Sleep slow-wave oscillations trigger seizures in a genetic epilepsy model of Dravet syndrome

Sleep is the brain state when cortical activity decreases and memory consolidates. However, in human epileptic patients, including genetic epileptic seizures such as Dravet syndrome, sleep is the preferential period when epileptic spike-wave discharges (SWDs) appear, with more severe epileptic symptoms in female patients than male patients, which influencing patient sleep quality and memory. Currently, seizure onset mechanisms during sleep period still remain unknown. Our previous work has shown that the sleep-like state-dependent synaptic potentiation mechanism can trigger epileptic SWDs (Zhang et al., 2021). In this study, using one heterozygous (het) knock-in (KI) transgenic mice (GABAA receptor γ2 subunit Gabrg2Q390X mutation) and an optogenetic method, we hypothesized that slow-wave oscillations (SWOs) themselves in vivo could trigger epileptic seizures. We found that epileptic SWDs in het Gabrg2+/Q390X KI mice exhibited preferential incidence during NREM sleep period, accompanied by motor immobility/ facial myoclonus/vibrissal twitching, with more frequent incidence in female het KI mice than male het KI mice. Optogenetic induced SWOs in vivo significantly increased epileptic seizure incidence in het Gabrg2+/Q390X KI mice with increased duration of NREM sleep or quiet-wakeful states. Furthermore, suppression of SWO-related homeostatic synaptic potentiation by 4-(diethylamino)-benzaldehyde (DEAB) injection (i.p.) greatly decreased seizure incidence in het KI mice, suggesting that SWOs did trigger seizure activity in het KI mice. In addition, EEG delta-frequency (0.1-4 Hz) power spectral density during NREM sleep was significantly larger in female het Gabrg2+/Q390X KI mice than male het Gabrg2+/Q390X KI mice, which likely contributes to the gender difference in seizure incidence during NREM sleep/quiet-wake as that in human patients.

On the issue of the electroencephalographic phenomenon «burst-suppression»: variants of outcomes and possible neurophysiological mechanisms

Objective: to evaluate the indicators of electrical activity of the brain using frequency- spectral analysis and data of three- dimensional localization of sources of pathological activity for an approach to the analysis of possible neurophysiological mechanisms of the brain of patients whose EEG recorded the phenomenon of ‘burst- suppression’.Material and methods: 45 electroencephalograms recorded in 22 patients (average age 51.05; 11 women, 11 men) were analyzed. In 12 patients, the EEG study was performed in dynamics from 1 to 8 times. At the time of the first registration, the ‘burst- suppression’phenomenon was recorded in the EEG of all patients. The level of wakefulness of all patients, with the exception of patients who were under anesthesia, was 3 points on the Glasgow coma scale.EEG recording was performed on electroencephalographs ‘Encephalan- EEGR-19/26’, ‘Mitsar- EEG-10/70–201’, ‘Mitsar- EEG-SmartBCI’, ‘Neuron- Spectrum-5’and ‘Neuron- Spectrum-65’in accordance with the International scheme of arrangement of electrodes 10–20 %. A frequency- spectral analysis of the power of the ‘burst’and ‘suppression’periods was carried out — the fast Fourier transform method was used. The program ‘BrainLoc 6.1’(Russia) was used for localization of equivalent dipole sources of pathological electrical activity of the ‘burst’period.Results: during the first EEG recording, the ‘burst- suppression’phenomenon was recorded in all patients. In seven patients, the ‘burst’period in the ‘burstsuppression’phenomenon was visually represented by slow-wave oscillations, in 15 patients, the ‘burst’periods resembled epileptiform discharges. In frequency- spectral analysis EEG in all patients in the ‘burst’period, the dominance of the power of slow-wave oscillations (mainly in the delta range) was noted. According to the program ‘BrainLoc 6.1’, equivalent dipole sources of pathological activity of the ‘burst’period were recorded at the level of the thalamus, in the medio- basal parts of the frontal and temporal lobes on both sides. A favorable outcome of the ‘burst- suppression’phenomenon was observed in only five patients of 22, all other patients had an unfavorable outcome.Conclusion: a favorable outcome of the ‘burst- suppression’phenomenon was observed only in patients under sevorane anesthesia and in some patients after acute poisoning with drugs that affect the central nervous system, while patients after brain anoxia had an unfavorable outcome. In prognostic terms, our data are comparable to the literature data. The changes revealed during the frequency-spectral analysis of the EEG in the form of the dominance of the power of slow-wave oscillations (mainly in the delta range), as well as the localization of the supposed generators of electrical activity in the ‘burst’ period at the level of the thalamus, in the mediobasal parts of the frontal and temporal lobes (according to the ‘BrainLoc 6.1’program), may to some extent be consistent with the data of experimental works and mathematical models of the ‘burst–suppression’phenomenon If the ‘burst- suppression’ phenomenon is detected during EEG registration, it is advisableto conduct a dynamic EEG study or EEG monitoring.

Network-specific synchronization of electrical slow-wave oscillations regulates sleep in Drosophila

Slow-wave rhythms characteristic of deep sleep oscillate in the delta band (0.5-4 Hz) and can be found across various brain regions in vertebrates. Across systems it is however unclear how oscillations arise and whether they are the causal functional unit steering behavior. Here, for the first time in any invertebrate, we discover sleep-relevant delta oscillations in Drosophila. We find that slow-wave oscillations in the sleep-regulating R2 network increase with sleep need. Optical multi-unit voltage recordings reveal that single R2 neurons get synchronized by sensory and circadian input pathways. We show that this synchronization depends on NMDA receptor (NMDARs) coincidence detector function and on an interplay of cholinergic and glutamatergic inputs setting a resonance frequency. Genetically targeting the coincidence detector function of NMDARs in R2, and thus the uncovered mechanism underlying synchronization, abolished network-specific slow-wave oscillations. It also disrupted sleep and facilitated light-induced wakening, directly establishing a causal role for slow-wave oscillations in regulating sleep and sensory gating. We therefore propose that the synchronization-based increase in oscillatory power likely represents an evolutionarily conserved, potentially optimal, strategy for constructing sleep-regulating sensory gates.

A balance of outward and linear inward ionic currents is required for generation of slow-wave oscillations

Pacemaker neuron-generated rhythmic activity requires the activation of at least one inward and one outward current. We have previously shown that the inward current can be a linear current (with negative conductance). Using this simple mechanism, here we demonstrate that the inward current conductance must be in relative balance with the outward current conductances to generate oscillatory activity. Surprisingly, an excess of outward conductances completely precludes the possibility of achieving such a balance.