Novel Electrophysiological Signatures of Learning and Forgetting in Human Rapid Eye Movement Sleep.

Despite the known behavioral benefits of rapid eye movement (REM) sleep, discrete neural oscillatory events in human scalp electroencephalography (EEG) linked with behavior have not been discovered. This knowledge gap hinders mechanistic understanding of the function of sleep, as well as the development of biophysical models and REM-based causal interventions. We designed a detection algorithm to identify bursts of activity in high-density, scalp EEG within theta (4-8 Hz) and alpha (8-13 Hz) bands during REM sleep. Across 38 nights of sleep, we characterized the burst events (i.e., count, duration, density, peak frequency, amplitude) in healthy, young male and female human participants (38; 21F) and investigated burst activity in relation to sleep-dependent memory tasks: hippocampal-dependent episodic verbal memory and nonhippocampal visual perceptual learning. We found greater burst count during the more REM-intensive second half of the night (p < 0.05), longer burst duration during the first half of the night (p < 0.05), but no differences across the night in density or power (p > 0.05). Moreover, increased alpha burst power was associated with increased overnight forgetting for episodic memory (p < 0.05). Furthermore, we show that increased REM theta burst activity in retinotopically specific regions was associated with better visual perceptual performance. Our work provides a critical bridge between discrete REM sleep events in human scalp EEG that support cognitive processes and the identification of similar activity patterns in animal models that allow for further mechanistic characterization.

Slow oscillations promote long-range effective communication: The key for memory consolidation in a broken-down network.

A prominent and robust finding in cognitive neuroscience is the strengthening of memories during nonrapid eye movement (NREM) sleep, with slow oscillations (SOs;<1Hz) playing a critical role in systems-level consolidation. However, NREM generally shows a breakdown in connectivity and reduction of synaptic plasticity with increasing depth: a brain state seemingly unfavorable to memory consolidation. Here, we present an approach to address this apparent paradox that leverages an event-related causality measure to estimate directional information flow during NREM in epochs with and without SOs. Our results confirm that NREM is generally a state of dampened neural communication but reveals that SOs provide two windows of enhanced large-scale communication before and after the SO trough. These peaks in communication are significantly higher when SOs are coupled with sleep spindles compared with uncoupled SOs. To probe the functional relevance of these SO-selective peaks of information flow, we tested the temporal and topographic conditions that predict overnight episodic memory improvement. Our results show that global, long-range communication during SOs promotes sleep-dependent systems consolidation of episodic memories. A significant correlation between peaks of information flow and memory improvement lends predictive validity to our measurements of effective connectivity. In other words, we were able to predict memory improvement based on independent electrophysiological observations during sleep. This work introduces a noninvasive approach to understanding information processing during sleep and provides a mechanism for how systems-level brain communication can occur during an otherwise low connectivity sleep state. In short, SOs are a gating mechanism for large-scale neural communication, a necessary substrate for systems consolidation and long-term memory formation.

Understanding the roles of central and autonomic activity during sleep in the improvement of working memory and episodic memory.

The last decade has seen significant progress in identifying sleep mechanisms that support cognition. Most of these studies focus on the link between electrophysiological events of the central nervous system during sleep and improvements in different cognitive domains, while the dynamic shifts of the autonomic nervous system across sleep have been largely overlooked. Recent studies, however, have identified significant contributions of autonomic inputs during sleep to cognition. Yet, there remain considerable gaps in understanding how central and autonomic systems work together during sleep to facilitate cognitive improvement. In this article we examine the evidence for the independent and interactive roles of central and autonomic activities during sleep and wake in cognitive processing. We specifically focus on the prefrontal-subcortical structures supporting working memory and mechanisms underlying the formation of hippocampal-dependent episodic memory. Our Slow Oscillation Switch Model identifies separate and competing underlying mechanisms supporting the two memory domains at the synaptic, systems, and behavioral levels. We propose that sleep is a competitive arena in which both memory domains vie for limited resources, experimentally demonstrated when boosting one system leads to a functional trade-off in electrophysiological and behavioral outcomes. As these findings inevitably lead to further questions, we suggest areas of future research to better understand how the brain and body interact to support a wide range of cognitive domains during a single sleep episode.

Sleep facilitates spatial memory but not navigation using the Minecraft Memory and Navigation task.

Sleep facilitates hippocampal-dependent memories, supporting the acquisition and maintenance of internal representation of spatial relations within an environment. In humans, however, findings have been mixed regarding sleep's contribution to spatial memory and navigation, which may be due to task designs or outcome measurements. We developed the Minecraft Memory and Navigation (MMN) task for the purpose of disentangling how spatial memory accuracy and navigation change over time, and to study sleep's independent contributions to each. In the MMN task, participants learned the locations of objects through free exploration of an open field computerized environment. At test, they were teleported to random positions around the environment and required to navigate to the remembered location of each object. In study 1, we developed and validated four unique MMN environments with the goal of equating baseline learning and immediate test performance. A total of 86 participants were administered the training phases and immediate test. Participants' baseline performance was equivalent across all four environments, supporting the use of the MMN task. In study 2, 29 participants were trained, tested immediately, and again 12 h later after a period of sleep or wake. We found that the metric accuracy of object locations, i.e., spatial memory, was maintained over a night of sleep, while after wake, metric accuracy declined. In contrast, spatial navigation improved over both sleep and wake delays. Our findings support the role of sleep in retaining the precise spatial relationships within a cognitive map; however, they do not support a specific role of sleep in navigation.

Competitive dynamics underlie cognitive improvements during sleep.

We provide evidence that human sleep is a competitive arena in which cognitive domains vie for limited resources. Using pharmacology and effective connectivity analysis, we demonstrate that long-term memory and working memory are served by distinct offline neural mechanisms that are mutually antagonistic. Specifically, we administered zolpidem to increase central sigma activity and demonstrated targeted suppression of autonomic vagal activity. With effective connectivity, we determined the central activity has greater causal influence over autonomic activity, and the magnitude of this influence during sleep produced a behavioral trade-off between offline long-term and working memory processing. These findings suggest a sleep switch mechanism that toggles between central sigma-dependent long-term memory and autonomic vagal-dependent working memory processing.

The role of sleep for episodic memory consolidation: Stabilizing or rescuing?

Prior studies suggest a role for sleep in memory consolidation, with specific contributions from slow oscillations and sleep spindles (Rasch & Born, 2013). However, recent studies failed to replicate sleep's superiority over wake in strengthening memory against interference (Cordi & Rasch, 2021). The goal of the current study is to investigate whether sleep protects newly formed memory from unspecific interference induced by daytime experiences over 24 h, as well as to elucidate the sleep features that are involved. 56 healthy adults were randomly assigned to either the Sleep First or Wake First group. The Sleep First group encoded word pairs at night before sleep, while the Wake First group encoded word pairs in the morning before a day of wakefulness. Memory was tested 30 min, 12 h, and 24 h after encoding for both groups. The Sleep First group performed significantly better 12 h after encoding, replicating prior findings that memory is better after a period of sleep compared to wake. However, after 24 h, the two groups performed similarly. The Wake First group showed a positive correlation between overnight memory improvement and the theta and delta band power during slow wave sleep, an effect not found in the Sleep First group. These correlations suggest the possibility that after a day of waking interference, the brain recruits extra sleep resources to rescue memories from further forgetting. Our results are not consistent with prior studies showing a significant role for sleep in stabilizing memory from future interference, but they may suggest that sleep rescues memories after interference has occurred.

The effect of interference, offline sleep, and wake on spatial statistical learning.

Statistical learning, the ability of the human brain to uncover patterns organized according to probabilistic relationships between elements and events of the environment, is a powerful learning mechanism underlying many cognitive processes. Here we examined how memory for statistical learning of probabilistic spatial configurations is impacted by interference at the time of initial exposure and varying degrees of wakefulness and sleep during subsequent offline processing. We manipulated levels of interference at learning by varying the time between exposures of different spatial configurations. During the subsequent offline period, participants either remained awake (active wake or quiet wake) or took a nap comprised of either non-rapid eye movement (NREM) sleep only or NREM and rapid eye movement (REM) sleep. Recognition of the trained spatial configurations, as well as a novel configuration exposed after the offline period, was tested approximately 6-7 h after initial exposure. We found that the sleep conditions did not provide any additional memory benefit compared to wakefulness for spatial statistical learning with low interference. For high interference, we found some evidence that memory may be impaired following quiet wake and NREM sleep only, but not active wake or combined NREM and REM sleep. These results indicate that learning conditions may interact with offline brain states to influence the long-term retention of spatial statistical learning.

Autonomic central coupling during daytime sleep differs between older and younger people.

Decreased functioning in the elderly is mirrored by independent changes in central and autonomic nervous systems. Additionally, recent work suggests that the coupling of these systems may also serve an important role. In young adults, Autonomic and Central Events (ACEs), measured in the temporal coincidence of heart rate bursts (HRBs) and increased slow-wave-activity (SWA, 0.5-1 Hz) and sigma activity (12-15 Hz), followed by parasympathetic surge (RRHF) during non-rapid eye movement (NREM) sleep, predicted cognitive improvements. However, ACEs have not been examined in the elderly. Thus, the current study compared ACEs during wake and daytime sleep in older and younger adults and examined associations with working memory improvement before and after a nap. Compared to youngers, older adults showed lower amplitude of ACEs during NREM sleep, but not during wake. Furthermore, while younger adults demonstrated a parasympathetic surge after HRBs, older adults showed an earlier rise and longer maintenance of the RRHF. Taken together, our results demonstrate that autonomic-central coupling declines with age. Pathological aging implicates independent roles for decreased autonomic and central nervous system functioning, the current findings suggest that the coupling of these systems may also deserve attention.

Progressive muscle relaxation increases slow-wave sleep during a daytime nap.

Sleep is critical for health, cognition, and restorative processes, and yet, many experience chronic sleep restriction. Sleep interventions have been designed to enhance overnight sleep quality and physiology. Components of these interventions, like relaxation-based progressive muscle relaxation (PMR), have been studied in isolation and have shown direct effects on sleep architecture, including increasing time in restorative, slow-wave sleep (SWS). These relaxation methods have been understudied in naps, which are effective fatigue countermeasures that reduce deleterious effects of chronic sleep restriction. We hypothesised that PMR should boost SWS in a nap, as compared to an active control. We used a between-subject design in which healthy young adults underwent PMR training or listened to Mozart music (control) prior to a 90-min nap opportunity. We assessed changes in the amount and lateralisation of SWS, as evidence suggests left hemispheric lateralisation may be a proxy for recuperative sleep needs, and changes to state-dependent anxiety and fatigue before and after the nap to assess intervention success. We found PMR participants spent ~10 min more in SWS, equivalent to 125% more time, than the control group, and concomitantly, significantly less time in rapid eye movement sleep. PMR participants also had greater right lateralised slow-wave activity and delta activity compared to the control suggesting a more well-rested brain profile during sleep. Further, pre-sleep anxiety levels predicted nap architecture in the intervention group, suggesting benefits may be impacted by anxiety. The feasibility and accessibility of PMR prior to a nap make this an interesting research avenue to pursue with strong translational application.

Psychostimulants may block long-term memory formation via degraded sleep in healthy adults.

Sleep is vital for biological function and long-term memory formation, with preferential enhancement of emotionally laden content. A growing trend in healthy young adults is the non-medical use of psychostimulants, or "smart drugs", to prevent sleep and, hopefully, enhance cognition. However, the effect of these drugs on sleep-dependent memory processes are unclear. Here, in a within-subject, double-blind, placebo-controlled design, we investigated the impact of morning administration of dextroamphetamine on memory retention of negative and neutral pictures after 1) 12 h of wake, and 2) 24 h with sleep. After 12-hrs of wake, stimulants increased hit rate for neutral, but not negative, pictures, compared to placebo. No differences in memory discrimination were found. In addition, stimulants impaired nighttime sleep and significantly reduced memory for neutral pictures at 24-hrs, compared to placebo. Again, no performance differences between drug conditions were found for negative pictures. Together, these findings suggest that stimulants impairment of nighttime sleep likely leads to next day memory costs.

Autonomic Activity during a Daytime Nap Facilitates Working Memory Improvement.

Recent investigations have implicated the parasympathetic branch of the autonomic nervous system in higher-order executive functions. These actions are purported to occur through autonomic nervous system's modulation of the pFC, with parasympathetic activity during wake associated with working memory (WM) ability. Compared with wake, sleep is a period with substantially greater parasympathetic tone. Recent work has reported that sleep may also contribute to improvement in WM. Here, we examined the role of cardiac parasympathetic activity during sleep on WM improvement in healthy young adults. Participants were tested in an operation span task in the morning and evening, and during the intertest period, participants experienced either a nap or wake. We measured high-frequency heart rate variability as an index of cardiac, parasympathetic activity during both wake and sleep. Participants showed the expected boost in parasympathetic activity during nap, compared with wake. Furthermore, parasympathetic activity during sleep, but not wake, was significantly correlated with WM improvement. Together, these results indicate that the natural boost in parasympathetic activity during sleep may benefit gains in prefrontal executive function in young adults. We present a conceptual model illustrating the interaction between sleep, autonomic activity, and prefrontal brain function and highlight open research questions that will facilitate understanding of the factors that contribute to executive abilities in young adults as well as in cognitive aging.

Autonomic/central coupling benefits working memory in healthy young adults.

Working memory (WM) is an executive function that can improve with training. However, the precise mechanism for this improvement is not known. Studies have shown greater WM gains after a period of sleep than a similar period of wake, and correlations between WM improvement and slow wave activity (SWA; 0.5-1 Hz) during slow wave sleep (SWS). A different body of literature has suggested an important role for autonomic activity during wake for WM. A recent study from our group reported that the temporal coupling of Autonomic/CentralEvents (ACEs) during sleep was associated with memory consolidation. We found that heart rate bursts (HR bursts) during non-rapid eye movement (NREM) sleep are accompanied by increases in SWA and sigma (12-15 Hz) power, as well as increases in the high-frequency (HF) component of the RR interval, reflecting vagal rebound. In addition, ACEs predict long-term, episodic memory improvement. Building on these previous results, we examined whether ACEs also contribute to gains in WM. We tested 104 young adults in an operation span task (OSPAN) in the morning and evening, with either a nap (n = 53; with electroencephalography (EEG) and electrocardiography (ECG)) or wake (n = 51) between testing sessions. We identified HR bursts in the ECG and replicated the increases in SWA and sigma prior to peak of the HR burst, as well as vagal rebound after the peak. Furthermore, we showed sleep-dependent WM improvement, which was predicted by ACE activity. Using regression analyses, we discovered that significantly more variance in WM improvement could be explained with ACE variables than with overall sleep activity not time-locked with ECG. These results provide the first evidence that coordinated autonomic and central events play a significant role in sleep-related WM improvement and implicate the potential of autonomic interventions during sleep for cognitive enhancement.

Transient cholinergic enhancement does not significantly affect either the magnitude or selectivity of perceptual learning of visual texture discrimination.

Perceptual learning (PL), often characterized by improvements in perceptual performance with training that are specific to the stimulus conditions used during training, exemplifies experience-dependent cortical plasticity. An improved understanding of how neuromodulatory systems shape PL promises to provide new insights into the mechanisms of plasticity, and by extension how PL can be generated and applied most efficiently. Previous studies have reported enhanced PL in human subjects following administration of drugs that increase signaling through acetylcholine (ACh) receptors, and physiological evidence indicates that ACh sharpens neuronal selectivity, suggesting that this neuromodulator supports PL and its stimulus specificity. Here we explored the effects of enhancing endogenous cholinergic signaling during PL of a visual texture discrimination task. We found that training on this task in the lower visual field yielded significant behavioral improvement at the trained location. However, a single dose of the cholinesterase inhibitor donepezil, administered before training, did not significantly impact either the magnitude or the location specificity of texture discrimination learning compared with placebo. We discuss potential explanations for discrepant findings in the literature regarding the role of ACh in visual PL, including possible differences in plasticity mechanisms in the dorsal and ventral cortical processing streams.

Timing between Cortical Slow Oscillations and Heart Rate Bursts during Sleep Predicts Temporal Processing Speed, but Not Offline Consolidation.

Central and autonomic nervous system activities are coupled during sleep. Cortical slow oscillations (SOs; <1 Hz) coincide with brief bursts in heart rate (HR), but the functional consequence of this coupling in cognition remains elusive. We measured SO-HR temporal coupling (i.e., the peak-to-peak interval between downstate of SO event and HR burst) during a daytime nap and asked whether this SO-HR timing measure was associated with temporal processing speed and learning on a texture discrimination task by testing participants before and after a nap. The coherence of SO-HR events during sleep strongly correlated with an individual's temporal processing speed in the morning and evening test sessions, but not with their change in performance after the nap (i.e., consolidation). We confirmed this result in two additional experimental visits and also discovered that this association was visit-specific, indicating a state (not trait) marker. Thus, we introduce a novel physiological index that may be a useful marker of state-dependent processing speed of an individual.

Coupling of autonomic and central events during sleep benefits declarative memory consolidation.

While anatomical pathways between forebrain cognitive and brainstem autonomic nervous centers are well-defined, autonomic-central interactions during sleep and their contribution to waking performance are not understood. Here, we analyzed simultaneous central activity via electroencephalography (EEG) and autonomic heart beat-to-beat intervals (RR intervals) from electrocardiography (ECG) during wake and daytime sleep. We identified bursts of ECG activity that lasted 4-5 s and predominated in non-rapid-eye-movement sleep (NREM). Using event-based analysis of NREM sleep, we found an increase in delta (0.5-4 Hz) and sigma (12-15 Hz) power and an elevated density of slow oscillations (0.5-1 Hz) about 5 s prior to peak of the heart rate burst, as well as a surge in vagal activity, assessed by high-frequency (HF) component of RR intervals. Using regression framework, we show that these Autonomic/Central Events (ACE) positively predicted post-nap improvement in a declarative memory task after controlling for the effects of spindles and slow oscillations from sleep periods without ACE. No such relation was found between memory performance and a control nap. Additionally, NREM ACE negatively correlated with REM sleep and learning in a non-declarative memory task. These results provide the first evidence that coordinated autonomic and central events play a significant role in declarative memory consolidation.

Impact of sex steroids and reproductive stage on sleep-dependent memory consolidation in women.

Age and sex are two of the three major risk factors for Alzheimer's disease (ApoE-e4 allele is the third), with women having a twofold greater risk for Alzheimer's disease after the age of 75 years. Sex differences have been shown across a wide range of cognitive skills in young and older adults, and evidence supports a role for sex steroids, especially estradiol, in protecting against the development of cognitive decline in women. Sleep may also be a protective factor against age-related cognitive decline, since specific electrophysiological sleep events (e.g. sleep spindle/slow oscillation coupling) are critical for offline memory consolidation. Furthermore, studies in young women have shown fluctuations in sleep events and sleep-dependent memory consolidation during different phases of the menstrual cycle that are associated with the levels of sex steroids. An under-appreciated possibility is that there may be an important interaction between these two protective factors (sex steroids and sleep) that may play a role in daily fluctuations in cognitive processing, in particular memory, across a woman's lifespan. Here, we summarize the current knowledge of sex steroid-dependent influences on sleep and cognition across the lifespan in women, with special emphasis on sleep-dependent memory processing. We further indicate gaps in knowledge that require further experimental examination in order to fully appreciate the complex and changing landscape of sex steroids and cognition. Lastly, we propose a series of testable predictions for how sex steroids impact sleep events and sleep-dependent cognition across the three major reproductive stages in women (reproductive years, menopause transition, and post-menopause).

Autonomic activity during sleep predicts memory consolidation in humans.

Throughout history, psychologists and philosophers have proposed that good sleep benefits memory, yet current studies focusing on the relationship between traditionally reported sleep features (e.g., minutes in sleep stages) and changes in memory performance show contradictory findings. This discrepancy suggests that there are events occurring during sleep that have not yet been considered. The autonomic nervous system (ANS) shows strong variation across sleep stages. Also, increases in ANS activity during waking, as measured by heart rate variability (HRV), have been correlated with memory improvement. However, the role of ANS in sleep-dependent memory consolidation has never been examined. Here, we examined whether changes in cardiac ANS activity (HRV) during a daytime nap were related to performance on two memory conditions (Primed and Repeated) and a nonmemory control condition on the Remote Associates Test. In line with prior studies, we found sleep-dependent improvement in the Primed condition compared with the Quiet Wake control condition. Using regression analyses, we compared the proportion of variance in performance associated with traditionally reported sleep features (model 1) vs. sleep features and HRV during sleep (model 2). For both the Primed and Repeated conditions, model 2 (sleep + HRV) predicted performance significantly better (73% and 58% of variance explained, respectively) compared with model 1 (sleep only, 46% and 26% of variance explained, respectively). These findings present the first evidence, to our knowledge, that ANS activity may be one potential mechanism driving sleep-dependent plasticity.

To Nap, Perchance to DREAM: A Factor Analysis of College Students' Self-Reported Reasons for Napping.

Although napping has received attention because of its associations with health and use as a method to understand the function of sleep, to our knowledge no study has systematically and statistically assessed reasons for napping. Using factor analysis, we determined the underlying structure of reasons for napping in diverse undergraduates (N = 430, 59% female) and examined their relationships with self-reported sleep, psychological health, and physical health. The five reasons for napping can be summarized using the acronym DREAM (Dysregulative, Restorative, Emotional, Appetitive, and Mindful). Only Emotional reasons for napping were uniformly related to lower well-being. The use of factor analysis raises possibilities for future research, including examining the stability, structure, and psychological and physical health processes related to napping throughout the lifespan.

The effect of sex and menstrual phase on memory formation during a nap.

Memory formation can be influenced by sleep and sex hormones in both men and women, and by the menstrual cycle in women. Though many studies have shown that sleep benefits the consolidation of memories, it is not clear whether this effect differs between men and women in general or according to menstrual phase in women. The present study investigated the effect of sex and menstrual cycle on memory consolidation of face-name associations (FNA) following a daytime nap. Recognition memory was tested using a face-name paired associates task with a polysomnographic nap between morning and evening testing. Seventeen healthy women (age: 20.75 (1.98) years) were studied at two time points of their menstrual cycles, defined from self-report and separated by 2weeks (perimenses: -5days to +6days from the start of menses, and non-perimenses: outside of the perimenses phase), and compared with eighteen healthy men (age: 22.01 (2.91) years). Regardless of menstrual phase, women had better pre-nap performance than men. Further, menstrual phase affected post-nap memory consolidation, with women showing greater forgetting in their perimenses phase compared with their non-perimenses phase and men. Interestingly, post-nap performance correlated with electrophysiological events during sleep (slow oscillations, spindles, and temporal coupling between the two), however, these correlations differed according to menstrual phase and sex. Men's performance improvement was associated with the temporal coupling of spindles and slow oscillations (i.e., spindle/SO coincidence) as well as spindles. Women, however, showed an association with slow oscillations during non-perimenses, whereas when they were in their perimenses phase of their cycle, women appeared to show an association only with sleep spindle events for consolidation. These findings add to the growing literature demonstrating sex and menstrual phase effects on memory formation during sleep.

REM sleep rescues learning from interference.

Classical human memory studies investigating the acquisition of temporally-linked events have found that the memories for two events will interfere with each other and cause forgetting (i.e., interference; Wixted, 2004). Importantly, sleep helps consolidate memories and protect them from subsequent interference (Ellenbogen, Hulbert, Stickgold, Dinges, & Thompson-Schill, 2006). We asked whether sleep can also repair memories that have already been damaged by interference. Using a perceptual learning paradigm, we induced interference either before or after a consolidation period. We varied brain states during consolidation by comparing active wake, quiet wake, and naps with either non-rapid eye movement sleep (NREM), or both NREM and REM sleep. When interference occurred after consolidation, sleep and wake both produced learning. However, interference prior to consolidation impaired memory, with retroactive interference showing more disruption than proactive interference. Sleep rescued learning damaged by interference. Critically, only naps that contained REM sleep were able to rescue learning that was highly disrupted by retroactive interference. Furthermore, the magnitude of rescued learning was correlated with the amount of REM sleep. We demonstrate the first evidence of a process by which the brain can rescue and consolidate memories damaged by interference, and that this process requires REM sleep. We explain these results within a theoretical model that considers how interference during encoding interacts with consolidation processes to predict which memories are retained or lost.