title: Abnormal cognitive network interactions in Lennox-Gastaut syndrome: A potential mechanism of epileptic encephalopathy.
abstract: In patients with Lennox-Gastaut syndrome (LGS), recurrent epileptic activity is thought to contribute to impaired cognition (epileptic encephalopathy). Using concurrent electroencephalography-functional magnetic resonance imaging (EEG-fMRI), we recently showed that epileptiform discharges in LGS recruit large-scale networks that normally support key cognitive processes. In LGS, given that epileptic activity engages cognitive networks, and cognition is pervasively impaired, we hypothesized that cognitive network interactions in LGS are persistently abnormal.
  
  
  
  We studied 15 LGS patients (mean age ± 1 standard deviation [SD] = 28.7 ± 10.6 years) and 17 healthy controls (mean age ± 1 SD = 27.6 ± 6.6 years) using task-free EEG-fMRI. Four networks of interest (default-mode, dorsal attention, executive control, and anterior salience) were defined using group-level independent components analysis (ICA). Functional connectivity within and between networks was determined for each subject, and then LGS network interactions were compared to network behavior in the control group. To test whether group differences were present in periods without scalp-detectable epileptiform discharges (i.e., persistent), we separately assessed discharge-affected and discharge-unaffected epochs in six patients with sufficient data for this analysis.
  
  
  
  In LGS, cognitive networks showed (1) reduced within-network integration, including weaker connectivity within the default-mode network, and (2) impaired between-network segregation, including stronger connectivity between the default-mode and dorsal attention networks. Abnormal interactions were present during fMRI periods with and without discharges, indicating that impaired network behavior may endure during periods without scalp-detectable epileptic activity.
  
  
  
  In LGS, cognitive network interactions are persistently abnormal. Given that cognition typically worsens with the onset of LGS, and may improve after seizure control, our findings are consistent with the hypothesis that the epileptic process in LGS may initiate and perhaps sustain abnormal network behavior. We propose that epileptic encephalopathy may be a consequence of persistently disrupted cognitive network interactions.
authors.affiliation: Department of Medicine, The University of Melbourne, Heidelberg, Victoria, Australia.
authors.forename: Aaron E L
authors.initials: AE
authors.lastname: Warren
authors.affiliation: Department of Medicine, The University of Melbourne, Heidelberg, Victoria, Australia.|The Florey Institute of Neuroscience and Mental Health, Heidelberg, Victoria, Australia.
authors.forename: David F
authors.initials: DF
authors.lastname: Abbott
authors.affiliation: The Florey Institute of Neuroscience and Mental Health, Heidelberg, Victoria, Australia.|Department of Neurology, Austin Health, Heidelberg, Victoria, Australia.
authors.forename: David N
authors.initials: DN
authors.lastname: Vaughan
authors.affiliation: Department of Medicine, The University of Melbourne, Heidelberg, Victoria, Australia.|The Florey Institute of Neuroscience and Mental Health, Heidelberg, Victoria, Australia.|Department of Neurology, Austin Health, Heidelberg, Victoria, Australia.
authors.forename: Graeme D
authors.initials: GD
authors.lastname: Jackson
authors.affiliation: Department of Medicine, The University of Melbourne, Heidelberg, Victoria, Australia.|The Florey Institute of Neuroscience and Mental Health, Heidelberg, Victoria, Australia.|Department of Neurology, Austin Health, Heidelberg, Victoria, Australia.
authors.forename: John S
authors.initials: JS
authors.lastname: Archer
mesh_terms: D000293:Adolescent; D000328:Adult; D001921:Brain / Q000000981:diagnostic imaging / Q000473:pathology* / Q000503:physiopathology; D001931:Brain Mapping; D016022:Case-Control Studies; D002648:Child; D003072:Cognition Disorders / Q000000981:diagnostic imaging / Q000209:etiology* / Q000473:pathology*; D004569:Electroencephalography; D005260:Female; D006801:Humans; D065768:Lennox Gastaut Syndrome / Q000150:complications*; D008279:Magnetic Resonance Imaging; D008297:Male; D025341:Principal Component Analysis; D055815:Young Adult
keywords: Epileptic encephalopathy; ICA; Lennox-Gastaut syndrome; Networks; fMRI