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.

White Matter Microstructure Alterations in Early Psychosis and Schizophrenia

“…Thus, RD and MD were the most affected, while AD differences were less significant. Our study confirms previous DTI 5, 15,16,82 , dMRI microstructure 73,83 and post-mortem cytoarchitectural 20 alterations found already at the EP stage, and the widespread reduced FA and increased MD 4–8,12,14–16,18,48 , RD and AD 8, 13,84,85 in areas commonly reported in EP and chronic SZ.…”

“…Thus, RD and MD were the most affected, while AD differences were less significant. Our study confirms previous DTI 4,17,67 , dMRI microstructure 63,72 and post-mortem cytoarchitectural 3 alterations found already at the EP stage, and the widespread reduced FA and increased MD [4][5][6][13][14][15]17,19,38,67,73 , RD and AD 6,16,74,75 in areas commonly reported in both EP and chronic SZ. In addition, WM kurtosis was lower for both patient groups, but also more pronounced in EP, and more particularly in the radial direction with a moderate effect size, representing a decrease in tissue complexity and heterogeneity 26,27,44 .…”

“…However, the disorder etiology remains only partially understood and considered multifactorial, involving a complex interplay of genetic, environmental, and neurobiological factors 2,3 . Many clinical studies investigating the psychosis spectrum [4][5][6][7][8][9] reported pathological white matter (WM) as a common feature of the disease. Most in vivo studies of WM abnormalities in psychosis use diffusion magnetic resonance imaging (dMRI), an MRI technique that relies on the random motion of water molecules to explore the cellular environment and thus infer the microstructural properties of the underlying biological tissue 10 .…”

“…Many clinical studies used diffusion magnetic resonance imaging (dMRI) and reported pathological white matter (WM) as a common feature of the disturbances of the psychosis spectrum 4–11 . The great majority of these studies focus on Diffusion Tensor Imaging (DTI) and its scalar metrics: the most frequently reported and accepted dMRI patterns are reduced fractional anisotropy (FA) and increased mean diffusivity (MD) in patients with chronic SZ 4,6,7,10,12,13 and early psychosis 4,6–8,14–18 (EP), often reported widespread but with limited spatial consistency 4,5,10,19 . Such heterogeneity may arise not only from the patients themselves 19 but also from different pathological processes affecting the WM, with tracts showing non-degenerating early maturational shifts, or displaying accelerated aging 5 .…”

Associations between Verbal Fluency and Asymmetry of White Matter Integrity in the Superior Longitudinal Fasciculus in At-Risk Mental States for Psychosis

“…It was reported that the FA values of the right SLF are lower in patients with FES than in HC subjects [ 13 ]. Mega-analyses have shown that the FA values of white matter, including the SLF, are lower in adolescents with early-onset schizophrenia than in HC subjects [ 14 ]. The SLF is involved in cognitive functions, such as working memory, attention, and verbal processing, and this suggests that the SLF may be involved in the pathogenesis of psychosis [ 14 ].…”