An Introduction to the Clinical Correlates of Disrupted Slow-Wave Sleep
Thomas Roth, PhD (Moderator)
Department of Sleep Medicine, Henry Ford Hospital, Detroit; and the Department of Psychiatry, University of Michigan College of Medicine, Ann Arbor
Ruth M. Benca, MD, PhD
Departments of Psychology and Psychiatry, and the Center for Sleep Medicine and Sleep Research, University of Wisconsin, Madison
Milton Erman, MD
Department of Psychiatry, University of California, San Diego School of Medicine, San Diego; Avastra USA, Irvine, California; and the Department of Neuropharmacology, The Scripps Research Institute, La Jolla, California
Sleep disorders affect a substantial portion of the US population, with the prevalence of insomnia estimated at 10% to 14% and disturbed sleep at about 30%.1,2 The focus of treating insomnia has traditionally been on increasing the amount of time that the patient spends in sleep by decreasing the latency to sleep onset, increasing the amount of time the patients stays asleep after sleep onset, or both.2,3 More recently, focus has increased on sleep architecture and sleep quality, especially on the amount of time spent in slow-wave sleep (SWS). This brief review presents an overview of sleep architecture focusing on the role of SWS in sleep physiology, discusses the clinical and psychological disorders associated with deficits in SWS, and summarizes current and developing pharmacologic and nonpharmacologic therapies that address SWS.
Clinical and Physiologic Significance of SWS
Sleep is a state where the brain, although very active, is less responsive to external stimuli. The need to sleep represents an essential physiologic drive that accumulates during wakefulness, with chronic sleep deficits leading to a degradation of cognitive skills, decreased memory consolidation, and pathological changes in several physiologic functions.4-6
During sleep, the brain repetitively cycles through 2 distinct neural states approximately every 90 minutes.2 These states, which can be monitored and defined using electrophysiologic recordings of electroencephalograms (EEGs), electro-oculograms (EOGs), and electromyograms (EMGs), are rapid eye movement (REM) sleep and non-REM (NREM) sleep. NREM sleep constitutes about 75% to 80% of sleep activity, and can be divided into stages N1 through N3. Stage N1 is light or transitional sleep; stage N2, which comprises at least half of a night’s sleep, has characteristic sleep spindles and occasional slow waves; and stage N3, or SWS, is characterized by increasing amounts of slow-wave activity (delta sleep).2,7 The amount of time spent in each sleep stage varies with age. As age increases, SWS (stage N3) decreases, stage N1 sleep increases, and the other sleep stages remain fairly constant ().8
Slow-wave activity in sleep has been linked to cognition and synaptic plasticity.2,9–11 Experimental evidence5,12–14 has indicated that SWS is important for memory consolidation, recall, and visual and motor skill learning. However, other studies15,16 have suggested that, for some memory tasks such as learning word-pairs and simple motor tasks, sleep spindles and not SWS or REM sleep may be most important.
In addition to cognitive function, other physiologic functions fluctuate with the NREM-REM cycle.17 The balance of sympathetic and parasympathetic tone oscillates in synchrony with the sleep cycle, with sympathetic tone diminishing during NREM sleep at the same time that vagal tone increases.17–19 During the transition to REM sleep, sympathetic activity increases. Endocrine and autonomic functions also show variability during SWS. Growth hormone release is associated with SWS, and decreased SWS in men has been correlated with decreases in growth hormone secretion.20,21 The initiation of SWS also correlates with hormonal changes that affect glucose regulation. Selective deprivation of SWS in young, healthy adults without a change in total sleep time was found to decrease insulin sensitivity without a compensatory increase in insulin release, resulting in reduced glucose tolerance and possible increased diabetes risk.22 Sympathetic activation, assessed through the measurement of heart rate variability during wakefulness, suggested that the subjects had a shift toward sympathetic dominance in association with decreased SWS.17,22
In summary, deficits in SWS have been linked with changes in normal cognitive and physiologic functions, although more studies are needed to better define these interrelations. The conclusion that is emerging from these and other studies is that all stages of sleep are important for healthy physiologic and cognitive function; therefore, understanding and treating changes in sleep architecture may be as important as increasing total sleep time in patients with sleep deficits.
Medical and Psychiatric Conditions Associated With Deficits in SWS
Changes in SWS have been associated with several medical and psychiatric conditions, including sleep apnea, insomnia, mood disorders, schizophrenia, and alcoholism. One study23 on sleep-disordered breathing (SDB) compared 18 subjects aged 18 to 56 years with mild SDB with 18 controls. Arousals were scored according to the American Sleep Disorders Association criteria. Comparisons between the 2 groups indicated a significantly higher number of awakenings < 1 minute among subjects with SDB (P < .01). Arousal indexes for total sleep time, NREM sleep, and SWS were all significantly higher in SDB subjects relative to controls (P < .01, P = .02, and P < .01, respectively). Although the REM sleep arousals were higher in SDB subjects, the difference from controls was not significant.23 The authors concluded that sleep architecture, even in subjects with mild SDB, is characterized by a high degree of sleep fragmentation. In another study,24 the effects of continuous positive airway pressure (CPAP) on the respiratory arousal indexes of 38 patients with obstructive sleep apnea syndrome were examined. CPAP was found to significantly decrease the number of arousals in all sleep stages, including SWS and REM sleep (P < .01). Therefore, CPAP caused a rebound in SWS as well as REM sleep.
Loss of SWS, both in terms of number of minutes of SWS recorded during the night and SWS percentage of total sleep, is often found in studies of insomnia patients, as evidenced from a meta-analytic review25 of sleep in subjects with insomnia, with psychiatric disorders, or without these conditions. This review also found decreases in SWS and SWS percentage in patients with affective disorders compared with controls; no other psychiatric groups of patients showed significant deficits in SWS.25 In contrast, REM latency was decreased in patients with affective disorders, whereas the time spent in REM sleep relative to total sleep time increased (); no changes in REM sleep were seen in subjects with insomnia.25
Yang and Winkelman26 examined the relationship between sleep EEG parameters and clinical symptom severity in patients with schizophrenia by comparing EEG recordings from a diagnostically homogeneous group of 15 drug-free schizophrenia inpatients who met DSM-IV-TR criteria for undifferentiated schizophrenia with data from 15 age- and sex-matched controls. Researchers found that, not only did the schizophrenia patients suffer from profound disturbances in sleep continuity and sleep architecture, but SWS also was inversely correlated with cognitive symptoms (including difficulty in abstract, stereotyped thinking; cognitive disorganization; lack of judgment and insight; poor attention; tension; and mannerisms and posturing; P = .013).26
Alcohol-dependent patients experience many types of sleep problems, including prolonged latency to sleep induction, decreased sleep efficiency, shorter sleep duration, loss of SWS time, and decreased SWS percentage compared with healthy controls.27 These SWS deficits can persist for more than 1 year after the start of alcohol abstinence.27 Furthermore, alcoholics have been reported to have smaller increases in SWS and delta power following sleep deprivation compared with controls, suggesting an abnormality in the generation of slow waves related to their alcohol use.28
In summary, deficits in SWS are commonly seen in a variety of clinical and psychiatric disorders, although these deficits have not been found in all studies. These results indicate that SWS parameters might have a diagnostic and prognostic utility. The question that still needs to be addressed is whether interventions that improve SWS in patients with these clinical and psychiatric disorders lead to improvement in these patients’ symptoms.
Nonpharmacologic and Pharmacologic Management of SWS Deficiency: Current and Emerging Therapies
Several approved and experimental interventions have been found to increase SWS and improve overall sleep architecture. Cognitive-behavioral therapy (CBT) has been shown to be effective for the treatment of both primary and comorbid insomnia,29–34 as well as for improving sleep architecture and slow-wave activity.35 Although effective, CBT is often underutilized because it involves repeated visits to sleep specialists, who may not be available to patients either due to insurance issues or the lack of trained individuals in some regions.2 Exercise or passive body heating in the afternoon has also been found to increase SWS during the first half of the sleep period.36
Pharmacotherapies currently FDA-approved for insomnia include benzodiazepine receptor agonists, including both benzodiazepines and nonbenzodiazepines.2 Examples of nonbenzodiazepines include zolpidem, zaleplon, zopiclone, and eszopiclone. Nonbenzodiazepines bind at the benzodiazepine receptors of the GABA-A complex. Clinically, nonbenzodiazepines increase total sleep time by decreasing the amount of time it takes to fall asleep and/or decreasing the time awake during the night.2 These agents typically consolidate sleep architecture while active in the body without significant changes in percentages of SWS recorded.
Advances in understanding sleep mechanisms and the neurons and ion channels involved in sleep have led to the development of novel hypnotic drugs with more specific targets.2 Several of these drugs have been found to improve sleep architecture and increase SWS. Novel drugs in development include calcium channel α2δ subunit blockers and serotonin 5-HT2A receptor antagonists.2 α2δ Calcium channel blockers include the antiepileptics pregabalin and gabapentin; these drugs have been found to increase SWS and improve sleep architecture in healthy adults.37,38 5-HT2A Receptor antagonists, such as ritanserin, have also been found to increase SWS in healthy adults ().39 5-HT2A Receptor antagonists in development include eplivanserin, pruvanserin, and volinanserin, which have also been reported to increase the amount of SWS in healthy subjects.2,40
Evidence shows that deficits in SWS are related to medical, psychiatric, and sleep disorders. With increasing knowledge of sleep mechanisms and the neuropharmacology underlying sleep, novel therapies are being developed to improve sleep architecture and increase slow-wave activity in sleep. Future studies are needed to determine whether such apparent improvements in sleep architecture, with or without increases in the amount of time spent asleep, can lead to improvements in these disorders or lead to improvements in overall health.
eszopiclone (Lunesta), gabapentin (Neurontin and others), lorazepam (Ativan and others), pregabalin (Lyrica), zaleplon (Sonata and others), zolpidem (Ambien, Edluar, and others)
CBT = cognitive-behavioral therapy, CPAP = continuous positive airway pressure, DSM-IV-TR = Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision, EEG = electroencephalogram, EMG = electromyogram, EOG = electro-oculogram, FDA = US Food and Drug Administration, NREM = non–rapid eye movement, REM = rapid eye movement, SDB = sleep-disordered breathing, SWS = slow-wave sleep
Take the online posttest.
- National Sleep Foundation. 2008 Sleep in America Poll. http://www.sleepfoundation.org/sites/default/files/2008%20POLL%20SOF.PDF. Published March 3, 2008. Accessed August 27, 2009.
- Wafford KA, Ebert B. Emerging anti-insomnia drugs: tackling sleeplessness and the quality of wake time. Nat Rev Drug Discov. 2008;7(6):530–540.
- Neubauer DN. Insomnia. Prim Care. 2005;32(2):375–388.
- Banks S, Dinges DF. Behavioral and physiologic consequences of sleep restriction. J Clin Sleep Med. 2007;3(5):519–528.
- Walker MP. The role of sleep in cognition and emotion. Ann N Y Acad Sci. 2009;1156:168–197.
- Walker MP. Cognitive consequences of sleep and sleep loss. Sleep Med. 2008;9(suppl 1):S29–S32.
- Silber MH, Ancoli-Israel S, Bonnet MH, et al. The visual scoring of sleep in adults. J Clin Sleep Med. 2007;3(2):121–131.
- Williams RL, Karacan I, Hursch CJ. Electroencephalography (EEG) of Human Sleep: Clinical Applications. New York, NY: John Wiley & Sons; 1974.
- Huber R, Tononi G, Cirelli C. Exploratory behavior, cortical BDNF expression, and sleep homeostasis. Sleep. 2007;30(2):129–139.
- Huber R, Ghilardi MF, Massimini M, et al. Local sleep and learning. Nature. 2004;430(6995):78–81.
- Huber R, Ghilardi MF, Massimini M, et al. Arm immobilization causes cortical plastic changes and locally decreases sleep slow wave activity. Nat Neurosci. 2006;9(9):1169–1176.
- Walker MP, Stickgold R. Sleep-dependent learning and memory consolidation. Neuron. 2004;44(1):121–133.
- Tucker MA, Fishbein W. Enhancement of declarative memory performance following a daytime nap is contingent on strength of initial task acquisition. Sleep. 2008;31(2):197–203.
- Marshall L, Helgadottir H, Molle M, et al. Boosting slow oscillations during sleep potentiates memory. Nature. 2006;444(7119):610–613.
- Genzel L, Dresler M, Wehrle R, et al. Slow wave sleep and REM sleep awakenings do not affect sleep dependent memory consolidation. Sleep. 2009;32(3):302–310.
- Schabus M, Gruber G, Parapatics S, et al. Sleep spindles and their significance for declarative memory consolidation. Sleep. 2004;27(8):1479–1485.
- Dijk DJ. Slow-wave sleep, diabetes, and the sympathetic nervous system. Proc Natl Acad Sci U S A. 2008;105(4):1107–1108.
- Brandenberger G, Ehrhart J, Piquard F, et al. Inverse coupling between ultradian oscillations in delta wave activity and heart rate variability during sleep. Clin Neurophysiol. 2001;112(6):992–996.
- Somers VK, Dyken ME, Mark AL, et al. Sympathetic-nerve activity during sleep in normal subjects. N Engl J Med. 1993;328(4):303–307.
- Van Cauter E. Slow wave sleep and release of growth hormone. JAMA. 2000;284(21):2717–2718.
- Van Cauter E, Leproult R, Plat L. Age-related changes in slow wave sleep and REM sleep and relationship with growth hormone and cortisol levels in healthy men. JAMA. 2000;284(7):861–868.
- Tasali E, Leproult R, Ehrmann DA, et al. Slow-wave sleep and the risk of type 2 diabetes in humans. Proc Natl Acad Sci U S A. 2008;105(3):1044–1049.
- Ondze B, Espa F, Dauvilliers Y, et al. Sleep architecture, slow wave activity and sleep spindles in mild sleep disordered breathing. Clin Neurophysiol. 2003;114(5):867–874.
- Fietze I, Quispe-Bravo S, Hansch T, et al. Arousals and sleep stages in patients with obstructive sleep apnoea syndrome: changes under nCPAP treatment. J Sleep Res. 1997;6(2):128–133.
- Benca RM, Obermeyer WH, Thisted RA, et al. Sleep and psychiatric disorders: a meta-analysis. Arch Gen Psychiatry. 1992;49(8):651–668.
- Yang C, Winkelman JW. Clinical significance of sleep EEG abnormalities in chronic schizophrenia. Schizophr Res. 2006;82(2–3):251–260.
- Landolt HP, Gillin JC. Sleep abnormalities during abstinence in alcohol-dependent patients: aetiology and management. CNS Drugs. 2001;15(5):413–425.
- Irwin M, Gillin JC, Dang J, et al. Sleep deprivation as a probe of homeostatic sleep regulation in primary alcoholics. Biol Psychiatry. 2002;51(8):632–641.
- National Institutes of Health. NIH State-of-the-Science Conference Statement on manifestations and management of chronic insomnia in adults. NIH Consens State Sci Statements. 2005;22(2):1–30.
- Morin CM. Cognitive-behavioral approaches to the treatment of insomnia. J Clin Psychiatry. 2004;65 (suppl 16):33–40.
- Morin CM, Culbert JP, Schwartz SM. Nonpharmacological interventions for insomnia: a meta-analysis of treatment efficacy. Am J Psychiatry. 1994;151(8):1172–1180.
- Edinger JD, Wohlgemuth WK, Radtke RA, et al. Cognitive behavioral therapy for treatment of chronic primary insomnia: a randomized controlled trial. JAMA. 2001;285(14):1856–1864.
- Sivertsen B, Omvik S, Pallesen S, et al. Cognitive behavioral therapy vs zopiclone for treatment of chronic primary insomnia in older adults: a randomized controlled trial. JAMA. 2006;295(24):2851–2858.
- Rybarczyk B, Stepanski E, Fogg L, et al. A placebo-controlled test of cognitive-behavioral therapy for comorbid insomnia in older adults. J Consult Clin Psychol. 2005;73(6):1164–1174.
- Cervena K, Dauvilliers Y, Espa F, et al. Effect of cognitive behavioural therapy for insomnia on sleep architecture and sleep EEG power spectra in psychophysiologic insomnia. J Sleep Res. 2004;13(4):385–393.
- Horne JA, Porter JM. Exercise and human sleep. Nature. 1975;256(5518):573–575.
- Hindmarch I, Dawson J, Stanley N. A double-blind study in healthy volunteers to assess the effects on sleep of pregabalin compared with alprazolam and placebo. Sleep. 2005;28(2):187–193.
- Foldvary-Schaefer N, De Leon Sanchez I, Karafa M, et al. Gabapentin increases slow-wave sleep in normal adults. Epilepsia. 2002;43(12):1493–1497.
- van Laar M, Volkerts E, Verbaten M. Subchronic effects of the GABA-agonist lorazepam and the 5-HT2A/2C antagonist ritanserin on driving performance, slow wave sleep and daytime sleepiness in healthy volunteers. Psychopharmacology (Berl). 2001;154(2):189–197.
- Sanger DJ, Soubrane C, Scatton B. New perspectives for the treatment of disorders of sleep and arousal. Ann Pharm Fr. 2007;65(4):268–274.