Developmental Alterations in the Diffusion Tensor Imaging Analysis Along the Perivascular Space Index Suggest Possible Glymphatic-Related Mechanisms Underlying 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) in 85 individuals with 22q11.2 deletion syndrome (22q11DS), a neurodevelopmental condition associated with elevated psychosis risk (143 scans), with cross-sectional magnetic resonance spectroscopy in a subset of 39 individuals with 22q11DS. Glymphatic function was estimated indirectly using the DTI analysis along the perivascular space (ALPS) index, a diffusion-based proxy derived from manual and automated region of interest placement. Excitation/inhibition ratio was assessed in the right hippocampus via cerebrospinal fluid–corrected combined glutamate-glutamine signal (Glx) and GABA (gamma-aminobutyric acid) levels. Results The ALPS index was significantly reduced in individuals with 22q11DS compared with control participants ( p = .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− individuals (group × age interaction: p = .009). In a subset with spectroscopy data ( n = 39), lower ALPS index predicted higher Glx/GABA ratio in the right hippocampus ( p = .002). Conclusions These findings provide in vivo evidence that glymphatic-related dysfunction, as indexed by the DTI-ALPS proxy, emerges early and follows atypical developmental trajectories in individuals at risk for psychosis. An impaired ALPS index 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.