Subsequent Slow-wave Sleep Research Articles

0095 Magnitude of Temperature Drop Prior to Sleep Onset May Predict Increase in Slow Wave Sleep

Abstract Introduction Neural circuitry implicated in thermoregulation is known to be interdependent with that implicated in regulation of sleep-wake state. In addition, previous studies in both rodent and human have shown that the sleep-associated decline in core body temperature (CBT) is associated with subsequent slow wave sleep. We sought to replicate this association in cognitively normal older adults, and extend upon previous studies by using automated telemetric methods to measure CBT. Methods Thirty-one cognitively normal and mildly cognitively impaired (MCI) older adults (age 68 ± 6 years, 18 female, 3 MCI) underwent measurement of CBT for two consecutive nights with a telemetric sensor, during which lab nocturnal polysomnography was simultaneously performed. Data from the second night were used. A validated algorithm was used to preprocess CBT to exclude and fill artifactual data outliers and small gaps, respectively. The sleep-associated CBT was calculated with an automated procedure by identifying the CBT decrease between the first peak in CBT identified prior to ‘Lights Out’ and the lowest value following Lights Out. Slow wave activity (SWA) increase was calculated as increase relative to baseline in the relative spectral power (0.5-4.0 Hz, F3-M2) in the first 5 second epoch following lights out. Results Of the 31 participants, 21 had both good quality EEG and CBT data, with an average total sleep time of 7.5 ± 1.5 hours, and an average duration 46.6 ± 18.5 hours of CBT data collected. There was a strong positive correlation between the magnitude of CBT decline and subsequent SWA (rho = 0.70, p < 0.001 Spearman’s Rank correlation), supporting previous results. Conclusion This is one of the first studies to obtain simultaneous CBT and NPSG data in older adults using an ingestible telemetric sensor. Our results support the previous research that there is a significant relationship between sleep-associated body cooling prior to sleep onset and increase in SWA. This highlights the potential for future therapeutic thermal intervention in older adults to improve sleep and sleep mediated health conditions. Further research with a bigger sample size will be necessary to control for variables such as obstructive sleep apnea and cognition status. Support (if any) NIH R01AG070866, R21AG055002, K25HL151912,

Hypnotic enhancement of slow-wave sleep increases sleep-associated hormone secretion and reduces sympathetic predominance in healthy humans

Sleep is important for normal brain and body functioning, and for this, slow-wave sleep (SWS), the deepest stage of sleep, is assumed to be especially relevant. Previous studies employing methods to enhance SWS have focused on central nervous components of this sleep stage. However, SWS is also characterized by specific changes in the body periphery, which are essential mediators of the health-benefitting effects of sleep. Here we show that enhancing SWS in healthy humans using hypnotic suggestions profoundly affects the two major systems linking the brain with peripheral body functions, i.e., the endocrine and the autonomic nervous systems (ANS). Specifically, hypnotic suggestions presented at the beginning of a 90-min afternoon nap to promote subsequent SWS strongly increased the release of growth hormone (GH) and, to a lesser extent, of prolactin and aldosterone, and shifted the sympathovagal balance towards reduced sympathetic predominance. Thus, the hypnotic suggestions induced a whole-body pattern characteristic of natural SWS. Given that the affected parameters regulate fundamental physiological functions like metabolism, cardiovascular activity, and immunity, our findings open up a wide range of potential applications of hypnotic SWS enhancement, in addition to advancing our knowledge on the physiology of human SWS.

Role of Sleep in Formation of Relational Associative Memory.

Relational memory, the ability to make and remember associations between objects, is an essential component of mammalian reasoning. In relational memory tasks, it has been shown that periods of offline processing, such as sleep, are critical to making indirect associations. To understand biophysical mechanisms behind the role of sleep in improving relational memory, we developed a model of the thalamocortical network to test how slow-wave sleep affects performance on an unordered relational memory task. First, the model was trained in the awake state on a paired associate inference task, in which the model learned to recall direct associations. After a period of subsequent slow-wave sleep, the model developed the ability to recall indirect associations. We found that replay, during sleep, of memory patterns learned in awake increased synaptic connectivity between neurons representing the item that was overlapping between tasks and neurons representing the unlinked items of the different tasks; this forms an attractor that enables indirect memory recall. Our study predicts that overlapping items between indirectly associated tasks are essential for relational memory, and sleep can reactivate pathways to and from overlapping items to the unlinked objects to strengthen these pathways and form new relational memories.SIGNIFICANCE STATEMENT Experimental studies have shown that some types of associative memory, such as transitive inference and relational memory, can improve after sleep. Still, it remains unknown what specific mechanisms are responsible for these sleep-related changes. In this new work, we addressed this problem by building a thalamocortical network model that can learn relational memory tasks and that can be simulated in awake or sleep states. We found that memory traces learned in awake were replayed during slow waves of NREM sleep and revealed that replay increased connections to and from overlapping memory items to form new relational memories. Our work discovered specific mechanisms behind the role of sleep in associative memory and made testable predictions about how sleep augments associative learning.

Systematic decrease of slow-wave sleep after a guided imagery designed to deepen sleep in low hypnotizable subjects.

Slow‐wave sleep is one of the most important restorative components of sleep and central for our health and cognitive functioning. Although the amount of slow‐wave sleep depends on sleep drive, age and other factors, also the pre‐sleep mental state might influence sleep depth. We had shown that a pre‐sleep hypnotic suggestion to sleep more deeply increased slow‐wave sleep duration in hypnotizable subjects. In contrast, low‐hypnotizable participants decreased sleep depth after this intervention. A possible reason might be an aversion to and active resistance against hypnosis. To overcome this potential opposition, we introduced the procedure as ‘guided imagery’. We replaced the hypnotic induction by a breathing relaxation. Importantly, the suggestion ‘to sleep more deeply’ remained identical. We expected that these changes would make it easier for low‐hypnotizable subjects to benefit from the suggestion. In contrast, young healthy low‐hypnotizable participants did not show positive effects. Similar to our previous studies, they exhibited a reduced slow‐wave sleep duration after the intervention. Additionally, the ratio between slow‐wave activity and beta band power decreased. Subjective sleep quality remained unaffected. Our results indicate that suggestions to sleep more deeply result in decreased sleep depth in low‐hypnotizable participants regardless of the mental technique (guided imagery versus hypnosis). Thus, the aversion against hypnosis per se cannot explain the detrimental effect of the intervention on slow‐wave sleep in low‐hypnotizable subjects. The results support the notion that our mental state before sleep can influence subsequent slow‐wave sleep. However, the mechanisms of the contradictory decrease in low‐hypnotizable subjects remain unknown.

0175 Light Improves Alertness and Mood During the Sleep Inertia Period Following Slow Wave Sleep

Abstract Introduction Waking from sleep, especially slow wave sleep (SWS), is associated with reduced alertness known as sleep inertia. Light improves alertness during sleep deprivation and circadian misalignment. In this study, we assessed the efficacy of light to improve alertness and mood immediately after waking from SWS. Methods Twelve participants kept a sleep schedule of 8.5 h for 5 nights and 5 h for one night prior to the overnight laboratory visit (confirmed by actigraphy). Participants went to bed at their scheduled habitual bedtime in the laboratory and were monitored by standard polysomnography. After at least 5 min of SWS, participants were awoken and exposed to either red ambient light (control) or blue-enriched bright light (light) for 1 h. During this time, participants completed a subjective scale of alertness (Karolinska Sleepiness Scale, KSS) and visual analogue scales (VAS) of mood at 2 min, 17 min, 32 min, and 47 min after waking. Following this sleep inertia measurement period, all lights were turned off and participants were allowed to return to sleep. They were then awoken again from their subsequent SWS period and exposed to the opposite condition (control or light). A linear mixed-effects model with fixed effects of condition, time, and condition*time and a random effect of participant was used to determine the impact of light across the testing period. An average of baseline responses (pre-sleep) was included as a covariate. Results Compared to the control condition, participants exposed to blue-enriched bright light reported feeling more alert (KSS: F1,77=4.955, p=.029; VASalert: F1,77=8.226, p=.005), more cheerful (VAScheerful: F1,77=8.615, p=.004), less depressed (VASdepressed: F1,77=4.649, p=.034), and less lethargic (VASlethargic: F1,77=5.652, p=.020). Conclusion Exposure to blue-enriched bright light immediately after waking from SWS may help to improve subjective alertness and mood. Future analyses will explore whether these findings extend to effects on cognitive performance. Support Naval Postgraduate School Grant. NASA Airspace Operations and Safety Program, System-Wide Safety Project.

Targeted Memory Reactivation during Sleep Elicits Neural Signals Related to Learning Content.

Retrieval of learning-related neural activity patterns is thought to drive memory stabilization. However, finding reliable, noninvasive, content-specific indicators of memory retrieval remains a central challenge. Here, we attempted to decode the content of retrieved memories in the EEG during sleep. During encoding, male and female human subjects learned to associate spatial locations of visual objects with left- or right-hand movements, and each object was accompanied by an inherently related sound. During subsequent slow-wave sleep within an afternoon nap, we presented half of the sound cues that were associated (during wake) with left- and right-hand movements before bringing subjects back for a final postnap test. We trained a classifier on sleep EEG data (focusing on lateralized EEG features that discriminated left- vs right-sided trials during wake) to predict learning content when we cued the memories during sleep. Discrimination performance was significantly above chance and predicted subsequent memory, supporting the idea that retrieval leads to memory stabilization. Moreover, these lateralized signals increased with postcue sleep spindle power, demonstrating that retrieval has a strong relationship with spindles. These results show that lateralized activity related to individual memories can be decoded from sleep EEG, providing an effective indicator of offline retrieval.SIGNIFICANCE STATEMENT Memories are thought to be retrieved during sleep, leading to their long-term stabilization. However, there has been relatively little work in humans linking neural measures of retrieval of individual memories during sleep to subsequent memory performance. This work leverages the prominent electrophysiological signal triggered by lateralized movements to robustly demonstrate the retrieval of specific cued memories during sleep. Moreover, these signals predict subsequent memory and are correlated with sleep spindles, neural oscillations that have previously been implicated in memory stabilization. Together, these findings link memory retrieval to stabilization and provide a powerful tool for investigating memory in a wide range of learning contexts and human populations.

Cued reactivation during slow-wave sleep induces brain connectivity changes related to memory stabilization

Memory reprocessing following acquisition enhances memory consolidation. Specifically, neural activity during encoding is thought to be ‘replayed’ during subsequent slow-wave sleep. Such memory replay is thought to contribute to the functional reorganization of neural memory traces. In particular, memory replay may facilitate the exchange of information across brain regions by inducing a reconfiguration of connectivity across the brain. Memory reactivation can be induced by external cues through a procedure known as “targeted memory reactivation”. Here, we analysed data from a published study with auditory cues used to reactivate visual object-location memories during slow-wave sleep. We characterized effects of memory reactivation on brain network connectivity using graph-theory. We found that cue presentation during slow-wave sleep increased global network integration of occipital cortex, a visual region that was also active during retrieval of object locations. Although cueing did not have an overall beneficial effect on the retention of cued versus uncued associations, individual differences in overnight memory stabilization were related to enhanced network integration of occipital cortex. Furthermore, occipital cortex displayed enhanced connectivity with mnemonic regions, namely the hippocampus, parahippocampal gyrus, thalamus and medial prefrontal cortex during cue sound presentation. Together, these results suggest a neural mechanism where cue-induced replay during sleep increases integration of task-relevant perceptual regions with mnemonic regions. This cross-regional integration may be instrumental for the consolidation and long-term storage of enduring memories.

Blindfolding during wakefulness causes decrease in sleep slow wave activity.

Slow wave activity (SWA, 0.5–4 Hz) represents the predominant EEG oscillatory activity during slow wave sleep (SWS). Its amplitude is considered in part a reflection of synaptic potentiation in cortical networks due to encoding of information during prior waking, with higher amplitude indicating stronger potentiation. Previous studies showed that increasing and diminishing specific motor behaviors produced corresponding changes in SWA in the respective motor cortical areas during subsequent SWS. Here, we tested whether this relationship can be generalized to the visual system, that is, whether diminishing encoding of visual information likewise leads to a localized decrease in SWA over the visual cortex. Experiments were performed in healthy men whose eyes on two different days were or were not covered for 10.5 h before bedtime. The subject's EEG was recorded during sleep and, after sleep, visual evoked potentials (VEPs) were recorded. SWA during nonrapid eye movement sleep (NonREM sleep) was lower after blindfolding than after eyes open (P < 0.01). The decrease in SWA that was most consistent during the first 20 min of NonREM sleep, did not remain restricted to visual cortex regions, with changes over frontal and parietal cortical regions being even more pronounced. In the morning after sleep, the N75‐P100 peak‐to‐peak‐amplitude of the VEP was significantly diminished in the blindfolded condition. Our findings confirm a link between reduced wake encoding and diminished SWA during ensuing NonREM sleep, although this link appears not to be restricted to sensory cortical areas.

Cued Reactivation of Motor Learning during Sleep Leads to Overnight Changes in Functional Brain Activity and Connectivity.

Sleep plays a role in memory consolidation. This is demonstrated by improved performance and neural plasticity underlying that improvement after sleep. Targeted memory reactivation (TMR) allows the manipulation of sleep-dependent consolidation through intentionally biasing the replay of specific memories in sleep, but the underlying neural basis of these altered memories remains unclear. We use functional magnetic resonance imaging (fMRI) to show a change in the neural representation of a motor memory after targeted reactivation in slow-wave sleep (SWS). Participants learned two serial reaction time task (SRTT) sequences associated with different auditory tones (high or low pitch). During subsequent SWS, one sequence was reactivated by replaying the associated tones. Participants were retested on both sequences the following day during fMRI. As predicted, they showed faster reaction times for the cued sequence after targeted memory reactivation. Furthermore, increased activity in bilateral caudate nucleus and hippocampus for the cued relative to uncued sequence was associated with time in SWS, while increased cerebellar and cortical motor activity was related to time in rapid eye movement (REM) sleep. Functional connectivity between the caudate nucleus and hippocampus was also increased after targeted memory reactivation. These findings suggest that the offline performance gains associated with memory reactivation are supported by altered functional activity in key cognitive and motor networks, and that this consolidation is differentially mediated by both REM sleep and SWS.

VTA neurons coordinate with the hippocampal reactivation of spatial experience.

Spatial learning requires the hippocampus, and the replay of spatial sequences during hippocampal sharp wave-ripple (SPW-R) events of quiet wakefulness and sleep is believed to play a crucial role. To test whether the coordination of VTA reward prediction error signals with these replayed spatial sequences could contribute to this process, we recorded from neuronal ensembles of the hippocampus and VTA as rats performed appetitive spatial tasks and subsequently slept. We found that many reward responsive (RR) VTA neurons coordinated with quiet wakefulness-associated hippocampal SPW-R events that replayed recent experience. In contrast, coordination between RR neurons and SPW-R events in subsequent slow wave sleep was diminished. Together, these results indicate distinct contributions of VTA reinforcement activity associated with hippocampal spatial replay to the processing of wake and SWS-associated spatial memory.DOI: http://dx.doi.org/10.7554/eLife.05360.001

Synaptic Homeostasis and Restructuring across the Sleep-Wake Cycle.

Sleep is critical for hippocampus-dependent memory consolidation. However, the underlying mechanisms of synaptic plasticity are poorly understood. The central controversy is on whether long-term potentiation (LTP) takes a role during sleep and which would be its specific effect on memory. To address this question, we used immunohistochemistry to measure phosphorylation of Ca2+/calmodulin-dependent protein kinase II (pCaMKIIα) in the rat hippocampus immediately after specific sleep-wake states were interrupted. Control animals not exposed to novel objects during waking (WK) showed stable pCaMKIIα levels across the sleep-wake cycle, but animals exposed to novel objects showed a decrease during subsequent slow-wave sleep (SWS) followed by a rebound during rapid-eye-movement sleep (REM). The levels of pCaMKIIα during REM were proportional to cortical spindles near SWS/REM transitions. Based on these results, we modeled sleep-dependent LTP on a network of fully connected excitatory neurons fed with spikes recorded from the rat hippocampus across WK, SWS and REM. Sleep without LTP orderly rescaled synaptic weights to a narrow range of intermediate values. In contrast, LTP triggered near the SWS/REM transition led to marked swaps in synaptic weight ranking. To better understand the interaction between rescaling and restructuring during sleep, we implemented synaptic homeostasis and embossing in a detailed hippocampal-cortical model with both excitatory and inhibitory neurons. Synaptic homeostasis was implemented by weakening potentiation and strengthening depression, while synaptic embossing was simulated by evoking LTP on selected synapses. We observed that synaptic homeostasis facilitates controlled synaptic restructuring. The results imply a mechanism for a cognitive synergy between SWS and REM, and suggest that LTP at the SWS/REM transition critically influences the effect of sleep: Its lack determines synaptic homeostasis, its presence causes synaptic restructuring.

Cognitive neuroscience. Unlearning implicit social biases during sleep.

Although people may endorse egalitarianism and tolerance, social biases can remain operative and drive harmful actions in an unconscious manner. Here, we investigated training to reduce implicit racial and gender bias. Forty participants processed counterstereotype information paired with one sound for each type of bias. Biases were reduced immediately after training. During subsequent slow-wave sleep, one sound was unobtrusively presented to each participant, repeatedly, to reactivate one type of training. Corresponding bias reductions were fortified in comparison with the social bias not externally reactivated during sleep. This advantage remained 1 week later, the magnitude of which was associated with time in slow-wave and rapid-eye-movement sleep after training. We conclude that memory reactivation during sleep enhances counterstereotype training and that maintaining a bias reduction is sleep-dependent.

Evidence for consolidation of neuronal assemblies after seizures in humans.

The establishment of memories involves reactivation of waking neuronal activity patterns and strengthening of associated neural circuits during slow-wave sleep (SWS), a process known as "cellular consolidation" (Dudai and Morris, 2013). Reactivation of neural activity patterns during waking behaviors that occurs on a timescale of seconds to minutes is thought to constitute memory recall (O'Keefe and Nadel, 1978), whereas consolidation of memory traces may be revealed and served by correlated firing (reactivation) that appears during sleep under conditions suitable for synaptic modification (Buhry et al., 2011). Although reactivation has been observed in human neuronal recordings (Gelbard-Sagiv et al., 2008; Miller et al., 2013), reactivation during sleep has not, likely because data are difficult to obtain and the effect is subtle. Seizures, however, provide intense and synchronous, yet sparse activation (Bower et al., 2012) that could produce a stronger consolidation effect if seizures activate learning-related mechanisms similar to those activated by learned tasks. Continuous wide-bandwidth recordings from patients undergoing intracranial monitoring for drug-resistant epilepsy revealed reactivation of seizure-related neuronal activity during subsequent SWS, but not wakefulness. Those neuronal assemblies that were most strongly activated during seizures showed the largest correlation changes, suggesting that consolidation selectively strengthened neuronal circuits activated by seizures. These results suggest that seizures "hijack" physiological learning mechanisms and also suggest a novel epilepsy therapy targeting neuronal dynamics during post-seizure sleep.

Sleep promotes branch-specific formation of dendritic spines after learning

How sleep helps learning and memory remains unknown. We report in mouse motor cortex that sleep after motor learning promotes the formation of postsynaptic dendritic spines on a subset of branches of individual layer V pyramidal neurons. New spines are formed on different sets of dendritic branches in response to different learning tasks and are protected from being eliminated when multiple tasks are learned. Neurons activated during learning of a motor task are reactivated during subsequent non-rapid eye movement sleep, and disrupting this neuronal reactivation prevents branch-specific spine formation. These findings indicate that sleep has a key role in promoting learning-dependent synapse formation and maintenance on selected dendritic branches, which contribute to memory storage.

Targeted memory reactivation during slow wave sleep facilitates emotional memory consolidation.

To investigate the mechanisms by which auditory targeted memory reactivation (TMR) during slow wave sleep (SWS) influences the consolidation of emotionally negative and neutral memories. Each of 72 (36 negative, 36 neutral) picture-location associations were encoded with a semantically related sound. During a subsequent nap, half of the sounds were replayed in SWS, before picture-location recall was examined in a final test. Manchester Sleep Laboratory, University of Manchester. 15 adults (3 male) mean age = 20.40 (standard deviation ± 3.07). TMR with auditory cues during SWS. Performance was assessed by memory accuracy and recall response times (RTs). Data were analyzed with a 2 (sound: replayed/not replayed) × 2 (emotion: negative/neutral) repeated measures analysis of covariance with SWS duration, and then SWS spindles, as the mean-centered covariate. Both analyses revealed a significant three-way interaction for RTs but not memory accuracy. Critically, SWS duration and SWS spindles predicted faster memory judgments for negative, relative to neutral, picture locations that were cued with TMR. TMR initiates an enhanced consolidation process during subsequent SWS, wherein sleep spindles mediate the selective enhancement of reactivated emotional memories.

Inferred Ising model unveils potentiation of pairwise neural interactions and replay of rule-learning related neural activity

In a recent experiment [1] the prefrontal cortex activity of rats was measured using multi-electtrode recordings during the awake epoch and during the previous and subsequent slow wave sleep (SWS) periods. During the awake epoch the animal faces a task, such as following a light in a Y-shaped maze, where rule learning is rewarded with food. Through the analysis of the recorded activity by means of Principal Component Analysis, the replay of the activity during the SWS after the task was shown to occur. Here we re-analyze those data with an Ising model inference algorithm (the Selective Cluster Expansion, introduced in [2]) and we show how valuable informations can be extracted from the inferred parameters in the context of neural activity replay and neuroplasticity. We start by binning, with a fixed bin-width of 10 ms, the recording of spiking times and by computing the set of probabilities that a single neuron is active in a single time-bin and the probabilities that a couple of neurons

Memory stabilization with targeted reactivation during human slow-wave sleep

It is believed that neural representations of recent experiences become reactivated during sleep, and that this process serves to stabilize associated memories in long-term memory. Here, we initiated this reactivation process for specific memories during slow-wave sleep. Participants studied 50 object-location associations with object-related sounds presented concurrently. For half of the associations, the related sounds were re-presented during subsequent slow-wave sleep while participants underwent functional MRI. Compared with control sounds, related sounds were associated with increased activation of right parahippocampal cortex. Postsleep memory accuracy was positively correlated with sound-related activation during sleep in various brain regions, including the thalamus, bilateral medial temporal lobe, and cerebellum. In addition, postsleep memory accuracy was also positively correlated with pre- to postsleep changes in parahippocampal-medial prefrontal connectivity during retrieval of reactivated associations. Our results suggest that the brain is differentially activated by studied and unstudied sounds during deep sleep and that the thalamus and medial temporal lobe are involved in establishing the mnemonic consequences of externally triggered reactivation of associative memories.

Quantification of short-term slow wave sleep homeostasis and its disruption by minocycline in the laboratory mouse

Electroencephalographic slow wave activity (SWA) during slow wave sleep (SWS) undergoes dynamic fluctuations in reaction to sleep/wake history. SWA increases as a consequence of prior waking and decreases as consequence of prior SWS. These fluctuations are evidence for a homeostatic regulatory process, the neurobiological underpinnings of which remain to be defined. The anti-neuroinflammatory agent minocycline abolishes the increase in SWA that normally occurs after 1- or 3-h sleep deprivation. We sought to determine whether this effect is also observed during spontaneous sleep. We describe a novel procedure for measuring the predictive relationship between spontaneous changes in sleep/wake states in the short-term (less than 30min) and subsequent SWA. In saline-treated mice, 16 or more minutes of spontaneous wakefulness during a 20-min interval causes an increase in SWA during subsequent SWS, and 16 or more minutes spent in SWS causes a decrease in SWA during subsequent SWS. Minocycline administration (45mg/kg) abolishes the increase caused by wakefulness but not the decrease caused by sleep. These data demonstrate that minocycline attenuates SWA dynamics in spontaneous sleep. Inflammatory events in the brain may underlie, in part, wakefulness-induced changes in the sleep electroencephalogram.

Hippocampal Sharp Waves and Reactivation during Awake States Depend on Repeated Sequential Experience

Hippocampal firing patterns during behavior are reactivated during rest and subsequent slow-wave sleep. These reactivations occur during transient local field potential (LFP) events, termed sharp waves. Theories of hippocampal processing suggest that sharp waves arise from strengthened plasticity, and that the strengthened plasticity depends on repeated cofiring of pyramidal cells. We tested these predictions by recording neural ensembles and LFPs from rats running tasks requiring different levels of behavioral repetition. The number of sharp waves emitted increased during sessions with more regular behaviors. Reactivation became more similar to behavioral firing patterns across the session. This enhanced reactivation also depended on the regularity of the behavior. Additional studies in CA3 and CA1 found that the number of sharp waves emitted also increased in CA3 recordings as well as CA1, but that the time courses were different between the two structures.

Are Spatial Memories Strengthened in the Human Hippocampus during Slow Wave Sleep?

In rats, the firing sequences observed in hippocampal ensembles during spatial learning are replayed during subsequent sleep, suggesting a role for posttraining sleep periods in the offline processing of spatial memories. Here, using regional cerebral blood flow measurements, we show that, in humans, hippocampal areas that are activated during route learning in a virtual town are likewise activated during subsequent slow wave sleep. Most importantly, we found that the amount of hippocampal activity expressed during slow wave sleep positively correlates with the improvement of performance in route retrieval on the next day. These findings suggest that learning-dependent modulation in hippocampal activity during human sleep reflects the offline processing of recent episodic and spatial memory traces, which eventually leads to the plastic changes underlying the subsequent improvement in performance.