Post-traumatic stress disorder (PTSD) is a psychiatric disorder with traumatic memories at its core. Post-treatment sleep may offer a unique time window to increase therapeutic efficacy through consolidation of therapeutically modified traumatic memories. Targeted memory reactivation (TMR) enhances memory consolidation by presenting reminder cues (e.g., sounds associated with a memory) during sleep. Here, we applied TMR in PTSD patients to strengthen therapeutic memories during sleep after one treatment session with eye movement desensitization and reprocessing (EMDR). PTSD patients received either slow oscillation (SO) phase-targeted TMR, using modeling-based closed-loop neurostimulation (M-CLNS) with EMDR clicks as a reactivation cue (n = 17), or sham stimulation (n = 16). Effects of TMR on sleep were assessed through high-density polysomnography. Effects on treatment outcome were assessed through subjective, autonomic, and fMRI responses to script-driven imagery (SDI) of the targeted traumatic memory and overall PTSD symptom level. Compared to sham stimulation, TMR led to stimulus-locked increases in SO and spindle dynamics, which correlated positively with PTSD symptom reduction in the TMR group. Given the role of SOs and spindles in memory consolidation, these findings suggest that TMR may have strengthened the consolidation of the EMDR-treatment memory. Clinically, TMR vs. sham stimulation resulted in a larger reduction of avoidance level during SDI. TMR did not disturb sleep or trigger nightmares. Together, these data provide first proof of principle that TMR may be a safe and viable future treatment augmentation strategy for PTSD. The required follow-up studies may implement multi-night TMR or TMR during REM sleep to further establish the clinical effect of TMR for traumatic 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.

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 ∼ 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.

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.

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.

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.

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 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.

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 (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.