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 8 HS — — 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 15 HS 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 10 HS 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 8 HS — — 2.0 (0.0–7.5) 4-finger flexion extension, active 1-finger tapping, active and passive 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 10 HS 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 15 HS 50.4 (34.0–68.0)10.0 (2.0–28.0) 5.5 (2.0–8.0) 4-finger flexion extension Foot flexion extension Greater activation — Positive correlation with T2-LL Rocca et al. (2003) [14 ] 13 SP 15 HS 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 Foot 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 15 HS 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 12 HS 38.0 (22.0–53.0) 37.3 (26.0–59.0) 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 16 HS 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 Object manipulation Greater activation in the SMA, SII, R cerebellum, SPG, and IFG Additional areas of activation during object manipulation — — Filippi et al. (2004) [86 ] 16 CIS 15 HS 31.7 (22–43)33.6 (21–45)34 days (18.0–64.0) 0.0 (0.0-1.0) 4-finger flexion extension Foot flexion extension Greater activation of the contralateral SMC, SII, and IFG — No significant results Rocca et al. (2005) [20 ] 16 CIS 14 RR ND 15 RR MD 12 SP 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) 0.0 (0.0-1.0) 1.0 (1.0–3.0) 4.5 (1.5–7.5) Four-finger flexion extension Cortical activation varies with disease phenotype No significant results — Ciccarelli et al. (2006) [18 ] PP 13 HS 16 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 10 HS 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 55 HS 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 HS 74 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 HS 28 29.0 (6.48)— — 4-finger flexion extension Foot flexion extension Greater activation — — Rocca et al. (2010) [15 ] 17 BMS 15 SP 17 HS 48.5 (38.0–63.0)48.6 (35.0–65.0)50.3 (36.0–68.0)24.0 (15.0–35.0) 22.0 (15.0–32.0) 2.0 (1.0–3.0) 6.5 (5.5–8.0) 4-finger flexion extension Grater activation in BMS only in the contralateral SMC Additional areas of activation in SP 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 10 HS 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 18 SP 15 HS 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) 6.0 (6.0–6.5) 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 14 HS 32.0 (21.0–43.0)30.0 (20.0–51.0)— — 1.0 (0.0–3.0) — 4-finger flexion extension Resting-state fMRI Greater activation in the R PFC Higher mean FC of the nondominant motor network — Cognitive Task Studies Staffen et al. (2002) [23 ] 21 RR 21 HS 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 10 HS 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 7 HS 45.8 (31.0–59.0) matched11.4 (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 22 HS 30.5 (22.0–50.0) matched9.0 (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 11 HS 37.0 (18.0–52.0) 37.0 (27.0–43.0) 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 HS 18 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 16 HS 39.0 (22.0–55.0) 39.0 (23.0–51.0) 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 10 HS 32.7 (8.5)— 2.13 (0.0–4.0)PASAT Greater activation in the L PFC — — Rachbauer et al. (2006) [28 ] 9 CIS 9 RR 18 HS 29.5 (5.8)28.2 (5.3)26.4 (5.4)17.5 (24.2) months0.0 (0.0-1.0) 0.0 (0.0–2.0) PVSAT Greater activation in the hippocampal and parahippocampal areas CIS vs RR and HS: greater activation in the ACC — — Sweet et al. (2006) [32 ] 15 RR 15 HS 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 10 HS — Matched — 1.65 (0.0–4.0)N-Back Greater activation bilaterally in the IFG and insula — — Morgen et al. (2007) [42 ] 19 RR 19 HS 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 ] 6 RR-D 6 HS34.3 (6.5)28.8 (6.9)33 .0 (5.0)8.5 (4.0–11.0) 6.0 (3.0–6.0) 3.0 (2.0–5.0) 2.5 (1.5–2.5) Attention (focused, divided) (D = attention deficit) RR + D vs HS: lower activation RR-D 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 15 HS 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 Incongruent > congruent: greater activation in the bilateral IFG Reaction time positively correlated with incongruent condition activation in the R IFG — Bonzano et al. (2009) [30 ] 23 RR 18 HS 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 12 HS 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 Lower FC between the L amygdala and PFC — — Pierno et al. (2009) [92 ] 15 RR 15 HS 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 19 HS 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 10 HS 44.0 (8.72)45.1 (9.42)<3.0 — Go/No Go Greater activation — — Bonnet et al. (2010) [40 ] 15 RR 20 HS 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 18 HS 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 None with EDSS or disease duration Rocca et al. (2010) [34 ] 16 PP 17 HS 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 CI vs CP: greater activation in the L PFC and IPL; lower in the bilateral SII, cerebellum, and R insula 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 15 HS 37.6 (6.8)33.9 (7.6)5.9 (3.6) —2.3 (1.3) —Alertness task N-Back ( ) Greater activation in simple tasks and greater deactivation at the highest task load — — Jehna et al. (2011) [95 ] 15 RR 15 HS 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 10 RR 10 SP 20 HS 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 RR vs CIS: greater activation, raising with cognitive demand SP vs CIS: idem Positive correlation with EDSS Positive correlation with BV; negative with T2LL Colorado et al. (2012) [96 ] 23 RR 28 HS 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 16 CI 30 HS 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 CI: lower activation in the hipp. — — Kern et al. (2012) [39 ] 18 RR 16 HS 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 12 HS 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 Additional areas in choice condition — — Forn et al. (2013) [98 ] 18 CIS 15 HS 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 52 HS 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 12 low LL 21 HS 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) 2.5 (1.5-6.0) Decision making (Iowa gambling task, choice, and feedback conditions) Greater activation in both NA-BT and affected areas for high LL None for low LL — — Tacchino et al. (2018) [99 ] 17 CIS 20 RR 20 HS 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 1.5 (1.0–3.5) — 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 —