846096
research-article2019
MSJ0010.1177/1352458519846096Multiple Sclerosis JournalL Prosperini and M Di Filippo
MULTIPLE
SCLEROSIS
JOURNAL
MSJ
Special Issue: Rehabilitation in MS
Beyond clinical changes: Rehabilitationinduced neuroplasticity in MS
Luca Prosperini
Multiple Sclerosis Journal
2019, Vol. 25(10) 1348­–1362
DOI: 10.1177/
https://doi.org/10.1177/1352458519846096
1352458519846096
https://doi.org/10.1177/1352458519846096
© The Author(s), 2019.
Article reuse guidelines:
sagepub.com/journalspermissions
and Massimiliano Di Filippo
Abstract
Background: Neural plasticity represents the substrate by which the damaged central nervous system
(CNS) re-learns lost behaviors in response to rehabilitation. In persons with multiple sclerosis (MS),
rehabilitation can therefore exploit the potential of neural plasticity to restore CNS functions beyond the
spontaneous mechanisms of recovery from MS-related damage.
Methods: Here, we reviewed the currently available evidence on the occurrence of mechanisms of structural and functional plasticity following rehabilitation, motor, and/or cognitive training. We presented
both data gained from basic laboratory research on animal models and data on persons with MS obtained
by advanced magnetic resonance imaging (MRI) techniques.
Results: Studies on physical and environmental enrichment in experimental MS models showed beneficial
effects mediated by both immune modulation and activity-dependent plasticity, lowering tissue destruction
and restoring of CNS network function. Translational researches in MS people demonstrated structural
and/or functional MRI changes after various interventions, but their heterogeneity and small sample sizes
(5–42 patients) raise concerns about the interpretation and generalization of the obtained results.
Discussion: We highlighted the limitations of published studies, focusing on the knowledge gaps to be
filled in terms of neuropathological correlations between changes detected in animal models and changes
detected in vivo by neuroimaging.
Correspondence to:
L Prosperini
Department of
Neurosciences, San CamilloForlanini Hospital, C.ne
Gianicolense 87, 00152
Rome, Italy.
luca.prosperini@gmail.com
Luca Prosperini
Department of
Neurosciences, San CamilloForlanini Hospital, Rome,
Italy
Massimiliano Di Filippo
Section of Neurology,
Department of Medicine,
University of Perugia,
Perugia, Italy
Keywords: Multiple sclerosis, animal model, functional MRI, MRI, quantitative MRI, rehabilitation
Date received: 10 January 2019; revised: 2 April 2019; accepted: 3 April 2019
Overview
Neural plasticity (i.e. the intrinsic property of the central nervous system (CNS) to structurally and functionally adapt itself in response to external stimuli,
environmental changes, or injuries) represents the
substrate by which the damaged brain re-learns lost
behaviors in response to rehabilitation.1 The anatomical basis of such plasticity in the human brain relies
on highly connected neural networks providing
redundancy of CNS even in case of brain damage.2
Multiple sclerosis (MS) is a long-lasting disease typically affecting young adults whose neuropathological
hallmarks are inflammation, axonal and neuronal
loss, demyelination, and astrocytic gliosis.3 From a
neuropathological viewpoint, CNS remodeling after
MS-related brain inflammatory and demyelinating
injuries is thought to be based on complex phenomena, including cell renewal, remyelination, molecular
1348
and ion channel modifications, and changes in the
number and function of synaptic contacts.4 Since
CNS tissues cannot be easily sampled, animal models
have been used to gain insights on such mechanisms,
specifically on the effects of physical and intellectual
activity on functional recovery and neural networks
plasticity in experimental models of MS.5
Clinically, MS is characterized by impairment of
motor and cognitive functions, with a certain degree
of overlap. Even if MS-related clinical deficits could
be reversible via several spontaneous mechanisms
that restore nerve conduction (e.g. resolution of
inflammation, remyelination and adaptive functional
reorganization of brain networks),6 rehabilitation has
the potential to further improve motor and cognitive
functions in persons with MS.7 Seminal studies have
shown that neural plasticity contributes to the potential for functional recovery despite an increasing
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L Prosperini and M Di Filippo
disease burden, suggesting that the accumulation of
disability in MS is not driven by exhaustion of plasticity, but rather is the consequence of specific functional impairments arising from pathology in critical
neural pathways combined with disability-related
deconditioning.8–10 In other words, the MS-related
clinical disability and CNS pathology reflect the
actual performance level, but they do not undermine
functional recovery. There is therefore evidence that
rehabilitation can exploit the individual patient’s
potential to restore CNS functions beyond the aforementioned spontaneous mechanisms of recovery from
MS-related damage6 and regardless of disability level
and tissue damage.9
Here, we sought to summarize the existing evidence
on rehabilitation-induced neuroplasticity in MS,
including basic laboratory research and animal models as well as studies using imaging techniques in persons with MS. We also discussed potential challenges
and opportunities ahead to chart the MS rehabilitation
research agenda in this area.
Cues from experimental models of MS
The structural and functional consequences of physical and environmental enrichment have been investigated in different experimental models of MS,
including experimental autoimmune encephalomyelitis (EAE) induced in mice by active sensitization with
a CNS antigen11–21 and T-cell transfer models in which
myelin-specific lymphocytes are intravenously transferred in naïve recipients.22 Exercise training protocols have been constituted by strategies including
voluntary wheel running,12,14,15,19 swimming pool
workload,13,16 or treadmill running.17,18,22 In some
cases, the experimental paradigm was designed to
reflect the effects of physical activity coupled with
intellectual and social stimulation, in a so-called
“enriched environment.” In this case, the presence of
running wheels coexisted in large cages with a variety
of sensory stimuli, including toys, tunnels, hiding
places, odorants, climbing ladders, paper, and nesting
materials.11,20,21
Exercise has been frequently found to attenuate the
severity of EAE,12–16,18 with only some reports
describing a lack of effect on disability scores.23,24
In parallel with its effects on disability, exercise was
found to induce profound changes in the brain and
spinal cord of EAE mice. Physical exercise influenced the production of interferon gamma (IFN-γ)
and interleukin-17 (IL-17) in the CNS, together
with markers of blood–brain barrier permeability,18
that are early key steps orchestrating the EAE/MS
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immunopathological process. Accordingly, the
pathological consequences of EAE, including CNS
mononuclear cell infiltrates, oxidative stress, myelin, and axonal damage have often been found attenuated in exercised mice.14,16,22 Exercise, for example,
resulted in a 50% overall decrease in total perivascular immune cell infiltrations, CD3+ T cells, and
Mac3+ macrophages in the spinal cord,22 with specific reductions of B cells, CD4+, and CD8 T
cells.16 Axonal damage15,16 and motor neuron loss in
the lumbar spinal cord15 have been found attenuated
in mice in response to exercise. Beneficial effects of
exercise on myelin have also been suggested to
occur both in the spinal cord15,16 and in cognitively
important cortical areas such as the hippocampus
CA1 and dentate gyrus,17 in this latter case coupled
with a partial rescue of EAE-induced memory deficits measured by a step-down avoidance task.
Such beneficial effects of exercise training on EAE
might be mediated by peripheral immunomodulation,
rather than on a direct effect on the CNS.22 The transfer of lymph node-derived T cells obtained from mice
immunized with a proteolipid protein (PLP) peptide
indeed results in a markedly attenuated EAE in recipient mice if donor mice are exercise trained,22 suggesting that exercise might attenuate EAE simply by
modulating the systemic immune system. One key
question thus deals with the difficulty to differentiate
the immune-modulating effects of exercise from the
direct effects that exercise might induce as “neuroprotective” or even “restorative” strategy. The fact that in
many studies exercise has been applied prior or immediately after the induction of EAE further complicates
this matter, as it has been suggested that when applied
after the onset of neurological deficits, exercise might
not be able to impact on disability scores in mice with
EAE.24
However, besides being able to impact on the immune
system and thus result in a milder form of EAE,21
other mechanisms have been proposed to explain the
“central” effect of physical and intellectual enrichment on experimental MS. Indeed, exercise and environmental enrichment have been found to promote
neural progenitor cell mobilization and recruitment at
lesion sites,11 to modulate the levels of brain neuroactive steroids,19 and to influence the expression of neurotrophic factors in the CNS of EAE mice.13,17,21,23
Specifically, the expression levels of brain-derived
neurotrophic factor (BDNF), a molecule known to
promote synaptic plasticity, have been found increased
during EAE in both the spinal cord and the brain13
with increased expression levels in key brain areas
such as the hypothalamus21 and the hippocampus.17
1349
Multiple Sclerosis Journal 25(10)
Figure 1. Schematic time course of experimental multiple sclerosis and summary of preclinical data on the proposed
beneficial effects of exercise both as immune modulator and enhancer of brain plasticity and recovery mechanisms.
The total brain levels of another neurotrophic factor,
nerve growth factor (NGF), were greater in exercised
EAE mice.23
Notably, exercise has been found to counteract the
marked reduction of spine density along the extent of
neuronal dendrites occurring in the nucleus striatum
of EAE mice,12 counterbalancing the loss of synaptic
contacts in brain structures playing key roles in motor
control, cognition, and behavior. Interestingly, this
effect was not found to be the consequence of a
reduced infiltration of immune cells in the striatum,
suggesting a direct effect of exercise on spine density.12 These “structural” effects of exercise are
accompanied by the restoration of functional synaptic
properties, with the normalization of the modulatory
effects of cannabinoid receptors in regulating striatal
gamma-aminobutyric acid (GABA) neurotransmission.12 Similarly, environmental enrichment was
found to ameliorate presynaptic defects in cortical
glutamatergic nerve endings in EAE mice, restoring
glutamate exocytosis,20 but this latter effect was coupled with a reduction of cortical cellular infiltrates,
suggesting that it could depend, at least in part, on the
reversal of an immune-mediated synaptopathy, an
event that is known to occur in the EAE brain.25
1350
EAE is partially different from human MS in terms of
immunopathology and response to therapy. However,
taken together, animal data suggest the presence of
significant effects of physical and cognitive stimulation on the dynamics of CNS networks, because of
both an immune-modulating effect and a restorative
effect on myelin, axonal integrity, and synaptic structure and function (Figure 1). Future preclinical studies should be designed with limited heterogeneity in
terms of exercise modality (type, timing, and intensity) and outcomes (physical and cognitive/behavioral disability and protein expression levels), to better
differentiate among the immunological, neuroprotective, or even restoring effects of exercise, with the aim
to eventually identify specific molecular pathways
underlying exercise-induced plasticity to be therapeutically targeted (Table 1).
From bench to bedside: the role of magnetic
resonance imaging
Conventional magnetic resonance imaging (MRI) is
essential for diagnosis and monitoring of MS, mainly
because of its ability to detect disease activity beyond
clinical measures. Focal white matter (WM) lesions
are the pathological hallmark of the disease, but gray
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L Prosperini and M Di Filippo
Table 1. Future directions in preclinical research on exercise-induced CNS plasticity.
1. Definition and application of standardized protocols to EAE studies (sample size calculation, randomization, blind
evaluation of outcomes, multi-center participation), similar to those applied to human studies
2. Better definition and standardization of exercise type, application (forced versus voluntary), and duration
3. Implementation of preclinical studies of exercise applied after the onset of disability, rather than before or
immediately after disease induction, to discern the peripheral immune effects of exercise from its effects on
structural and functional networks plasticity
4. Analysis of the effects of exercise on the main forms of brain synaptic plasticity, namely long-term potentiation
(LTP) and long-term depression (LTD) in different neural structures, through experimental electrophysiology
techniques
5. Identification of the mechanistic bases of exercise beneficial effects, to be pharmacologically targeted (e.g. the
molecular pathways underlying synaptic potentiation)
6. Testing the potential additive effects of exercise with pharmacological approaches targeting the cellular and/or
synaptic mechanisms of plasticity
7. Identification of exercise-induced molecular and protein expression changes in specific structures rather than in the
whole brain or spinal cord (e.g. cerebellum, thalamus, motor cortex), as well as in areas identified by human MRI
studies
8. Refinement of outcomes identification for preclinical studies beyond crude clinical scores of motor function (testing
for visuospatial function, memory, sensory deficits, sociality, depression like-behavior and anxiety)
CNS: central nervous system; EAE: experimental autoimmune encephalomyelitis; MRI: magnetic resonance imaging.
matter (GM) damage is also present since MS onset
and may become even more extensive than WM
involvement in long-lasting MS.3 However, conventional MRI measures are not specific to the different
pathological substrates and only partially explain the
clinical features of MS, thus raising the concept of the
so-called “clinical-radiological paradox,” that is, the
mismatch between CNS pathology and its clinical
expression.26 This issue has driven the application of
non-conventional advanced MRI techniques based on
higher-field MRI scanners, improved acquisition
methods and pre- and post-processing analyses,
allowing the assessment of macrostructural and
microstructural changes, metabolism, and function of
disease-modified CNS regions.27
Microstructural plasticity, including changes at cellular
and molecular level into the neuronal and extra-neuronal environments in WM and GM, can be explored
by basic research experiments on animal models as
result of learning-dependent and training-dependent
plasticity, as afore described. However, these microstructural changes also influence MRI signals; neuroimaging is therefore the most suitable tool to investigate
plasticity in vivo, despite the fact that MRI metrics are
difficult to relate unambiguously to underlying neuropathology features and rehabilitation-induced changes.4
The most informative MRI techniques are diffusion
tensor imaging (DTI), regional WM and GM volume
assessment, and magnetization transfer ratio (MTR)
for the investigation of the structural brain plasticity
and task-related functional magnetic resonance
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imaging (fMRI) and resting state functional magnetic
resonance imaging (RS-fMRI) for the investigation
of the functional brain plasticity.
DTI provides quantitative information on the integrity
of the myelin-axon unit based on the directional asymmetry of water diffusion by four so-called DTI scalars:
(1) fractional anisotropy (FA), a summary measure of
microstructural integrity that is highly sensitive to
changes, but less specific to the type of change; (2)
mean diffusivity (MD), an inverse measure of the
membrane density which increases during hypercellularity, edema, and necrosis; (3) axial diffusivity (AD),
a marker of axonal integrity that decreases in axonal
damage; and (4) radial diffusivity (RD), a marker of
myelin sheath integrity that increases during demyelination.28 However, DTI scalars should be interpreted
cautiously since they can be influenced by different
pathological substrates and age-related processes.
GM and WM volume analysis derives from the
acquisition of appropriate MRI sequences (typically
high-resolution 3D T1-weighted) that allow the measurement of changes in regional volumes over time
using segmentation-based and/or registration-based
analyses and dedicated software tools.29
MTR quantifies the amount of interactions between protons in free fluid and protons bound to macromolecules,
such as proteins or lipids, which are relatively immobile,
thus providing an estimation of the extent of tissue disruption when myelin or other cellular structures (e.g.
axons and neurons) are damaged by MS processes.30
1351
Multiple Sclerosis Journal 25(10)
fMRI techniques are based on the detection of changes
in the blood oxygenation level–dependent (BOLD)
signal in specific brain regions, which is in turn
affected by changes in neural activity and the underlying physiology or pathology.31 These changes reflect
system-level plasticity in brain networks that can be
detected either in a resting or task-negative state,32 to
explore the functional connectivity between different
brain regions (RS-fMRI), or during the execution of a
specific task (e.g. simple motor activity, sensory
stimulation, cognitive effort, etc.; task-related fMRI)
to explore patterns of change in brain activation due
to practice (decrease, increase, redistribution, and
reorganization).33
Decrease in extent or strength of activation is thought
to reflect more efficient information processing within
a network where less neurons are firing in response to
a task. Increased extent and/or strength of activation
within one network are thought to reflect additional
recruitment of cortical units or reinforcement of
response to a specific task, respectively. Redistribution
of activation refers to combined increase and decrease
within the same network involved in a specific task.
Reorganization processes include decreased activation in some areas and additional recruitment of new
cortical regions.
Translational research on persons with MS
While a number of cross-sectional studies have
described different patterns of tissue damage and
functional reorganization of the CNS according to the
different disease stages (thereby providing an indirect
evidence on the role of neural plasticity),27 fewer longitudinal studies have provided MRI-based evidences
of rehabilitation-enhanced functional and structural
plasticity in MS.34
We identified 15 articles regarding motor rehabilitation and 19 articles on cognitive rehabilitation.10,35–67
Structural plasticity was investigated more often
than functional plasticity following motor rehabilitation (nine articles)36–38,40,41,43–45,47 than following
cognitive rehabilitation (four articles),56,62,64,67 especially by means of DTI techniques. Functional plasticity was investigated in nine articles on motor
rehabilitation10,35,39,40,42,45–48 and always following
cognitive rehabilitation,49–65 with both task-related
fMRI and RS-fMRI in most articles. The effect of
motor and cognitive rehabilitation on regional brain
volumes was investigated in five articles;41,44,45,56,67
just one article used a MTR-based technique.62 A
multimodal MRI approach, combining techniques to
detect structural and functional plasticity promoted
1352
by rehabilitation, was only rarely applied.45,47,56,67
Finally, 18 articles reported correlations between
clinical improvement and structural or functional
MRI changes.10,38,39,43–46,48,51,52,57–60,63,64,66,67
Figure 2 provides a summary of brain regions targeted
by motor and cognitive rehabilitation according to the
currently published studies. The minimal duration
between consecutive MRI scans to detect WM structural changes was at least 2 months in both motor36–
38,40,43 and cognitive64 rehabilitation studies. Changes
in GM volumes were detected after a minimum of 2
or 3–6 weeks following motor45 and cognitive67 training, respectively. Functional changes at both taskrelated fMRI and RS-fMRI were detected in minimum
2 weeks following motor training10,45 and in minimum
3–4 weeks following cognitive training.49
Motor rehabilitation
Although they differed from each other, studies on
motor rehabilitation10,35–48 have suggested that taskoriented training10,37–39,43,45,48 rather than “holistic”
approaches35 can reveal rehabilitation-induced plasticity (Table 2). In other words, the plasticity of the
motor system seems to be “task-dependent,” that is,
closely related to the trained function. High-intensity
repetitive training accompanied by visual feedback
(e.g. visuomotor task training,10 exergames,38,39 and
action observation training45) as well as more “classical” rehabilitation (e.g. assisted physiotherapy,36,40
running training program,41 constraint-induced movement therapy,43 and resistance training44) were associated with positive structural changes in WM and GM.
The microstructural integrity of corpus callosum has
been reported as a target for facilitation-based physiotherapy interventions36,40 and constraint-induced
movement therapy.43 Passive upper limb rehabilitation was related to maladaptive structural plasticity
(likely triggered and sustained by deconditioning) of
corpus callosum and corticospinal tracts.37 Favorable
myelination-related processes along the bilateral
superior cerebellar peduncles38 and enhanced connectivity of the cerebellar network39 were detected after
balance training with active exergames. Rehabilitation
could also have a restorative effect on GM, as suggested by increased left pallidum volume and thickness of specific cortical regions (anterior cingulate
gyrus, temporal pole, orbital sulcus, and inferior temporal sulcus) after a start-to-run program for mildly
disabled patients41 and progressive resistance training,44 respectively.
Studies on functional brain changes detected with taskrelated fMRI provided mixed results (no effect,35,40
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L Prosperini and M Di Filippo
Figure 2. Brain regions targeted by motor and cognitive rehabilitation in persons with multiple sclerosis.
Triangles denote structural plasticity changes; circles denote functional plasticity changes; please note that the side of involved brain
regions is omitted.
reduced activation,10,47 and increased activation42,45),
whereas studies based on RS-fMRI always showed
increased connectivity of regions involved in motor
control (cerebellum,39 primary,42 or supplementary
motor areas45,48). The only study based on a multimodal MRI approach showed improvement of hand
motor performance after active observation training
mediated by functional and structural changes in
motor areas and mirror neuron system.45
Cognitive rehabilitation
Studies on cognitive rehabilitation,49–67 most of which
were focussed on computer-assisted training of attention or working memory, provided findings that, to
some extent, can be considered similar despite the
heterogeneity in the adopted fMRI tasks and RS-fMRI
analyses. Most of the articles provide indeed evidence
of increased activation in rehabilitation-targeted areas
at task-related fMRI and increased connectivity or
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reorganization of targeted brain networks at RS-fMRI
(Table 3).
Computer-assisted retraining of attention was associated with increased task-related activation of cingulate cortex,49,56 precuneus,49,56 prefrontal regions,49,56
cerebellum,50,58 and associative temporoparietal cortex62 and increased RS-fMRI connectivity of areas
involved in the frontal-executive network,51 salience
processing,56 and default-mode network (prefrontal
cortex, cingulate cortex, inferior parietal lobule, and
precuneus).56–59,63
Computer-assisted working memory training was
associated with increased task-related activation of
prefrontal and parietal areas involved in the working
memory network,60,66 precuneus, and cerebellum66
and increased RS-fMRI connectivity between frontoparietal areas and the default-mode network and
between nodes of the default-mode network itself.60
1353
1354
28
11
23
30
27
Rasova
et al.35
Ibrahim
et al.36
Tomassini
et al.10
Bonzano
et al.37
Prosperini
et al.38
14
20
Leonard
et al.42
Barghi
et al.43
35
42
Feys
et al.41
Kjølhede
et al.44
12
Rasova
et al.40
Tona
et al.39
Sample
size
References
Randomized
Controlled
Crossover
Randomized
Controlled
Parallel group
Randomized
Controlled
Parallel group
Randomized
Controlled
Parallel group
Non-randomized
Uncontrolled
Longitudinal
Randomized
Controlled
Crossover
Randomized
Controlled
Parallel group
Non-randomized
Uncontrolled
Longitudinal
Non-randomized
Uncontrolled
Longitudinal
Non-randomized
Controlled
Parallel group
Study design
Progressive
resistance training
versus wait list
Constraintinduced movement
therapy versus
complementary and
alternative medicine
Non-invasive tongue
stimulation versus
sham in combination
with cognitive
and physical
rehabilitation sham
“Start-to-run”
program versus
wait list
Motor program
activating therapy
Balance
rehabilitation with
exergames versus
wait list
Active versus
passive rehabilitation
of upper limb
functions
Home-based
visuomotor task
training
Operator-assisted
facilitation
physiotherapy
Eclectic sensorimotor learning and
adaptation versus no
intervention
Intervention(s)
Exergame group: ↓ postural instability = ↑
connectivity in the vermis, right cerebellum,
caudate nucleus, right prefrontal and
occipital cortices, orbitofrontal, and
temporal cortices
Not reported
Not reported
Not reported
Exergame group: ↑ connectivity of the
cerebellar network in several brain areas
(cerebellum, orbitofrontal, prefrontal,
temporal, and occipital cortices, precuneus,
right caudate nucleus)
1. ↑ FA and ↓ MD in CC
2. No effect
1. No effect
2. “start-to-run” program group: ↑ left
pallidum volume
Non-invasive tongue stimulation group: ↑
activation of left MA;
Sham group: ↑ activation of bilateral premotor cortex
Not specified
Twice weekly
24 weeks
3.5-hour sessions
Once daily
10 weeks
90-minute sessions
Twice daily
14 weeks
Not specified
3 times per week
12 weeks
60-minute sessions
2 times per week
2 months
Regional brain
volumes
DTI (TBSS)
Task-related fMRI
(gait imagery and
working memory)
1. DTI (TBSS)
2. Regional brain
volumes
1. DTI of CC
2. Task-related
fMRI (finger
movements)
RS-fMRI
DTI of cerebellar
connections
(Continued)
Progressive resistance training group: ↑ leg
muscle strength (dynamometer) = ↑ cortical
thickness in ACC
Exergame group: ↓ postural instability = ↑
FA and ↓ RD of SCPs
Exergame group: ↑ FA and ↓ RD of SCPs
30-minute sessions
5 times per week
12 weeks
Progressive resistance training group: ↑
cortical thickness in ACC, temporal pole,
orbital sulcus and inferior temporal sulcus
Not reported
Active rehabilitation group: ↑ RD of SLF
Passive rehabilitation group: ↓ FA and ↑ RD
of CC, CSTs, SLF
60-minute sessions
3 times per week
2 months
Constraint-induced movement therapy
group: ↑ motor activity log of more
impaired arm = ↑ FA of contralateral CC and
ipsilateral SOG
↓ tracking error in visuomotor task = ↓
activation in left superior lobule and right
occipital cortex
↓ activation in left precuneus, left cuneus,
and right supracalcarine cortex
Task-related fMRI
(visuomotor task)
12-minute sessions
Once daily
15 days
Constraint-induced movement therapy
group:
↑ FA of contralateral CC and ipsilateral
SOG;
↑ AD of ipsilateral STG;
↓ MD and RD of contralateral CST
Not reported
↑ FA and ↓ MD of CC
DTI of CC
DTI of CC, CST,
SLF
Not reported
No effect
Task-related fMRI
(finger-thumb
movement)
60-minute sessions
2 times per week
2 months
60-minute sessions
Once weekly
2 months
Correlation(s) between clinical and MRI
changes
Main finding(s)
MRI technique(s)
Intensity
Frequency
Duration
Table 2. Studies demonstrating structural and functional brain plasticity enhanced by motor rehabilitation.
Multiple Sclerosis Journal 25(10)
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41
8
29
14
Rocca
et al.45
Sandroff
et al.46
Tavazzi
et al.47
Fling at
al.48
Longitudinal
(only in the
active group,
the original
randomized
controlled trial
was analyzed)
Non-randomized
Longitudinal
Randomized
Controlled
Parallel group
Randomized
Controlled
Parallel group
Study design
Task-oriented
walking aid training
Resistance and
endurance training
Treadmill walking
exercise versus
wait list
Action observation
training versus
landscape watching
for upper limb
function
Intervention(s)
Treadmill walking exercise group: ↑ VO2
peak = ↑ SDMT scores = ↑ connectivity of
thalamo-cortical network
Not reported
Not reported
Treadmill walking exercise group: ↑
connectivity with right SFG gyrus and left
MFG
1. No effect
2. No effect
3. ↓ activation in the contralateral MA
4. ↑ connectivity of the primary sensorimotor cortex
↑ connectivity between SMA bilaterally
and primary motor cortex and putamen
bilaterally
↓ connectivity between SMA and
cerebellum
RS-fMRI (thalamus
seeded)
1. DTI of cingulum,
CST, CC
2. DTI (TBSS)
3. Task-related
fMRI (plantar dorsiflexion)
4. RS-fMRI
40-minute session
Once weekly
6 weeks
30- to 45-minute
sessions (twice every
day)
5 times per week
12 weeks
RS-fMRI (left and
right SMA seeded)
1. No correlation
2. Action observation training group:
↑ right finger tapping frequency = ↑ GM
volume of right IFG;
↑ FIM score and bilateral hand strength = ↑
GM volume of right SFG and IFG, ↓ GM
volume right SMA
↑ PASAT score = ↑ GM volume of right SFG
3. Action observation training group:
↑ right finger tapping frequency = ↑
activation of IFG bilaterally;
↑ right-hand strength = ↑ activation left
insula and bilateral, ↓ activation of AG and
MTG
↑ PASAT score = ↑ increased activation of
right IFG
4. ↑ PASAT score = ↑ connectivity in right
IFG (motor network)
1. No effect
2. Action observation training group:
↑ GM volume in left MOG, left SFG, right
IFG; and ↓ GM in right SMA;
control group: ↓ GM in MTG
3. Action observation group: ↑ activation of
left FG and right SFG (left-hand task), and
bilateral IFG and left insula (right-hand task)
4. Action observation training group: ↑
connectivity in left cerebellum and right IFG
(motor network), and in right cerebellum
and CS (mirror neuron system);
control group: ↑ connectivity in right SMA
(motor network) and left ACC (mirror
neuron system)
1. DTI (TBSS)
2. Regional brain
volumes
3. Task-related
fMRI (hand
manipulation task)
4. RS-fMRI
40-minute sessions
5 times per week
2 weeks
15- to 40-minute
sessions
3 times per week
12 weeks
Correlation(s) between clinical and MRI
changes
Main finding(s)
MRI technique(s)
Intensity
Frequency
Duration
ACC: anterior cingulate cortex; AD: axial diffusivity; AG: angular gyrus; CC: corpus callosum; CS: calcarine sulcus; CST(s): corticospinal tract(s); DTI: diffusion tensor imaging; FA: fractional anisotropy; fMRI: functional
magnetic resonance imaging; FG: frontal gyrus; FIM: Functional Independence Measure; GM: gray matter; IFG: inferior frontal gyrus; MA: motor area; MD: mean diffusivity; MFG: middle frontal gyrus; MOG: middle occipital
gyrus; MRI: magnetic resonance imaging; MTG: middle temporal gyrus; PASAT: Paced Auditory Serial Addition Test; PMA: pre-motor area; RD: radial diffusivity; RS: resting state; SCP(s): superior cerebellar peduncle(s);
SDMT: Symbol Digit Modalities Test; SFG: superior frontal gyrus; SLF: superior longitudinal fasciculus; SMA: supplementary motor area; SOG: superior occipital gyrus; STG: superior temporal gyrus; TBSS: tract-based spatial
statistic; VO2: peak oxygen uptake.
“↓” denotes reduced; “↑” denotes increased; “=” denotes associated with.
Sample
size
References
Table 2. (Continued)
L Prosperini and M Di Filippo
1355
1356
15
Sastre-Garriga
et al.50
120-minute
sessions
Once weekly
6 weeks
Task-related fMRI
(evocation of specific
personal memories and
sentence construction)
Mental visual imagery
training versus no
intervention
Not reported
Not reported
Modified Story Memory Technique
group: ↑ connectivity between the
left hippocampus and insula and
cerebellar vermis;
↑ connectivity between the right
hippocampus and postcentral gyrus;
↑ connectivity between the posterior
cingulum and thalamus
↑ activation of right cuneus, left
precuneus, SOG and IOG, and
bilateral temporal cortex
↓ activation of DLPFC and medial
PFC
(Continued)
Modified Story Memory
Technique group: ↑
responses at CVLT
short-delay free recall = ↑
activation of right MFG
Modified Story Memory Technique
group: ↑ activation of some areas
of frontal, parietal, temporal, and
occipital cortices and cerebellum
Task-related fMRI
(list learning and word
recognition task)
45- to 60-minute
sessions
2 times per week
5 weeks
Ernst et al.55
Non-randomized
Controlled
Parallel group
↑ z-score of attention test
(TMT, SDMT, and DS) = ↑
synchronization in frontalexecutive networks
↑ synchronization in the visual
medial, cerebellar, and frontalexecutive networks;
↓ synchronization in the auditory
network
Pseudo RS-fMRI
RS-fMRI (hippocampi
and posterior cingulum
seeded)
8
Not found
↑ activation of left anterior and
bilateral posterior cerebellar lobes
Task-related fMRI
(PASAT)
60-minute sessions
3 times per week
5 weeks
Not reported
Not reported
↑ activation of cingulum, precuneus,
and frontal cortex
Task-related fMRI
Not specified
Not specified
3–4 weeks
Modified Story Memory Technique
group: ↑ activation of MFG, IPL,
MOG, cerebellum (ROI analysis); ↑
IOG, IPL, medial temporal cortex
Correlation(s) between
clinical and MRI changes
Main finding(s)
MRI technique(s)
Intensity
Frequency
Duration
Leavitt et al.54
Modified Story
Memory Technique
versus story reading
and answering
questions
Computer-assisted
training of attention
plus game-like group
activities
Computer-assisted
training of attention
Intervention(s)
Task-related fMRI (word
encoding task) 6 months
after training
Randomized
Controlled
Parallel group
Non-randomized
Uncontrolled
Longitudinal
Non-randomized
Uncontrolled
Longitudinal
Study design
Dobryakova
et al.53
Chiaravalloti
et al.52
16
11
Penner and
Kappos49
Pareto et al.51
Sample
size
References
Table 3. Studies demonstrating structural and functional brain plasticity enhanced by cognitive rehabilitation.
Multiple Sclerosis Journal 25(10)
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journals.sagepub.com/home/msj
20
Filippi et al.56
23
32
5
10
Cerasa et al.58
Bonavita
et al.59
Hubacher
et al.60
Hubacher
et al.61
Parisi L
et al.57
Sample
size
References
Table 3. (Continued)
Randomized
Controlled
Parallel group
Non-randomized
Uncontrolled
Longitudinal
Non-randomized
Controlled
Parallel group
Randomized
Controlled
Parallel group
Randomized
Controlled
Parallel group
Study design
Computer-assisted
working memory
training (BrainStim)
versus no intervention
Computer-assisted
working memory
training (BrainStim)
versus no intervention
Computer-assisted
cognitive training
(RehaCom) versus
reading newspaper
Computer-assisted
cognitive training
(RehaCom)
versus visuomotor
coordination task
training
Computer-assisted
cognitive training
(RehaCom) versus no
intervention
Intervention(s)
↑ SDMT, WM test and
alertness scores = ↑
activation of working
memory network and ↑
subcomponents of DMN
1. ↑ activation of working memory
network
2. ↑ connectivity between
frontoparietal network and DMN and
between subcomponents of the DMN
45-minute sessions
4 days per week
4 weeks
45-minute sessions
4 days per week
4 weeks
Task-related fMRI (nback task)
1. Task-related fMRI (nback task)
2. RS-fMRI (DMN,
frontoparietal networks,
salience network)
(Continued)
↑ Stroop test scores = ↑
connectivity of PCC
RehaCom group: ↑ connectivity in
PCC and IPL, bilaterally
50-minute sessions
2 times per week
8 weeks
Not reported
↑ Stroop test scores = ↑
activation of right posterior
cerebellar lobule, left SPL,
precuneus, and DLPFC
RehaCom group: ↑ activation of the
right posterior cerebellar lobule and
left SPL
Task-related fMRI
(PVSAT)
BrainStim group: distinct individual
changes regarding activation patterns
after training
RehaCom group: ↑ PASAT
scores = ↑ connectivity of
the ACC with the right MFG
and right IPL
RehaCom group: ↑ connectivity
of the ACC with the right MFG
and right IPL; no intervention
group: ↓ connectivity with the right
cerebellum and right ITG
RS-fMRI (ACC seeded)
RS-fMRI (DMN)
Not reported
1. no effect
2. no effect
3. RehaCom group: ↑ activation
of PCC, precuneus and DLPFC
(bilaterally)
4. RehaCom group: ↑ connectivity
of ACC (salience processing),
left dorsolateral prefrontal cortex
(executive function), right IPL, PCC
and/or precuneus (default-mode
network I and II)e
1. DTI (TBSS)
2. Regional brain volumes
3. Task-related fMRI
(Stroop)
4. RS-fMRI
60-minute sessions
3 times per week
12 weeks
60-minute sessions
2 times per week
6 weeks
Correlation(s) between
clinical and MRI changes
Main finding(s)
MRI technique(s)
Intensity
Frequency
Duration
L Prosperini and M Di Filippo
1357
1358
38
22
Campbell at
al.62
De Giglio
et al.63
18
20
Bonzano
et al.66
Ernst et al.67
Randomized
Controlled
Parallel group
Randomized
Controlled
Parallel group
Randomized
Controlled
Parallel group
Randomized
Controlled
Parallel group
Randomized
Controlled
Parallel group
Study design
Mental visual imagery
training versus sham
verbal program
Home-based adaptive
versus non-adaptive
working memory
training (COGNITRAcK)
Modified Story
Memory Technique
versus story reading
and answering
questions
120-minute
sessions
Once or twice
weekly
3–6 weeks
30-minute sessions
5 days per week
8 weeks
45- to 60-minute
sessions
3 days per week
6 weeks
30-minute sessions
5 days per week
8 weeks
↑ PASAT scores = ↓ AD
of CC
Home-based video games group: ↓
AD of CC
Modified Story Memory Technique
group: ↑ activation of DLPFC, SMA,
and IPL
DTI of CC
Task-related fMRI (word
learning task)
1. Task-related fMRI
(evocation of specific
personal memories and
sentence construction)
2. RS-fMRI
3. Regional brain volumes
Task-related fMRI
(PVSAT)
↑ PASAT scores = ↑
activation of right IPL
↑ autobiographical memory
performance = ↑ volume of
left parahippocampal gyrus
Adaptive COGNI-TRAcK group:
↑ activation of left precuneus, SPL,
PCG, SFG, and right cerebellum
and IPL
1. ↑ activation of left MFG and right
thalamus
2. ↓ connectivity of precuneus and
cingulate cortex
3. ↑ volume of left parahippocampal
gyrus
Not reported
↑ SDMT scores = ↑
connectivity in bilateral
parietal cortices
↑ Stroop scores = ↑
connectivity in right lateral
parietal cortex
↑ PASAT scores = ↓
connectivity in the vermis
and right cerebellar
hemisphere
RS-fMRI (thalami seeded)
Home-based video games group:
↑ connectivity in PCC, precuneus,
and lateral parietal cortices; ↓
connectivity in vermis, cerebellar
hemispheres and left DLPFC
Not reported
1. no effect
2. RehaCom group: ↑ activation of
the right temporoparietal regions
(supramarginal and angular gyri)
1. Quantitative MTR
2. Task-related fMRI (nback task)
45-minute sessions
3 days per week
6 weeks
Home-based computerassisted cognitive
training (RehaCom)
versus watching DVDs
Home-based video
games versus wait list
Correlation(s) between
clinical and MRI changes
Main finding(s)
MRI technique(s)
Intensity
Frequency
Duration
Intervention(s)
ACC: anterior cingulate cortex; AD: axial diffusivity; CC: corpus callosum; CVLT: California Learning Verbal Test; COGNI-TRAcK: Cognitive Training Kit; DLPFC: dorsolateral prefrontal cortex; DMN: default-mode network;
DS: digit span; DTI: diffusion tensor imaging; DVDs: digital versatile disks; fMRI: functional magnetic resonance imaging; IFG: inferior frontal gyrus; IOG: inferior occipital gyrus; IPL: inferior parietal lobule; ITG: inferior
temporal gyrus; MFG: middle frontal gyrus; MOG: middle occipital gyrus; MRI: magnetic resonance imaging; MTR: magnetization transfer ratio; PASAT: Paced Auditory Serial Addition Test; PCC: posterior cingulate cortex;
PCG: pre-central gyrus; PFC: prefrontal cortex; PVSAT: Paced Visual Serial Addition Test; ROI: regions of interest; RS: resting state; SDMT: Symbol Digit Modalities Test; SFG: superior frontal gyrus; SMA: supplementary
motor area; SOG: superior occipital gyrus; SPL: superior parietal lobule; TBSS: tract-based spatial statistic; TMT: Trail-Making Test; WM: white matter.
“↓” denotes reduced; “↑” denotes increased; “=” denotes associated with.
16
Huiskamp
et al.65
De Giglio
et al.64
Sample
size
References
Table 3. (Continued)
Multiple Sclerosis Journal 25(10)
journals.sagepub.com/home/msj
L Prosperini and M Di Filippo
Studies on the imagery- and context-based memory
retraining program based on the modified Story
Memory Technique showed an increased task-related
activation of various associative areas of frontal, parietal, temporal, and occipital cortices52,53,65 and cerebellum.52,53 Increased RS-fMRI connectivity of
hippocampus with insula, parietal cortex, and cerebellum as well as increased RS-fMRI connectivity of
posterior cingulum and thalami were also reported.54
Studies on mental visual imagery aimed at restoring
autobiographic memory showed partially conflicting
results, because one article found increased taskrelated activation of posterior parietal and occipital
areas and bilateral temporal cortex and reduced taskrelated activation of some prefrontal areas,55 while
another article found increased task-related activation
of middle prefrontal regions and reduced RS-fMRI
connectivity of precuneus and posterior cingulum.67
Although no effect on structural plasticity of GM and
WM was reported after computer-assisted retraining
of attention,56,62 favorable microstructural DTI
changes of corpus callosum were described when this
type of training was delivered by commercial video
games.64 Finally, increased GM volume of parahippocampal gyrus was found after mental visual
imagery training.67
Limitations of current literature data and
knowledge gaps
Despite the encouraging and exciting results of published studies, there are a number of methodological
limitations that must be recognized: (1) small sample
sizes, ranging from 5 to 42 patients, leading to low
statistical power; (2) selection bias toward less severe
MS; (3) no intervention or wait list as control group or
even lack of randomization and/or control group; and
(4) longer-term post-intervention assessment were
scheduled only in few studies, and provided conflicting results, thus failing to establish if training-induced
clinical and MRI changes were retained over time.
This latter issue has also practical implications for
healthcare systems in scheduling the duration and frequency of physiotherapy sessions delivered in inpatient or outpatient setting and in offering affordable
and practical home-based training strategies to sustain
improvement gained in more complex and equipped
environments.
In conclusion, the current knowledge about rehabilitation-induced brain plasticity in MS is still fragmented and incomplete. Efforts for future clinical
research should be focused on establishing the neural
journals.sagepub.com/home/msj
correlates (both at cellular/molecular level and at system level) of clinical improvement after rehabilitation
by addressing the following issues: (1) increased
knowledge on strengths and limitations of non-conventional advanced MRI techniques in describing
neuropathological substrate of MS; (2) standardization of MRI acquisition and analysis to provide neuroimaging outcomes that are reliable, valid, sensitive
to changes, and applicable to multicentre study
designs;6,68,69 and (3) retention of rehabilitationinduced clinical and MRI improvement by scheduling
an appropriate post-intervention study phase.
Avenues for future research should encompass, but
not limited to, the following issues: (1) optimal style,
intensity, duration, and timing to exploit adaptive
plasticity as much as possible; (2) the potential additive or superadditive effect of combining rehabilitation with pharmacological treatments or with
non-invasive brain stimulation; (3) the prediction of
response to rehabilitation at individual level; and (4)
the possibility of transferring rehabilitation-promoted
improved performance from motor to cognitive
domains and vice versa by targeting brain areas with
overlapped motor and cognitive functions.70
Declaration of Conflicting Interests
The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: none declared.
Financial disclosures outside this work: L.P. received
research grants from Associazione Italiana Sclerosi
Multipla and Genzyme; participated on advisory
boards for and received consulting fees from Biogen,
Genzyme, Roche, and Novartis; received speaking
honoraria from Almirall, Biogen, Genzyme, Merck
Serono, Novartis, Roche, and Teva; and received
travel grants from Biogen, Genzyme, Roche, and
Teva. M.D.F. received research grants from
Associazione Italiana Sclerosi Multipla, the Italian
Ministry of Health and the Italian Ministry of
Education, Universities and Research and participated on advisory boards for and received speaking or
writing honoraria and funding for traveling from
Bayer, Biogen, Genzyme, Merck, Novartis, Roche,
and Teva.
Funding
The author(s) received no financial support for the
research, authorship, and/or publication of this
article.
ORCID iD
Luca Prosperini
-6267
https://orcid.org/0000-0003-3237
1359
Multiple Sclerosis Journal 25(10)
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