Comparing targeted memory reactivation during slow wave sleep and sleep stage 2.

Sleep facilitates declarative memory consolidation, which is assumed to rely on the reactivation of newly encoded memories orchestrated by the temporal interplay of slow oscillations (SO), fast spindles and ripples. SO as well as the number of spindles coupled to SO are more frequent during slow wave sleep (SWS) compared to lighter sleep stage 2 (S2). But, it is unclear whether memory reactivation is more effective during SWS than during S2. To test this question, we applied Targeted Memory Reactivation (TMR) in a declarative memory design by presenting learning-associated sound cues during SWS vs. S2 in a counterbalanced within-subject design. Contrary to our hypothesis, memory performance was not significantly better when cues were presented during SWS. Event-related potential (ERP) amplitudes were significantly higher for cues presented during SWS than S2, and the density of SO and SO-spindle complexes was generally higher during SWS than during S2. Whereas SO density increased during and after the TMR period, SO-spindle complexes decreased. None of the parameters were associated with memory performance. These findings suggest that the efficacy of TMR does not depend on whether it is administered during SWS or S2, despite differential processing of memory cues in these sleep stages.

An update on recent advances in targeted memory reactivation during sleep.

Targeted Memory Reactivation (TMR) is a noninvasive tool to manipulate memory consolidation during sleep. TMR builds on the brain's natural processes of memory reactivation during sleep and aims to facilitate or bias these processes in a certain direction. The basis of this technique is the association of learning content with sensory cues, such as odors or sounds, that are presented during subsequent sleep to promote memory reactivation. Research on TMR has drastically increased over the last decade with rapid developments. The aim of the present review is to highlight the most recent advances of this research. We focus on effects of TMR on the strengthening of memories in the declarative, procedural and emotional memory domain as well as on ways in which TMR can be used to promote forgetting. We then discuss advanced technical approaches to determine the optimal timing of TMR within the ongoing oscillatory activity of the sleeping brain as well as the specificity of TMR for certain memory contents. We further highlight the specific effects of TMR during REM sleep and in influencing dream content. Finally, we discuss recent evidence for potential applications of TMR for mental health, educational purposes and in the home setting. In conclusion, the last years of research have provided substantial advances in TMR that can guide future endeavors in research and application.

Fear memory in humans is consolidated over time independently of sleep.

Fear memories can be altered after acquisition by processes, such as fear memory consolidation or fear extinction, even without further exposure to the fear-eliciting stimuli, but factors contributing to these processes are not well understood. Sleep is known to consolidate, strengthen, and change newly acquired declarative and procedural memories. However, evidence on the role of time and sleep in the consolidation of fear memories is inconclusive. We used highly sensitive electrophysiological measures to examine the development of fear-conditioned responses over time and sleep in humans. We assessed event-related brain potentials (ERP) in 18 healthy, young individuals during fear conditioning before and after a 2-hour afternoon nap or a corresponding wake interval in a counterbalanced within-subject design. The procedure involved pairing a neutral tone (CS+) with a highly unpleasant sound. As a control, another neutral tone (CS-) was paired with a neutral sound. Fear responses were examined before the interval during a habituation phase and an acquisition phase as well as after the interval during an extinction phase and a reacquisition phase. Differential fear conditioning during acquisition was evidenced by a more negative slow ERP component (stimulus-preceding negativity) developing before the unconditioned stimulus (loud noise). This differential fear response was even stronger after the interval during reacquisition compared with initial acquisition, but this effect was similarly pronounced after sleep and wakefulness. These findings suggest that fear memories are consolidated over time, with this effect being independent of intervening sleep.

No difference between slow oscillation up- and down-state cueing for memory consolidation during sleep.

The beneficial effects of sleep for memory consolidation are assumed to rely on the reactivation of memories in conjunction with the coordinated interplay of sleep rhythms like slow oscillations and spindles. Specifically, slow oscillations are assumed to provide the temporal frame for spindles to occur in the slow oscillations up-states, enabling a redistribution of reactivated information within hippocampal-neocortical networks for long-term storage. Memory reactivation can also be triggered externally by presenting learning-associated cues (like odours or sounds) during sleep, but it is presently unclear whether there is an optimal time-window for the presentation of such cues in relation to the phase of the slow oscillations. In the present within-subject comparison, participants (n = 16) learnt word-pairs visually presented with auditory cues of the first syllable. These syllables were subsequently used for real-time cueing either in the up- or down-state of endogenous slow oscillations. Contrary to our hypothesis, we found differences in memory performance neither between up- and down-state cueing, nor between word-pairs that were cued versus uncued. In the up-state cueing condition, higher amounts of rapid eye movement sleep were associated with better memory for cued contents, whereas higher amounts of slow-wave sleep were associated with better memory for uncued contents. Evoked response analyses revealed signs of cue processing in both conditions. Interestingly, both up- and down-state cueing evoked a similar spindle response with the induced slow oscillations up-state at ~1000 ms post-cue. We speculate that our cueing procedure triggered generalised reactivation processes that facilitated the consolidation of both cued and uncued memories irrespective of the slow oscillation phase.

The effect of zolpidem on targeted memory reactivation during sleep.

According to the active system consolidation theory, memory consolidation during sleep relies on the reactivation of newly encoded memory representations. This reactivation is orchestrated by the interplay of sleep slow oscillations, spindles, and theta, which are in turn modulated by certain neurotransmitters like GABA to enable long-lasting plastic changes in the memory store. Here we asked whether the GABAergic system and associated changes in sleep oscillations are functionally related to memory reactivation during sleep. We administered the GABAA agonist zolpidem (10 mg) in a double-blind placebo-controlled study. To specifically focus on the effects on memory reactivation during sleep, we experimentally induced such reactivations by targeted memory reactivation (TMR) with learning-associated reminder cues presented during post-learning slow-wave sleep (SWS). Zolpidem significantly enhanced memory performance with TMR during sleep compared with placebo. Zolpidem also increased the coupling of fast spindles and theta to slow oscillations, although overall the power of slow spindles and theta was reduced compared with placebo. In an uncorrected exploratory analysis, memory performance was associated with slow spindle responses to TMR in the zolpidem condition, whereas it was associated with fast spindle responses in placebo. These findings provide tentative first evidence that GABAergic activity may be functionally implicated in memory reactivation processes during sleep, possibly via its effects on slow oscillations, spindles and theta as well as their interplay.

Sleep Facilitates Problem Solving With No Additional Gain Through Targeted Memory Reactivation.

According to the active systems consolidation theory, memories undergo reactivation during sleep that can give rise to qualitative changes of the representations. These changes may generate new knowledge such as gaining insight into solutions for problem solving. targeted memory reactivation (TMR) uses learning-associated cues, such as sounds or odors, which have been shown to improve memory consolidation when re-applied during sleep. Here we tested whether TMR during slow wave sleep (SWS) and/or rapid eye movement (REM) sleep increases problem solving. Young healthy volunteers participated in one of two experiments. Experiment 1 tested the effect of natural sleep on problem solving. Subjects were trained in a video game-based problem solving task until being presented with a non-solved challenge. Followed by a ~10-h incubation interval filled with nocturnal sleep or daytime wakefulness, subjects were tested on the problem solving challenge again. Experiment 2 tested the effect of TMR on problem solving, with subjects receiving auditory TMR either during SWS (SWSstim), REM sleep (REMstim), or wakefulness (Wakestim). In Experiment 1, sleep improved problem solving, with 62% of subjects from the Sleep group solving the problem compared to 24% of the Wake group. Subjects with higher amounts of SWS in the Sleep group had a higher chance to solve the problem. In Experiment 2, TMR did not change the sleep effect on problem solving: 56 and 58% of subjects from the SWSstim and REMstim groups solved the problem compared to 57% from the Wakestim group. These findings indicate that sleep, and particularly SWS, facilitates problem solving, whereas this effect is not further increased by TMR.

Reactivation during sleep with incomplete reminder cues rather than complete ones stabilizes long-term memory in humans.

Reactivation by reminder cues labilizes memories during wakefulness, requiring reconsolidation to persist. In contrast, during sleep, cued reactivation seems to directly stabilize memories. In reconsolidation, incomplete reminders are more effective in reactivating memories than complete reminders by inducing a mismatch, i.e. a discrepancy between expected and actual events. Whether mismatch is likewise detected during sleep is unclear. Here we test whether cued reactivation during sleep is more effective for mismatch-inducing incomplete than complete reminders. We first establish that only incomplete but not complete reminders labilize memories during wakefulness. When complete or incomplete reminders are presented during 40-min sleep, both reminders are equally effective in stabilizing memories. However, when extending the retention interval for another 7 hours (following 40-min sleep), only incomplete but not complete reminders stabilize memories, regardless of the extension containing wakefulness or sleep. We propose that, during sleep, only incomplete reminders initiate long-term memory stabilization via mismatch detection.

Sleep in disorders of consciousness: behavioral and polysomnographic recording.

BACKGROUND: Sleep-wakefulness cycles are an essential diagnostic criterion for disorders of consciousness (DOC), differentiating prolonged DOC from coma. Specific sleep features, like the presence of sleep spindles, are an important marker for the prognosis of recovery from DOC. Based on increasing evidence for a link between sleep and neuronal plasticity, understanding sleep in DOC might facilitate the development of novel methods for rehabilitation. Yet, well-controlled studies of sleep in DOC are lacking. Here, we aimed to quantify, on a reliable evaluation basis, the distribution of behavioral and neurophysiological sleep patterns in DOC over a 24-h period while controlling for environmental factors (by recruiting a group of conscious tetraplegic patients who resided in the same hospital). METHODS: We evaluated the distribution of sleep and wakefulness by means of polysomnography (EEG, EOG, EMG) and video recordings in 32 DOC patients (16 unresponsive wakefulness syndrome [UWS], 16 minimally conscious state [MCS]), and 10 clinical control patients with severe tetraplegia. Three independent raters scored the patients' polysomnographic recordings. RESULTS: All but one patient (UWS) showed behavioral and electrophysiological signs of sleep. Control and MCS patients spent significantly more time in sleep during the night than during daytime, a pattern that was not evident in UWS. DOC patients (particularly UWS) exhibited less REM sleep than control patients. Forty-four percent of UWS patients and 12% of MCS patients did not have any REM sleep, while all control patients (100%) showed signs of all sleep stages and sleep spindles. Furthermore, no sleep spindles were found in 62% of UWS patients and 21% of MCS patients. In the remaining DOC patients who had spindles, their number and amplitude were significantly lower than in controls. CONCLUSIONS: The distribution of sleep signs in DOC over 24 h differs significantly from the normal sleep-wakefulness pattern. These abnormalities of sleep in DOC are independent of external factors such as severe immobility and hospital environment.

Selective suppression of rapid eye movement sleep increases next-day negative affect and amygdala responses to social exclusion.

Healthy sleep, positive general affect, and the ability to regulate emotional experiences are fundamental for well-being. In contrast, various mental disorders are associated with altered rapid eye movement (REM) sleep, negative affect, and diminished emotion regulation abilities. However, the neural processes mediating the relationship between these different phenomena are still not fully understood. In the present study of 42 healthy volunteers, we investigated the effects of selective REM sleep suppression (REMS) on general affect, as well as on feelings of social exclusion, cognitive reappraisal (CRA) of emotions, and their neural underpinnings. Using functional magnetic resonance imaging we show that, on the morning following sleep suppression, REMS increases general negative affect, enhances amygdala responses and alters its functional connectivity with anterior cingulate cortex during passively experienced experimental social exclusion. However, we did not find effects of REMS on subjective emotional ratings in response to social exclusion, their regulation using CRA, nor on functional amygdala connectivity while participants employed CRA. Our study supports the notion that REM sleep is important for affective processes, but emphasizes the need for future research to systematically investigate how REMS impacts different domains of affective experience and their neural correlates, in both healthy and (sub-)clinical populations.

Time-of-day effects on prospective memory.

Cognitive performance fluctuates during the course of a day. Different cognitive functions show optimal performance at different times of the day, known as the 'time-of-day effect'. While this effect has been observed for a number of cognitive domains including declarative memory, it is presently unclear whether performance fluctuations are also seen in prospective memory, i.e. memory for intentions to be realized in the future. The present study examined time-of-day effects in four different prospective memory tasks with varying degrees of complexity, taking into account circadian preference (i.e. morningness-eveningness/chronotype) and attentional resources (in one of the tasks). In a pilot study (n = 48) and a main experiment (n = 39), prospective memory was compared between morning groups (˜09:00) and evening groups (˜21:00) of young adults. We found time-of-day effects, with better performance in the evening than in the morning, in a simple one-item prospective memory task (Red Pencil Task, p = .02), a classical event-based prospective memory task including the detection of cue syllables in a lexical decision ongoing task (Syllable Detection Task, p < .048), and a rather naturalistic complex planning task for breakfast preparation (Dresden Breakfast Task, including time-based prospective memory (p = .026) and event-based prospective memory (p = .054)). These time-of-day effects were neither modulated by circadian preference nor by attentional resources. Another simple one-item prospective memory task was not affected by time of day (Color Task, p = .14). Ongoing task performance in the Syllable Detection Task and the Dresden Breakfast Task, overall, did not differ significantly between morning and evening groups. These findings provide tentative evidence for time-of-day effects in prospective memory of young adults, with better performance in the evening hours.

Sleep accelerates re-stabilization of human declarative memories.

Consolidated memories can return to a labile state upon presentation of a reminder, followed by a period of re-stabilization known as reconsolidation. This period can take several hours, and if an amnesic agent (e.g. new learning) is administered inside the time window of reconsolidation (when the memory is still labile) the memory is impaired, whereas the memory remains unaffected if the amnesic agent is administered outside this time window. Sleep plays a fundamental role in the consolidation and integration of new memories, and recently sleep has also been implicated in memory reconsolidation. Here, we studied the role of sleep in accelerating the reconsolidation time window. On day 1, participants learned a list of syllable-pairs (List 1). On day 2, they received a reminder, followed by interference learning (List 2) administered either after 90 min of wakefulness, after 90 min of sleep, or after 10 h of wakefulness. On day 3, participants had to recall List 1 first, followed by List 2, and we assessed the Retrieval-Induced-Forgetting Effect (RIF) on List 2 as a measure of List 1 memory stability. We found that the 90 min sleep group showed an intact RIF effect similar to the 10 h wake group, reflecting stable List 1 memory after 90 min of sleep and after 10 h of wakefulness. However, the RIF effect was absent after 90 min of wakefulness, suggesting that the List 1 memory was still labile at that time. Moreover, the RIF effect in the 90 min sleep group was associated with power density in the slow oscillation frequency band (0.5-1 Hz) during SWS and S2. These findings suggest that 90 min of sleep accelerate memory re-stabilization after reminder presentation, shortening the reconsolidation time window and protecting the memory against subsequent interference. This rapid memory re-stabilization may depend on slow oscillation activity during NREM sleep.

Effects of sleep on the realization of complex plans.

Sleep consolidates newly encoded memories, particularly those memories that are relevant for future behaviour. This study explored whether sleep facilitates the successful execution of relatively complex plans in the future. We applied the Dresden Breakfast Task, in which subjects are instructed to prepare a virtual breakfast comprising several tasks (e.g. table-setting, preparing eggs). After forming a detailed plan how to realize these tasks, the sleep group (n = 17) spent a night of sleep at home, monitored by polysomnography, and the wake group (n = 19) spent a normal day awake, monitored by actigraphy. After a 12-h interval, all participants were asked to prepare the virtual breakfast. Contrary to our hypothesis, overall performance in breakfast preparation did not differ significantly between the sleep and wake groups. However, sleep participants performed better in one of six tasks, specifically the 'table-setting' task (P < 0.01), which was driven by higher scores in a subtask measuring the correct position of the tableware (P < 0.01). Additional exploratory analyses revealed that a significant number of wake participants performed below the minimal score of the sleep group (P < 0.01) and sleep participants achieved the maximal score in significantly more subtasks than wake participants (57% versus 27%; P = 0.018). Plan adherence, assessing how well participants adhered to their own previously developed plan, did not differ between the sleep and wake groups. These findings provide the first evidence that sleep may support some aspects of the realization of complex, somewhat naturalistic plans.

Sleep to be social: The critical role of sleep and memory for social interaction.

Humans are highly social animals who critically need to remember information from social episodes in order to successfully navigate future social interactions. We propose that such episodic memories about social encounters are processed during sleep, following the learning experience, with sleep abstracting and consolidating social gist knowledge (e.g., beliefs, first impressions, or stereotypes) about others that supports relationships and interpersonal communication.

Reactivation of interference during sleep does not impair ongoing memory consolidation.

Memory consolidation during sleep is assumed to rely on the repeated reactivation of newly encoded memories particularly during slow wave sleep (SWS). It has been proposed that reactivated memories during sleep - like during wakefulness - undergo a labilisation process, enabling the strengthening and integration of new memories into pre-existing networks. Here, we tested this idea by introducing interference directly during sleep in the reactivation/consolidation phase. We predicted that cueing interfering memories during sleep would impair the consolidation of recently learned memories. Participants learned a visuo-spatial memory task before they were allowed to sleep for 40 min. During sleep, and particularly during SWS, subjects were presented with interference via odour cueing (compared to a no interference vehicle condition). In contrast to our hypothesis, cueing of the interference during sleep did not impair consolidation of the newly learned memories: odour and vehicle conditions did not differ in memory recall after sleep. On the contrary, subjects even displayed significantly fewer intrusions from the interference during memory recall when the odour was presented during sleep. These findings suggest that interference presentation during sleep does not disrupt endogenous memory consolidation, but might even facilitate pattern separation and memory stabilisation through generalisation processes.

Odor cueing during slow-wave sleep benefits memory independently of low cholinergic tone.

RATIONALE: Sleep-dependent memory consolidation depends on the concerted reactivation of memories in the hippocampo-neocortical system. The communication of reactivated information from the hippocampus to the neocortex is assumed to be enabled by low levels of acetylcholine, particularly during slow-wave sleep (SWS). Recent studies suggest that the reactivation of memories does not only occur spontaneously but can also be externally triggered by re-presenting learning-associated cues during sleep. OBJECTIVES: Here we investigated whether the beneficial effect of cued memory reactivation during sleep depends on similar mechanisms as spontaneous reactivation, and specifically on low cholinergic tone. METHODS: In two experimental nights, healthy volunteers learned a visuo-spatial memory task in the presence of an odor before going to sleep for 40 min. In one night, subjects were presented with the odor again during SWS, whereas in the other night they received an odorless vehicle. In half of the subjects, the availability of acetylcholine during sleep was increased by administering the acetylcholine-esterase inhibitor physostigmine. RESULTS: Contrary to our hypothesis, increased cholinergic tone during sleep did not abolish the beneficial effect of odor cueing: memory performance was better after odor cueing compared to odorless vehicle, independent of physostigmine or placebo administration. CONCLUSIONS: This finding challenges the assumption that odor-cued and spontaneous memory reactivation rely on the same neuropharmacological mechanisms.

Sleep increases explicit solutions and reduces intuitive judgments of semantic coherence.

Sleep fosters the generation of explicit knowledge. Whether sleep also benefits implicit intuitive decisions about underlying patterns is unclear. We examined sleep's role in explicit and intuitive semantic coherence judgments. Participants encoded sets of three words and after a sleep or wake period were required to judge the potential convergence of these words on a common fourth associate. Compared with wakefulness, sleep increased the number of explicitly named common associates and decreased the number of intuitive judgments. This suggests that sleep enhances the extraction of explicit knowledge at the expense of the ability to make intuitive decisions about semantic coherence.

Sleep Supports the Slow Abstraction of Gist from Visual Perceptual Memories.

Sleep benefits the consolidation of individual episodic memories. In the long run, however, it may be more efficient to retain the abstract gist of single, related memories, which can be generalized to similar instances in the future. While episodic memory is enhanced after one night of sleep, effective gist abstraction is thought to require multiple nights. We tested this hypothesis using a visual Deese-Roediger-McDermott paradigm, examining gist abstraction and episodic-like memory consolidation after 20 min, after 10 hours, as well as after one year of retention. While after 10 hours, sleep enhanced episodic-like memory for single items, it did not affect gist abstraction. One year later, however, we found significant gist knowledge only if subjects had slept immediately after encoding, while there was no residual memory for individual items. These findings indicate that sleep after learning strengthens episodic-like memories in the short term and facilitates long-term gist abstraction.

Signs of enhanced sleep and sleep-associated memory processing following the anti-inflammatory antibiotic minocycline in men.

Pro-inflammatory cytokines can promote sleep and neuronal processes underlying memory formation. However, this has mainly been revealed in animal studies. In this double-blind, placebo-controlled within-subject designed study, we examined how changes in the balance between pro- and anti-inflammatory signalling affect sleep and sleep-associated memory consolidation in humans. After learning declarative memory tasks (word pairs, texts) and a procedural memory task (finger tapping) in the evening, 21 healthy young men orally received either 200 mg of the anti-inflammatory antibiotic minocycline or placebo shortly before nocturnal sleep. Sleep was allowed between 23:00 and 07:00 h and recorded polysomnographically. Retrieval of memories was tested two days later. Because of outliers or missing data, final sample size was reduced to n = 14-19. Our data suggest that rather than weakening sleep as expected based on animal studies, the anti-inflammatory agent promoted sleep and memory consolidation. Specifically, minocycline increased slow-wave activity (0.68-4.0 Hz) during non-rapid eye movement sleep stage 2 and selectively enhanced episodic aspects in memory (i.e. memory for the temporal order of events in the texts). In combination with previous results, our findings indicate that, in humans, reducing pro-inflammatory signalling can act towards deepening non-rapid eye movement sleep and enhancing its memory forming efficacy.

Sleep's role in the reconsolidation of declarative memories.

Sleep is known to support the consolidation of newly encoded and initially labile memories. Once consolidated, remote memories can return to a labile state upon reactivation and need to become reconsolidated in order to persist. Here we asked whether sleep also benefits the reconsolidation of remote memories after their reactivation and how reconsolidation during sleep compares to sleep-dependent consolidation processes. In three groups, participants were trained on a visuo-spatial learning task in the presence of a contextual odor. Participants in the 'reconsolidation' group learned the task on day 1. On day 2, they were subjected to a reactivation procedure by presenting the odor cue and a mock recall test in the learning context before a 40-min sleep or wake period. Participants in the 'remote consolidation' group followed the same procedure but did not receive reactivation on day 2. Participants in the 'recent consolidation' group skipped the procedure on day 1 and learned the task immediately before the sleep or wake period. After the sleep or wake interval, memory stability was tested in all subjects. The results show that this short 40-min sleep period significantly facilitated the reconsolidation of reactivated memories, whereas the consolidation of non-reactivated remote memories was less affected and recently encoded memories did not benefit at all. These findings tentatively suggest that sleep has a beneficial effect on the reconsolidation of remote memories, acting at a faster rate than sleep-associated consolidation.

Increasing Explicit Sequence Knowledge by Odor Cueing during Sleep in Men but not Women.

Sleep consolidates newly acquired memories. Beyond stabilizing memories, sleep is thought to reorganize memory representations such that invariant structures, statistical regularities and even new explicit knowledge are extracted. Whereas increasing evidence suggests that the stabilization of memories during sleep can be facilitated by cueing with learning-associated stimuli, the effect of cueing on memory reorganization is less well understood. Here we asked whether olfactory cueing during sleep enhances the generation of explicit knowledge about an implicitly learned procedural memory task. Subjects were trained on a serial reaction time task (SRTT) containing a hidden 12-element sequence in the presence of an odor. During subsequent sleep, half of the subjects were re-exposed to the odor during periods of slow wave sleep (SWS), while the other half received odorless vehicle. In the next morning, subjects were tested on their explicit knowledge about the underlying sequence in a free recall test and a generation task. Although odor cueing did not significantly affect overall explicit knowledge, differential effects were evident when analyzing male and female subjects separately. Explicit sequence knowledge, both in free recall and the generation task, was enhanced by odor cueing in men, whereas women showed no cueing effect. Procedural skill in the SRTT was not affected by cueing, neither in men nor in women. These findings suggest that olfactory memory reactivation can increase explicit knowledge about implicitly learned information, but only in men. Hormonal differences due to menstrual cycle phase and/or hormonal contraceptives might explain the lacking effect in women.