Disparate effects of hormones and vigabatrin on sleep slow waves in patients with West syndrome - An indication of their mode of action?

Synaptic downscaling during sleep, a physiological process to restore synaptic homeostasis and maintain learning efficiency and healthy brain development, has been related to a reduction of the slope of sleep slow waves (SSW). However, such synaptic downscaling seems not to be reflected in high-amplitude SSW. Recently we have shown reduced SSW slopes during hormonal treatment (adrenocorticotrophic hormone, prednisolone) in patients with West syndrome (WS). Yet, whether this reduction was related to successful treatment or reflects a specific effect of hormone therapy is unknown. Thus, we retrospectively analysed nap electroencephalograms of 61 patients with WS successfully treated with hormones, vigabatrin (VGB), or both. The slope of SSW during treatment (T1) and 2-7 months later (T2) when hormonal treatment was tapered off were compared between the treatment groups and healthy, age-matched controls. At T1 hormone treatment reduced the slope of low-amplitude SSW, whereas VGB increased the slope of high-amplitude SSW (linear mixed effect model: FGroup  = 7.04, p < 0.001; FAmplitude  = 1,646.68, p < 0.001; FGroup*Amplitude  = 3.38, p < 0.001). At T2, untreated patients did not differ anymore from healthy controls, whereas those still under VGB showed the same alterations as those with VGB at T1. This result indicates a disparate effect of VGB and hormone on the SSW slope. In particular, hormones seem to reduce the slope of cortical generated low-amplitude SSW, similar to the physiological synaptic downscaling during sleep. Thus, a loss of functional neuronal connectivity might be an alternative explanation of the antiepileptic effect of hormonal treatment.

Spike wave location and density disturb sleep slow waves in patients with CSWS (continuous spike waves during sleep).

OBJECTIVE: In CSWS (continuous spike waves during sleep) activation of spike waves during slow wave sleep has been causally linked to neuropsychological deficits, but the pathophysiologic mechanisms are still unknown. In healthy subjects, the overnight decrease of the slope of slow waves in NREM (non-rapid eye movement) sleep has been linked to brain recovery to regain optimal cognitive performance. Here, we investigated whether the electrophysiologic hallmark of CSWS, the spike waves during sleep, is related to an alteration in the overnight decrease of the slope, and if this alteration is linked to location and density of spike waves. METHODS: In a retrospective study, the slope of slow waves (0.5-2 Hz) in the first hour and last hour of sleep (19 electroencephalography [EEG] electrodes) of 14 patients with CSWS (3.1-13.5 years) was calculated. The spike wave "focus" was determined as the location of highest spike amplitude and the density of spike waves as spike wave index (SWI). RESULTS: There was no overnight change of the slope of slow waves in the "focus." Instead, in "nonfocal" regions, the slope decreased significantly. This difference in the overnight course resulted in a steeper slope in the "focus" compared to "nonfocal" electrodes during the last hour of sleep. Spike wave density was correlated with the impairment of the overnight slope decrease: The higher the SWI, the more hampered the slope decrease. SIGNIFICANCE: Location and density of spike waves are related to an alteration of the physiologic overnight decrease of the slow wave slope. This overnight decrease of the slope was shown to be closely related to the recovery function of sleep. Such recovery is necessary for optimal cognitive performance during wakefulness. Therefore we propose the impairment of this process by spike waves as a potential mechanism leading to neuropsychological deficits in CSWS. A PowerPoint slide summarizing this article is available for download in the Supporting Information section here.

Exploring the local field potential signal from the subthalamic nucleus for phase-targeted auditory stimulation in Parkinson's disease.

BACKGROUND: Enhancing slow waves, the electrophysiological (EEG) manifestation of non-rapid eye movement (NREM) sleep, could potentially benefit patients with Parkinson's disease (PD) by improving sleep quality and slowing disease progression. Phase-targeted auditory stimulation (PTAS) is an approach to enhance slow waves, which are detected in real-time in the surface EEG signal. OBJECTIVE: We aimed to test whether the local-field potential of the subthalamic nucleus (STN-LFP) can be used to detect frontal slow waves and assess the electrophysiological changes related to PTAS. METHODS: We recruited patients diagnosed with PD and undergoing Percept™ PC neurostimulator (Medtronic) implantation for deep brain stimulation of STN (STN-DBS) in a two-step surgery. Patients underwent three full-night recordings, including one between-surgeries recording and two during rehabilitation, one with DBS+ (on) and one with DBS- (off). Surface EEG and STN-LFP signals from Percept PC were recorded simultaneously, and PTAS was applied during sleep in all three recording sessions. RESULTS: Our results show that during NREM sleep, slow waves of the cortex and STN are time-locked. PTAS application resulted in power and coherence changes, which can be detected in STN-LFP. CONCLUSION: Our findings suggest the feasibility of implementing PTAS using solely STN-LFP signal for slow wave detection, thus without a need for an external EEG device alongside the implanted neurostimulator. Moreover, we propose options for more efficient STN-LFP signal preprocessing, including different referencing and filtering to enhance the reliability of cortical slow wave detection in STN-LFP recordings.

Characterization of overnight slow-wave slope changes across development in an age-, amplitude-, and region-dependent manner.

STUDY OBJECTIVES: The restorative function of sleep has been linked to a net reduction in synaptic strength. The slope of slow-waves, a major characteristic of non-rapid eye movement (NREM) sleep, has been shown to directly reflect synaptic strength, when accounting for amplitude changes across the night. In this study, we aimed to investigate overnight slope changes in the course of development in an age-, amplitude-, and region-dependent manner. METHODS: All-night high-density electroencephalography data were analyzed in a cross-sectional population of 60 healthy participants in the age range of 8-29 years. To control for amplitude changes across the night, we matched slow-waves from the first and the last hour of NREM sleep according to their amplitude. RESULTS: We found a reduction of slow-wave slopes from the first to the last hour of NREM sleep across all investigated ages, amplitudes, and most brain regions. The overnight slope change was largest in children and decreased toward early adulthood. A topographical analysis revealed regional differences in slope change. Specifically, for small amplitude waves the decrease was smallest in an occipital area, whereas for large amplitude waves, the decrease was smallest in a central area. CONCLUSIONS: The larger slope decrease in children might be indicative of a boosted renormalization of synapses during sleep in childhood, which, in turn, might be related to increased plasticity during brain maturation. Regional differences in the extent of slow-wave slope reduction may reflect a "smart" down-selection process or, alternatively, indicate amplitude-dependent differences in the generation of slow-waves.

Closed-Loop Acoustic Stimulation During Sleep in Children With Epilepsy: A Hypothesis-Driven Novel Approach to Interact With Spike-Wave Activity and Pilot Data Assessing Feasibility.

Slow waves, the electroencephalographic (EEG) hallmark of deep sleep, can be systematically manipulated by acoustic stimulation: stimulation time-locked to the down phase of slow waves reduces, whereas stimulation time-locked to the up phase increases slow waves. Spike-waves during sleep seem to be related to slow waves, raising the question of whether spike-waves can be systematically influenced by such acoustic stimulation. In five pediatric patients, all-night EEG was recorded, combined with real-time slow wave detection. Throughout the night, acoustic stimulation was performed in a 3 × 5-min-block design (no stimulation-stimulation-no stimulation). Tones were applied time-locked either to the up or to the down phase of the detected slow waves in an alternating pattern. All patients tolerated the acoustic stimulation during sleep well. They showed high sleep quality and no signs of clinical or non-convulsive electrographic seizures. Our preliminary analysis shows no systematic effect of acoustic stimulation on spike-wave activity. Moreover, with our stimulation approach tones were distributed over a rather broad phase-range during the DOWN or UP stimulation and showed inter-individual differences in their distribution. In this study, we applied for the first time an acoustic closed-loop slow wave stimulation tool for a non-invasive manipulation of spike-wave activity. Thus, our pilot data show that closed-loop acoustic stimulation is feasible and well tolerated in children with spike wave activity during sleep. Improved precision in phase targeting and personalized stimulation parameters in a larger sample of subjects might be needed to show systematic effects.

Local sleep-like events during wakefulness and their relationship to decreased alertness in astronauts on ISS.

Adequate sleep quantity and quality is required to maintain vigilance, cognitive and learning processes. A decrease of sleep quantity preflight and on the International Space Station (ISS) has been reported. Recent counter-measures have been implemented to better regulate sleep opportunities on ISS. In our study, astronauts were allocated enough time for sleep the night before the recordings. However, for proper sleep recovery, the quality of sleep is also critical. Unfortunately, data on sleep quality have yet to be acquired from the ISS. Here, we investigate sleep pressure markers during wakefulness in five astronauts throughout their 6-month space mission by the mean of electroencephalographic recordings. We show a global increase of theta oscillations (5-7 Hz) on the ISS compared to on Earth before the mission. We also show that local sleep-like events, another marker of sleep pressure, are more global in space (p < 0.001). By analysing the performances of the astronauts during a docking simulation, we found that local sleep-like events are more global when reaction times are slower (R 2 = 0.03, p = 0.006) and there is an increase of reaction times above 244 ms after 2 months in space (p = 0.012). Our analyses provide first evidence for increased sleep pressure in space and raise awareness on possible impacts on visuomotor performances in space.

Author Correction: Deep sleep maintains learning efficiency of the human brain.

This corrects the article DOI: 10.1038/ncomms15405.

Theta waves in children's waking electroencephalogram resemble local aspects of sleep during wakefulness.

Vyazovskiy and colleagues found in rats' multi-unit recordings brief periods of silence (off-states) in local populations of cortical neurons during wakefulness which closely resembled the characteristic off-states during sleep. These off-states became more global and frequent with increasing sleep pressure and were associated with the well-known increase of theta activity under sleep deprivation in the surface EEG. Moreover, the occurrence of such off-states was related to impaired performance. While these animal experiments were based on intracranial recordings, we aimed to explore whether the human surface EEG may also provide evidence for such a local sleep-like intrusion during wakefulness. Thus, we analysed high-density wake EEG recordings during an auditory attention task in the morning and evening in 12 children. We found that, theta waves became more widespread in the evening and the occurrence of widespread theta waves was associated with slower reaction times in the attention task. These results indicate that widespread theta events measured on the scalp might be markers of local sleep in humans. Moreover, such markers of local sleep, seem to be related to the well described performance decline under high sleep pressure.

Deep sleep maintains learning efficiency of the human brain.

It is hypothesized that deep sleep is essential for restoring the brain's capacity to learn efficiently, especially in regions heavily activated during the day. However, causal evidence in humans has been lacking due to the inability to sleep deprive one target area while keeping the natural sleep pattern intact. Here we introduce a novel approach to focally perturb deep sleep in motor cortex, and investigate the consequences on behavioural and neurophysiological markers of neuroplasticity arising from dedicated motor practice. We show that the capacity to undergo neuroplastic changes is reduced by wakefulness but restored during unperturbed sleep. This restorative process is markedly attenuated when slow waves are selectively perturbed in motor cortex, demonstrating that deep sleep is a requirement for maintaining sustainable learning efficiency.

Impaired slow wave sleep downscaling in patients with infantile spasms.

BACKGROUND: West syndrome is a severe epileptic encephalopathy of infancy, characterized by infantile spasms, global retardation, and a severely abnormal electroencephalogram (EEG) pattern known as hypsarrhythmia, which is most prominent during slow waves sleep. The restorative function of slow wave sleep has been linked to downscaling, a neuronal process ensuring a balance of global synaptic strength, which is important for normal cortical functioning and development. A key electrophysiological marker for this downscaling is the reduction of the slope of slow waves across the night. METHODS: We retrospectively compared the slope of slow waves between 14 untreated patients with infantile spasms and healthy age and gender matched controls. Patients were examined in one all-night sleep EEG before treatment, and in two follow-up nap recordings, under and after treatment with corticosteroids. RESULTS: In patients with infantile spasms the overnight reduction in the slope of slow waves was significantly diminished compared to controls (p = 0.009). Moreover, untreated patients revealed overall steeper slopes. During corticosteroid treatment the slope was reduced compared to controls (p = 0.001). After successful treatment the slope was similar between patients and controls. CONCLUSION: Our results provide evidence for reduced downscaling in patients with infantile spasms. Moreover, the marked reduction of the slope during corticosteroid treatment may reflect a loss of synaptic connections due to the effect of glucocorticoids. This altered sleep dependent regulation of synaptic strength in infantile spasms may contribute the underlying pathomechanism of the developmental regression. Furthermore the normalization of synaptic strength due to corticosteroids might provide a potential mechanistic explanation for this treatment strategy.

Overnight changes in the slope of sleep slow waves during infancy.

STUDY OBJECTIVES: Slow wave activity (SWA, 0.5-4.5 Hz) is a well-established marker for sleep pressure in adults. Recent studies have shown that increasing sleep pressure is reflected by an increased synchronized firing pattern of cortical neurons, which can be measured by the slope of sleep slow waves. Thus we aimed at investigating whether the slope of sleep slow waves might provide an alternative marker to study the homeostatic regulation of sleep during early human development. DESIGN: All-night sleep electroencephalography (EEG) was recorded longitudinally at 2, 4, 6, and 9 months after birth. SETTING: Home recording. PATIENTS OR PARTICIPANTS: 11 healthy full-term infants (5 male, 6 female). INTERVENTIONS: None. MEASUREMENTS AND RESULTS: The slope of sleep slow waves increased with age. At all ages the slope decreased from the first to the last hour of non rapid-eye-movement (NREM) sleep, even when controlling for amplitude differences (P < 0.002). The decrease of the slope was also present in the cycle-by-cycle time course across the night (P < 0.001) at the age of 6 months when the alternating pattern of low-delta activity (0.75-1.75 Hz) is most prominent. Moreover, we found distinct topographical differences exhibiting the steepest slope over the occipital cortex. CONCLUSIONS: The results suggest an age-dependent increase in synchronization of cortical activity during infancy, which might be due to increasing synaptogenesis. Previous studies have shown that during early postnatal development synaptogenesis is most pronounced over the occipital cortex, which could explain why the steepest slope was found in the occipital derivation. Our results provide evidence that the homeostatic regulation of sleep develops early in human infants.

Electroencephalogram approximate entropy influenced by both age and sleep.

The use of information-based measures to assess changes in conscious state is an increasingly popular topic. Though recent results have seemed to justify the merits of such methods, little has been done to investigate the applicability of such measures to children. For our work, we used the approximate entropy (ApEn), a measure previously shown to correlate with changes in conscious state when applied to the electroencephalogram (EEG), and sought to confirm whether previously reported trends in adult ApEn values across wake and sleep were present in children. Besides validating the prior findings that ApEn decreases from wake to sleep (including wake, rapid eye movement (REM) sleep, and non-REM sleep) in adults, we found that previously reported ApEn decreases across vigilance states in adults were also present in children (ApEn trends for both age groups: wake > REM sleep > non-REM sleep). When comparing ApEn values between age groups, adults had significantly larger ApEn values than children during wakefulness. After the application of an 8 Hz high-pass filter to the EEG signal, ApEn values were recalculated. The number of electrodes with significant vigilance state effects dropped from all 109 electrodes with the original 1 Hz filter to 1 electrode with the 8 Hz filter. The number of electrodes with significant age effects dropped from 10 to 4. Our results support the notion that ApEn can reliably distinguish between vigilance states, with low-frequency sleep-related oscillations implicated as the driver of changes between vigilance states. We suggest that the observed differences between adult and child ApEn values during wake may reflect differences in connectivity between age groups, a factor which may be important in the use of EEG to measure consciousness.