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Research Articles, Behavioral/Cognitive

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

Mark A. Kramer, Sally M. Stoyell, Dhinakaran Chinappen, Lauren M. Ostrowski, Elizabeth R. Spencer, Amy K. Morgan, Britt Carlson Emerton, Jin Jing, M. Brandon Westover, Uri T. Eden, Robert Stickgold, Dara S. Manoach and Catherine J. Chu
Journal of Neuroscience 24 February 2021, 41 (8) 1816-1829; DOI: https://doi.org/10.1523/JNEUROSCI.2009-20.2020
Mark A. Kramer
1Department of Mathematics and Statistics, Boston University, Boston, Massachusetts 02215
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Sally M. Stoyell
2Department of Neurology, Massachusetts General Hospital, Boston, Massachusetts 02114
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Dhinakaran Chinappen
2Department of Neurology, Massachusetts General Hospital, Boston, Massachusetts 02114
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Lauren M. Ostrowski
2Department of Neurology, Massachusetts General Hospital, Boston, Massachusetts 02114
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Elizabeth R. Spencer
1Department of Mathematics and Statistics, Boston University, Boston, Massachusetts 02215
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Amy K. Morgan
3Department of Psychiatry, Massachusetts General Hospital, Boston, Massachusetts 02114
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Britt Carlson Emerton
3Department of Psychiatry, Massachusetts General Hospital, Boston, Massachusetts 02114
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Jin Jing
2Department of Neurology, Massachusetts General Hospital, Boston, Massachusetts 02114
4Harvard Medical School, Boston, Massachusetts 02115
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M. Brandon Westover
2Department of Neurology, Massachusetts General Hospital, Boston, Massachusetts 02114
4Harvard Medical School, Boston, Massachusetts 02115
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Uri T. Eden
1Department of Mathematics and Statistics, Boston University, Boston, Massachusetts 02215
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Robert Stickgold
4Harvard Medical School, Boston, Massachusetts 02115
5Department of Psychiatry, Beth Israel Deaconess Medical Center, Boston, Massachusetts 02215
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Dara S. Manoach
3Department of Psychiatry, Massachusetts General Hospital, Boston, Massachusetts 02114
4Harvard Medical School, Boston, Massachusetts 02115
6Athinoula A. Martinos Center for Biomedical Imaging, Charlestown, Massachusetts 02129
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Catherine J. Chu
2Department of Neurology, Massachusetts General Hospital, Boston, Massachusetts 02114
5Department of Psychiatry, Beth Israel Deaconess Medical Center, Boston, Massachusetts 02215
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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.

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.

  • automated spindle detection
  • BECTS
  • CECTS
  • latent state model
  • Rolandic epilepsy

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The Journal of Neuroscience: 41 (8)
Journal of Neuroscience
Vol. 41, Issue 8
24 Feb 2021
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Focal Sleep Spindle Deficits Reveal Focal Thalamocortical Dysfunction and Predict Cognitive Deficits in Sleep Activated Developmental Epilepsy
Mark A. Kramer, Sally M. Stoyell, Dhinakaran Chinappen, Lauren M. Ostrowski, Elizabeth R. Spencer, Amy K. Morgan, Britt Carlson Emerton, Jin Jing, M. Brandon Westover, Uri T. Eden, Robert Stickgold, Dara S. Manoach, Catherine J. Chu
Journal of Neuroscience 24 February 2021, 41 (8) 1816-1829; DOI: 10.1523/JNEUROSCI.2009-20.2020

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Focal Sleep Spindle Deficits Reveal Focal Thalamocortical Dysfunction and Predict Cognitive Deficits in Sleep Activated Developmental Epilepsy
Mark A. Kramer, Sally M. Stoyell, Dhinakaran Chinappen, Lauren M. Ostrowski, Elizabeth R. Spencer, Amy K. Morgan, Britt Carlson Emerton, Jin Jing, M. Brandon Westover, Uri T. Eden, Robert Stickgold, Dara S. Manoach, Catherine J. Chu
Journal of Neuroscience 24 February 2021, 41 (8) 1816-1829; DOI: 10.1523/JNEUROSCI.2009-20.2020
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Keywords

  • automated spindle detection
  • BECTS
  • CECTS
  • latent state model
  • Rolandic epilepsy

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