Paul Reading Consultant 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 is the biggest mistake evolution ever made. Alan Rechtschaffen
Sleep is of the brain, by the brain and for the brain William Dement
The best bridge for repair between despair and hope is a good night’s sleep Joseph E Cossman Amazing breakthrough
Scientists have discovered a revolutionary new treatment that makes you live longer. It enhances your memory and makes you more creative. It makes you look more attractive. It keeps you slim and lowers food cravings. It protects you from cancer and dementia. It wards off colds and the ‘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 remains an enigma! numerous unanswered questions…
What neurophysiological events Why do all animals have occur below the surface EEG? an absolute need for it?
Why do we dream? How much do we need? SLEEP
What are the effects of sleep How is sleep orchestrated? deprivation (acute and chronic)
What are the triggers? What is the nature of sleepiness? Sleep what is it … and why do it ? WAKING
REM REMREM REM REM Sleep I
II typical hypnogram III of young adult N3 { IV
slow-wave sleep (SWS) ≈ marker of sleep quality (>90 mins per night) numerous “sleep toxins” may increase proportion of light non-REM sleep
1 2 3 4 5 6 7 time (hours through night) The effects of normal ageing sleep “quality” deteriorates
∑ sleep less consolidated nocturnal 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, >75 μv) reduces > 25 yrs in ♂
- - earliest biomarker of ageing? - due to normal cortical pruning? ∑ reduced “sleep-ability” homeostasis impaired? elderly not sleepier
∑ “clocks” advance SWA activity wave slow ~30 mins per decade What is the function of sleep? unitary or multiple?
“metabolic” “plasticity/memory” (cellular) restorative improved cognitive function active or passive process?
thermoregulation synthesis of memory synaptic macromolecules consolidation strengthening
recovery from synaptic energy savings downscaling oxidative/ER stress; brain development protein misfolding replenishment of energy substrates for brain ∑ 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 man 7 hours for a woman 8 hours for a fool Napoleon “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?) Total Sleep Deprivation is it fatal in humans?
∑ 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 ” 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 axial diffusivity axial diffusion changes correlate with poor subjective sleepiness 14 h 23 h awake awake subjective ≠ objective sleepiness
0 140 14 8 hrs/night PVT = psychomotor vigilance test 6 hrs/night 4 hrs/night data suggest increasing signs of sleepiness despite regular 6 hours of nocturnal sleep 0 hrs/night but subjective sleepiness ≠ objective sleepiness Van Dongen et al Sleep 2002 Lack of sleep
acute effects Sleep Deprivation (measurable) acute consequences
∑ sleepiness - subjective ≠ objective - eye-blinks slower (more frequent) - pupillary “instability” ∑ - sleep latency (on MSLT) ~3 min if 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 concern note the eyes can be open (~30%) more impulsive more less risk averse less Anderson 2011) Anderson (Groeger 2008) (Venkatraman 2007 and reduced learning and reduced effects of night night shift of effects morning types especially types morning about losses when losses gambling; when about affected by (acute) adverse by affected increased increased distraction (Venkatraman 2011) sleep deprivation biases deprivation sleep (Anderson 2013, Basner2013, (Anderson 2008) seen on mundane and (driving) mundane seen on rather than avoidance loss than of avoidance rather towards (greedy) of gain towards pursuit complex tasks (baggage screening) tasks complex (baggage bank bank traders medical staff medical (Horne 2012) (Horne politicians / politiciansdiplomats
on/after on/after night shift poor decision making (Killgore 2011) (Couyoumdjian 2009) less trustful less (Libedinsky 2011) Anderson 2010) Anderson “values” associated associated “values” (van der 2010; der (van Helm dealing with unexpected events; unexpected with dealing increased mistakes when shifting when increased mistakes and visual reward altered reward and visual (Horne 2011) (Horne stimulant drugs (cocaine…?) (cocaine…?) reduce stimulant drugs not improve impaired impaired improve risk assessment not rapidly between tasks between cognitive simple rapidly sleepiness do but and alertness improve sleepiness strategic decisions strategic with making economic with decision poor recognition emotions; of poor recognition at night impairs military impairs at night sudden waking sleep waking during sudden Lack of sleep associations and chronic effects hypertension metabolic syndrome
depression
(chronic) lack of (“good”) sleep immunity ↓ diabetes
cancer Short sleep and incidence of coronary heart disease
Cappuccio FP et al. Eur Heart J 2011; 32: 1484-92 Poor sleep and incidence of type 2 diabetes
short sleep
impaired sleep onset
impaired sleep maintenance
Cappuccio FP et al. Diabetes Care; 2010; 33: 414-20 hypertension metabolic syndrome mortality ↑ depression
(chronic) lack of (“good”) sleep
immunity ↓ diabetes
cancer Sleep duration and mortality chance of death within 6 yrs follow-up 1.5 n > 1 100 000 Men Kripke et al , 2002 1.4 Women
1.3 ~20% report 6 hours or less
1.2 hazard ratio hazard 1.1
1 3 4 5 6 7 8 9≥10 reported hours of sleep hypertension metabolic syndrome mortality ↑ depression
(chronic) lack of (“good”) sleep
immunity ↓ dementia diabetes “sleep is of the brain, cancer by the brain and for the brain”
is reduced sleep (or prolonged “wake”) actually neurotoxic ? Chronic sleep problems as a marker for subsequent cognitive decline Does (objective) poor quality sleep predict 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
th ↑ 22% if K higher by 1 SD KRA 10 percentile risk of developing AD RA
th KRA 90 percentile
th KRA 90 percentile
th KRA 10 percentile ___ APOE ɛ4 - --- APOE ɛ4 +
time / years
∑ better sleep continuity (↓KRA ) attenuates negative impact of ɛ4 allele on AD risk
∑ 201 brains (from 737) analysed at post mortem :
reduced K RA (low sleep fragmentation) protected ɛ4 effects on AD pathology - density of tau neurofibrillary tangles ( not amyloid plaques) Protein mis-folding in neurons (glia?) is a fundamental 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 plaques tau in tangles
Parkinson’s synuclein in cytoplasm (Lewy bodies)
CJD prion protein
trinucleotide repeat disease proteins with e.g. Huntington’s polyglutamine stretches
MND SOD1, TDP-43, FUS Could improving sleep in neurodegenerative disease provide “neuroprotection”?
∑ mouse AD model (APPswe/PS1dE9) develops amyloid plaques at ~12w >8 wks treatment with hypocretin antagonist vehicle intra-peritoneal Almorexant : Almorexant
- total sleep amount increased (>10%) - amyloid plaques virtually abolished in all brain areas studies Kang Science 2009
∑ 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 factors potentially affecting sleep-wake cycle “secondary” (co-morbid) insomnia Medical causes
• Obstructive sleep apnoea Neurological causes • Nocturnal asthma • Oesophageal reflux • Restless legs syndrome • Prostatism / nocturia • Narcolepsy • Pain syndromes • Parkinson’s disease diabetic neuropathy, • Multiple sclerosis fibromyalgia • Dementia • Morvan’s syndrome • Fatal familial insomnia
Psychiatric causes “sleep toxins” adversely affecting sleep quality • Medication related (stimulating anti inhibit progression from depressants) light non-REM sleep to • Withdrawal-related deep slow wave sleep • Anxiety disorders don’t forget the environment : • Mood disorders light, temperature extremes, discomfort, noise, snoring partner! Obstructive Sleep Apnoea (syndrome)
∑ 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 loss CPAP MAD’s surgery Restless legs syndrome (RLS) and periodic 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…) Drugs and sleep quality
∑ commonly used drugs to treat symptoms associated with poor sleep (e.g. neuropathic pain, anxiety, depression) may facilitate sleep onset and increase its duration but 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 that may enhance deep sleep and improve “quality” ∑ Pregabalin ∑ Gabapentin * only drug with specific ∑ Tiagabine (Gabatril) indication for insomnia ∑ 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….?)