Multiscale characterization of cortical signatures in positive and negative schizotypy:a worldwide ENIGMA study

Positive and negative schizotypy reflect distinct patterns of subclinical traits in the general population associated with neurodevelopmental and schizophrenia-spectrum pathologies. Yet, a comprehensive characterization of the unique and shared neuroanatomical signatures of these schizotypy dimensions is lacking. Leveraging 3D brain MRI data from 2730 unmedicated healthy individuals, we identified neuroanatomical profiles of positive and negative schizotypy and systematically compared them with disorder-specific, microarchitectural, neurotransmitter-level, and connectome measures. Positive and negative schizotypy were associated with distinct cortical signatures, of predominantly thinner frontal and thicker paralimbic cortical areas, respectively. These cortical signatures of positive and negative schizotypy were differentially linked to brain-wide cortical patterns of schizophrenia-spectrum (clinical high-risk for psychosis, schizophrenia) and neurodevelopmental conditions (ADHD, autism spectrum disorder and 22q11.2 deletion syndrome). Additionally, the positive and negative schizotypy-related cortical profiles mapped onto different local attributes of gene expression, cortical myelination, D1, and histamine receptor distributions. Network models further showed that positive and negative schizotypy cortical signatures were spatially associated with cortical hubs, suggesting that highly interconnected regions are more vulnerable to the morphological differences associated with both schizotypy dimensions. Finally, predominantly sensorimotor-to-association and paralimbic areas emerged as epicenters with connectivity profiles significantly linked to the schizotypy-related cortical patterns. Collectively, this study identified cortical signatures of positive and negative schizotypy traits that are embedded along multiple scales of cortical organization and neuropsychiatric pathologies. Our work yields novel insights into how neurobiology and brain architecture may guide neuroanatomical vulnerability and resilience to psychopathology in the general population.

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VU Research Portal
Published
2026-09-01
DOI
https://doi.org/10.1038/s41380-026-03547-x
Primary Topic
Functional Brain Connectivity Studies
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article
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article

Multiscale characterization of cortical signatures in positive and negative schizotypy:a worldwide ENIGMA study

Kristina Wiebels, Josselin Houenou, Tina Meller, Gemma Modinos et al.
VU Research Portal
Functional Brain Connectivity Studies
article

Multiscale characterization of cortical signatures in positive and negative schizotypy:a worldwide ENIGMA study

Kristina Wiebels, Josselin Houenou, Tina Meller, Gemma Modinos, Haeme R. P. Park, Christos Pantelis, Indrit Bègue, Stefan Kaiser, Mélodie Derome, Mathilde Antoniades, Preethi Premkumar, Casey Paquola, Veena Kumari, Ulrich Ettinger, Yann Quidé, Sanne Koops, Dennis Hernaus, Pamela DeRosse, Wulf Rössler, Sara Larivière, Leda Kennedy, Mark A. Bellgrove, Imke Jansen, Axel Krug, Martin Debbané, Bianca Besteher, Lukasz Smigielski, Christian Gaser, Aurina Arnatkevičiūtė, Jeggan Tiego, Theo G.M. van Erp, S. L. Valk, Alex Fornito, Raymond Chan, C. Barkhau, Asia Ferrari, Phillip Grant, Melissa Green, Kelly Diederen, Alain Dagher, Bratislav Misic, Matthias Kirschner, Elisabeth J. Leehr, Alexander Tomyshev, Susanne Meinert, Igor Nenadić, Justine Y. Hansen, Maria Jalbrzikowski, Raymond Salvador, Tilo Kircher, Boris Bernhardt, Paul Allen, Iris Sommer, Jan Bernard Marsman, Benazir Hodzic-Santor, Tim Hahn, Edith Pomarol-Clotet, Janik Goltermann, Dominik Grotegerd, Bin Wan, Andre Aleman, Udo Dannlowski, Tiana Borgers, Paul M. Thompson, Yi Wang, Irina Lebedeva, Kira Flinkenflügel, Tom J. Spencer, Jessica A. Turner, Anne Kathrin; id_orcid 0000-0003-0282-273X Fett, Joscha Böhnlein, James Gilleen
article en

Abstract

Positive and negative schizotypy reflect distinct patterns of subclinical traits in the general population associated with neurodevelopmental and schizophrenia-spectrum pathologies. Yet, a comprehensive characterization of the unique and shared neuroanatomical signatures of these schizotypy dimensions is lacking. Leveraging 3D brain MRI data from 2730 unmedicated healthy individuals, we identified neuroanatomical profiles of positive and negative schizotypy and systematically compared them with disorder-specific, microarchitectural, neurotransmitter-level, and connectome measures. Positive and negative schizotypy were associated with distinct cortical signatures, of predominantly thinner frontal and thicker paralimbic cortical areas, respectively. These cortical signatures of positive and negative schizotypy were differentially linked to brain-wide cortical patterns of schizophrenia-spectrum (clinical high-risk for psychosis, schizophrenia) and neurodevelopmental conditions (ADHD, autism spectrum disorder and 22q11.2 deletion syndrome). Additionally, the positive and negative schizotypy-related cortical profiles mapped onto different local attributes of gene expression, cortical myelination, D1, and histamine receptor distributions. Network models further showed that positive and negative schizotypy cortical signatures were spatially associated with cortical hubs, suggesting that highly interconnected regions are more vulnerable to the morphological differences associated with both schizotypy dimensions. Finally, predominantly sensorimotor-to-association and paralimbic areas emerged as epicenters with connectivity profiles significantly linked to the schizotypy-related cortical patterns. Collectively, this study identified cortical signatures of positive and negative schizotypy traits that are embedded along multiple scales of cortical organization and neuropsychiatric pathologies. Our work yields novel insights into how neurobiology and brain architecture may guide neuroanatomical vulnerability and resilience to psychopathology in the general population.

VU Research Portal
University of Geneva (CH), University of Southern California (US), Academy of Medical Sciences (GB), Russian Academy of Sciences (RU), Université de Sherbrooke (CA), University of Bonn (DE), Hofstra University (US), University of Auckland (NZ), Philipps University of Marburg (DE), The University of Melbourne (AU), University of Groningen (NL), Forschungszentrum Jülich (DE), Universidade de São Paulo (BR), King's College London (GB), Bielefeld University (DE), University of Zurich (CH), University of California, Irvine (US), University of Münster (DE), California Southern University (US), Australian Regenerative Medicine Institute (AU), Ernst Ruska Centre (DE), Harvard University Press (US), University of Manchester (GB), UNSW Sydney (AU), Maastricht University (NL), University of California San Diego (US), California University of Pennsylvania (US), Center for Neurosciences (US), Fidmag Sisters Hospitallers (ES), Institute of Developmental Physiology (RU), Max Planck Institute for Human Cognitive and Brain Sciences (DE), Institute of Psychology, Chinese Academy of Sciences (CN), IntellADAPT (United States) (US), Hochschule Fresenius (DE), Zucker Hillside Hospital (US), Heinrich Heine University Düsseldorf (DE), University College London (GB), The Ohio State University (US), Monash University (AU), Brunel University of London (GB), Stony Brook University (US), Friedrich Schiller University Jena (DE), Charité - Universitätsmedizin Berlin (DE), Neuroscience Research Australia (AU), Vrije Universiteit Amsterdam (NL)
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