Human NREM Sleep Research Articles

Spindle-locked ripples mediate memory reactivation during human NREM sleep

Memory consolidation relies in part on the reactivation of previous experiences during sleep. The precise interplay of sleep-related oscillations (slow oscillations, spindles and ripples) is thought to coordinate the information flow between relevant brain areas, with ripples mediating memory reactivation. However, in humans empirical evidence for a role of ripples in memory reactivation is lacking. Here, we investigated the relevance of sleep oscillations and specifically ripples for memory reactivation during human sleep using targeted memory reactivation. Intracranial electrophysiology in epilepsy patients and scalp EEG in healthy participants revealed that elevated levels of slow oscillation - spindle activity coincided with the read-out of experimentally induced memory reactivation. Importantly, spindle-locked ripples recorded intracranially from the medial temporal lobe were found to be correlated with the identification of memory reactivation during non-rapid eye movement sleep. Our findings establish ripples as key-oscillation for sleep-related memory reactivation in humans and emphasize the importance of the coordinated interplay of the cardinal sleep oscillations.

K-complex and heart rate dynamics during varying arousal levels in human NREM sleep

K-complex and heart rate dynamics during varying arousal levels in human NREM sleep

0267 Development and validation of low-level Transcranial Electrical Stimulation to enhance slow oscillations during human NREM sleep

Abstract Introduction Sleep disruption, and in particular decreased NREM stage N3 sleep, has been implicated in cognition and pathogenesis of Alzheimer's Disease (AD). Several recent findings suggest that enhancing N3 sleep may mitigate impairments due to chronic sleep disruption. However, approaches such as transcranial electrical stimulation (TES) have been limited by discomfort, awakenings, and lack of blinding. In response to the need to develop low-level TES, our team first identified the source of slow oscillations (SOs) of N3 sleep using high-density EEG array modeling (Sourcerer®), which localized within anterior limbic brain structures. Next, we showed that low-level TES targeted to this region induced and enhanced SOs during N3 sleep in the laboratory. More recently, we developed a portable TES device with the minimum deployable set of stimulation electrodes targeting the anterior limbic SO-generating regions: Wireless Interface Sensor Pod (WISP). Methods Thirteen healthy adults (m = 42 years) participated in three all-night sleep EEG recordings where they received low level (0.5 mA) TES designed to target anterior limbic SO-generating regions and a sham stimulation (placebo). TES was initiated after 4 minutes of naturally occurring NREM N2 sleep and included five TES blocks of five minutes each separated by one minute rest periods. Subjects were blinded to stimulation and sham conditions, and outcomes included feasibility, acceptability, and total time in each sleep stage. A convolutional neural network (CNN) was developed, trained, and tested on manually scored EEG sleep staging for automated sleep scoring. Results Subjects rated that the WISP device was highly feasible and acceptable. Subjects were adequately blinded to sham versus stimulation. When compared to the sham session, limbic-targeted TES significantly increased the duration of N3 sleep and spectral power in the 0.5-1 Hz frequency band. Finally, our CNN was able to detect sleep stages with good accuracy (84%, kappa 0.77). Conclusion These results suggest that low-level portable TES using a minimum deployable set of electrodes, when specifically targeting anterior limbic sites, is feasible, acceptable, maintains blinding, and increases deep (N3) sleep. The WISP device is a promising method to both assess and manipulate sleep in the home setting. Support (if any) DoD MOMRP MTEC-21-06-MPAI-129

Thalamocortical coherence and causality in different sleep stages using deep brain stimulation recordings

Previous research has shown an interplay between the thalamus and cerebral cortex during NREM sleep in humans, however the directionality of the thalamocortical synchronization is as yet unknown. In this study thalamocortical connectivity during different NREM sleep stages using sleep scalp electroencephalograms and local field potentials from the left and right anterior thalamus was measured in three epilepsy patients implanted with deep brain stimulation electrodes. Connectivity was assessed as debiased weighted phase lag index and granger causality between the thalamus and cortex for the NREM sleep stages N1, N2 and N3. Results showed connectivity was most prominently directed from cortex to thalamus. Moreover, connectivity varied in strength between the different sleep stages, but barely in direction or frequency. These results imply relatively stable thalamocortical connectivity during NREM sleep directed from the cortex to the thalamus.

NREM delta power and AD-relevant tauopathy are associated with shared cortical gene networks

Reduced NREM sleep in humans is associated with AD neuropathology. Recent work has demonstrated a reduction in NREM sleep in preclinical AD, pointing to its potential utility as an early marker of dementia. We test the hypothesis that reduced NREM delta power and increased tauopathy are associated with shared underlying cortical molecular networks in preclinical AD. We integrate multi-omics data from two extensive public resources, a human Alzheimer’s disease cohort from the Mount Sinai Brain Bank (N = 125) reflecting AD progression and a (C57BL/6J × 129S1/SvImJ) F2 mouse population in which NREM delta power was measured (N = 98). Two cortical gene networks, including a CLOCK-dependent circadian network, are associated with NREM delta power and AD tauopathy progression. These networks were validated in independent mouse and human cohorts. Identifying gene networks related to preclinical AD elucidate possible mechanisms associated with the early disease phase and potential targets to alter the disease course.

Posterior Hippocampal Spindle Ripples Co-occur with Neocortical Theta Bursts and Downstates-Upstates, and Phase-Lock with Parietal Spindles during NREM Sleep in Humans.

Human anterior and posterior hippocampus (aHC, pHC) differ in connectivity and behavioral correlates. Here we report physiological differences in humans of both sexes. During NREM sleep, the human hippocampus generates sharpwave ripples (SWRs) similar to those which in rodents mark memory replay. We show that while pHC generates SWRs, it also generates approximately as many spindle ripples (SSR: ripples phase-locked to local spindles). In contrast, SSRs are rare in aHC. Like SWRs, SSRs often co-occur with neocortical theta bursts (TBs), downstates (DSs), sleep spindles (SSs), and upstates (USs), which coordinate cortico-hippocampal interactions and facilitate consolidation in rodents. SWRs co-occur with these waves in widespread cortical areas, especially frontocentral. These waves typically occur in the sequence TB-DS-SS-US, with SWRs usually occurring before SS-US. In contrast, SSRs occur ∼350 ms later, with a strong preference for co-occurrence with posterior-parietal SSs. pHC-SSs were strongly phase-locked with parietal-SSs, and pHC-SSRs were phase-coupled with pHC-SSs and parietal-SSs. Human SWRs (and associated replay events, if any) are separated by ∼5 s on average, whereas ripples on successive SSR peaks are separated by only ∼80 ms. These distinctive physiological properties of pHC-SSR enable an alternative mechanism for hippocampal engagement with neocortex.SIGNIFICANCE STATEMENT Rodent hippocampal neurons replay waking events during sharpwave ripples (SWRs) in NREM sleep, facilitating memory transfer to a permanent cortical store. We show that human anterior hippocampus also produces SWRs, but spindle ripples predominate in posterior. Whereas SWRs typically occur as cortex emerges from inactivity, spindle ripples typically occur at peak cortical activity. Furthermore, posterior hippocampal spindle ripples are tightly coupled to posterior parietal locations activated by conscious recollection. Finally, multiple spindle ripples can recur within a second, whereas SWRs are separated by ∼5 s. The human posterior hippocampus is considered homologous to rodent dorsal hippocampus, which is thought to be specialized for consolidation of specific memory details. We speculate that these distinct physiological characteristics of posterior hippocampal spindle ripples may support a related function in humans.

Theta Bursts Precede, and Spindles Follow, Cortical and Thalamic Downstates in Human NREM Sleep.

Since their discovery, slow oscillations have been observed to group spindles during non-REM sleep. Previous studies assert that the slow-oscillation downstate (DS) is preceded by slow spindles (10-12 Hz) and followed by fast spindles (12-16 Hz). Here, using both direct transcortical recordings in patients with intractable epilepsy (n = 10, 8 female), as well as scalp EEG recordings from a healthy cohort (n = 3, 1 female), we find in multiple cortical areas that both slow and fast spindles follow the DS. Although discrete oscillations do precede DSs, they are theta bursts (TBs) centered at 5-8 Hz. TBs were more pronounced for DSs in NREM stage 2 (N2) sleep compared with N3. TB with similar properties occur in the thalamus, but unlike spindles they have no clear temporal relationship with cortical TB. These differences in corticothalamic dynamics, as well as differences between spindles and theta in coupling high-frequency content, are consistent with NREM theta having separate generative mechanisms from spindles. The final inhibitory cycle of the TB coincides with the DS peak, suggesting that in N2, TB may help trigger the DS. Since the transition to N1 is marked by the appearance of theta, and the transition to N2 by the appearance of DS and thus spindles, a role of TB in triggering DS could help explain the sequence of electrophysiological events characterizing sleep. Finally, the coordinated appearance of spindles and DSs are implicated in memory consolidation processes, and the current findings redefine their temporal coupling with theta during NREM sleep.SIGNIFICANCE STATEMENT Sleep is characterized by large slow waves which modulate brain activity. Prominent among these are downstates (DSs), periods of a few tenths of a second when most cells stop firing, and spindles, oscillations at ∼12 times a second lasting for ∼a second. In this study, we provide the first detailed description of another kind of sleep wave: theta bursts (TBs), a brief oscillation at ∼six cycles per second. We show, recording during natural sleep directly from the human cortex and thalamus, as well as on the scalp, that TBs precede, and spindles follow DSs. TBs may help trigger DSs in some circumstances, and could organize cortical and thalamic activity so that memories can be consolidated during sleep.

Heterogeneous Origins of Human Sleep Spindles in Different Cortical Layers.

Sleep spindles are a cardinal feature in human NREM sleep and may be important for memory consolidation. We studied the intracortical organization of spindles in men and women by recording spontaneous sleep spindles from different cortical layers using linear microelectrode arrays. Two patterns of spindle generation were identified using visual inspection, and confirmed with factor analysis. Spindles (10-16 Hz) were largest and most common in upper and middle channels, with limited involvement of deep channels. Many spindles were observed in only upper or only middle channels, but approximately half occurred in both. In spindles involving both middle and upper channels, the spindle envelope onset in middle channels led upper by ∼25-50 ms on average. The phase relationship between spindle waves in upper and middle channels varied dynamically within spindle epochs, and across individuals. Current source density analysis demonstrated that upper and middle channel spindles were both generated by an excitatory supragranular current sink while an additional deep source was present for middle channel spindles only. Only middle channel spindles were accompanied by deep low (25-50 Hz) and high (70-170 Hz) gamma activity. These results suggest that upper channel spindles are generated by supragranular pyramids, and middle channel by infragranular. Possibly, middle channel spindles are generated by core thalamocortical afferents, and upper channel by matrix. The concurrence of these patterns could reflect engagement of cortical circuits in the integration of more focal (core) and distributed (matrix) aspects of memory. These results demonstrate that at least two distinct intracortical systems generate human sleep spindles.SIGNIFICANCE STATEMENT Bursts of ∼14 Hz oscillations, lasting ∼1 s, have been recognized for over 80 years as cardinal features of mammalian sleep. Recent findings suggest that they play a key role in organizing cortical activity during memory consolidation. We used linear microelectrode arrays to study their intracortical organization in humans. We found that spindles could be divided into two types. One mainly engages upper layers of the cortex, which are considered to be specialized for associative activity. The other engages both upper and middle layers, including those devoted to sensory input. The interaction of these two spindle types may help organize the interaction of sensory and associative aspects of memory consolidation.

実験動物およびヒトのノンレム睡眠で発生するリズム性咀嚼筋活動の生理学的類似性

実験動物およびヒトのノンレム睡眠で発生するリズム性咀嚼筋活動の生理学的類似性

Spindle Power Is Not Affected after Spontaneous K-Complexes during Human NREM Sleep

K-complexes and sleep spindles often grouped together characterize the second stage of NREM sleep and interest has been raised on a possible interaction of their underlying mechanisms. The reported inhibition of spindles power for about 15 seconds following evoked K-complexes has implications on their role in arousal. Our objective was to assess this inhibition following spontaneous K-complexes. We used time-frequency analysis of spontaneous K-complexes selected from whole-night EEG recordings of normal subjects. Our results show that spindles are most often observed at the positive phase following the peak of a spontaneous KC (70%). At latencies of 1–3 s following the peak of the K-complex, spindles almost disappear. Compared to long-term effects described for evoked KCs, sleep spindle power is not affected by spontaneous KCs for latencies of 5–15 s. Observation of the recurrence rate of sporadic spindles suggests that the reduction of power at 1–3 s most likely reflects a refractory period of spindles lasting for 1–2 s, rather than an effect of KCs. These results suggest that the mechanisms underlying spontaneous KCs do not affect spindle power as in the case of evoked KCs.

Power spectrum analysis and heart rate variability in Stage 4 and REM sleep: evidence for state-specific changes in autonomic dominance.

The present study investigated autonomic activity during NREM and REM sleep stages and wakefulness by spectral analysis of heart rate variability. The results demonstrated that NREM sleep in humans was characterized by a widely different autonomic activation pattern than REM sleep: high parasympathetic activity was found in NREM, while REM was characterized by attenuated vagal tone, and augmented sympathetic activity. The overall pattern during wakefulness showed an intermediate position between NREM and REM patterns; parasympathetic activity was lower than in NREM and higher than in REM, with an opposite trend for sympathetic activity.

Auditory event-related potentials during stage 2 NREM sleep in humans.

Event-related potential (ERP) recordings were used to investigate the nature of auditory stimulus evaluation during stage 2 sleep. Frequent and rare stimuli, differing in intensity and frequency, were presented to six adult subjects while awake and asleep. The latency and voltage distribution of one of the long-latency components evoked during sleep resembled the P3 component evoked while awake. However, it was attenuated in voltage and superimposed on N3, a large late negative component, most probably the slow potential of the K complex. The identification of a P3-like potential during sleep suggests that the P3 potential is not solely a marker of active cognitive processes, but contains a small component which reflects automatic, pre-attentive evaluation of deviant stimuli.

Hyperinflation and expiratory muscle recruitment during NREM sleep in humans

The purpose of this study was to determine the effect of hyperinflation on expiratory muscle recruitment during NREM sleep in healthy humans. Hyperinflation was produced by negative pressure in a tank ventilator or application of positive end-expiratory pressure (PEEP). Expiratory and inspiratory electromyograms (EMGexp and EMGinsp) were measured using transcutaneously implanted wire and surface electrodes, respectively. During wakefulness, sustained hyperinflation (3–5 min, + 0.72 ± 0.31 L) in the tank respirator caused augmentation of EMGexp (+77%, P < 0.05) and EMGinsp (+27%, P < 0.05) in all subjects. Brief hyperinflation with PEEP (5 breaths, +0.53 ± 0.32 L) augmented EMGexp in 3 of 6 subjects and EMGinsp in 5 of 5 subjects (+98%, P < 0.05). During NREM sleep, sustained hyperinflation (+0.54 ± 0.17 L) in the tank respirator caused no change in EMGexp and a small increase in EMGinsp (+9%, P < 0.001). Brief hyperinflation with PEEP (0.29 ± 0.10 L) caused no change in EMGexp or EMGinsp. Sustained hyperinflation with PEEP activated EMGexp only in subjects whose end-tidal CO 2 increased. We concluded that moderate hyperinflation does not recruit expiratory muscles during NREM sleep as it does during wakefulness.