Disrupted Structure–Function Integration in Systemic Lupus Erythematosus and Its Impact on Cognitive Flexibility

Systemic lupus erythematosus (SLE) is a chronic autoimmune disease, with cognitive dysfunction being one of its most common neuropsychiatric manifestations. Cognitive flexibility relies on the integration of brain structure and function, with white matter networks providing anatomical constraints for functional dynamics. Reduced cognitive flexibility is frequently observed in SLE, but the underlying structure–function integration changes remain poorly understood. This study investigated whether brain structure–function integration is altered in SLE and how it links to cognitive flexibility. We examined 22 SLE patients without clinically overt neuropsychiatric manifestation (age: 34.99 ± 10.67; 18 females) and 60 healthy controls (HCs) (age: 28.43 ± 8.56; 29 females). Using diffusion MRI and task-based fMRI acquired during the Montreal Card Sorting Test (MCST), a cognitive flexibility task, we derived brain structural–functional alignment and liberality, which quantify the extent to which brain functional signals are either coupled with or deviate from the underlying anatomical network. We found SLE patients exhibited globally higher liberality and lower alignment compared to HCs, and this was driven by the disrupted structure–function integration in the executive control network (ECN). The ECN comprises three subnetworks: ECN-A and ECN-B comprise key lateral fronto-parietal executive control areas, while ECN-C is anatomically closer to the default mode network. Further analyses revealed that SLE had higher liberality in ECN-A and ECN-B regions, alongside lower alignment in ECN-A, while ECN-C did not show these alterations. Importantly, increased liberality and decreased alignment in the ECN regions were associated with poorer cognitive flexibility (MCST performance) in SLE participants. This association was also observed across all participants. In SLE individuals specifically, liberality and alignment in the fronto-parietal ECN were further linked to clinical variables, including serum albumin and corticosteroid dosage. Additionally, the liberality and alignment in the ECN and its subnetworks were associated with cognitive performance outside the scanner (measured by Automated Neuropsychological Assessment Metrics) across all participants. Our findings suggest that aberrant structure–function integration, particularly within the fronto-parietal ECN, impacts cognitive flexibility and may contribute to the development of cognitive impairment in SLE.