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Altered EEG markers of synaptic plasticity in a human model of NMDA receptor deficiency: Anti-NMDA receptor encephalitis


Gefferie, Silvano R; Maric, Angelina; Critelli, Hanne; Gueden, Sophie; Kurlemann, Gerhard; Kurth, Salome; Nosadini, Margherita; Plecko, Barbara; Ringli, Maya; Rostásy, Kevin; Sartori, Stefano; Schmitt, Bernhard; Suppiej, Agnese; Van Bogaert, Patrick; Wehrle, Flavia M; Huber, Reto; Bölsterli, Bigna K (2021). Altered EEG markers of synaptic plasticity in a human model of NMDA receptor deficiency: Anti-NMDA receptor encephalitis. NeuroImage, 239:118281.

Abstract

Plasticity of synaptic strength and density is a vital mechanism enabling memory consolidation, learning, and neurodevelopment. It is strongly dependent on the intact function of N-Methyl-d-Aspartate Receptors (NMDAR). The importance of NMDAR is further evident as their dysfunction is involved in many diseases such as schizophrenia, Alzheimer's disease, neurodevelopmental disorders, and epilepsies. Synaptic plasticity is thought to be reflected by changes of sleep slow wave slopes across the night, namely higher slopes after wakefulness at the beginning of sleep than after a night of sleep. Hence, a functional NMDAR deficiency should theoretically lead to altered overnight changes of slow wave slopes. Here we investigated whether pediatric patients with anti-NMDAR encephalitis, being a very rare but unique human model of NMDAR deficiency due to autoantibodies against receptor subunits, indeed show alterations in this sleep EEG marker for synaptic plasticity. We retrospectively analyzed 12 whole-night EEGs of 9 patients (age 4.3-20.8 years, 7 females) and compared them to a control group of 45 healthy individuals with the same age distribution. Slow wave slopes were calculated for the first and last hour of Non-Rapid Eye Movement (NREM) sleep (factor 'hour') for patients and controls (factor 'group'). There was a significant interaction between 'hour' and 'group' (p = 0.013), with patients showing a smaller overnight decrease of slow wave slopes than controls. Moreover, we found smaller slopes during the first hour in patients (p = 0.022), whereas there was no group difference during the last hour of NREM sleep (p = 0.980). Importantly, the distribution of sleep stages was not different between the groups, and in our main analyses of patients without severe disturbance of sleep architecture, neither was the incidence of slow waves. These possible confounders could therefore not account for the differences in the slow wave slope values, which we also saw in the analysis of the whole sample of EEGs. These results suggest that quantitative EEG analysis of slow wave characteristics may reveal impaired synaptic plasticity in patients with anti-NMDAR encephalitis, a human model of functional NMDAR deficiency. Thus, in the future, the changes of sleep slow wave slopes may contribute to the development of electrophysiological biomarkers of functional NMDAR deficiency and synaptic plasticity in general.

Abstract

Plasticity of synaptic strength and density is a vital mechanism enabling memory consolidation, learning, and neurodevelopment. It is strongly dependent on the intact function of N-Methyl-d-Aspartate Receptors (NMDAR). The importance of NMDAR is further evident as their dysfunction is involved in many diseases such as schizophrenia, Alzheimer's disease, neurodevelopmental disorders, and epilepsies. Synaptic plasticity is thought to be reflected by changes of sleep slow wave slopes across the night, namely higher slopes after wakefulness at the beginning of sleep than after a night of sleep. Hence, a functional NMDAR deficiency should theoretically lead to altered overnight changes of slow wave slopes. Here we investigated whether pediatric patients with anti-NMDAR encephalitis, being a very rare but unique human model of NMDAR deficiency due to autoantibodies against receptor subunits, indeed show alterations in this sleep EEG marker for synaptic plasticity. We retrospectively analyzed 12 whole-night EEGs of 9 patients (age 4.3-20.8 years, 7 females) and compared them to a control group of 45 healthy individuals with the same age distribution. Slow wave slopes were calculated for the first and last hour of Non-Rapid Eye Movement (NREM) sleep (factor 'hour') for patients and controls (factor 'group'). There was a significant interaction between 'hour' and 'group' (p = 0.013), with patients showing a smaller overnight decrease of slow wave slopes than controls. Moreover, we found smaller slopes during the first hour in patients (p = 0.022), whereas there was no group difference during the last hour of NREM sleep (p = 0.980). Importantly, the distribution of sleep stages was not different between the groups, and in our main analyses of patients without severe disturbance of sleep architecture, neither was the incidence of slow waves. These possible confounders could therefore not account for the differences in the slow wave slope values, which we also saw in the analysis of the whole sample of EEGs. These results suggest that quantitative EEG analysis of slow wave characteristics may reveal impaired synaptic plasticity in patients with anti-NMDAR encephalitis, a human model of functional NMDAR deficiency. Thus, in the future, the changes of sleep slow wave slopes may contribute to the development of electrophysiological biomarkers of functional NMDAR deficiency and synaptic plasticity in general.

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Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > University Children's Hospital Zurich > Medical Clinic
04 Faculty of Medicine > University Hospital Zurich > Clinic for Neurology
04 Faculty of Medicine > Psychiatric University Hospital Zurich > Department of Child and Adolescent Psychiatry
04 Faculty of Medicine > University Hospital Zurich > Clinic for Pneumology
Dewey Decimal Classification:610 Medicine & health
Scopus Subject Areas:Life Sciences > Neurology
Life Sciences > Cognitive Neuroscience
Uncontrolled Keywords:Encephalitis, NMDA receptor, Sleep homeostasis, Slow waves, Synaptic plasticity
Language:English
Date:1 October 2021
Deposited On:16 Sep 2021 05:14
Last Modified:25 Apr 2024 01:39
Publisher:Elsevier
ISSN:1053-8119
OA Status:Gold
Free access at:Publisher DOI. An embargo period may apply.
Publisher DOI:https://doi.org/10.1016/j.neuroimage.2021.118281
PubMed ID:34147627
Project Information:
  • : FunderSNSF
  • : Grant IDPCEFP1_181279
  • : Project Titlea window of opportunity for fostering healthy development
  • : FunderSNSF
  • : Grant ID320030_179443
  • : Project Titlemethod optimization and proof of concept study in childhood epilepsy
  • : FunderSNSF
  • : Grant ID320030_153387
  • : Project TitleExploring diurnal changes in markers of cortical plasticity using multimodal imaging in healthy children and adolescents and in patients with Attention Deficit Hyperactivity Disorder
  • : Funderradiz - Rare Disease Initiative Zurich
  • : Grant ID
  • : Project Title
  • : FunderUZH
  • : Grant ID
  • : Project TitleClinical Research Priority Program Sleep and Health
  • : FunderAnna Müller Grocholski foundation
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  • : FunderEMDO foundation
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  • Content: Published Version
  • Language: English
  • Licence: Creative Commons: Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0)