White matter abnormalities across the lifespan of schizophrenia: a harmonized multi-site diffusion MRI study


Several prominent theories of schizophrenia suggest that structural white matter pathologies may follow a developmental, maturational, and/or degenerative process. However, a lack of lifespan studies has precluded verification of these theories. Here, we analyze the largest sample of carefully harmonized diffusion MRI data to comprehensively characterize age-related white matter trajectories, as measured by fractional anisotropy (FA), across the course of schizophrenia. Our analysis comprises diffusion scans of 600 schizophrenia patients and 492 healthy controls at different illness stages and ages (14–65 years), which were gathered from 13 sites. We determined the pattern of age-related FA changes by cross-sectionally assessing the timing of the structural neuropathology associated with schizophrenia. Quadratic curves were used to model between-group FA differences across whole-brain white matter and fiber tracts at each age; fiber tracts were then clustered according to both the effect-sizes and pattern of lifespan white matter FA differences. In whole-brain white matter, FA was significantly lower across the lifespan (up to 7%; p < 0.0033) and reached peak maturation younger in patients (27 years) compared to controls (33 years). Additionally, three distinct patterns of neuropathology emerged when investigating white matter fiber tracts in patients: (1) developmental abnormalities in limbic fibers, (2) accelerated aging and abnormal maturation in long-range association fibers, (3) severe developmental abnormalities and accelerated aging in callosal fibers. Our findings strongly suggest that white matter in schizophrenia is affected across entire stages of the disease. Perhaps most strikingly, we show that white matter changes in schizophrenia involve dynamic interactions between neuropathological processes in a tract-specific manner.

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Code availability

Our multi-site diffusion MRI harmonization software is available per request. Please request an access through e-mail: skarayumak@bwh.harvard.edu.


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    early onset, first episode, early course, chronic

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    Forceps major (posterior forceps), forceps minor (anterior forceps), for the rest left and right hemisphere separately: cingulum (cingulate gyrus portion (CING1) and hippocampal (CING2) portion separately), inferior fronto-occipital fasciculus (IFOF), inferior longitudinal fasciculus (ILF), superior longitudinal fasciculus (SLF), uncinate fasciculus (UF).

  3. 3.

    Bonferroni correction was performed to control for the number of fibers and whole-brain (n = 15).


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We gratefully acknowledge funding provided by the following National Institutes of Health (NIH) grants: R01MH102377, K24MH110807 (PI: Dr. Marek Kubicki), R01MH119222 (PI: Dr. Yogesh Rathi), R03 MH110745, K01 MH115247–01A1 (PI: Dr. Amanda Lyall), VA Merit Award and U01 MH109977 (PI: Dr. Martha Shenton), R01MH108574 (PI: Dr. Pasternak), MRC G0500092 (PI: Dr. Anthony James), R01MH076995, P30MH090590, P50MH080173 (PI: Dr. Philip Szeszko), R01MH092440, R01MH078113 (PI: Dr. Matcheri Keshavan), R01MH077851 (PI: Dr. Carol Tamminga), R01MH077945 (PI: Dr. Godfrey Pearlson), R01MH077852 (PI: Dr. Gunvant Thaker), R01MH077862 (PI: Dr. John Sweeney). We also acknowledge funding provided by the Swiss National Science Foundation (SNF) grant 152619 (PI: Dr. Sebastian Walther) and National Research Foundation of Korea (NRF) grant NRF-2012R1A1A1006514) (PI: Dr. Jungsun Lee).

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Cetin-Karayumak, S., Di Biase, M.A., Chunga, N. et al. White matter abnormalities across the lifespan of schizophrenia: a harmonized multi-site diffusion MRI study. Mol Psychiatry 25, 3208–3219 (2020). https://doi.org/10.1038/s41380-019-0509-y

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