Disorders of sleep and wakefulness

Neurobiology of sleep and wakefulness
Insomnia and hypnotics
Excessive daytime sleepiness

“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 sleep
This 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

A study by Dr Thomas Wehr at the National Institute of Mental Health:
demonstrated that volonteers
deprived 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.

"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.“

 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.

 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.

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

 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.

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).

 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.

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

TMN SCN VLPO

WAKE PROMOTER: CENTRAL CLOCK: SLEEP
Tuberomammillary Suprachiasmatic PROMOTER:
nucleus –TMN-of the nucleus of the Ventrolateral
hypothalamus promotes hypothalamus is the preoptic area –
wakefulness (produces switch from VLPO-of the
histamine) wakefulness to sleep. hypothalamus
promotes sleep
Light – ON (produces GABA)
Melatonin - OFF

Aside from the Central
Clock, there are
Peripheral clocks in various
tissues

Exogenous Cues (Zeitgebers) Endogenous Cues (clock
-light, controlling genes)
-temperature,
-Bmal
-social interactions,
-Clock
-pharmacological
-Cryptochrome (Cry)
manipulation, -exercise,
-Period (Per)
-eating/drinking patterns
-Rev-ErbA (REV-ERB)

POSITIVE REGULATORS
CLOCK 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

-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.

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.

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.

NREM SEIZURES:
Nocturnal Frontal Lobe Epilepsy
Nocturnal Paroxysmal Dystonia
Episodic Nocturnal Wanderings

NREM Slow Wave Sleep REM Behavior Disorder
Time 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 Simple, eyes closed
open

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 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.

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

 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

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

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

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).


 Benzodiazepines bind to 4 of the 6 different types of GABA-A alpha subunits: alpha
1, alpha 2, alpha 3 and alpha 5.


GABA A receptors containing GABA A receptors containing
alpha 1 subunits are involved in alpha 2 or alpha 3 subunits
Sleep. are involved in anxiety.

 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.


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


 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.)


Most psychiatrists disregard
Ramelteon, but it deserves a second
look.
Remelteon is a melatonin 1 and 2
agonist and provides sleep onset, but
not sleep maintenance (because of short
half life).

A preliminary study suggests that
Ramelteon has antidepressant effects.

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.

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

 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

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Disorders of sleep and wakefulness