Altered states and transitions in major depressive disorder and their clinical and molecular associations

Metastability reflects the brain's dynamic balance between integration and segregation across networks, supporting flexible cognitive and behavioral functions. Although abnormal brain dynamics have been implicated in major depressive disorder (MDD), the alterations in metastable brain states and their clinical and transcriptomic correlates remain unclear. In this study, we analyzed resting-state functional magnetic resonance imaging (rs-fMRI) data from 569 patients with MDD and 563 healthy controls using leading eigenvector dynamics analysis (LEiDA), a phase-based method that captures transient brain states without predefined time windows. Between-group comparisons were performed at both global and modular levels, assessed their associations with clinical symptoms and their ability to predict depression severity. To explore underlying mechanisms, we integrated gene expression, cell-type specificity, and protein-protein interaction (PPI) networks. Patients with MDD exhibited widespread disruptions, including reduced global synchronization and metastability, but increased switching between states, particularly more frequent transitions from a globally coherent state (Global state) to a default mode-dominant state (DMN state). They also exhibited lower fractional occupancy of the Global state and higher fractional occupancy of a sensorimotor-dominant state. These disruptions were associated with symptoms such as insomnia and impaired insight, and predicted depression severity. Transcriptome-neuroimaging analysis revealed DMN state-related genes were enriched in pathways involved in presynaptic signal transduction and presynapse-to-nucleus signaling, and were preferentially expressed in excitatory and inhibitory neurons. CSMD1 emerged as a key hub gene in the PPI network. Our findings reveal widespread dynamic brain alterations in MDD and uncover their potential molecular mechanisms, providing new insights into the disorder's neurobiology.