Orthostatic tremor: a cerebellar pathology?

Abstract

SEE MUTHURAMAN ET AL DOI101093/AWW164 FOR A SCIENTIFIC COMMENTARY ON THIS ARTICLE: Primary orthostatic tremor is characterized by high frequency tremor affecting the legs and trunk during the standing position. Cerebellar defects were suggested in orthostatic tremor without direct evidence. We aimed to characterize the anatomo-functional defects of the cerebellar motor pathways in orthostatic tremor. We used multimodal neuroimaging to compare 17 patients with orthostatic tremor and 17 age- and gender-matched healthy volunteers. Nine of the patients with orthostatic tremor underwent repetitive transcranial stimulation applied over the cerebellum during five consecutive days. We quantified the duration of standing position and tremor severity through electromyographic recordings. Compared to healthy volunteers, grey matter volume in patients with orthostatic tremor was (i) increased in the cerebellar vermis and correlated positively with the duration of the standing position; and (ii) increased in the supplementary motor area and decreased in the lateral cerebellum, which both correlated with the disease duration. Functional connectivity between the lateral cerebellum and the supplementary motor area was abnormally increased in patients with orthostatic tremor, and correlated positively with tremor severity. After repetitive transcranial stimulation, tremor severity and functional connectivity between the lateral cerebellum and the supplementary motor area were reduced. We provide an explanation for orthostatic tremor pathophysiology, and demonstrate the functional relevance of cerebello-thalamo-cortical connections in tremor related to cerebellar defects.

Keywords: cerebellar function; frontal lobe; motor cortex; movement disorder; tremor.

See Muthuraman et al. (doi:10.1093/aww164) for a scientific commentary on this article. The pathophysiology of orthostatic tremor is unclear. Using neuroimaging to investigate the cerebellar motor pathways in patients, Gallea et al. reveal anatomo-functional changes in the cerebellar vermis, lateral cerebellum and supplementary motor area. Repetitive transcranial cerebellar stimulation reduces the amplitude of the tremor frequency peak and modifies cerebello-cortical connectivity.

Figure 1

Group differences in voxel-based morphometry. Statistical parametric maps of the comparison between patients and healthy volunteers, showing (clusters are significant at P < 0.05, corrected for multiple comparisons at the cluster level) decreased grey matter (GM) volume in the cerebellum (A) and increased grey matter volume in both SMAs and superior cerebellar vermis (B). HV = healthy volunteer; OT = orthostatic tremor.

Figure 2

Correlation of VBM changes with clinical scores and tremor severity. (A and B) Multiple regression showing that grey matter volume in the cerebellum correlated negatively with disease duration (blue) and positively with clinical scores [SUR = stand upright station (yellow), FAB = Fullerton Assessment of Balance (magenta)]. (C) Multiple regression showing that grey matter volume in the SMA correlated positively with disease duration (red) and tremor characteristics (green). A = area of the tremor power spectrum measured from EMG recordings). The clusters are superimposed on the SPM canonical brain. The cerebral parameters (individual values) showing the correlations with clinical parameters were calculated voxel-by-voxel in the regions of interest of cerebello-thalamo-cortical network (see regions of interest definition). Graphics are used as a display to report data dispersion and the direction of the correlation. GM = grey matter.

Figure 3

Group differences in ALFF and correlation of ALFF with clinical scores and tremor severity. (A) Statistical parametric maps showing the increase in ALFF in both SMA and superior cerebellar vermis of the patients with orthostatic tremor as compared with the healthy controls (clusters are significant at P < 0.05, corrected for multiple comparisons). (B) Multiple regression showing that ALFF in the SMA correlated with clinical scores (yellow) and tremor characteristics (green). Clusters are superimposed on the SPM canonical brain. Plots show the correlation between the global maximum in SMA (see Table 2 for statistical details and MNI coordinates). The cerebral parameters (individual values) showing the correlations with clinical parameters were calculated voxel-by-voxel in the regions of interest of cerebellar- motor circuit (see definition of regions of interest). (C) ALFF extracted from cerebellar clusters with lower and/or upper limb representation. Yellow–red = regions of lower limb representation (lobule IV and IX). Blue = regions of upper limb representation (lobule V and VIII). Purple = regions of complex representations of both lower and upper limbs (lobule VI). Graphs represent the average ALFF in each group (light = healthy volunteers, dark = patients with orthostatic tremor). Asterisks represent a significant group difference at P < 0.05 corrected for multiple comparisons. NS = non-significant; LH = left hemisphere; RH = right hemisphere; IV = cerebellar lobule IV; V = cerebellar lobule V; VI = cerebellar lobule VI; VIII = cerebellar lobule VIII; IX = cerebellar lobule IX; OT = orthostatic tremor; ROI = region of interest; SUR = stand upright station.

Figure 4

Results of functional connectivity of cerebellar motor networks. (A) Increased functional connectivity between the cerebellar lobule VI and both the lower limb representation of M1 and the SMA in patients with orthostatic tremor (OT) compared to healthy volunteers (HV) displayed on the SPM canonical brain (top) and represented graphically (bottom). (B) Multiple regression results showing that functional connectivity between the cerebellum VI and the SMA correlated with tremor characteristics on the SPM canonical brain (top) and represented graphically (bottom). All group differences and multiple regression results are significant at P < 0.05 corrected at the level of the cluster. Clusters are superimposed on the SPM canonical brain. Plots display the dispersion of data points extracted from the global maximum (see Table 3 for statistical details).

Figure 5

Results of functional connectivity of cerebellar motor networks for the open label trial with repetitive TMS of the cerebellum. (A) Effect of repetitive TMS on the clinical and electrophysiological characteristics of tremor. Asterisks represent a significant effect of repetitive TMS between Day 26 and baseline. (B) Compared to baseline, patients with orthostatic tremor had a decrease of functional connectivity (FC) after repetitive TMS (rTMS) treatment between the bilateral cerebellar lobule VI and both the lower limb representation in M1 and the SMA. Group differences are significant at P < 0.05 corrected at the level of the cluster. (C) Multiple regression showing that functional connectivity between the cerebellum VI and the SMA correlated with tremor characteristics positively at baseline (green) but negatively at Day 26 (cyan). This correlation was not significant at Day 5 (grey). Clusters are superimposed on the SPM canonical brain. Plots show the data dispersion and the direction of the correlation (see Table 3 for statistical details and MNI coordinates).