PROJECT SUMMARY Fatigue is one of the most common symptoms in neurological and psychiatric syndromes. However, its nature has made it one of the most controversial and least understood phenomena despite its prevalence. The primary goal of this proposal is to test a novel theoretical approach to understanding fatigue, beginning with cognitive (mental) fatigue. Specifically, this proposal tests a model based in neuroscience and uses neuroimaging as a means to measure and understand the neurologic circuits underlying cognitive fatigue, which directly aligns with NCCIH’s objectives to advance the understanding of and support the development of novel models and methodologies to understand the neurological aspects of hard-to-manage symptoms. Background: Patients with clinical syndromes generally report the cognitive component of fatigue to be the most distressing aspect of their fatigue, affecting their ability to engage in work and making activities of daily living more difficult. Previous research has examined the influence of reward and effort separately on cognitive fatigue; however, these processes have not been integrated explicitly to test whether the interaction between effort and reward induces cognitive fatigue. To address this gap, this study aims to evaluate whether an effort- reward imbalance, a model based in cognitive neuroscience, could explain cognitive fatigue in a neurological population, namely multiple sclerosis (MS), in which cognitive fatigue is a pervasive symptom. This study will use self-report measures of fatigue, a computerized switching-task, and modern neuroimaging techniques. Notably, the switching-task manipulates both levels of cognitive control (to induce changes in effort) and reward to explain cognitive fatigue. Objectives: We hypothesize that cognitive fatigue results from a mismatch between effort and reward processing. We will test the specific hypotheses that (1) across conditions of an effort-demanding cognitive control task with different levels of reward, the effort-reward interaction will predict cognitive fatigue and (2) fronto-striatal circuit anatomical integrity and recruitment of fronto-striatal regions will be associated with the effort-reward tradeoffs and cognitive fatigue. Methods: The current study will recruit 20 right-handed individuals, 18 to 60 years old with a pre-existing diagnosis of MS (remitting-relapsing subtype) with reported complaints of cognitive fatigue, and 20 age, education, and sex-matched healthy controls meeting all inclusion criteria. In a within-subjects design, subjects will provide responses on psychosocial, neuropsychological, and subjective fatigue measures. A DTI scan and fMRI data will be collected during a computerized switching task with independent effort and reward manipulations. Implications: If cognitive fatigue results from combinations of dysfunctional cognitive control and reward processes, evidenced by both behavior and pathophysiology, we could develop a model ...