Table 1.
Cross-sectional t-fMRI papers.
| 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) matched |
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 22 HS |
30.5 (22.0–50.0) matched |
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 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) months | 0.0 (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 (n = 1, 2, 3) | 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 RR-D 6 HS |
34.3 (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 (n = 1, 2, 3) |
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 (n = 0.2) | 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 (n = 0, 1, 2, 3) | 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 | — |
∗fMRI main results are reported with reference to the patient group, unless specified otherwise. MS: multiple sclerosis patients; PP: primary progressive MS; SP: secondary progressive MS; RR: relapsing-remitting MS; CIS: clinically isolated syndrome; BMS: benign MS; HS: healthy subjects; CI: cognitively impaired; CP: cognitively preserved; CC: corpus callosum; CG: cingulate gyrus; ACC: anterior cingulate cortex; IPL: inferior parietal lobule; hipp.: hippocampus; MFG: medial frontal gyrus; PCC: posterior cingulate cortex; PFC: prefrontal cortex; DLPFC: dorsolateral PFC; STG: superior temporal gyrus; SMC: sensorimotor cortex; SPG: superior parietal gyrus; SMA: supplementary motor area; SII: secondary sensorimotor cortex; TP: temporal pole; L: left; R: right; PASAT: Paced Auditory Serial Addition Task; PVSAT: Paced Visual Serial Addition Task; SDMT: Symbol Digit Modalities Test; EDSS: expanded disability status scale; DF: dominant foot; NDF: nondominant foot; DH dominant foot; NDH: nondominant hand; FA: fractional anisotropy; MD: mean diffusivity; MTR: magnetization transfer rate; FC: functional connectivity; EC: effective connectivity (assessed with dynamic causal modelling); NA: normal appearing; GM: grey matter; WM: white matter; BT: brain tissue; BV: brain volume; LL: lesion load; T1-LL: T1 lesion load; T2-LL: T2 lesion load; LI: lateralization index.