physiology of sleep

see also:

• sleep hygiene
• insomnia
• fatigue
• shift work
• Managing jet lag and your body clock

• During a single 24 hour day we have a period of 6-10 hours when we are very sleepy. This is the time when we normally sleep. During the remaining 14-18 hours we are usually awake; however, only a portion of that waking time is suitable for intellectual effort. This period of maximum alertness may last as little as 2-6 hours. We should plan our day in such a way that sleep comes at the time of maximum sleepiness, while activities that demand maximum focus or creativity fall into the hours of maximum alertness. It is very difficult and usually very unhealthy to force your body and your body clock to do what you wish. It is far easier to do the opposite: adapt your life to your body clock. ¹⁾
• sleep patterns change throughout life
• number of hours sleep required each night varies significantly between individuals, children and adolescents need 9-10hrs, while adults need at least 7.5hrs.
• as people age, they tend to have shorter overall sleep period & spend more time in the lighter sleep stages, with less REM sleep, often being interrupted by brief periods of wakefulness
  • older workers do not tolerate irregular shifts or disrupted sleep as well as younger workers
• until recently, it was thought adolescents needed less sleep than pre-pubertals, but this has been challenged and it is now thought adolescents need 9-10 hours sleep per night to ensure the pubertal neural reorganisation occurs normally.
  • unfortunately, the tendency for later sleep times for adolescents due to both circadian and social events (eg. TV, computer, etc) combined with fixed school start times results in chronic sleep debt for many, and risk of behavioural issues and depression, and perhaps schizophrenia.
• alertness throughout the day is determined by two main opposing biologic factors:
  • circadian rhythm
  • homeostatic sleep drive
• determinants of alertness and performance include:²⁾
  • biological time of day based on circadian cycle
  • consecutive waking hours (homeostatic sleep drive)
  • nightly sleep duration (or sleep debt)
  • sleep inertia - waking after a nap > 20-30min duration (when in NREM sleep) results in a groggy feeling

• this is a wake drive for alertness which in humans is minimum in early am and maximal in late afternoon (to oppose higher drive for sleep via homeostatic drive, the longer it is that one has been awake)
• this is a property of all higher life forms
• humans evolved to work during daylight hours
• the human circadian cycle is generally 25 hours long, hence it is easier to go to bed later each night than earlier each night.
• “after-hours” work is a recent societal need that is out of harmony with our evolutionary inheritance
• this clock can be changed by external factors (Zeitgebers) such as:
  • light (which suppresses melatonin secretion by the pineal gland) which is more potent than social cues
    • bright light (>3000lux) very early in the morning can cause a phase advance, and can reduce fatigue for those forced to work overnight
    • ultrabrief exposures (< 1 msec) to bright light every minute for 60 minutes can also act as a Zeitgeber
  • brief aerobic exercise
• one can force circadian phase to shift by 1-2 hours each day at most, thus it takes at least a week to adjust to a new shift time!

• in mammals, a master circadian “clock” resides in the suprachiasmatic nuclei (SCN) of the anterior hypothalamus and slave clocks in most peripheral cell types (eg.kidney, liver, etc).
• The SCN clock is composed of multiple, single-cell circadian oscillators, which, when synchronized, generate coordinated circadian outputs that regulate overt rhythms.
• The SCN is entrained by the photoperiod via synaptic connections with the retina (retino–hypothalamic tract, RHT)
• Our current understanding of the clock architecture consists of 3 negative and 1 positive loop of transcription, translation, and posttranslational events.
• The daily light-dark cycle ultimately impinges on the control of two clock genes that reset the core clock mechanism in the SCN. Clock-controlled genes are also generated by the central clock mechanism, but their protein products transduce downstream effects. Peripheral oscillators are controlled by the SCN and provide local control of overt rhythm expression.
• The phase of peripheral clocks can be completely uncoupled from the SCN pacemaker by restricted feeding.
  • Thus, feeding time, while not affecting the phase of the SCN pacemaker, is a dominant Zeitgeber for peripheral circadian oscillators. Glucocorticoid hormones inhibit the uncoupling of peripheral and central circadian oscillators by altered feeding time.³⁾
• the locus coeruleus (LC) has a key role in arousal
  • it is a 2cm long area of a dense group of cells in the in the lateral part of the pontine tegmentum of the brain stem.
  • it is present in all vertebrates
  • it projects to almost every part of the brain and brainstem and secretes, and is the primary source of, norepinephrine (NE) as a neuromodulator in the brain to stimulate neurons to stay awake and has key roles in many cognitive processes.
    • it is the sole source of NE in many forebrain regions that have been implicated in cognition (e.g., cortex and hippocampus)
  • LC neurons are spontaneously active and their rate of discharge is positively correlated to behavioral and electroencephalographic indices of arousal
  • it is is finely tuned by co-regulation between the endogenous opioids, enkephalin (ENK) and dynorphin (DYN), and corticotropin releasing factor (CRF). Opioids have have direct inhibitory effects on the soma, as well as presynaptic inhibitory effects. ⁴⁾
  • it is densely innervated by 5-HT fibers ⁵⁾
  • its stimulating activity must reduce to initiate sleep, and must cease to allow REM sleep
  • as we age, the more reactive the locus coeruleus is during the day, the poorer the perceived quality of sleep and the less intense the REM sleep
  • REM sleep seems important in sorting out the synapses that need to be retained or eliminated during sleep and enabling a new day, full of new experiences.
  • it is also involved intensively in modulating pain and stress-related disorders (e.g., major depressive disorder and anxiety) and in their comorbidity⁶⁾
    • acute nociceptive insult activates LC.
    • chemogenetic activation of LC leads to an anxiogenic and vigilant state that is reminiscent of the natural response to stress.
    • activation of the LC → prefrontal cortex module is aversive and anxiogenic.
    • analgesic activity is mainly driven by the LC ipsilateral to the site of the pain stimulus, and it appears to be produced by activation of the descending LC pathway to the SC, which enhances the NE release that would in turn contribute to the blockade of nociceptive ascending inputs. NE released from descending pathways in the spinal dorsal horn suppresses pain through the inhibitory influence of α2A adrenoceptors on central terminals of primary afferent nociceptors (presynaptic inhibition), as well as by direct α2-adrenergic action on pain-relay neurons (postsynaptic inhibition) and by α1 adrenoceptor–mediated activation of inhibitory interneurons. Disruption of the normal LC-NE circuit may result in increased pain sensitivity.⁷⁾
  • LC neurons are lost in the course of several neurodegenerative disorders, including Alzheimer's and Parkinson's diseases

• “Although our understanding of the molecular basis for the circadian rhythm is continually evolving, the current model involves a complex interplay between environmental and endogenous factors, which include a core set of circadian genes. Transcriptional and post-transcriptional interactions among these gene products results in an autoregulatory feedback system, which allows for predictable cycling of the core circadian elements. In addition, many of the circadian genes operate as transcriptional regulators for transcripts outside of the circadian system, and recent evidence indicates that as many as 10% of all mammalian genes may be regulated to some degree by the circadian oscillatory mechanism. As a result, disturbance of the circadian system, either through environmental exposures, or through genetic alterations in the key circadian genes, may have important implications for a variety of biological pathways.”⁸⁾

• Eight clock genes have been cloned that are involved in interacting transcriptional-/translational-feedback loops that compose the molecular clockwork.
• genetic polymorphisms result in some people being “early birds” while others are “night owls”. Some have a delayed sleep phase syndrome and are “extreme night owls” - these people may respond to agomelatine (Valdoxan), a new antidepressant which also acts on melatonin receptors to cause a phase advance.
• there are seven well-known variations, or polymorphisms, in human circadian CLOCK genes ⁹⁾
• there appears to be an association with some of these variations with risk of bipolar depression disorders.
• core circadian CLOCK genes include:
  • cryptochrome 1 (CRY1)
  • cryptochrome 2 (CRY2) - involved in the negative arm of the circadian feedback loop
    • CRY2 knockdown results in increased accumulation of mutagen-induced DNA damage¹⁰⁾
  • period 1 (PER1)
  • period 2 (PER2)
  • period 3 (PER3)
  • TIMELESS (TIM)
• in addition there appear to be a multitude of genes involved in peripheral tissues (liver, kidney, etc) which are involved in peripheral slave clocks and which control cell function in relation to diurnal and other rhythms.

• the GIT microbiome appears to have a role in various sleep disorders¹¹⁾

• essentially, the drive to sleep increases the longer one has been awake
• if there has been inadequate sleep overnight (either in duration or quality), daytime sleepiness may be evident even after being awake for only a couple of hours (as circadian wake drive is at a minimum and insufficient to oppose the sleep drive)
• if the awake period exceeds 18 hours, psychomotor function deteriorates to a level similar to that of a person with blood alcohol level of 0.05-0.10% ¹²⁾.
• if the awake period exceeds 24 hours for a doctor, clinical task performance falls to 7th percentile of rested doctors ¹³⁾, while EEG-documented attentional failures doubled ¹⁴⁾ for those doing > 16 hours of clinical duty with a 500% increase in diagnostic errors and 36% more serious errors!¹⁵⁾
• the relative risk for car accident on commute home for doctors doing an extended shift instead of a normal shift was 2.3! (Barger et al. NEJM 2005; 352:125-134))

• there is a well observed temporal incidence in adverse cardiovascular events, including transient myocardial ischemia, myocardial infarction, sudden cardiac death, and stroke,which occur most frequently in the early morning hours just after awakening, but also display a secondary more subtle peak in the late afternoon.
• these events correlate with diurnal rises in BP, HR, platelet aggregation tendency, fibrinogen levels, LDL and cortisol levels.
• peak blood pressure levels in humans occur during the mid morning (at about 10:00 AM) then decrease progressively throughout the remainder of the day to reach a trough value the following morning at around 3:00 AM. A slow but steady increase in blood pressure is then observed over the early morning hours before awakening, with an abrupt and steep increase at approximately 6:00 AM coincident with arousal and arising from overnight sleep.¹⁶⁾

• NREM comprises most normal sleep (with a 3:1 ratio for NREM: REM).
• although NREM dominates the early hours of sleep cycles, REM periods usually get longer toward the end.

• these stages are a gradual progression with no sharp demarcation
• as we descend into non-REM sleep our skeletal muscles start to relax although some people maintain a high level of muscle tone even in stage 4
• basic bodily functions are somewhat protected during deep sleep hence obstructive sleep apnoea is least likely in stage 3 or 4 non-REM sleep
• breathing tends to be regular in NREM sleep
• generally we descend rapidly through light sleep into deep sleep where we stay for some time in the early part of the night
• stage 1
  • a nebulous stage that bridges the gap between definitive wakefulness and definitive sleep
  • a slightly slower, higher amplitude EEG rhythm appears
• stage 2 light sleep
  • can waken readily to environmental stimuli
  • slower EEG rhythm
• stage 3 sleep
  • transitional phase
• stage 4 deep sleep
  • much harder to wake from this stage and if an awakening occurs it is often accompanied by a degree of disorientation which can last a few seconds to a few minutes
  • very large and slow EEG waves

• can appear quite suddenly, at intervals, through the night.
• approximately ninety minutes after first falling asleep and between two substantial spells of deep sleep we have our first, usually brief, REM sleep episode of the night
• as the night proceeds deep non-REM sleep becomes less frequent and REM sleep appears at regular intervals but for longer periods towards morning, interspersed with light sleep
• in contrast to non-REM sleep, a cardinal characteristic of REM sleep is an absence of tone so that our skeletal muscles are effectively paralysed, and breathing tends to be rapid and irregular
• concomitant with the general reduction in muscle tone are subtle changes in the respiratory system whereby the airway puts up a degree of resistance to the incoming air and in those with underlying respiratory issues this can lead to obstructive sleep apnoea
• EEG looks remarkably similar to wakefulness - 'waves' are shallow and are of mixed, but nevertheless, high frequencies
• can waken in response to environmental cues less readily than from Stage 2, but more easily than from Stages 3 and 4 of non-REM sleep
• generally are well orientated on waking from this state although we may be aware of having dreamed
• the increased tendency to report dreams on awakening from REM sleep that has earned it the secondary title of 'dreaming sleep'
• the REM sleep stage is closely associated with connections within and between the default mode network (DMN), the cingulo-opercular network (CON), and visual and auditory networks while the thalamus plays a central role in the REM connectome and acted as a relay station for sensory information during REM
  • it seems late-night sleep loss (3.30am-7am) has the most profound adverse affect REM sleep loss and DMN connectivity. ¹⁷⁾
• narcolepsy is a disorder of REM sleep itself

• it seems even short periods of sleep deprivation can result in impaired retrieval of memories formed around that period
  • it seems roflumilast, a type of anti-inflammatory drug, may be able to restore retrieval of social memories while vardenafil, that is currently used to treat erectile dysfunction, may be able to restore retrieval of spatial memories ¹⁸⁾
• sleep deprivation appears to result in awake time catch up of the brain cleansing processes by initiating pulses of CSF flow but this episodes result in failure of attention during the episodes¹⁹⁾

• snoring stems from a respiratory problem that is simply highlighted by sleep ²⁰⁾

• arises within sleep especially in stages 3 and 4 from a vibration of soft tissue in the pharynx as inspired air flows down a partially occluded airway
• is unlikely in REM sleep as breathing as a rule is at its shallowest during this stage
• light snorers generally snore uniformly throughout all sleep stages
• heavy snorers tended to snore more during slow-wave and REM sleep and wakefulness time after sleep onset and sleep efficiency correlates significantly with the snoring index ²¹⁾
• early in any history of snoring, an individual's pattern of snoring will be in part determined by the configuration of sleep staging across the night
• if respiratory weaknesses that underlie snoring develop, the individual may then cross a rubicon where the sleep pattern influences snoring less than it is influenced by the respiratory distress that gives rise to the snoring and normal sleep structure is undermined.
• the impact of outside factors on snoring will have a direct effect on respiration, on sleep staging and on the complex interplay between the two systems
  • alcohol:
    • suppresses the central respiratory drive and muscle tone, and causes changes in blood flow that are not conducive to easier respiration
    • reduces REM sleep and to encourage wakefulness in the latter part of the night
    • paradoxically REM sleep related apneoa may be seen to diminish
    • increases heart rate during sleep
  • sedative hypnotics:
    • have their own depressant effect on the respiratory system
    • unlike alcohol:
      • these are known to aggravate snoring associated with sleep apnoea
      • reduce deep sleep and enhance light sleep
      • overall effect therefore may be to increase the serious snoring as opposed to conventional snoring
• measurement
  • the number of snores per hour of sleep (snoring index)
  • number of snores per minute of snoring time (snoring frequency)
  • duration of loud snoring per night
  • duration of very loud snoring per night
  • maximal and mean nocturnal sound intensity (dBmax and dBmean, respectively)
  • Apple Watch can reasonably detect the sleep stages (via HR and arm movements) although least sensitive for REM sleep (67%) and often confuses it as being Light sleep
    • this can be used with a smartphone snoring audible recording app
• reducing snoring
  • avoid alcohol or sedatives
  • sleep on your side instead of on your back
  • avoid becoming over-tired - get enough sleep
  • lose weight if you are over-weight
  • avoid meals within 4 hours of sleep
  • light exercise in evening to reduce any fluid accumulation in your legs which may re-distribute to head when lying down
  • ensure your head is slightly elevated to reduce venous congestion
  • treat any nasal obstructive issues such as allergic rhinitis, deviated nasal septum
  • tonsillar hypertrophy in children may be a cause and may be an indication for tonsillectomy

• see obstructive sleep apnoea (OSA)
• characterized by loud snoring followed by periods of silence when breathing stops or nearly stops which usually occurs at least five times during every hour of sleep
• snoring associated with sleep apnoea is least likely to occur in stages 3 & 4 (deep sleep) and is most likely in REM sleep
  • inhibition of neuronal input to the hypoglossal nerve results in a reduction of genioglossal and pharyngeal muscle tone in REM sleep, thus increasing the propensity of severe upper airway collapse during REM sleep and OSA (prolonged apneas and hypopneas with minimum SpO2 and greater fluctuations in BP) ²²⁾
  • only when obstructive sleep apnoea becomes very severe and uniform throughout the night will deep non-REM stage 4 sleep be affected because light and REM sleep become so fragmented by apnoeas that the sufferer is not able to reach the point of descent into deep sleep, and it ceases to feature
  • increased sympathetic activity and haemodynamic control (such as increased BP and heart rate) in REM sleep may result in increased cardiac afterload and trigger ischaemic events in patients with vascular disease in those with OSA ²³⁾
• these apnoeas will splinter REM sleep with awakenings that permit the noisy recovery breaths and so start to erode the normal configuration of sleep staging across the night
• where REM alone is affected it can lead the sufferer to be chronically but specifically REM sleep deprived with a consequent propensity to fall into this particular state of sleep during the day otherwise, to fall from wakefulness directly to REM sleep is only normal in young babies
• sedatives may aggravate snoring associated with sleep apnoea by depressing the respiratory system, reducing deep non-REM sleep, and increasing light sleep at the expense of REM sleep.
• adverse effects of OSA
  • poor sleep causing daytime sleepiness and difficulty concentrating, poor attention span
  • morning headaches
  • sore throat upon awakening
  • high blood pressure
  • may affect your partner's sleep

• discovered in 2012, the glymphatic system is a “pseudo-lymphatic” perivascular network distributed throughout the brain, responsible for replenishing as well as cleansing the brain.
• glymphatic clearance is the macroscopic process of convective fluid transport in which harmful interstitial metabolic waste products are removed from the brain intima
• sleep is a primary driver of glymphatic clearance - there appears to be a 90% reduction in glymphatic clearance during wakefulness, and twice the amount of protein clearance from the brain intima during sleep - and it appears that the majority of glymphatic clearance activity occurs during N3 sleep which occurs in non-REM deep sleep and glymphatic transport is most efficient in the right lateral sleeping position, with more CSF clearance occurring compared to supine and prone. ²⁴⁾
• it appears to reduce in efficiency as we age
• low doses of alcohol (0.5 g/kg) appears to increase glymphatic clearance b ut higher levels reduce it
• glymphatic clearance can be manipulated by sleep deprivation, cisterna magna puncture, acetazolamide or genetic deletion of AQP4 channels

• the circadian clock has been found to exist in almost all organs and to regulate physiological processes including DNA repair, cell cycle, mitochondrial dynamics, metabolism, and specific functioning in certain organs or cells
• accumulating evidence suggests disruption of sleep rhythm to induce adverse effects on multiple physiological systems
• delaying sleep may increase exposure to artificial lighting and caloric intake at night, which may confer additional damage to human health
• objective sleep traits appear to provide a greater than 20% attributable risk burden to over 92 diseases (eg. Parkinsons, type II diabetes, acute kidney failure) in a 2025 study and inflammatory factors including leukocytes, eosinophils, and C-reactive protein contributed significantly to all these newly identified sleep–disease associations ²⁵⁾
  • the associations of diseases with different sleep dimensions were highly independent as 57.6% of diseases were associated with only one sleep dimension
  • sleeping with stable sleep timing every day = high interdaily stability
  • sleeping at motionless night = high relative amplitude, when compared with vigorous daytime sleep
  • sleep rhythm - lowest versus highest quartile of interdaily sleep stability
    • 3.36 hazard ratio (HR) for age-related physical debility
    • 2.61 HR for gangrene
    • 22% attributable risk for type II diabetes
  • going to sleep after 0030hrs:
    • 2.57 HR for liver cirrhosis
  • low relative amplitude:
    • 32% attributable risk for Parkinsons
  • objective prolonged length of sleep did not appear to be as problematic as noted in prior subjective studies as in these studies presumably as they actually had short sleep periods but long bed stays