Processing in Relation Chapter to Sleep Philippe Peigneux and Carlyle Smith 29 Abstract reexpression of behavior-specific neural patterns during post- training sleep, and still others have probed the effects of Although each of us empirically recognizes the utmost impor- within-sleep stimulation on sleep patterns and overnight mem- tance of sleep for the quality of our everyday life, its functions ories. Besides-demonstrating a role of sleep in memory con- have long remained shrouded in mystery. Beyond its putative solidation processes, these studies have also indicated that physiologic functions, there is now growing evidence that sleep stages are functionally different, in that they may sub- sleep plays a prominent role in brain plasticity and in memory- serve distinct memory processes. Available evidence reveals consolidation processes. According to this proposal, memory complex interactions between systems, in traces formed during a learning episode are not immediately agreement with the fact that memory is a complex construct stored in their definitive form. Rather, they are initially kept of specialized memory subdomains, and that sleep is com- in a labile, fragile state, during which they can be easily dis- posed of distinct stages characterized by specific physiologic rupted. Over time and especially during sleep, they subse- mechanisms. Despite advances that have refined our under- quently undergo a series of transformations during which standing of the relationships between sleep and cognitive pro- they will be consolidated and fully integrated into long-term cesses, the underlying mechanisms still remain to be fully memory. In this chapter, we present experimental data that elucidated. Further steps are now required to understand how provide support for the hypothesis that sleep exerts a promot- sleep disorders and pathologies accompanied by sleep distur- ing effect on plastic processes of . Some bances affect cognitive functions, and especially learning and studies have assessed the effects of posttraining sleep depriva- memory consolidation in humans, eventually leading to reme- tion on memory consolidation and on the reorganization of dial interventions. the neural substrates of long-term . Others have investigated the effects of learning on posttraining sleep and

In 1867, Hervey de Saint Denys, fascinated by his dreams Before approaching the subject, however, we will briefly since the age of 14, published Les Rêves et les Moyens de les introduce the concepts of memory consolidation and Diriger.1 In his book, he reported a series of ingenious memory systems in humans. Previous chapters have shown experiments showing that experienced events are incorpo- that sleep is a multidimensional state of vigilance, com- rated into our dreams, in which they can be combined to posed of rapid eye movement (REM) and non-REM create original associations between “memory images” of (NREM) episodes that present distinctive features and rely the past. Hence, he strongly opposed the idea that sleep on specific neuroanatomic substrates.4 From both cogni- may be a sudden drop in a state of cognitive “non-being” tive and neurophysiologic perspectives, memory is not a in which our resting brain is disconnected. On the con- unitary phenomenon. Rather, memory should be seen as a trary, he claimed that “a sleep without dreams cannot exist, generic concept for information , encompassing just as a wake state without mentation does not exist.” a series of specific subdomains.5 Consequently, the interac- Besides dreaming activity, however, addressed in Section tion between multidimensional states of sleep and distinc- 7 of this book, we know that the sleeping brain houses a tive memory systems makes it logical that not all sleep wide of cognitive processes, including the ongoing manipulations will have the same impact on performance, treatment of elaborated external stimuli, the revival of depending on the various parameters embedded in the experiences, and last, but not least, the consolidation of memory task.2,6,7 We will examine the growing number of new information in memory. Interestingly, recognition behavioral studies that have enlightened our understand- that persistence of mental activity in the sleeper may be an ing of the role played by sleep episodes in memory integral part of the physiologic processes that subtend consolidation. The rapid evolution of neurophysiologic memory consolidation arose only in the last quarter of the techniques and analytical approaches allows scrutiny of the 20th century. The hypothesis had to wait till now to receive complex relations between cognitive processes and their widespread acknowledgement, as illustrated by the fact underlying neural substrates. Part of this chapter will focus that for the first time a chapter devoted to sleep in relation on the neurophysiologic mechanisms acting in sleep to to memory has been introduced in this fifth edition of support, or at least favor, memory consolidation processes. Principles and Practices in Sleep Medicine. Molecular biology of memory consolidation is beyond the This chapter introduces the issues surrounding the role scope of this chapter and is reviewed elsewhere.4 The rela- that sleep may play in memory consolidation, focusing on tionship between consolidation of learning and sleep is a human data. Reviews about relationships between sleep crucial issue because memory is at the root of most of our and memory in animals are addressed can be found else- daily behaviors, such as simple skill acquisition (e.g., type- where.2-4 We will here outline key findings and milestones writing), sophisticated operational procedures (e.g., using in probing the sleep-for-memory hypothesis, as well as computer-based systems), and keeping track of personal ongoing debates and thoughtful questions that remain. events and relationships. L

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MEMORY SYSTEMS AND MEMORY Distinctive features of nondeclarative memories are that they are not easily accessible to verbal description and can CONSOLIDATION be acquired and reexpressed implicitly. Thus, our behav- We are able to learn, store, and remember various types ioral performance can be affected by the new memory even of information in different ways and for variable periods if we are not consciously aware that new information has of time, from conscious acquisition strategies to incidental been encoded or is being retrieved. Memory abilities detection of environmental events. Cerebral damage can aggregated under the nondeclarative label also gather dif- selectively alter some of these processes while leaving ferent forms: skills, habits, priming, and conditioning. others undisturbed. These simple observations have led to Although grouped under the nondeclarative label, these the proposal that memory is not a unitary phenomenon various processes are subtended by distinct neuroanatomic but rather a complex construct of more or less specialized substrates in both humans and animals, further suggesting memory subdomains.5 First, a seminal distinction that their relative independence.5 dates back to William James is made between short- and Besides the transverse division between long-term long-term memory stores. The former is dedicated to the memory subsystems proposed by these influential models, temporary storage of volatile information for up to seconds, there is a dynamic longitudinal process. Newly acquired whereas the latter, the main focus in this chapter, houses information is not immediately stored at the time of potentially lasting information that is deemed consolidated learning in its final form, if such a stable state exists. and less susceptible to disruption. Long-term memories in Rather, memories undergo a series of transformations humans may further belong to multiple systems, primarily over hours, days, or even years, during which time they delineated between declarative and nondeclarative memo- are gradually incorporated into preexisting sets of mne- ries (Fig. 29-1). monic representations,8-10 or are subjected to .11 Distinguishing features of declarative memory are that This is the concept of memory consolidation, which can information is easily accessible to verbal description and be defined as the time-dependent process that converts that or retrieval is usually carried out explicitly— labile memory traces into more permanent or enhanced that is, the subject is aware that the stored information forms.12 These transformations are made possible by our exists and is being accessed. Declarative memory is further brain plasticity—that is, the capacity of the brain to modify composed of semantic and components. its structure and function over time, within certain bound- is the receptacle for our general knowl- aries.13 Eventually, time-dependent processes of consolida- edge about the world, regardless of the spatiotemporal tion and the ensuing robust memory trace will enduringly context of knowledge acquisition (e.g., we know that Paris adjust the behavioral responses to the recent environ- is the capital of France, and that fuel is combustible, but mental changes, thereby enlarging the organism’s behav- we are probably unable to recollect how and when we ioral repertoire.14 learned these facts). Episodic memory, on the other hand, Scientific evidence suggests that sleep and the associated refers to the system that stores events and information processes of brain plasticity4 are major players in time- along with their contextual location in time and space (e.g., dependent processes of memory consolidation, acting as I can vividly remember having visited the British Museum key constituents in the chain of transformations that help with my cousin on a rainy day in the fall of 1993). integrate information for the long term. Furthermore, these studies suggest that distinct sleep stages may have distinct memory-related functions, which has been inter- preted in two different but nonexclusive ways. According to the dual-process hypotheses, REM and NREM sleep Declarative memory act differently on memory traces depending on the memory system or process to which they belong. For example, it has been proposed that slow-wave sleep (SWS)—the Episodic Semantic memory memory deepest stage of NREM sleep—facilitates consolidation of declarative and spatial memories, whereas REM sleep 15,16 Personally Facts and concepts facilitates consolidation of nondeclarative memories. experienced events, about the world, Another interpretation is that particular sequences of sleep spatial and temporal general knowledge Emotion memory features states reflect the succession of brain processing events sup- porting memory consolidation.17 An example is the pro- Nondeclarative posal that REM sleep actively consolidates or integrates memory complex associative information, whereas NREM sleep passively prevents retroactive interference of recently acquired complex associative information.18 In this view, Skills and Priming Conditioning habits SWS and REM sleep play complementary roles and have to act serially to consolidate the new memory trace, in a double-step process.19,20 Both approaches assume that it is “How to” knowledge, Processing Elementary perceptual, motor facilitation after associative sleep on the first posttraining night that is important for memory and cognitive abilities prior exposure memory consolidation. Nonetheless, it would be prema- ture to claim that only sleep may achieve the necessary Figure 29-1 Schematic organization of long-term memory conditions to consolidate novel memories in the nervous L systems. system, as both sleeplike cognitive and neural processes of

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memory consolidation have also been observed during sleep in the second part of the night for the consolidation wakefulness.21-23 of motor memories.27,28 Hence, sleep deprivation studies have suggested that each stage of human sleep (REM sleep, SWS, stage 2 sleep) might be involved in a distinctive way METHODS FOR STUDYING THE 6,7 ROLE OF SLEEP FOR MEMORY in learning and memory consolidation processes. In the recent past, neuroimaging investigations have CONSOLIDATION complemented these findings using functional magnetic Three experimental approaches have been used to test the resonance imaging (fMRI). As in behavioral paradigms, hypothesis that sleep exerts a favorable or promoting effect subjects are trained to the task and then either deprived of on memory consolidation. These approaches focus on (1) sleep or allowed to sleep on the following night. A few days the effects of posttraining sleep deprivation on memory later, cerebral activity is recorded during memory retrieval consolidation and on the reorganization of the neural sub- and the two posttraining sleep conditions are compared. strates of long-term memories, (2) the effects of learning One or two additional nights of regular sleep are usually on posttraining sleep and reexpression of behavior-specific allowed after the posttraining night before testing in the neural patterns during posttraining sleep, or (3) the effects scanner, to avoid different arousal states that may con- of within-sleep stimulation on sleep patterns and overnight found neural activity associated with memory retrieval memories. between sleeping and sleep-deprived subjects. These neu- roimaging studies have yielded two important contribu- Posttraining Sleep Deprivation tions. First, they have demonstrated that sleep deprivation The first and probably most ancient line of investigation during the posttraining night eventually impedes the reor- has probed the putatively detrimental effect of sleep depri- ganization and optimization of the cerebral activity, sub- vation on the night after learning, based on the assumption tending delayed retrieval of consolidated memories during that memory performance over the long term will be better wakefulness.29-32 Second, they have shown that sleep- if participants are allowed to sleep after learning rather dependent changes in memory-related brain activity pat- than being deprived of sleep. In classic procedures, subjects terns may be present even when similarity in behavioral learn new material. Afterward, some participants are performance between posttraining sleep conditions sug- allowed to sleep normally whereas others either do not gests an absence of sleep-related effect on memory.30,32 sleep at all (total sleep deprivation), are awakened at the The latter results further indicate that long-term memory onset of occurrences of the sleep stage under study (selec- performance can be achieved using different cerebral strat- tive sleep deprivation), are kept awake during the period egies initiated as a function of the status of sleep during of the night in which the sleep stage is predominant (partial the posttraining night. sleep deprivation), or have a shortened sleep duration (sleep restriction). Finally, prenight and postnight memory Posttraining Sleep Modifications measures are compared between sleeping and sleep- The second line of investigation stemmed from the rea- deprived subgroups, either the next day or several days soning that if newly acquired information underwent an later. Jenkins and Dalenbach24 used this approach about 85 ongoing process of consolidation during sleep, then this years ago and found that the for newly should be reflected in neural and physiologic features of learned verbal material described by the German psychol- posttraining sleep. Using electroencephalographic (EEG) ogist Ebinghaus was significantly dampened by the pres- recording techniques, numerous animal studies have ence of an intermediate period of sleep. Nonetheless, they reported changes in, or memory-related associations with, did not attribute this effect to a specific role of sleep per a series of postlearning sleep parameters, including sleep se in memory processing but merely to the protective role stage duration or proportion relative to total sleep time, that sleep may have against “interference, inhibition, or density of rapid eye movements, power increase in selected obliteration of the old by the new.”24 However, this EEG frequency ranges, changes in density and duration of hypothesis of a purely passive role for sleep in memory phasic events (e.g., spindles, ponto-geniculo-occipital processes has been challenged by studies of selective sleep waves), and reexpression of learning-specific neural pat- deprivation that attribute a specific role to REM sleep in terns (for reviews, see references 3, 4, 6, 33, 34). memory storage and consolidation, in both human and Likewise, in humans, numerous EEG studies have evi- animal species.25 Also, it was demonstrated that memory denced that both the architecture of sleep and distinctive over an interval with relatively high amounts of stage 4 features of sleep stages can be affected by prior learning sleep (i.e., in the first half of the night) was superior to experience. For example, postlearning sleep modifications memory over an interval with relatively high amounts of have been shown when looking at absolute or proportional REM sleep (i.e., in the second half of the night).26 This (i.e., relative to total sleep time) increases in the duration seemingly apparent contradiction was resolved later, with of REM sleep,6,20,35-37 stage 2 sleep38 and SWS20 episodes. the demonstration that of paired-associate lists was Other studies have reported increased density of rapid eye significantly better after sleep than wakefulness in the first movements39,40 and stage 2 spindle activity in the sigma part of the night only, whereas consolidation of mirror- frequency band,41-50 as well as increases in REM sleep theta tracing skills specifically benefited from sleep in the second power.51 Many found statistical correlations between quan- part of the night.15 Results showed that memories belong- titative parameters of sleep and overnight performance ing to the declarative and nondeclarative systems do not improvements20,37,41-44,48-50 or levels of performance at the benefit from the same sleep components. Other experi- end of learning,45 suggesting a close link between changes mental manipulations inferred a specific role for stage 2 in sleep physiology and memory consolidation. In support L

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of the double-step hypothesis described earlier, others would indicate that active plastic processes are taking place studies evidenced relationships between performance during sleep. changes and the organization of NREM/REM sleep In line with animal studies,33 preliminary data have indi- cycles.19,52 Hence, these investigations, mostly based on cated the possibility of heart rate conditioning in man noninvasive electrophysiologic techniques, have consis- during NREM sleep,64 suggesting plasticity during sleep. tently demonstrated that physiology of sleep is influenced On the other hand, no learning effect was found for lists by prior learning during the day. Additionally, waking of paired-associate words presented during either REM or experience was shown to influence the content of hypna- stage 2 sleep and tested immediately afterward.65 Although gogic hallucinations53 and of dreams collected on awaken- these results suggest a limitation in learning capacity ing from sleep stages54,55 on the postexposure night, during sleep, there is consistent evidence that sleeping although delayed incorporations of up to weeks have also subjects remain able to detect and discriminate external been reported often.55 sensory events as indexed by event-related auditory poten- Noninvasive neuroimaging studies, especially using pos- tials (ERPs).66,67 Likewise, nociceptive stimulations during itron emission tomography (PET) measurements, with sleep persistently elicit evoked responses.68 ERP and fMRI their better spatial resolution and whole brain coverage, data also indicated higher sensitivity to external stimuli have been used to look more precisely at the neural cor- during tonic than phasic periods of REM sleep.69,70 Higher- relates of postlearning modifications during sleep. They level processing of externally presented events was also have shown that neural activity occurring during waking found during sleep, as auditory ERPs are elicited after task practice in learning-dedicated cerebral structures can hearing one’s own name both while sleeping and awake.71 be reexpressed or continued during both REM56,57 and Nonetheless, brain responsiveness during sleep is not inde- NREM58 stages of sleep, as well as during posttraining pendent of prior waking experience. Learning semantic wakefulness.21 These data were in close agreement with associations72 or discriminating auditory patterns67 during intracerebral recording studies in animals, which demon- wakefulness leads to changes in evoked response potentials strated neuronal reactivation during sleep.59,60 The animal during sleep,72 even up to 2 days later.67 These results data suggested reactivation of coherent memory traces in support the idea that external events can be processed key cerebral structures during sleep that was deemed to during certain periods of sleep, and that signifi- contribute to or reflect the result of the memory consolida- cance affects this processing. tion process. However, these seminal animal studies did Further demonstrating an active role for sleep in memory not experimentally establish the behavioral relevance of consolidation processes, several studies have established reactivations in neuronal ensembles, as they never sought that stimulations in the posttraining sleep period may to show a relationship with subsequent behavioral modifi- enhance performance as compared with a standard, cations. A significant contribution of human neuroimaging unmodified posttraining night.73-77 Presentation of non- data was to show that experience-dependent reactivations awakening auditory stimulations during REM sleep after of local—that is, hippocampal—activity during SWS are Morse code learning73 or re-presentation during REM correlated to overnight gains in memory performance after sleep of sounds heard in background while learning a spatial navigation.58 On the other hand, levels of implicit complex logic task74 increased overnight memory. This procedural learning achieved before sleep correlated with effect was present only when auditory stimulations were the amplitude of reactivation in cortical areas during REM displayed in coincidence with the bursts of rapid eye move- sleep,57 at which time connectivity patterns between learn- ments that reflect phasic ponto-geniculo-occipital (PGO) ing-related areas were additionally reinforced.61 Taken activity in man. Likewise, presentation during SWS of together, human reactivation studies have suggested the odors that were used as contextual cues during the learning neuronal replay of previous experience during sleep, and episode triggered hippocampal responses and improved that posttraining sleep activity in brain areas involved overnight retention of declarative memories.77 Transcra- during the learning episode represents a neural signature nial direct-current stimulation that modulates excitability of memory-related cognitive processes. Another (but not in cortical areas improved declarative memory when exclusive) hypothesis is that learning in the awake state applied during SWS,76 especially when application of oscil- induces local synaptic changes that themselves induce local lating potentials at about 0.75 Hz induced slow oscillation- changes in slow-wave activity (SWA), the main marker of like potential fields that mimic the slow oscillations of deep sleep homeostasis, and that these changes are ultimately NREM sleep.75 Finally, artificially maintaining high levels beneficial to imprint novel memories.62 In support of this of cortisol feedback and cholinergic tone during SWS view, high-density electrophysiologic recordings have impairs hippocampus-dependent declarative memory for- demonstrated local increases in SWA in learning-related mation,78-80 suggesting that the natural shift in central areas during posttraining NREM sleep, correlating with nervous system cholinergic tone from high levels during overnight performance improvements.63 acquisition-related wakefulness periods to minimal levels during SWS optimizes declarative memory consolida- Within-Sleep Stimulations tion.81 On the other hand, preventing natural increases in Finally, a third approach to demonstrate memory process- cortisol during REM sleep periods appears to enhance ing during sleep has been to provide specific stimulations amygdala-dependent emotional memory.80 These studies during sleep with the aim of investigating whether mean- have demonstrated beneficial (or detrimental) effects of ingful stimuli could be recognized or new associations various stimulations and manipulations in the posttraining formed, or whether presleep learning can be modified by sleep periods on overnight gains in performance, and L nonawakening stimulations. Evidence for such phenomena therefore have provided interesting evidences that sleep

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does not play a merely passive role in memory processing mPFC sites when initial encoding was followed by a night by protecting novel memories from interference. Rather, of sleep than by sleep deprivation, suggesting that sleep they support the hypothesis that sleep acts in a complex leads to long-lasting changes in the representation of manner in providing optimal conditions for the consolida- memories at the neuroanatomic level.31 These results may tion of novel memories in the nervous system. be consistent with the hypothesis that sleep exerts an effect on the gradual semanticization of the learned material. SLEEP AND DECLARATIVE MEMORY Episodic Memory As discussed, long-term declarative memory comprises The effect of sleep on episodic memory has been semantic and episodic memory components. Experimental extensively studied using a series of declarative memory data indicate that the role of sleep in consolidating these paradigms encompassing learning of verbal material two memory components may be dissociated to a certain such as lists of words or paired-associate extent, and that emotional variables play a modulatory role words15,31,41,42,50,51,75,76,78,79,84-89 and sentences or prose pas- in episodic memory consolidation. These aspects will be sages,90 and explicit encoding of landscapes,83 objects’ covered in the following section. locations,77 faces,91 visuospatial memory,16,48 and naviga- tion in virtual30,32,58,92 or natural93 environments. Semantic Memory Among these, most studies using partial behavioral15,16,31,85 Few studies have looked at the role of sleep for consolida- or pharmacologic79 sleep deprivation have consistently tion of semantic information, although ERP studies have found that SWS, or at least the first half of the night of demonstrated that semantic processing of externally pre- sleep (which is rich in SWS), is beneficial for the consoli- sented stimuli is possible during REM and stage 2 sleep, dation of novel declarative memories. Consolidation of but not during SWS.66,71,72 Also, it has been shown that the declarative learning was also linked to increased spindle semantic priming (i.e., the facilitatory processing effect activity during posttraining stage 2 sleep,41,42,48-50 as well as resulting from prior presentation of semantically related to the alteration of SWS94 and spindles95 in schizophrenia. material) qualitatively differs upon awakening from stage Spindles are strong candidates to subtend memory consoli- 2 and REM sleep.82 Despite evidence for residual semantic dation processes during sleep because they are thought to processing, attempts to create novel semantic associations support neural plasticity.96 As well, declarative learning using direct auditory stimulation during sleep have been abilities have been linked with increased spindle activity unsuccessful.65 Other evidence for a role of sleep in pro- during stage 2 sleep44,97 and periodic arousal fluctuations cessing newly acquired semantic memories are not fully during non-REM sleep98 in healthy subjects. On the other conclusive because the tasks that have been used comprise hand, declarative memory deficits are associated with other cognitive components that may obscure the inter- decreased sleep spindle activity in patients with Alzheim- pretation.2 For example, improvement in a French immer- er’s disease,99 and NREM sleep duration and number of sion course over 6 weeks was correlated with REM sleep cycles in patients with chronic nonrestorative sleep.100 increases,36 but learning a novel language is a task that However, others reported that overnight performance involves episodic memory processes as well as the creation gains on declarative depend primarily on of novel semantic associations. Likewise, learning Morse preserved organization of sleep cycles—that is, sleep con- code, which was found to be associated with increases in tinuity—rather than on the integrity of a specific sleep REM sleep parameters,37 may be viewed as a specific form stage per se.19 These studies may stand in contrast with of cognitive procedural learning of novel associations. much older ones that showed impairment in recall of sen- Also, it is believed that transfer of novel information from tences and short stories101 or lists of words102 after selective hippocampus-dependent episodic memory stores to neo- REM sleep deprivation. Also, a more recent study found cortical, semantic, decontextualized memory representa- that REM sleep deprivation specifically impaired recall of tions is a gradual process that may take years to complete.8 spatial and temporal features of memories, as well as the Therefore, protocols in which initial encoding, posttrain- subject’s confidence in his own remembering,89 these ing sleep periods and retrieval are temporally close are parameters being considered as genuine components of probably not best suited to segregate the semantic compo- episodic memory, as opposed to general recall, which may nent of memory from other constituents. partially rely on semantic, decontextualized memories.2 A few neuroimaging studies have investigated the cere- Accordingly, it has been reported that consolidation bral correlates of declarative memory retrieval after during sleep enhances explicit recollection in recognition extended periods of time (up to 6 months) using paired- memory103 and strengthens the original temporal sequence associate list of words31 or pictures of landscapes.83 structure for lists of triplet words.104 Although these experiments were not specifically designed to probe whether the memorized material was semanti- Emotion in Episodic Memory cized at the time of retesting, neuroimaging results clearly The role of emotional variables in sleep-dependent pro- indicated a transfer from activity in hippocampal locations, cesses has been a focus of recent interest.80,90,105-108 Emotion observed early after learning, toward activity in medial can be seen as an important contextual cue in retention prefrontal cortical (mPFC) sites recorded 6 months later of episodic memories, although it is not necessarily pro- during memory retrieval.31,83 Furthermore, total sleep cessed explicitly. Nonetheless, emotional material was deprivation on the postlearning night hindered this gradual found to be better recalled after REM than after NREM process of consolidation. Six months after learning verbal sleep90 and to be altered after sleep deprivation,105 although material, memory retrieval more strongly activated the more for the emotional content than the context of the L

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information.108 However, others have found emotional sleep. There is further evidence of the complementary memories to be better preserved, or at least less disrupted, roles of sleep stages in the offline (i.e., occurring outside than neutral memories after total sleep deprivation.80,106 of actual practice) processes of consolidation for visual These latter results suggest that consolidation of emo- perceptual learning. Indeed, others have found that tional memories also occurs efficiently during awake repeated practice on a task within the same day does not periods, an effect that may be explained by the important lead to any improvement and can even result in perfor- ecologic value of rapidly acquiring emotional stimulus– mance deterioration for the trained visual quadrant, unless response associations. Similarly, it was found that sleep there is an intervening sleep episode.123 But most impor- deprivation does not alter behavioral performance in an tantly, they demonstrated that the duration of the sleep ecologically valid virtual navigation task.30,32 Importantly, episode and its constituent phases is crucial in this process, a lack of behavioral effect does not guarantee that sleep as 30-minute daytime naps merely discontinued perfor- was without any consequence on memory consolidation mance deterioration over repeated sessions,123 60-minute processes, as, in the case of both navigation and emotional naps reverted performance to its original level,123 and memories, underlying patterns of brain activity at retrieval 90-minute naps yielded improvement in discrimination were effectively altered by sleep deprivation on the post- performance.122 The main differences were more time training night.30,32,106 spent in NREM sleep in the 60-minute nap than in the 30-minute nap, and the occurrence of REM sleep in the SLEEP AND NONDECLARATIVE 90-minute nap. Other studies confirm the importance of MEMORIES posttraining sleep in the consolidation of coarse visual discrimination119 as well as the effect of visual adaptation As mentioned, memory abilities aggregated under the paradigms on subsequent sleep parameters,54 thus demon- nondeclarative label may be relatively independent from strating the importance of both REM and NREM sleep both cognitive and neuroanatomic standpoints.5 Skills stages for consolidation of procedural abilities in the visual and habits that refer to the gradual acquisition of novel system. perceptual, motor, and cognitive abilities through repeated However, sleep-dependent improvements cannot yet be practice (e.g., discriminating figures, playing piano, riding fully generalized across modalities, as contradictory results a bicycle, detecting environmental regularities) have been have been reported in the auditory domain. Whereas some the most widely investigated in relation to sleep. In authors have reported a beneficial influence of sleep on this respect, numerous studies have found that post- acquisition of auditory discrimination skills118,134 and per- training sleep boosts acquisition levels on nonverbal ceptual generalization of phonologic categories,117 others motor,35,46,109-115 perceptual,20,54,116-124 and perceptual– have found that the same amount of time spent in the motor15,27,29,43,45,56,57,61,63,125-129 procedural learning tasks. awake state is sufficient to allow the development of audi- Additionally, a few studies have found that sleep par- tory identification abilities.135,136 With respect to more ticularly enhances performance in sophisticated auditory discrimination abilities, however, it brain-damaged individuals,130,131 but not in patients suf- has been shown that integration of newly learned spoken fering from degenerative Parkinson’s disease,132 suggesting word forms, which must be discriminated from similar- the importance of sleep in motor rehabilitation programs. sounding entries during auditory word recognition, Next, we further describe the role of sleep in (1) per- requires an incubation-like period containing sleep.137 ceptual, (2) motor, and (3) perceptual–, and (4) priming. Sleep and Motor Learning Using a simple sequential thumb-to-fingers opposition Sleep and Perceptual Learning task, Karni and coworkers investigated the time-dependent One of the most consistent findings in the literature is the evolution of motor learning.10 They showed that skilled prominent role of sleep in the development of visual dis- performance on this task is acquired across an initial, crimination abilities. Most studies have used the texture within-session, fast learning phase, followed by a slow discrimination task initially proposed by Karni and Sagi,133 phase of consolidation and optimization that can extend where learning is retinotopic (i.e., specific to the trained for several weeks of repeated practice. Using the same task visual quadrant).20,116,120-124 It was initially found that selec- or a keyboard-presses variant, others subsequently found tive REM sleep deprivation, but not SWS deprivation, that posttraining sleep significantly enhanced performance abolished overnight performance improvement during in the absence of further practice, as compared with the visual perceptual learning, whereas no or only feeble same amount of time elapsed awake.46,109,111,112 However, improvements occurred over episodes of wakefulness.133 contrary to the observations made using perceptual visual However, another study using the same task found that discrimination tasks described in the prior section, it improvement in visual discrimination skills was mostly dis- cannot be claimed here that posttraining time spent awake rupted by early sleep deprivation (i.e., rich in SWS), and prevents the formation of long-term motor memories, as even more so by total sleep deprivation.116 This apparent performance merely stabilizes at the level achieved at the contradiction was partially resolved with the finding that end of learning and does not deteriorate but rather mod- overnight improvement was a direct function of both the estly improves over repeated practice sessions. Still, a tran- amount of SWS in the first quarter of the night and the sitory boost in performance that is observed 5 to 30 minutes amount of REM sleep in the late quarter of the night,20 after the end of learning138 disappears if tested without an suggesting that SWS prompts memory formation, which intermediate sleep period more than 4 hours later.46,138 L is possibly, but not necessarily, consolidated during REM Interestingly, performance improvement over the 5- to

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30-minute boost predicts performance levels after a night perceptual–motor learning domain might be explained by of sleep.138 This precocious posttraining period appears differences in initial skill levels of participants. Indeed, an important for the initial stabilization of motor memories,21 was reported between performance improve- as learning an interfering sequence of movements during ment on the pursuit rotor task and stage 2 spindle activity 30 minutes to 2 hours after training disrupts delayed, in highly skilled subjects, whereas a similar relationship sleep-dependent consolidation of the original mate- was established with REM density in less skilled subjects,128 rial,109,114 unless a nap is allowed.114 This role of sleep for in line with the proposal that motor skills tasks involving motor memory consolidation extends beyond a genuine REM and stage 2 sleep might depend on two separate, but motor component, as training-related changes in sleep overlapping, neural systems.28 architecture are observed after practice of a sequence of This interpretation may be consistent with neuroimag- finger movements but not after random key-presses,110 as ing data that have established a relationship between post- well as after acquiring new and complex motor patterns training REM sleep activity and the consolidation of such as trampolining35,115 but not after the familiar and higher-order perceptual–motor cognitive skills. Indeed, well-learned motor activities of soccer or dancing.115 These subcortical and neocortical areas already activated during latter results are in line with the demonstration that sleep practice on a probabilistic sequence-learning task140 (i.e., a provides maximal benefit for motor-skill procedures that paradigm of implicit sequence learning) were reactivated proved to be most difficult during learning.113 Motor learn- during posttraining REM sleep in subjects previously ing–related changes in posttraining sleep parameters were trained to the task.56,57,61 It was further demonstrated that mostly observed during stage 2 sleep,46,110,111 although these reactivations were not merely activity dependent but others have reported links with REM sleep115,139 or sleep- occurred specifically because a rules-based sequence was cycle organization.35 Further studies are needed to delin- implicitly learned during prior practice,57 supporting the eate precisely the role and benefit of sleep on motor hypothesis that REM sleep is deeply involved in the repro- learning. cessing and optimization of the high-order information contained in the material to be learned, as opposed to its Sleep and Perceptual–Motor Learning motor component alone. Moreover, it was found in a The motor learning tasks just described have definite fea- 40-hour constant routine protocol in which subjects were tures. They are self-initiated, and acquisition is initially allowed 75 minutes of sleep every 150 minutes that carried out in an explicit, almost declarative manner, as sequence learning improved after naps, and most especially the motor sequence of movements to be generated is after naps that followed the circadian peak of REM sleep already known and can even be verbalized. In this respect, and in which REM sleep was present.141 motor procedural learning reflects the optimization of Nonetheless, further studies using sequence-learning predefined motor forms possibly created with the con­ tasks have raised several issues, and some of these remain tribution of episodic memory processes. In contrast, to be solved. It has been claimed that sleep is beneficial for perceptual–motor procedural learning entails a motor sequence learning only when acquisition of the sequential performance triggered by external stimulations, but the regularities practiced during the task was explicit, with organization of the material to be learned is not neces- time alone being sufficient for the consolidation of implic- sarily obvious to the subject, although it affects its per- itly acquired sequences.23,142 These results appear to formance. This type of task potentially allows us to contradict the findings of REM-sleep dependency for distinguish the role of sleep for consolidation of uncon- high-order probabilistic sequence learning, in which learn- sciously as opposed to consciously formed memories. We ing was undoubtedly implicit.57,140,141 However, one over- will cover this aspect after reviewing perceptual–motor looked difference between these studies and those claiming studies. a sleep dependency exclusively for explicit sequential mate- It was initially found that performance improvement on rial is that the latter have used deterministic, repeated the pursuit rotor task was blocked by total sleep depriva- sequences, whereas the probabilistic sequences used in the tion and by sleep deprivation of the second part of the former studies are much more ambiguous. It is therefore night, but not by selective REM sleep deprivation.27 Task possible that sleep (and especially REM sleep) mostly sup- improvement was also associated with increased sleep ports the consolidation of implicitly acquired complex spindle activity,45,51 suggesting that consolidation of motor relationships. This interpretation may be in line with the adaptive memories is mostly dependent on stage 2 sleep. proposal that different aspects of a procedural memory are Functional MRI additionally showed that posttraining processed separately during consolidation, such as the total sleep deprivation hampered both performance movement sequence in itself (e.g., a repeated, deterministic improvement and the reorganization of brain activity on a sequence) improves over daytime wakefulness periods visuomotor pursuit task with hidden regularities in the independently of sleep, whereas its goal (e.g., the complex, target’s trajectory.29 However, mirror-tracing skills were abstract rules for item succession in a probabilistic reported to improve more during the late part of the sequence) improves after a night of sleep.129 How and night,15 and to be associated with REM sleep increases in whether offline processes of memory consolidation do well-performing individuals,51 suggesting that this latter actually benefit from posttraining sleep may also be a func- task is rather REM sleep dependent. Still, performance tion of the circadian moment of the day when the material improvement on mirror tracing was also found to occur is acquired,127 as well as the nature of the complex interac- after naps dominated by stage 2 sleep125 and to correlate tions between declarative and procedural memory with stage 2 sleep spindle activity.43 This apparent discrep- systems.22 The complexity of these interactions is further ancy between sleep stages and task associations in the illustrated by the demonstration that learning-related L

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cerebral responses in cerebral structures linked to proce- REM sleep may represent one of the natural physiologic dural (i.e., striatum) and declarative (i.e., hippocampus) processes of memory, possibly through the synchroniza- memory systems are both linearly related to an overnight tion of fast oscillations that would convey experience- gain in performance in an implicit oculomotor sequence- dependent information in thalamocortical and intracortical learning task.143 circuits.153 Despite evidence from animal studies, a direct demon- Sleep and Priming stration of the association between PGO activity and Perceptual priming refers to the facilitation or bias in the memory consolidation during REM sleep in humans has processing of a stimulus as a function of a recent encounter yet to be done. Nonetheless, the hypothesis is supported with that stimulus.144 The few studies that have investi- by studies showing an increase in the density of rapid eye gated a role for sleep in consolidating the memory repre- movements during REM sleep after procedural learn- sentations subtending priming16,145,146 or priming-like147,148 ing40,154 and intensive learning periods,39 or a correlation effects have yielded discrepant results. Although studies between retention levels after learning Morse code and the have found that intervening deprivation of sleep, and espe- frequency of rapid eye movements during posttraining cially REM sleep, alters priming effects in word-stem REM sleep.37 Also, presenting sounds in the background completion16 as well as in face processing,145 and enhances while learning a complex logic task in the awake state reactivity for emotional pictures,147 another study (using enhanced next-morning performance when the same better controlled tachistoscopic identification of drawings) sounds were presented again during REM sleep. Most failed to disclose sleep-dependent effects.146 A variant of interestingly, however, enhancement was found only when priming is the “mere exposure effect,” obtained when inci- sounds were coincident with the bursts of posttraining dental exposure to initially novel stimuli (e.g., nonsense rapid eye movements that reflect PGO activity,74 further words, line drawings, ideograms, faces, novel three-dimen- suggesting the association of REM sleep with memory sional objects) increases the likelihood that they will be consolidation processes. Also, it has been proposed that favored over nonpresented items later on during a prefer- during human phasic REM sleep, propagation of PGO ence judgment.144 Using this task to investigate the effects activity in the parahippocampal or hippocampal area is of time, postexposure sleep, and cerebral lateralization, it linked with verbal learning performance and was found that although detrimental in both hemispheres, retention values.155 total sleep deprivation did not affect performances to the same extent, suggesting interhemispheric differences in Hippocampal Rhythms sleep-dependent processes of memory consolidation.148 The theta rhythm (i.e., regular sinusoidal oscillations in Indeed, sleep deprivation abolished all memory effects the frequency range of 4 to 7 Hz recorded in the hippo- only in the right hemisphere.148 Interhemispheric differ- campal EEG) is a prominent signature of REM sleep in ences in wake- and sleep-dependent memory consolidation mammals, including humans.156 Theta represents the processes should therefore be investigated in more detail online state of the hippocampus, believed to be critical for in the future. temporal coding or decoding of active neuronal ensembles and the modification of synaptic weights.156 Additionally, SLEEP-DEPENDENT MECHANISMS OF population synchrony of pyramidal cells is maximal during BRAIN PLASTICITY AND MEMORY quiet wakefulness and SWS associated with sharp waves (i.e., sharp waves of SWS are the consequence of synchro- CONSOLIDATION nous discharge of bursting CA3 pyramidal neurons) and In this section, we provide a rapid overview of specific fast ripples (140 to 200 Hz). Sharp waves and ripples mechanisms viewed as particularly important to support during SWS constitute good candidates to induce neuro- sleep-stage–related processes of brain plasticity and nal plasticity.157 Thus, the alternation between both REM memory consolidation: PGO waves, hippocampal rhythms, sleep/active-awake theta activity and SWS/quiet-wakeful- and sleep spindles. ness sharp waves and ripples could contribute to brain plasticity. According to the two-stage model of memory PGO Waves formation,157 neocortical information activates the ento- Ponto-geniculo-occipital waves are prominent phasic bio- rhinal input, which will cause synaptic changes to occur in electrical potentials, closely related to rapid eye move- the hippocampal CA3 system during learning associated ments, occurring in isolation or in bursts during the with active waking and REM sleep theta rhythmic activity transition from NREM to REM sleep or during REM in the hippocampus. In the subsequent nontheta state (i.e., sleep itself. PGO waves are a fundamental process of REM SWS, but possibly also quiet wakefulness), previously acti- sleep in animals, playing a significant role in central vated neurons are reactivated during sharp wave bursts, nervous system maturation.34 Intracerebral recordings in and the memory representation transiently stored in the epileptic patients,149 and noninvasive PET,150 fMRI,151 and CA3 region can be transferred to neocortical targets for magnetoencephalography152 scanning in healthy volun- the long term. teers, indicate that the rapid eye movements observed Accordingly, human brain imaging studies have dem- during REM sleep are generated by mechanisms similar or onstrated after spatial navigation in a virtual town the identical to PGO waves in animals. Most importantly, experience-dependent reactivation of hippocampal activity animal data have suggested that PGO activity during REM during SWS, but not during REM sleep.58 Similarly, an sleep is associated with learning and memory consolida- odor-cued activation in hippocampus-related memory L tion,34 suggesting that activation of this generator during areas was observed during SWS,77 eventually leading to

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overnight performance improvement. These studies also spindle activity (14 to 16 Hz) was correlated with perfor- found long-term transfer of hippocampal memories mance at central and parietal sites. Moreover, subjects who toward neocortical stores,31,83 an effect disturbed by sleep did not nap on a regular basis did not benefit from an deprivation on the posttraining night.31 In parallel, neu- experimental nap in the study design.162 In another study roimaging data have suggested the offline persistence of using a longer (60- to 90-minute) nap after motor perfor- memory-related cerebral activity during active wakefulness mance for the finger-tapping task, it was found that those and its dynamic evolution in the hippocampus.21 Although subjects with the most significant increases in motor per- this model is well supported by the these data and may formance also had the largest increases in stage 2 sleep, account for the offline processing of declarative material, with a significant correlation between spindle density and the fact that reactivations have been observed during both postnap performance that was confined to the learning posttraining REM sleep56,57 and wakefulness21 after pro- hemisphere.46 Finally, a marked increase in stage 2 spindle cedural, nonhippocampal learning suggests that other densities was observed after acquisition of the finger-tap- routes for consolidation exist, which should likewise be ping task, but not after a control motor task, indicating investigated. that the changes were not the result of general motor activ- ity.110 That spindles have been related to consolidation for Sleep Spindles and Slow Waves both declarative and nondeclarative memories indicates Traditionally, the sleep spindle has been defined as the their prominent role in sleep-dependent memory presence of rhythmic 12- to 14-Hz activity lasting a processes. minimum of 0.5 seconds and displaying an increasing, then Still, it should be noticed that although stage 2 has been decreasing, amplitude envelope. This definition has the predominant stage of sleep involved, closer examina- expanded to 12 to 16 Hz and includes both slow (11.5- to tion showed that REM sleep appeared to be more impor- 14-Hz) and fast (14- to 16-Hz) spindles, which may reflect tant for some participants after perceptual–motor two separate spindle generators with different brain topog- learning.128 To explain this, it has been proposed that there raphies.158,159 Although spindles occur most frequently in are two independent neural systems for sleep-dependent stage 2, they also appear to a lesser extent in delta sleep memory consolidation, one involved with stage 2 sleep, the (stages 3 and 4). A negative reciprocal relationship between other with REM sleep. In this respect, subjects who report SWA and spindle occurrence seems to exist in NREM the perceptual–motor task as being a novel experience sleep.158 Spindle mechanisms have been studied in the show an increase in density of rapid eye movements during cat.160,161 They are considered to result from intrinsic prop- postacquisition REM sleep, but no changes in stage 2 sleep erties and from the connectivity patterns of the thalamic parameters. On the other hand, those individuals who find neurons. Spindle generation seems an ideal mechanism the task to be similar to others they have already experi- for neural plasticity.96 Therefore, spindles may play an enced in their lives (as shown by reasonably good perfor- important role in the processes of memory consolidation mance on the first few trials of the task) will show an during sleep. increase in spindle density during stage 2 sleep but no Accordingly, several studies have reported links between changes in REM sleep. These latter subjects are consid- the consolidation of verbal declarative memory and ered to be refining an existing motor program rather than increases in spindle density during the nocturnal and learning a new one.28 diurnal sleep that follows learning.41,42,44,49 Verbal memory In addition, spindle oscillations are grouped and regu- association with spindle density increased in the left fron- lated by slow waves163 that are thought to be important for tocentral scalp location at night, whereas memory for faces memory consolidation, as discussed earlier. Indeed, expe- did not elicit this effect.49 Similarly, postlearning increases rience-dependent regional increases in delta activity are observed during daytime napping in low-frequency have been shown during NREM sleep,63 suggesting local spectral power (11.25 to 13.75 Hz), particularly in the left homeostatic mechanisms for memory consolidation.62 Fur- frontal scalp region. Additionally, these increases are posi- thermore, coherence was found to increase after learning tively correlated with learning performance in the difficult in the depolarizing phase of the slow oscillations below the word-association task, but not in the easy word-association 1-Hz frequency.163 On the other hand, transcranial direct task or control condition.42 Similarly for procedural current stimulation that may contribute to modulation of memory, posttraining stage 2 sleep deprivation impaired cortical excitability was found to improve the overnight memory for a perceptual–motor task,27 and the amount of retention of declarative memories when applied during stage 2 correlated with learning progress on the finger- NREM sleep at a slow rhythm whose frequency (less than tapping task.109,111 Also, intensive training on perceptual– 1 Hz) approximates these slow oscillations,75 further sug- motor learning tasks results in marked increases in number gesting a facilitatory role of slow oscillatory EEG activity and density of spindles during subsequent stage 2 sleep47 in neuronal plasticity and the ongoing transformations and as well as an increase in average spindle duration.51 Post- consolidation of memory traces. training increases in slow sigma power (12 to 14 Hz) have been observed in frontal and occipital regions with no changes in high-frequency sigma.51 Napping studies using Conclusions the same task provided similar results: subjects who regu- Although their results are at times elusive, studies sup- larly napped showed positive correlations between postnap porting the proposal that sleep is an integral component performance and stage 2 spindle density.162 In this case, in the offline processes that subtend memory consolida- low-frequency spindles (12 to 14 Hz) were correlated with tion have now substantially flourished. Still, when com- performance at frontal sites, whereas high-frequency pared with other domains of cognition, the field remains L

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