Participants
Thirty-one PwMS and 29 healthy age and sex-matched controls participated in this study. There were no significant differences between PwMS and controls for age or sex. Of the PwMS, 15 were identified as fallers (≥1 fall in the past month) and 16 were identified as non-fallers (0 falls in the past month). Notably, our MS group had low disability and was highly ambulatory (mean EDSS of 3.8). Further demographic information is presented in Table 1.
Table 1. Demographics, Functional Measures among individuals with MS, Control, MS Fallers, and MS Non-Fallers
|
Healthy Control (n=29)
|
MS
(n=31)
|
MS Fallers (n=15)
|
MS Non-Fallers (n=16)
|
Age (years)
|
50.8 (11.6)
|
49.48 (11.6)
|
50.3 (12.6)
|
48.7 (11.0)
|
Sex
|
9 M; 20F
|
12M; 19F
|
6M; 9F
|
6M; 10F
|
Symptom Duration (years)
|
-
|
12.5 (9.6)
|
13.9 (11.1)
|
11.2 (8.1)
|
EDSS
|
-
|
3.8 [1.0-6.5]
|
4.0 [1-6.5]
|
3.5 [1-6.5]
|
TUG (s)
|
5.8 (1.1)
|
7.9 (2.4)*
|
8.6 (2.7)*
|
7.2 (2.0)*
|
T25FW (s)
|
4.1 (0.71)
|
5.6 (2.3)*
|
6.4 (2.7)*
|
4.9 (1.5)*
|
Walk Velocity
|
2.0 (0.32)
|
1.6 (0.5)*
|
1.4 (0.5)*
|
1.7 (0.6)
|
2MWT (m)
|
200.8 (32.3)
|
161.2 (46.4)*
|
147.2 (44.6)*
|
173.2 (46.0)
|
Summed Strength (pounds)
|
303.9 (65.2)
|
205.3 (95.1)*
|
206.1 (109.7)*
|
204.6 (82.9)*
|
SSST (seconds)
|
6.7 (1.4)
|
10.3 (4.0)*
|
11.1 (4.1)*
|
9.62 (3.9)*
|
Balance (#Romberg)
|
6.0 (0.0)
|
4.7 (1.1)*
|
4.6 (1.1)*
|
4.75 (1.1)*
|
Vibration Sensation Avg (vu)
|
2.6 (1.6)
|
6.2 (3.3)*
|
6.3 (3.4)*
|
6.1 (3.2)*
|
SDMT
|
59.7 (6.0)
|
47.3 (12.3)*
|
41.8 (11.7) *†
|
52.8 (10.6)*
|
MSWS-12
|
-
|
43.1 (27.5)
|
49.7 (23.6)
|
36.8 (30.1)
|
BPI Severity
|
0.75 (0.85)
|
2.1 (2.2)*
|
2.8 (2.7)*
|
1.5 (1.6)
|
BPI Interference
|
0.26 (0.63)
|
1.8 (2.5)*
|
2.7 (3.1)*
|
1.0 (1.5)*
|
MSQoL fatigue
|
-
|
45.6 (20.8)
|
34.2 (16.4) †
|
55.5 (19.4)
|
MSQoL mental
|
-
|
69.5 (21.5)
|
58.4 (22.4) †
|
79.9 (14.8)
|
MSQoL physical
|
-
|
59.9 (16.2)
|
52.1 (14.3) †
|
67.3 (14.5)
|
SF-36 mental
|
55.3 (5.2)
|
48.4 (11.1)*
|
42.1 (11.1)* †
|
54.2 (7.5)
|
SF-36 physical
|
51.4 (7.0)
|
38.3 (9.2)*
|
35.0 (7.9)*
|
41.4 (9.6)*
|
All values are listed as mean (SD). Expanded Disability Status Scale (EDSS); Timed Up and Go (TUG); Timed 25 Foot Walk (T25FW); Two Minute Walk Test (2MWT); Six Spot Step Test (SSST); vibration units (vu); Symbol Digit Modalities Test (SDMT); Multiple Sclerosis 12-item Walking Scale (MSWS-12); Brief Pain Inventory (BPI); Multiple Sclerosis Quality of Life (MSQoL); Short Form-36 (SF-36). Mann-Whitney U tests were used to test significant differences between groups. * Indicates a significant difference between healthy controls and PwMS; † indicates a significant difference between MS fallers and MS non-fallers (p < 0.05).
Functional Performance in MS and HC
PwMS performed significantly worse on motor measures compared to HCs. Specifically, PwMS had a slower time to complete the TUG and T25FW, slower walking velocity, a shorter distance walked on the 2MWT, decreased summed strength, slower performance on the SSST, poorer balance, and worse vibration sensation (all p < 0.05). PwMS also performed significantly worse on the SDMT, had greater pain severity and interference, as well as worse mental and physical quality of life on the SF-36 compared to controls (all p < 0.05), see Table 1.
Cerebellar Volume Measures in MS and HC
HCs exhibited significantly greater volume measures in the corpus medullare, lobules I-III, and lobule V when compared to PwMS (Supplementary Table 1). There was no significant difference in the other individual lobules, Crus I and II, or the combined motor and cognitive lobule volumes between PwMS and HCs (see Supplementary Table 1).
Supplementary Table 1. Comparison of Cerebellar Volumes among MS fallers, MS non-fallers, and HCs
|
MS
(n=31)
|
MS Faller
(n=15)
|
MS Non-Faller (n=16)
|
HC
(n=29)
|
Corpus Medullare
|
11980.81* (1055.54)
|
11564.73*† (1106.28)
|
12370.88 (866.40)
|
12649.83 (1516.50)
|
Lobules I-III
|
1137.55* (323.50)
|
1657.13* (262.52)
|
1812.94 (363.95)
|
1901.79 (377.42)
|
Lobule IV
|
6125.71 (705.63)
|
6063.27 (850.74)
|
6184.25 (559.26)
|
6131.24 (837.50)
|
Lobule V
|
6310.26* (999.08)
|
6136.33* (988.50)
|
6473.31 (1012.78)
|
7043.07 (1019.20)
|
Lobule VI
|
16830.68 (2498.76)
|
15941.73*† (2227.01)
|
17664.06 (2515.48)
|
17639.34 (2502.42)
|
Crus I
|
24327.58 (3712.18)
|
23280.07* (3099.90)
|
25309.63 (4057.81)
|
25311.72 (2928.88)
|
Crus II
|
15100.10 (1909.33)
|
14843.47 (1500.53)
|
15340.69 (2249.89)
|
15304.00 (2480.83)
|
Lobule VIIB
|
10287.26 (1486.58)
|
10086.07 (1163.91)
|
10475.88 (1754.14)
|
10775.59 (1612.21)
|
Lobule VIIIA
|
9897.97 (2386.80)
|
9471.07 (1924.60)
|
10298.19 (2753.79)
|
9011.38 (1706.95)
|
Lobule VIIIB
|
6137.87 (861.57)
|
6250.13 (853.04)
|
6032.63 (883.75)
|
6471.41 (942.73)
|
Lobule IX
|
5677.81 (915.02)
|
5735.07 (1095.31)
|
5624.13 (740.58)
|
6166.03 (1166.55)
|
Lobule X
|
889.58
(158.15)
|
894.07
(156.82)
|
885.38 (164.41)
|
899.69
(164.73)
|
Vermis VI
|
1421.16 (244.70)
|
1403.93 (238.77)
|
1437.31 (256.85)
|
1417.97 (146.04)
|
Vermis VII
|
970.74 (194.20)
|
976.80 (151.02)
|
965.06 (232.53)
|
1038.69 (185.15)
|
Vermis VIII
|
1828.03 (300.18)
|
1765.33 (188.99)
|
1886.81 (373.18)
|
1867.34 (358.95)
|
Vermis IX
|
965.61 (131.83)
|
913.67† (131.42)
|
1014.31 (115.81)
|
993.86 (191.70)
|
Vermis X
|
319.39
(50.53)
|
299.00*† (52.38)
|
338.50 (41.71)
|
340.62
(66.58)
|
Motor Lobules (I-V, VIII)
|
30209.4 (3318.3)
|
29577.9 (2509.2)
|
30801.3 (3920.9)
|
30558.9 (2905.2)
|
Cognitive Lobules (VI, VII, Crus I-II)
|
66545.6 (6382.9)
|
64151.3*† (5202.9)
|
68790.3 (6716.5)
|
69030.7 (6748.5)
|
All volumes are in mm3 and listed as mean (SD). * Indicates significantly different from HC at p < 0.05. † Indicates significantly different from non-fallers (see Table 2 for p-values).
Relationships between Cerebellar Volume and Clinical Function
Motor and Sensory Measures
Lower volume of lobules I-III was associated with significantly longer times to complete the TUG, the T25FW and the SSST, slower walking velocity, worse strength, poorer balance, and higher (worse) vibratory threshold (see Figure 1 and Table 2). Lower volume of lobule V was associated with poorer balance (Table 2), but no other motor measures. There were no significant relationships among function and other motor lobules (lobules IV, VIIIA, VIIIB).
Table 2. Relationships among Cerebellar Volumes and Functional Performance in persons with MS and HC.
|
Lobules I-III
|
Lobule IV
|
Lobule V
|
Lobule VI
|
Crus I
|
Crus II
|
Lobule VIIB
|
Lobule VIIIA
|
Lobule VIIIB
|
Lobule IX
|
Lobule X
|
Motor Lobules
|
Cognitive Lobules
|
Motor Measures
|
|
|
TUG
|
-.304
.019
|
.027
.839
|
-.158
.233
|
-.227
.084
|
-.353
.006
|
-.207
.115
|
.094
.480
|
.070
.597
|
.108
.414
|
-.291
.025
|
.039
.768
|
.034
.799
|
-.289
.026
|
T25FW
|
-.370
.004
|
.038
.776
|
-.125
.345
|
-.264
.044
|
-.302
.020
|
-.243
.063
|
-.009
.943
|
-.070
.596
|
.082
.539
|
-.294
.024
|
.066
.618
|
-.094
.480
|
-.333
.010
|
Walk Velocity
|
.266
.040
|
-.029
.827
|
.076
.564
|
.419
< .001
|
.341
.008
|
.294
.023
|
.073
.579
|
.084
.524
|
-.102
.439
|
.293
.023
|
.005
.968
|
.067
.611
|
.428
< .001
|
2MWT
|
.249
.067
|
.031
.823
|
.113
.412
|
.263
.052
|
.337
.012
|
.179
.190
|
-.109
.427
|
-.089
.520
|
-.193
.159
|
.300
.026
|
-.068
.621
|
-.033
.814
|
.284
.036
|
Summed Strength
|
.445
< .001
|
-.023
.863
|
.227
.081
|
.283
.028
|
.335
.009
|
.195
.135
|
.071
.591
|
.178
.175
|
.224
.086
|
.277
.032
|
.226
.083
|
.247
.057
|
.330
.010
|
SSST
|
-.361
.006
|
-.005
.969
|
-.161
.233
|
-.353
.007
|
-.367
.005
|
-.262
.049
|
.000
.998
|
.118
.381
|
-.023
.866
|
-.281
.034
|
-.020
.883
|
.016
.908
|
-.406
.002
|
Balance
|
.297
.021
|
-.046
.727
|
.309
.016
|
.213
.103
|
.322
.012
|
.111
.397
|
.053
.689
|
-.144
.272
|
.091
.489
|
.156
.235
|
-.023
.861
|
.040
.759
|
.254
.051
|
Vibration
Sensation
|
-.366
.004
|
.119
.367
|
-.250
0.054
|
-.121
0.357
|
-.125
0.343
|
-.022
.868
|
.004
.978
|
.040
.762
|
-.092
.485
|
-.139
.291
|
-.004
.977
|
-.045
.736
|
-.065
.622
|
Cognitive Measure
|
|
|
SDMT
|
.343
.008
|
.066
.622
|
.247
.059
|
.431
<.001
|
.310
.017
|
.236
.072
|
.134
.312
|
-.047
.723
|
.072
.588
|
.181
.171
|
.087
.513
|
.121
.361
|
.411
.001
|
All values listed Spearman’s rho (p). Bolded and shaded values indicate significance at p<0.05. Timed Up and Go (TUG); Timed 25 Foot Walk (T25FW); Two Minute Walk Test (2MWT). Six Spot Step Test (SSST); Symbol Digit Modalities Test (SDMT); Motor lobules indicates the sum of lobules I-V and VIII); Cognitive lobules indicate the sum of lobules VI-VII and Crus I-II
Lower volumes in lobules VI and crus I were significantly associated with slower time to complete the T25FW and SSST, slower walking velocity, and worse strength (Table 2). Lower Crus I volume was also significantly correlated with slower time to complete the TUG, shorter distance covered by the 2MWT, and poorer balance (Table 2). Lower volume in crus II was associated with significantly reduced walking velocity and longer time to complete the SSST, but no other measures. There were no significant relationships among function and the other cognitive lobule (lobule VIIB).
Interestingly, lobule IX also demonstrated significant associations with motor functions, with lower volume significantly correlated with slower time to complete the TUG, the T25FW, the SSST, slower walking velocity, less distance covered in the 2MWT, and worse strength (Table 2).
Cognitive Measures
Poorer performance on the SDMT was associated not only with lower volumes in cognitive lobules VI and crus I, but also with reduced volume in lobules I-III, which are typically characterized as motor lobules (Figure 1, Table 2).
MS fallers vs. non-fallers
As expected, MS fallers performed significantly worse than MS non-fallers on the SDMT and reported lower scores on measures of quality of life (excluding SF-36); however, there were no significant differences between fallers and non-fallers on any motor measures (Table 1). There was no significant difference between non-fallers and HC on waking velocity, 2MWT, pain severity, or SF-36 mental sub score, while fallers performed significantly worse than HCs on these measures (Table 1). Significant differences in MS fallers and MS non-fallers volume measures were found at the corpus medullare (p = 0.027), lobule VI (p = 0.041), vermis IX (p = 0.033), vermis X (p = 0.017) and in the combined cognitive lobules (p = 0.007) (Table 3). When compared to HCs, MS fallers demonstrate significantly reduced volume in the corpus medullare (p = 0.013), lobules I-III (p = 0.024), lobule V (p = 0.012), lobule VI (p = 0.009), crus I (p = 0.046), vermis X (p = 0.032) and cognitive lobules (p = 0.022). Interestingly, there were no significant differences in cerebellar volumes between MS non-fallers and controls, suggesting that the difference between MS and control groups may be driven by the fallers (Table 3). Further, when all non-fallers are combined into a single group (including both HC non-fallers and MS non-fallers) and compared to the group of MS fallers, fallers demonstrates significantly reduced volume of corpus medullare (p = 0.008), lobules I-III (p = 0.030), lobule V (p = 0.035), lobule VI (p = 0.007), crus I (p = 0.047), vermis X (p = 0.012), and the cognitive lobules (p = 0.006) (Table 3).
Table 3. Differences in Regional Cerebellar Volumes among MS fallers, MS non-fallers, and HCs
Cerebellar region
|
Control v. MS Faller
|
Control v.
MS Non-Faller
|
MS Faller v. MS Non-Faller
|
MS Faller v. All Non-Faller (MS + Control)
|
Corpus Medullare
|
.013
|
.222
|
.027
|
.008
|
Lobules I-III
|
.024
|
.361
|
.163
|
.030
|
Lobule IV
|
.701
|
.813
|
.401
|
.522
|
Lobule V
|
.012
|
.107
|
.401
|
.035
|
Lobule VI
|
.009
|
.868
|
.041
|
.007
|
Crus I
|
.046
|
.962
|
.163
|
.047
|
Crus II
|
.612
|
.831
|
.338
|
.437
|
Lobule VIIB
|
.194
|
.687
|
.423
|
.210
|
Lobule VIIIA
|
.496
|
.148
|
.470
|
.878
|
Lobule VIIIB
|
.379
|
.180
|
.495
|
.765
|
Lobule IX
|
.194
|
.059
|
.770
|
.447
|
Lobule X
|
.970
|
.594
|
.599
|
.831
|
Vermis VI
|
.701
|
.906
|
.999
|
.791
|
Vermis VII
|
.310
|
.209
|
.520
|
.676
|
Vermis VIII
|
.240
|
.803
|
.119
|
.135
|
Vermis IX
|
.235
|
.470
|
.033
|
.082
|
Vermis X
|
.032
|
.868
|
.017
|
.012
|
Motor Lobules (I-V, VIIIA-B)
|
.328
|
.924
|
.423
|
.302
|
Cognitive Lobules (VI, VIIB, Crus I-II)
|
.022
|
.758
|
.007
|
.006
|
All values listed are p-values resulting from Mann-Whitney U tests comparing MS fallers, MS non-fallers, and matched HCs. Significant values (p < 0.05) are indicated with bolding and grey shading.