Stroke is one of the leading causes of long-term upper limb disability worldwide (Feigin et al., 2014). It is reported that up to 75% of post-stroke patients live with upper limb functional impairment, which results in restrictions in functional tasks and daily activities, even after traditional rehabilitation programs (Feigin et al., 2017). Impaired motor function is associated with a decrease in corticospinal excitability of the affected hemisphere after stroke (McDonnell and Stinear, 2017). Also, according to neuroimaging studies, the unaffected primary motor cortex (M1) appears to be overactivated during movement control of the affected hand in stroke patients (Grefkes and Ward, 2014). Repetitive transcranial magnetic stimulation (rTMS) is a promising non-invasive technique to modulate the excitability of specific brain areas that have been reported to be robust in the recovery of motor function after stroke (Li et al., 2020). Intermittent theta burst stimulation (iTBS) is a specific type of rTMS that effectively improves cortex excitability by generating facilitatory or inhibitory effects on synaptic transmission (Huang et al., 2005). As an excitatory rTMS, the underlying mechanism of iTBS can be attributed in part to the removal of magnesium ion blockages in the N-methyl-D-aspartate glutamate receptors during depolarization, resulting in intracellular calcium entry and enhancing the postsynaptic response to behavioral learning (Zhang et al., 2022). This repetitive stimulation pattern has been shown to induce long-term potentiation (LTP) in the neural circuits associated with motor function (Koch et al., 2008). The persistent motor deficits poststroke may be due to abnormal cortical excitability and brain network connection (Desowska and Turner, 2019). Therefore, better clinical outcomes for the affected limb result from the reduction of asymmetry of corticomotor excitability (Cabral et al., 2022). With shorter stimulation and lower stimulation intensity, iTBS has been suggested to be a promising rTMS option compared to traditional rTMS in clinical treatment (Talelli et al., 2007). iTBS become more frequently applied with conventional rehabilitation to enhance the improvement in motor function after stroke. However, individual studies have yielded inconsistent or conflicting findings, possibly due to the limitations associated with an individual study and the small sample size. Although cortical excitability of the M1 was significantly increased after multiple sessions of iTBS in one study (Sung et al., 2013), Watanabe et al. (2018) found that the motor performance did not reach statistical significance, and Zhang et al. (2022) found that motor outcomes showed a significantly greater improvement than the sham group. To clarify these conflicting results and to better evaluate the relationship between iTBS and upper limb motor recovery in stroke patients, we performed a meta-analysis of published studies. The aim of this article is to evaluate the influence of intermittent theta-burst stimulation on upper limb motor recovery and quality of life.

The aim of this article is to systematically review the influence of iTBS on the function of upper limb motor recovery and improving the quality of life in stroke patients. According to the included studies, iTBS, consisting of the delivery of a 2 s train of theta-burst stimulation (bursts of 3 stimuli at 50 Hz with an interburst interval of 200 ms) repeated every 10 s, was commonly delivered at 70–90% AMT of nonparetic FDI to ipsilesional M1 with 600 pulses or 1,200 pulses. After delivery five times/week for 2 consecutive weeks, the majority of studies yielded positive results in motor function of the upper limbs, while some demonstrated no positive effect on the excitability of the cortex, which may need more robust evidence due to inadequate data. According to the results of the meta-analysis, the iTBS group had significant improvement in FMA, ARAT, MAS, and BI compared to the control group. However, no significant differences were found in MEP amplitude and MEP latency between the iTBS group and the control group. Considering that the sample size we used was limited, this result is not very convincing, which warrants further evidence and a larger sample size.

Regarding iTBS for upper limb motor impairment after stroke, patients’ FMA scores improved significantly after iTBS intervention treatment. Based on subgroup analysis of stroke duration patients benefit more in the early phase than in the chronic stage in FMA. These results are consistent with those of previous studies. Facilitatory iTBS combined with upper limb training was found to enhance fine upper limb movement and the recovery of gross manual dexterity in acute, subacute, and chronic stroke (Hsu et al., 2013; Chen, 2018; Watanabe et al., 2018). This can be explained by the vicariation theory that the brain areas induced by iTBS are reorganized to substitute the functions of nearby injured areas (Murphy and Corbett, 2009). It is accepted that gross and fine motor function can be controlled by M1 and corticospinal tract (Lang and Schieber, 2004). As the stimulation point, the regulation of M1 and the corticospinal tract can account for the improvement in FMA. Several studies have shown increased neuroplasticity and greater behavioral recovery in the early post-stroke period (Maulden et al., 2005; Murphy and Corbett, 2009). As far as we know, the first 6 months after stroke are the ideal time for recovering motor function. From the results of the meta-analysis, iTBS is a promising adjuvant to therapy delivered at the early stage of stroke.

Regarding iTBS for upper limb functional activities after stroke, patients’ ARAT scores improved significantly after iTBS intervention treatment. The mean difference in improvement in the ARAT score was modest, which may be explained by the fact that the improvement of the majority of stroke patients included in the analysis lasted more than 6 months (Talelli et al., 2012; Ackerley et al., 2016; Chen, 2018; Zhang et al., 2022). The likelihood of motor recovery was lower in the chronic phase. Talelli et al. (2012) and Zhang et al. (2022) reported that iTBS did not significantly augment the gains from a retraining protocol for the upper limbs in those with chronic stroke in small sample sizes. However, Ackerley et al. (2016), Chen (2018), and Chen Y. H. et al. (2021) demonstrated that iTBS induced a greater increase in ARAT in the iTBS group than in the control group. A reason for this controversial finding might be that the spontaneous reorganization of chronic stroke is nearing completion, which may limit the induction of neural plasticity and the enhancement of training effects (Volz et al., 2016). Further studies on a larger scale are warranted to confirm this controversial finding.

Regarding iTBS for upper limb muscle tone after stroke, patients’ MAS scores improved significantly after iTBS intervention treatment. The results indicated that iTBS significantly reduced spasticity in stroke patients. Our results were partially compatible with those of previous iTBS studies (Chen, 2018; Watanabe et al., 2018; Chen Y. et al., 2021; Chen Y. H. et al., 2021; El Nahas et al., 2022). The postulated pathophysiology of spasticity is that upper motor neuron lesions impair supraspinal inhibitory inputs, leading to increased excitability of alpha and gamma motor neurons and spinal interneurons (Gharooni et al., 2018). iTBS has been found to induce a phenomenon called long-term potentiation (LTP), a process of strengthening synapses between neurons (Huang et al., 2017) and functional connectivity of brain that leads to a reorganization of neural pathways (Mori et al., 2010). However, Chen (2018) found no significant difference in corticospinal excitability assessment between the iTBS and sham groups. Further neurophysiological studies are therefore warranted to identify the underlying mechanism.

Regarding iTBS for corticomotor excitability after stroke, no significant differences were found after iTBS intervention treatment. First, the sample size included in the studies was limited. Second, of note, not all the MEPs of stroke patients in the ipsilesional hemisphere could be elicited, especially in severely impaired patients (Ding et al., 2022). The corticomotor excitability among participants could influence the response to iTBS. Using various electrophysiological indicators, Ding et al. (2021) found an increase in interhemispheric functional connectivity and global efficiency using EEG after iTBS intervention. Volz et al. (2016) demonstrated that M1 connectivity with motor areas of the contralesional hemisphere and ipsilesional areas significantly increased using fMRI in the iTBS group (Volz et al., 2016). Third, the heterogeneity in the sample characteristics could contribute to the lack of consistent effects on corticomotor excitability. To acknowledge the limitations and potential sources of heterogeneity, the results must be interpreted with caution.

Regarding iTBS for the ability to perform activities of daily living after stroke, patients’ BI scores improved significantly after iTBS intervention treatment, but there were no differences between the groups. Preliminary evidence was not sufficient to support that iTBS could augment the effect of conventional therapy in activities of daily living after 10 administration sessions.

Last but not least, iTBS was well tolerated and no significant adverse events were found in any included studies.

Our review has several limitations that need to be recognized. First, due to the multiple outcomes included in the studies, only a small amount of evidence was available, which caused the limited sample size. Further research and well-designed randomized controlled trials are needed to clarify the effects of iTBS. Second, it is not yet possible to determine the optimal stimulation parameters, location, and patient characteristics for different functional improvements in iTBS intervention. Parameters such as burst frequency, intensity, and duration are being optimized to induce more robust neuroplastic changes. Some studies are experimenting with priming iTBS (Zhang and Fong, 2020) or paired-pulse TMS (Rawji et al., 2021) to explore their potential advantages over traditional iTBS. To date, M1 stimulation has primarily been investigated, and the cerebellum is also considered to be involved in motor adaptation and learning processes (Liao et al., 2021). Finally, the MEP results are usually not recordable in patients with severe motor impairments and in the early stage of stroke. More sensitive and direct methods, such as EEG, fMRI, or fNIRs, could be used to reflect electrophysiological measures and corticomotor excitability. It is crucial to identify patients who are more likely to benefit from iTBS. Advanced neuroimaging and neurophysiological markers are being investigated to predict responders. This will allow more targeted use of iTBS, optimizing resources and enhancing the motor recovery prospects for stroke survivors.

The current study systematically reviewed existing research investigating the effects of iTBS on upper limb motor recovery after stroke. Our results showed that iTBS significantly improved motor impairment, functional activities, and muscle tone of the upper limbs, thereby increasing the ability to perform ADL in stroke patients, while no significant differences were found in MEPs. In conclusion, while iTBS is a promising non-invasive brain stimulation as an adjunct to therapy and enhances the therapeutic effect of conventional physical therapy, further studies are needed to investigate the neurophysiological effects.

The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding authors.

SC: Writing – original draft, Writing – review & editing. SZ: Writing – review & editing. WY: Writing – review & editing. YC: Writing – review & editing. BW: Writing – review & editing. JC: Writing – review & editing. XL: Writing – review & editing. LX: Writing – review & editing. HH: Writing – review & editing. YZ: Writing – review & editing. LT: Writing – review & editing. WJ: Data curation, Methodology, Supervision, Writing – original draft. XW: Writing – original draft, Data curation, Formal analysis, Methodology. YL: Writing – review & editing. HL: Writing – original draft, Writing – review & editing.