<p>Define Sleep</p>
<p><u>Sleep</u></p>
<ul> <li>Condition of body and mind</li> <li>Typically recurs for several hours per day</li> <li>Eyes are closed, postural muscles relaxed, and consciousness is practically suspended.</li></ul>
<p>What issleep associated with?(6)</p>
<p><u>Properties of Sleep</u></p>
<ul> <li>Specific postures</li> <li>Inactivity</li> <li>Reduced responsiveness</li> <li>Rapidly reversible</li> <li>Eyes Closed</li> <li>Beahvioural preludes <ul> <li>Pre-sleep behaviour</li> </ul> </li></ul>
<p>What are some wayssleep can be measured? (3)</p>
<ul> <li>EEG: Typically in 30 second epochs <ul> <li>Summed brain-wave activity</li> </ul> </li> <li>EOG <ul> <li>Eye movement</li> </ul> </li> <li>EMG <ul> <li>Muscle Tone</li> </ul> </li></ul>
<p>EEG activity of Wakefulness (Open and Close)</p>
<ul> <li>Wakefulness (Eye open; Active) <ul> <li>Beta Activity (13-30Hz)</li> <li>Desynchrony (Low amplitutde, High Frequency)</li> </ul> </li> <li>Wakefulness (Eye close) <ul> <li>Alpha Activity (8-12Hz)</li> </ul> </li> <li>EEG synchrony develops with sleep (High Amplitude, Low Frequency)</li></ul>
<p>What isthe EEG, EOG, EMG of Wakefulness</p>
<p><u>Wakefulness</u></p>
<p>EEG:</p>
<ul> <li>Mixture of Alpha (dominant) and Beta Waves <ul> <li>"Relaxed Wakefulness"</li> </ul> </li></ul>
<p>EOG:</p>
<ul> <li>High Amplitude</li> <li>Sharp waves represents eyeball movement</li></ul>
<p>EMG:</p>
<ul> <li>Muscle activity present</li></ul>
<p>Describe the EEG, EOG, EMG of Stage 1 NREM</p>
<p><u>Stage 1: Non-REM</u></p>
<p><u>EEG</u></p>
<ul> <li><strong>Theta </strong>Activity (4-7Hz), characteristic of Stage 1</li></ul>
<p><u>EOG:</u></p>
<ul> <li>Slow eye-rolling to reflect dozing off</li></ul>
<p><u>EMG:</u></p>
<ul> <li>Muscle activity present but reduced</li></ul>
<p>Describe the EEG and EOG of Stage 2 NREM</p>
<p><u>Stage 2: Non-REM</u></p>
<ul></ul>
<p><u>EEG:</u></p>
<ul> <li><strong>K Complex</strong> <ul> <li>EEG from negative (up) to positive (down) to baseline quickly</li> <li>Amplitutde >75mV; >0.5s</li> </ul> </li> <li><strong>Sleep Spindle</strong> (Characteristic) <ul> <li>Period of fast/high activity greater than alpha activity.</li> <li>Between 11-16 Hz; > 1s</li> </ul> </li></ul>
<p><u>EOG</u></p>
<ul> <li>Activity picked up likely from EEG</li></ul>
<p>Describe the EOG and EEG of 3.) Non-Rem Sleep</p>
<p>Stage 3: Non-REM</p>
<p><u>EOG</u></p>
<ul> <li>Activity picked up likely from EEG</li></ul>
<p><u>EEG:</u></p>
<ul> <li>Delta Waves <ul> <li>K complexes occurring together</li> <li>Waves large ampltitude, slow frequency waves <ul> <li>>75mV, 0.5-2s</li> </ul> </li> <li>More than 20% of the epochs (6s) contains delta waves (20-50%)</li> </ul> </li></ul>
<p></p>
<p>Describe the EEG and EMG of 4.) Non-Rem Sleep</p>
<p><u>Stage 4: Non-REM</u></p>
<p><u>EEG:</u></p>
<ul> <li>Delta Waves <ul> <li>K complexes occurring together</li> <li>Waves large ampltitude, low frequency <ul> <li>>75mV; 0.5-2s</li> </ul> </li> <li>Once more than 50% of the epochs (6s) contains delta waves</li> </ul> </li></ul>
<p><u>EMG</u></p>
<ul> <li>Muscle tone drops substantially</li></ul>
<p>Summary of Non-REM Sleep</p>
<p>Stage 1: N1</p>
<ul> <li>ThetaActivity <ul> <li>4-7Hz</li> <li>Low in amplitude.</li> </ul> </li></ul>
<p>Stage 2: N2</p>
<ul> <li>K Complexes and Sleep Spindles</li> <li>When K-Complexes get larger and start to merge, delta waves (slow, large amplitude waves)</li></ul>
<p>Stage 3: N3/SWS</p>
<ul> <li>Delta waves >20% of epoch</li></ul>
<p>Stage 4: N3/SWS</p>
<ul> <li>Delta waves >50% of epoch</li></ul>
<p>What are other physiological markers (respiration, heart rate, muscle activity, cognitive activity) of NREM?</p>
<p><u>Respiration and HR</u></p>
<ul> <li>Stable and Regular respiration and HR <ul> <li>Slightly lower than wake</li> </ul> </li></ul>
<p><u>Muscle Tone:</u></p>
<ul> <li>Present (lower than wake)</li></ul>
<p><u>Cognitive Activity</u></p>
<ul> <li>Cognitive activity <ul> <li>Thought-like, rational</li> <li>If woken, would respond rationally (e.g. they’ll say they were thinking about what they were doing during the day). This is different from REM sleep.</li> </ul> </li></ul>
<p>Difficult to rouse from SWS</p>
<p></p>
<p>Describe the EEG, EOG, EMG of REM Sleep</p>
<p><u>REM Sleep</u></p>
<p><u>EEG:</u></p>
<ul> <li>Theta Activity (4-7Hz) <ul> <li>Desyncrhonized EEG Pattern, similar to Stage 1 NREM</li> </ul> </li> <li>"<strong>Sawtooth Waves</strong>" <ul> <li>Small negative to positive deflections</li> <li>Necessary but insufficient for REM (REM + Low muscle activity + Theta)</li> </ul> </li></ul>
<p><u>EOG:</u></p>
<ul> <li><strong>Rapid Eye Movement</strong> <ul> <li>Distinguish from NREM</li> </ul> </li></ul>
<p><u>EMG</u></p>
<ul> <li>Loss of muscle tone/paralysis (except respiration and eye muscle)</li></ul>
<p>What are other physiological variables (respiration and heart rate) during REM? And what are properties of dreams</p>
<p><u>REM</u></p>
<ul> <li>Respiration, heart rate and blood pressure is much more variable during REM sleep and they matchdream content <ul> <li>Dreams are vivid and emotional</li> </ul> </li></ul>
<p>What is the sexual status during REM sleep</p>
<p>Signs of sexual arousal</p>
<ul> <li>REM sleep as an impotence test</li></ul>
<p>Summary of REM Sleep Markers (7)</p>
<ul> <li>Theta activity (desynchronized EEG pattern)</li> <li>Enhanced and variable respiration and blood pressure</li> <li>Rapid eye movements (REM)</li> <li>Pontine-Geniculate-Occipital (PGO) waves</li> <li>Loss of muscle tone (paralysis, except breathing and eye muscles)</li> <li>Vivid, emotional dreams</li> <li>Signs of sexual arousal</li></ul>
<p>Summarize Non-REM and REM Sleep Stages (% Asleep)</p>
<p><u>Non-Rem Stage 1: N1</u></p>
<ul> <li>5%</li></ul>
<p><u>Non-Rem Stage 2: N2</u></p>
<ul> <li>45%</li></ul>
<p><u>Non-Rem Stage 3: N3/SWS</u></p>
<ul> <li>12%</li></ul>
<p><u>Non-Rem Stage 4: N3/SWS</u></p>
<ul> <li>13%</li></ul>
<p><u>REM:</u></p>
<ul> <li>25%</li></ul>
<p>Summarize Awake, Non-REM and REM Sleep Stages (EEG)</p>
<p><u>Awake</u></p>
<ul> <li>Beta (>12Hz)</li></ul>
<p><u>Relaxed</u></p>
<ul> <li>Alpha (8-12Hz)</li></ul>
<p><u>Non-Rem Stage 1: N1</u></p>
<ul> <li>Theta (4-8Hz)</li></ul>
<p><u>Non-Rem Stage 2: N2</u></p>
<ul> <li>Theta (4-8Hz), K-Complex (>= 75mV, >0.5s). Sleep Spindles (11-16Hz, about 1s)</li></ul>
<p><u>Non-Rem Stage 3: N3/SWS</u></p>
<ul> <li>Delta (>= 75mV, 0.5-2Hz), Theta</li></ul>
<p><u>Non-Rem Stage 4: N3/SWS</u></p>
<ul> <li>Delta (>= 75mV, 0.5-2Hz),Theta</li></ul>
<p><u>REM:</u></p>
<ul> <li>Theta (4-8Hz)</li></ul>
<p>What is the structure of sleep through the night?</p>
<p>Stage: 90 minutes</p>
<p>Stage 1 (Transition) > Stage 2 > Stage 3+4 (Deep Sleep) > Short bout of REM > Repeat</p>
<ul> <li>First few cycles, predominance of deep sleep</li> <li>End ofnight, predominance of REM sleep. <ul> <li>REM sleep occurs most typically in the morning (About an hour in last cycle in REM)</li> </ul> </li></ul>
<p></p>
<p>What is the ontogenetic development of sleep</p>
<p><u>Age 0/Birth</u></p>
<ul> <li>16 hours of the day asleep <ul> <li>50% of sleep is REM</li> </ul> </li></ul>
<p><u>Age 2</u></p>
<ul> <li>%of REM sleep decreases dramatically <ul> <li>25% of sleep is REM.</li> </ul> </li></ul>
<p><u>Age 2 - Adoloscene</u></p>
<ul> <li>Decline of Sleep for both REM and NREM till 8 hours <ul> <li>20-25% of sleep is REM</li> </ul> </li> <li>Plateaus from here to about 65</li></ul>
<p>TLDR:</p>
<p>Proportion of REM drops then, both REM/NREM drops, then plateau from adoloscene onwards.</p>
<p>Theory behind the control of sleep</p>
<p><u>Borbley 2 Factor Model</u></p>
<ul> <li>Homeostatic factor (Process S) <ul> <li>Increaseexponentially during wakefulness (sleep drive increases)</li> <li>Decrease exponentially during sleep (sleep drive decreases)</li> </ul> </li> <li>Circadian factor (Process C) <ul> <li>Sine-Wave</li> <li>Internal Biological Clock</li> </ul> </li></ul>
<p>Magnitude of the difference between the functions defines the propensity to sleep. When 2 lines intersect = Wake up</p>
<p>Process S: How does it ensure appropriate sleep occur?How is this reflected?</p>
<p><u>Process S</u></p>
<ul> <li>Regulatory process (e.g., rebound effects)are activated to ensure that appropriate levels of sleep occur <ul> <li>When sleep is reduced, there are negative consequences</li> </ul> </li></ul>
<p>This is reflected in SWS</p>
<ul> <li>SWS amount diminishes assleep cycles go on.</li> <li>Sleep-deprived indiviudal has substnatially elevatedSWS</li></ul>
<p>Process C: Elaboration. Give one example.</p>
<p><u>Circadian rhythms</u></p>
<ul> <li>Endogenous (internally generated) biological clock (~24 hours)</li> <li>(Light is an external cue which can set the circadian rhythm)</li></ul>
<p><u>Example</u></p>
<ul> <li>Consistent with day-time hours, the plant would open up its leaves (despite not getting any light)</li></ul>
<p>Describe the constant environment experiment for Process C</p>
<p><u>Human</u></p>
<ul> <li>No time cues</li> <li>Day 1-20: Lights</li> <li>Day 21: Participants told they could control light <ul> <li>Participants gradually go to bed later and wake up later</li> </ul> </li></ul>
<p>Intepretations of the constant environment experiment</p>
<p><u>Constant Environment Experiment</u></p>
<ul> <li>Rhythmicity must be <strong>internal</strong> <ul> <li><strong></strong>Sleep-wake cycle remains rhythmical despite the external time and light cues removed</li> </ul> </li> <li>Period of the internal clock must be<strong> greater than 24 hours (24.5)</strong> <ul> <li>24-hour period must be from external factors (e.g., lights and clocks)</li> </ul> </li></ul>
What are limitations of Process S and C
Process S
- Can only be measured while asleep as process S is reflected in SWS
- During naps, SWS was proportional to time awake (Later nap = More SWS) - Consistent with theory
Process C
- Not exactly sine wave (Regular or Smooth)
- Circardian dip around 1-3pm
What is the hypnotoxin theory of sleep? What is the experiment?
Hypnotoxin theory of sleep
- Hypotoxin/ Sleep toxin builds up when awake and increase need for sleep
Experiment
- CSF of dogs deprived of sleep (up to 10 days) were injected into brains of well-rested dogs and induced sleep
What is the key mechanism behind process S? What is it?
Adenosine (Hypnotoxin)
- Nucleoside that forms from ATP breakdown
- 4 Receptors: A1 ; A2A ; A2B; A3
- A1 ; A2A : Brain
- A2A : Caffeine antagonist
Evidences for Adenosine behind Process S. (3)
Evidence for Adenosine behind Process S
- Coffee before bed inhibits (a) Sleep Onset; (b) Reduce SWS amount
- Brain adenosine increases in an activity-dependent fashion
- Injection of adenosine or Adenosine reuptake blockers induce SWS
What is an animal evidence for adenosine behind process S
Animal evidence for adenosine process S
In cats, adenosine levels in basal forebrain
- Rise during prolonged waking
- Fall during recovery sleep
Evidence for adenosine behind process S:
Individual Sleep Requirement
Strong correlation between reported sleep need, SWS amplitude and SWS amount and the form of adenosine deaminase (short or long) that an individual has.
Adenosine deaminase
- Breaks down adenosine
- Large genetic variability
- Need more sleep = Long acting form of adenosine deaminase = Need more time to break down adenosine in the body
Evidence for adenosine not behind Process S. Methods and Results
Zeitzer Sleep (2006):
Methods:
- Microdiaysis probe in amygdala
- Measuring adenosine during sleep deprivation and recovery in epileptic patients
Results
- Baseline sleep period
- Adenosine decreases (as expected)
- Wakefulness
- Adenosine decreases (not expected)
- Adenosine should increase gradually over sleep deprivation period
- Recovery sleep
- Adenosine increases
What are criticisms of Zeitzer Sleep (2006) study. (3)
- Generalisability: Epileptic patients
- Microdialysis probe might block adenosine from getting in [but in the recovery period, there was a rise in adenosine] (so this probably isn’t a limitation)
- Only on the amygdala (e..g., Basal forebrain; other areas might increase)
Further evidence, other than Zeiter (2006), for adenosine not being sole factor for process S. (3)
- Vast adenosine receptors in brain regions responsible for wakefulness
- Dynamics of adenosine build up and decay don’t match to process S (Exponential)
- Extreme activity (increases adenosine) should result in SWS increase but not observed
- e.g. marathoners
What are other factors which may be responsible for process S?
- Cytokines: Protein produced by leukocytes and other cell functioning
- Shown to promote sleep
- Other Sleep and Immune Factors
- Shown to promote sleep
What are circadian rhythms? What are the 4 key properties? When is it observed?
Circadian Rhythms
- Self-sustaining, daily oscillations approximately 24 - 24.5 hours
Properties
- Persist without time cue
- (Plants, Constant Environment)
- Phase can be shifted by lights/drugs
- (e.g., different time zone)
- Period can be entrained (if near intrinsic period)
- by lights, clocks, etc
- Not temperature-dependent
When is it observed
Observed in any bodily function/system – in sleep we commonly look at circadian rhythms in respect to core body temperature, Melatonin, Cortisol and lots of other variables (e.g. heart rate, breathing, blood pressure)
What is the circadian rhythm in other body systems: Temperature; Rectal temperature; Cortisol levels
Other bodily systems: Evidence for circadian rhythms
- Body temperature
- Fluctuation is constant despite manipulating light
- Rectal temperature
- Sine wave looking function
- Increases during daytime hours and decreases during night
- Sine wave looking function
- Cortisol levels
- Linear decrease during the day, where it reaches its lowest levels at night and rises back up again
What is the biological basis for circadian rhythm? Evidences for this biological basis?
SCN
- SCN contains a biological clock that governs circadian rhythms
Evidences
- Lesion disrupt circadian rhythm (Animal Study)
- SCN cells use chemical signals and do not require direct neural connections
- Animal can restore circadian rhythm by being implanted SCN
What is the behaviour after lesion of SCN in hamsters?
Before SCN-lesion
- Most of time drinking at night
After SCN-lesion
- Drinking behavior no longer restricted to nighttime
- But if you implant an SCN from a healthy animal, the circadian rhythm will recover and the pattern will revert
How do SCN cells know the time/ exhibit circadian rhythms?
- Individual SCN cells exhibit circadian rhythms
- The rhythm is set by proteins (per and tim) that inhibit their own production above a certain level
- The "clock" is set by how long it takes for protein to build up to threshold and how long it takes for it to be broken down to reach the lowest level
How do SCN cells get information about rhythm? (Inputs)(2)
SCN Inputs
Lights
- Ganglion cells in retina
- Contains Melanospin (Light-sensitive protein)
- Relay light information to SCN via retinohypothalamic tract, setting the clock
Activity
- Intergeniculate leaflet of LGN
- Information about lights AND other activities
- E.g., in blind people, circadian rhythm is set by using regular activities (e.g., waking time) to set this rhythm
What is Melatonin - How is it secreated and what is the function?
Melatonin
- Secreted naturally in the dark by pineal gland, by receiving information from SCN
Function
- Slight hypnotic effect (makes one sleepy)
- Feedback to SCN to phase shift the circadian rhythm
- Although, light is much more efficient at phase shifting
Evidences for Process S and C independence. (5)
S + C
- During forced desynchrony protocol, C and S process are independent
S
- SWS rebound after deprivation
- SWS negatively correlated with time-awake in daytime naps
C
- Circadian oscillator can be phase shifted without affecting SWS
- Animals with lesioned circadian cells show homeostatistic drive (e.g., rebound SWS)
What is the forced desynchronny protocol?
Forced desynchronny protocol
- lsolated from time and in constant dim light
- 28/20 Hour Day (Cannot entrainment)
- Circadian "free runs"
- Sleep at all circadian phases without sleep deprivation
Evidence against Process C and S independence (2)
- In forced desychrony protocol, slight interaction between the circadian and homeostatic systems
- Less SWS when out of rhythm
- Circadian phase slightly alter amount of SWS
- Sleep deprivation reduces the phase setting ability of light
- Sleeping well (S) = Entrain (C) is easier
Wakefulness System
- NT involved
- Location
Wakefulness System
- Cholinergic Neurons
- In LDT, PPT, BF
- Monoaminergic neurons
- NA, 5HT, Histamergic, DA
- In LC, Raphe, TMN, PAG
Example of Noradrenergic Pathway: How it links to sleep.
- NA cells in LC project to all areas of brain (esp. thalamus and hypothalamus)
- NA cells in LC more active in wake
- Agents promote NA increases wakefulness
- Agents inhibit NA deceases wakefulness
What is Orexin/Hypocretin - Location & Function
Orexin/Hypocretin: Master control
- Cells located in lateral hypothalamus
- Active during wake
- Excitatory projections to
- TMN (Histamine), Raphe (5HT), LC (NA)
- PPT, LDT, BF (Ache)
- and Cortex
Summary: Wakefulness
- Wakefulness is maintained by numerous cell groups projecting to thalamus, hypothalamus, basal forebrain and ultimately cortex.
- Orexin/hypocretin cells in the lateral hypothalamus have a general excitatory influence over this system and act as the master controller of wakefulness
Explain the Sleep System.
Sleep System (VLPO and BF)
- VLPO
- In anterior hypothalamus
- Inhibits all nuclei (incl. orexin) in wake
- Uses GABA and Galanin (Inhibitory NTs)
- BF
- Uses GABAnergic neurons
Bidirectional: TMN, LC, Raphe also inhibit VLPO (bidirectional)
When are VLPO neurons activated?
Elevated during sleep; not sleep deprivation
- VLPO activity does not make one sleepy, but it shuts wakefulness centres during sleep
What are the regions of VLPO? What happens if lesioned?
2 Regions
- VLPO Core
- NREM Loss of Sleep (50%)
- VLPO Extended
- REM Loss of Sleep (50%)
Note: Since 50%, suggest there are other processess in sleep.
Animal study: When basal forebrain (BF) is stimulated and lesioned. Results
Cats:
Stimulation Study Results
- Stimulation GABAregion in BF Induced sleep
Lesion Study Results
- Lesion of BF neurons led to reduced REM sleep and extended wake
- After 6 weeks, sleep recovers to normal
- Suggests neuroplasticity and VLPO compensating for BF loss
Explain the Flip-Flip Switch for Wake/Sleep
Sleep
- Homeostatic drive and Circadian 'hypnotic' signal pushes VLPO (Core and extended)
- VLPO neurons inhibits wake regions (orexin, TMN, etc)
Wake
- Lack of homeostatisic drive and Circadian 'Alerting' signal pushes wake regions (orexin, TMN, etc...)
- Wake regions inhibit VLPO
(Mutual inhibition)
Flip-Flop Switch: What are REM Sleep-on Neurons
REM Sleep-On Neurons
- Cholinergic cells (in LDT/PPT): Responsible for REM
- REM: Very active; Wakefulness: Moderately active; NREM: Inactive
- Activate GABA neurons in SLD (Region of pons active in REM)
- Inhibiting REM-off neurons
- Leading to REM-on.
- LDT/PPT also stimulate other pontine structures responsible for REM
Flip-Flop Switch: What are REM Sleep-off Neurons
REM Sleep-Off Neurons
- vlPAG/LPT GABA neurons inhibit REM.
- Inactive during REM; Active during Non-REM and waking.
- When active, inhibitis SLD and REM
- Activated by LC and Raphe (“finger” on switch) > REM-on
- Inhibited by the extended VLPO neurons. > REM-off
What is the role of orexin in REM
Orexin in REM
- Stimulates arousal and inhibits VLPO
- Associated stimulation of LC and Raphe inhibits REM
- During sleep, low level of Orexin activity
- Allows REM sleep
- During wake, low level of Orexin activity
- Make it difficult to maintain wakefulness
- Allow intrusion of REM
- During sleep, low level of Orexin activity
Explain the flip-flop switch NREM/REM
REM-On
- PPT/LDT (Switch) activate SLD
- SLD inhibits vlPAG, LPT
- PPT, LDT inhibits vlPAG, LPT
- ExVLPO inhibits vlPAG, LPT
REM-Off
- LC (Switch) activate vLPAG, LPT
- vlPAG, LPT inhibits SLD
- LC inhibit SLD
Define Sleep Paralysis (SP)
Sleep Paralysis
- Temporary period of paralysis prior to falling asleep (hypnogogic) or waking from sleep (hypnopompic)
What is SP associated with? (6)
Sleep paralysis (isolated or recurring) is associated with:
- Hallucinations
- REM at sleep onset
- Narcolepsy
- Familial inheritance
- Supine sleeping (on back)
- During episodes individuals are able to hear and open their eyes but unable to move.
What are the 3 types of SP
- Intruder
- Incubus
- Vestibular-Motor (V-M)
SP Type 1: Intruder
SP Intruder
Threatening presence with other hallucinations (e.g., footsteps, voices, humanoid apparitions, and feeling as though being touched or grabbed)
SP Type 2: Incubus
SP Incubus
Breathing difficulties, feelings of suffocation, bodily pressure, pain, morbid thoughts of impending death
(Moderate correlation between Intruder, Incubus, and fear)
SP Type 3: Vestibular-Motor
SP Vestibular-Motor
Sensations of linear and angular acceleration, floating, flying or falling, autoscopy (out of body experiences)
(Less related to Intruder/Incubus/Fear)
What increases the incidence of SP?
SP tend to result in fear
- Exposure to trauma (e.g., PTSD), heightened stress, poor sleep quality and anxiety symptoms can increase the incidence of SP
What is the biological basis for SP? (2)
- Disturbance of Sleep-Wake System
- Fear can arise during episode due to suppression of respiratory movement
- Poor breathing during REM but awake
- May also be involvement from activation of amygdala and brain tries to resolve emotional response by creating a threat
Prevalence, onset and progression of SP
Prevalance
- Varying. 3% - 62%
- Isolated/Recurrent
-
Prevalent in shift-work population
Onset
- Predominantly occurs in adolescents
- Median = 16, Common age range 13-18
Progression
- Decreases with age
What are the 4 classic features of Narcolepsy. (4)
Narcolepsy
Mandatory
- Excessive daytime sleepiness (EDS)
Typically present
- Cataplexy (60-70%)
- Sudden loss of muscle tone in response to emotional (positive) stimuli
- Knee-jerk reflex reduced
- Hypnagogic or hypnopompic hallucinations (30-60%)
- Pre or post-sleep
- Sleep paralysis (25-50%)
General basis for narcolyptic symptoms
REM sleep components intruding into wake (REM appearing at sleep onset and MSLT)
REM Sleep Atonia (Muscle Paralysis)
- Cataplexy
- Sleep paralysis
Intrusion of Dreams
- Hallucination
Neurobiological basis for Narcolypsy
Orexin signalling is altered in Narcolepsy (Less obvious flip-flop switch)
- Absent/very low orexin in most cases (Hence, inducing sleep)
- Possible receptor abnormality instead
Why do narcolyptic patients have disrupted sleep
Absent/Low orexin > Do not have additional inhibition on wake neurons during sleep (reliant on VLPO inhibitions)
Hence, they wake up more frequency and the flip flop switch is less obvious
Neurobiological basis for narcolyptic symptom: ESD
- Orexin stimulates all wakefulness promoting regions
- Without orexin these cells don’t act in concert (some firing, some not)
- So in wake some neruons are not firing well and person lacks direct cortical activation from orexin too.
Neurobiological basis for narcolyptic symptom: Cataplaxy
SP & Cataplexy
- Amygdala projects to both the REM-off/on neurons.
- No orexin + Strong emotional stimuli (Amygdala)
- > Amygdala has greater influence on SLD
- > SLD projects to medulla, spinal cord
- > which have inhibitory projections to alpha motor neurons.
- > Cataplaxy
What is the prevalance and onset of Narcolypsy
Prevalence/Onset
- 0.02-0.05%. Huge cross-cultural variability
- Israel - 0.002%
- Japan - 0.18%
- Equally in males and females
- Onset in adolesence (Teens-20s), sometimes following an illness/vaccination indicating an auto-immune component.
Diagnosis: Narcolypsy
Diagnosis: Narcoypsy
- Abnormal immune function
- HLA subtype where immune system attacks orexin
- Sleep study
- Short sleep onset latency (SOL)
- Short REM latency
- Increased wake
- Multiple Sleep Latency Test (MSLT) - Nap in day
- Rapid sleep onset
- REM onset
Narcolepsy – Treatment (3)
Treatment of Narcolepsy: Only can treat symptoms
- Excessive Daytime Sleepiness
- Planned naps
- CNS stimulants (dex-amphetamine, modafinil)
- Sodium oxybate
- Puts people to sleep almost instantly
- Cataplexy
- Antidepressants (clomipramine, fluoxetine)
- Sodium oxybate
- Research attempts to find orexin receptor agonists.
- Orexin can’t cross BBB so can't give orexin pill
What is REM Behaviour Disorder (RBD). What does it often precede.
RBD
- Loss of atonia in REM, resulting in dreams acting out
- Often precedes degenerative disease by many years (e.g., Parkinson’s)
Mechanism of REM muscle without atonia: Experiment
Rats
SLD lesion > REM sleep without atonia
SLD have projections through the pons and medulla to the spinal ventral horn (contain the alpha-motor neurons).
Mechanism behind RBD: Why can we still get REM without SLD
Two populations of SLD neurons:
- Flip flop switch
- Atonia
- With RBD, Flip-flop is working but not atonia
PPT/LDT might be involved too but it is unclear.
What are study methodologies of sleep (3)
- Disrupt sleep and look at consequences (e.g, sleep-deprivation on EF task)
- Modify “function factor” and look at sleep (e.g., give immune drug and see if it affects sleep)
- Evolution/comparative aspects (e.g. cross species)
What are considerations of sleep research (2)
- Most research looks at correlation versus causation
-
REM versus NREM sleep (might serve different function)
Rechtschaffen et al. (1989) Sleep Study: Method
‘Disk over Water Method’
- Totally sleep-deprived the rats
- EEG electrodes in brains and EMG electrodes in musculature
- When sleeping, slippery disc will rotate and rat will get wet
- Both groups (Sleep-deprived & yoked control) subjected to same conditions except sleep
Rechtschaffen et al. (1989) Sleep Study: Results (3)
Results
1.) Total Sleep Deprivation Rats died after 11-32 days
- Yoked controls were sacrificed within 30 minutes of their experimental pair dying.
- Causes was ambiguous
2.) Rats deprived of food (ad lib water) lived about 30 days.
3.) Rats deprived of REM died after 16 - 54 days
Rechtschaffen et al. (1989) Sleep Study: Conclusion (6)
Extended sleep loss reliably produces a syndrome of specific, substantial physiological changes
- Mortality (Ambigious cause)
- Scrawny appearance
- Localised severe skin lesions
- Intial rise in intraperitonal temperature, followed by large reduction
- > Food intake; > Energy Expenditure; < Body weight (Theory of Energy Conservation)
- Total recovery from symptoms after recovery sleep
Explain Energy Conservation Theory: Weak and Strong Form
Weak Form
- Immobility itself conserves energy
- Immobility is associated with lower levels of energy expenditure than activity.
- Sitting still and not moving = Expending less energy than you are moving around
Strong Form
- Sleep actively lowers energy expenditure below that of immobile wakefulness
- Lying in bed awake expands more energy than if you are lying in bed asleep.
First human evidence for Energy Conservation Theory? (And limitation)
Energy expenditure is measured by input/ ouput of O2/CO2
- Drop in O2 input and CO2 output in sleep
- Evidence that we are trying to conserve energy
- Increase in O2 input and CO2 output before waking up
- Possible that it is ciracadian-related
Second human evidence for Energy Conservation Theory?
Energy expenditure falls with sleep and time
- Condition 1: Regular
- Big reduction in energy expenditure sustained across the night
- Condition 2: Stay awake for the first three hours of the sleep period
- Larger drop in energy expenditure when you let them sleep
- Condition 3: Deprive the person of sleep the whole night up until an hour before they would usually go to bed
- Energy expenditure is sustained throughout the night and then has a massive drop when the person is allowed to sleep.
Suggest it's not a circadian effect
Evidence that energy intake affects sleep
Collet et al. (2016)
- Day 1: Baseline with caloric intake fixed at required level
- Day 2-3: Caloric restriction to 10% of requirements
- Day 4-6: Ad lib food recover
Results
- Calorie restirction increases Stage 4 Sleep (SWS) [Not REM/Light]
- Suggest Stage 4 has a conservative function
What are criticisms of energy conservation theory? (3)
- Fall in metabolic rate during sleep is small in magnitude (energy conserved in sleep is small ~160 calories)
- Active heat loss is associated with sleep onset (counterintuitive)
- Negative correlation over species between absolute basal metabolic rate and sleep duration in mammals (e.g., elephant should sleep more than mouse as they burn more energy but mouse sleep more) not birds
Do all animals sleep?
Depends on defintion of sleep:
Definition 1: Prolong inactivity, Ciracidan organisation, Reduced Responsiveness, specific posture
- All
Definition 2: Homostaetic Sleep Drive
- All but mollusc (snails), which is ?
Definition 3: SWS
- Primates, mammals, monotremes, birds
- Not reptiles, fish, mollusc, insects
Definiton 4: REM/NREM sleep
- Primates
- Mammals (except cetaleans)
- Monotremes (REM mixed with SWS)
- Birds
- Not reptiles, fish, mollsuc, insects
Phylogenetic studies on sleep: Explaining different sleep across species
What are three factors regarding animals and sleep.
After a point, evolution favoured a type of sleep and this type of sleep developed in these animals separately.
3 Factors
1.) Body Mass
2.) Encephalisation
3.) Predators
Factor 1: Does body mass relate to sleep?
Negative correlation between physical size and sleep need, but effect is exclusive to herbivore.
Herbivores
- Negative correlation between the sleep duration and body mass
- Possible that time taken for herbivore to eat outweigh benefits of sleep
Carnivores and Omnivores
- No correlation
- Possible that they source food easier and have more time to sleep
Factor 2: Degree of enchephalisation (Brain size) and sleep
The size of the brain relative to the body is:
- Positively related to %REM, but not SWS
- But this is a weak relationship (r2=0.04)
- Negatively related to sleep cycle length
- 10 mins in mice (relative large brain)
- 90 mins in humans
- 120 mins in elephants (relative small brain)
Factor 3: Predators and sleep
Number of predators
- Negatively related to amount of sleep
- More predator = Less Sleep
What is the immobility hypothesis?
Immobility Hypothesis
- Circadian system causes rest-activity cycle.
- Sleep has evolved to ensure immobility during the rest phase.
- Therefore, sleep acts to support and reinforce circadian organisation of behaviour
What is the implication of immobility hypothesis?
Implication
Sleep no longer serves a purpose in humans as we have so engineered our environment that food is always available and it is no longer dangerous to be active during the dark phase.
However, because the mechanism still exists we are obliged to continue to sleep.
Evidence for/against the immobility hypothesis?
Sleep of species appears to fit with their ecologic niche.
However, argument is retrospective and circular
(Do we stay still to sleep? Or do we sleep and because we sleep we stay still?)
Conclusions from phylogenetic studies (3)
- Large variation in sleep amounts
- Variation not predicted by phylogenetic order (e.g. primates as a group are not distinguishable from other species)
- While there is some relationship between sleep duration/cycle duration and animal characteristics
- Function of sleep is still unknown.
Sleep properties in the cetaceans (dolphins): 4
- Unihemispheric SWS sleep
- Allows to sleep in water
- One hemisphere of the brain is asleep (SWS)
- Other hemisphere of the brain is active
- No REM sleep
- Avoid atonia
- Many subspecies are rarely immobile (some species do float, or rest on the bottom)
- Limited evidence suggests weak rebound (Reduced hemeostatic effect)
Postpartum sleep in cetaceans?
Sleep is minimal in both neonate and mother postpartum.
Do not sleep for weeks and show very little rebound.
Sleep of Fur Seals: Winter + Summer
Winter (In water)
- Unihemispheric SWA
- Severely reduced REM sleep
- Motor asymmetry
- Flipper contra-lateral to the sleeping hemisphere is immobile
- Whiskers contra-lateral to the awake hemisphere used to monitor position
Summer (On land)
- Bilateral NREM and REM
- No REM rebound during the immediate post-winter period
Sleep of White Crowned Sparrow: Background and Sleep
Background
- Non-migration: Normal cycle of sleep
- During migration: Fly at night, but still active during the day. Therefore, they have minimal sleep
Sleep
- No apparent sleep deprivation effects
- Show the same seasonal activity patterns when confined to the laboratory, despite not migrating
Sleep of Frigatebirds
Evidence of unihemspheric, bihemispheric, REM during flights
What are the evidences that sleep serves a function (5)
- Numerous brain pathways to maintain sleep/redundancy in the system
- Serious physiological changes/death result from prolonged sleep deprivation of animals (e.g. rat)
- Sleep is found among mammals, birds and reptiles; and probably exists in amphibians, fish and invertebrates.
- Sleep has persisted in evolution even though it is apparently maladaptive with respect to other functions.
- Accommodations are made to permit sleep in different environments and life styles.
Broad evidences for sleep for body restoration (3)
- Exercise
- Physical Injury
- Immune Function
Sleep for Body Restoration: Exercise (2)
- Acute exercise has minimal effect on sleep
- Severe exercise can negatively impact sleep.
Sleep for Body Restoration: Physical Injury (2)
- Physical injury increases sleepiness,
- But medications, inflammation cytokines may contribute.
Sleep for Body Restoration: Immune Function (2)
Immune Function
- Immune function reduced when sleep deprived
- 165 people exposed to common cold virus after a week of actigraphy to assess sleep
- Negative association between getting a cold and sleep duration
- Fever (to fight infection) impaired when sleep deprived
Evidences for Sleep for Brain Restoration
1.) Glymphatic System
2.) Synaptic Homeostasis Hypothesis (SHY)
3.) Neural Network Theory
What is the Glymphatic system? (2)
Glymphatic system
- Pathway of fluid flow in the brain for clearance of macroscopic waste
- Ensures even distribution of macromolecules throughout the brain, allowing functioning
% of fluid in the brain?
10% blood vessels
10-15% CSF
20% in cells
50-60% between cells (interstitial fluid)
Explain CSF liquid flow in the brain and its link to glymphatic system (2)
- CSF and interstitial fluid continuously interchange (through gap)
- Waste products are collected from the interstitial space and exit the brain via the glymphatic system.
Explain Glympahtic system's role in sleep (Awake and Sleep - 2 ea)
Awake
- Astrocytes are big
- Reduced interstitial space > Lack of fluid flow > Metabolite accumulates
Asleep: Glymphatic flow dramatically increased in sleep.
- Astrocytes shrink
- More interstitial space > Increased convective flow > Augmented metabolite clearance
Gylmphatics in neurodegenration
Beta-aymloid builds up and form plagues in AD, but 65% of the brain beta-amyloid is removed through glymphatic system in sleep.
Sleep problems are common in AD and poor sleep increases risk of developing AD (particularly in patients who are genetically predisposed for AD)
[Causation unclear: Poor Sleep causes AD or AD causes poor sleep? > Likely causal]
Sleep and Memory: Experiment (2)
Walker (2004)
- Motor Task
- Dramatic improvement after sleep
- Visual Skill Task
- Sleep after learning the task is crucial
Why is the sleep-memory relationship complex? (3)
- Very few studies look at memory encoding in the presence of sleep deprivation, only consolidation
- Different memory types
- Different components of sleep
How does learning and Memory occur at a cellular level (2)
Neuronal firing: (increased) neuronal firing of connections that already exist
Neuronal connections: (New) Neuronal connections
What is Synaptic Homeostasis Hypothesis (SHY) (2)
- Wakefulness is associated with synaptic potentiation in cortical circuits.
- Net increase in synaptic weight
- Energy and space costs
- Changes are use dependent
- Function of sleep is Synaptic Downscaling
- Returning synaptic weight to baseline by creating more efficient pathways
How is synaptic weight reflected? (3)
- Synaptic weight is reflected in the amplitude of EEG waves and thus SWA
- Synaptic down scaling is a consequence of SWA, thus the exponential fall in SWA (SWA falls over the night)
More neuronal connection > More synchronous firing > Incresed SWA > Down-scaled throughout night > SWA reduces over the night
SHY: Implications for Learning and Memory (3)
- If synaptic changes occur during wakefulness, any change in relative strength of a connection should be present prior to sleep (no improvement after sleep)
- SHY suggests down-scaling improves the signal-to-noise ratio, but only if synapses are lost when their strength falls below a threshold
- Synaptic down scaling may be of benefit by creating “space” for new learning
Evidence in support of SHY (2)
- Genes involved in synaptic plasticity (LTP) are upregulated in wakefulness.
- Structural evidence in Drosophila show the expected synaptic size/number changes during wake/sleep
- More simplistic structure after sleep (Downscaling)
Evidence for local sleep in rats (4)
SWS sleep may occur as a local response to the activation of a brain region
- Unilateral sensory stimulation during wakefulness in rats
- Cut whisker on one side (reduce contralateral cortex input)
- SWA relatively higher in hemisphere contra-lateral to intact whiskers
- Fall in local, use-dependent SWA effect as a function of time asleep
Human evidence that sleep is local (2) SHY
(Easy vs Hard) Motor learning task before sleeping with EEG
- General sleep architecture was the same in the two conditions
- Power spectra averaged over all sites in 1-4 Hz range over the first 30 minutes of sleep was the same in the two conditions.
- But when SWA distribution were specifically compared, the hard condition produced a local increase in SWA in the right parietal region (expected)
What does neural network theory suggest? (2)
- Sleep is initiated at a local level in response to local brain activity, rather than being imposed by sleep regulatory networks
- Arose out of the observation of the existence of cortical columns.
What are Cortical Columns
- Collections of highly inter-connected neurons that often focus on particular tasks
- More intercellular connectivity within columns than between columns, making each column a functional unit
- 1,000 to 10,000 cells per column
- About 100,000 columns in brain
Evidence for sleep at a local level (2) NNT
Sleep should occur (in a column) independent of other columns.
- Comparing EEG of the left and right hemispheres
- Regions where both the hemispheres are doing separate things
- e.g. one hemisphere has a negative-positive-negative deflection while the other has the opposite
Evidence for sleep at local level (from epilepsy studies) NNT
- Implanted EEG electrodes in epilepsy
-
Different part of the brain can simultaneously be in different states (some wake, some sleep, etc)
Anecdotal Evidence for Local Sleep (5)
- Sleep Disorders
- Sleep walking
- Marine mammals
- Unihemispheric sleep
- Normal sleep unfolds regionally
- Amount of SWS is regionally use-dependent
- Explain sleep phenomena such as sleep inertia and performance lapses during prolonged wake
How is Global Sleep achieved? (3)
Use dependent local sleep: Why does brain act in concert
- Parallel independent processes have almost same homeostatic drive.
- Sleep may be “contagious” between cortical columns (cortical columns affect the other one)
- Independent processes entrain each other.
What is the definition of insomnia? (3)
Difficulty initiating or maintaining sleep
- No hard specification
- Initiation: Sleep onset >20-30 mins
- Maintenance: Wake after sleep onset >30mins
- >3x a week for 4 weeks
- Can be primary (no causes) or secondary (from cause)
- Daytime distress or impairment
What is the relationship between insomnia and mental health (2)
Bidirectional relationship
- High comorbaility between insomnia and psychiatric disorder
- Insomnia is a risk factor for future mood disorder
What casues insomnia?
Unclear, but we know there is hyperarousal (elevated cortical and physiological arousal)
Elevated Cortical Arousal in insomnia (4)
Elevated Cortical Arousal
- Subjective perceived increased cognitive activites, sensory, info processing
- Spectral Analysis/EEG
- Increased high frequency power during REM/NREM
- ERP
- Increased sensitivity to auditory stimuli at wake and sleep onset (unclear at deep sleep)
- MSLT
- EEG shows 24-hour hyperarousal
Elevated physiological arousal in insomnia (4)
Elevated Physiological Arousal
- Autonomic Variables
- Increased HR during pre-sleep & sleep
- Increased sympathetic activity (Fight/Flight); Decrease parasympathetic activity (Rest/Digest)
- Increased whole-body metabolic rate
- Increased core body temperature in elderly patients
- Increased night time cortisol production
How is insomnia treated? What are its components (4)?
CBTi: Longer lasting benefits than sedatives
- Sleep hygiene and education
- Sleep restriction (Build up sleep drive to find optimal amount)
- Stimulus control (Get out of bed if not sleepy - breaks association)
- Cognitive restructuring (reduce catastrophy about insomnia)
What is the link between depression and sleep? What do PSG studies show?
Bidirectional
- 50% of depression have comorbid insomnia
- Insomnia is a risk factor for depression
PSG studies:
Insomnia:
- Reduced TST, SE (sleep efficiency), SWS%, Increased SOL
Depression (added REM component):
- REM latency (earlier REM), REM%
How does depression drugs work on sleep? (3)
Depression drugs (e.g., SSRI) abolish or greatly reduce REM
- Increasing Raphe neurons with 5HT
- Inhibits REM-on neurons (SLD)
- Activates REM sleep-off neurons (VlPAG/LPT)
CBTi + Drugs on Depresion and Insomnia
Adding 7 sessions of CBTi in addition to AD (drugs) doubles remission rate on depression.
(Over and above)
How is sleep related to bipolar disorder?
Sleep disturbance is a key symptom of bipolar disorder
- Manic Phase: Reduced need for sleep
- Depressive Phase: Insomnia/Hypersomnia
Sleep deprivation can trigger a episode
Actigraphy in Bipolar Disorder
Actigraphy
- Manic = Massive movement
- Depressive = No movement
Supports idea that manic don't sleep much but depressive sleep alot.
What is the link between Schizophrenia and Sleep (3). What does PSG show (2)
- 45% of SZ patients have insomnia
- Sleep distrubance predisposes individual to SZ
- CBTi improved delusion in a pilot trial
PSG
- Reduced TST, SE, Increased SOL
- No sleep architecture changes (No REM changes unlike depression) but Reduced spindles (Stage 2)
What is the sleep phase like in SZ? (3)
Delayed sleep phase: (Go bed late, wake up late)
- Circadian phase abnormalities
- Persists with treatment in 50% of the people
- Sleep distrurbance remain post treatment, even those with restored circadian function
Limitations of delayed sleep phase SZ research (3)
Limitations
- Lack of imposed schedules (e.g., work), light exposure
- Drug effects, Excessive dopamine activity (might influence rhythm)
- No evidence that ACh, orexin, GABA involved
What is the link between sleep and depression in Adoloscene (2)
Vulnerable period for depression and occurance of depression predisposes to subsequent episodes
Multiple maturation changes [Brain; Sleep; Ciracian Rhythm; Life-style factors (e.g., peer)]
What is the synaptic connections and SWS changes in life development?
Why?
- Synaptogenesis in early years (0-4)
- Synaptic pruning in adoloscene, reducing synaptic density
- Massive reduction of EEG Delta (SWS)
- The reason we get delta is due to synchronous firing
Why
- Adoloscene prune off inefficient synapses
What are circadian changes across Early Adolescence:
Study (Methods, Results, Implications)
Methods
- Younger vs Old Kids in 36-hr constant routine
- Sleep latency test and melatonin measured
Results
- Phase delay in adoloscene (older)
- Melatonin onset was later in adoloscene (older)
Implications
- Delayed Circadian Phase in adoloscene due to puberty (not abnormal like SZ)
- Occurs in animals and across-cultures
Sleep in adoloscene: Socio-cultural factors (4)
- Social – cultural factors encourage adolescents to remain awake in the evening.
- Changes in the sleep and circadian systems are permissive of delayed wakefulness.
- Delayed wakefulness further phase delays the circadian system through a phase shifting effect of household lighting.
- Thus, sleep onset progressively delays through adolescence.
- Time of awakening is constrained by school and remains constant during adolescence. This reduces sleep duartion and increase deprivation.
- Reflected in rebound recovery sleep on the weekend and during school holidays
Results from SENSE study: Intervention on At-risk Adoloscents
At-risk adoloscent were compared CBTi vs Study Education
CBT & Mindfulness-based sleep intervention
- Improved subjective sleep measures (Global, SOL, TST, Daytime sleepiness)
- Improved objective sleep measures (SOL, less variability)
- Lower psychopathology (Anxiety, Ocd, Pre-sleep arousal)
- Increased sleep knowledge
Implications and follow-up from SENSE study: Intervention on At-risk Adoloscents
At 2 year follow up:
- Intervention reduced GAD than controls. but depression rates unchanged (onset rate same)
