Reduced glymphatic clearance in early psychosis.

Psychosis involves neuroinflammation and oxidative stress, both affecting the glymphatic system, the lymphatic-like, fluid-transport system in the brain. However, it is unclear whether early psychosis is related to impairments in glymphatic functions. In resting-state fMRI, it has been recently established in a number of neurodegenerative diseases that the coupling relationship between cortical blood-oxygen-level-dependent (BOLD) signal and ventricular cerebrospinal fluid (CSF) flow is associated with brain waste clearance, a key glymphatic function that has not been examined in psychosis or any other psychiatric populations. In a large dataset (total n = 137, age = 23.86 ± 4.16), we demonstrated that glymphatic clearance marked by BOLD-CSF coupling was weaker and more delayed in patients with early psychosis compared to healthy controls. BOLD-CSF coupling also varied between the non-affective and affective psychosis groups with group differences most prominent in high-order but not low-order cortical regions. Finally, reduced global BOLD-CSF coupling was associated with cognitive decline and more severe psychotic symptoms. We provided novel evidence highlighting dysregulated coupling between cortical activity and macroscopic CSF flow as a biomarker for early psychosis. Similar to recent observations in neurodegenerative disorders, the association between reduced BOLD-CSF coupling and psychotic symptoms suggested that waste clearance is disrupted in psychosis which shed light on the pathophysiology of this disease from a glymphatic point of view.