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Paul Reading Consultant Neurologist James Cook University Hospital Journal of the Canadian Medical Association, 2006 ∑ I

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Paul Reading Consultant Neurologist James Cook University Hospital Journal of the Canadian Medical Association, 2006 ∑ I 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%) dealing with unexpected events; increased distraction increased mistakes when shifting seen on mundane (driving) and rapidly between simple cognitive tasks complex tasks (baggage screening) (Couyoumdjian 2009) (Anderson 2013, Basner 2008) poor recognition of emotions; morning types especially less trustful affected by adverse (acute) (van der Helm 2010; effects of night shift Anderson 2010) (Groeger 2008) sudden waking during sleep poor decision making at night impairs military on/after night shift less risk averse strategic decisions (Horne 2012) (Horne 2011) and reduced learning medical staff about losses when gambling; “values” associated politicians / diplomats more impulsive with economic decision making bank traders (Venkatraman 2007 and visual reward altered Anderson 2011) (Libedinsky 2011) sleep deprivation biases stimulant drugs (cocaine…?) reduce towards pursuit of gain (greedy) sleepiness and improve alertness but do rather than avoidance of loss not improve impaired risk assessment (Venkatraman 2011) (Killgore 2011) 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
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