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- Chronic insomnia health consequences, slower
response to challenging reaction-time tasks,reduced
repeated difficulty with the initiation, duration,
quality of life -- comparable to that experienced by
maintenance, or quality of sleep that occurs despite
patients with such conditions as diabetes, arthritis,
adequate time and opportunity for sleep and results in
and heart disease, impaired occupational and social
some form of daytime impairment.
Keluhan pasien difficulty falling asleep, awakening - Insomnia is associated with higher healthcare use,
early or easily, problems with returning to sleep after
including a 2-fold increase in hospitalizations and
awakening, or a general poor quality of sleep.
office visits.
In order to be considered a disorder, the insomnia
- Insomnia can be a risk factor for depression and a
should be accompanied by daytime sleepiness, loss of
symptom of medical, psychiatric, and sleep
concentration, irritability, worries about sleep, loss of
motivation, or other evidence of daytime impairment - Insomnia appears to be predictive of a number of
disorders, including depression, anxiety, alcohol
dependence, drug dependence, and suicide.
- Approximately one third of adults report some
- Insomnia often persists despite treatment of the
difficulty falling asleep and/or staying asleep during
underlying medical or psychiatric condition.
the past 12 months, with 17% reporting this problem
as a significant one.


up to 1 week
referred to as adjustment sleep disorder because it
most often occurs in the context of an acute
situational stress, such as a new job or an
upcoming deadline or examination
resolves when the stressor is no longer present or
the individual adapts to the stressor.
often recurs when new or similar stresses arise in
the patients life
1-6 months
more persistent stressful factors, may be
situational (eg, death or illness) or environmental
(eg, noise)
> 6 months
associated w/ underlying predisposition to
insomnia, medical and psychiatric conditions,
involves conditioned sleep difficulty
Primary/ psychophysiologic
- Despite inadequate sleep, many patients with
insomnia do not complain of excessive daytime
sleepiness, such as involuntary episodes of
drowsiness in boring, monotonous, nonstimulating
situations. However, they do complain of feeling tired
and fatigued, with poor concentration. This may be
related to a physiological state of hyperarousal.

Promotion of wakefulness

Brain areas critical for wakefulness include the

tuberomammillary nucleus (TMN) in the posterior
hypothalamus. The TMN contains histamine neurons,
which project stimulatory inputs to brainstem arousal
centers such as the locus coeruleus (LC)
(norepinephrine), the dorsal raphe nuclei (DRN)
(serotonin), the ventral tegmental area (VTA)
(dopamine), and the basal forebrain (acetylcholine).
These brainstem arousal centers (see the image
below) project diffusely to cortical areas to promote
The TMN also inhibits sleep-promoting areas, such as the
anterior hypothalamus. Similarly, the brainstem arousal
regions inhibit sleep-promoting regions in the anterior
hypothalamus. Adenosine, a neurotransmitter,
accumulates in the brain during prolonged wakefulness
and inhibits wake-promoting regions in the posterior
hypothalamus and the basal forebrain. Acetylcholine in
the basal forebrain also projects diffusely to cortical areas
and the TMN to promote wakefulness.
The ascending arousal system. Adapted from Saper et al.
Hypothalamic Regulation of Sleep and Circadian
Rhythms. Nature 2005;437:1257-1263.

Promotion of sleep
The anterior hypothalamus includes the ventrolateral
preoptic nucleus (VLPO), containing gammaaminobutyric acid (GABA) and the peptide galanin,
which are inhibitory and promote sleep (see the image
below). They project to the TMN and the brainstem

arousal regions to inhibit wakefulness. GABA is the

predominant inhibitory neurotransmitter in the central
nervous system (CNS).
Ventrolateral pre-optic nucleus inhibitory projections to
main components of the arousal system to promote sleep.

The homeostatic and circadian processes

Both animal and human studies support a model of 2
processes that regulate sleep and wakefulness:
homeostatic and circadian. The homeostatic process is the
drive to sleep that is influenced by the duration of
wakefulness. The circadian process transmits stimulatory
signals to arousal networks to promote wakefulness in
opposition to the homeostatic drive to sleep. (See the
image below.)
Sleep-wake cycle.

Melatonin and the circadian process

The suprachiasmatic nucleus (SCN) is entrained to the
external environment by the cycle of light and darkness.
The retinal ganglion cells transmit light signals via the
retinohypothalamic tract to stimulate the SCN. A
multisynaptic pathway from the SCN projects to the
pineal gland, which produces melatonin.
Melatonin synthesis is inhibited by light and stimulated
by darkness. The nocturnal rise in melatonin increases
between 8 and 10 am and peaks between 2 and 4 am, then
declines gradually over the morning.[13] Melatonin acts
via 2 specific melatonin receptors: MT1 attenuates the
alerting signal and MT2 phase shifts the SCN clock. The
novel sleep-promoting drug ramelteon acts specifically at
the MT1 and MT2 receptors to promote sleep.

The flip-flop switch model

Saper and colleagues proposed the flip-flop switch model
of sleep-wake regulation.[14] This flip-flop circuit consists
of 2 sets of mutually inhibitory components. The sleep
side is the VLPO and the arousal side includes TMN
histaminergic neurons and brainstem arousal regions (the
DRN serotonergic neurons, VTA dopaminergic neurons,
and LC noradrenergic neurons).
Each side of the switch inhibits the other. For example,
when activation of one side is slightly stronger, the
weaker side has increased inhibition, thus further tipping
the balance toward the stronger side. This flip-flop switch
allows for rapid state transitions. (See the schematic flipflop switch model in the image below.)
Schematic flip-flop switch model. Adapted from Saper C
et al. Hypothalamic regulation of sleep and circadian
rhythms. Nature 2005;437:1257-1263.
Hypocretin neurons in the posterolateral hypothalamus
are active during wakefulness and project to all of the
wakefulness arousal systems described above. Hypocretin
neurons interact with both the sleep-active and the sleeppromoting systems and act as stabilizers between
wakefulness-maintaining and sleep-promoting systems to

prevent sudden and inappropriate transitions between the

2 systems.[15]
Narcolepsy with cataplexy illustrates the disruption of
this system. These patients have a greater than 90% loss