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.

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.

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.

Does Targeted Memory Reactivation during SWS and REM sleep have differential effects on mnemonic discrimination and generalization?

Targeted memory reactivation (TMR), or the presentation of learning-related cues during sleep, has been shown to benefit memory consolidation for specific memory traces when applied during non-rapid eye movement (NREM) sleep. Prior studies suggest that TMR during REM sleep may play a role in memory generalization processes, but evidence remains scarce. We tested the hypothesis that TMR exerts a differential effect on distinct mnemonic processes as a function of the sleep state (REM vs. NREM) in which TMR is delivered. Mnemonic discrimination and generalization of semantic categories were investigated using an adapted version of the Mnemonic Similarity Task, before and after sleep. Forty-eight participants encoded pictures from eight semantic categories, each associated with a sound. In the pre-sleep immediate test, they had to discriminate "old" (targets) from "similar" (lures) or "new" (foils) pictures. During sleep, half of the sounds were replayed in slow wave sleep (SWS) or REM sleep. Recognition, discrimination, and generalization memory indices were tested in the morning. These indices did not differ between SWS and REM TMR groups or reactivated and non-reactivated item categories. Additional results suggest a positive effect of TMR on performance for highly similar items mostly relying on mnemonic discrimination processes. During sleep, EEG activity after cue presentation increased in the delta-theta and sigma band in the SWS group, and in the beta band in the REM TMR group. These results do not support the hypothesis of a differential processing of novel memory traces when TMR is administered in distinctive physiological sleep states.

No Benefit in Memory Performance after Nocturnal Memory Reactivation Coupled with Theta-tACS.

Targeted memory reactivation (TMR) is an effective technique to enhance sleep-associated memory consolidation. The successful reactivation of memories by external reminder cues is typically accompanied by an event-related increase in theta oscillations, preceding better memory recall after sleep. However, it remains unclear whether the increase in theta oscillations is a causal factor or an epiphenomenon of successful TMR. Here, we used transcranial alternating current stimulation (tACS) to examine the causal role of theta oscillations for TMR during non-rapid eye movement (non-REM) sleep. Thirty-seven healthy participants learned Dutch-German word pairs before sleep. During non-REM sleep, we applied either theta-tACS or control-tACS (23 Hz) in blocks (9 min) in a randomised order, according to a within-subject design. One group of participants received tACS coupled with TMR time-locked two seconds after the reminder cue (time-locked group). Another group received tACS in a continuous manner while TMR cues were presented (continuous group). Contrary to our predictions, we observed no frequency-specific benefit of theta-tACS coupled with TMR during sleep on memory performance, neither for continuous nor time-locked stimulation. In fact, both stimulation protocols blocked the TMR-induced memory benefits during sleep, resulting in no memory enhancement by TMR in both the theta and control conditions. No frequency-specific effect was found on the power analyses of the electroencephalogram. We conclude that tACS might have an unspecific blocking effect on memory benefits typically observed after TMR during non-REM sleep.

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.

Effects of Targeted Memory Reactivation on Cortical Networks.

Sleep is a complex physiological process with an important role in memory consolidation characterised by a series of spatiotemporal changes in brain activity and connectivity. Here, we investigate how task-related responses differ between pre-sleep wake, sleep, and post-sleep wake. To this end, we trained participants on a serial reaction time task using both right and left hands using Targeted Memory Reactivation (TMR), in which auditory cues are associated with learned material and then re-presented in subsequent wake or sleep periods in order to elicit memory reactivation. The neural responses just after each cue showed increased theta band connectivity between frontal and other cortical regions, as well as between hemispheres, in slow wave sleep compared to pre- or post-sleep wake. This pattern was consistent across the cues associated with both right- and left-handed movements. We also searched for hand-specific connectivity and found that this could be identified in within-hemisphere connectivity after TMR cues during sleep and post-sleep sessions. The fact that we could identify which hand had been cued during sleep suggests that these connectivity measures could potentially be used to determine how successfully memory is reactivated by our manipulation. Collectively, these findings indicate that TMR modulates the brain cortical networks showing clear differences between wake and sleep connectivity patterns.

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.

Targeted memory reactivation in human REM sleep elicits detectable reactivation.

It is now well established that memories can reactivate during non-rapid eye movement (non-REM) sleep, but the question of whether equivalent reactivation can be detected in rapid eye movement (REM) sleep is hotly debated. To examine this, we used a technique called targeted memory reactivation (TMR) in which sounds are paired with learned material in wake, and then re-presented in subsequent sleep, in this case REM, to trigger reactivation. We then used machine learning classifiers to identify reactivation of task-related motor imagery from wake in REM sleep. Interestingly, the strength of measured reactivation positively predicted overnight performance improvement. These findings provide the first evidence for memory reactivation in human REM sleep after TMR that is directly related to brain activity during wakeful task performance.

Sleep is crucial for rest and recovery, but it also allows the brain to process things it has learned while awake. This is why a person may go to bed frustrated with learning a tune on the piano but wake up the next morning ready to play it without fumbling. For this to happen, it is thought that memories must be reactivated during sleep ­ something which can be studied by monitoring brain activity. While it has been shown that memory reactivation occurs in some stages of human sleep, it was unclear whether it occurred in a specific stage known as REM sleep ­ which is important for learning. To study memory reactivation during REM sleep, Abdellahi et al. recruited volunteers and monitored their brain activity during an 'adaptation night' when certain sounds played as they slept. The following day, memories ­ such as an image or pressing a certain button ­ were paired with the sounds, which were replayed during REM sleep the following night to trigger memory reactivation (experimental night). Abdellahi et al. measured how strongly brain activity during each night related to the waking activity when the sound pairing tasks were imagined and compared the adaptation and experimental nights. The experimental night showed clear signs of memory reactivation after the sounds were played during REM sleep, suggesting that the sounds triggered memories of the associated images or buttons. These findings show that in humans, brain activity patterns that indicate memory reactivation can be identified during REM sleep. The work paves the way for future studies into the characteristics of this memory reactivation and how to trigger it in a way that leads to improvements in memory.

Erratum: Targeted memory reactivation during REM sleep in patients with social anxiety disorder.

[This corrects the article DOI: 10.3389/fpsyt.2022.904704.].

Memory consolidation during sleep involves context reinstatement in humans.

New memories are not quarantined from each other when first encoded; rather, they are interlinked with memories that were encoded in temporal proximity or that share semantic features. By selectively biasing memory processing during sleep, here we test whether context influences sleep consolidation. Participants first formed 18 idiosyncratic narratives, each linking four objects together. Before sleep, they also memorized an on-screen position for each object. During sleep, 12 object-specific sounds were unobtrusively presented, thereby cuing the corresponding spatial memories and impacting spatial recall as a function of initial memory strength. As hypothesized, we find that recall for non-cued objects contextually linked with cued objects also changed. Post-cue electrophysiological responses suggest that activity in the sigma band supports context reinstatement and predicts context-related memory benefits. Concurrently, context-specific electrophysiological activity patterns emerge during sleep. We conclude that reactivation of individual memories during sleep evokes reinstatement of their context, thereby impacting consolidation of associated knowledge.

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.

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.

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.

Targeted memory reactivation during sleep influences social bias as a function of slow-oscillation phase and delta power.

To understand how memories are reactivated and consolidated during sleep, experimenters have employed the unobtrusive re-presentation of memory cues from a variety of pre-sleep learning tasks. Using this procedure, known as targeted memory reactivation (TMR), we previously found that reactivation of counter-social-bias training during post-training sleep could selectively enhance training effects in reducing unintentional social biases. Here, we describe re-analyses of electroencephalographic (EEG) data from this previous study to characterize neurophysiological correlates of TMR-induced bias reduction. We found that TMR benefits in bias reduction were associated with (a) the timing of memory-related cue presentation relative to the 0.1-1.5 Hz slow-oscillation phase and (b) cue-elicited EEG power within the 1-4 Hz delta range. Although cue delivery was at a fixed rate in this study and not contingent on the slow-oscillation phase, cues were found to be clustered in slow-oscillation upstates for those participants with stronger TMR benefits. Similarly, higher cue-elicited delta power 250-1000 ms after cue onset was also linked with larger TMR benefits. These electrophysiological results substantiate the claim that memory reactivation altered social bias in the original study, while also informing neural explanations of these benefits. Future research should consider these sleep physiology parameters in relation to TMR applications and to memory reactivation in general.

Updating memories of unwanted emotions during human sleep.

Post-learning sleep contributes to memory consolidation. Yet it remains contentious whether sleep affords opportunities to modify or update emotional memories, particularly when people would prefer to forget those memories. Here, we attempted to update memories during sleep, using spoken positive words paired with cues to recent memories of aversive events. Affective updating using positive words during human non-rapid eye movement (NREM) sleep, compared with using neutral words instead, reduced negative affective judgments in post-sleep tests, suggesting that the recalled events were perceived as less aversive. Electroencephalogram (EEG) analyses showed that positive words modulated theta and spindle/sigma activity; specifically, to the extent that theta power was larger for the positive words than for the memory cues that followed, participants judged the memory cues less negatively. Moreover, to the extent that sigma power was larger for the positive words than for the memory cues that followed, participants forgot more episodic details about aversive events. Notably, when the onset of individual positive words coincided with the up-phase of slow oscillations (a state characterized by increased cortical excitability during NREM sleep), affective updating was more successful. In sum, we altered the affective content of memories via the strategic pairing of positive words and memory cues during sleep, linked with EEG theta power increases and the slow oscillation up-phase. These findings suggest novel possibilities for modifying unwanted memories during sleep, which would not require people to consciously confront memories that they prefer to avoid.

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.

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.

Enhancing imagery rehearsal therapy for nightmares with targeted memory reactivation.

Nightmare disorder (ND) is characterized by dreams with strong negative emotions occurring during rapid eye movement (REM) sleep. ND is mainly treated by imagery rehearsal therapy (IRT), where the patients are asked to change the negative story line of their nightmare to a more positive one. We here used targeted memory reactivation (TMR) during REM sleep to strengthen IRT-related memories and accelerate remission of ND. Thirty-six patients with ND were asked to perform an initial IRT session and, while they generated a positive outcome of their nightmare, half of the patients were exposed to a sound (TMR group), while no such pairing took place for the other half (control group). During the next 2 weeks, all patients performed IRT every evening at home and were exposed to the sound during REM sleep with a wireless headband, which automatically detected sleep stages. The frequency of nightmares per week at 2 weeks was used as the primary outcome measure. We found that the TMR group had less frequent nightmares and more positive dream emotions than the control group after 2 weeks of IRT and a sustained decrease of nightmares after 3 months. By demonstrating the effectiveness of TMR during sleep to potentiate therapy, these results have clinical implications for the management of ND, with relevance to other psychiatric disorders too. Additionally, these findings show that TMR applied during REM sleep can modulate emotions in dreams.

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.