In vivo white matter microstructure in adolescents with early-onset psychosis: a multi-site mega-analysis

Abstract

Emerging evidence suggests brain white matter alterations in adolescents with early-onset psychosis (EOP; age of onset <18 years). However, as neuroimaging methods vary and sample sizes are modest, results remain inconclusive. Using harmonized data processing protocols and a mega-analytic approach, we compared white matter microstructure in EOP and healthy controls using diffusion tensor imaging (DTI). Our sample included 321 adolescents with EOP (median age = 16.6 years, interquartile range (IQR) = 2.14, 46.4% females) and 265 adolescent healthy controls (median age = 16.2 years, IQR = 2.43, 57.7% females) pooled from nine sites. All sites extracted mean fractional anisotropy (FA), mean diffusivity (MD), radial diffusivity (RD), and axial diffusivity (AD) for 25 white matter regions of interest per participant. ComBat harmonization was performed for all DTI measures to adjust for scanner differences. Multiple linear regression models were fitted to investigate case-control differences and associations with clinical variables in regional DTI measures. We found widespread lower FA in EOP compared to healthy controls, with the largest effect sizes in the superior longitudinal fasciculus (Cohen's d = 0.37), posterior corona radiata (d = 0.32), and superior fronto-occipital fasciculus (d = 0.31). We also found widespread higher RD and more localized higher MD and AD. We detected significant effects of diagnostic subgroup, sex, and duration of illness, but not medication status. Using the largest EOP DTI sample to date, our findings suggest a profile of widespread white matter microstructure alterations in adolescents with EOP, most prominently in male individuals with early-onset schizophrenia and individuals with a shorter duration of illness.

Fig. 1. Cohen’s d values for differences in diffusion measures between adolescents with early-onset psychosis and healthy controls.

Cohen’s d values and their standard errors are displayed, sorted by effect size. Stars and dashed lines indicate significant results (p ≤ 0.002). FA fractional anisotropy, MD mean diffusivity, RD radial diffusivity, AD axial diffusivity. For white matter tract abbreviations, see Table 1.

Fig. 2. Fractional anisotropy (FA) differences between adolescents with early-onset psychosis and healthy controls, stratified by diagnostic subgroups.

Cohen’s d values and their standard errors are displayed, sorted by effect size for EOS. Stars and dashed lines indicate significant results (p ≤ 0.002). Abbreviations: EOS = early-onset schizophrenia (n = 180), AFP affective psychosis (n = 95), OTP other psychosis (n = 46). For white matter tract abbreviations see Table 1.

Fig. 3. Fractional anisotropy (FA) differences between adolescents with early-onset psychosis and healthy controls, stratified by sex.

A Cohen’s d values and their standard errors are displayed, sorted by effect size for males. Stars and dashed lines indicate significant results (p ≤ 0.002) for males only*. In females, FA did not differ significantly between individuals with EOP and healthy controls. For white matter tract abbreviations see Table 1. B Marginal plots with distributions displaying average FA across the entire skeleton and age for females (upper panel) and males (lower panel) by diagnostic group. Diagnostic group-specific regression lines are shown.

Fig. 4. Cohen’s d effect sizes in early-onset psychosis (EOP) and adult schizophrenia (SCZ) relative to healthy controls from a prior publication¹.

A Meta-analytically derived effect sizes for tract-specific fractional anisotropy (FA) in EOP relative to healthy controls and in adult schizophrenia relative to healthy controls. B Mega-analytically derived effect sizes for tract-specific FA in EOP relative to healthy controls and meta-analytically derived effect sizes in adult schizophrenia relative to healthy controls. C Correlation in meta-analytically derived effect sizes of tract-specific FA between EOP and adult schizophrenia. D Correlation in mega- and meta-analytically derived effect sizes of tract-specific FA between EOP and adult schizophrenia, respectively. In both EOP and SCZ, meta-analytic results were adjusted for age, sex, and linear and nonlinear age and sex interactions (age-by-sex interaction, age [2], and age [2]-by-sex interaction). Cohen’s d values and their standard errors are displayed. SK provided values for SCZ.