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.

Salvator Dali: Sleep 1937

Another definition…

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.

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0,01,02,03,04,05,06,07,08,09,0

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Sleep Duration Time Trends in US AdultsH

rs p

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ight

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

Kripke DF et al. Arch Gen Psychiatry 2002;59:131-136

Sleep: facts III.

The U-Shaped Association between Sleep Duration and The U-Shaped Association between Sleep Duration and Total MortalityTotal Mortality

7,56,8

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25,2

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23,0

24,0

25,0

26,0

27,0

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1910 1975 2005

Sleep duration in US adults

BMI in US adults

02468

10121416

<=10h 10.5-11h =>11.5h

Duration of sleep

Overweight Obese

%

Sleep duration and obesity in children Sleep duration and obesity in children

von Kries R et al. Int J Obesity 2002;26:710-6

Leptinplays a key role in regulating energy intake and energy expenditure, including appetite. It is one of the most important adipose derived hormones.

Ghrelincounterpart of the hormone leptin,

stimulates hunger

0

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2

3

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<=5 6 7 8 >8Hours of Sleep

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Sleep Duration and Risk of Diabetes

The Massachusetts Male Aging Study

Anatomy of wakefullness and sleep

Reticular Activating System

• Thalamocortical pathway (Yellow)

• Activates thalamic relay neurons, crucial for transmission of information to cerebral cortex

• 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

Active in wakefullness and REM sleep

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 System• Extrathalamic pathway (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 inhibit VLPO = inhibit suppression of monoamine nucleimonoamine nuclei, , hypocretin, cholinergic PPT, LDT hypocretin, cholinergic PPT, LDT neurons neurons hypocretin reinforces monoaminergic tone (no hypocretin hypocretin reinforces monoaminergic tone (no hypocretin receptors on VLPO)receptors on VLPO)

In sleep, firing of VLPO inhibits monoaminergic cell groups, In sleep, firing of VLPO inhibits monoaminergic cell groups, relieving its own inhibition. (enhancing its own activity) relieving its own inhibition. (enhancing its own activity) VLPO then inhibits hypocretinVLPO then inhibits hypocretinhypocretin, in both cases, believed to stabilize this unstable hypocretin, in both cases, believed to stabilize this unstable switchswitch

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

The Sleep “Switch”

Regulation of sleep: Two Process Model

Circadian rhythm

Sleep pressure

Process S

9AM 3PM 9PM 3AM 9AM

“Sleep Load”

Sleep

Wake

Interleukins

DSIP

GHRH

PgD2

Serotonin

ADENOSINE

From Aldrich, M. S. Sleep Medicine. Oxford University Press 1999

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 HypothalamusEEG 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

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

Insomnia - definition

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. 2000:597-661Czeisler CA et al. Harrison’s Principles of Internal Medicine” 15th ed. 2001: 155-163

Acute = adjustment insomnia

Chronic insomnia

SecondarSecondary due to a medical condition

due to a psychiatric disorder

due to medication

Paradoxical = Sleep misperception

Psychophysiologic

Idiopathic

Types of insomnia

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

• – Alcohol– Plant preparations– Chloral hydrate– Barbiturates

• – Nonbenzodiazepine

hypnotics (Z – drugs)– Benzodiazepine hypnotics– Selective melatonin

receptor agonist– Sedative antidepressants– Sedative antipsychotics– Antihistamines

Pharmacological treatment

GABA A receptor

• 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

CBT treatment

• 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

Hypothyroidism

Acromegaly

Marfan’s Syndrome

Amyloidosis

Craniofacial syndromes

Myotonic Dystrophy

Associated disorders

PATENT Vs COLLAPSED AIRWAY

ObstructiveObstructive MixedMixed CentralCentral

Airflow

Respiratoryeffort

Apnea patterns

Apnea – complete cessation of breathing for at least 10s

Hypopnoe – 25-50% cessation of breathing for at least 10s associated with desaturation

EEG

10 sec

Arousal

Airflow

Effort(Pes)

SaO2

Effort(Abdomen)

Effort(Rib Cage)

Obstructive apnea

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 driveMinute 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

9

24

2 40

5

10

15

20

25

Female Male

AHI>5+EDS

AHI>5

N=3513 questionnaires (1843F, 1670M)

602 underwent PSG (250F, 352M), Age 30-60 year

Percen

t

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

2006 American Academy of Sleep Medicine

Positive airway pressure

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

Arousals following limb movements

Limb movements

Periodic Limb Movement disorder

EEG1EOG

EMG Chin

Airflow

Resp Effort

EMG Leg

EEG2EEG3EEG4

Arousals following limb movements

Limb Movements