MODULE 10A - SLEEP HEALTH

SLEEP PHYSIOLOGY

MAJOR BRAIN AREAS IMPORTANT FOR SLEEP AND WAKE

Hypothalamic Areas
  1. Lateral Hypothalamus
    • Neurons in the lateral and posterior hypothalamus are the sole source of the awake-promoting neuropeptides hypocretin 1 (Hcrt1) and hypocretin 2 (Hcrt2), also known as Orexin A and Orexin B, respectively.
    • Patients with narcolepsy with cataplexy have loss of 90% or more of orexin-producing neurons and have low to undetectable cerebrospinal fluid levels of Orexin A.
    • Orexin neurons send abundant excitatory projections to the dorsal raphe nucleus, the locus coeruleus, and the tuberomammillary nucleus.
    • Orexin neurons have a strong excitatory effect on the cholinergic neurons of the basal forebrain that contribute to cortical arousal.
    • Orexin neurons are relatively inactive in quiet waking but are transiently activated during sensory stimulation.
    • Orexin cells appear to be activated during emotional and sensorimotor conditions.
  2. Ventrolateral Preoptic Nucleus
    • The VLPO is an area in the hypothalamus containing neurons active during sleep.
    • Most sleep-active neurons in the VLPO are believed to be active both during NREM and REM sleep.
    • Many VLPO neurons are activated by sleep-inducing factors including adenosine and prostaglandin D2.
    • These neurons are sensitive to warmth, and heating this area of the brain increases their activity and decreases wake.
    • Neurons in the VLPO contain the neurotransmitters/neuromodulators GABA and galanin.
  3. Tuberomammillary Nucleus
    • Histaminergic neurons are confined to the posterior hypothalamus in the area called the tuberomammillary nucleus.
    • Histamine acting at H1 receptors is associated with wakefulness, and antihistamines (H1 receptor blockers) cause drowsiness or sleep.
    • Firing is high during wake, lower during NREM, and absent during REM.
    • Low CSF histamine has been found in patients with narcolepsy with and without low orexin. The low histamine may be a marker rather than a cause of sleepiness because lesions of the TMN have minimal effect on wakefulness.
    • This may simply mean that histamine is not essential for wakefulness in general. Histamine may be important at the onset of wakefulness.


Brainstem Regions

Dopamine Regions
  • Neurons producing dopamine are abundant in the substantia nigra and the ventral tegmental area.
  • Dopamine levels are high in several brain regions during wakefulness.
  • Dopamine agonists acting at D1, D2, and D3 receptors increase waking and decrease NREM and REM sleep.
  • Dopamine blockers of D1 and D2 receptors can promote sleep.
  • Amphetamines promote wakefulness by increasing dopamine signaling.

Reticular Formation
  • A loose connection of neurons extending from the caudal medulla to the core of the midbrain.
  • Sections above the mid pons produce coma or hypersomnolence.
  • Wakefulness depends on the activity of the ascending reticular activating system (ARAS).
  • Dorsal RAS
    • Neurons here are cholinergic
    • Some of the neurons are active during wake and REM sleep (wake/REM-on), whereas others are active mainly during REM sleep (REM-on).
    • Acetylcholine release in the thalamus is high during wake and REM sleep.
    • During wake and REM sleep, these cholinergic neurons depolarize thalamic relay neurons, thereby activating thalamocortical signaling and produce fast cortical rhythms.
    • During NREM sleep, these neurons are inactive.
    • Rem-on neurons are active during REM sleep but not wake or NREM sleep.
    • Wake/REM-on neurons are active during wake and REM sleep.
  • Ventral RAS
    • Contain neurons that project to the cortex
    • Composed of projections from the dorsal raphe nucleus (5HT) and locus coeruleus (norepinephrine).
  • Dorsal Raphe Nucleus
    • DRN serotonergic neurons are active during wake, less active during NREM, and minimally active during sleep.
    • The influences of DRN neurons are mainly stimulatory.
    • They are part of the RAS network.
  • Locus Coeruleus
    • Neurons in the LC utilize norepinephrine as the neurotransmitter and innervate wide areas of the brain with chiefly stimulatory effects.
    • Firing rates are high during wake, lower during NREM, and absent during REM sleep.

Basal Forebrain
  • Cholinergic neurons in the basal forebrain excite cortical pyramidal cells
  • GABA BF neurons disinhibit cortical neurons

NREM SLEEP
  • VLPO neurons are active and inhibit the firing of neurons in the TMN, DRN, and LC.
  • The Orexin neurons do not innervate the VLPO but stimulate the TMN, DRN, or LC more or less depending on the sleep state.
  • Orexin neurons are active during wake.
  • This mutually inhibitory system functions as a flip-flop switch transitioning between the two states.

REM SLEEP
The major tonic and phasic features are listed in the table below (Table 2).
  • ​There are several models proposed for the control of REM sleep.
  • In one model, the activity of REM-on neurons in the lateral dorsal tegmentum and pedunculopontine tegmentum nuclei is high whereas that in the monoaminergic centers is low (TMN, DRN, and LC).
  • The REM-on neurons simulate effector cells in the medial pontine reticular formation and infuse it with cholinergic agonists resulting in many of the manifestations of REM sleep.
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cardiovascular physiology


The first NREM sleep cycle, from sleep onset, is characterized by a period of relative autonomic stability, with vagus nerve dominance and heightened baroreceptor gain. During inspiration, heart rate accelerates to accommodate increased venous return, increasing cardiac output, followed by progressive rate slowing during expiration. This normal sinus variability in HR, particularly during NREM, is indicative of cardiac health, whereas absence of intrinsic variability has been associated with cardiac pathology and advancing age.

An important consideration in preserving circulatory homeostasis during sleep is coordination of control over two systems: the respiratory system, essential for oxygen exchange, and the cardiovascular system, for blood transport. The coordination of two motor systems, one for somatic musculature (i.e., diaphragmatic, intercostal, abdominal, and upper airway musculature) and the other for autonomic regulation ( to the heart and vasculature), is a formidable task during sleep and is particularly challenging in patients with diseased respiratory or cardiovascular systems, especially in apnea or heart failure, or in infants, whose developing control systems may become compromised.

HR and BP physiologically decrease during nighttime as compared with daytime ambulant subjects, as well as in subjects kept in the supine position for 24 hours. Specifically, the normal 24-hour BP pattern consists of a 10% or greater systolic blood pressure reduction during sleep compared with daytime, a reduction that is commonly referred to as “dipping”.
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Clinical Pearls
  • REM sleep is characterized by surges in sympathetic and vagus nerve activity, which are well tolerated in normal individuals but may result in cardiac arrhythmias, myocardial ischemia, and myocardial infarction in those with heart disease.
  • During NREM sleep, systemic blood pressure may fall, potentially reducing flow through stenotic coronary vessels, which may precipitate myocardial ischemia or infarction.
  • In essence, sleep constitutes an autonomic stress test for the heart, and nighttime monitoring of cardiorespiratory function is of considerable diagnostic value.
  • Sleep loss, alterations in sleep quality, and sleep disorders are associated with persistence of high sympathetic activity during night and reduction in physiologic nocturnal blood pressure dipping. These effects lead to sustained sympathetic activation with increased blood pressure during the succeeding days.

respiratory physiology

Sleep is a state of vulnerability for the respiratory system. Central to the pathogenesis of a variety of sleep-related breathing disorders is loss of a wakefulness stimulus that sustains adequate breathing in wakefulness. In parallel with the realization that sleep onset is not simply the passive withdrawal of wakefulness, breathing during sleep is not simply due to the passive withdrawal of the wakefulness stimulus.

NREM sleep and REM sleep are fundamentally different neurobiologic states that exert distinct effects on the control of respiratory neurons and motoneurons.

Neurons that are less influenced by the respiratory oscillator are most affected by the transition from wakefulness to NREM sleep, such that their activity can even cease during sleep. Neurons that presumably are strongly coupled to and controlled by the respiratory oscillator are least affected by the transition from wakefulness to NREM sleep.

REM sleep is characterized by (1) overall depression of the ventilatory responses to hypercapnia and hypoxia; (2) periods of profound suppression of motor activity in respiratory muscles and non-respiratory muscles; and (3) occasional periods of slowing of respiratory rate. Periods of sporadic respiratory slowing in REM sleep is are associated with increased release of acetylcholine into the pontine reticular formation. It is not correct, however, to consider REM sleep as a state of overall depression of central respiratory neurons because, as for most cells in the CNS, the activity of brainstem respiratory neurons typically is greater in REM sleep than in NREM sleep.
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Clinical Pearl
  • Current evidence identifies neurons of the aminergic arousal system and reticular neurons as providing the key components of the wakefulness stimulus. Withdrawal of this tonic excitatory drive to the muscles of the upper airway is thought to underlie the normal sleep-related increase in upper airway resistance, and the hypoventilation, flow limitation, and obstructive sleep apnea observed in susceptible persons (e.g. those with already anatomically narrow upper airways).
  • Patients with restrictive lung diseases and neuromuscular weakness rely, to various degrees, on the activation of nondiaphragmatic respiratory muscles to help maintain adequate ventilation in the awake state, but this compensation can be reduced or absent in sleep, leading to severe hypoventilation, as the essential tonic excitatory drive that is present in wakefulness is withdrawn
  • REM sleep mechanisms also lead to inhibition of respiratory motoneurons, thereby explaining the typically increased severity of abnormal breathing events in REM sleep compared with NREM sleep.
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sleep and host defense


Sleepiness, like fever, is commonly experienced at the onset of infection or other cause of systemic inflammation. Changes in sleep in response to microbes appear to be one facet of the acute phase response. Typically, soon after infectious challenge, time spent in NREM sleep increases and REM sleep is suppressed.

There is a common perception that sleep loss renders one vulnerable to infection. Some studies demonstrate that sleep impairs acquired immunity, and many studies have shown that sleep deprivation alters selected aspects of the innate immune response. A few studies have combined sleep deprivation with infectious challenge. After mild sleep deprivation, several immune system parameters (e.g., NK cell activity) change, and resistance to a viral challenge is decreased in individuals who spontaneously sleep less. Studies have not yet been done to determine the effects of sleep deprivation on recovery from an infection.
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The molecular mechanisms responsible for the changes in sleep associated with infection appear to be an amplification of a physiologic sleep regulatory biochemical cascade. Sleep regulatory mechanisms and the immune system share regulatory molecules. The best characterized are IL-1 and TNF, which are involved in physiologic NREM sleep regulation. IL-1 and TNF are key players in the development of the acute phase response induced by infectious agents. During the initial response to infectious challenge these proinflammatory cytokines are upregulated, leading to the acute phase sleep response. This chain of events includes well-known immune response modifiers such as prostaglandins, nitric oxide, and adenosine. Each of these substances, and their receptors, is a normal constituent of the brain, and each is involved in physiologic sleep regulation.


endocrine physiology

In healthy adults, reproducible changes of essentially hormonal and metabolic variables occur during sleep and around wake-sleep and sleep-wake transitions. These daily events reflect the interaction of central circadian rhythmicity and sleep-wake homeostasis. Pathways by which circadian rhythmicity and sleep-wake homeostasis affect peripheral endocrine function and metabolism include the modulation of the activity of the hypothalamic releasing and inhibiting factors, the autonomous nervous system control of endocrine organs, and the 24-hour periodicity of circulating glucocorticoids. Findings from genome-wide association and epidemiologic studies also support a role of circulating melatonin levels on specific endocrine targets, including the pancreatic beta cells.

Circadian oscillations can be generated in many peripheral organs, including tissues that release endocrine signals such as adipocytes, liver, adrenal glands, and pancreatic beta cells. These “local” oscillators appear to be under the control of the central pacemaker in the suprachiasmatic nuclei either directly through neural or endocrine signals, or indirectly through its control of behavioral rhythms such as the sleep-wake cycle and feeding schedule.

The following changes occur in the endocrine system in relation to sleep:
  • In healthy adults, the 24-hour profile of plasma growth hormone (GH) levels consists of stable low levels abruptly interrupted by bursts of secretion. The most reproducible GH pulse occurs shortly after sleep onset. Maximal GH release has been found to occur within minutes of the onset of slow wave sleep (SWS).
  • Sleep is normally initiated when corticotropic activity is quiescent. Reactivation of ACTH and cortisol secretion occurs abruptly a few hours before the usual waking time.
  • A number of studies have indicated that sleep onset is reliably associated with a short-term inhibition of cortisol secretion. This effect may not be detectable when sleep is initiated at the time of the daily highest corticotropic activity, that is , in the morning.
  • Daytime levels of plasma TSH are low and relatively stable until the initiation of a rapid elevation in the early evening resulting in maximal concentrations around the beginning of the sleep period.
  • The later part of sleep is associated with a progressive decline in TSH levels, and daytime values resume shortly after morning awakening.
  • A marked decrease in glucose tolerance is apparent during nighttime as well as daytime sleep.
  • During nocturnal sleep, the overall increase in plasma glucose ranged from 20% to 30%, despite the maintenance of rigorously constant rates of caloric intake, that is, constant glucose infusion. Maximal levels are reached around the middle of the sleep period.
  • During the later part of the night, glucose tolerance begins to improve, and glucose levels progressively decrease toward morning values.
  • It is estimated that about 2/3s of the fall in overall body glucose use during early sleep is due to a decrease in brain glucose metabolism related to the predominance of slow wave stages, which are associated with a 30% to 40% reduction in cerebral glucose metabolism compared with the waking state.
  • The remainder of the fall would then reflect decreased peripheral use, including diminished muscle tone and rapid hyperglycemic effects of the sleep-onset GH pulse.
  • The nocturnal elevation of melatonin levels could contribute to the nocturnal decrease in glucose tolerance because of an inhibitory effect of melatonin on insulin release from beta cells.
  • During the later part of the sleep period, glucose levels and insulin secretion decrease to return to pre-sleep values, and this decrease appears to be partially due to the increase in wake and REM stages.
  • Glucose use during the REM and wake stages is higher than during NREM stages.
  • Orexins are hypothalamic excitatory neuropeptides that have potent wake-promoting effects.. Orexin activity is inhibited by leptin, a satiety hormone, and stimulated by ghrelin, an appetite-promoting hormone.
  • Leptin is released by the adipocytes and provides information about energy status to regulatory centers in the hypothalamus. There is a marked rise in nocturnal leptin which has been thought to suppress the hunger during the overnight fast.
  • Ghrelin, a peptide produced predominantly in the stomach, is also involved in regulating energy balance. There is a marked nocturnal rise of ghrelin levels which partly represents the rebound of ghrelin following the dinner meal.
  • Despite the persistence of the fasting condition, ghrelin levels do not continue to increase across the entire sleep period and instead decrease during the later part of the night, consistent with an inhibitory effect of sleep on ghrelin release.


Clinical Pearls
Recurrent sleep restriction has been found to result in the following:
  • Alteration in nocturnal GH release such that a GH pulse occurs consistently before sleep onset.
  • Alteration of the 24-hour cortisol profile, including elevated levels in the evening.
  • In middle-aged overweight adults exposed to moderate sleep restriction over a 14-day period, TSH and free T4 levels were lower after 14 days of sleep restriction compared with normal sleep.
  • Higher glucose response to breakfast despite similar insulin secretion. This is consistent with a state of impaired glucose tolerance.
  • Decrease in the proportion of weight lost as fat and an increase in the loss of fat-free mass.
  • 20-30% reduction of the satiety hormone leptin
  • Daytime ghrelin levels increased by 28%
  • Appetite for nutrients with high carbohydrate content was increased by more than 30%
  • The caloric cost of wakefulness under recumbent conditions compared with sleep averaged only 17 kcal/hour. Thus, the stimulation of hunger and food intake far exceeds the caloric needs of extended wakefulness.
  • A large number of studies have examined associations between sleep duration and the prevalence and incidence of obesity and type 2 diabetes and most had found significant association.
​REVIEW QUESTIONS

Which of the following brain areas is active during NREM and REM sleep?
a. Tuberomammillary Nucleus
b. Locus Coeruleus
c. Dorsal Raphe Nuclei
d. Ventrolateral Preoptic Nucleus  

What is the neurotransmitter of VLPO neurons?
a. GABA, galanine
b. Serotonin
c. Histamine
d. Norepinephrine  

Which of the following is NOT true about orexin neurons?
a. Stabilize wake-sleep transitions
b. Active during wake
c. Located in the lateral hypothalamus
d. Provide inhibitory input to the LC, DRN.  

Explain 5 physiologic changes that normally occur during sleep.
List 5 adverse effects of recurrent sleep restriction.
ARTICLE REVIEW
Metabolic, Endocrine, and Immune Consequences of Sleep Deprivation 
Sleep and Obesity
TASK - Reflective Journal
Topics covered:
  • Sleep Physiology
References:
  1. Hall, John E. Guyton and Hall Textbook of Medical Physiology, 13th ed. Philadelphia, USA: Elsevier, Inc., 2016.
  2. Jameson, J. Larry, et al, Harrison’s Principles of Internal Medicine, 20th ed. McGraw-Hill Education, 2018.
  3. Berry, Richard. Fundamentals of Sleep Medicine. Philadelphia, USA: Saunders, Elsevier Ince., 2012.
  4. Kryger, Meir, et al, Principles and Practice of Sleep Medicine, 6th ed. Philadelphia, USA: Elsevier, Inc., 2017.