Abnormal cognitive network interactions in Lennox‐Gastaut syndrome: A potential mechanism of epileptic encephalopathy

Abstract

SUMMARYObjective: 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 largescale 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 AE 1 standard deviation [SD] = 28.7 AE 10.6 years) and 17 healthy controls (mean age AE 1 SD = 27.6 AE 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 defaultmode 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.

Thalamocortical functional connectivity in Lennox–Gastaut syndrome is abnormally enhanced in executive‐control and default‐mode networks

“…We previously found that widespread areas of the executive‐control and default‐mode networks are recruited during tonic seizures and epileptiform discharges in LGS. Additionally, LGS patients show abnormal functional connectivity within the default‐mode network, and between the default‐mode and executive‐control networks . Considered together, these results raise the hypothesis that the expression of epileptic activity in thalamus–executive‐control and thalamus–default‐mode circuits disrupts normal connectivity, potentially contributing to impaired cognition in LGS.…”

“…Task‐free fMRI data were acquired as part of a larger multisite study of LGS . All subjects were scanned using T 2 *‐weighted gradient‐recalled echo‐planar image sequences (for detailed acquisition parameters, refer to Methods ).…”

“…All subjects were scanned using T 2 *‐weighted gradient‐recalled echo‐planar image sequences (for detailed acquisition parameters, refer to Methods ). Thirty‐one subjects (15 patients and 16 controls) were scanned using a 3‐T GE Signa LX MRI, as we have previously described . A further 15 subjects (five patients and 10 controls) were scanned using a 3‐T Siemens Trio MRI utilizing a similar imaging protocol.…”

“…We previously observed that patients with LGS show persistently disrupted corticocortical functional connectivity, as assessed using task‐free fMRI by measuring low‐frequency temporal correlations in the blood oxygen level–dependent signal. Specifically, we examined interactions among cortical networks known to be involved in the expression of epileptic activity in LGS, and found reduced functional connectivity within the default‐mode network, and abnormally enhanced connectivity between the default‐mode and executive‐control networks . In the healthy brain, the thalamus plays a critical role in mediating normal interactions among these cortical networks .…”

Interictal activity is an important contributor to abnormal intrinsic network connectivity in paediatric focal epilepsy

“…The increased rate of epileptiform discharges has been associated with lower performance on cognitive functioning and attention-sensitive tasks [Kasteleijn-Nolst et al, 1987, 1988Ebus et al, 2012;Nicolai et al, 2012], which is dependent on when and where the activity occurs [Kleen et al, 2013]. Non-transient effects of IEDs are less well characterised although there is some evidence that a worse cognitive outcome in the long term is related to increased frequency of epileptic discharges in focal epilepsies [S anchez Fern andez et al, 2015] and at onset of Lennox-Gastaut syndrome [Warren et al, 2016].…”