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

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.

Topography of sleep slow wave activity in children with attention-deficit/hyperactivity disorder.

INTRODUCTION: Sleep slow wave activity (SWA, EEG power between 1 and 4.5 Hz) is a major characteristic of non-rapid eye movement (NREM) sleep, which seems to be critically involved in cortical plasticity. Studies using high-density electroencephalography (hd-EEG) showed that the topographical distribution of SWA mirrors cortical maturation, expressing a local maximum that is characteristic for a certain age range. We compared the sleep EEG of children with attention-deficit/hyperactivity disorder (ADHD) with healthy controls to explore differences in sleep SWA. METHODS: All-night hd-EEG recordings (128 electrodes) were performed in a group of nine children diagnosed with ADHD and nine age- and sex-matched healthy controls. SWA topography was calculated and contrasted between the groups. RESULTS: We found a local increase of SWA in a cluster of six electrodes over central regions in children with ADHD compared to control children (+17% ± 6% SE, p < .01). This group difference was specific for the SWA range and stable across the night. CONCLUSIONS: Children with ADHD showed a less mature topographical SWA distribution in comparison to healthy children of the same age and sex. This neuromaturational delay in ADHD is in accordance with neuroimaging and behavioral studies. Thus, our study supports the use of sleep SWA topography as a reliable imaging tool for the study of cortical plasticity.