Disruptions in White Matter Maturation and Mediation of Cognitive Development in Youths on the Psychosis Spectrum

Abstract

BACKGROUND: Psychosis onset typically occurs in adolescence, and subclinical psychotic experiences peak in adolescence. Adolescence is also a time of critical neural and cognitive maturation. Using cross-sectional data from the Philadelphia Neurodevelopmental Cohort, we examined whether regional white matter (WM) development is disrupted in youths with psychosis spectrum (PS) features and whether WM maturation mediates the relationship between age and cognition in typically developing (TD) youths and youths with PS features. METHODS: We examined WM microstructure, as assessed via diffusion tensor imaging, in 670 individuals (age 10-22 years; 499 TD group, 171 PS group) by using tract-based spatial statistics. Multiple regressions were used to evaluate age × group interactions on regional WM indices. Mediation analyses were conducted on four cognitive domains-executive control, complex cognition, episodic memory, and social cognition-using a bootstrapping approach. RESULTS: There were age × group interactions on fractional anisotropy (FA) in the superior longitudinal fasciculus (SLF) and retrolenticular internal capsule. Follow-up analyses revealed these effects were significant in both hemispheres. Bilateral SLF FA mediated the relationship between age and complex cognition in the TD group, but not the PS group. Regional FA did not mediate the age-associated increase in any of the other cognitive domains. CONCLUSIONS: Our results showed aberrant age-related effects in SLF and retrolenticular internal capsule FA in youths with PS features. SLF development supports emergence of specific higher-order cognitive functions in TD youths, but not in youths with PS features. Future mechanistic explanations for these relationships could facilitate development of earlier and refined targets for therapeutic interventions.

Deviations from normative brain white and gray matter structure are associated with psychopathology in youth

“…Strongest evidence was found for an association between psychosis positive and prodromal symptoms and normative deviations in FA, indicating lower mean FA with higher symptom levels. While it is unclear to which degree the clinical domain scores reflect future risk of developing schizophrenia or other severe psychotic disorders, prior studies have reported similar global reductions in FA in both early psychosis and in the prodromal phase in youth aged 11–20 from the PNC sample ( Hegarty et al, 2019 ), and among early-onset ( Tamnes and Agartz, 2016 ) and adult patients with schizophrenia compared to healthy controls ( Kelly et al, 2018 , Tønnesen et al, 2018 ).…”

Decoding Early Psychoses: Unraveling Stable Microstructural Features Associated with Psychopathology Across Independent Cohorts

“…These tracts, reflecting recent findings on subcortical volume changes in the HCP-EP dataset (67), are crucial for brain connectivity and efficiency. Taken together, this again highlights the strength of PLS, in which tracts that might typically be of interest in schizophrenia such as the SLF and cingulum (13,(68)(69)(70)(71)(72)(73)(74), are identified but in addition, a profile of subcortical microstructural changes also emerged.…”

Microstructural changes along the cingulum in young adolescents with psychotic experiences: An along‐tract analysis

“…In recent years, evidence has emerged, which suggests that psychotic disorders and PEs are associated with connectivity and white matter abnormalities throughout the brain, particularly in the limbic system (Hegarty et al, 2019; O’Neill et al, 2020). Diffusion‐weighted imaging (DWI) is an MRI technique that models brain tracts by analysing the water diffusion properties of white matter.…”