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….?)