Background Fatigue is the most prevalent and debilitating long COVID symptom, however risk factors and pathophysiology of this condition remain unknown. We assessed risk factors for long COVID fatigue and explored its possible pathophysiology. Methods Nested case-control study in a COVID recovery clinic. Individuals with (cases) and without (controls) significant fatigue were included. We performed a multidimensional assessment evaluating various parameters, including pulmonary function tests and cardiopulmonary exercise testing, and implemented multivariable logistic regression to assess risk factors for significant long COVID fatigue. Results Total of 141 individuals were included. Mean age was 47 (SD 13) years; 115 (82%) were recovering from mild COVID-19. Mean time for evaluation was 8 months following COVID-19. Sixty-six (47%) individuals were classified with significant long COVID fatigue. They had significantly higher number of children, lower proportion of hypothyroidism, higher proportion of sore throat during acute illness and long COVID symptoms, and of physical limitation in daily activities. Individuals with fatigue had poorer sleep quality and higher degree of depression. They had significantly lower heart rate [153.52 (22.64) vs 163.52 (18.53), p=0.038] and oxygen consumption per Kg [27.69 (7.52) vs 30.71 (7.52), p=0.036] at peak exercise. The two independent risk factors for fatigue identified in multivariable analysis were peak exercise heart rate (odds ratio [OR] 0.79 per 10 beats/minute, 95% confidence interval [CI] 0.65-0.96, p=0.019); and long COVID memory impairment (OR 3.76, 95% CI 1.57-9.01, p=0.003). Conclusions Long COVID fatigue may be related to autonomic dysfunction, impaired cognition and decreased mood. This may suggest a limbic-vagal pathophysiology. Clinical Trial registration: NCT04851561

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Humans are goal‐directed; however, goal‐unrelated information still affects us, but how? The Stroop task is often used to answer this question, relying on conflict (incongruency) between attributes, one targeted by the task and another irrelevant to the task. The frontal regions of the brain are known to play a crucial role in processing such conflict, as they show increased activity when we encounter incongruent stimuli. Notably, the Stroop stimuli also consist of conceptual dimensions, such as semantic or emotional content, that are independent of the attributes that define the conflict. Since the non‐targeted attribute usually refers to the same conceptual dimension as the targeted‐attribute, it is relevant to the task at hand. For example, when naming the emotion of an emotional face superimposed by an emotional word, both the targeted‐attribute and the non‐targeted attribute refer to the conceptual dimension “emotion”. We designed an fMRI paradigm to investigate how conflicts between different conceptual dimensions impact us. Even though the conflict was task‐irrelevant, incongruent stimuli resulted in longer reaction times, indicating a behavioral congruency effect. When examining the neural mechanisms that underlie this effect, we found that the frontal regions exhibited repetition suppression, while the bilateral intraparietal sulcus (IPS) showed a congruency effect linked to the behavioral effect. Taken together, these findings suggest that individuals are unable to completely ignore task‐irrelevant information, and that the IPS plays a crucial role in processing such information.

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