Altered EEG markers of synaptic plasticity in a human model of NMDA receptor deficiency: Anti-NMDA receptor encephalitis
Silvano R. Gefferie,
Angelina Maric,
Hanne Critelli,
Sophie Gueden,
Gerhard Kurlemann,
Salome Kurth,
Margherita Nosadini,
Barbara Plecko,
Maya Ringli,
Kevin Rostásy,
Stefano Sartori,
Bernhard Schmitt,
Agnese Suppiej,
Patrick Van Bogaert,
Flavia M. Wehrle,
Reto Huber,
Bigna K. Bölsterli
Affiliations
Silvano R. Gefferie
Department of Neuropediatrics, University Children's Hospital Zurich, University of Zurich, 8032, Zurich, Switzerland; Children's Research Center, University Children's Hospital Zurich, University of Zurich, 8032, Zurich, Switzerland; Stichting Epilepsie Instellingen Nederland (SEIN), 2103 SW, Heemstede, Netherlands
Angelina Maric
Department of Neurology, University Hospital Zurich, University of Zurich, 8091, Zurich, Switzerland
Hanne Critelli
Department of Neuropediatrics, University Children's Hospital Zurich, University of Zurich, 8032, Zurich, Switzerland; Children's Research Center, University Children's Hospital Zurich, University of Zurich, 8032, Zurich, Switzerland
Sophie Gueden
Service de Pédiatrie, CHU d'Angers, 49933, Angers, France
Gerhard Kurlemann
Children's Hospital Bonifatius Klinik, 49808, Lingen, Germany
Salome Kurth
Pulmonary Clinic, University Hospital Zurich, University of Zurich, 8091, Zurich, Switzerland; Department of Psychology, University of Fribourg, 1700, Fribourg, Switzerland
Margherita Nosadini
Pediatric Neurology and Neurophysiology Unit, Department of Women's and Children's Health, University of Padua, 35122, Padua, Italy
Barbara Plecko
Department of Neuropediatrics, University Children's Hospital Zurich, University of Zurich, 8032, Zurich, Switzerland; Children's Research Center, University Children's Hospital Zurich, University of Zurich, 8032, Zurich, Switzerland; Department of Pediatrics and Adolescent Medicine, Division of General Pediatrics, Medical University of Graz, 8036, Graz, Austria
Maya Ringli
Department of Neurology, Inselspital, University Hospital Bern, 3010, Bern, Switzerland
Kevin Rostásy
Department of Pediatric Neurology, Children's Hospital Datteln, Witten/Herdecke University, 58448, Datteln/Witten, Germany
Stefano Sartori
Pediatric Neurology and Neurophysiology Unit, Department of Women's and Children's Health, University of Padua, 35122, Padua, Italy
Bernhard Schmitt
Department of Neuropediatrics, University Children's Hospital Zurich, University of Zurich, 8032, Zurich, Switzerland; Children's Research Center, University Children's Hospital Zurich, University of Zurich, 8032, Zurich, Switzerland
Agnese Suppiej
Pediatric Neurology and Neurophysiology Unit, Department of Women's and Children's Health, University of Padua, 35122, Padua, Italy; Department of Medical Sciences, Pediatric Section, University of Ferrara, 44121, Ferrara, Italy
Patrick Van Bogaert
Service de Pédiatrie, CHU d'Angers, 49933, Angers, France
Flavia M. Wehrle
Children's Research Center, University Children's Hospital Zurich, University of Zurich, 8032, Zurich, Switzerland; Child Development Center, University Children's Hospital Zurich, University of Zurich, 8032, Zurich, Switzerland; Department of Neonatology and Pediatric Intensive Care, University Children's Hospital Zurich, University of Zurich, 8032, Zurich, Switzerland
Reto Huber
Children's Research Center, University Children's Hospital Zurich, University of Zurich, 8032, Zurich, Switzerland; Child Development Center, University Children's Hospital Zurich, University of Zurich, 8032, Zurich, Switzerland; Department of Child and Adolescent Psychiatry and Psychotherapy, Psychiatric Hospital, University of Zurich, 8091, Zurich, Switzerland
Bigna K. Bölsterli
Department of Neuropediatrics, University Children's Hospital Zurich, University of Zurich, 8032, Zurich, Switzerland; Children's Research Center, University Children's Hospital Zurich, University of Zurich, 8032, Zurich, Switzerland; Corresponding author.
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.
