A novel pathogenic SLC12A5 missense variant in epilepsy of infancy with migrating focal seizures causes impaired KCC2 chloride extrusion.

The potassium-chloride co-transporter 2, KCC2, is a neuron-specific ion transporter that plays a multifunctional role in neuronal development. In mature neurons, KCC2 maintains a low enough intracellular chloride concentration essential for inhibitory neurotransmission. During recent years, pathogenic variants in the KCC2 encoding gene SLC12A5 affecting the functionality or expression of the transporter protein have been described in several patients with epilepsy of infancy with migrating focal seizures (EIMFS), a devastating early-onset developmental and epileptic encephalopathy. In this study, we identified a novel recessively inherited SLC12A5 c.692G>A, p. (R231H) variant in a patient diagnosed with severe and drug-resistant EIMFS and profound intellectual disability. The functionality of the variant was assessed in vitro by means of gramicidin-perforated patch-clamp experiments and ammonium flux assay, both of which indicated a significant reduction in chloride extrusion. Based on surface immunolabeling, the variant showed a reduction in membrane expression. These findings implicate pathogenicity of the SLC12A5 variant that leads to impaired inhibitory neurotransmission, increasing probability for hyperexcitability and epileptogenesis.

Effect of sleep deprivation and NREM sleep stage on physiological brain pulsations.

Introduction: Sleep increases brain fluid transport and the power of pulsations driving the fluids. We investigated how sleep deprivation or electrophysiologically different stages of non-rapid-eye-movement (NREM) sleep affect the human brain pulsations. Methods: Fast functional magnetic resonance imaging (fMRI) was performed in healthy subjects (n = 23) with synchronous electroencephalography (EEG), that was used to verify arousal states (awake, N1 and N2 sleep). Cardiorespiratory rates were verified with physiological monitoring. Spectral power analysis assessed the strength, and spectral entropy assessed the stability of the pulsations. Results: In N1 sleep, the power of vasomotor (VLF < 0.1 Hz), but not cardiorespiratory pulsations, intensified after sleep deprived vs. non-sleep deprived subjects. The power of all three pulsations increased as a function of arousal state (N2 > N1 > awake) encompassing brain tissue in both sleep stages, but extra-axial CSF spaces only in N2 sleep. Spectral entropy of full band and respiratory pulsations decreased most in N2 sleep stage, while cardiac spectral entropy increased in ventricles. Discussion: In summary, the sleep deprivation and sleep depth, both increase the power and harmonize the spectral content of human brain pulsations.

Infra-slow fluctuations in cortical potentials and respiration drive fast cortical EEG rhythms in sleeping and waking states.

OBJECTIVE: Infra-slow fluctuations (ISF, 0.008-0.1 Hz) characterize hemodynamic and electric potential signals of human brain. ISFs correlate with the amplitude dynamics of fast (>1 Hz) neuronal oscillations, and may arise from permeability fluctuations of the blood-brain barrier (BBB). It is unclear if physiological rhythms like respiration drive or track fast cortical oscillations, and the role of sleep in this coupling is unknown. METHODS: We used high-density full-band electroencephalography (EEG) in healthy human volunteers (N = 21) to measure concurrently the ISFs, respiratory pulsations, and fast neuronal oscillations during periods of wakefulness and sleep, and to assess the strength and direction of their phase-amplitude coupling. RESULTS: The phases of ISFs and respiration were both coupled with the amplitude of fast neuronal oscillations, with stronger ISF coupling being evident during sleep. Phases of ISF and respiration drove the amplitude dynamics of fast oscillations in sleeping and waking states, with different contributions. CONCLUSIONS: ISFs in slow cortical potentials and respiration together significantly determine the dynamics of fast cortical oscillations. SIGNIFICANCE: We propose that these slow physiological phases play a significant role in coordinating cortical excitability, which is a fundamental aspect of brain function.

Human NREM Sleep Promotes Brain-Wide Vasomotor and Respiratory Pulsations.

The physiological underpinnings of the necessity of sleep remain uncertain. Recent evidence suggests that sleep increases the convection of cerebrospinal fluid (CSF) and promotes the export of interstitial solutes, thus providing a framework to explain why all vertebrate species require sleep. Cardiovascular, respiratory and vasomotor brain pulsations have each been shown to drive CSF flow along perivascular spaces, yet it is unknown how such pulsations may change during sleep in humans. To investigate these pulsation phenomena in relation to sleep, we simultaneously recorded fast fMRI, magnetic resonance encephalography (MREG), and electroencephalography (EEG) signals in a group of healthy volunteers. We quantified sleep-related changes in the signal frequency distributions by spectral entropy analysis and calculated the strength of the physiological (vasomotor, respiratory, and cardiac) brain pulsations by power sum analysis in 15 subjects (age 26.5 ± 4.2 years, 6 females). Finally, we identified spatial similarities between EEG slow oscillation (0.2-2 Hz) power and MREG pulsations. Compared with wakefulness, nonrapid eye movement (NREM) sleep was characterized by reduced spectral entropy and increased brain pulsation intensity. These effects were most pronounced in posterior brain areas for very low-frequency (≤0.1 Hz) vasomotor pulsations but were also evident brain-wide for respiratory pulsations, and to a lesser extent for cardiac brain pulsations. There was increased EEG slow oscillation power in brain regions spatially overlapping with those showing sleep-related MREG pulsation changes. We suggest that reduced spectral entropy and enhanced pulsation intensity are characteristic of NREM sleep. With our findings of increased power of slow oscillation, the present results support the proposition that sleep promotes fluid transport in human brain.SIGNIFICANCE STATEMENT We report that the spectral power of physiological brain pulsation mechanisms driven by vasomotor, respiration, and cardiac rhythms in human brain increase during sleep, extending previous observations of their association with glymphatic brain clearance during sleep in rodents. The magnitudes of increased pulsations follow the rank order of vasomotor greater than respiratory greater than cardiac pulsations, with correspondingly declining spatial extents. Spectral entropy, previously known as vigilance and as an anesthesia metric, decreased during NREM sleep compared with the awake state in very low and respiratory frequencies, indicating reduced signal complexity. An EEG slow oscillation power increase occurring in the early sleep phase (NREM 1-2) spatially overlapped with pulsation changes, indicating reciprocal mechanisms between those measures.

Decreased occipital alpha oscillation in children who stutter during a visual Go/Nogo task.

OBJECTIVE: Our goal was to discover attention- and inhibitory control-related differences in the main oscillations of the brain of children who stutter (CWS) compared to typically developed children (TDC). METHODS: We performed a time-frequency analysis using wavelets, fast Fourier transformation (FFT) and the Alpha/Theta power ratio of EEG data collected during a visual Go/Nogo task in 7-9 year old CWS and TDC, including also the time window between consecutive tasks. RESULTS: CWS showed significantly reduced occipital alpha power and Alpha/Theta ratio in the "resting" or preparatory period between visual stimuli especially in the Nogo condition. CONCLUSIONS: The CWS demonstrate reduced inhibition of the visual cortex and information processing in the absence of visual stimuli, which may be related to problems in attentional gating. SIGNIFICANCE: Occipital alpha oscillation is elementary in the control and inhibition of visual attention and the lack of occipital alpha modulation indicate fundamental differences in the regulation of visual information processing in CWS. Our findings support the view of stuttering as part of a wide-ranging brain dysfunction most likely involving also attentional and inhibitory networks.

Atypical brain activation in children who stutter in a visual Go/Nogo task: An ERP study.

OBJECTIVE: The aim of the study was to investigate inhibitory control by evaluating possible differences in the strength and distribution of the brain activity in a visual Go/Nogo task in children who stutter (CWS) compared to typically developing children (TDC). METHODS: Eleven CWS and 19 TDC participated. Event related potentials (ERP) were recorded using a 64-channel EEG-cap during an equiprobable visual Go/Nogo task. The global field power (GFP) as well as the mean amplitudes in the P3 time frame were compared between groups. Additionally, the potential maps of the groups were investigated visually in the N2 and P3 time windows. RESULTS: The groups differed significantly in the right frontal area especially in the Nogo condition (p<0.001) with CWS showing smaller (less positive) mean amplitudes, most likely due to a prolonged and asymmetrical N2 component. Also the fronto-central Nogo P3 component was rather indistinct in CWS, but easily recognizable in TDC in the potential maps. CONCLUSIONS: The CWS show atypical brain activation compared to the TDC in a Go/Nogo task as indexed by the excessive N2-related activity in both conditions and reduced P3-related activity in Nogo condition. SIGNIFICANCE: These findings indicate atypical stimulus evaluation and response inhibition processes in CWS.

Delayed N2 response in Go condition in a visual Go/Nogo ERP study in children who stutter.

PURPOSE OF THE STUDY: The main aim of the study was to investigate the attentional and inhibitory abilities and their underlying processes of children who stutter by using behavioural measurement and event-related potentials (ERP) in a visual Go/Nogo paradigm. METHODS: Participants were 11 children who stutter (CWS; mean age 8.1, age range 6.3-9.5 years) and 19 typically developed children (TDC; mean age 8.1, age range 5.8-9.6 years). They performed a visual Go/Nogo task with simultaneous EEG recording to obtain ERP responses. RESULTS: Results showed that CWS had longer N2 and P3 latencies in the Go condition compared to the TDC. In contrast, the groups did not differ significantly in the Nogo condition or behavioural measures. CONCLUSIONS: Our findings did not confirm less efficient inhibitory control in CWS but suggest atypical attentional processing such as stimulus evaluation and response selection. EDUCATIONAL OBJECTIVES: The reader will be able to (a) describe recent findings on attention and inhibitory control in children who stutter, (b) describe the measurement of attentional processing, including inhibitory control, and (c) describe the findings on attentional processing in children who stutter as indexed by the event-related potentials in a visual Go/Nogo paradigm.