| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
The University of Arizona, Department of Psychology, Tucson, Arizona 85721, USA
ABSTRACT
We discuss the relationship between sleep, dreams, and memory, proposing that the content of dreams reflects aspects of memory consolidation taking place during the different stages of sleep. Although we acknowledge the likely involvement of various neuromodulators in these phenomena, we focus on the hormone cortisol, which is known to exert influence on many of the brain systems involved in memory. The concentration of cortisol escalates over the course of the night's sleep, in ways that we propose can help explain the changing nature of dreams across the sleep cycle.
,
2002,
2004;
Kali and Dayan 2004). It is generally assumed that long-term memory consolidation involves interactions among multiple brain systems, modulated by various neurotransmitters and neurohormones. We propose that the characteristics of dreams are best understood in the context of this neuromodulatory impact on the brain systems involved in memory consolidation. Although a number of neurotransmitters and neurohormones are likely involved, we focus our attention in particular on the stress hormone cortisol, which has widespread effects on memory during waking life through its impact on many of the critical brain structures implicated in memory function.
Our hypothesis, briefly stated, is that variations in cortisol (and other
neurotransmitters) determine the functional status of hippocampal 
neocortical circuits, thereby influencing the memory consolidation processes
that transpire during sleep. The status of these circuits largely determines
the phenomenology of dreams, providing an explanation for why we dream and of
what. As a corollary, dreams can be thought of as windows onto the inner
workings of our memory systems, at least those of which we can become
conscious.
In addition to exploring these ideas in more detail, we provide some background concerning (1) the states of sleep and the role of various neurotransmitters in switching from one sleep state to another, (2) how the characteristics of dreams vary as a function of sleep state, (3) the memory content typically associated with dreaming in different dream states, and (4) the role of sleep in the consolidation of memory.
Background to the hypothesis
Stages of sleep
There are two major types of sleep. The first, rapid eye movement or REM
sleep, occurs in 
90-min cycles and alternates with four additional stages
known collectively as NREM sleep—the second type of sleep. Slow wave
sleep (SWS) is the deepest of the NREM phases and is the phase from which
people have the most difficulty being awakened. REM sleep is characterized by
low-amplitude, fast electroencephalographic (EEG) oscillations, rapid eye
movements (Aserinsky and Kleitman
1953), and decreased muscle tone, whereas SWS is characterized by
large-amplitude, low-frequency EEG oscillations
(Maquet 2001). More than 80%
of SWS is concentrated in the first half of the typical 8-h night, whereas the
second half of the night contains roughly twice as much REM sleep as does the
first half. This domination of early sleep by SWS, and of late sleep by REM,
likely has important functional consequences but also makes it difficult at
this time to know which distinction is critical: NREM sleep versus REM sleep
or early sleep versus late sleep. We will use the terms NREM/early sleep and
REM/late sleep, where necessary, to reflect this current ambiguity.
Neurotransmitters, particularly the monoamines (largely serotonin [5-HT]
and norepinephrine [NE]) and acetylcholine, play a critical role in switching
the brain from one sleep stage to another. REM sleep occurs when activity in
the aminergic system has decreased enough to allow the reticular system to
escape its inhibitory influence (Hobson et al.
1975,
1998). The release from
aminergic inhibition stimulates cholinergic reticular neurons in the brainstem
and switches the sleeping brain into the highly active REM state, in which
acetylcholine levels are as high as in the waking state. 5-HT and NE, on the
other hand, are virtually absent during REM. SWS, conversely, is associated
with an absence of acetylcholine and nearly normal levels of 5-HT and NE
(Hobson and Pace-Schott
2002).
The distribution of dreams
In the study of dreams, a major distinction has been drawn between REM and
NREM sleep. Until recently, virtually all dream research focused on REM sleep,
and indeed, dreams are prevalent during REM. In a recent review of 29 REM and
33 NREM recall studies, Nielsen
(2000) reported an average REM
dream recall rate of 81.8%. Importantly, however, he also reported an average
NREM recall rate of 50%. Some NREM dreams are similar in content to REM
dreams; the majority of these come from those few NREM periods occurring early
in the morning, during the peak phase of the diurnal rhythm, when cortisol
levels are at their zenith (Kondo et al.
1989). Foulkes
(1985) has argued for the
existence of NREM dreaming and against a simple "REM sleep =
dreaming" view. By simply changing the question asked of awakened
subjects from "Did you dream?" to "Did you experience any
mental content?," Foulkes was able to show a far higher percentage of
dream reports from NREM stages than original studies had suggested. These
dream reports after NREM awakenings led Foulkes and others to conclude that
the stream of consciousness never ceases during sleep and that the brain
engages in cognitive activity of some sort during all sleep stages
(Antrobus 1990).
Dreams and episodic memory content
Typical REM and NREM dreams are quite distinct, particularly with respect
to episodic memory content. Episodic memory refers to knowledge about the past
that incorporates information about where and when particular events occurred.
It is typically contrasted with semantic memory, which consists of knowledge
(e.g., facts, word meanings) that has been uncoupled from place and time,
existing on its own (Tulving
1983). When examining REM sleep dreams for memory content, one
finds that episodic memories are rare (see
Baylor and Cavallero 2001) and
typically emerge as disconnected fragments that are often difficult to relate
to waking life events (see Schwartz
2003). These fragmented REM dreams often have bizarre content
(Stickgold et al. 2001;
Hobson 2002). For example, the
normal rules of space and time can be ignored or disobeyed, so that in REM
dreams it is possible to walk through walls, fly, interact with an entirely
unknown person as if she was your mother, or stroll through Paris past the
Empire State Building. NREM dreams, however, are quite different
(Cavallero et al. 1992). Here,
episodic memories do appear in dream content (see
Foulkes 1962; Cicogna et al.
1986,
1991;
Cavallero et al. 1992;
Baylor and Cavallero 2001).
Recent episodes are predominant, but remote memories occasionally appear as
well. This pattern of results suggests to us that the memory systems needed to
generate complete episodic retrieval are functional in NREM sleep but not in
REM sleep. Although we do not fully understand how nightly neurochemical
fluctuations account for this difference, some clues are available.
Sleep and memory consolidation
One important clue is that different types of memory (e.g., procedural,
episodic) appear to be best consolidated during specific stages of sleep. REM
sleep may be preferentially important for the consolidation of procedural
memories and some types of emotional information (see
Karni et al. 1994;
Plihal and Born 1999a;
Kuriyama et al. 2004;
Smith et al. 2004), whereas
NREM, especially SWS, appears to be critical for explicit, episodic memory
consolidation (Plihal and Born
1997,
1999a,b;
Rubin et al. 1999; also see
Peigneux et al. 2001). This
role for SWS appears to apply both to verbal tasks (e.g., list learning,
paired-associated learning tasks; Plihal
and Born 1997) and spatial tasks (e.g., spatial rotation;
Plihal and Born 1999a). For
example, Plihal and Born
(1997) tested both episodic
and procedural memory after retention intervals defined over early sleep
(dominated by SWS) and late sleep (dominated by REM). Subjects were trained to
criterion in the recall of a paired-associate word list (episodic) and a
mirror-tracing task (procedural) and were retested after 3-h retention
intervals, during either early or late nocturnal sleep. Recall of paired
associates improved significantly more after a 3-h sleep period rich in SWS
than after a 3-h sleep period rich in REM or after a 3-h period of wake.
Mirror tracing, on the other hand, improved significantly more after a 3-h
sleep period rich in REM than after 3 h spent either in SWS or awake. The fact
that memories for personal episodes only undergo effective consolidation early
in the night, when NREM (SWS) is particularly prominent, provides another
indication that episodic memory systems are functional during NREM sleep.
Summary of background
This brief review highlights several points:
These points raise two critical questions:
Are neurotransmitters the key, as some have suggested (see
Hobson 1988)? Is it strictly
the REM/NREM distinction, or alternatively, could it be fundamental
differences in early versus late sleep? It is important to note that Plihal
and Born's studies (1997,
1999a) used late versus early
sleep as the manipulation, not REM versus NREM per se. Moreover, late night
NREM dreams are more "dream-like" and are thus often
indistinguishable from REM dreams (Kondo
et al. 1989), so perhaps something about late night sleep accounts
for differences in dream content and memory consolidation. These are just some
of the issues that arise within the framework we propose.
The hypothesis in brief
Our hypothesis focuses on how cortisol influences the hippocampal
formation. In doing so we do not seek to minimize the role of
neurotransmitters such as acetylcholine, NE, and 5-HT, all of which play
important roles in controlling sleep (see
Hobson and Pace-Schott 2002),
dreams (see Hobson 1988;
Stickgold et al. 2001), and
memory function (see Cahill and McGaugh
1998; Hasselmo
1999). Each of these neurotransmitters, in addition to having
independent effects on memory, likely interacts with cortisol in important
ways that may affect memory consolidation and dreaming. In this article we
limit our focus to cortisol because it is known that high levels of cortisol
can disrupt hippocampal function, interfering with interactions between the
hippocampal system and its neocortical neighbors
(Kim and Diamond 2002). These
effects on hippocampal function thus provide a possible basis for
understanding the interplay among sleep, dreams, and memory.
Assumptions
These assumptions lead to several testable hypotheses:
neocortical
communication and hence should seem fragmented and often bizarre. We claim that differences in dream content and memory consolidation between NREM/early sleep and REM/late sleep reflect different levels of critical modulatory factors in these states. In particular, high levels of cortisol during REM interfere with hippocampal—neocortical interactions, disrupting consolidation of episodic material and altering the episodic coherence of dreams. We now discuss some of these points at greater length, starting with a discussion about memory and memory processing that should help ground our ideas.
What is memory consolidation?
The phrase "memory consolidation" gets used frequently, and in rather different contexts, but is rarely clearly defined, except in the most abstract sense of postencoding processes that contribute to the stabilization of long-term memory. There has been much focus on molecular and cellular level events taking place during consolidation, and knowing about these is of both intrinsic and practical interest. But there is also a psychological dimension to memory consolidation that we believe speaks to the content and nature of dreams. So, what is memory consolidation all about?
We assume that during consolidation specific neural circuits are strengthened. But which ones, and what part of memory are they? What information do they represent? We believe that memory consolidation involves both the strengthening of traces representing the episodic details of experience, and the parallel integration of information extracted from experience with previously acquired semantic knowledge. In this view, episodic and semantic knowledge are processed in parallel interacting systems, and much of what happens during memory consolidation involves these parallel processors communicating with each other and sharing aspects of their knowledge.
A framework for thinking about this neural interaction builds on the idea
that the hippocampal formation and neocortical structures use different
computational strategies for storing information
(O'Keefe and Nadel 1978;
McClelland et al. 1992,
1995;
Kali and Dayan 2004). The
hippocampal formation is specialized to store unique representations, and its
circuitry permits both the separation of similar input patterns and the
completion of a pattern from partial inputs. Many parts of the neocortex, by
contrast, are specialized to store overlapping representations, in which the
extent of similarity determines the overlap. Thus, these two systems are well
suited for episodic and semantic memory representations, respectively.
McClelland et al. (1995)
argued that because of the superpositional nature of representation within
neocortical networks, it is critical for changes in these networks to be
accomplished incrementally. Fast change would destabilize previously stored
representations. Slow change permits the integration of old with new in a
fashion that does not lead to "catastrophic interference." They
argued that one way to accomplish incremental change in neocortical circuits
was to provide multiple iterations of the input, and that replay of an
episodic representation from hippocampal formation to neocortical circuits
during certain phases of sleep could accomplish this goal.
The functions of memory consolidation and memory replay
Building on these insights, we see replay within the episodic and semantic
systems during sleep as an example of the communication between the systems
referred to above. This communication has a number of consequences for memory
consolidation. First, representations within neocortical sites are slowly
strengthened, capturing feature information about the objects, actors, and
events of experience. The information being captured concerns similarity
relations and statistical regularities—not unique occurrences (cf. taxon
systems; O'Keefe and Nadel
1978). Second, representations within the hippocampal formation
are strengthened, as suggested in the "multiple trace theory" (see
Nadel and Moscovitch 1997).
These representations are about particular experiences, their contexts of
occurrence, and unique relations between objects and actors in those
experiences. Third, connections between hippocampal "episode"
traces and neocortical "feature" traces are strengthened, making
it easier for the former to activate the latter, enhancing retrieval of
properly detailed memories. This aspect of memory consolidation is
particularly important in maintaining links between the hippocampal episode
trace and the neocortical feature traces because the latter are subject to
continual "drift" as new information is acquired. This drift would
eventually sever the connections between an episode and its details unless
constant adjustments were made. Replay provides the basis for these
adjustments (Kali and Dayan
2004). Finally, fourth, neocortical—neocortical connections
are enhanced, allowing for strengthening of links between loosely related
concepts and distant-but-related experiences, a process that eventually
results in "semantic" or schematized versions of some (but
certainly not all) episodic memories
(Nadel and Moscovitch 1998).
These semantic memories, in the absence of any hippocampal contribution, have
lost much of their context and detail but have gained associations with
similar knowledge and experience. Thus, the individual episode is lost, but a
stronger schema for similar experience is gained.
All these consequences of replay reflect what happens when hippocampal and
neocortical systems are communicating properly, for example, during SWS sleep
early in the night. Matters change later when cortisol levels rise, and as a
consequence, there is a disruption of the processing of episodes as coherent
units because high cortisol levels can disrupt the function of the hippocampal
formation (Plihal and Born
1999a; Kim and Diamond
2002). This loss of coherence leads to "inefficient
consolidation" as measured by memory testing (Plihal and Born
1997,
1999a), but also to the
activation of memory fragments in isolation. We think it is these memory
fragments that compose the disconnected sounds and images and the bizarre plot
lines that constitute many REM sleep dreams. More specifically, hippocampal
neocortical communication is disrupted because high cortisol levels
exert a negative influence on the primary output field of the hippocampus, the
CA1 region (for more detail, see below). As a result, disconnected fragments,
stored in dispersed neocortical regions, become activated in the absence of
the spatial and temporal contexts that situate them as episodic memories.
Dreams can be extremely fragmented, but they are rarely experienced as
random sequences of associated images. Rather, they exhibit varying degrees of
narrative and thematic coherence (see
Foulkes 1999). We have argued
that when the waking brain is confronted with fragmented information, it
attempts to synthesize these fragments into narrative themes
(Jacobs and Nadel 1998), even
if the themes make little sense (Holden
and French 2002), and we believe the same principle holds for the
sleeping brain. Activated memory fragments and internally constructed
narrative themes constitute dreams. In addition to being described as
"fragmented and bizarre," dreams are often described as creative,
and perhaps this is why we find them so intriguing. In the absence of
hippocampal input during most of REM sleep, neocortical-neocortical
communication proceeds normally. Thus, disrupted hippocampal communication
during REM may actually aid the linking of loosely related concepts
(Stickgold et al. 1999;
Stickgold and Walker 2004),
perhaps inspiring new ideas, the ability to see relationships between
previously unrelated concepts, and the often noted creative insight inspired
by dreams (see Wagner et al.
2004).
Potential mechanisms
We have suggested that because high cortisol levels disrupt hippocampal-neocortical interactions they can alter dream content. To understand better the ways in which this alteration occurs, and the form it takes, we need to look more closely at the actual mechanisms proposed to cause it. How, for example, do fluctuations in neuromodulators control patterns of neural interaction during the various stages of sleep?
The functionality of hippocampal neocortical interaction varies
across the sleep cycles, as we have already observed. Buzsaki
(1996) suggested that
hippocampal neocortical communication is reduced in REM sleep compared
with NREM sleep or wake. During wake, information about the external world
first activates the neocortex and then reaches the hippocampus via the
entorhinal cortex. A similar pattern of communication is seen during REM
sleep, when information largely flows out of neocortex and into hippocampus
(neocortex hippocampus). Hasselmo
(1999) attributes this
directionality to acetylcholine, contending that because acetylcholine is
linked to encoding processes in the awake brain, it follows that in REM sleep,
when acetylcholine levels are as high as during wake, the directionality of
hippocampal-neocortical interaction should mimic that of initial information
processing in the waking state (neocortex hippocampus).
During SWS the direction of information flow could be reversed, reflecting
hippocampal neuronal bursts called "sharp waves"
(Buzsaki 1998). These bursts,
the most prominent hippocampal pattern during SWS, reflect transient
activation of CA3-CA1 pyramidal cells associated with a sharp wave in stratum
radiatum and fast field oscillation (140- to 200-Hz ripple) in the CA1
pyramidal layer (Buzsaki et al.
1992; Chrobak and Buzsaki
1996). Thus, in SWS, information is likely reactivated in the
hippocampus and then flows back to neocortex. A recent article
(Sirota et al. 2003), however,
suggests that information might flow in both directions (hippocampus
neocortex) during SWS. These investigators demonstrated temporal coupling of
neuronal activity between the neocortex and hippocampus on both slow and fine
time scales during SWS. Neocortical neuronal discharges, associated with the
delta wave and spindle events of NREM sleep, may "select" via the
entorhinal input which hippocampal neurons will participate in the triggered
ripple events. These specific inputs can select burst initiators of the
hippocampal sharp wave events, and in turn, the sharp wave/ripple-related
discharge of neurons in the hippocampus will provide a synchronous output
preferably to those neocortical cell assemblies that continue to participate
in the spindle event. Thus, the hippocampal output likely coexists with the
postsynaptic discharge of a specific group of neocortical cells
(Sirota et al. 2003). In
contrast to the situation during REM sleep, in which hippocampal output to the
neocortex is severely diminished, the neocortical-hippocampal-neocortical
circuit may remain functionally intact during SWS. The coupling between
neocortical and hippocampal networks demonstrated by Sirota et al.
(2003) may provide the
temporal framework for coordinated information exchange between the two
structures during SWS.
How can these differences in the directionality of hippocampal-neocortical communication across the two main stages of sleep be accounted for? Why are hippocampal outputs to neocortex disrupted during REM sleep, whereas the entire neocortical-hippocampal-neocortical circuit seems to remain intact during SWS? The above discussion about the functional relationships between hippocampus and neocortex is based on rodent data. Thus, it is important to remain cautious when using these results to speculate about human sleep and memory consolidation.
The role of cortisol
We suggest that nightly variations in cortisol, and interactions between
cortisol and other neurotransmitters that fluctuate during sleep
(acetylcholine, 5-HT, NE), play a critical role in these phenomena. Cortisol
level varies over the course of the night's sleep; it begins to rise in the
middle of the sleep period and slowly escalates with a series of pulses that
tend to coincide with REM sleep until peaking in the early morning hours
(Weitzman et al. 1971).
Cortisol has both quick and delayed effects on neural function. The former,
nongenomic, effects involve increases in excitatory amino acids
(Venero and Borrell 1999). The
latter, genomic, effects are mediated by receptors located within the cell
nuclei (McEwen 1991). Within
the central nervous system (CNS), two kinds of receptors are activated by
cortisol: so-called glucocorticoid receptors (GRs; type II), and
mineralocorticoid receptors (MRs; type I). When a neuron contains receptors of
both types, as many within the hippocampus do, cortisol level affects the
function of the hippocampus in an inverted U-shaped fashion (see
Diamond et al. 1992;
Pavlides and McEwen 2000). For
example, Diamond et al. (1992)
demonstrated that glucocortidcoids facilitate LTP at low levels but impair it
at high levels.
The mechanisms producing this complex interaction are interesting. Type I (MR) receptors have a considerably higher affinity for cortisol than do type II (GR) receptors. Until all or virtually all the MRs are occupied, there is little occupancy of GRs. With extensive activation of the MR receptors, and the possibility of activation of GRs, the falling limb of the inverted U emerges. Thus, impairment of hippocampal function by high levels of cortisol depends upon the colocalization of MRs and GRs.
Recent work (Han et al.
2002; Patel and Bulloch
2003) has confirmed that MRs and GRs are colocalized in the
dentate gyrus and the CA1 field, but much less so in the CA2 and CA3
fields, where concentrations of GR are much diminished. This difference
has potentially critical functional implications. Most prominently, it means
that at high levels of cortisol, communication between the hippocampus and the
neocortex, which is mediated by CA1 subiculum rhinal cortex
connectivity, will be altered or disrupted. At the same time, communication
within parts of the hippocampus itself, most prominently CA3, could remain
intact2. Thus, as the
night progresses and cortisol levels increase, hippocampal-neocortical
communication will eventually be altered. Note that levels between 10 and 30
µg/dL are associated with memory impairment during wake (see Kirschbaum
1996; de Quervain et al.
2000), and early in the morning (prior to waking), cortisol levels
vary between 15 and 20 µg/dL. However, neither cortical-cortical activity
itself nor activity within the CA3 circuits of the hippocampal formation will
necessarily be disrupted. This interruption of hippocampal-neocortical
communication would halt the consolidation of aspects of memory requiring it,
for example, episodic memory (cf. Plihal and Born,
1997,
1999a), but not the neuronal
replay in CA3 seen in recent experiments (see
Battaglia et al. 2004), or
consolidation within procedural memory circuits.
High levels of cortisol during late night REM sleep could do more than
interfere with episodic memory consolidation. By virtue of the same
mechanisms, high cortisol levels could affect the nature of dreams. It is
generally assumed that episodes consist of events involving actors, actions,
and consequences, all playing out in settings composed of various objects
bound to a specific spatial and temporal context (see
Paller and Voss 2004). The
hippocampal system, as noted earlier, is critical to this binding process,
perhaps by contributing the spatial context to which the bits and pieces of an
episode are attached and woven into a cohesive whole
(Nadel and Moscovitch, 1998;
Nadel and Payne, 2002;
Nadel et al. 2002). When this
binding context is absent, neocortical circuits can generate only semantic
knowledge, or "episode-like" fragments that can be rather bizarre.
It is worth noting the similarities between the nature of dreams and the kind
of memories created during stress or trauma. Clinical evidence suggests that
memory for stressful experience lacks coherence, context, and episodic detail
and thus is experienced as "fragmented"
(Golier et al. 1997;
Bremner 1999;
Gray and Lombardo 2001;
van der Kolk et al. 2001). For
example, fragmentation is an important feature of posttraumatic stress
disorder (PTSD), in which patients sometimes describe gaps in recalled
experiences, not only of trauma but of other personal experiences as well
(Bremner 1999).
It seems likely that in dreams, as in waking life, retrieved fragments are
subject to narrative smoothing, in which educated guesses are made about what
might have occurred. This process may begin during the dream and likely
continues upon awakening as cortisol continues to rise. Constructing
narratives is a normal function of memory. The hippocampal system works
together with the neocortex to recreate episodic memories from representations
of the various attributes or features of the event. We have suggested that
high levels of cortisol undermine this normal process, leading to false
memories (see Payne et al.
2002,
2004) and, in the case of
dreams, fragmentation that leads to the bizarre narratives we attempt to make
sense of upon awakening.
In addition to clinical evidence, there is experimental evidence that high
levels of cortisol alter memory function. Patient populations with chronically
elevated levels of cortisol, such as Cushing's syndrome, major depression, and
schizophrenia, as well as asthmatic patients treated with the glucocorticoid
prednisone are characterized by impaired memory function
(Starkman et al. 1992;
Mauri et al. 1993;
Keenan et al. 1995;
Sheline et al. 1999;
Sapolsky 2000;
Rasmusson et al. 2001). As
might be expected given our discussion thus far, patients with Cushing's
syndrome and major depression not only have memory impairments associated with
high cortisol levels but also have differences in their ratios of SWS and REM
sleep. Because these disorders are associated with high levels of cortisol, it
follows that SWS should be diminished in the sleep of these patients. Indeed,
Friedman et al. (1994)
demonstrated that patients with Cushing's syndrome spent much less time in SWS
than did healthy controls. REM sleep, however, was not significantly different
between groups in this study. Not surprisingly, however, REM sleep in patients
with Cushing's syndrome is strikingly similar to the sleep of patients with
major depression, with REM latency being shortened and REM density being
increased (see Shipley et al.
1992).
In addition to the clinical evidence, experimental studies of acute stress
and memory have been carried out in animals (for reviews, see
Lupien and McEwen 1997; Lupien
and LaPage 2001; Kim and Diamond
2002), and several well-controlled studies have recently been
conducted in humans. For example, Kirschbaum et al.
(1996) demonstrated that a
single, low dose of hydrocortisone (10 mg) led to a deficit in verbal episodic
memory. In this study, subjects who received hydrocortisone recalled fewer
words (via a cued recall test) from a previously learned word list than did
control subjects when recall occurred 60 min after receiving the drug.
Further, Lupien et al. (1998)
demonstrated that prolonged cortisol elevations in older adults are associated
with reduced hippocampal volume and impairments in hippocampally dependent
memory tasks. Aging is another condition that is associated not only with
elevated levels of cortisol and memory impairments but also with sleep
deficits. As might be expected, the sleep deficits occur primarily in SWS (see
Kern et al. 1996;
Van Cauter et al. 2000),
perhaps helping to explain the episodic memory impairments often associated
with aging. Although a complete review of this growing literature is beyond
the scope of this article, many other studies have shown a relationship
between high levels of glucocorticoids and episodic memory deficits (see
Wolkowitz et al. 1990,
1993; Newcomer et al.
1994,
1999; de Quervain et al.
2000,
2003;
Payne et al. 2002; E.D.
Jackson, J.D. Payne, L. Nadel, and W.J. Jacobs, in prep.; J.D. Payne, E.D.
Jackson, S. Hoscheidt, W.J. Jacobs, and L. Nadel, in
prep.)3.
Because high cortisol levels produce memory deficits during the waking
state, they likely also prevent episodic memory consolidation late in the
night when REM sleep is abundant (as shown by Plihal and Born
1997,
1999a). This idea, central to
our proposal, is supported by several recent studies. Plihal and Born
(1999b), for example, using
the early versus late sleep procedure (Plihal and Born
1997,
1999a), showed that increasing
plasma cortisol concentrations during early sleep eradicated the benefit SWS
sleep typically bestows on episodic memory. Recall that subjects who study a
list of paired-associates before retiring to bed typically show great
improvement after 3 h of sleep dominated by SWS, but not after 3 h of REM.
Plihal and Born (1999b) showed
that infusing cortisol during the 3-h SWS retention interval undercuts the
facilitation of episodic memory that would otherwise be observed during this
time. However, cortisol infusion failed to disrupt retrieval of the procedural
memory task. Gais and Born
(2004) have recently shown
precisely the same effect with injection of an anticholinesterase agent that
increases acetylcholine levels. Whether acetylcholine triggers the rise in
cortisol, which then alters hippocampal function is not known at this
time4 but is a fit topic for
future study.
It is worth noting that cortisol in the Plihal and Born
(1999b) study was elevated
just enough to mimic the late night peak of circadian HPA activity (15.2 +
0.68 mg/dL). This is similar to cortisol levels observed in response to a mild
to moderate stressor (10 to 30 mg/dL) and, as mentioned, is a sufficient
dose to disrupt episodic memory function (see
Kirschbaum et al. 1996;
de Quervain et al. 2000).
Thus, cortisol levels, not sleep stage or time of night per se, could
determine both the nature of dreams and episodic memory consolidation effects.
To repeat, elevated cortisol leads to binding problems and fragmentation. When
the brain is confronted with decontextualized fragments, it imposes a
narrative upon them, leading to distorted memories or, in the case of dreams,
to bizarre reconstructions.
Two caveats
We have argued that diurnal elevations in cortisol may help explain the
nature of dreams. We do not mean to suggest that cortisol is the only factor
affecting the structure and content of dreams. Several of the
neurotransmitters that fluctuate across the sleep cycle are also known to
affect memory function during wake (e.g., acetylcholine, see
Hasselmo 1999; NE, see
Cahill and McGaugh 1998), and
there has been much speculation about their influence on memory processing
during sleep (Hobson 1988;
Solms 2000). Moreover, these
neurotransmitters likely interact with cortisol during sleep. For example,
acetylcholine and cortisol are both diminished during SWS (they are also both
elevated during REM sleep). Levels of cholinergic activity and cortisol
production during SWS are both quite low, and this appears necessary for
episodic memories to undergo effective consolidation; experimentally elevating
either substance impairs performance on verbal episodic memory tasks
(Plihal and Born 1999b;
Gais and Born 2004). In
addition to cortisol then, acetylcholine is another candidate modulator of
dreams; a thorough consideration of this possibility is beyond the scope of
the present paper.
Recent neuroimaging evidence demonstrates a selective inactivation of
portions of the frontal cortex during REM sleep (see
Braun et al. 1997;
Nofzinger et al. 1997). These
studies demonstrated a prominent decrease in activity of the dorsolateral
prefrontal cortex, and disruption in this region has been associated with
confabulatory syndromes that are in some ways similar to dreaming. Moreover,
as the prefrontal cortex is thought to play a role, along with the
hippocampus, in binding the elements of a memory together
(Mitchell et al. 2000),
deactivation seen in this region could be related to the fragmented nature of
dreams. Interestingly, frontal deactivation may also underlie our tendency to
blithely accept dream fragments and bizarre themes as commonplace and normal.
This notion is consistent with evidence that the frontal lobes contribute to
reality monitoring (Johnson
1991), working memory
(Goldman-Rakic 1992), and
other executive functions (Smith and
Jonides 1999) during the waking state.
Conclusions
We have proposed that the hormone cortisol plays an important role in
controlling the state of memory systems during sleep. High levels of cortisol,
as are observed late at night and, typically in the context of REM sleep,
disrupt normal hippocampal neocortical communication, thereby
interfering with forms of memory consolidation dependent upon this
communication. At the same time, the content of dreams is also affected. In
SWS dream content reflects the normal interaction between hippocampal and
neocortical circuits, allowing for typical episodic memories to emerge. In REM
sleep, however, dream content reflects only neocortical activation, which we
assume accounts for the fragmented, often bizarre, nature of these dreams.
The fact that normal episodic memories are only retrieved during SWS when
hippocampal-neocortical communication is functional has interesting
implications for a current debate about the storage of remote episode
memories. Some (see Alvarez and Squire
1994) believe that remote episode memories are ultimately stored
in the neocortex, after consolidation has been completed. Others (see
Nadel and Moscovitch 1997)
have argued that the hippocampal complex is always involved in the retrieval
of fully elaborated episode memories. The absence of proper episodic retrieval
in dreams during REM sleep, when hippocampal-neocortical communication is
disrupted, but neocortical-neocortical communication is preserved, is
consistent with the latter position. If fully consolidated episode memories
could be elaborated in the neocortex, we should expect to observe their
retrieval during REM dreams—but this does not appear to be the case, at
least in the few studies reported to date. Closer examination of the nature of
dreams in REM sleep, and the presence, or absence, of remote memories in these
dreams, would provide important clues in this ongoing debate about the nature
of memory storage in the brain.
In addition to telling us something about the contributions hippocampal and neocortical circuits make to episodic memory, to the consolidation of episodic and semantic memory, and to the content of dreams, our proposal suggests some intriguing possibilities about creativity and the generation of novel thoughts. One stage of consolidation likely involves the integration of information with pre-existing knowledge and the linking of distant but related concepts. We dream when we become aware of these activated traces, which are often fragmented images and sounds coupled with motor activity. Similar to memories created under stress, these fragments are immediately subjected to a process of narrative smoothing, and the result is typically a story that is often confabulatory, quite bizarre, but possibly also creative.
Although it is true that accurate recall is adaptive in many cases, there may nonetheless be a positive side to a process that produces fragmentation—both during wake and during sleep. All new ideas are based upon previously stored information. These fragments, or pieces and patches of knowledge, are bound into representations that we use to recall information about personal experience and to help us understand and act in the world. When these bonds are weakened, this information can be recombined, either in dreams or misremembered episodes—perhaps resulting in a process leading us down unusual paths to creative insights and new ideas.
Dreams are but interludes which fancy makesWhen monarch reason sleeps, this mimic wakes.
Compounds a medley of disjointed things
A mob of cobblers and a court of Kings.
John Dryden (1700)
FOOTNOTES
Article and publication are at http://www.learnmem.org/cgi/doi/10.1101/lm.77104.
2 This observation seems, at first glance, to conflict with the fact that CA3
is highly susceptible to the toxic effects of chronic stress
(Sapolsky, 2000). However, the
impact of acute and chronic stress clearly differs in a number of ways, and
this conflict may be more apparent than real. 
3 Not all glucocorticoid effects on memory are negative. For example, there
is ample evidence that glucocorticoids released during or after emotionally
arousing experiences play a critical role in the formation of lasting memories
(Roozendaal 2003), and memory
for emotional materials is actually facilitated by cortisol (see
Buchanan and Lovallo 2001; J.D.
Payne, E.D. Jackson, S. Hoscheidt, W.J. Jacob, and L. Nadel, in prep.). Memory
for emotionally neutral experiences, by contrast, is typically negatively
affected by acute stressors or administration of cortisol (for a review, see
Payne et al. 2004). Along
these lines it is interesting to note that many dreams are distinctly
emotional, often involving intense fear, and that emotional dreams are among
the most well-remembered.
4 Although Gais and Born
(2004) failed to show a
corresponding increase in cortisol after administration of a small dose of the
acetylcholine agonist physostigmine (0.75 mg), it remains possible that higher
levels of acetylcholine may trigger a concomitant rise in cortisol.
1 E-mail nadel{at}u.arizona.edu; fax (520) 621-9306.
REFERENCES
Antrobus, J. 1990. The neurocognition of sleep mentation: Rapid eye movements, visual imagery, and dreaming. In Sleep and cognition (eds. R.R. Bootzin, et al.), pp.1 -24. APA Books, Washington, D.C.
Aserinsky, E. and Kleitman, N. 1953. Regularly
occurring periods of eye motility and concurrent phenomena during sleep.
Science 118:273
-274.
Battaglia, F.P., Sutherland, G.R., and McNaughton, B.L.2004 . Hippocampal sharp wave bursts coincide with neocortical "up-state" transitions. Learn. Mem. (this issue).
Baylor, G.W. and Cavallero, C. 2001. Memory sources associated with REM and NREM dream reports throughout the night: A new look at the data. Sleep 24:165 .[Medline]
Braun, A.R., Balkin, T.J., Wesenten, N.J., Carson, R.E., Varga, M.,
Baldwin, P., Selbie, S., Belenky, G., and Herscovitch, P. 1997.
Regional cerebral blood flow throughout the sleep-wake cycle. An H2(15)O PET
study. Brain 120:1173
-1197.
Bremner, J.D. 1999. Does stress damage the brain? Biol. Psychiatry 45:797 -805.[CrossRef][Medline]
Buchanan, T.W. and Lovallo, W.R. 2001. Enhanced memory for emotional material following stress-level cortisol treatment in humans. Psychoneuroendocrinology 26:307 -317.[CrossRef][Medline]
Buzsaki, G. 1996. The hippocampo-neocortical dialogue.
Cerebral Cortex 6:81
-92.
____. 1998. Memory consolidation during sleep: A neurophysiological perspective. J. Sleep Res. 7(Suppl):17 -23.
Buzsaki, G., Horvath, Z., Urioste, R., Hetke, J., and Wise, K.1992
. High frequency network oscillation in the hippocampus.
Science 256:1025
-1027.
Cahill, L. and McGaugh, J.L. 1998. Mechanisms of emotional arousal and lasting declarative memory. Trends Neurosci. 21:294 -299.[CrossRef][Medline]
Cavallero, C., Cicogna, P., Natale, V., Occhionero, M., and Zito, A. 1992. Slow wave sleep dreaming. Sleep 15:562 -566.[Medline]
Chrobak, J.J. and Buzsaki, G. 1996. High-frequency
oscillations in the output networks of the hippocampal-entorhinal axis of the
freely behaving rat. J. Neurosci.
16:3056
-3066.
Cicogna, P., Cavallero, C., and Bosinelli, M. 1986. Differential access to memory traces in the production of mental experience. Int. J. Psychophysiol. 4: 209-216.[CrossRef][Medline]
____. 1991. Cognitive aspects of mental activity during sleep. Am. J. Psychol. 104:413 -425.[CrossRef][Medline]
deQuervain, D.J.F., Roozendaal, B., Nitsch, R.M., McGaugh, J.L., and Hock, C. 2000. Acute cortisone administration impairs retrieval of long-term declarative memory in humans. Nat. Neurosci. 3:313 -314.[CrossRef][Medline]
de Quervain, D.J., Henke, K., Aerni, A., Treyer, V., McGaugh, J.L., Berthold, T., Nitsch, R.M., Buck, A., Roozendaal, B., and Hock, C.2003 . Glucocorticoid-induced impairment of declarative memory retrieval is associated with reduced blood flow in the medial temporal lobe. Eur. J. Neurosci. 17:1296 -1302.[CrossRef][Medline]
Diamond, D.M., Bennet, M.C., Fleshner, M., and Rose, G.M.1992 . Inverted U relationship between the level of peripheral corticosterone and the magnitude of hippocampal primed burst potentiation. Hippocampus 2:421 -430.[CrossRef][Medline]
Foulkes, W.D. 1962. Dream reports from different stages of sleep. J. Abnormal Social Psychol. 65: 14-25.
____. 1985. Dreaming: A cognitive-psychological analysis. Lawrence Erlbaum Associates, NJ.
____. 1999. Children's dreaming and the development of consciousness. Harvard University Press; Cambridge, MA.
Friedman, T.C., Garcia-Borreguero, D., Hardwick, D., Akuete, C.N.,
Doppman, J.L., Dorn, L.D., Barker, C.N., Yanovski, J.A., and Chrousos, G.P.1994
. Decreased 
-sleep and plasma -sleep-inducing
peptide in patients with Cushing syndrome.
Neuroendocrinology 60:626
-634.[Medline]
Gais, S. and Born, J. 2004. Low acetylcholine during
slow-wave sleep is critical for declarative memory consolidation.
Proc. Natl. Acad. Sci.
101:2140
-2144.
Goldman-Rakic, P.S. 1992. Working memory and the mind. Sci. Am. 267:111 -117.
Golier, J.A., Yehuda, R., and Southwick, S.M. 1997. Memory and posttraumatic stress disorder. In Trauma and memory (eds. P.S. Appelbaum et al.), pp.225 -242. Oxford University Press, London.
Gray, M.J. and Lombardo, T.W. 2001. Complexity of trauma narratives as an index of fragmented memory in PTSD: A critical analysis. Appl. Cogn. Psychol. 15:S171 -S186.[CrossRef]
Han, J.-S., Bizon, J.L., Chun, H.-J., Maus, C.E., and Gallagher, M.2002 . Decreased glucocorticoid receptor mRNA and dysfunction of HPA axis in rats after removal of the cholinergic innervation to hippocampus. Eur. J. Neurosci. 16:1399 -1404.[CrossRef][Medline]
Hasselmo, M.E. 1999. Neuromodulation: Acetylcholine and memory consolidation. Trends Cogn. Sci. 3: 351-359.[CrossRef][Medline]
Hobson, J.A. 1988. The dreaming brain: How the brain creates both the sense and the nonsense of dreams. Basic Books, NY.
____. 2002. Dreaming: An introduction to the science of sleep. Oxford University Press, London.
Hobson, J.A., McCarley, R.W., and Wyzinski, P.W. 1975. Sleep cycle oscillation: Reciprocal discharge by two brainstem neuronal groups. Science 189:55 -58.
Hobson, J.A., Stickgold, R., and Pace-Schott, E.F.1998 . The neuropsychology of REM sleep dreaming. NeuroReport 9:R1 -R14.[Medline]
Hobson, J.A. and Pace-Schott, E.F. 2002. The cognitive neuroscience of sleep: Neuronal systems, consciousness and learning. Nature Rev. Neurosci. 3:679 -693.[CrossRef][Medline]
Holden, K.J. and French, C.C. 2002. Alien abduction experiences: Some clues from neuropsychology and neuropsychiatry. Cogn. Neuropsychiatry 7:163 -178.[CrossRef]
Jacobs, W.J. and Nadel, L. 1998. Neurobiology of reconstructed memory. Psychol. Public Policy Law 4:1110 -1134.[CrossRef]
Johnson, M.K. 1991. Reality monitoring: Evidence from confabulation in organic brain disease patients. In Awareness of deficit after brain injury (eds. G. Prigatano and D.L. Schacter), pp. 176-197. Oxford University Press, Oxford, UK.
Kali, S. and Dayan, P. 2004. Off-line replay maintains declarative memories in a model of hippocampal-neocortical interactions. Nat. Neurosci. 7:286 -294.[CrossRef][Medline]
Karni, A., Tanne, D., Rubenstein, B.S., Askenasy, J.J., and Sagi,
D. 1994. Dependence on REM sleep of overnight improvement of a
perceptual skill. Science
265:679
-682.
Keenan, P.A., Jacobson, M.W., Soleymani, R.M., and Newcomer, J.W.1995 . Commonly used therapeutic doses of glucocorticoids impair explicit memory. Ann. NY Acad. Sci. 761:400 -402.[Medline]
Kern, W., Dodt, C., Born, J., and Fehm, H.L. 1996. Changes in cortisol and growth hormone secretion during nocturnal sleep in the course of aging. J. Gerontol. A 51: M3-M9.
Kim, J.J. and Diamond, D.M. 2002. The stressed hippocampus, synaptic plasticity and lost memories. Nat. Rev. Neurosci. 3:453 -462.[CrossRef][Medline]
Kirschbaum, C., Wolf, O.T., May, M., Wippich, W., and Hellhammer, D.H. 1996. Stress and treatment induced elevations of cortisol levels associated with impaired declarative memory in healthy adults. Life Sci. 58:1475 -1483.[CrossRef][Medline]
Kondo, T., Antrobus, J., and Fein, G. 1989. Later REM activation and sleep mentation. Sleep Res. 18: 147.
Kuriyama, K., Stickgold, R., and Walker, M.P. 2004. Sleep-dependent learning and motor skill complexity. Learn. Mem. (this issue).
Lavie, P. 1996. The enchanted world of sleep. Yale University Press, New Haven, CT.
Lupien, S.J. and LePage, M. 2001. Stress, memory and the hippocampus: Can't live with it, can't live without it. Behav. Brain Res. 127:137 -158.[CrossRef][Medline]
Lupien, S.J. and McEwen, B.S. 1997. The acute effects of corticosteroids on cognition: Integration of animal and human model studies. Brain Res. Rev. 24: 1-27[CrossRef][Medline]
Lupien, S.J., de Leon, M., de Santi, S., Convit, A., Tarshish, C., Nair, N.P., Thakur, M., McEwen, B.S., Hauger, R.L., and Meaney, M.J.1998 . Cortisol levels during human aging predict hippocampal atrophy and memory deficits. Nat. Neurosci. 1: 3-4.[CrossRef][Medline]
Maquet, P. 2001. The role of sleep in learning and
memory. Science 294:1048
-1052.
Mauri, M., Sinforiani, E., Bono, G., Vignati, F., Berselli, M.E., Attanasio, R., and Nappi, G. 1993. Memory impairment in Cushing's disease. Acta Neurologica Scandinavica 87: 52-55.[Medline]
McClelland, J.L., McNaughton, B.L., O'Reilly, R., and Nadel, L.1992 . Complementary roles of hippocampus and neocortex in learning and memory. Society for Neuroscience Abstracts,22 .
McClelland, J.L., McNaughton, B.L., and O'Reilly, R.C.1995 . Why there are complementary learning systems in the hippocampus and neocortex: Insights from the successes and failures of connectionist models of learning and memory. Psychol. Rev. 102:419 -457.[CrossRef][Medline]
McEwen, B. 1991. Nongenomic and genomic effects of steroids on neural activity. Trends Pharmacol. Sci. 12:141 -147.[CrossRef][Medline]
Mitchell, K.J., Johnson, M.K., Raye, C.L., and D'Esposito, M.2000 . fMRI evidence of age-related hippocampal dysfunction in feature binding in working memory. Cogn. Brain Res. 10:197 -206.[CrossRef][Medline]
Nadel, L. and Moscovitch, M. 1997. Memory consolidation, retrograde amnesia and the hippocampal complex. Curr. Opin. Neurobiol. 7: 217-227.[CrossRef][Medline]
____. 1998. Hippocampal contribution to cortical plasticity. Neuropharmacology 37:431 -440.[CrossRef][Medline]
Nadel, L. and Payne, J.D. 2002. The hippocampus, wayfinding, and episodic memory. In The neural basis of navigation: Evidence from single cell recording (ed. P. Sharp), pp.235 -247. Kluwer Academic Publishers, Boston.
Nadel, L., Payne, J.D., and Jacobs, W.J. 2002. The relationship between episodic memory and context: Clues from memory errors made while under stress. Physiol. Res. 51: S3-S11.
Newcomer, J.W., Craft, S., Hershey, T., Askins, K., and Bardgett, M.E. 1994. Glucocorticoid-induced impairment in declarative memory performance in adult humans. J. Neurosci. 14:2047 -2053.[Abstract]
Newcomer, J.W., Selke, G., Melson, A.K., Hershey, T., Craft, S.,
Richards, K., and Alderson, A.L. 1999. Decreased memory
performance in healthy humans induced by stress-level cortisol treatment.
Arch. Gen. Psychiatry
56:527
-533.
Nielsen, T.A. 2000. A review of mentation in REM and NREM sleep: "Covert" REM sleep as a possible reconciliation of two opposing models. Behav. Brain Sci. 23: 851-866, 904-1121.[CrossRef][Medline]
Nofzinger, E.A., Mintun, M.A., Wiseman, M., Kupfer, D.J., and Moore, R.Y. 1997. Forebrain activation in REM sleep: An FDG PET study. Brain Res. 770:192 -201.[CrossRef][Medline]
O'Keefe, J. and Nadel, L. 1978. The hippocampus as a cognitive map. The Clarendon Press, Oxford, UK.
Paller, K.A. and Voss, J.L. 2004. Memory reactivation and consolidation during sleep. Learn. Mem. (this issue).
Patel, A. and Bulloch, K. 2003. Type II glucocorticoid receptor immunoreactivity in the mossy cells of the rat and the mouse hippocampus. Hippocampus 13: 59-66.[CrossRef][Medline]
Pavlides, D. and McEwen, B.S. 2000. Effects of mineralocorticoid and glucocorticoid receptors on long-term potentiation in the CA3 hippocampal field. Brain Res. 851:204 -214.
Payne, J.D., Nadel, L., Allen, J.J.B., Thomas, K.G.F., and Jacobs, W.J. 2002. The effects of experimentally induced stress on false recognition. Memory 10:1 -6.[CrossRef][Medline]
Payne, J.D., Nadel, L., Britton, W.B., and Jacobs, W.J.2004 . The biopsychology of trauma and memory. In Memory and emotion (eds. D. Reisberg and P. Hertel), pp. 76-128. Oxford University Press, London.
Peigneux, P., Laureys, S., Delbeuck, X., and Maquet, P.2001 . Sleeping brain, learning brain. The role of sleep for memory systems. Neuroreport. 12:A111 -A124.[CrossRef][Medline]
Plihal, W. and Born, J. 1997. Effects of early and late nocturnal sleep on declarative and procedural memory. J. Cogn. Neurosci. 9:534 -547.[Abstract]
____. 1999a. Effects of early and late nocturnal sleep on priming and spatial memory. Psychophysiology 36:571 -582.[CrossRef][Medline]
____. 1999b. Memory consolidation in human sleep depends on inhibition of glucocorticoid release. Neuroreport 10:2741 -2747.[Medline]
Rasmusson, A.M., Lipschitz, D.S., Wang, S., Hu, S., Vojvoda, D., Bremner, J.D., Southwick, S.M., and Charney, D.S. 2001. Increased pituitary and adrenal reactivity in premenopausal women with posttraumatic stress disorder. Biol. Psychiatry 50:965 -977.[CrossRef][Medline]
Roozendaal, B. 2003. Systems mediating acute glucocorticoid effects on memory consolidation and retrieval. Progress Neuropsychopharmaco. Biol. Psychiatry 27:1213 -1223.
Rubin, S.R., Bootzin, R.R., Franzen, P.L., and Al-Shajlawi, A.1999 . Memory performance after normal sleep or selective sleep fragmentation. Sleep Res. Online 2(Suppl 1):241 .
Sapolsky, R.M. 2000. Glucocorticoids and hippocampal
atrophy in neuropsychiatric disorders. Arch. Gen.
Psychiatry 57:925
-935.
Schwartz, S. 2003. Are life episodes replayed during dreaming. Trends Cogn. Sci. 7: 325-327.[CrossRef][Medline]
Sheline, Y.I., Sanghavi, M., Mintun, M.A., and Gado, M.H.1999
. Depression duration but not age predicts hippocampal volume
loss in medically healthy women with recurrent major depression. J.
Neurosci. 19:5034
-5043.
Shipley, J.E., Schteingart, D.E., Tandon, R., and Starkman, M.N.1992 . Sleep architecture and sleep apnea in patients with Cushing's disease. Sleep 15:514 -518.[Medline]
Sirota, A., Csicsvari, J., Buhl, D., and Buzsaki, G.2003
. Communication between neocortex and hippocampus during
sleep in rodents. Proc. Natl. Acad. Sci.
100:2065
-2069.
Smith, E.E. and Jonides, J. 1999. Storage and
executive processes in the frontal lobes. Science
283:1657
-1661.
Smith, C., Nixon, M., and Nader, R. 2004. Posttraining increases in REM sleep intensity implicate REM sleep in memory processing and provide a biological marker of learning potential. Learn. Mem. (this issue).
Solms, M. 2000. Dreaming and REM sleep are controlled by different brain mechanisms. Behav. Brain Sci. 23: 843-850, 904-1121.[CrossRef][Medline]
Starkman, M.N., Gebarski, S.S., Berent, S., and Schteingart, D.E.1992 . Hippocampal formation volume, memory dysfunction, and cortisol levels in patients with Cushing's syndrome. Biol. Psychiatry 32:756 -765.[CrossRef][Medline]
Stickgold, R. and Walker, M. 2004. To sleep, perchance to gain creative insight? Trends Cogn. Sci. 8: 191-192.[CrossRef][Medline]
Stickgold, R., Scott, L., Rittenhouse, C., and Hobson, J.A.1999
. Sleep-induced changes in associative memory. J.
Cogn. Neurosci. 11:182
-193.
Stickgold, R., Hobson, J.A., Fosse, R., and Fosse, M.2001
. Sleep, learning, and dreams: Off-line memory reprocessing.
Science 294:1052
-1057.
Tulving, E. 1983. Elements of episodic memory. Oxford University Press, London.
Van Cauter, E., Leproult, R., and Plat, L. 2000.
Age-related changes in slow wave sleep and REM sleep and relationship with
growth hormone and cortisol levels in healthy men.
JAMA 284:861
-868.
van der Kolk, B.A., Hopper, J.W., and Osterman, J.E.2001 . Exploring the nature of traumatic memory: Combining clinical knowledge with laboratory methods. J. Aggression Maltreatment Trauma 4:9 -13.
Venero, C. and Borrell, J. 1999. Rapid glucocorticoid effects on excitatory amino acid levels in the hippocampus: A microdialysis study in freely moving rats. Eur. J. Neurosci. 11:2465 -2473.[CrossRef][Medline]
Wagner, U., Gais, S., Haider, H., Verleger, R., and Born, J.2004 . Sleep inspires insight. Nature 427:352 -355.[CrossRef][Medline]
Weitzman, E.D., Fukushima, D., Nogeire, C., Roffwarg, H., Gallagher, T.F., and Hellman, L. 1971. Twenty-four-hour pattern of the episodic secretion of cortisol in normal subjects. J. Clin. Endocrinol. Metabo. 33:14 -22.
Winson, J. 1985. Brain and psyche: The biology of the unconscious. Anchor Press/Doubleday, Garden City, NY.
____. 2002. The meaning of dreams. Sci. Am. 12:54 -61.
____. 2004. To sleep, perchance to dream. Learn. Mem. (this issue).
Wolkowitz, O.M., Reus, V.I., and Weingartner, H. 1990.
Cognitive effects of corticosteroids. Am. J.
Psychiatry 147:1297
-1303.
Wolkowitz, O.M., Weingartner, H., Rubinow, D.R., and Jimerson, D.1993 . Steroid modulation of human memory: Biochemical correlates. Biol. Psychiatry 33:744 -746.[CrossRef][Medline]
CiteULike 
Connotea 
Del.icio.us 
Digg 
Reddit 
