Hindawi Publishing Corporation

Neural Plasticity
Volume 2015, Article ID 481574, 12 pages
http://dx.doi.org/10.1155/2015/481574

Review Article
Functional and Structural Brain Plasticity Enhanced by
Motor and Cognitive Rehabilitation in Multiple Sclerosis

Luca Prosperini,1 Maria Cristina Piattella,1 Costanza Giannì,2 and Patrizia Pantano1,3
1
Department of Neurology and Psychiatry, Sapienza University, Viale dell’Università 30, 00185 Rome, Italy
2
Department of Radiological Sciences, Oncology and Pathology, Sapienza University, Rome, Italy
3
IRCCS Neuromed, Pozzilli, Italy

Correspondence should be addressed to Patrizia Pantano; [email protected]

Received 12 February 2015; Accepted 16 April 2015

Academic Editor: Michael G. Stewart

Copyright © 2015 Luca Prosperini et al. This is an open access article distributed under the Creative Commons Attribution License,
which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Rehabilitation is recognized to be important in ameliorating motor and cognitive functions, reducing disease burden, and
improving quality of life in patients with multiple sclerosis (MS). In this systematic review, we summarize the existing evidences
that motor and cognitive rehabilitation may enhance functional and structural brain plasticity in patients with MS, as assessed
by means of the most advanced neuroimaging techniques, including diffusion tensor imaging and task-related and resting-state
functional magnetic resonance imaging (MRI). In most cases, the rehabilitation program was based on computer-assisted/video
game exercises performed in either an outpatient or home setting. Despite their heterogeneity, all the included studies describe
changes in white matter microarchitecture, in task-related activation, and/or in functional connectivity following both task-oriented
and selective training. When explored, relevant correlation between improved function and MRI-detected brain changes was often
found, supporting the hypothesis that training-induced brain plasticity is specifically linked to the trained domain. Small sample
sizes, lack of randomization and/or an active control group, as well as missed relationship between MRI-detected changes and
clinical performance, are the major drawbacks of the selected studies. Knowledge gaps in this field of research are also discussed to
provide a framework for future investigations.

1. Introduction to a paradigm shift towards earlier diagnosis and treat-

ment [5, 6]. In spite of this, either the actually available
Multiple sclerosis (MS) is a long-lasting disease typically disease-modifying treatment or the other pharmacological
affecting young adults characterized by the presence of approaches have little or no impact on permanent impair-
multifocal inflammatory demyelinated plaques distributed ments, with motor symptoms and cognitive deficit reported,
over time and space within the central nervous system (CNS) respectively, by 45–90% and 40–65% of patients throughout
[1]. Pathological features of MS include breakdown of the their disease, with a certain degree of overlap [7–9].
blood-brain barrier, multifocal inflammation, demyelination, Consequently, the management of motor and cogni-
oligodendrocyte loss, reactive gliosis, and various degrees tive disturbances still relies on rehabilitative strategies [10,
of axonal damage, ranging from transient dysfunction to 11], which have been reported to be effective in amelio-
irreversible loss, even at early stages of the disease [2]. rating these functional domains, suggesting that remedi-
Although acute inflammation usually causes reversible neu- ation/compensation may occur into even damaged brain
rological dysfunction, MS relapses may also lead to residual structures [12]. This may imply that rehabilitation is able to
irreversible disability involving both motor and cognitive enhance neuroplasticity, that is, the intrinsic property of the
functions [3, 4]. CNS to structurally and functionally adapt itself in response
In the last decade, improved diagnostic criteria and to external stimuli, environmental changes, or injuries [13].
availability of effective disease-modifying drugs have led While in healthy individuals the plasticity represents the basis
2 Neural Plasticity

of brain development, learning, and memory, in the context period restrictions were applied, and the latest search was
of MS this term encompasses molecular, synaptic, cellular undertaken on January 20, 2015.
events and even reorganization of the brain cortex or fibers Attempts to identify further articles were done by search-
that result in recovery of function after an acute or chronic ing the references of the studies. We were not familiar with
damage [14]. any study currently in progress that could be considered
The most promising advanced magnetic resonance imag- for inclusion, except for one study from our group recently
ing (MRI) techniques for investigating brain plasticity are submitted. Published conference abstracts, articles not avail-
the functional MRI (fMRI) and diffusion tensor imaging able in English, and those including patients also affected by
(DTI) [15]. The fMRI is based on the detection of changes neurological conditions other than multiple sclerosis were
in the blood oxygenation level-dependent (BOLD) signal, excluded.
which is in turn affected by changes in neural activity in To fit the main purpose of this systematic review,
a specific brain region and the underlying physiology or that is, summarize the existing MRI-based evidences of
pathology. Changes in BOLD signals can be investigated rehabilitation-enhanced functional and structural plasticity
during the execution of a specific task (e.g., simple motor in MS, we also excluded studies whose training was based
activity, sensory stimulation, and cognitive effort) [16] or at on short-term learning, those in which MRI was used to
rest to explore the functional connectivity (FC), that is, the predict the outcome of rehabilitation, and those in which
functional interaction between different brain regions [17]. the occurrence of brain plasticity was assessed by means
The DTI is a method to assess myelin integrity in vivo, pro- of techniques other than MRI (e.g., transcranial magnetic
viding information on the integrity of the myelin-axon unit stimulation, electroencephalogram, etc.).
based on the directional asymmetry of water diffusion, that Abstracts of resulting articles were then examined in
is, the so-called fractional anisotropy (FA) [18]. The FA value order to select studies that met eligibility criteria. To assess
is determined by the ratio of axial diffusivity (AD) and radial eligibility, two investigators (Surnames are provided) inde-
diffusivity (RD), and decreased AD and increased RD are pendently searched for articles, and agreement between them
considered as markers of axonal damage and demyelination, was required in order to include an article. In case of disagree-
respectively, thus representing parameters that are sensitive ment, the decision was made by the most experienced author
to underlying pathological processes of MS [19]. (P. Pantano) after reading the whole article.
Using these advanced MRI techniques, it has been First author, year of publication, sample size, study design,
recently demonstrated that rapid-onset plasticity and func- type and duration of intervention, clinical and MRI outcome
tionally relevant chronic reorganization processes are pre- measures, and interpretation of findings were extracted from
served even in the most advanced stage of the disease and included articles and recorded on an electronic spreadsheet
that these phenomena are functionally relevant to maintain (M. C. Piattella).
motor and cognitive function [16, 20, 21]. Methodological quality of included articles was assessed
All these findings support the hypothesis that neuro- using the scale developed by the Physiotherapy Evidence
plasticity may be enhanced by rehabilitation [12]. In this Database (PEDro) initiative [25]. The purpose of the PEDro
view, advanced MRI may address knowledge gaps between scale is to determine the external validity (criterion 1), inter-
the observed clinical improvement and the neural mecha- nal validity (criteria 2–9), and statistical soundness (criteria
nisms underlying the improved function after rehabilitation, 10-11) of a study included in a systematic review. Studies
providing a powerful tool to investigate functional and scoring equal or above 9 on the PEDro scale were considered
structural brain changes related to recovery of function [22]. methodologically “excellent,” studies ranging from 6–8 were
However, only few studies have investigated the mechanisms considered “good,” studies scoring 4-5 were of “fair” quality,
of rehabilitation-induced neuroplasticity so far, providing studies scoring below 4 were felt to be of “poor” quality.
fragmented and incomplete data, in spite of the fact that
rehabilitation is recognized as having a key role in the 3. Results
management of patients with MS [23].
Therefore, in this systematic review, we sought to sum- The strategy search initially yielded 216 and 231 articles in
marize the existing MRI-based evidences that motor and the PubMed and Scopus databases, respectively; additional 10
cognitive rehabilitation may induce functional and structural articles were found from other sources (references of selected
plasticity into the brain of patients with MS. papers). After applying the inclusion/exclusion criteria and
checking full-text articles for eligibility, a total of 16 articles
2. Methods were included in the qualitative synthesis, as shown in the
flow diagram in Figure 1.
Search Strategy and Article Selection. According to the Pre- Six studies investigated whether motor rehabilitation
ferred Reporting Items for Systematic Review and Meta- strategies enhance brain plasticity, as evaluated by either task-
Analyses (PRISMA) statement [24], two electronic databases related fMRI (𝑛 = 2) [26, 27], DTI (𝑛 = 3) [28–30], or both
(PubMed and Scopus) were searched for English-language techniques (𝑛 = 1) [31] (see Table 1).
articles focusing on human studies. Ten studies investigated whether cognitive rehabilitation
The search was run using the following terms: (“train- strategies enhance brain plasticity, as evaluated by either task-
ing” OR “rehabilitation”) AND “imaging” AND “multiple related fMRI (𝑛 = 5) [32–35, 37] (see Table 2) or resting-
sclerosis” [All Fields]. No article type limitations or time state (RS)-fMRI (𝑛 = 4) (see Table 3) [38–41]; just one article
Neural Plasticity 3

Records identified through Records identified through Additional records identified

Identification
PubMed searching Scopus searching through other sources
(n = 231) (n = 231) (n = 10)

Records after duplicates removal

(n = 216)
Screening

Records screened
Records excluded
(inclusion/exclusion criteria applied)
(n = 188)
(n = 216)
Eligibility

Full-text articles Full-text articles

assessed for eligibility excluded, with reasons
(n = 28) (n = 12)
Included

Studies included
in qualitative synthesis
(n = 16)

Figure 1: Flow diagram mapping the review according to PRISMA statement [24].

provided findings by combining task-related fMRI and RS- was found in the active group when compared with the con-
fMRI with structural MRI for mapping changes in white trol group, the authors failed to demonstrate between-group
matter (WM) and grey matter (GM) (included in Table 2) differences in the amplitude of fMRI signal of four areas con-
[36]. tributing to sensorimotor learning (primary sensorimotor
The qualitative assessment of included studies is shown cortex, supplementary motor cortex, nucleus dentatus, and
in Table 4. Data from PEDro scale showed that selected putamen), as well as increased interhemispheric dependence.
article scored between 4 and 10 of 11 total points. Studies Moreover, there was no relationship between changes in
based on nonrandomized design [26–28, 31–33, 35, 40] or clinical parameters and in brain activation. The authors
those without an alternative “sham” training as control group concluded that the unpredictable course of the disease and
obtained lower scores [30, 36, 38, 41]. the heterogeneous, symptom-tailored rehabilitation strategy
hampered the detection of changes at group-level in fMRI
activation, questioning about the appropriateness of fMRI for
3.1. Brain Plasticity Enhanced by Motor Rehabilitation. The
investigating motor plasticity.
first attempt to demonstrate the occurrence of brain plasticity
The same group explored the impact of operator-assisted
following motor rehabilitation was done by Rasova and
facilitation physiotherapy on microstructural properties of
colleagues [26] who selected (without randomization) 28
the corpus callosum in 11 right-handed patients with MS [28].
patients with MS. Of them, 17 received a 2-month outpatient
They were scanned in two separate occasions 1 month apart
physiotherapy program (1-hour sessions, twice per week) (run-in period) and then after the 2-month rehabilitation
based on sensorimotor learning and adaptation by combining (2-hours per week). Increased callosal FA, reduced mean
different disciplines (Vojta’s reflective locomotion, Bobath diffusivity (MD) and RD were found after the intervention
concept, sensorimotor stimulation, proprioceptive neuro- (by approaching the values of 11 healthy controls), while no
muscular facilitation, Burger concept, and yoga), while the difference was observed during the run-in period. Improved
remaining 11 patients did not undergo any special training. A scores at the Paced Auditory Serial Addition Test (PASAT)
control group of 13 healthy subjects was also enrolled to inves- and a trend towards an improvement of the Expanded
tigate whether rehabilitation might lead brain function to Disability Status Scale (EDSS) score are reported by the
approach “standard” (i.e., values found in healthy group), as authors, but the relationship between clinical improvement
evaluated by task-related fMRI consisting of repetitive thumb and MRI changes was not reported.
and index flexions at a 3-second frequency, according to a More recently, a similar study was conducted to inves-
visual stimulus. Each group was scanned twice at enrolment tigate the immediate and long-term effects of a 2-month
and 2 months later. Although a relevant clinical improvement motor program activation therapy (1-hour sessions, twice
 4

Table 1: Summary of studies investigating the effect of motor rehabilitation or training on brain plasticity, assessed by nonconventional functional or structural MRI techniques.
Intervention(s) and setting
Authors (year) Sample size Main clinical characteristics Study design Clinical outcome(s) MRI study outcome(s)
[setting and schedule]
Active group: outpatient eclectic
sensori-motor learning and adaptation The 9-HPT, 25-FWT, PASAT,
Non-randomized No changes detectable by task-related
Rasova et al. (2005) [26] 28 (13)∗ N/R [1-hour sessions, 2 times per week, for 2 postural reactions, MS QoL-54,
parallel group trial fMRI
months] and BDI improved in active group
Control group: no special exercise (MS)
Mean age: ∼43 years
Non-randomized Operator-assisted facilitation Significant increase of FA and decrease
∗ Mean MS duration: ∼6 years PASAT improved after the
Ibrahim et al. (2011) [28] 11 (11) pre-post comparison physiotherapy [2-hour sessions, once a in MD and RD were observed after the
Median EDSS: 3.5 intervention
study week, for 2 months] intervention
Course: 11 RR
Mean age: ∼45 years After the training, a significant
Non-randomized Home-based visuo-motor task training Overall tracking error during the
∗ Mean MS duration: ∼12 years reduction in fMRI activation was
Tomassini et al. (2012) [27] 23 (12) pre-post comparison [12-minute sessions, once a day, for 15 visu-motor task execution
Median EDSS: 4.0 observed in the occipital and parietal
study days] decreased afte the training
Course: N/R cortices
Active group: outpatient active motor
rehabilitation of upper limbs [1-hour
Mean age: ∼43 years sessions, 3 times per week, for about 2 Both groups improved on Reduced FA and increased RD of
Mean MS duration: ∼18 years Randomized months] unimanual motor performance, corticospinal tracts and corpus callosum
Bonzano et al. (2014) [29] 30
Median EDSS: 4.0 controlled trial Control group: outpatient passive but bimanual coordination were found in control group, as detected
Course: 22 RR, 18 SP motor rehabilitation of upper limbs worsened in control group by DT-MRI measures
[1-hour sessions, 3 times per week, for
about 2 months]
Increased FA and reduced RD of
Mean age: ∼36 years Active group: home-based video game
Randomized Static balance detected at static superior cerebellar peduncles were
Mean MS duration: ∼10 years balance board [30-minute sessions, 5
Prosperini et al. (2014) [30] 27 two-period posturography improved in active found in active group, as detected by
Median EDSS: 3.0 times per week for 12 weeks]
cross-over trial group DT-MRI; DTI changes were significantly
Course: 26 RR, 1 SP Control group: no intervention
related to improved static balance
The MAS, 25-FWT, 9-HPT, and Increased FA and reduced MD of corpus
Mean age: ∼40 years
Non-randomized Motor programme activating therapy cerebellar functions improved callosum immediately after and one
Mean MS duration: ∼7 years
Rasova et al. (2015) [31] 12 uncontrolled [1-hour sessions, 2 times per week, for immediately after and one month month apart from the end of
Median EDSS: 3.5
comparison trial about 2 months] apart from the end of rehabilitation; no changes were detected
Course: 11 RR, 1 PP
rehabilitation with task-related fMRI
9-HPT: 9-hole peg test; 25-FWT: 25-foot walking test; BDI: Beck Depression Inventory; DTI: diffusion tensor imaging; EDSS: Expanded Disability Status Scale; fMRI: functional magnetic resonance imaging; FA:
fractional anisotropy; MAS: Modified Ashworth Scale; MD: mean diffusivity; MS QoL-54: 54-item Multiple Sclerosis Quality of Life; N/R: not reported; PASAT: Paced Auditory Serial Addition Test; PP: primary
progressive; RR: relapsing-remitting; SP: secondary progressive.
∗
The number within parentheses refers to the sample size of healthy subjects.
Neural Plasticity
 Neural Plasticity

Table 2: Summary of studies investigating the effect of cognitive rehabilitation or training on brain plasticity, assessed by task-related fMRI.
Intervention(s) and setting
Authors (year) Sample size Main clinical characteristics Study design Clinical outcome(s) MRI outcome(s)
[intervention schedule]
Nonrandomized Increased activation of regions in the
Penner and Kappos (2006) Computer-assisted attention training with
11 N/R pre-/postcomparison Not reported cingulate gyrus, precuneus, and frontal
[32] the AIXTENT package [3-4 weeks]
study cortex was found after the training
Mean age: ∼51 years Mixed intervention: computer-assisted Increased activation of right posterior
Nonrandomized
∗ Mean MS duration ∼14 years cognitive rehabilitation and game-like group Improvement in digit span cerebellar lobe and left anterior and
Sastre-Garriga et al. (2011) [33] 15 (5) pre-/postcomparison
Median EDSS: 6.0 activities [1-hour sessions, 3 times per week, after the intervention posterior cerebellar lobe after the
study
Course: SP 10, RR 3, and PP 2 for 5 weeks] intervention
Active group: modified story memory
Mean age: ∼48 years technique [45–60-minute sessions, 2 times per
Double-blind CVLT short-delay free Increased activation of some areas of
Mean MS duration ∼15 years week, for 5 weeks]
Chiaravalloti et al. (2012) [34] 16 randomized recall improved in active frontal, parietal, temporal, and occipital
Median EDSS: N/R Control group: story reading and answering
controlled group group lobes and cerebellum in active group
Course: 13 RR, 2 PP, and 1 SP questions [45–60-minute sessions, 2 times per
week, for 5 weeks]
Increased activation of some areas
Mean age: ∼38 years
Active group: Motor visual imagery training located in posterior regions (right
Mean MS duration ∼14 years Nonrandomized Autobiographic memory
Ernst et al. (2012) [35] 8 [2-hour sessions, 1 time per week, for 6 weeks] cuneus, left precuneus, left inferior and
Median EDSS: 2.0 controlled trial improved in active group
Control group: no intervention superior occipital gyri, and left lateral
Course: 8 RR
temporal cortex)
(i) Increased activation of posterior
cingulated cortex and/or prefrontal
cortex (bilaterally) in active group;
(ii) increased activation at rest of
Mean age: ∼46 years Active group: outpatient cognitive training
The PASAT, WCST, and anterior cingulated cortex (salience
Mean MS duration ∼14 years Randomized using the RehaCom package [1-hour sessions, 3
Filippi et al. (2012) [36] 20 oral word association test processing), left dorsolateral prefrontal
Median EDSS: 2.0 controlled trial times per week, for 12 weeks]
improved in active group cortex (executive function), right
Course: 20 RR Control group: no intervention
inferior parietal lobule and posterior
cingulated cortex, and/or precuneus
(default-mode networks I and II); (iii)
no significant WM and GM changes
Active group: outpatient cognitive training
using the RehaCom package [1-hour sessions, 2
Mean age: ∼32 years
Double-blind times per week, for 6 weeks] Increased activation of the right
Mean MS duration ∼9 years The Stroop test improved
Cerasa et al. (2013) [37] 23 randomized Control group: home-based training with a posterior cerebellar lobule and left
Median EDSS: 2.5 in active group
controlled trial simple visuomotor coordination task (in-house superior parietal lobule in active group
Course: 23 RR
software) [1-hour sessions, 2 times per week,
for 6 weeks]
CVLT: California Verbal Learning Test; GM: grey matter; N/R: not reported; PASAT: Paced Auditory Serial Addition Test; PP: primary progressive; RR: relapsing-remitting; SP: secondary progressive; WCST:
Wisconsin Card Sort Test; WM: white matter.
∗
The number within parentheses refers to the sample size of healthy subjects.
5
 6

Table 3: Summary of studies investigating the effect of cognitive rehabilitation or training on brain plasticity, assessed by RS-fMRI.
Intervention(s) and setting
Authors (year) Sample size Main clinical characteristics Study design Clinical outcome(s) MRI study outcome(s)
[setting and schedule]
Increased connectivity of the anterior
Active group: outpatient cognitive
Mean age: ∼46 years cingulum with the right inferior
training using the RehaCom package The PASAT, WCST, and
Mean MS duration ∼14 years Randomized parietal lobule and decreased
Parisi et al. (2014) [38] 20 [1-hour sessions, 3 times per week, for oral word association test
Median EDSS: 2.0 controlled trial connectivity of the anterior cingulum
12 weeks] improved in active group
Course: 20 RR with the right inferior temporal gyrus
Control group: no intervention
were found in active group
Active group: modified story memory
Increased connectivity (default-mode
technique [45–60-minute sessions, 2
Mean age: ∼49 years Just a nonsignificant network) of insula and pyramids of
Double-blind times per week, for 5 weeks]
Mean MS duration ∼14 years improvement of CVLT vermis (left hippocampus seeded),
Leavitt et al. (2012) [39] 14 randomized Control group: story reading and
Median EDSS: N/R short-delay free recall postcentral gyrus (right hippocampus
controlled group answering relative questions
Course: 9 RR, 3 SP, and 2 PP was found in active group seeded), and thalamus (posterior
[45–60-minute sessions, 2 times per
cingulated cortex seeded)
week, for 5 weeks]
Active group: outpatient cognitive
training using the RehaCom package
Increased functional connectivity
Mean age: ∼47 years [50-minute sessions, 2 times per week
The SDMT, PASAT, (default-mode network) of the
Mean MS duration ∼21 years Nonrandomized for 8 weeks]
Bonavita et al. (2015) [40] 32 SRT-D, and SPART-D posterior cingulated cortex and
Median EDSS: 4.5 parallel group trial Control group: newspaper reading
improved in active group inferior parietal cortex (bilaterally)
Course: 32 RR and content referring
was found in active group
[30-minute sessions, 2 times per week,
for 8 weeks]
Active group: home-based training Increased thalamocortical
Mean age: ∼42 years
Randomized with an educational video game Improved PASAT and connectivity was found in brain areas
De Giglio et al. (2015) Mean MS duration ∼13 years
24 wait-list controlled [30-minute sessions, 5 days per week, Stroop was found in corresponding to the posterior
[41] Median EDSS: 2.0
study for 8 weeks] active group component of the default-mode
Course: 24 RR
Control Group: wait-list network (thalami seeded)
CVLT: California Verbal Learning Test; PASAT: Paced Auditory Serial Addition Test; SDMT: Symbol Digit Modalities Test; SPART-D: Spatial Recall Test-delayed recall; SRT-D: Selective Reminding Test-delayed
recall; WCST: Wisconsin Card Sort Test.
Neural Plasticity
Neural Plasticity 7

Table 4: Included articles rating according to the PEDro scale [25].

#1 #2 #3 #4 #5 #6 #7 #8 #9 #10 #11 Score

Rasova et al. (2005) [26] ✓ M M ✓ M M M ✓ ✓ ✓ ✓ 6/11
Ibrahim et al. (2011) [28] ✓ M M M M M ✓ ✓ ✓ ✓ ✓ 6/11
Articles on motor Tomassini et al. (2012) [20] ✓ M M M M M M ✓ ✓ N/A ✓ 5/11
rehabilitation Bonzano et al. (2014) [29] ✓ ✓ ✓ ✓ M M M ✓ ✓ ✓ ✓ 8/11
Prosperini et al. (2014) [30] ✓ ✓ ✓ ✓ M M ✓ M ✓ ✓ ✓ 8/11
Rasova et al. (2015) [31] ✓ M M M M M M ✓ ✓ M ✓ 4/11
Penner and Kappos (2006) [32] ✓ M M M M M M ✓ ✓ N/A ✓ 4/11
Sastre-Garriga et al. (2011) [33] ✓ M M M M M ✓ ✓ ✓ N/A ✓ 5/11
Chiaravalloti et al. (2012) [34] ✓ ✓ ✓ ✓ ✓ M ✓ ✓ ✓ ✓ ✓ 10/11
Ernst et al. (2012) [35] ✓ M M M M M M ✓ ✓ ✓ ✓ 5/11
Articles on cognitive Filippi et al. (2012) [36] ✓ ✓ ✓ ✓ M M ✓ ✓ ✓ ✓ ✓ 9/11
rehabilitation
Leavitt et al. (2012) [39] ✓ ✓ ✓ ✓ ✓ M ✓ ✓ ✓ ✓ ✓ 10/11
Cerasa et al. (2013) [37] ✓ ✓ ✓ ✓ ✓ M ✓ ✓ ✓ ✓ ✓ 10/11
Parisi et al. (2014) [38] ✓ ✓ ✓ ✓ M M ✓ ✓ ✓ ✓ ✓ 9/11
Bonavita et al. (2015) [40] ✓ M M ✓ M M ✓ ✓ ✓ ✓ ✓ 7/11
De Giglio et al. (2015) [41] ✓ ✓ ✓ ✓ M M ✓ M ✓ ✓ ✓ 7/11
N/A: data not available.
Criterion 1: specified eligibility criteria.
Criterion 2: randomized allocation.
Criterion 3: concealed allocation.
Criterion 4: similarity between groups at baseline.
Criterion 5: blinding of subjects.
Criterion 6: blinding of therapists.
Criterion 7: blinding of assessors.
Criterion 8: outcome measures obtained from at least 85% of initially allocated subjects.
Criterion 9: all received treatment, or key outcome, was analyzed by “intention-to-treat.”
Criterion 10: between-group statistical comparison.
Criterion 11: both point and variability measures provided.

weekly) [31]. Patients were clinically evaluated and scanned was found to be related to smaller changes in task-related
four times to obtain DTI data of the corpus callosum activation over time in the left superior lobule and right
and motor task-related fMRI (flexion and extension of lateral occipital cortex, but this correlation failed to reach
metacarpophalangeal joints). Follow-up data were available a statistical significance. Long-term postintervention fMRI
for 12 patients who experienced a significant improvement in changes observed in patients differed from those found in
some clinical scales and in DTI metrics of corpus callosum healthy subjects who showed reduced task-related activation
(increased FA and reduced MD) immediately after and even only in the occipital cortex. The authors concluded that
one month after the end of the intervention, while no relevant adaptive plasticity is preserved even in chronically disabled
change was found in terms of fMRI data. patients with MS, but this plasticity is modulated by brain
Tomassini and colleagues [27] submitted 23 patients and systems different from those acting in healthy subjects.
13 healthy controls to short-term and long-term practice of To investigate the possibility that rehabilitation induces
a visuomotor task. The short-term and long-term training microstructural changes of WM bundles involved in volun-
consisted of 12-minute training, done during the first fMRI tary motor control, Bonzano and colleagues [29] randomized
session, and 13-minute home-based sessions, once daily, for (in a 1 : 1 ratio) 30 patients with MS to receive either 2-month
15 days, respectively; at the end of the training, patients and active, task-oriented motor rehabilitation (active group) or
healthy subjects had a second fMRI session. From a clinical a 2-month passive motor rehabilitation (control group) of
standpoint, although patients performed poorer than healthy the upper limbs (1-hour sessions, thrice per week). Before
subjects in terms of overall tracking error for the visuomotor and after rehabilitation, DTI data of the corpus callosum,
task, the MS group improved similar to healthy group after left and right corticospinal tracts, and left and right superior
both short-term and long-term practices, regardless of MRI longitudinal fasciculus were obtained. After rehabilitation,
measures of brain damage and disability. After the long-term the unimanual motor performance improved in both groups,
practice that may be considered as equivalent to a short while the bimanual coordination task worsened in control
rehabilitative intervention, a significant reduction in task- group and remained stable in active group. Accordingly,
related activation of the occipital and parietal cortices was reduced FA and increased RD of corticospinal tracts and
found in patients. Greater long-term clinical improvement corpus callosum were found in the control group, but not in
8 Neural Plasticity

the active one. The authors concluded that active (voluntary),

but not passive, rehabilitation preserves WM integrity of
brain structures specifically involved in the trained function,
thus supporting the beneficial effect of task-oriented rehabil-
itation.
Based on data from a randomized, two-period, crossover
pilot study, showing a beneficial effect of the Nintendo Figure 2: Regions of interest outlining the superior cerebellar
Wii balance board on static balance [42], Prosperini and peduncle dissected by means of streamline tractography; this white
colleagues investigated whether DTI parameters of cerebellar matter bundle showed significant changes indicating improved
connections significantly changed after intervention and structural integrity following the 12-week home-based training
using the Nintendo Wii balance board (modified from [30]).
whether these changes correlated with clinical improvement
[30]. A total of 36 patients with MS were randomized in a
1 : 1 ratio to two counterbalanced groups: group A received
30-minute sessions, 5 days per week for 12 consecutive weeks underpowered to detect relevant clinical changes owing the
of home-based video game training (intervention period), small sample size [33].
followed by a 12-week period without any specific interven- A double-blind, placebo-controlled, randomized clinical
tion (observation period); group B was given the treatment trial was designed to investigate changes in brain activation
in reverse order. Patients were clinically evaluated and MRI following modified Story Memory Technique (mSMT), a
scanned at study beginning and at the end of the first and the rehabilitative approach used for treating new learning and
second study periods; MRI data were available for 27 patients. memory deficits [34]. A total of 16 patients were randomized
Improved DTI measures of superior cerebellar peduncles either to a 5-week treatment using mSMT (active group) or
were found after the training (increased FA and reduced to story reading and answering related questions (control
RD), suggesting the occurrence of activity-dependent myelo- group), with the same schedule (45–60-minute sessions,
modulation in partially damaged pathways (see Figure 2). twice per week). Both groups were scanned to obtain task-
These microstructural changes were also significantly related related fMRI data during list-learning and word-recognition
to clinical improvement of static balance, supporting the tasks. The proportion of patients who improved memory
hypothesis that structural plasticity may be enhanced in brain performance on California Verbal Learning Test short-delay
areas specifically involved in the function trained with high- free recall after the intervention was greater in the active than
intensity, task-oriented rehabilitation. However, there was no in the control group. Compared to controls, patients in the
retention of training-induced improvement in clinical and active group showed an increased activation in some areas of
MRI measures. frontal, parietal, temporal, and occipital cortices and in the
cerebellum. There was also a significant correlation between
3.2. Brain Plasticity Enhanced by Cognitive Rehabilitation. In improved memory performance and increased activation
a preliminary study, 11 patients with MS suffering from mild of the right middle frontal gyrus, which is known to be
to severe cognitive impairment were submitted to a 3-4-week associated with visual and context-dependent learning.
intervention with the AIXTENT software to train alertness, Some patients originally enrolled in this latter study
divided attention, selective attention, and vigilance [32]. By underwent also RS-fMRI, in order to explore FC using
comparing pre- and posttraining clinical findings and task- the left and the right hippocampus (implicated in memory
related fMRI features, Penner and Kappos demonstrated both function) and posterior cingulated cortex (involved in the
a clinical improvement and an increased activation of regions default-mode network) as seeding points [39]. Out of the
in the cingulate gyrus, precuneus, and frontal cortex; all these two analyses performed, the less conservative one showed
areas are known to be involved in a network functionally that after the training the active group had an increased
related to attention processing. connectivity between the left hippocampus, the insula, and
The effect of a mixed intervention (game-like group pyramids of vermis, between the right hippocampus and
activities and computer-aided training) was investigated by the postcentral gyrus, and between the posterior cingulated
Sastre-Garriga and colleagues [33] in an open-label, proof- cortex and thalamus.
of-concept trial. Fifteen patients with MS underwent an Brain activation changes following a 6-week visual
extensive neuropsychological evaluation and were scanned imagery training (2-hour sessions, once weekly) were inves-
to obtain task-related (PASAT) fMRI before and after a 5- tigated in 4 patients with MS [35]. They underwent pre-
week run-in period. Further clinical and fMRI data were and posttraining clinical evaluations and task-related fMRI
collected at the end of a 5-week cognitive training period (1- (evocation of specific personal memories). A significant
hour sessions, thrice per week). Five healthy subjects who improvement of autobiographic memory performance, cou-
were scanned at the same time-points served as healthy pled with increased activation of posterior cerebral areas
controls. After the training, patients exhibited an improved specifically involved in memory retrieval (right cuneus, left
performance in backward version of digit span and increased precuneus, left inferior and superior occipital gyri, and left
fMRI activation in right posterior lobe (uvula and declive) lateral temporal cortex), was found after the rehabilitation.
and left anterior and posterior lobes of cerebellum (declive Cerasa and colleagues [37] performed a randomized,
and culmen). However, clinical findings and fMRI changes double-blind, controlled trial in which 26 patients with MS
did not significantly correlate, likely because the study was were allocated to receive a 6-week computer-aided training
Neural Plasticity 9

(1-hour sessions, twice per week) either with the RehaCom

package, a modular system developed to treat a wide spec-
trum of cognitive functioning, including alertness, attention,
memory, executive functions, and visual field (active group),
or with a simple visuomotor coordination task (control
group). Before and after the intervention, both groups were
clinically examined and scanned to obtain task-related fMRI Figure 3: Areas of increased thalamic connectivity (posterior
data (visual PASAT). Performance at Stroop test improved in cingulate gyrus, precuneus, and lateral parietal cortex, bilaterally)
the active group only, which also showed increased activation following the 8-week home-based training using the Nintendo Dr.
of brain areas subserving refreshing phonological stimuli and Kawashima Brain Training (modified from [41], courtesy of Dr. De
short-term information storage, that is, the right posterior Giglio).
cerebellar lobule and left superior parietal lobule.
Filippi and colleagues [36] used functional and struc-
tural MRI to investigate brain changes after a 12-week
8-week home-based playing period with the Dr. Kawashima
computer-assisted training with RehaCom. Twenty patients
Nintendo Brain Training, an educational video game aimed at
with MS were randomly allocated either to the active group
training memory, attention, visuospatial processing, and cal-
(𝑛 = 10) or to the control group, which did not undergo
culations. The active group exhibited a significant improve-
any intervention (𝑛 = 10). Before and after the 12-week
ment in sustained/divided attention and some aspects of
study period, both groups were assessed by a complete
executive functions [44]. In a post hoc analysis recently
neuropsychological evaluation and scanned to map changes
submitted for publication, 24 patients enrolled in the original
in WM and GM structures and to obtain task-related fMRI
trial underwent RS-fMRI before and after the cognitive train-
(Stroop test) and RS-fMRI data. The active group showed a
ing [41]. We found that this type of cognitive rehabilitative
clinical improvement in some tests of attention, information
training induced an increased thalamic FC in brain areas
processing, and executive functions, an increased activation
corresponding to the posterior component of the default-
of posterior cingulated cortex and/or precuneus and dorso-
mode network (cingulum, precuneus, and bilateral parietal
lateral prefrontal cortex (bilaterally) during the task-related
cortex) and a decreased connectivity in the vermis and
fMRI, and increased RS-FC of the anterior cingulated cor-
left dorsolateral prefrontal cortex (see Figure 3). Moreover,
tex (salience processing), left dorsolateral prefrontal cortex
positive correlations were found between improved cognitive
(executive function), right inferior parietal lobule, poste-
performance (PASAT, Symbol Digit Modalities Test, and
rior cingulated cortex, and/or precuneus (default-mode net-
Stroop test) and increased FC in areas belonging to the
work). Neither WM nor GM microarchitecture, assessed with
default-mode network.
DTI and voxel-based morphometry [43], was impacted by
the rehabilitation. The authors concluded that rehabilitation
of attention, information processing speed, and executive 4. Discussion
function enhance recruitment of brain networks subserving
the trained functions. Brain plasticity represents the substrate for interventions
In another study, data from the same population were promoting functional recovery, by means of neural restora-
reanalyzed using the anterior cingulated cortex as seed to tion or compensation [12, 20, 21]. Findings from the present
explore its RS-FC [38]. At follow-up, the anterior cingulum systematic review suggest that there is MRI-based evidence
showed an increased FC with the right inferior parietal that functional or structural plasticity occurred following
lobule and decreased FC with the right inferior temporal motor or cognitive rehabilitation in patients with MS. In
gyrus in the active group only; some of these FC changes addition, some studies also showed relevant relationship
were significantly related to improved PASAT scores after the between improved function and MRI-detected brain changes
training. [27, 30, 34, 36–38, 40, 41]. This latter feature supports the
Bonavita and colleagues [40] performed a nonrandom- notion that training-induced plasticity is specifically linked
ized parallel-group trial in which 18 patients were trained to the trained function and it is not merely a general effect of
using the RehaCom package (active group) and 14 patients any rehabilitation.
were submitted to newspaper reading and content referring Although they differed from each other, studies on motor
for 8 consecutive weeks. Both groups underwent an extensive rehabilitation support the notion that brain plasticity is
neuropsychological evaluation and RS-fMRI study at entry enhanced by task-dependent and target-selected training [27,
and at the end of follow-up. Several neuropsychological tests 29, 30], rather than by an “holistic” approach [26]. Improved
of information processing speed and verbal and visual sus- microstructural properties of corpus callosum were found
tained memory improved in the active, but not in the control, following high-intensity, repetitive training of motor func-
group after the 8-week study period. Likewise, increased RS- tions involving the lower limbs and task-oriented exercises
FC in the posterior cingulated cortex and inferior parietal aimed at improving upper limb functions [28, 29, 31]. Callosal
cortex bilaterally (subserving the default-mode network) was fibers connect homologous cortical areas of the two hemi-
found in the active group. spheres, thus subserving a wide range of motor and cognitive
Lastly, De Giglio and colleagues performed a randomized, function, including gait and bimanual coordination [45–48].
wait-list controlled study to investigate the effectiveness of Favourable changes in the microarchitecture of the superior
10 Neural Plasticity

cerebellar connections were reported after a video game- The lack of statistical inferences aimed at exploring
based training of balance [30]. Superior cerebellar peduncles correlations between imaging results and clinical outcomes
mainly contain output fibers projecting from cerebellum to represents another major limit of some studies [26, 28, 29,
the neocortex, contributing to a high-level sensory weighting 31, 32, 34, 35, 40] since there is recommendation that MRI
for postural control [49]. However, the interpretation of DTI changes following the rehabilitative interventions should be
parameters in relation to pathological changes derived is quantified and compared with clinically relevant, sensitive,
still controversial [50], and some authors argued that RD and reproducible outcomes [20, 60].
does not selectively measures demyelination due to MS but Postintervention study phases were planned only rarely,
represents more complex tissue changes [51]. In addition, the but they may provide important information about the reten-
reliability and sensitivity to changes of DTI measures are not tion of rehabilitation-induced clinical and MRI improve-
well elucidated yet [19]. ments, especially for defining the most appropriate duration
Studies on cognitive rehabilitation are somewhat more and timing of rehabilitation. Therefore, efforts for future
consistent than those on motor rehabilitation, not only in research should be focused on establishing (i) the most
terms of trained functions but also in their results. The appropriate strategies for effective rehabilitation; (ii) stan-
majority of intervention strategies consisted of computer- dardised, valid, and reliable endpoints to assess the efficacy
assisted training of attention, short-term memory, and execu- of rehabilitation, taking into account the concept of ecological
tive functions [32, 33, 36–38, 40, 41]. Despite some differences validity and patient-centered outcomes; and (iii) clinical and
regarding the neuropsychological scales and clinical outcome MRI measures that most effectively detect the occurrence of
measures adopted, task-related fMRI and RS-fMRI findings beneficial brain plasticity after specific training.
are quite consistent, pointing out the role of some specific Another new intriguing field of research that is worth
brain regions such as the cingulated cortex [32, 34, 36, 38, developing encompasses the possibility of combining rehabil-
40, 41], precuneus [32, 34–36, 41], and cerebellum [33, 34, itation with pharmacologic treatments or neuromodulation,
37, 39]. The cingulated cortex is known to cover emotion for- to obtain a synergistic or even a more than additive effect
mation and processing, learning, and memory, thus linking on brain plasticity, as demonstrated in other pathological
behavioral outcomes to motivational learning [52–54]. The conditions [61–63].
precuneus is involved in episodic memory and visuospatial In conclusion, the current knowledge about the rehabili-
imagery and it has been suggested to be a specific target for tation-induced brain plasticity in MS is still fragmented and
visual mirror therapy and virtual reality-based rehabilitation incomplete. The ultimate goal should be to demonstrate, at an
[55, 56]. Being connected with many association networks evidence-based level, that effective rehabilitation favourably
[57], the cerebellum has been now recognized to be not affects the brain structures, improves the trained function,
only involved in motor planning and learning, but also in and promotes the patient’s quality of life.
different cognitive domains, including attention, memory,
and learning, executive control, language, and visuospatial
function [58, 59]. Conflict of Interests
Despite some encouraging findings reported above, the The authors declare that there is no conflict of interests
studies included in the present systematic review suffer from regarding the publication of this paper.
several drawbacks, mainly concerning the small sample size
and the absence of a nonactive control group, blindness,
and/or randomization in the study design. Moreover, the References
selected articles are not comparable because clinical outcome
[1] A. Compston and A. Coles, “Multiple sclerosis,” The Lancet, vol.
measures, MRI biomarkers, and intervention are not stan-
359, no. 9313, pp. 1221–1231, 2002.
dardized.
Only few articles report data about the occurrence of [2] R. Dutta and B. D. Trapp, “Mechanisms of neuronal dysfunction
acute relapses and disability progression [28, 30, 37, 38, 41] and degeneration in multiple sclerosis,” Progress in Neurobiol-
ogy, vol. 93, no. 1, pp. 1–12, 2011.
or information on disease-modifying and symptomatic treat-
ments taken by patients while on study [28, 29]. However, [3] F. D. Lublin, M. Baier, and G. Cutter, “Effect of relapses on
this should have not biased findings/interpretation of the development of residual deficit in multiple sclerosis,” Neurology,
included studies for several reasons: (i) no patients relapsed vol. 61, no. 11, pp. 1528–1532, 2003.
or experienced disability progression (when reported) [28, [4] A. Traboulsee, “MRI relapses have significant pathologic and
30, 37, 38, 41]; (ii) it is very unlikely that relapses and clinical implications in multiple sclerosis,” Journal of the Neu-
disability progression might have occurred, given the short rological Sciences, vol. 256, no. 1, pp. S19–S22, 2007.
duration of the studies (from a minimum of 15 days to [5] M. S. Freedman, “’Time is brain’ also in multiple sclerosis,”
a maximum of 24 weeks) in the remaining studies [26, Multiple Sclerosis, vol. 15, no. 10, pp. 1133–1134, 2009.
27, 29, 31–36, 39, 40]; (iii) as per inclusion criteria only [6] C. H. Polman, S. C. Reingold, B. Banwell et al., “Diagnostic
patients in a stable phase of the disease were enrolled; (iv) criteria for multiple sclerosis: 2010 revisions to the McDonald
the randomization procedure (when applied) should have criteria,” Annals of Neurology, vol. 69, no. 2, pp. 292–302, 2011.
prevented any imbalance in known and unknown baseline [7] P. van Asch, “Impact of mobility impairment in multiple sclero-
characteristics between treatment and control groups [29, 30, sis 2-patients’ perspectives,” European Neurological Review, vol.
34, 36–39, 41]. 6, no. 2, pp. 115–120, 2011.
Neural Plasticity 11

[8] R. H. B. Benedict and R. Zivadinov, “Risk factors for and [26] K. Rasova, J. Krasenksy, E. Havrdova et al., “Is it possible to
management of cognitive dysfunction in multiple sclerosis,” actively and purposely make use of plasticity and adaptability in
Nature Reviews Neurology, vol. 7, no. 6, pp. 332–342, 2011. the neurorehabilitation treatment of multiple scelorsis patients?
[9] C. Leone, F. Patti, and P. Feys, “Measuring the cost of cognitive- A pilot project,” Clinical Rehabilitation, vol. 19, no. 2, pp. 170–181,
motor dual tasking during walking in multiple sclerosis,” 2005.
Multiple Sclerosis Journal, vol. 21, no. 2, pp. 123–131, 2015. [27] V. Tomassini, H. Johansen-Berg, S. Jbabdi et al., “Relating brain
[10] J. Kesselring and S. Beer, “Symptomatic therapy and neuroreha- damage to brain plasticity in patients with multiple sclerosis,”
bilitation in multiple sclerosis,” The Lancet Neurology, vol. 4, no. Neurorehabilitation & Neural Repair, vol. 26, no. 6, pp. 581–593,
10, pp. 643–652, 2005. 2012.
[11] S. Beer, F. Khan, and J. Kesselring, “Rehabilitation interventions [28] I. Ibrahim, J. Tintera, A. Skoch et al., “Fractional anisotropy
in multiple sclerosis: an overview,” Journal of Neurology, vol. 259, and mean diffusivity in the corpus callosum of patients with
no. 9, pp. 1994–2008, 2012. multiple sclerosis: the effect of physiotherapy,” Neuroradiology,
vol. 53, no. 11, pp. 917–926, 2011.
[12] J. A. Kleim, “Neural plasticity and neurorehabilitation: teaching
the new brain old tricks,” Journal of Communication Disorders, [29] L. Bonzano, A. Tacchino, G. Brichetto et al., “Upper limb motor
vol. 44, no. 5, pp. 521–528, 2011. rehabilitation impacts white matter microstructure in multiple
sclerosis,” NeuroImage, vol. 90, pp. 107–116, 2014.
[13] A. Pascual-Leone, A. Amedi, F. Fregni, and L. B. Merabet, “The
plastic human brain cortex,” Annual Review of Neuroscience, vol. [30] L. Prosperini, F. Fanelli, N. Petsas et al., “Multiple sclerosis:
28, no. 1, pp. 377–401, 2005. changes in microarchitecture of white matter tracts after train-
ing with a video game balance board,” Radiology, vol. 273, no. 2,
[14] D. Zeller and J. Classen, “Plasticity of the motor system in
pp. 529–538, 2014.
multiple sclerosis,” Neuroscience, vol. 283, pp. 222–230, 2014.
[31] K. Rasova, M. Prochazkova, J. Tintera, I. Ibrahim, D. Zimova,
[15] P. S. Giacomini and D. L. Arnold, “Non-conventional MRI and I. Stetkarova, “Motor programme activating therapy influ-
techniques for measuring neuroprotection, repair and plasticity ences adaptive brain functions in multiple sclerosis: clinical and
in multiple sclerosis,” Current Opinion in Neurology, vol. 21, no. MRI study,” International Journal of Rehabilitation Research, vol.
3, pp. 272–277, 2008. 38, no. 1, pp. 49–54, 2015.
[16] P. Pantano, C. Mainero, and F. Caramia, “Functional brain reor- [32] I.-K. Penner and L. Kappos, “Retraining attention in MS,”
ganization in multiple sclerosis: evidence from fMRI studies,” Journal of the Neurological Sciences, vol. 245, no. 1-2, pp. 147–151,
Journal of Neuroimaging, vol. 16, no. 2, pp. 104–114, 2006. 2006.
[17] R. Sacco, S. Bonavita, F. Esposito, G. Tedeschi, and A. Gallo, [33] J. Sastre-Garriga, J. Alonso, M. Renom et al., “A functional
“The contribution of resting state networks to the study of magnetic resonance proof of concept pilot trial of cognitive
cortical reorganization in MS,” Multiple Sclerosis International, rehabilitation in multiple sclerosis,” Multiple Sclerosis, vol. 17, no.
vol. 2013, Article ID 857807, 7 pages, 2013. 4, pp. 457–467, 2011.
[18] S. Mori and J. Zhang, “Principles of diffusion tensor imaging [34] N. D. Chiaravalloti, G. Wylie, V. Leavitt, and J. DeLuca,
and its applications to basic neuroscience research,” Neuron, vol. “Increased cerebral activation after behavioral treatment for
51, no. 5, pp. 527–539, 2006. memory deficits in MS,” Journal of Neurology, vol. 259, no. 7,
[19] E. Sbardella, F. Tona, N. Petsas, and P. Pantano, “DTI measure- pp. 1337–1346, 2012.
ments in multiple sclerosis: evaluation of brain damage and [35] A. Ernst, A. Botzung, D. Gounot et al., “Induced brain plasticity
clinical implications,” Multiple Sclerosis International, vol. 2013, after a facilitation programme for autobiographical memory
Article ID 671730, 11 pages, 2013. in multiple sclerosis: a preliminary study,” Multiple Sclerosis
[20] V. Tomassini, P. M. Matthews, A. J. Thompson et al., “Neuro- International, vol. 2012, Article ID 820240, 12 pages, 2012.
plasticity and functional recovery in multiple sclerosis,” Nature [36] M. Filippi, G. Riccitelli, F. Mattioli et al., “Multiple sclerosis:
Reviews Neurology, vol. 8, no. 11, pp. 635–646, 2012. effects of cognitive rehabilitation on structural and functional
[21] C. Mainero, P. Pantano, F. Caramia, and C. Pozzilli, “Brain MR imaging measures—an explorative study,” Radiology, vol.
reorganization during attention and memory tasks in multiple 262, no. 3, pp. 932–940, 2012.
sclerosis: insights from functional MRI studies,” Journal of the [37] A. Cerasa, M. C. Gioia, P. Valentino et al., “Computer-assisted
Neurological Sciences, vol. 245, no. 1-2, pp. 93–98, 2006. cognitive rehabilitation of attention deficits for multiple sclero-
[22] M. Filippi, A. Charil, M. Rovaris, M. Absinta, and M. A. Rocca, sis: a randomized trial with fMRI correlates,” Neurorehabilita-
“Insights from magnetic resonance imaging,” in Handbook of tion and Neural Repair, vol. 27, no. 4, pp. 284–295, 2013.
Clinical Neurology, vol. 122 of Multiple Sclerosis and Related [38] L. Parisi, M. A. Rocca, P. Valsasina, L. Panicari, F. Mattioli,
Disorders, chapter 6, pp. 115–149, 2014. and M. Filippi, “Cognitive rehabilitation correlates with the
[23] J. Deluca and U. Nocentini, “Neuropsychological, medical and functional connectivity of the anterior cingulate cortex in
rehabilitative management of persons with multiple sclerosis,” patients with multiple sclerosis,” Brain Imaging and Behavior,
NeuroRehabilitation, vol. 29, no. 3, pp. 197–219, 2011. vol. 8, no. 3, pp. 387–393, 2014.
[24] D. Moher, A. Liberati, J. Tetzlaff, D. G. Altman, and PRISMA [39] V. M. Leavitt, G. R. Wylie, P. A. Girgis, J. Deluca, and N.
Group, “Preferred reporting items for systematic reviews and D. Chiaravalloti, “Increased functional connectivity within
meta-analyses: the PRISMA statement,” British Medical Journal, memory networks following memory rehabilitation in multiple
vol. 339, Article ID b2535, 2009. sclerosis,” Brain Imaging and Behavior, vol. 8, no. 3, pp. 394–402,
[25] C. G. Maher, C. Sherrington, R. D. Herbert, A. M. Moseley, and 2012.
M. Elkins, “Reliability of the PEDro scale for rating quality of [40] S. Bonavita, R. Sacco, M. D. Corte et al., “Computer-aided
randomized controlled trials,” Physical Therapy, vol. 83, no. 8, cognitive rehabilitation improves cognitive performances and
pp. 713–721, 2003. induces brain functional connectivity changes in relapsing
12 Neural Plasticity

remitting multiple sclerosis patients: an exploratory study,” [57] R. L. Buckner, “The cerebellum and cognitive function: 25 years
Journal of Neurology, vol. 262, no. 1, pp. 91–100, 2015. of insight from anatomy and neuroimaging,” Neuron, vol. 80,
[41] L. de Giglio, F. Tona, N. Petsas et al., “Changes in thalamic no. 3, pp. 807–815, 2013.
resting-state functional connectivity induced by a home-based [58] D. Timmann and I. Daum, “Cerebellar contributions to cogni-
cognitive rehabilitation program in patients with multiple tive functions: a progress report after two decades of research,”
sclerosis,” in Proceedings of the 20th Annual RIMS Conference, Cerebellum, vol. 6, no. 3, pp. 159–162, 2007.
Milan, Italy, April 2015. [59] L. F. Koziol, D. Budding, N. Andreasen et al., “Consensus paper:
[42] L. Prosperini, D. Fortuna, C. Giannı̀, L. Leonardi, M. R. the cerebellum’s role in movement and cognition,” Cerebellum,
Marchetti, and C. Pozzilli, “Home-based balance training using vol. 13, no. 1, pp. 151–177, 2014.
the Wii balance board: a randomized, crossover pilot study in [60] I. Lipp and V. Tomassini, “Neuroplasticity and motor rehabili-
multiple sclerosis,” Neurorehabilitation and Neural Repair, vol. tation in multiple sclerosis,” Frontiers in Neurology, 2015.
27, no. 6, pp. 516–525, 2013. [61] H. Duffau, “Brain plasticity: from pathophysiological mecha-
[43] J. Ashburner and K. J. Friston, “Voxel-based morphometry—the nisms to therapeutic applications,” Journal of Clinical Neuro-
methods,” NeuroImage, vol. 11, no. 6 I, pp. 805–821, 2000. science, vol. 13, no. 9, pp. 885–897, 2006.
[44] L. de Giglio, F. de Luca, L. Prosperini et al., “A low-cost cognitive [62] S.-L. Liew, E. Santarnecchi, E. R. Buch, and L. G. Cohen,
rehabilitation with a commercial video game improves sus- “Non-invasive brain stimulation in neurorehabilitation: local
tained attention and executive functions in multiple sclerosis: and distant effects for motor recovery,” Frontiers in Human
a pilot study,” Neurorehabilitation & Neural Repair, 2014. Neuroscience, vol. 8, article 378, 2014.
[45] S. W. Kennerley, J. Diedrichsen, E. Hazeltine, A. Semjen, and [63] D. M. Martin, R. Liu, A. Alonzo, M. Green, and C. K. Loo, “Use
R. B. Ivry, “Callosotomy patients exhibit temporal uncoupling of transcranial direct current stimulation (tDCS) to enhance
during continuous bimanual movements,” Nature Neuroscience, cognitive training: effect of timing of stimulation,” Experimental
vol. 5, no. 4, pp. 376–381, 2002. Brain Research, vol. 232, no. 10, pp. 3345–3351, 2014.
[46] B. W. Fling, J. A. Bernard, J. Bo, and J. Langan, “Corpus callosum
and bimanual coordination in multiple sclerosis,” Journal of
Neuroscience, vol. 28, no. 29, pp. 7248–7249, 2008.
[47] A. Ozturk, S. A. Smith, E. M. Gordon-Lipkin et al., “MRI
of the corpus callosum in multiple sclerosis: association with
disability,” Multiple Sclerosis, vol. 16, no. 2, pp. 166–177, 2010.
[48] C. Ryberg, E. Rostrup, O. B. Paulson et al., “Corpus callosum
atrophy as a predictor of age-related cognitive and motor
impairment: a 3-year follow-up of the LADIS study cohort,”
Journal of the Neurological Sciences, vol. 307, no. 1-2, pp. 100–
105, 2011.
[49] M. Manto, J. M. Bower, A. B. Conforto et al., “Consensus paper:
roles of the cerebellum in motor control-the diversity of ideas on
cerebellar involvement in movement,” Cerebellum, vol. 11, no. 2,
pp. 457–487, 2012.
[50] C. Beaulieu, “The basis of anisotropic water diffusion in the
nervous system—a technical review,” NMR in Biomedicine, vol.
15, no. 7-8, pp. 435–455, 2002.
[51] S. Cader, H. Johansen-Berg, M. Wylezinska et al., “Discordant
white matter N-acetylasparate and diffusion MRI measures sug-
gest that chronic metabolic dysfunction contributes to axonal
pathology in multiple sclerosis,” NeuroImage, vol. 36, no. 1, pp.
19–27, 2007.
[52] B. Faw, “Pre-frontal executive committee for perception, work-
ing memory, attention, long-term memory, motor control, and
thinking: a tutorial review,” Consciousness and Cognition, vol. 12,
no. 1, pp. 83–139, 2003.
[53] P. J. Morgane, J. R. Galler, and D. J. Mokler, “A review of systems
and networks of the limbic forebrain/limbic midbrain,” Progress
in Neurobiology, vol. 75, no. 2, pp. 143–160, 2005.
[54] B. Y. Hayden and M. L. Platt, “Neurons in anterior cingulate
cortex multiplex information about reward and action,” The
Journal of Neuroscience, vol. 30, no. 9, pp. 3339–3346, 2010.
[55] A. E. Cavanna and M. R. Trimble, “The precuneus: a review of
its functional anatomy and behavioural correlates,” Brain, vol.
129, no. 3, pp. 564–583, 2006.
[56] C. Dohle, K. M. Stephan, J. T. Valvoda et al., “Representation
of virtual arm movements in precuneus,” Experimental Brain
Research, vol. 208, no. 4, pp. 543–555, 2011.
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