State-dependent signatures of Anti-NMDA Receptor Encephalitis: a dynamic functional connectivity study

Objective Traditional static functional connectivity (FC) analyses have shown functional network alterations in patients with anti-NMDA receptor encephalitis (NMDARE). Here, we use a dynamic FC approach that increases the temporal resolution of connectivity analyses from minutes to seconds. We hereby explore the spatiotemporal variability of large-scale brain network activity in NMDARE and assess the discriminatory power of functional brain states in a supervised classification approach. Methods We included resting-state fMRI data from 57 patients and 61 controls to extract four discrete connectivity states and assess state-wise group differences in FC, dwell time, transition frequency, fraction time and occurrence rate. Additionally, for each state, logistic regression models with embedded feature selection were trained to predict group status in a leave-one-out cross-validation scheme. Results Compared to controls, patients exhibited diverging dynamic FC patterns in three out of four states mainly encompassing the default-mode network and frontal areas. This was accompanied by a characteristic shift in the dwell time pattern and higher volatility of state transitions in patients. Moreover, dynamic FC measures were associated with disease severity, disease duration and positive and negative schizophrenia-like symptoms. Predictive power was highest in dynamic FC models and outperformed static analyses, reaching up to 78.6% classification accuracy. Conclusions By applying time-resolved analyses, we disentangle state-specific FC impairments and characteristic changes in temporal dynamics not detected in static analyses, offering new perspectives on functional reorganization underlying NMDARE. Correlation of dynamic FC measures with disease symptoms and severity indicates their clinical relevance and potential as prognostic biomarkers in NMDARE. ### Competing Interest Statement NS, SK, JH, HP, and CF have nothing to disclose. FP reports grants and personal fees from Bayer, Biogen Idec, Merck Serono, Alexion, Guthy Jackson Foundation, Viela Bio, Novartis, Roche, and Sanofi Genzyme. FP is Academic Editor of Plos One, and Associate Editor of Neurology, Neuroimmunology & Neuroinflammation. FP receives personal fees from Mitsubishi Tanabe PC (MTPC), and from UCB, outside the submitted work.