Physiology and Neuroanatomy of sleep BY AHMAD YOUNES PROFESSOR OF THORACIC MEDICINE

1. Physiology and Neuroanatomy of sleep BYAHMAD YOUNESPROFESSOR OF THORACIC MEDICINE Mansoura Faculty of Medicine

2. Behavioral Definition: • Wakefulness:is a state in which the person is aware of and responds to sensory input from the environment. • Sleep: is a state of behavioral quiescence accompanied by an elevated arousal threshold and a species-specific sleep posture (recumbent sleep posture, closed eyes, diminished responsiveness to external stimuli and decrease in or absence of movements) • Sleep is an ACTIVE process. It is a reversible state of unresponsiveness to stimuli of the outside world and to responses within the brain which underlie perception. • Sleep is a state of reversibleun-conciousness in which the brain is relatively more responsive to internal than external stimuli  

3. Sleep function • Memory consolidation • Energy conservation • Body growth • Regulation of immune function • Protective behavioral adaptation

4. Sleep architecture • Sleep architecture is a term used to describe the division of sleep among the different sleep stages using specific EEG, EOG, and chin EMG criteria. It also involves the relationship of the individual sleep stages to each other . • Sleep can be differentiated into NREM sleep and REM sleep. NREM sleep can be further subdivided into stages 1, 2, 3, and 4 sleep. NREM stages 3 and 4 sleep are often collectively referred to as slow wave or delta wave sleep.

5. Sleep Architecture W 1 REM 2 3+4 (SWS) 1 2 3 4 5 6 7 8 75% SWS 75% REM

7. General information • NREM and REM occur in alternating cycles, each lasting approximately 90-100 minutes, with a total of 4-5 cycles. • In the healthy young adult, NREM sleep accounts for 75-90% of sleep time (3-5% stage I, 50-60% stage II, and 10-20% stages III and IV). REM sleep accounts for 10-25% of sleep time. • Total sleep time in the healthy young adult approximates 6-8 hours. • The newborn sleeps approximately 16-20 hours per day; these numbers decline to a mean of 10 hours during childhood. • In the full-term newborn, sleep cycles last approximately 60 minutes (50% NREM, 50% REM, alternating through a 3-4 h inter-feeding period).

8. General information • Pregnancy: st trimester (increase in total sleep time ,daytime sleepiness and nocturnal awakening ) 2nd trimester (normal sleep ) 3rd trimester (increased nocturnal awakening with subsequent daytime sleepiness and decreased total sleep time) • In elderly, SWS decrease and N2 compensatory increase, increase in latency to fall asleep and the number and duration of overnight arousal periods, time in bed increase with subsequent complaint of insomnia .

9. Regulation of Sleep and Wakefulness: • Two basic intrinsic components 1-Circadian rhythm (process C) 2-Sleep homeostasis (process S), Sleep homeostasis is characterized by an increase in sleep pressure following sleep deprivation that is related to the duration of prior wakefulness followed by a decline in sleep need as sleep accumulates. Circadian process There are two circadian peaks in wakefulness : one occurring (early evening) and a second peak (late morning). Sleep propensity is least during these peaks of circadian rhythms of arousal Greatest sleep propensity during periods of (overnight between 3:00 and 5:00 am; early-mid afternoon between 3:00 and 5:00 pm). 3-Sleep inertia (process W), refers to the short-lived reduction of alertness that occurs immediately following awakening from sleep and disappears within 2 to 4 hours.

10. Brain Mechanisms Controlling Sleep • Sleep is promoted by a complex set of neural and chemical mechanisms • Daily rhythm of sleep and arousal • Supra-chiasmatic nucleus of the hypothalamus (body clock) • pineal gland’s secretion of melatonin • Light is called a Zeitgeber, a German word meaning time-giver because it set the supra-chiasmatic clock • Altering light/dark cycles produces phase shift and entrainment

12. Evidence for the SCN as biological clock • Circadian = diurnal + nocturnal • Zeitgebers and the SCN: Biological clock • Altering light/dark cycles produces phase shift and entrainment • SCN lesions disrupt circadian rhythms • Transplanted SCNs set rhythms of donor animal

13. Light and Melatonin The pineal gland is a tiny endocrine gland situated at the centre of the brain • The major pineal hormone, however, is melatonin, a derivative of the amino acid tryptophan. • Melatonin secreted by pineal gland signals brain that it is time to sleep • Light suppresses melatonin secretion. • Bright light very early in the morning can cause a phase advance • Bright lighting can reduce fatigue for workers forced to work at night

14. Neuroanatomy of Wakefulness The reticular activating system (RAS) is located in the brain stem. it is believed to play a role in sleep and waking, behavioral motivation, breathing, and the beating of the heart. RF has two major ascending projections into the forebrain: 1. Dorsal pathway →thalamus →cerebral cortex (thalamocortical system) 2. Ventral pathway → subthalamus and posterior hypothalamus → basal forebrain and septum →cerebral cortex • The ascending reticular activating system also receives input from visceral,somatic, and special sensory systems. • The descending RAS connects to the cerebellum and to nerves responsible for the various senses. • Neurotransmitters Acetylcholine , Dopamine ,Glutamate ,Histamine ,Hypocretin (orexin) ,Norepinephrine, Serotonin

16. Most wake circuits originate in the Brain stem arousal nuclei (BAN), which stimulate the thalamus, hypothalamus (Hyp) and basal forebrain.These projections also inhibit sleep centers

17. Neuroanatomy of NREM sleep • NREM sleep Forebrain (anterior hypothalamus-preoptic region, including ventrolateral preoptic area [VLPO] and basal forebrain) • Neurotransmitters serotonin and gammaaminobutyric acid (GABA). Other neurotransmitters include adenosine, norepinephrine,

18. The ventrolateral preoptic nucleus (VLPO) in the hypothalamus inhibits the BAN and the parts of the hypothalamus involved in wakefulness. This leads to inhibition of other wake-centers including the thalamus, basal forebrain, and the cortex, and thus the initiation and maintenance of sleep.

19. Neuroanatomy of REM sleep • REM sleepPons (pedunculopontine tegmental nuclei and the laterodorsal tegmental nuclei) Brainstem reticular formation, especially oral pontine reticular formation ,Other brainstem (lower medullary) and spinal cord neurons • Neurotransmitters: The main REM sleep neurotransmitter is acetylcholine. Other neurotransmitters include GABA and glycine.

20. The SCN is the circadian “pacemaker” and is influenced by light, activity, and melatonin to promote either wake or sleep. Signals from the SCN are amplified by the SPZ and the DMN, which project to the VLPO (promotes sleep), the lateral hypothalamus (promotes wakefulness), and the PVN (controls pineal melatoninrelease).

21. The PVN is stimulated by the SCN, in a circadian fashion, to produce corticotrophin-releasing factor (CRF). This acts on the pituitary gland (Pit), which in turn produces adrenocorticotrophic hormone (ACTH). ACTH is then released into the bloodstream where it initiates the release of cortisol from the adrenal glands. Cortisol is one of the factors involved in the sleep/wake cycle through a feedback system whereby it can then influence activity in the hypothalamus. Thus the HPA axis is important to regulation of sleep and arousal.

22. Summary • Circadian arousal is largely influenced by ocular exposure to light; thus it rises in the morning, declines with a gradual slope throughout the day, and then declines further beginning in the late evening. • Body temperature is also at its lowest in the early morning, rising throughout the morning and then staying fairly steady until it begins to decline again in the late evening. • Combined with this, a morning pulse of cortisol, which binds to circadian hypothalamic receptors, stimulates arousal from sleep with levels declining throughout the day. • In addition, certain brain chemicals (e.g., adenosine, a byproduct of energy metabolism), accumulate during waking time and decline during sleep. The varying levels of these chemicals affect one’s wake propensity, with wake propensity declining as they accumulate and then increasing as the sleep debt is paid.

23. Hyperarousal is considered an underlying cause of insomnia and may be related to dysfunction of the HPA axis.With hypoarousal, there is thought to be reduced basal ACTH secretion and a reduction of central CRF. Extreme hypoarousal underlies excessive sleepiness present in numerous sleep/wake disorders.

25. Autonomic nervous system physiology • Parasympathetic tone increase and sympathetic tone decrease during NREM sleep • During arousals , sympathetic tone increase in bursts . • DuringtonicREM sleep ,Parasympathetic tone increase even further whereas sympathetic tone reaches its lowest level . • DuringphasicREM sleepsympathetic tone transiently increases . • Muscle tone is maximal during wakefulness but decrease during NREM sleep and decrease even further during REM sleep • During REM sleep , myotonic bursts (phasic twitches ) as evidenced by intermittent surges in EMG . • Overall decrease in upper airway dilator muscles during NREM sleep ,the reduction is even greater during REM sleep .

26. Respiratory physiology • Minute ventilation falls by 0.5-1.5 liters during NREM sleep due to a reduction in tidal volume rather than in respiratory rate . • During REM sleep the fall in minute ventilation is similar but being irregular during phasic REM. • Functional residual capacity decrease by 10% during sleep. • Arterial Pao2 decrease by 3-10 mmHg and Sao2 decrease by <2%. • Arterial Paco2 increase by 2-8 mmHg during sleep .

27. Respiratory physiology • Hypoxic ventillatory response and hyper-capnic ventillatory response decrease during NREM sleep and decrease further during REM sleep due to decreased chemo-sensitivities. • Cough reflex decrease during NREM and REM sleep .

28. The Upper Airway as a Collapsible Cylinder • Upper airway patency is influenced by several factors, including its collapsibility, length, and caliber, and pressure gradient against its wall. • Intraluminal extrathoracic airway pressure decreases during inspiration, leading to a narrowing of the airway. Narrowing of the airway initially accelerates airflow, which further promotes airway narrowing. • The critical closing pressure (Pcrit) is the intraluminal pressure at which the upper airway collapses and airflow ceases. Pcrit is progressively less negative as one goes from non-snorers, to snorers, to persons with predominantly hypopnea, and, finally, to those with apnea whose Pcrit is generally near atmospheric pressure.

29. The Upper Airway as a Collapsible Cylinder • Activation of upper airway dilator muscles decreases Pcrit (reduces airway collapsibility) and increases airflow. • The activity of the upper airway dilator muscles is diminished by sleep, alcohol ingestion, and the use of muscle relaxants. • During wakefulness, reflex upper airway dilator muscle activation is triggered by negative subatmospheric intraluminal pressure. This Reflex is diminished as sleep progresses from NREM to REM sleep. • Upper airway dilator response to hypoxia and hypercapnia is suppressed during NREM sleep and may be completely abolished during REM sleep. • Activation of upper airway muscles preceding activation of the diaphragm

33. Cardio-vascular physiology • Heart rate decrease during NREM sleep but fluctuate greatly during REM sleep . • Brady-tachycardia seen during phasic REM sleep is due to variations of both parasympathetic and sympathetic activities • Cardiac output decrease during both NREM and REM sleep. • Pulmonary blood pressure increase slightly during sleep • Arterial blood pressure decrease by 10% during NREM sleep ,during phasic REM sleep fluctuate due to sympathetic activities . • Cerebral blood flow decrease 5-20% during NREM sleep ,during REM sleep an increase in blood flow by up to 40%

34. Endocrine physiology • Melatonin release peaks during sleep • Growth hormone peak 90 minutes after sleep onset (closely associated with slow wave sleep) • Cortisol secretion is independent of sleep. Its peak is in the early morning . • Thyroid stimulating hormone decrease during sleep. • Testosterone increase during sleep . • No relation between GTH ,LH, FSH and sleep . • Prolactin level increase during sleep .

35. Gastro-intestinal physiology • Lower esophageal sphincter tone show no circadian variation . • Transient lower esophageal sphincter relaxation lead to GERD during awakening from sleep rather than during sleep . • Most events of GERD occur during stage 2 may be due to increased vagal tone which decreases lower esophageal sphincter tone. • Basal gastric acid secretion displays a circadian rhythmicity, with a peak secretion between 10:00 pm and 2:00 am (as a result of increased parasympathetic activity) and a nadir in the morning between 5:00 and 11:00 am. • Swallowing 25/h during the day but 5/h during sleep • Gastric emptying decrease during sleep but esophageal motility shows little circadian variation .

37. Studying sleep • Electroencephalogram (EEG) • Electromyogram (EMG) • Electro-oculogram (EOG)  

41. Brain wave activity  Wakefulness • Alpha waves • Beta waves

43. Beta Activity • A waveform of 14 to 30 Hz • Originates in the frontal and central regions • Present during wakefulness and drowsiness • May become persistent during drowsiness, diminish during SWS, and reemerge during REM sleep • Enhanced or persistent activity suggests use of sedative-hypnotic medications

44. Alpha Activity • A waveform of 8 to 14 Hz • Originates in the occipital regions bilaterally • Seen during quite alertness with eyes closed • Eye opening causes the alpha waves to decrease in amplitude • Has a crescendo-decrescendo appearance • Has diminished frequency with aging

45. Theta Activity • A waveform of 3 to 7 Hz • Originates in the central vertex region • The most common sleep frequency

46. Delta Activity • A waveform of 0.5 to 2 Hz • Seen predominantly in the frontal region • Delta activity has an amplitude criterion of 75 µV • Stage-3 sleep defined when 20% to 50% of the epoch is scored as delta activity • Stage-4 sleep defined when >50% of the epoch is scored as delta activity • In AASM ,stage 3,4 are named N3

48. Sleep Spindles • A waveform of 12 to 14 Hz • Originates in the central vertex region • Has a duration criterion of 0.5 to 2-3 seconds • Typically occurs in stage N2 sleep but can be seen in other stages

49. K Complexes • Defined as slow waves, with a biphasic morphology (first negative and then positive deflection) • Predominantly central vertex in origin • Duration must be at least 0.5 seconds • Indicative of stage N2 sleep.

50. Vertex sharp wave : •Sharply contoured waves • Duration < 0.5 sec • Maximal over the central region (derivations containing C3, C4, Cz) and distinguishable from the background activity (higher amplitude). • Occurs in stage N1 often near transition to stage N2