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While You Were Sleeping (CAMS-UA 161)

September 4th, 2018

Good sleep

1 Fall asleep easily

2 Sleep through the night

3 Wake up rested

Bad events:

● Exxon Valdez (oil spill)

● Challenger crash

● Chernobyl Nuclear meltdown

○ Lowest attention span = 1-2 am until 4-5 am

● Over 40 year period, Americans have reduced avg total sleep time by > 2 hours

● Elevated threshold for arousal/reactivity

● Rapid awakening w/ moderate stimulation

● Rebound recovery (increased sleep following deprivation)

*sleep ​= reversible behavioural state of perceptual disengagement from, + unresponsiveness to, the environment

synchrony produces higher amplitude on the EEG

Polysomnography

● Video-taped observation

● EEG - brain activity

● EMG (electromyogram) ​- muscle movement

● EOG (electrooculogram) ​- eye movement

● Vital signs

Actigraphy

● Measure of human rest/activity cycles

● Continually records movements

○ E.g: apple watch

BEARS

People who don’t dream:

● May be terrified of revealing themselves

● Sleep too deeply/too groggy to focus

● Sleep deprivation

● Medication/marijuana

Assumptions

1 Assume all dreams have meaning (stem from unconscious)

2 Assume they have a unique language

3 You are ultimate authority of the meaning of your dreams

4 Your dreams are about your life + are on your side

September 11th, 2018

Sleep in Antiquity

● References appear in Bible, Veda, Koran

● Opium poppy or belladonna & alcohol known to induce sleep

● Premonitory qualities of dreams

● Early forms of hypnosis and lucid dreaming

● Sleep disturbances described in Egyptian, Greek, & Chinese medicine

Early Theories of Sleep

● Alcmaeon

○ Sleep secondary to blood drainage from vessels on surface of body

● Aristotle

○ Vapors from food digesting in stomach rose to heart (brain) to cause sleep

● Galen

○ Sleep necessary to rebalance the body’s humours:

○ Hydraulic Model of Sleep

■ The pineal gland responsible for keeping the cerebral ventricles full to maintain alertness in the waking state

17​​th ​​Century ​​Thomas Willis

● The London Practice of Physick

○ Four chapters devoted to disorders producing sleepiness & insomnia

○ Coffee could prevent sleep

○ “Sleep”, not a disease but a symptom of underlying causes

○ Animal spirits undergo rest during sleep; those in the cerebellum become active during sleep to maintain control over physiology & cause dreaming

● Restless Legs Syndrome​: first described as an escape of these animal humours into the nerves of the limbs

○ Noted treatment was powdered opium

Sleep is a Passive State

● Before 1950s sleep was regarded as a passive state

● No clear distinction between sleep & other states with reduced awareness of

surroundings, such as coma, stupor, intoxication, and hibernation

○ Toxins and fatigue products accumulated during the day ultimately causing sleep

○ Toxins gradually eliminated during sleep

● Toxins built up during day and cause sleep

● As one slept, the toxins slowly drained away

Evidence for Hypnotoxins

○ (& in 1913 Legendre and Pieron)

● Suggested that hypnotoxin accumulates during wakefulness and dissipates during sleep

● Injected brain and blood extracts from sleep deprived dogs into awake dogs who fell asleep

● Great skepticism until it was replicated in 1960s with rabbits

Nathaniel Kleitman

● 1920s- observed that sleep deprived subjects were less impaired and sleepy next

morning than in the middle of night

● Kleitman argued that this observation is incompatible with hypnotoxin theory

● Lived for a month with “days” of 28 hours to study circadian rhythms

● In reality there are two systems that contribute to sleep, so they were both right (daily rhythm AND time spent awake)

EEG beginnings

● Richard Carton​ measures electrical activity in dogs’ brains after removing part of the

through the EEG

○ Clear differences when subjects were awake or asleep

○ Recordings of sleep were done for a few minutes per hour to save paper (no grants)

● He cut out/resected the nervous pathways that bring sensory stimulation to the brain

● This led Frederic Bremer to “isolate” cat brains

○ A Comatose after the resection of all sensorial info from the body (except olfactory & visual)

○ B Normal sleep and wake pattern; maintain face sensorial stimulation as resection is below cranial sensory centers (but above spinal centers)

○ Bremer concluded that the sleep is due to lack of stimulation of the cerebral cortex “demonstrating” that sleep is

a passive phenomenon

■ Correct experiment, wrong conclusion

Encephalitis Lethargica

● 1915-1926- epidemic spread around the world

○ No recurrence has since been reported, though isolated cases continue to occur

● Some patients affected had extreme somnolence, often leading to coma and death

● Others had hypokinetic form presenting with insomnia

● Don’t know what caused it

Von Economo

○ Two different cerebral areas affected in the “sleepiness form” and “insomnia agitation” form

○ Excessive sleepiness: in patients with damage in central area of brain (junction of midbrain and posterior hypothalamus)

○ Insomnia: in parents with damage in preoptic area/basal forebrain (behind eyes) and in front of hypothalamus (anterior hypothalamus)

● Diagonal hatching = hypersomnolence

○ Horizontal hatching = insomnia

○ Lesions at the arrow induce narcolepsy

■ These findings suggested that these two areas were the neural circuitry of sleep and wakefulness

Ascending Reticular Activating System

● Moruzzi and Magoun demonstrated that they could awaken sleeping cats by stimulating part of their brain

● Implanted electrodes into the brains of the cats, anesthetized them, zapped them,

leading to a desynchronized EEG (awake state pattern)

Psychoanalysis

● Dreams were seen as guardians of sleep and to occur in response to disturbance

● Dreams would keep sleeper asleep

● Freud believed that dreams discharged instinctual drives

○ Dreaming became seen as a safety valve of the mind

REM Sleep

● Kleitman and Eugene Aserinsky studying infant sleep noted a rhythm in eye movements

○ Same in adults as well

(REM)

● Woke people up during these phases

○ in REM they were reliably dreaming

○ rarely (and more confusedly) in NREM

● REM sleep EEG showed pattern close or identical to wakefulness

● Published in 1953

● Sleep is passive no more

● Came up with 4 sleep stages of NREM + REM

REM Atonia

● Dement noted that when cats started REM sleep their muscle tone disappeared

completely

● French researcher Michel Jouvet described the existence of REM in animals and

reported that REM was associated with atonia (1959)

● 1960- Dement and Hodes made same observation with humans

4 Silene Capensis/African Dream Root (brewed into a tea)

5 Mugwort (1 ounce dried herb to 1 pint boiling water, 5-10 minutes)

6 Calea Zacatechichi (tea or capsules)

Writing Dreams Down

● Carl Jung​ created concept of “automatic handwriting”

○ Using non-dominant hand to write down dreams (dominant hand intrinsically bound to conscious mind)

● Three Adjective Rule

○ Choose person from your dream & spontaneously identify 3 adjectives to

describe that person

■ If a professor you view as harsh, critical, and dismissive shows up in your dream, then perhaps this represents an aspect of your critical character

○ REM latency​ = time from sleep onset to first occurrence of REM sleep

○ REM density ​= how many rapid eye movements you have in 30 seconds

○ REM rebound​ = phenomenon after sleep deprivation where one enters REM sleep more quickly after sleep onset

○ Sleep onset REM period​ = the actual occurrence of entering REM sleep more quickly after sleep deprivation

● ​Waves

○ Gamma

■ Awake and excited

■ Awake or REM sleep

■ Open eyes and/or engaged intellectually

○ Alpha

■ Awake, closed eyes, relaxed

○ Theta

■ Awake or asleep

■ Often seen during light sleep or REM sleep or “trance” like states

■ Awake, N1, and REM

○ 2 Assign stage to each epoch

○ 3 If 2 or more stages coexist during a single epoch, assign the stage comprising the greatest portion of the epoch

● Wakefulness

○ Beta waves dominate

○ Gamma and theta also possible

○ Alpha waves appear most notably when eyes are shut (drowsy or not)

○ Wakefulness counts for less than 5% of the night in most adults

○ Anterograde amnesia for 1-3 minutes before sleep onset

● Sleep stages

○ Stage 1 (N1)

■ Low voltage, mixed frequency EEG

■ Defined by exclusion (devoid of sleep spindles and K-complexes, minimal slow wave activity)

■ Defined by presence of sleep spindles and/or K-complexes

■ Accounts for 45-55% of total adult sleep

● Sleep spindles​ = EEG waveforms in with a sinusoidal rhythm or 12-14 cps waxes and wanes for 1-2 seconds

○ Occur every 10-30 seconds

○ Occur in NREM stages 2 & 3 but are hard to see in stage 3 (bc of high amplitude slow waves)

● K-complexes​ = EEG waveform with a well delineated negative sharp wave followed by a slower positive component

○ Can occur in response to a stimulus (external) but may be spontaneous as well (internal)

○ Stage 3 (N3, slow wave)

■ High amplitude slow waves

■ Sleep spindles and K-complexes may or may not be seen (but often occur)

■ Delta (slow) waves occur at about 2 cps with high voltage peaks (75 microvolts)

■ Accounts for 13-23% of total adult sleep

○ REM sleep

■ Saccadic eye movements

■ Low voltage, mixed frequency EEG

■ Very low level of below the brain EMG activity

■ Characterized by sawtooth waves

● Lucid dreaming

○ Dream in which the dreamer is aware he/she is dreaming

○ Term not used until 1913

dreams in which he knew he was dreaming

○ References to LD exist as far back as 415, the year in which St Augustine

penned a letter recalling a LD experience

○ This phenomenon was subject of many 20th century books

■ Both personal accounts + tools for LD work

○ Stephen LaBerge

■ Brought LD study into scientific reading

○ Scientists still unsure what structure within brain causes LD

○ Tends to occur towards end of night

○ False awakening ​= dreamer thinks he/she is awake but is actually dreaming

■ Originate in the thalamus

■ Thought to represent periods when the brain is inhibiting processing to keep the sleeper tranquil

○ K-complexes

■ Originate widely in cortex

■ Occur naturally in response to external stimuli

■ Aid in sleep based memory consolidation (usually followed by bursts of sleep spindles)

○ Delta waves

■ Originate in thalamus or cortex

■ Stimulate release of several hormones (GHRH/Prolactin)

■ Inhibit release of TSH

■ Important in declarative memory consolidation

● Point of REM?

○ Important for developing brain, especially during infancy & childhood

■ May provide a “workout” or stimulation for the developing brain, leads to more growth

○ Muscles most relaxed during REM

■ Cell repair

■ Immune system operations

○ Important for procedural memory

● NREM physiological changes

○ Autonomic slowing

○ Maintain thermoregulation

○ Episodic, involuntary movements

○ Reduced blood flow

○ Little dreaming

● REM physiological changes

○ Increased physiological activity

○ Autonomic activation

○ Altered thermoregulation

■ Cells in anterior hypothalamus cease firing, which makes us essentially poikilothermic (cold blooded)

■ REM sleep lost during temperature extremes

○ Partial or full penile erections (significant vaginal lubrication)

○ Skeletal muscle paralysis (muscle atonia)

● Sleep cycle

○ REM periods every 90-120 minutes

○ First REM is shortest

○ Most sleep occurs during stages 3 & 4

● Basic Rest Activity Cycle ​​(BRAC)

○ For many years been hypothesized to exist

○ Based upon observation that about every 90 minutes while awake (or asleep) our body rhythms cycle

■ Ultradian rhythm of CNS

■ Integrates somatic, visceral, and behavioural functions

● GI activity, sexual fantasies, resting HR, eye movements, EEG frequencies, eating, etc

● Synaptic Homeostasis Hypothesis (SHY)

○ Lots of stimulation = creates many pathways among neurons

○ EEG irregular and low voltage

■ 34 weeks

● NREM appears

● Limited body movements

● Regular heart and respiratory rate

● Higher EEG voltage

○ Newborns

■ Active sleep becomes REM sleep

● Uneven respiration

● Muscle atonia, many myoclonic jerks (muscle jerks)

● Continuous EEG activity

● Rapid eye movements

■ Quiet sleep becomes NREM sleep

● Even respiration

● Body is inactive

● Discontinuous EEG (tracé alternant)

○ Different electrical activity

○ Babies’ brains are smaller

● No eye movements

■ Indeterminate sleep

■ 16-18 hours of sleep a day

■ 3-4 hour sleep-wake cycles

■ Shorter sleep cycles (50 min)

■ REM sleep is 50%

■ At 4 weeks, circadian rhythm of core body temperature

■ At 3 months, circadian rhythm of melatonin and cortisol

■ The more immature you are born, the more REM you have

● Baby horse vs baby kitten

○ Infant sleep consolidation

■ Unpredictability of waking episodes for first 3 months

■ Rhythm with an approx 25-h period emerges at about 5 weeks

■ Well consolidated pattern at around 15 weeks

■ Sleeping through night achieved at 4-6 months

○ SIDS (Sudden Infant Death Syndrome)

■ Under age 1

■ Cause unknown but possibly due to:

● Problems with baby’s ability to wake up (sleep arousal)

● Inability for baby’s body to detect a buildup of carbon dioxide in the blood

■ SIDS rates have dropped dramatically since 1992

■ Still kills about 2500 per year

● 3rd leading cause of death among US infants

■ Peak between 2-4 months

■ Risk factors:

● Sleeping on the stomach

● Cigarette smoke/illegal drug use

● Elevated room temperature

● Co-sleeping

● Soft bedding in the crib

● Multiple birth babies (being a twin, triplet, etc.)

● Premature birth

● Family history of SIDS

● Short time period between pregnancies

● Late/no prenatal care

■ Proportion of SWS decreases to adult levels

■ Night owl tendency

■ Adolescents still need around 9 hours

■ Sleep deprived, social jet lag, sleep marathons on weekends

○ Sleep EEGs

■ As more neurons grow and become more synchronized, deep sleep becomes higher voltage

● Higher wave forms bc more nerves are doing the same thing

■ Later see a reduction in deep sleep voltage around teen years as brain prunes

○ Aging

■ SWS decreases during adulthood and may disappear completely by age

60

■ Men begin losing SWS at 30, women after menopause

■ Amount of REM sleep is preserved in healthy elderly adults, but less rems

■ 6-7 hours

■ Unclear whether elderly have a decreased need for sleep or simply a different distribution of sleep

■ Increased fragmentation of sleep

■ Prolonged latency to sleep onset

■ Increased number of arousals

■ More time spent awake

■ Increase of primary sleep disorders

■ Tendency to wake earlier and feel more alert

● Sleep in women

○ Sexual differences affecting brain and body (different hormonal profile)

○ Childbearing and childrearing/family + social roles

○ Main differences:

■ Duration (sleep longer)

■ Changes with aging

● Sleep better until menopause

● Have more SWS throughout life and less light stage sleep

■ Disorder profiles

● More likely to have insomnia while men more likely to snore/have sleep apnea

■ Distribution of sleep stages

■ More fragmented and disrupted sleep in the perimenopausal period

● Show more Alpha rhythm during sleep, in part secondary to hormonal changes

■ Report more difficulties falling asleep and decreased sleep efficiency

○ 75% report disturbed sleep during pregnancy esp during 2nd/3rd trimester

○ Estimated that in first year of of a child, parents lose 400-750 hours of sleep

○ Parents of infants and toddlers who have difficulties sleeping are more prone to depression and anxiety

● Co-sleeping

○ Average US rates on the rise

○ Cultural norm for black children (70%) and Latino (20%) in the US

○ Less than 12% of middle class white children share a room

● Sleep in Homo Sapiens

■ 94 volunteers wearing devices recording level of movement and vasoconstriction

■ People from all 3 groups slept between 5.7 and 7.1 hours

● Very similar to industrial society

● Bedtime seemed to be regulated by body temperature rather than daylight

● Rarely napped in summer, never in winter

● Hunter-gatherers had bigger seasonal variation in the amount of sleep (1 hour more in winter)

● Barely suffered from insomnia

October 16th

● The human brain

○ Consumes > 20% body’s energy

○ Comprised of > 100 billion neurons

○ Reptilian brain ​= brainstem & cerebellum, part of brain focused solely on warmth, survival, etc (no higher level functions)

○ Limbic brain​ = amygdala, hippocampus, hypothalamus, thalamus, basal ganglia,

○ Neocortex​ = part of cerebral cortex concerned with sight and hearing

○ Melatonin is produced in pineal gland

■ Hormone, not neurotransmitter

○ Agonists​ & ​antagonists

■ Agonists mimic neurotransmitter, antagonists block

○ Death of neurons → lack of function executed by those neurons

○ Neurotransmitters = receptors = lock-key

● Anatomy

○ Anterior​ = in front

○ Posterior​ = behind

○ Lateral ​= from the side

○ Sagittal ​= down the middle

○ Coronal​ ​= crown, from above or below

● Arousal and sleep

○ Von Economo​ identified brain areas important for arousal and sleep:

■ Insomniacs had lesion to the anterior hypothalamus (VLPO)

■ Hypersolomnments had a lesion to the posterior hypothalamus

○ Bremer​ demonstrated an ​ascending reticular activating system (ARAS)

■ Misinterpreted his experiment

■ Upper transection of the cat brain resulted in coma

○ Moruzzi & Magoun​ demonstrated that they could awaken sleeping cats by

stimulating the ARAS

● VLPO (Ventrolateral preoptic nucleus)

○ Group of neurons in the hypothalamus that are particularly active during NREM sleep

● NTs/Reasons for sleepiness/awakeness

○ Worried about an exam → brain releases noradrenaline

○ About to win the lottery → brain produces dopamine

○ Taking Benadryl → blocks histamine

○ Drinking coffee → blocks adenosine

● Hormones vs NTs

○ NTs

■ Released by neurons

■ Act quickly & locally

■ E.g GABA, dopamine, noradrenaline, serotonin

○ Redundancy in the wake promoting brain centers (nuclei)

○ Likewise, redundancy in messengers (NTs & hormones)

○ Nicotine acts on ACh pathways, addictive bc acts on dopamine

disrupted sleep/wake cycle

○ Wake promoting but ​active in REM

■ Because brain waves are the same in REM as they are in wakefulness

○ Rewards increase the level of dopamine transmission in the brain

○ Some highly addictive substances (cocaine, amphetamine) act directly on the dopamine system

● Serotonin

○ Wake promoting

○ Regulates mood, impulsivity, anxiety, appetite, and sleep

○ From median raphe nuclei

○ Vast majority of serotonin is in the gut

○ SSRIs can disrupt normal sleep (reduce REM and cataplexy in those with

narcolepsy)

● Histamine

○ Wake promoting

○ Produces widespread excitatory “waking” effects throughout the brain

○ From posterior hypothalamus and tuberomammillary nuclei

○ Mediates immune response and appetite

○ Histaminergic cells can be recorded firing just before an animal shows signs of waking

○ Antihistamines block the allergic response and cause sedation (Benadryl)

● Norepinephrine (Noradrenaline)

○ Wake promoting

○ The stress neurotransmitter

○ From the locus coeruleus (LC) brainstem/ARAS

○ Released in “fight or flight”

● Orexin/Hypocretin

○ Wake promoting

○ Lack of orexin receptors results in narcolepsy in dogs

○ Peptide NT, key to staying awake

○ From hypothalamus

○ Stimulates ​ALL​ wakefulness centers and increases release of wakefulness NTs

○ Central injections suppress NREM and REM

○ Increases appetite

● GABA (Y-Aminobutyric Acid)

○ Sleep promoting

○ Primary inhibitory NT in the brain

○ GABA from the VLPO inhibits wake promoting nuclei during sleep

○ Medications that increase GABA induce sleep, reduce anxiety, and stop seizures

● Adenosine​ ​(ATP)

○ Sleep promoting

○ Neither stored or released as a classical NT

○ Formed inside cells or on their surface

○ Extracellular concentration of adenosine increases in the cortex and basal forebrain during prolonged wakefulness and decreases after sleep

○ Causes cerebral blood vessel dilation to let in more O2

○ Receptor is blocked by caffeine

● Melanin concentrating hormone (MCH)

○ REM promoting

○ From hypothalamus

○ Feeding behaviour, mood, sleep/wake cycle and energy balance

○ MCH expressing neurons are located very close to those of Orexin

● Melatonin

○ Hormone that comes from pineal gland (“pine core”)

○ Modulates sleep/wake patterns

○ First peak midday and second (higher) in the evening

October 23rd, 2018

● Randy Gardner

○ 1965 San Diego high school student

○ Didn’t sleep for 264 hours

○ Dement noted no problems, he is reported to have suffered short term memory problems, paranoia, hallucinations and confusion

○ After 14:40 hours recovery sleep on day #1 and 10:30 hours day two, he was well and no subsequent sequela have been observed

● Common Myths

○ A large lunch/boring meeting/warm room makes me sleepy

○ Make you bored; not sleepy

■ May unmask sleepiness that is already present

● Sleepy Foods

○ Sugar leads to insulin production

○ Large insulin releases cause more tryptophan to be absorbed by the brain

(melatonin/serotonin)

○ Bread, chips, crackers and other simple high-carb foods act like high sugar foods

by releasing insulin

● How much sleep do we really need

○ Thomas Wehr​ 1992 study

■ Volunteers began with 8 hours sleep each night for a week (washout period)

■ Then had 14 hours in the darkness each night with 8 hours outside of the sleep lab daily

■ For the first 3 weeks people averaged 12 hours of sleep each night

■ By the 4th week, they settled into 8.25 hours of sleep each night (range: 7.5-9 hours)

● Biphasic​ = having two phases

● People tended to sleep in two 4-hour blocks with 1-2 hours awake

in between

● Biphasic sleep

○ Throughout evolution it is hypothesized that people had biphasic sleep pattern

■ Two 4 hour segments

● First sleep/deep sleep

● An hour or so in between or activity

● Second sleep/morning sleep

○ Electricity is proposed to have forced us into our current monophasic sleep pattern

● Sleep needs over the life cycle

○ Adults/older persons = 7 - 9 hours

● Multiple Sleep Latency Test (MSLT)

○ Measures sleep latency in two hour intervals

■ Generally at 10am, 12/2/4 and 6pm

■ Duration is 20 minutes if no sleep occurs, 15 minutes from onset of nap (if patient falls asleep)

○ Alertness is determined based upon how long it takes you to fall asleep

■ 0 - 5 minutes = severe (“​twilight zone​”)

○ To draw in more O2 & expel CO2

■ But putting people into O2 rich environment doesn’t decrease yawning

■ Similarly, decreasing amount CO2 doesn’t prevent it

○ Brain temperature control

■ One experiment found that when people had cool packs attached to their heads, they yawned less

● Deleterious effects of sleep loss

● Neurobehavioural effects of sleep loss

○ Sleep deprivation adversely affects functions mediated by prefrontal cortex, esp attention and working memory, upon which most cognition depends

○ Adolescents are the demographic with most trouble with decision-making,

engaging in high risk behaviour, etc… and the demographic that is most sleep deprived

● Neurocognitive effects of sleep disruption

○ Attention and memory

○ Psychometric testing

■ Sleep deprivation shown to:

● Reduce computational speed

● Impair verbal fluency

● Decrease creativity and abstract problem solving ability

■ Severe sleep fragmentation may result in reduced IQ

● Psychomotor Vigilance Test

○ Subject pushes a button as soon as a light appears on a computer screen

■ Not an assessment of reaction time but rather a measure of sustained attention

○ Light flashes every 2 - 10 seconds for 10 minutes

● Libby Zion

○ The Bell Commission

■ Dr Bertrand Bell organized investigation into medical resident student hours

■ Recommended an 80 hour work week

● No more than 24 hours of straight work

● Residents receive more attending physician supervision

● ACGME​ Resident Work Rules

○ 80 hour work week

○ At least 10 hours off between shifts

○ No more than 16 hour shift for interns

○ No more than 24 hour shift for residents (+6 hours of indirect patient care to help with hand-offs)

○ At least 1 day off in 7

● Institute of Medicine Report (2008)

○ Working for more than 16 consecutive hours is unsafe for physicians-in-training and their patients

○ Sleep loss impairs brain function, concentration, coordination, and increases the risk of error

○ After 24 hours w/o sleep:

■ Attention failures double,

■ Impairment of reaction time is comparable to being legally drunk,

■ Physicians’ clinical performance drops to the 7th percentile of their performance when well-rested

○ Often sleep deprived individuals do not realize impairment

○ 30 hour shifts = 36% more serious medical errors caring for ICU patients

■ Including 464% more diagnostic errors than those scheduled to work 16 hours

■ 168% increase risk of motor vehicle accident when coming home

■ 73% more likely to stab themselves with a needle/scalpel when performing procedure after working 20 hours than during a 12 hour shift