Long-range connections are more severely damaged and relevant for cognition in multiple sclerosis

Abstract

An efficient network such as the human brain features a combination of global integration of information, driven by long-range connections, and local processing involving short-range connections. Whether these connections are equally damaged in multiple sclerosis is unknown, as is their relevance for cognitive impairment and brain function. Therefore, we cross-sectionally investigated the association between damage to short- and long-range connections with structural network efficiency, the functional connectome and cognition. From the Amsterdam multiple sclerosis cohort, 133 patients (age = 54.2 ± 9.6) with long-standing multiple sclerosis and 48 healthy controls (age = 50.8 ± 7.0) with neuropsychological testing and MRI were included. Structural connectivity was estimated from diffusion tensor images using probabilistic tractography (MRtrix 3.0) between pairs of brain regions. Structural connections were divided into short- (length < quartile 1) and long-range (length > quartile 3) connections, based on the mean distribution of tract lengths in healthy controls. To determine the severity of damage within these connections, (i) fractional anisotropy as a measure for integrity; (ii) total number of fibres; and (iii) percentage of tract affected by lesions were computed for each connecting tract and averaged for short- and long-range connections separately. To investigate the impact of damage in these connections for structural network efficiency, global efficiency was computed. Additionally, resting-state functional connectivity was computed between each pair of brain regions, after artefact removal with FMRIB's ICA-based X-noiseifier. The functional connectivity similarity index was computed by correlating individual functional connectivity matrices with an average healthy control connectivity matrix. Our results showed that the structural network had a reduced efficiency and integrity in multiple sclerosis relative to healthy controls (both P < 0.05). The long-range connections showed the largest reduction in fractional anisotropy (z = -1.03, P < 0.001) and total number of fibres (z = -0.44, P < 0.01), whereas in the short-range connections only fractional anisotropy was affected (z = -0.34, P = 0.03). Long-range connections also demonstrated a higher percentage of tract affected by lesions than short-range connections, independent of tract length (P < 0.001). Damage to long-range connections was more strongly related to structural network efficiency and cognition (fractional anisotropy: r = 0.329 and r = 0.447. number of fibres r = 0.321 and r = 0.278. and percentage of lesions: r = -0.219; r = -0.426, respectively) than damage to short-range connections. Only damage to long-distance connections correlated with a more abnormal functional network (fractional anisotropy: r = 0.226). Our findings indicate that long-range connections are more severely affected by multiple sclerosis-specific damage than short-range connections. Moreover compared to short-range connections, damage to long-range connections better explains network efficiency and cognition.

Keywords: MRI; cognition; functional brain network; multiple sclerosis; structural brain network.

Figure 1

Determining the degree of damage in short- and long-range white matter tracts. (A) Based on the distribution of the tract lengths in healthy controls (HC), structural connections were categorized into short-range (<75 mm) and long-range connections (>158 mm). (B) For these short-and long-range connections three different measures that reflect the severity of structural damage were extracted, namely (i) fractional anisotropy (FA); (ii) total number of fibres; and (iii) percentage of tract affected by lesions (case example).

Figure 2

Fractional anisotropy and number of fibres within short- and long-range connections. Lower fractional anisotropy (FA) values were observed in (A) short-range (P = 0.03) and (B) long-range connections (P < 0.001) in multiple sclerosis patients (MS) relative to healthy controls (HC). The number of fibres was only reduced in (C) long-range connections (P = 0.001) in multiple sclerosis patients relative to healthy controls. In the violin plots the median and interquartile interval are represented as dashed lines. Arms indicate a significant difference (*P < 0.05, FDR-corrected).

Figure 3

Severity of structural damage in short- and long-range connections. (A) Loss of white matter (WM) integrity as measured by fractional anisotropy, (B) loss of the number of fibres and (C) the percentage of lesions were all more severely affected in long-range than short-range connections (all P < 0.001). In the violin plots the median and interquartile interval are represented as dashed lines. Arms indicate a significant difference (*P < 0.05, FDR-corrected).