SECTION 6 - PEDIATRICS

Sleep and Early Brain Development and Plasticity

Background

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 during sleep.

Understanding the 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.

Progress 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 at birth.

- National guidelines for the regulation of light intensity in neonatal intensive care units have been established.

Research Recommendations

- 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.