Developmental Glymphatic Dysfunction Underlies Excitation/Inhibition Imbalance and Psychosis Vulnerability in 22q11.2 Deletion Syndrome

Background Impairment of the glymphatic system may contribute to atypical brain development and increased vulnerability to psychiatric conditions such as psychosis. In particular, disrupted glymphatic efficiency may affect neurochemical homeostasis during critical maturational windows, leading to structural and circuit-level alterations. However, its role in early neurodevelopmental trajectories remains largely unexplored. Methods We combined longitudinal diffusion tensor imaging (DTI) and magnetic resonance spectroscopy (MRS) in individuals with 22q11.2 deletion syndrome (22q11DS), a condition associated with elevated psychosis risk. Glymphatic function was estimated using the DTI-ALPS index, based on both manual and automated ROI placement. Excitation/inhibition ratio was assessed in the right hippocampus via CSF-corrected Glx and GABA levels. Results ALPS index was significantly reduced in 22q11DS compared to controls (p = 0.017), especially in the right hemisphere. Individuals with positive psychotic symptoms (PPS+) showed a divergent developmental trajectory, failing to exhibit the age-related ALPS increase seen in PPS− (group x age interaction: p = 0.009). In a subset with spectroscopy data (n = 39), lower ALPS predicted higher Glx/GABA ratio in the right hippocampus (p = 0.002). Conclusions These findings provide in vivo evidence that glymphatic dysfunction emerges early and follows atypical developmental trajectories in those at risk for psychosis. Impaired clearance is also associated with excitatory/inhibitory imbalance. This dysfunction may represent a novel pathway contributing to psychosis vulnerability and a potential target for early intervention.