The ENIGMA-Epilepsy working group: Mapping disease from large data sets

Sanjay M Sisodiya^{1

2}, Christopher D Whelan³, Sean N Hatton⁴, Khoa Huynh⁴, Andre Altmann⁵, Mina Ryten⁶, Annamaria Vezzani⁷, Maria Eugenia Caligiuri⁸, Angelo Labate^{8

9}, Antonio Gambardella^{8

9}, Victoria Ives-Deliperi¹⁰, Stefano Meletti^{11

12}, Brent C Munsell^{13

14}, Leonardo Bonilha¹⁵, Manuela Tondelli¹², Michael Rebsamen¹⁶, Christian Rummel¹⁶, Anna Elisabetta Vaudano^{11

12}, Roland Wiest¹⁶, Akshara R Balachandra^{4

17}, Núria Bargalló^{18

19}, Emanuele Bartolini²⁰, Andrea Bernasconi²¹, Neda Bernasconi²¹, Boris Bernhardt²², Benoit Caldairou²¹, Sarah J A Carr²³, Gianpiero L Cavalleri^{24

25}, Fernando Cendes²⁶, Luis Concha²⁷, Patricia M Desmond²⁸, Martin Domin²⁹, John S Duncan^{1

2}, Niels K Focke³⁰, Renzo Guerrini³¹, Khalid Hamandi^{32

33}, Graeme D Jackson^{34

35}, Neda Jahanshad³⁶, Reetta Kälviäinen^{37

38}, Simon S Keller^{39

40}, Peter Kochunov⁴¹, Magdalena A Kowalczyk³⁵, Barbara A K Kreilkamp^{39

40}, Patrick Kwan⁴², Sara Lariviere²², Matteo Lenge^{31

43}, Seymour M Lopez⁵, Pascal Martin⁴⁴, Mario Mascalchi⁴⁵, José C V Moreira²⁶, Marcia E Morita-Sherman^{26

46}, Heath R Pardoe⁴⁷, Jose C Pariente¹⁸, Kotikalapudi Raviteja^{44

48

49}, Cristiane S Rocha²⁶, Raúl Rodríguez-Cruces^{27

50}, Margitta Seeck⁵¹, Mira K H G Semmelroch^{35

52}, Benjamin Sinclair^{53

54}, Hamid Soltanian-Zadeh^{55

56}, Dan J Stein⁵⁷, Pasquale Striano^{58

59}, Peter N Taylor⁶⁰, Rhys H Thomas⁶¹, Sophia I Thomopoulos³⁶, Dennis Velakoulis^{62

63}, Lucy Vivash^{53

64}, Bernd Weber⁶⁵, Clarissa Lin Yasuda²⁶, Junsong Zhang⁶⁶, Paul M Thompson³⁶, Carrie R McDonald⁶⁷; ENIGMA Consortium Epilepsy Working Group

Affiliations

¹ Department of Clinical and Experimental Epilepsy, UCL Queen Square Institute of Neurology, London, UK.
² Chalfont Centre for Epilepsy, Bucks, UK.
³ Department of Molecular and Cellular Therapeutics, The Royal College of Surgeons in Ireland, Dublin, Ireland.
⁴ Center for Multimodal Imaging and Genetics, University of California San Diego, La Jolla, California, USA.
⁵ Centre for Medical Image Computing, Department of Medical Physics and Biomedical Engineering, University College London, London, UK.
⁶ UCL Queen Square Institute of Neurology, London, UK.
⁷ Department of Neuroscience, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milan, Italy.
⁸ Neuroscience Research Center, Department of Medical and Surgical Sciences, University "Magna Graecia" of Catanzaro, Catanzaro, Italy.
⁹ Institute of Neurology, University "Magna Graecia" of Catanzaro, Catanzaro, Italy.
¹⁰ Neuroscience Institute, University of Cape Town, Cape Town, South Africa.
¹¹ Department of Biomedical, Metabolic, and Neural Sciences, University of Modena and Reggio Emilia, Modena, Italy.
¹² Neurology Unit, OCB Hospital, AOU Modena, Modena, Italy.
¹³ Department of Psychiatry, University of North Carolina, Chapel Hill, North Carolina, USA.
¹⁴ Department of Computer Science, University of North Carolina, Chapel Hill, North Carolina, USA.
¹⁵ Department of Neurology, Medical University of South Carolina, Charleston, South Carolina, USA.
¹⁶ Support Center for Advanced Neuroimaging, University Institute of Diagnostic and Interventional Neuroradiology, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland.
¹⁷ Boston University School of Medicine, Boston, Massachusetts, USA.
¹⁸ Magnetic Resonance Image Core Facility, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Universitat de Barcelona, Barcelona, Spain.
¹⁹ Radiology Department of Center of Image Diagnosis, Hospital Clinic de Barcelona, Barcelona, Spain.
²⁰ Neurology Unit, USL Centro Toscana, Nuovo Ospedale Santo Stefano, Prato, Italy.
²¹ Neuroimaging of Epilepsy Laboratory, Montreal Neurological Institute, McGill University, Montreal, Québec, Canada.
²² McConnell Brain Imaging Center, Montreal Neurological Institute, McGill University, Montreal, Québec, Canada.
²³ Neuroscience, Institute of Psychiatry, Psychology and Neuroscience, London, UK.
²⁴ School of Pharmacy and Biomolecular Sciences, The Royal College of Surgeons in Ireland, Dublin, Ireland.
²⁵ FutureNeuro SFI Research Centre, Dublin, Ireland.
²⁶ Department of Neurology and Neuroimaging Laboratory, University of Campinas - UNICAMP, Campinas, São Paulo, Brazil.
²⁷ Instituto de Neurobiología, Universidad Nacional Autónoma de México, Querétaro, Mexico.
²⁸ Department of Radiology, Royal Melbourne Hospital, University of Melbourne, Melbourne, Victoria, Australia.
²⁹ Functional Imaging Unit, Department of Diagnostic Radiology and Neuroradiology, University Medicine Greifswald, Greifswald, Germany.
³⁰ University Medicine Göttingen, Clinical Neurophysiology, Göttingen, Germany.
³¹ Pediatric Neurology, Neurogenetics and Neurobiology Unit and Laboratories, Children's Hospital A. Meyer-University of Florence, Florence, Italy.
³² The Wales Epilepsy Unit, Department of Neurology, University Hospital of Wales, Cardiff, UK.
³³ Cardiff University Brain Research Imaging Centre, School of Psychology, Cardiff University, Cardiff, UK.
³⁴ Department of Neurology, Austin Health, Heidelberg, Victoria, Australia.
³⁵ Florey Department of Neuroscience and Mental Health, University of Melbourne, Victoria, Australia.
³⁶ Imaging Genetics Center, Mark and Mary Stevens Institute for Neuroimaging and Informatics, Keck School of Medicine, University of Southern California, Marina del Rey, California, USA.
³⁷ Kuopio University Hospital, Member of EpiCARE ERN, Kuopio, Finland.
³⁸ Institute of Clinical Medicine, Neurology, University of Eastern Finland, Kuopio, Finland.
³⁹ Institute of Systems, Molecular and Integrative Biology, University of Liverpool, Liverpool, UK.
⁴⁰ The Walton Centre, NHS Foundation Trust, Liverpool, UK.
⁴¹ Department of Psychiatry, University of Maryland School of Medicine, Baltimore, Maryland, USA.
⁴² Department of Neuroscience, Central Clinical School, Monash University, Melbourne, Victoria, Australia.
⁴³ Functional and Epilepsy Neurosurgery Unit, Neurosurgery Department, Children's Hospital A. Meyer-University of Florence, Florence, Italy.
⁴⁴ Department of Neurology and Epileptology, Hertie Institute for Clinical Brain Research, University Hospital Tübingen, Tübingen, Germany.
⁴⁵ 'Mario Serio' Department of Clinical and Experimental Medical Sciences, University of Florence, Florence, Italy.
⁴⁶ Cleveland Clinic Neurological Institute, Cleveland, Ohio, USA.
⁴⁷ Department of Neurology, New York University School of Medicine, New York, New York, USA.
⁴⁸ Department of Diagnostic and Interventional Neuroradiology, University Hospitals Tübingen, Tübingen, Germany.
⁴⁹ Department of Clinical Neurophysiology, University Hospital Göttingen, Goettingen, Germany.
⁵⁰ Montreal Neurological Institute and Hospital, McGill University, Montreal, Québec, Canada.
⁵¹ EEG and Epilepsy Unit, Geneva, Switzerland.
⁵² The Florey Institute of Neuroscience and Mental Health, Austin Campus, Heidelberg, Victoria, Australia.
⁵³ Department of Neuroscience, Monash University, Melbourne, Victoria, Australia.
⁵⁴ Alfred Health, Melbourne, Victoria, Australia.
⁵⁵ Radiology and Research Administration, Henry Ford Health System, Detroit, Michigan, USA.
⁵⁶ School of Electrical and Computer Engineering, College of Engineering, University of Tehran, Tehran, Iran.
⁵⁷ South African Medical Research Council Unit on Risk & Resilience in Mental Disorders, Dept of Psychiatry & Neuroscience Institute, University of Cape Townon Risk & Resilience in Mental Disorders, Cape Town, South Africa.
⁵⁸ Pediatric Neurology and Muscular Diseases Unit, IRCCS Istituto 'G. Gaslini', Genova, Italy.
⁵⁹ Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, University of Genova, Italy.
⁶⁰ School of Computing, Newcastle University, Newcastle upon Tyne, UK.
⁶¹ Institute of Translational and Clinical Research, Newcastle University, Newcastle upon Tyne, UK.
⁶² Department of Medicine, Royal Melbourne Hospital, University of Melbourne, Parkville, Victoria, UK.
⁶³ Department of Neuropsychiatry, Royal Melbourne Hospital, Parkville, Victoria, Australia.
⁶⁴ Department of Neurology, Royal Melbourne Hospital, Melbourne, Victoria, Australia.
⁶⁵ Institute of Experimental Epileptology and Cognition Research, University of Bonn, Bonn, Germany.
⁶⁶ Cognitive Science Department, School of Informatics, Xiamen University, Xiamen, China.
⁶⁷ Department of Psychiatry, University of California San Diego, La Jolla, California, USA.

PMID: 32468614
PMCID: PMC8675408
DOI: 10.1002/hbm.25037

Review

The ENIGMA-Epilepsy working group: Mapping disease from large data sets

Sanjay M Sisodiya et al. Hum Brain Mapp. 2020.

. 2020 May 29;43(1):113-128.

doi: 10.1002/hbm.25037. Online ahead of print.

Authors

Affiliations

¹ Department of Clinical and Experimental Epilepsy, UCL Queen Square Institute of Neurology, London, UK.
² Chalfont Centre for Epilepsy, Bucks, UK.
³ Department of Molecular and Cellular Therapeutics, The Royal College of Surgeons in Ireland, Dublin, Ireland.
⁴ Center for Multimodal Imaging and Genetics, University of California San Diego, La Jolla, California, USA.
⁵ Centre for Medical Image Computing, Department of Medical Physics and Biomedical Engineering, University College London, London, UK.
⁶ UCL Queen Square Institute of Neurology, London, UK.
⁷ Department of Neuroscience, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milan, Italy.
⁸ Neuroscience Research Center, Department of Medical and Surgical Sciences, University "Magna Graecia" of Catanzaro, Catanzaro, Italy.
⁹ Institute of Neurology, University "Magna Graecia" of Catanzaro, Catanzaro, Italy.
¹⁰ Neuroscience Institute, University of Cape Town, Cape Town, South Africa.
¹¹ Department of Biomedical, Metabolic, and Neural Sciences, University of Modena and Reggio Emilia, Modena, Italy.
¹² Neurology Unit, OCB Hospital, AOU Modena, Modena, Italy.
¹³ Department of Psychiatry, University of North Carolina, Chapel Hill, North Carolina, USA.
¹⁴ Department of Computer Science, University of North Carolina, Chapel Hill, North Carolina, USA.
¹⁵ Department of Neurology, Medical University of South Carolina, Charleston, South Carolina, USA.
¹⁶ Support Center for Advanced Neuroimaging, University Institute of Diagnostic and Interventional Neuroradiology, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland.
¹⁷ Boston University School of Medicine, Boston, Massachusetts, USA.
¹⁸ Magnetic Resonance Image Core Facility, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Universitat de Barcelona, Barcelona, Spain.
¹⁹ Radiology Department of Center of Image Diagnosis, Hospital Clinic de Barcelona, Barcelona, Spain.
²⁰ Neurology Unit, USL Centro Toscana, Nuovo Ospedale Santo Stefano, Prato, Italy.
²¹ Neuroimaging of Epilepsy Laboratory, Montreal Neurological Institute, McGill University, Montreal, Québec, Canada.
²² McConnell Brain Imaging Center, Montreal Neurological Institute, McGill University, Montreal, Québec, Canada.
²³ Neuroscience, Institute of Psychiatry, Psychology and Neuroscience, London, UK.
²⁴ School of Pharmacy and Biomolecular Sciences, The Royal College of Surgeons in Ireland, Dublin, Ireland.
²⁵ FutureNeuro SFI Research Centre, Dublin, Ireland.
²⁶ Department of Neurology and Neuroimaging Laboratory, University of Campinas - UNICAMP, Campinas, São Paulo, Brazil.
²⁷ Instituto de Neurobiología, Universidad Nacional Autónoma de México, Querétaro, Mexico.
²⁸ Department of Radiology, Royal Melbourne Hospital, University of Melbourne, Melbourne, Victoria, Australia.
²⁹ Functional Imaging Unit, Department of Diagnostic Radiology and Neuroradiology, University Medicine Greifswald, Greifswald, Germany.
³⁰ University Medicine Göttingen, Clinical Neurophysiology, Göttingen, Germany.
³¹ Pediatric Neurology, Neurogenetics and Neurobiology Unit and Laboratories, Children's Hospital A. Meyer-University of Florence, Florence, Italy.
³² The Wales Epilepsy Unit, Department of Neurology, University Hospital of Wales, Cardiff, UK.
³³ Cardiff University Brain Research Imaging Centre, School of Psychology, Cardiff University, Cardiff, UK.
³⁴ Department of Neurology, Austin Health, Heidelberg, Victoria, Australia.
³⁵ Florey Department of Neuroscience and Mental Health, University of Melbourne, Victoria, Australia.
³⁶ Imaging Genetics Center, Mark and Mary Stevens Institute for Neuroimaging and Informatics, Keck School of Medicine, University of Southern California, Marina del Rey, California, USA.
³⁷ Kuopio University Hospital, Member of EpiCARE ERN, Kuopio, Finland.
³⁸ Institute of Clinical Medicine, Neurology, University of Eastern Finland, Kuopio, Finland.
³⁹ Institute of Systems, Molecular and Integrative Biology, University of Liverpool, Liverpool, UK.
⁴⁰ The Walton Centre, NHS Foundation Trust, Liverpool, UK.
⁴¹ Department of Psychiatry, University of Maryland School of Medicine, Baltimore, Maryland, USA.
⁴² Department of Neuroscience, Central Clinical School, Monash University, Melbourne, Victoria, Australia.
⁴³ Functional and Epilepsy Neurosurgery Unit, Neurosurgery Department, Children's Hospital A. Meyer-University of Florence, Florence, Italy.
⁴⁴ Department of Neurology and Epileptology, Hertie Institute for Clinical Brain Research, University Hospital Tübingen, Tübingen, Germany.
⁴⁵ 'Mario Serio' Department of Clinical and Experimental Medical Sciences, University of Florence, Florence, Italy.
⁴⁶ Cleveland Clinic Neurological Institute, Cleveland, Ohio, USA.
⁴⁷ Department of Neurology, New York University School of Medicine, New York, New York, USA.
⁴⁸ Department of Diagnostic and Interventional Neuroradiology, University Hospitals Tübingen, Tübingen, Germany.
⁴⁹ Department of Clinical Neurophysiology, University Hospital Göttingen, Goettingen, Germany.
⁵⁰ Montreal Neurological Institute and Hospital, McGill University, Montreal, Québec, Canada.
⁵¹ EEG and Epilepsy Unit, Geneva, Switzerland.
⁵² The Florey Institute of Neuroscience and Mental Health, Austin Campus, Heidelberg, Victoria, Australia.
⁵³ Department of Neuroscience, Monash University, Melbourne, Victoria, Australia.
⁵⁴ Alfred Health, Melbourne, Victoria, Australia.
⁵⁵ Radiology and Research Administration, Henry Ford Health System, Detroit, Michigan, USA.
⁵⁶ School of Electrical and Computer Engineering, College of Engineering, University of Tehran, Tehran, Iran.
⁵⁷ South African Medical Research Council Unit on Risk & Resilience in Mental Disorders, Dept of Psychiatry & Neuroscience Institute, University of Cape Townon Risk & Resilience in Mental Disorders, Cape Town, South Africa.
⁵⁸ Pediatric Neurology and Muscular Diseases Unit, IRCCS Istituto 'G. Gaslini', Genova, Italy.
⁵⁹ Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, University of Genova, Italy.
⁶⁰ School of Computing, Newcastle University, Newcastle upon Tyne, UK.
⁶¹ Institute of Translational and Clinical Research, Newcastle University, Newcastle upon Tyne, UK.
⁶² Department of Medicine, Royal Melbourne Hospital, University of Melbourne, Parkville, Victoria, UK.
⁶³ Department of Neuropsychiatry, Royal Melbourne Hospital, Parkville, Victoria, Australia.
⁶⁴ Department of Neurology, Royal Melbourne Hospital, Melbourne, Victoria, Australia.
⁶⁵ Institute of Experimental Epileptology and Cognition Research, University of Bonn, Bonn, Germany.
⁶⁶ Cognitive Science Department, School of Informatics, Xiamen University, Xiamen, China.
⁶⁷ Department of Psychiatry, University of California San Diego, La Jolla, California, USA.

PMID: 32468614
PMCID: PMC8675408
DOI: 10.1002/hbm.25037

Abstract

Epilepsy is a common and serious neurological disorder, with many different constituent conditions characterized by their electro clinical, imaging, and genetic features. MRI has been fundamental in advancing our understanding of brain processes in the epilepsies. Smaller-scale studies have identified many interesting imaging phenomena, with implications both for understanding pathophysiology and improving clinical care. Through the infrastructure and concepts now well-established by the ENIGMA Consortium, ENIGMA-Epilepsy was established to strengthen epilepsy neuroscience by greatly increasing sample sizes, leveraging ideas and methods established in other ENIGMA projects, and generating a body of collaborating scientists and clinicians to drive forward robust research. Here we review published, current, and future projects, that include structural MRI, diffusion tensor imaging (DTI), and resting state functional MRI (rsfMRI), and that employ advanced methods including structural covariance, and event-based modeling analysis. We explore age of onset- and duration-related features, as well as phenomena-specific work focusing on particular epilepsy syndromes or phenotypes, multimodal analyses focused on understanding the biology of disease progression, and deep learning approaches. We encourage groups who may be interested in participating to make contact to further grow and develop ENIGMA-Epilepsy.

Keywords: DTI; MRI; covariance; deep learning; event-based modeling; gene expression; genetics; imaging; quantitative; rsfMRI.

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Figures

**FIGURE 1**
Organizational diagram of ENIGMA‐Epilepsy. The flowchart on the left shows the group set up, illustrating source of data used in subsequent studies. The current workflow is illustrated on the right. ILAE, International League Against Epilepsy; MOU, Memorandum of Understanding

**FIGURE 2**
An illustration of results from the first ENIGMA‐Epilepsy study, of brain structural changes in epilepsy using quantitative structural MRI. Cohen's d effect size estimates for case–control differences in cortical thickness, across the (a) all‐epilepsies, (b) mesial temporal lobe epilepsies with left hippocampal sclerosis (c) mesial temporal lobe epilepsies with right hippocampal sclerosis, (d) idiopathic generalized epilepsies, and (e) all‐other‐epilepsies groups. Cohen's d effect sizes were extracted using multiple linear regressions, and pooled across research centers using random‐effects meta‐analysis. Cortical structures with p‐values <1.49 × 10⁻⁴ are shown in heatmap colors; strength of heat map is determined by the size of the Cohen's d (d < 0 = blue, d > 0 = yellow/red). HS, hippocampal sclerosis. From Whelan et al.,

**FIGURE 3**
White matter abnormalities across different epilepsy syndromes in adults. Top: FA and MD across all patients with epilepsy. BCC, body of corpus callosum, GCC, genu of corpus callosum; SCC, splenium of corpus callosum; ACR, anterior corona radiata; ALIC, anterior limb of internal capsule; CGC, cingulum (cingulate gyrus); CGH, cingulum (hippocampal); CST, corticospinal tract; EC, external capsule; FX.ST, fornix (stria terminalis); PCR, posterior corona radiata; PLIC, posterior limb of internal capsule; PTR, posterior thalamic radiation; RLIC, rentrolenticular part of internal capsule; SCR, superior corona radiata; SFO, superior fronto‐occipital fasciculus; SLF, superior longitudinal fasciculus; SS, sagittal stratum; TAP, tapetum; UNC, uncinate. Bottom: Radar plots of FA (left) and MD (right) across epilepsy syndromes

**FIGURE 4**
Gene expression and brain maps. The study strategy leading to implication of microglia in cortical thinning. eQTL, expression quantitative trait loci; ILAE, International League against Epilepsy; EpiPGX, Epilepsy Pharmacogenomics: delivering biomarkers for clinical use project, www.epipgx.eu; LD, linkage disequilibrium; LPS, lipopolysaccharide

See this image and copyright information in PMC

References

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The ENIGMA-Epilepsy working group: Mapping disease from large data sets

Affiliations

The ENIGMA-Epilepsy working group: Mapping disease from large data sets

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