Structural Brain Network Alterations in Relation to Treatment and Illness Severity in Bipolar Disorder

Background: Large-scale T1-weighted MRI studies have established grey-matter abnormalities in bipolar disorder (BD), with our group contributing to consensus findings. However, structural connectivity, particularly within emotion- and reward-related circuits, remains poorly understood. Diffusion-weighted MRI (dMRI) enables investigation of white-matter pathways, yet prior work is constrained by small samples, methodological heterogeneity, and unclear medication effects. We conducted the largest dMRI network analysis in BD, relating symptom burden and polypharmacy to tractography-derived connectivity and graph-theoretic metrics. Methods: Cross-sectional structural and diffusion MRI scans from 449 individuals with BD (35.7±12.6 years) and 510 controls (33.3±12.6 years), aged 18-65, were analyzed across 16 ENIGMA-BD sites. Standardized segmentation/parcellation and constrained spherical deconvolution tractography generated individual structural connectivity matrices. Graph-theoretic metrics of global and subnetwork organization were related to symptom severity and medications. Results: BD showed widespread network alterations (lower density and efficiency, longer path length, and higher betweenness centrality), altered microstructural organization in a limbic-basal ganglia circuit, and abnormal streamline counts in a default-mode/salience/fronto-limbic-basal ganglia network. Longer illness duration, later onset, and psychosis history were associated with greater abnormalities in network architecture, whereas more manic episodes were associated with greater fronto-limbic connectivity. Antidepressant (particularly SSRI), anticonvulsant, and antipsychotic use related to poorer global and fronto-limbic connectivity; no clear lithium effects emerged. Conclusions: As the largest structural connectivity study in BD, we reveal widespread disruption in reward and emotion-regulation networks influenced by illness severity and medication use. Results show that multisite harmonization is feasible and highlight ENIGMA-BD as a scalable framework for identifying reproducible neurobiological markers.

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bioRxiv (Cold Spring Harbor Laboratory)
Published
2026-03-31
DOI
https://doi.org/10.64898/2026.03.28.714565
Primary Topic
Bipolar Disorder and Treatment
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article
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article

Structural Brain Network Alterations in Relation to Treatment and Illness Severity in Bipolar Disorder

Christopher R. K. Ching, Genevieve McPhilemy, Brian P. Hallahan, Mircea Polosan et al.
bioRxiv (Cold Spring Harbor Laboratory)
Bipolar Disorder and Treatment
article

Structural Brain Network Alterations in Relation to Treatment and Illness Severity in Bipolar Disorder

Christopher R. K. Ching, Genevieve McPhilemy, Brian P. Hallahan, Mircea Polosan, Orwa Dandash, Paul Thompson, Nina Alexander, M. Bellani, Fiona M. Martyn, Leila Nabulsi, Fleur M. Howells, Michèle Wessa, Arnaud Pouchon, Freda Scheffler, Nadine Parker, Olaf Steinstraeter, E. Vieta, ENIGMA Bipolar Disorder Working Group, Melody J.Y. Kang, P. Favre, Erick J. Canales-Rodríguez, J. Houenou, Susanne Meinert, Dan J. Stein, Raymond Salvador, Ole A. Andreassen, Michael Berk, Chao Suo, Sophia I. Thomopoulos, Mary L. Phillips, Gloria Roberts, Andriana Karuk, David C. Glahn, Tilo Kircher, Udo Dannlowski, Tim Hahn, Bartholomeus Haarman, Andreas Jansen, Kira Flinkenflugel, Stefani O'Donoghue, Lea Teutenberg, Amanda Rodrigue, Jonathan Repple, Frederike Stein, Paolo Brambilla, Benjamin Straube, Paula L. Usemann, Dominik Grotegerd, Tiana Borgers, Joaquim Radua, Elisabeth J. Lehr, Colm McDonald, Neda Jahanshad, Edith Pomarol-Clotet, Dara M. Cannon, Henk S. Temmingh, Florian Thomas-Odenthal
article en

Abstract

Background: Large-scale T1-weighted MRI studies have established grey-matter abnormalities in bipolar disorder (BD), with our group contributing to consensus findings. However, structural connectivity, particularly within emotion- and reward-related circuits, remains poorly understood. Diffusion-weighted MRI (dMRI) enables investigation of white-matter pathways, yet prior work is constrained by small samples, methodological heterogeneity, and unclear medication effects. We conducted the largest dMRI network analysis in BD, relating symptom burden and polypharmacy to tractography-derived connectivity and graph-theoretic metrics. Methods: Cross-sectional structural and diffusion MRI scans from 449 individuals with BD (35.7±12.6 years) and 510 controls (33.3±12.6 years), aged 18-65, were analyzed across 16 ENIGMA-BD sites. Standardized segmentation/parcellation and constrained spherical deconvolution tractography generated individual structural connectivity matrices. Graph-theoretic metrics of global and subnetwork organization were related to symptom severity and medications. Results: BD showed widespread network alterations (lower density and efficiency, longer path length, and higher betweenness centrality), altered microstructural organization in a limbic-basal ganglia circuit, and abnormal streamline counts in a default-mode/salience/fronto-limbic-basal ganglia network. Longer illness duration, later onset, and psychosis history were associated with greater abnormalities in network architecture, whereas more manic episodes were associated with greater fronto-limbic connectivity. Antidepressant (particularly SSRI), anticonvulsant, and antipsychotic use related to poorer global and fronto-limbic connectivity; no clear lithium effects emerged. Conclusions: As the largest structural connectivity study in BD, we reveal widespread disruption in reward and emotion-regulation networks influenced by illness severity and medication use. Results show that multisite harmonization is feasible and highlight ENIGMA-BD as a scalable framework for identifying reproducible neurobiological markers.

bioRxiv (Cold Spring Harbor Laboratory)
South African Medical Research Council (ZA), Goethe University Frankfurt (DE), University of Southern California (US), University of Verona (IT), Oslo University Hospital (NO), Boston Children's Hospital (US), Barwon Health (AU), Harvard University (US), Deakin University (AU), Inserm (FR), University of Cape Town (ZA), Philipps University of Marburg (DE), The University of Melbourne (AU), University of Pittsburgh (US), German Cancer Research Center (DE), University of Oslo (NO), Neurosciences Institute (US), Ollscoil na Gaillimhe – University of Galway (IE), University of Milan (IT), Northern Health (AU), Université Paris-Est Créteil (FR), Heidelberg University (DE), University of Münster (DE), Commissariat à l'Énergie Atomique et aux Énergies Alternatives (FR), Centre Hospitalier Universitaire de Grenoble (FR), Instituto de Salud Carlos III (ES), University Hospital Heidelberg (DE), Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico (IT), UNSW Sydney (AU), Centro de Investigación Biomédica en Red de Salud Mental (ES), Orygen Youth Health (AU), Central Institute of Mental Health (DE), Orygen (AU), Brain (Germany) (DE), Monash Health (AU), Fidmag Sisters Hospitallers (ES), CEA Paris-Saclay (FR), Grenoble Institute of Neurosciences (FR), University Medical Centre Mannheim (DE), Melbourne Health (AU), Consorci Institut D'Investigacions Biomediques August Pi I Sunyer (ES), École Polytechnique Fédérale de Lausanne (CH), Monash University (AU), Bethel University (US), Université Grenoble Alpes (FR)
Fondation de l'Avenir pour la Recherche Médicale Appliquée, Health Research Board, Deutsche Forschungsgemeinschaft, Fondation pour la Recherche Médicale, Else Kröner-Fresenius-Stiftung, NordForsk, Norges Forskningsråd
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