1. Neurobiology of sleep Christian Benedict Dept. of Neuroscience, UU

2. Why do we sleep?

4. Neural systems involved in human sleep/wakefulness
TMN = tuberomammillary nucleus
VLPO = Ventrolateral preoptic nucleus
PPT/LDT = pedunculopontine and laterodorsal tegmental nucleus

5. Transition from wake to sleep
TMN = tuberomammillary nucleus
VLPO = Ventrolateral preoptic nucleus
PPT/LDT = pedunculopontine and laterodorsal tegmental nucleus

6. Transition from wake to sleep

7. Sleep polysomnography

8. Sleep stages, hypnogram

9. Sleep stages, neurochemical conditions
Neurotransmitter
Wakefulness
NREM sleep
REM sleep
Acetylcholine ↑↑ —
Monoamines ↑
Orexin/Hypocretin
GABA

10. Sleep stages, hypnogram

11. Sleep stage 1
First stage of sleep (stage 1) is marked by the emergence of theta activity ( Hz).
Stage 1 is a transition stage between sleep and wakefulness. A person can easily be awakened at this stage.

12. Sleep stage 1

13. Sleep stages, hypnogram

14. Sleep stage 2
Sleep spindles (periodic 1 to 2 second bursts of rapid brain-wave activity, 12 to 15 Hz).
K-Complex (largest event in healthy human EEG, suppressing cortical arousal in response to stimuli that the sleeping brain evaluates not to signal danger).

15. Sleep stage 2

16. Sleep stages, hypnogram

17. Sleep stage SWS
also known as deep sleep.
high-amplitude waves occurring at less than 3.5 Hz.
less responsive to environment and difficult to awaken.

18. Sleep stage SWS

19. Sleep stages, hypnogram

20. Sleep stage REM
The associated EEG is very similar to that of the waking brain. Heartbeat and respiration become irregular and the eyes move rapidly back and forth.
Rapid eye movements
Emotional dream phase
Paralysis

21. Sleep stage REM

24. Pharmacological Therapies
Benzodiazepines
Many end in “pam” or “lam”
clonazepam (Klonopin)
lorazepam (Ativan)
diazepam (Valium)
alprazolam (Xanax)
temazepam (Restoril)
triazolam (Halcion)
These are all commonly used, but only benzodiazepines, non-benzodiazepine hypnotics and melatonin receptor agonists are approved by the FDA for insomnia.

25. GABA receptor
BZ’s bind to the gamma-subunit of the GABA rec

26. The Bad Side of Benzos Daytime sedation Decreased reaction time
Reduced SWS and REM sleep
Unsteadiness of gait—can lead to falls
Cognitive impairment & memory problems
Risk of tolerance
Risk of withdrawal (and rebound insomnia)
Risk of abuse

27. Neurobiologic Mechanism Clinical Effects
Examples
Pharmacologic Effect
Neurobiologic Mechanism
Clinical Effects
    Selective serotonin reuptake inhibitors (SSRIs)
Fluoxetine
Increase extracellular levels of 5-HT
5-HT inhibits REM sleep-producing cells
Decreased REM sleep
Fluvoxamine
Citalopram
    Tricyclic antidepressants
Amitriptyline
Increase extracellular levels of 5-HT and NE
5-HT and NE inhibit REM sleep-producing cells
Nortriptyline
Clomipramine
Desipramine
    Traditional, amphetamine-like stimulants
Amphetamine
Increase extracellular levels of DA and NE
Increased DA and NE signaling
Increased wakefulness
Dextroamphetamine
Methylphenidate
    Wake-promoting, non-traditional stimulants
Modafinil
Increase extracellular levels of DA
Increased DA signaling
Armodafinil
    Benzodiazepines
Diazepam
Enhance GABA signaling via GABAA receptors
GABA inhibits the arousal systems
Increased sleep
Clonazepam
Lorazepam
Triazolam
    Non-benzodiazepine sedative hypnotics
Zolpidem
Zaleplon
Zopiclone
    Classic antihistamines
Diphenhydramine
Block HA H1 receptors
Reduced HA signaling
Triprolidine
    Typical antipsychotics
Haloperidol
Block DA receptors
Reduced DA signaling
Chlorpromazine

28. Caffeine

30. Practice points - Caffeine
Assessment of patients’ caffeine intake must be comprehensive including a wide
variety of dietary sources and it should be recognized that low dose caffeine use has risks.
Regular use of even low caffeine doses can be disruptive of sleep and contribute to patients’
insomnia complaints.
Sleepiness is a common discontinuation effect of caffeine and could be a factor in
patients’ morning sleepiness following over-night abstinence.
Caffeine use should be considered in assessing sleep disturbance or daytime sleepiness
in children and adolescents.
Persistent caffeine use and inability to discontinue may reflect caffeine dependence
which requires a clinician guided gradual reduction of caffeine intake.
Discontinuation of caffeine within a day or across time can be a potential cause or
contributing factor in patients complaining of excessive sleepiness.