NEUROBIOLOGY OF SLEEP

CHAIRPERSON- DR. K. PATHAK

MODERATOR- DR. K. DEB
PRESENTER- DR. BIJAYITA BORAH
OVERVIEW
 History and introduction
 Sleep stages
 Organization of sleep
 Physiology in sleep
 Effects of age on sleep
 Neuroanatomy & Neurochemistry
 Conclusion
 References
HISTORY OF SLEEP RESEARCH
 Aristotle concocted an interesting (and
altogether wrong) theory in the 4th Century
BC. He believed that the digestion of food
created warm vapors that rise from the
stomach and collect in the head, where they
cool and condense, flowing down to the heart
(which he believed to be the body’s sensory
centre), which then caused sleep as it cooled
 Romanian neurologist Constantin Von Economo
pinpoints the origin of sleep and wake signals
in the hypothalamus area of the brain in1916.
Invention of the electroencephalogram by the German sleep
researcher Hans Berger in the late 1920s, and his subsequent
realization that brain waves change as wakefulness gave way to
sleep, prompted a rapid expansion of sleep study in the 1930s, 1940s
and 1950s.
•Nathaniel Kleitman and his colleagues first pointed out the
different types of REM and non-REM sleep in1953

•William C. Dement showed that a night's sleep consists of several

repeating sleep cycles, each composed of different sleep stages.
By 1968, the different sleep stages had become standardized

•Romanian-born scientist Franz Halberg(the “father of

chronobiology”) researches circadian rhythms and first uses the
term “circadian” in1959

•Japanese-American neurobiologist Joseph Takahashi identifies and

clones the CLOCK circadian gene in 1997
DEFINITION
 From a behavioral standpoint, sleep is
defined as a state of decreased awareness of
environmental stimuli that is distinguished
from states such as coma or hibernation by
its relatively rapid reversibility
 For clinical and research purposes, sleep is
generally defined by combining behavioral
observation with electrophysiological
recordings
TYPES AND STAGES OF SLEEP
Sleep consists of two strikingly different states:

1. Rapid eye movement (REM) sleep

2. Non-REM (NREM) sleeep
 RAPID EYE MOVEMENT SLEEP( REM SLEEP):-
 Frequent bursts of eye movement activity occurs
 Also referred to as paradoxical sleep (EEG during REM
sleep is similar to that of waking)
 Activated EEG and increased neuronal activity and
cerebral blood flow
 NREM sleep
 orthodox sleep
 Characterized by decreased activation of EEG
 Rhythmic slow waves, indicating marked
synchronization
Electrophysiological Recordings

Polysomnography is the “gold standard”

technique.
It simultaneously records three physiological
measures
 Electromyogram(EMG)- Muscle tone
 Electro-oculogram(EOG)- Eye movements
 Electroencephalogram(EEG)- Brain activity
STAGE OF SLEEP – ELECTROPHYSIOLOGICAL
CRITERIA (RECHTSCHAFFEN AND KALES,1968)
 NREM sleep usually precedes REM sleep
 Sleep usually entered through a transitional state -
stage I sleep; may not be perceived as sleep, although
there is a decreased awareness of sensory stimuli;
motor activity may persist for a number of seconds
 Occasionally, sudden muscle contractions - hypnic jerks
are noted; generally benign
 After a few minutes sleep usually progresses to stage II,
heralded by appearance of sleep spindles and K
complexes
 Particularly at the beginning of night, stage II is
followed by a period comprised of stages III and
IV; also referred to as slow wave sleep
(SWS)/delta sleep/ deep sleep
 REM sleep -
 Tonic (persistent) components
 activated EEG similar to that of stage I
 generalized atonia of skeletal muscles, except

for extraocular muscles and diaphragm

 Phasic (episodic) components
 superimposed on tonic stage
 irregular bursts of REMs

 muscle twitches
ORGANIZATION OF SLEEP

 most adults need 7 to 9 hours of sleep per night

to function optimally
 A healthy adult -approx 5 % of sleep in stage N1 ,
50 % in stage N2, and 20-25 % in each of stages
N3 and R.
 Sleep occurs in cycles of NREM-REM sleep , each
lasting approximately 90-110 mins.
 SWS(stage N3)-most prominent early in the
night, diminishes as night progresses.
 As SWS wanes, REM sleep lengthens showing
greater phasic activity and more intense
dreaming later in night
EFFECTS OF AGE: INFANTS
 16-18 hours of sleep per day
 Short sleep wake cycle
 Enter sleep through REM
 Starts initiating sleep with NREM at 3-4
months of age
 REM constitute 50% of total sleep
EARLY CHILDHOOD
 REM sleep drops to adult level- 20-25%
 Total sleep time decreases
 Highest percentage of SWS- with high arousal
thresholds, high incidence of bed-wetting, SWS-
related parasomnias such as sleepwalking and
night terrors.

ADOLESCENCE
 Timing of sleep is later
 SWS decrease significantly.
 Total sleep time is decreased
EFFECTS OF AGE: OLDER
ADULTS
 SWS declines across adulthood and may
disappear entirely by age 60
 Sleep fragmentation
 Prolonged latency to sleep onset
 Daytime napping
 More time spent awake during sleep period
 Normal individuals- small decline in REM sleep
 Alzheimer’s disease and other degenerative
conditions of CNS-loss of REM sleep and
deterioration in diurnal patterns of sleep-
wakefulness
PHYSIOLOGIC FUNCTIONS IN
SLEEP
AUTONOMIC NERVOUS SYSTEM

 NREM sleep and tonic REM sleep-

parasympathetic activity > sympathetic
activity.
 Phasic REM sleep- brief surges in both
parasympathetic and sympathetic activity
resulting in autonomic instability.
 SWS sleep-most stable state in comparison to
wakefulness.
BP, heart rate, respiratory rate are
at their lowest mean values and least variable.
CARDIOVASCULAR SYSTEM
 NREM sleep: BP, HR, cardiac output- decrease, least
variable in SWS sleep.

 REM sleep: these parameters remain somewhat

reduced in comparison to waking, they attain peak
values in REM sleep.
Arrhythmias are more prevalent in REM
sleep, may contribute to increased rates of
cardiovascular mortality in the early morning
Depressed patients- increased REM sleep with
greater phasic activity-increased rates of mortality
due to cardiovascular causes seen in major
depression.
 RESPIRATORY SYSTEM
 Onset of sleep-temporary breathing
instability and/or periodic breathing
 Decreased respiratory rate and minute
ventilation during sleep, increased upper
airway resistance-most significantly during
REM sleep
 These changes contribute to exacerbations
of underlying pulmonary disease as well as
sleep-realated breathing disorders such as
sleep apnea
THERMOREGULATION
 Sleep and body temperature-functionally
inter-related.
 Neurons that regulate sleep and temperature
are located in the preoptic and anterior
hypothalamus.
 NREM sleep: brain and body temperature are
downregulated , particularly SWS
 REM sleep: thermoregulatory responses are
reduced even further,decreased ability to
regulate body temperature through sweating
and shivering
 NEUROENDOCRINE CHANGES
 Growth hormone- released primarily during early part
of night, enhanced by SWS.
 Prolactin- peaks after GH, middle part of night.
Both have feedback effects on sleep. GH
enhances SWS, prolactin may increase REM sleep
 TSH-peaks in the evening, prior to sleep. TSH is
inhibited by sleep and stimulated by sleep deprivation.
 Hypothalamic-pituitary-adrenal axis (HPA axis)-
inactive state at sleep onset.
 ACTH and cortisol-rises shortly before awakening.
 Melatonin-secretion mediated by circadian rhythm and
effects od light-dark cycle- it can only be released at
night if it is dark; darkness during the day does not
stimulate melatonin secretion.
 SEXUAL FUNCTION
 REM sleep in men- penile erection
 In women- increased vaginal blood flow and
clitoral erection
REGULATION OF SLEEP AND WAKEFULNESS
TWO PROCESS MODEL
 Proposed by Alexander Borbely

 Sleep is regulated by two basic processes:

1) Homeostatic process (S)
2) Circadian process(C)

 Nocturnal sleep onset is driven by process S,

whereas process C maintains sleep
HOMEOSTATIC PROCESS
 Depends on the amount of prior sleep and
wakefulness
 If normal amount of sleep is reduced

Homeostatic drive is increased

Increased need for sleep(sleep pressure)

Sleepiness during day and increased deep sleep

at night
Adenosine- byproduct of energy metabolism
‘Homeostatic modulator of sleep’
CIRCADIAN PROCESS/RHYTHM
 the term circadian comes from the Latin circa,
meaning “approximately,” and dia, meaning “day.”
 Suprachiasmatic nucleus-pacemaker or “master
biologic clock” located in anterior hypothalamus
 SCN controls the timing of sleep, but sleep itself is
controlled by other brain structures
 Circadian clock is synchronized to environmental cues
(zeitgebers) by a process called entrainment
 Light-dark cycle is the most potent entraining stimulus
 Entrainment of SCN cells is mediated through
glutamate stimulating NMDA receptors
 The SCN regulates the pineal gland’s secretion of
melatonin.
 Light hitting retina release of
glutamate through retinohypothalamic tract
projecting to SCN

Entrainment of SCN cells

Release of melatonin from pineal gland is

signaled by circadian rhythm and melatonin
can also shift the circadian clock
NEUROBIOLOGY OF SLEEP AND
WAKEFULNESS
 Sleep and wakefulness governed by separate,
yet interacting systems

 Specific mechanism is not fully understood, but

it is clear that multiple structures and systems
in brainstem, hypothalamus, and basal forebrain
are involved
 WAKEFULNESS
Neurobiology:-

 Maintenance of wakefulness - dependent on

ascending reticular activating system (ARAS)
 comprising of inputs from pontine, midbrain
tegmentum, and posterior hypothalamus

 produces cortical activation via input to

thalamus, as well as through an extrathalamic
pathway with projections to hypothalamus and
basal forebrain
 2 anatomical branches of ARAS-
1. Cholinergic cells in pedunculopontine tegmental
(PPT) and lateral dorsal tegmental (LDT) nuclei-
excitatory cholinergic projections to the midline and
intralaminar nuclei of the thalamus.

2. Monoaminergic group- bypasses thalamus, projects

to lateral hypothalamus, basal forebrain and
cerebral cortex
Noradrenergic cells in locus coeruleus (LC)
Histaminergic cells in tuberomammillary nucleus
(TMN) of posterior hypothalamus
Dopaminergic neurons in ventral tegmental area
and substantia nigra
Serotonergic neurons of dorasal raphe nucleus
 Cholinergic cells:
 promote cortical activation through inputs to thalamus,
hypothalamus, and basal forebrain
 cholinergic cell bodies in basal forebrain receive input from
ARAS and, in turn, provide excitatory input to the entire
cortex.
 fire at high rates during wakefulness and REM sleep, but
reduce firing in NREM sleep
 Drugs with anticholinergic activity,including TCAs and
atropine can cause sedation, supress REM sleep and can
increase slow wave activity.
 Cholinergic agonists(eg. Nicotine) and anticholinesterase
inhibitors(eg. Neostigmine) enhance arousal
 Noradrenergic cells:
 project from LC directly throughout forebrain and cerebral
cortex
 Highest firing during wakefulness, decrease firing- NREM
sleep and cease firing- REM sleep
 Histaminergic neurons:
 histaminergic tuberomamillary nucleus neurons
project throughout cortex; fire highest during
wakefulness and cease during sleep.
 Histamine promote wakefulness through H1
receptors.
 In thalamus, cortex, forebrain and pontine
tegmentum- it promotes wakefulness by enhancing
glutamatergic and cholinergic transmission
 histamine infusion into CNS – arousal; experimental
lesions of TMN -hypersomnia
DOPAMINERGIC SYSTEM:
 DA-producing neurons are most abundant in the
substantia nigra and ventral tegmental area
 exerts potent wake-promoting effects
 in general, have not been found to alter their rates
of firing across sleep and wakefulness.Nevertheless,
extracellular levels of DA are high during periods of
wakefulness and lower during NREM sleep
 Sleepiness- DA antagonists such as haloperidol and
chlorpromazine
 D2 agonists like ropinirole can produce sleepiness
via activation of autoinhibitory D2 receptors that
reduce DA signaling
 stimulants such as methylphenidate and
amphetamine increase extracellular levels of DA by
disrupting the function of the DA transporter (DAT)
 Hypocretin (orexin):
 Itis a peptide
 produced by cells in lateral hypothalamus that provide
excitatory input to all components of ARAS
 most active during waking, almost stop firing during
NREM and REM sleep
 Narcolepsy-loss of hypocretin cells in brain, and
hypocretin protein in CSF
 Recently, hypocretin cell loss has been described in
Parkinson’s disease which is often associated in sleep
disturbamce like narcolepsy
 Serotonergic cells:
 wide projection from dorsal raphe nucleus to cortex;
fire at higher levels in waking and lower levels in sleep
 role in sleep not straightforward; also evidence that it
may be involved in sleep induction
NREM SLEEP
 The centers that facilitate sleep include the
VLPO( located in anterior hypothalamus) and the
median preoptic nucleus (MnPN).
 These areas are active at the transition from

waking to sleep and inhibit the firing of arousal

centers for sleep initiation and maintenance.
VLPO
 sustained discharge during sleep, increased activity
only after sleep onset in sleep deprivation
 Has important inhibitory inputs (GABA and galanin) to
wakefulness promoting centers- histaminergic neurons
of the TMN, cholinergic LDT/PPT and monoaminergic
LC and DR.
 orexin neurons of the LH also receive inhibitory input
from the VLPO
 Bidirectional relationship-All major monoaminergic
nuclei send inhibitory projections to the VLPO so that
the sleep and wake systems are reciprocally
connected.
 Experimental ablation of VLPO area in animals - ↓
NREM and REM sleeps
MEDIAN PREOPTIC NUCLEUS
 uses GABA to send inhibitory projections to
many of the same arousal targets, similar to
VLPO
 The nuclei differ in the temporal pattern of
discharge during routine sleep and following
sleep deprivation
 Highest activity early in NREM sleep with
gradual decline through the sleep period
 peak activity during sleep deprivation,before
the onset of recovery sleep.
 No unique sleep factor has been identified
 GABA
 thalamocortical oscillations and VLPO-mediated
inhibition of waking centers
 most hypnotics-barbituarates, BZD, non-BZD act by
enhancing GABA transmission

 Adenosine
 accumulates in basal forebrain during prolonged
wakefulness and decreases during sleep
 Inhibits cholinergic neurons in pons and basal
forebrain
 Adenosine infusion-promotes NREM,
 caffeine - stimulant effects by blocking adenosine
receptors
Serotonin
 Early studies raised possibility that it might also be
involved in NREM sleep (lesions in DR led to
insomnia)
 Decrease firing rates in NREM and stops firing in
REM sleep
 Possibility that they may help in sleep onset, by
inhibiting cholinergic neurons
 Remains controversial as to how much serotonin
contributes to sleep versus arousal

Other substances - attributed with sleep-promoting

properties - a variety of hormones (melatonin, α-MSH,
GHRF, insulin, CCK); cytokines (IL-1, IL-6 and TNF);
muramyl peptides from gut bacteria etc
REM SLEEP
 Areas involved - mesopontine tegmentum, thalamus, posterior
cortical areas, and limbic areas (particularly anygdala) are
highly activated
 Frontal and parietal cortices- deactivated
 Pons and caudal midbrain both necessary and final common
pathway for REM sleep
 The most important REM sleep center in the pons is the
sublaterodorsal nucleus (SLD), which appears to govern
switching in and out of REM sleep
 PGO( ponto-geniculo-occipital) waves are as characteristic of
REM sleep-eye movements during REM sleep tightly linked to
PGO waves
 path of travel-from the pons through the lateral geniculate
nucleus of the thalamus to the occipital area, begin about
80 seconds before the start of a REM period
Reciprocal interaction hypothesis (Hobson
and McCarley)
 to explain NREM-REM cycles
 based on interactions between cholinergic and
aminergic neurons in mesopontine junction
 NAgic/serotoninergic - REM-off cells - inhibitory
to REM-on cells; most active during waking;
decrease activity during NREM sleep
 Cholinoceptive/cholinergic - REM-on cells in PPT
and LDT regions - activated during REM sleep
 REM sleep terminated because REM-on cells are
self inhibitory and provide excitatory input to
REM-off cell
 GABAergic and glutamatergic neurons also
important in REM sleep
REM SLEEP CONTD..
 Cholinergic agonists- physostigmine,
pilocarpine,arecoline –prolonged REM sleep
 TCAs and MAOI with anticholinergic effects-
REM sleep suppression
 Tryptophan deficient diet- decreased
serotonin- facilitate REM sleep
ROLE OF HYPOTHALAMUS
 “flip-flop switch”
1. Tuberomamillary nucleus(TMN) in posterior
hypothalamus- mainly excitatory histaminergic,
2. lateral hypothalamus- excitatory
orexinergic, - “on” switch
3. VLPO in anterior hypothalamus- inhibitory
GABAergic, “off” switch
 LH- orexinergic projections activate TMN
neurons,RAS neurons and excitatory basal
forebrain(cholinergic), which serves to raise the
excitability of the cortex
 VLPO inhibits RAS, LH, basal forebrain and cortex
ROLE OF THALAMUS
 Thalamic pacemaker hypothesis- rhythmic activity is
generated in thalamus and communicated to the cortex- seen
as oscillations in slow wave sleep.
 The thalamus contains two major types of neurons-

1.glutamatergic thalamocortical projection neurons-relay

sensory, motor, and limbic information to the cortex,
2. reticular nucleus- thin sheet of inhibitory GABAergic
neurons,that are innervated by the projection neurons and
cortex and in turn inhibit the projection neurons
 Thalamocortical cells are hyperpolarised and reticulothalamic
cells are facilitated and further inhibit thalamocortical cells
 Sensory stimuli are gated at thalamic level and often fail to
reach the cortex
 Rebound firing due to the activation of intrinsic currents in
thalamocortical cells leads to the oscillations in the spindle
frequency range within thalamoreticular circuits.
ROLE OF THALAMUS
 slow oscillations are the results of
hyperpolarisation of cortical neurons – seen as a
high amplitude negative wave in surface EEG.
 K complexes are made up of the cortical
depolarisation phase followed by its triggered
spindle.
 During wakefulness and REM sleep, ACh
depolarizes thalamic neurons, inhibits bursting
and suppress spindles and slow waves
SLEEP AND PSYCHIATRY
 Depression-reduced REM sleep latency, increased
frequency of eye movements in REM sleep,increased
percentage of time spent in REM sleep and loss of SWS
 REM sleep abnormalities similar to depression have been
described in some patients with schizophrenia,
alcoholism, eating disorders and borderline personality
disorder.
 Sleep loss can induce or perpetuate mania
 People with insomnia have higher rates of psychiatric
disorders- particularly mood disorders and anxiety
 Patients with panic disorder may have panic attacks
arising from sleep, usually at transition to SWS
 Narcolepsy-abnormal intrusion of REM sleep phenomena
into wakefulness
 Sedation by antipsychotics, TCAs, BZDs,
antiparkinsonian agents
 Antidepressants may precipitate periodic
movements in sleep,
 Abrupt withdrawal of REM-supressing
antidepressants including TCAs, MAOIs and
SSRIs –REM sleep rebound- increased duration
and intensity of REM sleep
 Sleep apnea- maybe exacerbated by muscle
relaxants(BZDs, barbiturates) or wieght
gain( antipsychotics, antidepressants and mood
stabilizers)
FUNCTIONS OF SLEEP

Exact function is not known, commonly accepted

hypothesis are;

 Neural plasticity, restoring metabolic functions

 Learning, memory,
 Immune system maintenance
 Energy conservation
 CONCLUSION

 Knowledge of normal sleep physiology gives us

insight about abnormality associated with it
 Sleep is important for us to learn in terms of aetiology,
clinical features, treatment aspects of mental disorders
 Certain aspects of sleep have been found to have value
as endophenotypic markers for certain mental
disorders
 Enquiring about simple aspects of our patients' sleep –
amount, continuity, quality, dreams and content could
have importance in planning further management
 REFERENCES
 Sadock BJ. Sadock VA. Comprehensive Textbook
of Psychiatry 9th Ed. Vol 1 ,pg-361-375
 Neurobiology of Sleep ,Brandon S. Lu, Phyllis C.
Zee.
 Sleep Neurobiology for the Clinician—España and
Scammell ,SLEEP, Vol. 34, No. 7, 2011
 The Neuroscience of Sleep, edited by Robert
Stickgold and Matthew Walker
THANK YOU