This study investigates the response to different grip force levels in the cerebellum and its dentate nucleus in MS. We found that cerebellar responses were functionally parcellated; with linear effects in the anterior cerebellum and complex nonlinear responses in the posterior cerebellum. This behaviour is consistent with healthy subjects (nonlinear responses in bilateral lobules V-VI and ipsilateral VIII), although MS subjects additionally show a strong linear response in lobule I-IV and nonlinear responses primarily localised in lobules V-VI. In the dentate nucleus, the motor portion in MS was silent as compared to the healthy subjects.
Subjects: 16 right-handed (RH) HV (12 females; mean age 32 (±4.75) years) and 16 RH relapsing-remitting MS (RRMS) patients (11 females; mean age 36 (±5.21) years; median expanded disability status (EDSS) 4, range (1.5-6.5)).
MRI protocol: 3.0 T MRI (Philips Achieva, Philips-Healthcare, Best, The Netherlands) with a 32-channel head coil. Imaging protocol: 1) BOLD sensitive T2*-weighted EPI: TE/TR=35/2500ms, voxel size =3×3×2.7mm3, inter-slice gap=0.3mm, SENSE =2, 46 slices acquired with descending order, FOV=192×192mm2, 200 volumes, flip angle=90°; 2) 3D anatomical T1-weighted 1x1x1mm3 reference scan.
FMRI paradigm: A dynamic event-related power grip paradigm with the right (dominant) hand was designed using an MR-compatible squeeze ball. 75 active trials (3s each) were divided equally into 5 GF targets (20, 30, 40, 50, and 60 % of the subject’s maximum voluntary contraction), randomised with 75 rests. Visual cue was used for instructions.
Image pre-processing and statistical analyses: Pre-processing steps used the spatially unbiased infratentorial template (SUIT) software5 for cerebellum and its DN implemented within SPM126. Pre-processing included slice timing, realignment, and co-registration to T1-weighted volumes. The within-subject first level analysis model included five regressors of interest comprising polynomial functions of GF (up to the 4th order). The 0th order term represents the main effect of grip compared to rest, over force levels. The 1st order models BOLD linear effects; higher-orders model complex nonlinear relationships (e.g. U-shaped captured by +2nd order or more complicated neurometric functions that can be approximated by 3rd and 4th polynomial orders). At this level, t-statistics were used to test for the effects of each polynomial coefficient. Then, the SUIT normalization to the cerebellum template was performed. The normalized cerebellum functional contrast images (of each polynomial order) from each subject were smoothed (kernel =8mm). A (between-subjects) second level random effects analysis was applied to test for increasingly higher-order nonlinear effects with one or two sample t-tests for within- and between-group effects, respectively. Significance was corrected (FWE) at the cluster level (P<0.05). The resulting SPMs were visualized on the flattened cerebellum template7 using Caret8. Data was subsequently normalised using a lower smoothing kernel (4mm) together with the SUIT DN template9 to investigate the effect in the DN. Correlations with the EDSS were explored.
Figures 1 and 2 show activations projected onto the flattened cerebellum for HV and MS. In both groups, a main effect (i.e. irrespective of GF (0th order)) was detected in the anterior and posterior cerebellum. Positive 1st order effects were seen only in MS within the anterior cerebellum and lobule VI (medially). Areas following a positive 2nd order term (U-shaped profile) were seen in both groups in the superior cerebellum (lobules V-VI bilaterally). Negative 3rd order effects were observed in lobule VI bilaterally in both groups (although with a smaller effect size in MS) and in lobule VII in HV only.
The ventral part of the DN was activated (0th order only) in both groups, whereas the dorsal part was primarily activated in HV. Figures 3 and 4 show the main effect of gripping in the DN.
In the 0th, +1st and +2nd orders, the BOLD effects were negatively correlated with the EDSS in most of the anterior cerebellar lobules.
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