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Fatigue and cognitive performance change in MS: multifactorial with disparate influences Short title: Predictors of fatigue and performance change in MS

Background Fatigue is a common and disabling symptom in Multiple Sclerosis (MS) with a variety of direct and indirect influences, but remains poorly understood. Performance-based and self-report measures of fatigue are only weakly correlated and may have independent predictors. We adopted a multifactorial approach, utilising a measure of concurrent cognitive performance change in order to examine the clinical, psychological, and cognitive factors influencing subjective and objective fatigue in MS. Methods Sixty-one people with MS were assessed. Subjective fatigue was measured using the Modified Fatigue Impact Scale, Fatigue Assessment Instrument, and a Visual Analogue Scale (VAS). The Conners Continuous Performance Test 3 (CCPT3) and VAS were administered before and after two hours of cognitive testing, representing a period of cognitive effort. The differences in scores formed measures of objective performance fatigue and subjective fatigue change, respectively. We examined differences across baseline fatigue, fatigue change and performance change classifications, using regression analysis to uncover predictors of subjective fatigue and performance change. Table 1. Demographic and clinical features of the sample Results Depression, sleep, and emotion-focused coping each predicted baseline fatigue and together explained 53.5% of variance. Increased subjective fatigue was linked with anxiety, lower self-efficacy and gender. Cognitive performance change on the CCPT3 was however predicted by estimated general cognitive ability, self-efficacy and post-intervention fatigue. Conclusion Subjective fatigue in MS is a multifactorial construct, with subjective and objective cognitive performance fatigue largely influenced by indirect psychological and cognitive factors. The varying factors driving subjective and objective fatigue suggest that future studies need to take into account these disparate aspects when developing fatigue assessment tools. Targeting influential fatigue drivers such as psychological variables, and even using gender specific interventions may have the potential to improve the burden of fatigue and quality of life of people with MS.