['To use magnetic resonance (MR) imaging and advanced analysis to assess the role of lesions in normal-appearing white matter ( NAWM normal-appearing white matter ) and gray matter ( GM gray matter ) damage, global versus regional damage, and atrophy versus microstructural abnormalities in the pathogenesis of fatigue in multiple sclerosis ( MS multiple sclerosis ).', 'Local ethics committee approval and written informed consent were obtained. Dual-echo, double inversion-recovery, high-resolution T1-weighted and diffusion-tensor ( DT diffusion tensor ) MR was performed in 31 fatigued patients, 32 nonfatigued patients, and 35 control subjects. Global and regional atrophy and DT diffusion tensor MR measures of damage to lesions, NAWM normal-appearing white matter , and GM gray matter were compared (analysis of variance).', 'Lesional, atrophy, and DT diffusion tensor MR measures of global damage to brain, white matter ( WM white matter ), and GM gray matter 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 inferior temporal gyrus ) (Montreal Neurological Institute [ MNI Montreal Neurological Institute ] coordinates: 51, -51, -11; t value, 4.83), left superior frontal gyrus ( MNI Montreal Neurological Institute coordinates: -10, 49, 24; t value, 3.40), and forceps major ( MNI Montreal Neurological Institute coordinates: 11, -91, 18; t value, 3.37). They also had lower fractional anisotropy ( FA fractional anisotropy ) of forceps major ( MNI Montreal Neurological Institute coordinates: -17, -78, 6), left inferior fronto-occipital fasciculus ( MNI Montreal Neurological Institute coordinates: -25, 2, -11), and right anterior thalamic radiation ( ATR anterior thalamic radiation ) ( MNI Montreal Neurological Institute coordinates: 11, 2, -6) (P < .05, corrected). More lesions were found at T2-weighted imaging in fatigued patients. Multivariable model was used to identify right ITG inferior temporal gyrus atrophy (odds ratio, 0.83; 95% confidence interval [ CI confidence interval ]: 0.82, 0.97; P = .009) and right ATR anterior thalamic radiation FA fractional anisotropy (odds ratio, 0.74; 95% CI confidence interval : 0.61, 0.90; P = .003) as covariates independently associated with fatigue (C statistic, 0.85).'] Does regional but not global brain damage contribute to fatigue in multiple sclerosis?