sleep

1. PHYSIOLOGY OF SLEEPPHYSIOLOGY OF SLEEP
REGULATION : ANREGULATION : AN
OVERVIEWOVERVIEW
Presenter – Dr. Soumitra DasPresenter – Dr. Soumitra Das
Chairperson – Dr. Rekha MathewChairperson – Dr. Rekha Mathew

2. IntroductionIntroduction
 Sleep is universal behaviourSleep is universal behaviour
demonstrated in every animaldemonstrated in every animal
species – from insects to mammalsspecies – from insects to mammals
 System regulating sleep and emotionSystem regulating sleep and emotion
and other behaviour areand other behaviour are
interconnectedinterconnected

3. DefinitionsDefinitions
Can be defined from – [CTP KAPLAN]Can be defined from – [CTP KAPLAN]
 Sleep a behavioural standpoint – aSleep a behavioural standpoint – a
state of decreased awareness ofstate of decreased awareness of
environmental stimuli ( distinguishedenvironmental stimuli ( distinguished
from coma or hibernation by its rapidfrom coma or hibernation by its rapid
reversibility)reversibility)
 A clinical and research standpoint – itA clinical and research standpoint – it
is defined by combining behaviouralis defined by combining behavioural
observation with electrophysiologicalobservation with electrophysiological
recording : as REM and NREM sleeprecording : as REM and NREM sleep

4.  REM (Rapid Eye Movement) sleepREM (Rapid Eye Movement) sleep
- Frequent bursts of eye movement activity- Frequent bursts of eye movement activity
- EEG similar to waking state(- EEG similar to waking state( paradoxicalparadoxical
sleep)sleep)
-Children>active sleep(phasic muscle-Children>active sleep(phasic muscle
twich)twich)
 NREM (Non REM) or sleepNREM (Non REM) or sleep
- No eye movement- No eye movement
- decreased activation of EEG(orthodox- decreased activation of EEG(orthodox
sleep)sleep)
(EEG different from waking state)(EEG different from waking state)
-Children >quiet sleep-Children >quiet sleep

5. Stages of SleepStages of Sleep
 There is further classification ofThere is further classification of
sleep based on the EEG(Electrosleep based on the EEG(Electro
encephalogram), EOGencephalogram), EOG
(electrooculogram), EMG (Electro(electrooculogram), EMG (Electro
myogram)myogram)
 Allan Rechtschaffen and Anthony Kales inAllan Rechtschaffen and Anthony Kales in
19681968
 American Academy of Sleep MedicineAmerican Academy of Sleep Medicine
(AASM) in The AASM Manual for the(AASM) in The AASM Manual for the
Scoring of Sleep and Associated Events.Scoring of Sleep and Associated Events.

6. Electrophysiological critieria forElectrophysiological critieria for
stages of sleepstages of sleep
EEGEEG EOGEOG EMGEMG
WakefulWakeful
Ness,Ness,
stagestage
WW
Low voltageLow voltage
mixed frequencymixed frequency
activity (eyes open),activity (eyes open),
Alpha activity (eyesAlpha activity (eyes
closed,8-13closed,8-13
hz,occiput mainly)hz,occiput mainly)
movtmovt
andand
blinkblink
HighHigh
tonictonic
activityactivity
and vol.and vol.
movts.movts.
NREMNREM
N1N1
Loss of alpha, LowLoss of alpha, Low
voltage mixedvoltage mixed
frequency, Thetafrequency, Theta
activity(4-7),vertexactivity(4-7),vertex
SlowSlow
rollingrolling
RelaxesRelaxes
Microsle
ep

7. N2N2 SleepSleep
spindles(11-16hzspindles(11-16hz
last .5sec, Klast .5sec, K
complexes(highcomplexes(high
ampl negampl neg
sharp>positivesharp>positive
slow)slow)
NoNo
movtmovt
Low tonicLow tonic
activityactivity
N3(slowN3(slow
wave,deltwave,delt
a,deep)a,deep)
slow waves(.5-slow waves(.5-
2hz) occupying2hz) occupying
20-50%20-50%
of epochof epoch
DecreDecre
asesases
furtherfurther
DecreaseDecrease
s furthers further
ArousalArousal
thresoldthresold
Increases N1 toIncreases N1 to
N2N2

10. REM EEG EOGEOG EMGEMG
Tonic
(persistent)
similar to that of
stage N1,
increased activity
in the theta ,
Sawtooth waves,
trains of
triangular,
serrated 2 to 6 Hz
waves
generalized
decrease of the
tone of skeletal
muscles except
for the extraocular
muscles and the
diaphragm
Phasic
(episodic)
irregular bursts of
rapid eye
movements
muscle twitches

11. Organization of SleepOrganization of Sleep
 Adult: 7 to 9 hours, may be 6 or 12Adult: 7 to 9 hours, may be 6 or 12
 Time of stages constantTime of stages constant
 N1>5%,N2>50%,N3 with R>20-25%N1>5%,N2>50%,N3 with R>20-25%
 Each 90-110 minsEach 90-110 mins

12. Physiology of sleepPhysiology of sleep
Autonomic nervous systemAutonomic nervous system
NREM and tonic REM –NREM and tonic REM –
parasympathetic dominanceparasympathetic dominance
Phasic REMPhasic REM – Both sympathetic– Both sympathetic
and parasympathetic dominanceand parasympathetic dominance
Cardiovascular systemCardiovascular system
NREM – BP, HR, cardiac outputNREM – BP, HR, cardiac output
decrease,SWS>>lowest ,leastdecrease,SWS>>lowest ,least
variabilityvariability
REM – BP, HR, CO increase butREM – BP, HR, CO increase but
less than awakening,Arrythmias.less than awakening,Arrythmias.

13. Pulmonary system:Pulmonary system: TemporaryTemporary
instability, or periodic breath.instability, or periodic breath.
Resp. rate, minute vol. decreaseResp. rate, minute vol. decrease
ThermoregulationThermoregulation
NREM – Temp. set point decreases –NREM – Temp. set point decreases –
so body temperature decreasesso body temperature decreases
REM – No significant changeREM – No significant change
Neuroendocrine systemNeuroendocrine system
GH secretion - in slow wave sleepGH secretion - in slow wave sleep
(SWS) and enhances SWS(SWS) and enhances SWS
Prolactin – in REM sleep andProlactin – in REM sleep and
enhances itenhances it
ACTH, cortisol – increase at end ofACTH, cortisol – increase at end of
sleep, deprivation stimulate HPAsleep, deprivation stimulate HPA
axisaxis

14. Physiology (Continued)Physiology (Continued)
Melatonin – secretion in the darkMelatonin – secretion in the dark
at night, feedback on circadianat night, feedback on circadian
clock.clock.
Sexual function – in REM sleepSexual function – in REM sleep
males – penile erectionmales – penile erection
females – increased vaginalfemales – increased vaginal
blood flow and clitoral erectionblood flow and clitoral erection

16. Functions of sleepFunctions of sleep
 Chemicals replenished duringChemicals replenished during
sleep – glycogen in glial cells,sleep – glycogen in glial cells,
Ca in pre-synaptic store,Ca in pre-synaptic store,
Glutamate vesicles, transfer ofGlutamate vesicles, transfer of
protein along axonsprotein along axons
 Sensory disconnection thatSensory disconnection that
occurs in sleep decreasesoccurs in sleep decreases
interference with ongoinginterference with ongoing
activities and helps inactivities and helps in
consolidation of previouslyconsolidation of previously
acquired memory.acquired memory.

17. NEUROANATOMNEUROANATOM
YY
RETICULARRETICULAR
FORMATIONFORMATION

18. Neurobiology of sleep andNeurobiology of sleep and
wakefulnesswakefulness
 Wakefulness is maintained by AscendingWakefulness is maintained by Ascending
reticular activating system (ARAS) whichreticular activating system (ARAS) which
has inputs from oral pontine, midbrainhas inputs from oral pontine, midbrain
tegmentum and post. Hypothalamustegmentum and post. Hypothalamus
 For wakefulness –For wakefulness –
Locus ceruleus (NE and gene expession)Locus ceruleus (NE and gene expession)
Pedunculopontine tegmentum (Ach),Pedunculopontine tegmentum (Ach),
Lat. Dorsal tegmentum (ACh),Lat. Dorsal tegmentum (ACh),
Tuberomammillary nucleus (Histamine),Tuberomammillary nucleus (Histamine),
Dopamine,serotoninDopamine,serotonin
Glutaminergic neurons are responsible.Glutaminergic neurons are responsible.

19. The ascending arousal systemThe ascending arousal system

20. HYPOCRETIN (OREXIN)HYPOCRETIN (OREXIN)
 A recently discovered peptide has beenA recently discovered peptide has been
given attribution for wakefulnessgiven attribution for wakefulness
 Produced in Lateral hypothalamusProduced in Lateral hypothalamus
 Provides excitatory inputs to allProvides excitatory inputs to all
components of ARAS including LC, PPT,components of ARAS including LC, PPT,
LDT, Ventral Tegmental Area, basalLDT, Ventral Tegmental Area, basal
forebrain and TMN.forebrain and TMN.
 Deficiency seen in narcolepsyDeficiency seen in narcolepsy
 Sleep disorder in Parkinsonism.Sleep disorder in Parkinsonism.

21. NREM sleepNREM sleep
 Work in animals has shown that shortlyWork in animals has shown that shortly
before transition from waking to sleep,before transition from waking to sleep,
changes in activity of cholinergic, norchanges in activity of cholinergic, nor
adrenergic, histaminergic andadrenergic, histaminergic and
glutamatergic neuromodulatory system withglutamatergic neuromodulatory system with
diffuse projection todiffuse projection to ARAS bring change ofARAS bring change of
firing mode of thalamus and corticalfiring mode of thalamus and cortical
neurons.neurons.

22. - Thalamocortical cells areThalamocortical cells are
hyperpolarised.hyperpolarised.
-- Reticulo thalamic cells areReticulo thalamic cells are
facilitated and further inhibitfacilitated and further inhibit
thalamocortical cells resulting inthalamocortical cells resulting in
inability of sensory stimuli to reachinability of sensory stimuli to reach
cortex through thalamus.cortex through thalamus.

23.  VVentrolateral preoptic (VLPO) areaentrolateral preoptic (VLPO) area
acts as a possible sleep switch. Itacts as a possible sleep switch. It
has inputs (through release ofhas inputs (through release of
GABA and galanin) to wakefulnessGABA and galanin) to wakefulness
promoting centre in TMN, LC ,promoting centre in TMN, LC ,
Dorsal raphe, and cholinergicDorsal raphe, and cholinergic
regions in pons and basal forebrain.regions in pons and basal forebrain.
All these areas provide reciprocalAll these areas provide reciprocal
inputs to VLPO area probably ofinputs to VLPO area probably of
inhibiting nature.inhibiting nature.

24.  There are some other substancesThere are some other substances
having sleep promoting functionhaving sleep promoting function
like adenosine, melatonin,like adenosine, melatonin, αα MSH,MSH,
GHRH , insulin , Cholecystokinin,GHRH , insulin , Cholecystokinin,
cytokines like interleukin – 1 ,cytokines like interleukin – 1 ,
interleukin- 6, tumor necrosisinterleukin- 6, tumor necrosis
factor.factor.
 Adenosine accumulates in basalAdenosine accumulates in basal
forebrain during prolongedforebrain during prolonged
wakefulness and decreases duringwakefulness and decreases during
sleep suggesting homeostaticsleep suggesting homeostatic
signal for sleep.signal for sleep.

25. REM SLEEPREM SLEEP
Area activatedArea activated AreaArea
deactivateddeactivated
 Mesopontine tegmentum Frontal andMesopontine tegmentum Frontal and
 ThalamusThalamus parietalparietal
corticescortices
 Posterior cortical areaPosterior cortical area
 Limbic area (particularlyLimbic area (particularly
amygdala)amygdala)

26.  Cholinergic-Monoaminergic interactions regulateCholinergic-Monoaminergic interactions regulate
REM sleep.REM sleep.
 Cholinergic agonists like carbachol if infused inCholinergic agonists like carbachol if infused in
LDT and PPT of cat or systemic administrationLDT and PPT of cat or systemic administration
of physostigmine in human produces prolongedof physostigmine in human produces prolonged
REM sleep. REM sleep can also be due toREM sleep. REM sleep can also be due to
depletion of norepinephrine, serotonine.(Causedepletion of norepinephrine, serotonine.(Cause
of dominance of REM sleep in depression)of dominance of REM sleep in depression)

27.  Tonic hyperpolarization of spinalTonic hyperpolarization of spinal
motor neurons during REM sleep ismotor neurons during REM sleep is
mediated by glycine (cause of lackmediated by glycine (cause of lack
of muscle tone in REM sleep).of muscle tone in REM sleep).
Phasic muscle twitches in REMPhasic muscle twitches in REM
sleep are mediated by glutamatesleep are mediated by glutamate
acting at NMDA receptors.acting at NMDA receptors.

29. Regulation of sleepRegulation of sleep
 Two key components :Two key components : --
CircadianCircadian
-- HomeostaticHomeostatic
 Two process modelTwo process model
(Alexander , Borbely )(Alexander , Borbely )
• Sleep propensity is based onSleep propensity is based on
homeostatic process S and thehomeostatic process S and the
circadian process C.circadian process C.
• Process S builds up across the day inProcess S builds up across the day in
response to increased sleep pressureresponse to increased sleep pressure
caused by wakefulness and decreasescaused by wakefulness and decreases

30.  Thus nocturnal sleep onset is primarilyThus nocturnal sleep onset is primarily
driven by process S, whereas process Cdriven by process S, whereas process C
maintains sleep through later part of night.maintains sleep through later part of night.
DayDay NightNight
Process SProcess S Sleep is initiated.Sleep is initiated.
builds upbuilds up process C buildsprocess C builds
up and maintainsup and maintains
sleepsleep

31. Circadian RhythmCircadian Rhythm
 In human and other mammals , theIn human and other mammals , the
primary pacemaker for generatingprimary pacemaker for generating
circadian rhythm lies in the supracircadian rhythm lies in the supra
chiasmatic nucleus (SCN) of thechiasmatic nucleus (SCN) of the
hypothalmus.hypothalmus.
 SCN regulates a number ofSCN regulates a number of
neuroendocrine and behavioralneuroendocrine and behavioral
parameters, including sleep propensity asparameters, including sleep propensity as
measured by process C, to coordinate themeasured by process C, to coordinate the
state of organism with 24 hrs light darkstate of organism with 24 hrs light dark
cycle.cycle.

32.  Sleep tendency is greater on theSleep tendency is greater on the
falling phase of temperature curve,falling phase of temperature curve,
during night. Arousal levels areduring night. Arousal levels are
maximum with rise of bodymaximum with rise of body
temperature across the day.temperature across the day.
 One of the major driver of circadianOne of the major driver of circadian
rhythms is HPA (Hypothalamusrhythms is HPA (Hypothalamus
pituitary adrenal axis). It alsopituitary adrenal axis). It also
controls other activities likecontrols other activities like
temperature regulation. CRHtemperature regulation. CRH
(Corticotropin releasing(Corticotropin releasing
hormone)Secretion.hormone)Secretion.

33. Homeostatic Regulation of SleepHomeostatic Regulation of Sleep
 Sleep deprivation producesSleep deprivation produces
sleepiness and increased sleepsleepiness and increased sleep
pressure. Sleep deprivation ispressure. Sleep deprivation is
followed by sleep rebound i.efollowed by sleep rebound i.e
compensatory increase of durationcompensatory increase of duration
or intensity or both; sleep latencyor intensity or both; sleep latency
is decreased , sleep efficiency isis decreased , sleep efficiency is
increased i.e. sleep is lessincreased i.e. sleep is less
fragmented.fragmented.

34. Slow Wave ActivitySlow Wave Activity
Model of SleepModel of Sleep
regulationregulation
(Achermann, Borbely, 2003)(Achermann, Borbely, 2003)
The level of EEG slow waveThe level of EEG slow wave
activity (SWA) is determined byactivity (SWA) is determined by
the duration of prior sleep andthe duration of prior sleep and
waking. SWA is a marker ofwaking. SWA is a marker of
NREM sleep intensity and mayNREM sleep intensity and may
serve as an indicator of sleepserve as an indicator of sleep
homeostasis.homeostasis.

35. Ultradian pattern of sleepUltradian pattern of sleep
(Theresa, Buckey, Alan,(Theresa, Buckey, Alan,
2005)2005)
 It is characterized by alternatingIt is characterized by alternating
and repeating cycles of REM andand repeating cycles of REM and
NREM sleep that occur throughoutNREM sleep that occur throughout
the night.the night.
 Cycles of REM sleep tend to beginCycles of REM sleep tend to begin
as cortisol level falls and cycles ofas cortisol level falls and cycles of
SWS tend to begin with rising levelSWS tend to begin with rising level
of cortisol.of cortisol.

36.  Hypothalamus Secretes CRH whichHypothalamus Secretes CRH which
stimulates secretion of cortisol throughstimulates secretion of cortisol through
adrenal cortex.adrenal cortex.
 Cortisol suppresses CRH byCortisol suppresses CRH by
mineralocorticoid receptor (MR) mediatedmineralocorticoid receptor (MR) mediated
hypothalmic paraventricular nucleus (PVN)hypothalmic paraventricular nucleus (PVN)
inhibition via hippocampus.inhibition via hippocampus.
 In contrast , higher level of cortisol wouldIn contrast , higher level of cortisol would
additionally occupy glucocorticoid receptoradditionally occupy glucocorticoid receptor
(GR) which exerts either inhibitory (via(GR) which exerts either inhibitory (via
PVN) or excitatory feedback (viaPVN) or excitatory feedback (via
Amygdala) on CRH.Amygdala) on CRH.

37. •CortisolCortisol →→ ↓↓ CRH through MR.CRH through MR.
•Higher level of cortisolHigher level of cortisol →→ activates GRactivates GR
++ --
CRHCRH CRHCRH
(via amygdala)(via amygdala) (via PVN)(via PVN)
•CRHCRH →→ ↑↑ cortisolcortisol
Lesser level of cortisol induces REM sleepLesser level of cortisol induces REM sleep
Greater level of cortisol induces SW sleepGreater level of cortisol induces SW sleep

38.  Elevated CRH increases sleep EEGElevated CRH increases sleep EEG
frequency;frequency;
CRH reciprocally activates the LC (NECRH reciprocally activates the LC (NE
system),system),
thereby increasing wakefulness throughthereby increasing wakefulness through
the ascending reticular activating systemthe ascending reticular activating system
Leading to waking from sleepsLeading to waking from sleeps

39. Clinical AspectsClinical Aspects
 Inadequate sleep hygiene :Inadequate sleep hygiene :
unfavorable life style (bed time,unfavorable life style (bed time,
arousal, excessive caffeine intake etc)arousal, excessive caffeine intake etc)
leads to disturbed sleep.leads to disturbed sleep.
 Circadian rhythm sleep disturbances:Circadian rhythm sleep disturbances:
1.1. Delayed sleep-phase syndrome.Delayed sleep-phase syndrome.
2.2. Advanced sleep phase syndrome :Advanced sleep phase syndrome :
Rhythm of sleep and waking isRhythm of sleep and waking is
advanced. Bright light in earlyadvanced. Bright light in early
evenings brings timely sleep. (Causeevenings brings timely sleep. (Cause
of early morning awakening inof early morning awakening in
depression).depression).

40. 3.3. Jet lag and shift work: There isJet lag and shift work: There is
desynchronization between one’sdesynchronization between one’s
internal sleep-wake rhythm andinternal sleep-wake rhythm and
that of external world. Melatonin/that of external world. Melatonin/
hypnotic may be given to shifthypnotic may be given to shift
deranged sleep wake cycle toderanged sleep wake cycle to
adjust with external environment.adjust with external environment.

41.  Narcolepsy : abnormality of function ofNarcolepsy : abnormality of function of
neuromodulator orexin(hypocretin) inneuromodulator orexin(hypocretin) in
hypothalamus resulting in lack ofhypothalamus resulting in lack of
excitatory inputs to all components ofexcitatory inputs to all components of
ARAS leadings to decreasedARAS leadings to decreased
wakefulness in day time.wakefulness in day time.
 Obstructive sleep apnea:Obstructive sleep apnea:
Periodic functional obstruction of upperPeriodic functional obstruction of upper
airway during sleepairway during sleep →→ arterial O2arterial O2
saturationsaturation ↓↓ →→ transient arousaltransient arousal →→
disturbed HPA axisdisturbed HPA axis →→ excessive dayexcessive day
time somnolence.time somnolence.

42.  In depression :In depression : Reduced REMReduced REM
latency,latency,
loss of SWS.loss of SWS.
AdvanceAdvance
sleep phase.sleep phase.
 REM sleep abnormality:REM sleep abnormality:
Is also found in schizophrenia ,Is also found in schizophrenia ,
alcoholism , eating disorder,alcoholism , eating disorder,
borderline personality disorder.borderline personality disorder.

43.  Measuring of day time sleepiness:Measuring of day time sleepiness:
1.1. Multiple sleep latency test (MSLT) ;Multiple sleep latency test (MSLT) ;
It measures the propensity to fallIt measures the propensity to fall
asleep. Individual is asked to lieasleep. Individual is asked to lie
quietly in a darkened room and toquietly in a darkened room and to
allow themselves to fall asleep. Theallow themselves to fall asleep. The
latency to sleep onset is measured.latency to sleep onset is measured.
If sleep does not occur within 20 min.If sleep does not occur within 20 min.
the test is terminated. Result morethe test is terminated. Result more
than 15 min is normal , less than 5than 15 min is normal , less than 5
min reflects excessive sleepiness.min reflects excessive sleepiness.
Multiple sleep latency test result isMultiple sleep latency test result is
abnormal (low) in narcolepsy.abnormal (low) in narcolepsy.

44. 2. Maintainence of wakefulness:2. Maintainence of wakefulness:
In the similar condition ,In the similar condition ,
individual is asked to stayindividual is asked to stay
awake. A mean sleep latencyawake. A mean sleep latency
greater than 35 min is normal.greater than 35 min is normal.

45. ConclusionConclusion
 Sleep is necessary for various reasons.Sleep is necessary for various reasons.
During sleep with the changes of stagesDuring sleep with the changes of stages
of sleep, there are other physiologicalof sleep, there are other physiological
changes. Replenishment of somechanges. Replenishment of some
neurotransmitters occurs. Glycogen inneurotransmitters occurs. Glycogen in
glial cells is replenished. Sleep isglial cells is replenished. Sleep is
necessary for sound memory.necessary for sound memory.
 Sleep and wakefulness mechanism areSleep and wakefulness mechanism are
interrelated and governed by circadianinterrelated and governed by circadian
pacemaker in suprachiasmatic nucleus ofpacemaker in suprachiasmatic nucleus of
hypothalamushypothalamus

46.  The other process that governs isThe other process that governs is
homeostatic regulation by process S.homeostatic regulation by process S.
 There are various models of sleepThere are various models of sleep
regulationregulation
– Two process model. (circadian,Two process model. (circadian,
homeostatic)homeostatic)
– Slow wave activity model – SWSSlow wave activity model – SWS
serves as marker of sleepserves as marker of sleep
homeostasishomeostasis
– Ultradian model : correlation ofUltradian model : correlation of
cortisol , CRH with REM , NREM sleepcortisol , CRH with REM , NREM sleep
and waking.and waking.

47.  Sleep deregulation may beSleep deregulation may be
primary or secondaryprimary or secondary
 Secondary deregulation may beSecondary deregulation may be
due physical or mental illnessdue physical or mental illness
 Clarifying function andClarifying function and
mechanism of sleep is likely tomechanism of sleep is likely to
provide greater understanding ofprovide greater understanding of
the basic electrophysiologicalthe basic electrophysiological
events & their correlates to someevents & their correlates to some
psychiatric disorders and theirpsychiatric disorders and their
treatment.treatment.

48. ReferencesReferences
 Kaplan and Sadok”s text of psychiatryKaplan and Sadok”s text of psychiatry
 Ganong”s pshysiologyGanong”s pshysiology

49. THANK YOU