Neurobiology of Sleep-Wake States Daniel J. Buysse, M.D. Professor of Psychiatry University of Pittsburgh School of Medicine Pittsburgh Mind-Body Center Short Course on Sleep Pittsburgh, PA December 8, 2006
Neurobiology of Sleep-Wake States Assessment of sleep-wake states Characteristics of wakefulness, NREM, and REM sleep Physiological regulation of sleep-wake states Neuroanatomy and neurobiology Neurochemical control of sleep-wake states Integration of sleep-wake states and circadian rhythms
Overview: Functions of sleep Ecological/ environmental advantage Improves the quality of wakefulness –Alertness –Mood –Cognitive (especially frontal lobe) functions Integration of experience; learning Resensitization of receptors (e.g., norepinephrine, serotonin) Metabolic, inflammatory effects Longevity
Sleepiness and sleep deprivation Belenky, J. Sleep Research, 2003
Performance and sleep deprivation Belenky, J. Sleep Research, 2003
Sleep deprivation effects on cognitive function Drummond et al., Neuroreport, 1999 Normal sleep – Activation of PFC, parietal, pre-motor cortex Following sleep deprivation – Decreased activation fMRI during serial subtraction task
Effect of sleep and sleep deprivation on motor task performance Walker and Strickgold, Neuron, 2004 = pre sleep = post sleep * = significant change n = 15
© American Academy of Sleep Medicine Surgery: 20% more errors and 14% more time required to perform simulated laparoscopy post-call (two studies) Taffinder et al, 1998; Grantcharov et al, 2001 Internal Medicine: efficiency and accuracy of ECG interpretation impaired in sleep-deprived interns Lingenfelser et al, 1994 Pediatrics: time required to place an intra-arterial line increased significantly in sleep-deprived Storer et al, 1989 Sleep deprivation in medical trainees
Effects of sleep deprivation on mood in medical residents Baldwin and Daugherty, Sleep, 2004
Sleep duration and body mass Taheri et al., PLoS Med, 2004 n = 1024 Body Mass Index
Sleep duration, leptin, and ghrelin Taheri et al., PLoS Med, 2004 Leptin Ghrelin
Sleep restriction: Metabolic and endocrine effects Spiegel et al., J Clin End & Metab, 2004 n = 11
Assessment of sleep-wake states Self-report questionnaires Sleep-wake diaries: Daily recording of sleep times and characteristics Observer ratings: Unreliable Actigraphy: Motion-sensitive accelerometer worn on wrist Polysomnography (PSG): Modification of electroencephalography (EEG) –EEG –Eye movements –Muscle tone
Graphic sleep diary: Baseline
Graphic sleep diary: Post-intervention
Actigraphy
Polysomnography: Relaxed wakefulness (Stage w) C3-REF C4-REF O1-REF O2-REF LOC-REF ROC-REF EMG A REMs
Neurobiology of Sleep-Wake States Assessment of sleep-wake states Characteristics of wakefulness, NREM, and REM sleep Physiological regulation of sleep-wake states Neuroanatomy and neurobiology Neurochemical control of sleep-wake states Integration of sleep-wake states and circadian rhythms
Wakefulness, NREM, and REM WakeNREMREM ArousabilityHighLowestLow EEG amplitude LowHighLow EEG frequency FastSlow Mixed fast Muscle tone VariableLowAbsent Eye movements VoluntaryInfrequentRapid Heart Rate, Blood Pressure, Respiratory Rate Variable Slow/ low, regular Variable O2, CO2 response FullLowerLowest Thermoregulation Behavioral/ Physiological Physiological Reduced physiological Mental activity Full None/ limited Story-like dreams
PSG: Stage 1 sleep A B C EMG ROC-REF LOC-REF C3-REF C4-REF O1-REF O2-REF
PSG: Stage 2 sleep C3-REF C4-REF LOC-REF O1-REF 02-REF ROC-REF EMG SK
PSG: Stage 3 sleep
PSG: Stage 4 sleep LOC-REF C3-REF C4-REF O1-REF O2-REF ROC-REF EMG
PSG: Rapid-eye-movement (REM) sleep C3-REF C4-REF O1-REF 02-REF LOC-REF ROC-REF EMG
Factors that affect sleep Age –Increased wakefulness during sleep period –Decreased Stage 3/4 NREM –Earlier timing –Greater daytime sleepiness Sex (women have longer sleep, more Stage 3/4 NREM) Timing: Sleep is best at night! Illnesses, medications
Sleep in healthy young and older adults 20 year old woman 71 year old woman
Sleep stages across the life span Ohayon et al., SLEEP 2004; 27: Minutes Age (years)
Homeostatic and circadian regulation of human sleep Borbely et al., 2001 Time of Day
“Opponent Process” model of sleep regulation Edgar, J Neurosci, 1993
Sleep-Wake State Switching System VLPO “Sleep Switch” LHA “Wake Stabilizer” Homeostatic Sleep Drive Circadian Timing System Sleep-Wake Regulatory System Thalamus Cognitive-Affective System Dorsal (Cognitive) System Ventral (Affective) System Model of sleep-wake regulation relevant to insomnia Solid arrows indicate direct anatomic or physiologic pathways. Dotted arrows indicate indirect pathways. VLPO = Ventrolateral preoptic area. LHA = Lateral hypothalamus peri-fornical area. LC = locus coeruleus. LDT = Laterodorsal pontine tegmentum. PPT = Pedunculopontine tegmentum. TMN = Tuberomamillary nucleus of the posterior hypothalamus. Brainstem-Hypothalamic Arousal System LC, Raphe, LDT/PPT, TMN
Brainstem and hypothalamic arousal systems Saper, Nature, 2005;
Effect of VLPO on arousal systems Saper, Nature, 2005;
The “flip-flop” sleep switch Saper, Nature 2005; 437:
Extracellular adenosine in basal forebrain 3 Prolonged waking Adenosine (% of hour 2) Hours Recovery Adenosine and sleep-wake regulation Porkka-Heiskanen, Science, 1997
REM sleep systems “REM-On” Laterodorsal and pedunculopontine tegmentum (Ach) “REM-Off” Locus coeruleus (NE) and raphe nuclei (5-HT)
Reciprocal interaction model of NREM-REM sleep Pace-Schott and Hobson, 2002
Sleep stages and physiological activity Saper, TINS, 2001 WakeNREMREM EEG Fast, low voltage Slow, high voltage Fast, low voltage Eye movement Vision-related Slow, irregular Rapid Muscle tone +++0 LDT/PPT+0++ LC/DR/TMN+++0 VLPO (Cluster) 0+++? VLPO (Extended) 0+?++ Hypocretin++0?0?
The “flip-flop” sleep-wake switch Saper, TINS, 2001
Neurochemical control of sleep-wake states NeurotransmitterLocationAction Acetylcholine LDT, PPT (pons) REM, wake Histamine TMN (posterior hypothalamus) Wake GABA, galanin VLPO NREM sleep Serotonin Raphe nuclei Wake, NREM Norepinephrine Locus coeruleus Wake Hypocretin Later hypothal Wake
Neurochemical control of sleep-wake states Dopamine Adenosine Nitrous oxide Cytokines (IL-1, IL-6, TNF-α) Prostaglandins Hormones: melatonin, growth hormone, VIP NPY Delta sleep-inducing peptide
Neurobiology of Sleep-Wake States Assessment of sleep-wake states Characteristics of wakefulness, NREM, and REM sleep Physiological regulation of sleep-wake states Neuroanatomy and neurobiology Neurochemical control of sleep-wake states Integration of sleep-wake states and circadian rhythms
Integration of circadian rhythms and sleep-wake states Pace-Schott and Hobson, 2002