REVIEW

CURRENT
OPINION Advances in physical rehabilitation of
multiple sclerosis
Diego Centonze a,b, Letizia Leocani c, and Peter Feys d

Purpose of review
Multiple sclerosis (MS) is a neurological disorder that heavily affects quality of life (QoL) and demands a
multidisciplinary therapeutic approach. This includes multiple protocols and techniques of physical
rehabilitation, ranging from conventional exercise paradigms to noninvasive brain stimulation (NIBS).
Recently, studies showing the clinical efficacy of physical rehabilitation have remarkably increased,
suggesting its disease-modifying potential.
Recent findings
Downloaded from http://journals.lww.com/co-neurology by BhDMf5ePHKbH4TTImqenVMvFrBEFsYEgKmMjXA5sXWis9de/iNtS2wZpQs18WLgKcj3dmJnlJqE= on 05/24/2020

Studies in animal models of MS have shown that physical exercise ameliorates the main disease
pathological hallmarks, acting as a pro-myelinating and immunomodulatory therapy. NIBS techniques have
been successfully applied to treat pain and urinary symptoms and lower limb function and spasticity,
especially in combination with physical rehabilitation. Physical rehabilitation is reported to be well
tolerated and effective in improving muscle function and fitness even in more disabled patients, and to
enhance balance, walking and upper limb functional movements. Moreover, the dual motor–cognitive task
performance can be improved by combined training protocols.
Summary
The literature here reviewed indicates the importance of clinical and preclinical research in addressing the
impact of neurorehabilitation on MS disability, highlighting the need of further studies to reach a more
comprehensive understanding of the mechanisms involved, the best combination of techniques and the
proper timing of application.
Keywords
immunomodulation, neuroprotection, noninvasive brain stimulation, rehabilitation

INTRODUCTION recently, it has been addressed the disease-modify-

In the context of multiple sclerosis (MS), physical
rehabilitation, hereafter also referred to as exercise,
has long viewed only as a supportive care useful to
control symptoms and to prevent further functional
worsening and sedentary life-style-related conse-
quences [1]. Recently, the raise of studies showing
the clinical efficacy of different forms of rehabilita-
tion have changed our vision of exercise, turning it
into a therapeutic rather than a preventive or a
&& &
symptomatic approach [2,3 ,4 ]. Rehabilitation
programs are currently fully included in the man-
agement of people living with MS (pwMS) [5].
Patients undergoing rehabilitation show a general
improvement of quality of life (QoL) and engage-
ment in daily activities [6,7]. Exercise is reported to
improve ambulatory performance [8], cardiovascu-
lar and neuromuscular functions [9,10], as well as
depression [11]. In spite of some inconsistencies
among studies [12], cognitive functions seem to
be positively influenced by exercise [13]. Only
ing potential of exercise, evaluating its impact on
brain structure and function [14–16], even in com-
bination with inflammatory peripheral markers
[17]. Nevertheless, the underlying mechanisms have
not yet been clarified.
Physical rehabilitation can be tailored to
patient’s disability level, making it successfully
applied to both relapsing—remitting MS (RRMS)
a
Synaptic Immunopathology Lab, Department of Systems Medicine, Tor
Vergata University, Rome, bUnit of Neurology, IRCCS Neuromed, Pozzilli,
IS, cNeurorehabilitation Unit and INSPE-Institute of Experimental Neu-
rology, San Raffaele Hospital, Milan, Italy and dREVAL Rehabilitation
Research Center, Faculty of Rehabilitation Sciences, UHasselt, Belgium
Correspondence to Diego Centonze, MD, PhD, Department of Systems
Medicine, Tor Vergata University, Via Montpellier, 1, 00133 Rome, Italy.
Tel: +39 6 7259 6010; fax: +39 6 7259 6006;
e-mail: centonze@uniroma2.it
Curr Opin Neurol 2020, 33:255–261
DOI:10.1097/WCO.0000000000000816

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Multiple sclerosis
KEY POINTS
 Data from animal models of MS indicate the disease-
modifying efficacy of exercise.
 Physical rehabilitation is reported to restore function in
MS and likely to slow down disease progression.
 NIBS can enhance the effect of physical rehabilitation
in MS.
and progressive MS (PMS) [18]. Moreover, the ther-
apeutic portfolio is quickly expanding in terms of
technology and possibility of self-administration of
exercise protocols. Indeed, conventional rehabilita-
tion, based on active therapeutic exercises of differ-
ent intensities and modalities, can be performed at
home through tele-rehabilitation programs, avoid-
ing the necessity for patients to reach the healthcare
facility [19]. In addition to this, several devices for
robot-assisted therapy and noninvasive brain stim-
ulation (NIBS) protocols are available, providing
different types of ‘passive’ exercises. NIBS proce-
dures are particularly appealing, because of the pos-
sibility to activate brain areas involved in specific MS
symptoms [20].
Here, we will review the proposed neurobiologi-
cal mechanisms of action of physical rehabilitation
as evidenced in preclinical studies of MS and current
advances in both NIBS techniques and conventional
rehabilitation.
NEUROBIOLOGY OF
NEUROREHABILITATION AS RECENTLY
EMERGED IN ANIMAL MODEL OF
MULTIPLE SCLEROSIS
Over the last decades, translational research based
on animal models of MS has been instrumental for
understanding MS pathophysiological mechanisms,
discovering and testing new therapies, including
exercise.
In humans, physical rehabilitation implicates a
broad spectrum of interventions, which are mainly
resistance/strength and endurance training or a
combination of the two. Similar protocols as well
as behavioral interventions, like voluntary exercise
and environmental enrichment, have been tested in
experimental MS [21,22]. Following the increasing
clinical interest in rehabilitation, the rate of publi-
cation on this topic has recently enhanced, expand-
ing from former studies focused exclusively on the
most used MS model, the experimental autoim-
mune encephalomyelitis (EAE), to more recent
investigations in demyelinating models.
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Data collected so far point to the beneficial effects
of exercise on MS pathological processes, including
immune dysregulation, demyelination, axonal loss,
and neurodegeneration [21,22]. Notably, these results
have been gained mainly through a preventive regi-
men of exercise, whereas MS studies, as elsewhere
critically discussed, have been mostly conducted in a
‘late’ therapeutic window and not in early disease
&
phases [4 ]. Such discrepancy between human and
experimental studies underlies the importance of
deepening the role of exercise in both fields of research.
In EAE, research has mainly focused on the
peripheral immunomodulatory activity of exercise.
Among others, one study has provided a detailed
description of the effects of two protocols of preven-
tive resistance training and endurance training exer-
cise [23]. Of note, a significant increase of markers of
T regulatory cells (Tregs) in resistance training mice
was shown, suggesting enhancement of immuno-
suppressive functions. However, the causal relation
between exercise-mediated immunomodulation
and improvement of neurological disability has
been clarified in another study, through a passive
&&
immunization protocol [24 ,25]. Recipient seden-
tary mice receiving T cells from donor exercise-
preconditioned EAE mice, showed a reduced clinical
disability together with attenuated axonal and mye-
lin loss than recipient mice immunized with T cells
&&
derived from sedentary donor mice [24 ].
In EAE mice undergoing exercise, other MS
neuropathological features, like infiltrating immune
cells, microgliosis, astrogliosis, and cytokine levels,
have been found attenuated, likely as a consequence
of peripheral immunomodulation [21,22]. Interest-
ingly, a recent article has first highlighted an axis
between brain and peripheral immune function EAE
mice during environmental enrichment. This study
has demonstrated the leading role of environmental
enrichment-induced raises of the brain-derived
neurotrophic factor (BDNF) in the hypothalamus,
in orchestrating the immunomodulatory activity
mediated by the glucocorticoid receptor expressed
&&
in thymocytes [26 ].
Direct central anti-inflammatory and pro-mye-
linating effects of exercise have been demonstrated
in demyelinating models. Six-week voluntary exer-
cise attenuated astrogliosis, microgliosis, and mye-
lin loss in the corpus callosum and the striatum of
mice exposed to cuprizone (CPZ) [27]. Moreover,
voluntary exercise induced the proliferation of
oligodendrocyte precursor cells (OPCs), their differ-
entiation into oligodendrocytes, and axonal remye-
lination in mice injected with lysolecithin (LCT), in a
mechanism involving activation of the peroxisome
proliferator-activated receptor gamma co-activator
1-alpha (PGC1a) in oligodendrocytes [28].
Volume 33  Number 3  June 2020
 Advances in physical rehabilitation of MS Centonze et al

FIGURE 1. Proposed mechanisms involved in physical exercise in experimental multiple sclerosis. Different protocols of physical
exercise have been tested in animal models of MS. Despite the lack of a comprehensive analysis, data indicate the occurrence of
two main mechanisms activated by exercise, namely a direct effect on the brain and an immunomodulatory activity in peripheral
organs, like thymus, spleen, and lymph nodes. Both mechanisms influence each other (see double arrow in the figure), but most
of the findings suggest that modifications in brain disease is downstream to peripheral immunoregulatory effects. Exercise
positively shape immune response in animal models of MS, by reducing the levels of T-helper type 1 cells (Th1) in favor of Treg
and by attenuating the dysregulated activation of antigen-presenting cells (APCs). At brain level, this translates into attenuated
neuroinflammation, with reduced astrogliosis and microgliosis, improved remyelination and neuroprotection. MS, multiple
sclerosis.

With the above few exceptions, the search for
molecular and cellular mechanisms of exercise-ben-
eficial effects has just started and needs further
analysis to translate into human studies (Fig. 1).
NONINVASIVE BRAIN STIMULATION AND
NEUROREHABILITATION IN MULTIPLE
SCLEROSIS
NIBS, mainly repetitive transcranial magnetic stim-
ulation (rTMS), magnetic theta burst stimulation
(TBS) and transcranial direct current stimulation
(tDCS), have been widely applied to treat several
symptoms in pwMS [29]. Although all these techni-
ques have the potential to affect brain excitability in
both directions (excitatory and inhibitory) accord-
ing to stimulation parameters, studies addressing
MS symptoms or deficits have used only excitatory
NIBS, for example, high-frequency rTMS, intermit-
tent TBS (iTBS), or anodal tDCS. Magnetic and direct
current stimulation are supposed to act by enhanc-
ing neural plasticity, and both have been reported to
increase BDNF production [30,31]. Therefore, ide-
ally the best use of NIBS would be to potentiate the
effects of rehabilitation. Vice-versa, engaging in
rehabilitation or other forms of training (e.g. cogni-
tive), would be the best way to grant the strongest
therapeutic effects of NIBS. However, improvement
after NIBS has been reported for pain [32,33] and
urinary symptoms [32]. Less consistent results have

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Multiple sclerosis
been found for fatigue, upper limb function, and
spasticity.
In the treatment of fatigue, NIBS has been
reported as negative [34], positive after real tDCS
and not after sham but without group difference
[35] or group comparisons [36], positive in compari-
son with sham [37–39]. Studies on fatigue are char-
acterized by heterogeneity on clinical features of
patients included, primary outcome measure, brain
target and stimulation modality, with homoge-
neous treatment duration of five daily sessions with
some exceptions with longer duration [35,39]. No
studies so far explored the possibility to combine
NIBS with other pharmacological, behavioural or
physical interventions for fatigue treatment.
A significant improvement of hand dexterity
has been reported after 5 Hz rTMS [40] and iTBS
[41] over the hand motor cortex compared with
sham. However, the added advantage of concomi-
tant rehabilitation treatment was not studied in
these studies. Moreover, in the study by Azin et al.
[41], treatment assignment was not randomized.
Most studies combining physical rehabilitation
and NIBS have addressed lower limb dysfunction
and spasticity. One first study [42] reported signifi-
cant improvement of spasticity tested with the mod-
ified Ashworth scale (MAS) and with the H/M ratio
after iTBS administered on the motor cortical repre-
sentation of the more affected lower limb during
10 sessions over 2 weeks. Improvement lasted up to
2 weeks beyond the last stimulation session.
Subsequently, the clinical benefits of rehabilita-
tion or iTBS on pwMS and spasticity have been
reported to be lower when administered alone than
when preceding each of 10 daily rehabilitation ses-
sions administered over 2 weeks [43]. In that study,
iTBS alone had effect on MAS alone and rehabilita-
tion alone, outlasting iTBS for 2 more weeks, was
effective at the 2-month follow-up. Combination of
rehabilitation and iTBS was significantly effective
not only on MAS but also on the MS spasticity scale-
88 and measures of fatigue and QoL. Another study
tested the efficacy of 10 sessions of physical therapy
with high-frequency rTMS (20 Hz) or iTBS on the left
lower limb motor cortex in 34 pwMS with a second-
ary progressive course, with significant effects in
reducing MAS up to 12 weeks, more evident after
iTBS [44]. On the other hand, 20 Hz rTMS signifi-
cantly reduced fatigue and pain.
Beneficial effect of iTBS, delivered during the
first half of a 5-week rehabilitation program, has
been found also on a spasticity visual analog in
17 pwMS compared with sham [45]. However, no
significant group effect was found on the MAS. In
that study, magnitude of spasticity improvement
correlated with increased functional connectivity
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between the cortical motor areas of the two hemi-
spheres. In a pilot study, 11 sessions of high fre-
quency rTMS on the lower limb motor cortex
administered with the H-coil significantly improved
walking speed and endurance and reduced spasticity
in pwMS undergoing intensive rehabilitation over 3
weeks. Conversely, no significant advantage of
anodal tDCS over sham delivered over the leg motor
cortex for five consecutive days has been found in
reducing spasticity measured with MAS on 20 pwMS
[46]. This negative finding may be consistent with a
failure of tDCS in improving motor consolidation in
pwMS compared with healthy volunteers, as from a
single-session, cross-over study [47]. However, fail-
ure in reducing spasticity cannot be ascribed only to
the stimulation method, as there was no combina-
tion with rehabilitation, and stimulation was per-
formed only for 5 days. It is well possible that the
benefit of tDCS may require more than one single or
five sessions to become manifest.
For treating lower limb spasticity in pwMS, level
B of evidence (probable efficacy) has been consid-
ered for iTBS to the leg motor cortical representa-
tion. Notably, converging evidence comes from
three studies [43–45] using iTBS in combination
with rehabilitation over a nonnegligible duration
of time (at least 10 sessions).
In addition to the need for larger, multicenter
confirmatory phase III studies, several issues need to
be further clarified, such as the most effective NIBS
techniques and parameters, the best timing and
sequence between NIBS and rehabilitation, and
the prognostic markers that will help selecting the
ideal candidates whom will most benefit from NIBS.
PHYSICAL REHABILITATION IN MULTIPLE
SCLEROSIS
Rehabilitation is increasingly acknowledged as an
essential part of comprehensive care for pwMS, and
can enhance effects of medical treatment options
[48,49].
Rehabilitation and symptomatic treatment aim
to improve functioning, which has been proposed
by the WHO as the third health indicator in addition
to mortality and morbidity [50]. The international
classification of functioning (ICF) developed by the
WHO distinguishes body function, activity, and
participation levels in interaction with personal
and environmental factors. The ICF framework chal-
lenges the rehabilitation physicians and physio-
therapists to understand social context and
personal preferences of pwMS, and highlights the
importance of goal setting, which is extending
beyond body function and structures level. The
WHO is currently strengthening functioning and
Volume 33  Number 3  June 2020

rehabilitation to be integrated in health systems
[51,52].
Progress has been made with accumulating evi-
dence supporting rehabilitation summarized
recently in an overview of Cochrane systematic
reviews [53]. Physical rehabilitation has been shown
to improve physical function and walking. It
includes exercise and task-oriented training meth-
ods that can be considered valid as long they are
accompanied with individualized goal setting, and
include a focus on real daily life functioning and
participation as well [54].
Exercise typically consists of repeated move-
ments during resistance training or endurance train-
ing aiming to improve muscle strength and physical
fitness in pwMS, even in more disabled patients, and
in RRMS and PMS [12,18,55]. Exercise is shown to be
well tolerated, including the high-intensity training
modalities [56,57]. Physical rehabilitation can
improve walking, likely up to EDSS 6 [1,58] and is
thought to have multidimensional effects also
reducing (impact of) fatigue, increasing alertness
and improving health-related QoL. Aerobic training
is now being investigated on its potential to also
affect information processing speed in the large
scale COGEX trial. Longitudinal trials following
physically (in)active pwMS are warranted, com-
bined with intensive exercise interventions.
Task-oriented training is typically applied for
balance, walking and upper limb functional move-
ments [59–61]. It is thought to facilitate activity-
dependent neuroplasticity involving spinal pattern
generators or motor pathways in the brain [1], and
has been shown to modulate brain integrity/volume
and functional connectivity [62]. Effects can be
reinforced by motor imagery and rhythms [63–
65]. Task-oriented training should include motor
learning principles, transparent intensity and pro-
gression rules while avoiding deterioration of move-
ment quality, given that pwMS may start using
compensatory movements when a task is too diffi-
cult or when one is fatigued [66]. Contemporary
methods now incorporate physical management of
the trunk (or so-called core) to facilitate upper and
lower extremities control [67]. For more disabled
patients, task-oriented gait training that includes
the well tolerated and correct use of a walking aid
may reduce falls in pwMS [68], and perhaps more
than exercise [69]. Robot-assisted gait and upper
limb therapy are often considered as task-specific
training and especially promising for more severe
disability; however, most of the devices practice
repetitive movements, which are sometimes goal-
directed, so it could also be considered as training at
body function instead of activity level [70]. When
walking is not possible anymore, a home-based
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Advances in physical rehabilitation of MS Centonze et al
standing frame programme can enhance motor
functions and reduce musculoskeletal pain [71].
Task-oriented training also includes attention to
performance of both physical and cognitive tasks at
the same time. The latter is often required during
daily life, for example, keeping your balance while
cooking, while having kids needing attention or
slowing down during walking when you are chat-
ting with a friend. It is thought that a substantial
number of pwMS experience difficulties in dual task
performance, which also may relate to higher fall
risk [72]. It was recently reported that pwMS show
abnormal higher frontal activation during dual tasks
illustrating higher demands of cognitive control of
movement [73]. Moreover, cognitive–motor inter-
ference can reduce after combined motor–cognitive
dual task training compared with single motor train-
ing [74]. Another phenomenon likely related to a
combination of reduced attentional resources and
neural drive functioning is fatigability that refers to
a decrease in functioning when performing tasks for
a longer time, like reductions in muscle power,
walking speed or cognitive processing tasks over
time [75–77]. Although specific assessment meth-
ods now become available illustrating the preva-
lence of fatigability, especially in more disabled
pwMS, evidence for specific rehabilitation strategies
are currently lacking.
CONCLUSION
Progress has been made in evidence supporting a
variety of physical treatment methods that address
physical function and other domains as fatigue, emo-
tions, and daily life functioning. Supervised therapy
is valued for individualized assessment, monitoring,
and tailored rehabilitation interventions. It should
also be noted these goals can be pursued by imple-
menting clinical practice with structural and func-
tional MR studies, which can highlight the residual
CNS plasticity for better targeted interventions [62].
In addition, to avoid sedentary behavior [78] rehabil-
itation should incorporate empowerment to adopt
an active lifestyle, which can integrate (group) chal-
lenges in one’s community [79]. However, the avail-
ability of skilled physical rehabilitation is very
different worldwide, which is not acceptable when
knowing that effects are likely related to exposure
time [80,81].
Acknowledgements
D.C. thanks Dr Antonietta Gentile for figure preparation.
Financial support and sponsorship
This work was supported by FISM-Fondazione Italiana
Sclerosi Multipla cod.2019/S/1 to D.C.
www.co-neurology.com 259
Multiple sclerosis
Conflicts of interest
There are no conflicts of interest.
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