Focal Thalamocortical Circuit Dysfunction Mediates Motor and Cognitive Deficits in Developmental Epilepsy

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Project Summary / Abstract Benign epilepsy with centrotemporal spikes (BECTS) is the most common focal childhood epilepsy syndrome, characterized by a transient period of seizures and abundant epileptiform spikes arising from the sensorimotor cortex during non-REM (NREM) sleep. Recent findings indicate that BECTS is a developmental disorder with a wider range of severity than previously appreciated. In addition to seizures, children have deficits in attention and motor coordination. The motor and cognitive symptoms in BECTS exist on a spectrum of severity, clinically and genetically overlapping with severe epileptic encephalopathies, which are characterized by permanent and progressive declines in cerebral function coincident with sleep activated spikes. There are currently no proven treatment strategies to address the neuropsychological deficits in BECTS or other epileptic encephalopathies. Several lines of evidence, including our preliminary findings, suggest a dysfunction in thalamocortical circuitry drives the motor and cognitive abnormalities in BECTS. First, thalamocortical structural circuits are abnormal in BECTS. Second, children with BECTS have reduced sleep spindles, oscillations that are critical for memory consolidation during NREM sleep and generated and propagated by thalamocortical circuitry. Third, thalamocortical sensory gating is impaired in children with centrotemporal spikes, like those observed in BECTS. Effective dampening or “gating” of irrelevant sensory information prior to reaching the cortex, mediates performance on attentional tasks. Despite this evidence, the relationship between thalamocortical electrophysiology, connectivity, and cognitive symptoms in BECTS has not been investigated. The long term goal of this project is to test the hypothesis that focal thalamocortical circuit dysfunction mediates the motor and cognitive symptoms in BECTS. Our interdisciplinary team - consisting of a pediatric epileptologist, a neuropsychologist, and a computational neuroscientist – will use validated experimental paradigms and computational tools to collect and analyze multimodal data to link thalamocortical circuit abnormalities to cognitive deficits in children with BECTS. First, we will determine whether children with BECTS show abnormal sleep spindle activity that relates to impaired sleep-dependent memory consolidation. Second, we will determine whether impaired sensory gating and thalamocortical connectivity relate to impaired attention in BECTS. Third, we will test the impact of medication and closed loop auditory stimulation on thalamocortical spindles, gating, and cognitive function in BECTS. Completion of the proposal goals will represent significant progress towards understanding the pathophysiological mechanisms underlying cognitive dysfunction in BECTS, and the identification of new targets and approaches for treating cognitive deficits in BECTS and related epileptic encephalopathies. .