Network-based atrophy modeling in the common epilepsies: A worldwide ENIGMA study

Sara Larivière¹, Raúl Rodríguez-Cruces¹, Jessica Royer¹, Maria Eugenia Caligiuri², Antonio Gambardella^{2

3}, Luis Concha⁴, Simon S Keller^{5

6}, Fernando Cendes⁷, Clarissa Yasuda⁷, Leonardo Bonilha⁸, Ezequiel Gleichgerrcht⁸, Niels K Focke⁹, Martin Domin¹⁰, Felix von Podewills¹¹, Soenke Langner¹², Christian Rummel¹³, Roland Wiest¹³, Pascal Martin¹⁴, Raviteja Kotikalapudi¹⁴, Terence J O'Brien^{15

16}, Benjamin Sinclair^{15

16}, Lucy Vivash^{15

16}, Patricia M Desmond¹⁶, Saud Alhusaini^{17

18}, Colin P Doherty^{19

20}, Gianpiero L Cavalleri^{17

20}, Norman Delanty^{17

20}, Reetta Kälviäinen^{21

22}, Graeme D Jackson²³, Magdalena Kowalczyk²³, Mario Mascalchi²⁴, Mira Semmelroch²³, Rhys H Thomas²⁵, Hamid Soltanian-Zadeh^{26

27}, Esmaeil Davoodi-Bojd²⁸, Junsong Zhang²⁹, Matteo Lenge^{30

31}, Renzo Guerrini³⁰, Emanuele Bartolini³², Khalid Hamandi^{33

34}, Sonya Foley³⁴, Bernd Weber³⁵, Chantal Depondt³⁶, Julie Absil³⁷, Sarah J A Carr³⁸, Eugenio Abela³⁸, Mark P Richardson³⁸, Orrin Devinsky³⁹, Mariasavina Severino⁴⁰, Pasquale Striano⁴⁰, Domenico Tortora⁴⁰, Sean N Hatton⁴¹, Sjoerd B Vos^{42

43

44}, John S Duncan^{42

43}, Christopher D Whelan¹⁷, Paul M Thompson⁴⁵, Sanjay M Sisodiya^{42

43}, Andrea Bernasconi⁴⁶, Angelo Labate^{2

3}, Carrie R McDonald⁴⁷, Neda Bernasconi⁴⁶, Boris C Bernhardt⁴⁸

Affiliations

¹ Multimodal Imaging and Connectome Analysis Laboratory, McConnell Brain Imaging Centre, Montreal Neurological Institute and Hospital, McGill University, Montreal, QC, Canada.
² Neuroscience Research Center, University Magna Græcia, Catanzaro, CZ, Italy.
³ Institute of Neurology, University Magna Græcia, Catanzaro, CZ, Italy.
⁴ Institute of Neurobiology, Universidad Nacional Autónoma de México, Querétaro, México.
⁵ Institute of Systems, Molecular and Integrative Biology, University of Liverpool, Liverpool, UK.
⁶ Walton Centre NHS Foundation Trust, Liverpool, UK.
⁷ Department of Neurology, University of Campinas-UNICAMP, Campinas, São Paulo, Brazil.
⁸ Department of Neurology, Medical University of South Carolina, Charleston, SC, USA.
⁹ Department of Clinical Neurophysiology, University of Medicine Göttingen, Göttingen, Germany.
¹⁰ Institute of Diagnostic Radiology and Neuroradiology, Functional Imaging Unit, University Medicine Greifswald, Greifswald, Germany.
¹¹ Department of Neurology, University Medicine Greifswald, Greifswald, Germany.
¹² Institute of Diagnostic Radiology and Neuroradiology, University Medicine Greifswald, Greifswald, Germany.
¹³ Support Center for Advanced Neuroimaging (SCAN), University Institute of Diagnostic and Interventional Neuroradiology, University Hospital Bern, Bern, Switzerland.
¹⁴ Department of Neurology and Epileptology, Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany.
¹⁵ Department of Neuroscience, Central Clinical School, Alfred Hospital, Monash University, Melbourne, Victoria, Australia.
¹⁶ Departments of Medicine and Radiology, The Royal Melbourne Hospital, The University of Melbourne, Parkville, Victoria, Australia.
¹⁷ Department of Molecular and Cellular Therapeutics, The Royal College of Surgeons in Ireland, Dublin, Ireland.
¹⁸ Department of Neurology, Yale University School of Medicine, New Haven, CT, USA.
¹⁹ Department of Neurology, St. James' Hospital, Dublin, Ireland.
²⁰ FutureNeuro SFI Research Centre, Dublin, Ireland.
²¹ Epilepsy Center, Neuro Center, Kuopio University Hospital, European Reference Network for Rare and Complex Epilepsies EpiCARE, Kuopio, Finland.
²² Faculty of Health Sciences, School of Medicine, Institute of Clinical Medicine, University of Eastern Finland, Kuopio, Finland.
²³ Florey Institute of Neuroscience and Mental Health, University of Melbourne, Melbourne, Victoria 3010, Australia.
²⁴ Neuroradiology Research Program, Meyer Children Hospital of Florence, University of Florence, Florence, Italy.
²⁵ Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, UK.
²⁶ Control and Intelligent Processing Center of Excellence (CIPCE), School of Electrical and Computer Engineering, University of Tehran, Tehran, Iran.
²⁷ Departments of Research Administration and Radiology, Henry Ford Health System, Detroit, MI, USA.
²⁸ Department of Neurology, Henry Ford Health System, Detroit, MI, USA.
²⁹ Cognitive Science Department, Xiamen University, Xiamen, China.
³⁰ Child Neurology Unit and Laboratories, Neuroscience Department, Children's Hospital A. Meyer-University of Florence, Italy.
³¹ Functional and Epilepsy Neurosurgery Unit, Neurosurgery Department, Children's Hospital A. Meyer-University of Florence, Italy.
³² USL Centro Toscana, Neurology Unit, Nuovo Ospedale Santo Stefano, Prato, Italy.
³³ Cardiff University Brain Research Imaging Centre (CUBRIC), College of Biomedical Sciences, Cardiff University, Cardiff, UK.
³⁴ Welsh Epilepsy Unit, Department of Neurology, University Hospital of Wales, Cardiff, UK.
³⁵ Institute of Experimental Epileptology and Cognition Research, University Hospital Bonn, Bonn, Germany.
³⁶ Department of Neurology, Hôpital Erasme, Université Libre de Bruxelles, Brussels, Belgium.
³⁷ Department of Radiology, Hôpital Erasme, Université Libre de Bruxelles, Brussels, Belgium.
³⁸ Division of Neuroscience, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.
³⁹ Department of Neurology, NYU Grossman School of Medicine, New York, NY, USA.
⁴⁰ IRCCS Istituto Giannina Gaslini, Genova, Italy.
⁴¹ Department of Neurosciences, Center for Multimodal Imaging and Genetics, University of California San Diego, La Jolla, CA, USA.
⁴² Department of Clinical and Experimental Epilepsy, UCL Institute of Neurology, London, UK.
⁴³ Chalfont Centre for Epilepsy, Bucks, UK.
⁴⁴ Centre for Medical Image Computing, University College London, London, UK.
⁴⁵ Imaging Genetics Center, Mark and Mary Stevens Institute for Neuroimaging and Informatics, USC Keck School of Medicine, Los Angeles, CA, USA.
⁴⁶ Neuroimaging of Epilepsy Laboratory, McConnell Brain Imaging Centre, Montreal Neurological Institute and Hospital, McGill University, Montreal, QC, Canada.
⁴⁷ Department of Psychiatry, Center for Multimodal Imaging and Genetics, University of California San Diego, La Jolla, CA, USA.
⁴⁸ Multimodal Imaging and Connectome Analysis Laboratory, McConnell Brain Imaging Centre, Montreal Neurological Institute and Hospital, McGill University, Montreal, QC, Canada. boris.bernhardt@mcgill.ca.

PMID: 33208365
PMCID: PMC7673818
DOI: 10.1126/sciadv.abc6457

Network-based atrophy modeling in the common epilepsies: A worldwide ENIGMA study

Sara Larivière et al. Sci Adv. 2020.

. 2020 Nov 18;6(47):eabc6457.

doi: 10.1126/sciadv.abc6457. Print 2020 Nov.

Authors

Affiliations

¹ Multimodal Imaging and Connectome Analysis Laboratory, McConnell Brain Imaging Centre, Montreal Neurological Institute and Hospital, McGill University, Montreal, QC, Canada.
² Neuroscience Research Center, University Magna Græcia, Catanzaro, CZ, Italy.
³ Institute of Neurology, University Magna Græcia, Catanzaro, CZ, Italy.
⁴ Institute of Neurobiology, Universidad Nacional Autónoma de México, Querétaro, México.
⁵ Institute of Systems, Molecular and Integrative Biology, University of Liverpool, Liverpool, UK.
⁶ Walton Centre NHS Foundation Trust, Liverpool, UK.
⁷ Department of Neurology, University of Campinas-UNICAMP, Campinas, São Paulo, Brazil.
⁸ Department of Neurology, Medical University of South Carolina, Charleston, SC, USA.
⁹ Department of Clinical Neurophysiology, University of Medicine Göttingen, Göttingen, Germany.
¹⁰ Institute of Diagnostic Radiology and Neuroradiology, Functional Imaging Unit, University Medicine Greifswald, Greifswald, Germany.
¹¹ Department of Neurology, University Medicine Greifswald, Greifswald, Germany.
¹² Institute of Diagnostic Radiology and Neuroradiology, University Medicine Greifswald, Greifswald, Germany.
¹³ Support Center for Advanced Neuroimaging (SCAN), University Institute of Diagnostic and Interventional Neuroradiology, University Hospital Bern, Bern, Switzerland.
¹⁴ Department of Neurology and Epileptology, Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany.
¹⁵ Department of Neuroscience, Central Clinical School, Alfred Hospital, Monash University, Melbourne, Victoria, Australia.
¹⁶ Departments of Medicine and Radiology, The Royal Melbourne Hospital, The University of Melbourne, Parkville, Victoria, Australia.
¹⁷ Department of Molecular and Cellular Therapeutics, The Royal College of Surgeons in Ireland, Dublin, Ireland.
¹⁸ Department of Neurology, Yale University School of Medicine, New Haven, CT, USA.
¹⁹ Department of Neurology, St. James' Hospital, Dublin, Ireland.
²⁰ FutureNeuro SFI Research Centre, Dublin, Ireland.
²¹ Epilepsy Center, Neuro Center, Kuopio University Hospital, European Reference Network for Rare and Complex Epilepsies EpiCARE, Kuopio, Finland.
²² Faculty of Health Sciences, School of Medicine, Institute of Clinical Medicine, University of Eastern Finland, Kuopio, Finland.
²³ Florey Institute of Neuroscience and Mental Health, University of Melbourne, Melbourne, Victoria 3010, Australia.
²⁴ Neuroradiology Research Program, Meyer Children Hospital of Florence, University of Florence, Florence, Italy.
²⁵ Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, UK.
²⁶ Control and Intelligent Processing Center of Excellence (CIPCE), School of Electrical and Computer Engineering, University of Tehran, Tehran, Iran.
²⁷ Departments of Research Administration and Radiology, Henry Ford Health System, Detroit, MI, USA.
²⁸ Department of Neurology, Henry Ford Health System, Detroit, MI, USA.
²⁹ Cognitive Science Department, Xiamen University, Xiamen, China.
³⁰ Child Neurology Unit and Laboratories, Neuroscience Department, Children's Hospital A. Meyer-University of Florence, Italy.
³¹ Functional and Epilepsy Neurosurgery Unit, Neurosurgery Department, Children's Hospital A. Meyer-University of Florence, Italy.
³² USL Centro Toscana, Neurology Unit, Nuovo Ospedale Santo Stefano, Prato, Italy.
³³ Cardiff University Brain Research Imaging Centre (CUBRIC), College of Biomedical Sciences, Cardiff University, Cardiff, UK.
³⁴ Welsh Epilepsy Unit, Department of Neurology, University Hospital of Wales, Cardiff, UK.
³⁵ Institute of Experimental Epileptology and Cognition Research, University Hospital Bonn, Bonn, Germany.
³⁶ Department of Neurology, Hôpital Erasme, Université Libre de Bruxelles, Brussels, Belgium.
³⁷ Department of Radiology, Hôpital Erasme, Université Libre de Bruxelles, Brussels, Belgium.
³⁸ Division of Neuroscience, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.
³⁹ Department of Neurology, NYU Grossman School of Medicine, New York, NY, USA.
⁴⁰ IRCCS Istituto Giannina Gaslini, Genova, Italy.
⁴¹ Department of Neurosciences, Center for Multimodal Imaging and Genetics, University of California San Diego, La Jolla, CA, USA.
⁴² Department of Clinical and Experimental Epilepsy, UCL Institute of Neurology, London, UK.
⁴³ Chalfont Centre for Epilepsy, Bucks, UK.
⁴⁴ Centre for Medical Image Computing, University College London, London, UK.
⁴⁵ Imaging Genetics Center, Mark and Mary Stevens Institute for Neuroimaging and Informatics, USC Keck School of Medicine, Los Angeles, CA, USA.
⁴⁶ Neuroimaging of Epilepsy Laboratory, McConnell Brain Imaging Centre, Montreal Neurological Institute and Hospital, McGill University, Montreal, QC, Canada.
⁴⁷ Department of Psychiatry, Center for Multimodal Imaging and Genetics, University of California San Diego, La Jolla, CA, USA.
⁴⁸ Multimodal Imaging and Connectome Analysis Laboratory, McConnell Brain Imaging Centre, Montreal Neurological Institute and Hospital, McGill University, Montreal, QC, Canada. boris.bernhardt@mcgill.ca.

PMID: 33208365
PMCID: PMC7673818
DOI: 10.1126/sciadv.abc6457

Abstract

Epilepsy is increasingly conceptualized as a network disorder. In this cross-sectional mega-analysis, we integrated neuroimaging and connectome analysis to identify network associations with atrophy patterns in 1021 adults with epilepsy compared to 1564 healthy controls from 19 international sites. In temporal lobe epilepsy, areas of atrophy colocalized with highly interconnected cortical hub regions, whereas idiopathic generalized epilepsy showed preferential subcortical hub involvement. These morphological abnormalities were anchored to the connectivity profiles of distinct disease epicenters, pointing to temporo-limbic cortices in temporal lobe epilepsy and fronto-central cortices in idiopathic generalized epilepsy. Negative effects of age on atrophy further revealed a strong influence of connectome architecture in temporal lobe, but not idiopathic generalized, epilepsy. Our findings were reproduced across individual sites and single patients and were robust across different analytical methods. Through worldwide collaboration in ENIGMA-Epilepsy, we provided deeper insights into the macroscale features that shape the pathophysiology of common epilepsies.

Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC).

PubMed Disclaimer

Figures

**Fig. 1. Cortical thickness and subcortical volume in TLE and IGE.**
(A) Cortical thickness and subcortical volume reductions in TLE (n = 732), compared to healthy controls (n = 1418), spanned bilateral precuneus (P_FDR < 4 × 10⁻³⁶), precentral (P_FDR < 8 × 10⁻³⁶), paracentral (P_FDR < 6 × 10⁻²⁹), and superior temporal (P_FDR < 3 × 10⁻¹⁴) cortices and ipsilateral hippocampus (P_FDR < 2 × 10⁻¹⁹⁹) and thalamus (P_FDR < 5 × 10⁻⁶⁴). (B) In contrast, gray matter cortical and subcortical atrophy in IGE (n = 289), relative to controls (n = 1075), was more subtle and affected predominantly bilateral precentral cortical regions (P_FDR < 9 × 10⁻¹⁰) and the thalamus (P_FDR < 3 × 10⁻⁶). Negative log₁₀-transformed FDR-corrected P values are shown.

**Fig. 2. Epilepsy-related atrophy correlates with hub organization.**
(A) Normative functional and structural network organization, derived from the HCP dataset, was used to identify hubs (i.e., regions with greater degree centrality). (B) Schematic of the figure layout is pictured in the middle. Gray matter atrophy related to node-level functional (left) and structural (right) maps of degree centrality, with greater atrophy in hub compared to nonhub regions. Stratifying findings across TLE and IGE, we observed stronger associations between cortico-cortical functional hubs and cortical atrophy patterns in TLE (P_spin < 0.0001) and between subcortical volume loss and subcortico-cortical structural hubs in IGE (P_shuf < 0.01).

**Fig. 3. Syndrome-specific disease epicenters.**
(A) Disease epicenter mapping schema. Spatial correlations between cortical atrophy patterns and seed-based cortico- and subcortico-cortical connectivity were used to identify disease epicenters in TLE and IGE. Epicenters are regions whose connectivity profiles significantly correlated with the syndrome-specific atrophy map; statistical significance was assessed using spin permutation tests. This procedure was repeated systematically to assess the epicenter value of every cortical and subcortical region, as well as in both functional and structural connectivity matrices. (B and C) Correlation coefficients indexing spatial similarity between TLE- and IGE-specific atrophy and seed-based functional (left) and structural (right) connectivity measures for every cortical and subcortical region. Regions with significant associations were ranked in descending order based on their correlation coefficients, with the first five regions identified as disease epicenters (white outline). In TLE, ipsilateral temporo-limbic cortices (functional: P_spin < 0.05, structural: P_spin < 0.1) and subcortical areas—including ipsilateral amygdala (functional: P_spin < 0.05), thalamus (functional: P_spin < 0.05, structural: P_spin < 0.01), pallidum (functional: P_spin < 0.05), putamen (functional: P_spin < 0.05), and hippocampus (functional: P_spin < 0.1)—emerged as disease epicenters. In IGE, the highest ranked disease epicenters were located in bilateral fronto-central cortices, including postcentral gyri (functional: P_spin < 0.05, structural: P_spin < 0.05), left (functional: P_spin < 0.005, structural: P_spin < 0.1) and right amygdala (functional: P_spin < 0.005), and left pallidum (structural: P_spin < 0.1). *P_spin < 0.1, n.s., nonsignificant.

**Fig. 4. Negative effects of age on cortical thickness and subcortical volume in TLE.**
(A) Significant age-related differences on gray matter atrophy between individuals with TLE and healthy controls for all cortical and subcortical regions. Patients with TLE showed a negative effect of age on cortical thickness in bilateral temporo-parietal (P_FDR < 0.005) and sensorimotor (P_FDR < 0.01) cortices and on subcortical volume in ipsilateral hippocampus (P_FDR < 5 × 10⁻⁷) and bilateral thalamus (P_FDR < 0.05). Negative log₁₀-transformed FDR-corrected P values are shown. (B) Schematic of the figure layout is provided in the middle. Scatterplots depict relationships between the age-related effects and functional (red) and structural (blue) maps of degree centrality (left) and disease epicenter (right). Significant associations were observed between age-related effects and every hub and epicenter measures, with the exception of structural subcortical degree centrality, suggesting a role of connectome organization on age-related effects in TLE.

**Fig. 5. Patient-tailored atrophy modeling.**
(A) Patient-specific associations between degree centrality (denoting hub distribution) and individualized atrophy maps showed high stability between functional cortico-cortical hubs and cortical atrophy in TLE (P_spin < 0.05 in 22.4% of patients) and high stability between structural cortico-cortical hubs and cortical atrophy in IGE (P_spin < 0.05 in 15.2% of patients). (B) We identified patient-specific structural and functional disease epicenters by keeping brain regions whose connectivity profiles significantly correlated with the patient’s atrophy map (P_spin < 0.05). In TLE, ipsilateral temporo-limbic regions and subcortical areas (including the hippocampus) were most often identified as epicenters of gray matter atrophy, whereas in IGE, bilateral fronto-central (including sensorimotor cortices) and subcortical areas most often emerged as disease epicenters. Disease epicenters in individual patients strongly resembled those seen across the group as a whole.

See this image and copyright information in PMC

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Network-based atrophy modeling in the common epilepsies: A worldwide ENIGMA study

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Network-based atrophy modeling in the common epilepsies: A worldwide ENIGMA study

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