Increased Activity of the Glymphatic System in First-Episode Psychosis: Relationship With Cortical Thinning.

Objective: First-episode psychosis (FEP) in pediatric onset is a pivotal window for preventing chronic disability and optimizing long-term outcomes. Improved understanding of psychosis biomarkers is essential to clarify the pathophysiology, guide individualized intervention, and improve prognostication for patients. We evaluated the glymphatic system (GS) as a potential mechanistic biomarker and assessed whether developmental processes influence GS function and cortical thinning in a cohort of FEP adolescents. We also explored the impact of age on GS function and cortical thinning. Method: A total of 21 FEP patient research participants (PRP) were recruited from a Psychiatry and Behavioral Health unit. The experimental battery included clinical and neuropsychological assessments and a magnetic resonance imaging session in which both T1 and diffusion-weighted sequences were acquired. PRP were compared to a normative set of 42 community control participants (CCP) from the same scanner. Across both groups, analysis along the perivascular space (ALPS), an approximation of glymphatic activity, was generated from the diffusion images, and whole-brain cortical thickness was compared between groups using Freesurfer software and statistical models. Results: Consistent with previous findings, significant and widespread reductions in cortical thickness were evident in the FEP population relative to the CCP. However, in contrast to expectations, ALPS was significantly elevated in PRP, suggesting increased GS functioning. Cortical thinning partially explained ALPS. Conclusion: In contrast to the few published studies in adults with schizophrenia, which have found significant reductions in ALPS, these results suggest that pediatric PRP with FEP have increased activation of the GS. Our findings suggest that this may relate to excessive cortical thinning in some brain regions (a hypothesis that we are currently exploring), although the directionality of this relationship is unclear. These findings may further indicate to a differential GS response in early vs late phases of disease or other differential pathologies related to development or disease phase, and to a differential role of GS and cortical thinning across groups.