Correlation between structural and functional connectivity impairment in amyotrophic lateral sclerosis

Abstract

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease, characterized by progressive loss of motor function. While the pathogenesis of ALS remains largely unknown, imaging studies of the brain should lead to more insight into structural and functional disease effects on the brain network, which may provide valuable information on the underlying disease process. This study investigates the correlation between changes in structural connectivity (SC) and functional connectivity (FC) of the brain network in ALS. Structural reconstructions of the brain network, derived from diffusion weighted imaging (DWI), were obtained from 64 patients and 27 healthy controls. Functional interactions between brain regions were derived from resting-state fMRI. Our results show that (i) the most structurally affected connections considerably overlap with the most functionally impaired connections, (ii) direct connections of the motor cortex are both structurally and functionally more affected than connections at greater topological distance from the motor cortex, and (iii) there is a strong positive correlation between changes in SC and FC averaged per brain region (r = 0.44, P < 0.0001). Our findings indicate that structural and functional network degeneration in ALS is coupled, suggesting the pathogenic process affects both SC and FC of the brain, with the most prominent effects in SC.

Keywords: amyotrophic lateral sclerosis; connectivity; diffusion weighted imaging; magnetic resonance imaging; resting-state.

Figure 1

(a) Determination of changes in structural and functional connectivity in patients compared with healthy controls using difference matrices, i.e., the difference between the average connectivity matrix in healthy controls and the average connectivity matrix in patients. (b) Selection of connections between rings of nodes surrounding the motor cortex. [Color figure can be viewed in the online issue, which is available at http://wileyonlinelibrary.com.]

Figure 2

Connectomic representation of the brain network in which the top 10% most impaired SC connections (left) and the top 10% most impaired FC connections (right) as well as the overlapping connections are colored. The locations of homologous nodes, based on anatomy, have been symmetrized. [Color figure can be viewed in the online issue, which is available at http://wileyonlinelibrary.com.]

Figure 3

Observed overlap between the most impaired structural and the most impaired functional connections in patients (blue). Overlaps were determined for selections (x‐axis) ranging from the top 1% to the top 30%, corresponding to the most impaired 5–138 of a total of 460 connections. The average overlaps, along with 95% confidence intervals, found between randomly selected connections are displayed for comparison (green). The observed overlap for the top 10% most impaired structural and functional connections are higher than expected for random connections (P = 0.003). [Color figure can be viewed in the online issue, which is available at http://wileyonlinelibrary.com.]

Figure 4

Nodes connected to the right motor cortex are displayed in rings with a radius proportional to the topological distance from the right motor cortex. Connections in red or green correspond to structural or functional connections for which, respectively, reduced FA or FC was measured. (1) and (2) mark the first and second ring of nodes surrounding the motor cortex. The anatomical distribution of the cortical first and second ring nodes is shown in the medial and lateral brain images. First and second ring nodes are listed in Table 3, starting from (1) and (2) going round clockwise. [Color figure can be viewed in the online issue, which is available at http://wileyonlinelibrary.com.]

Figure 5

FA and FC differences in patients at increasing topological distance from the right motor cortex. (*) Denotes significant differences between healthy controls and patients, (**) indicates impairment of the first and second ring differ significantly.

Figure 6

Scatter plot of ALSFRS‐R scores versus first ring SC impairments of the left (a) and right (b) motor cortices. (*) denotes statistical significance of the correlation (P = 0.02). [Color figure can be viewed in the online issue, which is available at http://wileyonlinelibrary.com.]

Figure 7

Scatter plot of changes in FA and FC in patients averaged over each node's direct connections fitted by a line with a positive gradient, indicating a positive correlation between changes in FA and FC. Positive connectivity changes denote impairments and negative connectivity changes mark enhancements. The color scheme to distinguish between motor cortex, first ring and second ring nodes (Table 3) corresponds with that of Figure 4. [Color figure can be viewed in the online issue, which is available at http://wileyonlinelibrary.com.]