Iron-Deficiency Anemia is Associated with Altered Characteristics of Sleep Spindles in NREM Sleep in Infancy

Objective To determine the effects of iron-deficiency anemia on the development of non-rapid-eye-movement (NREM) sleep stages, as indexed by sleep spindles. Study design Patterns of sleep spindles during NREM sleep stages 2 and 3–4 (slow-wave-sleep, SWS) were compared in 26 otherwise healthy 6-month-old Chilean infants with iron-deficiency anemia and 18 non-anemic control infants. From polygraphic recordings, EEG activity was analyzed for sleep spindles to assess their number (density), duration, frequency, and inter-spindle interval. Results Iron-deficient anemic infants differed from the control group by having sleep spindles with reduced density, lower frequency, and longer inter-spindle intervals in NREM sleep stage 2 and SWS. Conclusions These results provide evidence of delayed sleep spindle patterns in iron-deficient anemic infants, suggesting that iron is an essential micronutrient for the normal progression of NREM sleep pattern development in the human. Special issue dedicated to Dr. Moussa Youdim.     

Statistical Analysis of Sleep Spindle Occurrences

Spindles - a hallmark of stage II sleep - are a transient oscillatory phenomenon in the EEG believed to reflect thalamocortical activity contributing to unresponsiveness during sleep. Currently spindles are often classified into two classes: fast spindles, with a frequency of around 14 Hz, occurring in the centro-parietal region; and slow spindles, with a frequency of around 12 Hz, prevalent in the frontal region. Here we aim to establish whether the spindle generation process also exhibits spatial heterogeneity. Electroencephalographic recordings from 20 subjects were automatically scanned to detect spindles and the time occurrences of spindles were used for statistical analysis. Gamma distribution parameters were fit to each inter-spindle interval distribution, and a modified Wald-Wolfowitz lag-1 correlation test was applied. Results indicate that not all spindles are generated by the same statistical process, but this dissociation is not spindle-type specific. Although this dissociation is not topographically specific, a single generator for all spindle types appears unlikely.     

Sleep intensity and the evolution of human cognition

Over the past four decades, scientists have made substantial progress in understanding the evolution of sleep patterns across the Tree of Life. 1 , 2 Remarkably, the specifics of sleep along the human lineage have been slow to emerge. This is surprising, given our unique mental and behavioral capacity and the importance of sleep for individual cognitive performance. 3 - 5 One view is that our species' sleep architecture is in accord with patterns documented in other mammals. 6 We promote an alternative view, that human sleep is highly derived relative to that of other primates. Based on new and existing evidence, we specifically propose that humans are more efficient in their sleep patterns than are other primates, and that human sleep is shorter, deeper, and exhibits a higher proportion of REM than expected. Thus, we propose the sleep intensity hypothesis: Early humans experienced selective pressure to fulfill sleep needs in the shortest time possible. Several factors likely served as selective pressures for more efficient sleep, including increased predation risk in terrestrial environments, threats from intergroup conflict, and benefits arising from increased social interaction. Less sleep would enable longer active periods in which to acquire and transmit new skills and knowledge, while deeper sleep may be critical for the consolidation of those skills, leading to enhanced cognitive abilities in early humans.     

Divergent Cortical Generators of MEG and EEG during Human Sleep Spindles Suggested by Distributed Source Modeling

Background

Sleep spindles are ∼1-second bursts of 10–15 Hz activity, occurring during normal stage 2 sleep. In animals, sleep spindles can be synchronous across multiple cortical and thalamic locations, suggesting a distributed stable phase-locked generating system. The high synchrony of spindles across scalp EEG sites suggests that this may also be true in humans. However, prior MEG studies suggest multiple and varying generators.

Methodology/Principal Findings

We recorded 306 channels of MEG simultaneously with 60 channels of EEG during naturally occurring spindles of stage 2 sleep in 7 healthy subjects. High-resolution structural MRI was obtained in each subject, to define the shells for a boundary element forward solution and to reconstruct the cortex providing the solution space for a noise-normalized minimum norm source estimation procedure. Integrated across the entire duration of all spindles, sources estimated from EEG and MEG are similar, diffuse and widespread, including all lobes from both hemispheres. However, the locations, phase and amplitude of sources simultaneously estimated from MEG versus EEG are highly distinct during the same spindles. Specifically, the sources estimated from EEG are highly synchronous across the cortex, whereas those from MEG rapidly shift in phase, hemisphere, and the location within the hemisphere.

Conclusions/Significance

The heterogeneity of MEG sources implies that multiple generators are active during human sleep spindles. If the source modeling is correct, then EEG spindles are generated by a different, diffusely synchronous system. Animal studies have identified two thalamo-cortical systems, core and matrix, that produce focal or diffuse activation and thus could underlie MEG and EEG spindles, respectively. Alternatively, EEG spindles could reflect overlap at the sensors of the same sources as are seen from the MEG. Although our results generally match human intracranial recordings, additional improvements are possible and simultaneous intra- and extra-cranial measures are needed to test their accuracy.     

Synchronization and Propagation of Global Sleep Spindles

Sleep spindles occur thousands of times during normal sleep and can be easily detected by visual inspection of EEG signals. These characteristics make spindles one of the most studied EEG structures in mammalian sleep. In this work we considered global spindles, which are spindles that are observed simultaneously in all EEG channels. We propose a methodology that investigates both the signal envelope and phase/frequency of each global spindle. By analysing the global spindle phase we showed that 90% of spindles synchronize with an average latency time of 0.1 s. We also measured the frequency modulation (chirp) of global spindles and found that global spindle chirp and synchronization are not correlated. By investigating the signal envelopes and implementing a homogeneous and isotropic propagation model, we could estimate both the signal origin and velocity in global spindles. Our results indicate that this simple and non-invasive approach could determine with reasonable precision the spindle origin, and allowed us to estimate a signal speed of 0.12 m/s. Finally, we consider whether synchronization might be useful as a non-invasive diagnostic tool.     

Coupling of Thalamocortical Sleep Oscillations Are Important for Memory Consolidation in Humans

Sleep, specifically non-rapid eye movement (NREM) sleep, is thought to play a critical role in the consolidation of recent memories. Two main oscillatory activities observed during NREM, cortical slow oscillations (SO, 0.5–1.0Hz) and thalamic spindles (12–15Hz), have been shown to independently correlate with memory improvement. Yet, it is not known how these thalamocortical events interact, or the significance of this interaction, during the consolidation process. Here, we found that systemic administration of the GABAergic drug (zolpidem) increased both the phase-amplitude coupling between SO and spindles, and verbal memory improvement in humans. These results suggest that thalamic spindles that occur during transitions to the cortical SO Up state are optimal for memory consolidation. Our study predicts that the timely interactions between cortical and thalamic events during consolidation, contribute to memory improvement and is mediated by the level of inhibitory neurotransmission.     

The Significance of Sigma Neurofeedback Training on Sleep Spindles and Aspects of Declarative Memory

The functional significance of sleep spindles for overnight memory consolidation and general learning aptitude as well as the effect of four 10-minute sessions of spindle frequency (11.6–16 Hz, sigma) neurofeedback-training on subsequent sleep spindle activity and overnight performance change was investigated. Before sleep, subjects were trained on a paired-associate word list task after having received either neurofeedback training (NFT) or pseudofeedback training (PFT).Although NFT had no significant impact on subsequent spindle activity and behavioral outcomes, there was a trend for enhanced sigma band-power during NREM (stage 2 to 4) sleep after NFT as compared to PFT. Furthermore, a significant positive correlation between spindle activity during slow wave sleep (in the first night half) and overall memory performance was revealed. The results support the view that the considerable inter-individual variance in sleep spindle activity can at least be partly explained by differences in the ability to acquire new declarative information.We conclude that the short NFT before sleep was not sufficient to efficiently enhance phasic spindle activity and/or to influence memory processing. NFT was, however, successful in increasing sigma power, presumably because sigma NFT effects become more easily evident in actually trained frequency bands than in associated phasic spindle activity.The authors contributed equally to manuscipt     

Dynamic Interaction of Spindles and Gamma Activity during Cortical Slow Oscillations and Its Modulation by Subcortical Afferents

Slow oscillations are a hallmark of slow wave sleep. They provide a temporal framework for a variety of phasic events to occur and interact during sleep, including the expression of high-frequency oscillations and the discharge of neurons across the entire brain. Evidence shows that the emergence of distinct high-frequency oscillations during slow oscillations facilitates the communication among brain regions whose activity was correlated during the preceding waking period. While the frequencies of oscillations involved in such interactions have been identified, their dynamics and the correlations between them require further investigation. Here we analyzed the structure and dynamics of these signals in anesthetized rats. We show that spindles and gamma oscillations coexist but have distinct temporal dynamics across the slow oscillation cycle. Furthermore, we observed that spindles and gamma are functionally coupled to the slow oscillations and between each other. Following the activation of ascending pathways from the brainstem by means of a carbachol injection in the pedunculopontine nucleus, we were able to modify the gain in the gamma oscillations that are independent of the spindles while the spindle amplitude was reduced. Furthermore, carbachol produced a decoupling of the gamma oscillations that are dependent on the spindles but with no effect on their amplitude. None of the changes in the high-frequency oscillations affected the onset or shape of the slow oscillations, suggesting that slow oscillations occur independently of the phasic events that coexist with them. Our results provide novel insights into the regulation, dynamics and homeostasis of cortical slow oscillations.     

Sleep and nesting behavior in primates: A review

Sleep is a universal behavior in vertebrate and invertebrate animals, suggesting it originated in the very first life forms. Given the vital function of sleep, sleeping patterns and sleep architecture follow dynamic and adaptive processes reflecting trade-offs to different selective pressures. Here, we review responses in sleep and sleep-related behavior to environmental constraints across primate species, focusing on the role of great ape nest building in hominid evolution. We summarize and synthesize major hypotheses explaining the proximate and ultimate functions of great ape nest building across all species and subspecies; we draw on 46 original studies published between 2000 and 2017. In addition, we integrate the most recent data brought together by researchers from a complementary range of disciplines in the frame of the symposium “Burning the midnight oil” held at the 26th Congress of the International Primatological Society, Chicago, August 2016, as well as some additional contributors, each of which is included as a “stand-alone” article in this “Primate Sleep” symposium set. In doing so, we present crucial factors to be considered in describing scenarios of human sleep evolution: (a) the implications of nest construction for sleep quality and cognition; (b) the tree-to-ground transition in early hominids; (c) the peculiarities of human sleep. We propose bridging disciplines such as neurobiology, endocrinology, medicine, and evolutionary ecology, so that future research may disentangle the major functions of sleep in human and nonhuman primates, namely its role in energy allocation, health, and cognition.     

A Laboratory Study of Sleep and Dreaming in a Case of Asperger's Syndrome

Asperger's Syndrome (AS) is a pervasive developmental disorder whose continuity with High-Functioning Autism is still a matter of debate. Clinical observations suggest that patients with AS may present the same sleep disorders as autistic patients, including difficulties in initiating and maintaining sleep as well as poor dream recall. We recorded the sleep of a 25-year-old male patient with AS for two nights using a full EEG montage and compared the second night to that of a group of normal participants. We found low levels of slow wave sleep (SWS: stages 3 + 4), high levels of stage 1, and a large number of awakenings. The organization of REM sleep was unremarkable, including normal REM density. Analyses of phasic EEG events revealed a very low incidence of sleep spindles and a normal number of K-complexes over bilateral frontal and central EEG leads. In order to collect dream reports, the patient was awakened three times over two nights following at least 15 minutes of REM sleep in each case. On each occasion the patient was not aware of any mental activity happening just prior to awakening. These observations are discussed with regards to the connections that may exist between EEG sleep spindle activity, selective attention, and the capacity to generate a dream report.     

The Sleep Cycle Modelled as a Cortical Phase Transition

We present a mean-field model of the cortex that attempts to describe the gross changes in brain electrical activity for the cycles of natural sleep. We incorporate within the model two major sleep modulatory effects: slow changes in both synaptic efficiency and in neuron resting voltage caused by the ∼90-min cycling in acetylcholine, together with even slower changes in resting voltage caused by gradual elimination during sleep of somnogens (fatigue agents) such as adenosine. We argue that the change from slow-wave sleep (SWS) to rapid-eye-movement (REM) sleep can be understood as a first-order phase transition from a low-firing, coherent state to a high-firing, desychronized cortical state. We show that the model predictions for changes in EEG power, spectral distribution, and correlation time at the SWS-to-REM transition are consistent not only with those observed in clinical recordings of a sleeping human subject, but also with the on-cortex EEG patterns recently reported by Destexhe et al. [J. Neurosci. 19(11), (1999) 4595–4608] for the sleeping cat.     

No Effects of Successful Bidirectional SMR Feedback Training on Objective and Subjective Sleep in Healthy Subjects

There is a growing interest in the application of psychophysiological signals in more applied settings. Unidirectional sensory motor rhythm-training (SMR) has demonstrated consistent effects on sleep. In this study the main aim was to analyze to what extent participants could gain voluntary control over sleep-related parameters and secondarily to assess possible influences of this training on sleep metrics. Bidirectional training of SMR as well as heart rate variability (HRV) was used to assess the feasibility of training these parameters as possible brain computer interfaces (BCI) signals, and assess effects normally associated with unidirectional SMR training such as the influence on objective and subjective sleep parameters. Participants (n?=?26) received between 11 and 21 training sessions during 7 weeks in which they received feedback on their personalized threshold for either SMR or HRV activity, for both up- and down regulation. During a pre- and post-test a sleep log was kept and participants used a wrist actigraph. Participants were asked to take an afternoon nap on the first day at the testing facility. During napping, sleep spindles were assessed as well as self-reported sleep measures of the nap. Although the training demonstrated successful learning to increase and decrease SMR and HRV activity, no effects were found of bidirectional training on sleep spindles, actigraphy, sleep diaries, and self-reported sleep quality. As such it is concluded that bidirectional SMR and HRV training can be safely used as a BCI and participants were able to improve their control over physiological signals with bidirectional training, whereas the application of bidirectional SMR and HRV training did not lead to significant changes of sleep quality in this healthy population.     

Sleep in birds: lying on the continuum of activity and rest

Abstract

Sleep is highly organized activity which is associated with decreased muscular activity and reduced response to environmental stimuli. The sleep is regulated by both, circadian and homeostatic mechanisms. Sleep patterns can be studied by behavioral assays by observing different sleep behaviors or by neuronal activity such as EEG (electroencephalogram), EOG (electro-oculogram), and EMG (electromyogram). Sleep is organized into non-rapid eye movement (NREM) and rapid eye movement. The sleep pattern in birds are similar to that in mammals, however, few differences such as existence of unihemispheric sleep (UHS) in almost all birds compared to few marine mammals do exist. The UHS results in asymmetry of the brain function measured as slow wave activity (SWA). Several migrants exhibit sleeplessness and they compensate it by NREM. They employ UHS during their migratory flight to remain alert while sleeping and maintain the balance while flying which is advantageous for these birds. Thus, sleep is of fundamental significance for the animal as it lies on the continuum of activity and rest. The present review focuses on some of above mentioned facts about sleep in higher vertebrates particularly in birds.     

Sleep enhances plasticity in the developing visual cortex

During a critical period of brain development, occluding the vision of one eye causes a rapid remodeling of the visual cortex and its inputs. Sleep has been linked to other processes thought to depend on synaptic remodeling, but a role for sleep in this form of cortical plasticity has not been demonstrated. We found that sleep enhanced the effects of a preceding period of monocular deprivation on visual cortical responses, but wakefulness in complete darkness did not do so. The enhancement of plasticity by sleep was at least as great as that produced by an equal amount of additional deprivation. These findings demonstrate that sleep and sleep loss modify experience-dependent cortical plasticity in vivo. They suggest that sleep in early life may play a crucial role in brain development.     

The Temporal Structure of Behaviour and Sleep Homeostasis

The amount and architecture of vigilance states are governed by two distinct processes, which occur at different time scales. The first, a slow one, is related to a wake/sleep dependent homeostatic Process S, which occurs on a time scale of hours, and is reflected in the dynamics of NREM sleep EEG slow-wave activity. The second, a fast one, is manifested in a regular alternation of two sleep states – NREM and REM sleep, which occur, in rodents, on a time scale of ∼5–10 minutes. Neither the mechanisms underlying the time constants of these two processes – the slow one and the fast one, nor their functional significance are understood. Notably, both processes are primarily apparent during sleep, while their potential manifestation during wakefulness is obscured by ongoing behaviour. Here, we find, in mice provided with running wheels, that the two sleep processes become clearly apparent also during waking at the level of behavior and brain activity. Specifically, the slow process was manifested in the total duration of waking periods starting from dark onset, while the fast process was apparent in a regular occurrence of running bouts during the waking periods. The dynamics of both processes were stable within individual animals, but showed large interindividual variability. Importantly, the two processes were not independent: the periodic structure of waking behaviour (fast process) appeared to be a strong predictor of the capacity to sustain continuous wakefulness (slow process). The data indicate that the temporal organization of vigilance states on both the fast and the slow time scales may arise from a common neurophysiologic mechanism.     

The dynamics of spindles and EEG slow-wave activity in NREM sleep in mice

A quantitative analysis of spindles and spindle-related EEG activity was performed in C57BL/6 mice. The hypothesis that spindles are involved in sleep regulatory mechanisms was tested by investigating their occurrence during 24 h and after 6 h sleep deprivation (SD; n = 7). In the frontal derivation distinct spindle events were characterized as EEG oscillations with a dominant frequency approximately at 11 Hz. Spindles were most prominent during NREM sleep and increased before NREM-REM sleep transitions. Whereas spindles increased concomitantly with slow wave activity (SWA, EEG power between 0.5 and 4.0 Hz) at the beginning of the NREM sleep episode, these measures showed an opposite evolution prior to the transition to REM sleep. The 24-h time course of spindles showed a maximum at the end of the 12-h light period, and was a mirror image of SWA in NREM sleep. After 6 h SD the spindles in NREM sleep were initially suppressed, and showed a delayed rebound. In contrast, spindles occurring immediately before the transition to REM sleep were enhanced during the first 2 h of recovery. The data suggest that spindles in NREM sleep may be involved in sleep maintenance, while spindles heralding the transition to REM sleep may be related to mechanisms of REM sleep initiation.     

Assessment of Human Sleep Depth Is Being De-Standardized by Recently Advised EEG Electrode Locations

Human sleep depth was traditionally assessed by scoring electro-encephalographic slow-wave amplitudes at the globally standardized C4-M1 electrode derivation. Since 2007, the American Association of Sleep Medicine (AASM) has accepted three additional derivations for the same purpose. These might well differ in slow wave amplitudes which would bias the scorings. Some derivations might also introduce large inter-individual variability. We compared mean and variability of slow wave amplitudes between six derivations including the four AASM ones. Slow wave amplitudes in those derivations were simultaneously measured using automated analysis in 29 patients. Each amplitude was divided by the average from the six derivations, thus removing shared factors such as age, gender and sleep depth while retaining factors that differ between the derivations such as caused by local skull characteristics, electrode distance and neuronal dipole orientation. The remaining inter-individual variability differed significantly and up to a factor of two between the AASM derivations. The amplitudes differed significantly and up to 60% between the AASM derivations, causing substantial scoring bias between centres using different derivations. The resulting de-standardization most likely affects any patient group because the amplitude differences were consistent over diagnoses, genders, and age. Derivation-dependent amplitude thresholds were proposed to reduce the scoring bias. However, it would be better to settle on just one derivation, for instance Cz-Oz or Fpz-Cz because these have lowest variability while matching the traditional C4-M1 amplitudes.     

Sleep spindle characteristics in overweight adolescents with obstructive sleep apnea syndrome

Sleep and Biological Rhythms - Sleep spindles may display a sleep protective function. Thus, their activity is also a stable marker of sleep disturbances. We investigated whether spindle activity...     

Polygenic impact of morningness on the overnight dynamics of sleep spindle amplitude

Sleep spindles are thalamocortical oscillations that contribute to sleep maintenance and sleep‐related brain plasticity. The current study is an explorative study of the circadian dynamics of sleep spindles in relation to a polygenic score (PGS) for circadian preference towards morningness. The participants represent the 17‐year follow‐up of a birth cohort having both genome‐wide data and an ambulatory sleep electroencephalography measurement available ( N = 154, Mean age = 16.9, SD = 0.1 years, 57% girls). Based on a recent genome‐wide association study, we calculated a PGS for circadian preference towards morningness across the whole genome, including 354 single‐nucleotide polymorphisms. Stage 2 slow (9‐12.5 Hz, N = 186 739) and fast (12.5‐16 Hz, N = 135 504) sleep spindles were detected using an automated algorithm with individual time tags and amplitudes for each spindle. There was a significant interaction of PGS for morningness and timing of sleep spindles across the night. These growth curve models showed a curvilinear trajectory of spindle amplitudes: those with a higher PGS for morningness showed higher slow spindle amplitudes in frontal derivations, and a faster dissipation of spindle amplitude in central derivations. Overall, the findings provide new evidence on how individual sleep spindle trajectories are influenced by genetic factors associated with circadian type. The finding may lead to new hypotheses on the associations previously observed between circadian types, psychiatric problems and spindle activity.     

Modeling the effect of sleep regulation on a neural mass model

In mammals, sleep is categorized by two main sleep stages, rapid eye movement (REM) and non-REM (NREM) sleep that are known to fulfill different functional roles, the most notable being the consolidation of memory. While REM sleep is characterized by brain activity similar to wakefulness, the EEG activity changes drastically with the emergence of K-complexes, sleep spindles and slow oscillations during NREM sleep. These changes are regulated by circadian and ultradian rhythms, which emerge from an intricate interplay between multiple neuronal populations in the brainstem, forebrain and hypothalamus and the resulting varying levels of neuromodulators. Recently, there has been progress in the understanding of those rhythms both from a physiological as well as theoretical perspective. However, how these neuromodulators affect the generation of the different EEG patterns and their temporal dynamics is poorly understood. Here, we build upon previous work on a neural mass model of the sleeping cortex and investigate the effect of those neuromodulators on the dynamics of the cortex and the corresponding transition between wakefulness and the different sleep stages. We show that our simplified model is sufficient to generate the essential features of human EEG over a full day. This approach builds a bridge between sleep regulatory networks and EEG generating neural mass models and provides a valuable tool for model validation.