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

1. Cycle Eli-Lilly « Le stress dans tous ses états » 14 Mars 2011 Stress, fatigue et troubles du sommeil : un trio sociétal moderne ? Daniel Neu, M.D. Laboratoire du Sommeil & Unité de Chronobiologie U78

2. Evolutions sociétales versus adaptations évolutives … ? … une question sur la comparaison d’inégalités au niveau des vitesses ! Surcharge d’informations (‘overflow’) Exigences de l’immédiateté ?

4. 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 !)

6. Liens… ? Directionalités…Causalités (étiopathogenèse)…Réciprocités • Stress • Fatigue • Troubles du sommeil

7. Plan… • Epidémiologies • Cliniques • Réflexions

8. En Belgique :  Plaintes de sommeil non-récupérateur : 38 %  Plaintes de fatigue anormale et intense : 34 %

9. Fatigue et sommeil : population générale Pop. N = 150 [1] & [2] [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

11. 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

12. Prévalences de l’insomnie..suite Prévalence augment avec l’âge 1. Weyerer and Dilling, Sleep.1991 Oct;14(5):392-8 2. Le Bon O, Neu D. et al. Sleep 2008;31(Suppl):221

13. 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 symptôme le plus fréquent : 75,8 % • la dyssomnie avec éveil matinal précoce vient en 2e position : 62 %

15. S & F differentiation abilities …? 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 Le Bon O, Neu D, et al. Sleep 2008;31(Suppl):221 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 Mairesse O, Neu D, Vandersmissen R, Cluydts R. Fatigue, sleepiness and sleep quality perception, in day, night and shift workers. BASS Autumn meeting 2008

16. 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

17. Definitions de concepts... Comprendre la fatigue ? Sleepiness : 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). Fatigue : 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. 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

18. Fatigue (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. • Excessive daytime sleepiness (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.

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

20. Fatigue : Functional Modelization ? [intensity of fatigue] F1 : anti-homeostatic ?? F2 : circadian component(s) ?? [time of day] Wake up Neu D. et al. Clinical semantics, semiology and auto-evaluation. The challenging case of fatigue and sleepiness.Eur Neuropsychopharmacol. 2009; 19(S3): 346

21. intersections…impairments associated to both phenomena S F Performances depending upon the level/intesity of stimuli(s) ..better if high stimulation Attentional deficits, Vigilance, Concentration Performances not depending upon stimuli level/intensity ..less if higher stimulation Neu D, Kajosch H, Peigneux P, Verbanck P, et al. Cognitive impairment in fatigue and sleepiness associated conditions. Psychiatry Research, 2010 (in press)

22. Intersections…& relations S F Objective quality ? Subjective quality ?? « sleep quality »? 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

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

25. Pharmacol Ther. 2011 Immune 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.

26. ? Maisc’est quoi la “qualité” du sommeil ….? ? Quelles sont les caractéristiques d’un sommeil « récupérateur » ..?

27. 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’)

28. Can PSG contribute to distinguish between F & S ? …. « yes we can ?! » Total absolute power over complete TIB (N=330) 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

29. “too much love will kill you..” Brian May, 1988 • SWS => Sleepiness • SWS => Fatigue ? a desperate try of quantitative compensation for a qualitative altered function ..?

30. …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 unpublished data

31. Evolutions sociétales versus adaptations évolutives … ? … une question sur la comparaison d’inégalités au niveau des vitesses ! ? Surcharge d’informations (‘overflow’) Exigences de l’immédiateté

32. the future directions… 4 Axes : Expansions to other clinical models (MS, PR, HIV, Lymphoma, MDD, insomnia, narcolepsy, HI, sleep deprivations .. Pre-clinical models (murine forced swim test vs sleep deprivation, hypocaloric intakes vs sleep restriction..) Functional neuroimaging (fatiguability tasks vs sleep restriction Molecular genetics, cellular energy metabolism, broader investigations of neurotransmitter turnovers and of differential cytokine activations

33. Laboratoire du Sommeil & Unité de Chronobiologie U78 CHU Brugmann U.L.B. Daniel Neu, Guy Hoffmann, Monique Kentos, Axelle Ransquin, Luc Stulens, Fatiha Mebarka, Marleen Bocken, Philippe Dupont, Paul Verbanck