Exercise and Physical Activity

Historically, individuals living with multiple sclerosis were advised to avoid physical exertion for fear that physical activity will make them feel worse. On one hand, the symptoms associated with MS can make participating in physical activity challenging: disability can hinder mobility and lead to significant pain and fatigue, while overheating during strenuous physical activity is a real risk for people living with MS. On the other hand, limiting physical activity can have negative health consequences and potentially lead to even greater weakness and fatigue in the long-run. Over the past few decades, new research has uncovered considerable benefits associated with increased physical activity, and perceptions among the MS community have shifted toward encouraging a more active lifestyle.

An American study published in 1996 was largely responsible for shifting the paradigm regarding attitudes toward exercise and MS. Dr. Jack Petajan (University of Utah) and colleagues 1 examined the effects of 15 weeks of aerobic exercise in people with MS compared to those who did not participate in exercise. They found that those who participated in the exercise program experienced reduced fatigue, depression and anger and improved overall quality of life. Many studies have since then supported the notion that physical activity, whether it be exercise or other forms of fitness and movement, is safe and beneficial for individuals living with MS, and is now recognized as an important part of care 2.

The goals of exercise in people living with MS are to improve aerobic endurance, muscular strength and endurance, flexibility, mobility, and to prevent secondary diseases such as cardiovascular disease (CVD) or diabetes 3,4. There is evidence that physical activity and exercise can help to maintain the individual's independence, enhance their quality of life, and lead to improved cognitive functioning due to the beneficial effects of physical activity on brain health 5. However with 80% of people living with relapsing remitting MS not achieving recommended public health guidelines of moderate-to-vigorous physical activity, pinpointing the barriers to physical activity and identifying ways to overcome those barriers are a key focus of MS-related research 6,7.

The following sections highlight the most up-to-date research that is examining if and how physical activity affects the MS disease course, emotional health and overall wellbeing. This page also identifies challenges associated with physical activity research, and lists resources that are useful for Canadians affected by MS.

Resources for Canadians

Canadian Physical Activity Guidelines

Dr. Amy Latimer-Cheung from Queen's University in Kingston, Ontario published an extensive collection of scientific data on the effects of exercise in MS 45. The review included 54 studies and concluded that exercise training may lead to improved mobility, fatigue and quality of life among people living with MS.

On the heels of this review, Dr. Latimer-Cheung developed the Canadian Physical Activity Guidelines for Adults with MS, and is working with MS Society-funded researcher Dr. Audrey Hicks on ways to effectively implement the guidelines in the community.

Other Resources:

MS Wellness Survey

In August 2015 the MS Society of Canada reached out to the community to better understand how people living with multiple sclerosis view wellness, including exercise and physical activity. Some questions the survey was able to answer include: do people with MS partake in physical activity? What are some barriers to participating in physical activity and how can they be overcome? Who do people with MS turn to to talk about daily physical and emotional challenges? The results of the survey will serve as a crucial foundation for informing and inspiring future research in the area of physical activity and overall wellness.

Click here to read more information about the MS Wellness Survey

Influence of Physical Activity on Disease Course and Symptom Management

A number of clinical trials are underway around the world that are providing clearer answers as to whether physical activity interventions may improve MS and overall health. One question on the minds of people living with MS is: what kinds of physical activity are beneficial and best suited for different levels of mobility and fatigue? Some of the recent research examining the effects of different types of physical activity on MS is summarized below.

Aerobic Fitness

Aerobic fitness, also referred to as cardiorespiratory fitness, refers to the body's ability to take in and supply oxygen and energy to the muscles. Examples of activities that improve one's aerobic fitness include walking, cycling and swimming.

In addition to being an overall positive indicator of health, aerobic fitness has been shown to be associated with brain health in individuals living with MS. An influential study 8 showed that individuals with MS who had higher levels of aerobic fitness experienced less overall brain tissue degeneration compared to less fit individuals. More fit participants similarly exhibited higher performance in a series of cognitive tasks, suggesting that high aerobic fitness, preservation of brain tissue and cognitive function are all interrelated in people living with MS.

Suggested activities for engaging in aerobic activity are included in the MS Get Fit Toolkit and the Physical Activity Guide.

Walking

Several studies have examined the effects of walking on overall fitness and cognitive function in people living with MS:

  • In one small study9, researchers compared the effectiveness of one week of treadmill walking versus leg strength training on ambulation in people living with MS with moderate disability. The study found that treadmill walking was superior to strength training in improving walking in people with MS.
  • A small pilot study led by Dr. Brian Sandroff and colleagues 10 examined the effects of varying intensities of treadmill walking on reaction time, a measure of cognitive impairment. While treadmill walking in general improved reaction time compared to quiet rest, the authors found no difference between light, moderate and vigorous walking, thus demonstrating that even light walking can have beneficial effects.
  • A study by the same group11 compared different types of exercise, including treadmill walking, cycling and yoga, and their effects on cognitive performance, including improving attention and blocking distraction. Although all three exercises resulted in some benefit, walking in particular appeared to have the strongest effect on cognitive performance.
  • Similar benefits from physical activity, particularly walking and running, have been seen in children and adolescents living with MS. In a study supported by the MS Society of Canada and MS Scientific Research Foundation, Drs. Ann Yeh, Brenda Banwell and a team of collaborators combined questionnaires with clinical data to evaluate the association between different intensities of physical activity with relapse rate, brain lesions, fatigue and depression in youth living with either MS or monophasic acute demyelinating syndrome 12. They found that in the MS group, those who spent less time participating in fast walking experienced greater overall fatigue during the day. Moreover, running and jogging was linked with smaller brain lesions and a lower relapse rate, suggesting that strenuous physical activity can potentially be protective in youth living with MS.

Cycling

In addition to walking, cycling is generally regarded as a beneficial form of aerobic exercise. The support provided by the bicycle can minimize stress and impact on joints, which can be beneficial for people living with MS. Several pilot studies have evaluated the effects of cycling in people living with MS.

  • A Scottish study13 was conducted to determine the effects of a 15-minute bout of moderate-intensity cycling on symptoms such as pain and fatigue in people living with MS. They found that, for up to 24 hours following cycling, there were no negative effects on MS symptoms.
  • Cycling has also been paired with other interventions to maximize rehabilitation benefit for people living with more advanced disability. A pilot study 14 evaluated functional electrical stimulation (FES – which stimulates the leg muscles and is used as a rehabilitation technique for spinal cord injury) paired with cycling three times a week (1 hour per session) for 6 months in participants with primary and secondary progressive forms of MS. At the end of the study, participants showed improvements in walking speed and endurance, leg muscle strength, as well as measures of quality of life.

Aquatic training

Overheating is a common and often debilitating symptom experienced by people living with MS, and increased physical activity can significantly worsen the feeling of elevated temperature. One solution to prevent overheating is to engage in aquatic exercises. This form of exercise allows efficient heat transfer from the body to the water, and in individuals who are prone to falls, the buoyancy provided by water lowers the risks of falls and fractures 15.

  • To evaluate the effects of aquatic exercise programs on pain and fatigue in people living with MS, a research group in Spain 16 conducted a randomized controlled trial in 73 people living with MS. They found that a 20-week, 40-session treatment program of Ai-Chi aquatic exercise – which combines underwater exercise and relaxation – produced measurable, although subtle, improvements in pain, fatigue, spasms and depression in people who participated in the program versus those who did not.

Strength Training

In contrast to aerobic training, strength training (also known as resistance training) focuses on improving muscle strength and endurance, and has been attributed to improvements in bone and muscle health, increased metabolism, and reduced obesity. A number of studies have evaluated the potential benefits of strength training for people living with MS, both in isolation and in combination with other types of physical activity.

  • One area of research interest has been evaluating the effects of leg strength training on mobility deficits (like walking with a limp or foot drop) and impaired balance in people living with MS. Of the two randomized controlled trials 17,18 focused on this area, neither found any benefit of strength training on improving mobility, although one of them 18 did find that two 10-week periods (five, 60-minute sessions every two weeks) of leg resistance strength training (leg press, leg extension, leg curl) caused significant improvements in balance among 36 participants living with MS.
  • Strength training has demonstrated benefits for alleviating fatigue and improving quality of life (using standardized tests) in people living with MS, based on the outcomes of two randomized controlled clinical trials 17,19 which evaluated progressive resistance training regimens (i.e. increasing sets, repetitions and loads) including exercises like leg press, knee extension, hip flexion, hamstring curl and hip extension. One non-randomized controlled trial, on the other hand, did not reveal improvements in quality of life following strength training, although participants did experience lessened fatigue 20.
  • A study in Belgium involving 34 people living with MS found that strength training (leg press, leg curl, leg extension, arm curl, chest press) combined with high intensity aerobic exercise (cycling and treadmill walking/running) produced the greatest gains in muscle strength and exercise endurance, compared to lack of activity 21. Although strenuous aerobic training and strength training can be too prohibitive for individuals with high levels of physical disability, this exercise regimen is a potential option for those with milder disability.

Yoga

Yoga and other "mind-body" approaches that combine breathing, relaxation, balancing and stretching techniques are emerging as popular alternatives to more vigorous forms of physical activity for symptom management in people living with MS.

  • A study involving 60 women with MS assessed the effects of a 3-month, pain-managing yoga program on physical pain and overall quality of life 22. Both pain management and quality of life exhibited marked improvements in those participating in the yoga program compared to those who did not.
  • A recent, smaller study conducted in eight people living with MS demonstrated improvements in balance, fatigue, and walking performance following bi-weekly yoga over the course of 3 months 23.
  • An uncontrolled study in 24 individuals showed that a 4-month yoga program brought about modest improvements in balance and functional strength 24.
  • On the other hand, spasticity (a common symptom that involves muscle cramping and/or spasms) did not appear to be affected by a yoga intervention in 20 people living with MS 25.

While research to date appears to suggest that yoga is safe and effective for controlling symptoms of MS, more thorough research as part of larger clinical trials is needed to determine what kind of yoga regimens are most effective for people living with MS, and how to effectively incorporate yoga into a treatment plan.

Exercise and Video Gaming

A major challenge faced by people living with MS when incorporating physical activity in their routines is that, oftentimes, exercise facilities and equipment may be inaccessible or impractical. Additionally, some people find exercise to be tedious and unenjoyable, which can lead to poor compliance with exercise routines. One solution that has come along with the advent of sophisticated gaming technology is referred to as "exergaming". Exergaming uses a combination of video game platforms and body movement-tracking technology to produce an immersive and enjoyable experience for users engaged in physical activity. Exergaming technology is relatively new, so studies examining the effects on exergaming on symptom management in people living with MS are only beginning to emerge.

  • A recent randomized, controlled trial in 56 participants with MS with mild disability explored whether exergaming could improve balance in people living with MS compared to traditional balance training or no training at all 26. The authors found that exergaming offered similar balance improvements to traditional balance training, while being more motivating and improving the likelihood that people living with MS will stick to the training.
  • The results from the above study largely mirror earlier studies exploring the influence of exergaming on balance rehabilitation 27-29, although the authors of one study warned that the risk of training-related injuries should be carefully balanced with the potential benefits 28.

Influence of Physical Activity on Overall Wellbeing

While studies examining the effects of different types of physical activity on MS symptoms and physical health are a crucial avenue of research, the broader implications of physical activity on mental, emotional and social wellbeing deserve equal scrutiny. A number of key studies have been conducted examining factors that affect participation in physical activity. Also explored are the consequences of physical activity on mental health and emotional wellbeing.

Lifestyle

For people living with MS, a number of personal, social and environmental factors play a major part in their decision to engage in physical activity.

  • Drs. Yvonne Learmonth and Robert Motl examined nineteen research studies in order to catalogue perceived determinants (influencing factors) and consequences of physical activity for people living with MS 30. Some barriers they identified include: lack of accessible exercise facilities; minimal or conflicting advice from healthcare professionals; fatigue; fear and apprehension. On the other hand, factors that motivated people to engage in physical activity included peer support, feelings of accomplishment, increased social participation, and feelings of self-management and control.
  • People living with MS who are non-ambulatory and confined to wheelchairs face a unique set of challenges in incorporating physical activity into their lives. A study conducted by Dr. Robert Motl's group used an interview-based questionnaire to solicit feedback from 15 wheelchair users with MS to identify perceived barriers, facilitators, and benefits to physical activity and exercise 31. Important themes included the need for adaptive, tailor-made exercise and accessible environments to help incorporate physical activity into the home and workplace, as well as to increase involvement by health-care professionals to encourage participation in physical activity.
  • A similar study went even further to explore factors influencing adherence to exercise across all levels of disability, particularly in older individuals with MS. The MS Society-funded study, conducted by Dr. Michelle Ploughman (Memorial University) and her team, analyzed survey data from 743 people with MS as part of the Canadian Survey of Health, Lifestyle and Aging with MS 32. Not surprisingly, factors like poor ambulation and high disability, low perseverance, high fatigue, and accompanying cardiovascular conditions were associated with a lower likelihood of exercising, whereas older age, social support and financial resources, gender, and support of health care professionals were not.
  • In order to aid in implementing physical activity as part of the daily routine, researchers are exploring new models for exercise-based education programs that empower people living with MS to maintain an active lifestyle in the long-term. A pilot study conducted in Germany explored the effectiveness of an education program in fifteen participants; the program was designed to educate participants in training principles, address participants' fear about exercise, and increase empowerment 33. The authors found that the 12-week education program followed by 32 weeks of self-initiated training improved many aspects of fitness such as fatigue and increased self-confidence in carrying out physical activity independently.

Mental Health and Emotional Wellbeing

Research demonstrates that physical activity leads to improvements in overall quality of life for people living with MS. Health-related quality of life specifically refers to physical, social and mental/emotional aspects, and only a handful of studies have taken the additional step of parsing out mental health and emotional wellbeing to determine how physical activity affects these factors.

  • A questionnaire-based study conducted in Germany compared both physical function and mental health between a total of 265 active and inactive participants 34. The authors found that physically active participants scored higher in measures of vitality (i.e. feeling energetic), general health perception and social functioning than inactive participants, and were less likely to experience mood disorders such as depression.
  • The findings by Dr. Tallner and colleagues complemented several questionnaire-based studies that mapped out the association between physical activity and health-related quality of life in people living with MS over time. An American study showed that those who increased their participation in physical activity over 6 months reported improved emotional wellbeing and social function 35.
  • Similarly, a study of 2,469 individuals across 57 countries found that by increasing participation in physical activity over time, individuals living with MS experienced increased levels of energy and social function and lower burden of mental disorders, regardless of disability 36. Together, these findings suggest that physical activity can have tangible benefits for emotional wellbeing for people living with MS.

Non-human Research

Observational and interventional studies in people living with MS provide critical, real-world information about how physical activity and exercise affect disease course, symptom management, and mental and emotional wellbeing. Even so, studying animals with an MS-like disease can provide important insights into some of the detailed mechanisms at the cell or tissue level that simply aren't possible in humans. Questions that can be answered in animals models include: Does exercise lead to remyelination and/or neuroprotection, and if so, how? Does exercise reduce inflammation?

Studies outside of the MS field have built a strong body of evidence linking exercise with brain health in animals. For example, research involving mice and rats showed increased production of brain chemicals and new nerve cells that promote learning and memory, along with increased neuroplasticity following exercise37,38. Other studies show that exercise impacts the immune system and thus can influence vulnerability to infection 39. These discoveries lay the groundwork for exploring a more definitive connection between MS and exercise.

While early studies in mice with an MS-like disease examined exercise as a potential stressful factor that might worsen the disease 40,41, more recent research has shifted the focus to exploring the beneficial effects of exercise for diminishing the severity of the disease.

  • A study by a research group in Italy examined the effects of voluntary exercise on both severity of disability and brain function in mice with an MS-like disease 42. They found that mice who exercised had reduced disability and improved brain function compared to those who could not, even though the degree of inflammation was similar between the two groups.
  • Another study43 found that mice who exercised had elevated levels of a protein linked to growth and survival of nerve cells, reduced clinical disability, and reduced myelin loss compared to mice that didn't exercise.
  • The effects of exercise on specific symptoms of MS have also been studied in animal models. In an MS Society-funded study, Dr. Bradley Kerr and colleagues at the University of Alberta set out to determine whether running could mitigate both disease progression and pain in mice with an MS-like disease 44. They showed that running one hour a day on a wheel for several days delayed the onset of symptoms and reduced pain sensitivity compared to mice without running access. They noted that running likely promoted a healthier cellular environment in the spinal cords of the mice.

Challenges

Conducting a well-designed physical activity study or clinical trial, as well as translating evidence to real-world practice, can at times present a unique set of challenges such as those described below.

  • For questionnaire-based studies, participants may be asked to recall or record the type, duration and intensity of physical activity that they engage in. Self-reporting can often be unreliable and skewed by subjective bias (e.g. one person's "vigorous" activity can be another person's "moderate" activity).
  • Comparing and pooling results from different studies can be difficult due to differences in experimental methodology, such as type of exercise, regimen, data collection and analysis.
  • Compliance with exercise programs in interventional studies can be variable, which affects the accuracy of the collected information.
  • Causation and correlation need to be carefully considered; for example, does exercise lead to improved health, or are individuals who exercise generally more healthy and more cognizant of their health and lifestyle that those who don't? Questions like these need to be addressed by well-designed studies that take into account confounding factors in order to parse out cause and effect.

 

References
  1. Petajan JH, Gappmaier E, White AT, Spencer MK, Mino L, Hicks RW. Impact of aerobic training on fitness and quality of life in multiple sclerosis. Ann Neurol. 1996;39(4):432-441.
  2. Rietberg MB, Brooks D, Uitdehaag BM, Kwakkel G. Exercise therapy for multiple sclerosis. Cochrane Database Syst Rev. 2005(1):CD003980.
  3. White LJ, Dressendorfer RH. Exercise and multiple sclerosis. Sports Med. 2004;34(15):1077-1100.
  4. Latimer-Cheung AE, Martin Ginis KA, Hicks AL, et al. Development of evidence-informed physical activity guidelines for adults with multiple sclerosis. Arch Phys Med Rehabil. 2013;94(9):1829-1836.e1827.
  5. Döring A, Pfueller CF, Paul F, Dörr J. Exercise in multiple sclerosis -- an integral component of disease management. EPMA J. 2011;3(1):2.
  6. Ploughman M, Austin MW, Murdoch M, Kearney A, Godwin M, Stefanelli M. The path to self-management: a qualitative study involving older people with multiple sclerosis. Physiother Can. 2012;64(1):6-17.
  7. Klaren RE, Motl RW, Dlugonski D, Sandroff BM, Pilutti LA. Objectively quantified physical activity in persons with multiple sclerosis. Arch Phys Med Rehabil. 2013;94(12):2342-2348.
  8. Prakash RS, Snook EM, Motl RW, Kramer AF. Aerobic fitness is associated with gray matter volume and white matter integrity in multiple sclerosis. Brain Res. 2010;1341:41-51.
  9. Braendvik SM, Koret T, Helbostad JL, et al. Treadmill Training or Progressive Strength Training to Improve Walking in People with Multiple Sclerosis? A Randomized Parallel Group Trial. Physiother Res Int. 2015.
  10. Sandroff BM, Hillman CH, Benedict RH, Motl RW. Acute effects of varying intensities of treadmill walking exercise on inhibitory control in persons with multiple sclerosis: A pilot investigation. Physiol Behav. 2016;154:20-27.
  11. Sandroff BM, Hillman CH, Benedict RH, Motl RW. Acute effects of walking, cycling, and yoga exercise on cognition in persons with relapsing-remitting multiple sclerosis without impaired cognitive processing speed. J Clin Exp Neuropsychol. 2015;37(2):209-219.
  12. Grover SA, Aubert-Broche B, Fetco D, et al. Lower physical activity is associated with higher disease burden in pediatric multiple sclerosis. Neurology. 2015;85(19):1663-1669.
  13. Learmonth YC, Paul L, McFadyen AK, et al. Short-term effect of aerobic exercise on symptoms in multiple sclerosis and chronic fatigue syndrome: a pilot study. Int J MS Care. 2014;16(2):76-82.
  14. Ratchford JN, Shore W, Hammond ER, et al. A pilot study of functional electrical stimulation cycling in progressive multiple sclerosis. NeuroRehabilitation. 2010;27(2):121-128.
  15. Frohman AN, Okuda DT, Beh S, et al. Aquatic training in MS: neurotherapeutic impact upon quality of life. Ann Clin Transl Neurol. 2015;2(8):864-872.
  16. Castro-Sánchez AM, Matarán-Peñarrocha GA, Lara-Palomo I, Saavedra-Hernández M, Arroyo-Morales M, Moreno-Lorenzo C. Hydrotherapy for the treatment of pain in people with multiple sclerosis: a randomized controlled trial. Evid Based Complement Alternat Med. 2012;2012:473963.
  17. Dodd KJ, Taylor NF, Shields N, Prasad D, McDonald E, Gillon A. Progressive resistance training did not improve walking but can improve muscle performance, quality of life and fatigue in adults with multiple sclerosis: a randomized controlled trial. Mult Scler. 2011;17(11):1362-1374.
  18. Broekmans T, Roelants M, Feys P, et al. Effects of long-term resistance training and simultaneous electro-stimulation on muscle strength and functional mobility in multiple sclerosis. Mult Scler. 2011;17(4):468-477.
  19. Dalgas U, Stenager E, Jakobsen J, et al. Fatigue, mood and quality of life improve in MS patients after progressive resistance training. Mult Scler. 2010;16(4):480-490.
  20. Sabapathy NM, Minahan CL, Turner GT, Broadley SA. Comparing endurance- and resistance-exercise training in people with multiple sclerosis: a randomized pilot study. Clin Rehabil. 2011;25(1):14-24.
  21. Wens I, Dalgas U, Vandenabeele F, et al. High Intensity Exercise in Multiple Sclerosis: Effects on Muscle Contractile Characteristics and Exercise Capacity, a Randomised Controlled Trial. PLoS One. 2015;10(9):e0133697.
  22. Doulatabad SN, Nooreyan K, Doulatabad AN, Noubandegani ZM. The effects of pranayama, hatha and raja yoga on physical pain and the quality of life of women with multiple sclerosis. Afr J Tradit Complement Altern Med. 2012;10(1):49-52.
  23. Guner S, Inanici F. Yoga therapy and ambulatory multiple sclerosis Assessment of gait analysis parameters, fatigue and balance. J Bodyw Mov Ther. 2015;19(1):72-81.
  24. Salgado BC, Jones M, Ilgun S, McCord G, Loper-Powers M, van Houten P. Effects of a 4-month Ananda Yoga program on physical and mental health outcomes for persons with multiple sclerosis. Int J Yoga Therap. 2013(23):27-38.
  25. Velikonja O, Curić K, Ozura A, Jazbec SS. Influence of sports climbing and yoga on spasticity, cognitive function, mood and fatigue in patients with multiple sclerosis. Clin Neurol Neurosurg. 2010;112(7):597-601.
  26. Robinson J, Dixon J, Macsween A, van Schaik P, Martin D. The effects of exergaming on balance, gait, technology acceptance and flow experience in people with multiple sclerosis: a randomized controlled trial. BMC Sports Sci Med Rehabil. 2015;7:8.
  27. Brichetto G, Spallarossa P, de Carvalho ML, Battaglia MA. The effect of Nintendo® Wii® on balance in people with multiple sclerosis: a pilot randomized control study. Mult Scler. 2013;19(9):1219-1221.
  28. Prosperini L, Fortuna D, Giannì C, Leonardi L, Marchetti MR, Pozzilli C. Home-based balance training using the Wii balance board: a randomized, crossover pilot study in multiple sclerosis. Neurorehabil Neural Repair. 2013;27(6):516-525.
  29. Kramer A, Dettmers C, Gruber M. Exergaming with additional postural demands improves balance and gait in patients with multiple sclerosis as much as conventional balance training and leads to high adherence to home-based balance training. Arch Phys Med Rehabil. 2014;95(10):1803-1809.
  30. Learmonth YC, Motl RW. Physical activity and exercise training in multiple sclerosis: a review and content analysis of qualitative research identifying perceived determinants and consequences. Disabil Rehabil. 2015:1-16.
  31. Learmonth YC, Rice IM, Ostler T, Rice LA, Motl RW. Perspectives on Physical Activity Among People with Multiple Sclerosis Who Are Wheelchair Users: Informing the Design of Future Interventions. Int J MS Care. 2015;17(3):109-119.
  32. Ploughman M, Harris C, Wallack EM, et al. Predictors of exercise participation in ambulatory and non-ambulatory older people with multiple sclerosis. PeerJ. 2015;3:e1158.
  33. Kersten S, Mahli M, Drosselmeyer J, et al. A pilot study of an exercise-based patient education program in people with multiple sclerosis. Mult Scler Int. 2014;2014:306878.
  34. Tallner A, Waschbisch A, Hentschke C, Pfeifer K, Mäurer M. Mental Health in Multiple Sclerosis Patients without Limitation of Physical Function: The Role of Physical Activity. Int J Mol Sci. 2015;16(7):14901-14911.
  35. Motl RW, McAuley E. Physical activity and health-related quality of life over time in adults with multiple sclerosis. Rehabil Psychol. 2014;59(4):415-421.
  36. Marck CH, Hadgkiss EJ, Weiland TJ, van der Meer DM, Pereira NG, Jelinek GA. Physical activity and associated levels of disability and quality of life in people with multiple sclerosis: a large international survey. BMC Neurol. 2014;14:143.
  37. Cotman CW, Berchtold NC, Christie LA. Exercise builds brain health: key roles of growth factor cascades and inflammation. Trends Neurosci. 2007;30(9):464-472.
  38. Gibbons TE, Pence BD, Petr G, et al. Voluntary wheel running, but not a diet containing (-)-epigallocatechin-3-gallate and β-alanine, improves learning, memory and hippocampal neurogenesis in aged mice. Behav Brain Res. 2014;272:131-140.
  39. Pedersen BK, Hoffman-Goetz L. Exercise and the immune system: regulation, integration, and adaptation. Physiol Rev. 2000;80(3):1055-1081.
  40. Le Page C, Ferry A, Rieu M. Effect of muscular exercise on chronic relapsing experimental autoimmune encephalomyelitis. J Appl Physiol (1985). 1994;77(5):2341-2347.
  41. Le Page C, Bourdoulous S, Béraud E, Couraud PO, Rieu M, Ferry A. Effect of physical exercise on adoptive experimental auto-immune encephalomyelitis in rats. Eur J Appl Physiol Occup Physiol. 1996;73(1-2):130-135.
  42. Rossi S, Furlan R, De Chiara V, et al. Exercise attenuates the clinical, synaptic and dendritic abnormalities of experimental autoimmune encephalomyelitis. Neurobiol Dis. 2009;36(1):51-59.
  43. Bernardes D, Oliveira-Lima OC, Silva TV, et al. Differential brain and spinal cord cytokine and BDNF levels in experimental autoimmune encephalomyelitis are modulated by prior and regular exercise. J Neuroimmunol. 2013;264(1-2):24-34.
  44. Benson C, Paylor JW, Tenorio G, Winship I, Baker G, Kerr BJ. Voluntary wheel running delays disease onset and reduces pain hypersensitivity in early experimental autoimmune encephalomyelitis (EAE). Exp Neurol. 2015;271:279-290.
  45. Latimer-Cheung AE, Pilutti LA, Hicks AL, et al. Effects of exercise training on fitness, mobility, fatigue, and health-related quality of life among adults with multiple sclerosis: a systematic review to inform guideline development. Arch Phys Med Rehabil. 2013;94(9):1800-1828.e1803.