W21 Sleep and Insomnia (RT)

Question 1

What is the definition of sleep?

Answer 1

A readily reversible state of reduced responsiveness to, and interaction with, the environment

Question 2

What are the functions of sleep? (4)

Answer 2

Functions of sleep
– restorative – rest, relaxation, repair
– adaptation – protection from nocturnal predators
– energy conservation
– memory consolidation and integration

Question 3

What are the circadian rhythms of sleep?

Answer 3

• Internal (biological clock) and external
  cues
• Normal time cues set regular sleep
  cycles
  – Absence of time cues causes progressive
  shift in cycle
  – Day/night length adjusts to 26 not 24 hours
• Cycle set by retinal inputs to nucleus in
  anterior hypothalamus (suprachiasmatic nucleus) – Nobel prize 2016/17

Question 4

EEG Reminder: Synchronous activity gives rise to EEG rhythms

Answer 4

• Records from population and sums (many thousands of neurons)
• Desynchronized – leads to flat lines when summed
• Frequency determines how fast neurones are firing
• Amplitude (power) reflects number of neurones in synchrony

Question 5

Sedation and the induction of sleep

Answer 5

• Sleep occurs in several levels (on the basis of CNS activity).
• 25% Rapid Eye Movement sleep (REM)
  – associated with dreaming
• 75% Non-REM sleep i.e. ‘Slow Wave’ sleep (SW)
  – deepest level of sleep
  – Stages 1-4

Question 6

Sleep cycle throughout night:

Answer 6

• Alternate periods of deep, non-rapid eye movement (non- REM) and REM sleep.
• Each cycle has shorter and shallower non-REM periods and longer REM periods

Question 7

The sleep cycle

Answer 7

• Rapid eye movement (REM) sleep
• ~20-40 min
• dreaming
• Non-rapid eye movement (NREM) sleep
• Stages I-4
• 60-90 min
• non-dreaming (?)
• Repeated cycle 4-6 x

Question 8

Important areas for control of sleep

Answer 8

• Reticular Activating system (RAS)
  – Network of neurons in brain stem
  – Control sleep waking (fight or flight)
  – Consists of many different types of neurones
• Many different neurotransmitters
• Reticular Activating system
  – brain stem lesions result in coma and sleep
  – brain stem stimulation induces wakefulness
• Thalamic stimulation induces sleep
• Thalamo-cortical inputs control sleep

Ascending
* RAS projections
* Origins in brain stem
* To the thalamus and then the cortex
* To hypothalamus
* Cause arousal

Question 9

Ascending reticular activating system (RAS)

Answer 9

Control:
* RAS - Increased thalamic and
cortical excitation
– Cholinergic neurones
– serotonergic (5HT) neurones
– Noradrenergic neurones
* Other neurones that contribute
excitation
– Histamine neurones near hypothalamus
– Orexin neurones in hypothalamus
* Inhibition:
– RAS/histamine inhibited by GABA neurones
in hypothalamus (sleep promoting)

Question 10

What is Insomnia?

Answer 10

• Reflects a disturbance of arousal and/or sleep systems in the brain
• Insomnia can be caused by any factor which increases activity in arousal systems or decreases activity in sleep systems

Question 11

What are some different types of sleep disorders (insomnias)?

Answer 11

• Transient insomnia
  – noise, shift work, jet lag
• Short term insomnia
  – emotional issues, stress, anxiety
• Chronic insomnia
  – pain, depression, alcohol abuse, breathing disorder
• Fatal familial insomnia
  – rare prion disease
• Insomnia disorders treated with hypnotic drugs

Question 12

Benzodiazepine and related hypnotics

Answer 12

• Potentiate GABA inhibition by enhancing GABAA-receptors
• GABAA Ionotropic receptors
• Most prevalent receptor in mammalian brain consists of two α, two β and one γ-subunit
• Multiple isoforms of α, β and γ subunits
• GABA binds between α and β-subunits – 2 molecules to activate receptor
• Receptor pharmacology, probability of channel opening, Cl- permeability, duration of channel opening - ALL subunit-dependent
• Inhibitory effect depends on composition of subunits
• Differential spatial distribution of receptors

Question 13

Benzodiazepine and related hypnotics

Answer 13

• Benzodiazepines
• Bind across alpha and gamma
• Enhance open confirmation
  – Short acting (t1/2 < 8 hr) e.g. loprazolam,
  temazepam,
  – Long acting (t1/2 >20 hr) e.g. nitrazepam,
  flurazepam, diazepam
  – problems with tolerance and dependence, and rebound insomnia

Question 14

Benzodiazepines
How can they treat insomnia?

Answer 14

-Most benzodiazepines
* decrease the time taken to get to sleep
* in individuals who habitually sleep <6 hr, they increase the duration of sleep
A few short acting BDZs recommended for insomnia (short term treatment- max 2-4 weeks)
Should be used only when it is severe, disabling, or causing the patient extreme distress

Question 15

Other potential hypnotics: Melatonin

Answer 15

• Melatonin receptor agonists
  – melatonin, ramelton
  – Hormone produced by the pineal gland, which regulates the circadian rhythm of sleep
  – It begins to be released once it becomes dark, continues until first light of day
  – Decreases with age
  – Melatonin promotes sleep initiation and
  resets circadian clock
  – Prolonged release melatonin available for primary insomnia in over 55yr olds