Individualized Structural Brain Deviations in Bipolar I Disorder: a Normative Modeling Study of 4 660 ENIGMA Participants

Abstract Bipolar disorder (BD) is a prevalent psychiatric condition characterized by marked clinical and neuroanatomical heterogeneity. Prior neuroimaging studies have used case-control comparisons yielding small to moderate effect sizes for group differences. Large and diverse samples are needed to map heterogeneity within BD. Here, we used individualized brain morphometry deviations derived from normative modeling for three MRI-based measures (regional cortical thickness, regional surface area, and subcortical volumes). We applied this approach to a large international sample of 4 660 individuals (1 145 with bipolar I disorder and 3 515 healthy controls) from the ENIGMA Bipolar Disorder Working Group consortium (age range = 8–80, female = 53.15%) and examined the distribution of deviations within the bipolar disorder group, differences between healthy controls and individuals with bipolar disorder, and associations between neuroanatomical deviations and clinical variables. We found that individuals with bipolar disorder showed a higher proportion of localized extreme deviations, notably negative cortical thickness deviations in regions consistently reported as thinner in prior studies (the left superior frontal gyrus, bilateral inferior frontal gyrus (pars opercularis), left precuneus) and subcortical volume negative deviations in the left hippocampus. In addition, ROI-level deviations in the left middle temporal gyrus and the left inferior temporal gyrus were associated with longer illness duration. This is the largest study to date exploring individualized deviations as neuroanatomical features associated with bipolar disorder. Our findings suggest that neuroanatomical heterogeneity is a core feature of bipolar disorder, with preferential left-lateralized cortical-hippocampal involvement pointing to spatially structured heterogeneity.

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Journal
Research Square
Published
2026-11-04
DOI
https://doi.org/10.21203/rs.3.rs-11169891/v1
Primary Topic
Bipolar Disorder and Treatment
Type
preprint
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preprint

Individualized Structural Brain Deviations in Bipolar I Disorder: a Normative Modeling Study of 4 660 ENIGMA Participants

Nathan Neu, Edith Pomarol‐Clotet, Anna Luisa Klahn, Lars Tjelta Westlye et al.
Research Square
Bipolar Disorder and Treatment
preprint

Individualized Structural Brain Deviations in Bipolar I Disorder: a Normative Modeling Study of 4 660 ENIGMA Participants

Nathan Neu, Edith Pomarol‐Clotet, Anna Luisa Klahn, Lars Tjelta Westlye, Roberto Goya‐Maldonado, Josselin Houenou, Mon‐Ju Wu, Édouard Duchesnay, Benjamin I. Goldstein, Mehmet Cagdas Eker, Fabio Sambataro, Kody G. Kennedy, Godfrey D. Pearlson, Raymond M. Salvador, Bartholomeus C. M. Haarman, Neda Jahanshad, Lejla Čolić, Dag Alnæs, Mikael Landén, Bradley J. MacIntosh, Dominik Grotegerd, Ali Saffet Gönül, Pauline Favre, Benson Mwangi, Joaquim Raduà, Lakshmi N. Yatham, Francesco Benedetti, Elisa Maria Teresa Melloni, Beatrice Bravi, Erick Jorge Canales-Rodríguez, Yann Quidé, Andriana Karuk, Henk S. Temmingh, Ole A. Andreasson, James J. Prisciandaro, Tim Hahn, Ian H. Gotlib, Dara M. Cannon, Eduard Vieta, Leila Nabulsi, Fleur Margaret Howells, Eva Mennigen, Udo Dannlowski, Tilo T. J. Kircher, Amanda Rodrigue, Pedro Rosa, Hilary P. Blumberg, Kang Sim, Charles Laidi, David C. Glahn, Colm McDonald, Freda Scheffler, Tamsyn E. Van Rheenen, Nadine Parker, Jair C. Soares, Bronwyn J. Overs, Marcus V. Zanetti, Melissa J. Green, Maurício Henriques Serpa, Enric Vilajosana, Paul M. Thompson, Matthew D. Sacchet, Philip Bowden Mitchell, Monica Di Giuliano, Ezgi Key, Melody Kang, Dan Stein, Gloria Roberts, Christopher Ching, Sabrina Teckentrup, Sara Papenbrock, Theodore Satterthwaite, Yanghee Im, Giovana Zunta Soares, Tiffany Avancini, Annabella Di Girogio, Geraldo Busatto, Susan Rossel, Janice Fullerton
preprint en

Abstract

Abstract Bipolar disorder (BD) is a prevalent psychiatric condition characterized by marked clinical and neuroanatomical heterogeneity. Prior neuroimaging studies have used case-control comparisons yielding small to moderate effect sizes for group differences. Large and diverse samples are needed to map heterogeneity within BD. Here, we used individualized brain morphometry deviations derived from normative modeling for three MRI-based measures (regional cortical thickness, regional surface area, and subcortical volumes). We applied this approach to a large international sample of 4 660 individuals (1 145 with bipolar I disorder and 3 515 healthy controls) from the ENIGMA Bipolar Disorder Working Group consortium (age range = 8–80, female = 53.15%) and examined the distribution of deviations within the bipolar disorder group, differences between healthy controls and individuals with bipolar disorder, and associations between neuroanatomical deviations and clinical variables. We found that individuals with bipolar disorder showed a higher proportion of localized extreme deviations, notably negative cortical thickness deviations in regions consistently reported as thinner in prior studies (the left superior frontal gyrus, bilateral inferior frontal gyrus (pars opercularis), left precuneus) and subcortical volume negative deviations in the left hippocampus. In addition, ROI-level deviations in the left middle temporal gyrus and the left inferior temporal gyrus were associated with longer illness duration. This is the largest study to date exploring individualized deviations as neuroanatomical features associated with bipolar disorder. Our findings suggest that neuroanatomical heterogeneity is a core feature of bipolar disorder, with preferential left-lateralized cortical-hippocampal involvement pointing to spatially structured heterogeneity.

Research Square
University of Southern California (US), Boston Children's Hospital (US), Harvard University (US), University of British Columbia (CA), Medical University of South Carolina (US), Vita-Salute San Raffaele University (IT), Inserm (FR), University of Cape Town (ZA), Philipps University of Marburg (DE), The University of Melbourne (AU), Universidade de São Paulo (BR), King's College London (GB), University of Oslo (NO), Ollscoil na Gaillimhe – University of Galway (IE), University of Münster (DE), Commissariat à l'Énergie Atomique et aux Énergies Alternatives (FR), CEA Paris-Saclay - Etablissement de Saclay (FR), UNSW Sydney (AU), Yale University (US), Universitätsmedizin Göttingen (DE), Fidmag Sisters Hospitallers (ES), CEA Paris-Saclay (FR), IRCCS Ospedale San Raffaele (IT), Jena University Hospital (DE), Institute of Mental Health (SG), Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo (BR), Boston Children's Museum (US), Consorci Institut D'Investigacions Biomediques August Pi I Sunyer (ES), Sunnybrook Hospital (CA), École Polytechnique Fédérale de Lausanne (CH), Universitat de Barcelona (ES), Neuroscience Research Australia (AU), University of Gothenburg (SE), The University of Texas Health Science Center at Houston (US), Stanford University (US)
Bipolar Disorder and Treatment
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