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

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

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

Matthias Kirschner
, Benazir Hodzic-Santor
, Leda Kennedy
, Justine Y. Hansen
, Mathilde Antoniades
, Igor Nenadic
, Tilo Kircher
, Alex Krug
, Tina Meller
, Udo Dannlowski
, Dominik Grotegerd
, Kira Flinkenflügel
, Susanne L Meinert
, Tiana Borgers
, Janik Goltermann
, Tim Hahn
, Joscha Böhnlein
, Elisabeth J. Leehr
, Carlotta Barkhau
, Alex Fornito

Aurina Arnatkeviciute, Mark A. Bellgrove, Jeggan Tiego, Pamela DeRosse, Melissa J. Green, Yann Quidé, Christos Pantelis, Raymond C. K. Chan, Yi Wang, Ulrich Ettinger, Martin Debbané, Melodie Derome, Christian Gaser, Bianca Besteher, Kelly Diederen, Tom Spencer, Josselin Houenou, Edith Pomarol-Clotet, Raymond Salvador, Wulf Rössler, Lukasz Smigielski, Veena Kumari, Preethi Premkumar, Haeme R.P. Park, Kristina Wiebels, Imke L.J. Lemmers-Jansen, James Gilleen, Paul Allen, Jan Bernard C. Marsman, Irina P. Lebedeva, Alexander Tomyshev, Anne-Kathrin J. Fett, Iris E. C. Sommer, Sanne Koops, Phillip Grant, Asia Ferrari, Bin Wan, Indrit Begue, Dennis Hernaus, Maria Jalbrzikowski, Casey Paquola, Sara Larivière, Boris C Bernhardt, Sofie L Valk, Bratislav Misic, Theo G.M. van Erp , Jessica A Turner, Paul M. Thompson, Andre Aleman, Alain Dagher, Stefan Kaiser, Gemma Modinos

McConnell Brain Imaging Centre
University of Zürich
Psychiatrische Universitätsklinik
Geneva University Hospitals
McGill University
University of California, San Diego
King's College London
University of Pennsylvania
Icahn School of Medicine at Mount Sinai
Friedrich Schiller University Jena
Universitatsklinikum Hamburg-Eppendorf und Medizinische Fakultat
Philipps-Universitat
Institut für Kernphysik
Bielefeld University
University of Münster
Monash Medical School
Monash University
Zucker Hillside Hospital
Zucker School of Medicine
Feinstein Institute for Medical Research
UNSW University of New South Wales
Randwick
Kensington
University of Melbourne
Chinese Academy of Sciences
University of Geneva
Global Health Institute
University of Roehampton
CHU Lille
Royal Holloway, University of London
Combined Universities Brain Imaging Centre (CUBIC)
University Hospital of Jena
INSERM
CNRS Centre National de la Recerche Scientifique
Assistance Publique-Hôpitaux de Paris
U955
Germanes Hospitalàries
University of Zaragoza; Instituto de Investigacion Sanitaria de Aragon (IIS) and Centro de Investigacion Biomedica en Red de Salud Mental (CIBERSAM), Zaragoza, Spain.
Institute for Radiology, CCM
Universidade de Sao Paulo - USP
Universitatsspital Zurich
Brunel University London
University of Auckland
VU Amsterdam
Institute for Brain and Behavior Amsterdam (IBBA)
University Medical Center Groningen
Mental Health Research Center
City, University of London
UCL University College London
London University
City St George's, University of London
Utrecht University
UMC University Medical Center Utrecht
Learning Disability Psychiatry Department
Imperial College London
MRC Clinical Sciences Centre
Rudolf Magnus Institute of Neuroscience
University of Bergen
Langara College
Hochschule Fresenius
University Hospital of Lausanne, Lausanne, Switzerland; Geriatric Psychiatry, Department of Mental Health and Psychiatry, Geneva University Hospitals, Geneva, Switzerland.
University of Maryland
Maastricht University
University of California, Los Angeles
University of Pittsburgh
University of Pittsburgh School of Medicine
Harvard Medical School
Boston Children's Hospital
Research Center Jülich
University of California, Irvine
University of California
Georgia State University
USC University of Southern California
Keck School of Medicine of USC
University of California at Los Angeles

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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 2,730 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.

Original language	English
Journal	Molecular Psychiatry
Publication status	Accepted/In press - 10 Mar 2026

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Multiscale characterization of cortical signatures_Accepted VersionFinal published version, 5.02 MBLicence: CC BY

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Kirschner, M., Hodzic-Santor, B., Kennedy, L., Hansen, J. Y., Antoniades, M., Nenadic, I., Kircher, T., Krug, A., Meller, T., Dannlowski, U., Grotegerd, D., Flinkenflügel, K., Meinert, S. L., Borgers, T., Goltermann, J., Hahn, T., Böhnlein, J., Leehr, E. J., Barkhau, C., ... Modinos, G. (Accepted/In press). Multiscale characterization of cortical signatures in positive and negative schizotypy: A worldwide ENIGMA study. Molecular Psychiatry.

@article{7b71d15146214c0e81827c5521194b30,

title = "Multiscale characterization of cortical signatures in positive and negative schizotypy: A worldwide ENIGMA study",

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 2,730 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.",

author = "Matthias Kirschner and Benazir Hodzic-Santor and Leda Kennedy and Hansen, \{Justine Y.\} and Mathilde Antoniades and Igor Nenadic and Tilo Kircher and Alex Krug and Tina Meller and Udo Dannlowski and Dominik Grotegerd and Kira Flinkenfl{\"u}gel and Meinert, \{Susanne L\} and Tiana Borgers and Janik Goltermann and Tim Hahn and Joscha B{\"o}hnlein and Leehr, \{Elisabeth J.\} and Carlotta Barkhau and Alex Fornito and Aurina Arnatkeviciute and Bellgrove, \{Mark A.\} and Jeggan Tiego and Pamela DeRosse and Green, \{Melissa J.\} and Yann Quid{\'e} and Christos Pantelis and Chan, \{Raymond C. K.\} and Yi Wang and Ulrich Ettinger and Martin Debban{\'e} and Melodie Derome and Christian Gaser and Bianca Besteher and Kelly Diederen and Tom Spencer and Josselin Houenou and Edith Pomarol-Clotet and Raymond Salvador and Wulf R{\"o}ssler and Lukasz Smigielski and Veena Kumari and Preethi Premkumar and Park, \{Haeme R.P.\} and Kristina Wiebels and Lemmers-Jansen, \{Imke L.J.\} and James Gilleen and Paul Allen and Marsman, \{Jan Bernard C.\} and Lebedeva, \{Irina P.\} and Alexander Tomyshev and Fett, \{Anne-Kathrin J.\} and Sommer, \{Iris E. C.\} and Sanne Koops and Phillip Grant and Asia Ferrari and Bin Wan and Indrit Begue and Dennis Hernaus and Maria Jalbrzikowski and Casey Paquola and Sara Larivi{\`e}re and Bernhardt, \{Boris C\} and Valk, \{Sofie L\} and Bratislav Misic and \{van Erp\}, \{Theo G.M.\} and Turner, \{Jessica A\} and Thompson, \{Paul M.\} and Andre Aleman and Alain Dagher and Stefan Kaiser and Gemma Modinos",

year = "2026",

month = mar,

day = "10",

language = "English",

journal = "Molecular Psychiatry",

issn = "1359-4184",

publisher = "Springer Nature [academic journals on nature.com]",

}

Kirschner, M, Hodzic-Santor, B, Kennedy, L, Hansen, JY, Antoniades, M, Nenadic, I, Kircher, T, Krug, A, Meller, T, Dannlowski, U, Grotegerd, D, Flinkenflügel, K, Meinert, SL, Borgers, T, Goltermann, J, Hahn, T, Böhnlein, J, Leehr, EJ, Barkhau, C, Fornito, A, Arnatkeviciute, A, Bellgrove, MA, Tiego, J, DeRosse, P, Green, MJ, Quidé, Y, Pantelis, C, Chan, RCK, Wang, Y, Ettinger, U, Debbané, M, Derome, M, Gaser, C, Besteher, B, Diederen, K , Spencer, T, Houenou, J, Pomarol-Clotet, E, Salvador, R, Rössler, W, Smigielski, L, Kumari, V, Premkumar, P, Park, HRP, Wiebels, K, Lemmers-Jansen, ILJ, Gilleen, J, Allen, P, Marsman, JBC, Lebedeva, IP, Tomyshev, A, Fett, A-KJ, Sommer, IEC, Koops, S, Grant, P, Ferrari, A, Wan, B, Begue, I, Hernaus, D, Jalbrzikowski, M, Paquola, C, Larivière, S, Bernhardt, BC, Valk, SL, Misic, B, van Erp , TGM, Turner, JA, Thompson, PM, Aleman, A, Dagher, A, Kaiser, S & Modinos, G 2026, 'Multiscale characterization of cortical signatures in positive and negative schizotypy: A worldwide ENIGMA study', Molecular Psychiatry.

TY - JOUR

T1 - Multiscale characterization of cortical signatures in positive and negative schizotypy

T2 - A worldwide ENIGMA study

AU - Kirschner, Matthias

AU - Hodzic-Santor, Benazir

AU - Kennedy, Leda

AU - Hansen, Justine Y.

AU - Antoniades, Mathilde

AU - Nenadic, Igor

AU - Kircher, Tilo

AU - Krug, Alex

AU - Meller, Tina

AU - Dannlowski, Udo

AU - Grotegerd, Dominik

AU - Flinkenflügel, Kira

AU - Meinert, Susanne L

AU - Borgers, Tiana

AU - Goltermann, Janik

AU - Hahn, Tim

AU - Böhnlein, Joscha

AU - Leehr, Elisabeth J.

AU - Barkhau, Carlotta

AU - Fornito, Alex

AU - Arnatkeviciute, Aurina

AU - Bellgrove, Mark A.

AU - Tiego, Jeggan

AU - DeRosse, Pamela

AU - Green, Melissa J.

AU - Quidé, Yann

AU - Pantelis, Christos

AU - Chan, Raymond C. K.

AU - Wang, Yi

AU - Ettinger, Ulrich

AU - Debbané, Martin

AU - Derome, Melodie

AU - Gaser, Christian

AU - Besteher, Bianca

AU - Diederen, Kelly

AU - Spencer, Tom

AU - Houenou, Josselin

AU - Pomarol-Clotet, Edith

AU - Salvador, Raymond

AU - Rössler, Wulf

AU - Smigielski, Lukasz

AU - Kumari, Veena

AU - Premkumar, Preethi

AU - Park, Haeme R.P.

AU - Wiebels, Kristina

AU - Lemmers-Jansen, Imke L.J.

AU - Gilleen, James

AU - Allen, Paul

AU - Marsman, Jan Bernard C.

AU - Lebedeva, Irina P.

AU - Tomyshev, Alexander

AU - Fett, Anne-Kathrin J.

AU - Sommer, Iris E. C.

AU - Koops, Sanne

AU - Grant, Phillip

AU - Ferrari, Asia

AU - Wan, Bin

AU - Begue, Indrit

AU - Hernaus, Dennis

AU - Jalbrzikowski, Maria

AU - Paquola, Casey

AU - Larivière, Sara

AU - Bernhardt, Boris C

AU - Valk, Sofie L

AU - Misic, Bratislav

AU - van Erp , Theo G.M.

AU - Turner, Jessica A

AU - Thompson, Paul M.

AU - Aleman, Andre

AU - Dagher, Alain

AU - Kaiser, Stefan

AU - Modinos, Gemma

PY - 2026/3/10

Y1 - 2026/3/10

N2 - 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 2,730 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.

AB - 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 2,730 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.

M3 - Article

SN - 1359-4184

JO - Molecular Psychiatry

JF - Molecular Psychiatry

ER -

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

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