Neurology Update – Neurobiology of Sleep

Dr. Prithika Chary*

Senior Consultant, Neurology, Neurosurgery and Epileptology, Kauvery Hospital, Chennai, Tamilnadu, Trichy, India

*Correspondence: drprithikachary@gmail.com

The earliest information about the neurobiology of sleep and wakefulness was in the 1930’s. Since then, advances in the neurosciences have been explosive and we know more about the body’s natural rhythms and the sleep/wake cycle today.

Lack of sleep and disorders of sleep/awake function is a common health problem in the modern world. Shift work, travel across time zones, maladaptive sleep habits, overuse of blue light emitting devices further compound the harm to the body’ s natural biological rhythms.

A coordinated sleep/wake cycle is necessary for us to maintain health and optimal cognitive function.

There are two main processes involved in this

  • The Circadian process – the internal clock, melatonin & adenosine and Zeitgebers
  • The Homeostatic process – need for sleep, time since last adequate sleep

The Circadian Process

The internal clock is present in all cells of the body.

Melatonin and Adenosine are sleep promoting chemicals

Zeitgebers – in German – time givers – sensitive to our routines – sleep/wake routine, physical activity, eating, light is a very important zeitgeber, especially blue light which has both positive and negative effects on sleep.

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The Circadian rhythm is closely related to light. When light hits the retina of the eye, it is taken to the suprachiasmatic nucleus of the hypothalamus, which will signal the pineal gland to turn off melatonin production. So, during daylight, we stay awake.

In the dark, there is no input from the retina to the SCN and darkness will signal the pineal gland to produce melatonin inducing sleep. As it gets darker melatonin levels rise and peak in the middle of the night and slowly come down again towards early morning.

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The Homeostatic Process

This is really a need for sleep and is dependent on the last time you had adequate sleep. If you have not had adequate sleep for a while, the homeostatic mechanism will kick in forcing you to sleep.

The Flip Flop Switch

Has three essential elements

The orexin neurons

The wakefulness neurons – they directly promote wakefulness and also stimulate the mono aminergic nuclei (LC, RN, TMN) which promote wakefulness and inhibit sleep promoting neurons in the VLPO, which in turn relieves inhibition of the monoaminergic cells and the Orexin neurons. Orexin A also regulates prolactin, growth hormone, and corticosterone levels, possibly through a direct effect on hypothalamic neurons. Taken together, these observations suggest that orexin A plays an important role in orchestrating the electrophysiological, behavioral, and endocrine aspects of the sleep-wake cycle.

The monoaminergic nuclei – The locus coeruleus, raphe nucleus and tuberomammillary nucleus

They directly promote wakefulness and also inhibit sleep promoting neurons in the VLPO, which in turn relieves inhibition of the monoaminergic cells and the Orexin neurons.

The ventrolateral preoptic neurons – promote sleep

Summary – the orexin and monoaminergic neurons promote wakefulness directly; the monoaminergic neurons also inhibit the VLPO sleep promoting neurons.

How does sleep occur?

The VLPO neurons promote sleep

The VLPO neurons inhibit the monoaminergic neurons and in turn relieve their own inhibition

The disinhibition of the VLPO neurons inhibits orexin neurons which in turn prevents activation of monoaminergic neurons

An overview of the flip flop switch model

During wakefulness – the orexin stimulates wakefulness, the monoaminergic nuclei stimulate wakefulness, and the orexin also pushes the monoaminergic nuclei to stimulate wakefulness as well. Also, the monoaminergic nuclei inhibit the sleep promoting VLPO nuclei.

Time to sleep – VLPO kicks in. It also inhibits orexin, and the monoaminergic nuclei and promotes sleep

The importance of light as a Zeitgeber

We are exposed to a range of light including ultraviolet light which we cannot see. We are surrounded by blue light. Seeing the computer, phone, TV, LED lights, are all blue light.

Blue light exposure during the day suppresses melatonin secretion to keep us awake and is important for entrainment of the circadian rhythm

It is important to maintain the well-being of the organism, alertness and cognitive performance during the day.

Chronic, low intensity blue light exposure directly before bedtime has serious implication on sleep quality, circadian phase and cycle durations. Can lead to insomnia.

We can wear blue light filtering spectacles at night to minimize these effects.

Sleep has three distinct stages

  • Wakefulness
  • Non-REM sleep
  • REM sleep

The brain is designed to wakefulness during the day and the two stages of sleep usually only at night.

There are many ways in which the brain makes this happen in a smooth manner transitioning automatically from one stage to another.

During wakefulness, there is normal muscle tone and neuronal functioning for alertness and good cognitive functioning and associated with alpha brain waves.

At night sleep occurs in a predictable pattern of alternating REM and non-REM sleep. Non-REM sleep occurs first, and is associated with relaxed muscle tone and slower frequency of brain waves, and supports deep, restorative sleep. REM sleep normally only occurs at night, and is more frequent as the night goes on. This stage is associated with loss of muscle tone, and fast frequency brain waves and dreaming. There are stable boundaries between each of these stages and features of one stage do not occur in another maintaining a healthy sleep/wake cycle.

Regulation of this sleep wake cycle is a natural body rhythm.

Regulation of this sleep wake cycle is a natural body rhythm.

Hypocretin neurons are wake stabilizing neurons that promote and stabilize wakefulness during the day. They promote wakefulness by directly activating the cortical and subcortical neurons. They also promote wakefulness indirectly by stimulating the histamine neurons, and other wake promoting neurons like acetyl choline neurons, dopamine neurons, serotonin neurons, norepinephrine neurons. Histamine and other wake promoting neurons as above stabilize wakefulness by inhibiting non-REM sleep promoting neurons.

Hypocretin neurons also inhibit sleep promoting REM sleep neurons. This is done through Histamine neurons which perform similar functions at these same regions.

Insomnia and hyperarousal

Indications of hyperarousal are

  • EEG changes – increased fast frequencies during sleep
  • Increased REM sleep arousals
  • Increased daytime sleep onset latency
  • Short sleep duration

The systemic effects of this are increased metabolic rate, increased body temperature, increased heart rate, altered heart rate variability, increased activity of the pituitary adrenal axis producing high cortisol levels.

In insomnia, there may be overactivation of the arousal system and the emotion regulating system. There is also hypoactivation of the prefrontal cortex and the cognitive system and this leads to daytime fatigue.

While treating insomnia, it is important to address both the hyperarousal and the cognitive fatigue resulting from poor sleep.

When we look at the reticular activating system and its role in the sleep/wake cycle, we realize there is a huge interplay between several brain regions and neurotransmitters and hormones. These include Orexin, GABA, histamine, noradrenaline, acetyl choline, melatonin, 5 HT etc.

Causes of sleep disturbances

Misalignment of the circadian process leading to phase delays or advances (prolonged sleep onset latency) – difficulty falling asleep.

Delayed or advanced melatonin secretion – excessive exposure to blue light.

Dysfunction of the homeostatic process – the time that has elapsed since the last episode of sleep.

Maladaptive behaviors reducing the homeostatic process – not sleeping when you are actually feeling sleepy.

Reduced GABAergic activity or orexigenic over activity – GABA promotes sleep and reducing hyperarousal which produces anxiety, orexin is a wakefulness neuron.

Over activity in the hypothalamus, hippocampus, amygdala and prefrontal cortex hypoactivation (cognitive fatigue).

The hyperarousal model of insomnia describes an increased activation of cognitive, emotional, behavioral and autonomous processes during waking and sleeping hours.

Comorbid psychological or medical issues, as well as genetic vulnerabilities, also exacerbate this imbalance between arousal and sleep-inducing brain activity.

Common Sleep Disorders

Narcolepsy

Excessive daytime sleepiness and abnormal REM sleep

Cause not known

Pathology – 85–95% neuronal loss seen in the hypothalamic regions responsible for producing orexin/hypocretin – dorsal and lateral hypothalamus, locus coeruleus, thalamus and cerebral cortex. The gliosis seen in the orexin cell region suggests that narcolepsy is a neurodegenerative process.

Genetic and environmental triggers may influence occurrence

Disorders Of Fragmented Sleep

Obstructive sleep apnoea

Repeated episodes of apneoa/hypoapnoea leading to arousal and consequent hypoxemia and hypercapnia and sympathetic stimulation, mediated by chemoreceptors in the carotid body and brainstem.

OSA is associated with hypertension, cardiovascular disease, depression

Patients with OSA have a higher incidence of TIA’s and stroke.

Restless legs syndrome

Strong urge to move the legs, or sometimes the arms, trunk, or head and neck as well.

Paraesthesiae at rest, worse at night, relieved by movement interfere with sleep

Strong familial tendency seen

Pathology – possible impaired iron metabolism – low iron levels in substantia nigra and putamen (which control voluntary movement) – interferes with normal dopamine signaling.

RLS is common in iron deficiency anaemia. Dopamine antagonists aggravate RLS and sleep disturbances

Circadian rhythm sleep disorders

Due to chronic disturbance in relationship between the circadian pacemaker and environmental cues, e.g., light dark cycle

The American Academy of Sleep Disorders identifies nine types including the following:

  • Delayed sleep phase
  • Advanced sleep phase
  • Shift work
  • Nonentrained sleep-wake
  • Irregular sleep-wake
  • Jet lag

Shift work disorder

Seen in 32% of night shift workers and 26% or rotating shift workers.

Insomnia or excessive sleepiness during work hours scheduled during normal sleep periods.

Due to misalignment between circadian regulation and sleep-wake behavior.

Total sleep time is often reduced by 1–4 h, sleep quality is poor, there is difficulty in initiation and awakening, diminished alertness, may impair mental ability and work performance.

Total sleep time is often reduced by 1–4 h, sleep quality is poor, there is difficulty in initiation and awakening, diminished alertness, may impair mental ability and work performance.

Health risks are increased cardiovascular and gastrointestinal disease, depression and inadequate socializing.

Sleep disorders associated with comorbidities

Alzheimer’s disease – a variety of sleep and behavioral disturbances can occur but their pathogenesis is unknown. There is a higher prevalence of OSA in these patients.

Parkinson’s disease – this is a dopaminergic disease. The neurodegeneration seen in dopaminergic pathways result in REM sleep disturbances and may even precede the onset of overt disease.

There are many more specific sleep disorders which are beyond the scope of this article.

There are many more specific sleep disorders which are beyond the scope of this article.

References

  • Siegel JM. The neurobiology of sleep. Semin Neurol. 2009;29(4):277–96.
  • Brown RE, Basheer R, McKenna JT, Strecker RE, McCarley RW. Control of sleep and wakefulness. Physiol Rev. 2012;92(3):1087–187.
  • Steriade M, McCarley RW. Brain control of wakefulness and sleep. Kluwer Academic/Plenum Publishers; New York: 2005.
  • Saper CB, Chou TC, Scammell TE. The sleep switch: hypothalamic control of sleep and wakefulness. Trends Neurosci. 2001;24(12):726–31.
  • Anaclet C, Parmentier R, Ouk K, Guidon G, Buda C, Jean-Pierre S. Orexin/hypocretin and histamine: distinct roles in the control of wakefulness demonstrated using knock-out mouse models. J Neurosci. 2009;29(46):14423–38.
  • Date Y, Ueta Y, Yamashita H, Matsukura S, Kangawa K, Sakurai T. Orexins, orexigenic hypothalamic peptides, interact with autonomic, neuroendocrine and neuroregulatory systems. Proc Nat Acad Sci USA. 1999;96(2):748–53.

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