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Background:
Systematic Review

Effect of Aerobic Exercise versus Non-Invasive Brain Stimulation on Cognitive Function in Multiple Sclerosis: A Systematic Review and Meta-Analysis

by
Mahmoud Elkhooly
1,
Arianna Di Stadio
2,3 and
Evanthia Bernitsas
4,*
1
Department of Neurology, Southern Illinois University School of Medicine, Springfield, IL 62702, USA
2
Department of GF Ingrassia, University of Catania, 95121 Catania, Italy
3
IRCSS Santa Lucia, 00179 Rome, Italy
4
Department of Neurology, Wayne State University, Detroit, MI 48201, USA
*
Author to whom correspondence should be addressed.
Brain Sci. 2024, 14(8), 771; https://doi.org/10.3390/brainsci14080771
Submission received: 29 June 2024 / Revised: 23 July 2024 / Accepted: 29 July 2024 / Published: 30 July 2024
(This article belongs to the Special Issue Cognitive Health in Individuals with Multiple Sclerosis)
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Abstract

:
Objective: In this study, we investigated the effects of noninvasive brain stimulation (NIBS) and exercise on cognition in patients with multiple sclerosis (pwMS). Methods: A literature search was performed using the Cochrane Library, Scopus, PubMed and Web of Science. The time interval used for database construction was up to February 2024; the collected trials were subsequently screened, and the data were extracted. Results: We identified 12 studies with 208 pwMS treated with noninvasive brain stimulation. Seven of the twelve studies concluded that NIBS was effective in improving reaction time, attention and processing speed. Additionally, 26 articles investigated the effect of various types of exercise on cognition among 708 pwMS. Twelve studies used aerobic exercise only, three studies used resistance only, one used yoga, and ten studies used mixed forms of exercise, such as Pilates, resistance and Frenkel coordination. Aerobic exercise was effective in improving at least one cognitive domain in ten studies. Resistance exercise was found to improve cognition in three studies. Yoga failed to show any improvement in one study. Conclusions: NIBS might be an effective intervention for cognition improvement among pwMS. Aerobic exercise and combined forms of exercise are the most frequently investigated and applied and found to be effective. Further studies are needed, especially for resistance, balance and stretching exercises.

1. Introduction

Multiple sclerosis (MS) is an autoimmune, chronic, demyelinating, inflammatory disease of the central nervous system that is characterized by demyelination and axonal degeneration [1]. MS is classified as primary progressive, secondary progressive or relapsing–remitting [2]. MS prevalence frequently demonstrates a trend of rapid global expansion, with the highest prevalence in North America and Europe [3,4]. It is typically characterized by a range of clinical presentations, including cognitive impairment (attention deficit and executive function), motor impairments, sensory abnormalities and visual impairments (e.g., optic nerve dysfunction) [5].
Cognitive impairment is common in MS and impacts 45–70% of patients of people with MS (pwMS) [6]. It may manifest early in the disease and deteriorate as the disease progresses, impairing work performance and worsening quality of life [7]. MS–cognitive impairment can be multifactorial, mainly related to cortical and subcortical pathology with a possible contribution from the white matter [8,9]. Currently, there is no FDA-approved treatment to stabilize cognitive decline and clinicians are using different, non-pharmacological ways to manage cognitive dysfunction in pwMS [10]. Disease-modifying therapies (DMTs) decrease the frequency of MS flare-ups and delay the disease’s natural progression. Therefore, DMT administration may have a positive effect on fatigue and cognition [11,12]. Nevertheless, a subset of pwMS may encounter adverse effects, prompting the exploration of supplementary and alternative therapies with the aim of achieving a harmonious equilibrium between the effectiveness and safety of the medication [13]. Moreover, the role of education and cognitive enrichment may serve as a cognitive reserve and prevent or stall cognitive decline [14]. MS symptoms, such as fatigue, depression and sleep deprivation, can negatively impact cognition and should be promptly addressed.
Recently, noninvasive brain stimulation (NIBS) has garnered considerable scholarly interest [15] as a supplementary therapeutic approach for neurological disorders. NIBS is generally recognized for its ability to noninvasively induce excitatory changes in the underlying cerebral cortex via the application of electromagnetic energy. Furthermore, it can potentially induce long-lasting neuroplasticity changes [16]. The most frequently used NIBS techniques in clinical settings are repetitive transcranial magnetic stimulation (rTMS) and transcranial direct current stimulation (tDCS) [17,18]. To date, researchers have experimentally explored the effects of the NIBS technology on the cognitive function of pwMS. However, because of the different designs, the experimental results remain controversial, to some extent. This necessitates a more rigorous investigation into the impacts of NIBS on MS.
There are few behavioral interventions to manage cognitive impairment with exercise training and cognitive rehabilitation. There is growing evidence regarding the impact of exercise on cognition among pwMS, with conflicting results. Ozkul et al. [19] discovered a link between improvements in mood, quality of life and cognition following exercise, as well as the positive benefits of combining aerobic and Pilates exercise on cognitively impaired pwMS. Furthermore, Sandroff et al. [20,21,22] demonstrated that exercise is a potentially useful treatment for MS-related cognitive impairment. However, Savšek et al. reported improved walking speed and brain-derived neurotrophic factor (BDNF) levels after aerobic exercise but did not demonstrate a positive effect on cognitive function [22]. According to Langeskov-Christensen et al., 24 weeks of supervised progressive aerobic exercise did not affect MS patients’ cognitive function [23]. Additionally, Kooshiar et al. [24] demonstrated the benefit of aquatic exercise on fatigue alleviation and quality of life in pwMS but not on cognitive performance.
As no consensus between experts has been reached and results on the role of NIBS and exercise are still non-conclusive, we performed a systematic review to present data from clinical randomized trials on the effects of current NIBS techniques and different forms of exercise on MS-related cognitive impairment.

2. Methods

In accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) recommendations, a comprehensive and systematic literature search was conducted by two reviewers (ME and EB) that was resolved through discussion among the reviewers until agreement was achieved. We included papers from January 2004 to February 2024. This systematic review adheres to the PRISMA guidelines (http://www.prisma-statment.org (accessed on 10 July 2024)) and has PRISMA registration number 567,064. The review’s characteristics did not necessitate approval from an Institutional Review Board. Four distinct electronic databases (PubMed, Scopus, Cochrane, and Web of Science) were searched [25], as shown in Figure 1. The protocols outlined by the NHS Centre for Reviews and Dissemination were strictly followed [26].
The subsequent word combinations were employed in our search: “cognition”, “exercise”, “noninvasive brain stimulation, “stabilization”, “balance”, “core”, “aerobic”, “Symbol digit modality test”, “stretching”, “resistance”, “Yoga”, “PASAT” and “memory impairment.” Furthermore, a comprehensive search was conducted on ClinicalTrials.gov, a database operated by the National Institutes of Health, to locate related registered and ongoing trials. The search was conducted through February 2024 and included studies published since 2004. Articles written in a language other than English were excluded. Additionally, we excluded any studies not related to the research question.
To maintain the standard of this evaluation, precise inclusion and exclusion criteria were implemented. Per the inclusion criteria, pwMS must have a confirmed diagnosis of MS according to the 2005, 2010 and 2017 McDonald criteria, being older than 18 years old, being exposed to NIBS, and engaged in exercise with an outcome evaluated using diverse cognitive assessment modalities [27,28,29]. The exclusion criteria included studies not pertaining to exercise or NIBS, studies with subjects younger than 18 years old, and those lacking a certain outcome. Once eligible studies were identified, the subsequent information was extracted from each article: authors’ names and title, year of the study, sample size and study design, type, frequency and duration of each intervention, main outcome and outcome metrics. The risk of bias in the included studies was analyzed using Robvis software for bias assessment [30]. The assessment categories consist of random sequence generation, allocation concealment, blinding of participants and personnel, blinding of outcome assessment, inadequate outcome data, selective reporting and other biases.

Data Extraction and Statistical Analyses

We extracted the following data—when available—to perform statistical analyses: improvement, method used to examine the cognitive function and numeric scores of cognitive tests before and after treatment. Nominal data were analyzed using Fisher (F) test whether numeric data were analyzed via one-way ANOVA. p-value was considered significant <0.05. PRISM 10 was used to perform statistical analyses.

3. Results

A total of thirty-eight studies with 1641 participants (310 i in NIBS group; 1331 in exercise group) were included. A total of 916 patients were analyzed as an intervention group (708 in the exercise and 208 in NIBS). We included 725 participants as a control in both the NIBS and exercise groups. In most studies, no data about the extent of the cognitive impairment in the control/intervention group were found. The control group in the NIBS received either sham tDCS or cognitive training (CT). The control participants in the exercise group received either no intervention, regular physical therapy, relaxation exercise or non-structured home-based exercise.
Various tools to screen for cognitive function were used; fifteen studies used Symbol–Digit Modalities Test (SDMT), twelve used the Paced Auditory Serial Attention Test (PASAT), five used California Verbal Learning (CVLT), five used the Brief Visual Memory Test (BVMT), five used Multiple Sclerosis Quality of Life-54 (MSQOL-54) and four used the Modified Fatigue Impact Scale (MFIS). Some studies used other tools such as Selective Reminding Test (SRT), Word List Generation (WLG), Stroop Color–Word Interference (SCWT), Brief International Cognitive Assessment in MS (BICAMS), Spatial Recall Test (SPART), Regensburg Verbal Fluency Test (RWT), Basic and complex attention (ANT), Test battery for Attention (TAP), Verbal Learning Memory Test (VLMT), Trail Making Test (TMT) and Reaction Time (RT).
Because of the lack of homogeneous methodology to evaluate mental cognition and the presence of numeric scores in four (33.3%) of twelve NIBS studies and eight (30.7%) of the twenty-six exercise studies that would negative impact on the analyses of data creating a bias, we only used improvement or non-improvement as parameter to use in the statical analyses.

3.1. Effect of NIBS on Cognition among pwMS

Twelve studies with 310 participants (208 in the intervention group and 102 in the control group) were included. Six crossover studies and six parallel (each participant remains in the assigned group until the end of the study) were performed. Overall, 83% of studies used transcranial direct current stimulation (tCDS), and 8.3% of studies used transcranial random noise stimulation (tRANS) and transcranial alternating current stimulation (tACS). The intensity of the NIBS ranged from 1 to 2 mA. Electrode placement is usually carried out according to the international 10-20 system for EEG electrodes [31]. The selection of the electrode location depends on the brain area involved in the cognitive function of interest, for example, the prefrontal cortex, which controls most higher cognitive functions [32]. Moreover, the function of interest might be lateralized; that is, one of the hemispheres mainly supports it. In this scenario, the actively stimulating electrode is positioned on the left (F3) or right (F4) prefrontal cortex. A central arrangement of the active electrode is possible if no lateralization is anticipated (Fz) [33]. The location of the secondary “reference” electrode is more critical for tDCS than for tACS or tRNS, as a direct current is more sensitive to current flow direction, which results in distinguishing excitatory and inhibitory (anodal and cathodal stimulation) effects, respectively [34,35]. In our review, a variable electrode location was found. Anodes were placed in F3 (nine studies) and C3 (two studies), and one study used P4. Cathodes were placed in different locations, including the right shoulder (three studies), supraorbital (two studies), and F4 (two studies), and one study used each of the other locations, such as the forehead: FP2, CZ and AF4.
In 58% of the studies (7/12), improvement was reported. After analysis of the cognitive domains, attention was improved in 25%, while executive function, speed and cognitive fatigue improved in 16.6% of studies.
In this cohort, SDMT was the most frequently used tool in five studies, followed by basic and complex attention (ANT) and reaction time (RT) (two studies each). Table 1 presents essential study information, including the type of intervention and outcome.

3.2. Effect of Exercise on Cognition among pwMS

Twenty-six studies with 1331 participants were included (708 as an intervention group and 623 as a control group). In most studies, no data were provided on the cognitive status of the participants in the control group. Twelve studies used aerobic exercise alone, one study used yoga, three used resistance exercise and ten used mixed types, such as Pilates and strength exercises. SDMTs were the most frequently used tool, even in combination with other tools (twelve studies), followed by the PASAT-3 test (ten studies), MSQOL-54 (four studies) and MFIS (four studies). Others (nine studies) used different scales, either alone or in combination with other tools for cognitive evaluation, such as CVLT, BVMT, SRT, WLG, SCWT, BICAMS, SPART, RWT, TUG, TAP, VLMT and TMT. Ten studies yielded cognitive memory data measured by at least one of the five different methods: BVMT-R (five studies), CVLT (five studies), SRT (three studies), SPART (three studies) and VLMT (one study). Data on the processing speed were obtained from 17 studies, which were assessed using SDMT, PASAT, IC-RT, DSST and TAP. Furthermore, data on executive function were reported in nine studies, which were evaluated using WLG (three studies), DKFFS (one study), TMT (one study), RWT (one study), MFT (one study), TUG (one study) and SCWT (one study).
Among the twelve studies that used aerobic exercise, eight of them (66%) showed an improvement in cognition when using a variety of tools (PASAT, SPART, SRT, DSST and SDMT), while resistance exercise was used in three studies, and all of them (100%) showed improvement when using MSQOL, MFSC and PASAT tests. Core stabilization was used in one study and was effective in improving cognition when using CVLT, BVMT-R and SDMT. Yoga was used in only one study and failed to show any improvement. Mixed exercises were used in 10 studies, and 90% of them showed an improvement in at least one cognitive domain.
Table 2 summarizes the effect of different types of exercise on cognition among pwMS.

3.3. Risk of Bias Assessment

Figure 2 outlines the evaluation of bias risk for every study included. Most studies had a low risk of bias; however, the allocation concealment and the blinding of participants and personnel were common challenges. Out of the thirty-eight studies, twenty-three showed a high risk of bias in allocation concealment, and nineteen studies showed a high risk of bias in participant and study staff blinding.

Comparison between NIBS and Exercise on Cognition

We did not identify any statistically significant difference between NIBS and exercise (F: p = 0.5) (Figure 3) when comparing the patients who recovered and those who did not recover.
In fact, looking at the likelihood of recovery using the treatment, 77.7% of the sample improved their cognitive skills using NIBS (Figure 4A), and 75.8% of patients who performed aerobic exercise independently from the exercise they did (Figure 4B).

4. Discussion

Overall, the results of our study showed that both NIBS and aerobic exercise can benefit cognition in MS patients. We included a total of 38 English-language papers that investigated 1641 pwMS. Out of the twelve studies that examined the effects of NIBS, seven studies that included 241 participants reported a NIBS-associated improvement in cognition versus five studies that included 69 participants that showed no benefit. Factors that predispose pwMS to respond in a positive way and improve have not been established. Age, disability and comorbidities might play a role in cognitive improvement after NIBS. Li et al. concluded that pwMS younger than 45 years old and those with EDSS scores below 3.5 benefit more from NIBS in terms of improved motor function than older, more disabled patients. In other words, NIBS might be more efficient in younger patients with less functional impairment [6]. Our results showed that NIBS might have positive effects mainly on attention, with limited effects on executive functions and processing speed.
There is an ongoing debate on the mechanism of NIBS related to cognitive improvement, with the most likely explanation being related to changes in neuroplasticity [71] or cortical excitability [72]. The mechanisms through which different types of NIBS can affect neurological function vary amongst cognitive neuroscience models. For example, transcranial electric stimulation (tES) can induce subthreshold polarization of neurons in the stimulated area, whereas transcranial magnetic stimulation (TMS) can induce suprathreshold depolarization of the neurons [73]. Most studies in our review applied tCDS as an intervention technique.
Ten out of the seventeen studies examining the effect of exercise on processing speed showed improvement. The exercise was mostly aerobic, performed two to three times a week for a duration from six to twenty-four weeks. Despite the relatively small number of studies where resistance training was applied, it was found to be entirely successful in improving cognition. Our results are in line with previous observations by Li’ et al. and support the overall positive impact of exercise on cognition among pwMS. [74]. On the contrary, Gharakhanlou et al. reported [75] that exercise training had no appreciable impact on global memory or any of the cognitive subdomains. Executive functions have been examined in nine studies, with four of them (44%) showing improvements using a variety of tools (WLG, TUG and TMT). It seems that using a combination of different exercise types has the best outcome rather than using a single intervention.
Different mechanisms have been proposed to explain the effect of exercise on cognition, such as stimulation of the cellular and molecular processes of angiogenesis, neurogenesis and synaptogenesis [76]. It was reported that exercise can increase the levels of BDNF, which might offer neuroprotection. Moreover, a previous study showed that individuals with diminished BDNF expression in the hippocampus and temporal cortex are more susceptible to neurodegenerative disorders. Additionally, BDNF levels can rise two to three times following acute exercise in comparison to controls, and this increase is positively correlated with enhanced cognitive function [77,78].
Our findings support a moderate effect of aerobic exercise and a more favorable effect of resistance training on cognition. Although most MS experts do not incorporate exercise into their MS treatment regimens, it is now accepted that pwMS may benefit from regular exercise as a means of improving their cognitive function and wellbeing [19,22,60,70,79]. Despite the lack of many details supporting such interventions in MS, it is acknowledged that there is an inverse relationship between the intensity of exercise and the degree of cognitive decline [80].
On a longitudinal basis, exercise is an effective way to prevent and improve cognitive deterioration because, as demonstrated by De la Rosa et al. [81], it can positively impact cognitive function over an extended period of time by improving peripheral redox regulation, delaying physiological memory loss and increasing associated neurotrophy.
Interestingly, both NIBS and exercise showed equally positive results, with no significant difference between them being found. Subsequently, our data do not support the use of one over the other in terms of improving cognitive outcomes. Exercise promotes the anti-inflammatory state in pwMS, and different NIBS techniques may decrease neuroinflammation in MS and stroke. Given that neuroinflammation could contribute to cognitive dysfunction in pwMS [82,83], the results are not surprising [84], and both modalities can be used based on individual characteristics and preferences to prevent cognitive worsening in pwMS.

5. Limitations

It is necessary to acknowledge the limitations of this study. First, the exercise interventions were not blinded, which could introduce bias, as our trials were RCTs. Second, various studies have utilized different kinds of cognitive assessment tools, which can occasionally provide inconsistent improvements. Third, we were unable to comprehend the effects of varying exercise intensities on cognitive performance in pwMS since many of the included studies did not describe the intensity of the exercise intervention. Fourth, RRMS was the most prevalent type in our review, while progressive forms of MS were not studied that extensively. Further, several studies only reported the improvement without specifying the magnitude of it; for this reason, we were obliged to consider only nominal data and not numeric values. Obviously, this limitation reduced the power of our statistical analyses. Fifth, we could not evaluate the effect of different disease-modifying therapies on cognitive outcomes. Furthermore, most studies did not include the actual cognitive status of the control group, thus interfering with comparison and data accuracy. Finally, it is important to consider that the study on physical activity has a series of cofounders that might impact our results, i.e., variable exercise protocols; therefore, this is something to keep in mind when we interpret our findings.

6. Conclusions

NIBS might have a positive impact on attention, with no effect on executive functions. NIBS and aerobic exercise could represent a potential intervention for cognitively impaired pwMS.
Aerobic exercise was found to be associated with improved processing speed, mainly with frequency 2–3 times/week and with at least a 6-week duration. A longer study duration is needed for more consistent results. Eliminating the variability of study tools in the assessment of different cognitive domains will make analysis more feasible. Combined forms of exercise were found to be more effective in improving cognition among pwMS. Overall, exercise has a positive impact on processing speed and executive functions.

Author Contributions

Conceptualization, M.E., A.D.S. and E.B.; Writing—original draft, M.E. and E.B.; Writing—review and editing, M.E., A.D.S. and E.B.; Supervision E.B. All authors have read and agreed to the published version of the manuscript.

Funding

This research received no external funding.

Conflicts of Interest

The authors declare no conflicts of interest.

References

  1. Ghasemi, N.; Razavi, S.; Nikzad, E. Multiple Sclerosis: Pathogenesis, Symptoms, Diagnoses and Cell-Based Therapy. Cell J. 2017, 19, 1–10. [Google Scholar] [CrossRef] [PubMed]
  2. Planche, V.; Gibelin, M.; Cregut, D.; Pereira, B.; Clavelou, P. Cognitive impairment in a population-based study of patients with multiple sclerosis: Differences between late relapsing−remitting, secondary progressive and primary progressive multiple sclerosis. Eur. J. Neurol. 2015, 23, 282–289. [Google Scholar] [CrossRef] [PubMed]
  3. Koch-Henriksen, N.; Magyari, M. Apparent changes in the epidemiology and severity of multiple sclerosis. Nat. Rev. Neurol. 2021, 17, 676–688. [Google Scholar] [CrossRef]
  4. Oh, J.; Vidal-Jordana, A.; Montalban, X. Multiple sclerosis: Clinical aspects. Curr. Opin. Neurol. 2018, 31, 752–759. [Google Scholar] [CrossRef] [PubMed]
  5. Maggio, M.G.; Russo, M.; Cuzzola, M.F.; Destro, M.; La Rosa, G.; Molonia, F.; Bramanti, P.; Lombardo, G.; De Luca, R.; Calabrò, R.S. Virtual reality in multiple sclerosis rehabilitation: A review on cognitive and motor outcomes. J. Clin. Neurosci. 2019, 65, 106–111. [Google Scholar] [CrossRef] [PubMed]
  6. Li, S.; Zhang, Q.; Zheng, S.; Li, G.; Li, S.; He, L.; Zeng, Y.; Chen, L.; Chen, S.; Zheng, X.; et al. Efficacy of non-invasive brain stimulation on cognitive and motor functions in multiple sclerosis: A systematic review and meta-analysis. Front. Neurol. 2023, 14, 1091252. [Google Scholar] [CrossRef]
  7. Lin, X.; Zhang, X.; Liu, Q.; Zhao, P.; Zhong, J.; Pan, P.; Wang, G.; Yi, Z. Social cognition in multiple sclerosis and its subtypes: A meta-analysis. Mult. Scler. Relat. Disord. 2021, 52, 102973. [Google Scholar] [CrossRef] [PubMed]
  8. Elkhooly, M.; Bao, F.; Raghib, M.; Millis, S.; Bernitsas, E. Role of white matter in cognitive impairment among relapsing remitting multiple sclerosis patients. Mult. Scler. Relat. Disord. 2023, 79, 105030. [Google Scholar] [CrossRef] [PubMed]
  9. Bross, M.; Hackett, M.; Bernitsas, M.M.; Bao, F.; Carla Santiago, M.; Bernitsas, E. Cortical surface thickness, subcortical volumes and disability between races in relapsing-remitting multiple sclerosis. Mult. Scler. Relat. Disord. 2021, 53, 103025. [Google Scholar] [CrossRef] [PubMed]
  10. Amato, M.P.; Langdon, D.; Montalban, X.; Benedict, R.H.B.; DeLuca, J.; Krupp, L.B.; Thompson, A.J.; Comi, G. Treatment of cognitive impairment in multiple sclerosis: Position paper. J. Neurol. 2012, 260, 1452–1468. [Google Scholar] [CrossRef] [PubMed]
  11. Elkhooly, M.; Bao, F.; Bernitsas, E. Impact of Disease Modifying Therapy on MS-Related Fatigue: A Narrative Review. Brain Sci. 2023, 14, 4. [Google Scholar] [CrossRef] [PubMed]
  12. Bross, M.; Hackett, M.; Bernitsas, E. Approved and emerging disease modifying therapies on neurodegeneration in multiple sclerosis. Int. J. Mol. Sci. 2020, 21, 4312. [Google Scholar] [CrossRef] [PubMed]
  13. Leocani, L.; Chieffo, R.; Gentile, A.; Centonze, D. Beyond rehabilitation in MS: Insights from non-invasive brain stimulation. Mult. Scler. 2019, 25, 1363–1371. [Google Scholar] [CrossRef] [PubMed]
  14. Grant, J.G.; Rapport, L.J.; Darling, R.; Waldron-Perrine, B.; Lumley, M.A.; Whitfield, K.E.; Bernitsas, E. Cognitive enrichment and education quality moderate cognitive dysfunction in black and white adults with multiple sclerosis. Mult. Scler. Relat. Disord. 2023, 78, 104916. [Google Scholar] [CrossRef] [PubMed]
  15. Begemann, M.J.; Brand, B.A.; Ćurčić-Blake, B.; Aleman, A.; Sommer, I.E. Efficacy of non-invasive brain stimulation on cognitive functioning in brain disorders: A meta-analysis. Psychol. Med. 2020, 50, 2465–2486. [Google Scholar] [CrossRef] [PubMed]
  16. Liao, Y.-C.; Guo, N.-W.; Su, B.-Y.; Chen, S.-J.; Tsai, H.-F.; Lee, K.-Y. Frontal Beta Activity in the Meta-Intention of Children With Attention Deficit Hyperactivity Disorder. Clin. EEG Neurosci. 2020, 52, 136–143. [Google Scholar] [CrossRef] [PubMed]
  17. Boes, A.D.; Kelly, M.S.; Trapp, N.T.; Stern, A.P.; Press, D.Z.; Pascual-Leone, A. Noninvasive Brain Stimulation: Challenges and Opportunities for a New Clinical Specialty. J. Neuropsychiatry Clin. Neurosci. 2018, 30, 173–179. [Google Scholar] [CrossRef] [PubMed]
  18. Di Lazzaro, V.; Rothwell, J.; Capogna, M. Noninvasive Stimulation of the Human Brain: Activation of Multiple Cortical Circuits. Neuroscientist 2017, 24, 246–260. [Google Scholar] [CrossRef] [PubMed]
  19. Ozkul, C.; Guclu-Gunduz, A.; Eldemir, K.; Apaydin, Y.; Yazici, G.; Irkec, C. Combined exercise training improves cognitive functions in multiple sclerosis patients with cognitive impairment: A single-blinded randomized controlled trial. Mult. Scler. Relat. Disord. 2020, 45, 102419. [Google Scholar] [CrossRef] [PubMed]
  20. Sandroff, B.M.; Wylie, G.R.; Sutton, B.P.; Johnson, C.L.; DeLuca, J.; Motl, R.W. Treadmill walking exercise training and brain function in multiple sclerosis: Preliminary evidence setting the stage for a network-based approach to rehabilitation. Mult. Scler. J. Exp. Transl. Clin. 2018, 4, 2055217318760641. [Google Scholar] [CrossRef] [PubMed]
  21. Sandroff, B.M.; Johnson, C.L.; Motl, R.W. Exercise training effects on memory and hippocampal viscoelasticity in multiple sclerosis: A novel application of magnetic resonance elastography. Neuroradiology 2016, 59, 61–67. [Google Scholar] [CrossRef] [PubMed]
  22. Sandroff, B.M.; Klaren, R.E.; Pilutti, L.A.; Dlugonski, D.; Benedict, R.H.B.; Motl, R.W. Randomized controlled trial of physical activity, cognition, and walking in multiple sclerosis. J. Neurol. 2013, 261, 363–372. [Google Scholar] [CrossRef] [PubMed]
  23. Langeskov-Christensen, M.; Grondahl Hvid, L.; Boye Jensen, H.; Hvilsted Nielsen, H.; Petersen, T.; Stenager, E.; Hamalainen, P.; Dalgas, U. High-intensity aerobic exercise does not improve cognitive performance in people with multiple sclerosis: A randomised controlled trial. Mult. Scler. J. 2019, 25, 900–901. [Google Scholar] [CrossRef]
  24. Kooshiar, H.; Moshtagh, M.; Sardar, M.A.; Foroughipour, M.; Shakeri, M.T.; Vahdatinia, B. Fatigue and quality of life of women with multiple sclerosis: A randomized controlled clinical trial. J. Sports Med. Phys. Fit. 2015, 55, 668–674. [Google Scholar]
  25. Moher, D.; Shamseer, L.; Clarke, M.; Ghersi, D.; Liberati, A.; Petticrew, M.; Shekelle, P.; Stewart, L.A.; Group, P.-P. Preferred reporting items for systematic review and meta-analysis protocols (PRISMA-P) 2015 statement. Syst. Rev. 2015, 4, 1. [Google Scholar] [CrossRef] [PubMed]
  26. Centre for Reviews and Dissemination (CRD). Encyclopedia of Public Health; Springer: Dordrecht, The Netherlands, 2008; p. 105. [Google Scholar] [CrossRef]
  27. Polman, C.H.; Reingold, S.C.; Banwell, B.; Clanet, M.; Cohen, J.A.; Filippi, M.; Fujihara, K.; Havrdova, E.; Hutchinson, M.; Kappos, L.; et al. Diagnostic criteria for multiple sclerosis: 2010 revisions to the McDonald criteria. Ann. Neurol. 2011, 69, 292–302. [Google Scholar] [CrossRef] [PubMed]
  28. Polman, C.H.; Reingold, S.C.; Edan, G.; Filippi, M.; Hartung, H.P.; Kappos, L.; Lublin, F.D.; Metz, L.M.; McFarland, H.F.; O’Connor, P.W.; et al. Diagnostic criteria for multiple sclerosis: 2005 revisions to the “McDonald Criteria”. Ann. Neurol. 2005, 58, 840–846. [Google Scholar] [CrossRef] [PubMed]
  29. Thompson, A.J.; Banwell, B.L.; Barkhof, F.; Carroll, W.M.; Coetzee, T.; Comi, G.; Correale, J.; Fazekas, F.; Filippi, M.; Freedman, M.S.; et al. Diagnosis of multiple sclerosis: 2017 revisions of the McDonald criteria. Lancet Neurol. 2018, 17, 162–173. [Google Scholar] [CrossRef]
  30. McGuinness, L.A.; Higgins, J.P.T. Risk-of-bias VISualization (robvis): An R package and Shiny web app for visualizing risk-of-bias assessments. Res. Synth. Methods 2020, 12, 55–61. [Google Scholar] [CrossRef] [PubMed]
  31. Cobb, W.; London, G.B.; Gastaut, H.; Hess, R., Jr.; Jung, R.; Magnus, O.; Terzian, H. Report of the committee on methods of clinical examination in electroencephalography. Electroencephalogr. Clin. Neurophysiol. 1958, 10, 370–375. [Google Scholar]
  32. Hartwigsen, G.; Silvanto, J. Noninvasive brain stimulation: Multiple effects on cognition. Neuroscientist 2023, 29, 639–653. [Google Scholar] [CrossRef] [PubMed]
  33. Mehta, A.R.; Pogosyan, A.; Brown, P.; Brittain, J.-S. Montage matters: The influence of transcranial alternating current stimulation on human physiological tremor. Brain Stimul. 2015, 8, 260–268. [Google Scholar] [CrossRef] [PubMed]
  34. Woods, A.J.; Antal, A.; Bikson, M.; Boggio, P.S.; Brunoni, A.R.; Celnik, P.; Cohen, L.G.; Fregni, F.; Herrmann, C.S.; Kappenman, E.S. A technical guide to tDCS, and related non-invasive brain stimulation tools. Clin. Neurophysiol. 2016, 127, 1031–1048. [Google Scholar] [CrossRef] [PubMed]
  35. Veniero, D.; Strüber, D.; Thut, G.; Herrmann, C.S. Noninvasive brain stimulation techniques can modulate cognitive processing. Organ. Res. Methods 2019, 22, 116–147. [Google Scholar] [CrossRef]
  36. Hsu, W.Y.; Zanto, T.; Park, J.E.; Gazzaley, A.; Bove, R.M. Effects of transcranial alternating current stimulation on cognitive function in people with multiple sclerosis: A randomized controlled trial. Mult. Scler. Relat. Disord. 2023, 80, 105090. [Google Scholar] [CrossRef] [PubMed]
  37. Simani, L.; Roozbeh, M.; Shojaei, M.; Ramezani, M.; Roozbeh, M.; Gharehgozli, K.; Rostami, M. The effectiveness of anodal tDCS and cognitive training on cognitive functions in multiple sclerosis; a randomized, double-blind, parallel-group study. Mult. Scler. Relat. Disord. 2022, 68, 104392. [Google Scholar] [CrossRef] [PubMed]
  38. Gholami, M.; Nami, M.; Shamsi, F.; Jaberi, K.R.; Kateb, B.; Rahimi Jaberi, A. Effects of transcranial direct current stimulation on cognitive dysfunction in multiple sclerosis. Neurophysiol. Clin. 2021, 51, 319–328. [Google Scholar] [CrossRef] [PubMed]
  39. Seelmann-Eggebert, H.; Stoppe, M.; Then Bergh, F.; Classen, J.; Rumpf, J.-J. Motor Sequence Learning across Multiple Sessions Is Not Facilitated by Targeting Consolidation with Posttraining tDCS in Patients with Progressive Multiple Sclerosis. Neural Plast. 2021, 2021, 6696341. [Google Scholar] [CrossRef] [PubMed]
  40. Grigorescu, C.; Chalah, M.A.; Lefaucheur, J.-P.; Kümpfel, T.; Padberg, F.; Ayache, S.S.; Palm, U. Effects of transcranial direct current stimulation on information processing speed, working memory, attention, and social cognition in multiple sclerosis. Front. Neurol. 2020, 11, 545377. [Google Scholar] [CrossRef] [PubMed]
  41. Fiene, M.; Rufener, K.S.; Kuehne, M.; Matzke, M.; Heinze, H.J.; Zaehle, T. Electrophysiological and behavioral effects of frontal transcranial direct current stimulation on cognitive fatigue in multiple sclerosis. J. Neurol. 2018, 265, 607–617. [Google Scholar] [CrossRef]
  42. Charvet, L.; Shaw, M.; Dobbs, B.; Frontario, A.; Sherman, K.; Bikson, M.; Datta, A.; Krupp, L.; Zeinapour, E.; Kasschau, M. Remotely supervised transcranial direct current stimulation increases the benefit of at-home cognitive training in multiple sclerosis. Neuromodulation Technol. Neural Interface 2018, 21, 383–389. [Google Scholar] [CrossRef] [PubMed]
  43. Ayache, S.S.; Palm, U.; Chalah, M.A.; Al-Ani, T.; Brignol, A.; Abdellaoui, M.; Dimitri, D.; Sorel, M.; Créange, A.; Lefaucheur, J.-P. Prefrontal tDCS decreases pain in patients with multiple sclerosis. Front. Neurosci. 2016, 10, 147. [Google Scholar] [CrossRef] [PubMed]
  44. Chalah, M.A.; Riachi, N.; Ahdab, R.; Mhalla, A.; Abdellaoui, M.; Créange, A.; Lefaucheur, J.-P.; Ayache, S.S. Effects of left DLPFC versus right PPC tDCS on multiple sclerosis fatigue. J. Neurol. Sci. 2017, 372, 131–137. [Google Scholar] [CrossRef] [PubMed]
  45. Hanken, K.; Bosse, M.; Möhrke, K.; Eling, P.; Kastrup, A.; Antal, A.; Hildebrandt, H. Counteracting Fatigue in Multiple Sclerosis with Right Parietal Anodal Transcranial Direct Current Stimulation. Front. Neurol. 2016, 7, 154. [Google Scholar] [CrossRef] [PubMed]
  46. Palm, U.; Chalah, M.A.; Padberg, F.; Al-Ani, T.; Abdellaoui, M.; Sorel, M.; Dimitri, D.; Créange, A.; Lefaucheur, J.-P.; Ayache, S.S. Effects of transcranial random noise stimulation (tRNS) on affect, pain and attention in multiple sclerosis. Restor. Neurol. Neurosci. 2016, 34, 189–199. [Google Scholar] [CrossRef] [PubMed]
  47. Mattioli, F.; Bellomi, F.; Stampatori, C.; Capra, R.; Miniussi, C. Neuroenhancement through cognitive training and anodal tDCS in multiple sclerosis. Mult. Scler. 2016, 22, 222–230. [Google Scholar] [CrossRef] [PubMed]
  48. Tasci, I.; Demir, C.F.; Bilek, F.; Albayrak, S. Physical exercise may improve problem-solving skills and emotional intelligence in patients with relapsing-remitting multiple sclerosis: A cross-sectional study. Mult. Scler. Relat. Disord. 2022, 59, 103641. [Google Scholar] [CrossRef]
  49. Açık, M.; Şenışık, S.; Taşkıran, D.; Akşit, T.; Aydınoğlu, R.; Yüceyar, A.N. Exercise Improves Physical Capacity, Cognition, Quality of Life and Promotes Neurotrophic Factors in Patients with Multiple Sclerosis. Noro Psikiyatr. Ars. 2023, 60, 335–343. [Google Scholar] [CrossRef] [PubMed]
  50. Galperin, I.; Mirelman, A.; Schmitz-Hubsch, T.; Hsieh, K.L.; Regev, K.; Karni, A.; Brozgol, M.; Cornejo Thumm, P.; Lynch, S.G.; Paul, F.; et al. Treadmill training with virtual reality to enhance gait and cognitive function among people with multiple sclerosis: A randomized controlled trial. J. Neurol. 2023, 270, 1388–1401. [Google Scholar] [CrossRef] [PubMed]
  51. Andreu-Caravaca, L.; Ramos-Campo, D.J.; Chung, L.H.; Manonelles, P.; Abellán-Aynés, O.; Rubio-Arias, J. Effects of fast-velocity concentric resistance training in people with multiple sclerosis: A randomized controlled trial. Acta Neurol. Scand. 2022, 146, 652–661. [Google Scholar] [CrossRef] [PubMed]
  52. Bilek, F.; Cetisli-Korkmaz, N.; Ercan, Z.; Deniz, G.; Demir, C.F. Aerobic exercise increases irisin serum levels and improves depression and fatigue in patients with relapsing remitting multiple sclerosis: A randomized controlled trial. Mult. Scler. Relat. Disord. 2022, 61, 103742. [Google Scholar] [CrossRef] [PubMed]
  53. Jeong, I.c.; Karpatkin, H.; Finkelstein, J. Physical Telerehabilitation Improves Quality of Life in Patients with Multiple Sclerosis. In Studies in Health Technology and Informatics; IOS Press: Amsterdam, The Netherlands, 2021. [Google Scholar] [CrossRef]
  54. Langeskov-Christensen, M.; Hvid, L.G.; Jensen, H.B.; Nielsen, H.H.; Petersen, T.; Stenager, E.; Hämäläinen, P.; Dalgas, U. Efficacy of high-intensity aerobic exercise on cognitive performance in people with multiple sclerosis: A randomized controlled trial. Mult. Scler. J. 2020, 27, 1585–1596. [Google Scholar] [CrossRef] [PubMed]
  55. Savšek, L.; Stergar, T.; Strojnik, V.; Ihan, A.; Koren, A.; Špiclin, Ž.; Šega Jazbec, S. Impact of aerobic exercise on clinical and magnetic resonance imaging biomarkers in persons with multiple sclerosis: An exploratory randomized controlled trial. J. Rehabil. Med. 2021, 53, jrm00178. [Google Scholar] [CrossRef] [PubMed]
  56. Backus, D.; Moldavskiy, M.; Sweatman, W.M. Effects of functional electrical stimulation cycling on fatigue and quality of life in people with multiple sclerosis who are nonambulatory. Int. J. MS Care 2020, 22, 193–200. [Google Scholar] [CrossRef] [PubMed]
  57. Ozdogar, A.T.; Ertekin, O.; Kahraman, T.; Yigit, P.; Ozakbas, S. Effect of video-based exergaming on arm and cognitive function in persons with multiple sclerosis: A randomized controlled trial. Mult. Scler. Relat. Disord. 2020, 40, 101966. [Google Scholar] [CrossRef] [PubMed]
  58. Feys, P.; Moumdjian, L.; Van Halewyck, F.; Wens, I.; Eijnde, B.O.; Van Wijmeersch, B.; Popescu, V.; Van Asch, P. Effects of an individual 12-week community-located “start-to-run” program on physical capacity, walking, fatigue, cognitive function, brain volumes, and structures in persons with multiple sclerosis. Mult. Scler. J. 2019, 25, 92–103. [Google Scholar] [CrossRef] [PubMed]
  59. Baquet, L.; Hasselmann, H.; Patra, S.; Stellmann, J.-P.; Vettorazzi, E.; Engel, A.K.; Rosenkranz, S.C.; Poettgen, J.; Gold, S.M.; Schulz, K.-H.; et al. Short-term interval aerobic exercise training does not improve memory functioning in relapsing-remitting multiple sclerosis-a randomized controlled trial. PeerJ 2018, 6, e6037. [Google Scholar] [CrossRef] [PubMed]
  60. Sebastião, E.; McAuley, E.; Shigematsu, R.; Adamson, B.C.; Bollaert, R.E.; Motl, R.W. Home-based, square-stepping exercise program among older adults with multiple sclerosis: Results of a feasibility randomized controlled study. Contemp. Clin. Trials 2018, 73, 136–144. [Google Scholar] [CrossRef] [PubMed]
  61. Kara, B.; Küçük, F.; Poyraz, E.C.; Tomruk, M.S.; İdıman, E. Different types of exercise in Multiple Sclerosis: Aerobic exercise or Pilates, a single-blind clinical study. J. Back. Musculoskelet. Rehabil. 2017, 30, 565–573. [Google Scholar] [CrossRef] [PubMed]
  62. Kjølhede, T.; Siemonsen, S.; Wenzel, D.; Stellmann, J.-P.; Ringgaard, S.; Pedersen, B.G.; Stenager, E.; Petersen, T.; Vissing, K.; Heesen, C. Can resistance training impact MRI outcomes in relapsing-remitting multiple sclerosis? Mult. Scler. J. 2018, 24, 1356–1365. [Google Scholar] [CrossRef] [PubMed]
  63. Sandroff, B.M.; Bollaert, R.E.; Pilutti, L.A.; Peterson, M.L.; Baynard, T.; Fernhall, B.; McAuley, E.; Motl, R.W. Multimodal exercise training in multiple sclerosis: A randomized controlled trial in persons with substantial mobility disability. Contemp. Clin. Trials 2017, 61, 39–47. [Google Scholar] [CrossRef] [PubMed]
  64. Carter, A.; Daley, A.; Humphreys, L.; Snowdon, N.; Woodroofe, N.; Petty, J.; Roalfe, A.; Tosh, J.; Sharrack, B.; Saxton, J. Pragmatic intervention for increasing self-directed exercise behaviour and improving important health outcomes in people with multiple sclerosis: A randomised controlled trial. Mult. Scler. J. 2014, 20, 1112–1122. [Google Scholar] [CrossRef] [PubMed]
  65. Hoang, P.; Schoene, D.; Gandevia, S.; Smith, S.; Lord, S.R. Effects of a home-based step training programme on balance, stepping, cognition and functional performance in people with multiple sclerosis–a randomized controlled trial. Mult. Scler. J. 2016, 22, 94–103. [Google Scholar] [CrossRef] [PubMed]
  66. Oken, B.S.; Kishiyama, S.; Zajdel, D.; Bourdette, D.; Carlsen, J.; Haas, M.; Hugos, C.; Kraemer, D.F.; Lawrence, J.; Mass, M. Randomized controlled trial of yoga and exercise in multiple sclerosis. Neurology 2004, 62, 2058–2064. [Google Scholar] [CrossRef] [PubMed]
  67. Sandroff, B.M.; Dlugonski, D.; Pilutti, L.A.; Pula, J.H.; Benedict, R.H.B.; Motl, R.W. Physical activity is associated with cognitive processing speed in persons with multiple sclerosis. Mult. Scler. Relat. Disord. 2014, 3, 123–128. [Google Scholar] [CrossRef] [PubMed]
  68. Leavitt, V.; Cohen, A.; Farag, A.; Cirnigliaro, C.; Chiaravalloti, N.; Sumowski, J.; DeLuca, J. Aerobic exercise increases hippocampal volume and improves memory in persons with multiple sclerosis: Pilot findings from a randomized controlled trial. Neurology 2013, 80, 695–697. [Google Scholar] [CrossRef]
  69. Briken, S.; Gold, S.M.; Patra, S.; Vettorazzi, E.; Harbs, D.; Tallner, A.; Ketels, G.; Schulz, K.H.; Heesen, C. Effects of exercise on fitness and cognition in progressive MS: A randomized, controlled pilot trial. Mult. Scler. 2014, 20, 382–390. [Google Scholar] [CrossRef] [PubMed]
  70. Romberg, A.; Virtanen, A.; Ruutiainen, J. Long–term exercise improves functional impairment but not quality of life in multiple sclerosis. J. Neurol. 2005, 252, 839–845. [Google Scholar] [CrossRef] [PubMed]
  71. Baione, V.; Belvisi, D.; Cortese, A.; Cetta, I.; Tartaglia, M.; Millefiorini, E.; Berardelli, A.; Conte, A. Cortical M1 plasticity and metaplasticity in patients with multiple sclerosis. Mult. Scler. Relat. Disord. 2020, 38, 101494. [Google Scholar] [CrossRef]
  72. Rocca, M.A.; Filippi, M. Modulation of cortical excitability to normalise brain function and improve cognition in multiple sclerosis. J. Neurol. Neurosurg. Amp Psychiatry 2016, 88, 373. [Google Scholar] [CrossRef] [PubMed]
  73. Miniussi, C.; Harris, J.A.; Ruzzoli, M. Modelling non-invasive brain stimulation in cognitive neuroscience. Neurosci. Amp Biobehav. Rev. 2013, 37, 1702–1712. [Google Scholar] [CrossRef] [PubMed]
  74. Li, G.; You, Q.; Hou, X.; Zhang, S.; Du, L.; Lv, Y.; Yu, L. The effect of exercise on cognitive function in people with multiple sclerosis: A systematic review and meta-analysis of randomized controlled trials. J. Neurol. 2023, 270, 2908–2923. [Google Scholar] [CrossRef] [PubMed]
  75. Gharakhanlou, R.; Wesselmann, L.; Rademacher, A.; Lampit, A.; Negaresh, R.; Kaviani, M.; Oberste, M.; Motl, R.W.; Sandroff, B.M.; Bansi, J. Exercise training and cognitive performance in persons with multiple sclerosis: A systematic review and multilevel meta-analysis of clinical trials. Mult. Scler. J. 2021, 27, 1977–1993. [Google Scholar] [CrossRef] [PubMed]
  76. Van Praag, H.; Christie, B.R.; Sejnowski, T.J.; Gage, F.H. Running enhances neurogenesis, learning, and long-term potentiation in mice. Proc. Natl. Acad. Sci. USA 1999, 96, 13427–13431. [Google Scholar] [CrossRef] [PubMed]
  77. Rasmussen, P.; Brassard, P.; Adser, H.; Pedersen, M.V.; Leick, L.; Hart, E.; Secher, N.H.; Pedersen, B.K.; Pilegaard, H. Evidence for a release of brain-derived neurotrophic factor from the brain during exercise. Exp. Physiol. 2009, 94, 1062–1069. [Google Scholar] [PubMed]
  78. Kong, L.; Miu, L.; Yao, W.; Shi, Z. Effect of regular aerobic exercise on cognitive function, depression level and regulative role of neurotrophic factor: A prospective cohort study in the young and the middle-aged sample. Risk Manag. Healthc. Policy 2024, 17, 935–943. [Google Scholar] [CrossRef] [PubMed]
  79. Proschinger, S.; Joisten, N.; Rademacher, A.; Schlagheck, M.L.; Walzik, D.; Metcalfe, A.J.; Oberste, M.; Warnke, C.; Bloch, W.; Schenk, A.; et al. Influence of combined functional resistance and endurance exercise over 12 weeks on matrix metalloproteinase-2 serum concentration in persons with relapsing-remitting multiple sclerosis—A community-based randomized controlled trial. BMC Neurol. 2019, 19, 314. [Google Scholar] [CrossRef]
  80. Laurin, D.; Verreault, R.; Lindsay, J.; MacPherson, K.; Rockwood, K. Physical activity and risk of cognitive impairment and dementia in elderly persons. Arch. Neurol. 2001, 58, 498–504. [Google Scholar] [CrossRef] [PubMed]
  81. De la Rosa, A.; Solana, E.; Corpas, R.; Bartrés-Faz, D.; Pallàs, M.; Vina, J.; Sanfeliu, C.; Gomez-Cabrera, M.C. Long-term exercise training improves memory in middle-aged men and modulates peripheral levels of BDNF and Cathepsin B. Sci. Rep. 2019, 9, 3337. [Google Scholar] [CrossRef] [PubMed]
  82. Faramarzi, M.; Banitalebi, E.; Raisi, Z.; Samieyan, M.; Saberi, Z.; Ghahfarrokhi, M.M.; Negaresh, R.; Motl, R.W. Effect of combined exercise training on pentraxins and pro-inflammatory cytokines in people with multiple sclerosis as a function of disability status. Cytokine 2020, 134, 155196. [Google Scholar] [CrossRef] [PubMed]
  83. Stampanoni Bassi, M.; Gilio, L.; Buttari, F.; Maffei, P.; Marfia, G.A.; Restivo, D.A.; Centonze, D.; Iezzi, E. Remodeling functional connectivity in multiple sclerosis: A challenging therapeutic approach. Front. Neurosci. 2017, 11, 710. [Google Scholar] [CrossRef] [PubMed]
  84. Shao, Y.; Chen, C.; Zhu, T.; Sun, Z.; Li, S.; Gong, L.; Dong, X.; Shen, W.; Zeng, L.; Xie, Y. TRPM2 contributes to neuroinflammation and cognitive deficits in a cuprizone-induced multiple sclerosis model via NLRP3 inflammasome. Neurobiol. Dis. 2021, 160, 105534. [Google Scholar] [CrossRef] [PubMed]
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Figure 1. Flow diagram of identification process for eligible studies per PRISMA guidelines. *All the identified records from different databases. ** All the excluded records including topics unrelated to cognition, MS, Exercise, non-invasive brain stimulation and others (as not written in English).
Figure 1. Flow diagram of identification process for eligible studies per PRISMA guidelines. *All the identified records from different databases. ** All the excluded records including topics unrelated to cognition, MS, Exercise, non-invasive brain stimulation and others (as not written in English).
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Figure 2. Risk of bias in the included studies [19,21,24,36,37,38,39,40,41,42,43,44,45,46,47,48,49,50,51,52,53,54,55,56,57,58,59,60,61,62,63,64,65,66,67,68,69,70].
Figure 2. Risk of bias in the included studies [19,21,24,36,37,38,39,40,41,42,43,44,45,46,47,48,49,50,51,52,53,54,55,56,57,58,59,60,61,62,63,64,65,66,67,68,69,70].
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Figure 3. The comparison between NIBS (noninvasive brain stimulation) and aerobic exercise shows no statistically significant differences between the two treatments. To note, there was a statistically significant difference between the number of the patients allocated in the two groups: 310 patients in NIBS and 708 in the exercise.
Figure 3. The comparison between NIBS (noninvasive brain stimulation) and aerobic exercise shows no statistically significant differences between the two treatments. To note, there was a statistically significant difference between the number of the patients allocated in the two groups: 310 patients in NIBS and 708 in the exercise.
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Figure 4. (A,B) Looking at the prevalence of improvement in the two groups, it appears clear that both NIBS and aerobic exercise offer an amelioration of the cognitive function in patients with MS.
Figure 4. (A,B) Looking at the prevalence of improvement in the two groups, it appears clear that both NIBS and aerobic exercise offer an amelioration of the cognitive function in patients with MS.
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Table 1. Effect of noninvasive brain stimulation on cognition.
Table 1. Effect of noninvasive brain stimulation on cognition.
Study/Year/CountryDesignParticipantInterventionLocationIntensityDurationTool/Outcome
ExperimentalControlExperimentalControl
Hsu/2023/USA [36]parallel191820tACSShamNA2 mA,
1 mA		20 minSDMT improved with both 1 and 2 mA.
Simani et al./2022/Iran [37]parallel2020tDCS,
CT		CTA: F3
C: right shoulder		2 mA30 minIVA-2
Improved attention and inhibitory control
Gholami et al. (2021)/Iran/2021 [38]parallel1212tDCSsham tDCSA: F3
C: FP2		2 mA20 minCBS-CP improved reasoning and executive function
Seelmann-Eggebert/Germany/2021 [39]Crossover16tDCS and sham 4 weeks washoutA: C3
C: supra orbital		1 mA15 minSDMT: no improvement
Grigorescu et al./Germany/2020 [40]Crossover11tDCS or sham with 3-week washout intervalA: F3
C: F4		2 mA20SDMT: not improved
Fiene er al./Germany/2018
[41]		Crossover15tDCS with one-week washout intervalA; F3
C: right shoulder		1.5 mA30RT: cognitive fatigue improves
Charvet et al./USA/2018 [42]parallel2520RS tDCS,
CT		CTA: F3
C: F4		1.5 mA20 minBICAMS, ANT, IV
Improve complex attention and response variability
Ayache et al./France/2016
[43]		Crossover16block of tDCS active or sham with 3 w washoutA: F3
C: Supraorbital		2 mA20 minSDMT not improved
Chalah et al./France/2016 [44]Crossover10block tDCS active or sham with 3 w washoutA: F3 or P4
C: CZ		2 mA20 minANT: not improved
Hanken et al./Germany/2016
[45]		parallel2020tDCS,
Vigilant task		Sham
tDCS Vigilant		A: P4
C: forehead		1.5 mA20RT: improved
Palm/Germnay/2016
[46]		Crossover16blocks of tRANS followed by 3 w washoutA: F3
C: AF4		2NAANT not improved
Mattioli et al./Italy/2015
[47]		parallel1010tDCS CTSham tDCS CTA:F3
C: Right shoulder		220PASAT, WCST and SDMT improve attention and executive function
Abbreviations: IVA-2: Integrated Visual and Auditory Test; CBS-CP: Cambridge Brain Science Cognitive Platform; SDMT: Symbol–Digit Modalities Test; RT: Reaction Time; tCDS: transcranial direct current stimulation; RS tDCS: remotely supervised transcranial direct current stimulation; CT: cognitive training; BICAMS: Brief International Cognitive Assessment in MS; ANT: basic and complex attention; IV: intra-individual response variability; tRNS: transcranial random noise stimulation; transcranial alternating current stimulation (tACS); WCST: Wisconsin Card Sorting Test; PASAT Paced Auditory Serial Attention Test.
Table 2. Effect of different exercises on cognition among pwMS.
Table 2. Effect of different exercises on cognition among pwMS.
Study/Year/CountryDesignParticipantInterventionFrequencyDurationDuration Per SessionTool/Outcome
Exp.ControlExperimentalControl
Tasci/2023/Turkey [48]RCT1818Aerobic, strengthNo intervention312 wNAPBI, MFIS improved
Açık/2023/Turkey [49]RCTAerobic
16		Strength
11		16Aerobic, strengthNo intervention312 wNABICAMS improved
Galperin//2023/USA
[50]		RCT, parallel6262Treadmill training with virtual realitytreadmill training36 wNASDMT improved
Andreu-Caravaca et al./2022/Germany [51]RCT, parallel1812ResistanceNo intervention3/W10 wNAMSQOL-54 cognition improved
Bilek/2022/Turkey
[52]		RCT, parallel3434Aerobic and Frenkel coordination exerciseFrenkel coordination only3 w6 w30 minPASAT improved
Jeong/2021/USA
[53]		RCT, parallel2916Telerehabilitation system plus home-based exerciseHome-based exercise only7/w12 WNAMSQOL cognitive improved
Langeskov-Christense/2021/Denmark
[54]		RCT, parallel4343Supervised progressive aerobic exercise followed by self-guided physical exerciseHabitual lifestyle then supervised progressive aerobic exercise2/w24 w60 minSRT-LT
SRT-C
SRT-D
SPART-D
WLG
PASAST,
SDMT only improved; the rest, no effect
Savšek/2021/Slovenia
[55]		RCT, parallel1414AerobicNo intervention212 w60 minMFIS
SDMT
BVMT-R
CVLT-II
No improvement
Bckusi et al. (2020)/USA
[56]		RCT, parallel66Aerobic/Functional electrical stimulationNo intervention3/w12 W30 minMSQOL-54 cognition improved
Ozdogar/2020/Turkey
[57]		RCT, ParallelVideo-based, 21;
conventional, 19		20Video-based core stabilization and vs. conventional rehab vs. control group1/w8 W45 minCVLT, BVMT-R,
SDMT: all are improved
Ozk
§0/Turkey [19]		RCT, parallel1717Aerobic and PilatesRelaxation exercise3/w8 w90 minSRT-ST
SRT-LT
SDMT,
SPART-T, SPART-D,
PASAST,
WLG
Improved verbal memory, visuospatial, verbal fluency in the
Feys/2019/Belgium [58]RCT, parallel2121AerobicNo intervention312 wNAPASAT, WLG, SPART, SRT, DSST all improved
Baquet/2018/Germany [59]RCT, parallel3434AerobicNo intervention212 w54.5SDMT, PASAT, TAP, BVMT, RWT
no improvement
Sebastião,/2018/USA [60]RCT, parallel1510AerobicNo intervention212 w20 minSDMT, CVLT, BVMT, PASAT no improvement due to small sample size
Kargarfard/2017/Iran [61]RCT, parallel1715Aerobic functional exercise and balanceNo intervention38 w60 minMFIS improved
Kjølhede/2017/Denmark [62]RCT, parallel1712ResistanceNo intervention224 w55 minMSFC improved,
TUG
Sandroff/2017/USA [63]RCT, parallel3230Aerobic, balance and resistanceStretching324 w60 minSDMT not improved, PASAT improved
Sandroff/2016/USA [21]RCT, parallel44Aerobic, treadmillNA312 W20 minCVLT-II improved,
MFT, DKFFS,
Kooshiar/2015/Iran [24]RCT, parallel1819StretchingNo intervention38 w45 minMFIS, PASAT cognitive no improved
Carter/2014/UK [64]RCT, parallel6060AerobicNo intervention36 w60 minMSQOL improved.
PASAT.
Hoang/2016/Australia [65]RCT, parallel2822AerobicRegular physical therapy212 w30 minSDMT, TMT, TUG all are improved
Oken/2004/turkey [66]RCT, parallel1520AerobicNo intervention124 w90 minSCWT no improvement
Oken/2004/turkey [66]RCT, parallel2220YogaNo intervention124 w90 minSCWT no improvement
Sandroff/2014/USA [67]RCT3739AerobicNo interventionNA24 wNASDMT improved
Leavitt/2014/USA [68]RCT, parallel11AerobicNo interventionNA12 WNACVLT-II
BVMT-R
SDMT
All were improved.
Briken/2014/Germany
[69]		RCT progressive MSTotal: 32
Arm:10
Rowing:11
Bicycle:11		10Arm, rowing, and bicycleNo intervention2–3/8–10 W20 minSDMT no effect
LPS no improvement
VLMT improved.
TAP improved
Romberg/2005/Finland [70]RCT, parallel, RRMS4748ResistanceNo intervention324 wNAPASAT
MSQOL-cognitive
Both improved
Abbreviations: RCTs: Randomized Controlled Trials; MSQOL-54: Multiple Sclerosis Quality of Life-54; CVLT-II, California Verbal Learning; BVMT-R, Brief Visual Memory Test; SRT-LT, Selective Reminding Test—long term; SRT-ST, Selective Reminding Test—short term; SRT-C, Selective Reminding Test—consistent; SDMT, Symbol Digit Modalities Test; PASAT, Paced Auditory Serial Attention Test; WLG, Word List Generation; MFIS, Modified Fatigue Impact Scale; EXP, experimental group; CON, control group; MFIS, Modified Fatigue Impact Scale; FIS, Fatigue Impact Scale; DKEFS, Delis–Kaplan Executive Function System; MFT, modified flanker task; IC-RT, interference control of reaction time; CLTR, consistent long-term retrieval; SPART, Spatial Recall Test; SPART-D, Spatial Recall Test delayed; SPART-T, Spatial Recall Test—total; SCWT, Stroop Color–Word Interference; MSQol-54, Multiple Sclerosis Quality of Life-54; DSST, Digit Symbol Substitution Test; VLMT, Verbal Learning Memory Test; TAP, test battery for attention; RWT, Regensburg Verbal Fluency Test; TMT, Trail Making Test; TUG, timed up-and-go; PDQ, Perceived Deficit Questionnaire; PBI, Problem Solving Inventory.
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MDPI and ACS Style

Elkhooly, M.; Di Stadio, A.; Bernitsas, E. Effect of Aerobic Exercise versus Non-Invasive Brain Stimulation on Cognitive Function in Multiple Sclerosis: A Systematic Review and Meta-Analysis. Brain Sci. 2024, 14, 771. https://doi.org/10.3390/brainsci14080771

AMA Style

Elkhooly M, Di Stadio A, Bernitsas E. Effect of Aerobic Exercise versus Non-Invasive Brain Stimulation on Cognitive Function in Multiple Sclerosis: A Systematic Review and Meta-Analysis. Brain Sciences. 2024; 14(8):771. https://doi.org/10.3390/brainsci14080771

Chicago/Turabian Style

Elkhooly, Mahmoud, Arianna Di Stadio, and Evanthia Bernitsas. 2024. "Effect of Aerobic Exercise versus Non-Invasive Brain Stimulation on Cognitive Function in Multiple Sclerosis: A Systematic Review and Meta-Analysis" Brain Sciences 14, no. 8: 771. https://doi.org/10.3390/brainsci14080771

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