Objective. To explore sequential brain activities throughout cognitive set-shifting, which is critical to understanding the basic pathophysiology of cognitive dysfunction, in patients with new-onset systemic lupus erythematosus (SLE) without neuropsychiatric symptoms.Methods. Fourteen patients with new-onset SLE but without neuropsychiatric symptoms and 14 healthy controls matched for age, sex, education level, and intelligence quotient with the patients performed a cognitive set-shifting task derived from the Wisconsin Card Sorting Test while they were undergoing eventrelated functional magnetic resonance imaging of the brain. Blood oxygen level-dependent signals were compared between different stages of cognitive set-shifting in the lupus patients and in the healthy subjects.Results. Lupus patients and healthy subjects demonstrated comparable cognitive function performance, but the cortico-basal ganglia-thalamic-cortical circuit and amygdala-hippocampus coupling, which were involved in response inhibition and active forgetting-learning dynamics, respectively, were demonstrated to be compromised in patients with SLE. Moreover, an increase in contralateral cerebellar-frontal activity was found to compensate for the compromised cortico-basal ganglia-thalamic-cortical circuit in lupus patients in order to maintain their cognitive test performance as comparable to that of the healthy subjects.Conclusion. Our study revealed significant differences in the sequential brain signals during cognitive set-shifting between patients with SLE without neuropsychiatric symptoms and healthy subjects. The results prompt further in-depth investigation for the functional neural basis of cognitive dysfunction involving the aforementioned neural circuits and compensatory pathways in patients with SLE.Systemic lupus erythematosus (SLE) is a chronic and multisystemic autoimmune disorder characterized by protean clinical manifestations. Neuropsychiatric SLE (NPSLE) is one of the most common manifestations of lupus, and it has hindered improvements in the survival of these patients over the last 5 decades (1). Of the various symptoms of NPSLE, cognitive impairment, which primarily affects attention, planning, reasoning, working memory, and executive function, has been frequently described (2). It is evident that the cognitive functioning of patients with NPSLE is inferior to that of lupus patients without neuropsychiatric symptoms and that of healthy individuals (3,4), as they demonstrate poorer performance in a number of domains of cognitive function testing, in particular, attention, information processing, learning, memory, and executive function (3-5).Real-time functional magnetic resonance imaging (fMRI) of the brain while subjects were performing cognitive function tasks revealed that brain activities, which were manifested by blood oxygen leveldependent (BOLD) signals, were significantly altered in patients with NPSLE as compared with healthy subjects (6,7). However, since these fMRI studies involved lupus