Aversive memories can be weakened during human sleep via the reactivation of positive interfering memories.

Recollecting painful or traumatic experiences can be deeply troubling. Sleep may offer an opportunity to reduce such suffering. We developed a procedure to weaken older aversive memories by reactivating newer positive memories during sleep. Participants viewed 48 nonsense words each paired with a unique aversive image, followed by an overnight sleep. In the next evening, participants learned associations between half of the words and additional positive images, creating interference. During the following non-rapid-eye-movement sleep, auditory memory cues were unobtrusively delivered. Upon waking, presenting cues associated with both aversive and positive images during sleep, as opposed to not presenting cues, weakened aversive memory recall while increasing positive memory intrusions. Substantiating these memory benefits, computational modeling revealed that cueing facilitated evidence accumulation toward positive affect judgments. Moreover, cue-elicited theta brain rhythms during sleep predominantly predicted the recall of positive memories. A noninvasive sleep intervention can thus modify aversive recollection and affective responses.

Memory Reactivation during Sleep Does Not Act Holistically on Object Memory.

Memory reactivation during sleep is thought to facilitate memory consolidation. Most sleep reactivation research has examined how reactivation of specific facts, objects, and associations benefits their overall retention. However, our memories are not unitary, and not all features of a memory persist in tandem over time. Instead, our memories are transformed, with some features strengthened and others weakened. Does sleep reactivation drive memory transformation? We leveraged the Targeted Memory Reactivation technique in an object category learning paradigm to examine this question. Participants (20 female, 14 male) learned three categories of novel objects, where each object had unique, distinguishing features as well as features shared with other members of its category. We used a real-time EEG protocol to cue the reactivation of these objects during sleep at moments optimized to generate reactivation events. We found that reactivation improved memory for distinguishing features while worsening memory for shared features, suggesting a differentiation process. The results indicate that sleep reactivation does not act holistically on object memories, instead supporting a transformation where some features are enhanced over others.

Delineating memory reactivation in sleep with verbal and non-verbal retrieval cues.

Sleep supports memory consolidation via the reactivation of newly formed memory traces. One way to investigate memory reactivation in sleep is by exposing the sleeping brain to auditory retrieval cues; a paradigm known as targeted memory reactivation. To what extent the acoustic properties of memory cues influence the effectiveness of targeted memory reactivation, however, has received limited attention. We addressed this question by exploring how verbal and non-verbal memory cues affect oscillatory activity linked to memory reactivation in sleep. Fifty-one healthy male adults learned to associate visual stimuli with spoken words (verbal cues) and environmental sounds (non-verbal cues). Subsets of the verbal and non-verbal memory cues were then replayed during sleep. The voice of the verbal cues was either matched or mismatched to learning. Memory cues (relative to unheard control cues) prompted an increase in theta/alpha and spindle power, which have been heavily implicated in sleep-associated memory processing. Moreover, verbal memory cues were associated with a stronger increase in spindle power than non-verbal memory cues. There were no significant differences between the matched and mismatched verbal cues. Our findings suggest that verbal memory cues may be most effective for triggering memory reactivation in sleep, as indicated by an amplified spindle response.

Shaping overnight consolidation via slow-oscillation closed-loop targeted memory reactivation.

Sleep constitutes a privileged state for new memories to reactivate and consolidate. Previous work has demonstrated that consolidation can be bolstered experimentally either via delivery of reminder cues (targeted memory reactivation [TMR]) or via noninvasive brain stimulation geared toward enhancing endogenous sleep rhythms. Here, we combined both approaches, controlling the timing of TMR cues with respect to ongoing slow-oscillation (SO) phases. Prior to sleep, participants learned associations between unique words and a set of repeating images (e.g., car) while hearing a prototypical image sound (e.g., engine starting). Memory performance on an immediate test vs. a test the next morning quantified overnight memory consolidation. Importantly, two image sounds were designated as TMR cues, with one cue delivered at SO UP states and the other delivered at SO DOWN states. A novel sound was used as a TMR control condition. Behavioral results revealed a significant reduction of overnight forgetting for words associated with UP-state TMR compared with words associated with DOWN-state TMR. Electrophysiological results showed that UP-state cueing led to enhancement of the ongoing UP state and was followed by greater spindle power than DOWN-state cueing. Moreover, UP-state (and not DOWN-state) cueing led to reinstatement of target image representations. Together, these results unveil the behavioral and mechanistic effects of delivering reminder cues at specific phases of endogenous sleep rhythms and mark an important step for the endeavor to experimentally modulate memories during sleep.

Rule Abstraction Is Facilitated by Auditory Cuing in REM Sleep.

Sleep facilitates abstraction, but the exact mechanisms underpinning this are unknown. Here, we aimed to determine whether triggering reactivation in sleep could facilitate this process. We paired abstraction problems with sounds, then replayed these during either slow-wave sleep (SWS) or rapid eye movement (REM) sleep to trigger memory reactivation in 27 human participants (19 female). This revealed performance improvements on abstraction problems that were cued in REM, but not problems cued in SWS. Interestingly, the cue-related improvement was not significant until a follow-up retest 1 week after the manipulation, suggesting that REM may initiate a sequence of plasticity events that requires more time to be implemented. Furthermore, memory-linked trigger sounds evoked distinct neural responses in REM, but not SWS. Overall, our findings suggest that targeted memory reactivation in REM can facilitate visual rule abstraction, although this effect takes time to unfold.SIGNIFICANCE STATEMENT The ability to abstract rules from a corpus of experiences is a building block of human reasoning. Sleep is known to facilitate rule abstraction, but it remains unclear whether we can manipulate this process actively and which stage of sleep is most important. Targeted memory reactivation (TMR) is a technique that uses re-exposure to learning-related sensory cues during sleep to enhance memory consolidation. Here, we show that TMR, when applied during REM sleep, can facilitate the complex recombining of information needed for rule abstraction. Furthermore, we show that this qualitative REM-related benefit emerges over the course of a week after learning, suggesting that memory integration may require a slower form of plasticity.

Manipulated overlapping reactivation of multiple memories promotes explicit gist abstraction.

Sleep is considered to promote gist abstraction on the basis of spontaneous memory reactivation. As speculated in the theory of 'information overlap to abstract (iOtA)', 'overlap' between reactivated memories, beyond reactivation, is crucial to gist abstraction. Yet so far, empirical research has not tested this theory by manipulating the factor of 'overlap'. In the current study, 'overlap' itself was manipulated by targeted memory reactivation (TMR), through simultaneously reactivating multiple memories that either contain or do not contain spatially overlapped gist information, to investigate the effect of overlapping reactivation on gist abstraction. This study had a factorial design of 2 factors with 2 levels respectively (spatial overlap/no spatial overlap, TMR/no-TMR). Accordingly, 82 healthy college students (aged 19 âˆ¼ 25, 57 females) were randomized into four groups. After learning 16 pictures, paired with 4 auditory cues (4 pictures - 1 cue) according to the grouping, participants were given a 90-minute nap opportunity. Then TMR cueing was conducted during N2 and slow wave sleep of the nap. Performance in memory task was used to measure gist abstraction. The results showed a significant main effect of TMR on both implicit and explicit gist abstraction, and a marginally significant interaction effect on explicit gist abstraction. Further analyses showed that explicit gist abstraction in the spatial overlap & TMR group was significantly better than in the control group. Moreover, explicit gist abstraction was positively correlated with spindle density. The current study thus indicates that TMR facilitates gist abstraction, and explicit gist abstraction may benefit more from overlapping reactivation.

Targeted memory reactivation during post-learning sleep does not enhance motor memory consolidation in older adults.

Targeted memory reactivation (TMR) during sleep enhances memory consolidation in young adults by modulating electrophysiological markers of neuroplasticity. Interestingly, older adults exhibit deficits in motor memory consolidation, an impairment that has been linked to age-related degradations in the same sleep features sensitive to TMR. We hypothesised that TMR would enhance consolidation in older adults via the modulation of these markers. A total of 17 older participants were trained on a motor task involving two auditory-cued sequences. During a post-learning nap, two auditory cues were played: one associated to a learned (i.e., reactivated) sequence and one control. Performance during two delayed re-tests did not differ between reactivated and non-reactivated sequences. Moreover, both associated and control sounds modulated brain responses, yet there were no consistent differences between the auditory cue types. Our results collectively demonstrate that older adults do not benefit from specific reactivation of a motor memory trace by an associated auditory cue during post-learning sleep. Based on previous research, it is possible that auditory stimulation during post-learning sleep could have boosted motor memory consolidation in a non-specific manner.

Somatosensory targeted memory reactivation enhances motor performance via hippocampal-mediated plasticity.

Increasing evidence suggests that reactivation of newly acquired memory traces during postlearning wakefulness plays an important role in memory consolidation. Here, we sought to boost the reactivation of a motor memory trace during postlearning wakefulness (quiet rest) immediately following learning using somatosensory targeted memory reactivation (TMR). Using functional magnetic resonance imaging, we examined the neural correlates of the reactivation process as well as the effect of the TMR intervention on brain responses elicited by task practice on 24 healthy young adults. Behavioral data of the post-TMR retest session showed a faster learning rate for the motor sequence that was reactivated as compared to the not-reactivated sequence. Brain imaging data revealed that motor, parietal, frontal, and cerebellar brain regions, which were recruited during initial motor learning, were specifically reactivated during the TMR episode and that hippocampo-frontal connectivity was modulated by the reactivation process. Importantly, the TMR-induced behavioral advantage was paralleled by dynamical changes in hippocampal activity and hippocampo-motor connectivity during task practice. Altogether, the present results suggest that somatosensory TMR during postlearning quiet rest can enhance motor performance via the modulation of hippocampo-cortical responses.

Provoking lucid dreams at home with sensory cues paired with pre-sleep cognitive training.

The ability to realize that you're dreaming - lucid dreaming - has value for personal goals and for consciousness research. One route to lucid dreaming is to first undergo pre-sleep training with sensory cues and then receive those cues during REM sleep. This method, Targeted Lucidity Reactivation (TLR), does not demand extensive personal effort but generally requires concurrent polysomnography to guide cue delivery. Here we translated TLR from a laboratory procedure to a smartphone-based procedure without polysomnography. In a first experiment, participants reported increased lucid dreaming with TLR compared to during the prior week. In a second experiment, we showed increased lucidity with TLR compared to blinded control procedures on alternate nights. Cues during sleep were effective when they were the same sounds from pre-sleep training. Increased lucid dreaming can be ascribed to a strong link formed during training between the sounds and a mindset of carefully analyzing one's current experience.

Enhancing and advancing the understanding and study of dreaming and memory consolidation: Reflections, challenges, theoretical clarity, and methodological considerations.

Empirical investigations that search for a link between dreaming and sleep-dependent memory consolidation have focused on testing for an association between dreaming of what was learned, and improved memory performance for learned material. Empirical support for this is mixed, perhaps owing to the inherent challenges presented by the nature of dreams, and methodological inconsistencies. The purpose of this paper is to address critically prevalent assumptions and practices, with the aim of clarifying and enhancing research on this topic, chiefly by providing a theoretical synthesis of existing models and evidence. Also, it recommends the method of Targeted Memory Reactivation (TMR) as a means for investigating if dream content can be linked to specific cued activations. Other recommendations to enhance research practice and enquiry on this subject are also provided, focusing on the HOW and WHY we search for memory sources in dreams, and what purpose (if any) they might serve.

Targeting targeted memory reactivation: Characteristics of cued reactivation in sleep.

Targeted memory reactivation (TMR) is a technique in which sensory cues associated with memories during wake are used to trigger memory reactivation during subsequent sleep. The characteristics of such cued reactivation, and the optimal placement of TMR cues, remain to be determined. We built an EEG classification pipeline that discriminated reactivation of right- and left-handed movements and found that cues which fall on the up-going transition of the slow oscillation (SO) are more likely to elicit a classifiable reactivation. We also used a novel machine learning pipeline to predict the likelihood of eliciting a classifiable reactivation after each TMR cue using the presence of spindles and features of SOs. Finally, we found that reactivations occurred either immediately after the cue or one second later. These findings greatly extend our understanding of memory reactivation and pave the way for development of wearable technologies to efficiently enhance memory through cueing in sleep.

Neural correlates of sleep-induced benefits on traumatic memory processing.

Recent findings indicate that sleep after trauma compared to sleep loss inhibits intrusive memory development, possibly by promoting adequate memory consolidation and integration. However, the underlying neural mechanisms are still unknown. Here, we examined the neural correlates underlying the effects of sleep on traumatic memory development in 110 healthy participants using a trauma film paradigm and an implicit memory task with fMRI recordings in a between-subjects design. To further facilitate memory integration, we used targeted memory reactivation (TMR) to reactivate traumatic memories during sleep. We found that sleep (i.e., nap) compared to wakefulness reduced the number of intrusive traumatic memories for the experimental trauma groups. TMR during sleep only descriptively reduced the intrusions further. On the level of brain activity, increased activity in the anterior and posterior cingulate cortex, retrosplenial cortex and precuneus was found in the experimental trauma group compared to the control group after wakefulness. After sleep, on the other hand, these findings could not be found in the experimental trauma groups compared to the control group. Sleep compared to wakefulness increased activity in the cerebellum, fusiform gyrus, inferior temporal lobe, hippocampus, and amygdala during implicit retrieval of trauma memories in the experimental trauma groups. Activity in the hippocampus and the amygdala predicted subsequent intrusions. Results demonstrate the beneficial behavioral and neural effects of sleep after experimental trauma and provide indications for early neural predictor factors. This study has implications for understanding the important role of sleep for personalized treatment and prevention in posttraumatic stress disorder.

Cueing emotional memories during slow wave sleep modulates next-day activity in the orbitofrontal cortex and the amygdala.

Emotional memories are preferentially consolidated during sleep, through the process of memory reactivation. Targeted memory reactivation (TMR) has been shown to boost memory consolidation during sleep, but its neural correlates remain unclear, particularly for emotional memories. Here, we aimed to examine how TMR of emotional material during slow wave sleep (SWS) impacts upon neural processing during a subsequent arousal rating task. Participants were trained on a spatial memory task including negative and neutral pictures paired with semantically matching sounds. The picture-sound pairs were rated for emotional arousal before and after the spatial memory task. Then, half of the sounds from each emotional category (negative and neutral) were cued during SWS. The next day, participants were retested on both the arousal rating and the spatial memory task inside an MRI scanner, followed by another retest session a week later. Memory consolidation and arousal processing did not differ between cued and non-cued items of either emotional category. We found increased responses to emotional stimuli in the amygdala and orbitofrontal cortex (OFC), and a cueing versus emotion interaction in the OFC, whereby cueing neutral stimuli led to an increase in OFC activity, while cueing negative stimuli led to decreased OFC activation. Interestingly, the effect of cueing on amygdala activation was modulated by time spent in REM sleep. We conclude that SWS TMR impacts OFC activity, while REM sleep plays a role in mediating the effect of such cueing on amygdala.

Real-time, closed-loop, or open-loop stimulation? Navigating a terminological jungle.

Recent advancements in real-time brain stimulation in the sleep field have led to many exciting findings. However, they have also opened up terminological ambiguities about what constitutes "open-loop", "closed-loop", and "real-time" designs. Here, we address core theoretical aspects of these terms in the hopes of strengthening future research on this topic.

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.

Memory and Sleep: How Sleep Cognition Can Change the Waking Mind for the Better.

The memories that we retain can serve many functions. They guide our future actions, form a scaffold for constructing the self, and continue to shape both the self and the way we perceive the world. Although most memories we acquire each day are forgotten, those integrated within the structure of multiple prior memories tend to endure. A rapidly growing body of research is steadily elucidating how the consolidation of memories depends on their reactivation during sleep. Processing memories during sleep not only helps counteract their weakening but also supports problem solving, creativity, and emotional regulation. Yet, sleep-based processing might become maladaptive, such as when worries are excessively revisited. Advances in research on memory and sleep can thus shed light on how this processing influences our waking life, which can further inspire the development of novel strategies for decreasing detrimental rumination-like activity during sleep and for promoting beneficial sleep cognition.

Stimulation Augments Spike Sequence Replay and Memory Consolidation during Slow-Wave Sleep.

Newly acquired memory traces are spontaneously reactivated during slow-wave sleep (SWS), leading to the consolidation of recent memories. Empirical studies found that sensory stimulation during SWS can selectively enhance memory consolidation with the effect depending on the phase of stimulation. In this new study, we aimed to understand the mechanisms behind the role of sensory stimulation on memory consolidation using computational models implementing effects of neuromodulators to simulate transitions between awake and SWS sleep, and synaptic plasticity to allow the change of synaptic connections due to the training in awake or replay during sleep. We found that when closed-loop stimulation was applied during the Down states of sleep slow oscillation, particularly right before the transition from Down to Up state, it significantly affected the spatiotemporal pattern of the slow waves and maximized memory replay. In contrast, when the stimulation was presented during the Up states, it did not have a significant impact on the slow waves or memory performance after sleep. For multiple memories trained in awake, presenting stimulation cues associated with specific memory trace could selectively augment replay and enhance consolidation of that memory and interfere with consolidation of the others (particularly weak) memories. Our study proposes a synaptic-level mechanism of how memory consolidation is affected by sensory stimulation during sleep.SIGNIFICANCE STATEMENT Stimulation, such as training-associated cues or auditory stimulation, during sleep can augment consolidation of the newly encoded memories. In this study, we used a computational model of the thalamocortical system to describe the mechanisms behind the role of stimulation in memory consolidation during slow-wave sleep. Our study suggests that stimulation preferentially strengthens memory traces when delivered at a specific phase of the slow oscillation, just before the Down to Up state transition when it makes the largest impact on the spatiotemporal pattern of sleep slow waves. In the presence of multiple memories, presenting sensory cues during sleep could selectively strengthen selected memories. Our study proposes a synaptic-level mechanism of how memory consolidation is affected by sensory stimulation during sleep.

Long term effects of cueing procedural memory reactivation during NREM sleep.

Targeted memory reactivation (TMR) has recently emerged as a promising tool to manipulate and study the sleeping brain. Although the technique is developing rapidly, only a few studies have examined how the effects of TMR develop over time. Here, we use a bimanual serial reaction time task (SRTT) to investigate whether the difference between the cued and un-cued sequence of button presses persists long-term. We further explore the relationship between the TMR benefit and sleep spindles, as well as their coupling with slow oscillations. Our behavioural analysis shows better performance for the dominant hand. Importantly, there was a strong effect of TMR, with improved performance on the cued sequence after sleep. Closer examination revealed a significant benefit of TMR at 10 days post-encoding, but not 24 h or 6 weeks post-encoding. Time spent in stage 2, but not stage 3, of NREM sleep predicted cueing benefit. We also found a significant increase in spindle density and SO-spindle coupling during the cue period, when compared to the no-cue period. Together, our results demonstrate that TMR effects evolve over several weeks post-cueing, as well as emphasising the importance of stage 2, spindles and the SO-spindle coupling in procedural memory consolidation.

Whole-body procedural learning benefits from targeted memory reactivation in REM sleep and task-related dreaming.

Sleep facilitates memory consolidation through offline reactivations of memory traces. Dreaming may play a role in memory improvement and may reflect these memory reactivations. To experimentally address this question, we used targeted memory reactivation (TMR), i.e., application, during sleep, of a stimulus that was previously associated with learning, to assess whether it influences task-related dream imagery (or task-dream reactivations). Specifically, we asked if TMR or task-dream reactivations in either slow-wave (SWS) or rapid eye movement (REM) sleep benefit whole-body procedural learning. Healthy participants completed a virtual reality (VR) flying task prior to and following a morning nap or rest period during which task-associated tones were readministered in either SWS, REM sleep, wake or not at all. Findings indicate that learning benefits most from TMR when applied in REM sleep compared to a Control-sleep group. REM dreams that reactivated kinesthetic elements of the VR task (e.g., flying, accelerating) were also associated with higher improvement on the task than were dreams that reactivated visual elements (e.g., landscapes) or that had no reactivations. TMR did not itself influence dream content but its effects on performance were greater when coexisting with task-dream reactivations in REM sleep. Findings may help explain the mechanistic relationships between dream and memory reactivations and may contribute to the development of sleep-based methods to optimize complex skill learning.

Does memory reactivation during sleep support generalization at the cost of memory specifics?

Sleep is important for memory, but does it favor consolidation of specific details or extraction of generalized information? Both may occur together when memories are reactivated during sleep, or a loss of certain memory details may facilitate generalization. To examine these issues, we tested memory in participants who viewed landscape paintings by six artists. Paintings were cropped to show only a section of the scene. During a learning phase, each painting section was presented with the artist's name and with a nonverbal sound that had been uniquely associated with that artist. In a test of memory for specifics, participants were shown arrays of six painting sections, all by the same artist. Participants attempted to select the one that was seen in the learning phase. Generalization was tested by asking participants to view new paintings and, for each one, decide which of the six artists created it. After this testing, participants had a 90-minute sleep opportunity with polysomnographic monitoring. When slow-wave sleep was detected, three of the sound cues associated with the artists were repeatedly presented without waking the participants. After sleep, participants were again tested for memory specifics and generalization. Memory reactivation during sleep due to the sound cues led to a relative decline in accuracy on the specifics test, which could indicate the transition to a loss of detail that facilitates generalization, particularly details such as the borders. Generalization performance showed very little change after sleep and was unaffected by the sound cues. Although results tentatively implicate sleep in memory transformation, further research is needed to examine memory change across longer time periods.