RT Journal Article
SR Electronic
T1 Focal Sleep Spindle Deficits Reveal Focal Thalamocortical Dysfunction and Predict Cognitive Deficits in Sleep Activated Developmental Epilepsy
JF The Journal of Neuroscience
JO J. Neurosci.
FD Society for Neuroscience
SP 1816
OP 1829
DO 10.1523/JNEUROSCI.2009-20.2020
VO 41
IS 8
A1 Mark A. Kramer
A1 Sally M. Stoyell
A1 Dhinakaran Chinappen
A1 Lauren M. Ostrowski
A1 Elizabeth R. Spencer
A1 Amy K. Morgan
A1 Britt Carlson Emerton
A1 Jin Jing
A1 M. Brandon Westover
A1 Uri T. Eden
A1 Robert Stickgold
A1 Dara S. Manoach
A1 Catherine J. Chu
YR 2021
UL http://www.jneurosci.org/content/41/8/1816.abstract
AB 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.SIGNIFICANCE STATEMENT Childhood epilepsy with centrotemporal spikes is the most common idiopathic focal epilepsy syndrome, characterized by self-limited focal seizures and cognitive symptoms. Here, we provide the first evidence that focal thalamocortical circuit dysfunction underlies the shared seizures and cognitive dysfunction observed. In doing so, we identify sleep spindles as a mechanistic biomarker, and potential treatment target, of cognitive dysfunction in this common developmental epilepsy and provide a novel method to reliably quantify spindles in brain recordings from patients with epilepsy.