Connectome-Wide Phenotypical and Genotypical Associations in Focal Dystonia

Abstract

Isolated focal dystonia is a debilitating movement disorder of unknown pathophysiology. Early studies in focal dystonias have pointed to segregated changes in brain activity and connectivity. Only recently has the notion that dystonia pathophysiology may lie in abnormalities of large-scale brain networks appeared in the literature. Here, we outline a novel concept of functional connectome-wide alterations that are linked to dystonia phenotype and genotype. Using a neural community detection strategy and graph theoretical analysis of functional MRI data in human patients with the laryngeal form of dystonia (LD) and healthy controls (both males and females), we identified an abnormally widespread hub formation in LD, which particularly affected the primary sensorimotor and parietal cortices and thalamus. Left thalamic regions formed a delineated functional community that highlighted differences in network topology between LD patients with and without family history of dystonia. Conversely, marked differences in the topological organization of parietal regions were found between phenotypically different forms of LD. The interface between sporadic genotype and adductor phenotype of LD yielded four functional communities that were primarily governed by intramodular hub regions. Conversely, the interface between familial genotype and abductor phenotype was associated with numerous long-range hub nodes and an abnormal integration of left thalamus and basal ganglia. Our findings provide the first comprehensive atlas of functional topology across different phenotypes and genotypes of focal dystonia. As such, this study constitutes an important step toward defining dystonia as a large-scale network disorder, understanding its causative pathophysiology, and identifying disorder-specific markers.

Neuroimaging Applications in Dystonia

“…These findings pointed to the unified pathophysiological mechanism underlying different forms of dystonia due to common network alterations, while suggesting the concurrent presence of pathophysiologically divergent mechanisms contributing to different forms of dystonia. In line with this assumption, another study using a similar analytic approach mapped marked differences in the topological organization of parietal regions between phenotypically different forms of laryngeal dystonia (Fuertinger & Simonyan, 2017) (Fig. 5B).…”

“…doi:10.1093/cercor/bhv313. Panel (B): Adapted from Fuertinger, S., & Simonyan, K. (2017). Connectome-wide phenotypical and genotypical associations in focal dystonia .…”

Functional and structural neural bases of task specificity in isolated focal dystonia

“…The ICs were visual inspected for their spatial distribution in order to extract the sensorimotor components 9,15 as a network most significantly implied in dystonia pathophysiology. 3,6,8,[16][17][18] The group-averaged sensorimotor ICs were concatenated and used in a dual regression to generate subject-specific spatial maps and associated time-series. 6,19,20 For each group comparison, independent two-tailed t-tests were performed on the individual Z-score maps derived from dual regression to determine between-group differences at a family-wise error (FWE)-corrected P ≤ 0.01 with a voxel-wise P ≤ 0.001 using spatial autocorrelation function.…”

Task‐specificity in focal dystonia is shaped by aberrant diversity of a functional network kernel

“…13,15 The pairwise interaction of regions of interest was estimated using normalized mutual information coefficients. 6,16,17 Group-specific mean networks were constructed by averaging weights of edges present in at least 50% of subject networks 13,18 within each group while controlling for connectedness of the mean graph. To assess the architecture of the constructed functional networks, a community detection analysis was performed following the strategy described earlier 17 (see details of network construction in the Supplementary Methods).…”

“…Several lines of evidence suggest that dystonia can be viewed as a functional network disorder with common abnormalities in basal ganglia, thalamus, cerebellum, and sensorimotor cortex. [3][4][5][6][7] On the other hand, it appears that different forms of dystonia, especially among TSFD, follow divergent pathophysiological mechanisms precipitated by different triggers. 7,8 These data raise the subsequent questions: What mechanisms are at the core of large-scale network abnormalities?…”