Table 2: Summary of studies investigating the effect of cognitive rehabilitation or training on brain plasticity, assessed by task-related fMRI.

Authors (year)Sample sizeMain clinical characteristicsStudy designIntervention(s) and setting intervention scheduleClinical outcome(s)MRI outcome(s)

Penner and Kappos (2006) [32]11N/RNonrandomized pre-/postcomparison studyComputer-assisted attention training with the AIXTENT package 3-4 weeksNot reportedIncreased activation of regions in the cingulate gyrus, precuneus, and frontal cortex was found after the training

Sastre-Garriga et al. (2011) [33]15 Mean age: ~51 years
Mean MS duration ~14 years
Median EDSS: 6.0
Course: SP 10, RR 3, and PP 2
Nonrandomized pre-/postcomparison studyMixed intervention: computer-assisted cognitive rehabilitation and game-like group activities 1-hour sessions, 3 times per week, for 5 weeksImprovement in digit span after the interventionIncreased activation of right posterior cerebellar lobe and left anterior and posterior cerebellar lobe after the intervention

Chiaravalloti et al. (2012) [34]16Mean age: ~48 years
Mean MS duration ~15 years
Median EDSS: N/R
Course: 13 RR, 2 PP, and 1 SP
Double-blind randomized controlled groupActive group: modified story memory technique 45–60-minute sessions, 2 times per week, for 5 weeks
Control group: story reading and answering questions 45–60-minute sessions, 2 times per week, for 5 weeks
CVLT short-delay free recall improved in active groupIncreased activation of some areas of frontal, parietal, temporal, and occipital lobes and cerebellum in active group

Ernst et al. (2012) [35]8Mean age: ~38 years
Mean MS duration ~14 years
Median EDSS: 2.0
Course: 8 RR
Nonrandomized controlled trialActive group: Motor visual imagery training 2-hour sessions, 1 time per week, for 6 weeks
Control group: no intervention
Autobiographic memory improved in active groupIncreased activation of some areas located in posterior regions (right cuneus, left precuneus, left inferior and superior occipital gyri, and left lateral temporal cortex)

Filippi et al. (2012) [36]20Mean age: ~46 years
Mean MS duration ~14 years
Median EDSS: 2.0
Course: 20 RR
Randomized controlled trialActive group: outpatient cognitive training using the RehaCom package 1-hour sessions, 3 times per week, for 12 weeks
Control group: no intervention
The PASAT, WCST, and oral word association test improved in active group(i) Increased activation of posterior cingulated cortex and/or prefrontal cortex (bilaterally) in active group;
(ii) increased activation at rest of anterior cingulated cortex (salience processing), left dorsolateral prefrontal cortex (executive function), right inferior parietal lobule and posterior cingulated cortex, and/or precuneus (default-mode networks I and II); (iii) no significant WM and GM changes

Cerasa et al. (2013) [37]23Mean age: ~32 years
Mean MS duration ~9 years
Median EDSS: 2.5
Course: 23 RR
Double-blind randomized controlled trialActive group: outpatient cognitive training using the RehaCom package 1-hour sessions, 2 times per week, for 6 weeks
Control group: home-based training with a simple visuomotor coordination task (in-house software) 1-hour sessions, 2 times per week, for 6 weeks
The Stroop test improved in active groupIncreased activation of the right posterior cerebellar lobule and left superior parietal lobule in active group

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.