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 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.

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.

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.

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.

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.

The role of sleep in motor sequence consolidation: stabilization rather than enhancement.

Sleep supports the consolidation of motor sequence memories, yet it remains unclear whether sleep stabilizes or actually enhances motor sequence performance. Here we assessed the time course of motor memory consolidation in humans, taking early boosts in performance into account and varying the time between training and sleep. Two groups of subjects, each participating in a short wake condition and a longer sleep condition, were trained on the sequential finger-tapping task in the evening and were tested (1) after wake intervals of either 30 min or 4 h and (2) after a night of sleep that ensued either 30 min or 4 h after training. The results show an early boost in performance 30 min after training and a subsequent decay across the 4 h wake interval. When sleep followed 30 min after training, post-sleep performance was stabilized at the early boost level. Sleep at 4 h after training restored performance to the early boost level, such that, 12 h after training, performance was comparable regardless of whether sleep occurred 30 min or 4 h after training. These findings indicate that sleep does not enhance but rather stabilizes motor sequence performance without producing additional gains.

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.

The memory function of sleep.

Sleep has been identified as a state that optimizes the consolidation of newly acquired information in memory, depending on the specific conditions of learning and the timing of sleep. Consolidation during sleep promotes both quantitative and qualitative changes of memory representations. Through specific patterns of neuromodulatory activity and electric field potential oscillations, slow-wave sleep (SWS) and rapid eye movement (REM) sleep support system consolidation and synaptic consolidation, respectively. During SWS, slow oscillations, spindles and ripples - at minimum cholinergic activity - coordinate the re-activation and redistribution of hippocampus-dependent memories to neocortical sites, whereas during REM sleep, local increases in plasticity-related immediate-early gene activity - at high cholinergic and theta activity - might favour the subsequent synaptic consolidation of memories in the cortex.

Effects of an interleukin-1 receptor antagonist on human sleep, sleep-associated memory consolidation, and blood monocytes.

Pro-inflammatory cytokines like interleukin-1 beta (IL-1) are major players in the interaction between the immune system and the central nervous system. Various animal studies report a sleep-promoting effect of IL-1 leading to enhanced slow wave sleep (SWS). Moreover, this cytokine was shown to affect hippocampus-dependent memory. However, the role of IL-1 in human sleep and memory is not yet understood. We administered the synthetic IL-1 receptor antagonist anakinra (IL-1ra) in healthy humans (100mg, subcutaneously, before sleep; n=16) to investigate the role of IL-1 signaling in sleep regulation and sleep-dependent declarative memory consolidation. Inasmuch monocytes have been considered a model for central nervous microglia, we monitored cytokine production in classical and non-classical blood monocytes to gain clues about how central nervous effects of IL-1ra are conveyed. Contrary to our expectation, IL-1ra increased EEG slow wave activity during SWS and non-rapid eye movement (NonREM) sleep, indicating a deepening of sleep, while sleep-associated memory consolidation remained unchanged. Moreover, IL-1ra slightly increased prolactin and reduced cortisol levels during sleep. Production of IL-1 by classical monocytes was diminished after IL-1ra. The discrepancy to findings in animal studies might reflect species differences and underlines the importance of studying cytokine effects in humans.

Changing maladaptive memories through reconsolidation: A role for sleep in psychotherapy?

Like Lane et al., we believe that change in psychotherapy comes about by updating dysfunctional memories with new adaptive experiences. We suggest that sleep is essential to (re-)consolidate such corrective experiences. Sleep is well-known to strengthen and integrate new memories into pre-existing networks. Targeted sleep interventions might be promising tools to boost this process and thereby increase therapy effectiveness.

Reactivating memories during sleep by odors: odor specificity and associated changes in sleep oscillations.

Memories are reactivated during sleep. Re-exposure to olfactory cues during sleep triggers this reactivation and improves later recall performance. Here, we tested if the effects of odor-induced memory reactivations are odor-specific, that is, requiring the same odor during learning and subsequent sleep. We also tested whether odor-induced memory reactivation affects oscillatory EEG activity during sleep, as a putative mechanism underlying memory processing during sleep. Participants learned a visuospatial memory task under the presence of an odor. During subsequent SWS, the same odor, a different odor, or an odorless vehicle was presented. We found that odor re-exposure during sleep significantly improves memory only when the same odor was presented again, whereas exposure to a new odor or the odorless vehicle had no effect. The memory-enhancing effect of the congruent odor was accompanied by significant increases in frontal delta (1.5-4.5 Hz) and parietal fast spindle (13.0-15.0 Hz) power as well as by an increased negative-to-positive slope of the frontal slow oscillation. Our results indicate that odor-induced memory reactivations are odor specific and trigger changes in slow-wave and spindle power possibly reflecting a bottom-up influence of hippocampal memory replay on cortical slow oscillations as well as thalamo-cortical sleep spindles.

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.

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.

Napping to renew learning capacity: enhanced encoding after stimulation of sleep slow oscillations.

As well as consolidating memory, sleep has been proposed to serve a second important function for memory, i.e. to free capacities for the learning of new information during succeeding wakefulness. The slow wave activity (SWA) that is a hallmark of slow wave sleep could be involved in both functions. Here, we aimed to demonstrate a causative role for SWA in enhancing the capacity for encoding of information during subsequent wakefulness, using transcranial slow oscillation stimulation (tSOS) oscillating at 0.75 Hz to induce SWA in healthy humans during an afternoon nap. Encoding following the nap was tested for hippocampus-dependent declarative materials (pictures, word pairs, and word lists) and procedural skills (finger sequence tapping). As compared with a sham stimulation control condition, tSOS during the nap enhanced SWA and significantly improved subsequent encoding on all three declarative tasks (picture recognition, cued recall of word pairs, and free recall of word lists), whereas procedural finger sequence tapping skill was not affected. Our results indicate that sleep SWA enhances the capacity for encoding of declarative materials, possibly by down-scaling hippocampal synaptic networks that were potentiated towards saturation during the preceding period of wakefulness.

Sleep after vaccination boosts immunological memory.

Sleep regulates immune functions. We asked whether sleep can influence immunological memory formation. Twenty-seven healthy men were vaccinated against hepatitis A three times, at weeks 0, 8, and 16 with conditions of sleep versus wakefulness in the following night. Sleep was recorded polysomnographically, and hormone levels were assessed throughout the night. Vaccination-induced Th cell and Ab responses were repeatedly monitored for 1 y. Compared with the wake condition, sleep after vaccination doubled the frequency of Ag-specific Th cells and increased the fraction of Th1 cytokine-producing cells in this population. Moreover, sleep markedly increased Ag-specific IgG1. The effects were followed up for 1 y and were associated with high sleep slow-wave activity during the postvaccination night as well as with accompanying levels of immunoregulatory hormones (i.e., increased growth hormone and prolactin but decreased cortisol release). Our findings provide novel evidence that sleep promotes human Th1 immune responses, implicating a critical role for slow-wave sleep in this process. The proinflammatory milieu induced during this sleep stage apparently acts as adjuvant that facilitates the transfer of antigenic information from APCs to Ag-specific Th cells. Like the nervous system, the immune system takes advantage of the offline conditions during sleep to foster adaptive immune responses resulting in improved immunological memory.

Sleep selectively enhances memory expected to be of future relevance.

The brain encodes huge amounts of information, but only a small fraction is stored for a longer time. There is now compelling evidence that the long-term storage of memories preferentially occurs during sleep. However, the factors mediating the selectivity of sleep-associated memory consolidation are poorly understood. Here, we show that the mere expectancy that a memory will be used in a future test determines whether or not sleep significantly benefits consolidation of this memory. Human subjects learned declarative memories (word paired associates) before retention periods of sleep or wakefulness. Postlearning sleep compared with wakefulness produced a strong improvement at delayed retrieval only if the subjects had been informed about the retrieval test after the learning period. If they had not been informed, retrieval after retention sleep did not differ from that after the wake retention interval. Retention during the wake intervals was not affected by retrieval expectancy. Retrieval expectancy also enhanced sleep-associated consolidation of visuospatial (two-dimensional object location task) and procedural motor memories (finger sequence tapping). Subjects expecting the retrieval displayed a robust increase in slow oscillation activity and sleep spindle count during postlearning slow-wave sleep (SWS). Sleep-associated consolidation of declarative memory was strongly correlated to slow oscillation activity and spindle count, but only if the subjects expected the retrieval test. In conclusion, our work shows that sleep preferentially benefits consolidation of memories that are relevant for future behavior, presumably through a SWS-dependent reprocessing of these memories.