6 - PEDIATRICS
Sleep and Early Brain Development and Plasticity
Sleep may have important
roles in adult brain plasticity related to learning and memory
consolidation. Unlike adults, the human fetus and neonate spend
a remarkable proportion of their time sleeping, with approximately
80% of their day in active (REM) sleep and the remainder in
quiet (non-REM) sleep and wakefulness. By 5-6 months of age,
human infants spend only 20-30% of their time in REM sleep,
with the remainder of time equally spent in non-REM sleep and
wakefulness. Reasons for such increased requirements for sleep,
particularly REM sleep, in early life are not well understood,
but improved understanding of these developmental requirements
may provide insight into the functions of sleep throughout life.
The high percentage
of time spent in REM sleep during the critical period in human
brain growth and maturation in late fetal and early postnatal
life may indicate that the neural activity controlled by REM
state mechanisms may be developmentally functional and contribute
directly to physiological and structural brain maturation. REM
sleep may be important in providing early stimulation and activity
requirements of the growing brain. Subsequent recognition of
activity-dependent development of neural connections in utero
provides a specific mechanism by which endogenously controlled,
correlated, spontaneous neural activity mediates brain maturation.
The resulting hypothesis is that one function of REM sleep is
to generate specific patterns of intrinsic activity in neuronal
populations whose development is dependent upon activity. The
classic example of activity-dependent maturation is the visual
system, in which spontaneous neural activity in each retina
in the fetus (before visual experience) is necessary for the
anatomic segregation of eye-specific synaptic connections in
the lateral geniculate nucleus. Research studies in experimental
models support the idea that activity-dependent maturation occurs
roles of sleep in brain maturation and plasticity is of critical
importance since perturbations during fetal life or early postnatal
life can have major impact on developmental processes and thus
on adult phenotype. Suppression of neonatal REM sleep in rats,
for example, alters ventilatory pattern, metabolism, and regional
brain concentrations of neurotransmitters and their receptors
at maturity, suggesting adverse adult consequences on brain
re-wiring due to disruptions in sleep in early life. Furthermore,
early hyperoxic exposures as may occur in mechanically ventilated
premature infants, or sleep-associated episodic hypoxemia such
as occurring in apnea of prematurity, may result in permanent
impairments in cardiovascular and respiratory control. Thus,
despite the existence of redundant protective mechanisms and
increased system plasticity at these early stages of development,
the fetus and newborn are likely extremely susceptible to disruption
of the normal homeostatic processes for normal tissue and organ
growth and function. Furthermore, although the interactions
between sleep processes and early life perturbations are unknown,
it is reasonable to assume that these early disruptive events
may alter the hierarchical organization of functional gene clusters
and lead to both early and late increases in vulnerability to
specific disease states.
Those at greatest
risk for early disruptions in sleep and sleep-related brain
maturation are premature infants in intensive care nurseries.
Sleep deprivation in this setting is a major problem due largely
to the absence of a diurnal rhythm of light/dark cycles, and
sleep interruption by constant medical and nursing procedures.
The functional short-term and long-term implications associated
with disruption of the normal sleep cycles at such early stages
of development are just beginning to be understood. Premature
infants exposed to bright/dim light cycles in the nursery are
more likely to sleep longer, begin to feed earlier, and grow
better than those under constant bright lights. There has been
extensive progress in understanding the functional properties
and cellular and molecular mechanisms regulating sleep-wake
periodicities and the circadian clock, but little is known about
the maturation of such systems, especially considering the huge
alterations in sleep-wake schedules that accompany fetal and
early postnatal development.
In The Last 5 Years
- In kittens at the
peak critical period of the maturation of the visual cortex,
sleep has been shown to enhance the effects of a preceding period
of monocular deprivation on visual cortical responses. These
findings demonstrate that sleep and sleep loss modify experience-driven
cortical plasticity in vivo, and support a crucial role for
sleep in early life upon brain development.
- Sleep and sleep
loss have been shown to modify the expression of several genes
and gene products that appear to be important for synaptic plasticity.
- Studies in neonatal
animals indicate that suppression of REM sleep can lead to behavioral,
anatomic, and biochemical deficiencies, including respiratory,
that extend into adulthood. Neonatal active sleep may be a critical
factor in the normal development and expression of respiration.
- The functional
properties of the suprachiasmatic nucleus are developing and
become functional from mid-to-late gestation in experimental
animals, allowing for sleep-wake rhythm entrainment before and
- National guidelines
for the regulation of light intensity in neonatal intensive
care units have been established.
- The ontogeny of
fundamental biological mechanisms mediating the regulation of
sleep and waking needs to be established in order to better
understand the normal and abnormal consequences of the development
of such systems.
- Studies are needed
to elucidate the underlying mechanisms of changes in circadian
rhythmicity during early postnatal life in full-term and premature
animal models and in humans.
- Studies are needed
to assess the effects of prematurity per se and of treatment
conditions (e.g., light-darkness cycles) in intensive care nurseries
on cognitive function and brain development and on the physiological
maturation of circadian regulation.
- Increase our basic
understanding of the specific effects of sleep state on neural
plasticity and synaptic connectivity in developing mammals.
- Investigate the
neurochemical, cellular, and molecular aspects of human sleep
ontogeny, including the use of mapping techniques in postmortem
human fetal and infant brains.
- Study the short
and long term consequences of medical conditions associated
with disruption of normal pregnancy and/or early postnatal life
(e.g., maternal cigarette smoking, cocaine or opiate addiction,
materno-fetal insufficiency, prematurity). These results may
yield a better understanding of altered sleep and cardiorespiratory
control in early life, and may provide insight into regulatory
mechanisms ultimately responsible for the occurrence of disorders
such as apnea of prematurity, SIDS, congenital central hypoventilation
syndrome, and developmental neurobehavioral deficits.