Focal Sleep Spindle Deficits Reveal Focal Thalamocortical Dysfunction and Predict Cognitive Deficits in Sleep Activated Developmental Epilepsy

Abstract

Childhood epilepsy with centrotemporal spikes (CECTS) is the most common focal epilepsy syndrome, yet the cause of this disease remains unknown. Now recognized as a mild epileptic encephalopathy, children exhibit sleep-activated focal epileptiform discharges and cognitive difficulties during the active phase of the disease. The association between the abnormal electrophysiology and sleep suggests disruption to thalamocortical circuits. Thalamocortical circuit dysfunction resulting in pathologic epileptiform activity could hinder the production of sleep spindles, a brain rhythm essential for memory processes. Despite this pathophysiologic connection, the relationship between spindles and cognitive symptoms in epileptic encephalopathies has not been previously evaluated. A significant challenge limiting such work has been the poor performance of available automated spindle detection methods in the setting of sharp activities, such as epileptic spikes. Here, we validate a robust new method to accurately measure sleep spindles in patients with epilepsy. We then apply this detector to a prospective cohort of male and female children with CECTS with combined high-density EEGs during sleep and cognitive testing at varying time points of disease. We show that: (1) children have a transient, focal deficit in spindles during the symptomatic phase of disease; (2) spindle rate anticorrelates with spike rate; and (3) spindle rate, but not spike rate, predicts performance on cognitive tasks. These findings demonstrate focal thalamocortical circuit dysfunction and provide a pathophysiological explanation for the shared seizures and cognitive symptoms in CECTS. Further, this work identifies sleep spindles as a potential treatment target of cognitive dysfunction in this common epileptic encephalopathy.

Computational Evidence for a Competitive Thalamocortical Model of Spikes and Spindle Activity in Rolandic Epilepsy

“…is consistent with the competitive relationship observed between spikes and spindles in patients with Rolandic epilepsy (see Figure 5 in Kramer et al, 2021).…”

“…Most recently, children with RE were reported to have focal spindle deficits in the Rolandic cortex that predicted their cognitive deficits (Kramer et al, 2021). Consistent with experimental observations in rodent models (Clementeperez et al, 2017) and cell culture (Beenhakker and Huguenard, 2009) that pathologic spikes competitively "hijack" the thalamocortical circuit that normally generates NREM sleep spindles, spindle rate anticorrelates with spike rate in RE patients (Kramer et al, 2021). As sleep spindles originate from a well-characterized thalamocortical circuit (Beenhakker and Huguenard, 2009), these findings provide a concrete pathophysiological model for RE.…”

“…Thalamic abnormalities have also been observed in related developmental epilepsies characterized by NREM sleep-activated spikes (Fernández et al, 2012(Fernández et al, , 2017. Most recently, children with RE were reported to have focal spindle deficits in the Rolandic cortex that predicted their cognitive deficits (Kramer et al, 2021). Consistent with experimental observations in rodent models (Clementeperez et al, 2017) and cell culture (Beenhakker and Huguenard, 2009) that pathologic spikes competitively "hijack" the thalamocortical circuit that normally generates NREM sleep spindles, spindle rate anticorrelates with spike rate in RE patients (Kramer et al, 2021).…”

“…Somatosensory thalamocortical neurons from the ventrobasal (VB) thalamus process sensory information delivered between the periphery and the cortex, and also modulate thalamocortical states including sleep and seizures (Kramer et al, 2021). The VB consists of the ventral posteromedial nucleus (VPM) and the ventral posterolateral nucleus (VPL) (Jones, 2007).…”

“…In this study, we introduce a new neural mass model for Rolandic epilepsy (RE-NMM) incorporating the thalamocortical circuit underlying spikes and spindles in recent human and rodent studies (Clementeperez et al, 2017;Kramer et al, 2021) and genetic findings in RE (Lemke et al, 2013;Xiong and Zhou, 2017). This model extends the existing Costa model in Costa et al (2016b) in three ways: (1) to target the dynamics of the Rolandic thalamocortical system, we include excitatory cells from the ventroposteriomedial (VPM) and ventroposteriolateral (VPL) thalamic nuclei and two types of inhibitory cells (parvocellular, PV; and somatostatin, SOM) from the reticular nucleus of the thalamus (TRN); (2) consistent with recent genetic studies in RE and idiopathic focal epilepsies (Lemke et al, 2013;Xiong and Zhou, 2017), an extra NMDA receptor-mediated current (NMDA current) is introduced in PV and SOM populations;…”