In this topic, we will discuss the neurobiology of sleep, sleep disorders, and pharmacologic options for sleep disorders.

Sleep is Important! Here’s why

• Sleep is restorative. The body needs to be repaired after the day’s use! Sleep is especially important for children because this is why a lot of growth and brain development occurs.
• Sleep helps conserve energy and reduces metabolism
• Sleep allows the brain time to reorganize memory to help with learning and cognition.

Stages of Sleep

1. Waking state (Beta): the high-frequency and low-amplitude state
2. Stage I (Theta): The first non-REM state where EEG is decreasing and amplitude is increasing
3. Stage II (Sleep spindles): The second non-REM state where there is an oscillation in hertz. This only last seconds.
4. Stage III and IV (Delta): This is the last non-REM state characterized by slower waves
5. REM Sleep: The wave is similar to the waking state – low-voltage and high-frequency
   • REM sleep should account for 25% of total sleep in adults.
   • In this state, the neurons are actively firing. This firing is due to two different nuclei: pedunculopontine (PPN) and laterodorsal tegmental (LDTN)
   • Due to the increased activity, brain temperature and metabolic rate tend to increase as well.
   • This is where most dreams occur.
   • This state is critical for brain development.
   • Children have more REM sleep than adults.

Neurobiology of Sleep

There are two opposing processes when we learn about sleep: The arousal process and the sleep process.

The reticular activating system (RAS) mediates the arousal process.

The ventrolateral preoptic area (VLPO) mediates the sleep process.

The hypothalamus acts as a switch between the two processes. Orexin is the molecule that goes between the two processes.

RAS: The Arousal Processes

There are two pathways involved in the RAS. Both are active during the waking period.

• The cholinergic pathway:
  • Pedunculopontine nucleus (PPT): The main neurotransmitters are ACh and glutamate
  • Laterodorsal tegmental nucleus (LDT): The main neurotransmitter is ACh
  • Both of these work to release glutamate into the frontal cortex
• Monoaminergic pathway:
  • Locus coeruleus (NE)
  • Dorsal raphe nucleus (5-HT)
  • Ventral periaqueductal grey area (DA)
  • Tuberomammillary nucleus (HA)

During the waking period, the RAS sends signals that inhibit VLPO.

VLPO: The Sleep Processes

This involves a group of nuclei in the hypothalamus that has axons to the RAS to inhibit the RAS activation.

They use GABA and galanin as their primary inhibitory neurotransmitters.

During the sleeping period, the VLPO sends signals that inhibit RAS.

Hypothalamus

It is important to note that even though the hypothalamus works as a switch, it’s really more of a spectrum of arousal and sleep.

An overstimulation of arousal can be detrimental, and vice versa.

Orexin (also known as hypocretin) is a peptide produced in the lateral hypothalamus. They are produced from a precursor protein (propeptide) called preprophypocretin, which is cleaved into two proteins: orexin A and orexin B.

Orexin A and orexin B bind to two different G-protein coupled receptors, OX1R and OX2R. Their activity follows a circadian rhythm. They have excitatory actions and are active during the waking moment and inactive during sleep.

OX1Rs are found in locus coeruleus (NE.) Suppressing this receptor leads to a reduction in intracellular calcium and reduce NE release.

OX2Rs are found in tuberomammilary nucleus (HA.) Suppressing this receptor leads to alter expression of NMDA glutamate receptor and histamine.

Sleep Disorders

The most common sleep disorders are narcolepsy, insomnia, restless legs syndrome, and REM sleep behavior disorder.

Narcolepsy

Narcolepsy is a chronic problem that affects about 250,000 in the United States. Narcolepsy is characterized by frequent REM sleep attacks during the daytime, where the patient goes from wakefulness straight to a REM state.

Narcolepsy last anywhere from 30 seconds to 30 minutes, and the onset can be abrupt. Some narcolepsy can cause cataplexy and sleep paralysis.

A common presentation of narcolepsy is hyponogogic hallucinations, which are not the same as nights. This hallucination is a vivid dream-like sensation that feels very real that starts to occur as the person starts to fall asleep. It is more common in teens and young adults.

Genetic study suggests that there could be a genetic association between narcolepsy and the HLA DR2 gene.

Post-mortem brain studies have shown that patients with narcolepsy have low orexin precursors, low orexin A, or loss of the ability to produce orexin. This is why low level of orexin A has been used as a diagnostic tool for narcolepsy.

Insomnia

Insomnia is the inability to sleep for a sufficient length of time. This shouldn’t be considered a disease but more of a symptom. It affects roughly 25% of the population and can have multiple etiologies. Most insomnia is short-term.

There are two types of insomnia: sleep-onset insomnia and sleep-maintenance insomnia.

Restless Legs Syndrome

Patients with RLS have unpleasant crawling, prickling, or tingling sensations in their limbs. Many have the urge to move to find relief. The etiology is not completely understood.

REM Sleep Behavior Disorders

These are a collection of disorders where the REM state is incomplete or absent. Some patients have a tendency to act out dreams that is vivid, intense, and violent. It is often associated with other neurodegenerative disorders, such as Parkinson’s.

Treatment of Insomnia

A more in-depth overview of the medications will be discussed in a later section.

Medications that are commonly used in the treatment of insomnia are:

• Benzodiazepines
  • MoA: GABA-A positive allosteric modulation. They increase the amount of GABA, leading an increased frequency of Cl channel openings.
• Z-drugs
  • MoA: GABA-A positive allosteric modulations like BZDs, but they have higher specificity (a1 subtype), leading to only inducing sleep effects and having fewer general side effects.
• Barbiturates
  • MoA: Co-agonist at GABA-A receptor that leads to an increase in the duration of channel opening. They also act as AMPA receptor antagonists.
• Antihistamines
  • MoA: Competitive inhibitor of H1 receptors. They prevent the second messenger in the histamine pathway and lead to drowsiness.
  • Their action centered around tuberomammilary nucleus, which synthesizes histamines.
• Melatonin receptor agonists
  • MoA: inhibit MT1 and MT2 receptors on the SCN and induce natural sleep.
  • Ramelteon
• Antidepressants
  • TCA
  • Trazodone (reduce arousal and drowsiness): Antagonists of H1 receptors
• Orexin receptor antagonists
  • Dual orexin receptor antagonists (DORAs)
  • MoA: Inhibit the action of orexin. This leads to both initiation of sleep and maintenance of sleep
    • They have also been shown to block a number of neurotransmitters that activate the RAS (NE, HA, glutamate) as well.
  • Belsomra

Treatment of RLS

• Dopamine agonists – ropinirole or pramipexole
• Iron replacement for those deficient
• Dopamine precursor: levodopa
• Gabapentinoids
• BZDs

Treatment of Narcolepsy

The treatment of narcolepsy depends on the presentation of the patients, whether or not they have cataplexy as well.

Primary medications are those that stimulate the arousal process: modafinil (DAT inhibitor), amphetamine (stimulation of frontal cortex and RAS), methylphenidate (increase levels of DA and NE through DAT and NET inhibition), and Xyrem (GHB – partial agonist of GABA-B –> improving slow-wave sleep and reducing cataplexy)

Antidepressants are also used in the treatment of cataplexy.