Reticular Formation And Sleep
Sleep
Sleep is a
characteristic of all mammals and is defined behaviourally as a reduced
responsiveness to environmental stimuli, and electrophysiologically by specific
changes in electroencephalographic (EEG) activity. In addition, there are a
number of changes associated with autonomic nervous system (ANS) function.
Normal patterns of sleep
are essential for human wellbeing, although it is still unclear why we need to
dream.
EEG patterns during
states of consciousness and slow-wave sleep
EEG recordings from
normal awake subjects at rest show a characteristic high-frequency (13–30 Hz, β
activity) low-voltage pattern. This desynchronized activity changes as the
subject closes their eyes and becomes drowsy, with the new EEG pattern having a lower
frequency (8–13 Hz, α activity) but slightly higher voltage.
This pattern is said to
be synchronized and results from the simultaneous firing of many cortical
neurones following thalamocortical activity.
EEG studies have
revealed that sleep occurs in stages.
· As the subject falls asleep (stage
1), the EEG is similar to the awake EEG (low-voltage, fast activity).
· As sleep deepens through stages 2
and 3 to stage 4, the EEG amplitude progressively increases and its frequency
falls. Stage 3 and 4 sleep is called collectively slow-wave sleep (SWS) or non-rapid eye movement (non-REM) sleep because the eyes are still.
· After about 90 minutes of sleep, the
EEG changes back to a low-voltage, fast pattern that is indistinguishable from
stage 1 non-REM sleep. However, during this phase of sleep there are rapid eye
movements. This type of sleep is called rapid eye movement sleep (REM
sleep), or paradoxical sleep because although the
EEG is similar to that
of an awake person, sleepers are difficult to arouse and muscle tone is absent.
Most dreaming occurs during REM sleep, although that which takes place during
non-REM sleep is said to have a higher emotional content with less detail.
Neural mechanisms of
sleep
Sleep is an active
process involving a number of neurotransmitter systems.
· Cholinergic neurones in the ascending
reticular activating system project via two pathways: a dorsal route
through the medial thalamus and a ventral one through the lateral hypothalamus,
basal ganglia and forebrain. Extensive thalamocortical projections provide the
basis for widespread changes in cortical cell excitability. Activity in
cholinergic neurones lead to an increase in arousal and cortical desynchrony. Activity
in this system is also responsible for the pontine – geniculo – occipital (PGO)
waves, at the onset of REM sleep.
· Both noradrenergic neurones in the
locus coeruleus and serotoninergic (5-hydroxytryptamine [5-HT]) neurones in the
raphé nuclei are involved in controlling the balance between different sleep
stages and sleep and arousal.
· Neurones in the ventrolateral
preoptic area (VLPA) send an inhibitory γ-aminobutyric acid (GABA)-mediated
input to the locus coeruleus, raphé nuclei and tuberomammillary nucleus. The
latter contains histaminergic neurones, which are likely to be the substrate
for the sedative effects of antihistamine drugs.
· Other brain regions implicated in
sleep and arousal patterns include the suprachiasmatic nucleus of the
hypothalamus.
· A number of peptides have been
identified as being associated with sleep states (e.g. orexins and delta
sleep-inducing peptide [DSIP]) and appear to be involved in switching
sleep–wake cycles.
Sleep disorders
Insomnia
Insomnia is the most common sleep disorder.
It can be defined as the failure to obtain the required amount or quality of sleep
to function normally during the day. Primary insomnia supposedly
brought about by dysfunction of sleep mechanisms in the brain is rare, but
these patients may require treatment with hypnotic drugs. Causes of secondary
insomnia include psychiatric disease (especially depression and anxiety
disorders), physical disorders, chronic pain, drug misuse (e.g. excessive
alcohol, caffeine), and old age.
Management of
insomnia
Hypnotics are drugs that
promote sleep. They include drugs acting at the benzodiazepine receptor (benzodiazepines
and Z-drugs), chloral hydrate, chlormethiazole and barbiturates.
Benzodiazepines and the more recent Z-drugs are by far the most widely used
hypnotics. They also have anxiolytic, anticonvulsant, muscle relaxant and
amnesic actions.
· All the actions of benzodiazepines
are believed to be caused by the enhancement of GABA-mediated inhibition in the
CNS. GABAA receptors possess several ‘modulatory’ sites including
one for benzodiazepines, which when activated causes a conformational change in
the GABA receptor. This increases the affinity of GABA binding and enhances the
actions of GABA on the Cl− conductance of the neuronal membrane. Any
benzodiazepine given at night will induce sleep but a rapidly
eliminated drug (e.g. temazepam) is usually preferred to avoid daytime
sedation. Adverse effects of benzodiazepines include drowsiness, impaired
alertness and ataxia as well as a low-grade dependence after a few weeks’ use.
Suddenly stopping the drug may cause a physical withdrawal syndrome (anxiety,
insomnia) that may last for weeks.
• Some
newer drugs do not have the benzodiazepine structure but are
benzodiazepine-receptor agonists. These are the so-called Z-drugs, zopiclone,
zolpidem and zaleplon. The Z-drugs have shorter half-lives than the
benzodiazepines and are less likely to cause daytime sedation. They have a
reduced propensity to tolerance and withdrawal and are becoming increasingly
popular for the management of insomnia.
For many cases of insomnia,
psychological strategies may be effective alternatives to drugs.
Hypersomnia (daytime
sleepiness)
This is a serious but
less common complaint than insomnia. Common causes of persistent daytime sleepiness
include narcolepsy, obstructive sleep apnoea, drugs (e.g. benzodiazepines,
alcohol) and depression (20% have hypersomnia rather than insomnia).
Narcolepsy
Narcolepsy is characterized by irresistible
sleep episodes lasting 5–30 minutes during the day, often in association with
cataplexy (loss of muscle tone and temporary paralysis) usually provoked by
emotion, e.g. laughter, anger, as well as sleep paralysis and hallucinations at
the time of going to or waking up from sleep. It has a very strong histocompatibility
locus antigen (HLA) association (DR2/DQW1) and, while no pathological abnormalities
have been detected in these patients, it is likely that there are abnormalities
in the brainstem structures underlying sleep, as there is evidence of short latency
REM sleep during normal waking hours. In addition, deficiencies in hypocretins
or orexins have recently been described in narcolepsy in some patients. The
syndrome has a devastating effect on quality of life, which may be improved by
long-term treatment with stimulants, e.g. dexamfeta- mine, methylphenidate and
modafinil. Clomipramine is used to treat the cataplexy.
Obstructive sleep
apnoea syndrome
This occurs if the upper
airway at the back of the throat collapses when the patient breathes during
sleep. This reduces the oxygen in the blood, which arouses the patient causing
him or her to momentarily awake and prevents a normal sleep pattern. The
patient, usually an overweight man, is often unaware of these awakenings, but
the disruption to sleep results in daytime sleepiness and impaired daytime
performance. It can be treated by weight loss, positive ventilatory support at
night and, occasionally, oropharyngeal surgery. If sleep apnoea is not treated
it can lead to long-term cardiorespiratory problems such as pulmonary
hypertension and right heart failure. It is also known that sleep apnoea can
have a central nervous system origin.
