NEURO 03: Introduction to Pathophysiology of Sleep

NORMAL BRAIN RHYTHMS 🧠⚡

Think of brainwaves like different radio frequencies that your brain tunes into depending on what you're doing. These waves are generated when groups of neurons fire together in a synchronized way.

How We Measure Brainwaves

• We use an EEG (ElectroEncephaloGram), which involves electrodes placed on the scalp.

• The EEG picks up electrical signals from neurons and records brain activity as wave patterns.

Types of Brainwaves & When They Occur

Each brainwave has a different frequency (speed) and is associated with a specific mental state:

📝 Important Note:

• Brainwaves can become abnormal in certain conditions. Example: 3 Hz spike-wave EEG is seen in absence epilepsy (where a person briefly "zones out").

WHAT IS SLEEP? 😴

Sleep is a reversible state where your body and brain temporarily disconnect from the environment.

• Happens in all vertebrates (so your dog, fish, and even birds sleep too!).

• Usually comes with closed eyes, reduced movement (quiescence), and a relaxed posture.

TWO MAIN TYPES OF SLEEP 💤

Your sleep is divided into two big categories:
1⃣ Non-Rapid Eye Movement (NREM) Sleep
2⃣ Rapid Eye Movement (REM) Sleep

To track sleep stages, we measure:
📊 EEG (Electroencephalogram): Brain wave activity
👀 EOG (Electrooculogram): Eye movements
💪 EMG (Electromyogram): Muscle tone

WHAT HAPPENS TO YOUR BRAIN WAVES AS YOU FALL ASLEEP?

When you're awake, your EEG shows fast, small waves (high frequency, low amplitude). As you fall asleep:
1⃣ Stage 1 (Light sleep) → Brain waves slow down slightly.
2⃣ Stage 2 → Sleep spindles and K-complexes appear (brief bursts of brain activity).
3⃣ Stage 3 → Deep sleep begins (Delta waves appear).
4⃣ Stage 4 (Deepest sleep) → Brain shows big, slow Delta waves (low frequency, high amplitude).

🌀 REM Sleep → Your EEG looks almost identical to when you're awake (fast, desynchronized waves). This is when dreaming happens!

💡 Key Takeaway:

• NREM sleep = deeper, slower brainwaves 💤

• REM sleep = fast brainwaves, like being awake, but your body is "paralyzed" 🤯

BEHAVIORAL STATES OF WAKEFULNESS & SLEEP 😴💤

Your brain and body behave very differently depending on whether you're awake, in NREM sleep, or in REM sleep. These differences can be tracked using:
📊 EEG (brain waves)
👀 EOG (eye movements)
💪 EMG (muscle tone)

1⃣ Wakefulness (Fully alert and awake)

• 👀 EOG: Eyes are moving normally.

• 💪 EMG: Muscles are active (high muscle tone).

• ⚡ EEG: "Desynchronized" (low voltage, high frequency) = brain is active!

2⃣ Non-REM (NREM) Sleep 💤 (Stages 1-4)

• 👀 EOG: Eye movement slows down.

• 💪 EMG: Muscle activity decreases but still present.

• ⚡ EEG: Synchronized (high amplitude, slow waves) → Brain is less active.

3⃣ REM Sleep ("Paradoxical Sleep") 🌀

• 👀 EOG: Rapid eye movements (bursts of movement).

• 💪 EMG: Muscle paralysis (atonia) due to glycine inhibiting motor neurons.

• ⚡ EEG: "Desynchronized" again (low amplitude, high frequency) = brain is highly active like when awake.

TONIC vs. PHASIC REM SLEEP

REM sleep isn't all the same—it has two phases:
🟢 Tonic REM → Paralysis, minimal eye movement.
🔴 Phasic REM → Muscle twitches, rapid eye movement bursts.

QUANTIFYING SLEEP: HOW SLEEP CHANGES OVER THE NIGHT 🕰💤

A sleep histogram shows the NREM and REM sleep cycles across an 8-hour sleep period.

🛏 Key patterns:
✔ NREM & REM alternate in cycles throughout the night (around 90-minute cycles).
✔ Deep sleep (stages 3 & 4) mostly happens in the first 1/3 of sleep.
✔ REM sleep dominates the last 1/3 of sleep (near morning).

• If you wake up too early, you lose REM sleep (dreams, memory processing).

• If you go to bed too late, you lose deep sleep (physical restoration, growth).

NEUROTRANSMITTERS & SLEEP REGULATION 🧠💊

Different neurotransmitters (NTs) control wakefulness, NREM sleep, and REM sleep.

1⃣ Wakefulness 🏃‍♂

• Controlled by the Reticular Activating System (RAS) in the brainstem.

• Key neurotransmitters:
  🔹 Noradrenaline (NA)
  🔹 Acetylcholine (ACh)
  🔹 Histamine (HA)
  🔹 Orexins (hypocretins)

💊 Blocking these = Drowsiness (e.g., antihistamines make you sleepy!).

2⃣ NREM Sleep 😴

• Brain slows down = synchronization of brain waves.

• Key neurotransmitters:
  🔹 Serotonin (5-HT) → Helps initiate sleep.
  🔹 GABA → Inhibitory, promotes relaxation.
  🔹 Adenosine → Builds up when you're awake, makes you sleepy.

💊 Caffeine is an adenosine antagonist, so it keeps you awake!

3⃣ REM Sleep 🌀

• Originates from the pontine reticular formation in the brainstem.

• Acetylcholine (ACh) is the key neurotransmitter!

• 💊 Blocking ACh (e.g., antidepressants, antihistamines) can decrease REM sleep.

AUTONOMIC NERVOUS SYSTEM & SLEEP ⚡🛑

Your sympathetic (fight-or-flight) & parasympathetic (rest-digest) systems also change during sleep.

🔹 NREM Sleep → Sympathetic stays the same, but parasympathetic increases = Heart rate and breathing slow down.
🔹 REM Sleep:

• Tonic REM = Parasympathetic dominates.

• Phasic REM = Both sympathetic & parasympathetic activity spike at the same time! → Like hitting the gas and brake together!

SENSORY & SEXUAL CHANGES IN SLEEP 🛌🔥

• Sensory perception (hearing, touch, smell, pain) is reduced during sleep.

• Sexual activity can still happen during REM sleep!

  • Men: Erections occur (used to test for erectile dysfunction—if you get REM erections, the issue is psychological, not physical).

  • Women: Increased vaginal blood flow.

KEY TAKEAWAYS 🎯

• Wakefulness = active brain, active body.

• NREM = slow brain activity, relaxed but movable body.

• REM = super active brain, but body is fully paralyzed.

• Neurotransmitters:

  • Wakefulness → NA, ACh, Histamine, Orexin

  • NREM → Serotonin, GABA, Adenosine

  • REM → Acetylcholine

• Parasympathetic system dominates sleep, but REM sleep has unpredictable autonomic surges.

NEED FOR SLEEP: VARIATION WITH AGE

• Babies spend about 50% of their sleep time in REM sleep.

• By adulthood, REM sleep is only ~20% of total sleep time.

• As people age, REM sleep gradually decreases further.

• Total sleep time declines over the lifespan. Infants need the most sleep, while older adults get less.

How Much Sleep Do We Really Need?

• It varies! Some people function well on as little as 3 hours, while others need more than 11 hours.

• Restricted sleep over time can lead to:

  • Cognitive issues (poor memory, difficulty concentrating)

  • Increased daytime fatigue

  • Higher pain sensitivity

  • Weaker immune function

  • Weight gain

HOW SLEEP PATTERNS CHANGE WITH AGE

• Total sleep time (TST) decreases.

• Sleep efficiency (how well we sleep) declines.

• Deep sleep (delta wave/slow-wave sleep) is reduced.

• Sleep becomes more fragmented (more awakenings at night).

• Sleep latency increases (it takes longer to fall asleep).

• Circadian rhythm shifts—older adults tend to sleep and wake up earlier.

• REM sleep is relatively preserved but gradually decreases over time.

➡ These changes result in less satisfying sleep for many older adults.

FUNCTION OF SLEEP: WHAT DOES IT DO?

(We don’t fully know, but we have some good ideas!)

• Vital for brain function—we spend 1/3 of our lives sleeping, so it must serve a crucial role.

• Important for brain development (cerebral cortex, eye movements).

• Helps organize neural circuits as we grow.

• REM sleep is essential for:

  • Learning & memory consolidation

  • Pain regulation

  • Clearing out toxic proteins (e.g., beta-amyloid in Alzheimer's) through the glymphatic system

  • Synaptic pruning (removing unnecessary brain connections to maintain a healthy brain size)

"If sleep serves no purpose, then did Nature mess up?" 🤔 (Probably not!)

SLEEP DISORDERS

Sleep disorders were first formally classified in the 1970s into four major groups:

1. DIMS = Disorders of Initiating and Maintaining Sleep

   • Examples: Insomnia, sleep apnea, restless legs syndrome

2. DOES = Disorders of Excessive Somnolence

   • Example: Narcolepsy

3. DOSS = Disorders of Sleep Stages and/or Partial Arousals

   • Example: REM behavior disorder

4. DSWS = Disorders of Sleep-Wake Schedule

   • Examples: Jet lag, shift work disorder

INSOMNIA

Defined as the perception of inadequate sleep, including:

• Difficulty falling asleep

• Short sleep time

• Frequent awakenings

❗ Up to 40% of the general population reports struggling with insomnia!

📌 Types of Insomnia

• Transient insomnia = Lasts a few days

• Short-term insomnia = Lasts 1-2 weeks

• Chronic insomnia = Lasts 3+ weeks

CAUSES OF TRANSIENT & SHORT-TERM INSOMNIA

(Usually due to temporary stress or environmental factors)

• Acute stress: Exams, bereavement, hospitalization

• Pain

• Traveling across time zones (jet lag)

• Major disasters (earthquakes, etc.)

• Stimulants (caffeine) or depressants (alcohol)

• Rebound insomnia after stopping sleep medications (e.g., benzodiazepines, Z-drugs)

CHRONIC INSOMNIA

Requires a full medical evaluation to check for:

• Psychiatric disorders: Anxiety, panic attacks

• Alcohol/substance abuse

• Medical conditions: Hypertension, rheumatoid arthritis

• Conditioned insomnia: "The harder you try to sleep, the worse it gets!"

• Chronic pain

• Sleep apnea: Feeling exhausted all day but unable to enter deep sleep

• Restless legs syndrome (RLS) & nocturnal myoclonus (uncontrollable leg movements at night)

• Shift work disorder (night shifts disrupt sleep cycles)

Sleep Apnea (DIMS)

There are two types of sleep apnea: Obstructive Sleep Apnea (OSA) and Central (Neurogenic) Sleep Apnea (CSA).

Obstructive Sleep Apnea (OSA)

What Happens?

• In OSA, breathing stops during sleep due to an obstruction in the upper airway (caused by soft tissues like the tongue, uvula, or soft palate collapsing and blocking airflow).

• Leads to frequent awakenings, restless sleep, and excessive daytime sleepiness.

• Loud snoring is a common symptom (sometimes louder than 65 decibels).

• Common in obese individuals due to fat deposits around the neck that narrow the airway.

• Diagnosed via overnight polysomnography (either in a sleep lab or at home).

• Apnea Index (AI) measures severity (events/hour):

  • Normal: AI < 5

  • Mild: 5 ≤ AI < 15

  • Moderate: 15 ≤ AI < 30

  • Severe: AI ≥ 30

Complications of Untreated OSA

• Increased risk of:

  • Hypertension, heart disease (heart attacks, heart failure), stroke, and Type 2 diabetes.

  • Daytime fatigue, cognitive impairment, and irritability.

  • Hormonal changes: Low testosterone, decreased libido, erectile dysfunction.

  • Weakened pain tolerance (chronic sleep deprivation lowers pain thresholds).

  • Weakened immune function, anxiety, and depression.

Treatment Approaches

Non-Pharmacological

1. Weight loss (reduces neck thickness and improves airway patency).

2. Exercise & Diet Changes (increases muscle tone).

3. CPAP (Continuous Positive Airway Pressure) Therapy

   • A machine blows air through a nasal mask to keep the airway open.

   • Highly effective but has compliance issues (due to sneezing, nasal dryness, discomfort, claustrophobia).

4. Custom dental appliances (keep the tongue from blocking the airway).

5. Surgery (Laser-assisted uvuloplasty for severe cases that don’t respond to other treatments).

Pharmacological

1. Modafinil (used to reduce daytime sleepiness in patients using CPAP).

2. Protriptyline (a tricyclic antidepressant that increases tongue muscle tone to reduce airway collapse).

3. Avoid CNS depressants: Alcohol, opioids, benzodiazepines, and hypnotics worsen apnea and can be life-threatening.

Neurogenic (Central) Sleep Apnea (CSA)

What Happens?

• No airway blockage—instead, the brain fails to send signals to the respiratory muscles (chest & diaphragm).

• Causes:

  • Neurodegenerative diseases (Alzheimer’s, Parkinson’s).

  • Brain injuries (e.g., stroke, encephalitis, spinal cord injuries).

  • CNS depressant drugs (e.g., opioids, alcohol, benzodiazepines, barbiturates).

• Harder to detect than OSA: No loud snoring.

• Diagnosis: Check if breathing effort is absent (vs. OSA where effort is present).

Complications

1. Severe fatigue (frequent awakenings prevent restful sleep).

2. Cardiovascular problems (low oxygen levels worsen heart disease and increase risk of abnormal heart rhythms).

Treatment Approaches

Non-Pharmacological

1. Treat underlying conditions (e.g., heart disease).

2. Adjust medications that contribute to CSA (e.g., stop opioids).

3. CPAP or BiPAP (Bilevel Positive Airway Pressure) and oxygen therapy.

Pharmacological

1. Acetazolamide (Diamox®): Stimulates breathing by affecting acid-base balance.

2. Theophylline (Theo-24®, Theochron®): A stimulant that helps drive breathing.

3. Zolpidem (Ambien®) (off-label): Helps regulate sleep patterns and reduce CSA events.

Narcolepsy (DOES)

Characterized by a "tetrad" of symptoms:

1. Cataplexy: Sudden muscle weakness triggered by strong emotions (e.g., laughter, excitement).

2. Sleep paralysis: Temporary inability to move when waking up or falling asleep.

3. Excessive daytime sleepiness (often the first symptom).

4. Hypnagogic hallucinations: Vivid, dream-like hallucinations when falling asleep or waking up.

• Onset: Usually in puberty.

• Cause:

  • Likely genetic.

  • Loss of hypocretin (orexin) neurons in the hypothalamus, which normally regulate wakefulness and REM sleep.

  • Increased cholinergic drive (which promotes REM sleep and muscle atonia).

Cataplexy Mechanism

• Normally, motor neurons stay active when awake.

• In narcolepsy, the brain mistakenly activates the "paralysis" circuits (glycine release in the spinal cord inhibits motor neurons), causing sudden muscle weakness.

Treatment Approaches

CNS Stimulants (for daytime sleepiness)

• Modafinil (Provigil®, Alertec®)

• Methylphenidate (Ritalin®, Concerta®)

Anti-Cataplectic Agents (for muscle paralysis attacks)

• Tricyclic antidepressants (protriptyline, amitriptyline, desipramine)

• SSRIs (fluoxetine, reboxetine, etc.)

Key Takeaways

1. OSA = physical obstruction of airway → loud snoring, frequent awakenings, daytime sleepiness.

2. CSA = brain fails to signal breathing → harder to detect, no snoring.

3. Narcolepsy = REM sleep intrusion into wakefulness → sudden muscle weakness (cataplexy), hallucinations, excessive daytime sleepiness.

REM Behavior Disorder (RBD)

What happens?

• Normally, during REM sleep, your muscles are paralyzed so you don’t act out your dreams.

• But in REM Behavior Disorder (RBD), that paralysis fails, leading to violent or aggressive movements in response to vivid or scary dreams.

• It’s most common in elderly men (50+ years old).

• People with RBD might punch, kick, or even injure themselves or their bed partners while acting out their dreams!

Why does this happen? (Pathophysiology)

• The exact cause isn’t fully known.

• It’s suspected that there’s a lack of inhibitory signals (or too many excitatory ones) affecting motor neurons during REM sleep.

• There’s also an unclear link to Parkinson’s Disease—some people with RBD may later develop Parkinson’s.

How do we treat it?

• Clonazepam (a benzodiazepine) → Helps reduce movements and restore muscle atonia (paralysis during REM sleep).

Restless Legs Syndrome (RLS)

What happens?

• RLS happens before sleep onset and causes an uncontrollable urge to move the legs.

• People describe it as a “creepy crawly” sensation deep in the leg muscles.

• Moving the legs temporarily relieves the discomfort, but it comes back in cycles.

• It disrupts sleep and can lead to severe insomnia.

• In some cases, it’s associated with pain that can lead to suicidal depression (serious impact on mental health).

Types of RLS

1. Primary (Idiopathic) RLS → No known cause.

2. Secondary RLS → Linked to medical conditions like:

   • Iron-deficiency anemia

   • Kidney disease

   • Peripheral neuropathy (e.g., diabetes, HIV, alcoholism)

   • Pregnancy

   • Certain medications (antidepressants, anti-epileptics, antipsychotics)

   • Lifestyle factors (alcohol and cigarette smoking can worsen it).

Why does this happen? (Pathophysiology)

• The exact cause is unknown, but dopamine (DA) dysfunction plays a major role.

• Post-mortem studies show:

  • No abnormalities in dopamine neurons in the nigrostriatal pathway.

  • Lower ferritin (iron-binding protein) in nigrostriatal neurons.

  • Since dopamine-producing neurons exist in the hypothalamus and also project to the spinal cord, there might be a connection between dopamine, sleep, and pain regulation.

• Iron deficiency may be a key factor → Low iron can disrupt dopamine function, worsening RLS symptoms.

How do we treat it?

Pharmacotherapy options:

1. Iron supplements (for iron-deficient patients).

2. L-Dopa (Sinemet®) – Boosts dopamine levels.

3. Dopamine agonists – Ropinirole (Requip®), Pramipexole (Mirapex®) → Help regulate dopamine.

4. Opioids – Sometimes used for severe cases.

5. Benzodiazepines – May help with sleep.

Final Takeaways:

• RBD = Acting out dreams due to failure of REM muscle paralysis.

• RLS = Creepy crawly sensations before sleep, relieved by movement but disrupts sleep.

• Dopamine and iron seem to play key roles in RLS.

• Clonazepam for RBD, Dopamine agonists & iron supplements for RLS.

Summary of Key Concepts:

1. Normal Brain Rhythms: Brain rhythms refer to the different electrical patterns generated by the brain during various stages of sleep and wakefulness. These rhythms are categorized into delta waves (deep sleep), theta waves (light sleep), alpha waves (relaxed but awake), and beta waves (active mental states).

2. States of Sleep: There are two main categories of sleep:

   • Non-REM (NREM) Sleep: Includes stages 1-3, with a decrease in brain activity and body functions.

   • REM Sleep: Characterized by rapid eye movement, vivid dreams, and muscle atonia (paralysis).

3. Polygraphic Parameters: These are used to distinguish sleep from wakefulness:

   • EEG (Electroencephalogram): Measures brain waves.

   • EOG (Electrooculogram): Measures eye movements, particularly in REM sleep.

   • EMG (Electromyogram): Measures muscle activity, showing the muscle atonia in REM sleep.

4. Normal Sleep Histogram: A sleep histogram shows the distribution of sleep stages throughout the night, typically with periods of deep sleep (NREM stages 3-4) followed by REM sleep in cycles.

5. Neurotransmitters:

   • Wakefulness: Mainly regulated by norepinephrine and serotonin.

   • Sleep: GABA plays a key role in promoting sleep.

   • REM Sleep: Acetylcholine is important for initiating REM sleep.

6. Physiological Changes During Sleep: During sleep, there’s a decrease in heart rate, blood pressure, and respiration, while certain body systems, such as the immune system, become more active.

7. Need and Function of Sleep: Sleep is essential for physical restoration, memory consolidation, and cognitive function. It helps maintain immune function, hormone regulation, and overall well-being.

8. Categories of Insomnia:

   • Transient: Short-term insomnia caused by stress (e.g., one night of poor sleep due to an exam).

   • Short-term: Lasts up to three months, often due to situational stress (e.g., loss of a job).

   • Chronic: Ongoing insomnia lasting more than three months, often with underlying psychological or medical conditions.

9. Clinical Features of Sleep Disorders:

   • Sleep Apnea: Interruption of breathing during sleep, leading to oxygen deprivation and fragmented sleep.

   • Narcolepsy: Sudden and uncontrollable episodes of sleep during the day.

   • REM Behavior Disorder (RBD): Acting out vivid dreams, often with violent movements, typically during REM sleep.

   • Restless Legs Syndrome (RLS): An irresistible urge to move the legs due to uncomfortable sensations.

10. Pathophysiology of Sleep Disorders:

• Sleep Apnea: Caused by obstruction of the airway or a failure of the brain to signal breathing.

• Narcolepsy: Linked to a deficiency of hypocretin, a neurotransmitter involved in wakefulness regulation.

• RBD: Likely due to loss of muscle atonia during REM sleep, possibly related to neurodegenerative conditions.

• RLS: Associated with dopamine dysfunction and iron deficiency.

11. Pharmacological Approaches:

• Sleep Apnea: CPAP therapy, and medications like modafinil for daytime sleepiness.

• Narcolepsy: Stimulants (e.g., modafinil) and antidepressants to manage symptoms.

• RBD: Benzodiazepines (e.g., clonazepam) to reduce violent movements.

• RLS: Dopamine agonists (e.g., pramipexole), iron supplements, and sometimes opioids.