Non-rapid Eye Movement Slow Wave Research Articles

Optogenetic targeting of astrocytes restores slow brain rhythm function and slows Alzheimer’s disease pathology

Patients with Alzheimer’s disease (AD) exhibit non-rapid eye movement (NREM) sleep disturbances in addition to memory deficits. Disruption of NREM slow waves occurs early in the disease progression and is recapitulated in transgenic mouse models of beta-amyloidosis. However, the mechanisms underlying slow-wave disruptions remain unknown. Because astrocytes contribute to slow-wave activity, we used multiphoton microscopy and optogenetics to investigate whether they contribute to slow-wave disruptions in APP/PS1 mice. The power but not the frequency of astrocytic calcium transients was reduced in APP/PS1 mice compared to nontransgenic controls. Optogenetic activation of astrocytes at the endogenous frequency of slow waves restored slow-wave power, reduced amyloid deposition, prevented neuronal calcium elevations, and improved memory performance. Our findings revealed malfunction of the astrocytic network driving slow-wave disruptions. Thus, targeting astrocytes to restore circuit activity underlying sleep and memory disruptions in AD could ameliorate disease progression.

Maturational trajectories of non-rapid eye movement slow wave activity and odds ratio product in a population-based sample of youth

BackgroundBrain maturation is reflected in the sleep electroencephalogram (EEG) by a decline in non-rapid eye movement (NREM) slow wave activity (SWA) throughout adolescence and a related decrease in sleep depth. However, this trajectory and its sex and pubertal differences lack replication in population-based samples. We tested age-related changes in SWA (0.4–4 Hz) power and odds ratio product (ORP), a standardized measure of sleep depth. MethodsWe analyzed the sleep EEG of 572 subjects aged 6-21 y (48% female, 26% racial/ethnic minority) and 332 subjects 5-12 y followed-up at 12-22 y. Multivariable-adjusted analyses tested age-related cross-sectional and longitudinal trajectories of SWA and ORP. ResultsSWA remained stable from age 6 to 10, decreased between ages 11 and 17, and plateaued from age 18 to 21 (p-cubic<0.001); females showed a longitudinal decline 23% greater than males by 13 y, while males experienced a steeper slope after 14 y and their longitudinal decline was 21% greater by 19 y. More mature adolescents (75% female) experienced a greater longitudinal decline in SWA than less mature adolescents by 14 y. ORP showed an age-related increasing trajectory (p-linear<0.001) with no sex or pubertal differences. ConclusionsWe provide population-level evidence for the maturational decline and sex and pubertal differences in SWA in the transition from childhood to adolescence, while introducing ORP as a novel metric in youth. Along with previous studies, the distinct trajectories observed suggest that age-related changes in SWA reflect brain maturation and local/synaptic processes during this developmental period, while those of ORP may reflect global/state control of NREM sleep depth.

Slow wave activity moderates the association between new learning and traumatic brain injury severity.

Sleep-wake complaints and difficulties in making new learning are among the most persistent and challenging long-term sequelea following moderate to severe traumatic brain injury (TBI). Yet, it is unclear whether, and to what extent, sleep characteristics during the chronic stage of TBI contribute to sleep-wake and cognitive complaints. We aimed to characterize sleep architecture in chronic moderate to severe TBI adults and assess whether non-rapid eye movement slow wave activity (SWA) is associated to next day performance in episodic memory tasks according to TBI severity. Forty-two moderate to severe TBI participants, 12-47 months post-injury, and 38 healthy controls were tested with one night of in-laboratory polysomnography, followed the next morning by questionnaires (sleep quality, fatigue, and sleepiness) and neuropsychological assessment. We used multiple regression analyses to assess the moderator effect of SWA power on TBI severity and next-day memory performance. We found that TBI participants reported worse sleep quality and fatigue, and had worse cognitive performance than controls. No between group differences were found on macro- and micro-architecture of sleep. However, SWA significantly interacted with TBI severity to explain next-day memory performance: higher SWA was more strongly associated to better memory performance in more severe TBI compared to milder TBI. This study provides evidence that the injured brain is able to produce macro- and micro-architecture of sleep comparable to what is seen in healthy controls. However, with increasing TBI severity, lower non-rapid eye movement SWA power is associated with reduced ability to learn and memorise new information the following day.

Intersection between sleep and neurovascular coupling as the driving pathophysiology of Alzheimer’s disease

Alzheimer’s disease (AD) is the commonest cause of dementia. There are tremendous personal and systemic costs associated with the disease. Although there has been significant progress in understanding the disease process, the precise pathophysiologic mechanism remains elusive. The amyloid hypothesis is the leading theory with impaired clearance of the amyloid beta (Aβ) believed to be the underpinning disease process. However, what triggers and propagates the accumulation of Aβ remains unclear. We propose that the impairment of neurovascular coupling triggers a cascade that ultimately leads to impaired Aβ clearance. With aging there is a generalized decline in cerebral blood flow and impairment of cerebrovascular reactivity. With impairment of this neurovascular coupling, the normal bulk clearance of cerebrospinal fluid and interstitial fluid (ISF) becomes hindered. We postulate that this clearance process occurs during non-rapid eye movement slow wave sleep, driven by the tight neurovascular coupling, via a pump-like action. The impairment of ISF clearance results in change in the interstitial microenvironment from accumulation of metabolites, reactive oxygen species, metal ions and results in decreased pH. The changes in the microenvironment promotes the accumulation and aggregation of Aβ, heralding the disease process.

Integrity of Corpus Callosum Is Essential for theCross-Hemispheric Propagation of Sleep Slow Waves:A High-Density EEG Study in Split-Brain Patients.

The slow waves of non-rapid eye movement (NREM) sleep reflect experience-dependent plasticity and play a direct role in the restorative functions of sleep. Importantly, slow waves behave as traveling waves, and their propagation is assumed to occur through cortico-cortical white matter connections. In this light, the corpus callosum (CC) may represent the main responsible for cross-hemispheric slow-wave propagation. To verify this hypothesis, we performed overnight high-density (hd)-EEG recordings in five patients who underwent total callosotomy due to drug-resistant epilepsy (CPs; two females), in three noncallosotomized neurologic patients (NPs; two females), and in a sample of 24 healthy adult subjects (HSs; 13 females). In all CPs slow waves displayed a significantly reduced probability of cross-hemispheric propagation and a stronger inter-hemispheric asymmetry. In both CPs and HSs, the incidence of large slow waves within individual NREM epochs tended to differ across hemispheres, with a relative overall predominance of the right over the left hemisphere. The absolute magnitude of this asymmetry was greater in CPs relative to HSs. However, the CC resection had no significant effects on the distribution of slow-wave origin probability across hemispheres. The present results indicate that CC integrity is essential for the cross-hemispheric traveling of slow waves in human sleep, which is in line with the assumption of a direct relationship between white matter integrity and slow-wave propagation. Our findings also revealed a residual cross-hemispheric slow-wave propagation that may rely on alternative pathways, including cortico-subcortico-cortical loops. Finally, these data indicate that the lack of the CC does not lead to differences in slow-wave generation across brain hemispheres.SIGNIFICANCE STATEMENT The slow waves of NREM sleep behave as traveling waves, and their propagation has been suggested to reflect the integrity of white matter cortico-cortical connections. To directly assess this hypothesis, here we investigated the role of the corpus callosum in the cortical spreading of NREM slow waves through the study of a rare population of totally callosotomized patients. Our results demonstrate a causal role of the corpus callosum in the cross-hemispheric traveling of sleep slow waves. Additionally, we found that callosotomy does not affect the relative tendency of each hemisphere at generating slow waves. Incidentally, we also found that slow waves tend to originate more often in the right than in the left hemisphere in both callosotomized and healthy adult individuals.

Haplotype of the astrocytic water channel AQP4 is associated with slow wave energy regulation in human NREM sleep.

Cerebrospinal fluid (CSF) flow through the brain parenchyma is facilitated by the astrocytic water channel aquaporin 4 (AQP4). Homeostatically regulated electroencephalographic (EEG) slow waves are a hallmark of deep non-rapid eye movement (NREM) sleep and have been implicated in the regulation of parenchymal CSF flow and brain clearance. The human AQP4 gene harbors several single nucleotide polymorphisms (SNPs) associated with AQP4 expression, brain-water homeostasis, and neurodegenerative diseases. To date, their role in sleep-wake regulation is unknown. To investigate whether functional variants in AQP4 modulate human sleep, nocturnal EEG recordings and cognitive performance were investigated in 123 healthy participants genotyped for a common eight-SNP AQP4-haplotype. We show that this AQP4-haplotype is associated with distinct modulations of NREM slow wave energy, strongest in early sleep and mirrored by changes in sleepiness and reaction times during extended wakefulness. The study provides the first human evidence for a link between AQP4, deep NREM sleep, and cognitive consequences of prolonged wakefulness.

Visual imagery and visual perception induce similar changes in occipital slow waves of sleep.

Previous studies have shown that regional slow-wave activity (SWA) during non-rapid eye movement (NREM) sleep is modulated by prior experience and learning. Although this effect has been convincingly demonstrated for the sensorimotor domain, attempts to extend these findings to the visual system have provided mixed results. In this study we asked whether depriving subjects of external visual stimuli during daytime would lead to regional changes in slow waves during sleep and whether the degree of "internal visual stimulation" (spontaneous imagery) would influence such changes. In two 8-h sessions spaced 1 wk apart, 12 healthy volunteers either were blindfolded while listening to audiobooks or watched movies (control condition), after which their sleep was recorded with high-density EEG. We found that during NREM sleep, the number of small, local slow waves in the occipital cortex decreased after listening with blindfolding relative to movie watching in a way that depended on the degree of visual imagery subjects reported during blindfolding: subjects with low visual imagery showed a significant reduction of occipital sleep slow waves, whereas those who reported a high degree of visual imagery did not. We also found a positive relationship between the reliance on visual imagery during blindfolding and audiobook listening and the degree of correlation in sleep SWA between visual areas and language-related areas. These preliminary results demonstrate that short-term alterations in visual experience may trigger slow-wave changes in cortical visual areas. Furthermore, they suggest that plasticity-related EEG changes during sleep may reflect externally induced ("bottom up") visual experiences, as well as internally generated ("top down") processes. NEW & NOTEWORTHY Previous work has shown that slow-wave activity, a marker of sleep depth, is linked to neural plasticity in the sensorimotor cortex. We show that after short-term visual deprivation, subjects who reported little visual imagery had a reduced incidence of occipital slow waves. This effect was absent in subjects who reported strong spontaneous visual imagery. These findings suggest that visual imagery may "substitute" for visual perception and induce similar changes in non-rapid eye movement slow waves.

Human Hippocampal Structure: A Novel Biomarker Predicting Mnemonic Vulnerability to, and Recovery from, Sleep Deprivation.

Sleep deprivation impairs the formation of new memories. However, marked interindividual variability exists in the degree to which sleep loss compromises learning, the mechanistic reasons for which are unclear. Furthermore, which physiological sleep processes restore learning ability following sleep deprivation are similarly unknown. Here, we demonstrate that the structural morphology of human hippocampal subfields represents one factor determining vulnerability (and conversely, resilience) to the impact of sleep deprivation on memory formation. Moreover, this same measure of brain morphology was further associated with the quality of nonrapid eye movement slow wave oscillations during recovery sleep, and by way of such activity, determined the success of memory restoration. Such findings provide a novel human biomarker of cognitive susceptibility to, and recovery from, sleep deprivation. Moreover, this metric may be of special predictive utility for professions in which memory function is paramount yet insufficient sleep is pervasive (e.g., aviation, military, and medicine).

β-amyloid disrupts human NREM slow waves and related hippocampus-dependent memory consolidation.

Independent evidence associates β-amyloid pathology with both NREM sleep disruption and memory impairment in older adults. However, whether the influence of β-amyloid pathology on hippocampus-dependent memory is, in part, driven by impairments of NREM slow wave activity (SWA) and associated overnight memory consolidation is unknown. Here, we show that β-amyloid burden within medial prefrontal cortex (mPFC) is significantly correlated with the severity of impairment in NREM SWA generation. Moreover, reduced NREM SWA generation was further associated with impaired overnight memory consolidation and impoverished hippocampal-neocortical memory transformation. Furthermore, structural equation models revealed that the association between mPFC β-amyloid pathology and impaired hippocampus-dependent memory consolidation is not direct, but instead, statistically depends on the intermediary factor of diminished NREM SWA. By linking β-amyloid pathology with impaired NREM SWA, these data implicate sleep disruption as a novel mechanistic pathway through which β-amyloid pathology may contribute to hippocampus-dependent cognitive decline in the elderly.

A single-dose, randomized, double-blind, double dummy, placebo and positive-controlled, five-way cross-over study to assess the pharmacodynamic effects of lorediplon in a phase advance model of insomnia in healthy Caucasian adult male subjects.

A 5-h phase advance model of insomnia was used to evaluate the efficacy of lorediplon, a new non-benzodiazepine hypnotic. Thirty-five male, healthy subjects were included in a five-way randomized cross-over study. During each of the periods, sleep was recorded, and residual effects were measured. All subjects received lorediplon 1, 5, and 10 mg, placebo, and zolpidem 10 mg (i.e., active control). Polysomnographic evaluation revealed that lorediplon (5 and 10 mg) significantly decreased wake after sleep onset (WASO) and increased total sleep time. Analysis by quarters of the night showed a progressive increasing effectiveness of lorediplon 10 mg across the first three quarters. Lorediplon increased non-rapid eye movement slow wave sleep and stage N2 sleep in the second and third quarters. The magnitude of these effects was dose related, with minimal effects seen with 1 mg. No residual effects were observed 13 h post dose. Lorediplon demonstrated a dose-dependent improvement in sleep, whereas zolpidem showed a more sustained WASO effect. No next-day hangover effects were observed. These sleep effects are also consistent with the pharmacokinetic profile of lorediplon. These results warrant clinical trials in patients with insomnia.

Sex Chromosomes Regulate Nighttime Sleep Propensity during Recovery from Sleep Loss in Mice

Sex differences in spontaneous sleep amount are largely dependent on reproductive hormones; however, in mice some sex differences in sleep amount during the active phase are preserved after gonadectomy and may be driven by non-hormonal factors. In this study, we sought to determine whether or not these sex differences are driven by sex chromosome complement. Mice from the four core genotype (FCG) mouse model, whose sex chromosome complement (XY, XX) is independent of phenotype (male or female), were implanted with electroencephalographic (EEG) and electromyographic (EMG) electrodes for the recording of sleep-wake states and underwent a 24-hr baseline recording followed by six hours of forced wakefulness. During baseline conditions in mice whose gonads remained intact, males had more total sleep and non-rapid eye movement sleep than females during the active phase. Gonadectomized FCG mice exhibited no sex differences in rest-phase sleep amount; however, during the mid-active-phase (nighttime), XX males had more spontaneous non-rapid eye movement (NREM) sleep than XX females. The XY mice did not exhibit sex differences in sleep amount. Following forced wakefulness there was a change in the factors regulating sleep. XY females slept more during their mid-active phase siestas than XX females and had higher NREM slow wave activity, a measure of sleep propensity. These findings suggest that the process that regulates sleep propensity is sex-linked, and that sleep amount and sleep propensity are regulated differently in males and females following sleep loss.

Prefrontal atrophy, disrupted NREM slow waves and impaired hippocampal-dependent memory in aging

Aging has independently been associated with regional brain atrophy, reduced non-rapid eye movement (NREM) slow-wave activity (SWA), and impaired long-term retention of episodic memories. However, that the interaction of these factors represents a neuropatholgical pathway associated with cognitive decline in later life remains unknown. Here, we show that age-related medial prefrontal cortex (mPFC) grey-matter atrophy is associated with reduced NREM SWA activity in older adults, the extent to which statistically mediates the impairment of overnight sleep-dependent memory retention. Moreover, this memory impairment was further associated with persistent hippocampal activation and reduced task-related hippocampal-prefrontal cortex connectivity, potentially representing impoverished hippocampal-neocortical memory transformation. Together, these data support a model in which age-related mPFC atrophy diminishes SWA, the functional consequence of which is impaired long-term memory. Such findings suggest that sleep disruption in the elderly, mediated by structural brain changes, represent a novel contributing factor to age-related cognitive decline in later life.

Wake deterioration and sleep restoration of human learning

Summary While the benefit of sleep after learning in offline consolidation is established [1], a role for sleep before learning in promoting initial memory formation remains largely uncharacterized. Existing theoretical frameworks speculate that accrued time awake, associated with ongoing experience, decreases learning capacity, while specific non-rapid-eye-movement (NREM) oscillations support restoration of learning ability [1,2]. Despite these model predictions, it remains untested whether episodic learning capacity remains stable across the day, or is progressively compromised by continued time awake. Furthermore, it is similarly unclear whether the presence, rather than the detrimental absence, of sleep restores efficient learning ability, and if so, what aspect(s) of sleep physiology support such reinstatement [3,4]. We have tested these related hypotheses, and report here a learning interaction, such that episodic encoding capacity deteriorates across a daytime waking interval, but sleep and associated NREM spindle oscillations restore efficient learning ability.

Rapid Eye Movement Sleep Deprivation Contributes to Reduction of Neurogenesis in the Hippocampal Dentate Gyrus of the Adult Rat

The dentate gyrus (DG) of the adult hippocampus contains progenitor cells, which have potential to differentiate into neurons. Previously we reported that 96 hours of total sleep deprivation reduces neurogenesis in the DG of adult rats. Loss of either non-rapid eye movement (NREM) or rapid eye movement (REM) sleep could have contributed to the effect of total sleep deprivation. The present study assessed the effect of 4 days of REM sleep deprivation (REMD) on neurogenesis. REMD was achieved by brief treadmill movement initiated by automatic online detection of REM sleep. A yoked-control (YC) rat was placed in the same treadmill and experienced the identical movement regardless the stage of the sleep-wake cycle. The thymidine analog 5- bromo- 2'- deoxy-uridine and the intrinsic proliferation marker, Ki-67, were both used to label proliferating cells. Basic neurophysiology laboratory. Male Sprague-Dawley male rats (300-320 g). REM sleep was reduced by 85% in REMD rats and by 43% in YC, compared with cage control animals and by 79% in REMD rats compared with YC. NREM sleep and slow wave activity within NREM did not differ in REMD and YC groups. Cell proliferation was reduced by 63 % in REMD compared with YC rats, and by 82% and 51%, respectively, in REMD and YC rats compared with cage controls. Across all animals, cell proliferation exhibited a positive correlation with the percentage of REM sleep (r = 0.84, P < 0.001). Reduced cell proliferation in REMD rats was confirmed with the intrinsic proliferation marker, Ki-67. REMD also reduced the percentage of proliferating cells that later expressed a mature neuronal marker. The present findings support a hypothesis that REM sleep-associated processes facilitate proliferation of granule cells in the adult hippocampal DG.

Ritanserin, A 5-HT2 Receptor Blocker, as Add-on Treatment in Narcolepsy

In a double-blind placebo-controlled trial, ritanserin (a 5-HT2 receptor blocker) 5 mg/day or placebo was added to the usual medication in 28 patients with narcolepsy during 4 wk. The effect was assessed by means of polysomnography, daily and weekly subjective evaluations, and Multiple sleep latency tests (MSLT). During the night ritanserin increased the amount of nonrapid eye movement slow wave sleep and reduced wakefulness after sleep onset. It improved the feeling of being refreshed in the morning after awakening and reduced subjective daytime sleepiness. The drug did not significantly influence sleep latency in the MSLT.