Cellular and extracellular white matter alterations indicate conversion to psychosis among individuals at clinical high-risk for psychosis

Abstract

Objectives

It is important to find biomarkers associated with transition to illness in individuals at clinical high-risk for psychosis (CHR). Here, we use free-water imaging, an advanced diffusion MRI technique, to identify white matter alterations in the brains of CHR subjects who subsequently develop psychosis (CHR-P) compared to those who do not (CHR-NP).

Methods

Twenty-four healthy controls (HC) and 30 CHR individuals, 8 of whom converted to schizophrenia after a mean follow-up of 15.16 months, received baseline MRI scans. Maps of fractional anisotropy (FA), FA of cellular tissue (FA_T), and extracellular free-water (FW) were extracted using tract-based spatial statistics after which voxel-wise non-parametric group statistics and correlations with symptom severity were performed.

Results

There were no significant differences between HCs and the combined CHR group. However, prior to conversion, CHR-P showed widespread lower FA compared to CHR-NP (p_FWE < 0.05). FA changes in CHR-P were associated with significantly lower FA_T and higher FW, compared to CHR-NP. Positive symptoms correlated significantly with diffusion parameters in similar regions as those discriminating CHR-P from CHR-NP.

Conclusions

Our study suggests that cellular (FA_T) and extracellular (FW) white matter alterations are associated with positive symptom severity and indicate an elevated illness risk among CHR individuals.

Keywords:

• MRI
• free water imaging
• psychosis
• prodromal state of schizophrenia
• biological psychiatry

Acknowledgments

We thank all participants who contributed their time to this study. This work was prepared in the context of F.L.N.’s doctoral dissertation at the Faculty of Medicine, University of Hamburg, Hamburg, Germany.

Statement of interest

The authors report no conflict of interest.

Additional information

Funding

This work was funded by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) - SFB 936 – C6 to C.M.; the Claussen-Simon-Stiftung under Grant Dissertation Plus to F.L.N; the National Institutes of Health under Grants NIH R03 MH110745 and NIH K01 MH115247 to A.E.L, NIH R01 MH102377 and NIH K24 MH110807 to M.K., NIH R01 MH108574 to O.P.; and the U.S. Department of Veterans Affairs under Grant VA Merit Award 2 I01 CX00176 to M.E.S.