Dottorato in NEUROSCIENZE CLINICO-SPERIMENTALI E PSICHIATRIA

Titolo della tesi: Structural and functional connectivity alterations in focal dystonia: a focus on the cerebellum and basal ganglia.

Background and aims: Neuroimaging studies suggest that changes in the cerebellar-basal ganglia-thalamo-cortical sensorimotor circuit are a pathophysiological feature of focal dystonia. However, it remains unclear whether structural and functional alterations vary in different forms of focal dystonia. Thus, in patients with cervical dystonia (CD) and blepharospasm (BSP), we aimed at investigating structural and microstructural damage, and resting-state functional alterations of the whole brain and in specific regions/circuits of interest, to identify common and distinguishing features. Specifically, we applied voxel- and surface-based morphometry, and a probabilistic tractography approach to reveal global brain structural alterations and microstructural damage of specific subcortical-cortical white matter (WM) tracts, respectively. Also, using whole-brain and seed-based approaches we tested the hypothesis of possible functional connectivity (FC) alterations in specific circuits, including the cerebellum, basal ganglia, and cerebral cortex, in the context of preserved global functional connectivity (FC). Methods: Seventeen CD patients, 18 BSP patients, and 17 healthy subjects (HS) were studied cross-sectionally with multimodal 3T MRI. 3D T1-weighted images were used to calculate brain volumes and cortical thickness; with diffusion tensor imaging (DTI) we performed tractography and extracted DTI metrics from WM tracts reconstructed between primary motor, primary somatosensory and supplementary motor cortices, and thalamus, globus pallidus and putamen; with functional MRI at rest we studied both FC of the dentate nucleus and globus pallidus with a seed-based approach, and whole-brain FC with a graph theory approach. Results: CD patients, BSP patients, and HS did not differ in terms of cortical or subcortical volumes. Significant between-group differences in DTI metrics, namely in mean diffusivity (MD), radial diffusivity (RD) and axial diffusivity (AD), were found in the majority of the reconstructed WM tracts, with CD and BSP patients exhibiting higher MD, RD and AD compared to HS. In patients with BSP, a significant positive correlation was found between blepharospasm severity and both MD and RD of WM bundles. Compared to HS, common and distinguishing FC pattern changes in CD and BSP emerged. Both CD and BSP patients had a loss of dentate FC anticorrelation with the sensorimotor cortex. CD and BSP patients showed increased pallidal FC with the cerebellum, supplementary motor area, and prefrontal cortices with respect to HS. Increased dentate FC with the cerebellum and thalamus and increased pallidal FC with the bilateral thalamus, sensorimotor and temporo-occipital cortices, and right putamen were present in CD but not BSP patients, as compared to HS. Measures of global FC, i.e., global efficiency and small-worldness, did not differ between patients and HS. Conclusion: Despite the absence of focal damage and WM volume loss in focal dystonia, our data point to a diffuse and extensive alterations in WM integrity, i.e., axonal and myelin loss, as a common feature in CD and BSP, indicative of microstructural disruption of basal ganglia-thalamo-cortical circuit. Both CD and BSP patients showed altered dentate and pallidal FC with regions belonging to the integrated cerebellar-basal ganglia-thalamo-cortical sensorimotor circuit, supporting the concept that focal dystonia is a disorder of specific networks, and not merely a result of basal ganglia alterations. This study provides new insights into the role of microstructural and functional alterations of the integrated cerebellar-basal ganglia-thalamo-cortical sensorimotor circuit in CD and BSP pathophysiology, in the context of an intact whole brain macrostructural and functional architecture, with differences in functional interplay among specific brain structures potentially distinguishing the two clinical phenotypes.