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Home , Encoding (memory), Jessica Payne, Learning, Memory, Motor learning, Procedural memory

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Jessica D. Payne, PhD

KEYWORDS Slow wave sleep Memory    

About one-third of a person’s life is spent sleeping, functional consequences but also makes it difficult yet in spite of the advances in the to know which distinction is critical for memory processes that generate and maintain sleep, the processing: NREM versus REM sleep or early functional significance of sleep remains a mystery. versus late sleep. Numerous theories regarding the role of sleep , particularly the monoamines have been proposed, including homeostatic resto- (5-HT) and norepinephrine (NE), and ration, thermoregulation, tissue repair, and immune (ACh), a critical role in switching control. A theory that has received enormous the from one sleep stage to another. REM support in the last decade concerns sleep’s role in sleep occurs when activity in the aminergic system processing and storing . This article has decreased enough to allow the reticular reviews some of the evidence suggesting that sleep system to escape its inhibitory influence.1 The is critical for long-lasting memories. This body of release from aminergic inhibition stimulates evidence has grown impressively large and covers reticular in the and a range of studies at the molecular, cellular, physio- switches the sleeping brain into the highly active logic, and behavioral levels of analysis. REM state, in which ACh levels are as high as in the waking state. Overall, REM sleep is also associated with higher levels of than DEFINING NREM sleep. 5-HT and NE, on the other hand, Stages of Sleep are virtually absent during REM sleep. SWS, conversely, is associated with an absence of There are 2 main types of sleep. The first, rapid eye ACh and low levels of cortisol but detectable levels movement (REM) sleep, occurs in roughly 90- of 5-HT and NE.2,3 minute cycles throughout the night and alternates with 4 additional stages (stages 1–4) known collec- tively as non-REM (NREM) sleep, which comprises Stages of Memory Formation, and the second type of sleep.1 Slow wave sleep (SWS) Different Memory Types is the deepest of the NREM sleep phases and is characterized by high-amplitude, low-frequency is the process by which oscillations seen in the electroencephalogram newly acquired , initially fragile, is inte- (EEG). REM sleep, on the other hand, is a lighter grated and stabilized into long-term memory.4 stage of sleep characterized by rapid eye move- Evidence overwhelmingly suggests that sleep ments (REMs), decreased muscle tone, and low- plays a role in the consolidation of a range of amplitude fast EEG oscillations. More than 80% memory tasks, with the different stages of sleep of SWS is concentrated in the first half of the typical selectively benefiting the consolidation of different 8-hour night, whereas the second half of the night types of memory.2,5–10 contains roughly twice as much REM sleep than Like sleep, memory is also divided into several the first half (Fig. 1). key stages and types.11 First, there are various This domination of early sleep by SWS and of types of memories that can be recalled explicitly, late sleep by REM sleep not only has important including episodic memories, or memories of the

Department of , University of Notre Dame, Haggar Hall, Room 122-B, Notre Dame, Indiana 46556, USA E-mail address: [email protected]

Sleep Med Clin 6 (2011) 15–30 doi:10.1016/j.jsmc.2010.12.005

1556-407X/11/$ – see front matter Ó 2011 Elsevier Inc. All rights reserved. sleep.theclinics.com Author's personal copy 16 Payne

Fig. 1. A sleep histogram showing the typical distribution of SWS and REM sleep.

events in our lives. Retrieving an differently during sleep. Although somewhat from one’s past requires access to defining oversimplified,15 there is a general consensus contextual features of the event, such as specific that NREM sleep, especially SWS, is important details about the place and of its occurrence. for the consolidation of explicit episodic and Because of this emphasis on spatial context, spatial memories, both of which rely on the hippo- episodic memories and spatial memories are campus for their consolidation,16 whereas REM closely connected. Second, there are semantic sleep selectively benefits procedural and memories, which are concerned with the knowl- emotional memories.17,18 edge one acquires during events but is itself sepa- In addition to these distinct types, memory rated from the specific event in question. Thus, our consolidation also consists of different stages. about the meaning of words and facts Although our of memory occurs at about the world, even though acquired in the the moment of retrieval when information about context of some specific experience, appears to the initial experience returns to conscious aware- be stored in a context-independent format (eg, ness, successful retrieval is contingent on the not bound to the originating context). Third, there successful completion of at least 2 earlier stages are “how to” memories for the various skills, of memory formation. First, the experience or procedures, and habits that we acquire through information must be properly encoded. experience. Because these memories are not so involves transforming new information into a repre- easily made explicit and are usually only evident sentation capable of being stored in memory, just in , they are referred to as procedural or as the key presses that are made on a keyboard implicit memories. Finally, there are emotional must be converted to a format that can be stored memories for the positive and negative experi- in a computer. Second, the information must be ences in our lives. This class of memories is espe- consolidated or durably stored in a manner that cially concerned with learning about fearful and can withstand the passage of time. Only if these negative stimuli, although evidence suggests it processes occur successfully will it be possible plays a role in learning about pleasant information for information from the initial event to be retrieved as well.12 later in time. Although this article mostly focuses Evidence suggests that each of these memory on memory consolidation, it also briefly reviews types is subserved by distinct neural systems.11–13 new evidence that sleep is essential for effective Whereas episodic and spatial memories are gov- memory encoding. erned by the hippocampus and surrounding medial temporal areas, procedural or implicit SLEEP BENEFITS IMPLICIT AND PROCEDURAL memories are to be independent of the MEMORIES hippocampus and anatomically related regions, relying instead on various neocortical and subcor- Sleep seems to benefit the consolidation of both tical structures. The emotional memory system is implicit and explicit forms of memory. Converging centered in the , a limbic structure that data suggest that most procedural skills and abil- is richly connected to the hippocampus.14 Impor- ities (eg, performing a surgery, riding a bike) are tantly, evidence suggests that information depen- acquired slowly and are not attained solely during dent on each of these systems is processed the learning episode. While some learning certainly Author's personal copy Sleep and Memory 17 develops quickly, performance on various proce- a 50% greater improvement was observed (see dural tasks improves further and without additional Fig. 3B). Critically, another group of subjects was practice simply through the passage of time, sleep deprived on the first night after . particularly if these periods contain sleep. These These subjects were allowed 2 full nights of slow off-line improvements occur as newly recovery sleep before being retested 3 days later. acquired information, initially fragile, is integrated The subjects failed to show any residual learning, and stabilized into long-term memory. suggesting that performance enhancements Early investigating the effect of sleep on depend on a normal first night of sleep (see used a visual texture discrimination Fig. 3B). Time alone is clearly not enough to task (VDT) originally developed by Karni and Sagi.19 produce long-term benefits from VDT training. It The task requires participants to determine the seems that sleep is also required.22 orientation (vertical or horizontal) of an array of diag- Initially, improvement on this task seemed to onal bars that is embedded in one visual quadrant depend solely on REM sleep, because subjects against a background of exclusively horizontal who underwent selective deprivation of REM sleep bars (Fig. 2). At the center of the screen is the fixa- showed no improvement on the task.20 Later tion target, which is either the letter T or the letter studies, however, showed that optimal perfor- L. This target screen is succeeded first by a blank mance on this task requires both SWS and REM screen for a variable interstimulus interval (ISI) and sleep.23 then by a mask (a screen covered with randomly When subjects were trained and their subse- oriented V’s with a superimposed T and L in the quent sleep monitored in the sleep laboratory, center). Subjects must determine the orientation of the amount of improvement was proportional to the array, and the performance is estimated by the the amount of SWS during the first quarter of the ISI corresponding to 80% correct responses.19,20 night (Fig. 4A), as well as to the amount of REM Amnesic patients with damage to the hippo- sleep in the last quarter (see Fig. 4B). Indeed, the campal complex, who cannot acquire knowledge product of these 2 sleep parameters explained explicitly, show normal performance improve- more than 80% of the intersubject variance (see ments on the VDT.21 In neurologically normal Fig. 4D). No significant correlations were found subjects, improvement on the VDT develops for sleep stage during other parts of the night slowly after training,19,22 with no improvement (see Fig. 4C) or for the amount of stage 2 sleep when retesting occurs on the same day as training at any time during the night. (Fig. 3A). Instead, improvement is only observed Gais and colleagues24 came to a similar conclu- after a night of sleep (see Fig. 3A). This observa- sion by examining improvement after 3 hours of tion was true even for a group of subjects who sleep either early or late in the night. They found were retested only 9 hours after training. Impor- that 3 hours of early night sleep, which was rich tantly, there was not even a trend to greater in SWS, produced an 8-millisecond improvement, improvement when the training-retest interval but after a full night of sleep, which added REM- was increased from 9.0 to 22.5 hours, suggesting rich sleep late in the night, a 26-millisecond that additional wake time after the night of sleep improvement was observed, 3 that seen provided no additional benefit. Whereas further with early sleep alone. However, 3 hours of REM- wake time provided no benefit, additional nights rich, late night sleep actually produced deteriora- of sleep did produce incremental improvement. tion in performance.24 These results are further When subjects were retested 2 to 7 days after corroborated by daytime studies. Afternoon training rather than after a single night of sleep as short as 60 to 90 minutes also lead to

Fig. 2. (A–C) Sample screens from the VDT. Author's personal copy 18 Payne

A B 30 Daytime 20 Overnight 25 * 20 * * 10 15

10 Improvement (ms) Improvement (ms) Improvement 5 0 6 12 18 24 0 012347 Test interval (h) Days Fig. 3. Sleep-dependent improvement on the VDT. All subjects were trained and then retested only once. Each point in (A) and each green bar in (B) represents a separate group of subjects. Error bars in (A) and (B) are SEM. (A) There was no improvement when retesting occurred on the same day as training (open circles), but there was improvement after a night of sleep (closed circles). Asterisks indicate significant effects. (B)(Green bars) Improvement in performance of subjects when retested 2 to 7 days of training. (Red bar) No improvement in performance of subjects who were sleep deprived on the first night of training. ms, milliseconds. (From Stickgold R, James L, Hobson JA. Visual requires post-training sleep. Nat Neurosci 2000;2 (12):1237–8; with permission; and Stickgold R, Whidbee D, Schirmer B, et al. Visual discrimination task improve- ment: a multi-step process occurring during sleep. J Cognit Neurosci 2000;12:246–54; with permission.)

performance benefits on the VDT, especially when type of that may or may not share they contain REM and NREM sleep.25,26 its sleep dependency with other procedural tasks. At this point, sleep’s role in visual discrimination This specificity raises the question of whether the learning (as measured by VDT performance) is sleep effects observed with the VDT generalize clear. But the VDT represents a very specific to other forms of . Studies of

A B 40 r = 0.76 r = 0.70 40 P = .012 P = .004 30 30

20 20

10 10 Improvement (ms)

0 Improvement (ms) 0 15 20 5 5 10 15 20 1st quartile SWS (% of night) 4th quartile REM (% of night) C 0.8 D P = .01 40 r = 0.89 P < .0001 0.6 P = .05 30 0.4

0.2 20 Pearson r 0.0 10 Improvement (ms) 1234 0 Quartile 50 100 150 200

SWS REM SWS1 x REM4 (% x %)

Fig. 4. (A–D) REM sleep and SWS dependence of VDT learning. ms, milliseconds; REM4, 4th quartile of REM sleep; SWS1, 1st quartile of SWS. (From Stickgold R, Whidbee D, Schirmer B, et al. Visual discrimination task improve- ment: a multi-step process occurring during sleep. J Cognit Neurosci 2000;12:246–54; with permission.) Author's personal copy Sleep and Memory 19 sleep-dependent learning strongly improvement on this task correlated with the suggest that they do. amount of stage 2 NREM sleep during the night, As an example, Walker and colleagues27 have especially during the last quarter of the night. demonstrated sleep-dependent improvements on These findings are in agreement with those of a finger tapping task. The task requires subjects Fogel and colleagues,28 Smith and MacNeill,29 to repeatedly type the numeric sequence 4-1-3- and Tweed and colleagues,30 who have also 2-4 as quickly and accurately as possible with the shown that stage 2 sleep and possibly the sleep non-dominant hand. Training consisted of twelve spindles that reach peak density during late night 30-second trials separated by 30-second rest stage 2 sleep are critical for simple motor memory periods. All subjects show considerable improve- consolidation. This role of sleep spindles seems ment during the 12 trials of the training session (a plausible because they have been proposed to fast learning component), but 12 hours later, the trigger intracellular mechanisms that are required subjects performed differently depending on for .31 whether the 12-hour interval was spent sleeping This motor sequence task has been examined to or awake. When trained in the morning and determine where precisely in the retested 12 hours later, only an additional nonsig- this sleep-dependent improvement occurs.32 In nificant 4% improvement was seen in perfor- the sequence mentioned earlier (4-1-3-2-4), there mance, but when tested again the next morning, are 4 unique key-press transitions: 4 to 1, 1 to 3, a large and robust (14%) improvement was seen 3 to 2, and 2 to 4. When the speed between tran- (Fig. 5A). The failure to improve during the daytime sitions was analyzed for individual subjects before could not be caused by interference from related sleep, “sticking points” emerged. Whereas some motor activity because subjects who were required transitions were easy (ie, fast), others were prob- to wear mittens and refrain from fine motor activi- lematic (ie, slow), as if the sequence was being ties during this time showed a similar pattern of parsed or chunked into smaller bits during wake/sleep improvement (see Fig. 5B). presleep learning.21 After a night of sleep, these In contrast, when subjects were trained in the problematic points were preferentially improved, evening, improvement was observed the following whereas transitions that had already been morning (after sleep) but not across an additional mastered before sleep did not change. Subjects 12 hours of wake (see Fig. 5C). Thus, improved who were trained and retested after a daytime performance resulted specifically from a night of wake interval showed no such improvements. sleep as opposed to the simple passage of time. These findings suggest that the sleep- Curiously, unlike the findings for the VDT, overnight dependent consolidation process involves the

Fig. 5. (A–C) Sleep-dependent . Improvement in speed was seen in all 3 groups over a night of sleep but not over 12 hours of daytime wake. (From Walker M, Brakefield T, Morgan A, et al. Practice with sleep makes perfect: sleep dependent motor skill learning. 2002;35:205–11; with permission.) Author's personal copy 20 Payne

unification of smaller motor memory units into improvement on the task (compared with a single motor memory representation, thereby randomly generated sequences) reflects implicitly improving problem points in the sequence. Impor- acquired knowledge of this grammar.37 tantly, this finding suggests that the role of sleep is Neuroimaging was performed on 3 groups of subtle and complex and that sleep does more subjects. One group was scanned while they than simply strengthen memories; sleep may were awake, both at rest and during performance encourage the restructuring and reorganization of of the task, providing information about which memories, an important and often-overlooked brain regions are typically activated by the task. aspect of memory consolidation. The author re- A second group of subjects was trained on the turns to this later in the article. task during the afternoon and then scanned the Moving to another type of motor memory, motor night after training, both while awake and during , Maquet and colleagues33 showed that various sleep stages. Thus, group 2 was included sleep benefits performance on a motor pursuit to determine if similar brain regions were reacti- task. Participants were trained to use a joystick vated during sleep. A postsleep session was also to keep the cursor on a target when the target conducted to verify that learning had indeed trajectory was predictable only on the horizontal occurred. Finally, a third group, never trained on axis, which meant that optimal performance could the task, was scanned while sleeping to ensure only be achieved by developing an implicit model that the pattern of activation present in natural of the motion characteristics of the learned trajec- sleep was different from the pattern of activation tory. Half of the subjects were sleep deprived on present after training. the first posttraining night, whereas the other half Results showed that during REM sleep, as were allowed to sleep normally. Three days later, compared with resting , several brain after 2 full nights of recovery sleep, performance areas used during task performance were more was superior in the sleep group compared with active in trained than in nontrained subjects. These the sleep-deprived group, and functional magnetic areas included occipital, parietal, anterior cingu- resonance imaging (fMRI) revealed that that the late, motor, and premotor cortices and the cere- (STS) was differentially bellum, all activations that are consistent with the more active for the learned trajectory in subjects component processes involved in the visual and who slept than in the sleep-deprived subjects. motor functioning involved in this task. Behavioral Moreover, increased functional connectivity was data confirmed that trained subjects improved observed between the STS and the significantly more across the night. and between the supplementary and frontal eye Peigneux and colleagues,38 using the same task, fields, suggestive of sleep-related plastic changes showed that the level of acquisition of probabilistic during motor skill consolidation in areas involved in rules attained before sleep was correlated with the smooth pursuit and eye movements. increase in activation of task-related cortical areas Admittedly, visual discrimination, finger tapping, during posttraining REM sleep. This observation and motor adaptation are all relatively basic low- suggests that cerebral reactivation is modulated level procedural tasks that may become auto- by the strength of the memory traces developed mated fairly quickly. What about the more during the learning episode, and as such, these complex implicit and procedural tasks? Work on data provide the first experimental evidence linking clearly demonstrates that complex tasks behavioral performance to reactivation during (eg, instrumental conditioning, avoidance, or REM sleep.38 Together with studies,39,40 maze learning) benefit from sleep, with rats these findings suggest that it is not simply experi- showing increases in REM sleep that continue until encing the task, but the process of memory the tasks are mastered.34–36 consolidation associated with successful learning REM sleep has been implicated in complex of the task that modifies sleep physiology. procedural learning in humans as well. In a positron These results support the idea that implicit/ emission tomographic study of visuomotor skill procedural memory traces in humans can be reac- memory using the serial reaction time task,37 6 tivated during REM sleep, and that this reactiva- spatially permanent position markers were shown tion is linked to improved consolidation. Indeed, on a computer screen and subjects watched for looking a bit more closely at the literature, stimuli to appear below these markers. When REM sleep has also been linked to memory for a appeared in a particular position, complex logic games, to foreign language acquisi- subjects reacted as quickly as possible by tion, and to intensive studying.41 It is interesting pressing a corresponding key on the keyboard. that these more-complex conceptual-procedural Because the stimuli were generated in an order tasks often show REM sleep relationships, defined by a probabilistic finite-state grammar, whereas more basic procedural tasks benefit Author's personal copy Sleep and Memory 21 mainly from NREM sleep. The above-mentioned There is a general consensus that NREM sleep, findings provide encouraging evidence that especially SWS, is important for the consolidation sleep-based processes can aid in procedural of hippocampus-dependent episodic and consolidation, not only for basic forms memories.16 In a landmark study, Plihal and of sensory and motor memory in humans but Born50 assessed the of word pairs (an also for complex procedural and conceptual episodic memory task) and improvement in mirror knowledge. Moreover, these findings indicate tracing (a procedural memory task) after retention that the consolidation of familiar skills, or those intervals of early sleep (the first 3–4 hours of the that are similar to other well-learned skills, may ), which, as noted in the previous be reliant on NREM sleep stages (particularly sections, is dominated by SWS, and late sleep stage 2 NREM sleep), whereas REM sleep may (the last 3–4 hours of the sleep cycle), which is be required for the integration of new dominated by REM sleep. Recall of word pairs or skills with preexisting information stored in improved more significantly after a 3-hour sleep memory.42 This is an important that period rich in SWS than after a 3-hour sleep period warrants future investigation. rich in REM sleep or a 3-hour period of wakeful- Clearly, sleep is crucial to the consolidation of ness. Mirror tracing, on the other hand, improved procedural memory. Although both the stabilization significantly more after a 3-hour sleep period rich of explicitly learned motor skills and off-line in REM sleep than after 3 hours spent either in improvements in pure implicit tasks may evolve SWS or awake. over time spent awake,43,44 the posttraining Similarly, using a nap , Tucker and enhancement of motor skills seems to be exclu- colleagues51 found that naps containing only sively dependent on sleep.27 Participants with NREM sleep enhanced memory for word pairs show impaired sleep-related procedural but did not benefit mirror tracing. After an after- memory consolidation compared with participants noon training session, performance on these tasks with undisturbed sleep,45 and , which was assessed after a 6-hour delay, either with or is associated with changes in sleep, particularly in without an intervening nap. The subjects who stage 2 NREM sleep spindles,46,47 is also associ- were allowed a nap not only recalled more word ated with procedural memory deficits.48 More pairs than the subjects who remained awake recently, Dresler and colleagues49 demonstrated (Fig. 6) but also showed a weak correlation that off-line procedural memory consolidation is between improved recall and the amount of SWS also disturbed in depression, another condition in the nap. associated with changes in sleep architecture. These results are consistent with neurophysio- logical evidence derived from electrophysiological SLEEP BENEFITS EXPLICIT MEMORIES studies in , which demonstrate that patterns of hippocampal activity first This section describes the relationship between seen during waking exploration are later reex- sleep and the consolidation of explicit memories. pressed during postlearning SWS.52–54 Similarly,

Fig. 6. (A, B) A brief daytime nap benefits episodic memory. Note that the nap (which did not contain REM sleep) benefited episodic, but not procedural memory. Asterisks indicate significant differences between groups. (From Tucker MA, Hirota Y, Wamsley EJ, et al. A daytime nap containing solely non-REM sleep enhances declarative but not procedural memory. Neurobiol Learn Mem 2006;86(2):241–7; with permission.) Author's personal copy 22 Payne

several neuroimaging studies in humans have sug- during NREM SWS, a process that in turn gested an important role for SWS in hippocampus- enhances behavioral performance. dependent memory consolidation. The first of these studies investigated performance on a hippo- 55 campally-dependent virtual maze task. Daytime SLEEP BENEFITS EMOTIONAL MEMORY learning of the task was associated with hippo- CONSOLIDATION campal activity. During posttraining sleep, there was a reemergence of hippocampal activation, Sleep also contributes to the consolidation of and this activation occurred specifically during emotional episodic memories. As noted in the SWS. The most compelling finding, however, is previous section, sleep clearly benefits memory that the increase in hippocampal activation seen for neutral episodic memory materials across during posttraining SWS was proportional to the both verbal and spatial modalities.5,16 However, amount of improvement seen the next day. This when emotional (especially emotionally negative) finding suggests that the reexpression of hippo- episodic items are intermixed with neutral items campal activation during SWS reflects the off-line in a study, sleep disproportionately benefits the reprocessing of spatial episodic memory traces, consolidation of emotional memories relative to which in turn leads to the plastic changes under- neutral memories. For example, Hu and lying the improvement in memory performance colleagues58 examined the effect of a full night’s seen the next day. Similarly, Rasch and sleep on both axes of emotional , valence colleagues56 exposed human subjects to an odor (positive/negative) and (high/low), across while they were learning object-location pairings both “remember” and “know” judgments of in a task similar to the memory game “concentra- memory for pictures. Results showed that a night tion;” subjects who were reexposed to the odor of sleep improved memory accuracy for emotion- during SWS (but not REM sleep) showed enhanced ally arousing pictures relative to an equivalent hippocampal activity and enhanced memory for period of daytime wakefulness, but only for know the memory pairings. judgments. No differences were observed for Another study57 investigated the time course of remember judgments. Moreover, memory bias episodic memory consolidation across 90 days. changed across a night of sleep relative to wake, Subjects studied 360 photographs of landscapes such that subjects became more conservative and were then tested on subsets of the photo- when making remember judgments, especially graphs either after a nap the same day or after 2, for emotionally arousing pictures. No bias differ- 30, or 90 days. Before each test, subjects studied ences were observed for know judgments 80 new pictures and then were tested on 80 of the between sleep and wake. original pictures and the 80 new ones as well as REM sleep may be particularly important for 80 pictures that they had never seen before. All the consolidation of emotional memories, which memory retrieval sessions occurred during fMRI rely critically on the amygdala for their scanning. After the initial 90-minute nap, stage 2 consolidation.7,59 Wagner and colleagues59 found sleep was positively correlated with successful that 3 hours of late night REM-rich sleep (but not 3 recall of both remote and recent items, indicating hours of early night slow wave–rich sleep or 3 a nonspecific benefit of stage 2 NREM sleep on hours of wakefulness) facilitated memory for nega- episodic memory. This is an intriguing finding, given tive arousing , an effect that could still be that stage 2 is when sleep spindles are most prom- observed years later when the subjects were re- inent (see section on neurophysiological and contacted for a follow-up memory test.60 Consis- neurochemical evidence for sleep’s role in memory tent with these findings, the amygdala and consolidation later). SWS, on the other hand, was hippocampus are among the most active brain correlated only with memory for remote (but not regions during REM sleep, with some evidence recent) items. Because performance on remote suggesting that they are more active during REM items increased with longer SWS duration, but sleep than during wakefulness.61 This observation performance for recent items did not, the effect suggests that emotional memory processing may on memory performance for remote items cannot be a primary goal of REM sleep. Moreover, several be explained by a general effect of SWS on memory studies have correlated features of REM sleep, retrieval processes. These findings strongly including oscillatory activity in the theta frequency suggest that episodic memories can undergo initial band range,17 with enhanced emotional memory consolidation within a rather short time frame and consolidation.10,62 These findings strongly that this consolidation is promoted by SWS. suggest a role for sleep, especially REM sleep, in These observations suggest that learning trig- the processing of memory for emotional gers the reactivation of episodic memory traces . Author's personal copy Sleep and Memory 23

SLEEP TRANSFORMS MEMORIES IN negative arousing memories change across USEFUL WAYS periods of sleep versus wakefulness. Emotional scenes could be stored as intact units, suffering The findings reviewed in the previous sections some over time but retaining the same provide compelling evidence that sleep plays an relative vividness for all components. Alternatively, important role in solidifying experience into long- the components of an experience could undergo term memory in a veridical manner, more or less 63 differential memory processing, perhaps with true to its form at initial encoding. However, it a selective emphasis on what is most salient and has long been known that memories change with 64 worthy of remembering. the passage of time, suggesting that the process Participants viewed scenes depicting negative of consolidation does not always yield exact repre- or neutral objects embedded on neutral back- sentations of past experiences. On the face of it, grounds at 9 AM or 9 PM. Twelve hours later, after this process may seem strikingly maladaptive, a day spent awake or a night including at least yet such flexibility in memory representation 6 hours of sleep, they were tested on their memory allows the emergence of key cognitive abilities, for objects and backgrounds separately to such as generalization and inference,65 future 66 examine how these individual components of thought, and selective preservation of useful emotional memories change across periods of information extracted from a barrage of incoming 67,68 sleep and wake (see Fig. 7 for example stimuli). stimulations and experiences. Consistent Daytime wakefulness led to forgetting of nega- with these , growing evidence suggests that tive arousing scenes in their entirety, with both sleep does more than simply consolidating objects and backgrounds being forgotten at memories in a veridical form; it also transforms similar rates. Sleep, however, led to a selective them in ways rendering the memories less accu- preservation of negative objects but not their rate in some respects but more useful and adap- accompanying backgrounds, suggesting that the tive in the long run. Sleep leads to flexible 2 components undergo differential processing restructuring of memory traces so that insights during sleep. This finding suggests that rather can be made,69 inferences can be drawn,64 and 68 than preserving intact representations of scenes both integration and can occur. In the sleeping brain effectively unbinds scenes to each of these cases, sleep confers a flexibility to consolidate only their most emotionally salient, memory that may at times be more advantageous and perhaps adaptive, elements (see68,69 for addi- than a literal representation of experience. tional examples of potential unbinding during As a specific example of such qualitative sleep). changes in memory representation, recent studies Paralleling these behavioral findings, a recent demonstrate that sleep transforms the emotional 7,67 fMRI study provided evidence that a single night memory trace. Payne and colleagues exam- of sleep is sufficient to provoke changes in the ined how the different components of complex emotional memory circuitry, leading to increased

Fig. 7. Example stimuli for emotional trade-off task, where a neutral (intact car, A) or negative (crashed car, B) object is embedded on a neutral background scene (street). (From Payne JD, Kensinger EA. Sleep’s role in the consolidation of emotional episodic memories. Curr Dir Psychol Sci 2010;19(5):290–5; with permission.) Author's personal copy 24 Payne

activity within the amygdala and the ventromedial sleep stages but are not perfectly correlated with and strengthened connectivity them. For example, SWS is associated with between the amygdala and both the hippocampus cortical slow oscillations (slow, <1 Hz oscillatory and ventromedial prefrontal cortex during activity during SWS), sleep spindles (faster, retrieval.70 These findings are consistent with 11–16 Hz, bursts of coherent brain activity), and a study by Sterpenich and colleagues71 and hippocampal sharp wave-ripple complexes suggest that sleep strengthens the modulatory (approximately 200 Hz), all of which have been effect of the amygdala on other regions of the associated with episodic memory consolidation. emotional memory network as memories undergo Indeed, the co-occurrence of these electrophysio- consolidation.14 Whether these selective effects of logical events may underlie the coordinated infor- sleep on emotional memory consolidation depend mation flow back and forth between the on REM sleep is an interesting question for future hippocampus and as memories are research. integrated within neocortical long-term sites.13 BEYOND SLEEP STAGES For example, slow oscillations are intensified when SWS is preceded by a learning The above-mentioned results should not be taken experience73–75 and hippocampus-dependent to mean that SWS strictly mediates the consolida- memories are specifically enhanced when slow tion of episodic memories, whereas REM sleep oscillations are induced during SWS by transcrani- only mediates the consolidation of procedural al electrical at 0.75 Hz (but not 5 Hz).76 and emotional memories. Matters are clearly not Several human studies have shown a correlation so simple. As mentioned in the previous sections, between hippocampus-dependent episodic learn- improvement on a visual discrimination task ing and cortical sleep spindles. In one such study,77 depends on SWS as well as REM,24 and improve- subjects studied a long list of unrelated word pairs 1 ment on a motor task correlates with stage 2 hour before sleep, on 2 separate occasions at least NREM sleep.29 Moreover, emotionally charged a week apart. In one case, they were instructed to episodic memories may rely on both REM sleep imagine a relationship between the 2 nominally and SWS for their consolidation.7,72 unrelated words, whereas in the other they were There are 2 possible interpretations of these simply asked to count the number of letters contain- apparent contradictions. First, the sleep stage ing curved lines in each word pair. Such instructions dependency of these various memory tasks may lead to deep hippocampally mediated encoding depend on aspects of the task other than simply and shallow cortically mediated encoding, respec- whether they are episodic or procedural, perhaps tively. During the subsequent nights of sleep, depending more on the intensity of training, the subjects showed significantly higher spindle densi- emotional of the task, or even the manner ties on the nights after deep encoding, averaging in which information is encoded (eg, deep vs 34% more spindles in the first 90 minutes of sleep. shallow encoding or implicit vs explicit). The Moreover, density was positively second possibility involves an inherent oversimpli- correlated both with immediate recall tested in the fication in correlating performance improvements final stage of training and with recall the next with sleep stages as they are classically defined. morning, after sleep. Thus, those who learned better Indeed, mounting evidence points to several elec- had more spindles the following night and those trophysiological, , and neuroen- with more spindles showed a greater performance docrine mechanisms that may underlie these gain the next morning.78–80 effects and that do not necessarily correlate with Hippocampal network oscillations such as any single sleep stage, and sleep staging, as it sharp wave-ripple complexes may also help has been defined for 40 years, may not capture promote the synaptic plasticity necessary for all the key elements that lead to memory consoli- memory consolidation. Such events can accom- dation enhanced by sleep. pany the reactivation of hippocampal neuron ensembles that were activated during prior waking NEUROPHYSIOLOGICAL AND training. Moreover, inducing long-term potentia- NEUROCHEMICAL EVIDENCE FOR SLEEP’S tion, a neurophysiological mechanism of learning ROLE IN MEMORY CONSOLIDATION and memory, can trigger the generation of sharp wave-ripple complexes in the rat hippocampus,81 Each of the above-mentioned sleep stages is char- suggesting that strengthened synaptic coupling acterized by a unique collection of electrophysio- can lead to neurons firing synchronously during logical, neurotransmitter, and neuroendocrine formation of sharp wave-ripples complexes. Con- properties that tend to overlap with the different necting these events to behavior, Eschenko and Author's personal copy Sleep and Memory 25 colleagues82 demonstrated that rats learning is at its nadir during early-night slow wave–rich odor-reward associations produced an increase sleep and reaches its zenith during late-night in the number and size of ripple events for 2 hours REM-rich sleep. Indeed, the difference between during subsequent SWS. Moreover, episodic the cortisol level in the blood at and memory consolidation in human epileptic patients at awakening is so great that the interpretation of correlates with the number of ripples recorded cortisol blood levels is meaningless without from the major output regions of the hippocampus knowing exactly when the sample was taken.89–91 (perirhinal and entorhinal cortices),83 and selective Moreover, the secretion of cortisol is not contin- disruption of hippocampal ripples by electric stim- uous but composed of gradually increasing peaks ulation during postlearning rest phases in rats that tend to coincide with REM sleep (Fig. 8). REM impairs formation of long-lasting spatial memories, sleep thus tends to co-occur with cortisol suggesting that ripples could have a causal role in elevations.90,92 sleep-based memory consolidation.84 The early night reduction in ACh and cortisol Recent work also suggests that there is a close levels may be necessary for hippocampus- temporal relationship between the occurrence of dependent memories to undergo effective consol- slow oscillations, spindles, and sharp wave- idation because experimentally elevating the ripple complexes during SWS that may coordinate levels of either substance during early sleep bidirectional information flow between the hippo- impairs performance on episodic memory tasks. campus and neocortex as memories are inte- Gais and Born93 trained subjects on word pair grated within long-term storage sites. task and mirror tracing tasks before 3 hours of nocturnal sleep or wakefulness during which they NEUROTRANSMITTERS AND received a or an infusion of the cholines- NEUROHORMONES terase inhibitor (which increases cholinergic tone). When tested after 3 hours of There is also evidence to suggest that nocturnal early sleep rich in SWS, recall on the paired asso- changes in neurotransmitter and neurohormone ciates task was markedly impaired in the physo- levels contribute to memory consolidation. ACh, stigmine group, while the procedural memory norepinephrine, 5-HT, and cortisol play important performance was unaffected. Using a similar roles both in modulating sleep85 and memory design, Plihal and Born94 showed that when .86–88 Cortisol levels, for instance, follow cortisol was infused during the early SWS-rich a marked circadian rhythm, whereby the hormone interval, retention of episodic information that is

Fig. 8. The relationship between sleep stage architecture and circulating levels of growth hormone and cortisol. Note both the linear increase in cortisol levels across the night and also the cortisol peaks riding on top of the REM periods. Author's personal copy 26 Payne

normally facilitated during this time was impaired. memory processing. Thus, the neurobiological Thus, enhancing plasma cortisol concentrations properties of early sleep and late sleep, as during early sleep eradicated the benefit typically opposed to SWS and REM sleep per se, may be observed for episodic memory while leaving essential for the consolidation of different types procedural memory unimpaired (Fig. 9). of memory. Plihal and Born94 concluded that because In line with the above-mentioned findings, eleva- episodic, but not procedural, memory relies on tion of cortisol levels during wakefulness can also hippocampal function, cortisol inhibition during impair performance on episodic memory.89,95 early nocturnal sleep is necessary for episodic The cortisol level in the Plihal and Born94 study memory consolidation. Thus, because cortisol (15.2 1 0.68 mg/dL) was elevated just enough to release is normally inhibited during early night mimic the late night peak of circadian cortisol periods dense in SWS, this time window may activity and is proportionate to the amount of provide the ideal physiologic environment for cortisol typically released in response to a mild to episodic memory consolidation. REM sleep, on moderate stressor (approximately 10–30 mg/dL) the other hand, is an inefficient time to consolidate and is a sufficient dose to disrupt episodic memory episodes because of the deleterious effect of function during wakefulness,89,92,96,97 particularly elevated cortisol on hippocampus-dependent when administered prior to consolidation or at

Fig. 9. (A, top) Experimental design for examining the effect of cortisol on memory consolidation during a 3-hour period of early nocturnal sleep rich in SWS, illustrated by an individual sleep profile. Before sleep, subjects learned episodic and procedural memory tasks to a criterion. Recall was tested 15 to 30 minutes after awakening. Infusion of cortisol or placebo began at 11 PM and was discontinued after 2.5 hours. (Bottom) Mean plasma cortisol concentrations during administration of placebo (dotted line) and cortisol (solid line). (B) Cortisol infu- sion during sleep, compared with placebo, impaired hippocampus-dependent episodic memories for word pairs across sleep (top), but did not affect hippocampus-independent procedural memory (speed in mirror tracing, bottom). N 5 14, *P<.05, **P<.01. Aw, awake; IV, intravenous, Li, lights; S, stage; W, wake. (Data from Plihal W, Born J. Memory consolidation in human sleep depends on inhibition of release. Neuroreport 1999;10(13):2741–7.) Author's personal copy Sleep and Memory 27 retrieval.95,98 Elevations in cortisol levels seen remain to be answered about sleep-dependent during late night REM sleep may help explain why memory consolidation in the clinical realm. Future replay of episodic memories in REM sleep research in the field should thus target clinical dreaming is so scarce99 and perhaps also why conditions that are characterized by sleep deficits, are difficult to remember on assessing to what degree sleep dysfunction is awakening.87,100 associated with impaired memory consolidation, In addition to cortisol, other hormones (eg, and, equally importantly, determining whether growth hormone) are also known to affect memory sleep treatment will yield cognitive, emotional, function in the waking state and vary across sleep, and physical benefits. suggesting that they might modulate sleep-based memory consolidation as well. 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