Andre Altmann1, Mina Ryten2, Martina Di Nunzio3, Teresa Ravizza3, Daniele Tolomeo3, Regina H Reynolds2, Alyma Somani4, Marco Bacigaluppi5, Valentina Iori3, Edoardo Micotti3, Rossella Di Sapia3, Milica Cerovic3, Eleonora Palma6, Gabriele Ruffolo6, Juan A Botía2,7, Julie Absil8, Saud Alhusaini9,10, Marina K M Alvim11, Pia Auvinen12,13, Nuria Bargallo14,15, Emanuele Bartolini16,17, Benjamin Bender18, Felipe P G Bergo11, Tauana Bernardes11, Andrea Bernasconi19, Neda Bernasconi19, Boris C Bernhardt20, Karen Blackmon21, Barbara Braga11, Maria Eugenia Caligiuri22, Anna Calvo14, Chad Carlson23,24, Sarah J A Carr25, Gianpiero L Cavalleri9,26, Fernando Cendes11, Jian Chen27, Shuai Chen28,29, Andrea Cherubini22, Luis Concha30, Philippe David8, Norman Delanty9,26,31, Chantal Depondt32, Orrin Devinsky33, Colin P Doherty26,34, Martin Domin35, Niels K Focke36,37, Sonya Foley38, Wendy Franca11, Antonio Gambardella22,39, Renzo Guerrini16, Khalid Hamandi38,40, Derrek P Hibar41, Dmitry Isaev41, Graeme D Jackson42,43, Neda Jahanshad41, Reetta Kälviäinen12,13, Simon S Keller44, Peter Kochunov45, Raviteja Kotikalapudi18,35,36, Magdalena A Kowalczyk42, Ruben Kuzniecky46, Patrick Kwan47, Angelo Labate22,39, Soenke Langner35, Matteo Lenge16, Min Liu19, Pascal Martin36, Mario Mascalchi48, Stefano Meletti49, Marcia E Morita-Sherman11,50, Terence J O'Brien47,51, Jose C Pariente14, Mark P Richardson25,52, Raul Rodriguez-Cruces20,30, Christian Rummel53, Taavi Saavalainen13,54, Mira K Semmelroch42,43, Mariasavina Severino55, Pasquale Striano56, Thomas Thesen23, Rhys H Thomas57, Manuela Tondelli50, Domenico Tortora55, Anna Elisabetta Vaudano49, Lucy Vivash47,58, Felix von Podewils59, Jan Wagner60, Bernd Weber61, Roland Wiest53, Clarissa L Yasuda11, Guohao Zhang62, Junsong Zhang28,29, Costin Leu63,64,65, Andreja Avbersek64, Maria Thom4,65, Christopher D Whelan9,41, Paul Thompson41, Carrie R McDonald66,67, Annamaria Vezzani3, Sanjay M Sisodiya65,68. 1. Centre for Medical Image Computing, University College London, London, UK. 2. Department of Neurodegenerative Disease, UCL Queen Square Institute of Neurology, London, UK. 3. Department of Neuroscience, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milan, Italy. 4. Division of Neuropathology, UCL Queen Square Institute of Neurology, London, UK. 5. Department of Neurology, San Raffaele Scientific Institute and Vita Salute San Raffaele University, Milan, Italy. 6. Department of Physiology and Pharmacology, Sapienza University of Rome, Rome, Italy. 7. Departamento de Ingeniería de la Información y las Comunicaciones, Universidad de Murcia, Murcia, Spain. 8. Department of Radiology, Hôpital Erasme, Universite Libre de Bruxelles, Brussels, Belgium. 9. Department of Molecular and Cellular Therapeutics, Royal College of Surgeons in Ireland, Dublin, Ireland. 10. Neurology Department, Yale University School of Medicine, New Haven, CT, USA. 11. Department of Neurology, University of Campinas, Campinas, Brazil. 12. Epilepsy Center, Department of Neurology, Kuopio University, Kuopio, Finland. 13. Institute of Clinical Medicine, Neurology, University of Eastern Finland, Kuopio, Finland. 14. Magnetic Resonance Image Core Facility, IDIBAPS, Barcelona, Spain. 15. Centre de Diagnostic Per la Imatge (CDIC), Hospital Clinic, Barcelona, Spain. 16. Pediatric Neurology Unit, Children's Hospital A. Meyer-University of Florence, Florence, Italy. 17. Neurology Unit, USL Centro Toscana, Nuovo Ospedale Santo Stefano, Prato, Italy. 18. Department of Diagnostic and Interventional Neuroradiology, University of Tübingen, Tübingen, Germany. 19. Neuroimaging of Epilepsy Laboratory, Montreal Neurological Institute and Hospital, McGill University, Montreal, Quebec, Canada. 20. Multimodal Imaging and Connectome Analysis Lab, Montreal Neurological Institute and Hospital, McGill University, Montreal, Quebec, Canada. 21. Psychiatry and Psychology, Mayo Clinic, Jacksonville, FL, USA. 22. Neuroscience Research Center, Department of Medical and Surgical Sciences, University "Magna Graecia" of Catanzaro, Catanzaro, Italy. 23. Comprehensive Epilepsy Center, Department of Neurology, New York University School of Medicine, New York, New York, USA. 24. Department of Neurology, Medical College of Wisconsin, Milwaukee, Wisconsin, USA. 25. Department of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK. 26. FutureNeuro Research Centre, RCSI, Dublin, Ireland. 27. Department of Computer Science and Engineering, The Ohio State University, Columbus, Ohio, USA. 28. Cognitive Science Department, Xiamen University, Xiamen, China. 29. Fujian Key Laboratory of the Brain-like Intelligent Systems, Xiamen, China. 30. Instituto de Neurobiología, Universidad Nacional Autónoma de México, Querétaro, Mexico. 31. Division of Neurology, Beaumont Hospital, Dublin 9, Ireland. 32. Department of Neurology, Hôpital Erasme, Universite Libre de Bruxelles, Brussels, Belgium. 33. Department of Neurology, Langone School of Medicine, New York University, New York, NY, USA. 34. School of Medicine, Trinity College Dublin, Dublin, Ireland. 35. Functional Imaging Unit, Institute of Diagnostic Radiology and Neuroradiology, University Medicine Greifswald, Greifswald, Germany. 36. Department of Neurology and Epileptology, Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany. 37. Department of Clinical Neurophysiology, University Medicine Göttingen, Göttingen, Germany. 38. The Welsh Epilepsy Unit, Department of Neurology, University Hospital of Wales, Cardiff, UK. 39. Institute of Neurology, University "Magna Graecia", Catanzaro, Italy. 40. Cardiff University Brain Research Imaging Centre, School of Psychology, Cardiff University, Cardiff, UK. 41. Imaging Genetics Center, Mark and Mary Stevens Neuroimaging and Informatics Institute, University of Southern California, Los Angeles, California, USA. 42. The Florey Institute of Neuroscience and Mental Health, Austin Campus, Melbourne, Victoria, Australia. 43. Florey Department of Neuroscience and Mental Health, The University of Melbourne, Melbourne, Victoria, Australia. 44. Institute of Systems, Molecular and Integrative Biology, University of Liverpool, Liverpool, UK. 45. Maryland Psychiatric Research Center, Department of Psychiatry, University of Maryland School of Medicine, Baltimore, Maryland, USA. 46. Department of Neurology, Zucker Hofstra School of Medicine, New York, New York, USA. 47. Department of Neuroscience, Central Clinical School, Monash University, Melbourne, Victoria, Australia. 48. "Mario Serio" Department of Experimental and Clinical Biomedical Sciences, University of Florence, Florence, Italy. 49. Department of Biomedical, Metabolic, and Neural Science, University of Modena and Reggio Emilia, NOCSE Hospital, Modena, Italy. 50. Cleveland Clinic Neurological Institute, Cleveland, USA. 51. The Department of Medicine (The Royal Melbourne Hospital), The University of Melbourne, Parkville, Victoria, Australia. 52. Department of Neurology, King's College Hospital, London, UK. 53. Support Center for Advanced Neuroimaging (SCAN), University Institute for Diagnostic and Interventional Neuroradiology, Inselspital, University of Bern, Bern, Switzerland. 54. Medical Imaging Unit, Central Finland Central Hospital, Jyväskylä, Finland. 55. Neuroradiology Unit, Department of Head and Neck and Neurosciences, Istituto Giannina Gaslini, Genoa, Italy. 56. Pediatric Neurology and Muscular Diseases Unit, Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, University of Genoa, Genoa, Italy. 57. Institute of Translational and Clinical Research, Newcastle University, Newcastle upon Tyne, UK. 58. Melbourne Brain Centre, Department of Medicine, University of Melbourne, Parkville, Victoria, Australia. 59. Department of Neurology, University Medicine Greifswald, Greifswald, Germany. 60. Department of Neurology, University of Ulm and Universitäts- and Rehabilitationskliniken Ulm, Ulm, Germany. 61. Institute of Experimental Epileptology and Cognition Research, University of Bonn, Bonn, Germany. 62. Department of Computer Science and Electrical Engineering, University of Maryland, Baltimore County, Baltimore, Maryland, USA. 63. Genomic Medicine Institute, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA. 64. Stanley Center for Psychiatric Research, Broad Institute of Harvard and MIT, Cambridge, Massachusetts, USA. 65. Department of Clinical and Experimental Epilepsy, UCL Queen Square Institute of Neurology, London, UK. 66. Multimodal Imaging Laboratory, University of California San Diego, San Diego, California, USA. 67. Department of Psychiatry, University of California San Diego, San Diego, California, USA. 68. Chalfont Centre for Epilepsy, Bucks, UK.
Abstract
AIMS: The causes of distinct patterns of reduced cortical thickness in the common human epilepsies, detectable on neuroimaging and with important clinical consequences, are unknown. We investigated the underlying mechanisms of cortical thinning using a systems-level analysis. METHODS: Imaging-based cortical structural maps from a large-scale epilepsy neuroimaging study were overlaid with highly spatially resolved human brain gene expression data from the Allen Human Brain Atlas. Cell-type deconvolution, differential expression analysis and cell-type enrichment analyses were used to identify differences in cell-type distribution. These differences were followed up in post-mortem brain tissue from humans with epilepsy using Iba1 immunolabelling. Furthermore, to investigate a causal effect in cortical thinning, cell-type-specific depletion was used in a murine model of acquired epilepsy. RESULTS: We identified elevated fractions of microglia and endothelial cells in regions of reduced cortical thickness. Differentially expressed genes showed enrichment for microglial markers and, in particular, activated microglial states. Analysis of post-mortem brain tissue from humans with epilepsy confirmed excess activated microglia. In the murine model, transient depletion of activated microglia during the early phase of the disease development prevented cortical thinning and neuronal cell loss in the temporal cortex. Although the development of chronic seizures was unaffected, the epileptic mice with early depletion of activated microglia did not develop deficits in a non-spatial memory test seen in epileptic mice not depleted of microglia. CONCLUSIONS: These convergent data strongly implicate activated microglia in cortical thinning, representing a new dimension for concern and disease modification in the epilepsies, potentially distinct from seizure control.
AIMS: The causes of distinct patterns of reduced cortical thickness in the common human epilepsies, detectable on neuroimaging and with important clinical consequences, are unknown. We investigated the underlying mechanisms of cortical thinning using a systems-level analysis. METHODS: Imaging-based cortical structural maps from a large-scale epilepsy neuroimaging study were overlaid with highly spatially resolved human brain gene expression data from the Allen Human Brain Atlas. Cell-type deconvolution, differential expression analysis and cell-type enrichment analyses were used to identify differences in cell-type distribution. These differences were followed up in post-mortem brain tissue from humans with epilepsy using Iba1 immunolabelling. Furthermore, to investigate a causal effect in cortical thinning, cell-type-specific depletion was used in a murine model of acquired epilepsy. RESULTS: We identified elevated fractions of microglia and endothelial cells in regions of reduced cortical thickness. Differentially expressed genes showed enrichment for microglial markers and, in particular, activated microglial states. Analysis of post-mortem brain tissue from humans with epilepsy confirmed excess activated microglia. In the murine model, transient depletion of activated microglia during the early phase of the disease development prevented cortical thinning and neuronal cell loss in the temporal cortex. Although the development of chronic seizures was unaffected, the epileptic mice with early depletion of activated microglia did not develop deficits in a non-spatial memory test seen in epileptic mice not depleted of microglia. CONCLUSIONS: These convergent data strongly implicate activated microglia in cortical thinning, representing a new dimension for concern and disease modification in the epilepsies, potentially distinct from seizure control.
Authors: Gail S Bell; Aidan Neligan; Christina Giavasi; Mark R Keezer; Jan Novy; Janet L Peacock; Anthony L Johnson; David M G Goodridge; Simon D Shorvon; Josemir W Sander Journal: J Neurol Neurosurg Psychiatry Date: 2016-01-18 Impact factor: 10.154
Authors: Monica R P Elmore; Allison R Najafi; Maya A Koike; Nabil N Dagher; Elizabeth E Spangenberg; Rachel A Rice; Masashi Kitazawa; Bernice Matusow; Hoa Nguyen; Brian L West; Kim N Green Journal: Neuron Date: 2014-04-16 Impact factor: 17.173
Authors: Inge R Holtman; Divya D Raj; Jeremy A Miller; Wandert Schaafsma; Zhuoran Yin; Nieske Brouwer; Paul D Wes; Thomas Möller; Marie Orre; Willem Kamphuis; Elly M Hol; Erik W G M Boddeke; Bart J L Eggen Journal: Acta Neuropathol Commun Date: 2015-05-23 Impact factor: 7.801
Authors: Christopher D Whelan; Andre Altmann; Juan A Botía; Neda Jahanshad; Derrek P Hibar; Julie Absil; Saud Alhusaini; Marina K M Alvim; Pia Auvinen; Emanuele Bartolini; Felipe P G Bergo; Tauana Bernardes; Karen Blackmon; Barbara Braga; Maria Eugenia Caligiuri; Anna Calvo; Sarah J Carr; Jian Chen; Shuai Chen; Andrea Cherubini; Philippe David; Martin Domin; Sonya Foley; Wendy França; Gerrit Haaker; Dmitry Isaev; Simon S Keller; Raviteja Kotikalapudi; Magdalena A Kowalczyk; Ruben Kuzniecky; Soenke Langner; Matteo Lenge; Kelly M Leyden; Min Liu; Richard Q Loi; Pascal Martin; Mario Mascalchi; Marcia E Morita; Jose C Pariente; Raul Rodríguez-Cruces; Christian Rummel; Taavi Saavalainen; Mira K Semmelroch; Mariasavina Severino; Rhys H Thomas; Manuela Tondelli; Domenico Tortora; Anna Elisabetta Vaudano; Lucy Vivash; Felix von Podewils; Jan Wagner; Bernd Weber; Yi Yao; Clarissa L Yasuda; Guohao Zhang; Nuria Bargalló; Benjamin Bender; Neda Bernasconi; Andrea Bernasconi; Boris C Bernhardt; Ingmar Blümcke; Chad Carlson; Gianpiero L Cavalleri; Fernando Cendes; Luis Concha; Norman Delanty; Chantal Depondt; Orrin Devinsky; Colin P Doherty; Niels K Focke; Antonio Gambardella; Renzo Guerrini; Khalid Hamandi; Graeme D Jackson; Reetta Kälviäinen; Peter Kochunov; Patrick Kwan; Angelo Labate; Carrie R McDonald; Stefano Meletti; Terence J O'Brien; Sebastien Ourselin; Mark P Richardson; Pasquale Striano; Thomas Thesen; Roland Wiest; Junsong Zhang; Annamaria Vezzani; Mina Ryten; Paul M Thompson; Sanjay M Sisodiya Journal: Brain Date: 2018-02-01 Impact factor: 13.501
Authors: Dong Ah Lee; Bong Soo Park; Junghae Ko; Si Hyung Park; Yoo Jin Lee; Il Hwan Kim; Jin Han Park; Kang Min Park Journal: Epilepsia Open Date: 2022-03-27
Authors: Elisha Hayden; Holly Holliday; Rebecca Lehmann; Aaminah Khan; Maria Tsoli; Benjamin S Rayner; David S Ziegler Journal: Cancers (Basel) Date: 2021-12-13 Impact factor: 6.639
Authors: Sanjay M Sisodiya; Christopher D Whelan; Sean N Hatton; Khoa Huynh; Andre Altmann; Mina Ryten; Annamaria Vezzani; Maria Eugenia Caligiuri; Angelo Labate; Antonio Gambardella; Victoria Ives-Deliperi; Stefano Meletti; Brent C Munsell; Leonardo Bonilha; Manuela Tondelli; Michael Rebsamen; Christian Rummel; Anna Elisabetta Vaudano; Roland Wiest; Akshara R Balachandra; Núria Bargalló; Emanuele Bartolini; Andrea Bernasconi; Neda Bernasconi; Boris Bernhardt; Benoit Caldairou; Sarah J A Carr; Gianpiero L Cavalleri; Fernando Cendes; Luis Concha; Patricia M Desmond; Martin Domin; John S Duncan; Niels K Focke; Renzo Guerrini; Khalid Hamandi; Graeme D Jackson; Neda Jahanshad; Reetta Kälviäinen; Simon S Keller; Peter Kochunov; Magdalena A Kowalczyk; Barbara A K Kreilkamp; Patrick Kwan; Sara Lariviere; Matteo Lenge; Seymour M Lopez; Pascal Martin; Mario Mascalchi; José C V Moreira; Marcia E Morita-Sherman; Heath R Pardoe; Jose C Pariente; Kotikalapudi Raviteja; Cristiane S Rocha; Raúl Rodríguez-Cruces; Margitta Seeck; Mira K H G Semmelroch; Benjamin Sinclair; Hamid Soltanian-Zadeh; Dan J Stein; Pasquale Striano; Peter N Taylor; Rhys H Thomas; Sophia I Thomopoulos; Dennis Velakoulis; Lucy Vivash; Bernd Weber; Clarissa Lin Yasuda; Junsong Zhang; Paul M Thompson; Carrie R McDonald Journal: Hum Brain Mapp Date: 2020-05-29 Impact factor: 5.038