Review articleLong-term sleep disturbances in children: A cause of neuronal loss
Introduction
Recent research activities in various fields of sleep medicine force us to view the wake–sleep states as an interrelated and orchestrated change in behavioural, cognitive, genetic, anatomical, electrical, molecular, cellular, biochemical, and endocrine functions in which the pineal melatonin plays an important role.1 Viewing sleep as a complex, neurological process rather than an independent state promotes better understanding of sleep disorders and their adverse effects on cognition, behaviour and health. The purpose of this review is to discuss the neuronal, metabolic and other mechanisms of sleep, based on recent scientific advances; then to summarise and integrate the evidence which supports the hypothesis that in childhood chronic sleep deprivation can lead to permanent neurological damage especially during early critical developmental periods. Sleep deprivation is generally defined in sleep medicine as sufficient loss of sleep during a period of time which results in impairment of neurological and physical functions. Sleep deprivation not only depends on the quantity but also on the restorative quality and timing of sleep. Children require more sleep than adults with individual variations. Sleep deprivation can be short or long-term, partial or total. Short-term sleep deprivation could be caused by loss of a few hours of sleep. It is more difficult to define chronic or long-term partial sleep loss but in clinical practice children with neurodevelopmental disabilities frequently exhibit persistent sleep disturbances with inadequate hours of sleep for years or even lifetime. Partial and also total short-term sleep loss has been studied mainly in animals, less frequently in healthy adults but only on rare occasions in children.2, 3, 4 Research on the permanent adverse effects of sleep loss on neurodevelopment is still minimal.5 There are no controlled studies in children, which is not surprising as such experiments are unethical to perform, due to adverse psychological and medical consequences.
One of the anecdotal total long-term sleep deprivation experiments involved a top radio personality, Peter Tripp, who in 1959 wanted to break the world record for staying awake for the longest period of time. He succeeded in breaking the record by staying awake for 201 h but became psychotic towards the end of his ordeal. Following this event, those close to him felt that his personality had permanently changed. He lost his job, had difficulties settling and his wife divorced him.6 Since then others have broken the world record for staying awake but all of them had serious cognitive and behavioural changes during their attempts. The long-term neurological and psychological consequences were not studied. The experiment of Peter Tripp illustrates the critical importance of sleep for survival. Indeed, complete lack of sleep in animal experiments leads to death within 3 weeks.7, 8
In typically developing children, with exceptions, the sleep difficulties tend to be partial, short term and respond favourably to appropriate management.9 In contrast, in children with neurodevelopmental disabilities (NDD) the prevalence rates of sleep difficulties may be as high as 75–80% and the sleep disturbances tend to last for years or even for a lifetime. While they can be helped by therapies or environmental changes they may respond less readily than typical children.10, 11, 12 Sleep disturbances are associated with many neurological conditions, alone or in combinations, such as intellectual disability,13 epilepsy,14 cerebral palsy,15 visual impairment,16 autism,17 attention deficit hyperactivity disorder,18 fetal alcohol spectrum disorders19 and brain maldevelopment.20 Not infrequently such children only sleep for 3–4 h a night for years or for their entire lives. The number of coexisting neurological disorders and their severity proportionately predispose to disturbed sleep.21 Untreated sleep deprivation may lead to deterioration of the already impaired brain functions as evidenced by increased difficulties in learning, memory, verbal creativity, attention, abstract reasoning and many other perceptual, cognitive and motor functions.22, 23, 24 Sleep problems are more common in remedial classes for children with various forms of NDD than in primary schools.23, 25 In children with obstructive sleep apnea the degree of sleep disturbance and the severity of intellectual and behavioural changes are strongly linked. For example, among first grade students with the lowest marks, there was a 6–9-fold increase in the expected prevalence of sleep apnea.26 Thus, the possibility exists that a vicious cycle may be created which feeds back to itself as sleep disorders in children with NDD lead to increasingly impaired cognition and further deterioration of sleep.
The three most common sleep disturbances in children with NDD are difficulties falling asleep, frequent awakenings during the night and early morning arousals alone or in combinations. Although diagnostic sleep studies in the NDD population are scarce, these sleep disturbances are generally considered to be circadian rhythm sleep disorders and they tend to be associated with abnormally timed, or reduced pineal melatonin production and secretion.27 When sleep disorders are appropriately treated, even after years of delay, caregiver reports show that there is significant improvement in intellectual function, behaviour and health.28 However, a strong possibility still exists that the delay in treatment adversely affects the ultimate intellectual potentials of these children. Chronic sleep deprivation may occur at any age, but the adverse consequences are much more likely to occur in younger children, whose immature brains are rapidly developing in contrast to adults with mature central nervous systems.
Section snippets
Critical developmental periods
Our sensory systems respond to environmental information by transducing it to electrical activity in the brain. The vast number of neuronal groups, ‘modules’ or ‘assemblies’, also communicates by means of electrical oscillations. Because of environmental exposure during development, competition occurs between neuronal assemblies which results in the creation of neural pathways and anatomical regions responsible for later cognition and mature behaviour. The timing and duration of environmental
Electrical activity of the brain
The purpose of this section is to describe the electrical changes in sleep and relate these to brain functions, sleep disturbances and development. The global electrical activity of the brain is the summation of oscillatory frequencies between myriads of neuronal modules. In both mammals and humans, these frequencies and patterns are very different in wakefulness, drowsiness and in certain sleep stages.31 Based on these and clinical differences, sleep patterns in the electroencephalogram (EEG)
Homeostatic mechanisms in sleep
During early sleep research, Borbely introduced theories explaining the influence of circadian and homeostatic mechanisms on sleep.47 He suggested that the circadian rhythm oscillators in the suprachiasmatic nuclei of the hypothalamus control the sleep–wake cycles and the homeostatic process regulates sleep need, which increases during the day and decreases during NREM sleep. It was hypothesized that the accumulation of one or more unknown substances in the brain during the waking hours were
Imaging studies
Neurons dynamically create oscillating electrical currents and induce corresponding magnetic fields which process requires large amount of energy. Depending on the types of functions performed during testing different regions of the brain are activated. Functional magnetic resonance imaging (fMRI) and positron emission tomography techniques detect these changes because of the underlying metabolic and hemodynamic responses. The generated electrical activity and the corresponding magnetic fields
Cellular stress during sleep deprivation
The most convincing evidence for permanent neuronal damage resulting from sleep loss comes from cellular studies in which animal experiments are indispensable. There is increasing evidence that even brief periods of total sleep deprivation may permanently imprint on neuronal plasticity. For example, during critical developmental periods the adverse effects of sleep loss on the visual system have been clearly shown.87 Occlusion of one eye causes rapid remodelling of the visual cortex and its
The effects of sleep deprivation on the hippocampus
The hippocampal structures play a major cognitive role and have received considerable attention with regard to sleep deprivation. They participate in learning and memory formation through reciprocal connections to various regions of the brain and also in emotional processes involving the amygdala and prefrontal cortex. The hippocampal formation is in the medial temporal lobe and includes the dentate gyrus, the hippocampus and a number of other areas that can be clearly identified at birth.
Melatonin
The daily variations of light are transduced into electrical impulses by specialized retinal ganglion cells which then communicate this information to the suprachiasmatic nuclei in the hypothalamus.130 In turn, the suprachiasmatic nuclei signal the pineal gland to down-regulate the melatonin production.131 In the absence of light the pineal gland is relieved of the inhibitory influence of the suprachiasmatic nuclei and melatonin production occurs with its rapid release into the blood and
Conclusions
During the last few years, research activities have markedly increased in electrophysiology, anatomical studies, structural and functional brain imaging, cellular, molecular, and genetic, biochemical and other areas of sleep medicine. It is important for pediatric neurologists and physicians in other clinical fields to be familiar with some of these advances. NREM sleep is most important in restoring homeostatic balance following wakefulness, whereas REM sleep provides a supportive role in
Acknowledgements
The authors wish to thank C. Cirelli MD, PhD of University of Wisconsin–Madison for reviewing the manuscript.
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