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.SIGNIFICANCE STATEMENT The architecture of the functional connectome in focal dystonia was analyzed in a large population of patients with laryngeal dystonia. Breaking with the empirical concept of dystonia as a basal ganglia disorder, we discovered large-scale alterations of neural communities that are significantly influenced by the disorder's clinical phenotype and genotype.

Keywords: dystonia; functional connectome; genotype-phenotype interactions; spasmodic dysphonia.

Copyright © 2017 the authors 0270-6474/17/377438-12$15.00/0.

Figures

Figure 1.

Functional architecture of the group-averaged LD network compared with healthy individuals. A, Spatial topology of detected functional communities in the group-averaged healthy control (left) and LD patient network (right) is shown on 3D brain renderings in the axial and sagittal views, where regional module affiliation is illustrated by nodal color. B, Bivariate (with respect to strength and degree) provincial (yellow) and connector hubs (red) and their connectivity profile with high-influence nodes (purple; nodes with degree and strength in the top 25% of the network) in the group-averaged healthy volunteer network (left) and in the mean LD graph (right). C, Visualization of variations in degree (light gray) and strength (dark gray) across provincial (yellow) and connector hubs (red) in the group-averaged healthy control and LD patient networks (left and right, respectively). White circles indicate nodes that did not qualify as hubs in the respective graph. 3b/6/17, Areas 3b/6/17; 4a, anterior part of area 4; 5L/5M, subdivisions of area 5; 7A/7M/7P/7PC, subdivisions of area 7; CbI-I/IV/Cbl-V/Cbl-VI/Cbl-VIIIav/Cbl-VIIbv, cerebellar lobules I/IV/V/VI/VIIIa vermis; Cu/PCu, cuneus/precuneus; FG, fusiform gyrus; IOG, inferior occipital gyrus; LG, lingual gyrus; MCC/PCC, middle and posterior cingulate cortex; PF, area PF in the inferior parietal cortex; SOG, superior occipital gyrus; Tp/Tpf/Tt, parietal/prefronta/temporal subdivisions of the thalamus; hOC5v, ventral part of area hOC5; L, left; R, right.

Figure 2.

Functional architecture of the group-averaged familial LD and sporadic LD networks with mixed phenotype. A, Spatial topology of detected functional communities in the group-averaged mixed-phenotype familial LD (left) and sporadic LD networks (right) is shown on 3D brain renderings in the axial and sagittal views, where regional module affiliation is illustrated by nodal color. B, Bivariate (with respect to strength and degree) provincial (yellow) and connector hubs (red) and their connectivity profile with high-influence nodes (purple; nodes with degree and strength in the top 25% of the network) in the group-averaged mixed-phenotype familial LD (left) and in the mean mixed-phenotype sporadic LD graph (right). C, Visualization of variations in degree (light gray) and strength (dark gray) across provincial (yellow) and connector hubs (red) in the group-averaged mixed phenotype familial and sporadic LD networks (left and right, respectively). White circles indicate nodes that did not qualify as hubs in the respective graph. 6/17/18, areas 6/17/18; 4p, posterior part of area 4; 5L/5M/7P, subdivisions of parietal areas 5 and 7; CbI-I/IV/Cbl-V/Cbl-VI/Cbl-VIIIav/Cbl-VIIa/Cr1, cerebellar lobules I/IV/V/VI/VIIIa vermis/VIIa crus I; Cu/PCu, cuneus/precuneus; FG, fusiform gyrus; IOG/MOG/SOG, inferior/middle/superior orbital gyrus; LG, lingual gyrus; MCC/PCC, middle/posterior cingulate cortex; OP1, subdivision 1 of the operculum; PF/PFcm, areas PF/PFcm in the inferior parietal cortex; Tm/Tp/Tpf/Ts/Tt, motor/parietal/prefrontal/somatosensory/temporal subdivisions of the thalamus; hOC3v/hOC4v, ventral parts of areas hOC3/hOC4; L, left; R, right.

Figure 3.

Functional architecture of the group-averaged familial LD and sporadic LD networks with adductor phenotype. A, Spatial topology of detected functional communities in the group-averaged adductor familial LD (left) and adductor sporadic LD network (right) is shown on 3D brain renderings in the axial and sagittal views, where regional module affiliation is illustrated by nodal color. B, Bivariate (with respect to strength and degree) provincial (yellow) and connector hubs (red) and their connectivity profile with high-influence nodes (purple; nodes with degree and strength in the top 25% of the network) in the group-averaged adductor familial LD (left) and in the mean adductor sporadic LD graph (right). C, Visualization of variations in degree (light gray) and strength (dark gray) across provincial (yellow) and connector hubs (red) in the group-averaged adductor familial and adductor sporadic LD networks (left and right, respectively). White circles indicate nodes that did not qualify as hubs in the respective graph. 6/17/18, areas 6/17/18; 4a, anterior part of area 4; 5L/5M/7P, subdivisions of parietal areas 5/7; CbI-I/IV/Cbl-IXv/Cbl-V/Cbl-VI/Cbl-VIIIav/Cbl-VIIIb, cerebellar lobules I/IV/IX vermis/V/VI/VIIIa vermis/VIIIb; Cu/PCu, cuneus/precuneus; FG, fusiform gyrus; IOG/MOG/SOG, inferior/middle/superior occipital gyrus; Ig1, insula subdivision Ig1; LG, lingual gyrus; MCC/PCC, middle/posterior cingulate cortex; OP1, part 1 of the operculum; PF, parietal area PF; TE1.1, area TE1.1; Tm/Tp/Tpf/Ts/Tt, motor/parietal/prefrontal/somatosensory/temporal subdivisions of the thalamus; hOC3v/hOC4v, ventral parts of areas hOC3/hOC4; L, left; R, right.

Figure 4.

Functional architecture of the group-averaged abductor LD and adductor LD networks with sporadic genotype. A, Spatial topology of detected functional communities in the group-averaged abductor LD (left) and adductor LD networks with sporadic genotype (right) is shown on 3D brain renderings in the axial and sagittal views, where regional module affiliation is illustrated by nodal color. B, Bivariate (with respect to strength and degree) provincial (yellow) and connector hubs (red) and their connectivity profile with high-influence nodes (purple; nodes with degree and strength in the top 25% of the network) in the group-averaged abductor LD (left) and in the mean adductor LD graph with sporadic genotype (right). C, Visualization of variations in degree (light gray) and strength (dark gray) across provincial (yellow) and connector hubs (red) in the group-averaged sporadic abductor and adductor LD networks (left and right, respectively). White circles indicate nodes that did not qualify as hubs in the respective graph. 6/17, area 6/17; 7A/7M/7P, subdivisions of area 7; CbI-I/IV/Cbl-V/Cbl-VI/Cbl-VIIIav/Cbl-VIv, cerebellar lobules I/IV/V/VI/VIIIa vermis/VI vermis; Cu/PCu, cuneus/precuneus; FG, fusiform gyrus; Ig1, part Ig1 of the insula; LG, lingual gyrus; MCC/PCC, middle/posterior cingulate cortex; PF, parietal area PF; SOG, superior orbital gyrus; Tp/Tpf/Ts/Tt, parietal/prefrontal/somatosensory/temporal subdivisions of the thalamus; hOC4v, ventral part of area hOC4; L, left; R, right.

Figure 5.

Functional architecture of the group-averaged abductor LD and adductor LD networks with mixed genotype. A, Spatial topology of detected functional communities in the group-averaged abductor LD (left) and adductor LD networks with mixed genotype (right) is shown on 3D brain renderings in the axial and sagittal views, where regional module affiliation is illustrated by nodal color. B, Bivariate (with respect to strength and degree) provincial (yellow) and connector hubs (red) and their connectivity profile with high-influence nodes (purple; nodes with degree and strength in the top 25% of the network) in the group-averaged abductor LD (left) and in the mean adductor LD graph with mixed genotype (right). C, Visualization of variations in degree (light gray) and strength (dark gray) across provincial (yellow) and connector hubs (red) in the group-averaged mixed-genotype abductor and adductor LD networks (left and right, respectively). White circles indicate nodes that did not qualify as hubs in the respective graph. 6/17, area 6/17; 7A/7P, subdivsions of area 7; CbI-I/IV/Cbl-V/Cbl-VI, cerebellar lobules I/IV/V/VI; Cu/PCu, cuneus/precuneus; FG, fusiform gyrus; Ig1, part Ig1 of the insula; LG, lingual gyrus; MCC/PCC, middle/posterior cingulate cortex; SOG, superior orbital gyrus; Tp/Tpf/Ts/Tt, parietal/prefrontal/somatosensory/temporal subdivisions of the thalamus; hOC4v, ventral part of area hOC4; L, left; R, right.