La fisiologia del sonno Luigi Ferini-Strambi Centro di Medicina del Sonno Università Vita-Salute San Raffaele, Milano

IL SONNO NEGLI ANIMALI IN BASE ALL’OSSERVAZIONE: (DURATA IN % DI 24 ORE) IN BASE ALL’OSSERVAZIONE: MUCCA 3 ELEFANTE 19 CAVALLO 29 GORILLA 70 IN BASE A REGISTRAZIONI EEG: ASINO 13 RATTO 50 GATTO 60 CONIGLIO 60

Organizzazione gerarchica delle strutture responsabili del sonno ( L Organizzazione gerarchica delle strutture responsabili del sonno ( L. Parmeggiani ) Veglia NREM REM corteccia ipotalamo tronco ipotalamo tronco corteccia tronco corteccia ipotalamo

PARAMETRI FISIOLOGICI PER LA DEFINIZIONE DEL SONNO M S D R

IPNOGRAMMA

Sleep Academic Award 12

Dijk and Edgar, 1999, Lung Biology in Health and Disease, vol.133

VARIAZIONI DEL CICLO SONNO-VEGLIA   Neonato / Bambino Adulto % REM / NREM 50 / 50 20 / 80 Periodicità stadi di sonno 50-60’ 90-100’ Esordio sonno REM NREM Organizzazione temporale stadi di sonno I cicli REM/NREM egualmente distribuiti durante il sonno I cicli NREM 3-4 nel primo terzo della notte; REM nell’ultimo terzo Maturazione pattern EEG 1 solo stadio NREM > stadi indeterminati K-complex Onde delta St. NREM differenti

Arousal 21

acute sleep deprivation No sleep 10 14 18 22 02 06 5 15 20 25 01 03 04 05 Cortisol (µg/dl) Thyrotropin (µU/ml) acute sleep deprivation Prolactin (ng/ml) Growth Hormone (µg/L) Clock Time

Cortisol rhythm

Impact of sleep debt on metabolic and endocrine function Spiegel K, et al. The Lancet 1999, 354:1435–1439. Intolleranza glucidica ↓Clearance glucosio 40% ↓Risposta insulinica al glucosio 30% Recupero sonno normalizza i valori

Grasso è bello ???

Self-reported Sleep and the Prevalence of Obesity in the US 9 25% 20% 8 15% Sleep (hours) Obesity prevalence 7 10% 6 Sleep (adult) 5% Obesity 5 0% 1950 1960 1970 1980 1990 2000 2010 29

DAYTIME LEPTIN AND GHRELIN LEVELS Continuous glucose infusion (5g/kg/24h) 3.5 3.0 LEPTIN (ng/ml) 2.5 AFTER 2 DAYS OF 2.0 10-H BEDTIMES 1.5 3.4 AFTER 2 DAYS OF GHRELIN (ng/ml) 4-H BEDTIMES 2.8 2.2 9 11 13 15 17 19 21 CLOCK TIME p level % change 9-21 leptin levels (ng/ml) 2.6 ± 0.5 2.1 ± 0.4 0.041 -19% 12-21 ghrelin levels (ng/ml) 2.6 ± 0.2 3.3 ± 0.2 0.038 +24% 30

PRIVAZIONE DI SONNO Diminuisce l’attività delle cellule “natural killers” nell’uomo Moldofsky, 1989 Impedisce nel topo messo a contatto con un virus influenzale di sviluppare “memoria immunitaria” Brown et al, 1989

sleep loss impairs the human antibody response to hepatisis A vaccination Subjects who had regular sleep after vaccination, displayed a nearly two-fold higher HAV antibody titer after 4 weeks than subjects staying awake on this night (p=.018). Compared with wakefulness, sleep after vaccination distinctly increased release of several immune-stimulating hormones including growth hormone, prolactin, and dopamine (p < .01). Data suggest that sleep compared with sleep deprivation on the night after vaccination improves the formation of antigen-specific immune defense as reflected by antibody production in humans. Sleep presumably acts by inducing a hormonal environment in secondary lymphoid tissues, enhancing lymphocyte proliferation and differentiation and finally antibody synthesis. Results underscore the importance of sleep for immunocompetence total loss of sleep in the night following vaccination impairs immune response 28 days later Lange et al (2003) Psychosomatic Medicine 65: 831-835 33

response to influenza vaccination is impaired in individuals with chronic partial sleep restriction Sleep deprivation at the time of vaccination reduced the response during the log phase of antibody production despite a prolonged period of sleep recovery after vaccination. These results suggest that the response to influenza vaccination may be impaired in individuals with chronic partial sleep restriction. …, our findings support the concept that adequate amounts of sleep are needed for optimal resistence to infectious challenge Sleep restriction to 4 hours/night, for 4 days before and 2 days after vaccination, impairs immune response to vaccination Spiegel et al (2002) JAMA 288: 1471-1472 34

Brain Structures That Did Not Show Decreased Metabolic Rate From Waking to Sleep States in Patients With Insomnia (A) and Brain Structures Where Relative Metabolism While Awake Was Significantly Higher in Healthy Subjects Than in Patients With Insomnia (B) Nofzinger et al. Am J Psychiatry 2004;161:2126-2128 35

Frontal Lobe dysfunctions Reduced cortical cholinergic activity SLEEP DEBT Increased Adenosine Frontal Lobe dysfunctions Reduced cortical cholinergic activity Harrison & Horne, 2000; Boonstra et al., 2007 PET studies One single night of sleep loss significantly reduces prefrontal metabolic activity Thomas et al., J Sleep Res, 2007, 9: 335-352 36

J Clin Sleep Med, 2007