Author(s) (year) Sample size Age (years) MS duration (years) EDSS Task(s) (setting and schedule) fMRI main result(s) Clinical correlation(s) Structural correlation(s) Sensorimotor task studies Reddy et al. (2000) [22 ] 9 MS — — 11.6 (3.3–23.2)3.0 (0.0–6.5) 4-finger flexion extension Greater activation of the ipsilateral SMC — Negative correlation with N-acetyl-aspartate concentration Filippi et al. (2002) [16 ] 26 PP 50.1 (34.0–68.0)48.3 (34.0–62.0)10.0 (2.0–28.0) 5.5 (2.0–8.0) 4-finger flexion extension Greater activation in the ipsilateral cerebellum, bilaterally in the STG, ipsilaterally in the MFG, contralaterally in the insula/claustrum — Positive correlation with the severity of brain and spine structural damage Pantano et al. (2002) [19 ] 10 CIS 32.0 (21.0–51.0)31.0 (8.0)1.8 (0.5–4.0)1.25 (0.0–2.5) Finger-to-thumb opposition Greater number of activated foci in the bilateral hemispheres Positive correlation with disease duration Positive correlation with T1-LL in the corticospinal tract Reddy et al. (2002) [13 ] 14 RR — — 2.0 (0.0–7.5) 4-finger flexion extension, active Greater activation distinctively produced by disability or tissue damage Positive correlation with disability Negative correlation with N-acetyl-aspartate concentration Pantano et al. (2002) [8 ] 20 CIS 31.7 (8.0)31.0 (8.0)24.3 (14.0)23.9 (20.0)1.25 (0.8)0.45 (0.6)Finger-to-thumb opposition Greater activation in CIS patients who had recovered from a motor deficit than in those who recovered from an optic neuritis and HS No significant correlation with EDSS Positive correlation with T1- and T2-LL Rocca et al. (2002) [17 ] 30 PP 50.4 (34.0–68.0)10.0 (2.0–28.0) 5.5 (2.0–8.0) 4-finger flexion extension Greater activation — Positive correlation with T2-LL Rocca et al. (2003) [14 ] 13 SP 48.5 (30.0–59.0)48.3 (34.0–52.0)13.0 (5.0–35.0)4.5 (1.5–7.5) 4-finger flexion extension Greater activation for both tasks — Positive correlation with MD and FA of NA-WM and NA-GM Rocca et al. (2003) [9 ] 16 CIS 31.7 (22.0–43.0)33.6 (21.0–45.0)<3 months (mean 34 days) 0.0 (0.0-1.0) 4-finger flexion extension Greater activation — Positive correlation with the concentration of N-acetyl-aspartate in the whole brain Rocca et al. (2003) [80 ] 12 RR 38.0 (22.0–53.0) 2.5 (2.0–17.0) 1.5 (0.0–6.0) 4-finger flexion extension Greater activation in the bilateral cortex and contralateral thalamus; lower in the contralateral parietooccipital GM and ipsilateral SMC Negative correlation with MD magnitude and positive correlation with MD location Filippi et al. (2004) [12 ] 16 RR 36.4 (18.0–60.0)34.6 (24.0–62.0)7.0 (2.0–17.0) 1.0 (0.0–3.0) 4-finger flexion extension Greater activation in the SMA, SII, R cerebellum, SPG, and IFG — — Filippi et al. (2004) [86 ] 16 CIS 31.7 (22–43)33.6 (21–45)34 days (18.0–64.0) 0.0 (0.0-1.0) 4-finger flexion extension Greater activation of the contralateral SMC, SII, and IFG — No significant results Rocca et al. (2005) [20 ] 16 CIS 31.7 (22–43)37.6 (24.0–54.0)35.4 (18.0–52.0)50.0 (30.0–59.0)0.1 (0.1–0.2)9.5 (2.0–22.0)8.0 (2.0–17.0)17.0 (5.0–35.0)0.0 (0.0-1.0) Four-finger flexion extension Cortical activation varies with disease phenotype No significant results — Ciccarelli et al. (2006) [18 ] PP 13 46.6 (11.3)37.3 (11.9)8.69 (7.49)4.0 (3.0–6.5) Foot flexion extension, active and passive Greater activation in the STG, Rolandic operculum, and putamen during passive movement Negative correlation with EDSS (active movement) Negative correlation with T2-LL (passive movement) Wang and Hier (2007) [87 ] 15 MS 41.9 45.8 11.8 3.7 (1.0–8.0) 4-finger flexion extension Greater activation in R PMC and R cognitive areas — Positive correlation with T2-LL Wegner et al. (2008) [88 ] 56 MS 35.0 (20.0–53.0)30.0 (19.0–48.0)6.7 (1.0–21.0)2.0 (0.0–7.5) Hand tapping Greater activation Positive correlation with age and manual dexterity Rocca et al. (2009) [79 ] MS 61 35.7 (7.4)30.7 (7.1)7.8 (5.3)2.5 (0.0–7.5) 4-finger flexion extension, DH Different effective connectivity No significant correlation with EDSS Negative correlation with T2-LL Harirchian et al. (2010) [10 ] CIS 26 29.0 (6.48)— — 4-finger flexion extension Greater activation — — Rocca et al. (2010) [15 ] 17 BMS 48.5 (38.0–63.0)48.6 (35.0–65.0)50.3 (36.0–68.0)24.0 (15.0–35.0) 2.0 (1.0–3.0) 4-finger flexion extension Grater activation in BMS only in the contralateral SMC All MS: negative correlation with EDSS in the R cerebellum Correlation in all MS with T2-LL, MD, and FA in NA-WM. Rico et al. (2011) [11 ] 8 CIS 30.0 (23.0–5.0)29.0 (22.0–9.0)0.3 (0.1–0.7)1.3 (0.0–3.0) 4-finger flexion extension Greater activation in the ACC — Positive correlation with T2-LL Petsas et al. (2013) [21 ] 13 RR 37.8 (10.4)49.8 (6.4)41.7 (9.0)7.6 (5.8)21.9 (8.6)1.5 (1.0–3.0) Passive four-finger flexion extension Progressive extension of ipsilateral motor activation and different deactivation of posterior cortical areas according to phenotype — Correlation with T2 and T1 lesion volume Faivre et al. (2015) [89 ] 13 early MS 32.0 (21.0–43.0)30.0 (20.0–51.0)— 1.0 (0.0–3.0) 4-finger flexion extension Greater activation in the R PFC — Cognitive Task Studies Staffen et al. (2002) [23 ] 21 RR 33.5 (7.5)31.8 (7.4)— — PVSAT Greater activation in the frontal, parietal, and cingulate cortexes — — Audoin (2003) et al. [24 ] 10 CIS 31.6 (7.57)26.1 (7.88)0.57 (0.28)1.25 (0.0–2.00)PASAT Greater activation in the R frontopolar cortex, bilateral lateral PFC, and R cerebellum No significant results No significant results Penner (2003) et al. [45 ] 14 MS 45.8 (31.0–59.0)11.4 (3.0–24.0) 3.3 (1.0–6.0) Attention Greater and more extended activation, not significant in more severe patients — — Mainero et al. (2004) [26 ] 22 RR 30.5 (22.0–50.0)9.0 (1.0–16.0) 1.5 (1.0–3.5) PASAT; memory recall task Greater and more extended activation, more significant in good than in poor performers No significant results Positive correlation with T2-LL Saini et al. (2004) [90 ] 14 RR 37.0 (18.0–52.0) 3.6 (8.0) 1.0 (1.0–2.5) Writing Greater activation in the R PMC No significant results No significant results Audoin et al. (2005) [25 ] 18 CIS 29.5 (7.0)25.3 (6.3)6.6 (4.94) months 1.0 (0.0–2.0) PASAT Greater activation in the lateral PFC (bilaterally in good performers, only R in poor performers) — Negative correlation with tissue damage in R PFC Cader et al. (2006) [31 ] 21 RR 39.0 (22.0–55.0) 6.0 (1.0–20.0) 2.0 (0.0–6.0) N-Back Lower activation in the SFG and ACC; smaller activation increases with greater task complexity No significant results No significant results Forn et al. (2006) [27 ] 15 RR 32.7 (8.5)— 2.13 (0.0–4.0)PASAT Greater activation in the L PFC — — Rachbauer et al. (2006) [28 ] 9 CIS 29.5 (5.8)28.2 (5.3)26.4 (5.4)17.5 (24.2) months0.0 (0.0-1.0) PVSAT Greater activation in the hippocampal and parahippocampal areas — — Sweet et al. (2006) [32 ] 15 RR 47.3 (6.8)48.1 (6.3)21.4 (4.6)1.5 N-Back ( 1-Back: greater activation in the PMC, SMA, and DLPFC; 2-,3-Back: lower activation in the L SFG, cingulate, and parahipp. gyri Positive correlation of difficulty level in the anterior cortex Positive correlation of 1-back activity with T2-LV Forn et al. (2007) [33 ] 17 RR — — 1.65 (0.0–4.0)N-Back Greater activation bilaterally in the IFG and insula — — Morgen et al. (2007) [42 ] 19 RR 32.4 (8.2)31.7 (7.5)20.0 (17.1)1.5 (1.1) Delayed recognition (encoding, maintenance, and recognition) Encoding: no significant differences Maintenance, recognition: greater activation in L IPL Correlation with PASAT Positive correlation with GM atrophy Nebel et al. (2007) [91 ] D 34.3 (6.5)28.8 (6.9)33 .0 (5.0)8.5 (4.0–11.0) 3.0 (2.0–5.0) Attention (focused, divided) (D = attention deficit)D vs HS: lower activationD vs HS: not significant — — Prakash et al. (2007) [29 ] 24 RR 44.7 (29.0–53.0)8.0 (1.0–18.0)2.6 (1.8)PVSAT Activation of prefrontal, parietal, temporal, and occipital regions in response to the PVSAT Peak oxygen consumption correlated positively in the R IFG-MFG and negatively in the ACC — Prakash et al. (2008) [43 ] 24 RR 45.86 44.74 8.0 (5.1)2.6 (1.7) Eriksen flanker task (congruent, incongruent, and baseline) Incongruent > baseline: greater activation in the R PFC Reaction time positively correlated with incongruent condition activation in the R IFG — Bonzano et al. (2009) [30 ] 23 RR 32.5 (4.2)6.9 (3.2)1.6 (0.0–3.0)PVSAT vs visual (control) task No group comparison reported — — Passamonti et al. (2009) [44 ] 12 RR 29.3 (8.1)28.7 (5.1)4.3 (2.8)1.5 (1.0–2.5) Emotion evoking (photos of faces) vs neutral (shapes) Greater activation in the ventrolateral PFC — — Pierno et al. (2009) [92 ] 15 RR 30.6 (19.0–44.0)34 .0 (24.0–54.0)16.2 (9.2)1.5 (1.0–3.0)Hand-grasping observation Greater activation — — Rocca et al. (2009) [81 ] 15 BMS 44.0 (35.0–61.0)41.7 (34.0–60.0)20 (20–30) 2.0 (1.0–3.0) STROOP Greater EC between the SMC and R IFG and R cerebellum; lower with the ACC Positive correlation with disease duration Correlations of average FA/MD with EC Smith et al. (2009) [93 ] 10 MS 44.0 (8.72)45.1 (9.42)<3.0 — Go/No Go Greater activation — — Bonnet et al. (2010) [40 ] 15 RR 35.4 (10.26)32.5 (9.77)29.8 (13.5)2.5 (0.0–6.0) Go/No Go (complex, initial), tonic alertness More extent activation; lower and less extent for more complex tasks Correlation with response times Positive correlation with lower mean NA-BT in the MTR Helekar et al. (2010) [94 ] 16 RR 39.6 (2.6)36 .0 (2.2)7.0 (2.0–15.0) 2.0 (1.0–6.0) STROOP; Wisconsin Card Sorting task No significant results Positive correlation for age with network sizes and spatial extent Rocca et al. (2010) [34 ] 16 PP 49.7 (39.0–68.0)49.9 (26.0–63.0)10.0 (4.0–21.9) 6.0 (3.0–7.0) N-Back Greater activation with differences between CI and CP Positive correlation with composite cognitive score Negative correlation with T2-LL in the PFC; positive in the SII Amann et al. (2011) [35 ] 15 MS 37.6 (6.8)33.9 (7.6)5.9 (3.6)2.3 (1.3)Alertness task Greater activation in simple tasks and greater deactivation at the highest task load — — Jehna et al. (2011) [95 ] 15 RR 29.5 (9.6)30.3 (10.6)7.3 (6.5)2.0 (0.0–3.5) Facial recognition of emotion Greater activation in the PCC and precuneus for anger or disgust; in the occipital fusiform gyri, ACC, and IFG for neutral — No significant results Loitfelder et al. (2011) [41 ] 10 CIS 33.4 (10.5)32.5 (7.5)46.5 (8.8)34.0 (8.1)1.1 (1.0)4.7 (4.1)16.2 (7.0)0.5 (0.0–2.0)1.6 (0.0–3.5)6.2 (3.5–7.5)Go/No Go All MS vs HS: lower deactivation Positive correlation with EDSS Positive correlation with BV; negative with T2LL Colorado et al. (2012) [96 ] 23 RR 41.8 (9.9)38.1 (12.5)7.4 (6.7)0.0 (0.0-1.5) Checkerboard, 4-finger flexion extension, N-back ( Greater activation for N-back and for nondominant hand movement — Positive correlation with T2-LL in both right and left motor tasks Hulst et al. (2012) [38 ] 34 CP 46.0 (9.2)50.3 (5.6)44.5 (8.8)11.4 (6.6)12.5 (7.3)4.1 (1.3)4.3 (1.5)Episodic memory encoding CP: greater activation in the hippocampal memory system — — Kern et al. (2012) [39 ] 18 RR 42.1 (23.0–54.5)35.2 (24.0–50.3)3.0 (1.0–5.0) 1.7 (1.0–3.0)Verbal task (encoding, recall) Greater activation in the L anterior hipp. (cornu ammonis) and bilateral ento- and perirhinal cortices Positive correlation with overall verbal memory performance Positive correlation with fornix FA Smith et al. (2012) [97 ] 12 MS 43.1 (8.5)43.1 (9.8)— <3 Information processing (semantic, choice) Greater activation the DLPFC, PCC, R STG, and R TP; lower in the L MTG, L STG, R SMA, and R IPL — — Forn et al. (2013) [98 ] 18 CIS 33.0 (8.8)32.3 (7.2)— 1.5 (0.0–3.5) SDMT Greater deactivation of the R posterior cingulate gyrus — Positive correlation with T2-LL Rocca et al. (2014) [36 ] 42 MS 39.6 (8.5)7.7 (2.0–15.0)2.0 (1.0–4.0) N-Back ( Negative correlation with disease duration; positive with cognitive performance Negative correlation with T2-LL Weygandt et al. (2017) [37 ] 18 high LL 49.8 (7.7)45.0 (9.9)49.1 (11.7)11.7 (7.2)5.8 (4.0)4.0 (2.5-6.0) Decision making (Iowa gambling task, choice, and feedback conditions) Greater activation in both NA-BT and affected areas for high LL — — Tacchino et al. (2018) [99 ] 17 CIS 35.5 (8.16)39.1 (9.5)34.0 (8.1)14.1 (8.2)2.3 (1.3)1.0 (0.0–2.0 Mental (vs actual) movement Greater activation in CIS vs RR or HS and in RR vs HS Positive correlation with mental performance in the MS group and RR; negative in CIS —
