Regional, not global, functional connectivity contributes to isolated focal dystonia

Abstract

Objective: To test the hypothesis that there is shared regional or global functional connectivity dysfunction in a large cohort of patients with isolated focal dystonia affecting different body regions compared to control participants. In this case-control study, we obtained resting-state MRI scans (three or four 7.3-minute runs) with eyes closed in participants with focal dystonia (cranial [17], cervical [13], laryngeal [18], or limb [10]) and age- and sex-matched controls.

Methods: Rigorous preprocessing for all analyses was performed to minimize effect of head motion during scan acquisition (dystonia n = 58, control n = 47 analyzed). We assessed regional functional connectivity by computing a seed-correlation map between putamen, pallidum, and sensorimotor cortex and all brain voxels. We assessed significant group differences on a cluster-wise basis. In a separate analysis, we applied 300 seed regions across the cortex, cerebellum, basal ganglia, and thalamus to comprehensively sample the whole brain. We obtained participant whole-brain correlation matrices by computing the correlation between seed average time courses for each seed pair. Weighted object-oriented data analysis assessed group-level whole-brain differences.

Results: Participants with focal dystonia had decreased functional connectivity at the regional level, within the striatum and between lateral primary sensorimotor cortex and ventral intraparietal area, whereas whole-brain correlation matrices did not differ between focal dystonia and control groups. Rigorous quality control measures eliminated spurious large-scale functional connectivity differences between groups.

Conclusion: Regional functional connectivity differences, not global network level dysfunction, contributes to common pathophysiologic mechanisms in isolated focal dystonia. Rigorous quality control eliminated spurious large-scale network differences between patients with focal dystonia and control participants.

© 2020 American Academy of Neurology.

Figures

Figure 1. Posterodorsal putamen functional connectivity (FC) in focal dystonia (FD) and controls

(A) Group average and subtraction (control − FD) correlation maps are depicted for the seeds defined in the left (top) and right (bottom) posterodorsal putamen. Color maps are thresholded at |z| ≥ 0.1 for control (CTL), dystonia (DYS), and CTL − DYS. Random effects analyses (voxel-wise t map) were done at the group level and t images were converted to equally probable Z-score images (bottom rows). Random effects color maps are thresholded at |Z| ≥ 2.0. Warm colors represent positive and cool colors represent negative correlations. The seeds are depicted in the top left corner. (B) Significantly decreased striatal FC in FD. The cluster of significant group difference for the group effect z-score subtraction map (control − FD) is shown in axial, sagittal, and coronal planes, thresholded at |z| ≥ 2.0, for the seed in left posterodorsal putamen. The FD group has significantly decreased positive FC with the right caudate and putamen, displayed here at a significance threshold of t ≥ 3.0 and a minimum cluster extent of 80 voxels. Images are oriented in radiologic convention.

Figure 2. Bilateral sensorimotor tongue functional connectivity (FC) in focal dystonia (FD) and controls

Group average and subtraction (controls − FD) correlation maps are depicted for the seed defined in the bilateral tongue representations in S1 and M1. Group average and subtraction color maps are thresholded at |z| ≥ 0.1 for control (CTL), dystonia (DYS), and CTL – DYS. Random effects analyses (voxel-wise t map) were done at the group level and t images were converted to equally probable Z-score images (random effects Z map), shown with color maps thresholded at |Z| ≥ 2.0. Cluster analysis revealed a cluster of significantly decreased negative FC in the left intraparietal sulcus, depicted in the axial, coronal, and sagittal planes (bottom) at a significance threshold of t ≥ 3.9 with a minimum cluster extent of 10 voxels. Warm colors represent positive and cool colors represent negative correlations. The seed is depicted in the top left corner. Images are oriented in radiologic convention.

Figure 3. Putamen functional connectivity (FC) in focal dystonia (FD) and controls

Group average and subtraction (control − FD) correlation maps are depicted for the seeds defined in (A). (A) Bilateral putamen at the area of peak difference in D1-like receptor binding in writer's cramp vs controls and (B) bilateral pallidum. Color maps are thresholded at |z| ≥ 0.1 for control (CTL), dystonia (DYS), and CTL – DYS. Random effects analyses (voxel-wise t map) were done at the group level and t images were converted to equally probable Z-score images (bottom row). Random effects color maps are thresholded at |Z| ≥ 2.0. Warm colors represent positive and cool colors represent negative correlations. The seed is depicted in the top left corner. Images are oriented in radiologic convention.

Figure 4. Preserved whole-brain correlation matrices in focal dystonia (FD)

Central weighted connectome object (g*) for (A) control and (B) FD groups, and (C) subtraction (control g* – FD g*). Upper triangles show composite block FC scores (average cross-correlation between regions of interest); the lower triangles show the matrix objects with all edges preserved. There is no difference between control and FD whole-brain correlation matrices structure (p = 0.23). (D) Multidimensional scaling shows clustering of FD subgroups and control whole-brain correlation matrices represented in 2D space. Diamonds indicate the central object for each group. AUD = auditory; BG = basal ganglia; CBL = cerebellum; CON = controls; DAN = dorsal attention network; DMN = default mode network; DYS = dystonia; FPN = fronto-pariatal network; MTL = medial temporal lobe; PMN = parietal memory network; REW = reward network; SAL = salience network; SMd = somatomotor dorsal; SMl = somatomotor lateral; THA = thalamus; VS = visual; VAN = ventral attention network.

Figure 5. Global signal regression (GSR) and frame censoring reduce motion-related correlations

Bar graphs show the number of significantly different correlations within the 300 × 300 region of interest whole-brain correlation matrix for (A) control (CTL) high vs CTL low mover participants, (B) focal dystonia (FD) high mover vs low mover participants, and (C) CTL vs FD motion-matched groups. GSR and frame censoring substantially reduce the number of spurious correlations arising from motion in all 3 comparisons. ****p < 0.0001.