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Significantly higher FC increases in patients than in controls were found only between the right insular seed and frontal and subcortical areas; these increases correlated with worsening of symptoms. Cognitive exertion can induce worsening of ME/CFS-related symptoms. These changes were here associated with strengthening of FC of the right insula with areas involved in reward processing and cognitive control. Cognitive exertion can induce worsening of ME/CFS-related symptoms. These changes were here associated with strengthening of FC of