Neurobiology of sleep
disorders
Zuzana Lattová
An intro to sleep: what is sleep?
Sleep: definition
A natural periodic reversible state of rest, in which
the consciousness is completely or partially lost, so
that there is a decrease in bodily movement and
responsiveness to external stimuli. During sleep the
brain in humans and other mammals undergoes a
characteristic cycle of brain-wave activity that
includes intervals of dreaming.
Another definition…
Salvator Dali: Sleep 1937
Sleep medicine
• is a medical (sub)specialty devoted to the diagnosis and
therapy of sleep disturbances/disorders
• Multidiciplinary approach: neurology, psychiatry,
pulmonary medicine, ENT, pediatrics
What’s normal sleep?
Adults usually need 7-8 hours per night
Adolescents need more, up to 10 hours per night
There are 4-5 awakenings per night
There are 10-15 brief arousals per hour
There are at least 4 cycles of REM sleep
Our ability to sleep changes across the life span
Epidemiology
Sleep: facts I.
Hrs per night
Sleep Duration Time Trends in US Adults
10,0
9,0
8,0
7,0
6,0
5,0
4,0
3,0
2,0
1,0
0,0
9,0
7,5
6,8
1910
1975
2005
Year
National Sleep Foundation. Sleep in America Poll
Sleep: facts II.
Average sleep duration of British Adults
Groeger JA et al. J Sleep Res. 2004; 13:359-71
Sleep duration is decreasing…
Association / Consequences
Sleep: facts III.
The U-Shaped Association between Sleep Duration and
Total Mortality
Kripke DF et al. Arch Gen Psychiatry 2002;59:131-136
28,0
26,9
27,0
26,0
BMI in US adults
25,2
25,0
24,0
23,0
23,0
22,0
21,0
1910
Sleep duration
in US adults
10,0
9,0
8,0
7,0
6,0
5,0
4,0
3,0
2,0
1,0
0,0
1975
2005
9,0
7,5
6,8
1910
1975
2005
Sleep duration and obesity in children
Overweight
Obese
16
14
12
10
% 8
6
4
2
0
<=10h
10.5-11h
=>11.5h
Duration of sleep
von Kries R et al. Int J Obesity 2002;26:710-6
Leptin
plays a key role in regulating
energy
intake
and
energy
expenditure, including appetite. It is
one of the most important adipose
derived hormones.
Ghrelin
counterpart of the hormone leptin,
stimulates hunger
Sleep Duration and Risk of Diabetes
6
Relative Risk
5
4
3
2
1
0
<=5
6
7
Hours of Sleep
The Massachusetts Male Aging Study
8
>8
Anatomy of wakefullness and
sleep
Reticular Activating
System
• Thalamocortical pathway
(Yellow)
• Activates thalamic relay
neurons, crucial for
transmission of information
to cerebral cortex
Active in
wakefullness
and REM
sleep
• 2 acetylcholine cell groups
– Pedunculo-pontine and
laterodorsal tegmental
nucleii (PPT, LDT)
– Major source of input to
thalamic relay nuclei and
reticular nucleus of the
thalamus
Gate control mechanims
– adequate flow of
excitation necessary for
wakefullness
•
Reticular Activating
System
Extrathalamic pathway
(Red)
• Activate neurons in basal
forebrain and lateral
hypothalamic area (medial
forebrain bundle)
• Originates from
monoaminergic neurons in
upper brainstem including;
– Noradrenergic locus
ceruleus (LC)
– Serotonergic dorsal and
median raphe
– Dopaminergic
periaqueductal grey
matter
– Histaminergic
tuberomamillary neurons
Active in
wakefullness,
NREM ↓,
REM 0
•
Reticular Activating
Extrathalamic pathway
System
(Red)
• Monoaminergic Neurons
– Norepinephrine,
Serotonin, Dopamine,
Histamine
• Input to cortex also
augmented by Lateral
hypothalamic (LHA)
neurons
• Melanin concentrating
hormone
• Hypocretin / Orexin
most active during
wakefulness
• Basal forebrain neurons,
including cholinergic and
GABA neurons
VentroLateral Preoptic Nucleus
(Hypothalamus)
VentroLateral Preoptic
Nucleus (Hypothalamus)
• VLPO neurons particularly active during NREM sleep, and
project inhibitory neurotransmitter GABA, and Galanin.
• VLPO damage inhibits sleep
• VLPO Cluster
More heavily innervates histaminergic neurons, closely
linked to transitions b/w arousal and wakefulness
• VLPO Extended
is main output to the LC and DR, damage to extended
VLPO inhibits REM sleep more specifically
The Flip Flop Switch
• Flip Flop circuits avoid transitional states because
when either side begins to overcome the other, the
switch flips into alternative state.
• Explains why sleep wake transitions are abrupt
Monoamine nuclei inhibit VLPO = inhibit suppression of
monoamine nuclei, hypocretin, cholinergic PPT, LDT
neurons
hypocretin reinforces monoaminergic tone (no hypocretin
receptors on VLPO)
In sleep, firing of VLPO inhibits monoaminergic cell groups,
relieving its own inhibition. (enhancing its own activity)
VLPO then inhibits hypocretin
hypocretin, in both cases, believed to stabilize this unstable
switch
The Sleep “Switch”
Orexin neurons in the lateral hypothalamic area innervate all of the components of
the ascending arousal system, as well as the cerebral cortex (CTX) itself.
Saper, CB., et.al. Trends in Neuroscience. Vol 24. No 12. Dec 2001
Regulation of sleep:
Two Process Model
Circadian
rhythm
Sleep
pressure
Process S
ADENOSINE
Interleukins
DSIP
“Sleep Load”
Wake
GHRH
PgD2
Serotonin
Sleep
9AM
3PM
9PM
3AM
From Aldrich, M. S. Sleep Medicine. Oxford University Press 1999
9AM
How to measure and examine
sleep
• The brain has 3 major states of activity and function.
• These states can be recorded by the EEG:
•
1. Wakefulness:
Facilitated by Ascending Reticular Activating System
(ARAS) & Posterior Hypothalamus
EEG demonstrates low voltage fast activity of mixed
alpha
(8-13 Hz) & beta (>13 Hz) frequencies.
•
2. Non Rapid Eye Movement Sleep (N-REM
Sleep)
•
3. Raid Eye Movement Sleep (REM Sleep)
EEG frequencies
• Alpha activity:
• Between 7.5 and 13 Hz
• It is the major rhythm seen in normal relaxed adults
with closed eyes.
• Present during most of life, beyond age 13 year
• Strongest over the occipital cortex.
•
•
•
•
Beta activity:
Has a frequency of 14 Hz and greater
Most evident frontally.
Dominant rhythm in those who are alert or anxious or
who have their eyes open and are listening and
thinking
EEG frequencies
• Theta activity:
• Has a frequency of 3.5 to 7.5 Hz and is classed as
"slow" activity.
• It reflects the state between wakefulness and sleep.
• It is abnormal in awake adults but normal in children up
to 13 years old.
•
•
•
•
Delta activity:
The lowest frequencies (less than 3.5 Hz).
Occur in deep sleep (stages 3 and 4 of sleep)
It is the dominant rhythm in infants up to one year of
age.
EEG frequencies
Sleep assessment:
Polysomnography
•EEG
•EOG
•EMG mm.mentales
•ECG
•Nasal and oral airflow (termistor)
•Respiratory effort (chest, abdomen)
•Breathing sounds (microphone)
•Peripheral pulse oxymetry
•EMG mm. tibiali anteriores
•Position
•Videomonitoring
Polysomnography
Sleep stages
• Relaxed wakefullness
• „alpha waves”
• eyes moving spontaneously in
a slow rolling eye movement
• heart and respiratory rates
vary depending on the
individual
• the individual has spontaneous
movements (i.e. changing
positions to become
comfortable)
Sleep stages – NREM sleep
•
•
•
•
Stage I:
EEG demonstrates “theta activity” (4-7 Hz)
EMG demonstrates decreased tonic activity
Slow rolling of eyes
• Stage II:
• EEG demonstrates “theta activity” + “sleep spindles” (brief
bursts of 12-14 Hz) + “K complexes“ (high amplitude,
slow frequency,electronegative wave followed by
electropositive wave)
• Decreased muscle tone
• Rare eye movement
Sleep stages – NREM sleep
•
•
•
•
Stages III & IV (slow wave sleep, SWS):
Deepest stages of sleep
Occurs mainly in the first sleep cycles
Epochs of sleep consisting of greater than 20%
(50%) of “delta wave activity” (0.5-3.0), high voltage
slow waves
• Atonia
• No eye movements
Sleep stages – REM sleep
• Brain electrically & metabolically activated, cerebral blood flow
(CBF) increased, desynchronised EEG acitivity
• Rapid eye movements
• Generalized muscle atonia
• Irregular heart- and respiratory rate
• Associated with psychical activities → dreaming
• Penile and clitoral engorgement
Hypnogram
Carskadon & Rechtschaffen 2005
Actigraphy
• monitoring human rest/activity cycles (not sleep!)
• movements are measured by a piezoelectric
accelerometer with a low pass filter which filters out
everything except the 2–3 Hz band, thereby
ensuring external vibrations are ignored
• non dominant hand or leg, for a number of days
Normal sleeper
Insomniac
Free running rhythm
Sleep questionaires
Epworth sleep questionnaire
• self-administered questionnaire with 8 questions
• used to determine the general level of daytime
sleepiness over a longer period of time
• usual chances of dozing off or falling asleep in 8
different situations
• world standard method, but not a diagnostic tool
• CAVE: sleepiness ≠ tiredness
Pitsburgh Sleep Quality Index
• self-rated questionnaire
• used to measure the quality and patterns of
sleep in adults
• it differentiates “poor” from “good” sleep by
measuring seven areas: subjective sleep quality,
sleep latency, sleep duration, habitual sleep
efficiency, sleep disturbances, use of sleeping
medication, and daytime dysfunction over the
last month
Sleep disordes
Insomnia - definition
Subjective complaint of difficulty falling asleep,
difficulty staying asleep, early morning awaking,
poor quality sleep, or inadequate sleep despite
adequate opportunity accompanied by clinically
significant impairment in daytime functioning
Sleep patterns in insomnia
• Sleep onset insomnia
– Difficulty falling asleep
– Longer time to sleep onset
• Sleep maintenance insomnia
– Difficulty staying asleep
– Frequent nocturnal awakenings
• Sleep offset insomnia
– Waking too early in the morning
• Nonrestorative sleep
– Fatigue despite adequate sleep duration
DSM-IV-TR. 4th ed. 2000:597-661
Czeisler CA et al. Harrison’s Principles of Internal Medicine” 15 th ed. 2001: 155-163
Types of insomnia
Acute = adjustment
insomnia
Chronic insomnia
Secondary
Secondar
Psychophysiologic
Idiopathic
Paradoxical =
Sleep misperception
due to a medical
condition
due to a psychiatric
disorder
due to medication
Causes of secondary insomnia
Evidence of Hyperarousal in
Primary Insomnia
• Increased global cerebral glucose metabolism
on PET
• During sleep, EEG shows decreased Theta &
Delta wave activity, increased Beta activity
• Increased 24-hour metabolic rate and heart rate
• Higher levels of secretion of both
Adrenocorticotropin & Cortisol
• Body temperature slighty higher
Epidemiology of insomnia
• 30-50% of American adults experience insomnia
during a 1 year period
• Prevalence of chronic/severe insomnia is 10%
• 49% of adults surveyed were dissatisfied with
their sleep > 5 nights per month
• 50% of patients presenting to primary care
physicians experience insomnia
Model of
psychophysiological insomnia
• Dysfunctional Cognition
– Worry over sleep loss
– Rumination over
consequences
– Unrealistic expectations
– Misattributions/
amplifications
• Arousal
– Emotional
– Cognitive
– Physiologic
• Consequences
–
–
–
–
Mood Disturbances
Fatigue
Performance impairments
Social discomfort
• Maladaptive Habits
–
–
–
–
Excessive time in bed
Irregular sleep schedule
Daytime napping
Sleep-incompatible
activities
Pharmacological treatment
•
•
–
–
–
–
Alcohol
Plant preparations
Chloral hydrate
Barbiturates
– Nonbenzodiazepine
hypnotics (Z – drugs)
– Benzodiazepine hypnotics
– Selective melatonin
receptor agonist
– Sedative antidepressants
– Sedative antipsychotics
– Antihistamines
GABA A receptor
CBT treatment
• Sleep hygiene education
– Specific behaviors will directly interfere with
the ability to sleep → can be changed with
education
• Sleep restriction therapy
– Increased propensity to sleep by increasing
homeostatic sleep drive with partial sleep
deprivation
– Systematic reduction of time in bed to the
amount of total sleep time from sleep log data
• Cut bedtime to the actual amount of time you
spend asleep (not in bed), but no less than 4
hours per night
• No additional sleep is allowed outside these hours
• Record on your daily sleep log the actual amount
of sleep obtained
• Compute sleep efficiency (total time asleep
divided by total time in bed)
• Based on average of 5 nights’ sleep efficiency,
increase sleep time by 15 minutes if efficiency is
>85%
• Stimulus control therapy
– Assumes that there is a learned associated between
wakefulness and the bedroom
– To break the cycle, the patient must not spend time
wide awake in the bedroom
– Go to bed only when sleepy
– Do not use the bedroom for sleep-incompatible
activities
– Leave the bedroom if awake for more than 20
minutes
– Return to bed only when sleepy
– Do not nap during the day
– Arise at the same time every morning
• Relaxation training
• Cognitive training - domains that contribute to
insomnia:
– Worry and rumination
– Attentional bias and monitoring for sleep-related
threat
– Unhelpful beliefs about sleep
– Misperception of sleep and daytime deficits
– The use of safety behaviors that maintain unhelpful
beliefs
Obstructive sleep apnea
• Sleep apnea is the intermittent cessation of
airflow at the nose and mouth during sleep
• Recurrent episodes of narrowing or collapse of
pharyngeal airway during sleep despite ongoing
breathing efforts (thorax, abdomen)
• These lead to
– Abrupt reductions in blood oxygen saturation (with
oxygen levels falling as much as 40 percent or more
in severe cases)
– Surges of sympathetic activation
– Periodic arousal from sleep (fragmented sleep)
Symptoms of
Obstructive Sleep Apnea
•
•
•
•
•
•
•
•
•
Loud snoring
Excessive Daytime Sleepiness (Hypersomnolence)
Problems with memory, concentration, attenttion
Personality changes - irritability
Impotence
Headaches upon waking
Nocturia
Sweating
GERD
Associated disorders
 Hypothyroidism
 Acromegaly
 Marfan’s Syndrome
 Amyloidosis
 Craniofacial syndromes
 Myotonic Dystrophy
PATENT Vs COLLAPSED AIRWAY
Apnea patterns
Obstructive
Mixed
Central
Airflow
Respiratory
effort
Apnea – complete cessation of breathing for at least 10s
Hypopnoe – 25-50% cessation of breathing for at least 10s associated with
desaturation
Obstructive apnea
EEG
Arousal
Airflow
Effort
(Rib Cage)
Effort
(Abdomen)
Effort
(Pes)
SaO2
10 sec
Severity of OSA
Normal
AHI <5
Mild
AHI 5-14
Moderate
AHI 15-30
Severe
AHI >30
Description of Sleep Apnea Event
•


•
•
•
•
Upper airway obstruction
Intermittent obstruction: snoring
Complete obstruction:
Alveolar hypoventilation
Decreased alveolar PO2 ; increased alveolar PCO2
Decreased arterial PO2 ; increased arterial PCO2
Stimulation of arterial chemoreceptors; central
chemoreceptors
• Arousal
Why Obstruction Occurs During Sleep
• Altered body position (supine position)
• Control of breathing during NREM sleep – depression of
respiratory drive
Minute volume decreases about 16%
PaCO2 increases 4-6 mmHg
SaO2 decreases as much as 2%
• Decreased tone of pharyngeal muscles
• Depressed reflexes, including pharyngeal dilator
• Depressed response to hypoxia
• REM sleep decreases tone of intercostal and accessory
muscles, less effect on diaphragm; depression of minute
volume, increase in CO2 not as great, depression of
response to hypoxia greater
Consequences ….
Prevalence of OSA
N=3513 questionnaires (1843F, 1670M)
602 underwent PSG (250F, 352M), Age 30-60 year
Percent
25
20
AHI>5+EDS
AHI>5
24
15
10
5
0
9
2
Female
4
Male
N Engl J Med,Young et al,1993;17:1230-35
Treatment possibilies
• Weight loss - highly effective method
10 – 15 % reduction in weight can lead to an
approximately 50 % reduction in sleep apnea
severity in moderately obese male patients
• Avoid supine sleep position
• Orthodontic procedures
• Surgery – uvulopalatopharyngoplasty (UPPP)
• CPAP
UPPP
Positive airway pressure
2006 American Academy of Sleep Medicine
Restless legs syndrome
• An urge to move the legs, usually accompanied or
caused by uncomfortable and unpleasant sensations
in the legs
• The urge to move or unpleasant sensations begin or
worsen during periods of rest or inactivity such as
lying or sitting
• The urge to move or unpleasant sensations are
partially or totally relieved by movement
• The urge to move or unpleasant sensations are
worse in the evening or night than during the day or
only occur in the evening or night
Allen, RA. 2003.
• Two types: idiopathic and secondary
– Idiopathic, more prevalent, found in younger patients
and felt to be familial
– Secondary due to Fe deficiency, pregnancy, renal
failure, poor gut Fe absorption (surgery)
• Seen at any age, but in young children uncommon
• Once have symptoms, they persist
Differential Diagnosis
•
•
•
•
•
•
•
•
Neuropathic pain syndromes
Peripheral neuropathy
Arthritis
Nocturnal leg cramps
Restless insomnia
Painful legs and moving toes
Vascular insufficiencies
Drug-induced akathisia
Pharmacologic Treatment
• Intermittent RLS symptoms
– Medications that can be taken as needed
– Levodopa with decarboxylase inhibitor
(carbidopa or benserazide)
– Mild- to moderate-strength opioid (codeine,
propoxyphene, tramadol, hydrocodone,
oxycodone)
– Sedative-hypnotics
– Dopamine agonist: low dose, if tolerated
Hering, WA. 2007. ; RLS Foundation
• Daily RLS symptoms
– Dopamine agonists: ropinirole, pramipexole
– Anticonvulsants: gabapentin
– Opioids: tramadol, oxycodone, hydrocodone,
extended-release forms
– Benzodiazepines: clonazepam
– Iron supplementation
Periodic Limb Movement disorder
EOG
EEG1
EEG2
EEG3
EEG4
EMG Chin
Arousals following limb
movements
Arousals following limb movements
Airflow
Resp Effort
EMGLimb
Legmovements
Limb Movements