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

By Catherine E. Hegarty, Dietsje D. Jolles, Eva Mennigen, Maria Jalbrzikowski, Carrie E. Bearden, Katherine H Karlsgodt

Posted 21 Sep 2018
bioRxiv DOI: 10.1101/423574 (published DOI: 10.1016/j.bpsc.2018.12.008)

Background: Psychosis onset typically occurs in adolescence, and subclinical psychotic experiences peak in adolescence as well. Adolescence is also a time of critical neural and cognitive maturation. Using cross-sectional data from the Philadelphia Neurodevelopmental Cohort, we examine whether regional white matter (WM) development is disrupted in psychosis spectrum (PS) youth whether WM maturation mediates the relationship between age and cognition in typically developing (TD) and PS youth. A third group with intermediate symptom severity (limited PS [LPS]) was included in follow-up analyses to determine whether age-related disruptions in WM scaled with symptom severity. Methods: We examined WM microstructure, as assessed via diffusion tensor imaging, in 707 individuals (aged 10 − 22 years; 499 TD, 171 PS, 37 LPS) by using Tract-Based Spatial Statistics. Multiple regressions were used to evaluate age x group interactions on regional WM indices. Mediation analyses were conducted using a bootstrapping approach. Results: There were age x group interactions on fractional anisotropy (FA) in the superior longitudinal fasciculus (SLF) and retrolenticular internal capsule (RLIC). SLF FA mediated the relationship between age and Complex Cognition in TD, but not PS. Further, inclusion of LPS youth showed that the relationship between age and SLF FA decreased with increasing symptom severity. Conclusions: Our results show aberrant age-related changes in SLF and RLIC FA in PS youth. SLF development supports emergence of specific higher-order cognitive functions in TD youth, but not in PS. Future mechanistic explanations for these relationships could facilitate development of earlier and refined targets for therapeutic interventions.

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