BRAIN ACTIVATION AND

SLEEP PHYSIOLOGY
DEBBIE C. LIQUETE, MD, FPNA
MARCH 22, 2016
OBJECTIVES

DEFINITION
IMPORTANCE OF SLEEP
BRAIN ACTIVATION
NEURAL CORRELATE (RF, NEUROTRANSMITTERS)
SLEEP STAGES AND EEG
SLEEP DISORDERS
SLEEP

A state of sustained immobility or quiescence in a

characteristic posture accompanied by reduced
responsiveness to external stimuli and a rapid return to
waking with moderate stimulation
 IMPORTANCE OF SLEEP

SLEEP DEPRIVATION CAUSES :

Impaired concentration,
Impaired memory
Impaired physical performance
Reduced ability to do calculations
Impaired decision making and judgment
Hallucinations, mood swings
Health problems (heart disease, diabetes,
obesity, stroke)
Rats deprived of REM sleep survive only 5 weeks on
average while normal rats live for 2-3 years
 SLEEP DEPRIVATION

CHALLENGER EXPLOSION

CHERNOBYL ACCIDENT

THREE MILE ISLAND

SLEEP IN ANIMALS
SLEEP IN ANIMALS
CONSCIOUSNESS SYSTEM

CONTROL OF THE LEVEL OF CONSCIOUSNESS INVOLVES 3 PROCESSES :

1. ALERTNESS - functioning of the brainstem and diencephalic arousal
circuits and the cortex

2. ATTENTION - same circuits, together with additional processing in

frontoparietal association cortex and other systems

3. AWARENESS - combines various higher-order forms of sensory, motor,

emotional, and mnemonic information from disparate regions of the
brain into a unified and efficient summary of mental activity
 1918
Viennese neurologist, Constantin von Economo
State of lethargy or coma before dying;
Sleeplessness before dying

LESIONS IN POST. HYPOTHALAMAUS OR UPPER

MIDBRAIN comatose before death (wakefulness
center)

LESIONS IN PREOPTIC AREA OF THE ANT

HYPOTHALAMUS sleeplessness before death (SLEEP
CENTER)

LESIONS IN BRAINSTEM deep sleep or coma

 1949 Giuseppe Moruzzi and Horace
Magoun
COMA : Used coaguation to destroy the
Reticular formation
Stimulating the RF awaken animals
from normal sleep
ASCENDING ACTIVATING RETICULAR
SYSTEM Wakefulness Center
Stimulating the Thalamus causes sleep
WHAT MAINTAINS ALERTNESS?

MULTIPLE parallel systems in the UPPER

BRAINSTEM, DIENCEPHALON and BASAL
FOREBRAIN

1. Upper brainstem NE, 5HT, Dopa, Ach

2. Pontomesencephalic Reticular formation

Glutamate

3. Posterior Hypothalamus Histamine, Orexin

4. Basal Forebrain Ach

5. Intralaminar thalamic nuclei/Medial

thalamic nuclei - Glutamate
WHAT ACTIVATES ALERTNESS?

INPUTS TO THE RETICULAR

FORMATION

1. Sensory pathways Anterolateral

system, Spinoreticular
2. Association cortex
3. Limbic cortex
4. Thalamus
5. Posterior hypothalamus
ACETYLCHOLINE

PNS major efferent neurotansmitter, NMJ,

preganglionic autonomic synapses
CNS more limited role
NEUROMODULATION

TWO LOCATIONS :
1. Pontomesencephalic region of the
brainstem
2. Basal forebrain

NEURONS OF THE CHOLINERGIC SYSTEM

1. Pedunculopontine tegmental nuclei
2. Laterodorsal tegmental nuclei
ACETYLCHOLINE

Cholinergic inputs project to the thalamus

then to widespread regions of the cortex
1. NUCELUS BASALIS OF MEYNERT projects
to entire cortex
2. MEDIAL SEPTAL NUCLEI projects to
hippocampal formation
3. NUCLEUS OF THE DIAGONAL BAND -
projects to hippocampal formation
MAIN FUNCTIONS :
ATTENTION, MEMORY, LEARNING
EX. Alzheimers disease
 DOPAMINE

1. NIGROSTRIATAL PATHWAY Snc projects

to striatum
Ex. Parkinsons Disease

2. MESOLIMBIC PATHWAY VTA projects to

limbic structures
Ex. Addiction, Schizophrenia
(Positive Sxs)

3. MESOCORTICAL PATHWAY VTA projects

to the prefrontal cortex
Ex. Working memory, Cognitive
deficits, Schizophrenia
(Negative Sxs)

MAIN SOURCE Substancia nigra pars compacta (SNc) and Ventral tegmental area (VTA)
NOREPINEPHRINE

SOURCE : Locus ceruleus, Lateral

tegmental area

PROJECTS to entire forebrain

EXCITATORY to the thalamus

INCREASES during wakefulness
DECREASED during sleep

FUNCTIONS:
Modulation of attention, Sleep wake
states, Mood and pain, sympathetic
function, BP control

* ADHD, MDD, GAD, OCD

SEROTONIN

SOURCE : Raphe nuclei of midbrain, pons &

medulla

INCREASES during wakefulness

DECREASES during sleep

1. ROSTRAL raphe nuclei - PROJECTS to

entire forebrain, cortex, thalamus, Basal
ganglia
Ex. MDD, GAD, OCD, Eating disorder

2. CAUDAL raphe nuclei PROJECTS to

cerebellum, medulla & Sp. Cord
Ex. Pain modulation, breathing, temp
HISTAMINE

SOURCE : TUBEROMAMILLARY NUCLEUS in

the Posterior Hypothalamus

PROJECTS to the forebrain

EXCITATORY to THALAMUS
EXCITATORY and INHIBITORY to cortical
neurons

IMPORTANT in maintaining the ALERT state

OTHER PROJECTING SYSTEMS

PEPTIDES and small-molecule neurotransmitters

ADENOSINE important in ALERTNESS

- INHIBITORY to thalamus & cortex
- INCREASES before onset of sleep
- * Caffeine blocks adenosine receptors

OREXIN (Hypocretin) - produced in neurons of

the posterior lateral hypothalamus
- Promotes the AWAKE state
- Projects to brainstem arousal systems &
cortex
ENCEPHALITIS LETHARGICA (VON ECONOMO DISEASE)

1917; Constantin Von Economo

Atypical for of encephalitis Sleepy sickness
Speechless, motionless, Sleep for long periods sometimes leading to death
PATHOLOGY : Damage in the posterior hypothalamus
Recently, Orexins (Hypocretins) were found to be crucial for wakefulness

Awakenings 1990 film which depicted Oliver Sacks work

with Encephalitis Lethargica patients
WIDESPREAD PROJECTION SYSTEMS IN THE NERVOUS SYSTEM
SLEEP PHYSIOLOGY

PHYSIOLOGICAL MEASURES
Electroencephalogram (EEG)
brain waves from scalp surface
Electrooculogram (EOG)
eye movements
Electromyogram (EMG)
muscle tone
 ELECTROENCEPHALOGRAM

Alpha activity:
A smooth electrical activity of 8 12 Hz recorded
from the brain
associated with a state of relaxation

Beta activity:
Irregular electrical activity of 13 30 Hz recorded
from the brain;
associated with a state of arousal, increased
concentration
 ELECTROENCEPHALOGRAM

Theta activity:
EEG activity of 3.5 7.5 Hz that occurs
intermittently
Seenin drowsiness and early stages of NREM &
REM sleep

Delta activity:
Regular,synchronous electrical activity of less than
4 Hz recorded from the brain
Seenduring the deepest stages of slow-wave
sleep.
 ELECTROENCEPHALOGRAM

REM sleep
Appears at 90 minutes (80-110 minutes)
Muscle tone decreases, Rapid eye movements
appear, Irregular respiration, loss of temp control,
penile erection
EEG resembles stage 1 sleep or transition from
wakefulness to stage 1 sleep
EEG : low voltage theta & alpha activity
No slow waves or sleep spindles
Absence of tonic muscle artifacts, REM seen at F7,
F8 electrode, increased random muscle twitches
SLEEP STAGES

1. NREM SLEEP - 80% of the night

A. Stage 1 theta activity 1-7 minutes (2-5%)
B. Stage 2 theta + sleep spindles, K complexes
10-25 minutes (45-55%)
C. Stage 3 delta activity > 25%
2-10 minutes (3-8%)
D. Stage 4 delta activity > 50%
20-40 minutes (10-15%)
Stage 3 and 4 SWS (Slow wave sleep)

2. REM SLEEP 20% of the night 1-5 minutes

Desynchronized (low voltage mixed frequency)
brain wave activity with muscle atonia & rapid eye
movements
STAGE EEG EYE MOVEMENT EMG

WAKEFULNESS Alpha waves Varied, fast High

NREM Theta waves Slow rolling eye Slightly lowered

1 (Drowsiness) movements

2 Theta waves, None Lowered

Sleep spindles, K
complexes

3 < 25% delta waves None Low

4 >50% delta waves None Low

REM Low voltage Rapid, jerky, Absent

mixed frequency lateral
PHYSIOLOGICAL CHANGES DURING NREM
AND REM
PHYSIOLOGICAL CHANGES DURING NREM
AND REM
NREM SLEEP

GABAergic neurons in the Ventrolateral Preoptic

area (VLPO) of the anterior hypothalamus send
INHIBITORY projections to Histaminergic&
Orexinergic neurons in the Posterior
Hypothalamus as well as brainstem arousal systems
(5HT, NE, Dopamine, Ach)

GALANIN contributes to the inhibitory pathway

together with GABA

VLPO promotes NREM sleep by inhibiting

Ascending activating systems that project to the
forebrain
REM SLEEP

REM on cells in the Pontine RF

1. GABAergic REM on cells (with GABAergic in

the VLPO) INHIBIT Norepinephrine and
Serotonin release

NE & 5HT reduced firing during NREM sleep

SILENT during REM sleep

SILENCE removes inhibition from Cholinergic

neurons resulting in Increased Ach to thalamus
Resembles AWAKE state

Produce PGO waves induces visual imagery

of dreams & REMs
REM SLEEP

REM on cells in the Pontine RF

2. GLUTAMATergic REM on cells activate

circuits involving GLYCINE IN THE MEDULLA &
SPINAL CORD
Lower motor neurons are inhibited causing
decreased muscle tone

Decreased tonic muscle activity

Phasic movements limbs & eye movts
* REM sleep behavioral disorder
REM SLEEP

PGO (Ponto-geniculo-
occipital)waves phasic electrical
activity in the pons followed by
activity in the lateral geniculate
nucleus & visual cortex

Desynchronized (low voltage mixed

frequency) brain wave activity
Decreased tonic muscle activity
Phasic movements
CIRCADIAN RHYTHM THE 24 HOUR CLOCK

Daily rhythms in physiology & behavior

Control sleep wake cycle, Modulate
physical activity & Food consumption,
regulate body temp, heart rate, muscle
tone
Generated by neural structures in the
hypothalamus that function as a
biological clock
Clock genes
Clock & Bmal1
SUPRACHIASMATIC NUCLEUS

SCN on sleep relays through dorsomedial

nucleus of the hypothalamus w/c signals Sleep-
wake systems

SCN to pineal gland secretes melatonin

(secreted at night & consolidates circadian
rhythms)

*Located in the hypothalamus, above the optic chiasm

*Regulates circadian rhythms
*Generates many body functions in a 24 hr cycle

*Receives direct input from photoreceptors w/c reset the

clock genes on a daily basis
 SLEEP DISORDERS

1. DYSSOMNIAS Characterized by HYPERSOMNIA or

INSOMNIA

INSOMNIA can be primary or 2 to another disorder

(Mood, Medical condition)
PRIMARY HYPERSOMNIA central origin
NARCOLEPSY
IDIOPATHIC HYPERSOMNIA
RECURRENT HYPERSOMNIA Kleine Levin syndrome
POSTTRAUMATIC HYPERSOMNIA
MENSTRUAL RELATED HYPERSOMNIA
 SLEEP DISORDERS

2. SLEEP DISORDERED BREATHING

SLEEP APNEA pauses in breathing or shallow breathing during sleep
SNORING

3. RESTLESS LEG SYNDROME while awake, irresistible urge to

move ones body to stop uncomfortable sensations

4. PERIODIC LIMB MOVEMENT DISORDER aka Nocturnal

myoclonus ;
Occurs during sleep where limbs move involuntarily during sleep
 SLEEP DISORDERS

5. CIRCADIAN RHYTHM SLEEP DISORDERS

ADVANCED SLEEP PHASE DISORDER - characterized by difficulty staying
awake in the evening and difficulty staying asleep in the morning

DELAYED SLEEP PHASE DISORDER - characterized by a much later than

normal timing of sleep onset and a period of peak alertness in the
middle of the night

NON 24 HOUR SLEEP WAKE DISORDER - Individual sleeps occur later

and later each day, with the period of peak alertness also
continuously moving around the clock from day to day
 SLEEP DISORDERS

6. PARASOMNIAS Sleep disorders that involve abnormal &

unnatural movements, behaviors, emotions, perceptions &
dreams in connection with sleep

SLEEP ENURESIS - bedwetting

BRUXISM repetitive clenching or grinding of teeth
CATATHRENIA nocturnal groaning; end inspiratory apnea &
expiratory groaning
EXPLODING HEAD SYNDROME - waking up in the night hearing
loud noises
SLEEP PARALYSIS temporary inability to move, speak or react
(Hypnagogic/Hypnopompic)
 SLEEP DISORDERS

6. PARASOMNIAS Sleep disorders that involve abnormal &

unnatural movements, behaviors, emotions, perceptions &
dreams in connection with sleep

SLEEP ENURESIS - bedwetting

BRUXISM repetitive clenching or grinding of teeth
CATATHRENIA nocturnal groaning; end inspiratory apnea &
expiratory groaning
EXPLODING HEAD SYNDROME - waking up in the night hearing
loud noises
SLEEP PARALYSIS temporary inability to move, speak or react
(Hypnagogic/Hypnopompic)
 SLEEP DISORDERS

6. PARASOMNIAS
SLEEP TERROR/ PAVOR NOCTURNUS sudden arousal from SWS
(Stage 3 or 4) accompanied by intense fear
MC : 3-12 y/o; 20-30 y/o
REM SLEEP BEHAVIOR DISORDER Loss of motor inhibition during
REM sleep (Acts out their dreams, can be violent in nature)
SLEEP WALKING/ SOMNAMBULISM arise from SWS (Stage 3 or 4) &
Pxs perform activities usually performed during full consciousness
SLEEP TALKING/SOMNILOQUY arise from SWS (occasionally REM
sleep) & Pxs talk aloud while asleep
SLEEP SEX/ SEXSOMNIA - condition in which a person will engage in
sexual activities while asleep
 SLEEP DISORDERS

6. PARASOMNIAS
SLEEP TERROR/ PAVOR NOCTURNUS sudden arousal from SWS
(Stage 3 or 4) accompanied by intense fear
MC : 3-12 y/o; 20-30 y/o
REM SLEEP BEHAVIOR DISORDER Loss of motor inhibition during
REM sleep (Acts out their dreams, can be violent in nature)
SLEEP WALKING/ SOMNAMBULISM arise from SWS (Stage 3 or 4)
& Pxs perform activities usually performed during full
consciousness
SLEEP TALKING/SOMNILOQUY arise from SWS (occasionally REM
sleep) & Pxs talk aloud while asleep
SLEEP SEX/ SEXSOMNIA - condition in which a person will engage
in sexual activities while asleep
SLEEP HYGIENE

1. Avoid napping during the day

2. Avoid stimulants such as caffeine, nicotine &
alcohol too close to bedtime
3. Exercise can promote good sleep
4. Food can be disruptive right before sleep
5. Ensure adequate exposure to natural light
6. Establish a regular relaxing bedtime routine
7. Associate your bed with sleep