Regional but not global brain damage contributes to fatigue in multiple sclerosis

Purpose: To use magnetic resonance (MR) imaging and advanced analysis to assess the role of lesions in normal-appearing white matter (NAWM) and gray matter (GM) damage, global versus regional damage, and atrophy versus microstructural abnormalities in the pathogenesis of fatigue in multiple sclerosis (MS).

Materials and Methods: Local ethics committee approval and written informed consent were obtained. Dual-echo, double inversion-recovery, high-resolution T1-weighted and diffusion-tensor (DT) MR was performed in 31 fatigued patients, 32 nonfatigued patients, and 35 control subjects. Global and regional atrophy and DT MR measures of damage to lesions, NAWM, and GM were compared (analysis of variance).

Results: Lesional, atrophy, and DT MR measures of global damage to brain, white matter (WM), and GM did not differ between fatigued and nonfatigued patients. Compared with nonfatigued patients and control subjects, fatigued patients experienced atrophy of the right side of the accumbens (mean volume±standard deviation, 0.37 mL±0.09 in control subjects; 0.39 mL±0.1 in nonfatigued patients; and 0.33 mL±0.09 in fatigued patients), right inferior temporal gyrus (ITG) (Montreal Neurological Institute [MNI] coordinates: 51, 251, 211; t value, 4.83), left superior frontal gyrus (MNI coordinates: 210, 49, 24; t value, 3.40), and forceps major (MNI coordinates: 11, 291, 18; t value, 3.37). They also had lower fractional anisotropy (FA) of forceps major (MNI coordinates: 217, 278, 6), left inferior fronto-occipital fasciculus (MNI coordinates: 225, 2, 211), and right anterior thalamic radiation (ATR) (MNI coordinates: 11, 2, 26) (P <.05, corrected). More lesions were found at T2-weighted imaging in fatigued patients. Multivariable model was used to identify right ITG atrophy (odds ratio, 0.83; 95% confidence interval [CI]: 0.82, 0.97; P = .009) and right ATR FA (odds ratio, 0.74; 95% CI: 0.61, 0.90; P = .003) as covariates independently associated with fatigue (C statistic, 0.85).

Conclusion: Damage to strategic brain WM and GM regions, in terms of microstructural abnormalities and atrophy, contributes to pathogenesis of fatigue in MS, whereas global lesional, WM, and GM damage does not seem to have a role.