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Paul ReadingConsultant Neurologist
James Cook University Hospital
Journal of the Canadian Medical Association, 2006
� I. Defining sleep- sleep “need” (a drive state)
- (adverse) effects of age- why do it?
� II. Effects of acute sleep deprivation - animal studies- cerebral imaging changes (structural changes?)
- neuropsychology
� III. Likely associations of chronically poor sleep- an early marker for cognitive decline- quality more important than quantity?- every chronic condition potentially affected
� IV. Causes of poor nocturnal sleep- many are reversible and go unrecognised- sedative drugs rarely improve sleep quality
Everyone and every animal(with a brain) needs to sleep!
If sleep doesn’t serve some vital function it isthe biggest mistake evolution ever made.
Alan Rechtschaffen
Sleep is of the brain, by the brain andfor the brain
William Dement
The best bridge for repair between despairand hope is a good night’s sleep
Joseph E Cossman
Amazing breakthrough
Scientists have discovered a revolutionary new treatment that makesyou live longer. It enhances your memoryand makes you more creative.It makes you look more attractive.It keeps you slim and lowers foodcravings. It protects you from cancerand dementia. It wards off colds andthe ‘flu. It lowers your risk of heart attacks and stroke, not to mention diabetes.You’ll even feel happier, less depressed,and less anxious.
Are you interested?
SLEEP
Sleep remains an enigma! numerous unanswered questions…
Why do all animals have
an absolute need for it?
Why do we dream?
What are the triggers? What is the nature of sleepiness?
How is sleep orchestrated?
What neurophysiological events
occur below the surface EEG?
What are the effects of sleep
deprivation (acute and chronic)
How much do we need?
Sleep
what is it …and why do it ?
1 2 3 4 5 6 7
time (hours through night)
WAKING
REM Sleep
I
II
III
IV
REMREM REM REM
slow-wave sleep (SWS) ≈ marker of sleep quality (>90 mins per night)
numerous “sleep toxins” may increase proportion of light non-REM sleep
N3 {typical hypnogram
of young adult
The effects of normal ageingsleep “quality” deteriorates
� sleep less consolidatednocturnal sleep generally less “efficient” (>90% young ; <80% old)
~6 (minor) EEG arousals during sleep are common if >65yr
� progressive “deterioration” in deep slow wave sleep (SWS)
amplitude and density ᵟ-waves
(<4Hz, >75μv)
reduces > 25 yrs in ♂- - earliest biomarker of ageing?- due to normal cortical pruning?
� reduced “sleep-ability”homeostasis impaired?
elderly not sleepier
� “clocks” advance~30 mins per decade
slo
w w
ave a
cti
vit
y S
WA
What is the function of sleep?unitary or multiple?
“metabolic”(cellular) restorative
“plasticity/memory”improved cognitive function
active or passive process?
synthesis of macromolecules
energy savings
replenishment of energy substrates
for brain
recovery from oxidative/ER stress;protein misfolding
memory consolidation
synaptic strengthening
synaptic downscaling
thermoregulation
brain development
� recent evidence suggests sleep allows detoxification by glial shrinkage
____________________________________________________
� sleep allows synaptic downscaling and aids memory consolidation
Sleep
how much ?
How much sleep is needed?
6 hours for a man6 hours for a man6 hours for a man6 hours for a man
7 hours for a woman7 hours for a woman7 hours for a woman7 hours for a woman
8 hours for a fool8 hours for a fool8 hours for a fool8 hours for a fool
NapoleonNapoleonNapoleonNapoleon
“Sleep is a criminal waste of time, inherited from our cave days”
Total sleep deprivation is fatal in rats
Mechanism of death?
- multi-organ failure- inflammatory markers ↑↑
- bacteraemia- wt loss despite ↑ food intake
- thermoregulation ↓
- seizures (no major pathology?)
� article from Psychological Review, 1859:
“ A Chinese merchant had been convicted of murdering his wife and
was sentenced to die by being deprived of sleep … The [three] police
guards relieved each other every alternate hour, preventing him from
sleep, night and day. He thus lived for nineteen days. At the
commencement of the eighth day, his sufferings were so intense that
he implored the authorities to grant him the blessed opportunity of
being strangulated, guillotined, burned to death, drowned, garrotted,
shot, quartered, blown up with gunpowder, or put to death in any
conceivable way which their humanity or ferocity could invent. This
will give a slight idea of the horrors of death from want of sleep ”
Total Sleep Deprivationis it fatal in humans?is it fatal in humans?is it fatal in humans?is it fatal in humans?
Structural imaging after acute sleep deprivation
� Recent evidence for significant white matter tract changes- diffusion tensor imaging (DTI) shows H2O diffusion across membranes
after 23h awake: significant ↓ in axial & mean diffusivity in many areas
fronto-temporal cortex, brainstem, thalamus
diffusion changescorrelate with poorsubjective sleepiness
23 h
awake
14 h
awakeaxia
l d
iffu
siv
ity
8 hrs/night
0 14 140
6 hrs/night
4 hrs/night
0 hrs/night
data suggest increasing signs of sleepinessdespite regular 6 hours of nocturnal sleep
but subjective sleepiness ≠ objective sleepiness
Van Dongen et al Sleep 2002
PVT = psychomotor vigilance test
subjective ≠ objective sleepiness
Lack of sleep
acute effects
� sleepiness- subjective ≠ objective
- eye-blinks slower (more frequent)
- pupillary “instability”�
- sleep latency (on MSLT) ~3 minif no previous overnight sleep
� slower - reaction times longer
brain “ages” by ~10 yrs for every 90 mins of sleep deprivation
- vigilance / sustained attention particularly affected
- brain has to work “harder” to complete cognitive tasks
-- lapses and “micro-sleeps” a common practical concernnote the eyes can be open (~30%)
Sleep Deprivation(measurable) acute consequences
poor decision makingon/after night shift
(Horne 2012)
medical staffpoliticians / diplomats
bank traders
dealing with unexpected events;
increased mistakes when shifting
rapidly between simple cognitive tasks
(Couyoumdjian 2009)
increased distraction
seen on mundane (driving) and
complex tasks (baggage screening)
(Anderson 2013, Basner 2008)
poor recognition of emotions;
less trustful
(van der Helm 2010;
Anderson 2010)
“values” associated
with economic decision making
and visual reward altered
(Libedinsky 2011)
less risk averse
and reduced learning
about losses when gambling;
more impulsive
(Venkatraman 2007
Anderson 2011)
morning types especially
affected by adverse (acute)
effects of night shift
(Groeger 2008)
stimulant drugs (cocaine…?) reduce
sleepiness and improve alertness but do
not improve impaired risk assessment
(Killgore 2011)
sudden waking during sleep
at night impairs military
strategic decisions
(Horne 2011)
sleep deprivation biases
towards pursuit of gain (greedy)
rather than avoidance of loss
(Venkatraman 2011)
Lack of sleep
associations and
chronic effects
(chronic) lack of (“good”) sleep
hypertension metabolicsyndrome
diabetes
cancer
depression
immunity↓
Short sleep and incidence ofcoronary heart disease
Cappuccio FP et al. Eur Heart J 2011; 32: 1484-92
Cappuccio FP et al.
Diabetes Care; 2010; 33: 414-20
Poor sleep and incidence of type 2 diabetes
short sleep
impaired sleeponset
impaired sleepmaintenance
(chronic) lack of (“good”) sleep
mortality↑
hypertension metabolicsyndrome
diabetes
cancer
depression
immunity↓
1
1.1
1.2
1.3
1.4
1.5
3 4 5 6 7 8 9 ≥10
ha
zard
ra
tio
reported hours of sleep
Men
Women
n > 1 100 000
Kripke et al, 2002
Sleep duration and mortality chance of death within 6 yrs follow-up
~20% report 6 hours or less
(chronic) lack of (“good”) sleep
mortality↑
hypertension metabolicsyndrome
diabetes
dementia
cancer
depression
“sleep is of the brain,
by the brain and
for the brain”
immunity↓
is reduced sleep (or prolonged “wake”) actually neurotoxic?
Chronic sleep problems as a marker forsubsequent cognitive decline
Does (objective) poor quality sleeppredict cognitive decline?
Sleep 2013; 36:1027-32
� 737 elderly Canadians without dementia followed over 6 yrs (13% developed AD)
- at study onset: 10 days actigraphy to measure sleep fragmentation
KRA = probability of movement in 15s epoch after 5 mins of rest / sleep
risk of developing AD ↑ 22% if KRA higher by 1 SD
KRA 90th percentile
KRA 10th percentile
KRA 10th percentile
KRA 90th percentile
� better sleep continuity (↓KRA) attenuates negative impact of ɛ4 allele on AD risk
� 201 brains (from 737) analysed at post mortem :
reduced KRA (low sleep fragmentation) protected ɛ4 effects on AD pathology
- density of tau neurofibrillary tangles (not amyloid plaques)
time / years
___ APOE ɛ4 ---- APOE ɛ4 +
Protein mis-folding in neurons (glia?) is afundamental feature of neurodegeneration
� can abnormal accumulation of mis-folded / insoluble proteins be
delayed or offset by improving the quality / quantity of nocturnal sleep?
- “detoxification” / altering the unfolded protein response (UPR)
Alzheimer’s amyloid plaquestau in tangles
Parkinson’s synuclein in cytoplasm(Lewy bodies)
CJD prion protein
trinucleotide repeat disease proteins withe.g. Huntington’s polyglutamine
stretches
MND SOD1, TDP-43, FUS
Could improving sleep in neurodegenerativedisease provide “neuroprotection”?
� mouse AD model (APPswe/PS1dE9) develops amyloid plaques at ~12w
>8 wks treatment with hypocretin antagonist
intra-peritoneal Almorexant :
- total sleep amount increased (>10%)
- amyloid plaques virtually abolished
in all brain areas studies
Kang Science 2009
vehicleAlmorexant
� APP/PS1 mice engineered to produce no hypocretin (Roh J Exp Med 2014)
- sleep time increased overall by ~18%, plaque burden reduced (>50%)
Poor nocturnal
sleep
(reversible?) causes
Medical causes
• Obstructive sleep apnoea• Nocturnal asthma• Oesophageal reflux• Prostatism / nocturia• Pain syndromes
diabetic neuropathy,
fibromyalgia
Neurological causes
• Restless legs syndrome• Narcolepsy • Parkinson’s disease• Multiple sclerosis• Dementia• Morvan’s syndrome• Fatal familial insomnia
Psychiatric causes
• Medication related(stimulating anti
depressants)• Withdrawal-related• Anxiety disorders• Mood disorders
factors potentially affecting sleep-wake cycle“secondary” (co-morbid) insomnia
“sleep toxins” adverselyaffecting sleep quality
inhibit progression fromlight non-REM sleep todeep slow wave sleep
don’t forget the environment :
light, temperature extremes,discomfort, noise, snoring partner!
� usually easy to pick up from history / phenotype
� male, overweight, neck circumference > 17”
� don’t overlook retrognathia, large tonsils
~4% middle-aged men (2% women)
� unrefreshing sleep with severe snoring & pauses
� nocturia, dry mouth in morning, worse > alcohol
� confirmed by investigations (oximetry or ambulatory home study)
apnoea/hypopnoea index (AHI) : <15 ~mild; 16-30 ~moderate; >31 ~severe
or oxygen desaturation index (ODI)
� treatment options: wt lossCPAPMAD’ssurgery
Obstructive Sleep Apnoea (syndrome)
Restless legs syndrome (RLS) andperiodic limb movements of sleep (PLMS)
associates with : neuropathy / anaemia (Fe↓) / renal failure
� U.R.G.E.
• URGE to move legs
• worse with REST
• better if you GET up
• worse in EVENING
Poor Sleep
effects of drugs(good and bad…)
� commonly used drugs to treat symptoms associated
with poor sleep (e.g. neuropathic pain, anxiety, depression)
may facilitate sleep onset and increase its durationbut not improve its overall quality :
� Opiates : REM ↓↓ SWS ↓↓ arousals ↑↑↑
� AED’s : REM ↓ SWS ↑ sleep quality poor
� Anti-dep : REM ↓(↓) SWS ↓↔ sleep maintenance ↓↔restless legs worse
� BZ’s / alc : REM ↓ SWS ↓ sleep maintenance ↑
� β-blockers : REM ↓ SWS ↔ bad dreams/nightmares; impaired sleep onset(note: melatonin inhibited)
Drugs and sleep quality
Drugs that may enhance deep sleep and improve “quality”
* only drug with specific
indication for insomnia
� Pregabalin
� Gabapentin
� Tiagabine (Gabatril)
� Sodium oxybate (Xyrem, GHB)
� Melatonin (Circadin) *
� Cannabis
� Agomelatine
� Trazadone?
� Mirtazepine?
� Vortioxetine?
Conclusions� The majority of population require ~7 hours of sleep
- sleep patterns change with age but little change in sleep need
� The consequences of inadequate sleep are profound- nocturnal sleep quality (slow wave sleep) as important as quantity- the effects of chronic sleep deprivation extend beyond the brain
� Will improving / extending sleep be neuroprotective?- early evidence from animal models in many degenerative disorders
� Reversible “sleep toxins” are often not recognised- obstructive sleep apnoea, restless legs syndrome, drug effects
sleep
thank you for listening(and staying awake….?)