Graph Theoretic Analysis of Brain Connectomics in Multiple Sclerosis: Reliability and Relationship with Cognition

Abstract

Research suggests that disruption of brain networks might explain cognitive deficits in multiple sclerosis (MS). The reliability and effectiveness of graph theoretic network metrics as measures of cognitive performance were tested in 37 people with MS and 23 controls. Specifically, relationships with cognitive performance (linear regression against the paced auditory serial addition test-3 seconds [PASAT-3], symbol digit modalities test [SDMT], and attention network test) and 1-month reliability (using the intraclass correlation coefficient [ICC]) of network metrics were measured using both resting-state functional and diffusion magnetic resonance imaging data. Cognitive impairment was directly related to measures of brain network segregation and inversely related to network integration (prediction of PASAT-3 by small worldness, modularity, characteristic path length, R² = 0.55; prediction of SDMT by small worldness, global efficiency, and characteristic path length, R² = 0.60). Reliability of the measures for 1 month in a subset of nine participants was mostly rated as good (ICC >0.6) for both controls and MS patients in both functional and diffusion data, but was highly dependent on the chosen parcellation and graph density, with the 0.2-0.5 density range being the most reliable. This suggests that disrupted network organization predicts cognitive impairment in MS and its measurement is reliable for a 1-month period. These new findings support the hypothesis of network disruption as a major determinant of cognitive deficits in MS and the future possibility of the application of derived metrics as surrogate outcomes in trials of therapies for cognitive impairment.

Keywords: brain networks; cognition; connectome; functional magnetic resonance imaging; multiple sclerosis; structural connectivity.

FIG. 1.

Boxplots of the normalized metric scores for each group. (Left) functional connectivity and (right) streamline density. Asterisks indicate significant differences.

FIG. 2.

Bar chart comparing reliability between network metrics in the cohort of MS participants and in healthy volunteers from previously reported studies. A higher ICC reflects greater reliability. The bars for the Harvard-Oxford Atlas and Destrieaux atlas are from people with MS. (Left) functional connectivity and (right) streamline density. Previous studies data from Welton et al. (2015). ICC, intraclass correlation; MS, multiple sclerosis.