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.

Keywords: Cognition; DTI; Development; Mediation; Psychosis spectrum; Psychotic-like experiences; Subclinical psychosis; Superior longitudinal fasciculus.

Figure 1.

Schematic of a simple mediation model. We examined whether regional fractional anisotropy (FA) significantly mediated the effect of age on cognition. In a mediation model, the relationship between an independent variable (X) and a dependent variable (Y) is influenced by the (nonobservable) mediator variable (M). Intercepts and residuals for each equation are denoted by i and e, respectively. The total effect (c) is the sum of both the direct (c′) and mediated (ab) effects. The total effect, c, was determined with equation (1). Coefficients a and b were determined with equation (2) and equation (3), respectively. The direct effect (c′) was determined with equation (2). Mediation is determined by assessing the significance of the mediated effect (ab) with a bootstrapping approach.

Figure 2.

Age-associated changes in the superior longitudinal fasciculus (SLF). (A) Three-dimensional representation of SLF tract. In analyses of typically developing (TD) and psychosis spectrum (PS) groups, there was a significant (p < .002) interaction between age and group on SLF fractional anisotropy (FA) (B). Follow-up analyses revealed additional significant (p < .025) age × group interactions on radial diffusivity (RD) (C) and mean diffusivity (MD) (D), but not on axial diffusivity (AD) (E). (F) Follow-up analyses including a third group, limited psychosis spectrum (LPS), also revealed a significant age × group interaction on SLF FA. Graphs show predicted margins with 95% confidence intervals. Significance values represent corrected p values for age × group interactions. p < .025. NS, not significant.

Figure 3.

Age-associated changes in the retrolenticular internal capsule (RLIC). (A) Three-dimensional representation of RLIC tract. In analyses of typically developing (TD) and psychosis spectrum (PS) groups, there was a significant interaction (p < .002) between age and group on RLIC fractional anisotropy (FA) (B). Follow-up analyses revealed significant age × group interactions (p < .025) on radial diffusivity (RD) (C) and mean diffusivity (MD) (D), but not on axial diffusivity (AD) (E). (F) Follow-up analyses including a third group, limited psychosis spectrum (LPS), also revealed a significant (p < .025) age × group interaction on RLIC FA. Graphs show predicted margins with 95% confidence intervals. Significance values represent corrected p values for age × group interactions. NS, not significant.

Figure 4.

Group differences in cognitive domains. Youths in the psychosis spectrum (PS) group consistently showed significantly (p < .0125) lower efficiency scores in all four cognitive domains: (A) executive control, (B) complex cognition, (C) episodic memory, and (D) social cognition. Efficiency scores reflect the average Z score (sum of Z score for accuracy and −1 multiplied by Z score for speed) per group, such that higher scores indicate better performance. Error bars represent ± SE of the group average. TD, typically developing.