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

Abstract

Rolandic epilepsy (RE) is the most common idiopathic focal childhood epilepsy syndrome, characterized by sleep-activated epileptiform spikes and seizures and cognitive deficits in school age children. Recent evidence suggests that this disease may be caused by disruptions to the Rolandic thalamocortical circuit, resulting in both an abundance of epileptiform spikes and a paucity of sleep spindles in the Rolandic cortex during non-rapid eye movement sleep (NREM); electrographic features linked to seizures and cognitive symptoms, respectively. The neuronal mechanisms that support the competitive shared thalamocortical circuitry between pathological epileptiform spikes and physiological sleep spindles are not well-understood. In this study we introduce a computational thalamocortical model for the sleep-activated epileptiform spikes observed in RE. The cellular and neuronal circuits of this model incorporate recent experimental observations in RE, and replicate the electrophysiological features of RE. Using this model, we demonstrate that: (1) epileptiform spikes can be triggered and promoted by either a reduced NMDA current or h-type current; and (2) changes in inhibitory transmission in the thalamic reticular nucleus mediates an antagonistic dynamic between epileptiform spikes and spindles. This work provides the first computational model that both recapitulates electrophysiological features and provides a mechanistic explanation for the thalamocortical switch between the pathological and physiological electrophysiological rhythms observed during NREM sleep in this common epileptic encephalopathy.

Diazepam induced sleep spindle increase correlates with cognitive recovery in a child with epileptic encephalopathy

“…Corticothalamic neurons send glutamatergic inputs back to the thalamus, producing a feedback loop regulated primarily by GABAergic and glutamatergic neurotransmission [ 54 ]. Given the important role that spindles have for learning and memory consolidation [ 17 – 19 ] their disruption could provide a mechanistic biomarker for cognitive dysfunction in epileptic encephalopathies [ 55 ].…”

Changing Agendas on Sleep, Treatment and Learning in Epilepsy (CASTLE) Sleep-E: a protocol for a randomised controlled trial comparing an online behavioural sleep intervention with standard care in children with Rolandic epilepsy

“…Epilepsy in children (5–<13 years) accounts for the annual loss of 2.6 million disability-adjusted life years, equivalent to 1.8% of the global burden of disease among children and adolescents 2. Rolandic epilepsy (RE) is the most common childhood epilepsy 3…”

“…2 Rolandic epilepsy (RE) is the most common childhood epilepsy. 3 In the UK, RE has a stable crude incidence rate of 5 in 100 000 children (<16 years) or 542 new cases annually. 4 Concurrent neurodevelopmental disorders are very common (35%).…”

Changing Agendas on Sleep, Treatment and Learning in Epilepsy (CASTLE) Sleep-E: A protocol for a randomised controlled trial comparing an online behavioural sleep intervention with standard care in children with Rolandic epilepsy

“…2 Rolandic Epilepsy (RE) is the most common childhood epilepsy. 3 In the UK, RE has a stable crude incidence rate of 5 in 100 000 children (<16 years) or 542 new cases annually. 4 Concurrent neuro-developmental disorders are very common (35 %).…”

“…Up to four weeks flexibility between consent and randomisation to allow delivery of actigraph and iPad 2. Randomisation may be performed once two weeks of actigraphy and the minimum dataset are complete 3. Electro-encephalogram (EEG)4 Optional trial component: Consenting participants are interviewed within 3 weeks of follow up visits 3 and 4…”