Salience network dysfunction in SLE: convergent roles of complement activation and altered serotonergic signaling

OBJECTIVES: The neural mechanisms underlying salience network (SN) dysfunction in SLE remain unclear. This study applied a comprehensive multimodal approach to characterize SN abnormalities in SLE patients. METHODS: We analysed the resting-state fMRI data from 76 SLE patients and 68 healthy controls using four complementary approaches: functional gradient mapping of brain organization, dynamic functional connectivity (dFC) and static functional connectivity (sFC) analyses of SN interactions with the sensorimotor (SMN) and default mode (DMN) networks, gene enrichment profiling combined with predictive modelling, and neurotransmitter system mapping. RESULTS: SLE patients revealed distinct alterations in brain functional network organization, showing reduced gradient values in both the SN and frontoparietal control network along with compressed gradient distance between the SN and SMN. sFC analyses revealed a decreased coupling between the SN and DMN but an enhanced sFC between the SN and SMN. The dFC analysis showed a significantly higher fractional occupations in the states with lower information integration in SLE. These network abnormalities are correlated with complement levels of C3, the most abundant component of the complement system. The SN gradient abnormalities were associated with specific molecular indicators, including enrichment in synaptic and protein-binding genes with WFDC1 as the strongest predictor, and showed significant relationships with 5-HT2A receptor expression patterns. CONCLUSION: Our study identifies a convergent mechanism in which complement-mediated inflammation, and serotonergic signalling alterations may collectively contribute to SN dysregulation in SLE. These findings provide new insights into potential biomarkers and therapeutic targets for SLE-related neural dysfunction.