2 Circadian Rhythms_Sleep_2015_1

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College PsychobiologieCircadiaan Ritme, Slaap en Waakritme

18 Mei 2015

Fernando Lopes da Silva


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Wat is de biologische endogene klok?

Hoe kan slaap gedefinieerd worden?

Welke zijn de controle systemen van slaap?

Wat is de evidentie dat slaap onder homeostatische controle staat?

Welke zijn de functies van slaap?

Wat zijn de gevolgen van slaapdeprivatie?

Kan slapen het geheugen verbeteren?

Algemeen: Handboeken:

-Breedlove, S. Marc and Watson, Neil V., Biological Psychology. An Introduction to Behavioral,Cognitive and Clinical Neuroscience. 7th Edition; Sinauer Ass, Inc. Publishers, Sunderland,

Massachusetts, 2013.Chapter 13: Homeostasis: active regulation of the internal environment, and

Chapter 14: Biological Rhythms, Sleep, and Dreaming,

- Purves, Dale et al. Neuroscience, 5th Edition.2012, Chapter 28: Sleep and Wakefulness.


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Circadiaan ritmiek: 24-uurs ritme

Een circadiaan ritme is een biologisch ritme waarvan de cyclus

ongeveer één dag duurt (Latijn: circa = ongeveer, dies = dag).

Een actieve periode wisselt af met een inactieve, of minder actieve,periode:

Dagdieren vertonen de meeste activiteit tijdens de lichtperiode.

Nachtdieren zijn meest actief tijdens het donker ( b.v. rat, muis, hamster)

Opname van voedsel en water vertoont een circadiane ritmiek dievergelijkbaar is met de ritmiciteit in activiteit;

Seizoenfactoren kunnen de ritmiciteit beïnvloeden ivm beschikbaarheid van

voedsel, veranderingen in temperatuur en daglengte.


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Figure 14.4 The Retinohypothalamic Pathway in Mammals


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Figure 14.3 Brain Transplants Prove That the SCN Contains a Clock

In the first part the hamster’s

activity pattern is entrained with

light.

After the SCN lesion the activity

pattern becomes random.

After transplantation of a SCN ofa fetal donor hamster and

placed in continuous light

environment the hamster shows

a “free-running” activity pattern,

with a periodicity equal to that of

the donor’s.In this case this donor carried a

mutation of the tau gene that

affects the duration of the

endogenous period.


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Doelstellingen College Slaap-waakritme

11 Vragen - Formuleer gepast antwoorden op de volgende vragen:

1. Hoe kan worden aangetoond dat de SCN is de generator van de circadiaan ritmiek?

2. Welke zijn de belangrijkste functies van de Nucleus Supra-Chiasmaticus?

3. Welke Hormoon wordt sterk verhoogd tijdens slaap?

4. Wat zijn de belangrijkste verschillen tussen SWS en REM-slaap?

5. Op welke leeftijd is de % van REM-slaap het hoogste?

6. Welke systemen in de hersenen vormen de kern van de neurale circuits van slaapregulatie

7. Hoe kan verminderde spiertonus in REM-slaap optreden?

8. Welk bewijs toont dat slaap is onder homeostatische controle?

9. Wat zijn slaapregulerende fysiologische variabelen?

10. Wat beïnvloedt prestaties het meest: een nacht van slaaptekort of een bloed-alcohool concentratie (BAC) van0.08%?

11. Hoe kan aangetoond worden dat slaap het geheugen beïnvloedt?


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SCN, Retino-hypothalamic-tact, Pineal gland and Melatonin

In mammals the SCN receives light information through the Retino-

Hypothalamic-Tract (RHT) and regulates pineal Melatonin synthesis. The

secretion of Melatonin (the so-called “hormone of darkness”) is restricted to

the night period and it inhibits night-time activity of the SCN.

Bell-Pedersen et al Circadian rhythms from multiple oscillators: lessons from diverse organisms. Nature Reviews

Drug Discovery 2005.


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Figure 28.5 Photoreceptors responsible for signaling circadian light changes

Circuit between the Retinal Ganglion Cells (Melanopsin) -

Hypothalamic ParaVenricular Nucleus (PVN) –- Sympathetic neurons in the lateral horns of the spinal cord

–

- Superior Cervical ganglia – Postganglionic axons project toPineal Gland


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Figure 14.6 A Molecular Clock in Flies and Mice

This is a simplified

view of the essential

step relating the RGC

activity to gene

transcription in theSCN molecular clock.

Several tissues have a

similar molecular

machinery but only the

SCN clock van be

entrained by light.

Cycle in Drosophila= Bmal1 in mammals


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Tjeerd.O.Scheper, Don Klinkenberg, Cyriel Pennartz,

Jaap. van Pelt, Model of Molecular CircadianPacemaker, J.Neurosci 1999.

r- production rate

q- degradation rate

Per & Cry

Clock &

Bmal1 or Cycle

The frequency and shape of Action potentials of

SCN neurons differs between day and night. The

low firing rate neurons that dominate at night have

larger amplitude than high firing rate (day) neurons

indicating higher ion channel density during the

night.

Atkinson et al . Cyclic AMP signaling control

of action potential firing rate and molecular

circadian pacemaking in the SCN. Journal

Biological Rhythms,2011.

It appears that SCN neurons via VIP/cAMP

modulate neuronal firing but the precisemechanism is not yet well known.

Achtergrond

informatie

Time delay


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How is the activity of the SCN molecular circadian clock transferred to

Behavior?

Campos et al Efferent projections of the SCN based on the

distribution of VIP and AVP immunoreactive fibers in thehypothalamus of Spajus apella, J Chem Neuroanatomy 2014

AHA – Anterior Hypothalamic Area

MPOA – Medial Pre-Optic Area

PVN – Paraventricular Nucleus

VMH – VentroMedial HypothalamusDMH – DorsoMedial Hypothalamus

SON – Supraoptic Nucleus

SCN has 3 main general

functions:

1. Pacemaker behavior: generating

autonomous circadian oscillations

even in the absence of external

agents: “clock in dish.

2. To Synchronize to light/dark cyclus;

3. To convey time clues to the rest of thebody.

In this way the SCN can realize

the following functions:

- Triggering hormone secretion;

- Controlling body temperature;

- Controlling hunger and satiety;

- Controlling wake-sleep cycles.

Hypothalamic targets:


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Synchronization of circadian timekeeping across the body

The primary SCN

pacemaker, entrained to

solar time by retinal

afferents, synchronizes

tissue-based clocks in the

major organ systems by a

blend of Endocrine

(ACTH, Gonadotrophins,

Metabolic hormones), Autonomic

(parasympathetic and

sympathetic nerve fibers)

and Behavioral (feeding-

related) cues, but with a

time delay of about 4 -

12hours.

Rhythmic Glucocorticoid

signaling is a prominent

mediator of SCN output

and acts as synchronizer

of important vital

physiological processes

such as cell division andnutrient metabolism.

Hastings, O’Neill and Maywood. Circadian clocks: regulators of endocrine and metabolicrhythms. J. of Endocrinology, 2007.

Hierarchical Model where

the SCN occupies the

leading role in the

organism


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D fi i i l


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Definitie van slaap

Een typisch voorbeeeld van een circadiaan ritme is de slaap-

waakritme.


Slaap is een periodiek terugkerend periode vanogenschijnlijke inactiviteit met omkeerbaar bewustzijnverlies

en met veranderingen in de autonome functies en de

spiertonus.

Slaap –Waak Ritme gaat gepaard met oscillaties in Temperatuur, in

Groeihormoon, in Cortisol niveaus en in het Electroencephalogram(EEG)

Fi 28 2 Ci di h th it f b d t t d th h & ti l l l


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Figure 28.2 Circadian rhythmcity of core body temperature and growth hormone & cortisol levels


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Fi 14 10 El t h i l i l C l t f Sl d W ki


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Figure 14.10 Electrophysiological Correlates of Sleep and Waking

Amzica, F- Science 2010

Leresche et al Eur J Physiol. 2012

SWS- Slow-Wave Sleep;

REM – Rapid Eye movements sleep;

K-complexes


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Figure 14 11 Sleep Stage Postures


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Figure 14.11 Sleep Stage Postures

Typical posture of

Slow-Wave Sleep

(SWS)

Typical posture of

REM sleep

Figure 14 12 A Typical Night of Sleep in a Young Adult


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Figure 14.12 A Typical Night of Sleep in a Young Adult

Young adult

Elderly


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“Slow Wave”(Delta) Slaap (SWS)

Algemene karakteristieken van SWS [of NREM, Niet-REM]slaap:• Wakker maken is moeilijk;

• De drempel voor het wakker maker neemt toe met de toename van SWS;

• Mensen gewekt uit de SWS hebben moeite dromen zich te herinneren;

• De spieren zijn verslap, maar er is nog tonus;

• De ogen maken langzaam rollende bewegingen;

• In het EEG: langzame golfbewegingen (Delta EEG activiteit) met frequenties van 0-4

Hertz, Incidenteel kunnen korte uitslagen op het EEG optreden aan het begin van deze

slaapfase, de zogenaamde slaapspoelen (13 – 16 Hz), alsmede een enkele grote uitslagdie K-complexen genoemd worden;

• Groeihormoon productie toeneemt;

• De Hartslag vertraagt;


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REM Slaap

Algemene karakteristieken van REM slaap:

• Tijdens REM slaap laat het EEG eenzeer gedesynchroniseerde

hersenactiviteit zien, hetgeen verrassend

genoeg overeenkomt met het soort

EEG-activiteit van de wakkere

toestand. Hierom wordt deze slaapfase

ook wel paradoxale slaap genoemd.

•Afname van spierspanning, maar snelle

oogbewegingen (REM);

• Verlies van autonome controle over

temperatuur en hart-ademhaling functies

– hartfrequentie: verhoogde, maar

onregelmatig; bloed druk stijgt;

ademhaling onregelmatig; penis erectie,

opgezwollen clitoris;

• Op ontwaken worden dromen vaak

vermeld, en beschreven.

PET (H215O) scans; The brain images are the differences in Cerebral Blood Flow (CBF)


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PET (H2 O) scans; The brain images are the differences in Cerebral Blood Flow (CBF)

between: - Waking and NREM sleep; - NREM and REM sleep; and - REM and Waking.

Hobson and Pace-Schott, The Cognitive Neuroscience of Sleep: Neuronal systems, consciousness

and learning. Nature Reviews/Neuroscience, 2002, 3: 679-693

Decreases in

activity from

Waking to

NREM: pre-

Frontal Cx,

Thalamus, Pons,

Caudate n.

Increases in

activity from

NREM to REM

sleep: Pons,

midbrain,

Thalamus,

Amygdala,

Hypothalamus,

Basal ganglia.

Increases from

REM to Waking:

Forebrain,Limbic and

Para-limbic

regions

Changes in Blood flow:Z-scores

l ll ll l k


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Figure 14 18 Human Sleep Patterns Change with Age


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Figure 14.18 Human Sleep Patterns Change with Age

D l lli C ll Sl k i


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10. Wat beïnvloedt prestaties het meest: een nacht van slaaptekort of een bloed-alcohool concentratie(BAC) van 0.08%?



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Thalamus

Sleep- Wake

rhythms are a

property of theCortico-

Thalamic-

Cortical

System:

S – W is the

result of the

Interaction

between

thalamus and

cortex.


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Hypothalamic and brainstem neural circuits

controlling sleep

Ascending arousal reticular system projects from the


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LDT/PPT: Lateral Dorsal

Tegmental Nuclei/Pedunculo

pontine Tegmental Nuclei;

Acetylcholine:

LC: Locus Coeruleus; Nor-Adrenaline;

Raphé Nuclei; Serotonin of 5-

HT..

TMN: Tuberomammilary

Nucleus;

Green arrows – Aminergic

projections:

Blue arrows – Acetylcholinergic projections

Saper, Chou and Scammell, The sleep switch: hypothalamic control of sleepand wakefulness. Trends in Neurosciences 2001, 24: 726 –731.

sce d g a ousa e cu a sys e p ojec s o e

brainstem to the Hypothalamus, Thalamus and Forebrain

Histamine

D di t (GABA ) j t f th H th l


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VLPO: ventrolateral

preoptic nucleus;

The VLPO projects to all

the other nuclei and

exerts an inhibitory

action by way of GABA

and galinin as

neurotransmitters.

VLPO : Ventro-Lateral-

Pre-optic Nucleus; in

red : GABAergic and

Galanin

Saper et al, TINS 2001, 24: 726 –731

Descending systems (GABAerg) project from the Hypothalamus,

to the mesencephalon and brain-stem

The Orexin (or Hypocretin, discovered in 1998) connection, a main switch in the


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The ORX/hypocretin

system innervates all ofthe components of the

ascending activating

reticular system, and

increase the firing of

neurons in:

LC, Raphé and TMN;

Thus the ORX system

prevents an inappropriate

switching from

wakefulness to sleep.

(Saper et al, TINS 2001, 24: 726 –731)

LH – “hongercentrum”(“orexinergic, bevat

Orexin/Hypocretin: van het Grieks

“oregein” = verlangen); stimulatie:

veroorzaakt overmatige

voedselopname: hyperfagie envetzucht - obesitas;

( yp )

sleep transitions : hypothalamic control of sleep and wakefulness.

u ua n on e ween an m nerg c nuc e


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Aminergic -HIST

Aminergic - NA Aminergic – 5-HT

GABA

Galinin

Ach

Dynamic FLIP - FLOP SWITCH

SLEEP AROUSAL

-

--

-

VLPODuring sleep

VLPO neurons

firing increase

Aminergic neurons fire during

arousal

REM

OREXIN

neurons firing

increase

during waking

During arousal

Aminergic

neurons

increase firing

Figure 28.8 Circuitry involved in decreased sensation and muscle paralysis during REM sleep


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How can muscle

atonia occur in

REM sleep?

GABA-A. GABA-B

Boucetta S, Cissé Y, Mainville L, Morales M, Jones BE.

Discharge Profiles across the Sleep–Waking Cycle of

Identified Cholinergic, GABAergic, and Glutamatergic

Neurons in the Pontomesencephalic Tegmentum of the

Rat. J of Neuroscience 2014

Doelstellingen College Slaap waakritme


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6. Welke systemen in de hersenen vormen de kern van de neurale circuits van slaapregulatie?








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6. Welke systemen in de hersenen vormen de kern van de neurale circuits van slaapregulatie?







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Sl f lfill ti l H t ti F ti i th h l


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• Sleep is homeostatically regulated and it is essential for survival.

• Sleep factors that accumulate in brain during prolonged wakefulness convey information of the

duration and intensity of the waking period.

Evidence that sleep is under homeostatic control:

Both SWS and REM increase in duration after total sleep deprivation, i.e. the longer the waking period, the more sleep pressure (S) is accumulated in the brain and the longer is takes todissipate it during sleep (recovery sleep).

Sleep fulfills an essential Homeostatic Function in the whole

organism

Tarja Porkka-Heiskanen. Sleep Homeostasis. Curr. Opinion Neurobiol. 2013

Daan, Beersma, Borbely. Timing of

human sleep – recovery process gated

by a circadian pacemaker. Am J.

Physiol. 1984.

Zavada, Strijkstra, Boerema, Daan,

Beersma. Evidence for differential

SWA regulation across the brain. Am J

Physiol. 2009

The “two-process” model of sleep


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The two process model of sleep

regulation consists of the following

elements:

1. A sleep-regulating physiological

variable (factor S) that increases during

wakefulness and decreases during sleep.

2. Sleep onset occurs when S reaches a

threshold H (sleep threshold); awakening

occurs when S reaches a threshold L

(wake threshold).

3. The thresholds are regulated by a

circadian pacemaker or process C.

4. SWA (Slow-wave Activity) is assumedto be proportional to the instantaneous

decay rate of Process S, but adaptation to

the SWA functions at different brain

locations has been introduced.

Daan, Beersma, Borbely. Timing of human sleep – recovery process gated by a circadian pacemaker. Am J. Physiol. 1984.

Zavada, Strijkstra, Boerema, Daan, Beersma. Evidence for differential SWA regulation across the brain. Am J Physiol. 2009 .

Homoestatic principle: S (more EEG

power) increases in the course of

wakefulness.

Circadian principle: longer

wakefulness followed by shorter

sleep (under normal conditions);



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11Vragen - Formuleer gepast antwoorden op de volgende vragen:












Which are the possible S factors?


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Which are the possible S factors?

The most important presently known sleep factor is

Adenosine – is a nucleoside, energy carrier, co-neurotransmitter (inhibitory

modulator at A1 receptors); increases during wakefulness and decreasesduring sleep. This increase in Adenosine is particularly evident in the basal

forebrain (BF) cholinergic area and in the cortex, locally, and depends on

intact cholinergic cells.

Adenosine inhibits via A2 receptors the wake-active neurons and promotes

sleep.

The increase of Adenosine, however,is not an isolated phenomenon, sinceit goes together with local changes in energy metabolism; associated with

PGD2, IL-1β and Growth-Hormone releasing factor (GnRH).

It remains to be clearly demonstrated whether, and how, Adenosine

represents the final S-factor.

BDNF – Brain-Derived Neural Growth Factor: synapse formation –upscaling during

waking and downscaling during sleep (possible in conjunction with glial TNFα =Tumor

Necrosis Factor α); BDNF administration increases sleep and suppression decreases

sleep.

PGD2 – Prostagalandin 2: increases adenosine;

Cellular defense components of the immune system are activated, namely INOS

(Induced Nitric Oxide Synthase) and cytokines (IL-1) expression is increased.

Metabolic pathways (in Neurons and

Glia cells) of Adenosine from ATP,

ADP, AMP; Adenosine receptors A1

and A2.

The rate of formation of adenosinedepends on neuronal activity; it is

released upon neuronal activation; it

acts as negative feedback signal that

decreases cellular activity and energy

needs, and thus has a neuroprotective

effect.

Excitatory

Inhibitory

Pokka-Heiskanen and Kalinchuk. Adenosine, energy

metabolism and sleep. Sleep Medicine Reviews 2011



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Wat zijn de functies van slaap


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Er bestaan een aantal niet-exclusieve

hypothesen:

1) Behoud van energie - het bevorderen van

herstelprocessen;

2) Optimaliseren van de psychomotorische

performance;

3) Optimaliseren van het immuunsysteem (?);

4) Rijping en Ontwikkeling van de hersenen;

5) Consolidatie van het geheugen.

• W. H. Moorcroft:• Behavioural Brain Research 69 (1995)

207-210.

• “The function of sleep may besummed up in one word:efficiency. Sleep provides thecircumstance for theachievement of many diversefunctions in a highly efficientmanner. An organism can beinefficient for a while but

eventually such inefficiency canbe very detrimental”.

The unifying picture that

emerges when all of the

research and theorizing todate is integrated is that

efficiency of the organism

may be the essential

function of sleep.

“The function of sleep remains unknown despite our

rapidly increasing understanding of the processes

generating and maintaining sleep”, Pierre Maquet

(2001)


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Lapses of

attention in

normal subjects

– “psychomotor

vigilance test”-

during a period

of sleep

restriction (SR)

– 5 nights with 4

hours time in

bed (TIB), and

one recovery

night with

different

durations:0h, 2h, 4h, 6h,

8h, and 10h

time-in-bed.

Basner, Rao, Goel, Dinges. Sleep deprivation and neurobehavioral dynamics. Curr Opinion

Neurobiology, 2013


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Impairments of performance after sleep deprivation

• The decrease in performance measured in a virtual car driving test resembles that seen afterintake of alcohol in excess.

• The performance after 1 night of total sleep deprivation, or of 7 consecutive nights of sleepreduced to 5 hours, is similar to that of a subject with a BAC of 0.08%.

• The impairments in performance caused by sleep deprivation and by excess alcohol areadditive.

(Bonnet and Arand 2003)



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g g p














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Motor Skill task learning:A k 1st 12h l t t t


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Walker and Stickgold. Sleep-dependent

learning and memory consolidation. Neuron,

2004

A : wake 1st; 12h later retest;

Following one night of sleep:

performance improvement.

B : Following 10pm training one

night normal sleep;;

Next morning:performance

improved;

C: Correlation “ overnight

improvement” vs “% stage 2 NREM

sleep in 4th quarter of the night”.

Visual skill task:D: performance in Wake subjects

retested on same day vs subjects

retested after one night’s Sleep.

E: Subjects retested at successivedays show improvement; Subjects

sleep deprived the 1st night after

training show no improvement

(green hatched column) even after

2 nights of recovery sleep.

F: Correlation “overnight

improvement” vs “% SWS in 1st

quarter & REM in last quarter.

The contribution of Sleep to the Hippocampus – dependent Memory System

Transcranial Magnetic stimulation (TMS) at the


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Marshall, L and Born, J. the contribution of sleep to hippocampus –dependent memoryconsolidation. Trends in Cognitive Sciences 2007

SPWs = Sharp Waves

Tested nextmorning with

TMS or sham

TMS 5 x

5 min

with 1min

breaks

EEG duringthe breaks;

Sham (white)

and TMS(black)

The up-state of Slow

Oscillation drives thereplay of encoded

memories

Replay activity

via Thalamo-

Cortical

spindles & LC

bursts leads to

memory

consolidation in

the cortex

Transcranial Magnetic stimulation (TMS) at the

frequency of the SWS oscillation (0.75 Hz)

applied between the pre-frontal

Cortex and Mastoids, boosts

declarative memory consolidation

Hypothesis


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Kort overzicht van Primaire Slaapstoornissen


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- Dyssomnia; Insomnie; Hypersomnie. Stoornissen in slaapduur, kwaliteit entijdstip van de slaap (dyssomnia): te korte (insomnie) of te lang (Hypersomnie).

Insomnie of slapeloosheid – moeilijk slaap te vatten, te vaak wakker worden, en/of te

handhaven, te vaak wakker worden (medische aandacht is nodig als de klachten 3 of

meer nachten per week zich voordoen, en langer dan ±3 maanden aanhouden; hetwordt geschat dat ± 7% van de Nederlanders heeft regelmatig last van slapeloosheid;

-

- Slaap-apneu – als de adem tijdens de slaap > 20 keer per nacht gedurende minimaal1s stokt; deze stoornis kan leiden tot insomnie tijdens de nacht en slaperigheid en

vermoeidheid overdag.

- Rusteloos been syndroom, en periodieke beenbewegingen – bij het slaap gaandrang om de benen te bewegen;

- Slaap-waak stoornissen – Narcolepsie – aandoening waarbij onweerstaanbareslaapaanvallen zich plotseling voordoen door ontregelingen van de biologische klok;

soms hebben narcolepsie - patiënten ook last van Kataplexie = aanvallen van plotseling

spierverslappingen.

- Parasomnie – verzamelnaam voor verschijnselen als slaapwandelen, nachtmerries,angstaanvallen;

- CRSDs = Circadian Rhythm Sleep Disorders - Uitgestelde of vertraagdeslaapfasestoornis (delayed sleep phase); Vervroegde slaapfasestoornis (advanced sleep

phase; Onregelmatig slaap-waakritme ; Het” free-running type”.

Stimulus: bright light pulse at

6-7a.m.

Open circles : after

light pulse exposure;

Closed circles at

constant routine

condition.

Y –axis: Plasma

Melatonin (pg/mL)

St Hilaire, MA, et al Human phase response curve to a 1h pulse of bright light.J. Physiol. 2012



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Further reading: handbooks and selected articles

Al H db k


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Algemeen: Handboeken:-Breedlove, S. Marc and Watson, Neil V., Biological Psychobiology. An Introduction to Behavioral, Cognitive

and Clinical Neuroscience. 7th Edition; Sinauer Ass, Inc. Publishers, Sunderland, Massachusetts, 2013.Chapter

13: Homeostasis: active regulation of the internal environment. Chapter 14: Biological Rhythms, Sleep, and

Dreaming.

- Purves, Dale et al. Neuroscience, 5th Edition.2012, Chapter 28: Sleep and Wakefulness.

Geselecteerde artikelen:Makkelijk:

Saper, Chou and Scammell, The sleep switch: hypothalamic control of sleep and wakefulness. Trends in

Neurosciences 2001, 24: 726 –731.

Bonnet, M. H. and Arand, D.L. Clinical effects of sleep fragmentation and sleep deprivation. A clinical review.

Sleep Medicine Reviews 2003, 7(4): 297 – 310.

Basheer R, Strecker, RE, Thakkar MM, Mccarley RW. Adenosine and sleep-wake regulation. Progr.

Neurobiology 2004.

Nir Y, Staba RJ, Andrillon T, Vyazovskiy VV, Cirelli C, Fried I. Regional slow waves and spindles in human sleep.

Neuron 2011.

Basner, Rao, Goel, Dinges. Sleep deprivation and neurobehavioral dynamics. Curr Opinion Neurobiology, 2013.

Porkka-Heiskannen, T. Sleep Homeostasis, Current Opinion in Neurobiology. 2013.

Moeilijk:

Zavada, Strijkstra, Boerema, Daan, Beersma. Evidence for differential SWA regulation across the brain. Am J

Physiol. 2009.

Narcolepsy is a disabling sleep disorder affecting humans and animals. It is

characterized by daytime sleepiness cataplexy (sudden muscular tone weakness)


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Lin Faraco Li Kadotani Rogers Lin Qiu de Jong Nishino Mignot The sleep disorder canine narcolepsy is

characterized by daytime sleepiness, cataplexy (sudden muscular tone weakness),

and striking transitions from wakefulness into rapid eye movement (REM) sleep

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