Opposite white matter abnormalities in post-infectious vs. gradual onset chronic fatigue syndrome revealed by diffusion MRI

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a complex and debilitating illness with an unknown pathogenesis. Although post-infectious (PI-ME/CFS) and gradual onset ME/CFS (GO-ME/CFS) manifest similar symptoms, it has long been suspected that different disease processes underlie them. However, the lack of biological evidence has left this question unanswered. In this study, we recruited PI-ME/CFS and GO-ME/CFS patients based on consensus diagnoses made by two experienced clinicians and compared their diffusion MRI features with those of rigorously matched healthy controls (HCs) with sedentary lifestyles. PI-ME/CFS patients showed significantly higher axial diffusivities (ADs) in several association and projection fibres compared to HCs. Higher AD values in PI-ME/CFS were significantly related to worse physical summary scores. In contrast, GO-ME/CFS patients exhibited significantly decreased ADs in the corpus callosum. Lower AD values in GO-ME/CFS patients were significantly associated with lower mental summary scores in commissural and projection fibres. Distinct patterns of AD alterations in PI-ME/CFS and GO-ME/CFS provide neurophysiological evidence of different disease processes and highlight the heterogeneities of ME/CFS. These results also help explain inconsistent findings in previous ME/CFS studies and guide future intervention design.