Human sleep and melatonin
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Relationship between Human sleep & Melatonin. How Melatonin related to human sleep via circadian clock?
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Human sleep and melatonin
- 1. MELATONIN & HUMAN SLEEP PREPARED BY: DEWAN MD. SUMSUZZMAN DEPARTMENT OF REHABILITATION SCIENCE INJE UNIVERSITY, SOUTH KOREA.
- 2. What is Sleep ? A state of loss of consciousness from which a subject can be aroused by appropriate stimuli. Sleep is a naturally recurring state characterized by reduced or absent consciousness, relatively suspended sensory activity, and inactivity of nearly all voluntary muscles. It is distinguished from wakefulness by a decreased ability to react to stimuli. It is to be distinguished from coma, which is unconsciousness from which the person cannot be aroused. Sleep is observed in all mammals, all birds and many reptiles, amphibians and fish.
- 3. Assessment of Sleep Sleep stages and other characteristics of sleep are commonly assessed by polysomnography in a specialized sleep laboratory. Polysomnography is a comprehensive recording of the biophysiological changes that occur during sleep. Measurements taken include electroencephalogram (EEG) of brain waves, electrooculography (EOG) of eye movements and electromyography (EMG) of skeletal muscle activity.
- 4. Brain waves The frequencies of brain waves range from 0.5-500 Hz. The most clinically relevant waves: 1. Alpha waves - 8-13 Hz 2. Beta waves - Greater than 13 Hz (18-30) 3. Theta waves - 3.5-7.5 Hz 4. Delta waves - 3 Hz or less
- 5. Brain waves Alpha waves occur most intensely in the occipital region but can also be recorded from the parietal and frontal regions of the scalp. Their voltage usually is about 50 µv. During deep sleep, the alpha waves disappear. Beta waves recorded mainly from the parietal and frontal regions during specific activation of these parts of the brain.
- 6. Brain waves They occur normally in the parietal and temporal regions in children, but they also occur during emotional stress in some adults, particularly during disappointment and frustration. Delta waves include all the waves of the EEG with frequencies less than 3.5 cycles per second, and they often have voltages two to four times greater than most other types of brain waves.
- 7. Sleep stages In mammals and birds, sleep is divided into two broad types: Rapid Eye Movement (REM) and Non-Rapid Eye Movement (NREM or non-REM) sleep – slow wave sleep. Each type has a distinct set of associated physiological, neurological and psychological features. The American Academy of Sleep Medicine (AASM) further divides NREM into three stages : N1, N2 and N3, the last of which is also called delta sleep or slow- wave sleep (SWS).
- 8. Sleep Stages and Cycles Stage 1 is where we drift in and out of very light sleep, and are easily awakened. Our brain and body systems remain nearly as active as when we are awake. Stage 2 is a more relaxed state than stage one, but sleep is light and we continue to be easily awakened. Some muscle restoration occurs in this stage. Stages 3 and 4 offer Restorative Sleep. This is a state of intensive rest. Many of our body systems operate at their slowest, but our immune systems switch on. Oxygen consumption, heart rate, and blood pressure are at their lowest. Blood is mostly directed to the muscles, to restore muscular energy, and our brains are minimally active. Overall, stages three and four repair and restore the health of the body. Stage 5 (REM Sleep) restores our minds. REM sleep occur when we are dreaming. In this stage our brains are very active, but our bodies our mostly paralyzed. Procedural, novel, and emotional memory are processed and stored in stage five.
- 10. Sleep Hours by age Age Average amount of sleep per day Newborn up to 18 hours 1–12 months 14–18 hours 1–3 years 12–15 hours 3–5 years 11–13 hours 5–12 years 9–11 hours Adolescents 9–10 hours Adults, including elderly 7–8 hours
- 11. How sleep work The sleep-wake cycle, is regulated by two separate biological mechanisms in the body, which interact together and balance each other. This model, first posited by the Swiss sleep researcher Alexander Borbély in the early 1982s, is often referred to as the two-process model of sleep-wake regulation. The two processes are: Circadian process, also known as Process C, which determining the timing of sleep & wakefulness. Homeostasis process, or Process S, which increase as a function of the duration of wakefulness.
- 12. Sleep Regulation
- 13. The sleep-wake cycle (image by Luke Mastin)
- 14. Circadian clock & Sleep The brain’s circadian clock regulates sleeping and feeding patterns, alertness, core body temperature, brain wave activity, hormone production, regulation of glucose and insulin levels, urine production, cell regeneration, and many other biological activities. The most important hormones affected by the circadian clock, at least insofar as they affect sleep, are melatonin (which is produced in the pineal gland in the brain, and which chemically causes drowsiness and lowers body temperature) and cortisol (produced in the adrenal gland, and used to form glucose or blood sugar and to enable anti-stress and anti-inflammatory functions in the body).
- 15. The human biological circadian clock (image from Wikipedia)
- 16. NEUROLOGICAL MECHANISMS OF SLEEP Neurons (nerve cells) in the brain and brainstem produce a variety of nerve- signaling chemicals called neurotransmitters in different parts of the brain. These neurotransmitters in turn act on different groups of neurons in various parts of the brain, which control whether we are asleep or awake. The ventrolateral preoptic nucleus (VLPO or VLPN) of the hypothalamus is one area of the brain that is particularly involved in the switch between wakefulness and sleep. Neurons in this small area help to promote sleep by inhibiting activity in areas of the brainstem that maintain wakefulness. Likewise, in a process of "mutual inhibition", during waking hours, those areas of the brain that are active in maintaining wakefulness by stimulating the cerebral cortex also work to inhibit the neurons of the VLPO. For this reason, the VLPO is often referred to as the “sleep switch”
- 17. VLPO promotes sleep by inhibiting activity in the brain's arousal centers (http://healthysleep.med.harvard.edu)
- 18. NEUROLOGICAL MECHANISMS OF SLEEP Another important chemical in the sleep-wake cycle is Orexin a neurotransmitter that regulates arousal, wakefulness and appetite. Orexin is only produced by some 10,000-20,000 neurons in the hypothalamus region of the brain, although axons from those neurons extend throughout the entire brain and spinal cord. Activation of orexin triggers wakefulness, while low levels of orexin at night serve to drive sleep. A deficiency of orexin results in sleep-state instability, leading to many short awakenings and mixed up REM and non-REM sleep states typical of sleep disorders like narcolepsy.
- 19. Orexin promoting wakefulness (http://www.nature.com/nm/journal/v13/n2/fig_tab/nm0207-126_F1.html)
- 20. Melatonin Melatonin, chemically (N-acetyl-5-methoxy-tryptamine) is a hormone secreted by pineal gland in the brain. Melatonin produced by the retina and the gastrointestinal (GI) tract acts as a paracrine hormone. It found in a wide spectrum of organisms including, animals, plants, bacteria and fungi. It helps regulate other hormones and maintains the body's circadian rhythm.
- 21. Chemical Structure of Melatonin Melatonin has the molecular formula (C13H16N2O2), and it has many chemical names such as (N-Acetyl-5- methoxytryptamine and the IUPAC name of melatonin is ( N-[2-(5-methoxy-1H-indol-3- yl)ethyl]acetamide).
- 23. Melatonin Secretion Under natural environment, melatonin is secreted during the night in the healthy human, as in all other species. Melatonin being a lipophilic molecule, it is not stored but directly released by diffusion of the pineal gland and released into the cerebrospinal fluid and the circulation. Although the eye contributes significantly to circulating melatonin levels in a few species(sea Bass, Frog, quail, pigeon), retinal melatonin acts primarily within the eye. In humans, serum concentrations of melatonin is low during the day and is significantly higher at night with peak between 02:00 am and 04:00 am, when measured with high-specificity assay. The onset of secretion usually takes place around 09:00 pm-02:00 am and the offset around 07:00 am- 09:00 am in adults in the temperate zone.
- 24. Melatonin Secretion (image by Luke Mastin)
- 25. Relationship between Melatonin & sleep via Circadian rhythms We all have an internal biological clock that regulates our 24-hour sleep-wake cycle, also known as our circadian rhythms. Light is the primary cue that influences circadian rhythms. At night, when there is less light, our brain triggers the release of melatonin, a hormone that makes us sleepy. When the sun comes up in the morning, the brain tells the body that it’s time to wake up. When your circadian rhythms are disrupted or thrown off, you may feel groggy, disoriented, and sleepy at inconvenient times. Circadian rhythms have been linked to a variety or sleeping problems and sleep disorders, as well as depression, bipolar disorder, and seasonal affective disorder (the winter blues).
- 26. Relationship between Melatonin & sleep via Circadian rhythms Melatonin secretion is suppressed by bright light (principally blue wavelengths) and hence levels increase during the night Over a prolonged period, melatonin secretion becomes entrained to anticipate the onset of darkness and the approach of day Melatonin functions to promote activity in nocturnal animals and conversely promotes sleep in diurnal animals (like humans) During sleep, necessary physiological changes occur in body temperature, brain wave activity and hormonal production Melatonin levels naturally decrease with age, leading to changes in sleeping patterns in the elderly
- 27. Melatonin Secretion by the Pineal Gland
- 28. Sleep Disorder A sleep disorder - technically known as a somnipathy or dyssomnia - is any medical disorder which negatively affects a person’s healthy sleep patterns. Usually this involves less than adequate sleep to the extent that this may interfere with the person’s normal physical, mental and emotional functioning, but excessive sleep (such as in hypersomnia and narcolepsy) can also be a problem.
- 29. Common Sleep Disorder 1. Jet Lag 2. Shift-Work Sleep Disorder 3. Primary Insomnia 4. Delayed Sleep Phase Syndrome (DSPS)
- 30. Time zone around the earth
- 31. Jet Lag & Melatonin Jet lag is a physiological condition resulting from a change to the body’s normal circadian rhythm. This alteration is caused by the body’s inability to rapidly adjust to a new time zone following extended air travel ('jet' lag) The pineal gland continues to secrete melatonin according to the old time zone so that the sleep schedule is not synchronized to the new time zone. As a result of these sleep disturbances, individuals suffering from jet lag will often experience symptoms associated with fatigue. Some health professionals recommend taking melatonin near the sleep time of the new time zone to help recalibrate the body.
- 32. Melatonin Treatment for Age-Related Insomnia Ref: Irina V. Zhdanova DOI: https://doi.org/10.1210/jcem.86.10.7901
- 33. Sleep efficiency in subjects with normal sleep (A) and age related insomnia (B) following melatonin or placebo treatment. *
- 34. Sleep efficiency in insomniacs during three consecutive parts (I, II, and III) of the night, following placebo (light bar) or melatonin (0.3 mg, dark bar) treatment. *
- 35. Plasma melatonin profiles after melatonin or placebo treatment 30 min before bedtime. Inset, daytime melatonin levels; circle, placebo; triangle, 0.1 mg; square, 0.3 mg; diamond, 3 mg.
- 36. Core body temperature profiles following melatonin or placebo treatment. Circle, placebo; triangle, 0.1 mg; square, 0.3 mg, diamond, 3 mg. *
- 37. Synopsis Pharmacological doses of melatonin do not increase the sleep-promoting effects of melatonin above those achieved by physiological doses and might even be less effective. Moreover, the pharmacological dose that used (3 mg) was associated with a significant decline in core body temperature, but the physiological doses (0.1 and 0.3 mg) had no such effect. This confirms that although nocturnal hypothermia is induced when plasma melatonin is raised to supraphysiological levels, this decline is not a prerequisite for melatonin to promote sleep. Hence, patients with age-related insomnia associated with low nocturnal melatonin levels might benefit from melatonin treatment using physiological doses administered at bedtime.
- 38. THANK YOU Have a sound sleep