Topological reorganization of functional hubs in patients with Parkinson's disease with freezing of gait

Abstract

Background and purpose: Resting-state functional MRI (rs-fMRI) studies in Parkinson's disease (PD) patients with freezing of gait (FOG) have implicated dysfunctional connectivity over multiple resting-state networks (RSNs). While these findings provided network-specific insights and information related to the aberrant or altered regional functional connectivity (FC), whether these alterations have any effect on topological reorganization in PD-FOG patients is incompletely understood. Understanding the higher order functional organization, which could be derived from the "hub" and the "rich-club" organization of the functional networks, could be crucial to identifying the distinct and unique pattern of the network connectivity associated with PD-FOG.

Methods: In this study, we use rs-fMRI data and graph theoretical approaches to explore the reorganization of RSN topology in PD-FOG when compared to those without FOG. We also compared the higher order functional organization derived using the hub and rich-club measures in the FC networks of these PD-FOG patients to understand whether there is a topological reorganization of these hubs in PD-FOG.

Results: We found that the PD-FOG patients showed a noticeable reorganization of hub regions. Regions that are part of the prefrontal cortex, primary somatosensory, motor, and visuomotor coordination areas were some of the regions exhibiting altered hub measures in PD-FOG patients. We also found a significantly altered feeder and local connectivity in PD-FOG.

Conclusions: Overall, our findings demonstrate a widespread topological reorganization and disrupted higher order functional network topology in PD-FOG that may further assist in improving our understanding of functional network disturbances associated with PD-FOG.

Keywords: Parkinson's disease; freezing of gait; functional connectivity; functional magnetic resonance imaging; graph theory.

FIGURE 1

Significantly altered global assortativity in the PD-FOG group. An asterisk (*) indicates significant (corrected p < .05) difference. The y-axis in the figure is the assortativity measure. NC, normal controls; PD-nFOG, Parkinson’s disease patients without freezing of gait; PD-FOG, Parkinson’s disease patients with freezing of gait. The red data points in the plot represent potential outliers.

FIGURE 2

Global network metrics in the study groups. (A) Small-worldness, (B) path length, (C) clustering coefficient, (D) global efficiency, (E) local efficiency, and (F) strength. The y-axis denotes the values of the global network metric as represented in the title of the subplot. The hash symbol (#) indicates uncorrected p < .05. NC, normal controls; PD-nFOG, Parkinson’s disease patients without freezing of gait; PD-FOG, Parkinson’s disease patients with freezing of gait. The red data points in the plot represent potential outliers.

FIGURE 3

The hub regions were significantly reorganized in the PD-FOG participants. The mean degree of each node in the reference group (x-axis) is plotted versus the difference between the mean degree of each node of the reference group and chosen group (y-axis). Hub disruption index (κ) was calculated as the slope of the line (shown in red) fitted to the scatterplot. (A) Reference group: control (NC); chosen group: PD-FOG. (B) Reference group: NC; chosen group: PD-nFOG. (C) Reference group: PD-nFOG; chosen group: PD-FOG. The red color denotes increased hubness, on average, in the chosen group compared to the reference group; blue denotes abnormally decreased hubness in the chosen group. The right panel in each of the subfigures is the cortical surface representation of the difference in mean degree between the reference and chosen group and the colors are the same as in the scatter plot. L, left; R, right.

FIGURE 4

Rich-club connectivity in the three study groups. (A) Feeder network strength and (B) local network strength are plotted as bar plots for the different groups. An asterisk (*) indicates statistical significance (corrected p < .05). NC, normal controls; PD-nFOG, Parkinson’s disease patients without freezing of gait; PD-FOG, Parkinson’s disease patients with freezing of gait; NW, network. Feeder network—edges connecting non-rich-club nodes and rich-club nodes; local network—edges between non-rich-club nodes. The red data points in the plot represent potential outliers.

FIGURE 5

Relationship between network measures and clinical measures. The correlation between (A) assortativity and PD duration (in years), and (B) path length and Freezing of Gait Questionnaire (FOGQ). The solid line indicates uncorrected p < .05 and the dashed line indicates p > .05. PD-nFOG, Parkinson’s disease patients without freezing of gait; PD-FOG, Parkinson’s disease patients with freezing of gait.