Disorders of sleep and wakefulness

Disorders of Sleep and Wakefulness

Adonis Sfera, MDNeurobiology of sleep and wakefulness

Insomnia and hypnoticsExcessive daytime sleepiness

History of Sleep In Three Slides

“Sleep and His Half-Brother Death" by John William Waterhouse

Current pattern of sleep and wakefulness consists of: 16 hours of wakefulness 8 hours of continuous sleepThis sleep/wakefulness pattern :-Unnatural-Recent in human history (since the industrial revolution/electricity).

From ancient times until approximately 150-200 years ago: 3-4 hours wakefulness 1-2 hoursSiesta 3-4 hours of wakefulness 1-3 hours evening wakefulness 3-4 hours of first sleep 2-3 hours of wakefulness during the night 3-4 hours of second sleep

The Tiv tribe in Nigeria employ the terms "first sleep" and "second sleep" to refer to specific periods of the night.

A. Roger Ekirch; At Day’s Close- Night in Times Past; W. W. Norton & Company, 2005

We humans don’t sleep the way we used to

A study by Dr Thomas Wehr at the National Institute of Mental Health: demonstrated that volonteersdeprived of artificial lighting for several weeks went back to the bimodal sleep pattern.

The typical subject evolved the following pattern: -lying awake in bed for an hour or two, -then four hours sleep, -then 2-3 hours of “non-anxious wakefulness” -a second sleep -waking for the day’s activities.

The majority of physicians fail to acknowledge that a

consolidated eight-hour sleep may be unnatural.

"And at the wakening of your first sleepe You shall have a hott drinke made, And at the wakening of your next sleepe Your sorrowes will have a slake.“

“Early English Ballad”, Old Robin of Portingale

So the next time you wake up in the middle of the night, think of your pre-industrial ancestors and relax. Lying awake could be good for you.

Modern Insomnia

Sleep and Wakefulness

Mankind has developed in an environment that is exposed to the rotation of the earth around its own axis, which results in daily rhythmic changes in light intensity.

Rhythms of Nature

Organisms responded by evolving cellular clock mechanisms sensitive to light, and by organizing their activities into circadian cycles.

Biological Clocks

Chronobiology is the science of the biological clocks developed by Franz Halberg.

It studies organisms that present with oscillators and organize their activities into 24-hour cycles, such as sleep and wakefulness.

Chronobiology

Quick Reminder of Sleep and Wakefulness

What Keeps Us Awake?

Histamine keeps the brain awake.

HISTAMINE IS PRODUCED IN THE TMN.

Histamine promotes the CALM wakefulness that helps problem solving, creativity and cognition(unlike the monoamines).

Tuberomammilary Nucleus (TMN) of Hypothalamus Is the Wakefulness Promoter (the coffee- house of the brain)

TMN of hypothalamus contains histamine producing neurons that are activated by glutamate and inhibited by GABA.

These neurons make up the wakefulness promoter.

*Lateral hypothalamus contains orexin neurons that promote weight loss in addition to wakefulness.

Ventro-Lateral Preoptic Nucleus of the Hypothalamus(VLPO) - the Sleep Promoter

VLPO nucleus contains GABA neurons that inhibit TMN and thus promote sleep.

The Balance of Sleep and Wakefulness

TMN SCN VLPO

CENTRAL CLOCK: Suprachiasmatic nucleus of the hypothalamus is the switch from wakefulness to sleep.

Light – ONMelatonin - OFF

WAKE PROMOTER: Tuberomammillary nucleus –TMN-of the hypothalamus promotes wakefulness (produces histamine)

SLEEP PROMOTER: Ventrolateral preoptic area –VLPO-of the hypothalamus promotes sleep (produces GABA)

The Central Clock (SCN)

Aside from the Central Clock, there arePeripheral clocks in various tissues

Who Controls the Central Clock?

Exogenous Cues (Zeitgebers) Endogenous Cues (clock controlling genes)-light,

-temperature, -social interactions,-pharmacological manipulation, -exercise, -eating/drinking patterns

-Bmal-Clock-Cryptochrome (Cry)-Period (Per)-Rev-ErbA (REV-ERB)

Clock Controlling Genes (CCG)

POSITIVE REGULATORSCLOCK and BMAL1are transcription factors, (live in the nucleus).

NEGATIVE REGULATORS(live in the cytoplasm):-cryptochrome gene family (CRY1 and CRY2) -period gene family (PER1, PER2, and PER3).

Other CCG:ROR REV-ERB,

Bmal Bipolar disorder

Clock Bipolar d/o, schizophrenia, depression

Cry Depression

Per Bipolar, Depression, Schizophrenia

REV-ERB Bipolar d/o

Disorders Of the Broken Clock

Where Does Melatonin Fit?

Pineal Gland

Pineal Gland Calcification

Quick Reminder of Sleep Architecture

-4-6 sleep cycles per night

-Stage 4, deep sleep, is longer early in the sleep period.

-Stage 5, REM, increases in frequency and length later during the sleep period.

- Stage 5, REM is 20-35% of sleep in adults.

Cortical Activation During REM Sleep

Vandekerckhove, M., & Cluydts, R. (2010). Sleep Medicine Reviews, 14(4), 219-226.

The more primitive brain structures including the thalamus and parts of the limbic system become functional first.

This suggests that a foundational primitive conscious state must be restored before higher order conscious activity can occur.

Primitive consciousness emerges first as you awaken from anesthesia

Know that you do not know! A lot is known about sleep, its pathophysiology, and

treatment, yet what we know scientifically about the dream state is far less than what we thought we knew a generation ago.

The evidence is overwhelming that REM sleep occurs without dreaming and dreaming without REM sleep.

Evidence remains equivocal as to whether any special relationship exists between REM sleep and dreaming.

What Do Physicians Need to Know About Dreams?

Sleep Related Violence

NREM SEIZURES:Nocturnal Frontal Lobe EpilepsyNocturnal Paroxysmal DystoniaEpisodic Nocturnal Wanderings

NREM Slow Wave Sleep REM Behavior DisorderTime Early (first 2 hours of sleep) Late (last few hours of sleep)

Memory of event No Yes

Arousability Difficult Easy

Postevent confusion Yes No

Age Children/Young adults Elderly

Genetic predisposition Likely Unlikely

Comorbidities Usually none Neurodegenerative disorders

Treatment Conservative Benzodiazepines

Behaviors More complicated, eyes open

Simple, eyes closed

Features of NREM vs REM Parasomnias

Polysomnogram

Polysomnography-four channels of EEG-right and left (EOG), -chin and limb (EMG), -EKG, -environmental noise recording (mean noise).

EEG represents stage 1 sleep with an arousal caused by a burst of ambient noise measuring 69 dB(A).

Phase Delayed and Advanced Circadian Rhythm

Phase delayed circadian rhythm: -common in adolescents and depressed patients (causes them to fall asleep late).

Phase advanced circadian rhythm:-common for elderly individuals (causes them to wake up early in the morning).

Phase Delay:*morning light *evening melatonin

Phase Advance:*evening light *morning melatonin

The Morningness-Eveningness Questionnaire (MEQ) is a self-assessment questionnaire.

Its main purpose is to measure whether a person's peak sleepiness and alertness is in the morning versus evening.

The MEQ consists of 19 multiple-choice questions, with each

question having four response options.

Morningness-Eveningness Questionnaire (MEQ) – Sleep Phase

Chronotherapies- Getting Back in Sync

Aim to reset the Central Clock. Can be used as monotherapy or in combination with medications.

The most common aproaches: Sleep phase advance/delay therapy Wake Therapy Bright light therapy Sleep deprivation

Light therapy as adjuvant to SSRIs(major depression) or lithium (bipolar disorder)

Light therapy for SAD and non-seasonal depression

Total sleep deprivation (Wake Therapy)

Partial sleep deprivation in the second half of the night

Phase advance of the sleep cycle

Dark or rest therapy to stop rapid cycling

Dark therapy for mania

Chronotherapies /Drugs Combo

Exposure to light alters circadian rhythms and suppresses melatonin release 10,000 lux (bright light) for 30 min/day Useful as a non-pharmacological intervention for depression during pregnancy

Bright light therapy

Novel Melatonergic Drugs

TIK-301 Melatonin receptor agonist Also has serotonin 5HT 2b and 5HT 2c

antagonism Recently finished Phase II clinical trials

Neu-P11 Melatonin agonist Also has affinity for: -serotonin 5-HT 1a, 5-HT 1b, 5-HT 2b Quera Salva MA et al. Current Pharm Des 2011;17(15):1459-70

Insomnia

What is insomnia?

Stahl's Essential Psychopharmacology: Neuroscientific Basis and Practical Applications 3rd Ed.2008;Cambridge University Press

What causes insomnia?


Causes of Insomnia

Good Sleep Hygiene


Oh, Man, I really should not have had that coffee in September!

Five benzodiazepines are FDA approved for insomnia : Flurazepam and Quazepam, (ultra-long half-lives); Triazolam (ultra-short half-life) Estazolam and Temazepam (moderate half-lives).

FDA Approved Benzodoazepine Hypnotics


Nonselective Benzodiazepines Benzodiazepines bind to 4 of the 6 different types of GABA-A alpha subunits: alpha 1,

alpha 2, alpha 3 and alpha 5.


Selectivity for GAB-A Receptor SubunitsGABA A receptors containingalpha 1 subunits are involved in Sleep.

GABA A receptors containing

alpha 2 or alpha 3 subunits are involved in anxiety.

Alpha 1 Selective Hypnotics - Zaleplon and Zolpidem

The hypnotics Zaleplon and Zolpidem bind selectively to GABA-A receptors that contain the alpha 1 subunit (sleep). This subunit is important for sleep and possibly for anticonvulsant and amnesic actions.


The rule of 150 applies. Less than 150 mg –H1 blockade More than 150 mg: SRI, NRI, H1, Alpha 2 and M1 blockade.

Trazodone


Doxepin

At low doses (1-6 mg/day), doxepin is selective for histamine 1 receptors and thus may be used as a hypnotic.


Diphenhydramine(Benadryl) Diphenhydramine is a histamine 1 receptor antagonist commonly used as

a hypnotic. Diphenhydramine is also a muscarinic 1 receptor antagonist and thus causes anticholinergic effects(blurred vision, constipation, memory problems, dry mouth, etc.)


Rozerem – The Healthy Hypnotic

A preliminary study suggests that Ramelteon has antidepressant effects.

Remelteon is a melatonin 1 and 2 agonist and provides sleep onset, but not sleep maintenance (because of short half life).

NEUROPROTECTION: Because Ramelteon has greater potency and affinity at melatonin receptors, it is suggested that it shares melatonin’s neuroprotective effects.

In almost all studies, Ramelteon, in various doses of 4, 8, or 16 mg, significantly reduced sleep latency and increased sleep duration.

Most psychiatrists disregard Ramelteon, but it deserves a second look.

Excessive Daytime Sleepiness (EDS): The inability to remain fully alert or awake during the wakefulness portion of the sleep/wake cycle.

Excessive Daytime Sleepiness

Modafinil The precise mechanism of action of modafinil is yet to be fully elucidated. It is known to bind to the dopamine transporter (DAT). Modafinil has low affinity for the DAT. It is possible that the increase in synaptic dopamine leads to increased tonic firing and downstream effects on neurotransmitters involved in wakefulness, such as histamine and orexin/hypocretin.


Disorders of sleep and wakefulness

Health & Medicine

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