White matter damage in multiple sclerosis disproportionately targets default mode, executive control, and salience networks

Multiple sclerosis (MS) and several other neurodegenerative disorders affect structurally- and functionally-connected brain networks. However, the extent of structural damage within specific networks relative to global white matter has not been systematically explored in MS. The aims of this study were therefore to investigate white matter within six brain networks – i.e., dorsal/ventral Default Mode, left/right Executive Control, and anterior/posterior Salience Networks – to: 1) determine whether MS white matter lesions are disproportionately prevalent in these regions compared to global white matter; 2) quantify microstructural degradation in these regions among persons with MS (pwMS) compared to healthy controls (HCs); and 3) ascertain whether network degradation is larger than expected compared to global white matter differences between pwMS and HCs. White matter lesion maps, global white matter masks, and whole-brain diffusion MRI maps of mean diffusivity from 104 pwMS (48±12 years; 85 female) and 100 HCs (39±16; 65 female), were analyzed using the UManitoba-JHU Functionally-Defined Human White Matter Atlases. Statistical analyses included parametric t-tests and post hoc non-parametric Wilcoxon tests. Among pwMS, 4/6 white matter networks contained disproportionately high lesion volumes (p < 0.008). All 6 networks exhibited lower microstructure among pwMS compared to HCs (p < 0.008); and even after controlling for subject-specific global white matter values, 5/6 white matter networks exhibited disproportionately reduced tissue microstructure among pwMS compared to HCs (p < 0.008). These findings suggest that MS disproportionately affects white matter structural connections underlying specific intrinsic brain networks, including the Default Mode, Executive Control, and Salience Networks. Significance statement White matter lesions and diffuse white matter damage are among the hallmark pathologies of multiple sclerosis (MS). However, although MS-related functional activity and connectivity changes throughout large-scale brain networks (including the Default Mode, Executive Control, and Salience Networks) have been previously characterized, the current study is the first to systematically examine the concentration of white matter lesions and the degree of diffuse white matter damage underlying these networks. Our findings suggest that white matter structural connections underlying the Default Mode, Executive Control, and Salience Networks are disproportionately affected in persons with MS, with higher-than-expected concentrations of cerebral white matter lesions and greater than expected amounts of diffuse white matter damage.