Stress, fatigue et troubles Stress, fatigue et troubles du sommeil : un trio du sommeil : un trio sociétal moderne ?sociétal moderne ?

Daniel Neu, Daniel Neu, M.D.M.D.

Laboratoire du Sommeil & Unité de Chronobiologie U78 Laboratoire du Sommeil & Unité de Chronobiologie U78

Cycle Eli-Lilly Cycle Eli-Lilly « Le stress dans tous ses états »« Le stress dans tous ses états »

14 Mars 201114 Mars 2011

Evolutions sociétales versus adaptations évolutives … ? … une question sur la comparaison d’inégalités au niveau des vitesses !

Surcharge d’informations (‘overflow’)

Exigences de l’immédiateté

?

Keyword search (recherche mots-clés): Fatigue, Stress, Sleep

Google (1 “AND”) : 7.300.000  Youtube : 451 (& 2820 pour “fatigue AND stress”)Google (2 “ , , ” ) : 10.600

Pubmed (NIH) : 589 (dont 147 articles de revue !)

•Stress

•Fatigue

•Troubles du sommeil

Liens… ?

Directionalités…Causalités (étiopathogenèse)…Réciprocités

• Epidémiologies

• Cliniques

• Réflexions

Plan…

En Belgique :En Belgique :

Plaintes de sommeil non-récupérateur : 38 %Plaintes de sommeil non-récupérateur : 38 % Plaintes de fatigue anormale et intense : 34 % Plaintes de fatigue anormale et intense : 34 %

Fatigue et sommeil : population générale

[1] Le Bon O, Neu D, Verbanck P, Linkowski P. Relationships between sleepiness, fatigue, affective symptoms and non-restorative sleep complaints. Sleep 2008;31(Suppl):221 [2] Neu D, et al. Do ‘sleepy’ and ‘tired’ go together? Neuroepidemiology 2010;35:1–11

Relationship of fatigue and affective symptom intensity

R2 = 0,3015p < 0.0001

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35

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Fatigue Severity Scale (FSS) mean scores

HA

D t

otal

sco

re

Variable NRS [-] NRS [+] P =

HST w (h) 7.11 (1.0) 6.65 (0.9) .013

HST we (h) 8.76 (2.3) 8.31 (2.7) NS

Work (h/week) 36.03 (12.2) 32.0 (13.9) NS

ESS 8.24 (4.1) 9.65 (3.6) (.059)

HAD_A 6.3 (3.1) 8.63 (3.8) .001

HAD_D 3.57 (2.8) 5.72 (3.9) .009

HAD total 9.87 (5.1) 14.35 (7.1) .001

FSS 3.04 (1.4) 4.03 (1.5) .001

Pop. N = 150

[1] & [2]

Prévalences de l’insomnie

• L’insomnie (transitoire, intermittente ou chronique) est l’un des troubles les plus courants du SNC; elle affecte environ 1/3 de la population générale.

• La prévalence de l’insomnie est plus élevée chez les femmes que chez les hommes; environ 2/3 des patients sont des femmes.

• La prévalence de l’insomnie augmente avec l’âge.

Weyerer and Dilling, Sleep.1991 Oct;14(5):392-8

Prévalences de l’insomnie..suite

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15-19 20-29 30-39 40-49 50-59 60-69 70+

Age

Pré

vale

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(%

)

Légère

Modérée/sévère

1. Weyerer and Dilling, Sleep.1991 Oct;14(5):392-82. Le Bon O, Neu D. et al. Sleep 2008;31(Suppl):221

Prévalence augment avec l’âge

CHU Brugmann, Clinique du Stress, Service de Psychiatrie, Université Libre de Bruxelles (U.L.B.)

Parmi les patients stressés, la fatigue est de loin le Parmi les patients stressés, la fatigue est de loin le symptôme le plus fréquent : 75,8 %symptôme le plus fréquent : 75,8 %

la dyssomnie avec éveil matinal précoce vient en 2e la dyssomnie avec éveil matinal précoce vient en 2e position : 62 %position : 62 %

S & F differentiation abilities …?Relation between

Sleepiness & Sleep quality

R2 = 0.238

R2 = 0.3738

R2 = 0.6446

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PSQI

ESS

SHIFT NIGHT DAY

Relations between Fatigue & Sleep quality

R2 = 0.0329R2 = 0.6297

R2 = 0.2954

0123456

0 2 4 6 8

PSQI

FSS

SHIFT NIGHT DAY

Relations between Sleepiness and Fatigue

R2 = 0.6774

R2 = 0.0265 R2 = 0.3623

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FSS SHIFT NIGHT DAY

Association Fatigue/sleepiness : General Population

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FSS

ESS

Scale Pre-Test Post-Test P value (t test paired measures)

VAS F9 50,19 (26.3) 49,38 (25.1) NS VAS F13 58,04 (21,88) 55,31 (25,39) NS VAS F17 68,73 (18,68) 60,46 (23,52) .049 VAS F21 72,77 (21,48) 64,58 (23,00) .022 VAS mean F 62,43 (14,26) 57,43 (20,37) .040 VAS S9 40,96 (29,03) 35,62 (23,14) (.057) VAS S13 44,50 (23,94) 45,50 (22,53) NS VAS S17 53,50 (27,21) 54,88 (25,21) NS VAS S21 58,58 (25,16) 60,04 (28,13) NS VAS mean S 49,38 (19,85) 49,00 (16,04) NS

Mairesse O, Neu D. Individual differences in the integration of homeostatic and circadian factors in sleepiness judgments. (Short, long and midrange sleepers) Sleep 2008;31(Suppl):53

Neu D, Cluydts R, et al. Clinical semantics, semiology and auto-evaluation. The challenging case of fatigue and sleepiness. Eur Neuropsychopharmacol. 2009; 19(S3): 346

Mairesse O, Neu D, Vandersmissen R, Cluydts R. Fatigue, sleepiness and sleep quality perception, in day, night and shift workers. BASS Autumn meeting 2008

Le Bon O, Neu D, et al. Sleep 2008;31(Suppl):221

discrimination abilities …?

Neu D, Mairesse O, et al. An inconvenient truth about sleepiness: “bad sleepers” discriminate better fatigue from sleepiness than “good sleepers” J Sleep Res 2010; 19(Suppl 2): 179

Definitions de concepts... Definitions de concepts...

1) Neu D, Mairesse O, Hoffmann G, et al. Do ‘sleepy’ and ‘tired’ go together? Neuroepidemiology 2010;35:1–11

2) Neu D, Linkowski P, Le Bon O. Clinical complaints of daytime sleepiness and fatigue: How to distinguish and treat them, especially when they are 'excessive' or 'chronic'? Acta Neurologica 2010; 110(1): 15-25

SleepinessSleepiness : trigger signal for spontaneous onset of sleep. Physiological phenomenon depending on previous sleep (S) and occurring at regular intervals following circadian (C) rhythms (two process model). In pathological conditions excessive daytime sleepiness (EDS) can be irrepressible. Sleepiness is best described by sleep propensity (1,2).

FatigueFatigue : generally a condition in which maintaining of motor or mental energy level gets more difficult with duration of exercise (1,2). Fatigue needs rest not sleep to recover from.

Comprendre la fatigue ?

Excessive daytime sleepinesssleepiness (EDS)

• associated with - sleep fragmentation or - sleep loss

• due to - a PSD (excepted insomnia) or - external factors.

• best described as a higher sleep propensity

• usually resolves with sleep.

FatigueFatigue (clinical symptom)

• associated with - faster decrease of performance levels following a given motor or mental activity task.- many systemic medical conditions (including MDD)

• in all cases, directly or indirectly related to the CNS.

• Altered sleep quality seems to worsen fatigue states or contribute to its maintenance.

• Sleep disorders such as insomnia also classically present with daytime complaints of fatigue

• Invalidating fatigue, which interferes significantly with major daytime functions, must be chronic by nature and definition.

• leads more rapidly to a state of exhaustion and needs higher (increased) amounts of rest to recover from.

Sleepiness : Functional Modelization

Borbély AA, 1982. A two process model of sleep regulation. Hum Neurobiology 1(3): 195-204

Neu D. et al. Clinical semantics, semiology and auto-evaluation. The challenging case of fatigue and sleepiness. Eur Neuropsychopharmacol. 2009; 19(S3): 346

Fatigue : Functional Modelization ?

F1 : anti-homeostatic ??

F2 : circadian component(s) ??

[intensity of fatigue]

[time of day]Wake up

intersections…impairments associated to both

phenomena

Attentional deficits,Vigilance,

Concentration

Performances depending upon the level/intesity of stimuli(s) ..better if high stimulation

Performances not depending upon stimuli level/intensity ..less if higher stimulation

SS FF

Neu D, Kajosch H, Peigneux P, Verbanck P, et al. Cognitive impairment in fatigue and sleepiness associated conditions. Psychiatry Research, 2010 (in press)

Intersections…& relations

Neu D. et al. Sleep quality perception in the chronic fatigue syndrome. Neuropsychobiology 2007; 56: 40-46

Neu D. et al. Qualité du sommeil : perceptions subjectives et observations objectives. Quels liens entre psychologie et physiologie? L’Encéphale 2009;35:6

Neu D. & Mairesse O. Fatigue, sleepiness and sleep quality perception, in day, night and shift workers. BASS Meeting 2008

« sleep quality »?

SSFF

Association Fatigue/sleepiness : General Population

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FSS

ESS

Relations between Sleepiness and Fatigue

R2 = 0.6774

R2 = 0.0265 R2 = 0.3623

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FSS SHIFT NIGHT DAY

Subjective quality ??Objective quality ?

Discrimination abilities ….TRDstudy of psychomotor and cognitive function in tt resist MDD

R 2 = 0.4959R 2 = 0.3422

R 2 = 0.1178

R 2 = 0.0488

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0 5 10 15 20 25 30 35 40 45H AMD

MDD HA MD / F S S T1

MDD HA MD / F S S T2

MDD HA MD / E S S T1

MDD HA MD / E S S T2

FSS

ESS

Neu D, Kornreich C, Montana X, Hoffmann G, Sentissi O, Verbanck P. Cognitive impairment and altered vigilance in treatment-resistant depression. European Psychiatry 2010; 25(S1): 299

Pharmacol Ther. 2011Immune system to brain signaling: Neuropsychopharmacological implications.Capuron L, Miller AH.

The immune system can influence the brain and behavior at any level. In the context of inflammation, pro-inflammatory cytokines that can access the CNS and interact with a cytokine network in the brain to influence virtually every aspect of brain function relevant to behavior including neurotransmitter metabolism, neuroendocrine function, synaptic plasticity, and neurocircuits that regulate mood, motor activity, motivation, anxiety and alarm. Behavioral consequences of these effects of the immune system on the brain include depression, anxiety, fatigue, psychomotor slowing, anorexia, cognitive dysfunction and sleep impairment; symptoms that overlap with those which characterize neuropsychiatric disorders, especially depression. Pathways that appear to be especially important in immune system effects on the brain include the cytokine signaling molecules, p38 mitogen-activated protein kinase and nuclear factor kappa B; indoleamine 2,3 dioxygenase and its downstream metabolites, kynurenine, quinolinic acid and kynurenic acid; the neurotransmitters, serotonin, dopamine and glutamate; and neurocircuits involving the basal ganglia and anterior cingulate cortex. A series of vulnerability factors including aging and obesity as well as chronic stress also appears to interact with immune to brain signaling to exacerbate immunologic contributions to neuropsychiatric disease.

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Etude du sommeil…polysomnographie ?

• α – δ sleep (intrusion d’actvités EEG ‘veille’ ds le SLP)

• CAP (‘cyclic alternating pattern’, motifs EEG récurrents…)

• idiopathic micro-arousals (éveils inconscients ultracourts sans cause objectivable)

• REM deficiency (diminution du %)

• delayed REMS onset (latence d’apparition SP ‘allongée’)

Neu D, Verbanck P, Linkowski P, Le Bon O. Fatigue, sleepiness, sleep quality and their relationships to affective symptom intensity in sleep-disordered patients. European Psychiatry 2010; 25(Suppl 1): 1445

Can PSG contribute to distinguish between F & S ?

…. « yes we can ?! »

Total absolute powerover complete TIB (N=330)

“too much love will kill you..”

• SWS => Sleepiness

• SWS => Fatigue ?

Brian May, 1988

a desperate try of quantitative compensation for a qualitative altered function ..?

unpublished data

…mapping fatigue ?About SWA deficits and “alpha-intrusion”

“less” energy in (ultra-)low range frequencies

…and “more” in high frequency ranges

..despite higher SWS duration

…and absolute similar coherences

vindication of “alpha-delta” sleep

Evolutions sociétales versus adaptations évolutives … ? … une question sur la comparaison d’inégalités au niveau des vitesses !

?

Surcharge d’informations (‘overflow’)

Exigences de l’immédiateté

the future directions… 4 Axes :

1. Expansions to other clinical models (MS, PR, HIV, Lymphoma, MDD, insomnia, narcolepsy, HI, sleep deprivations ..

2. Pre-clinical models (murine forced swim test vs sleep deprivation, hypocaloric intakes vs sleep restriction..)

3. Functional neuroimaging (fatiguability tasks vs sleep restriction

4. Molecular genetics, cellular energy metabolism, broader investigations of neurotransmitter turnovers and of differential cytokine activations

Laboratoire du Sommeil & Unité de Laboratoire du Sommeil & Unité de Chronobiologie U78Chronobiologie U78

CHU Brugmann U.L.B. CHU Brugmann U.L.B.

Daniel Neu, Guy Hoffmann, Monique Kentos, Axelle Ransquin, Daniel Neu, Guy Hoffmann, Monique Kentos, Axelle Ransquin, Luc Stulens, Fatiha Mebarka, Marleen Bocken, Philippe Dupont, Paul VerbanckLuc Stulens, Fatiha Mebarka, Marleen Bocken, Philippe Dupont, Paul Verbanck