Loss of inhibition in sensorimotor networks in focal hand dystonia

Abstract

Objective: To investigate GABA-ergic receptor density and associated brain functional and grey matter changes in focal hand dystonia (FHD).

Methods: 18 patients with FHD of the right hand and 18 age and gender matched healthy volunteers (HV) participated in this study. We measured the density of GABA-A receptors using [¹¹C] Flumazenil and perfusion using [¹⁵O] H₂O. Anatomical images were also used to measure grey matter volume with voxel-based morphometry (VBM).

Results: In FHD patients compared to HV, the vermis VI of the right cerebellum and the left sensorimotor cortex had a decrease of Flumazenil binding potential (FMZ-BP), whereas the striatum and the lateral cerebellum did not show significant change. Bilateral inferior prefrontal cortex had increased FMZ-BP and an increase of perfusion, which correlated negatively with disease duration. Only the left sensorimotor cortex showed a decrease of grey matter volume.

Interpretation: Impairments of GABAergic neurotransmission in the cerebellum and the sensorimotor cortical areas could explain different aspects of loss of inhibitory control in FHD, the former being involved in maladaptive plasticity, the latter in surround inhibition. Reorganization of the inferior prefrontal cortices, part of the associative network, might be compensatory for the loss of inhibitory control in sensorimotor circuits. These findings suggest that cerebellar and cerebral GABAergic abnormalities could play a role in the functional imbalance of striato-cerebello-cortical loops in dystonia.

Keywords: Cerebellum; Focal dystonia; Inhibition; Motor cortex; Movement disorder.

Fig. 1

Results of the two-sample t-test showing the spatial localization of clusters with group difference in flumazenil binding potential (FMZ-BP) (p < 0.05, FWE correction at the cluster level). A. Lower flumazenil binding potential in FHD patients compared to controls displayed on a glass brain (upper central view). Clusters localized in the left sensorimotor cortex, and the vermis of the cerebellum are displayed on the canonical brain of SPM. The results of the ROI analysis including the left putamen and the right cerebellar hemisphere (lobule VI) are displayed on the right. B. higher flumazenil binding potential in FHD patients compared to controls displayed on a glass brain (upper view). Clusters localized in the inferior frontal gyri are displayed on the canonical brain of SPM (lower views).

Fig. 2

Results of group comparison of rCBF PET and correlation analyses. A. Inferior prefrontal cortex, and caudate show an increase of rCBF in FHD patients compared to healthy controls (p < 0.05 with FWE correction over the whole brain). B. Overlap of areas showing an increase of rCBF and an increase of FMZ-BP, involving only the left prefrontal cortex. C. Correlation between rCBF in the left inferior prefrontal cortex and the FMZ-BP in the right cerebellar vermis (p = 0.004, Rho = − 0.54). D. Correlation between rCBF in the left inferior prefrontal cortex and the disease duration (p = 0.01, Rho = − 0.46). The significance of the correlation takes into account repeated measures (see Methods).

Fig. 3

Results of VBM analysis in regions of interest. A. Decrease of grey matter volume in the precentral gyrus, located in the dorsal premotor cortex (left panels) and the postcentral gyrus (right panels); p < 0.001, with FWE correction at the level of the cluster. B. In the left sensorimotor cortex, individual values of grey matter volume tended to correlate with individual values of BP-FMZ (p = 0.06, Rho = 0.46).