Supplement

For reprint orders, please contact: reprints@futuremedicine.com

Exercise therapy in multiple sclerosis and its

effects on function and the brain
Ulrik Dalgas*,1
1
Department of Public Health, Section of Sport Science, Aarhus University, Denmark
* Author for correspondence: dalgas@ph.au.dk

Exercise therapy is a promising nonpharmacological therapy in people with multiple sclerosis (MS). Al-
though exercise training may induce a transient worsening of symptoms in some MS patients, it is gen-
erally considered safe and does not increase the risk of relapses. Exercise training can lead to clinically
relevant improvements in physical function, but should be considered an adjunct to specific task-based
training. Exercise has also shown positive effects on the brain, including improvements in brain volume
and cognition. In summary, exercise therapy is a safe and potent nonpharmacological intervention in MS,
with beneficial effects on both functional capacity and the brain.

First draft submitted: 8 September 2017; Accepted for publication: 19 September 2017; Published
online: 16 November 2017

Keywords: brain • exercise therapy • multiple sclerosis • walking

Physical activity in multiple sclerosis

Individuals with multiple sclerosis (MS) are less physically active than matched healthy controls [1] and measures
of physical activity tend to worsen progressively over time [2]. Physical inactivity leads to muscle atrophy which, in
MS patients, is exacerbated by reduced neural drive to the muscles [3,4]. The result is decreased muscle strength,
with average muscle strength reductions of 25% in the lower limbs and 10% in the upper limbs of MS patients
compared with healthy controls [5]. As muscle strength is related to functional capacity [6], it must be maintained
as much as possible in people with MS.
MS also affects the cardiorespiratory system. Maximal oxygen consumption (VO2 max), a marker of cardiores-
piratory fitness, functional performance and health, is reduced by approximately 20% in MS patients [7,8]. The
combination of inactivity, reduced muscle strength and impaired cardiorespiratory function increases the risk of
cardiovascular diseases [9]. Taken together, MS affects a number of important functional and health-related factors,
relating to all levels of the International Classification of Functioning, Disability and Health model (Figure 1) [10,11].
Exercise has a positive impact on most of these parameters, which makes it a promising intervention.

Exercise therapy in MS
What is exercise therapy?
Exercise therapy is designed to restore health and prevent further impairment by utilizing an individualized plan
that provides advice about the type, intensity, duration and frequency of exercise, while taking into account the
patient’s current medical condition.
The exercise spectrum extends from endurance training (e.g., running) at one end to resistance training (e.g., body
building) at the other end, with a range of options in between. Endurance training involves continuous muscle
contractions against low loads and is predominantly fueled by aerobic metabolism; it can be sustained for a
prolonged period of time and affects both the muscular and cardiorespiratory systems. Resistance training, which
involves few contractions against heavy loads, is predominantly fueled by anaerobic metabolism; it can be sustained
for short periods only and influences mainly the muscular system and places a large strain on the nervous system.
The basic principles of exercise apply to everyone, including patients with MS:
r Individuals differ in their response to exercise and their recovery times;
r Practicing specific exercises increases proficiency in that particular activity;

10.2217/nmt-2017-0040 
C 2017 Future Medicine Ltd Neurodegener. Dis. Manag. (2017) 7(6s), 35–40 ISSN 1758-2024 35
Supplement Dalgas

Functional and health-related Patients with MS vs

parameters healthy controls
↓
Muscle strength
Muscle mass ↓
Muscle activation ↓
Aerobic capacity (VO2 max) ↓
CVD risk ↑
Depression ↑
Fatigue
↑
Daily activity level ↓
Functional capacity ↓
Balance ↓

QoL ↓

Figure 1. Effect of multiple sclerosis on functional and health-related factors: the International Classification of
Functioning, Disability and Health model.
CVD: Cardiovascular disease; MS: Multiple sclerosis; QoL: Quality of life; VO2 max: Maximal oxygen consumption.

r To keep improving one must keep ‘pushing the boundary’ (progressive overload);
r The effect of exercise is reversible: to maintain the benefit one must keep exercising (‘use it or lose it’).

Safety of exercise in MS
Until fairly recently, patients with MS were advised not to exercise because they often experienced exacerbation of
their symptoms. There was also some concern that exercise might provoke relapses. However, while a reasonable
proportion (40%) of MS patients were found to experience worsening symptoms during exercise, this normalized
within 30 min of exercise cessation in 85% of affected patients and within a couple of hours in the remaining
patients [12]. This phenomenon frequently tends to subside as patients become accustomed to exercise. Furthermore,
a systematic review found that MS patients undertaking exercise training had a lower annual relapse rate than control
patients (4.6 vs 6.3%; relative risk: 0.73) [13]. Taken together, exercise training is considered safe for patients with
MS.

Exercise therapy & function

A Danish study evaluated the effect of resistance training in MS patients with Expanded Disability Status Scale
(EDSS) scores between 3 and 5 [14]. Patients were randomized to resistance training (n = 19) or no intervention
(n = 19) for 12 weeks. Intervention consisted of 1 h of exercise on 2 days per week and involved five different
leg exercises. Resistance training led to improvements from baseline of 16% in knee extensor muscle strength and
22% in a composite functional score (6-min walk time [6MWT], timed 10-m walk test [10MWT], stair climbing,
and five-times sit-to-stand test) versus no improvement in the control group (Figure 2). The 6MWT increased
by 55 m, which is a clinically meaningful improvement given that the minimal clinically important difference in
6MWT from the perspective of the MS patient is 21.5 m [15].
To complete a road crossing while the pedestrian light is green requires walking at approximately 1.5 m/s; hence,
it is useful to look at the effect of exercise therapy on walking speed. In the above mentioned resistance training
study, patients’ walking speed increased from 1.29 baseline to 1.51 m/s after the intervention, thus meeting the
required speed threshold [14]. A meta-analysis has since confirmed that exercise therapy has a small but significant
effect on walking speed (mean difference in 10MWT: 1.76 s, 95% CI: 2.47 to -1.06) [16].
Nevertheless, general exercise is not a ‘wonder solution’. The principle of specificity states that to become better
at a particular exercise or task one must perform that exercise or task. Therefore, basic exercise therapy to improve
muscle strength or cardiorespiratory fitness should be regarded as a supplementary treatment to more specific
task-based training such as walking or stair climbing.

36 Neurodegener. Dis. Manag. (2017) 7(6s) future science group

 Exercise therapy in MS Supplement

30
*
Exercise
25 Control

*
20

15
Change (%)

10

-5

-10
KE MVC Functional score

Figure 2. Effect of resistance training on function in multiple sclerosis: change in muscle strength and functional
score after 12 weeks’ resistance training (n = 19) versus control group (n = 19).
Functional score: composite of 6-min walk time, timed 10-m walk test, stair climbing and five-times sit-to-stand test.
* p < 0.05.
KE MVC: Knee-extensor muscle strength.
Reproduced with permission from [14].

Exercise therapy & the brain

Exercise & MS disease progression
Several studies have suggested a link between exercise and MS progression, indicating that exercise affects the
CNS in people with MS. Moreover, a recent study has suggested that intense exercise may reduce the risk of
developing MS independently of established risk factors [17]. There is some evidence to indicate that exercise can
slow the progression of MS, although studies using better methodologies are needed [18]. A study in experimental
autoimmune encephalomyelitis found that animals allowed to exercise freely had much milder disease severity than
their nonexercising counterparts [19], although the difference may have reflected the enforced level of inactivity in
the control group. Additional indirect evidence of a disease-modifying effect of exercise was provided by a systematic
review that found a 27% lower risk of relapse in MS patients who underwent exercise training compared with
controls [13].

Effect of exercise on brain tissue

Several studies have reported promising findings on the relationship between exercise and various brain volumes. A
small cross-sectional study using MRI found an association between aerobic fitness and both grey matter volume
and white matter integrity in patients with MS [20]. Later, an accelerometry study reported correlations between the
level of moderate/vigorous physical activity and the volume of several areas of the brain including the hippocampus,
thalamus, caudate, putamen and pallidum [21]. A case study in MS found that hippocampal volume increased by
16.5% and memory improved by 53% after 12 weeks of aerobic exercise (30 min on 3 days/week) [22]. Finally, a
recent pilot study involving MS patients receiving first-line medical treatment (n = 35), reported a nonsignificant
trend towards reduced brain atrophy in the group of patients who underwent resistance training for 6 months
(2 days/week) compared with the waitlisted (control) group (Figure 3) [23].

Exercise & cognition

Several studies have linked exercise to brain functioning. The cognitive domains most often impaired in MS include
memory/learning, executive function, information processing and attention/concentration. In a systematic review

future science group www.futuremedicine.com 37

Supplement Dalgas

p = 0.08

Pre – post
0.5

0.0

PBVC (%)
-0.5

-1.0

-1.5

-2.0
Training Waitlist

Figure 3. Resistance training and brain volume in multiple sclerosis: mean percentage brain volume change in
patients who underwent 6 months’ resistance training versus control patients.
PBVC: Percentage brain volume change.
Reproduced with permission from [23].

of MS and cognition, five of eight studies reported a positive effect with exercise interventions [24]. However,
cognition was not a primary end point for most studies and methodological differences may have masked some
effects; for example, baseline levels of cognitive impairment and the types of exercise interventions used varied
across the studies [25]. Collectively, available data suggest that exercise has positive effects on the domains of
memory/learning, information processing and attention/concentration [26–32] although the evidence is somewhat
inconsistent.

Recommendations & future needs

Exercise therapy is a safe and potent nonpharmacological intervention in MS patients, with beneficial effects on the
brain and functional capacity. International guidelines on exercise therapy in MS are available [33]. Future research
may provide clearer evidence about whether exercise can influence the general clinical pattern of progression
observed in MS and whether exercise therapy should be regarded as an adjunct to medical treatment. Limitations
of exercise studies performed to date include small sample sizes, short-term interventions (<26 weeks), laboratory
rather than community settings, lower disability levels in most patients (EDSS scores <6), inclusion of mainly
relapsing-remitting MS or mixed-group patient populations and exclusion of patients with comorbidities.

Financial & competing interests disclosure

U Dalgas has received travel grants from Biogen Idec, Merck Serono and Sanofi Aventis; teaching honoraria from Almirall, Biogen
Idec, Merck Serono and Sanofi Aventis; research grants from Bayer Schering, Biogen Idec, Novartis and Sanofi Genzyme. The
author has no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or
financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.
Writing assistance was provided by Content Ed Net (Madrid, Spain), with funding from Almirall SA (Barcelona, Spain).

References
1. Motl RW, McAuley E, Snook EM. Physical activity and multiple sclerosis: a meta-analysis. Mult. Scler. 11(4), 459–463 (2005).
2. Motl RW, McAuley E, Sandroff BM. Longitudinal change in physical activity and its correlates in relapsing-remitting multiple sclerosis.
Phys. Ther. 93(8), 1037–1048 (2013).
3. Kent-Braun JA, Ng AV, Castro M et al. Strength, skeletal muscle composition, and enzyme activity in multiple sclerosis. J. Appl. Physiol.
(1985) 83(6), 1998–2004 (1997).
4. Scott SM, Hughes AR, Galloway SD, Hunter AM. Surface EMG characteristics of people with multiple sclerosis during static
contractions of the knee extensors. Clin. Physiol. Funct. Imaging. 31(1), 11–17 (2011).

38 Neurodegener. Dis. Manag. (2017) 7(6s) future science group

 Exercise therapy in MS Supplement

5. Jørgensen M, Dalgas U, Wens I, Hvid LG. Muscle strength and power in persons with multiple sclerosis – a systematic review and
meta-analysis. J. Neurol. Sci. 376, 225–241 (2017).
6. Kjølhede T, Vissing K, Langeskov-Christensen D, Stenager E, Petersen T, Dalgas U. Relationship between muscle strength parameters
and functional capacity in persons with mild to moderate degree multiple sclerosis. Mult. Scler. Relat. Disord. 4(2), 151–158 (2015).
7. Langeskov-Christensen M, Langeskov-Christensen D, Overgaard K, Møller AB, Dalgas U. Validity and reliability of VO2 max
measurements in persons with multiple sclerosis. J. Neurol. Sci. 342(1–2), 79–87 (2014).
8. Langeskov-Christensen M, Heine M, Kwakkel G, Dalgas U. Aerobic capacity in persons with multiple sclerosis: a systematic review and
meta-analysis. Sports Med. 45(6), 905–923 (2015).
9. Wens I, Dalgas U, Stenager E, Eijnde BO. Risk factors related to cardiovascular diseases and the metabolic syndrome in multiple sclerosis
– a systematic review. Mult. Scler. 19(12), 1556–1564 (2013).
10. Dalgas U, Stenager E, Ingemann-Hansen T. Multiple sclerosis and physical exercise: recommendations for the application of resistance-,
endurance- and combined training. Mult. Scler. 14(1), 35–53 (2008).
11. Motl RW, Pilutti LA. The benefits of exercise training in multiple sclerosis. Nat. Rev. Neurol. 8(9), 487–497 (2012).
12. Smith RM, Adeney-Steel M, Fulcher G, Longley WA. Symptom change with exercise is a temporary phenomenon for people with
multiple sclerosis. Arch. Phys. Med. Rehabil. 87(5), 723–727 (2006).
13. Pilutti LA, Platta ME, Motl RW, Latimer-Cheung AE. The safety of exercise training in multiple sclerosis: a systematic review. J. Neurol.
Sci. 343(1–2), 3–7 (2014).
14. Dalgas U, Stenager E, Jakobsen J et al. Resistance training improves muscle strength and functional capacity in multiple sclerosis.
Neurology 73(18), 1478–1484 (2009).
15. Baert I, Freeman J, Smedal T et al. Responsiveness and clinically meaningful improvement, according to disability level, of five walking
measures after rehabilitation in multiple sclerosis: a European multicenter study. Neurorehabil. Neural Repair. 28(7), 621–631 (2014).
16. Pearson M, Dieberg G, Smart N. Exercise as a therapy for improvement of walking ability in adults with multiple sclerosis: a
meta-analysis. Arch. Phys. Med. Rehabil. 96(7), 1339.e7–1348.e7 (2015).
17. Wesnes K, Myhr KM, Riise T et al. Physical activity is associated with a decreased multiple sclerosis risk: the EnvIMS study. Mult.
Scler. doi:10.1177/1352458517694088 (2017) (Epub ahead of print).
18. Dalgas U, Stenager E. Exercise and disease progression in multiple sclerosis: can exercise slow down the progression of multiple
sclerosis? Ther. Adv. Neurol. Disord. 5(2), 81–95 (2012).
19. Rossi S, Furlan R, De Chiara V et al. Exercise attenuates the clinical, synaptic and dendritic abnormalities of experimental autoimmune
encephalomyelitis. Neurobiol. Dis. 36(1), 51–59 (2009).
20. 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. 1341, 41–51 (2010).
21. Klaren RE, Hubbard EA, Motl RW, Pilutti LA, Wetter NC, Sutton BP. Objectively measured physical activity is associated with brain
volumetric measurements in multiple sclerosis. Behav. Neurol. 2015, 482536 (2015).
22. Leavitt VM, Cirnigliaro C, Cohen A et al. Aerobic exercise increase hippocampal volume and improves memory in multiple sclerosis:
preliminary findings. Neurocase 20, 695–697 (2014).
23. Kjølhede T, Siemonsen S, Wenzel D et al. Can resistance training impact MRI outcomes in relapsing-remitting multiple sclerosis? Mult.
Scler. doi:10.1177/1352458517722645 (2017) (Epub ahead of print).
24. Kalron A, Zeilig G. Efficacy of exercise intervention programs on cognition in people suffering from multiple sclerosis, stroke and
Parkinson’s disease: A systematic review and meta-analysis of current evidence. NeuroRehabilitation 37(2), 273–289 (2015).
25. Sandroff BM. Exercise and cognition in multiple sclerosis: the importance of acute exercise for developing better interventions. Neurosci.
Biobehav. Rev. 59, 173–183 (2015).
26. 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. 112(7), 597–601 (2010).
27. Beier M, Bombardier CH, Hartoonian N, Motl RW, Kraft GH. Improved physical fitness correlates with improved cognition in
multiple sclerosis. Arch. Phys. Med. Rehabil. 95(7), 1328–1334 (2014).
28. Briken S, Gold SM, Patra S et al. Effects of exercise on fitness and cognition in progressive MS: a randomized, controlled pilot trial.
Mult. Scler. 20(3), 382–390 (2014).
29. Sandroff BM, Dlugonski D, Pilutti LA, Pula JH, Benedict RH, Motl RW. Physical activity is associated with cognitive processing speed
in persons with multiple sclerosis. Mult. Scler. Relat. Disord. 3(1), 123–128 (2014).
30. Sandroff BM, Balto JM, Klaren RE, Sommer SK, DeLuca J, Motl RW. Systematically developed pilot randomized controlled trial of
exercise and cognition in persons with multiple sclerosis. Neurocase 22(5), 443–450 (2016).
31. Sandroff BM, Motl RW, Deluca J. The influence of cognitive impairment on the fitness-cognition relationship in multiple sclerosis.
Med. Sci. Sports Exerc. 49(6), 1184–1189 (2017).

future science group www.futuremedicine.com 39

Supplement Dalgas

32. Zimmer P, Bloch W, Schenk A et al. High-intensity interval exercise improvescognitive performance and reduces matrix
metalloproteinases-2 serum levels inpersons with multiple sclerosis: a randomized controlled trial. Mult. Scler. doi:
10.1177/1352458517728342 (2017) (Epub ahead of print).
33. 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. 94(9), 1829.e7–1836.e7 (2013).

40 Neurodegener. Dis. Manag. (2017) 7(6s) future science group