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FIZIOLOGIA SOMNULUI

&
CLASIFICAREA TULBURARILOR DE SOMN
Prof. Dr. Ovidiu Bajenaru

Universitatea de Medicina si Farmacie "Carol Davila" Bucuresti – Facultatea de Medicina


Departamentul de Neurostiinte Clinice
Spitalul Universitar de Urgenta Bucuresti – Clinica de Neurologie
• CONSTIENTA ( “awareness”, “consciousness” )
– mai mult decat STAREA DE VEGHE ( starea VIGILA )
– orientat in mediu si fata de sine
– perceptii normale ale stimulilor externi si interni
– reactivitate adecvata ( oculara, verbala, motorie: comportament )
• Scala de evaluare a constientei GLASGOW ( GCS ): O – V – M

INTERACTIVITATE CONTROLATA ( CONSTIENTA ) CU MEDIUL

• CONSTIINTA (“conscience” )
– participare emotionala si mentala
– continut cognitiv
– raportare la sisteme de referinta valorice ( moral, etic, social, profesional,
ideologic, etc. )
* Oxford English Dictionary: 12 definitii pentru “conscious” si 8 pentru “consciuousness”

• CUNOSTINTA ( “knowledge”, “cognition” )


• SOMN = stare fiziologica de pierdere,
reversibila a starii de constienta in care
responsivitatea creierului la stimuli externi
este semnificativ scazuta

• SOMN VEGHE
• Diferente:
– SOMNUL ANESTEZIC

– ALTERARILE PATOLOGICE ale STARII DE CONSTIENTA


• nespecifice etiologic ( confuzie, delirium, stupor, coma; mutism
akinetic, locked-in, stare vegetativa, starea de minima constienta )
• unele forme de epilepsie

• SOMNUL NORMAL:
– cicluri de somn caracteristice: NREM ( N1, N2, N3)/ REM
– comportament de somn:
• normal: miscari reduse, posturi stereotipe
• patologic: parasomnii ( de NREM, de REM )
– constienta pastrata: a adormirii, la trezirea din somn
• SOMNUL = componenta esentiala a integritatii si functionarii normale a
creierului si intregului organism al fiintelor umane si animale

• SOMNUL = stare activa a creierului, cu propriile sisteme de retele neuronale


functionale si mecanisme de control a homeostaziei specifice extrem de
complexe

• SOMNUL = componenta inseparabila a ciclurilor somn-veghe

D Somnul = o stare fiziologica de intrerupere a activitatii de veghe constiente,


cand creierul este relativ mai reactiv la stimuli interni decat la stimuli externi
- alternanta somn-veghe are o ciclicitate predictibila
( diferenta majora fata de starile patologice de pierdere a constientei )
- creierul isi scade gradual responsivitatea la stimuli vizuali, auditivi si alti
stimuli din mediu – tranzitia catre somn ( → stadiul I de somn NREM )
• 1931: Constantin von Economo → “encefalita letargica”
– trezirea este mediata de structuri din hipotalamusul posterior
si capatul rostral al trunchiului cerebral

• 1949: Moruzzi & Magoun → SRAA


- proiectiile talamice ale ncc. SR din reg. mediana a capatului
rostral al trunchiului cerebral )
• Proiectiile eferente ale FR trunchiului cerebral

1. rostral – spre creierul bazal anterior ( “forebrain”)

2. caudal – spre maduva spinarii

3. spre sistemele motorii & de reglare interna


Fig. Components of the consciousness system
• Somnul urmeaza un ritm circadian - cu periodicitate
reglata genetic independent de un “ceas biologic
intrinsec” ( in relatie cu factori-trigger externi: lumina,
intuneric, orele zilei, modalitatile de activitate, orele
meselor, etc.)

• Cand fiinta umana este privata de acesti factori-cheie


si supusa unui nivel constant de iluminare, ciclul
somn-veghe se alungeste la cca. 24,5 ore
CEASUL BIOLOGIC CIRCADIAN ( la om )
• “Ceasul biologic principal” la mamifere – nc. suprachiasmatic
( SCN ) din h-talamusul rostral ( sincronizeaza activitatile
diurne )
• Leziuni din SCN → pierderea organizarii circadiene

• Proiectii directe din retina


– la om, cel mai puternic agent de
sincronizare: LUMINA
– alternanta lumina / intuneric:
organizeaza ritmul biologic
• nevoia de adormire
• momentul trezirii
• Informatii aferente multiple de la caile
celorlalti stimuli externi reglatori

www.sleepfoundation.org
Reglarea ritmului veghe - somn
• Interactiune coordonata intre circuitele neuronale de control ale:

A. reglarii starii de veghe (stimuleaza activarea corticala & trezirea


comportamentala )
• nn. Ach-ergici din: TRUNCHI CEREBRAL si CREIERUL ANTERO-BAZAL
• nn. monoaminergici (NA, Hys-NH2, 5-HT2 ) din: TRUNCHIUL CEREBRAL si
HIPOTALAMUSUL POSTERIOR
• nn. orexigenici ( hipocretina ) din HIPOTALAMUSUL LATERAL
( distrugerea neuronilor orexinici → narcolepsia ! )
B. reglarii somnului
• inhibitia /disfacilitarea sistemelor de trezire prin:
– cell. ARIA PREOPTICA VENTRAL-LATERALA ( VLPO )
» galanina, GABA
– nc. PREOPTIC MEDIAN ( MnPN )
» GABA
Neuronii preoptici se activeaza in timpul somnului si se proiecteaza in
hipotalamusul posterior si trunchiul cerebral rostral ( → INHIBITIE )
( pattern de descarcare reciproc celui din sistemele de veghe )
OREXINELE ( HIPOCRETINELE )
• Orexins or hypocretins, which are produced by a small group of
neurons in the hypothalamus and whose actions are mediated by
two types of receptors: OX1R and OX2R

• Orexinergic neurons are projected widely into a number of


brainstem, cortical and limbic regions

• They have been related with the mechanisms that enable


regulation of the sleep-wake cycle, the ingestion of food and
drink, and some particular types of learning
• Further research will help to determine the
functioning of orexinergic neurons and the
interaction between the systems that
regulate emotion, energetic homeostasis and
the reward mechanisms, on the one hand,
and the systems that regulate the sleep-wake
cycle on the other
Reglarea ritmului veghe - somn
• Interactiune coordonata intre circuitele neuronale de control ale:

A. reglarii starii de veghe (stimuleaza activarea corticala & trezirea


comportamentala )
• nn. Ach-ergici din: TRUNCHI CEREBRAL si CREIERUL ANTERO-BAZAL
• nn. monoaminergici (NA, Hys-NH2, 5-HT2 ) din: TRUNCHIUL CEREBRAL si
HIPOTALAMUSUL POSTERIOR
• nn. orexigenici ( hipocretina ) din HIPOTALAMUSUL LATERAL
( distrugerea neuronilor orexinici → narcolepsia ! )
B. reglarii somnului
• inhibitia /disfacilitarea sistemelor de trezire prin:
– cell. ARIA PREOPTICA VENTRAL-LATERALA ( VLPO )
» galanina, GABA
– nc. PREOPTIC MEDIAN ( MnPN )
» GABA
Neuronii preoptici se activeaza in timpul somnului si se proiecteaza in
hipotalamusul posterior si trunchiul cerebral rostral ( → INHIBITIE )
( pattern de descarcare reciproc celui din sistemele de veghe )
Reglarea ritmului veghe - somn
Both homeostatic factors (factor S) and circadian factors (factor C) interact to
determine the timing and quality of sleep

The propensity to fall asleep varies throughout the day and depends upon both
time since the last sleep period (process S) and circadian factors (process C):
- the longer the time since the last sleep period, the greater will be
process S;
- its propensity will be modulated by process C

The circadian pressure to sleep:


- is greatest at ~2 am with a secondary peak at ~2 pm.
- it is least at ~6 am and ~6 pm.
STRUCTURA GENERALA A SOMNULUI
• 2 componente fundamentale ale somnului:
– non-REM ( NREM )
• Clasic: 4 stadii de profunzime: I, II ( somn superficial ), III, IV ( SWS )
• Clasificarea actuala AASM: N1, N2, N3
– REM
Diferente majore NREM / REM:
- circuite neuronale activate
- relatia creier / mediul exterior si intern (controlul homeostaziei sistemice,
activitatii motorii si receptivitatii informatiilor din afara SNC )
- tipul de activitate biochimica in metabolismul si
comunicarea interneuronala
* NREM: activitate mentala minima / absenta
* REM: activitate corticala intensa
- activitatea electrica a creierului →EEG
STRUCTURA SOMNULUI
• Sleep is divided into a 90 minute cycle of NREM sleep and REM
sleep

• This cycle is repeated 3-6 times during the night

• Generally, a night of sleep begins in NREM and progresses


through deeper NREM stages (stages 2, 3, and 4 using the
classic definitions, or stages N2 and N3 using the updated
definitions) before the first episode of REM sleep occurs
approximately 80 to 100 minutes later

• As the sleep cycle progresses through the night there is less


stage N3 NREM sleep and more REM sleep ( more REM sleep
on towards morning, which explains why when you awaken in
the morning, you generally awaken from a dream )
ARHITECTURA SOMNULUI
• American Academy of Sleep Medicine (AASM) terminology uses the
term N for NREM sleep stages and R for REM sleep stages:
– N1 and N2 are used instead of stage 1 and stage 2
– N3 is used to indicate the sum of stage 3 and stage 4 (slow-wave
sleep – SWS )

• In Phase N1, alpha waves with frequencies of 8-13 Hz change to theta


waves with frequencies of 4-7 Hz
• Phase N2 is marked with the advent of sleep spindles that range from
11-16 Hz and K-complexes
• Phase N3 (also called deep sleep) has an EEG pattern of 20%-50% high-
amplitude (> 75 microvolt), low-frequency (2 Hz) delta waves.
STRUCTURA SOMNULUI
• Stage 1 sleep is a very light stage of sleep with a low arousal
threshold. It generally lasts for less than 10 minutes, at sleep
onset. During this stage, the EEG shows alpha activity

• During stage 2 sleep, which accounts for 50 percent of total


sleep time, the EEG shows low-voltage activity
* the frequency is mixed, but slowing
* the EEG during stage 2 sleep also shows "sleep spindles,"
which are high-frequency bursts (12-16 Hz) of electrical
activity ( hypnotic agents have been shown to increase the
density of sleep spindles )
Activitatea EEG in diferite stadii de somn

Schupp M, Hanning CD - British Journal of Anaesthesia | CEPD Reviews | 2003; 3(3): 69 - 74


ARHITECTURA SOMNULUI
• Advancement to Stage 2 begins when K-complexes and sleep spindles that
last at least 0.5 second establish themselves on a background of theta
waves. The K-complex is the most prominent feature of Stage 2 and may be
elicited by an auditory stimulus.
• Muscle tone persists during Stage 2.
• Eye movements during Stage 2 are generally slow or absent, although they
may reappear for short intervals
• The induction of SWS is associated with the secretion of
γ-aminobutyric acid (GABA) from basal forebrain
neurones

( benzodiazepines and barbiturates, which act through


stimulation of GABA receptors in the CNS, induce sleep
or anaesthesia )
ARHITECTURA SOMNULUI
• An EEG pattern of 20%-50% high-amplitude, low frequency (2 Hz)
delta waves signifies the onset of STAGE 3. Sleep spindles and K-
complexes can still be identified

• Progression to STAGE 4 is defined as an EEG pattern of more than


50% high-amplitude, low-frequency waves

• Muscle tone and eye movement are greatly diminished or absent


during Stages 3 and 4 ( N3 )

Stadiul IV
• In starea de veghe: Ach, Hys-NH2, NA ( din trunchiul cerebral & hipotalamus ) au
efect activator asupra neuronilor talamo-corticali, blocand hiperpolarizarea prin
canalele de K+

• In stad.N2 NREM: inhibitia sincrona produsa de GABA: abundenta de fusuri de


somn

• In somnul SWS ( NREM-N3 ):


– scaderea Ach (→ dezinhibitia nc. reticular talamici ), prin reducerea
depolarizarii SRAA ( in somnul precoce ) permite un raspuns de tip
“burst-mode” dependent de un prag scazut al canalelor lente de Ca++
( descarcari de serii repetitive pe fond de hiperpolarizare )
ARHITECTURA SOMNULUI - somnul REM
• A specific subset of cholinergic neurons within the pontine
reticular formation seems to dictate the nature of REM sleep:
during SWS, these cholinergic neurons also suppress the
activities of aminergic neurons

• The transition from SWS to REM sleep can be partially attributed


to a reduction in the suppression of aminergic neurons

• REM sleep is defined by:


– EEG activation
– muscle atonia
– episodic bursts of rapid eye movements
ARHITECTURA SOMNULUI - somnul REM
• REM sleep usually is not divided into stages

• For research purposes:


– tonic (parasympathetically driven state ) REM sleep
( with no eye movements )
– phasic (sympathetically driven state ) REM sleep
( with eye movements that tend to occur in clusters )

• The most commonly used marker of REM sleep phasic activity in


human beings is the bursts of rapid eye movements

• Muscle twitches and cardiorespiratory irregularities often


accompany the sympathetically driven phasic REM bursts
ARHITECTURA SOMNULUI - somnul REM

1. The MENTAL ACTIVITY of human REM sleep is associated with DREAMING,


based on vivid dream recall reported after approximately 80% of arousals
from this state of sleep

2. Inhibition of spinal motor neurons by brainstem mechanisms mediates


SUPPRESSION OF POSTURAL MOTOR TONUS in REM sleep
( postsynaptic inhibition of motor neurons and membrane hyperpolarization;
in subjects with pontine damage, REM without atonia can occur – these
patients physically enact the events of their dreams )

• A shorthand definition of REM sleep:


“AN ACTIVATED BRAIN IN A PARALYZED BODY”
Somnul REM
• Classic EEG features of REM sleep include high-frequency, irregular
waveforms and the absence of K-complexes, sleep spindles, and low-
frequency waveforms

• The irregular waveforms unique to REM sleep have a “sawtooth appearance”


and are present in bursts lasting up to 5 seconds

• In terms of EEG readings, REM sleep most closely resembles the waking state

• REM sleep is also characterized by:


– diminished or absent deep tendon reflexes
– irregular breathing in both frequency and tidal volume
– poikilothermia ( cells in the preoptic/anterior hypothalamus which control
thermoregulation cease firing )
– penile tumescence
– increased variability in cardiac rhythm
– cerebral blood flow is also high during REM sleep
Neurotransmitters
Simplistic
Wake
high monoaminergic
high cholinergic
orexin ( hypocretin )
NREM
low monoaminergic
low cholinergic
REM
low monaminergic
high cholinergic

Monoaminergic: dopamine, serotonin, norepinephrine, hystamine


PHYSIOLOGICAL CHANGES DURING SLEEP
• Cardiovascular
* During NREM, there is an overall reduction in heart rate, cardiac
output and blood pressure ( “dip”), due to a general vasodilation
* During REM sleep, there are variations in blood pressure and heart
rate, but overall the rates are increased, especially during the phasic
events of REM sleep, probably due to a generalized vasoconstriction
seen in the skeletal muscles during phasic REM sleep
* Cardiac output is generally decreased during all sleep phases
* Cerebral blood flow (CBF) increases above the level of
resting wakefulness during tonic REM sleep and is even greater during
phasic REM sleep
* Cerebral metabolic rate, oxygen consumption and neuronal discharge
rate are reduced during NREM sleep but increased above resting
values during REM sleep
• The autonomic nervous system shows a general decrease in
sympathetic tone and an increase in parasympathetic tone, except in phasic
REM sleep.
PHYSIOLOGICAL CHANGES DURING SLEEP
• Respiration
* Overall, there is slight hypercapnia, a decrease in total ventilation, and
a decreased sensitivity to inspired CO2

* During NREM there is a slight hypoventilation ( relaxation of upper


airway muscles, as well as a decrease in the firing of inspiratory neurons,
which show a decreased sensitivity to stimuli )

* PCO2 levels raise while Po2 levels fall

* During NREM sleep, breathing is under chemical and mechanical


feedback control

* During REM there is an overall higher and variable respiratory rate


( it may be driven by higher cortical control, which may explain the
variable rate )
NERVOUS SYSTEM DURING SLEEP
• During NREM sleep there is a reduced discharge rate and reduced brain
metabolism (there is an active inhibition of the reticular activating system )
• During REM sleep, many parts of brain (visual cortex, limbic lobe) show
increased firing rate and metabolism

• During NREM sleep, brain transection studies have shown that the pons is
necessary and sufficient to generate the basic phenomena of REM sleep

• During NREM sleep, there is an increase in parasympathetic activity similar


to relaxed wakefulness; sympathetic drives remain at about the same level as
during relaxed wakefulness
• During tonic REM sleep, parasympathetic activity remains about the same as
during NREM sleep, but sympathetic activity decreases, resulting in an overall
predominance of parasympathetic activity
• However, during phasic REM sleep, both sympathetic and parasympathetic
activity increase; sympathetic activation is generally favored
Modificari fiziologice in cursul somnului

Schupp M, Hanning CD - British Journal of Anaesthesia | CEPD Reviews | 2003; 3(3): 69 - 74


RELATIA INERVATIEI CHOLINERGICE /
STAREA VIGILA si SOMNUL / MEMORIA
• Eliberarea corticala a Ach:
– crescuta in timpul starii de veghe
– maxima si exclusiva in somnul REM
– minima in somnul SWS

A. Starea de veghe: Ach creste


selectivitatea raspunsului neuronal la
informatia noua, favorizand retinerea ei
( encodarea )
RELATIA INERVATIEI CHOLINERGICE /
STAREA VIGILA si SOMNUL / MEMORIA
B. NREM: influenta benefica asupra memoriei declarative !
( neinfluentata de somnul REM )
* reactivarea achizitiilor mnestice recente (“replay”) in circuitele
hipocampice, NECESARA pentru transferul si integrarea lor in retelele
celulare neocorticale ( corelate cu prezenta in std.II NREM pe EEG a
fusurilor de somn si oscilatiilor lente, mai abundente dupa procesul de
“invatare declarativa” )
* reflecta activitatea neocorticala si talamica ( ncc. anteriori ):
inversarea fluxului informational ( hipocamp → neocortex )
* necesita reducerea stimularii Ach si cortizolice ( implicatii pentru AD
apneea de somn, nerespectarea orelor de somn, s.a.)

C. Somnul REM:
* consolidarea memoriei procedurale
* consolidarea memoriei declarative cu continut emotional bogat !
“Sleep to Remember !”