The reach of reactivation: Effects of consciously triggered versus unconsciously triggered reactivation of associative memory.

Consolidating memories for long-term storage depends on reactivation. Reactivation occurs both consciously, during wakefulness, and unconsciously, during wakefulness and sleep. While considerable work has examined conscious awake and unconscious sleep reactivation, in this study, we directly compare the consequences of conscious and unconscious reactivation during wakefulness. Forty-one participants learned associations consisting of adjective-object-position triads. Objects were clustered into distinct semantic groups (e.g., fruits, vehicles) such that we could examine consequences of reactivation on semantically related memories. After an intensive learning protocol, we systematically reactivated some of the triads by presenting the adjective as a cue. Reactivation was done so that it was consciously experienced for some triads, and only unconsciously processed for others. Memory for spatial positions, the most distal part of the association, was affected by reactivation in a consciousness-dependent and memory-strength-dependent manner. Conscious reactivation resulted in weakening of semantically related memories that were strong initially, resonating with prior findings of retrieval-induced forgetting. Unconscious reactivation, on the other hand, selectively benefited weak reactivated memories, as previously shown for reactivation during sleep. Semantically linked memories were not impaired, but rather were integrated with the reactivated memory. These results taken together demonstrate that conscious and unconscious reactivation have qualitatively different consequences. Results support a consciousness-dependent inhibition account, whereby unconscious reactivation entails less inhibition than conscious reactivation, thus allowing more liberal spread of activation. Findings set the stage for additional exploration into the role of conscious experience in memory storage and structuring.

Memory's gatekeeper: The role of PFC in the encoding of congruent events.

Theoretical models conventionally portray the consolidation of memories as a slow process that unfolds during sleep. According to the classical Complementary Learning Systems theory, the hippocampus (HPC) rapidly changes its connectivity during wakefulness to encode ongoing events and create memory ensembles that are later transferred to the prefrontal cortex (PFC) during sleep. However, recent experimental studies challenge this notion by showing that new information consistent with prior knowledge can be rapidly consolidated in PFC during wakefulness and that PFC lesions disrupt the encoding of congruent events in the HPC. The contributions of the PFC to memory encoding have therefore largely been overlooked. Moreover, most theoretical frameworks assume random and uncorrelated patterns representing memories, disregarding the correlations between our experiences. To address these shortcomings, we developed a HPC-PFC network model that simulates interactions between the HPC and PFC during the encoding of a memory (awake stage), and subsequent consolidation (sleeping stage) to examine the contributions of each region to the consolidation of novel and congruent memories. Our results show that the PFC network uses stored memory "schemas" consolidated during previous experiences to identify inputs that evoke congruent patterns of activity, quickly integrate it into its network, and gate which components are encoded in the HPC. More specifically, the PFC uses GABAergic long-range projections to inhibit HPC neurons representing input components correlated with a previously stored memory "schema," eliciting sparse hippocampal activity during exposure to congruent events, as it has been experimentally observed.

High frequency oscillations in human memory and cognition: a neurophysiological substrate of engrams?

Despite advances in understanding the cellular and molecular processes underlying memory and cognition, and recent successful modulation of cognitive performance in brain disorders, the neurophysiological mechanisms remain underexplored. High frequency oscillations beyond the classic electroencephalogram spectrum have emerged as a potential neural correlate of fundamental cognitive processes. High frequency oscillations are detected in the human mesial temporal lobe and neocortical intracranial recordings spanning gamma/epsilon (60-150 Hz), ripple (80-250 Hz) and higher frequency ranges. Separate from other non-oscillatory activities, these brief electrophysiological oscillations of distinct duration, frequency and amplitude are thought to be generated by coordinated spiking of neuronal ensembles within volumes as small as a single cortical column. Although the exact origins, mechanisms, and physiological roles in health and disease remain elusive, they have been associated with human memory consolidation and cognitive processing. Recent studies suggest their involvement in encoding and recall of episodic memory with a possible role in the formation and reactivation of memory traces. High frequency oscillations are detected during encoding, throughout maintenance, and right before recall of remembered items, meeting a basic definition for an engram activity. The temporal coordination of high frequency oscillations reactivated across cortical and subcortical neural networks is ideally suited for integrating multimodal memory representations, which can be replayed and consolidated during states of wakefulness and sleep. High frequency oscillations have been shown to reflect coordinated bursts of neuronal assembly firing and offer a promising substrate for tracking and modulation of the hypothetical electrophysiological engram.

Thalamic epileptic spikes disrupt sleep spindles in patients with epileptic encephalopathy.

In severe epileptic encephalopathies, epileptic activity contributes to progressive cognitive dysfunction. Epileptic encephalopathies share the trait of spike-wave activation during non-REM sleep (EE-SWAS), a sleep stage dominated by sleep spindles, which are brain oscillations known to coordinate offline memory consolidation. Epileptic activity has been proposed to hijack the circuits driving these thalamocortical oscillations, thereby contributing to cognitive impairment. Using a unique dataset of simultaneous human thalamic and cortical recordings in subjects with and without EE-SWAS, we provide evidence for epileptic spike interference of thalamic sleep spindle production in patients with EE-SWAS. First, we show that epileptic spikes and sleep spindles are both predicted by slow oscillations during stage two sleep (N2), but at different phases of the slow oscillation. Next, we demonstrate that sleep-activated cortical epileptic spikes propagate to the thalamus (thalamic spike rate increases after a cortical spike, P ≈ 0). We then show that epileptic spikes in the thalamus increase the thalamic spindle refractory period (P ≈ 0). Finally, we show that in three patients with EE-SWAS, there is a downregulation of sleep spindles for 30 s after each thalamic spike (P < 0.01). These direct human thalamocortical observations support a proposed mechanism for epileptiform activity to impact cognitive function, wherein epileptic spikes inhibit thalamic sleep spindles in epileptic encephalopathy with spike and wave activation during sleep.

Memory consolidation of sequence learning and dynamic adaptation during wakefulness.

Motor learning involves acquiring new movement sequences and adapting motor commands to novel conditions. Labile motor memories, acquired through sequence learning and dynamic adaptation, undergo a consolidation process during wakefulness after initial training. This process stabilizes the new memories, leading to long-term memory formation. However, it remains unclear if the consolidation processes underlying sequence learning and dynamic adaptation are independent and if distinct neural regions underpin memory consolidation associated with sequence learning and dynamic adaptation. Here, we first demonstrated that the initially labile memories formed during sequence learning and dynamic adaptation were stabilized against interference through time-dependent consolidation processes occurring during wakefulness. Furthermore, we found that sequence learning memory was not disrupted when immediately followed by dynamic adaptation and vice versa, indicating distinct mechanisms for sequence learning and dynamic adaptation consolidation. Finally, by applying patterned transcranial magnetic stimulation to selectively disrupt the activity in the primary motor (M1) or sensory (S1) cortices immediately after sequence learning or dynamic adaptation, we found that sequence learning consolidation depended on M1 but not S1, while dynamic adaptation consolidation relied on S1 but not M1. For the first time in a single experimental framework, this study revealed distinct neural underpinnings for sequence learning and dynamic adaptation consolidation during wakefulness, with significant implications for motor skill enhancement and rehabilitation.

Effect of cognitive load on time spent offline during wakefulness.

Humans continuously alternate between online attention to the current environment and offline attention to internally generated thought and imagery. This may be a fundamental feature of the waking brain, but remains poorly understood. Here, we took a data-driven approach to defining online and offline states of wakefulness, using machine learning methods applied to measures of sensory responsiveness, subjective report, electroencephalogram (EEG), and pupil diameter. We tested the effect of cognitive load on the structure and prevalence of online and offline states, hypothesizing that time spent offline would increase as cognitive load of an ongoing task decreased. We also expected that alternation between online and offline states would persist even in the absence of a cognitive task. As in prior studies, we arrived at a three-state model comprised of one online state and two offline states. As predicted, when cognitive load was high, more time was spent online. Also as predicted, the same three states were present even when participants were not performing a task. These observations confirm our method is successful at isolating seconds-long periods of offline time. Varying cognitive load may be a useful way to manipulate time spent in at least one of these offline states in future experimental studies.

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.

Reduced overnight memory consolidation and associated alterations in sleep spindles and slow oscillations in early Alzheimer's disease.

Spatial navigation critically underlies hippocampal-entorhinal circuit function that is early affected in Alzheimer's disease (AD). There is growing evidence that AD pathophysiology dynamically interacts with the sleep/wake cycle impairing hippocampal memory. To elucidate sleep-dependent consolidation in a cohort of symptomatic AD patients (n = 12, 71.25 ± 2.16 years), we tested hippocampal place learning by means of a virtual reality task and verbal memory by a word-pair association task before and after a night of sleep. Our results show an impaired overnight memory retention in AD compared with controls in the verbal task, together with a significant reduction of sleep spindle activity (i.e., lower amplitude of fast sleep spindles, p = 0.016) and increased duration of the slow oscillation (SO; p = 0.019). Higher spindle density, faster down-to-upstate transitions within SOs, and the time delay between SOs and nested spindles predicted better memory performance in healthy controls but not in AD patients. Our results show that mnemonic processing and memory consolidation in AD is slightly impaired as reflected by dysfunctional oscillatory dynamics and spindle-SO coupling during NonREM sleep. In this translational study based on experimental paradigms in animals and extending previous work in healthy aging and preclinical disease stages, our results in symptomatic AD further deepen the understanding of the memory decline within a bidirectional relationship of sleep and AD pathology.

The translational inhibitor and amnestic agent emetine also suppresses ongoing hippocampal neural activity similarly to other blockers of protein synthesis.

The consolidation of memory is thought to ultimately depend on the synthesis of new proteins, since translational inhibitors such as anisomycin and cycloheximide adversely affect the permanence of long-term memory. However, when applied directly in brain, these agents also profoundly suppress neural activity to an extent that is directly correlated to the degree of protein synthesis inhibition caused. Given that neural activity itself is likely to help mediate consolidation, this finding is a serious criticism of the strict de novo protein hypothesis of memory. Here, we test the neurophysiological effects of another translational inhibitor, emetine. Unilateral intra-hippocampal infusion of emetine suppressed ongoing local field and multiunit activity at ipsilateral sites as compared to the contralateral hippocampus in a fashion that was positively correlated to the degree of protein synthesis inhibition as confirmed by autoradiography. This suppression of activity was also specific to the circumscribed brain region in which protein synthesis inhibition took place. These experiments provide further evidence that ongoing protein synthesis is necessary and fundamental for neural function and suggest that the disruption of memory observed in behavioral experiments using translational inhibitors may be due, in large part, to neural suppression.

The effects of shared, depression-specific, and anxiety-specific internalizing symptoms on negative and neutral episodic memories following post-learning sleep.

Emotional memory bias is a common characteristic of internalizing symptomatology and is enhanced during sleep. The current study employs bifactor S-1 modeling to disentangle depression-specific anhedonia, anxiety-specific anxious arousal, and the common internalizing factor, general distress, and test whether these internalizing symptoms interact with sleep to influence memory for emotional and neutral information. Healthy adults (N = 281) encoded scenes featuring either negative objects (e.g., a vicious looking snake) or neutral objects (e.g., a chipmunk) placed on neutral backgrounds (e.g., an outdoor scene). After a 12-hour period of daytime wakefulness (n = 140) or nocturnal sleep (n = 141), participants judged whether objects and backgrounds were the same, similar, or new compared with what they viewed during encoding. Participants also completed the mini version of the Mood and Anxiety Symptom Questionnaire. Higher anxious arousal predicted worse memory across all stimuli features, but only after a day spent being awake-not following a night of sleep. No significant effects were found for general distress and anhedonia in either the sleep or wake condition. In this study, internalizing symptoms were not associated with enhanced emotional memory. Instead, memory performance specifically in individuals with higher anxious arousal was impaired overall, regardless of emotional valence, but this was only the case when the retention interval spanned wakefulness (i.e., not when it spanned sleep). This suggests that sleep may confer a protective effect on general memory impairments associated with anxiety.

Temporal cluster-based organization of sleep spindles underlies motor memory consolidation.

Sleep benefits motor memory consolidation, which is mediated by sleep spindle activity and associated memory reactivations during non-rapid eye movement (NREM) sleep. However, the particular role of NREM2 and NREM3 sleep spindles and the mechanisms triggering this memory consolidation process remain unclear. Here, simultaneous electroencephalographic and functional magnetic resonance imaging (EEG-fMRI) recordings were collected during night-time sleep following the learning of a motor sequence task. Adopting a time-based clustering approach, we provide evidence that spindles iteratively occur within clustered and temporally organized patterns during both NREM2 and NREM3 sleep. However, the clustering of spindles in trains is related to motor memory consolidation during NREM2 sleep only. Altogether, our findings suggest that spindles' clustering and rhythmic occurrence during NREM2 sleep may serve as an intrinsic rhythmic sleep mechanism for the timed reactivation and subsequent consolidation of motor memories, through synchronized oscillatory activity within a subcortical-cortical network involved during learning.

Consolidation of emotional memory during waking rest depends on trait anxiety.

A short period of eyes-closed waking rest improves long-term memory for recently learned information, including declarative, spatial, and procedural memory. However, the effect of rest on emotional memory consolidation remains unknown. This preregistered study aimed to establish whether post-encoding rest affects emotional memory and how anxiety levels might modulate this effect. Participants completed a modified version of the dot-probe attention task that involved reacting to and encoding word stimuli appearing underneath emotionally negative or neutral photos. We tested the effect of waking rest on memory for these words and pictures by manipulating the state that participants entered just after this task (rest vs. active wake). Trait anxiety levels were measured using the State-Trait Anxiety Inventory and examined as a covariate. Waking rest improved emotional memory consolidation for individuals high in trait anxiety. These results suggest that the beneficial effect of waking rest on memory extends into the emotional memory domain but depends on individual characteristics such as anxiety.

Effects of post-learning nap in the recognition memory for faces in habitual nappers.

This study investigated the effects of diurnal nap in the recognition memory for faces in habitual nappers. Thirty volunteers with habitual midday napping (assigned as the sleep group) and 28 non-nappers (assigned as the wake group) participated in this study. Participants were instructed to memorize faces, and subsequently to perform two recognition tasks before and after nap/wakefulness, i.e., an immediate recognition and a delayed recognition. There were three experimental conditions: same faces with the same view angle (S-S condition); same faces with a different view angle (22.5°) (S-D condition); and novel faces (NF condition). A mixed repeated-measures ANOVA revealed that the sleep group exhibited significantly longer reaction times (RT) following their nap compared to those of the wake group; no significant between-group differences were observed in accuracy or sensitivity (d'). Furthermore, both groups were more conservative in the delayed recognition task compared to the immediate recognition task, but the sleep group was more conservative after their nap (vs pre-nap), reflected by the criterion (ß, Ohit/Ofalse alarm). Further stepwise regression analysis revealed a positive relationship between duration of stage N3 sleep and normalized RT difference before/after nap on the S-S condition. These findings suggest that an immediate nap following face learning is associated with memory reorganization during N3 sleep in habitual nappers, rendering the memories not readily accessible.

The impact of sleep on factual memory retention over 24 hr.

Although a period of sleep seems to benefit the retention of declarative memories, recent studies have challenged both the size of this effect and its active influence on memory consolidation. This study aimed to further investigate the effect of sleep and its time dependency on the consolidation of factual information. In a within-subjects design, 48 participants (Mage = 24.37 ± 4.18 years, 31F) were asked to learn several facts in a multi-sensory "flashcard-like" memory task at 21:00 hours (sleep first condition) or at 09:00 hours (wake first condition). Then, in each condition, participants performed an immediate recall test (T0), and two delayed tests 12 hr (T1) and 24 hr (T2) later. Participants' sleep was recorded at their homes with a portable device. Results revealed that memory retention was better after a night of sleep compared with wakefulness, regardless of the delay from encoding (a few hr versus 12+ hr), but the sleep effect was modest. The decline in memory during the wake period following sleep was smaller compared with the decline observed during the 12 hr of wakefulness after encoding. However, after 24 hr from the encoding, when all participants experienced a period of both sleep and wakefulness, memory performance in the two conditions was similar. Overall, our data suggest that sleep exerts a small, yet beneficial, influence on memory retention by likely reducing interference and actively stabilizing memory traces.

Closed-loop auditory stimulation of slow-wave sleep in chronic insomnia: a pilot study.

Insomnia is a prevalent and disabling condition whose treatment is not always effective. This pilot study explores the feasibility and effects of closed-loop auditory stimulation (CLAS) as a potential non-invasive intervention to improve sleep, its subjective quality, and memory consolidation in patients with insomnia. A total of 27 patients with chronic insomnia underwent a crossover, sham-controlled study with 2 nights of either CLAS or sham stimulation. Polysomnography was used to record sleep parameters, while questionnaires and a word-pair memory task were administered to assess subjective sleep quality and memory consolidation. The initial analyses included 17 patients who completed the study, met the inclusion criteria, and received CLAS. From those, 10 (58%) received only a small number of stimuli. In the remaining seven (41%) patients with sufficient CLAS, we evaluated the acute and whole-night effect on sleep. CLAS led to a significant immediate increase in slow oscillation (0.5-1 Hz) amplitude and activity, and reduced delta (1-4 Hz) and sigma/sleep spindle (12-15 Hz) activity during slow-wave sleep across the whole night. All these fundamental sleep rhythms are implicated in sleep-dependent memory consolidation. Yet, CLAS did not change sleep-dependent memory consolidation or sleep macrostructure characteristics, number of arousals, or subjective perception of sleep quality. Results showed CLAS to be feasible in patients with insomnia. However, a high variance in the efficacy of our automated stimulation approach suggests that further research is needed to optimise stimulation protocols to better unlock potential CLAS benefits for sleep structure and subjective sleep quality in such clinical settings.

Sleep-dependent memory consolidation of televised content in infants.

Infants face the constant challenge of selecting information for encoding and storage from a continuous incoming stream of data. Sleep might help in this process by selectively consolidating new memory traces that are likely to be of future relevance. Using a deferred imitation paradigm and an experimental design, we asked whether 15- and 24-month-old infants (N = 105) who slept soon after encoding a televised demonstration of target actions would show higher imitation scores (retention) after a 24-h delay than same-aged infants who stayed awake for ≥4 h after encoding. In light of infants' well-known difficulties in learning and remembering information from screens, we tested if increasing the relevance of the televised content via standardised caregiver verbalisations might yield the highest imitation scores in the sleep condition. Regardless of sleep condition, 24-month-olds exhibited retention of target actions while 15-month-olds consistently failed to do so. For 24-month-olds, temporal recall was facilitated by sleep, but not by parental verbalisations. Correlational analyses revealed that more time asleep within 4 h after encoding was associated with better retention of the target actions and their temporal order in 24-months-olds. These results suggest that sleep facilitates memory consolidation of screen-based content in late infancy and that this effect might not hinge on caregivers' verbal engagement during viewing.

A daytime nap with REM sleep is linked to enhanced generalization of emotional stimuli.

How memory representations are shaped during and after their encoding is a central question in the study of human memory. Recognition responses to stimuli that are similar to those observed previously can hint at the fidelity of the memories or point to processes of generalization at the expense of precise memory representations. Experimental studies utilizing this approach showed that emotions and sleep both influence these responses. Sleep, and more specifically rapid eye movement sleep, is assumed to facilitate the generalization of emotional memories. We studied mnemonic discrimination by the emotional variant of the Mnemonic Separation Task in participants (N = 113) who spent a daytime nap between learning and testing compared with another group that spent an equivalent time awake between the two sessions. Our findings indicate that the discrimination of similar but previously not seen items from previously seen ones is enhanced in case of negative compared with neutral and positive stimuli. Moreover, whereas the sleep and the wake groups did not differ in memory performance, participants entering rapid eye movement sleep exhibited increased generalization of emotional memories. Our findings indicate that entering into rapid eye movement sleep during a daytime nap shapes emotional memories in a way that enhances recognition at the expense of detailed memory representations.

Slow wave sleep is associated with forgetting in patients with temporal lobe epilepsy.

While time spent in slow wave sleep (SWS) after learning promotes memory consolidation in the healthy brain, it is unclear if the same benefit is obtained in patients with temporal lobe epilepsy (TLE). Interictal epileptiform discharges (IEDs) are potentiated during SWS and thus may disrupt memory consolidation processes thought to depend on hippocampal-neocortical interactions. Here, we explored the relationship between SWS, IEDs, and overnight forgetting in patients with TLE. Nineteen patients with TLE studied object-scene pairs and memory was tested across a day of wakefulness (6 hrs) and across a night of sleep (16 hrs) while undergoing continuous scalp EEG monitoring. We found that time spent in SWS after learning was related to greater forgetting overnight. Longer duration in SWS and number of IEDs were each associated with greater forgetting, although the number of IEDs did not mediate the relationship between SWS and memory. Further research, particularly with intracranial recordings, is required to identify the mechanisms by which SWS and IEDs can be pathological to sleep-dependent memory consolidation in patients with TLE.

Long-term memory consolidation of new words in children with self-limited epilepsy with centro-temporal spikes.

Accelerated long-term forgetting has been studied and demonstrated in adults with epilepsy. In contrast, the question of long-term consolidation (delays > 1 day) in children with epilepsy shows conflicting results. However, childhood is a period of life in which the encoding and long-term storage of new words is essential for the development of knowledge and learning. The aim of this study was therefore to investigate long-term memory consolidation skills in children with self-limited epilepsy with centro-temporal spikes (SeLECTS), using a paradigm exploring new words encoding skills and their long-term consolidation over one-week delay. As lexical knowledge, working memory skills and executive/attentional skills has been shown to contribute to long-term memory/new word learning, we added standardized measures of oral language and executive/attentional functions to explore the involvement of these cognitive skills in new word encoding and consolidation. The results showed that children with SeLECTS needed more repetitions to encode new words, struggled to encode the phonological forms of words, and when they finally reached the level of the typically developing children, they retained what they had learned, but didn't show improved recall skills after a one-week delay, unlike the control participants. Lexical knowledge, verbal working memory skills and phonological skills contributed to encoding and/or recall abilities, and interference sensitivity appeared to be associated with the number of phonological errors during the pseudoword encoding phase. These results are consistent with the functional model linking working memory, phonology and vocabulary in a fronto-temporo-parietal network. As SeLECTS involves perisylvian dysfunction, the associations between impaired sequence storage (phonological working memory), phonological representation storage and new word learning are not surprising. This dual impairment in both encoding and long-term consolidation may result in large learning gap between children with and without epilepsy. Whether these results indicate differences in the sleep-induced benefits required for long-term consolidation or differences in the benefits of retrieval practice between the epilepsy group and healthy children remains open. As lexical development is associated with academic achievement and comprehension, the impact of such deficits in learning new words is certainly detrimental.

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.