Sleep and Development PDF

Sleep and Health Zurich Sleep and Development Reto Huber University Children’s Hospital Zurich Department of Child and Adolescent Psychiatry and Psychotherapy BI...

Sleep and Health Zurich Sleep and Development Reto Huber University Children’s Hospital Zurich Department of Child and Adolescent Psychiatry and Psychotherapy BIO 344: Development of the Nervous System, 2.12.2024 Why do children sleep so much? Sleep duration in childhood Iglowstein et al., Pediatrics 2003  Outline 1. Sleep basics 2. Sleep as a default state 3. Developmental changes in sleep structure and their relationship to brain maturation - REM sleep - Slow wave sleep 4. Learning and sleep slow waves 5. Synaptic homeostasis hypothesis 1. Sleep basics 2. Sleep as a default state 3. Developmental changes in sleep structure and their relationship to brain maturation - REM sleep - Slow wave sleep 4. Learning and sleep slow waves 5. Synaptic homeostasis hypothesis  Important endpoints Invention of Electroencephalography Discovery of REM sleep Sleep stages and sleep depth Neuronal correlates  Electroencephalography (EEG) EEG measures potential differences of large cortical networks. Berger 1929  Rapid eye-movement sleep Discovered first in humans (Aserinsky and Kleitman Science 1953) Later in cats (Dement, Electroencephalogr Clin Neurophysiol 1958) Started golden years of sleep research – sleep is not merely a shut-down of brain activity Sleep recordings Ground Electrooculogram (E1E2): eye movement Electromyogram (EMG): muscel movement Electroencephalogram (C3A2, C4A1): brain activity Achermann et al.  Vigilance states in humans Brain waves Eyes Muscles EEG BRAIN: EOG EYES: EMG MUSCLES: EEG EOG EMG WakingAWAKE NonREM Sleep Non-REM SLEEP STAGE 1 EEG: Electroencephalogram Stadium 1 N1 EOG: Electrooculogram STAGE 2 EMG: Electromyogram Stadium 2 N2 STAGE 3 Stadium 3 N3 STAGE 4 Stadium 4 REM Sleep REM SLEEP 0 1 2 3 4 5 0 1 2 3 4 5 0 1 2 3 4 5 Seconds Seconds Seconds Seconds  Sleep architecture Cycle Waking NonREM Stadium REM Sleep Time Changes in NonREM-REM sleep cycle characteristics across a sleep period: -Deep NonREM sleep (3+4) decreases -REM sleep duration increases Achermann et al.  EEG slow waves and sleep depth Helen Blake und R. W. Gerard Am J Physiol (1937) Slow waves Sleep depth Hours Number of slow waves and measures of sleep depth decrease in parallel across a sleep period  N ||||||||||||||||||| ||||||||||||||||||||||||||||| |||||||||||||| | ||||||||||||||||||||||||||||||||||| |||||||||||||||||||||| | ||||||||||||||||||||| |||||||||||||||||||||||| |||||||||||||||||||||||||||||||||||| | ||||||||||||||||||| R ||||||| ||| ||||||||||| |||||||||||||||||| |||||||| |||| ||||||| |||||||||||| Slow wave activity reflects sleep 23 homeostasis 1 3 5 7 23 1 3 5 Sleep deprivation Time of day Time of day Night 1 Night 2 SWA Daytime nap W || | | || | |||||||||||| || || | | | | |||| | | | | || | | | Night || |1 || | || N SWA N ||||||||||||||||||| ||||||||||||||||||||||||||||| |||||||||||||| | ||||||||||||||||||||||||||||||||||| |||||||||||||||||||||| | ||||||||||||||||||||| |||||||||||||||||||||||| |||||||||||||||||||||||||||||||||||| | |||||||||||||||||||| ||||||||||||||||||||| | R ||||||| ||| ||||||||||| |||||||||||||||||| |||||||| |||| ||||||| |||||||||||| |||||||||||||| || ||||||| 23 1 3 Sleep 5 7 deprivation 23 1 3 5 7 Time of day Time of| day pressure [a.u.] W ||||| | | | | ||| | ||||||||||||||| |||| Night 1 N ||||||||||||||||||||||||||||||||||||||||||||||||||||||| |||||||||||||||||||||||||||| | | ||||||||||||Night ||||||||||| || ||||||2 ||||||||||||| ||||||||||||||||||||||||||| ||||||||||||||||||||||||| ||||| ||||||||||||||||||||||||||| ||| ||||||||||||||||| ||||||||||| SWA SWA sleep R ||||| |||||| |||||||||| |||||||||||||||||||| ||||||||||||||||| |||||| |||||| 23 1 3 5 7 18 20 23 1 3 5 Daytime nap Time of day Time of day W || | | || | |||||||||||| || || | | | | |||| | | | | || | || || ||| | || N ||||||||||||||||||| ||||||||||||||||||||||||||||| |||||||||||||| | ||||||||||||||||||||||||||||Night ||| |||| |||||||||||||||1 ||||||| | ||||||||||||||||||||| |||||||||||||||||||||||| |||||||||||||||||||||||||||||||||||| | |||||||||||||||Night ||||| |||||||||||||||2 |||||| | SWA SWA R ||||||| ||| ||||||||||| |||||||||||||||||| |||||||| |||| ||||||| |||||||||||| |||||||||||||| || ||||||| 23 1 3 5 7 23 1 3 5 7 Time of day Time of day baseline condition W ||||| | | | | | N ||||||||||||||||||||||||||||||||||||||||||||||||||||||| |||||||||||||||||||||||||||| | | ||||||||||||||||||||||| || ||||||||||||||||||| ||||||||||||||||||||||||||| ||| | 23 ||||||||||||||| 1 ||||||||||||||||||||||||| ||||| Time 3 ||||||||||||||||||||||||||| of ||| ||||||||||day |||| 5 7 ||||||| ||||||||||||| ||||||||||||||||||||| || ||||| Model R ||||| |||||| |||||||||| |||||||||||||||||||| 1.0 || ||||||| ||| ||| | | ||| ||| |||||| |||||| ||||||| sleep deprivation 23 1 3 5 Daytime 7 18 20nap 23 1 3 5 7 daytime nap Time of day Time of day Night 1 Night 2 rocess S SWA 0.5 Adapted from Achermann & Borbély, 2003 W ||||| | | | | | ||| | ||||||||||||||| ||||  Sleep is a regulated process EEG slow waves reflect sleep homeostasis What is going on at the neuronal level?  Vigilance states in rodents STATE Waking NREM Sleep REM Sleep BEHAVIOR EEG EMG Seconds  Slow wave activity in rodents Rat Baseline Recovery after sleep deprivation Slow-wave activity (µV2) Franken et al., Am J Physiol 1991 W N R 0 Hours 6 0 Hours 6 Also in rodents slow wave activity reflects sleep homeostasis  Sleep slow oscillations Steriade et al., Science 2000 EEG Intra- cellular On the neuronal level EEG slow waves are reflected by an alternation between ON (spiking activity) and OFF (no activity) periods. ~2 s Sleep slow oscillations Wake Deep sleep  Relationship between synchronization and SWA Multi unit recordings in rats Early sleep Vyazovskiy et al., Neuron 2009 Late sleep High synchronization t Low synchronization  On the neuronal level slow waves are reflected by ON and OFF periods The level of synchronization is determining the size (i.e. amplitude) of slow waves Why do children sleep so much? 1. Sleep basics 2. Sleep as a default state 3. Developmental changes in sleep structure and their relationship to brain maturation - REM sleep - Slow wave sleep 4. Learning and sleep slow waves 5. Synaptic homeostasis hypothesis Cortical maturation in early years at birth at 6 months at 8 years Conel, 1959  Sleep in a dish 7 DVI 10 DVI Hinard et al., J Neurosci 2012 AWSE: array-wide synchronous electrodes DIV: days in vitro Sleep in isolated cortex Deep sleep REM sleep intact isolated Lemieux et al., J Neurosci 2014 1. Sleep basics 2. Sleep as a default state 3. Developmental changes in sleep structure and their relationship to brain maturation - REM sleep - Slow wave sleep 4. Learning and sleep slow waves 5. Synaptic homeostasis hypothesis  Rest-activity plot for the first year rest Age (days) activity feeding Time of day (hours) From poly- to monophasic sleep Adapted from Kleitman, 1954 Variability of sleep duration Age dependent inter-individual differences in sleep duration Iglowstein et al., Pediatrics 2003  Sleep stages during development 16 Total sleep time decreases 14 Amount of REM sleep 12 decrease during first years REM sleep (hours) 10 Hours 8 sleep 6 Non-REM sleep 4 2 0 0 0.5 1 2 4 8 12 17 25 40 60 85 age(years) Age (years) Roffwarg et al. Science 1956 1. Sleep basics 2. Sleep as a default state 3. Developmental changes in sleep structure and their relationship to brain maturation - REM sleep - Slow wave sleep 4. Learning and sleep slow waves 5. Synaptic homeostasis hypothesis Decrease of the amount of REM sleep Jouvet-Mounier et al., Dev Psychobiol 1970  Motor exploration during REM sleep twitching Blumberg et al., Curr Biol 2013 Linking motoneurons and muscles Blumberg et al., Curr Biol 2013 Active sleep in infants YouTube  Maturational switch Immature sleep/EEG Maturation of sleep/EEG Slow waves, spindles P8 - Eyes closed - Exploring starts SWITCH - Bias towards Synapses explode - Potentiation/depression balance strong potentiation - Plasticity dependent - Plasticity driven spontaneously on experience Cirelli and Tononi, Biol Psychiatry 2015 1. Sleep basics 2. Sleep as a default state 3. Developmental changes in sleep structure and their relationship to brain maturation - REM sleep - Slow wave sleep 4. Learning and sleep slow waves 5. Synaptic homeostasis hypothesis Slow wave activity during development 8 Slow wave activity (log) 7 6 5 4 3 0 5 10 15 20 25 Age (years) Kurth et al., J Neurosci 2010 Feinberg, J Psych Res 1982  Synapse density and energy consumption Synapse density Energy consumption Huttenlocher, 1997 Chugani, 1998 70 70 (LCMRglc in mol/min/100g) 60 Synapses/1003 µm3 60 Glucose utilization 50 Synapses/100 m 50 40 40 30 30 20 10 20 0 10 0 5 10 15 20 25 0 5 10 15 Age (years) Age (years) Age (years) Huttenlocher, J Comp Neurol 1997 Chugani, Prev Med 1998 Cortical maturation in early years at birth at 6 months at 8 years Conel, 1959  Network synchronization and amplitude of slow waves More and stronger synapses lead to increased network synchronization and larger slow waves  More synapses use more energy Pruning: Refining process during adolescence  Pruning during adolescence Synapses/mm3 Pruning During adolescence more synapses are eliminated than newly formed Huttenlocher Brain Res 1979 Hua et al. Nat Neurosci 2004  Refinment large-scale neural model of primary visual cortex and sections of the thalamus Hoel et al., J Neurophysiol 2016  Structural changes Two photon imaging in mice a b Zuo et al., Nature 2005  MRI cortical thickness Structural magnetic resonance imaging (MRI) Girl, 9.5 years Woman, 28.3 years  Local maturation Cortical gray matter maturation starts in the back and ends in the front Age of peak cortical thickness years Shaw et al., J Neurosci 2008  Age dependent SWA topography 2-5 5-8 8-11 11-14 14-17 17-20 y Slow wave activity (SWA) Kurth et al., J Neurosci 2010  Relationship to connectivity and behavior Synapse density SWA topography Skill development 70 2-5 y Visual Cortex (Synapse/100µm3) Pre-schoolers 60 Visual acuity (stripes/min) 1 50 2 40 4 30 8 20 16 10 32 Birth 0.5 1 2 5 10 15 20 adult 1 2 3 4 5 adult Age (years) Age (years) 70 100 Antisaccade task (Percent errors) Frontal Cortex (Synapse/100µm3) 17-20 y 60 Adolescents 75 50 40 50 30 20 25 10 0 Birth 0.5 1 2 5 10 15 20 adult 0 10 20 30 Age (years) Age (years) Ringli and Huber, Prog Brain Res, 2011  Predominance of SWA shifts from back to front Parallels anatomical (gray matter) and behavioral maturation What about white matter?  Gray versus white matter maturation Coherence Cortical white matter shows a linear increase across age  Diffusion tensor imaging Novel magnetic resonance imaging technique 50 40 FLSR length (cm) 30 20 10 0 10.4 16.3 29.1 years directed movement of H2O estimation of fiber bundles 1. Sleep basics 2. Sleep as a default state 3. Developmental changes in sleep structure and their relationship to brain maturation - REM sleep - Slow wave sleep 4. Learning and sleep slow waves 5. Synaptic homeostasis hypothesis Experience dependent plasticity Drives maturation Relates to learning Long term potentiation (LTP)  Local increase in slow-wave activity Huber et al., Nature 2004 Rotation learning Sleep EEG Retest Directional Motor 11 control pm 8 am error 12 pm % 30 Post-sleep performance Change in slow-wave activity (mean directional error) % r2=0.74 20 improvement 10 10 0 0 -10 0 10 20 30 40 50 % Slow-wave activity increase  Suppression of slow waves Evidence for a causal relationship between slow wave activity and sleep dependent performance improvements 10 Control 8 Performance improvement (%) 6 Slow wave activity 4 2 Acoustic suppression Acoustic suppression 0 Control -2 Hours of sleep -4 Landsness et al., Sleep 2009 Slow waves are related to sleep dependent performance changes. How does this look like in children? Local slow wave activity after learning in children, adolescents and adults Wilhelm et al., J Neurosci 2014  Relationship to markers of maturation EEG Slow wave activity Cortical gray matter volume *** Children Adolescents Adults Parietal SWA 1st 30 min 1.0 0.20 ** r = 0.70; p = 0.004 (rotation - control) 0.15 Parietal SWA 0.8 0.10 0.05 r = -0.06; 0.6 p = 0.85 0 0 -0.05 r = -0.26;p = 0.29 -0.10 0.5 0.6 0.7 0.8 0.9 1.0 1.1 1.2 Parietal SWA1 st 30 min  Critical periods motor/ higher sensory language cognition Hensch Cerebrum 2012  Ocular dominance plasticity and sleep Monocular deprivation (MD) Frank et al. Neuron 2001 Experience dependent increase in SWA is larger in children. This might explain why children sleep so deep. Do they also benefit more from sleep?  Does children’s performance benefit from sleep? Kinder 1. Lernen 2. Behalteintervall 3. Abfragen Erwachsene Langsamwellige Aktivität Anzahl erinnerte Abfolgen Anzahl korrekter Abfolgen Kinder Erwachsene Wilhelm et al., Nat Neurosci 2014 Strong relationship between learning related plasticity and sleep slow waves. How does that look on the neuronal level?  Changes in connectivity after learning Before learning After learning Learning related changes in synaptic strength Long term potentiation (LTP) Bliss & Lomo J Physiol 1973 Relationship between synaptic strength and slow waves  We learn a lot every day Ask yourself in the evening what you remember of the day? 1. Basic principles of sleep 2. Sleep as a default state 3. Developmental changes in sleep structure and their relationship to brain maturation - REM sleep - Slow wave sleep 4. Learning and sleep slow waves 5. Synaptic homeostasis hypothesis  Synaptic homeostasis hypothesis slow wave w=100 increase w=140 synaptic synaptic potentiation w=5 downscaling Saturation Benefits - receptor/synapse - energy savings w=80 density - space savings w=120 - neuronal energy - ↑ signal / noise expenditure learning slow wave decrease w=100 w=100 baseline Tononi and Cirelli, Neuron 2014  Synaptic homeostasis Holtmaat and Svoboda, Nat Rev Neurosci 2009 LTP LTD Synaptic strength is balanced across 24 hours (=synaptic homeostasis). Wakefulness favors synaptic potentiation Sleep favors synaptic depression Tononi and Cirelli, Neuron 2014  Changes in synaptic strength Rats Vyazovskiy et al., Nat Neurosci 2008 Waking NREMS REMS Slope (% of mean) Slope (% of mean) Wakefulness is associated with a net increase in synaptic strength Sleep is favoring synaptic depression  From spines to synapses Holtmaat and Svoboda, Nat Rev Neurosci 2009 Net change in the number of spines Two photon imaging in adolescent mice Maret et al., Nat Neurosci 2011 Changes in EM reconstructed axon-spine interface (ASI) across sleep de Vivo et al., Science 2017  Potentiation/synapse formation predominates during wakefulness Sleep favors synaptic depression (downscaling)/synapse elimination How does this translate into clinical population? Altered anatomical maturation in ADHD years Controls ADHD Shaw et al., Hum Brain Map 2010  Reduced slow wave activity in ADHD patients ADHD vs. Controls Reduction of slow wave activity (%) ADHD -5 Slow wave activity (µV2) -10 -15 -20 -25 Controls -30 Furrer et al., Transl Psychiatry, 2019 No upregulation of SWA after learning in ADHD F-value Asymmetry (%) Furrer et al., Sleep Med. 2020 Transcranial direct current stimulation in ADHD ADHD Controls ADHD with stim. Prehn-Kristensen et al., Brain Stim 2014  Conclusions » Sleep quantity and quality changes during development » Sleep slow waves mirror cortical maturation » Synaptic homeostasis may play a role during development Do we sleep enough? Weaver et al., JAMA Pediatrics 2018