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Individual deviations from normative models of brain structure in a large cross-sectional schizophrenia cohort

Abstract

The heterogeneity of schizophrenia has defied efforts to derive reproducible and definitive anatomical maps of structural brain changes associated with the disorder. We aimed to map deviations from normative ranges of brain structure for individual patients and evaluate whether the loci of individual deviations recapitulated group-average brain maps of schizophrenia pathology. For each of 48 white matter tracts and 68 cortical regions, normative percentiles of variation in fractional anisotropy (FA) and cortical thickness (CT) were established using diffusion-weighted and structural MRI from healthy adults (n = 195). Individuals with schizophrenia (n = 322) were classified as either within the normative range for healthy individuals of the same age and sex (5–95% percentiles), infra-normal (<5% percentile) or supra-normal (>95% percentile). Repeating this classification for each tract and region yielded a deviation map for each individual. Compared to the healthy comparison group, the schizophrenia group showed widespread reductions in FA and CT, involving virtually all white matter tracts and cortical regions. Paradoxically, however, no more than 15–20% of patients deviated from the normative range for any single tract or region. Furthermore, 79% of patients showed infra-normal deviations for at least one locus (healthy individuals: 59 ± 2%, p < 0.001). Thus, while infra-normal deviations were common among patients, their anatomical loci were highly inconsistent between individuals. Higher polygenic risk for schizophrenia associated with a greater number of regions with infra-normal deviations in CT (r = −0.17, p = 0.006). We conclude that anatomical loci of schizophrenia-related changes are highly heterogeneous across individuals to the extent that group-consensus pathological maps are not representative of most individual patients. Normative modeling can aid in parsing schizophrenia heterogeneity and guiding personalized interventions.

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Fig. 1: Percentile curves for an example cortical region and white matter tract.
Fig. 2: Deviation from normative ranges for measures of brain structure in individuals with schizophrenia.
Fig. 3: Loci of deviations from the normative range for two individuals with schizophrenia.
Fig. 4: Association between polygenic risk for schizophrenia and individual deviations from the normative range for measures of brain structure.

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Data availability

Genetic, clinical, neuropsychological and brain imaging data can be accessed from the Australian Schizophrenia Research Bank (ASRB), subject to approval of the ASRB Access Committee. Further details are available online (https://www.neura.edu.au/discovery-portal/asrb/).

Code availability

The Matlab function quantreg was used to perform quantile regression with bootstrapping confidence intervals. This code is publicly accessible.

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Acknowledgements

This study used samples and data from the Australian Schizophrenia Research Bank (ASRB), funded by a National Health and Medical Research Council (NHMRC) Enabling Grant (386500; CIs & ASRB Manager: Carr V, Schall U, Scott R, Jablensky A, Mowry B, Michie P, Catts S, Henskens F, Pantelis C, Loughland C), and the Pratt Foundation, Ramsay Health Care, the Viertel Charitable Foundation, and the Schizophrenia Research Institute, using an infrastructure grant from the NSW Ministry of Health. Individual funding support: JL supported by NHMRC Project Grant (ID: APP1142801). MDB (ID: APP1175754) and VC (ID: APP1177370) supported by NHMRC Emerging Leadership Investigator Grants. RC supported by NHMRC Project Grant (ID: APP1103252) and ARC DECRA Fellowship. LC supported by NHMRC Project Grants (ID: APP1099082 and APP1138711). PK supported by Adrian & Simone Frutiger Foundation. OP supported by NIH: R01MH108574. YT supported by NHMRC Project Grant (ID: APP1142801). LS (ID: APP1140764), CP (ID: APP1105825), FC (ID: APP1117724) and AZ (ID: APP1136649) supported by NHMRC Research Fellowships.

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Lv, J., Di Biase, M., Cash, R.F.H. et al. Individual deviations from normative models of brain structure in a large cross-sectional schizophrenia cohort. Mol Psychiatry 26, 3512–3523 (2021). https://doi.org/10.1038/s41380-020-00882-5

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