Deep sleep is critical for memory consolidation

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Gentle sound stimulation played during specific times during deep sleep enhanced deep or slow-wave sleep for people with mild cognitive impairment, who are at risk for Alzheimer’s disease.

The individuals whose brains responded the most robustly to the sound stimulation showed an improved memory response the following day.

“Our findings suggest slow-wave or deep sleep is a viable and potentially important therapeutic target in people with mild cognitive impairment,” said Dr. Roneil Malkani, assistant professor of neurology at Northwestern University Feinberg School of Medicine and a Northwestern Medicine sleep medicine physician.

“The results deepen our understanding of the importance of sleep in memory, even when there is memory loss.”

Deep sleep is critical for memory consolidation.

Several sleep disturbances have been observed in people with mild cognitive impairment.

The most pronounced changes include reduced amount of time spent in the deepest stage of sleep.

“There is a great need to identify new targets for treatment of mild cognitive impairment and Alzheimer’s disease,” Malkani added.

Northwestern scientists had previously shown that sound stimulation improved memory in older adults in a 2017 study.

Because the new study was small – nine participants – and some individuals responded more robustly than others, the improvement in memory was not considered statistically significant.

However, there was a significant relationship between the enhancement of deep sleep by sound and memory: the greater the deep sleep enhancement, the better the memory response.

“These results suggest that improving sleep is a promising novel approach to stave off dementia,” Malkani said.

The paper will be published June 28 in the Annals of Clinical and Translational Neurology.

For the study, Northwestern scientists conducted a trial of sound stimulation overnight in people with mild cognitive impairment.

Participants spent one night in the sleep laboratory and another night there about one week later.

Each participant received sounds on one of the nights and no sounds on the other.

The order of which night had sounds or no sounds was randomly assigned.

Participants did memory testing the night before and again in the morning.

Scientists then compared the difference in slow-wave sleep with sound stimulation and without sounds, and the change in memory across both nights for each participant.

The participants were tested on their recall of 44 word pairs.

The individuals who had 20% or more increase in their slow wave activity after the sound stimulation recalled about two more words in the memory test the next morning.

One person with a 40% increase in slow wave activity remembered nine more words.

The sound stimulation consisted of short pulses of pink noise, similar to white noise but deeper, during the slow waves.

The system monitored the participant’s brain activity.

When the person was asleep and slow brain waves were seen, the system delivered the sounds.

If the patient woke up, the sounds stopped playing.

“As a potential treatment, this would be something people could do every night,” Malkani said.

The next step, when funding is available, is to evaluate pink noise stimulation in a larger sample of people with mild cognitive impairment over multiple nights to confirm memory enhancement and see how long the effect lasts, Malkani said.


The capability to form memory is critical to the strategic adaptation of an organism to changing environmental demands. Observations indicating that sleep benefits memory date back to the beginning of experimental memory research, and since then have been fitted with quite different concepts. This review targets this field of “sleep and memory” research, which has experienced a unique renaissance during the last three decades. Although we have aimed at comprehensively covering the field, we might have missed out or overlooked some aspects, owing to the vast progress achieved in the last years. Before we begin, we will briefly introduce the core concepts of sleep and memory, respectively.

A. Sleep

Sleep is defined as a natural and reversible state of reduced responsiveness to external stimuli and relative inactivity, accompanied by a loss of consciousness. Sleep occurs in regular intervals and is homeostatically regulated, i.e., a loss or delay of sleep results in subsequently prolonged sleep (113). Sleep deprivation and sleep disruptions cause severe cognitive and emotional problems (1426341243), and animals deprived of sleep for several weeks show temperature and weight dysregulation and ultimately die of infections and tissue lesions (973). Sleep probably occurs in all vertebrates, including birds, fishes, and reptiles, and sleeplike states are similarly observed in invertebrates like flies, bees, and cockroaches (209).

Sleep in mammals consists of two core sleep stages: slow-wave sleep (SWS) and rapid-eye-movement (REM) sleep, which alternate in a cyclic manner (FIGURE 1A). In human nocturnal sleep, SWS is predominant during the early part and decreases in intensity and duration across the sleep period, whereas REM sleep becomes more intense and extensive towards the end of the sleep period. SWS is hallmarked by slow high-amplitude EEG oscillations (slow wave activity, SWA), whereas REM sleep (also termed paradoxical sleep) is characterized by wakelike fast and low-amplitude oscillatory brain activity. In addition, REM sleep is characterized by phasic REMs and by muscle atonia. Almost 50% of sleep in adult humans is marked by a lighter form of non-REM sleep (stage “N2”) that is characterized by the occurrence of distinct (waxing and waning) sleep spindles (FIGURE 1B) and K-complexes in the EEG, but minor SWA. Sleep stage N2 is not discriminated from SWS in rodents.

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Figure 1. Typical human sleep profile and sleep-related signals. A: sleep is characterized by the cyclic occurrence of rapid-eye-movement (REM) sleep and non-REM sleep. Non-REM sleep includes slow-wave sleep (SWS) corresponding to N3, and lighter sleep stages N1 and N2 (591). According to an earlier classification system by Rechtschaffen and Kales (974), SWS was divided into stage 3 and stage 4 sleep. The first part of the night (early sleep) is dominated by SWS, whereas REM sleep prevails during the second half (late sleep). B: the most prominent electrical field potential oscillations during SWS are the neocortical slow oscillations (∼0.8 Hz), thalamocortical spindles (waxing and waning activity between 10–15 Hz), and the hippocampal sharp wave-ripples (SW-R), i.e., fast depolarizing waves that are generated in CA3 and are superimposed by high-frequency (100–300 Hz) ripple oscillation. REM sleep, in animals, is characterized by ponto-geniculo-occipital (PGO) waves, which are associated with intense bursts of synchronized activity propagating from the pontine brain stem mainly to the lateral geniculate nucleus and visual cortex, and by hippocampal theta (4–8 Hz) activity. In humans, PGO and theta activity are less readily identified. C: sleep is accompanied by a dramatic change in activity levels of different neurotransmitters and neuromodulators. Compared with waking, cholinergic activity reaches a minimum during SWS, whereas levels during REM sleep are similar or even higher than those during waking. A similar pattern is observed for the stress hormone cortisol. Aminergic activity is high during waking, intermediate during SWS, and minimal during REM sleep. [Modified from Diekelmann and Born (293).]

Is sleep essential?

From an evolutionary perspective, reduced responsiveness to potentially threatening stimuli during sleep represents a significant danger to survival.

The fact that almost all animals sleep strongly argues in favor of an adaptive role of sleep in increasing the overall fitness of an organism, although its exact functions are still a matter of debate (4071077).

Sleep has been proposed as serving an energy-saving function (821311), the restoration of energy resources and the repairing of cell tissue (875), thermoregulation (973), metabolic regulation (6511229), and adaptive immune functions (695).

However, these functions could be likewise achieved in a state of quiet wakefulness and would not explain the loss of consciousness and responsiveness to external threats during sleep.

These prominent features of sleep strongly speak for the notion that sleep is mainly “for the brain” (553625). Here, different functions have been proposed, ranging from detoxication of the brain from free radicals (594978), glycogen replacement (1041) to an involvement of sleep in memory and synaptic plasticity (2931204). In this review we discuss this latter function, i.e., the critical role sleep serves in the formation of memory.

B. Memory

Memory processes

To form and retrieve memories is a fundamental ability of any living organism, enabling it to adapt its behavior to the demands of an ever-changing environment, and allowing it to appropriately select and improve the behaviors of a given repertoire.

Memory functions comprise three major subprocesses, i.e., encoding, consolidation, and retrieval.

During encoding, the perception of a stimulus results in the formation of a new memory trace, which is initially highly susceptible to disturbing influences and decay, i.e., forgetting. During consolidation, the labile memory trace is gradually stabilized possibly involving multiple waves of short and long-term consolidation processes (803), which serve to strengthen and integrate the memory into preexisting knowledge networks.

During retrieval, the stored memory is accessed and recalled.

This review discusses sleep’s critical role in the consolidation of memory.

We assume that whereas the waking brain is optimized for the acute processing of external stimuli that involves the encoding of new information and memory retrieval, the sleeping brain provides optimal conditions for consolidation processes that integrate newly encoded memory into a long-term store.

Encoding and consolidation might be mutually exclusive processes inasmuch they draw on overlapping neuronal resources. Thus sleep as a state of greatly reduced external information processing represents an optimal time window for consolidating memories.

The so-called consolidation account of memory processing was first proposed by Müller and Pilzecker (840) who, based on studies of retroactive interference between learning lists of syllables, concluded: “After all this, there is no alternative but to assume that after reading a list of syllables certain physiological processes, which serve to strengthen the associations induced during reading of that list, continue with decreasing intensity for a period of time.” (p. 196 in Ref. 840, cited based on Ref. 709).

The consolidation hypothesis is now widely accepted based on numerous studies showing that psychological, pharmacological, and electrophysiological manipulations, such as interference learning, the administration of norepinephrine and protein synthesis inhibitors or electroconvulsive shocks, can effectively impair or enhance memory, when administered after encoding (e.g., Refs. 8031332).

Importantly, these manipulations are time dependent and have strongest effects when applied immediately after learning (for reviews, see Refs. 194805).

The consolidation possibly involves multiple waves of stabilizing processes, which exhibit different time courses and depend on different underlying processes of neuronal plasticity. Recent evidence suggests that memory traces are not consolidated once but, upon their reactivation by a reminder or active retrieval, undergo a period of reconsolidation to persist for the long term (844).

At the neuronal level, memory formation is thought to be based on the change in the strength of synaptic connections in the network representing the memory. Encoding induces synaptic long-term potentiation (LTP) or long-term depression (LTD) as major forms of learning-induced synaptic plasticity (2225276166291209).

Activity reverberating in the neuronal representation following encoding is thought to promote two kinds of consolidation processes, termed “synaptic consolidation” and “systems consolidation” (330).

Synaptic consolidation leads to the remodeling of the synapses and spines of the neurons contributing to a memory representation, eventually producing enduring changes in the efficacy of the participating synapses (e.g., Refs. 555616977).

System consolidation builds on synaptic consolidation and refers to processes in which reverberating activity in newly encoded representations stimulate a redistribution of the neuronal representations to other neuronal circuitries for long-term storage (418).

Memory systems

In neuropsychology, declarative and nondeclarative memory systems are distinguished depending on the critical involvement of medial temporal lobe regions, particularly of the hippocampus, in the acquisition of memory (1134).

Declarative memory encompasses 1) episodic memories for events that are embedded in a spatiotemporal context (including autobiographical memories) and 2) semantic memories for facts that are stored independently of contextual knowledge (1218).

Declarative memories can be encoded intentionally or unintentionally, but are typically explicitly (i.e., with awareness) accessible by active recall attempts.

Episodic memories are learned very quickly, i.e., in one trial, but are also subject to fast forgetting (1332).

Semantic memories can be regarded as a result of the repeated encoding or activation of overlapping episodic memories (1327).

Integrity of hippocampal circuitry is a prerequisite for retaining an episode as well as spatial and temporal context information in memory for more than 15 min (231418).

In contrast to declarative memories, nondeclarative memories can be acquired without involvement of medial temporal lobe structures (1134).

Nondeclarative memory encompasses quite different memory systems that rely on different areas of the brain. It includes procedural memories for motor skills (motor areas, striatum, cerebellum) and perceptual skills (sensory cortices), certain forms of conditioning and implicit learning (priming), etc.

Nondeclarative memories can be implicitly (i.e., without awareness) acquired and recalled, and learning is slow, usually requiring multiple training trials.

It is of note that experimentally disentangling nondeclarative from declarative memory processing is often complicated by the fact that these memory systems interact during acquisition of new knowledge in the healthy brain.

Thus acquisition of skills like language learning and finger sequence tapping, especially at the initial stages, incorporates declarative in addition to procedural components (910).

The standard two-stage memory system

Why does the consolidation of memory have to take place during sleep?

The hypotheses that sleep serves memory consolidation is conceptually rooted in the standard two-stage memory system which is currently the most influential model of human memory, and has been developed as a solution to several key problems arising from simple associative network models of memory (175780800).

The foremost of these problems is that although simple association networks are in fact able to store information very rapidly, as is the case in the declarative memory system, the uptake of new conflicting information has a strong tendency to erase the older memories, thus inducing so-called “catastrophic interference” (1005).

The critical question is how the neuronal network can learn new patterns without simultaneously forgetting older memories, an issue that has also been referred to as the “stability-plasticity dilemma” (e.g., see Ref. 3).

In addition, unstructured recurrent networks have been demonstrated to face essential capacity constraints (723).

The two-stage memory formation mechanism first proposed by Marr (780) offers a solution to these problems.

It assumes that memories are initially encoded into a fast learning store (i.e., the hippocampus in the declarative memory system) and then gradually transferred to a slow learning store for long-term storage (i.e., the neocortex).

The fast learning store ensures quick and efficient encoding of memories, even in one attempt (one-trial learning).

Yet, these representations are unstable and vulnerable to (retroactive) interference by newly encoded information.

Over time, the information is gradually integrated in the slowly learning long-term store without overwriting older, more remote memories.

It is assumed that by the repeated reactivation of the new memories during off-line periods like sleep, the slowly learning long-term store is trained and the new memories are gradually strengthened and adapted to preexisting long-term memories.

The transformation new memory representations undergo in this system consolidation process comprises also the extraction of invariants and the development of prototypes and schemas, as the core of the newly learned information is reactivated more frequently than divergent details (7348001239).

For the declarative memory system, the two-stage model has received strong support from lesion studies, indicating that lesions of the hippocampus abolish the ability to acquire new declarative memory and simultaneously produce a temporally graded retrograde amnesia where older memories remain intact (231418).

The time interval for a memory to reach a state of hippocampus-independent retrieval can vary from one day to several months or years, depending on the acquired information and the schemas preexisting in long-term memory (12101308).

The standard two-stage model of memory has been also successfully applied to nondeclarative kinds of memory, like procedural memory (668), suggesting that the offline reactivation of recent memories and their redistribution from a fast encoding temporary to a slowly learning permanent store could be a general feature of long-term memory formation.


Provided by Northwestern University

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