Neurobiology of sleep Christian Benedict Dept. of Neuroscience, UU Email: christian.benedict@neuro.uu.se

Why do we sleep?

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

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

Transition from wake to sleep

Sleep polysomnography

Sleep stages, hypnogram

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

Sleep stages, hypnogram

Sleep stage 1 First stage of sleep (stage 1) is marked by the emergence of theta activity (3.5-7.5 Hz). Stage 1 is a transition stage between sleep and wakefulness. A person can easily be awakened at this stage.

Sleep stage 1

Sleep stages, hypnogram

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).

Sleep stage 2

Sleep stages, hypnogram

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.

Sleep stage SWS

Sleep stages, hypnogram

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

Sleep stage REM

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.

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

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

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

Caffeine

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.