title: Predicting novel histopathological microlesions in human epileptic brain through transcriptional clustering.
abstract: Although epilepsy is associated with a variety of abnormalities, exactly why some brain regions produce seizures and others do not is not known. We developed a method to identify cellular changes in human epileptic neocortex using transcriptional clustering. A paired analysis of high and low spiking tissues recorded in vivo from 15 patients predicted 11 cell-specific changes together with their 'cellular interactome'. These predictions were validated histologically revealing millimetre-sized 'microlesions' together with a global increase in vascularity and microglia. Microlesions were easily identified in deeper cortical layers using the neuronal marker NeuN, showed a marked reduction in neuronal processes, and were associated with nearby activation of MAPK/CREB signalling, a marker of epileptic activity, in superficial layers. Microlesions constitute a common, undiscovered layer-specific abnormality of neuronal connectivity in human neocortex that may be responsible for many 'non-lesional' forms of epilepsy. The transcriptional clustering approach used here could be applied more broadly to predict cellular differences in other brain and complex tissue disorders.
authors.affiliation: 1 Department of Neurology and Rehabilitation, University of Illinois at Chicago, Chicago, IL 60612, USA 2 The Centre for Molecular Medicine and Genetics, Wayne State University School of Medicine, Detroit, MI 48201, USA.
authors.forename: Fabien
authors.initials: F
authors.lastname: Dachet
authors.affiliation: 2 The Centre for Molecular Medicine and Genetics, Wayne State University School of Medicine, Detroit, MI 48201, USA.
authors.forename: Shruti
authors.initials: S
authors.lastname: Bagla
authors.affiliation: 3 Department of Chemistry and Biochemistry, Montana State University, Bozeman, MT 59717, USA.
authors.forename: Gal
authors.initials: G
authors.lastname: Keren-Aviram
authors.affiliation: 2 The Centre for Molecular Medicine and Genetics, Wayne State University School of Medicine, Detroit, MI 48201, USA.
authors.forename: Andrew
authors.initials: A
authors.lastname: Morton
authors.affiliation: 2 The Centre for Molecular Medicine and Genetics, Wayne State University School of Medicine, Detroit, MI 48201, USA.
authors.forename: Karina
authors.initials: K
authors.lastname: Balan
authors.affiliation: 1 Department of Neurology and Rehabilitation, University of Illinois at Chicago, Chicago, IL 60612, USA.
authors.forename: Laleh
authors.initials: L
authors.lastname: Saadat
authors.affiliation: 1 Department of Neurology and Rehabilitation, University of Illinois at Chicago, Chicago, IL 60612, USA 4 Department of Pathology, University of Illinois at Chicago, Chicago, IL 60612, USA.
authors.forename: Tibor
authors.initials: T
authors.lastname: Valyi-Nagy
authors.affiliation: 5 Department of Pathology; Wayne State University School of Medicine, Detroit, MI 48201, USA.
authors.forename: William
authors.initials: W
authors.lastname: Kupsky
authors.affiliation: 1 Department of Neurology and Rehabilitation, University of Illinois at Chicago, Chicago, IL 60612, USA 2 The Centre for Molecular Medicine and Genetics, Wayne State University School of Medicine, Detroit, MI 48201, USA.
authors.forename: Fei
authors.initials: F
authors.lastname: Song
authors.affiliation: 3 Department of Chemistry and Biochemistry, Montana State University, Bozeman, MT 59717, USA.
authors.forename: Edward
authors.initials: E
authors.lastname: Dratz
authors.affiliation: 1 Department of Neurology and Rehabilitation, University of Illinois at Chicago, Chicago, IL 60612, USA 2 The Centre for Molecular Medicine and Genetics, Wayne State University School of Medicine, Detroit, MI 48201, USA.
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Loeb
mesh_terms: D000293:Adolescent; D000328:Adult; D015415:Biomarkers; D001921:Brain / Q000473:pathology*; D002648:Child; D002675:Child, Preschool; D016000:Cluster Analysis; D004569:Electroencephalography; D004827:Epilepsy / Q000473:pathology* / Q000601:surgery; D005260:Female; D006801:Humans; D007223:Infant; D008297:Male; D046228:Microarray Analysis; D008875:Middle Aged; D019579:Neocortex / Q000473:pathology; D019635:Neurosurgical Procedures; D012313:RNA / Q000235:genetics; D014158:Transcription, Genetic; D055815:Young Adult
chemical_list: D015415:Biomarkers; D012313:RNA
keywords: epilepsy genetics; epilepsy surgery; localization-related epilepsy; refractory epilepsy; transcriptomics