Multiple sclerosis (MS) is a chronic, paroxysmal, autoimmune disease that is characterized by demyelination and axonal degeneration of the central nervous system (1). Clinically, multiple sclerosis is classified into primary progressive type, secondary progressive type, and relapsing remitting type (2). The prevalence of MS, which is correlated with region, often exhibits a trend of rapid growth worldwide, with North America and Europe having the highest prevalence (3, 4). Usually, the clinical manifestations of MS include various cognitive impairments (such as attention deficit and executive dysfunction), motor impairments (such as spasms and tremors), sensory abnormalities (such as pain), visual impairments (such as diplopia and optic nerve dysfunction), and behavioral abnormalities (5). Moreover, among the symptoms described above, cognitive impairments affect 45–70% of patients with MS (pwMS) (6), and cognitive impairment may appear early in the course of the disease and worsen as the disease progresses (7), resulting in diminished quality of life and social dysfunction (8). Besides, motor dysfunction, which can be caused by a variety of issues (such as spasms, muscle weakness, abnormal walking mechanics, balance, or exhaustion) (9), can affect roughly 80% of pwMS and has major consequences for their personal and professional lives (10). In addition, cognitive dysfunction in pwMS, which increases the risk of falls and impairs motor function, has been closely associated with motor dysfunction (11). Consequently, it is of particular importance to treat the cognitive and motor functions in pwMS, in order to improve their quality of life and well-being.

In MS, drugs can reduce the number of flare-ups and slow the natural course of the disease. However, some patients experience side effects and thus seek complementary and alternative treatments to strike an appropriate balance between drug efficacy and safety (12). Furthermore, considering the complexity of the clinical symptoms of this condition, additional personalized and multi-selective treatments for pwMS need to be identified. Recently, non-invasive brain stimulation (NIBS) has attracted significant attention in the academic world (9) as a complementary method for treating neurological diseases. In general, NIBS is known to induce excitatory changes via the application of electrical and/or magnetic energy in the underlying cerebral cortex in a non-invasive manner and may induce long-lasting neuroplasticity changes (13). Clinically, transcranial direct current stimulation (tDCS) and repetitive transcranial magnetic stimulation (rTMS) are the most widely used NIBS techniques (14, 15). To date, researchers have experimentally explored the effects of the NIBS technology on the cognitive function and motor function of pwMS. However, because of the different experimental designs, the experimental results remain controversial, to some extent. This calls for a more effective study of the effects of NIBS in MS. To the best of our knowledge, previous evidence-based medical studies have explored the effects of NIBS applied to MS, particularly on pain (16) and fatigue (17), whereas no such evidence has been reported regarding cognitive and motor functions. Notably, there are no guidelines for the therapeutic use of NIBS in MS (18), and the effect of its clinical application remains to be researched and discussed.

Given the uncertainty of the effect of its clinical use, here we searched and screened clinical randomized trials on the effects of existing NIBS techniques on pwMS, aiming to explore the impact of NIBS on the cognitive and motor functions of pwMS and to draw evidence-based medical conclusions to provide guidance for its clinical practice and applications.

The study protocol was designed in accordance with the Preferred Reporting for Systematic Reviews and Meta-analysis (PRISMA) statement (19) and was prospectively registered in PROSPERO (CRD42022301012).

In total, 17 articles written in English were included in this study, wherein 364 patients were examined. Our findings imply that although no significant deference that NIBS improves cognitive function was found, it might help pwMS patients with their motor function. Further subgroup analysis revealed findings suggesting that stimulation located on P4 did not improve patient cognition, as well as that TES may improve cognitive alertness in pwMS. In particular, NIBS contributed to the improvement of MAS/ PSFS scores in pwMS, while TMS as an intervention, stimulation of area M1 was found to possibly improve motor function in pwMS. Additionally, patients with EDSS scores under 3.5 and those under the age of 45 experienced a therapeutic benefit from NIBS according to the results.

We didn't found evidence to prove that NIBS can improve the cognitive function of pwMS and the differences between the studies were not statistically significant for the different stimulus intensities, single stimulus durations, outcome indicators, and patient characteristics (EDSS and Age). At present, the mechanism via which NIBS affects cognitive function in pwMS remains controversial; however, a possible mechanism consists in the modulation of patient function by modulating cortical excitability (41) or by affecting neuroplasticity (42). Among the non-invasive brain stimulation models in cognitive neuroscience, there are differences in the mechanisms via which the various types of NIBS can affect neurological function, such as the induction of the suprathreshold depolarization of neurons by TMS and the induction of the subthreshold polarization of neurons in the stimulated area by transcranial electric stimulation (tES) (43). In particular, the cognitive-related studies in our study only used tDCS or tRNS., the findings are only currently applicable to tDCS and tRNS in terms of NIBS intervention and require the generation of additional experimental data for validation and in-depth analysis.

It is also important to note the large heterogeneity among the included cognitive-related studies (I² > 75%), and sensitivity analysis found four articles (21, 23, 24, 26) with a large effect on heterogeneity. In terms of patients' characteristics, the mean age of Charvet et al.'s study was the oldest and its mean disease duration was deemed as the longest. Furthermore, the study of Chalah et al. had a 6:4 male-to-female ratio, which is inconsistent with MS onset characteristics; in terms of interventions, the study of Chalah et al. and Hanken et al. were the only experiments that acted on the right parietal cortex (P4); In terms of study design, neither Charvet et al. nor Fiene et al. used a double-blind design, and randomization methods and allocation concealment were not reported; these all could be the reasons for heterogeneity.

The ANT, developed to measure the function of the attentional networks (alertness, orientation, and execution/conflict) is based on a complex computer system and includes a total of five cognitive-related outcome indicators, two of which are generalized (mean reaction time and mean accuracy) (44, 45). The ANT parameters include five sections, and a subgroup analysis showed that alertness function was significantly improved. This may because alerting network is linked to thalamic and frontoparietal areas of the left hemisphere (46) and 3 trails among a total of 4 stimulated the left DLPFC. In addition, one study showed that attentional deficits were a “cognitive feature” of MS fatigue (23), and Chalah et al. (26) showed that left DLPFC helped to improve patients' fatigue and therefore attentional performance. Similarly, the site P4 helps to reduce task-related reaction time and the effect was influenced by the level of fatigue (23). Notably, tDCS over the right DLPFC also helps increase attention (47).

NIBS can improve the motor function of pwMS. Moreover, because the primary study indicators included in this study focused on lower-extremity function, this finding is more applicable to lower-extremity motor function. Early symptoms of MS include weakness in one or more limbs, with lower limb motor dysfunction being more severe than upper limb motor dysfunction (4, 48).

There was an improvement in outcome indicators for spasticity (MAS/ PSFS), a common symptom of MS and an important motor disorder that causes walking difficulties and even disability in pwMS (49, 50). This subgroup contained three trails, and to our knowledge, the study of Iodice et al. (36) is the only study examining the effect of tDCS on spasticity in MS patients, did not find significant improvement, contrary to the results of the other two TMS studies. More studies on the application of tDCS are needed to further confirm this result. TMS as an intervention or stimulation site on M1 can improve motor function and these findings are consistent with previous study (51). The promising results reported for the M1 region may because this region has multiple connections between the brain and peripheral areas and its effectiveness in treating spasticity have been reported (51). Moreover, a guideline has suggested for MS there is probable efficacy of iTBS of the leg area of M1 contralateral to the most affected limb (or both M1) in lower limb spasticity (Level B) (52).

We observed an improvement in motor function in patients under 45 years and patients with an EDSS score < 3.5 after the NIBS intervention in the subgroup analysis. EDSS is the most widely used disability and impairment rating scale in MS (53). With a total score of 10, the higher EDSS score stands for the more severe disability condition and 3.5 is the condition of fully ambulatory but with moderate disability in one function system (54). The regression analysis of these two characteristics of patients found that the trend of the regression line was consisted with the subgroup analysis result, but the regression did not achieve statistical significance. What should be noted is this does not mean that NIBS only improves motor function in the group of patients younger than 45 years or with an EDSS <3.5. This result may suggest that motor improvement is more pronounced in younger and less severely affected patients and leads us to recommend early NIBS intervention in clinical pwMS patients to achieve better intervention outcomes. The cut-off points were set based on data from the included studies, and additional studies would help to further validate this speculation as well as find more precise cut-off points. Furthermore, MS primarily affects people between the ages of 20 and 40 years. According to the findings of this study, most pwMS can benefit from NIBS to alleviate their motor dysfunction.

Previous evidence-based medical analyses have examined the effects of NIBS on functional problems related to pain, overall cognition, and fatigue in pwMS. To the best of our knowledge, no studies have analyzed motor and specific cognitive domains (attention); thus, this study reports the first meta-analysis aimed at exploring the effects of NIBS on attentional vigilance and orientation functions in pwMS. Our study included the broad category of non-invasive brain stimulation, which may serve as a reference for the use of NIBS techniques other than pharmacotherapy. Given that the majority of the research material focused on generic NIBS procedures, such as tDCS and rTMS, this study included therapies beyond those procedures, which has a certain reference value for the various choices of NIBS. In addition, we included a trial of remote tDCS techniques in this study, to provide some guidance regarding their different applications.

This paper explored the effects of NIBS on the cognitive and motor functions of pwMS; however, some limitations of this study should be pointed out. First, the number of trials included was not sufficient to further investigate the application of the NIBS technology and due to this biggest limitation, this article does not explore combined use of NIBS, in combination with traditional cognitive training, NIBS can be used to enhance the forms of neuroplasticity that facilitate functional recovery (55). Munoz-Paredes et al. (56) found that by participating in an exercise program and receiving tDCS separately pwMS underwent a positive impact. Tramontano et al. (57) reported that combined cerebellar iTBS and VR improves gait and balance abilities more than standard VR treatment in pwMS. In light of these findings, we suggest future studies to explore combined use of NIBS, including but not limited to combining other training (concurrently or separately), the use of multiple sites, etc. Then, the findings of our study are limited in some aspect, since the application of TMS was not included, the results of the cognitive function analysis were only applicable to tES; no distinction was made between MS subtypes, and only show the short-term effect of NIBS, limiting the findings to some extent. Third, English literature alone was included in the meta-analysis, which could have resulted in a linguistic bias. Moreover, this study indicated that the attention of pwMS in other areas needs to be improved urgently. Other constraints included the source, depth, and quality of the existing evidence, all of which are common in meta-analysis.

In conclusion, the results of this present study provide evidence that non-invasive brain stimulation could improve alertness in pwMS, but it did not improve overall cognitive function in pwMS. Furthermore, NIBS may help pwMS with motor function and those who are under 45 years of age or with EDSS < 3.5 improve their motor function. According to our findings, for the therapeutic use of NIBS, the recommended intervention modality is TMS as an intervention and located on the M1 and we also suggest early intervention to obtain more improvement. Because of the limited sample size, the conclusion of this study still needs to be verified in additional studies. We hope that this study will encourage researchers to pay more attention to pwMS and conduct relevant studies on the application of the NIBS technology in MS, to improve the quality of life of this population.

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

XZ, JZ, and QZeng: study conception and design. YZ, LC, and GL: literature search, studies selection, and data collection. ShuL, QZhang, and SZ: analysis and interpretation of data, preparing figures, and editing the draft. ShiL, LH, and SC: study supervision and reviewing of the final manuscript. All authors contributed to the article and approved the submitted version.