Exercise training induces beneficial effects on the central nervous system (CNS) in individuals with MS (Guo et al., 2020[50]). These changes can be observed through the reconstruction of brain structure, function and connectivity, ultimately resulting in improved physical and cognitive performances (White and Castellano, 2008[124]). For instance, long-term walking has a positive impact on both cognitive function and brain morphology of MS patients (Devasahayam et al., 2017[23]; Erickson et al., 2019[29]). The effectiveness of exercise training in inducing brain changes has been demonstrated through brain imaging (Ji et al., 2021[61]). Studies have shown that exercise induces adaptations in the brain, and these changes have been observed in MRI (Rasova et al., 2015[100]). These results can be seen in Figure 2(Fig. 2).

By affecting synapses through the activation of different brain areas, exercise can improve brain function (Prosperini et al., 2015[97]). Additionally, exercise induces the activation of the thalamus-motor cortex network, and an improvement of interneuron communication which is related to the changes that result from exercise training at the level of brain structure and at the molecular/cellular level, such as the increase of neurotrophic factors and angiogenesis in MS patients (Diechmann et al., 2021[24]).

Regular long-term exercise training improved the antioxidant capacity and decreased the levels of active oxygen species (Bogdanis et al., 2013[14]). These processes contribute to the improvement of blood-brain barrier function and reduction in its permeability to metabolites (Mokhtarzade et al., 2018[84]). By examining the effects of high-intensity interval training on the physiological indicators of the blood-brain barrier (Mokhtarzade et al., 2018[84]) (MMP-2 and MMP-9), a significant decrease in these indicators has been observed (Mokhtarzade et al., 2018[84]; Zimmer et al., 2018[131]). Physiological factors that play an important role in inflammatory processes and can affect the blood-brain bar-rier include MMP-2, for example, which could be reduced by the anti-inflammatory properties of physical training (Zimmer et al., 2018[131]). This factor can disrupt the blood-brain barrier. In a neurodegenerative disease such as MS, the permeability of the BBB is altered, and exercise can reduce the factors involved in this process, such as MMP-2, leading to an improvement in cognitive function (Zimmer et al., 2018[131]).

Exercise training increases the neurotrophic factors' levels such as BDNF, resulting in improved cognitive performance (Shobeiri et al., 2022[108]). Further research is needed to investigate the effects of exercise training intensity and duration on the levels of those neurotrophic factors in individuals with MS (Banitalebi et al., 2020[8]). Studies have demonstrated that aquatic exercise leads to a reduction in catecholamine levels, confirming the impact of exercise on the sympathetic and parasympathetic states (Bansi et al., 2013[9]). Figure 3(Fig. 3) shows the effect of water exercises on patients with MS.

Various factors affect the level of neurotrophic factors such as BDNF which might be affected by exercise training, inflammation, metabolic state of the body, body weight (Mokhtarzade et al., 2018[84]). In many neurological diseases such as Alzheimer's, Parkinson's, MS, and Huntington's, a lot of neurodegeneration occurs in the brain, which is accompanied by the death of neuronal nuclei and neuronal structures (Manoharan et al., 2016[79]). Many studies have shown that the combination of physical activity and rich environment such as nutritional or cognitive interventions can help in reducing, inhibiting or delaying the progress of neurodegenerative diseases (Bhatti et al., 2020[13]; Pang and Hannan, 2013[89]). Meanwhile, BDNF neurotrophic factors are very important in protecting these neurons. Natural interventions, such as exercise, hormonal balance (e.g., steroid hormones such as cortisol and testosterone), and nutritional interventions (e.g., fasting, low-calorie intake, low-carbohydrate diet, selective nutrient intake), can reduce this level and increase the neurotrophic factor and this helps the plasticity of the brain (Waterhouse and Xu, 2009[122]).

Exercise training enhances immune system function by regulating and modulating cytokines (Alvarenga-Filho et al., 2016[2]; Faramarzi et al., 2020[33]). A study by Smith et al. (Smith et al., 2016[111]) examined the impact of 6 months of aerobic training on the secretion of interferon γ cytokine in patients and found a decrease in its level. Similarly, Moghadasi et al. (2015[83]) investigated the effect of 12 weeks of resistance training on the level of interleukin 6 and observed a decrease as well. Short-term exercise has been shown to maintain immune homeostasis by regulating cytokines, such as, C-reactive protein (CRP), IL-1, IL-6, IFNγ, with an increase in the level of IL-10 (Afzal et al., 2020[1]; Barry et al., 2016[11]). This cytokine regulation may have implications for the prevention and treatment of MS (Asano and Finlayson, 2014[7]). Short-term exercise training induces immune system homeostasis through cytokines' release (Fasczewski et al., 2018[34]), assisting in coping with immune system disorders during this process (Fasczewski et al., 2018[34]). While the precise mechanisms of this flow are yet to fully proven, studies suggest regular aerobic exercise induces changes in the levels of Th1 and Th2 family cytokines, potentially aiding in the treatment and control of MS (Lassmann et al., 2012[74]; Pau et al., 2020[91])

In MS, there exists a complex relationship between the endocrine glands and the immune system (Moynihan and Moore, 2010[86]). The disease involves the activation of Th1 segment leading to an excessive release of IL-12, TNFα, IFNγ and deficiency of IL-10 (Kaskow and Baecher-Allan, 2018[64]). This dysregulation can be influenced by axis stimulation and its impact on the immune system (Ysrraelit et al., 2008[129]). Notably, stress hormones can play a role in reducing demyelination in MS by altering Th2 factors (Karagkouni et al., 2013[63]). Cytokines, which are crucial in immune responses, are influenced by hormones and neural factors (Eskandari and Sternberg, 2002[31]). Catecholamines and glucocorticoids, which are two types of stress hormones, are particularly important in the production and release of cytokines (Elenkov and Chrousos, 2002[28]). Studies have shown that stress hormone regulatory systems can affect the immune system and this has been observed in patients with MS (Gold et al., 2005[43]). Regulation of these stress hormones, such as catecholamines and glucocorticoids, may reduce the extent of demyelination in MS, the mechanism being modulation of Th2 (Deckx et al., 2013[22]). As previously proven, physical activity and exercise can affect the progression of MS by modulating stress hormones (White and Castellano, 2008[125]).

Exercise training in patients with MS does not necessarily result in an increased perception of fatigue; rather, it can contribute to the management of fatigue. There are various reasons why exercise can lead to a reduction in the perception of fatigue in MS patient. One factor is the tendency for individuals with MS to become inactive and spend extended periods at home (Macdonald et al., 2022[78]), which can heighten the perception of fatigue whenever they will exercise afterwards, and also diminish overall performance (Kornek et al., 2000[69]). Engaging in exercise training prompts adaptation in individuals and can actually lead to an increase in delaying the perception of fatigue (Dalgas et al., 2019[21]).

Engaging in aerobic exercises by individuals with MS has been shown to lead to improvements in psychological factors, quality of life and aerobic capacity, furthermore, it has been to be generally well-tolerated and safe (Swank et al., 2013[114]). Studies suggest that a four-week aerobic exercise protocol can yield favorable gains in cardiorespiratory fitness for MS patients (Andreu-Caravaca et al., 2021[4]). Recommended exercises include performing light activities on a cadence bike and/or a treadmill with sufficient support (Latimer-Cheung et al., 2013[76]). Many studies utilizing a treadmill have reported significant positive outcomes in MS patients (Latimer-Cheung et al., 2013[76]). The recommended aerobic training program is 2 to 5 sessions per week (Döring et al., 2012[27]; Snyder, 2017[112]). Exercises intensity is suggested to be around 40-70 % of VO_2max, with the percentage of maximum heart rate at approximately 60-80 (or 40-60 % of heart rate reserve) (Asadi, 2022[5]; Humphreys, 2022[59]). Depending on the progression of the disease, the duration of training is planned in intervals of 10 to 40 minutes, divided into three segments of ten minutes each (Latimer-Cheung et al., 2013[76]). The rate of progression and training intensity serves as a key factor in the initial six months of training planning (Halabchi et al., 2017[51]).

Engaging in resistance exercises for individuals with MS necessitates the involvement of an experienced trainer to ensure both safety and effective performance monitoring (Barry et al., 2016[11]; Vartanian et al., 1995[117]). The resistance training program for MS patients should incorporate equipment and weight machines that minimize risks (Vartanian et al., 1995[117]). In cases where traditional bodybuilding machines are not available/feasible, using elastic bands or body weight exercises as resistance can be a suitable alternative (Bettelli et al., 2008[12]; Vartanian et al., 1995[117]). A training frequency of 2 to 3 gym sessions per week is considered appropriate for MS patients. Each session should be designed with 8 to 15 repetitions maximum (RM) at an intensity ranging from 60 % to 80 % of 1RM (Devasahayam et al., 2017[23]; Erickson et al., 2019[29]; Rasova et al., 2015[100]). Gradual increases in training intensity is strongly recommended (Bettelli et al., 2008[12]; Lassmann, 2019[73]), with a suggested load incremental of 2 to 5 % in each session to promote progress while preventing injuries (Bettelli et al., 2008[12]; Vartanian et al., 1995[117]).

Concerning the flexibility and stretching exercises, typically individuals with MS experience a decrease in joint range of motion due to inactivity. Flexibility exercises are a dependable and low-impact solution, contributing to increased muscle length, reduced muscle spasms, enhanced joint mobility, and improvements in balance and body posture (Bettelli et al., 2008[12]). In a training program, these exercises are recommended daily for 10 to 15 minutes (Bettelli et al., 2008[12]; Karagkouni et al., 2013[63]; Ysrraelit et al., 2008[129]). It is advisable to incorporate these movements both before and most importantly after the training session, encompassing both upper and lower body movements (Devasahayam et al., 2017[23]; Erickson et al., 2019[29]; Rasova et al., 2015[100]).

In individuals with MS, where the central nervous system is impacted, a heightened focus on enhancing balance and coordination is essential. These exercises involve the manipulation of their center of gravity. An effective method for improving coordination and balance is the Swiss ball exercise, which contributes to increased strength and flexibility (Halabchi et al., 2017[51]). Additionally, incorporating tai chi exercises with deliberately slow movements is another beneficial approach to enhance strength and balance. Water-based exercises are also noteworthy for increasing balance and flexibility, while reducing the risk of falling (Eyvaz et al., 2018[32]).

Respiratory muscle training is aimed at enhancing the efficiency of the respiratory muscles during exercise, paralleling the improvement seen in skeletal muscles (Gosselink et al., 2000[45]). In their examination of fatigue factors in individuals with MS, Foglio et al. (1994[38]) noted that respiratory muscle weakness could be one of these contributing factors to the rapid fatigue of patients with MS. In addition, improvement in these muscles has been observed following respiratory muscle training in people with MS, supporting the potential for using this technique as complementary training (Martín-Valero et al., 2014[80]).

The cardiovascular system's response to exercise activities is carried out by the autonomic nervous system. Research investigating the impact of exercise training on the cardiovascular response in individuals with MS has identified slight abnormalities at rest (Feltham et al., 2013[35]; Keytsman et al., 2019[66]). Ponichtera-Mulcare (1993[95]) conducted a study comparing the cardiovascular response to exercise in MS patients and those with physical disability. It is interesting to note that they did not find a significant difference in the cardiovascular response to exercise, because the severity of the disease is a key determinant in the response of the cardiovascular system to exercise in patients with MS (Heine et al., 2016[55]).

Aerobic capacity of MS patients has been demonstrated to decline, with researchers primarily attributing it to reduced engagement in physical activities (Proschinger et al., 2022[96]). Additionally, respiratory dysfunction may play a role in diminishing performance (Comi et al., 2001[19]), as compromised respiratory muscles can result in decreased respiratory function (Induruwa et al., 2012[60]). Weakened in muscles affected by central nervous system (CNS) dysfunction becomes apparent during maximal exercise tests, and this weakening and atrophy can stem from short-term non-use or spinal cord injury in individuals with MS (Dionyssiotis et al., 2014[25]). Studies have identified a lower presence of type I muscle fibers, along with a reduction in muscle size and enzyme activity, among MS patients who are not actively engaged in physical activities (Hansen et al., 2015[52]; Petajan and White, 1999[92]). This decline contributes to a decrease in functional capacity, highlighting the significance of implementing an exercise program to enhance muscles strength (Hansen et al., 2015[52]).

Various mechanisms contribute to the effects of physical activity on individuals with MS, including the reduction of fat tissue leading to diminished adipokines and the augmentation of an anti-inflammatory environment (Negaresh et al., 2018[88]). It is noteworthy that exercise training, irrespective of weight loss, serves as an intervention in chronic inflammatory diseases by influencing cytokines and adipokines, as highlighted in studies by Gleeson et al. (2011[42]) and Negaresh et al. (2018[88]).

In addition to the effect of exercise on physiological and molecular issues in patients with MS, improving the quality of life is a crucial aspect for individuals with MS, given the limited availability of curative treatments. Quality of life serves as a measure of an individual's happiness and overall enjoyment life (Barry et al., 2016[11]; Langeskov-Christensen et al., 2017[72]). Due to the lack of treatment solutions in patients with MS, improving the condition and quality of life of these patients can play an effective role in reducing stress and dampening the disease' symptoms (Schroeder et al., 2014[105]). Various studies indicate that individuals with MS experience adversity on multiple fronts (Borkoles et al., 2008[15]; Pust et al., 2020[98]). Research exploring the quality of life among MS patients reveals a notable trend that these individuals frequently experience with a lower quality of life compared to those with other conditions, even in comparison to patients with intestinal inflammation (Guerrero Aznar et al., 2022[49]; Visser et al., 2021[120]). This decline in life satisfaction is particularly pronounced in the early years of the onset of the disease (Patten et al., 2012[90]).

Encouraging and persuading individuals affected by loneliness and depression to engage in regular activities for fitness and interpersonal connections is crucial. Exercise training practices play a significant role in reducing feeling of loneliness and depression (Tollár et al., 2020[116]). The type and diversity of exercises has been shown to impact the quality of life for patients with MS (Heesen et al., 2006[54]; Tollár et al., 2020[116]). Among various exercise modalities, aerobic exercises have proven to be more effective, leading to an enhancement in these patients' overall quality of life (Andreu-Caravaca et al., 2021[4]). Studies investigating the duration of exercise have shown that two to three days a week are recommended, starting with two days a week and ending with three days a week. Each training session should be ten to thirty minutes, starting from ten minutes and progressing to thirty minutes. The intensity of each session can be between ten and thirteen on a twenty-point scale, or between 40 and 60 percent of the maximum oxygen consumption (VO₂peak) or maximum heart rate (HR_max). Overall improvement should begin with increasing duration or frequency. The method of training progress should be based on tolerance (Kalb et al., 2020[62]; Kim et al., 2019[67]). Figure 4(Fig. 4) illustrates the impact exercise on MS.

SS, KC, NY: Methodology; writing -original draft preparation; review and editing.. All authors have read and agreed to the published version of the manuscript.

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