Table 3: Summary of studies investigating the effect of cognitive rehabilitation or training on brain plasticity, assessed by RS-fMRI.

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

Parisi et al. (2014) [38] 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 groupIncreased connectivity of the anterior cingulum with the right inferior parietal lobule and decreased connectivity of the anterior cingulum with the right inferior temporal gyrus were found in active group

Leavitt et al. (2012) [39] 14Mean age: ~49 years
Mean MS duration ~14 years
Median EDSS: N/R
Course: 9 RR, 3 SP, and 2 PP
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 relative questions 45–60-minute sessions, 2 times per week, for 5 weeks
Just a nonsignificant improvement of CVLT short-delay free recall was found in active groupIncreased connectivity (default-mode network) of insula and pyramids of vermis (left hippocampus seeded), postcentral gyrus (right hippocampus seeded), and thalamus (posterior cingulated cortex seeded)

Bonavita et al. (2015) [40]32Mean age: ~47 years
Mean MS duration ~21 years
Median EDSS: 4.5
Course: 32 RR
Nonrandomized parallel group trialActive group: outpatient cognitive training using the RehaCom package 50-minute sessions, 2 times per week for 8 weeks
Control group: newspaper reading and content referring
30-minute sessions, 2 times per week, for 8 weeks
The SDMT, PASAT, SRT-D, and SPART-D improved in active groupIncreased functional connectivity (default-mode network) of the posterior cingulated cortex and inferior parietal cortex (bilaterally) was found in active group

De Giglio et al. (2015) [41]24Mean age: ~42 years
Mean MS duration ~13 years
Median EDSS: 2.0
Course: 24 RR
Randomized wait-list controlled studyActive group: home-based training with an educational video game 30-minute sessions, 5 days per week, for 8 weeks
Control Group: wait-list
Improved PASAT and Stroop was found in active groupIncreased thalamocortical connectivity was found in brain areas corresponding to the posterior component of the default-mode 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.