Memory for semantically related and unrelated declarative information: the benefit of sleep, the cost of wake

Numerous studies have examined sleep's influence on a range of hippocampus-dependent declarative memory tasks, from text learning to spatial navigation. In this study, we examined the impact of sleep, wake, and time-of-day influences on the processing of declarative information with strong semantic links (semantically related word pairs) and information requiring the formation of novel associations (unrelated word pairs). Participants encoded a set of related or unrelated word pairs at either 9 am or 9 pm, and were then tested after an interval of 30 min, 12 hr, or 24 hr. The time of day at which subjects were trained had no effect on training performance or initial memory of either word pair type. At 12 hr retest, memory overall was superior following a night of sleep compared to a day of wakefulness. However, this performance difference was a result of a pronounced deterioration in memory for unrelated word pairs across wake; there was no sleep-wake difference for related word pairs. At 24 hr retest, with all subjects having received both a full night of sleep and a full day of wakefulness, we found that memory was superior when sleep occurred shortly after learning rather than following a full day of wakefulness. Lastly, we present evidence that the rate of deterioration across wakefulness was significantly diminished when a night of sleep preceded the wake period compared to when no sleep preceded wake, suggesting that sleep served to stabilize the memories against the deleterious effects of subsequent wakefulness. Overall, our results demonstrate that 1) the impact of 12 hr of waking interference on memory retention is strongly determined by word-pair type, 2) sleep is most beneficial to memory 24 hr later if it occurs shortly after learning, and 3) sleep does in fact stabilize declarative memories, diminishing the negative impact of subsequent wakefulness.     

Comparing the Effects of Nocturnal Sleep and Daytime Napping on Declarative Memory Consolidation

Nocturnal sleep and daytime napping facilitate memory consolidation for semantically related and unrelated word pairs. We contrasted forgetting of both kinds of materials across a 12-hour interval involving either nocturnal sleep or daytime wakefulness (experiment 1) and a 2-hour interval involving either daytime napping or wakefulness (experiment 2). Beneficial effects of post-learning nocturnal sleep and daytime napping were greater for unrelated word pairs (Cohen’s d = 0.71 and 0.68) than for related ones (Cohen’s d = 0.58 and 0.15). While the size of nocturnal sleep and daytime napping effects was similar for unrelated word pairs, for related pairs, the effect of nocturnal sleep was more prominent. Together, these findings suggest that sleep preferentially facilitates offline memory processing of materials that are more susceptible to forgetting.     

Susceptibility to Declarative Memory Interference is Pronounced in Primary Insomnia

Sleep has been shown to stabilize memory traces and to protect against competing interference in both the procedural and declarative memory domain. Here, we focused on an interference learning paradigm by testing patients with primary insomnia (N = 27) and healthy control subjects (N = 21). In two separate experimental nights with full polysomnography it was revealed that after morning interference procedural memory performance (using a finger tapping task) was not impaired in insomnia patients while declarative memory (word pair association) was decreased following interference. More specifically, we demonstrate robust associations of central sleep spindles (in N3) with motor memory susceptibility to interference as well as (cortically more widespread) fast spindle associations with declarative memory susceptibility. In general the results suggest that insufficient sleep quality does not necessarily show up in worse overnight consolidation in insomnia but may only become evident (in the declarative memory domain) when interference is imposed.     

Memory consolidation in sleep; dream or reality

We discuss several lines of evidence refuting the hypothesis that procedural or declarative memories are processed/consolidated in sleep. One of the strongest arguments against a role for sleep in declarative memory involves the demonstration that the marked suppression or elimination of REM sleep in subjects on antidepressant drugs or with brainstem lesions produces no detrimental effects on cognition. Procedural memory, like declarative memory, undergoes a slow, time-dependent period of consolidation. A process has recently been described wherein performance on some procedural tasks improves with the mere passage of time and has been termed "enhancement." Some studies, but not others, have reported that the consolidation/enhancement of perceptual and motor skills is dependent on sleep. We suggest that consolidation or enhancement, initiated in waking with task acquisition, could in some instances extend to sleep, but sleep would serve no unique role in these processes. In sum, there is no compelling evidence to support a relationship between sleep and memory consolidation.     

A role for central nervous growth hormone-releasing hormone signaling in the consolidation of declarative memories

Contributions of somatotropic hormonal activity to memory functions in humans, which are suggested by clinical observations, have not been systematically examined. With previous experiments precluding a direct effect of systemic growth hormone (GH) on acute memory formation, we assessed the role of central nervous somatotropic signaling in declarative memory consolidation. We examined the effect of intranasally administered growth hormone releasing-hormone (GHRH; 600 μg) that has direct access to the brain and suppresses endogenous GHRH via an ultra-short negative feedback loop. Twelve healthy young men learned word-pair associates at 2030 h and were administered GHRH and placebo, respectively, at 2100 h. Retrieval was tested after 11 hours of wakefulness. Compared to placebo, intranasal GHRH blunted GH release within 3 hours after substance administration and reduced the number of correctly recalled word-pairs by ～12% (both P<0.05). The impairment of declarative memory consolidation was directly correlated to diminished GH concentrations (P<0.05). Procedural memory consolidation as examined by the parallel assessment of finger sequence tapping performance was not affected by GHRH administration. Our findings indicate that intranasal GHRH, by counteracting endogenous GHRH release, impairs hippocampal memory processing. They provide first evidence for a critical contribution of central nervous somatotropic activity to hippocampus-dependent memory consolidation.     

The timing of learning before night-time sleep differentially affects declarative and procedural long-term memory consolidation in adolescents

Sleep after learning has been shown to foster the consolidation of new memories. However, fundamental questions on the best timing of learning before night-time sleep persist. We tested the hypothesis that learning directly prior to night-time sleep compared to 7.5 hrs prior to night-time sleep provides better conditions for the consolidation of declarative and procedural memories. Fifty healthy female adolescents (aged 16-17 years) were trained on a declarative word-pair and a procedural finger-tapping task at 3 pm (afternoon group, n = 25) or at 9 pm (evening group, n = 25), followed by a sleep laboratory night. Retrieval was assessed 24 hours and 7 days after initial training. Subjects trained in the afternoon showed a significantly elevated retention rate of word-pairs compared to subjects trained in the evening after 24 hours, but not after 7 days. In contrast, off-line gains in finger-tapping performance were significantly higher in subjects trained in the evening compared to those trained in the afternoon after both retention intervals. The observed enhanced consolidation of procedural memories after training in the evening fits to current models of sleep-related memory consolidation. In contrast, the higher retention of declarative memories after encoding in the afternoon is surprising, appeared to be less robust and needs further investigation.     

Sleep improves memory: the effect of sleep on long term memory in early adolescence

Sleep plays an important role in the consolidation of memory. This has been most clearly shown in adults for procedural memory (i.e. skills and procedures) and declarative memory (e.g. recall of facts). The effects of sleep and memory are relatively unstudied in adolescents. Declarative memory is important in school performance and consequent social functioning in adolescents. This is the first study to specifically examine the effects of normal sleep on auditory declarative memory in an early adolescent sample. Given that the majority of adolescents do not obtain the recommended amount of sleep, it is critical to study the cognitive effects of normal sleep. Forty male and female normal, healthy adolescents between the ages of ten and fourteen years old were randomly assigned to sleep and no sleep conditions. Subjects were trained on a paired-associate declarative memory task and a control working memory task at 9am, and tested at night (12 hours later) without sleep. The same number of subjects was trained at 9pm and tested 9am following sleep. An increase of 20.6% in declarative memory, as measured by the number correct in a paired-associate test, following sleep was observed compared to the group which was tested at the same time interval without sleep (p<0.03). The performance on the control working memory task that involved encoding and memoranda manipulation was not affected by time of day or relationship to sleep. Declarative memory is significantly improved by sleep in a sample of normal adolescents.     

Memory processing in great apes: the effect of time and sleep

Following encoding, memory remains temporarily vulnerable to disruption. Consolidation refers to offline time-dependent processes that continue after encoding and stabilize, transform or enhance the memory trace. Memory consolidation resulting from sleep has been reported for declarative and non-declarative memories in humans. We first investigated the temporal course of memory retrieval in chimpanzees, bonobos and orangutans. We found that the amount of retrieved information was time dependent: apes' performance degraded after 1 and 2 h, stabilized after 4 h, started to increase after 8 and 12 h and fully recovered after 24 h. Second, we show that although memories during wakefulness were highly vulnerable to interference from events similar to those witnessed during the original encoding event, an intervening period of sleep not only stabilized apes' memories into more permanent ones but also protected them against interference.     

Interfering with theories of sleep and memory: sleep, declarative memory, and associative interference

Mounting behavioral evidence in humans supports the claim that sleep leads to improvements in recently acquired, nondeclarative memories. Examples include motor-sequence learning; visual-discrimination learning; and perceptual learning of a synthetic language. In contrast, there are limited human data supporting a benefit of sleep for declarative (hippocampus-mediated) memory in humans (for review, see). This is particularly surprising given that animal models (e.g.,) and neuroimaging studies (e.g.,) predict that sleep facilitates hippocampus-based memory consolidation. We hypothesized that we could unmask the benefits of sleep by challenging the declarative memory system with competing information (interference). This is the first study to demonstrate that sleep protects declarative memories from subsequent associative interference, and it has important implications for understanding the neurobiology of memory consolidation.     

Interaction of Sleep and Emotional Content on the Production of False Memories

Sleep benefits veridical memories, resulting in superior recall relative to off-line intervals spent awake. Sleep also increases false memory recall in the Deese-Roediger-McDermott (DRM) paradigm. Given the suggestion that emotional veridical memories are prioritized for consolidation over sleep, here we examined whether emotion modulates sleep’s effect on false memory formation. Participants listened to semantically related word lists lacking a critical lure representing each list’s “gist.” Free recall was tested after 12 hours containing sleep or wake. The Sleep group recalled more studied words than the Wake group but only for emotionally neutral lists. False memories of both negative and neutral critical lures were greater following sleep relative to wake. Morning and Evening control groups (20-minute delay) did not differ ruling out circadian accounts for these differences. These results support the adaptive function of sleep in both promoting the consolidation of veridical declarative memories and in extracting unifying aspects from memory details.     

Effect of daytime nap on consolidation of declarative memory in humans

We studied effects of a daytime nap (1 hour) with including only NREM sleep on performance of declarative memory task (60 semantically unrelated word pairs) and general functional state. During training, procedure of learning of 30 word pairs was presented once, and that of the other 30 pairs was repeated twice. Strength of the task acquisition was tested. Subjects participated in two experiments: basic and control one. After learning participants either took a nap (basic experiment) or kept awake looking movies (control experiment). In 4.5 hours after the training session all the subjects were retested. As compared to the subjects who stayed awake during the training-retesting interval, subjects who had a NREM nap demonstrated enhanced performance. Concerning the strength of task acquisition, sleep-dependent performance was observed only for the word pairs learned once. Naps did not affect the functional state assessed by the reaction time dynamics and psychological testing.     

Transcranial electrical currents to probe EEG brain rhythms and memory consolidation during sleep in humans

Previously the application of a weak electric anodal current oscillating with a frequency of the sleep slow oscillation (～0.75 Hz) during non-rapid eye movement sleep (NonREM) sleep boosted endogenous slow oscillation activity and enhanced sleep-associated memory consolidation. The slow oscillations occurring during NonREM sleep and theta oscillations present during REM sleep have been considered of critical relevance for memory formation. Here transcranial direct current stimulation (tDCS) oscillating at 5 Hz, i.e., within the theta frequency range (theta-tDCS) is applied during NonREM and REM sleep. Theta-tDCS during NonREM sleep produced a global decrease in slow oscillatory activity conjoint with a local reduction of frontal slow EEG spindle power (8-12 Hz) and a decrement in consolidation of declarative memory, underlining the relevance of these cortical oscillations for sleep-dependent memory consolidation. In contrast, during REM sleep theta-tDCS appears to increase global gamma (25-45 Hz) activity, indicating a clear brain state-dependency of theta-tDCS. More generally, results demonstrate the suitability of oscillating-tDCS as a tool to analyze functions of endogenous EEG rhythms and underlying endogenous electric fields as well as the interactions between EEG rhythms of different frequencies.     

Does Recall after Sleep-Dependent Memory Consolidation Reinstate Sensitivity to Retroactive Interference?

Previous studies have shown that newly encoded memories are more resistant to retroactive interference when participants are allowed to sleep after learning the original material, suggesting a sleep-related strengthening of memories. In the present study, we investigated delayed, long-term effects of sleep vs. sleep deprivation (SD) on the first post-training night on memory consolidation and resistance to interference. On day 1, participants learned a list of unrelated word pairs (AB), either in the morning or in the evening, then spent the post-training night in a sleep or sleep deprivation condition, in a within-subject paradigm. On day 4, at the same time of day, they learned a novel list of word pairs (AC) in which 50% of the word pairs stemmed with the same word than in the AB list, resulting in retroactive interference. Participants had then to recall items from the AB list upon presentation of the “A” stem. Recall was marginally improved in the evening, as compared to the morning learning group. Most importantly, retroactive interference effects were found in the sleep evening group only, contrary to the hypothesis that sleep exerts a protective role against intrusion by novel but similar learning. We tentatively suggest that these results can be explained in the framework of the memory reconsolidation theory, stating that exposure to similar information sets back consolidated items in a labile form again sensitive to retroactive interference. In this context, sleep might not protect against interference but would promote an update of existing episodic memories while preventing saturation of the memory network due to the accumulation of dual traces.     

Slow Oscillation Amplitudes and Up-State Lengths Relate to Memory Improvement

There is growing evidence of the active involvement of sleep in memory consolidation. Besides hippocampal sharp wave-ripple complexes and sleep spindles, slow oscillations appear to play a key role in the process of sleep-associated memory consolidation. Furthermore, slow oscillation amplitude and spectral power increase during the night after learning declarative and procedural memory tasks. However, it is unresolved whether learning-induced changes specifically alter characteristics of individual slow oscillations, such as the slow oscillation up-state length and amplitude, which are believed to be important for neuronal replay. 24 subjects (12 men) aged between 20 and 30 years participated in a randomized, within-subject, multicenter study. Subjects slept on three occasions for a whole night in the sleep laboratory with full polysomnography. Whereas the first night only served for adaptation purposes, the two remaining nights were preceded by a declarative word-pair task or by a non-learning control task. Slow oscillations were detected in non-rapid eye movement sleep over electrode Fz. Results indicate positive correlations between the length of the up-state as well as the amplitude of both slow oscillation phases and changes in memory performance from pre to post sleep. We speculate that the prolonged slow oscillation up-state length might extend the timeframe for the transfer of initial hippocampal to long-term cortical memory representations, whereas the increase in slow oscillation amplitudes possibly reflects changes in the net synaptic strength of cortical networks.     

Changes in brain glycogen after sleep deprivation vary with genotype

Sleep has been functionally implicated in brain energy homeostasis in that it could serve to replenish brain energy stores that become depleted while awake. Sleep deprivation (SD) should therefore lower brain glycogen content. We tested this hypothesis by sleep depriving mice of three inbred strains, i.e., AKR/J (AK), DBA/2J (D2), and C57BL/6J (B6), that differ greatly in their sleep regulation. After a 6-h SD, these mice and their controls were killed by microwave irradiation, and glycogen and glucose were quantified in the cerebral cortex, brain stem, and cerebellum. After SD, both measures significantly increased by approximately 40% in the cortex of B6 mice, while glycogen significantly decreased by 20-38% in brain stem and cerebellum of AK and D2 mice. In contrast, after SD, glucose content increased in all three structures in AK mice and did not change in D2 mice. The increase in glycogen after SD in B6 mice persisted under conditions of food deprivation that, by itself, lowered cortical glycogen. Furthermore, the strains that differ most in their compensatory response to sleep loss, i.e., AK and D2, did not differ in their glycogen response. Thus glycogen content per se is an unlikely end point of sleep's functional role in brain energy homeostasis.     

Some considerations on sleep and neural plasticity

A role for sleep in memory processes and neural plasticity has been suggested many times and in many different forms. However, we are far from a consensus on what this role might be and why it would be fulfilled preferentially by sleep. In this review, we distinguish between memory acquisition, consolidation, and maintenance, and we consider how sleep may specifically contribute to each of these phases. We also distinguish between declarative and nondeclarative memories and their relationships to different stages of sleep. Finally, we discuss whether different molecular and cellular aspects of neural plasticity may be associated preferentially with different behavioral states. A consideration of such molecular aspects could lead to more conclusive experiments concerning the relationship between sleep and plasticity.     

Sleep-Related Declarative Memory Consolidation and Verbal Replay during Sleep Talking in Patients with REM Sleep Behavior Disorder

Objective

To determine if sleep talkers with REM sleep behavior disorder (RBD) would utter during REM sleep sentences learned before sleep, and to evaluate their verbal memory consolidation during sleep.

Methods

Eighteen patients with RBD and 10 controls performed two verbal memory tasks (16 words from the Free and Cued Selective Reminding Test and a 220-263 word long modified Story Recall Test) in the evening, followed by nocturnal video-polysomnography and morning recall (night-time consolidation). In 9 patients with RBD, daytime consolidation (morning learning/recall, evening recall) was also evaluated with the modified Story Recall Test in a cross-over order. Two RBD patients with dementia were studied separately. Sleep talking was recorded using video-polysomnography, and the utterances were compared to the studied texts by two external judges.

Results

Sleep-related verbal memory consolidation was maintained in patients with RBD (+24±36% words) as in controls (+9±18%, p=0.3). The two demented patients with RBD also exhibited excellent nighttime consolidation. The post-sleep performance was unrelated to the sleep measures (including continuity, stages, fragmentation and apnea-hypopnea index). Daytime consolidation (-9±19%) was worse than night-time consolidation (+29±45%, p=0.03) in the subgroup of 9 patients with RBD. Eleven patients with RBD spoke during REM sleep and pronounced a median of 20 words, which represented 0.0003% of sleep with spoken language. A single patient uttered a sentence that was judged to be semantically (but not literally) related to the text learned before sleep.

Conclusion

Verbal declarative memory normally consolidates during sleep in patients with RBD. The incorporation of learned material within REM sleep-associated sleep talking in one patient (unbeknownst to himself) at the semantic level suggests a replay at a highly cognitive creative level.     

Increasing length of wakefulness and modulation of hypocretin-1 in the wake-consolidated squirrel monkey

The neuropeptides hypocretins (orexins), the loss of which results in the sleep disorder narcolepsy, are hypothesized to be involved in the consolidation of wakefulness and have been proposed to be part of the circadian-driven alertness signal. To elucidate the role of hypocretins in the consolidation of human wakefulness we examined the effect of wake extension on hypocretin-1 in squirrel monkeys, primates that consolidate wakefulness during the daytime as do humans. Wake was extended up to 7 h with hypocretin-1, cortisol, ghrelin, leptin, locomotion, and feeding, all being assayed. Hypocretin-1 (P < 0.01), cortisol (P < 0.001), and locomotion (P < 0.005) all increased with sleep deprivation, while ghrelin (P = 0.79) and leptin (P = 1.00) did not change with sleep deprivation. Using cross-correlation and multivariate modeling of these potential covariates along with homeostatic pressure (a measure of time awake/asleep), we found that time of day and homeostatic pressure together explained 44% of the variance in the hypocretin-1 data (P < 0.001), while cortisol did not significantly contribute to the overall hypocretin-1 variance. Locomotion during the daytime, but not during the nighttime, helped explain < 5% of the hypocretin-1 variance (P < 0.05). These data are consistent with earlier evidence indicating that in the squirrel monkey hypocretin-1 is mainly regulated by circadian inputs and homeostatic sleep pressure. Concomitants of wakefulness that affect hypocretin-1 in polyphasic species, such as locomotion, food intake, and food deprivation, likely have a more minor role in monophasic species, such as humans.     

Fatty-acid binding proteins modulate sleep and enhance long-term memory consolidation in Drosophila

Sleep is thought to be important for memory consolidation, since sleep deprivation has been shown to interfere with memory processing. However, the effects of augmenting sleep on memory formation are not well known, and testing the role of sleep in memory enhancement has been limited to pharmacological and behavioral approaches. Here we test the effect of overexpressing the brain-type fatty acid binding protein (Fabp7) on sleep and long-term memory (LTM) formation in Drosophila melanogaster. Transgenic flies carrying the murine Fabp7 or the Drosophila homologue dFabp had reduced baseline sleep but normal LTM, while Fabp induction produced increases in both net sleep and LTM. We also define a post-training consolidation "window" that is sufficient for the observed Fabp-mediated memory enhancement. Since Fabp overexpression increases consolidated daytime sleep bouts, these data support a role for longer naps in improving memory and provide a novel role for lipid-binding proteins in regulating memory consolidation concurrently with changes in behavioral state.     

The Sleeping Brain's Influence on Verbal Memory: Boosting Resistance to Interference

Memories evolve. After learning something new, the brain initiates a complex set of post-learning processing that facilitates recall (i.e., consolidation). Evidence points to sleep as one of the determinants of that change. But whenever a behavioral study of episodic memory shows a benefit of sleep, critics assert that sleep only leads to a temporary shelter from the damaging effects of interference that would otherwise accrue during wakefulness. To evaluate the potentially active role of sleep for verbal memory, we compared memory recall after sleep, with and without interference before testing. We demonstrated that recall performance for verbal memory was greater after sleep than after wakefulness. And when using interference testing, that difference was even more pronounced. By introducing interference after sleep, this study confirms an experimental paradigm that demonstrates the active role of sleep in consolidating memory, and unmasks the large magnitude of that benefit.