Developmental Brain Network Trajectories Differentiate Resilience and Vulnerability to Psychosis in 22q11.2 Deletion Syndrome

BACKGROUND Disrupted maturation of functional brain networks has been increasingly linked to elevated risk of psychosis, yet the spatiotemporal characteristics of these deviations remain unclear. We used longitudinal connectome fingerprinting and jointly analyzed the functional connectivity (FC) and intraclass correlation (ICC) to obtain age-dependent trajectories of functional brain organization in 22q11.2 deletion syndrome (22q11DS), a high-risk model for psychosis. METHODS Resting-state fMRI from 62 individuals with 22q11DS and 63 controls (ages 8–30, 2–5 visits) were analyzed. Patients were stratified by the presence of positive psychotic symptoms (PPS+, PPS–). The FC and ICC characterization of connectome fingerprints were projected into a joint principal component space, yielding three orthogonal axes of maturation: PC1 (Sensory-Association Axis), PC2 (Emotional-Cognitive Balance), and PC3 (Executive-Sensory Control). Longitudinal trajectories along these axes characterized the directionality and coordination of connectome maturation. RESULTS Controls showed a clear decrease in identifiability and stability during adolescence, followed by recovery into adulthood, reflecting coordinated, direct maturation along all three axes. PPS(–) individuals exhibited a partial decrease and subsequent recovery, preserving adaptive reorganization along PC3. In contrast, PPS(+) participants displayed disorganized and irregular trajectories in the PC space and a decline in PC3, indicating disrupted temporal coordination of network maturation and fragmented executive-sensory integration. CONCLUSION Loss of developmental synchrony in FC was associated with psychosis vulnerability in 22q11DS. The PCA-based multi-axis mapping reveals that resilience and vulnerability are determined by the direction and synchrony of brain maturation, rather than by stability alone, highlighting a novel marker for tracking neurodevelopmental risk across psychiatric disorders.