurons. Front Neurosci 14:558.
21.	Fujiki M, Kobayashi H, Abe T, Kamida T (2003) Repetitive transcranial magnetic stimulation for protection against delayed neuronal death induced by transient ischemia. J Neurosurg 99:1063-1069.
22.	Gattinger N, Moessnang G, Gleich B (2012) flexTMS--a novel repetitive transcranial magnetic stimulation device with freely programmable stimulus currents. IEEE Trans Biomed Eng 59:1962-1970.
23.	GBD 2016 Stroke Collaborators (2019) Global, regional, and national burden of stroke, 1990-2016: a systematic analysis for the Global Burden of Disease Study 2016. Lancet Neurol 18:439-458.
24.	Gerges ANH, Hordacre B, Pietro FD, Moseley GL, Berryman C (2022) Do adults with stroke have altered interhemispheric inhibition? A systematic review with meta-analysis. J Stroke Cerebrovasc Dis 31:106494.
25.	Grefkes C, Nowak DA, Wang LE, Dafotakis M, Eickhoff SB, Fink GR (2010) Modulating cortical connectivity in stroke patients by rTMS assessed with fMRI and dynamic causal modeling. Neuroimage 50:233-242.
26.	Guo N, Wang X, Duanmu D, Huang X, Li X, Fan Y, Li H, Liu Y, Yeung EHK, To MKT, Gu J, Wan F, Hu Y (2022) SSVEP-based brain computer interface controlled soft robotic glove for post-stroke hand function rehabilitation. IEEE Trans Neural Syst Rehabil Eng 30:1737-1744.
27.	Hannah R (2020) Transcranial magnetic stimulation: a non-invasive window into the excitatory circuits involved in human motor behavior. Exp Brain Res 238:1637-1644.
28.	Hollist M, Morgan L, Cabatbat R, Au K, Kirmani MF, Kirmani BF (2021) Acute stroke management: overview and recent updates. Aging Dis 12:1000-1009.
29.	Hong J, Chen J, Li C, An D, Tang Z, Wen H (2021) High-frequency rTMS improves cognitive function by regulating synaptic plasticity in cerebral ischemic rats. Neurochem Res 46:276-286.
30.	Hong JN, Chen JM, Zeng Y, Li C, Zhang X, He ZT, Wen HM (2022) Mechanism of high frequency rTMS on cognitive function in cerebral ischemic rats based on RNA sequencing. Zhonghua Yi Xue Za Zhi 102:73-79.
31.	Hong Y, Liu Q, Peng M, Bai M, Li J, Sun R, Guo H, Xu P, Xie Y, Li Y, Liu L, Du J, Liu X, Yang B, Xu G (2020) High-frequency repetitive transcranial magnetic stimulation improves functional recovery by inhibiting neurotoxic polarization of astrocytes in ischemic rats. J Neuroinflammation 17:150.
32.	Hsu WY, Cheng CH, Liao KK, Lee IH, Lin YY (2012) Effects of repetitive transcranial magnetic stimulation on motor functions in patients with stroke: a meta-analysis. Stroke 43:1849-1857.
33.	Ikeda T, Kobayashi S, Morimoto C (2018) Gene expression microarray data from mouse CBS treated with rTMS for 30 days, mouse cerebrum and CBS treated with rTMS for 40 days. Data Brief 17:1078-1081.
34.	Kadono Y, Koguchi K, Okada KI, Hosomi K, Hiraishi M, Ueguchi T, Kida I, Shah A, Liu G, Saitoh Y (2021) Repetitive transcranial magnetic stimulation restores altered functional connectivity of central poststroke pain model monkeys. Sci Rep 11:6126.
35.	Kanno M, Matsumoto M, Togashi H, Yoshioka M, Mano Y (2004) Effects of acute repetitive transcranial magnetic stimulation on dopamine release in the rat dorsolateral striatum. J Neurol Sci 217:73-81.
36.	Kim JY, Choi GS, Cho YW, Cho H, Hwang SJ, Ahn SH (2013) Attenuation of spinal cord injury-induced astroglial and microglial activation by repetitive transcranial magnetic stimulation in rats. J Korean Med Sci 28:295-299.
37.	Klomjai W, Lackmy-Vallée A, Roche N, Pradat-Diehl P, Marchand-Pauvert V, Katz R (2015) Repetitive transcranial magnetic stimulation and transcranial direct current stimulation in motor rehabilitation after stroke: an update. Ann Phys Rehabil Med 58:220-224.
38.	Lefaucheur JP, Aleman A, Baeken C, Benninger DH, Brunelin J, Di Lazzaro V, Filipović SR, Grefkes C, Hasan A, Hummel FC, Jääskeläinen SK, Langguth B, Leocani L, Londero A, Nardone R, Nguyen JP, Nyffeler T, Oliveira-Maia AJ, Oliviero A, Padberg F, et al. (2020) Evidence-based guidelines on the therapeutic use of repetitive transcranial magnetic stimulation (rTMS): an update (2014-2018). Clin Neurophysiol 131:474-528.
39.	Lenz M, Platschek S, Priesemann V, Becker D, Willems LM, Ziemann U, Deller T, Müller-Dahlhaus F, Jedlicka P, Vlachos A (2015) Repetitive magnetic stimulation induces plasticity of excitatory postsynapses on proximal dendrites of cultured mouse CA1 pyramidal neurons. Brain Struct Funct 220:3323-3337.
40.	Lenz M, Galanis C, Müller-Dahlhaus F, Opitz A, Wierenga CJ, Szabó G, Ziemann U, Deller T, Funke K, Vlachos A (2016) Repetitive magnetic stimulation induces plasticity of inhibitory synapses. Nat Commun 7:10020.
41.	Li H, Shang J, Zhang C, Lu R, Chen J, Zhou X (2020a) Repetitive transcranial magnetic stimulation alleviates neurological deficits after cerebral ischemia through interaction between RACK1 and BDNF exon IV by the phosphorylation-dependent factor MeCP2. Neurotherapeutics 17:651-663.
42.	Li J, Wang H, Yuan Y, Fan Y, Liu F, Zhu J, Xu Q, Chen L, Guo M, Ji Z, Chen Y, Yu Q, Gao T, Hua Y, Fan M, Sun L (2022) Effects of high frequency rTMS of contralesional dorsal premotor cortex in severe subcortical chronic stroke: protocol of a randomized controlled trial with multimodal neuroimaging assessments. BMC Neurol 22:125.
43.	Li MN, Jing YH, Wu C, Li X, Liang FY, Li G, Dai P, Yu HX, Pei Z, Xu GQ, Lan Y (2020b) Continuous theta burst stimulation dilates meningeal lymphatic vessels by up-regulating VEGF-C in meninges. Neurosci Lett 735:135197.
44.	Liew SL, Santarnecchi E, Buch ER, Cohen LG (2014) Non-invasive brain stimulation in neurorehabilitation: local and distant effects for motor recovery. Front Hum Neurosci 8:378.
45.	Lin Y, Jin J, Lv R, Luo Y, Dai W, Li W, Tang Y, Wang Y, Ye X, Lin WJ (2021) Repetitive transcranial magnetic stimulation increases the brain's drainage efficiency in a mouse model of Alzheimer's disease. Acta Neuropathol Commun 9:102.
46.	Liu H, Li G, Ma C, Chen Y, Wang J, Yang Y (2018) Repetitive magnetic stimulation promotes the proliferation of neural progenitor cells via modulating the expression of miR-106b. Int J Mol Med 42:3631-3639.
47.	Luo J, Feng Y, Li M, Yin M, Qin F, Hu X (2022a) Repetitive transcranial magnetic stimulation improves neurological function and promotes the anti-inflammatory polarization of microglia in ischemic rats. Front Cell Neurosci 16:878345.
48.	Luo L, Liu M, Fan Y, Zhang J, Liu L, Li Y, Zhang Q, Xie H, Jiang C, Wu J, Xiao X, Wu Y (2022b) Intermittent theta-burst stimulation improves motor function by inhibiting neuronal pyroptosis and regulating microglial polarization via TLR4/NFκB/NLRP3 signaling pathway in cerebral ischemic mice. J Neuroinflammation 19:141.
49.	Luo Y, Yang J, Wang H, Gan Z, Ran D (2019) Cellular mechanism underlying rTMS treatment for the neural plasticity of nervous system in drosophila brain. Int J Mol Sci 20:4625.
50.	Marjenin T, Scott P, Bajaj A, Bansal T, Berne B, Bowsher K, Costello A, Doucet J, Franca E, Ghosh C, Govindarajan A, Gutowski S, Gwinn K, Hinckley S, Keegan E, Lee H, Mathews B, Misra S, Patel S, Tang X, et al. (2020) FDA perspectives on the regulation of neuromodulation devices. Neuromodulation 23:3-9.
51.	Natale G, Pignataro A, Marino G, Campanelli F, Calabrese V, Cardinale A, Pelucchi S, Marcello E, Gardoni F, Viscomi MT, Picconi B, Ammassari-Teule M, Calabresi P, Ghiglieri V (2021) Transcranial magnetic stimulation exerts "rejuvenation" effects on corticostriatal synapses after partial dopamine depletion. Mov Disord 36:2254-2263.
52.	Ogiue-Ikeda M, Kawato S, Ueno S (2005) Acquisition of ischemic tolerance by repetitive transcranial magnetic stimulation in the rat hippocampus. Brain Res 1037:7-11.
53.	Park HK, Song MK, Kim WI, Han JY (2020) Regulation of gene expression after combined scalp acupuncture and transcranial magnetic stimulation in middle cerebral artery occlusion mice. Restor Neurol Neurosci 38:253-263.
54.	Paulus W, Peterchev AV, Ridding M (2013) Transcranial electric and magnetic stimulation: technique and paradigms. Handb Clin Neurol 116:329-342.
55.	Peng JJ, Sha R, Li MX, Chen LT, Han XH, Guo F, Chen H, Huang XL (2019) Repetitive transcranial magnetic stimulation promotes functional recovery and differentiation of human neural stem cells in rats after ischemic stroke. Exp Neurol 313:1-9.
56.	Priori A, Hallett M, Rothwell JC (2009) Repetitive transcranial magnetic stimulation or transcranial direct current stimulation? Brain Stimul 2:241-245.
57.	Pruvost-Robieux E, Benzakoun J, Turc G, Marchi A, Mancusi RL, Lamy C, Domigo V, Oppenheim C, Calvet D, Baron JC, Mas JL, Gavaret M (2021) Cathodal transcranial direct current stimulation in acute ischemic stroke: pilot randomized controlled trial. Stroke 52:1951-1960.
58.	Rossi S, Hallett M, Rossini PM, Pascual-Leone A (2009) Safety, ethical considerations, and application guidelines for the use of transcranial magnetic stimulation in clinical practice and research. Clin Neurophysiol 120:2008-2039.
59.	Rossi S, Antal A, Bestmann S, Bikson M, Brewer C, Brockmöller J, Carpenter LL, Cincotta M, Chen R, Daskalakis JD, Di Lazzaro V, Fox MD, George MS, Gilbert D, Kimiskidis VK, Koch G, Ilmoniemi RJ, Lefaucheur JP, Leocani L, Lisanby SH, et al. (2021) Safety and recommendations for TMS use in healthy subjects and patient populations, with updates on training, ethical and regulatory issues: expert Guidelines. Clin Neurophysiol 132:269-306.
60.	Sehle A, Stuerner J, Hassa T, Spiteri S, Schoenfeld MA, Liepert J (2021) Behavioral and neurophysiological effects of an intensified robot-assisted therapy in subacute stroke: a case control study. J Neuroeng Rehabil 18:6.
61.	Singh N, Saini M, Kumar N, Srivastava MVP, Mehndiratta A (2021) Evidence of neuroplasticity with robotic hand exoskeleton for post-stroke rehabilitation: a randomized controlled trial. J Neuroeng Rehabil 18:76.
62.	Smith MC, Stinear CM (2016) Transcranial magnetic stimulation (TMS) in stroke: ready for clinical practice? J Clin Neurosci 31:10-14.
63.	Starosta M, Cichoń N, Saluk-Bijak J, Miller E (2022) Benefits from repetitive transcranial magnetic stimulation in post-stroke rehabilitation. J Clin Med 11:2149.
64.	Takeuchi N, Chuma T, Matsuo Y, Watanabe I, Ikoma K (2005) Repetitive transcranial magnetic stimulation of contralesional primary motor cortex improves hand function after stroke. Stroke 36:2681-2686.
65.	Tan T, Xie J, Tong Z, Liu T, Chen X, Tian X (2013) Repetitive transcranial magnetic stimulation increases excitability of hippocampal CA1 pyramidal neurons. Brain Res 1520:23-35.
66.	Tang A, Thickbroom G, Rodger J (2017) Repetitive transcranial magnetic stimulation of the brain: mechanisms from animal and experimental models. Neuroscientist 23:82-94.
67.	Tang AD, Bennett W, Bindoff AD, Bolland S, Collins J, Langley RC, Garry MI, Summers JJ, Hinder MR, Rodger J, Canty AJ (2021) Subthreshold repetitive transcranial magnetic stimulation drives structural synaptic plasticity in the young and aged motor cortex. Brain Stimul 14:1498-1507.
68.	Taylor JJ, Newberger NG, Stern AP, Phillips A, Feifel D, Betensky RA, Press DZ (2021) Seizure risk with repetitive TMS: Survey results from over a half-million treatment sessions. Brain Stimul 14:965-973.
69.	Tokay T, Kirschstein T, Rohde M, Zschorlich V, Köhling R (2014) NMDA receptor-dependent metaplasticity by high-frequency magnetic stimulation. Neural Plast 2014:684238.
70.	Vlachos A, Müller-Dahlhaus F, Rosskopp J, Lenz M, Ziemann U, Deller T (2012) Repetitive magnetic stimulation induces functional and structural plasticity of excitatory postsynapses in mouse organotypic hippocampal slice cultures. J Neurosci 32:17514-17523.
71.	Walia P, Ghosh A, Singh S, Dutta A (2022) Portable neuroimaging-guided noninvasive brain stimulation of the cortico-cerebello-thalamo-cortical loop-hypothesis and theory in cannabis use disorder. Brain Sci 12:445.
72.	Wang Z, Baharani A, Wei Z, Truong D, Bi X, Wang F, Li XM, Verge VMK, Zhang Y (2021) Low field magnetic stimulation promotes myelin repair and cognitive recovery in chronic cuprizone mouse model. Clin Exp Pharmacol Physiol 48:1090-1102.
73.	Wassermann EM (1998) Risk and safety of repetitive transcranial magnetic stimulation: report and suggested guidelines from the International Workshop on the Safety of Repetitive Transcranial Magnetic Stimulation, June 5-7, 1996. Electroencephalogr Clin Neurophysiol 108:1-16.
74.	Xia P, Zheng Y, Dong L, Tian C (2021) Short-term extremely low-frequency electromagnetic field inhibits synaptic plasticity of schaffer collateral-CA1 synapses in rat hippocampus via the Ca(2+)/calcineurin pathway. ACS Chem Neurosci 12:3550-3557.
75.	Yan J, Zhang F, Niu L, Wang X, Lu X, Ma C, Zhang C, Song J, Zhang Z (2022) High-frequency repetitive transcranial magnetic stimulation mitigates depression-like behaviors in CUMS-induced rats via FGF2/FGFR1/p-ERK signaling pathway. Brain Res Bull 183:94-103.
76.	Yang L, Wang SH, Hu Y, Sui YF, Peng T, Guo TC (2018) Effects of repetitive transcranial magnetic stimulation on astrocytes proliferation and nNOS expression in neuropathic pain rats. Curr Med Sci 38:482-490.
77.	Yang L, Su Y, Guo F, Zhang H, Zhao Y, Huang Q, Xu H (2020) Deep rTMS mitigates behavioral and neuropathologic anomalies in cuprizone-exposed mice through reducing microglial proinflammatory cytokines. Front Integr Neurosci 14:556839.
78.	Yang R, Boldrey J, Jiles D, Schneider I, Que L (2021) On chip detection of glial cell-derived neurotrophic factor secreted from dopaminergic cells under magnetic stimulation. Biosens Bioelectron 182:113179.
79.	Yang SN, Tang YG, Zucker RS (1999) Selective induction of LTP and LTD by postsynaptic [Ca2+]i elevation. J Neurophysiol 81:781-787.
80.	Yue L, Xiao-lin H, Tao S (2009) The effects of chronic repetitive transcranial magnetic stimulation on glutamate and gamma-aminobutyric acid in rat brain. Brain Res 1260:94-99.
81.	Zeng Z, Koponen LM, Hamdan R, Li Z, Goetz SM, Peterchev AV (2022) Modular multilevel TMS device with wide output range and ultrabrief pulse capability for sound reduction. J Neural Eng 19:10.1088/1741-2552/ac1572c.
82.	Zhang H, Huang X, Wang C, Liang K (2022) Alteration of gamma-aminobutyric acid in the left dorsolateral prefrontal cortex of individuals with chronic insomnia: a combined transcranial magnetic stimulation-magnetic resonance spectroscopy study. Sleep Med 92:34-40.
83.	Zhao CG, Qin J, Sun W, Ju F, Zhao YL, Wang R, Sun XL, Mou X, Yuan H (2019) rTMS regulates the balance between proliferation and apoptosis of spinal cord derived neural stem/progenitor cells. Front Cell Neurosci 13:584.
84.	Zhong G, Yang Z, Jiang T (2021) Precise modulation strategies for transcranial magnetic stimulation: advances and future directions. Neurosci Bull 37:1718-1734.
85.	Zhu H, Xu G, Li Y, Fu R, Yin X, Xu B, Ding C (2021) Immediate and cumulative effects of high-frequency repetitive transcranial magnetic stimulation on cognition and neuronal excitability in mice. Neurosci Res 173:90-98.
86.	Zong X, Li Y, Liu C, Qi W, Han D, Tucker L, Dong Y, Hu S, Yan X, Zhang Q (2020a) Theta-burst transcranial magnetic stimulation promotes stroke recovery by vascular protection and neovascularization. Theranostics 10:12090-12110.
87.	Zong X, Dong Y, Li Y, Yang L, Li Y, Yang B, Tucker L, Zhao N, Brann DW, Yan X, Hu S, Zhang Q (2020b) Beneficial effects of theta-burst transcranial magnetic stimulation on stroke injury via improving neuronal microenvironment and mitochondrial integrity. Transl Stroke Res 11:450-467.