Table 3.

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

Authors (year)	Sample size	Main clinical characteristics	Study design	Intervention(s) and setting [setting and schedule]	Clinical outcome(s)	MRI study outcome(s)
Parisi et al. (2014) [38]	20	Mean age: ~46 years Mean MS duration ~14 years Median EDSS: 2.0 Course: 20 RR	Randomized controlled trial	Active 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	Increased 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]	14	Mean age: ~49 years Mean MS duration ~14 years Median EDSS: N/R Course: 9 RR, 3 SP, and 2 PP	Double-blind randomized controlled group	Active 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 group	Increased 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]	32	Mean age: ~47 years Mean MS duration ~21 years Median EDSS: 4.5 Course: 32 RR	Nonrandomized parallel group trial	Active 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 group	Increased 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]	24	Mean age: ~42 years Mean MS duration ~13 years Median EDSS: 2.0 Course: 24 RR	Randomized wait-list controlled study	Active 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 group	Increased 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.