Beruflich Dokumente
Kultur Dokumente
Preface vii
Chapter 1
Evolutionary Aspects of Sleep and Its REM and NREM States . . . . . . . . . . . . 1
J. Lee Kavanau
Chapter 2
Sleep Disturbances in Aging . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 33
Marci M. Loiselle, Melanie K. Means, and Jack D. Edinger
Chapter 3
Sleep and Learning in Animal Models . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 61
Barry W. Row and David Gozal
Chapter 4
Sleep Disordered Breathing in the Geriatric Patient Population . . . . . . . . . . . . 79
Alon Y. Avidan
Chapter 5
Sleep Associated Endocrine and Immune Changes in the Elderly . . . . . . . . . . . . 113
Boris Perras and Jan Born
Chapter 6
Neurotrophic Factors and Sleep . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 155
Mark P. Mattson
Chapter 7
Sleep and Aging: Molecular Approaches within a Systems
Neurobiology Context . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 165
Akira Terao and Thomas S. Kilduff
v
PREFACE
vii
viii Preface
Contents
1. Introduction
2. Evolutionary origin of sleep
2.1. Schwartzs admonition and Rauscheckers Fundamental Dogma
2.2. Restful waking, detailed focal vision, and conicting brain activities
2.3. Primitive sleep obviated potentially conicting brain activities
2.4. Vertebrates that never sleep
2.5. Need for sleep in congenitally and adventitiously blind mammals
2.6. Earliest sleep
2.7. Complex retinal processing
3. Warm-bloodedness and selective pressures for REM and NREM sleep
3.1. Historical
3.2. Sleep was non-uniform before the origin of REM and NREM states
3.3. Presence and absence of thermoregulation during sleep states
3.4. Implications for the evolution of sleep states
3.5. Inuences of ambient temperature
3.6. Actions of brain waves during waking
3.7. Actions of brain waves during sleep
3.8. Long-term memory maintenance
3.9. Basic links between muscle-controlling and visual circuits
3.10. Absence or lesser amounts of REM sleep in marine mammals and birds
3.11. Origin of fast waves of REM sleep
4. Evolutionary origin of sleep within a brain-wave paradigm
5. Sequential cycling of NREM and REM sleep
6. Overview
1. Introduction
Darwins discoveries in the eld of evolution did much more than open our eyes
to long-term inuences of the environment on higher plants and animals. They led
to enormously fruitful reorientations of studies in all elds of biology. Viewing
biological phenomena from an evolutionary perspective frequently yields insights
beyond those that can otherwise be discerned. However, paraphrasing Damasios
(1999) remark: one could almost say that, until the last decade, neuroscience and
cognitive science have proceeded as if Darwin never existed. In this chapter, I employ
a Darwinian approach to the origin and functions of sleep and sleep states.
Studies with the goal of identifying selective pressures that might have given
rise to sleep and its rapid-eye-movement (REM) and non-rapid-eye-movement
(NREM) states, could cast light on their functions. Being mostly medically oriented,
current studies of sleep have somewhat dierent objectives. Attention is directed
primarily to mechanisms, for example, inuences of various brain secretions on
vigilance states. While signicant medical progress, with great practical benets,
has been made along these lines, implications of the underlying mechanisms
for sleeps functions have been tenuous or non-existent. Further, one must
distinguish between the functions of sleep and the activities that occur during
sleep, and their benets. Sometimes, the functions have been equated with the
activities and benets.
Some treatments included evolutionary considerations, but they infrequently
probed underlying selective pressures. Almost all attention has been directed toward
comparative aspects, such as the degrees to which sleep and its REM and NREM
states occur in various species, and how they correlate with brain structures,
anatomy, behavior, and ecology. These analyses inevitably lean heavily on
information gleaned from evolutionary endpoints, perhaps millions of years
removed from the selective pressures of origin, and often arrived at along dierent
routes. Taken at face value, these endpoints can be misleading.
Even before probing for the basic or primitive function(s) of sleep, the
evolutionist anticipates that it will be expressible in terms of maintenance of an
overall high eciency of brain operation. No one would doubt that normal
waking brains operate at high levels of eciency, with responses to threatening
circumstances having the highest priority. Accordingly, the provision of a suitably
modied alternative vigilance state sleep in some animals, very likely functions
to maintain brain operations at overall high levels of eciency, by subsuming
non-urgent activities that cannot be accomplished eciently during a continuous
waking state.
2.2. Restful waking, detailed focal vision, and conflicting brain activities
The selective pressure for the origin of primitive sleep may have been the need to
ameliorate the developing conicts discussed earlier, by achieving a more profound
state of brain unresponsiveness to external occurrences during memory processing
than exists during restful waking. By relieving the brain of extensive needs to
process and respond to environmental, chiey detailed visual, inputs during a
portion of the 24-h cycle, memory processing could have proceeded without
impediment during that portion. As a result, those mnemonic activities that could
be delayed with minimal survival risk, such as establishing new memories
and reinforcing existing long-term memories, came to be carried out during the
new portion, namely, primitive sleep (Kavanau, 1997). It is a reasonable assumption
Evolutionary Aspects of Sleep and Its REM and NREM States 5
that sleep in present-day reptiles has changed very little from the primitive sleep of
their ancestors.
In line with the above proposals, the reason why invertebrates lacking
image-forming eyes, such as many mollusks, echinoderms, worms, and the like,
need no sleep, is because their sensory input processing during activity and
restful waking interferes minimally, or not at all, with other vital brain activities.
As indicated above, these would be largely memory consolidation and processing,
and other maintenance activities. In other words, because processing of non-visual
sensory information engages much less brain tissue, and in a very much simpler
manner than detailed visual input, it does not come into conict with other vital
brain activities. In this regard, with eyelids closed, or under anesthesia, region 18
of the feline visual cortex shows intrinsic patterns of EEG activity resembling
those produced by certain visual stimuli (see Ringach, 2003). These patterns
presumably reect ongoing unimpeded reinforcement of component circuits of visual
memories.
The key, overt, adaptive changes that accompanied selection for primitive sleep
probably were: (a) to close eyelids that previously were transparent and purely
protective, but were in the process of becoming increasingly opaque; and/or (b) to
retire to secure quarters, often in dim light or darkness. With the exclusion of light,
and without a need to process detailed visual inputs, and with correspondingly
decreased attentiveness to other sensory inputs, the sleeping brain would have been
almost totally occupied with some of those previous neural activities of waking that
could be delayed with minimal risk.
That the primitive sleep state subjected animals to greater risks than spending the
same periods awake, would not have been determining. The critical factor vis-a`-vis
natural selection would have been, whether primitive sleeps adaptive advantages
outweighed the greater risks entailed. The proposed adaptive advantages were the
maintenance of great eciency of brain function, both awake and asleep highly
ecient sensory processing and responding when awake, and highly eective
memory processing when asleep. Primitive sleep would have compensated for
a gradually developing potential conict, namely, the need to accomplish all
these interrelated neural activities in partially shared circuitry during a continuous
waking state.
In this connection, Moorcroft (1989) made a general suggestion similar to that
proposed here and earlier (Kavanau, 1996, 1997), namely, that sleep provides a
period when certain activities can occur most easily and most eciently. In a
similar vein, Maquet (2001) suggested that [s]leep could be a privileged period for
memory consolidation. . . . Some mental dysfunctions may exert their inuences
through reducing the eciency of brain operations. Thus, the cerebellum may
expedite the automation of motor and cognitive skills. Rutherford (2003) proposes
that cerebellar dysfunction slows or prevents this automation. Either circumstance
could take a toll on cerebral performance, aecting connections between the senses
and physical functions as well as the ability to organize, create, and complete
thoughts and tasks. This certainly seems to be the case for the cognitive and motor
functioning of patients who have cerebellar dysfunctions.
6 J. L. Kavanau
In incipient stages of sleeps evolution, the brain functions that now occur
independently during waking and sleep probably occurred competitively. However,
compelling evidence indicates that the conicting needs now have become
incompatible during wakefulness. Some memory consolidation involving detailed
visual discriminations cannot occur during waking. It absolutely requires sleep
(Gais et al., 2000; Stickgold et al., 2000). This unequivocal establishment of a
specic vision-related activity that requires sleep lends strong support to the
foregoing paradigm for the role of detailed focal vision in sleeps origin. This
paradigm already is persuasively supported by ndings that sleep occurs only
in animals with complex image-forming eyes, as opposed to eye spots and
light-sensitive pigment cups and tubes, that to sleep, many animals must block
visual input, by closing their eyelids or other means, and that, in some
animals, unihemispheric sleep automatically ensues when one eyelid is closed (see
Kavanau, 1997).
One should not lose sight of the circumstance that, despite the potential neural
processing conicts referred to earlier, continuous dynamic interactions of sensory
inputs with ongoing neural activities are intrinsic to waking brain function. Even
at its most basic levels the central nervous system (CNS) is not organized to yield
particular responses to particular stimuli, but instead, to accomplish particular
objectives. Rather than mirroring the external world, the CNS embodies a dialog
between internal states, generated by intrinsic electrical activity of nerve cells and
their connectivity, and sensory information. With respect to the visual input, which
is of greatest interest here, activity in the feline cortex depends not only on the
nature of a visual stimulus, but also on the cortical state at the time of stimulation
(see Ringach, 2003). Sensory stimuli gain their signicance by virtue of triggering a
preexisting disposition of the brain to be active in a particular way. If a stimulus is
not put in the context of thalamocortical reality by becoming correlated temporally
with ongoing neural activity, it does not exist as a functionally meaningful event
(Llinas and Pare, 1991; additional Refs. in Kavanau, 1997).
This proposal for the origin and function of primitive sleep does not
preclude subsequent or concomitant evolution of secondary functions that may
have become essential. Indeed, for birds and most mammals, secondary functions
of sleep come into play, some of which are discussed below, as well as deep-
seated rhythmical changes that engage many physiological systems (Vertes, 1990;
Everson, 1995).
The lifestyles of vertebrates that never sleep are fully consonant with the above
proposals. As would be expected, since genetically blind, cold-blooded vertebrates
that live in caves have no visual input, there can be no visual processing conict,
so no sleep is needed. However, many continuously swimming shes that possess
detailed focal vision, such as tunas and many sharks, do not sleep, either. Their
lack of a need for sleep can be attributed to their lifestyle, in which needs
for processing both sensory information, predominantly visual, and long-term
Evolutionary Aspects of Sleep and Its REM and NREM States 7
experiential memories, are greatly reduced and, therefore, do not conict with each
other. These reductions owe to the following aspects of shark and tuna behavior
and ecology: (1) their visual input is greatly reduced or absent during lengthy periods
of both diurnal and nocturnal activity; (2) schooling greatly reduces needs for
environmental sensory information, particularly visual; (3) their circuitry for most
inherited memories needs no supplemental reinforcement, because it is maintained
through almost continuous use; and (4) because they lead a comparatively routine,
monotonous existence in essentially featureless, open waters, they acquire, and have
need to reinforce, relatively few experiential memories. Analogous circumstances
could account for the ability of migratory birds to y for days without rest or sleep
(Kavanau, 1998a, 2001a).
In view of the proposed role of detailed focal vision in the evolution of sleep,
some comments are in order concerning the need for sleep in congenitally and
adventitiously blind mammals. The resolution of the seeming disparity hinges on
three principal factors: (a) the same amount of visual cortex, in need of extensive
reinforcement, exists in both sighted and blind animals; (b) the high metabolic rates
of endothermy (loosely speaking, warm-bloodedness), with an accompanying
relatively high rate of degradation and functional depletion of molecules essential
for synaptic function, and a correspondingly more frequent need for replenishment
of these molecules by reinforcement during sleep; and (c) the great plasticity and
high adaptability of visual cortices which, when unused for vision, take over the
implementation of other sensory modalities (Rauschecker, 1995). Secondary roles of
sleep rest, rejuvenation, etc. far removed from the functions of origin, also come
into play.
Concerning item (a), many neurological and neurophysiological studies in
non-genetically blind humans and/or cats have given uniform results. Although
the optic nerve, optic chiasm, and lateral geniculate nucleus may degenerate,
neocortical visual regions undergo no size reduction and show no evidence of
organic change. They remain highly active, metabolically and electrically, with
highest activity in the striate and prestriate regions (Wanet-Defalque et al., 1988;
Yaca et al., 1999; additional Refs. in Kavanau, 2001b). Moreover, in monkeys
and cats visually deprived since birth, the electrical activity that develops spon-
taneously in neurons of visual regions resembles that in non-deprived animals
(Roder et al., 1997).
The observations of item (a) probably are accounted for partly by the
development of cross-modal compensatory plasticity encompassed under item (c).
Evidence has been mounting of a great potential for such plasticity in vertebrate
visual neocortical regions, many of which take on supplemental auditory and tactile
functions. Many visual regions also normally process auditory and somatosensory
inputs (Rolls, 1991; Van Essen et al., 1992). These circumstances are well exemplied
by human cortical visual regions. Thus, the level of activity in the primary and
secondary visual cortices of congenitally and adventitiously blind subjects during
8 J. L. Kavanau
various auditory and tactile tasks is higher than in sighted, blindfolded controls
(Sadato et al., 1993), including the activation of cortical visual associative areas of
congenitally blind subjects during auditory localization tasks (Aziz-Sultan
et al., 1997).
Additionally, cross-modal compensatory plasticity is known in ferrets, Syrian
hamsters, rats, and blind mole rats (Rauschecker, 1991; Roe et al., 1992; Doron
and Wollberg, 1994). To these ndings, one can add the responsiveness of all
neurons in some regions of the visual cortices of cats to auditory stimuli, and
improved auditory localization by visually deprived animals (Diamond, 1982;
Rauschecker, 1991; Van Essen et al., 1992; Yaca et al., 1999). In essence, loss of
visual input to mammalian visual cortical regions does not lead to their inactivity
or size reduction; rather, the regions take on highly active roles in the service of
other sensory modalities (see also, Kavanau, 1999, 2001b).
With the knowledge that the occurrence of sleep, or lack thereof, in shes is
dependent upon their behavior and ecology, and that marine vertebrates preceded
land vertebrates, it is likely that the earliest vertebrate sleep occurred in shes.
Prominent among modern-day shes with detailed focal vision that engage in sleep
are many teleosts (bony shes) that occupy complex coral reef habitats. Teleosts,
however, date back only about 235 My (million years) to the early Triassic, so
the earliest primitive sleep in shes might have originated much earlier, say in
small, shallow-water or reef sharks the earliest jawed shes living in complex
habitats, during or more recently than the Ordovician period, about 450 My ago
(Kavanau, 1998a).
Sleep in invertebrates may have an even more ancient origin. Many trilobites,
which existed from the early Cambrian (543 My ago) to the late Permian (248
My ago), had advanced visual systems, mostly paired compound eyes. In many
cases, a huge variation in size and form of the eyes with eyes secondarily lost
in bottom dwellers at great depths seemingly was related to their behavior and
ecology. In the free-swimming trilobite, Opipeuter, the large eyes dominated the
head (cephalon), providing a 360 eld of vision (Levi-Setti, 1993). The lifestyles
of some of these trilobites may have been suciently complex to require sleep.
Among mollusks, sleep is known only in cephalopods, probably the most
intelligent invertebrates, many of which have large camera-type eyes. Ancestors of
the chambered, primitive, external-shelled Nautilus, date back to the Silurian
period (435 My ago), when they were dominant and a top predator. The nautilus is
still a major predator of crustaceans in the deep sea. Its brain is very complex,
though less specialized than in other cephalopods. The modern nautilus very likely
sleeps. It is inert and withdrawn in its shell during inactivity, with respiratory
movements scarcely perceptible (see Kavanau, 1998b). As with the trilobites,
lifestyles of some ancestral nautiluses also may have been suciently complex to
require sleep.
Evolutionary Aspects of Sleep and Its REM and NREM States 9
complex retinal processing, it also led to the most rapid neural transmission
(achieved in large, myelin-coated nerves), and the highest tolerable core temperatures
(nerve conduction speed increases with temperature, which is up to 4 C greater
during ight than rest). Modern birds possess a highly procient, very fast-acting,
essentially superreptilian visual system (Refs. in Kavanau, 1987).
A relatively high degree of complex retinal processing has persisted or been
reestablished in only a few species of mammals: it is known in the rabbit (Lepus
cuniculus); ground squirrel (Citellus mexicanus); rat (Rattus norvegicus); and in
the domestic cat (Felis catus), and surely exists in some related forms (Refs. in
Kavanau, 1997). While it has become a rule that characters of living forms, once lost,
are not regained, properties of eyes are among the notable exceptions.
The adaptations of vertebrate eyes for diurnality and nocturnality are thought to
. . . come and go in evolution as mutatory capacity and ecological expedient direct
(Walls, 1967). Even avian ight has been lost and regained (Paul, 2002; Kavanau,
in preparation).
3.1. Historical
3.2. Sleep was non-uniform before the origin of REM and NREM states
According to the above proposals, an ancient sleep state in one scenario REM
sleep, in another NREM sleep, in a third, primordial sleep evolved to include
Evolutionary Aspects of Sleep and Its REM and NREM States 11
both REM and NREM states. In considering the feasibility of these scenarios, an
answer was sought to the following general question. How could selective pressures
acting on animals engaged in a uniform condition of sleep have led to its evolution
into two dierent states? Such a result, it was concluded, could not have been
produced by selective pressures, alone. The very beginning and end of a uniform
sleep period might have undergone dierential selection because, as times of
opposite transitions, they dier initially from each other. But the period of sleep
itself, could not have been selected for dierentially unless it were adaptively non-
uniform. In other words, if no part of the period of primitive sleep were more
adaptive than any other part, there could have been no selection.
Since any initial departure from an adaptively uniform period of primitive sleep
could not have arisen solely through the actions of selective pressures, dierences
in sleeps adaptedness must have been caused initially by some other means.
Environmental inuences are the only feasible candidates. Once such dierences
arose, selection could have acted. Accordingly, it was concluded that primitive sleep
in evolving mammalian ancestors must have been adaptively non-uniform before
the origin of the REM and NREM states.
One environmental variable stood out as most likely to have been responsible for
a non-uniformity of primitive sleep. Knowledge of it was a guide to how its inuence
might have aected the physiology of sleeping mammalian ancestors evolving warm-
bloodedness. In turn, this led to proposals for a chain of other evolutionary
adaptations. The further topics addressed include the origin of the REM and NREM
states from sleep that was already non-uniform, how these sleep states appear to
relate to warm-bloodedness, major actions that are believed to take place during
sleep states, how these actions may contribute to the maintenance of long-term
memories, roles of REM sleep in reinforcing memory circuits for muscle
contractions and vision, and a basis for several cycles of the NREM and REM
states occurring during a nights sleep. For expository convenience, the modes of
origin of the three salient properties of REM sleep are dealt with in sequence.
However, these properties are revealed to be causally related, and are expected to
have evolved in parallel.
NREM sleep and waking, adult mammals maintain their deep-body temperature
close ( 2 C) to a species-specic level, known as the core value. The regulatory
system behind this thermostatic (set-point) control must have deep roots, because
local heat or cold application at virtually any site in the CNS, from the spinal cord to
the cortex, initiates widespread, coordinated responses to restore the core value
(Gordon and Heath, 1986).
On the contrary, during REM sleep, when much of the electrophysiology of
NREM sleep has become altered, set-point control of body temperature, in response
to ambient temperatures outside the core-value range, does not occur (Parmeggiani,
1980). Although some actions to initiate temperature regulation might take place,
just as during NREM sleep and waking, the skeletal muscles employed in such
regulation are atonic (lacking tone) and unable to respond. Moreover, the
responsiveness of preoptic hypothalamic temperature-sensitive neurons reaches its
lowest level then (Parmeggiani, 1980). But autonomic processes involving smooth
muscles and other cellular basal metabolic processes continue, as during NREM
sleep and waking. Some control of body temperature by sweat-gland activity can
occur during REM sleep, in response to ambient temperature changes, but the
control is less sensitive than during NREM sleep (Bach et al., 2002).
Adult mammals also usually pass from one sleep state to the other, following
certain changes in ambient temperature. When the ambient value is at and near the
core value, REM sleep prevails, without set-point temperature control. But at
ambient values above or below the core value, NREM sleep ensues, with body
temperature controlled (Parmeggiani, 1980).
which may have lasted 140 My an incomprehensible time span for us proved to
be a boon. It was favored by the uniquely warmer, on average, moist and moderate,
greenhouse, mid-to-late Triassic climates (240200 My ago), and the absence of
reptilian competitors in insect-rich, nocturnal niches (Crompton et al., 1978). This
very eective ecological partitioning allowed our ancestors to ourish as
contemporaries of the dinosaurs, rather than their competitors. Elsewhere,
prevailing views of this diurnal-to-nocturnal evolutionary transition, sometimes
referred to colorfully as the bottleneck theory, have been reviewed (Kavanau,
1997, 2002a).
During this lengthy nocturnal sojourn, mammalian ancestors became dramati-
cally reduced in size. They evolved from large (up to 250 kg), day-active,
carnivorous, advanced, mammal-like reptiles (therapsids), that for several My
were dominant, and the largest terrestrial carnivores. Most of these mammal-like
reptiles became extinct at the end of the Permian period. Survivors evolved
into relatively inconspicuous, nocturnal, terrestrial-arboreal, shrew-to-rat sized
(2040 g), mammalian insectivores, a representative of which is depicted in Fig. 1.
Fig. 1. Artists rendition of a representative nocturnal, insectivorous, primitive mammal from the late
Triassic, about 200 My ago. By Hermine Kavanau, after a sketch of the animals form by Crompton et al.
(1978).
14 J. L. Kavanau
had lived millions of years earlier (Groenewald et al., 2001). However, being
herbivores rather than insectivores, Trirachodon were not in the mammalian lineage.
Just as today, ancient ancestors of mammals probably were adept at nding or
constructing, and inhabiting, nests and other secluded cover that were inconspicuous
and/or inaccessible to potential predators, and provided a favorable milieu during
inhospitable external conditions (Lillegraven et al., 1979).
Before treating the circumstances postulated to have led to the origin of REM
and NREM sleep, some additional background information is desirable. Reptiles
get most of their bodily heat directly from the sun, and the temperature of all
except the largest of them tends to track the ambient value. While largest reptiles
achieve some degree of independence from ambient temperatures, most small
representatives are lethargic, or even helpless, in the cold of the night, and must
await being warmed by the sun to become active. Even during activity, however,
reptiles rely on a non-sustainable, anaerobic metabolism for almost all activities,
and they generally fatigue rapidly as a result of cellular lactic acid accumulation.
Mammals and birds, on the other hand, raise their body temperature mostly by
producing heat internally through prodigious rates of cellular oxygen consumption
and, as noted earlier, usually maintain a constant, elevated, species-specic core
value. This often requires bodily heating at some times, and cooling at others, and is
very costly energetically. The greater the skin, deep-body, or brain temperatures
deviate from their set-point values, the greater the magnitude of the heating and
cooling recovery eorts referred to as proportional control (Gordon and Heath,
1986). This ability to control body temperature, and an accompanying increased
aerobic scope for metabolism, confer great advantages. Animals so endowed usually
can sustain relatively high levels of activity full muscular power, with fully
functional sensory faculties in hunting or escaping for lengthy periods at any time
of the day or night, and in all seasons. They also can forage widely and undertake
long migrations.
The core temperatures of living primitive mammals, such as monotremes, are
in the range 3032 C, those of marsupials (giving pouch birth) in the range
3436.5 C, and those of most other mammals in the range 3638 C (Dawson, 1973).
All groups, however, are considered to be well adapted, because a suciently
high core value, and an accompanying nely tuned chemostatic system, have
great adaptive value. The specic values of the appropriate core temperatures
in mammals are greatly dependent on the niche occupied. The core value of the
shrew-to-rat sized ancestors of mammals, conned to nocturnal activity for tens of
My, is believed to have attained 2831 C, but not necessarily entailing an increase in
resting metabolic rate. Only after dinosaurs became extinct during the late
Cretaceous (9565 My ago), were many mammals able to resume daytime activity,
probably several times independently, and achieve todays higher core temperatures
and much greater sizes (Heath, 1968; Crompton et al., 1978).
By then, there had been considerable evolutionary radiation among marsupials
and placentals. Some descendants, including most families of insectivores, remained
in their more conservative nocturnal niches, and retained ancestral, reptilian, low
metabolic rates. Indeed, most shrews continue to rely more on their senses of
16 J. L. Kavanau
hearing, smell, and touch than on vision (Lillegraven et al., 1979). Additionally, eyes
of monotremes have retained their reptilian organization (Walls, 1967). Among all
living mammals, a marsupial, the common opossum, Didelphis virginiana,
most merits the title living fossil, with a skull reminiscent of a Triassic
mammal-like reptile, and a typically reptilian threat posture and manner of attack.
(MacLean, 1986).
favorable climates through the Jurassic and on into the Cretaceous), with monsoonal
precipitation, lengthy Carnian pluvial period, and moderate temperature regimes,
also assume great signicance in this regard. Their eect would have been to relieve
constraints on evaporative cooling and reduce needs for it during extended periods
of daytime sleep, both by providing moist conditions and comparatively moderate
maximum ambient temperatures.
For illustration, some inuences of moderate nest shading on present-day, 24-h
variations in ambient temperature and relative humidity are indicated in Fig. 2,
with sensors for temperature and relative humidity in the nest, that is, in a
partially foliage-shaded, wire-mesh enclosure (Kavanau and Rischer, 1973). Sunrise
began at about 5:40 a.m. with the enclosure temperature at about 15 C. Temperature
increased very gradually for 2 h to about 17.5 C. Thereafter, it increased rapidly
to about 25 C at 9:10 a.m., peaking at about 27 C at 3:10 p.m. After that, it dropped
rapidly to about 20 C at sunset, at about 6:10 p.m. On typical autumnal nights the
drop in enclosure temperature between sunset and sunrise was about 5 C. The
signicance of these present-day examples of weather variables and their changes
during the course of a day are limited in their implications for the warmer, on
average, more equable, Triassic climates. Only the lags in changes between light
level, enclosure temperature, and relative humidity may be roughly indicative for a
moderately sheltered nest.
It can be suggested that: (a) nest temperature after dawn, whatever its absolute
value, would have remained fairly constant, rising at most 2 C in the rst 2 h;
(b) although the greatest heat stress probably would have been in mid afternoon,
nest temperatures would have dropped relatively rapidly in the next 3 h; and (c) the
temperature in the nest probably was higher during late dusk than during early
dawn. Changes in weather variables induced by the eclipse suggest that nest
temperatures might have lagged light-level changes by about 1/2 h, and similarly for
the lag of nest relative humidity values, after changes in nest temperature.
The predominantly opposite changes in relative humidity with temperature largely
reect the relationship that, when the amount of water vapor remains unchanged,
the relative humidity decreases as the temperature rises, and vice versa. Also to be
taken into consideration are the circumstances that multivariable mechanisms
of acclimation would have played a role, possibly including toleration of limited
periods of late-afternoon mild dehydration during sleep.
Many living mammals maintain core temperatures that are well below daytime
ambient values. But this is achieved through various highly specialized anatomical,
physiological, and behavioral adaptations, even in most inhospitable climates. In
Mesozoic times, it was probably mostly the uniquely favorable climates that made it
possible. Further indicative of the key role played by water relations in the evolution
of warm-bloodedness, is a remarkable structural adaptation with beginnings also
thought to trace to Triassic ancestors. This is the development of a series of thin,
often highly convoluted sheets of bone in enlarged nasal passageways the turbinals
or respiratory conchae. These lie directly in the path of respired air, and are essential
for the high lung ventilation rates of warm-bloodedness. They are almost ubiquitous
among mammals and birds, but absent in ectotherms, which possess only the
18 J. L. Kavanau
Fig. 2. Daytime course of meteorological variables in a rooftop enclosure at UCLA, on the day of 60%
solar eclipse (09/11/1969). The recording occurred while studying the activity of an antelope ground
squirrel, Ammospermophilus leucurus, in a running-wheel enclosure. Each dot in the running record gives
instantaneous speed and direction at 2.4-s. intervals. Inuence of the partial eclipse on weather variables
reveals inherent interrelationships. Curve for light intensity is at left, with illuminance levels marked at
40,000 and 100,000 lux (meter-candles). Corresponding twilight curves are at the bottom and top, at
greater magnication, marked at 10-lux values. The curve for temperature within the partially shaded
enclosure is also at left, with corresponding increasing values indicated from left to right along abscissa.
Note the gradual, essentially monotonic, increase in temperature in the morning, the lagging arc of
temperature decrease following the partial eclipse, and the continued, essentially monotonic, increase until
mid afternoon, when it decreases again, as the light level declines rapidly (h indicated at right ordinate).
Percent relative humidity is recorded to left, with values declining rapidly from about 8:00 to 10:00 a.m.,
with the lowest values at about 2:30 p.m., scaled on abscissa from right to left at bottom left. The arc
of increasing humidity lags the arc of causative temperature decrease, following the reduced light level
(from Kavanau and Rischer, 1973).
Evolutionary Aspects of Sleep and Its REM and NREM States 19
olfactory counterparts (Hillenius, 1994). They recover much water from expired air,
and would have contributed greatly to both water and heat conservation by
Mesozoic mammalian ancestors during their nocturnal activity periods.
How did natural selection acting on non-uniform sleep, including periods with
and without control of body temperature, lead to the other salient properties of
REM and NREM sleep? In exploring this matter, it is essentially the dierences
between REM and NREM sleep for which an accounting is sought. Inasmuch as
almost all set-point mechanisms of body temperature control directly or indirectly
involve a variety of multifaceted behavioral and autonomic muscle contractile
systems including panting, respiratory rate, piloerection, shivering, licking, and
spreading of saliva the absence of a need for set-point temperature control during
certain periods of sleep in ancestors of mammals evolving warm-bloodedness, would
have translated directly into the absence of a need for almost all skeletal muscle
contractions.
But the very circumstance of skeletal muscles having been unused during certain
daily periods of sleep, if adaptive, would be expected to lead, evolutionarily
speaking, to relaxation and eventual absence of skeletal muscle tone (atonia) during
these periods the putative forerunners of REM sleep. Accordingly, assuming their
adaptedness, two salient properties of REM sleep in adult mammals have been
accounted for, namely, absences of both set-point temperature regulation and
skeletal muscle tone. Accounting for the third salient property, predominance of
fast brain waves ( 14 and up to 800 cycles/s Hz) of relatively low voltage in
electroencephalograms (EEGs) of REM sleep, as opposed to predominance of
slow waves ( 14 Hz) of greater voltage in EEGs of NREM sleep (Fig. 3), requires
an introductory discussion. This concerns some major actions eected by brain
waves during waking and sleep. As we shall see, it is to the great adaptedness of the
presence and actions of fast waves in REM sleep, that we can trace the adaptedness
of the other two salient properties aforementioned.
Both slow and fast brain waves are present during waking. The fast waves
greatly predominate, and all waves are of relatively low voltage. In fact, the EEGs
of most waking mammals are very similar to those of their REM sleep (Fig. 3).
Unsurprisingly then, the brain is believed to be engaged in many of the same
activities during these two vigilance states. Wakefulness, of course, is highly adaptive
in obvious ways. Accordingly, one can suspect, with considerable justication, in
view of the brain-wave similarities, that REM sleep probably is adaptive for at
least one of the same reasons as is wakefulness. As proposed above, the key to REM
sleeps principal adaptive feature, like one of the features of wakefulness, lies in
the presence and actions of fast waves, specically their roles in assembling and
reinforcing mnemonic neural circuitry.
Of pertinence to these actions, von der Malsburg (1981) proposed his cell
assembly hypothesis, according to which the thoughts, perceptions, and actions
(hereafter referred to as events) of conscious activity are brought about through
20 J. L. Kavanau
A major basis for dierences between NREM and REM sleep, as regards roles
in the long-term maintenance of memories, hinges on the well-established
circumstance mentioned earlier: individual component circuits of long-term
memories in brains of advanced organisms came to exist at widely separated
locations as the brains organization and specializations evolved. As a result of
having become distributed in this way during their establishment in memory
(the initial phase of memory formation, known as consolidation), contents of
component neural circuits have to be brought together and recombined to express
fully-formed memories in which they participate. Following the present analysis,
ability to accomplish these vital long-term memory maintenance processes
most eectively during sleep, rather than only during waking, awaited the evolu-
tion of warm-bloodedness, with the presence and actions of fast waves during
REM sleep.
Concerning the occurrence and actions of brain waves in reptiles, slow waves
generally predominate during rest and sleep. Fast waves, thought to accomplish
coordinated reinforcement, make their appearance during arousal and wakefulness
(reviewed in Kavanau, 1997, 2002a). Accordingly, it would follow from this
treatment that the basic function of the slow waves that characterize reptilian sleep
and NREM sleep in mammals and birds (aside from roles in memory consolidation)
is uncoordinated reinforcement, dened and discussed before as it is thought to
occur during waking. In this reinforcement process, weakened synaptic strengths
within individual component circuits become strengthened. Except that slow waves
are thought to act preferentially on most recently used or recalled circuits, they
probably act without selectivity on individual component circuits of all memories
(Kavanau, 2002a). Following this analysis, uncoordinated reinforcement would
have been the original sleep-associated mechanism of long-term memory mainte-
nance of cold-blooded vertebrates, inherited by mammals and birds as a chief
action of slow brain waves during NREM sleep.
It is well established that stimulation of circuits that control skeletal muscle
contractions during both the sleep of cold-blooded vertebrates and NREM sleep of
warm-blooded vertebrates, fails to produce contractions, because the innervated
muscles are hypotonic (partial loss of tone) at these times. Only uncoordinated
twitches often occur. Although the hypotonic muscles do not contract, the activated
component circuits that control their contractions become reinforced. Similar
stimulation and reinforcement of the individual component circuits of memories of
thoughts and perceptions also lead to reinforcement. However, they fail to lead to
22 J. L. Kavanau
awareness. But the latter failure is for a dierent reason than the failure of muscle
contractions. As suggested above, it is because mere fragments of memories (analogs
of muscle twitches) cannot penetrate consciousness, just as uncoordinated muscle
twitches cannot lead to contractions.
Fast waves of REM sleep also lead to reinforcement of circuits controlling skeletal
muscle contractions, but the muscles do not contract then, either because they are
completely without tone. But, contrary to circumstances during NREM sleep, fully-
formed, long-term memories of thoughts and perceptions are assembled, bound, and
reinforced by the fast waves (coordinated reinforcement) of REM sleep, just as
during waking. The crucial departure from the aftermath during waking, is that
reinforcement of events during REM sleep becomes manifested only as dreams.
Several known dierences from waking conditions, not mutually exclusive, that
result in these events being expressed only as dreams, are: atonia in large muscle
masses; a high (but not complete) degree of perceptual isolation from external
stimuli; all the dream events originating within the brain; and reduced behavioral
responsiveness, as characterized by sleep researchers (e.g., Rechtschaen, 1998).
The latter, perhaps, was achieved during evolution of REM sleep primarily by
selection for lower voltage fast waves, of somewhat dierent composition from those
of waking (Kavanau, 2002a) (see Fig. 3, noting voltage-scale dierences).
the two sleep states of mammals and birds, the NREM state most approximates
ancestral conditions. One should mention, in this connection, that minor
components of fast waves (e.g., ripples) persist during NREM sleep (see
Kavanau, 2002a,b). These could be responsible for small amounts of coordinated
reinforcement, probably contributing to NREM dreams, which are more thoughtlike
than those of REM sleep (Solms, 2000).
The primitive, retained reptilian mechanism of long-term memory maintenance
by slow waves during sleep hinges on an indirect strengthening of residual links
between individual, distributed, component circuits which, taken together, comprise
fully-formed memories. This mechanism of strengthening residual links (synaptic
connections) appears to depend on one of the most widely studied phenomena
in neuroscience, treated recently by Zhou et al. (2003). When two synapsed neurons
are activated in sequence within a few milliseconds, long-term changes (potentia-
tion or depression) are induced in their linking synapses. The type of change
is determined by the order of activation of the pre- and postsynaptic neurons.
With individual links reinforced indirectly in this way during NREM sleep, even
though with less overall eectiveness than by coordinated reinforcement of fully-
formed memories during REM sleep, long-term memories are stored and available
for recall. It is typically the case in such circumstances, that the more recent the
last recall or expression of a memory to which the links contribute, the stronger
the links are.
A fundamental basis for the very close interlinking of circuits that control skeletal
muscles and achieve vision, and for vivid visual accompaniments of movements in
dreams, probably owes to the following suggested correlation (Kavanau, 2002a).
Vision in vertebrates did not, as one might assume, evolve primarily for the sake of
the multiple advantages of excellent sight. Rather, it evolved primarily in response
to crucial, primordial, perceptual needs for precisely timed control of bodily
movements in hunting and escape (Milner and Goodale, 1995). This very close
association has recently received convincing experimental conrmation. Many
neurons in parietal, prefrontal, and motor cortical areas are activated both by
the particular movements that they control and by the visual stimuli that trigger
these movements (Toth and Assad, 2002). Such relationships are strikingly
illustrated in humans: the so-called mirror neurons in brain regions active during
a subjects motor activity, also are active when the subject views someone else
engaged in the same activity (Buccino et al., 2001). As a result of this intrinsic
linkage, when either type of circuitry (motor or visual) is activated during REM
sleep in the process of coordinated reinforcement and dreaming, the other type
often is activated as well.
Other signs of this primordial association also are evident. In many situations,
neuronal activity in primary visual cortex (region V1) is better correlated with
perception than with activity in higher visual regions. And region V1 has unique
properties, well-suited for participating in the control of behavioral movements: it is
24 J. L. Kavanau
the rst cortical region to receive aerents from the lateral geniculate nucleus; it is
the largest visual cortical region; it has the highest resolution retinotopic map
and smallest receptive elds; and it has independent input from both eyes
(Paradiso, 2002).
In view of the above, the very close ties between visual and movement perceptions
in dreams, and also between synaptic reinforcements that have the highest priority
during REM sleep, should be no cause for surprise (see Kavanau, 2002b). And the
critical need for skeletal muscle-controlling circuitry to be maintained in a high
degree of competence should apply with equal force to many visual (visuomotor)
circuits. In this connection, Solms (2000) has observed, [f ]ew people would disagree
that the average NREM dream is more thoughtlike than the average REM
dream. The above considerations help to account for this phenomenon. Since
memories for movements and vision have highest priority for reinforcement
during REM sleep, it falls to many thoughtlike memories to be reinforced during
NREM sleep, presumably mediated by the ripples and other minor fast-wave
components.
3.10. Absence or lesser amounts of REM sleep in marine mammals and birds
The pertinence of REM sleep for reinforcement of circuitry for vision and
gross bodily movements can be gauged by reference to the practices of mammals
that lack REM sleep. Several marine mammals, including dolphins, sea porpoises,
and white whales, are continually in motion, with their skeletal muscles and visual
systems in virtually continuous use. In this mode of life there is no need for
ancillary reinforcement of visual and muscle-controlling circuits. Accordingly,
there is no need for a sleep state in which gross bodily movements are inhibited
and, therefore, no need for, nor engagement in, REM sleep. These animals
engage only in NREM sleep, which usually occurs in only half of their brains at a
time (unihemispheric sleep), and with only one eye closed (Mukhametov, 1984;
Lyamin et al., 2002).
Moreover, these marine mammals have excellent memories. Their otherwise
normal existence with no evident memory handicap not only establishes that REM
sleep is not essential for their memory acquisition and maintenance, but also that
NREM sleep alone, achieves all mnemonic-supporting functions to the required
degree. These circumstances support the proposal that the original mnemonic
functions of REM sleep primarily supplemented those of NREM sleep.
The REM sleeps origin did not entail loss of the capability of NREM sleep to
reinforce circuitry, it merely accomplished a more eective specialization of these
capabilities, namely, coordinated reinforcement of fully-formed memories and links
between them.
The same selective forces, with very similar results, appear to have been in eect
for birds. Avian species that put their antigravity muscles to the greatest and most
lengthy continuous use need the least REM sleep, together with much lesser needs
for hypotonia in only 335% of REM episodes and with atonia rare (Amlaner
and Ball, 1994). This probably is because synaptic strengths in their heavily used
Evolutionary Aspects of Sleep and Its REM and NREM States 25
With this preamble, I consider the origin of the third salient, and proposed highly
adaptive, property of REM sleep, the presence and action of fast waves. As noted
earlier, with warm-bloodedness evolving, and the daytime-sleeping ancestors of
mammals exposed to ambient temperatures in their core ranges, set-point control of
body temperature would have ceased and skeletal muscles would have become
atonic, just as during REM sleep today. Since fast waves bring about the thoughts,
perceptions, and actions of the consciously active animal, they could not have been
present during primitive sleep. Had they been present, consciousness would not have
been lost (see, also, further discussion). This is the basis for the conclusion drawn
here, that slow waves activate only component circuits (fragments) of memories that
cannot penetrate consciousness. But upon attainment of a condition with set-point
control of body temperature suspended, and with skeletal muscles atonic, fast waves
no longer would have been maladaptive and selected against, since they could no
longer have disrupted sleep by stimulating gross movements.
Inasmuch as fast waves are thought to reinforce fully-formed, long-term
memories that control muscle contractions, rather than only individual fragments,
26 J. L. Kavanau
direct fast-wave reinforcement during atonic primitive sleep would have been
much more eective than indirect reinforcement by slow waves during hypotonic
periods. Accordingly, selective pressures, which favor most eective or ecient
mechanisms, would have favored persistence of the fast waves of waking during
those periods of primitive sleep in which muscles were atonic the putative
forerunners of REM sleep.
But anything adaptive for reinforcing circuits of long-term memories that
control muscle contractions, also would be expected to be adaptive for reinforcing
circuits for other fully-formed, long-term memories those of thoughts and per-
ceptions. In that event, just as seen above, selection would have even more heavily
favored sleep with fast waves present, thereby making possible reinforcement of
circuits for all events, but without conscious awareness. Awareness at these
times would have been only non-conscious, namely, dreaming, as accounted for
earlier.
Absence of set-point temperature control and skeletal muscle tone during REM
sleep may not, in themselves, be adaptive. In fact, their apparent maladaptedness, in
that they appear to leave the sleeper more vulnerable during REM sleep, has puzzled
sleep researchers ever since these properties were discovered. The properties appear
to gain adaptedness the greater vulnerability aspect being obviated largely by the
use of safe sleeping quarters (as discussed earlier) mainly by virtue of enabling the
persistence of fast waves during REM sleep. In this way, appreciable additional
periods beyond wakefulness are created for the actions of the putatively most highly
eective mechanism for reinforcing long-term memories, namely, for coordinated
reinforcement by fast waves.
It was concluded earlier, that the selective pressure for the origin of sleep was the
need to ameliorate conicts between the brains need to meet crucial, largely
unpredictable, moment-to-moment needs and, at the same time, meet needs to
acquire, consolidate, and reinforce memories, all being accomplished largely in
shared neural regions. The acquisition of sleep by ancient vertebrates is thought to
have resolved these conicts. In the light of the foregoing treatments of brain waves,
the resolution can now be dealt with more explicitly.
If the aforementioned conicts that led to selection of sleeps origin arose
from the increasing waking need to acquire and maintain large stores of memories
of new and old waking experiences, the new vigilance state of primitive sleep
should have provided the unrestricted opportunity to fulll this need. Since
the fast waves that activate and temporally bind distributed component circuits
of memories produce awareness during waking, it follows, as noted before, that
fast waves could not have been present during the evolving vigilance state of
primitive sleep.
Accordingly, at the neurophysiological level, the selective pressure for primitive
sleep would have favored a progressively reduced presence of fast waves during
restful waking, culminating in sleep. Indeed, this is what happens when we fall
Evolutionary Aspects of Sleep and Its REM and NREM States 27
6. Overview
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Advances in
Cell Aging and
Gerontology
Contents
1. Introduction
2. Normal sleep and the effects of the aging process
2.1. Age-related sleep and circadian changes
2.2. Gender differences in sleep and aging
2.3. Nocturia
3. Epidemiology
3.1. Prevalence
3.2. Risk factors
3.3. Morbidity
3.4. Mortality
4. Common sleep disorders in older age groups: nature and etiology
4.1. Sleep-disordered breathing (SDB)
4.2. Primary insomnia
4.3. Circadian rhythm disorders
4.4. Sleep-related movement disorders
4.5. Secondary sleep disturbances
5. Assessment and diagnosis of sleep problems in older adults
5.1. Clinical interview
5.2. Psychological assessment
5.3. Sleep logs
5.4. Actigraphy
5.5. Polysomnography (PSG)
5.6. Multiple sleep latency test (MSLT)
6. Treatment of sleep disturbances in older adults
6.1. Sleep-disordered breathing
6.2. Positive pressure devices
6.3. Primary insomnia
6.4. Secondary insomnia
1. Introduction
Human sleep patterns reect characteristic changes in brain wave activity that
can be quantied via electroencephalography (EEG) and categorized into two
distinct brain states: non-rapid eye movement (NREM) sleep and rapid eye
movement (REM) sleep. The NREM sleep consists of stages 1, 2, 3, and 4, reecting
a continuum of lighter to deeper sleep. Stage 1 is a transitional period of light sleep
that occurs when falling asleep. Stage 2 comprises the largest portion of sleep
throughout the night. Together, stages 3 and 4 represent deep sleep, during which
slow wave EEG activity dominates. The REM sleep is distinguished by vivid dream
activity, rapid eye movements, muscle atonia, and an EEG pattern that resembles
wakefulness. Adults typically cycle through deepening stages of NREM sleep
followed by an episode of REM sleep every 90120 min throughout the night.
Greater amounts of deep sleep (stages 3 and 4) occur in the rst half of the night,
with increased REM sleep in the latter half. Although the exact functions of sleep
are unknown, sucient amounts of both NREM and REM sleep are necessary for
full restorative benet (Morin, 1993).
100%
% of sleep period
80%
Wake
60%
Stage 1
40%
REM
20% Stage 2
Stages 3 & 4
0%
16-19 20-29 30-39 40-49 50-59 60-69 70-79
Age
Fig. 1. Objective sleep changes with aging. Data reported in Williams et al. (1974).
physiology (Prinz et al., 1990). As depicted in Fig. 1, older adults have increased
light sleep (stages 1 and 2) and corresponding reductions in deep sleep (Williams
et al., 1974). Compared to younger adults, older adults take longer to fall asleep
and spend more time awake during the night; their sleep is characterized by
frequent arousals and stage shifts reecting sleep fragmentation (Morgan, 2000;
Floyd, 2002). Although they spend longer periods of time in bed, they experience less
overall sleep time. In addition, age-related changes in breathing and ventilatory
responses may predispose older adults to sleep-disordered breathing (SDB) (Janssens
et al., 2000).
Older adults also experience changes in their endogenous circadian rhythms
thought to be the result of deterioration of the suprachiasmatic nucleus in the
hypothalamus (Bliwise, 2000b; Van Someren, 2000). These changes are characterized
by a attening of the circadian amplitude and a weakening of circadian entrain-
ment (Monk, 1989). Consequently, older adults are more sensitive to disturbances
in circadian timing and thus more susceptible to jet lag and shift work disorders
(Monk, 1989; Morgan, 2000). Age-related circadian changes cause a forward shift
in the sleep phase, associated with earlier bed and rising times. This advanced
sleep phase in part may explain the complaint of early morning awakening
common in this population.
From the above discussion, it is clear that age-related sleep changes result in a
deterioration of the nighttime sleep pattern. It is important to note, however, that the
process of aging does not guarantee the development of a sleep problem. Most
older adults experience the aforementioned age-related sleep and circadian changes,
whereas not all older adults complain of sleep disturbance. Thus, it appears that
sleep changes due to normal aging are predisposing but not sucient for the
development of sleep problems.
Men have greater diculty maintaining sleep with more wake time during the
night, more light sleep, and a higher incidence of primary sleep pathologies than do
36 M. M. Loiselle et al.
women (Gottlieb, 1990; Floyd, 2002). Despite these dierences, women are more
likely to report sleep problems and to use sleep medications (Bliwise, 2000b). Studies
also suggest that circadian phase advances are greater in women than in men
(Bliwise, 2000b). Furthermore, menopause aects sleep patterns via hormonal
mechanisms and is commonly associated with complaints of insomnia, sleep
disruption, and fatigue (Moe, 1999).
2.3. Nocturia
Nocturia, the need to urinate multiple times during the night with a consequent
disruption of sleep, increases signicantly with age and is very common in older
adults. By age 60, over half of all individuals experience nocturia, and this problem
increases to at least 80% of 80-year-olds (Donahue and Lowenthal, 1997; Jennum,
2002). Causes of nocturia include excessive nighttime urine production, reduced
bladder capacity, prostate problems, or other underlying medical conditions
(Jennum, 2002). In some cases, nocturia may be a result of untreated SDB (Bliwise,
2000b; Russo-Magno et al., 2001). Whatever its etiology, nocturia is a common
cause of sleep maintenance complaints in older adults (Bliwise, 2000b).
3. Epidemiology
3.1. Prevalence
Ancoli-Israel et al., 1991b). Restless legs syndrome and periodic limb movements are
common sleep-related movement disorders that respectively occur in 28% (Clark,
2001) and 45% (Ancoli-Israel et al., 1991a) of the aged population. Finally, disorders
involving unusual sleep-related events such as dangerous dream enactments or
motor paralysis upon awakening also show relative propensities to occur in older
adults (Wing et al., 1999; Mahowald and Schenck, 2000).
Since subjective sleep/wake complaints and various sleep disorders are relatively
prevalent among older adults, it is tempting to conclude that age operates as an
independent risk factor for sleep/wake pathology. However, aging itself is often
accompanied by marked changes in vocational status, social activity, health,
and lifestyle in general (Bliwise, 2000b; Krystal et al., in press). Each of these age-
related factors may have a powerful inuence on sleep/wake functioning
independent of the aging process alone. As such, age, per se, may not represent a
specic risk factor for either sleep complaints or specic sleep disorders. Rather, age
may only serve as a proxy for other factors that more directly enhance risk for such
conditions.
Clearly, complaints of insomnia and daytime somnolence are strongly inuenced
by various age-related risk factors. Declining health status often accompanies
aging and appears to operate as an independent risk factor for sleep/wake
dysfunction. Indeed, a variety of studies have shown that perceptions of poor health
as well as medical conditions such as angina, respiratory disorders, arthritis, chronic
pain, visual impairment, and nocturia all enhance risk for both nighttime sleep
disturbance and daytime sleepiness in older age groups (Blazer et al., 1995; Foley
et al., 1995; Newman et al., 1997; Maggi et al., 1998; Whitney et al., 1998; Roberts
et al., 1999; Bliwise, 2000b; Zizi et al., 2002; Byles et al., 2003). Additionally, various
studies have shown that the presence of psychiatric disorders and depression in
particular enhance risks for sleep/wake complaints in aged samples (Blazer et al.,
1995; Morgan and Clarke, 1997; Newman et al., 1997; Schechtman et al., 1997;
Maggi et al., 1998; Whitney et al., 1998; Roberts et al., 1999; Byles et al., 2003).
Furthermore, somatic and mental disorders seemingly account for a substantial
proportion of the increased sleep/wake dysfunction among older adults as
compared to younger age groups. In fact, when community-dwelling older adults
are thoroughly screened to exclude those with sleep-disruptive medical and
psychiatric conditions, fewer than 4% report signicant sleep-related diculties
(Vitiello et al., 2002).
However, even healthy older adults may be subject to certain age-related risk
factors that enhance their chances of suering sleep/wake diculties. In particular,
psychosocial and behavioral changes that accompany aging may have signicant
eects on sleep/wake functioning. Death of a spouse leading to extended
bereavement has been noted as a common cause of sleep diculty in older
populations (Hall et al., 1997). Many older adults face a reduction in their social and
physical activities after retiring from long-term employment. Such individuals
38 M. M. Loiselle et al.
often incur disturbance as a result of their limited physical and social activity
(Ohayon et al., 2001). Furthermore, the loss of a daily schedule accompanying
retirement often results in excessive free time for older adults. Those who attempt
to ll some of this time by spending excessive time in bed or taking daytime naps
often develop sleep diculties as a result of these poor sleep hygiene practices
(Ohayon et al., 1996).
3.3. Morbidity
3.4. Mortality
A very limited number of studies have examined the eects of insomnia and its
treatment on risk for mortality among older adults. One study (Pollak et al., 1990)
that statistically controlled for other risk factors showed severe insomnia among
men was related to increased risk for mortality during a 3-year follow-up period.
In a more recent study (Manabe et al., 2000), insomnia was found to be a signicant
Sleep Disturbances in Aging 39
This SDBs increased prevalence in older adults is due to multiple factors. The
incidence of SDB is higher in patients with neurological disorders, cardiac
conditions, cerebrovascular disease, and severe metabolic disorders, all of which
are more prevalent in older adults (Janssens et al., 2000). Snoring and obesity,
both risk factors for SDB, increase in prevalence through age 70 (Bliwise, 2000b;
Janssens et al., 2000). Although SDB is more common in men, postmenopausal
women are at an increased risk compared to their premenopausal counterparts
(Moe, 1999).
disturbances may complain that their sleep does not occur at a desirable time for
them or that their sleep is disrupted. They may also complain of insomnia, excessive
sleepiness, and general daytime dysfunction (Myers and Badia, 1995).
Given age-associated biologic, environmental, and psychosocial changes, older
adults are particularly vulnerable to advanced sleep phase syndrome, jet leg, and
irregular sleep/wake schedule disorders. Available data suggest that older adults
sleep/wake schedules are phase advanced approximately 90 mins (Neylan et al.,
1996). This phase advance causes older adults to become sleepy much earlier
(e.g., between 6:00 and 9:00 p.m.) and to waken much earlier (e.g., between 2:00 and
5:00 a.m.) than desired or required. In addition, older adults are relatively intolerant
of shifts in their sleep/wake schedules as might occur during a trip across several
time zones (Bliwise, 1993; Neylan et al., 1996). Finally, an irregular sleep/wake
schedule, characterized by random sleep throughout the 24-h day in place of a single
consolidated overnight sleep period, can emerge due to an absence of daytime
structure.
(Bliwise and Breus, 2000). A higher risk of sleep disturbance is not only due to the
increased utilization of prescription medication in this population, but also to
reduced drug metabolism, absorption, distribution, and elimination rates in
older adults (Lichstein, 2000). The main classes of prescription drugs that can
cause sleep disruption are antidepressants (particularly SSRIs), decongestants,
antihypertensives, bronchodilators, diuretics, beta-blockers, and corticosteroids
(Neubauer, 1999; Lichstein, 2000). Additionally, sedative-hypnotic use is especially
prevalent in older adults and, as discussed later, is associated with a number of
adverse side eects.
The initial assessment interview should elicit information about the duration,
course, severity, and frequency of the sleep problem. It is also important to ascertain
an understanding of contributing and alleviating factors, daytime consequences/
impairment, and responses to previous treatment. Assessment of poor sleep habits,
disruptive environmental inuences on sleep, sleep schedules, beliefs about sleep,
and family history of sleep disturbance should routinely be assessed (Reynolds, 1996;
White and Mitler, 1997). Inquiry about life events, medical illness, psychiatric
disturbance, and medication or substance use that coincided with the onset of the
sleep diculty can assist in determining etiological factors. Because individuals are
often unaware of sleep behaviors such as snoring, breathing cessation, or nocturnal
movements, interviewing the bed partner can contribute greatly to diagnostic
decision-making.
Medical history should include a review of systems most commonly associated
with sleep diculties, such as rheumatologic (e.g., arthritis, bromyalgia) pulmonary
(e.g., asthma, COPD), cardiac (e.g., heart disease), gastrointestinal (e.g., reux,
peptic ulcer disease), neurological (e.g., seizure disorder), endocrine (e.g.,
hyperthyroidism), and chronic pain disorders. Results of a medical history and
exam may uncover the need for laboratory testing (e.g., thyroid function, ferritin
levels in suspected sleep movement disorders). As mentioned previously, numerous
medications and substances cause or exacerbate sleep complaints. Current medi-
cation usage and use of illicit substances also should be evaluated. Additionally,
some individuals may resort to self-help remedies (e.g., melatonin, alcohol,
antihistamines) to promote sleep. Finally, inquiry regarding psychiatric symptoms
and history can help determine the inuence of psychological factors on the sleep
complaint and the need for further psychological assessment (discussed next).
5.4. Actigraphy
M. M. Loiselle et al.
count your final awakening here)
My awakenings lasted ____ minutes.
(List each awakening separately)
Today I woke up at ____a.m./p.m.
NOTE: This is your final awakening.
of the nocturnal sleep disturbance, assessing the 24 h sleep/wake activity pattern, and
identifying unreported daytime napping (Ancoli-Israel et al., 2003a; Standards of
Practice Committee of the American Academy of Sleep Medicine, 2003).
interventions). These treatments are reviewed briey here and discussed in more
detail in Chapter 6.
Positive pressure devices such as positive airway pressure (PAP) are the treatment
of choice for SDB. By delivering air pressure via a nasal mask, PAP prevents airway
obstruction during sleep and restores normal sleep and breathing patterns. Because
many patients use PAP only partially or are unable to use it long-term, compliance
with this treatment is a critical issue (Grunstein and Sullivan, 2000). Preliminary
studies in older adults with SDB suggest that a brief educational intervention
can enhance PAP use and that higher compliance is associated with greater
improvements in cognitive functioning (Aloia et al., 2001, 2003).
tension) and/or cognitive arousal (e.g., racing thoughts) associated with insomnia.
Treatment typically entails specic therapeutic exercises and relaxation skills
training. Once the patient gains mastery of relaxation skills, these techniques can
be used to facilitate sleep initiation by reducing sleep-related performance anxiety
and bedtime arousal.
6.3.2. Pharmacotherapy
6.3.2.1. Sedative-hypnotic medications
Pharmacological approaches for insomnia typically include benzodiazepine
receptor agonists (e.g., temazepam, zolpidem, zaleplon), sedating antidepressants
(e.g., trazodone, amitriptyline, mirtazapine), or antihistamines (e.g., diphenhydra-
mine). Although these medications eectively treat sleep disturbance, older
adults are at increased risk for drug interaction, accumulation, and toxicity due
to polypharmacy and age-related changes in pharmacokinetics and pharmacody-
namics (Gottlieb, 1990; Monane, 1992; Buysse and Reynolds, 2000). Thus, older
adults are particularly susceptible to the adverse eects of these medications, which
may include daytime sedation, respiratory depression, increased risk of falls, and
impairments in memory, cognition, and psychomotor functioning (Buysse and
Reynolds, 2000; Roehrs and Roth, 2000; Petrovic et al., 2003). Long-term use of
Sleep Disturbances in Aging 51
6.3.2.2. Melatonin
Melatonin is an endogenous hormone produced by the pineal gland. Released in a
circadian pattern during dark cycles, it functions to synchronize circadian rhythms.
Because older adults show age-related reductions in melatonin levels, melatonin
replacement has been tested as a treatment for insomnia. Although melatonin
supplementation in older adults with sleep complaints may improve sleep measures
(Buysse and Reynolds, 2000; Olde Rikkert and Rigaud, 2001) it is seldom
recommended as a long-term treatment for sleep diculties. The FDA does not
regulate the purity, quality, and exact dosage of over-the-counter melatonin
preparations, and little information exists concerning the safety, side eects, and
long-term use of this substance (Buysse and Reynolds, 2000; Martin et al., 2000).
Van Someren, 2000). Bright therapy also has been associated with cognitive
performance improvements in older adults (Murphy and Campbell, 1996).
6.6.1. Periodic limb movement disorder (PLMD) and restless legs syndrome (RLS)
Studies show PLMD and RLS are typically treated pharmacologically with
medications designed to reduce movement activity and/or improve sleep quality.
Dopaminergic agents (e.g., levodopa, pergolide, pramipexole) are the most
successful treatments (Chesson, et al., 1999b; Edinger, 2003). Other agents that
have shown treatment ecacy include opioids (e.g., oxycodone, propoxyphene),
benzodiazepines (e.g., clonazepam), and anticonvulsants (e.g., carbamazepine,
gabapentin). Iron supplementation can eectively treat RLS secondary to iron
deciency (Chesson et al., 1999b). Eective therapeutic management may also
include treatment of contributing medical disorders or discontinuation of
medications such as antidepressants that can exacerbate movement disorders.
7. Summary
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Advances in
Cell Aging and
Gerontology
Contents
1. Learning and memory
2. Learning, memory, and synaptic plasticity
3. Sleep and behavior
4. Learning-induced sleep alterations
5. Sleep deprivation and learning
6. Reactivation of neural activity patterns in sleep
7. Sleep and learning potential mechanisms
8. Summary
Over the last several decades, behavioral studies in both humans and animals
have implicated sleep in multiple forms of learning and memory, most notably
in those functions that involve the hippocampus. However, the proposed interaction
of sleep and its component stages with memory processes has been a source
of vigorous scientic controversy, primarily due to methodological limitations
in many of these studies (Vertes and Eastman, 2000; Siegel, 2001). Limitations
notwithstanding, animal experiments have been an essential component of
our eorts to dene the impact of sleep on the neural systems involved in learning,
memory, and synaptic plasticity. Animal learning models are especially important
in order to investigate the role of sleep at the cellular and molecular component
levels of synaptic plasticity, the fundamental biological substrates of learning
and memory.
Mammalian sleep can be broadly considered to comprise two distinct states,
namely, rapid-eye movement (REM) sleep (also referred to as paradoxical sleep)
Since the initial hypothesis by Ramon y Cajal that the strength of synaptic
connections is not xed, but it is plastic and malleable by neural activity, the
concept of synaptic plasticity has been central to the study of the neurobiology of
learning and memory (Llinas, 2003). Synaptic plasticity is generally thought
to underlie all forms of learning and memory, and consists of any activity-dependent
changes in the strength of connections between neurons, including alterations of
synaptic strength, the composition and number of receptor proteins, pre- and
postsynaptic signal transduction mechanisms, and the number and distribution of
synapses formed between neurons. Conceptual models of synaptic plasticity have
their origins in the theories of Donald Hebb, who postulated that neural
networks would have learning-related properties if only those synaptic inputs
which contribute more signicantly to activating the postsynaptic neuron, were
strengthened, while others were weakened (Hebb, 1949). Experimental ndings in
animals as well as humans suggest that several types of memory exist, and current
conceptual models of synaptic plasticity have attempted to account for the multiple
types of memory (for review see White and McDonald, 2002). The majority of
these models share a common framework, aptly stated as Activity-dependent
synaptic plasticity is induced at appropriate synapses during memory formation, and
is both necessary and sucient for the information storage underlying the type of
memory mediated by the brain area in which that plasticity is observed (Martin
et al., 2000). Although it is also sometimes suggested that plasticity is a general
property of the nervous system, the neuroplasticity that underlies information
storage in a particular system is thought to be localized exclusively within that
system.
64 B. W. Row and D. Gozal
Sleep is vital for the optimal performance of learning tasks, although the degree to
which sleep is involved in actual memory consolidation, as well as the relative
contributions of REM and NREM sleep stages, is currently a matter of debate
(Vertes and Eastman, 2000; Siegel, 2001). Several lines of evidence have traditionally
been used to support the hypothesis that sleep modulates the reorganization or
consolidation of memories in animals. First, observations that alterations in sleep
architecture occur following learning and/or exposure to environments which
promote synaptic plasticity have led some investigators to hypothesize that sleep
participates in memory consolidation. Second, sleep deprivation following learning
tasks have been shown to interfere with the subsequent retention and performance of
learning tasks. More recently, electrophysiological studies of cellular activity during
sleep have demonstrated that patterns of waking neuronal activity are reactivated
following learning, prompting the suggestion that consolidation of information
occurs during subsequent sleep. Although these approaches are suggestive of sleep as
a modulator of learning and memory, the inherent limitations of these methods have
failed to denitively answer the role of sleep in learning and memory. However, more
recent studies using clever learning algorithms and sophisticated molecular
techniques are beginning to provide us with critical insights into the mechanisms
whereby sleep aects underlying static and dynamic synaptic plasticity (Tononi and
Cirelli, 2003; Huber et al., 2004).
is one of the most widely used rodent learning tasks, and can be used to examine the
role of dierent neural systems via dierent congurations that share similar
sensory, motor, and motivational requirements (DHooge and De Deyn, 2001). In
the hippocampal-dependent spatial version of the Morris water maze, rodents learn
to nd a submerged, stable platform in a pool of opaque water that is located in a
constant position via distal, spatial cues. In the cued version of the Morris water
maze, which is hippocampus-independent, but sensitive to lesions of the striatum,
rodents learn to locate a visible platform, the position of which varies from trial to
trial. Smith and Rose (1997) found increases in REM sleep after training on the
hidden platform version of the Morris water maze. However, no changes were
observed after training on the visible (cued) version of the tasks (Smith and Rose,
1997). These ndings therefore suggested that the post-training enhancement of
REM sleep in rodents was selective for hippocampal-dependent tasks (Smith and
Rose, 1997).
Although ndings that REM sleep appears to be increased over baseline levels
during specic time periods following learning tasks in animals have been
consistently reported, there is considerable variability in the literature regarding the
timing of the phenomenon (Smith and Lapp, 1986; Smith, 1996b; Smith and Rose,
1997; Benington and Frank, 2003). This increased REM sleep that typically begins
after training and lasts for a limited period of time, has been termed the REM sleep
window and has been reported to occur as early as the rst 90 min of sleep
following a learning task, and as late as 6 days after completion of a learning task
(Smith, 1996b). In rodents, the REM sleep window varies substantially depending on
the species, strain, type of learning task, and whether a massed or distributed
learning protocol was used (Smith, 1985). This high degree of variability in the
timing of REM-learned task association has led some investigators to question the
validity of the phenomenon (Smith, 1996b; Siegel, 2001; Sanford et al., 2003a,b).
Changes in NREM sleep have been less widely reported following learning tasks
in rodents. However, some studies have shown that exposure to learning tasks, as
well as exposure to enriched environments, alter NREM sleep duration and intensity
(measured as the overall power of delta frequency), typically in conjunction with
increased REM sleep (Gutwein and Fishbein, 1980b; Mirmiran et al., 1982; van
Gool and Mirmiran, 1986; Giuditta et al., 1995; Piscopo et al., 2001). For example,
rats trained on a two-way active avoidance task displayed longer episodes of NREM
sleep, particularly in those sleep episodes that contained a subsequent transition to
REM sleep in the post-learning period (Ambrosini et al., 1995; Giuditta et al., 1995)
(sic). These observations have led some investigators to propose that memory
processing during sleep requires the initial participation of NREM sleep, in addition
to the subsequent involvement of REM sleep (Ambrosini and Giuditta, 2001).
It is important to note that many of the changes in sleep architecture that have
been reported to develop after exposure to learning tasks may not be directly related
to mnemonic processes themselves. Many of the studies have employed negatively
reinforced or aversive learning tasks, which substantially increase stress in
laboratory animals. Increased stress is capable of altering sleep, depending on the
intensity and duration of the stressor (Rampin et al., 1991; del et al., 1995; Siegel,
66 B. W. Row and D. Gozal
The use of post-training procedures is based on the hypothesis that the processes
underlying the storage of information are initiated by training and continue for some
period following the completion of training (McGaugh 1972a,b; McGaugh et al.,
1972). According to this hypothesis, it should be possible to modulate memory
storage by administering treatments shortly after training, without aecting the
acquisition of the task. Conversely, treatments administered shortly after training
that fail to modulate memory storage may be working through non-mnemonic
processes.
Studies of REM sleep deprivation have been most widely investigated in rodents.
In many cases, REM sleep deprivation following learning has been shown to block
improved task performance on subsequent retesting, although it should be noted
that not all studies have shown impaired learning following sleep deprivation, and
some studies have even shown facilitation of performance (Gisquet-Verrier and
Smith, 1989; Smith, 1996a; Vertes and Eastman, 2000; Benington and Frank, 2003).
The eects of sleep on learning are highly task-dependent and vary considerably
within and across animal species, which makes comparisons dicult (Smith, 1985).
More recently, sleep deprivation studies in rodents have selectively implicated sleep
deprivation in hippocampal function. As mentioned earlier, Smith and Rose (1996)
found that 4 h of sleep deprivation selectively impaired subsequent performance
on a spatial version of the water maze. In contrast, no eect of sleep deprivation
was observed on a cued version (Smith and Rose, 1996). Given that the hidden
and cued versions of the water maze share similar sensory, motor, and motivational
requirements, the dierential eect of sleep deprivation on these tasks suggests
that hippocampal function was selectively disrupted. A similar dissociation of
post-learning REM sleep deprivation was observed by Graves et al. (2003), who
compared the eect of immediate (05 h post-training) and delayed (510 h) sleep
deprivation on contextual and cued fear conditioning, tasks which are hippocampal-
dependent and hippocampal-independent, respectively (Graves et al., 2003; Sanders
et al., 2003). Post-training sleep deprivation from 0 to 5 h signicantly impaired
contextual fear conditioning, while PSD from 5 to 10 h had no eect. In contrast, on
a non-hippocampal dependent cued fear conditioning task, no eect of PSD was
observed, providing further support that hippocampal tasks are especially sensitive
to the eects of REM sleep deprivation (Graves et al., 2003).
The REM sleep deprivation ndings should be interpreted with caution, however.
Traditional methods of sleep deprivation are highly stressful, and this stress has been
a source of signicant criticism owing to the dramatic eects of stress on learning
and synaptic plasticity (Vertes and Eastman, 2000; Garcia, 2001). There is general
consensus among sleep researchers that the small platform method of sleep
deprivation produces results that are nonspecic for SD. Rodents are by nature
active creatures, and the relative immobilization associated with this type of sleep
deprivation alone is highly stressful to the animal, in addition to any other stresses
that may be associated with the technique, such as water aversion (Lee Kavanau,
2002). Animals sleep-deprived via the pedestal technique show substantial
activation of the HPA axis, elevations of plasma corticosterone, and weight loss
(Youngblood et al., 1997; Suchecki et al., 2002) and it is well-established that such
68 B. W. Row and D. Gozal
Fig. 1. Summary sketch summarizing the dierential eects on of sleep deprivation versus stress on
behavior, stress responses and various synaptic and membrane properties of CA1 hippocampal cells. nc,
not changed, increase, decrease, Modied from McDermott et al. (2003).
least partly due to stress, Wetzel et al. (2003) employed an alternative strategy to
investigate the eects of REM sleep on learning and memory. Using multiple
methods, they tested the hypothesis that increased REM sleep in the post-training
period would improve memory retention in rats. They found that selective post-
training REM sleep enhancement by injection of carbachol, CLIP (corticotropin-
like-intermediate-lobe peptide), or induction of REM sleep rebound, all produced
enhancement of hippocampal-dependent Y-maze discrimination learning in rats,
underscoring the fact that stress is insucient to fully account for the role of sleep in
learning memory and synaptic plasticity (Wetzel et al., 2003).
Observations that waking neuronal ring patterns are replayed during sleep
have also been used to support the hypothesis that sleep is involved in learning,
memory, and synaptic plasticity. Pavlides and Winson (1989) initially described
enhanced ring of hippocampal place cells activated during waking during
subsequent REM sleep, and it has been reported that in most cases the observed
ring patterns are temporally compressed or expanded (Pavlides and Winson, 1989;
Louie and Wilson, 2001). These ndings suggested that the neuronal activity of
hippocampal place cells in conscious states may inuence the ring characteristics of
these cells in the subsequent sleep episodes. Later studies have further shown that
pairs of hippocampal neurons whose activity is correlated during a learned behavior
are more likely to show correlated activity in NREM sleep subsequent to the prior
training period (Wilson and McNaughton, 1994; Kudrimoti et al., 1999) and that
the temporal sequence of neuronal ring is preserved in subsequent NREM sleep
(Skaggs and McNaughton, 1996; Lee and Wilson, 2002). This neuronal replay
phenomenon during sleep has also been reported to occur at an accelerated rate
(hence it is often referred to as being time-compressed), and may occur as long as
24 h after the task-specic activation of these neurons (Kudrimoti et al., 1999;
Nadasdy et al., 1999; Hirase et al., 2001; Lee and Wilson, 2002).
Although the replay phenomenon is intriguing, not all investigators have
found evidence for enhanced neuronal ring during REM sleep, or for temporal
alteration of activity patterns during sleep (Nadasdy et al., 1999; Poe et al., 2000).
Poe has attempted to explain these contradictory ndings by suggesting that
neuronal reactivation during REM sleep is modulated by the background theta
oscillation, which is essential for hippocampal-dependent learning, as well as for
cellular models of synaptic plasticity, such as long-term potentiation (Winson, 1978;
Pavlides et al., 1988). Poe et al. (2000) reported that hippocampal neurons previously
active during waking are reactivated during REM sleep in a manner that is highly
dependent upon their temporal phase in relation to underlying theta oscillations.
Neurons that were activated during a familiar maze-running task tended to re at the
troughs of the theta wave in subsequent REM sleep, while neurons that were
activated during a novel task tended to re at the peaks of the theta wave. Electrical
stimulation of the hippocampus at the peak of the theta frequency was predicted and
indeed associated with LTP in this structure, while stimulation at the trough was
70 B. W. Row and D. Gozal
Recent research has focused on the mechanisms whereby sleep could modulate
learning, memory, and synaptic plasticity. The synaptic plasticity underlying
learning and memory is thought to involve long-term changes in synaptic strength or
ecacy. These alterations of synaptic ecacy are generally thought to be mediated
by activity-induced modications of synapses that are established or consolidated
over time, and typically require new gene expression and protein synthesis
(Wittenberg and Tsien, 2002). The exact molecular mechanisms underlying such
long-lasting neural modications remain to be dened and likely occur via a number
of dierent mechanisms. Sleep has been hypothesized to aect the molecular
and biochemical events underlying memory consolidation by promoting the
synthesis of biologically active molecules that are necessary for the consolidation of
the waking experience. Furthermore, sleep could enhance the release of neuro-
humoral factors important for synaptic reorganization, and also lead to increased
transcription of genes underlying synaptic remodeling, as can be predicted from
the transient elevation of Ca2 concentrations typical of NREM sleep (Buzsaki,
1998; Gardi et al., 2002; Obal et al., 2003). Although this discussion is conned to
some of the cellular and molecular events whereby sleep may promote synaptic
plasticity, it is important to note that use-dependent plasticity has been proposed to
also occur at the network level, and likely participates in memory consolidation
during sleep (see Benington and Frank, 2003 for review).
Cholinergic modulation of the protein kinase A (PKA) signaling pathway and
protein synthesis have been proposed as a potential mechanism whereby sleep
could inuence learning, memory, and synaptic plasticity (Graves et al., 2001). Long-
term memory storage is acutely sensitive to inhibitors of both protein synthesis and
the protein kinase A (PKA) signaling pathway, when such inhibitors are admini-
stered at critical periods following training on learning tasks (Kesner et al., 1981;
Abel et al., 1997; Vazquez et al., 2000; Lattal and Abel, 2001; Bradley and
Finkbeiner, 2002; Naghdi et al., 2003). The ndings that molecular processes during
the post-training period are important for the consolidation of memory, and
observations that post-training sleep is important for memory consolidation, have
led to the suggestion that one of the eects of REM sleep may be to modulate
the PKA signaling cascade, ultimately leading to the induction of gene expression
Sleep and Learning in Animal Models 71
Fig. 2. Rat Cortical and Cerebellar Genes whose mRNA Levels Are Modulated by Sleep and Wakefulness
Independent of Time of Day (A) State-dependent transcripts (GeneChip RGU34A) in cerebral cortex (Cx)
and cerebellum (Cb) and their overlap. (B) Biological functions associated with transcripts with higher
expression in wakefulness (red box) and sleep (blue box). The tree on the left (dots and connecting paths)
represents biological processes; annotations according to the gene ontology hierarchy. Used with
permission from Cirelli, C., Gutierrez, C. M. and Tononi, G. (2004).
that REM sleep may contribute to memory functions via increased secretion of
neurotrophic factors (Sei et al., 2000).
8. Summary
The putative association between sleep states and learning has been strengthened
over the years by a long series of studies supporting a critical role for both
Sleep and Learning in Animal Models 73
global sleep and specic sleep states in the facilitation of synaptic plasticity. While
the exact mechanisms mediating the various roles of sleep on learning and
memory are for the most part still undened, the overwhelming evidence derived
from sleep deprivation and sleep modication paradigms points to sleep and its
component stages as an important modulator of the acquisition and retention of
learned behaviors. Thus, future studies examining the eects of biological aging
and aging-related disorders on memory and synaptic plasticity phenomena should
incorporate careful assessments of simultaneously occurring alterations in sleep
states, for the latter may markedly inuence the overall ndings of such studies.
Acknowledgments
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Advances in
Cell Aging and
Gerontology
Contents
1. Introduction
2. Age-related sleep changes
2.1. Sleep architectural changes
2.2. Sleepiness and aging
3. Age-related changes in respiratory physiology
4. Obstructive sleep apnea in the elderly
4.1. Epidemiology
5. Pathophysiology of sleep disordered breathing in aging
5.1. Obstructive sleep apnea
5.2. Obstructive sleep apnea and clinical consequences
5.3. Central sleep apnea
5.4. Risk factors for obstructive sleep apnea
5.5. Obstructive sleep patients with chronic obstructive
pulmonary disease (COPD)
5.6. Consequences of obstructive sleep apnea in the elderly
5.7. Diagnosis of sleep disordered breathing in the elderly
6. Management of sleep-disordered breathing
6.1. Conservative non-surgical medical management
6.2. Surgical management
7. Conclusion
Abstract. Sleep disordered breathing (SDB) is a spectrum of nocturnal breathing events. It consists
of obstructive, central, and mixed sleep apnea as well as upper airway resistance syndrome and
snoring. Obstructive sleep apnea is characterized by repetitive upper airway obstructive events.
The primary symptoms include excessive daytime sleepiness, snoring, and impairment of cognition.
In some cases, it can be associated with increased risk of motor vehicle accidents. Obstructive sleep
apnea (OSA) varies considerably in its distribution in age and its severity. The exact mechanism of
OSA is not yet fully delineated but multiple factors are generally associated with the development of
the sleep apnea (SA) syndrome. These factors include upper airway anatomic obstruction, as well
as mechanical, neurological, and possibly inammatory changes in the pharyngeal airspace. The
prevalence of the OSA increases with aging. Most studies report a prevalence rate ranging between
11 and 62%. It is further associated with increased mortality in the older patient population.
Central sleep apnea (CSA) occurs in higher frequency among patients with cerebral vascular
accidents, central nervous system (CNS) tumors, CNS infections, encephalopathies, and congestive
heart failure. Patients with cerebral vascular accidents have a markedly elevated prevalence of sleep
apnea mainly in the form of OSA and also have a poorer prognosis after an acute infarct. Patients
with Alzheimers disease also have more frequent SDcB. This SDB should certainly be considered
in the dierential diagnosis of reversible dementia as treatment of the underlying SDB improves
cognitive dysfunction. Medical management of SA relies on treatment with positive pressure
therapy and rarely with use of medications, or with surgery. The role of oral appliances has not
been clearly determined in elderly cohorts. The aim of this chapter is to help shed light on
the epidemiology, pathophysiology, diagnosis, and management of SDB in the geriatric patient
population.
1. Introduction
The older patient population is growing very fast in the United States and around
the world. In the year 2000, 34 million people in the US were older than 65 years. By
the year 2025, this number is expected to almost double to 62 million (Census 2000).
In light of this fact, geriatricians and other health care providers need to manage an
increased number of conditions which are exacerbated with aging. Sleep disordered
breathing is one of these conditions.
There are two distinct EEG states that occur during sleep: Rapid eye movement
sleep (REM) and the non-rapid eye movement (non-REM). The non-REM sleep is
subsequently divided into four stages, stages 1, 2, 3, and 4. The normal sleep cycle
consists of cycling from non-REM into REM sleep with a periodicity lasting on the
average for about 90 min. As the night goes on, stages 3 and 4 become shorter and
stage REM sleep becomes longer. The elderly patient experiences increased
fragmentation, decreased sleep eciency and quality of sleep, as well as a decrease
in the amplitude of delta waves which make up stages 3 and 4. There is also a total
reduction in the amount of slow-wave sleep, decreased density of REM sleep,
increasing sleep latency and increased fragmentations of the entire cycle (Avidan,
2002). These changes may be related to the underlying age-related neuronal loss as
well as a disruption of the suprachiasmatic circadian generator.
Sleep Disordered Breathing in the Geriatric Patient Population 81
As the lungs age, they undergo various predictable anatomic and physiologic
changes (Fig. 1). The major anatomic change is smaller airway size due to alterations
in the supporting connective tissue (Chan and Welsh, 1998). Additional anatomic
changes consist of decreased bronchiolar diameter, increase in the diameter of the
alveolar ducts and shallower alveolar sacs owing to changes in the proportion of
decreased elastic tissues and increased collagen that occur with aging. This
histological change translates physiologically to decreased elastic recoil of the
lung, decrease in oxygen diusion capacity, premature airway closure leading to
82
Diminishing of Smaller airway size-
ventilatory response Due to alteration in
to hypoxemia supporting
and hypercapnia connective tissue:
Increase diameter of
alveolar ducts-Alveolar
sac becomes shallower
Bronchiolar
Collagen
Narrowing Elastic
recoil
Elastic tissue
A. Y. Avidan
O2 diffusion capacity
INSPIRATORY INSPIRATORY
RESERVE VOLUME RESERVE VOLUME
TIDAL VOLUME
TIDAL VOLUME EXPIRATORY
RESERVE
EXPIRATORY VOLUME
RESERVE
VOLUME
RESIDUAL
VOLUME
RESIDUAL VOLUME
VITAL CAPACITY
FUNCTIONAL RESIDUAL CAPACITY
to hypercapnia was substantially lower (decreased to 60%) and that the response to
hypoxemia was also lowered (by as much as 75%) when compared to younger
patients (Kronenberg and Drage, 1973). This observation suggests an underlying
age-related decline in the ability to interpret and integrate information derived from
peripheral and central chemoreceptors and mechanoreceptors to generate an
appropriate neuronal feedback response (Kronenberg and Drage, 1973; Janssens
et al., 2000). During sleep, the hypoxic ventilatory response is diminished more
profoundly during non-REM than during REM sleep (Burger and Shephard,
1993). In addition, sleep deprivation further diminishes the nocturnal ventilatory
response to hypoxemia and hypercapnia (Grassino and Begin, 1990; Janssens et al.,
2000). The arousal response from sleep is often preserved during hypercapnia but is
often markedly impaired during hypoxemia. With aging, impaired ventilatory
response may lengthen the duration of the respiratory disturbances (apneas and
hypopneas) and may result in more profound hypoxemia, particularly during REM
sleep. Aging is also associated with diminished perception of added resistive loads
such as generated by upper airway collapse (Tack et al., 1981; Manning, 1993). Older
patients also have decreased ability to generate inspiratory eort during the
obstructive apneic spell compared to younger people (Krieger et al., 1997; Janssens
et al., 2000).
There are several dierent types of SDB. Obstructive sleep apnea (OSA), the
most ubiquitous type of SDB was rst described in 1976 (Guilleminault et al., 1976).
It is dened as a complete obstruction in the upper airway despite the subjects
attempt to resume normal respiration (Peppard et al., 2000). Obstructive sleep
apnea consists of repeated cessation in respiration during sleep. The episodes
which by denition last for ten seconds or longer can be complete (apneas) or there
may be a partial impairment in ventilation (hypopneas) in spite of continuous
respiratory eort (Fig. 3). Obstructive sleep apnea can result in a drop in oxyhe-
moglobin concentration and are often proceeded by a brief electroencephalogram
(EEG) arousal pattern as can be seen by a shift to a higher EEG frequency pattern
(Fig. 3). The gure also illustrates a delay (of about 15 s) in the desaturation
event from the beginning of the apnea. This lag between onset of apnea and
the drop in oxygen saturation is a reection of the lag due to circulatory delay during
which the physiologic response to hypoxemia takes places. Some patients
may experience cardiac arrhythmias in association with the desaturation event
which can some-times be fatal. There is also a surge of sympathetic activity
associated with elevation of blood pressure and tachycardia (Somers et al., 1995).
This increase in sympathetic tone has been proposed as a mechanism of action
implicating increased cardiovascular morbidity with OSA (Narkiewicz and Somers,
1997; Morgan et al., 1998; Young et al., 2002). Patients with OSA may also
experience symptoms such as hypersomnolence, concentration problems, memory
disturbances, nocturnal hypertension, nighttime arousals, confusion, and impair-
ment in the neuropsychologic functioning. Many of these problems can be found in
Sleep Disordered Breathing in the Geriatric Patient Population
1
Fig. 3. Obstructive sleep apnea. Illustrated in this gure is a 1 min epoch from a diagnostic polysomnogram of a 73 year old man with a history of nocturnal
breathing cessation, snoring, and daytime somnolence. Obstructive sleep apnea characterized by nasal oral (N/O) breathing cessation (1) in the presence of
persistent respiratory eort (2), and hypoxemia (3). Snoring was note electrographically and heard by the technicians monitoring the patients. (Snore channel,
prior to and subsequent to the apneic event). Channels are as follows: Electrooculogram (left: LOC-A2, right: ROC-A1), chin EMG (Chin-Chin), EEG [Left
85
central (C3-A2), right central (C4-A1), left occipital (O1-A2), right occipital (O2-A1)], electrocardiogram (ECG), limb EMG [left leg (LAT), right leg (RAT)],
snoring (SNORE), nasal-oral airow (N/O), respiratory eort [Thoracic (THOR), Abdominal (ABD)], nasal pressure (NPRE), and oxygen saturation (SpO2).
86 A. Y. Avidan
the elderly population cand many times are incorrectly attributed to the aging
process (Quinnell and Smith, 2004).
Bliwise has hypothesized that sleep apnea in the elderly may represent two
dierent conditions (Bliwise, 1993a). One form is age-related and the other is age-
dependent. The age-related sleep apnea develops in middle age. The age-dependent
sleep apnea is likely to develop with advancing age and may be secondary to other
age-dependent conditions such as increasing weight and increased upper airway
collapsibility. It is also related to a decreased pharyngeal muscle response to
negative pressure as well as to decreased airway size. This may be due to increased
parapharyngeal fat deposits as well as such other comorbidities such as endo-
crinopathies consisting of hypothyroidism as will be discussed later in the text. The
concept is that age-dependent sleep apnea is really a product of age itself. The longer
one lives, the more likely he or she is to develop the condition, which is in fact
the case based on observations of older community volunteers who are more
likely to develop OSA compared to their younger cohorts (Bliwise, 1993b, 2000).
Figure 4A illustrates the typical hypnogram of a patient with OSA. The x-axis is
the hours of recording during the night and the y-axis is the oximetry curve and sleep
stages. The rst half of the gure demarcates the baseline untreated (before positive
pressure therapy) portion of the night. The overall pattern is that multiple
awakenings and multiple episodes of hypoxemia produce disrupted nocturnal sleep
which can lead to excessive daytime somnolence, increased napping, and sleepiness.
Figure 4B illustrates the typical morphology of an apnea; breathing cessation,
terminating in a drop in the blood oxygen level leading to an EEG arousal response
permitting the subject to resume eective breathing. Once positive pressure therapy
begins (Fig. 4A), oximetry readings normalize, and the patient has consolidated
sleep. Figure 4C depicts resumption of normal breathing with positive pressure
therapy. The next set of questions that need to be addressed are how frequent is
sleep apnea in the elderly, and what is its epidemiology distribution among various
types of geriatric communities.
4.1. Epidemiology
PANEL A PANEL B
REM
30
PRES
0
100
Sp O2
70
Time 22:44:00 06:40:30
Hrs
Epoch 0 1 2 3 4 5 6 7 8
8 128 248 368 488 608 728 848 968
Fig. 4A. Sleep hypnogram depicting the baseline portion of a spilt night polysomnogram. Panel A demonstrates repeated hypoxemia (upper 70s) associated
with the apneic episodes which resolve once positive pressure (CPAP) is introduced in panel B. As higher CPAP levels are used (5 cm !7 cm !9 cm !11 cm
water), the sleep becomes less fragmented and hypoxemia is normalized. Channels are as follows: Electrooculogram (left: LOC-A2, right: ROC-A1), chin EMG,
EEG (left central, right central, left occipital, right occipital), electrocardiogram, limb EMG (left leg, right leg), snoring, nasal-oral airow, respiratory eort
87
(thoracic, abdominal), nasal pressure, and oxygen saturation.
88
A. Y. Avidan
#
*
** **
Fig. 4B. A 1 min epoch from the baseline portion (Panel-A) of the study demonstrating obstructive sleep apnea characterized by nasal oral (N/O) breathing
cessation (*) in the presence of persistent respiratory eort (**) EEG arousals () and hypoxemia ( ). An example of an hypopnea (#) is shown towards the end
of the epoch (#) demonstrating partial as opposed to complete (*) airway obstruction. Channels are as follows: Electrooculogram (left: LOC-A2, right: ROC-
A1), chin EMG (Chin-Chin), EEG [Left central (C3-A2), right central (C4-A1), left occipital (O1-A2), right occipital (O2-A1)], electrocardiogram (ECG), limb
EMG [left leg (LAT), right leg (RAT)], snoring (SNORE), nasal-oral airow (N/O), respiratory eort [Thoracic (THOR), Abdominal (ABD)], nasal pressure
(NPRE), and oxygen saturation (SpO2).
Sleep Disordered Breathing in the Geriatric Patient Population
Fig. 4C. Treatment with CPAP (Panel-B) showing resolution of the apneas, hypopneas, hypoxemia, and absence of sleep disruption and arousals. Channels are
as follows: Electrooculogram (left: LOC-A2, right: ROC-A1), chin EMG (Chin-Chin), EEG [Left central (C3-A2), right central (C4-A1), left occipital (O1-A2),
89
right occipital (O2-A1)], electrocardiogram (ECG), limb EMG [left leg (LAT), right leg (RAT)], snoring (SNORE), mask ow signal (MFLO), nasal-oral
airow (N/O), respiratory eort [Thoracic (THOR), Abdominal (ABD)], nasal pressure (NPRE), and oxygen saturation (SpO2).
90 A. Y. Avidan
this patient population. One of the earliest prevalence studies of sleep apnea in the
elderly population was performed in 1974 by Webb who found that nearly 75% of
healthy volunteer men had periodic breathing with apneas (Webb, 1974). Since then,
there have been other studies documenting the prevalence of sleep apnea in the
elderly patient population. These are summarized in Table 1 (Carskadon and
Dement, 1981; Coleman et al., 1981; Roehrs et al., 1983; Yesavage et al., 1985;
Ancoli-Israel et al., 1985, 1991a; Mosko et al., 1988). The studies show a wide
variability in the reported prevalence of OSA. This discrepancy in studies may be
due to analysis of small sample size and lack of studies evaluating randomly selected
patient population. Discrepancies may also be related to how we conduct
measurements in these studies; how we screen patients for sleep apnea, what criteria
of denition and quantication of respiratory events we use, and what tools we use
in evaluating patients (Janssens et al., 2000). A study by Hoch et al. (1990) looking
at the prevalence and severity of SDB in healthy 80-year-old subjects as compared
with 70 and 60-year-old subjects found that the Apnea Hypopnea Index (AHI)
increased signicantly across decades: 39.5% of 80-year olds, 33.3% of 70-year olds,
and 2.9% of 60-year olds had an AHI greater than or equal to 5 (Fig. 5). Signicant
gender dierences were noted in the proportion of subjects with AHI greater than
or equal to 10: 22.4% of men versus 5.4% of women. These data suggest that SDB
increases with advancing age even in the healthy elderly and may be more marked
in healthy men than women (Hoch et al., 1990).
The prevalence in women increases after menopause possibly due to declining
levels of estrogen and progesterone. The higher male prevalence and the severity of
OSA disappear in men older than 55 years, and menopause seems to play a pivotal
role in modulating both the presence and the degree of OSA (Resta et al., 2003).
In fact, data from a population-based sample of 589 women enrolled in the
Wisconsin Sleep Cohort Study demonstrated that the menopausal transition is
signicantly associated with an increased likelihood of having SDB, independent of
known confounding factors (Young et al., 2003). The authors proceed to suggest
that evaluation for SDB should be a priority for menopausal women with complaints
of snoring, daytime sleepiness, or unsatisfactory sleep (Young et al., 2003). The
role of hormone replacement therapy in SDB was examined in a cohort consisting
of 2852 women, 50 years of age or older, who participated in the Sleep Heart
Health Study (Shahar et al., 2003). The authors found that the prevalence of SDB
Sleep Disordered Breathing in the Geriatric Patient Population 91
40
35
30
25
% of
20
Subjects
AHI>5
15
AHI>10
10
5
0
60-69 70-70 80-89 total
Years of age
AHI = Apnea-hypopnea index (number of apneas and hypopneas per hour of sleep)
Studies indicate that OSA may occur at multiple levels of obstruction including
the nasopharynx, oropharynx, and hypopharynx (Fig. 6). Predisposed individuals
include patients with reduced oral pharyngeal airway including patients with
macroglossia, hypertrophy of the tonsils, and patients with long uvula (Shochat
and Pillar, 2003). This has led to further implications that the underlying
pathophysiology of OSA is due to abnormal anatomy. It is hypothesized that
with the onset of sleep, patients with obstructive sleep apnea lose the neuromus-
cular compensation present during wakefulness leading to airway collapse and
92
Progesterone ?
+
Nasopharynx Nasal-septopalsty
Positive pressure UPPP
therapy: CPAP, BiPAP Oropharynx
Maxillomandibular Advancement
SSRI CN XII
+ Hypopharynx
Genioglossus Advancement
Hyoid Myotomy
TCA
Trachea Tracheaostomy
A. Y. Avidan
REM
Oral Appliance
Central sleep apnea, a less frequent sleep disordered breathing syndrome, results
from a complete or partial impairment of airow in the absence of a respiratory
eort (Shochat and Pillar, 2003). Polysomnographic recording in CSA demonstrates
central breathing cessation for 10 s or longer and may be associated with frequent
arousals from sleep, bradytachycardia, and arterial oxygen desaturation.
Central sleep apnea can occur in the form of CheyneStokes respirations which
is a unique form of central sleep apnea whereby the respiratory pattern consists
of crescendodecrescendo pattern followed by a central apnea which cycles for
about a minute (Shochat and Pillar, 2003). This is a common and an important
form of SDB to consider in aging and especially in patients with an underlying
cerebrovascular accident, and congestive heart failure. Its presence is considered
as a poor prognostic indicator (Naughton and Bradlery, 1998).
94 A. Y. Avidan
Obstructive sleep apnea is associated with multiple risk factors. The main ones are
obesity, increased neck circumference, family history of OSA, alcohol consumption,
and endocrine disorders. Other risk factors or aggravating factors include tobacco,
sedative or hypnotic use, sleeping in a supine position, and sleep deprivation.
5.4.1. Obesity
A major risk factor for the development of OSA is obesity. The airways may
become compressed extrinsically by excessive deposition of parapharyngeal adipose
tissue which restricts the airway size making it prone to collapse (Quinnell and Smith,
2004). Upper airway morphology that is associated with sleep apnea includes reduced
pharyngeal cross sectional area and retrognathic mandible. While approximately
24% of the population is estimated to have OSA, the prevalence increases to
2040% in the obese population (Kyzer and Charuzi, 1998). In a longitudinal study
of OSA in obesity in an adult population over a 10-year period, even moderate gains
and reductions of weight were statistically signicant in their association with
signicant increase and decrease in respiratory disturbance index (RDI). Relative to
stable weight, a 10% weight gain predicted an approximate 32% increase in the RDI
and predicted a six fold increase in the odds of developing moderate-to-severe SDB.
A 10% weight loss predicted a 26% decrease in the RDI. (Peppard et al., 2000).
Longitudinal studies involving elderly patients ages 65 and above, demonstrated
changes of the respiratory disturbance index as a function of body mass index, rather
than age (Ancoli-Israel et al., 2001). In fact, the body mass index was found to be the
strongest predicator of sleep apnea in elderly patient populations (Ancoli-Israel et al.,
1991a; Shochat and Pillar, 2003).
5.4.4. Alcohol
Alcohol consumption can exacerbate SDB. It is well-established that alcohol
usage can increase upper airway resistance. Alcohols ability to worsen obstructive
sleep apnea may be accounted for by its ability to decrease pharyngeal airway size
and increase nasal resistance (Robinson et al., 1985). Alcohol may also cause
mucosal congestion, depress central respiratory drive, and enhance muscle
relaxation, all of which would exacerbate OSA (Quinnell and Smith, 2004).
5.4.5. Endocrinopathies
Sleep apnea is associated with endocrinopathies such as hypothyroidism
(Grunstein and Sullivan, 1988; Rosenow et al., 1998) and acromegaly (Weiss et al.,
2000). There is a high rate of clinically undetected thyroid dysfunction among the
healthy institutionalized geriatric population (Ayala et al., 2001). Hypothyroidism
is a known cause of secondary OSA causing oropharyngeal airway myopathy,
edema, and obesity all which predispose patients to upper airway collapse and
obstruction (Quinnell and Smith, 2004). Thyroid hormone replacement therapy
can improve and sometimes even resolve OSA in hypothyroid patients (Hattori et al.,
2003). An excess of growth hormone in adults causes acromegaly which is yet
another endocrinopathy associated with OSA. Excessive growth of the craniofacial
bones, enlargement of the tongue (macroglossia), and thickening and enlargement of
laryngeal region leads to further reduction of the upper airway anatomy. The upper
airway obstruction in acromegaly may result in severe hypoxemia and disruption
of normal sleep (Mezon et al., 1980). Treatment of OSA in acromegaly by
tracheostomy resulted in disappearance of the OSA-associated somnolence.
When compared to premenopausal women, and post-menopausal women who are
maintained on hormone replacement therapy, post-menopausal women are at risk
for developing OSA (Bixler et al., 2001).
5.5. Obstructive sleep patients with chronic obstructive pulmonary disease (COPD)
The frequency of OSA in COPD has been studied previously. Indeed COPD
is highly prevalent in elderly patients; 1015% of patients with COPD may have
obstructive sleep apnea. Those patients appear to have a lower baseline oxygen
saturation and higher partial pressure of carbon dioxide than patients with OSA
syndrome itself. These patients are also at a high risk for developing episodes of
prolonged hypoxemia during sleep, especially during REM sleep than patients
without COPD, and they are therefore more prone to suer from complications of
hypoxemia such as cor pulmanale, pulmonary hypertension, and polycythemia. The
recurring hypoxemic episodes that characterize OSA, particularly when associated
with chronic obstructive pulmonary disease and/or daytime hypoxemia, may lead
to both pulmonary and systemic hypertension, cardiac arrhythmias, and possibly
premature death.
96 A. Y. Avidan
vigilance due to the underlying somnolence (Bedard et al., 1991). Some have
suggested that cognitive impairment in patients with severe sleep apnea may be
associated with daytime sleepiness in patients with mild to or moderate sleep apnea.
Finally, mood instability and depression have also been associated with sleep apnea,
although not all studies have reported this relationship (Cohen-Zion et al., 2001).
The declining cognitive function associated with sleep apnea in the elderly is
associated primarily with increases in daytime sleepiness. One theoretical model
suggests that any relationship between sleep apnea and cognitive function may be
mediated by the eect of sleep apnea and resultant sleep fragmentation on daytime
sleepiness (Cohen-Zion et al., 2001).
namely have their pulse rate and blood pressure checked and have a good
cardiopulmonary examination. A neurologic exam is warranted with particular
emphasis on the mini mental state exam (MMSE) in demented patients with possible
OSA. The MMSE score may help when following these patients once they have been
treated for OSA.
Management of OSA in the elderly can be divided into conservative and non-
conservative approaches (Fig. 6). The question of the management of sleep apnea
in the elderly is currently under close investigation. At this point, there are limited
data showing the true impact of the treatment of the underlying sleep apnea as
a therapeutic intervention in the elderly on subjective complaints. It is possible that
the severity of the disorder rather than the advancing age should be the leading
factor when considering treatment of these disorders. It is in the authors experience
that before contemplating denitive therapy, clinicians need to thoroughly evaluate
the impact of sleep apnea on the patients lives and impact in the setting of other
comorbidities rather than treating the sleep study or the respiratory disturbance
index. For example, an elderly patient with an apneahypopnea index of 7 without
any clear symptoms of daytime sleepiness, or underlying cardiovascular disease, may
be followed clinically over time and not be subjected to therapy. On the other hand,
a patient with an AHI of 4 with history of witnessed apnea, daytime sleepiness in
the context of ischemic heart disease may be treated more aggressively.
100 A. Y. Avidan
As a general principle, patients with sleep apnea need to avoid situations that
may put them at risk for sleep apnea. These include avoidance of hypnotics and
psychotropic agents as these suppress respiratory drive and place patients at greater
risk of OSA due to increased frequency and length of apneas and hypopneas.
Dry mouth,
Check mask fit
mouth leak
Add a chinstrap
Are there other co-existing sleep disorders?
Check for air leaks-Pressure Parasomnias (i.e. RBD) causing sleep disruption?
Excessive noise
may be too high. If not,
Limiting use?
use earplugs
103
Fig. 7. Approach to the sleep apnea patient with residual daytime sleepiness despite appropriate therapy.
104 A. Y. Avidan
polyvinyl. The patient positions his/her teeth in the grooves, sticks his tongue
forward into the bubble until suction grabs and holds the tongue in place. The TRD
is especially useful in edentulous patients, patients with macroglossia, and poor
dental health.
Oral appliances are considered by many as very useful conservative non-surgical
approach for the treatment of mild to moderate obstructive sleep apnea and for
snoring. They are particularly advantageous as they require minimal upkeep and
are relatively simple to use which becomes an attractive option in elderly patients
with underlying neurocognitive impairment. The oral appliances are fabricated
and tted by dentists. It is recommended that a follow-up sleep study takes place
with the appliances in place to look for evidence of improvement. The oral
appliances are attractive for many patients because they are also much more mobile
compared to CPAP, and they are small and not expensive (Quinnell and Smith,
2004). They are a nice alternative to patients who are very claustrophobic with the
CPAP masks.
Adverse side eects attributed to the appliances may include temporal mandibular
joint (TMJ) dysfunction (which is also a contraindication for use), tooth and gum
pain, proprioceptive malocclusion, excessive/reduced salivation and at times, gum
disease. Elderly patients also have dental problems including the fact that many are
edentulous and the oral appliance (MAD) has to t over intact healthy teeth. In
some selected edentulous patients, TRD may be an option. However, in the authors
experience TRD devices are rarely tolerated beyond 34 h of use and compliance
is an obvious drawback. The principal challenge with prescribing either the MAD
or TRD is that there have been no studies looking at the ecacy of these therapies
in the elderly patient population.
6.1.5. Medications
Generally speaking, drug therapy for obstructive sleep apnea has been
unsuccessful and its use, especially in elderly patients may be discouraged due to
the higher likelihood of side eects in this patient group ranging from tolerance to
serious adverse side eects (Shochat and Pillar, 2003). Mechanisms of action of the
principal pharmacologic agents include reduction of OSA via respiratory drive
stimulation, REM sleep suppression and stimulation of upper airway muscle tone
(Quinnell and Smith, 2004).
Surgical treatment options for OSA target potential sites of airway obstruction.
Surgical techniques involve extirpation of soft tissue, secondary soft tissue
repositioning through primary skeletal mobilization, or bypass of the pharyngeal
airway. While surgery, especially in the form of tracheostomy, was commonly used
in the past for the management of OSA, it is increasingly underutilized owing to
the favorable responses with positive pressure therapy. There are three sites of
obstruction which include the nasopharynx, oropharynx, and the hypopharynx
(Fig. 6). Surgical procedures for the management of obstructive sleep apnea
have been chosen when there is a clear anatomical airway obstruction or when
106 A. Y. Avidan
medical management with nasal CPAP is not achieved. Patients need to be evaluated
by otolaryngologists and possibly, an oral-maxillofacial surgeon and undergo
extensive presurgical evaluation with cephalometric X-rays, and ber optic
endoscopy. Surgery may be targeted at the level of the upper airways preventing
their collapse.
6.2.5. Tracheostomy
Tracheostomy, which is designed to bypass the collapsible upper airway is used
in very refractory cases, and/or in severe, life threatening cases of OSA (He et al.,
1988). Tracheostomy may be used to bypass the oropharyngeal airway in sleep
Sleep Disordered Breathing in the Geriatric Patient Population 107
7. Conclusion
Obstructive sleep apnea is very common in elderly patients. It impacts this patient
population in that it may lower quality of life, and have adverse eects on almost
every organ system ranging from neurocognitive impairment to cardiovascular heart
disease. Elderly patients do not present with the typical symptoms of their younger
cohorts. Therefore lack of snoring and witnessed apneas per se is not a criterion for
dismissing the possibility of OSA in this age group. It is often dicult to establish the
diagnosis of OSA in the elderly as many of the studies conducted so far show no
uniform distribution of the apneahypopnea index. Treatment of this condition is
extremely important as it may improve neurocognitive disturbances, improve the
patients quality of life and optimize therapies for other chronic conditions such as
hypertension. The treatment of OSA can be extremely rewarding. Most patients
respond very well with positive pressure therapy. For others, dierent options may
be available.
Acknowledgments
The author wishes to thank Mrs. Karen Gowen for her assistance in the
preparation of the manuscript.
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Advances in
Cell Aging and
Gerontology
Contents
1. Introduction
2. Regulation of sleep-related endocrine systems in young humans
2.1. The HPA and somatotropic system
2.2. Vasopressin (VP)
2.3. Prolactin, melatonin, and other hormones
3. Regulation of sleep-related immune function in young humans
3.1. Undisturbed sleep
3.2. Deprivation of sleep
3.3. Cytokine effects on sleep
4. Sleep and endocrine regulation in the aged
4.1. Sleep-endocrine regulation of the HPA and the somatotropic system
4.2. Vasopressin in the elderly
4.3. Effects of hormone administration on sleep in the aged
5. Immune function during sleep in the aged
5.1. Immune system function in the aged
5.2. Sleep-associated immune function in the aged
5.3. Endocrine mediation of sleep-immune changes in the aged
6. Summary and conclusion
1. Introduction
wakefulness, but also inuences from various other factors modulating sleep
endocrine and sleepimmune interactions. Most important in this respect are
circadian oscillators playing a supra-ordinate role in sleepwake regulation.
In addition, environmental (e.g., light exposure) and behavioral conditions (e.g.,
stress), and factors such as gender and age are to be considered in this context as
potent modulators.
During the wake phase, neuroendocrine and neuroimmune mechanisms assist
the body in coping with stressful environmental and internal events. However
during sleep, stressors and stress responses are absent, and activity in the
neuroendocrine and immune systems becomes subjected to a spontaneous and basal
mode of self-regulation whose mechanisms are not yet fully understood. In the
course of aging, prominent sleep-related changes of endocrine secretion and immune
function occur and contribute to the morbidity and mortality in the elderly.
Here we review the interaction of neuro-endocrine as well as neuro-endocrine
immune regulation with sleep, rst in young and then in aged humans. The focus will
be on the hypothalamo-pituitary-adrenal (HPA) system, the somatotropic system,
and the vasopressinergic system. Apart from eerent inuences of the sleeping
brain on the release of hormones into the blood stream, the aerent eects of
circulating hormones and cytokines of the immune system on the sleeping brain will
also be discussed.
Together with the sympathetic nervous system, the bodys response to stressful
events during wakefulness is mediated through the secretory activity of both the
HPA axis and the somatotropic axis. Stress stimulates corticotropin-releasing
hormone (CRH), which is secreted from the hypothalamus with highest concen-
trations of the hormone found in the nucleus paraventricularis. This CRH induces
release of adrenocorticotropic hormone (ACTH) from the anterior pituitary into
the circulating blood, which subsequently induces the release of cortisol from
the adrenals. Stimulation of the HPA axis by physical, metabolic, and mental
stressors is in many cases paralleled by the secretion of growth hormone-releasing
hormone (GHRH) mainly from the basomedial hypothalamus, i.e., the arcuate
nucleus. This GHRH is the secretagogue of growth hormone (GH), which is released
from the anterior pituitary to regulate metabolic requirements at a cellular level,
mainly via stimulating the hepatic release of insulin-like growth factor I (IGF-I).
With the ending of the stress stimulus, the secretion of CRH and GHRH and all
subsequent hormones is terminated by negative feedback regulation. Since sleep is
generally regarded as a state devoid of stress, and in the light of the predominance of
stress-related activity in the wake phase, activity of the HPA and somatotropic
system during sleep can be expected to be low. However, examination of the
temporal patterns of ACTH/cortisol and GH secretion during sleep reveals a
complex and surprising relation between sleep, sleep stages, and hormonal activity.
Sleep Associated Endocrine and Immune Changes in the Elderly 115
Figure 1 illustrates the typical time course of HPA and somatotropic secretory
activity during nocturnal sleep in a healthy young man: the cyclic appearance of
nonREM sleep or slow wave sleep (SWS) and REM sleep over the night changes
in that the rst half of the night is characterized by a predominance of SWS while
the latter part of the night is dominated by REM sleep. In parallel, the changing
hormonal secretion shows very low ACTH and cortisol plasma concentrations
and concurrent bursts of plasma GH levels during the SWS-rich early part of sleep.
In contrast, in the second, late part of nocturnal sleep, the secretory activity of
W
REM
Sleep S1
S2
S3
S4
20.00 22.00 0.00 2.00 4.00 6.00 8.00 10.00 12.00 time
Cortisol ACTH 24 60
g/dl pg/ml
16 40
8 20
0 0
20.00 22.00 0.00 2.00 4.00 6.00 8.00 10.00 12.00 time
10
8
GH
ng/ml 6
4
2
0
20.00 22.00 0.00 2.00 4.00 6.00 8.00 10.00 12.00 time
Fig. 1. Time course of HPA and somatotropic secretory activity during nocturnal sleep in a healthy young
man. The upper panel shows the sleep prole characterized by a predominance of slow wave sleep (SWS)
during the early part of sleep, and a predominance of REM sleep during the late part. The middle panel
indicates associated plasma ACTH (dashed line) and cortisol (solid) levels indicating activity of the HPA
system. The lower panel shows the associated plasma growth hormone (GH) prole.
116 B. Perras and J. Born
the HPA system is distinctly increasing, while activity of the somatotropic system
is minimal.
For the secretion of various other hormones, rhythms have been identied that
appear to be linked to sleep, sleep stages, as well as to circadian oscillations. For
example, the secretion of prolactin is enhanced during sleep and appears to be
secreted in particular during the early periods of SWS (Haus et al., 1980; Follenius
et al., 1988; Spiegel et al., 1995). During REM sleep, prolactin secretion is
inhibited. Plasma concentrations of thyroid stimulating hormone display a circadian
Sleep Associated Endocrine and Immune Changes in the Elderly 119
variation with a peak in the evening before nocturnal sleep exerting an inhibitory
inuence on the release of this hormone (Brabant et al., 1990; Goichot et al., 1992;
Allan and Czeisler, 1994). A hormone that has attracted much interest in sleep
research is melatonin, a product of the pineal gland. Diurnal melatonin plasma
concentrations are low and secretion of the hormone can be totally inhibited by light.
With the onset of darkness, melatonin levels rise sharply to reach a peak in the middle
of the night, thus representing an excellent indicator of the circadian clock. Sleep per
se does not substantially change melatonin secretion. However, melatonin has been
consistently found to facilitate sleep, thus reecting the drive of circadian rhythm on
sleep propensity. Probably this eect is mediated by an inuence on sleep inducing
thermoregulatory mechanisms (Cajochen et al., 2003).
Further hormones for which nonREM-REM sleep and sleep-dependent rhythms
of secretion have been described, are luteinizing hormone (Fehm et al., 1991),
oxytocin (Forsling, 2000), renin (Brandenberger et al., 1998), and aldosterone
(Charloux et al., 1999; see Czeisler and Klerman, 1999; Steiger, 2003; Touitou and
Haus, 2000 for reviews). Also, there are hormones, such as atrial natriuretic
peptide, the secretion of which does not follow a clear nycthemeral pattern
(Follenius et al., 1992).
or even diminished by regular sleep. Some evidence supports the notion that
sleep may play a facilitating role in establishing a primary adaptive immune
response to an antigen.
production per se, but rather a decrease in the number of circulating cells producing
these cytokines.
In contrast with IL-1 and TNF-, concentrations of IL-6 in blood are
much higher, and this cytokine also acts as an important stimulus of pituitary
adrenal secretory activity (Spath-Schwalbe et al., 1996, 1998). However, reports
vary largely regarding a possible association of variations in IL-6 concentrations
with sleep. While some studies failed to nd any systematic changes in IL-6
concentrations across the 24-h cycle (Born et al., 1997b; Lissoni et al., 1998),
ndings from others suggest signicant maxima at dierent times of the day
(Gudewill et al., 1992; Zabel et al., 1993; Bauer et al., 1994; Sothern et al., 1995;
Vgontzas et al., 1999; Redwine et al., 2000). This divergence reects in part a
methodological problem. The IL-6 measurements obtained by frequent blood
sampling using an indwelling venous catheter over extended time periods have
been shown to produce spurious results, most likely due to local proinammatory
activity resulting from mechanical irritation of venous walls by the catheter
(Haack et al., 2002).
Distinct increases during nocturnal sleep have been observed for the production
of the T cell derived cytokine IL-2 (Born et al., 1997b; Lissoni et al., 1998). The
T-cellular production of IFN-
seemed likewise to be enhanced during nighttime
sleep (Hohagen et al., 1993; Petrovsky et al., 1994, 1998; Petrovsky and Harrison,
1998). The increase in production of these T cell cytokines in these studies started
already before the sleep period and are independent of changes in the number of
circulating T cells.
Petrovsky and Harrison (1997) examined 24-h variations in the ratio of IFN-
to IL-10 production as an indicator of the balance between T helper 1/T helper 2
(Th1/Th2) cytokine activity, considered an essential determinant for the selection
of the eector mechanisms of immune defense. The Th1 cells releasing mainly
IFN-
, aside from other cytokines including IL-2, become activated in response
to intracellular viral and bacterial challenges and support various cellular (type 1)
responses, including macrophage activation and antigen presentation. In contrast,
the cytokines characteristic of Th2 immunity, such as IL-4, IL-5, and IL-10, tend to
drive humoral (type 2) defense via stimulating mast cells, eosinophils, and B cells
against extracellular pathogens. Predominance of type 2 cytokines, as observed for
example in aged humans, has been associated with an inferior response to
vaccination (Ginaldi et al., 1999a). The work of Petrovsky and Harrison (1997, 1998)
suggests that nocturnal sleep favors a shift towards Th1 (predominance of IFN-
)
mediated immune defense, peaking around 03:00 h.
Sleep deprivation, especially if extended for more than one night represents a stressful
experience that via activation of the major stress hormonal systems can per se
inuence immune functions. However, in humans, when staying awake for a single
night voluntarily such side eects appear to be limited. In fact, assessment in humans
indicates that plasma levels of cortisol and catecholamines during deprivation
of nocturnal sleep on a single night, although signicantly enhanced in comparison
with sleep, do not reach the levels seen during daytime wakefulness or stress (e.g.,
Dodt et al., 1994a; Lange et al., 2003). Overall data from studies employing total
or partial deprivation of sleep in a single night conrm that sleep per se enhances
signs of adaptive immunity. For some parameters, the eect of sleep appears
to add synergistically to a circadian inuence. Thus, compared with a night awake
or partial sleep deprivation, regular nocturnal sleep was consistently found
to induce reductions in the number of granulocytes, monocytes, and
the major lymphocyte subsets, but to increase NK cell counts (McClintick et al.,
1994; Irwin et al., 1996; Born et al., 1997b). In parallel, production of T cell derived
IL-2 has been demonstrated to be enhanced during regular sleep as compared
to nocturnal wake conditions (Uthgenannt et al., 1995; Irwin et al., 1996). Also,
nocturnal sleep was shown to induce a shift in the Th1/Th2 cytokine balance
towards increased Th1 activity, as indicated by an increased ratio of IFN-
/IL-4
producing T helper cells. However, the Th1 shift was only of moderate size and
replaced by Th2 dominance during late sleep (Dimitrov et al., 2004a). Moreover,
recent studies provided the rst evidence for a facilitating eect of sleep on a
primary adaptive immune response to vaccination (Spiegel et al., 2002; Lange et al.,
2003). In the latter study healthy young humans either regularly slept or stayed
awake on the night following primary vaccination with inactivated hepatitis
A virus (at 9.00 am). Hepatitis A virus antibody titers measured 28 days
after vaccination, a time when antibody titers have reached a plateau, were
nearly two-fold higher in the subjects who had regular sleep following vaccination,
than in the subjects who stayed awake on this rst night.
Proinammatory cytokines of acute innate immunity, like IL-1 and TNF-
showed sleep associated decreases in comparisons with conditions of sleep
deprivation in some studies, although this again could reect mainly a sleep-related
decrease in the number of monocytes as a main source for these cytokines
(Uthgenannt et al., 1995; Born et al., 1997b).
In combination, results speak for an enhancing eect of sleep on processes
of adaptive immunity establishing antigen-specic defense, whereas acute innate
responses are less inuenced by sleep or even superior during times of
continued waking than during sleep. Indeed, periods of sleep deprivation
extended over 34 days have been found to be associated not only with distinctly
increased counts of neutrophils and monocytes as well as NK cell activity but
also with increased plasma IL-6 concentration (Dinges et al., 1994; Shearer et al.,
2001). Lymphocyte counts decreased under such conditions. Together this picture
speaks for a stress-like eect of extended periods of sleep deprivation, enhancing
in particular signs of non-specic phagocyte-related immunity (Boyum et al.,
1996).
Sleep Associated Endocrine and Immune Changes in the Elderly 123
20 140
r = 0.80 120
15 p< 0.001
100
10 80
60
5 40 r = 0.79
20 p< 0.001
0 0
15 25 35 45 55 65 75 85 95 15 25 35 45 55 65 75 85 95
age (years) age (years)
mental impairments can adversely aect the circadian timing system thereby
aggravating the circadian maladaptation in the aged.
The mechanisms accounting for the age-related sleep-endocrine changes are
presently unclear. A promising approach to this issue probably relies on a detailed
analysis of the mechanisms mediating the inhibition of HPA activity in conjunction
with the increase in somatotropic activity during early sleep. In addition, contri-
butions of impaired circadian control are to be considered. It has been proposed,
that in combination the phase advance and reduced amplitude of circadian rhythms
in aged lead to a desynchronization of major endogenous circadian rhythms, so
that rhythms like those of cortisol, melatonin, and temperature are not properly
coupled to the sleepwake cycle. This desynchronization may indeed account for
some of the sleep disturbances in the aged (Czeisler et al., 1992; Touitou and Haus,
2000; Pandi-Perumal et al., 2002).
(Bjorntorp, 2001; Vgontzas et al., 2001; Rosmond, 2003) . In the case of aging, it
has been hypothesized that repetitive stressful events during lifetime result in an
elevation of steroid plasma concentrations due to an increasing impairment of
feedback inhibition. Compelling evidence has been provided that elevated steroid
levels aect brain function adversely with the hippocampus being the structure in the
brain most susceptible to these eects (McEwen, 1999; Sousa et al., 2000). Following
repeated stress, reduced excitability of hippocampal neurons, suppression of
neurogenesis in the dentate gyrus and atrophy of the dendrites of the CA 3 region
of the hippocampus have been reported (Pavlides et al., 1995; Gould et al., 1997;
De Kloet et al., 1998; McEwen, 1999). As a consequence, the loss of MR leads in
the hippocampus to a weakening of the tonic basal inhibition of the HPA axis
(Sapolsky et al., 1986). Additionally, overactivity of the HPA system negatively
interferes with other neuronal functions in the hippocampus. Hippocampal
atrophy in the elderly is associated with mild cognitive impairment (Golomb et al.,
1994; Convit et al., 1995). Furthermore, enhanced cortisol plasma concentrations
seem to be correlated with impaired memory in parallel with reduced hippocampal
volume in the elderly humans (Lupien et al., 1998). Apart from aging, hippocampal
nerve atrophy has also been found in dementia, depressive illness, and Cushings
disease (De Leon et al., 1993; Sheline et al., 1996; Starkman et al., 1999).
Overall, the age-related dysfunction of the hippocampus primarily via loss of MR
expressing neurons gives rise to the overactivity of the pituitaryadrenal system seen
most consistently during the basal nadir activity of early sleep. The release of tonic
inhibition manifests in an augmented hypothalamic release and action of CRH at
the pituitary level. The CRH itself has a disturbing eect on sleep. In humans, the
intravenous administration of four repetitive boluses of 50 mg of CRH during the
early part of nocturnal sleep signicantly reduced the amount of SWS and REM
sleep (Holsboer et al., 1988). Furthermore, there is evidence suggesting a role of
CRH in the development of depression which is also often associated with age-like
disturbances of sleep, i.e., a reduction in sleep continuity and amounts of SWS
(Benca et al., 1992). In light of the similarity of the sleep disturbances in the elderly
and depressed patients to those resulting from administration of CRH, it has been
proposed that an increased release of CRH is the principal neuroendocrine factor
mediating the changes in sleep architecture in aging (Steiger, 2002).
et al., 1999; Jessop, 1999). Among them is atrial natriuretic peptide (ANP). Bierwolf
et al. (1998) showed in humans, that nocturnal ACTH and cortisol responses to
intravenous injections of a combination of CRH and VP were distinctly diminished
when the subjects were simultaneously infused with a low dose of ANP over a period
of 90 min, starting 15 min before CRH/VP injection. Plasma concentrations of ANP
are known to increase with age (e.g., Kato et al., 2002). However, whether ANP or
one of the related brain peptides functions as an inhibitor of HPA activity under
natural conditions during early humans sleep is unknown.
In contrast to ANP, GHRH is a substance whose inhibiting inuence on
pituitaryadrenal activity under natural conditions during early sleep is well
documented. The somatotropic axis exhibits distinctly enhanced activity exactly
at the time of the nadir of HPA activity. Repetitive intravenous injections of
GHRH during early sleep reduced plasma cortisol concentrations during sleep
(Steiger et al., 1992). This nding was conrmed using an intranasal route of GHRH
administration known to enable a direct access of the peptide to the cerebrospinal
uid compartment (Perras et al., 1999a, Born et al., 2002). Notably, in contrast to
the intravenous injection, intranasal GHRH simultaneously reduced secretion of
GH during early sleep supporting the view that the peptide acted mainly at the
hypothalamic level to induce inhibition of GHRH release. This hypothalamic
action obviously overrides stimulating eects on pituitary GH release resulting
from GHRH partly absorbed into the bloodstream. Together, the data indicate
that GHRH suppresses HPA activity probably mainly at the hypothalamic level.
The data lend themselves to suggest that decline in GHRH activity in the course
of aging signicantly contributes to the tonic overactivity of the HPA system during
sleep in elderly.
Another factor exerting inhibitory actions on HPA secretory activity during
nocturnal sleep is melatonin the secretion of which depends on darkness (Leproult
et al., 2001). Evidence for an inhibiting eect of melatonin on cortisol release
during early sleep has been provided by a recent study in totally blind persons
(Fischer et al., 2003). Aside from disturbed sleep patterns the blind in these
experiments showed temporal patterns of ACTH and cortisol secretion which did
not appear to be coupled to the sleep process. Specically, they did not show
minimum and maximum secretion of these hormones during early and late sleep,
respectively, but the average concentration of these hormones did not at all dier
between early and late halves of nocturnal sleep. The administration of melatonin
before sleep normalized this pattern leading to distinctly suppressed levels of
ACTH/cortisol during early sleep and increased levels during late sleep. The eects
of melatonin were accompanied by a slight enhancement of SWS. The gradual
decrease in nocturnal melatonin secretion occurring in the course of aging (e.g.,
Toutiou, 1995; Skene and Swaab, 2003) could thus well cause a desynchronisation
between the sleepwake rhythm and pituitaryadrenal activity during sleep in
the aged, expressing in relatively enhanced cortisol levels during early sleep. Of
note, since pineal melatonin secretion is triggered by darkness rather than sleep,
the decrease in melatonin represents a contribution of a circadian impairment to
the disturbed neuroendocrine pattern of sleep in the aged.
Sleep Associated Endocrine and Immune Changes in the Elderly 129
There are several further candidate substances that may act as CRIF, such as
preproTRH158183 whose analog in the rat has been shown to inhibit stimulated
cortisol release (Redei et al., 1995, 1998; McGivern et al., 1997), -endorphin
and substance P (Jessop, 1999). However, the central nervous eects of these
substances on HPA activity in humans are not clear, as well as their role during
sleep (Lieb et al., 2002).
Overall the available data suggest that the inhibition of HPA activity during
early sleep involves multiple mechanisms acting not only at the pituitary but also
at the hypothalamic (like GHRH, melatonin) level of this axis. Such signals
mediate a supra-ordinate feedback control exerted by the hippocampus as well
as a circadian control probably originating from the nucleus suprachiasmaticus.
Inecient inhibition of pituitaryadrenal activity during sleep in the aged could
thus reect a decline in production and release of substances acting as CRIFs
at the hypothalamic and pituitary level in this system. Impaired release of these
factors would add to the diminished hippocampal negative feedback sensitivity to
cortisol in the aged, and thereby further weaken the tonic inhibitory control of
ACTH/cortisol release.
HPA system. The view of a balance between the two systems is supported by a
body of evidence indicating opposite eects of these systems on sleep as well as
mutually inhibiting eects between the systems (Ehlers et al., 1986; Ehlers and
Kupfer, 1987; Steiger, 2002). Not only does GHRH promote SWS but also
suppresses pituitaryadrenal activity during early sleep. In contrast, overactivity of
CRH aside from stimulating ACTH/cortisol release results in sleep suppression.
Also, increased HPA activity exerts some inhibitory inuence on somatotropic
activity. In humans repeated intravenous administration of CRH in parallel
with reductions in SWS and REM sleep signicantly reduced the amount of
GH secreted during sleep (Holsboer et al., 1988).
Another reason for the reduced ecacy of GHRH in these studies could be, that
even with the administration of repeated boli in the elderly the amount of substance
reaching the brain is not sucient for inducing notable eects on sleep. Based on this
rationale Perras et al. (1999a) performed a study in the young and the elderly using
an intranasal administration of GHRH. This route of administration has been
proven in human studies to provide direct access of neuropeptides to the
cerebrospinal uid compartment (Born et al., 2002). After intranasal administration
of GHRH in the elderly before the night in the sleep laboratory substantially
improved several sleep-endocrine markers of aging (Perras et al., 1999a). The time in
SWS and also in REM sleep was enhanced, with these changes concentrating in the
late night. Remarkably, cortisol nadir concentrations in the aged after intranasal
GHRH were on average even lower than those in the young men after placebo. Peak
concentrations of cortisol were reached later in the night suggesting a phase delay of
circadian rhythm. However, as noted earlier, nocturnal GH concentrations were
signicantly reduced after GHRH in both young and aged indicating that intranasal
GHRH activates a short-loop negative feedback inhibition at the hypothalamic level
of this system. Also, increases in SWS and REM sleep were comparable for the
young and aged subjects, indicating that GHRH does not specically compensate for
the age related decits in sleep, although the brains sensitivity to GHRH appeared
to be preserved in the elderly.
4.3.3. Vasopressin
Vasopressin was among the rst neuropeptides whose eects on brain functions
were studied in detail in animals. From these studies an important role of VP for
memory and learning was inferred, although in humans the eects of vasopressin
administration on these functions appeared to be generally less consistent (Nebes
et al., 1984; Van Ree et al., 1985; De Wied et al., 1989; Dodt et al., 1994b; Born et al.,
1998c). The trials in humans also included aged subjects with and without memory
decits. Despite the well-known presence of VP in the nucleus suprachiasmaticus as
a circadian regulator of the sleepwake cycle, surprisingly few studies in animals
looked at the eects of VP on sleep (Urban et al., 1978; Danguir, 1983; Kruisbrink
et al., 1987; Arnauld et al., 1989; Brown et al., 1989). The results were interpreted in
terms of increased arousal induced by acute administration of VP.
Arousing inuences on sleep were observed also following acute administration of
VP in humans. In young subjects, VP consistently increased time spent in stage 2
sleep and awake regardless of whether administered intranasally or intravenously
(Timsit-Berthier et al., 1982; Born et al., 1992). Intravenous VP administration
also reduced REM sleep. Subjective sleep quality was not found to be changed
in one study following intranasal administration of an analog of VP (DGAVP,
Snel et al., 1987).
The failure to nd consistently improving eects on brain functions in the elderly
after single or short-term administration of VP led to the assumption that more
encouraging benets result perhaps from a more prolonged treatment with the
peptide. Perras et al. (1996) tested this assumption rst in a pilot study in two healthy
elderly persons. The focus of this study was on brain indicators of cognitive
134 B. Perras and J. Born
functions (event-related brain potentials), but sleep was also tested. The two
elderly persons were treated with VP twice daily (20 IU) for a period of three
months. An intranasal route of VP administration was used to assure direct brain
access of the peptide (Born et al., 2002). Surprisingly, results indicated most
pronounced changes in sleep rather than on neurocognitive functions. The time
spent in SWS was increased by about 100% with this enhancement emerging after six
weeks of treatment. Interestingly, this long-term eect was opposite to the arousing
eect of VP on sleep seen acutely after administration of a single dose of the peptide,
pointing to a dierent mechanism activated with prolonged VP treatment.
These results prompted more elaborate investigations of long-term intranasal
treatment with VP in the elderly (Perras et al., 1999b, 2003). In the rst of these
studies, 26 healthy elderly (14 women and 12 men >70 years) were tested, who did
not complain of poor sleep but, at the sleep laboratory, showed the typical
fragmentation of sleep and predominance of light sleep. After three placebo nights,
one group of subjects continued to take a placebo while the other group was
treated with VP according to the same protocol as used in the foregoing pilot study
(2 20 IU per day, Perras et al., 1996). The treatments were administered each
day in the morning and in the evening, for three months. Revaluation of sleep at
the end of the treatment epoch conrmed a pronounced increase in SWS in the
VP group averaging 20 min. Moreover, compared to the controls the VP treated
elderly slept longer (for 45 min) and displayed increased REM sleep (10 min,
Fig. 3). No cardiovascular side eects or uid retention were observed. The
improvement in polysomnographical sleep was not correlated with an improve-
ment of sleep quality ratings. However, this was probably a consequence of the fact
that the elderly selected for this trial perceived a good sleep quality already before
the study.
Considering this remarkable improvement of sleep after prolonged VP treatment
in the elderly, a further study (Perras et al., 2003) aimed to explore whether the
benecial eect is accompanied by changes in the neuroendocrine pattern of sleep in
the aged. In particular, pituitaryadrenal activity was of interest since VP is known
to be a potent co-stimulator of the pituitary release of ACTH following acute
administration (Spath-Schwalbe et al., 1987). The 26 healthy elderly (mean age 72.9
years) of this study, with only mild sleep complaints were treated with placebo or
intranasal VP for a period of 10 weeks, according to the same study protocol and
dosage of daily treatment as in the two previous studies with subchronic VP.
However, this time polysomnographical recordings in the beginning and end of
the treatment period were complemented by repeated blood sampling during the
nights. Again, the prolonged intranasal treatment with VP led to a profound increase
in SWS averaging 21.5 min. The VP-induced increase in SWS was persistent and
was also observed on a night following the last treatment, i.e., 24 h after the last
intake of VP, excluding any contributions of immediate eects of the peptide.
Notably, rather than increasing pituitaryadrenal activity, VP signicantly decreased
the cortisol nadir during early sleep on average by 0.5 mg/dl. Changes in GH
concentrations were not signicant. Again, no side eects regarding uid balance
or cardiovascular activity were observed. Overall, these results indicate a promoting
W W
23.00 0.00 1.00 2.00 3.00 4.00 5.00 6.00 7.00 time 23.00 0.00 1.00 2.00 3.00 4.00 5.00 6.00 7.00 time
W W
REM REM
S1 S1
S2 S2
S3 S3
S4 S4
23.00 0.00 1.00 2.00 3.00 4.00 5.00 6.00 7.00 time 23.00 0.00 1.00 2.00 3.00 4.00 5.00 6.00 7.00 time
Fig. 3. Sleep proles from two selected subjects (70 and 76 years old) before (left panel) and after (right panel) daily intranasal treatment with vasopressin
during a period of 3 months. Note, sleep time, time in SWS and in REM sleep are distinctly increased in both subjects. Lights were turned o at 11.00 pm
(23.00 h). W, awake time; S1, stage 1 sleep; S2, stage 2 sleep; S3, stage 3 sleep; S4, stage 4 sleep; S3+S4, SWS. (From Perras et al., 1999b).
135
136 B. Perras and J. Born
Aging is associated with multiple changes of immunity that have been collectively
termed immunosenescence. Its most prominent feature is a general decline in the
Sleep Associated Endocrine and Immune Changes in the Elderly 137
Th1/Th2 balance towards increased Th2 cytokine activity (Nagel et al., 1989; Born
et al., 1997b; Shearer, 1997; Dimitrov et al., 2004a). Moreover, both states have been
found to impair the formation of a primary adaptive immune response to vaccines
(Remarque, 1999; Looney et al., 2001; Lange et al., 2003). Regarding innate immune
functions, sleep deprivation like aging leads to increased numbers of circulating
NK cells but, a diminished NK cell activity when considered on a per cell basis
(Irwin et al., 1994; Solana and Mariani, 2000). Blood counts of activated T cells
(HLA-DR) have likewise been found to be increased after sleep deprivation and
in the aged (Sansoni et al., 1993; Born et al., 1997b). Also, the production of
proinammatory cytokines IL-1, TNF- and IL-6 has been found to be enhanced
in the aged as well as after sleep deprivation, although the eects of sleep deprivation
were in general less pronounced and, if cytokines were assessed in mitogen-
stimulated whole blood samples, appeared to primarily reect eects on circulating
monocytes (Born et al., 1997b; Rink et al., 1998).
Collectively these data suggest that the disturbances of sleep commonly present
in aged persons induce a state of chronic sleep decit that acts to suppress T cell
mediated functioning and, in turn, upregulates certain aspects of innate immune
functioning. However, there is currently no study providing a direct test of this
hypothesis. Sakami et al. (2003) examined relationships between insomnia
determined mainly as perception of insucient sleep and T cell cytokine activity
as well as NK cell activity in a larger sample of 254 men aged between 20 and
64 years. While age was inversely, but only moderately correlated with NK cell
activity as well as with the IFN-
to IL-4 ratio (r<0.19), the men suering from
insomnia had a signicantly lower production of IFN-
and, in fact, a shift towards
prevailing Th2 cytokine activity. The NK cell activity was found to be independent
of insomnia. On the background of the strong association between aging and
disturbed sleep, this result provides rst evidence that poor sleep, if present in an
elderly person, probably contributes to a decline in specic T cell functioning by
shifting the Th1/Th2 balance towards Th2. However, even though insomnia was
examined in that study, the change in the Th1/Th2 balance may not be specic to the
impairment of sleep but could likewise reect the non-specic impact of a stressor.
Stressors other than insomnia and chronic sleep decit have also the capability to
induce a dominance of Th2 cytokine activity, and such factors are dicult to
dissociate from those of altered sleep, particularly so in the aged (Decker et al., 1996;
Marshall and Agrarwal, 2000).
There are also clear dierences between the eects of sleep deprivation and
aging mainly regarding blood cell counts. Most obvious are the opposite eects
of both conditions on lymphocyte counts which increase during sleep deprivation
(e.g., Dinges et al., 1994) but decrease with aging due to thymic involution. The
increase in T and B cell counts in blood during sleep deprivation probably reects
a diminished emigration of these cells into extravascular and lymphoid tissues
(Dickstein et al., 2000). Such dierences underline that immunosenescence cannot
be simply reduced to disturbances of sleep playing in this context the role of a
modulating factor. Against this background, dierences in immune regulation
between old and young humans during sleep are expected to be a composite, on
Sleep Associated Endocrine and Immune Changes in the Elderly 139
the one hand, of changes due to biological aging and, on the other hand, due to
impairments of sleep.
In one study in humans, white blood cell dierential counts and cytokine
production was compared between young and elderly subjects before and
during regular nocturnal sleep (Born et al., 1995). All subjects were healthy
and did not suer from pathological sleep disturbances. The aged subjects
(mean SEM: 79.6 7.5 year) were recruited according to the strict criteria of the
SENIEUR protocol. As expected, sleep in the elderly persons was worse than in the
young persons, although total sleep time was roughly the same as in the young
sleepers. Compared to the young subjects the elderly spent much more time awake
(24.0 vs. 5.2%), and distinctly less time in SWS (7.7 vs. 20.0%) and REM sleep (10.0
vs. 19.9%). In parallel with this, the aged showed a general reduction in the number
of circulating white blood cells. Monocyte counts were unchanged, while the
circadian decrease in neutrophil counts in the late night appeared to be somewhat
more pronounced in the aged. The T and B cell counts as well as the number of
CD4 and CD8 were distinctly reduced at all times. The number of activated
T cells were more than twofold enhanced in the aged throughout the recordings.
Notably, only changes in NK cells appeared to depend on sleep. The NK cell
numbers were comparable before sleep in both groups but, in young subjects
decreased across nocturnal sleep, while in the aged, on an average, even a slight
increase was observed.
Contrary to expectations, there was no clear hint from this study at a decline in
the production of IL-2 and IFN-
by T cells in the aged. Although the production of
these cytokines per T cell before sleep was on average lower in the aged than in the
young, this dierence was not signicant, and this held true also during the time of
sleep. However, T cells in the aged expressed a higher number of IL-2 receptors. In
contrast with the T cell derived cytokines, the production of acute proinammatory
cytokines of innate immunity, IL-1 and TNF-, exhibited an increase in the aged
which was most pronounced during sleep. This was partly due to the fact that
average production of these cytokines tended to decrease across the sleep period only
in the young subjects which conrmed previous studies (Hohagen et al., 1993, Zabel
et al., 1993; Petrovsky et al., 1998). The sleep-associated enhancement in the
production of IL-1 and TNF- in the aged remained signicant also, when the
production of the cytokines were determined per monocyte representing the major
source of these cytokines in the stimulated whole blood samples. Together with the
increase in NK cell numbers, the enhanced proinammatory cytokine activity
during sleep may indeed reect acute consequences of the impaired sleep regulation
in the aged.
Another study in mice likewise failed to detect any sleep-related decline in signs of
adaptive immune function with age (Renegar et al., 1998). This study aimed at
dissociating eects of sleep deprivation on IgA and IgG levels in the upper and lower
respiratory tract mucosa and in serum in young and senescent mice 72 h after a viral
challenge test. The inuenza immune mice were sleep deprived once or twice for up
to 6 h on the day(s) before and after the viral challenge. While sleep deprivation
remained without eect in the young mice, the old mice showed even increased
140 B. Perras and J. Born
serum levels of inuenza specic IgG after viral challenge under one of the
deprivation conditions. The nding may t the predominance of Th2 cytokine
activity supporting specic antibody secretion from B cells. However, it would be
also consistent with an increased response in the old mice to the stress of sleep
deprivation. Whether sleep does at all exert regulatory inuences on a secondary
response in the solidly immune organism is questionable. In humans, an enhancing
eect of sleep has been found on antibody titers only in the context of a primary
immunization (Spiegel et al., 2002; Lange et al., 2003). In any case, it would be
premature to generalize these ndings in rodents to the human being, in light of the
fact that eects of age on immune reactions can widely dier among species.
In another animal study in rats, LPS was administered to examine eects of the
acute phase proinammatory cytokines on sleep in young and middle-aged rats
(Schielholz and Lancel, 2001). The LPS is a robust stimulus of the secretion of IL-
1, TNF- and IL-6 from monocytes in rats and humans. Sleep in the young and
middle-aged rats diered in this study mainly regarding REM sleep and pre-REM
sleep (a type of nonREM sleep at the transition into REM sleep) which were both
reduced in the middle aged rats. The intraperitoneal administration of LPS induced a
comparable increase in body temperature in both groups. However, while the young
rats showed increased amounts of SWS in response to LPS, in the middle-aged rats
EEG power decreased in most frequency bands pointing to attened sleep. This
response in the middle-aged rats resembles that seen in adult humans following
administration of higher pyrogenic doses of LPS (Pollmacher et al., 1995). This
result well agrees with the notion that the sensitivity of innate immunity to LPS is
enhanced with aging (e.g., Gabriel et al., 2002), and extends it to the acute phase
sleep response to immune challenge.
In sum these data indicate that the impaired sleep in aged is acutely associated
with a state of increased responsiveness of some innate immune functions. In the
case of acute infection increased amounts of circulating proinammatory cytokines
could contribute to a further attening of central nervous sleep processes in the
aged. Also, the reduced depth of sleep may support the predominance of Th2
cytokine activity in the elderly. However, although primary T cell cytokines like IL-2
and IFN-
have been shown to be acutely enhanced by sleep and to be generally
reduced with aging, so far no evidence has been provided that these cytokines
are particularly suppressed during the sleep period in aged. Thus, the decline
in lymphocyte generation and function representing one of the most prominent sign
of immunosenescence, appears to go in parallel with an insensitivity to the acute
consequences of poor sleep.
Sleep in the aged is associated with distinct endocrine changes. Many of the
hormones, the release of which is specically regulated during sleep, exert specic
immune-regulatory functions and, thus, could play an important role for the
manifestation of age-related changes in the immune system function, i.e., for the
acute changes emerging during the sleep period as well as for the persistent changes
Sleep Associated Endocrine and Immune Changes in the Elderly 141
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Advances in
Cell Aging and
Gerontology
Contents
1. Introduction
2. Circadian variations in neurotrophic factor expression
3. Effects of phase-shifts and sleep deprivation on neurotrophic factor signaling
4. Functions of neurotrophic factors in regulating sleep
5. Depression, neurotrophic factors, and sleep
6. Neurotrophic factors and normal aging
7. Neurotrophic factors and neurodegenerative disorders
7.1. Alzheimers disease
7.2. Parkinsons disease
7.3. Huntingtons disease
8. Conclusions
Abstract. Well known for their ability to promote the survival and outgrowth of neurons during
development of the brain, neurotrophic factors also serve multiple functions in the adult brain.
For example, the modulation of neurotransmitter signaling and neurogenesis by neurotrophic
factors may play a role in learning and memory. Important roles for neurotrophic factors in sleep
regulation and sleep disorders are suggested by circadian variations in their expression and
alterations in their expression in animal models of phase shift and sleep deprivation. Brain-derived
neurotrophic factor (BDNF) may play particularly important roles in sleep regulation and sleep
disorders because of its reciprocal interactions with serotonin, and its involvement in depression and
anxiety disorders. Perturbed neurotrophic factor signaling occurs in neurodegenerative disorders in
which sleep disturbance is prominent including Alzheimers, Parkinsons, and Huntingtons
diseases. A better understanding of the roles of neurotrophic factor signaling in sleep regulation
may lead to novel approaches for preventing and treating sleep disorders.
1. Introduction
During the past several decades, an increasing number of proteins that promote
the survival and growth of neurons have been identied. These include growth
factors originally identied because of their actions on non-neuronal cells such as
basic broblast growth factor (bFGF), epidermal growth factor (EGF) and
transforming growth factor-beta (TGF) (Plata-Salaman, 1991; Abe and Saito, 2001;
Unsicker and Krieglstein, 2002). Beginning with the discovery of nerve growth factor
(NGF), a novel family of neurotrophins was identied which includes brain-
derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3) and neurotrophin-4/5
(NT-4/5) (Thoenen, 2000; Dechant and Neumann, 2002). Each of these neurotrophic
factors and their receptors is expressed in one or more populations of neurons
involved in the regulation of sleep, including those in structures such as the
hypothalamus, brainstem, hippocampus and various regions of the cerebral cortex
(Hobson and Pace-Schott, 2002; Huang and Reichardt, 2003).
The expression of many neurotrophic factors is stimulated by activity in neuronal
circuits and by cellular stress (Hughes et al., 1999). For example, the production of
BDNF is increased in response to neurotransmitters that stimulate cyclic AMP
production and/or calcium inux including serotnin and glutamate (Jiang et al.,
2003; Russo-Neustadt et al., 2003). Neurotrophic factors exert their actions by
binding to cell surface receptors which, in turn, initiate kinase cascades resulting in
the activation of transcription factors. Some of the gene targets for neurotrophic
factors include those encoding enzymes involved in neurotransmitter synthesis or
transport, cell survival-promoting proteins, and proteins the regulate neurite
outgrowth and synaptic plasticity (Lu and Chow, 1999). The present article reviews
the evidence that neurotrophic factors play roles in regulating various aspects of
sleep, and discuss the possible roles of perturbed neurotrophic factor signaling in
sleep disorders.
The expression of several dierent neurotrophic factors changes during the light
dark cycle in brain regions involved in sleep regulation. The BDNF mRNA levels in
the suprachiasmatic nucleus (SCN) of rats maintained in constant darkness were
high during the early subjective day (Liang et al., 1998). Levels of BDNF and its
receptor trkB in the hippocampus were reported to oscillate during the lightdark
cycle in rats (Bova et al., 1998). Cirelli and Tononi (2000) reported that the amounts
of BDNF, phosphorylated CRE-binding protein (a transcriptional regulator of
BDNF expression) and Arc (an immediate early gene target of BDNF) are high
during waking and low during sleep in rats; and that the higher levels of these
proteins during waking depends on noradrenergic signaling. Levels of BDNF are
elevated during the light phase of the cycle in the retina, superior colliculus, and
primary visual cortex, but are decreased during the light phase in the hippocampus
and cerebellum (Pollock et al., 2001). Signicant circadian variations in trkB
(the high anity receptor for BDNF) expression were observed in dentate gyrus,
Neurotrophins and Sleep 157
entorhinal cortex, and the CA3 and hilar regions of the hippocampus; for each
region the highest expression occurred during the rst half of the dark period (Dolci
et al., 2003).
Forced changes in the lightdark cycle can change the levels of BDNF in brain
region-specic manner. For example an 8 h advance in the lightdark cycle in rats
resulted in increased levels of BDNF protein in the hippocampus, but not in the
cerebellum and brainstem (Sei et al., 2003). In another study rats were subjected to
either sleep deprivation for 8 h or a mild increase in ambient temperature (which
induces sleep), and levels of BDNF mRNA were measured in the cerebral cortex and
hippocampus (Taishi et al., 2001). Levels of BDNF mRNA were increased in the
cerebral cortex (but not in the hippocampus) of sleep-deprived rats, but were
unchanged by the increased temperature environment.
Infusion of NGF into the suprachiasmatic nucleus resulted in phase advances in
hamsters (Bina and Rusak, 1996). The REM sleep deprivation resulted in decreased
levels of BDNF protein levels in the cerebellum and brainstem, and decreased levels
of NGF protein in the hippocampus (Sei et al., 2000). Transforming growth factor-
alpha (TGFalpha) is expressed rhythmically in the suprachiasmatic nucleus, and
infusion of TGFalpha into the third ventricle suppresses locomotor activity and
disrupts sleepwake cycles (Kramer et al., 2001). Those actions of TGFalpha are
mediated by EGF receptors as indicated by increased daytime locomotor activity in
mice with a hypomorphic EGF receptor mutation. Changes in neurotrophic factor
levels in association with sleepwake cycles, particular stages of sleep, and sleep
deprivation suggest roles for these factors in sleep regulation.
The ability of neurotrophic factors to alter aspects of sleep has been documented
in several studies. Intracerebroventricular infusion of BDNF increased the amount
of time spent in non-REM sleep in adult rats and rabbits (Kushikata et al., 1999).
The latter investigators also found that intracerebroventricular infusion of NT-3 and
NT-4 increased the time spent in non-REM sleep when infused at dark onset
(Kushikata et al., 2003). In other studies, manipulations of BDNF signaling have
been shown to modify the circadian regulation of the SCN. For example, when
BDNF was infused into the SCN of rats their free-running rhythm in constant
darkness exhibited large phase advances in response to light, which contrasted
with saline-infused control rats whose rhythm did not exhibit a response to light
(Liang et al., 2000). Also, BDNF did not aect either the phase-delaying or phase-
advancing eects of light on the activity rhythm during the day. In BDNF
heterozygous mice with reduced BDNF levels there was a decrease in the amplitude
of light-induced phase shifts during the light period (Liang et al., 2000). The latter
study further showed that an inhibitor of trkB can inhibit both the phase-advancing
and phase-delaying eects of light during the light phase.
158 M. P. Mattson
Serotonin plays major roles in both depression and sleep. Most patients with
clinical depression have severely disturbed sleep and exhibit reduced levels of
serotonin; the most eective antidepressants including serotonin-selective reuptake
inhibitors and monoamine oxidase inhibitors act, in large part, by increasing
serotonergic signaling (Vaswani et al., 2003). Levels of serotonergic tone decrease in
the brainstem during REM sleep and patients taking antidepressants have reduced
amounts of REM sleep. Interestingly, sleep deprivation increases serotonin levels
and can have antidepressant eects, suggesting that insomnia in depressed patients
may actually be an adaptive response (Adrien, 2002). Antidepressants that increase
serotonergic signaling are very eective in upregulating the expression of BDNF,
and increasing evidence suggests that BDNF plays a major role in the improvement
of symptoms in depressed patients (Russo-Neustadt, 2003). Treatments that have
Neurotrophins and Sleep 159
extracellular plaques that are often associated with degenerated neurons. A wealth of
genetic and experimental evidence suggests that A plays a major role in promoting
the dysfunction and degeneration of neurons in AD (Mattson, 2004).
In addition to its adverse eects on learning and memory, the increased
production of A may contribute to sleep disturbances in AD because transgenic
mice with increased levels of A in their brains exhibit abnormalities in the sleep-
wake cycle (Huitron-Resendiz et al., 2002). The mechanism by which A disturbs
circadian rhythms may involve impairment of neurotrophic factor signaling.
As evidence, levels of BDNF are decreased in several brain regions of AD patients
(Hock et al., 2000), and exposure of neurons to A results in impairment of CREB
activation (Tong et al., 2001). It will be of considerable interest to determine the
mechanisms responsible for perturbed sleep regulation in mouse models of AD,
and to elucidate the roles of neurotrophic factors. Sleep disturbances can occur
relatively early in the course of AD, perhaps even prior to cognitive dysfunction,
and may therefore not simply be the consequence of neuronal death.
and locus ceruleus (Kremer et al., 1990; Zweig et al., 1992), and HD patients exhibit
sleep disturbances including increased sleep onset latency, reduced sleep eciency,
frequent nocturnal wakings, and reduced amounts of slow wave sleep (Wiegand
et al., 1991). Both HD patients and the transgenic huntingtin mutant mice exhibit
reduced levels of BDNF in basal ganglia (Ferrer et al., 2000; Zucatto et al., 2001;
Duan et al., 2003). Dietary restriction and administration of the antidepressant
paroxetine can increase BDNF levels, suppress the neurodegenerative process and
extend the life of huntingtin mutant mice (Duan et al., 2003, 2004). Analyses of sleep
have not been performed in mouse models of HD, and it therefore remains to be
determined if such mice can be used to elucidate the cellular and molecular
mechanisms responsible for sleep disturbances in HD patients.
8. Conclusions
At this point in time our knowledge of the roles of neurotrophic factors in sleep
regulation and age- and disease-related sleep disturbances is sparse. However,
ndings described earlier and enumerated here are consistent with prominent roles
of neurotrophic factors in sleep regulation. (1) Neurotrophic factor expression
changes during the circadian cycle. (2) Neurons in brain regions involved in sleep
regulation are responsive to one or more neurotrophic factors. (3) Various aspects
of sleep are aected by infusion of neurotrophic factors into the brain.
(4) Neurotrophic factor levels are decreased in humans with, and rodent models
of, neurodegenerative disorders that are characterized by sleep disturbances.
(5) Treatments used to treat sleep disorders increase the expression of BDNF.
Considerable further work will be required to understand the inter-relationships
between neurotrophic factor signaling and the neurotransmitter and neuroendo-
crine systems that regulate sleep. Neurotrophic factors involved in sleep regulation
and components of their signal transduction pathways may prove to be useful
targets for the development of novel approaches for preventing and treating sleep
disorders.
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Advances in
Cell Aging and
Gerontology
Contents
1. Introduction
2. Sleep and aging
2.1. Sleep and the elderly
2.2. Sleep in aged rodents
3. Neurotransmitter systems involved in sleep and wakefulness
3.1. Discovery of the hypocretin/orexin system
3.2. The H/O system and the sleep disorder narcolepsy
3.3. A model for the role of the H/O system in sleep and wakefulness
3.4. H/O system and aging
3.5. Histaminergic system and aging
4. Sleep deprivation, recovery sleep, and gene expression
4.1. Homeostatic regulation of sleep
4.2. Gene expression studies of sleep deprivation and recovery sleep
5. Microarray studies of gene expression in the aged brain
6. Conclusions and future directions
1. Introduction
As the survivorship curve for humans in the developed world approaches the
rectangular ideal, improving the quality of life in advanced years is an increasing
concern. A major complaint of the elderly is poor sleep (Ballinger, 1976; Karacan
et al., 1976; Bliwise et al., 1992). Despite the fact that the elderly tend to spend
more hours in bed, they have less total sleep time (Feinberg et al., 1967; Kahn, 1970;
Webb and Swinburne, 1971; Prinz, 1995). In general, sleep eciency decreases with
age, mostly due to more and lengthier arousals, in other words, increased sleep
fragmentation (Feinberg et al., 1967; Kahn and Fisher, 1969; Prinz, 1977; Bliwise,
1993). In this chapter, we will review sleep characteristics of the elderly and introduce
the homeostatic regulation of sleep, discuss some of the neurotransmitter systems
known to play a role in sleep and wakefulness and how these systems change with
age, and describe gene expression studies of sleep and wakefulness undertaken
to identify the molecular mechanisms that underlie sleep homeostasis. We will
conclude with a discussion of the potential application of these latter approaches
to understand what goes awry with sleep during aging.
(Borbely, 1982; Edgar et al., 1993). Aging could alter either the wakefulness
promotion process, thought to be mediated via the circadian pacemaker in the SCN,
and/or the sleep homeostatic process (Edgar, 1994). The sleep homeostatic process is
measured by spectral analyses of the delta band of the EEG during sleep because of
the relationship between the duration of prior wakefulness and subsequent power in
this band during sleep (Borbely et al., 1981). As formulated in the two-process
model of sleep regulation (Borbely, 1982), EEG delta power (mostly occurring
during stages 3 and 4) reects the homeostatic drive to sleep and the restorative
process that occurs during sleep.
Because of the tantalizing possibility that delta power is directly related to a
function of sleep, it is of interest to know how it changes with aging. A considerable
change in the dynamics of delta power has been observed as early as middle age in a
study comparing young (2028 years) and middle-age (4256 years) men. Although
delta power was much higher at the beginning of the sleep period in the young group,
delta power declined throughout the sleep period to reach very similar levels at the
end of the night in both groups (Dijk et al., 1989). So, if delta power is a measure of a
function of sleep, it already undergoes considerable decline by middle-age. As
indicated above, elderly humans are well-known to exhibit a dramatic reduction in
delta power, particularly in the rst half of the night (Ehlers and Kupfer, 1989),
which suggests that their sleep may be less restorative.
Aside from these objective characteristics of sleep in the elderly, a key element is
the relationship between nocturnal sleep and alertness during the subsequent
daytime. Sleep quality in the elderly and its impact on subsequent wakefulness has
been assessed by the multiple sleep latency test (MSLT) (Carskadon et al., 1982).
Low MSLT scores, indicative of a low level of daytime alertness, correlated less with
total amount of prior sleep than with the extent to which sleep was fragmented.
Thus, insights into causes of poor sleep quality in the elderly are likely to come from
investigations of sleep structure.
human and animal studies are consistent with regard to the dominant change in sleep
that correlates best with decreased daytime alertness in the elderly.
A reduction in the amplitude of the diurnal rhythms of sleep and wakefulness
(sometimes reported as a reduced light/dark ratio) is also a consistently observed
characteristic of sleep in aged rats (Zepelin et al., 1972; Rosenberg et al., 1979; Van
Gool and Mirmiran, 1983; Witting et al., 1993; Li and Satino, 1995). However, this
reduction may be dependent upon environmental conditions since such a diminution
was not evident in sleep studies conducted in constant dim light (van Gool et al.,
1987; Mendelson and Bergmann, 1999a).
The third characteristic of sleep of elderly people, the reduction in EEG delta
activity, has been more controversial in animal studies. Although reduced delta in
NREM sleep is clearly present in the cat (Bowersox et al., 1984), early studies of the
rat were unable to document such changes (Zepelin et al., 1972; Rosenberg et al.,
1979; Van Gool and Mirmiran, 1983). However, it is likely that the failure to
identify changes in delta activity in these studies was due to methodological
problems. For example, the studies of Rosenberg et al. (Rosenberg et al., 1979)
ltered out EEG frequencies below 2 Hz and above 4 Hz and then quantied delta
activity by using zero-crossing and accumulated voltage over time. This method
misses a signicant part of the delta band (0.52 Hz) that is of considerable
signicance for studies of delta power. Furthermore, the quantitation of delta power
used in these early studies is not as sensitive as spectral analysis using a fast
Fourier transform (FFT). Using FFT analysis of the 2.03.6 Hz range, a reduction
in delta activity was documented during slow wave sleep (SWS) in F344 rats
(Tani and Ishihara, 1988). Subsequently, reduced delta activity during NREM sleep
was observed in aged hamsters (Naylor et al., 1998) and Fischer rats (Mendelson
and Bergmann, 1999a,b; Shiromani et al., 2000) but not in Sprague-Dawley rats
(Shiromani et al., 2000). High amplitude NREM sleep has also been reported to
decrease (Mendelson and Bergmann, 1999a) in Fischer rats, suggesting a similarity
with aged human sleep in which decits in stages 3 and 4 of NREM sleep are
observed. Thus, it is likely that the failure to report age-related changes in delta
activity in older studies was due to (1) inappropriate ltering and analyses and (2) a
lack of distinction between light and deep NREM states.
Heterogeneity of the aging process has become a dominant theme in the clinical
literature. A number of researchers studying processes such as cognitive function
(Ylikoski et al., 1999), molecular genetics (De Benedictis et al., 1999), and sleep
(Reynolds et al., 1993) have identied distinct clusters of the aged population that
represent successful, usual, and pathological aging. This concept has also inuenced
the design of animal studies. For example, in aged female Long-Evans rats, some
rats have been found to have severely disrupted circadian temperature rhythms
(CTRs) while other rats display sleep patterns and CTRs identical to those of young
animals (Li and Satino, 1995; Satino, 1998). Importantly, disruption of CTRs was
a good predictor of sleep pattern changes such as reduced amplitude of the
sleepwake rhythms and sleep fragmentation, particularly REM sleep (Li and
Satino, 1995). On the other hand, a study of male F344 rats did not identify
changes in CTRs despite signicant decreases in both sleep bout lengths and high
Sleep and Aging: Molecular Approaches within a Systems Neurobiology Context 169
voltage NREM sleep (Mendelson and Bergmann, 1999a). While strain, sex, and age
dierences may account for some of this dierence between these studies, the lack of
agreement may also be related to the heterogeneity of the aged population under
study and whether the experimental design focused on group versus individual
dierences.
The hypocretinsare a pair of peptides that were rst described early in 1998
(de Lecea et al., 1998; Sakurai et al., 1998) and were given this name because the
neurons expressing this gene were restricted to an area centered around the
perifornical nucleus of the hypothalamus (PFH) and because of a weak homology to
the gut peptide secretin. The name orexins stemmed from early studies which
indicated that intracerebroventricular (ICV) injections of either of these peptides into
rats stimulated food intake (Sakurai et al., 1998). The H/O system includes two
G protein-coupled receptors: the orexin-1 receptor (OX1R) was shown to
preferentially bind orexin-A (hypocretin-1) over orexin-B (hypocretin-2), whereas
the orexin-2 receptor (OX2R) binds both peptides at high anity (Sakurai et al.,
1998). In the rodent hypothalamus, there are a few thousand cell bodies that make
these peptides but these neurons project widely throughout the brain except for the
cerebellum (Peyron et al., 1998). The monoaminergic and cholinergic cell groups
classically implicated in arousal state regulation receive H/O input and cells in the
locus coeruleus (LC) are particularly highly innervated.
control. Of particular relevance to sleep and aging are two landmark papers
(Chemelli et al., 1999; Lin et al., 1999) which established that dysfunction of the
H/O system can result in the sleep disorder narcolepsy.
Narcolepsy is characterized by excessive daytime sleepiness (EDS), episodes of
muscle weakness (cataplexy) triggered by emotional stimulation, and abnormalities
of REM sleep. A genetic component of this disorder has been established in
both humans and dogs. A strong link with the HLA Class II antigens exists in
human narcoleptics (Juji et al., 1984): across ethnic groups, HLA DQB1*0602 is
presented in more than 85% of narcoleptic patients with denite cataplexy but
only 1238% of the general population (Mignot, 1998). Such close association with
the HLA system has led to the suggestion that narcolepsy may be an autoimmune
disease (Mignot et al., 1995).
In studies in narcoleptic dogs, the canarc-1 gene, transmitted in Doberman
pinschers and Labrador retrievers as an autosomal recessive trait with full
penetrance, was identied as a deletion mutation in the hypocretin receptor 2
(hcrtr2 OX2R) gene, resulting in a truncated, nonfunctional protein (Lin et al.,
1999). In a remarkable convergence, H/O null mutant mice were found to exhibit
periods of behavioral arrest that strongly resemble the cataplectic attacks and
sleep-onset REM periods characteristic of narcolepsy in other species (Chemelli et al.,
1999). These mice also have an altered sleep architecture, as evidenced by increased
levels of both REM and NREM sleep, short latency REM periods, and decreased
sleep bout lengths, primarily during the dark (active) period. Thus, these two articles
indicate that dysfunction of either the H/O ligand or one of its receptors can result in
narcolepsy.
Although these studies in narcoleptic dog and mouse models implicated the
H/O system, the cause of narcolepsy in humans was unknown until recently.
An abnormality in H/O neurotransmission in narcoleptic humans was rst
suggested by undetectable levels of Hcrt-1 in cerebrospinal uid (CSF) from 7 of 9
narcoleptic patients (Nishino et al., 2000). In postmortem analyses, H/O mRNA
was undetectable in two narcoleptic brains, although mRNA for MCH was
readily detectable in both controls and narcoleptics (Peyron et al., 2000).
Immunohistochemistry showed an 8595% reduction in the number of H/O-
containing cells in narcoleptic brains with no evident change in the number of MCH
cells (Thannickal et al., 2000). These studies suggest that degeneration of the H/O
cells may be the cause of human narcolepsy. Increased staining for glial brillary
acid protein in the PFH suggests that the H/O cells may degenerate by an
autoimmune mechanism(Thannickal et al., 2000). In animal models, targeted lesion
of the H/O neurons by either genetic (Hara et al., 2001) or pharmacological
(Gerashchenko et al., 2001) means results in sleep fragmentation and decreased
amplitude of the diurnal rhythm of sleep and wakefulness.
3.3. A model for the role of the H/O system in sleep and wakefulness
The region of the posterior hypothalamus (PH) containing the H/O cells has long
been implicated in arousal state control (Nauta, 1946). Since narcolepsy is
Sleep and Aging: Molecular Approaches within a Systems Neurobiology Context 171
characterized by both EDS and abnormal REM sleep, dysfunction of the H/O
system in narcoleptic dogs, mice, and humans suggests that this system plays an
important role in both waking and REM sleep regulation and raises the question of
the role of these peptides in normal sleep regulation. The ICV injections of
hypocretin-1 (Hcrt-1) into rats at light onset (the major sleep period) increases
arousal and locomotor activity and decreases REM sleep without aecting NREM
sleep (Hagan et al., 1999). The wakefulness induced by Hcrt-1 injections is associated
with an intense grooming response (Ida et al., 1999) and increased plasma
corticosterone (Hagan et al., 1999). These eects may be related to projections from
the H/O cells to monoaminergic cell groups classically implicated in arousal state
regulation, including histaminergic cells of the tuberomammillary nucleus (TMN)
(Chemelli et al., 1999), the serotonergic cells of the DRN (Chemelli et al., 1999), and
the noradrenergic cells of the LC (Horvath et al., 1999). The H/O terminals are also
in apposition with cholinergic cells in brain regions involved in the EEG
desynchronization characteristic of waking and REM sleep, including the
laterodorsal tegmental nucleus (LDT), the pedunculopontine nucleus (PPT), and
in basal forebrain (BF) regions, e.g., the horizontal and vertical limbs of the diagonal
band of Broca (Chemelli et al., 1999; Scammell et al., 2000). The preoptic area (POA)
also contains H/O terminals and is a sleep/arousal regulatory site; microinjection of
Hcrt-1 increased wakefulness and suppressed sleep for at least 70 min post-injection
(Methippara et al., 2000).
We have proposed a model whereby the H/O cells might be involved in arousal
state control and the EDS of narcolepsy (Kildu and Peyron, 2000) (Fig. 1).
A complementary model has been proposed to account for the role of this
system in descending motor control and cataplexy (Siegel, 1999). Our model
assumes that H/O cells have a wake/REM-related activity. Three types of neurons
have been electrophysiologically identied in the PH: wake-related neurons, wake/
REM-related neurons, and REM-related neurons (Vanni-Mercier et al., 1984;
Steininger et al., 1999). Although the neuronal populations recorded were not
Waking
Fig. 1. Model illustrating major connections from the H/O cells to some of the brain regions implicated in
arousal state control. See text for details and Kildu and Peyron (2000) for full explanation of model.
Abbreviations: 5-HT, serotonin; Ach, acetylcholine; DRN, dorsal raphe nucleus; LC, locus coeruleus;
LDT, laterodorsal tegmental nucleus; NE, norepinephrine; PPT, pedunculopontine nucleus; TMN,
tuberomammillary nucleus. Symbols: excitatory inputs j; inhibitory inputs 3.
172 A. Terao and T. S. Kilduff
As indicated above, the H/O system has been implicated in arousal state
regulation and energy metabolism. We hypothesize that the changes in the sleep of
elderly humans, particularly decreased amplitude of the diurnal sleepwake rhythms
and increased sleep fragmentation, may be due to an age-related dysfunction of the
H/O system. As an initial test of this hypothesis, we measured mRNA levels of
preprohcrt and the colocalized dynorphin in the hypothalamus, and hcrt receptor 1
(hcrtr1) and hcrtr2 in 8 brain regions of young (3 months), middle-aged (12 and 18
months) and old (24 months) male C57BL/6 mice (Terao et al., 2002b). The cDNA
synthesis and mRNA quantitation using a real-time uorescence detection method
was conducted as described previously (Terao et al., 2000). Expression of the
preprohcrt and dynorphin genes did not change with age. An age-related change in
the expression of hcrtr1 mRNA was observed only in the hippocampus (p 0.029).
In contrast, hcrtr2 mRNA levels showed an age-related variation in the
hippocampus (p 0.035), thalamus (p 0.002), pons (p 0.022), and medulla
(p 0.0001); these reductions in mRNA levels ranged from 33 to 44% (Fig. 2A).
Trends (p 0.1) toward age-related declines in hcrtr2 mRNA levels were also
observed in the basal forebrain and hypothalamus. Narcoleptic dogs have a non-
functional hcrtr2 gene and exhibit excessive sleepiness (Lin et al., 1999) and hcrtr2
A B
R1 Cx R1 Cx
Hp 27% Hp
Cb Cb
BF BF
Th Th
R2 Cx R2 Cx
Hp Hp
Cb Cb
BF 33% BF
Th Th 91%
44%
Hy Pn Hy Pn
Md Md
38%
R3 Cx
Hp
Cb
BF
Th
Hy Pn
Md
32%
173
Fig. 2. Summary of hypocretin/orexin (A) and histamine (B) receptor family gene mRNA expression changes across eight brain areas. Number indicates
percent change compared to 3 month old group, as determined by real-time RTPCR analysis. Abbreviations: Cx, cerebral cortex; Hp, hippocampus; Th,
thalamus; BF, basal forebrain; Hy, hypothalamus; Pn, pons; Md, medulla; Cb, cerebellum; NS no signicant dierence.
174 A. Terao and T. S. Kilduff
knockout mice (Willie et al., 2003) also exhibit disrupted sleep. Thus, these results
are consistent with the hypothesis that an age-related deterioration occurs in the H/O
system that may underlie age-related sleep disorders.
At the present time, the idea that such age-related changes in sleep parameters are
due, at least in part, to dysfunction of the H/O system is simply a hypothesis.
From both in vivo microinjection studies of the peptides (Hagan et al., 1999; Bourgin
et al., 2000; Methippara et al., 2000; Piper et al., 2000) and in vivo measurements of
Hcrt-1 (Fujiki et al., 2001; Yoshida et al., 2001), the H/O system appears to
potentiate wakefulness. A wakefulness-promoting role for the H/O system is also
supported by both animal and human studies in which EDS (and cataplexy)
results when this system is dysfunctional. This EDS contributes to an overall
dimunition of the diurnal rhythms of sleep and wakefulness in human narcoleptics.
In rats, neurotoxic destruction of the Hcrt receptor-bearing cells in the hypo-
thalamus attens the diurnal rhythm of sleepwake by increasing the amount of
sleep that occurs during the normal active period (Gerashchenko et al., 2001).
Thus, an age-related dysfunction of the H/O system could result in the reduced
amplitude of the diurnal rhythms of sleep and wakefulness characteristic of
both elderly humans and aged animals by blunting the normal wakefulness-
promoting activity of the H/O system. Age-related dysfunction of this system
may also have considerable impact on the regulation of energy metabolism (Willie
et al., 2001).
found at very low levels in the brain. To determine whether age-related changes
occur in the HA system in aging, we measured the expression of HDC, H1R, H2R,
and H3R mRNAs in eight brain regions of young (3 months), middle-aged (12 and
18 months) and old (24 months) male C57BL/6 mice (Terao et al., 2004).
Although HDC mRNA levels did not change with age in C57BL/6 mice,
signicant dierences were found in H1R, H2R, and H3R mRNA levels in several
brain regions (Fig. 2B). The most widespread changes were observed in H1R mRNA
levels, which were signicantly lower (2738%) in the cortex, hypothalamus,
hippocampus, and medulla of 24-month-old mice relative to 3-month-old animals.
Age-related changes in H2R mRNA levels were restricted to the pons and cerebellum
and decreased H3R mRNA was found only in the medulla.
Although there have been few studies of the HA system in aging, altered HA
turnover has been found in the cerebrospinal uid (CSF) of aged humans (Prell et al.,
1988; Prell and Green, 1994), and PET scan studies have revealed decreased H1
receptors in the aging human brain (Yanai et al., 1992). Functional studies indicate
that HA-stimulated adenylate cyclase activity is decreased in aged rabbits (Makman
et al., 1978) and K -stimulated HA release is lowered in in vitro experiments in aged
rat hypothalamus (Ferretti et al., 1998).
The age-related changes in HA receptor mRNA reported here may be related to
the decreased alertness seen in aging. The link between the HA system and
wakefulness originates from observations that sedation and drowsiness occur with
those antihistamines (H1 receptor antagonists) that cross the blood-brain barrier and
aect central nervous system activity whereas newer antihistamines that do not cross
the blood-brain barrier do not cause drowsiness (Simons, 1990). Depletion of brain
HA with the synthesis inhibitor alpha-uoromethylhistamine resulted in a reduction
of wakefulness and increased NREM sleep (Kiyono et al., 1985; Lin et al., 1988;
Monti et al., 1988). Central injections of HA or H1 agonists elicited behavioral
arousal (Kalivas, 1982), with a concomitant desynchronization of the electro-
encephalogram (EEG) (Monnier et al., 1970). Activation of the EEG was
accompanied by increased wakefulness and decreased NREM sleep, which was
blocked by the H1 receptor antagonist mepyramine (Tasaka et al., 1989; Monti,
1993; Lin et al., 1996). Increased wakefulness and decreased NREM sleep is also seen
following administration of the H3 autoreceptor antagonist thioperamide, which acts
to block autoinhibition of the HA neurons, while enhanced NREM sleep was seen
after administration of the H3 agonist R-alpha-methylhistamine (Lin et al., 1990;
Monti et al., 1991). The wakefulness-promoting eects of thioperamide were blocked
by the H1 antagonist mepyramine (Lin et al., 1990). In contrast, pharmacological
manipulation of the H2 receptor does not aect sleepwakefulness (Monti et al.,
1990). Together, this evidence indicates that the wakefulness eects of HA are
mediated through H1 and/or H3 receptors.
As indicated above, it is thought that the wakefulness-promoting eects of Hcrt-1
are mediated through the HA system (Huang et al., 2001). Evidence for direct
interactions between the H/O and HA neurotransmitter systems include the
presence of H/O peptidergic bers in the TMN that make synaptic contact with HA
neurons (Peyron et al., 1998; Eriksson et al., 2001), hcrtr2 mRNA in the TMN
176 A. Terao and T. S. Kilduff
Numerous studies of sleep deprivation (SD) in both man and animals indicate
that sleep is homeostatically regulated. Sleep loss produces proportional increases in
the drive to sleep, in subsequent sleep expression, and in slow wave activity (SWA)
recorded in the EEG during NREM sleep. This property of homeostatic regulation,
along with a circadian component, has been incorporated into the two-process
model of sleep regulation which addresses the timing of sleep (Borbely, 1982; Daan
et al., 1984). In this model, the homeostatic sleep-related Process S is proposed to
interact with input from the circadian system (Process C) to gate the occurrence of
sleep and wakefulness. Process S is proposed to be a neurochemical process(es)
which begins to build up at the onset of wakefulness. Once a threshold value is
reached, sleep will ensue only if Process C is in the appropriate circadian phase. This
model, although seemingly simplistic, accounts remarkably well for the timing of
sleep in humans and in other mammalian species (Borbely et al., 1981, 1984; Tobler
and Jaggi, 1987; Dijk and Daan, 1989; Deboer et al., 1994; Huber et al., 2000;
Franken et al., 2001).
A number of studies have suggested that EEG SWA, i.e., activity in the 0.54.0 Hz
(delta) range of the EEG during NREM sleep, is related to the underlying Process S.
When SWA in the delta range during sleep is subjected to Fourier analysis, the
spectral power measured has been found to increase in proportion to prior wake
duration in humans and other mammals. This EEG delta power also declines as
sleep time progresses, since Process S presumably diminishes during sleep. Thus,
EEG delta power has been interpreted to represent the cortical manifestation of the
recovery processes from prior waking activities that occurs during sleep (Borbely,
1982; Borbely and Tobler, 1989).
arrays and real-time quantitative RTPCR (TaqMan). The cDNA arrays were used
for initial screening to identify candidate genes since this method enables
measurement of the expression of hundreds to thousands of genes simultaneously.
TaqMan analysis was used to conrm the candidate genes obtained from the arrays
and to evaluate the expression of these genes in other brain regions. In the course of
screening DNA arrays with mRNAs isolated from the cerebral cortex of mice that
had undergone 6 h SD or 6 h SD followed by 4 h recovery sleep (RS; see Fig. 3), two
groups of genes were found to be upregulated: immediate early genes (IEGs) and
heat shock proteins (HSPs).
4.2.1. Expression of immediate early genes (IEGs) during sleep deprivation and
recovery sleep
Since our DNA array studies revealed widespread activation of IEG expression in
the cortex after SD, we examined the expression of 11 IEG family members by
Taqman in seven brain regions to thoroughly evaluate the expression of the IEG/
transcription factor family members in response to SD and RS (Terao et al., 2003a).
During SD, a widespread activation of IEG expression was observed (Fig. 4A and
4B) and, in particular, coordinate expression of c-fos, fosB and nur77 mRNAs at a
regional level across the experimental conditions. In contrast, increased junB and
egr-3 expression was restricted to the cerebral cortex, increased fra-1 expression was
restricted to the basal forebrain, increased fra-2 expression occurred in both the
basal forebrain and cerebellum, and increased egr-1 expression occurred in both the
A B
100 200
EEG Delta Power (%)
Total Sleep Time (%)
p<0.05
80
160
60
40
120
20
0 80
0 12 24 36 48 30 36
Time (h) Time (h)
Fig. 3. A. Hourly total sleep time values (mean S.E.M.) in male C57BL/6 mice (n 10) over a 24 h
period followed by 6 h of sleep deprivation (SD) and a subsequent 18 h recovery period. Black horizontal
bars indicate dark periods, and white bars indicate light period. B. EEG delta power values (mean
S.E.M.) in male C57BL/6 mice (n 10) during hours 3036, the rst 6 h of the recovery period subsequent
to the SD period illustrated in A. Baseline values (mean S.E.M.) are EEG delta power during the same
period on the prior baseline day (ZT 612). Note that sleep intensity, as measured by EEG delta power
during NREM sleep, is signicantly increased for the rst 5.5 h of the recovery period. From Terao et al.
(2003b) with permission.
Sleep Deprivation Recovery Sleep
178
A Cx Cx
c-fos fra-2
fosB Cb
junB Cb
BF c-fos BF
c-fos Th fosB Th
fosB c-fos fra-2
fra-1 fosB
fra-2 Pn Hy Pn
Hy
Md Md
B Cx Cx
egr-1
egr-3 egr-3
C ERp72 GRp78
Cx Cx GRp94
GRp78
Cb Cb
BF
Th GRp78 BF
GRp78 Th
HSP27
GRp94
Hy Pn Hy Pn
HSP27 Md Md
GRp78 GRp78
HSP70-1 GRp94
Fig. 4. Expression of (A) Fos/Jun family genes, (B) other IEGs, and (C) HSP family genes in seven brain areas during sleep deprivation and recovery sleep.
Number of arrows indicates x-fold change as determined by Taqman analysis. " indicates mRNA is signicantly upregulated but the magnitude is 1.5-fold or
less; "" indicates mRNA is signicantly upregulated and the magnitude is 1.5- to 2.5- fold; """ indicates mRNA is signicantly upregulated and the magnitude
is 2.5- to 3.5-fold, etc. Abbreviations: BF, basal forebrain; Cx,cortex; Th; thalamus, Hy; hypothalamus, Pn; pons, Cb; cerebellum, Md; medulla.
Sleep and Aging: Molecular Approaches within a Systems Neurobiology Context 179
cortex and basal forebrain. The IEGs c-jun and junD were invariant across
experimental conditions.
In contrast to the widespread activation of IEGs during SD, very limited changes
in IEG expression occurred during RS with increased expression of fra-2 and egr-3
mRNAs in the cortex being the only signicant changes. In the case of egr-3,
increased expression was observed in the cortex both after 6 h SD and RS (Fig. 4B).
Thus, it is conceivable that the increased levels of egr-3 mRNA observed in the RS
condition could reect persistence of a long-lived mRNA that was induced during
the preceding SD period. On the other hand, egr-3 has been reported to be a late
response gene and to be expressed after some delay in the expression of egr-1
(ODonovan et al., 1998). Therefore, the increased egr-3 expression observed during
RS could also be a consequence of increased Egr-1 expression during SD. However,
egr-1 levels were increased in the basal forebrain during SD and no subsequent
increase in egr-3 mRNA was observed during RS in this brain area (Fig. 4B). A time
course study in which mice are allowed dierent durations of RS after a xed time of
SD would help resolve these possibilities.
In the case of fra-2 mRNA, a signicant increase was only observed during RS
(Fig. 4A). There are many examples of increased fra-2 mRNA and/or Fra-2 protein
expression in the CNS including rhythmic expression in the pineal gland (Baler and
Klein, 1995) or induction in specic brain regions after photic (Schwartz et al., 2000),
osmotic (Miyata et al., 2001) or pharmacological (Nye and Nestler, 1996)
stimulation or after brain injury (Beer et al., 1998). The time course of fra-2
induction has been studied in the SCN after photic stimulation either early or late in
the subjective night. In both cases, fra-2 mRNA is induced as rapidly as c-fos mRNA
but is more long-lived (Schwartz et al., 2000). Similarly, Fra-2 protein is induced in
the SCN with the same time course as Fos. This Fra-2 can either activate or repress
gene transcription depending on its heterodimerization partner (Suzuki et al., 1991;
McCabe et al., 1996; Rutberg et al., 1997) and the extent of its phosphorylation
(Gruda et al., 1994; Murakami et al., 1999). Taken together, these observations
indicate that the increased fra-2 levels observed in the cortex during RS may have
considerable physiological signicance, particularly since fra-2 mRNA is induced
during RS in the apparent absence of c-fos mRNA.
Among the brain regions examined, the cerebral cortex, basal forebrain, and
cerebellum appear to be the most sensitive regions to SD, in terms of both the
number of IEGs induced and the magnitude of the responses. Induction of c-fos
mRNA was greatest in the cerebellum followed by the cortex and then thalamus,
consistent with previous observations in the rat brain after 6 h SD (OHara et al.,
1993). Expression of the transcription factors examined did not change signicantly
in the hypothalamus, pons and medulla; the pons and hypothalamus were reported
to undergo the smallest change in c-fos mRNA in the rat study (medulla was not
measured), although statistics were not used in that study (OHara et al., 1993).
The absence of a signicant change in gene expression in the hypothalamus is
somewhat surprising, given the implication of H/O cells in sleepwake regulation
(Kildu and Peyron, 2000; Willie et al., 2001; Taheri et al., 2002). However, the
hypothalamus is a heterogeneous tissue and there are only about 3000 hypocretin
180 A. Terao and T. S. Kilduff
neurons in this region (Peyron et al., 1998; Kildu and Peyron, 2000), so a change in
IEG expression in these cells may be dicult to detect by Taqman analysis within the
larger mass of the hypothalamus. Furthermore, our previous work showed no
signicant change in preprohypocretin expression in either the mouse or the rat in
response to 6 h SD (Terao et al., 2000). In our study of heat shock proteins
(discussed next), the cortex and basal forebrain were among the most responsive
brain regions to SD in terms of the number of mRNA species that changed whereas
the thalamus and pons were the least responsive. In both studies, the cerebral cortex
was the only region in which elevated mRNA expression was found during RS.
These observations are consistent with the suggestion that the cerebral cortex, a site
of neural plasticity, may undergo important molecular changes during sleep
(Cirelli and Tononi, 2000a).
As is well known, Fos proteins must dimerize to form AP-1 and aect
transcriptional activity. As indicated in Fig. 4A and 4B, a dierent set of mRNAs are
co-induced with c-fos in dierent brain areas and, thus, dimerization pairings may
show regional specicity within the brain. Neurons and glia exhibit basal levels of
both c-Jun and JunD whereas c-Fos and FosB are found at very low levels in
untreated animals. Promoter regions bearing a single AP-1 site are eciently
activated by c-Jun and this activation is inhibited by JunB (Deng and Karin, 1993).
Consequently, to the extent that mRNA induction is reected in protein levels,
the coordinate expression of c-fos, fosB and junB mRNAs in the cortex during SD,
for example, may have considerable functional consequences for the regulation
of target genes bearing AP-1 binding sites. If the restorative function of sleep is at
all related to transcriptional activity, the current results indicate that pathways
other than the Fos/Jun transcriptional regulation are involved. Furthermore, the
region-specic nature of the IEG induction suggests that sleep subserves dierent
functions among brain regions by aecting the synthesis of dierent sets of
macromolecules.
4.2.2. Expression of heat shock proteins (HSPs) during sleep deprivation and recovery
sleep
The other class of genes whose expression was elevated in our DNA array studies
in the mouse cortex after SD were the chaperone/heat shock protein family
members (Fig. 4C). To thoroughly evaluate the expression of the heat shock protein
(HSP) family members in response to SD and RS, we examined the expression of
six HSP family members(erp72, grp78, grp94, hsp27, hsp-70-1, hsp84 ) by Taqman in
seven brain regions (Terao et al., 2003b). Our studies revealed increased mRNA
levels for several HSPs in cortex, basal forebrain, hypothalamus, cerebellum, and
medulla during SD, whereas increased mRNA levels during RS were limited to grp78
and grp94 and were anatomically restricted to the cortex and medulla (Fig. 4C).
Immunohistochemical studies conrmed these results by identifying increased
numbers of GRp78-, GRp94-, and ERp72-immunoreactive cells in the dorsal and
lateral cortex during SD. During RS, however, the number of these cells increased
only in the lateral cortex. In the medulla, increased numbers of GRp94-ir cells were
observed in the nucleus tractus solitarius, dorsal motor nucleus of the vagus, and
Sleep and Aging: Molecular Approaches within a Systems Neurobiology Context 181
the rostroventrolateral medulla during RS. The widespread increase of HSP family
mRNAs in brain during SD may be a neuroprotective response to prolonged
wakefulness. In contrast, the relatively limited HSP family mRNA expression during
RS may be related to the role of HSPs in protein biogenesis and thus to the
restorative function of sleep.
As is evident in Fig. 4C, a dierent combination of HSP mRNAs was upregulated
during SD in each of the brain regions examined. In terms of the number of mRNAs
that changed, the cortex and basal forebrain were among the most responsive brain
regions to SD whereas the thalamus and pons were the least responsive. Dierential
expression of HSP mRNAs was also evident during RS (Fig. 4C). In a previous
study of the response of the rat brain to SD, we reported dierential IEG expression
among brain regions (OHara et al., 1993) and found the cerebellum and cortex to be
the most sensitive brain regions to SD. Future studies using tools that provide a
more encyclopedic view of gene expression among brain regions should allow
denitive determination of dierential sensitivity of brain regions to SD and
localization of where restorative processes occur in the brain during sleep.
What is the physiological signicance of these changes in HSP and GRP
expression in brain during SD and RS? Other than in response to SD (Cirelli and
Tononi, 2000b), the only examples of induction of the GRPs in brain are in
pathological conditions: GRp75, GRp78, GRp94 are induced in brain by ischemia
(Massa et al., 1995; Sharp et al., 1999) and status epilepticus (Little et al., 1996). The
GRp78 and HSP70 are also increased in several brain regions in response to dietary
restriction (Yu and Mattson, 1999; Guo et al., 2000). These GRp78 (BiP, a HSP70
homologue), GRp94 (ERp99, a HSP90 homologue), and ERp72 are glucose-
regulated proteins localized to the endoplasmic reticulum (ER). In other tissues,
GRp78 and GRp94, probably along with ERp72 and GRp170, have been shown to
act as molecular chaperones, playing a role in the proper folding of proteins that
pass through the ER such as thyroglobulin (Kuznetsov et al., 1997), the light and
heavy chains of immunoglobulins (Melnick et al., 1992, 1994), and procollagen
(Ferreira et al., 1994).
There appear to be several pathways for induction of GRPs. Misfolding of large
oligomeric glycoproteins in the ER is a potent stimulus for all of the ER-associated
GRPs, including GRp78, GRp94, GRp170 and ERp72 (Kuznetsov et al., 1997). The
GRPs also share a biochemical feature of being inducible by various compounds that
stress the ER and appear to protect cells against a variety of stimuli. Stimuli known
to induce GRPs include low glucose, agents that aect ER calcium levels (such as the
calcium ionophore A23187 or thapsigargin), and agents that inhibit protein
glycosylation in the ER (such as tunicamycin) (Sharp et al., 1999). Interestingly, the
calcium ionophore A23187 induces the GRPs but inhibits HSP70 expression (Elia
et al., 1996). Another route for induction of GRPs is related to mitogenesis, a
pathway distinct from the misfolding response. This pathway has been proposed to
control expression of the ER chaperones and folding enzymes needed to assist
protein biogenesis in the ER of normal, non-stressed cells (Brewer et al., 1997).
Based on these observations, we suggest that the widespread induction of HSPs and
GRPs in the brain during SD (Fig. 4C) may be a neuroprotective response to cellular
182 A. Terao and T. S. Kilduff
In this chapter, we have described the sleep characteristics of the elderly and
introduced the concept of homeostatic sleep regulation. The great diminution of
stage 3 and 4 sleep suggests a problem with generation of the delta frequencies in
the EEG and potentially a problem with sleep homeostasis in the elderly, although
SWA in the delta range can be observed in senior individuals after one nights sleep
deprivation. Animal studies have demonstrated a reduction in mRNA levels for
both hcrtr2 and for HA receptors in selected brain areas. Since the alerting eects
of the H/O neuropeptides are thought to be mediated through the HA system,
Sleep and Aging: Molecular Approaches within a Systems Neurobiology Context 183
A B
2 2
Expression Level
H-2T17
1 1
0 0
60 30
Expression Level
IL-1b
40 20
20 10
0 0
2 20
Expression Level
TNFa
1 10
0 0
150 30
Expression Level
MCP-1
100 20
50 10
0 0
4 1.5
Expression Level
c-fos
1.0
2
0.5
0 0
3 12 18 24 3 12 18 24
Age (Month) Age (Month)
Fig. 5. Comparison of expression patterns with age for ve genes as measured by GeneChip (A) and
real-timequantitative PCR (B). Open squares in both the panels represent data from untreated mice
whereas dark squares represent data from LPS-treated mice. For the GeneChip analysis 3 samples were
pooled per age. Basal data represent an average of two replicate experiments. Data from LPS-treated mice
are from a single experiment. For PCR analysis data represent means SEM of individual samples at
each age. N 5 or 6 for basal samples and 2 or 3 for samples from LPS-treated mice. y statistically
signicant (p < 0.05) compared to 3 months for all basal samples, by TukeyKramer post hoc test.
x statistically signicant (p < 0.05) compared to 3 months in samples from LPS-treated mice, by Tukey
Kramer post hoc test. * statistically signicant (p < 0.05) when samples from untreated and LPS-treated
mice were compared by TukeyKramer post hoc test. From Terao et al. (2002a) with permission.
184 A. Terao and T. S. Kilduff
Acknowledgments
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List of Contributors
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194 List of Contributors