As the population ages, the incidence of stroke continues to rise (1). Lower extremity dysfunction is a common post-stroke functional impairment. This dyskinesia persists for a long time, hindering daily activities, reducing muscle strength, and limiting work-related activities and social participation (2). Current rehabilitation approaches for post-stroke lower limb motor dysfunction mainly include repetitive task-oriented training, walking exercises, treadmill training, orthotics, and functional electrical stimulation (3). However, these traditional therapies are time-consuming and produce inconsistent results. Therefore, developing innovative treatment methods that enhance balance, walking ability, and performance of daily living activities is vital in stroke rehabilitation research.

Non-invasive brain stimulation (NiBS) includes emerging techniques used in neurorehabilitation to restore motor function after stroke by modulating the excitability of motor control centers (4). NiBS techniques include transcranial ultrasound stimulation, transcranial direct current stimulation (tDCS), and transcranial magnetic stimulation (TMS) (5). However, relatively few clinical studies have explored the effectiveness of transcranial ultrasound stimulation for poststroke motor function recovery (6). Based on various stimulation patterns, TMS techniques are classified into single-pulse TMS, dual-pulse TMS, repetitive TMS (rTMS), and the derived rTMS mode (theta burst stimulation, TBS) (7).

A considerable number of clinical studies have been published on treating poststroke lower limb movement disorders using NiBS techniques. These studies utilise different stimulation modes, including low-frequency rTMS (LF-rTMS), high-frequency rTMS (HF-rTMS), combined rTMS and transcranial direct current stimulation (rTMS + tDCS), intermittent TBS (iTBS), continuous TBS (cTBS), anodal tDCS (A-tDCS), dual-tDCS, and cathodal tDCS (C-tDCS). Reported outcomes include the Fugl–Meyer assessment for the lower extremity (FMA-LE), the Barthel index (BI), the Berg balance scale (BBS), and the timed up and go test (TUG) (8, 9). Based on these studies, several meta-analyses have evaluated the effectiveness of various NiBS therapies in treating post-stroke motor disorders (10, 11). Traditional meta-analyses, however, are limited to pairwise comparisons and cannot establish a comprehensive treatment hierarchy (network evidence), as their results are based on direct comparisons of relevant treatments. In contrast, network meta-analysis (NMA) is a relatively new statistical method that combines, compares, and integrates multiple interventions within a single analysis. Although a large number of traditional pairwise comparisons are needed to support such integration, NMA enables ranking of all interventions using both direct trial data and indirect evidence from cross-comparisons (12). To evaluate and compare the effectiveness of various NiBS treatments for lower extremity disorders in post-stroke patients, we conducted a literature search and synthesized the available evidence in this review.

The study protocol was registered in PROSPERO (CRD42024521395) on May 20, 2024.¹ We prepared the NMA following the Preferred Reporting Items for Systematic Review and Meta-analysis Protocols (PRISMA-P) statement (13).

To the best of our knowledge, this study represents the first NMA to examine the effectiveness of NiBS on poststroke lower extremity motor function. The analysis evaluated the efficacy of nine different NiBS treatments compared with placebo in 1319 participants with poststroke lower extremity disorders. For the primary outcome, measured using the FMA-LE, the NMA found that LF-rTMS and rTMS + tDCS were more effective than placebo. Pairwise meta-analysis also indicated that LF-rTMS, C-tDCS, and dual-tDCS were significantly more effective than placebo. Regarding walking function, assessed by the TUG test, both direct and indirect evidence showed that no NiBS intervention was more effective than placebo. The NMA assessment of body balance function revealed that iTBS and LF-rTMS were more effective than placebo. Pairwise meta-analysis suggested that iTBS, LF-rTMS, and HF-rTMS exceeded placebo in effectiveness. For activities of daily living, evaluated using the BI, direct evidence indicated that iTBS, A-tDCS, rTMS + tDCS, and LF-rTMS were more effective than placebo. The NMA results for BI demonstrated that iTBS, LF-rTMS, and rTMS + tDCS outperformed placebo.

The main stimulation modes of TMS included in this study were LF-rTMS and iTBS. For the recovery of hand motor function during the subacute phase of stroke, existing evidence and definite efficacy suggest a level A recommendation for LF-rTMS (42). A meta-analysis confirmed the therapeutic effect of LF-rTMS on lower limb movement disorders after stroke (3). Our research demonstrated that the effect of LF-rTMS on motor function recovery, body balance, and activities of daily living was superior to that of placebo in poststroke patients. iTBS, a novel TMS mode that functions in the opposite way of LF-rTMS, enhances nervous system excitability. iTBS should be considered a level B recommendation for treating lower-limb spasticity 字段 (42). Our investigation suggests that iTBS could improve activities of daily living and body balance in poststroke patients.

Regarding tDCS, previous meta-analyses and our own research have demonstrated its restorative effects in poststroke patients (11, 43). However, the number of RCTs assessing each effective tDCS mode was relatively small in this systematic review. Similarly, in the NMA of the primary outcome, although rTMS + tDCS appeared to be the most effective stimulation method, only two relevant RCTs were included (9, 41). Additional clinical studies are needed to evaluate the effects of tDCS in addressing lower extremity dysfunction after stroke.

To date, NiBS treatments for poststroke motor dysfunction mainly follow the interhemispheric inhibition model. This model indicates that the two hemispheres suppress each other’s excitability via nerve fiber bundles in the corpus callosum, maintaining a dynamic balance. After a stroke, the inhibitory effect of the affected hemisphere diminishes, disrupting this balance. The unaffected hemisphere then suppresses the excitability of the affected hemisphere through the corpus callosum, causing a decline in motor function (44). Nervous system excitability is affected by synaptic connections and efficacy, which NiBS modulates through mechanisms tied to long-term potentiation or depression (45, 46). To enhance poststroke limb dysfunction, inhibitory stimulation should be applied to the contralesional motor area (17, 31), whereas excitatory NiBS stimulation should focus on the ipsilesional motor area (4, 26, 36). Adhering to the interhemispheric inhibition model (HF-rTMS on the ipsilesional motor cortex and LF-rTMS on the contralesional side), one study investigated how rTMS influences motor function and cortical activation. Compared to the sham group, the real rTMS group exhibited motor improvements. fMRI data indicated a link between motor gains and increased cortical excitability caused by rTMS (47). Another study showed that applying A-tDCS to the primary motor cortex of stroke patients increased connectivity within the EEG network of the ipsilesional motor cortex. This heightened connectivity was linked to greater corticospinal excitability after A-tDCS (48). Notably, our NMA included a rare study exploring the effects of rTMS on the left dorsolateral prefrontal cortex (25), a region more commonly targeted to enhance cognitive function or treat depression (49). For poststroke motor dysfunction, the dorsolateral prefrontal cortex was rarely used as a stimulation target. Some included studies explored the improvement of poststroke lower limb dysfunction by using NiBS on the cerebellum (7, 27, 28, 30, 32). A study demonstrated that, compared to sham stimulation, cerebellar iTBS enhanced post-stroke body balance and lower limb function, along with an increase in motor-evoked potential amplitudes (28) regulatory center for movement. During exercise, the cerebellum receives and integrates information from the cerebral cortex, muscles, and joints. Based on this mechanism, the cerebellum presents a feasible target for modulating motor behavior and treating motor impairments caused by stroke (50). A study investigating poststroke dysphagia suggested that bilateral cerebellar iTBS can effectively enhance swallowing function (51). In treating post-stroke upper limb spasticity, cerebellar iTBS enhances the effects of conventional physical therapy (52). In a healthy population, another study found that active cerebellar rTMS restores swallowing accuracy and inhibitory effects caused by a cortical “virtual lesion” on pharyngeal motor-evoked potentials (53). In speech improvement, right cerebellar tDCS was found to significantly enhance phonemic fluency. This improvement is also linked to increased functional connectivity (54). Based on these promising findings, the cerebellum could be a crucial target for NiBS interventions in poststroke motor rehabilitation. However, more research is needed to develop a standardized approach to translate small-scale experimental results into a wide range of clinical practices (55).

Our investigation reported only one case of a severe adverse reaction (seizure) related to rTMS (20), Although causality between the seizure and rTMS treatment was not confirmed, numerous mild adverse events have been reported. These mainly involve skin sensations, are short in duration, and have no sequelae. According to the published TMS safety guidelines (56), seizure induction is the most severe acute adverse event; however, the risk of rTMS-induced seizures is definitely low. A review that included 41 reports published up to February 2020 examined TMS-induced seizures (57). Among these 41 reports, 13 involved healthy individuals, and 28 involved patients. Due to the inconsistent distribution of TMS patterns among the reports (19 HF-rTMS, 1 LF-rTMS, 8 single-pulse TMS, 9 deep TMS, 2 iTBS, 1 cTBS, and 1 unknown), it was difficult to identify a correlation between TMS-induced seizure and specific populations or TMS patterns. Regarding tDCS, our review found no severe adverse events and only mild adverse events similar to those of rTMS, with short duration and no sequelae. Previous safety guidelines have confirmed the safety of tDCS (58). However, given the widespread use of home-based tDCS devices (39), untrained application may cause burns, reduced accuracy, and other complications. Professional guidance is necessary before use. Theoretically, the combination of rTMS and tDCS could raise the incidence of severe adverse events (59); however, our review did not report any such cases (9, 41). Similarly, a study involving patients with depression reported no serious adverse events, except for increased scalp pain when rTMS was applied before tDCS (60). In a healthy population, another review found no serious adverse events related to combined interventions (61). In brief, there is no current evidence questioning the safety of the combination of tDCS and rTMS.

This study has several limitations. First, the analysis using TUG as the outcome measure indicated that, compared with the placebo group, NiBS did not appear to improve patients’ walking function. This result may be due to the fact that, in some of the included clinical studies, the baseline walking function of the experimental group was weaker than that of the control group (7, 29, 33). Second, previous studies reported varying efficacies of NiBS depending on the stage of stroke (5). Although our review included patients at different stages of stroke onset, a subgroup analysis of NiBS treatment effects by stroke stage was not performed due to limited relevant research. Additionally, the NMA did not encompass all NiBS interventions, such as tRNS, taVNS, and tACS. There is a lack of suitable studies on these interventions for lower-extremity motor function (11, 62).