OBJECTIVE: 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.
METHODS: 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.
RESULTS: 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.
SIGNIFICANCE: 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.