Mapping Individual Neuroanatomical Alterations to Schizophrenia Psychopathology with Normative Modeling
Abstract
Schizophrenia spectrum disorders (SSDs) are clinically and neurobiologically heterogeneous. Normative modeling addresses heterogeneity of structural brain alterations by focusing on individual-level deviations, but their relation to clinical features requires further investigation. We mapped the relationship between individual gray matter volume (GMV) deviations and schizophrenia diagnosis and symptoms. Normative models of GMV were established using cross-sectional, T1-weighted magnetic resonance imaging data from a large, multi-site, healthy reference cohort (N = 7957). Deviations were derived for SSD patients (n = 379) and healthy controls (HCs, n = 149). We replicated that SSD is characterized by a more negative global deviation compared to HCs, yet extreme negative deviations exhibit substantial spatial heterogeneity. Regional deviations predicted diagnostic status with adequate performance (AUC = 0.79). A more negative deviation was associated with higher symptom severity and lower cognitive functioning in SSD. Negative deviations were scattered across the brain, with the largest alterations in the salience network. Our findings strengthen the potential of normative modeling to disentangle the heterogeneous underpinnings of SSD and provide further evidence for individualized structural deviations, particularly in the salience network, as promising markers of illness severity in SSDs.
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BibTeX
@misc{spaeth2026mapping,
title = {{Mapping Individual Neuroanatomical Alterations to Schizophrenia Psychopathology with Normative Modeling}},
author = {Johanna Spaeth and Charlotte Fraza and Deniz Yilmaz and Lena Deller and BrainTrain Working Group and CDP Working Group and Genc Hasanaj and Marcel Kallweit and Maxim Korman and Mona Hussain and Emanuel Boudriot and Vladislav Yakimov and Joanna Moussiopoulou and Florian J. Raabe and Elias Wagner and Andrea Schmitt and Astrid Roeh and Peter Falkai and Daniel Keeser and Isabel Maurus and Lukas Roell},
howpublished = {medRxiv},
year = {2026},
month = nov,
doi = {10.64898/2026.03.31.26349848},
url = {https://doi.org/10.64898/2026.03.31.26349848},
note = {CC BY-ND 4.0},
}
RIS
TY - UNPB
TI - Mapping Individual Neuroanatomical Alterations to Schizophrenia Psychopathology with Normative Modeling
AU - Johanna Spaeth
AU - Charlotte Fraza
AU - Deniz Yilmaz
AU - Lena Deller
AU - BrainTrain Working Group
AU - CDP Working Group
AU - Genc Hasanaj
AU - Marcel Kallweit
AU - Maxim Korman
AU - Mona Hussain
AU - Emanuel Boudriot
AU - Vladislav Yakimov
AU - Joanna Moussiopoulou
AU - Florian J. Raabe
AU - Elias Wagner
AU - Andrea Schmitt
AU - Astrid Roeh
AU - Peter Falkai
AU - Daniel Keeser
AU - Isabel Maurus
AU - Lukas Roell
PY - 2026
DA - 2026/11/01
PB - medRxiv
DO - 10.64898/2026.03.31.26349848
UR - https://doi.org/10.64898/2026.03.31.26349848
AB - Schizophrenia spectrum disorders (SSDs) are clinically and neurobiologically heterogeneous. Normative modeling addresses heterogeneity of structural brain alterations by focusing on individual-level deviations, but their relation to clinical features requires further investigation. We mapped the relationship between individual gray matter volume (GMV) deviations and schizophrenia diagnosis and symptoms. Normative models of GMV were established using cross-sectional, T1-weighted magnetic resonance imaging data from a large, multi-site, healthy reference cohort (N = 7957). Deviations were derived for SSD patients (n = 379) and healthy controls (HCs, n = 149). We replicated that SSD is characterized by a more negative global deviation compared to HCs, yet extreme negative deviations exhibit substantial spatial heterogeneity. Regional deviations predicted diagnostic status with adequate performance (AUC = 0.79). A more negative deviation was associated with higher symptom severity and lower cognitive functioning in SSD. Negative deviations were scattered across the brain, with the largest alterations in the salience network. Our findings strengthen the potential of normative modeling to disentangle the heterogeneous underpinnings of SSD and provide further evidence for individualized structural deviations, particularly in the salience network, as promising markers of illness severity in SSDs.
ER -